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Tc 0.028 Tw -9.231 -1.062 Td (into cup and pull up)Tj 0 Tc 0 Tw 9.061 0 Td ( )Tj -0.029 Tc 0.028 Tw -9.061 -1.062 Td (all the liquid mixture.)Tj ET 0 0 0 0 k /GS0 gs 451.305 268.78 109.389 108.54 re f q 451.305 268.78 109.389 108.54 re W n q 0 Tc 0 Tw 0 g 0 G /GS2 gs 0 TL/Fm3 Do Q Q BT 0 0 0 1 k /GS1 gs 8 0 0 8 455.2699 446.44 Tm [(W)8.8 (ith the child seated upright)-29 ( )]TJ 0 -1.062 Td [(or slightly inclined \(tilted)-28.9 ( )]TJ 0 -1.062 Td [(back\), place the oral syringe)-29.2 ( )]TJ 0 -1.062 Td [(into the mouth with the tip)-28.9 ( )]TJ 0 -1.062 Td (along either cheek.)Tj 0 -1.647 Td [(Slowly push the plunger all)-28.8 ( )]TJ 0 -1.062 Td [(the way down to give)-29.2 ( )]TJ 0 Tc 0 Tw 9.867 0 Td ( )Tj -0.029 Tc 0.028 Tw -9.867 -1.062 Td (all medicine in the syringe.)Tj ET 0 0 0 0 k /GS0 gs 41.375 497.02 94.952 95.04 re f /PlacedPDF /MC2 BDC q 41.375 497.02 94.952 95.04 re W n q 1 0 0 1 89.2675 551.0305 cm 0 0 m -2.967 0.791 -4.551 1.582 v f Q 0 0 0 1 k /GS1 gs q 1 0 0 1 89.2675 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6.878 c 6.744 8.588 13.256 3.958 y 14.86 -0.535 9.696 -3.958 v 3.178 -1.908 0.23 -0.453 v f Q 0 0 0 1 k /GS1 gs q 1 0 0 1 61.0479 553.7068 cm 0 0 m -0.661 6.103 3.682 9.274 9.2 6.347 c 10.656 5.684 12.049 4.911 13.395 4.042 c 13.912 2.5 13.752 0.793 13.084 -0.691 c 12.38 -2.184 11.133 -3.376 9.776 -4.282 c 6.525 -3.221 3.272 -2.091 0.246 -0.478 c 2.882 -1.4 7.01 -2.812 9.812 -3.676 c 9.56 -3.711 l 12.07 -2.107 13.973 0.862 13.16 3.912 c 12.193 4.541 10.487 5.645 9.117 6.153 c 3.475 8.586 0.219 5.715 0 0 c f Q 0 0 0 0 k /GS0 gs q 1 0 0 1 58.2664 553.6038 cm 0 0 m -4.906 -1.875 -4.708 -9.394 v 2.611 -15.725 14.285 -16.912 v 19.825 -12.955 18.836 -8.206 v 14.047 -4.947 0.989 0.198 v h f Q 0 0 0 1 k /GS1 gs q 1 0 0 1 58.2664 553.6038 cm 0 0 m -3.475 -1.653 -4.807 -5.775 -4.613 -9.391 c 0.579 -13.267 7.594 -15.948 14.315 -16.62 c 14.114 -16.673 l 15.446 -15.67 16.659 -14.421 17.547 -13 c 18.431 -11.585 18.953 -9.894 18.626 -8.251 c 18.715 -8.383 l 17.363 -7.488 15.912 -6.692 14.464 -5.923 c 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7.501 -15.056 4.354 -14.075 c 1.217 -13.093 -1.806 -11.727 -4.512 -9.826 c -4.925 -6.049 -3.351 -1.978 0 0 c f Q 0 0 0 0 k /GS0 gs q 1 0 0 1 49.3392 532.5253 cm 0 0 m -2.654 -0.508 -2.113 -6.121 v 2.262 -12.186 10.461 -12.489 v 14.11 -9.251 13.165 -5.748 v 10.057 -2.996 0.679 0.198 v f Q 0 0 0 1 k /GS1 gs q 1 0 0 1 49.3392 532.5253 cm 0 0 m -2.275 -0.977 -2.136 -4.02 -1.986 -6.109 c -0.67 -7.677 1.477 -9.519 3.57 -10.502 c 5.706 -11.61 8.08 -12.148 10.469 -12.278 c 10.321 -12.331 l 11.219 -11.493 12 -10.478 12.542 -9.369 c 13.138 -8.372 13.209 -6.635 13.058 -5.869 c 9.375 -3.107 4.957 -1.438 0.679 0.198 c 5.082 -1.26 9.546 -2.869 13.31 -5.658 c 14.01 -8.287 12.43 -10.868 10.602 -12.647 c 5.711 -12.681 0.736 -10.012 -2.241 -6.135 c -2.396 -4.015 -2.357 -0.882 0 0 c f Q 0 0 0 0 k /GS0 gs q 1 0 0 1 73.1692 557.5434 cm 0 0 m 0.738 -3.612 -2.214 -6.083 v -7.008 -4.373 l -7.377 0.761 -4.427 1.521 v h f Q 0 0 0 1 k /GS1 gs q 1 0 0 1 73.1692 557.5434 cm 0 0 m 0.41 -2.212 -0.386 -4.876 -2.245 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-4.487 l -8.365 -4.451 l -8.149 -1.847 -7.832 1.913 -4.933 2.869 c -3.26 1.929 -1.619 0.951 0 0 c 0 0 m -1.582 0.875 -3.638 1.872 -4.924 2.679 c -7.624 1.696 -7.872 -1.877 -8.062 -4.348 c -8.162 -4.205 l -3.034 -6.033 l -1.628 -4.783 0.013 -2.317 0 0 c f Q 0 0 0 0 k /GS0 gs q 1 0 0 1 61.6695 526.0356 cm 0 0 m 0.079 -2.886 -2.456 -4.975 v -6.577 -3.529 l -6.498 1.607 -3.961 2.248 v h f Q 0 0 0 1 k /GS1 gs q 1 0 0 1 61.6695 526.0356 cm 0 0 m -0.009 -1.902 -0.939 -3.961 -2.483 -5.05 c -6.616 -3.642 l -6.7 -3.613 l -6.523 -1.507 -6.288 1.539 -3.951 2.328 c -2.61 1.566 -1.296 0.773 0 0 c 0 0 m -1.267 0.71 -2.918 1.521 -3.943 2.176 c -6.119 1.363 -6.301 -1.532 -6.456 -3.53 c -6.536 -3.415 l -2.43 -4.898 l -1.307 -3.883 0.004 -1.883 0 0 c f Q 0 0 0 0 k /GS0 gs q 1 0 0 1 61.4719 516.3129 cm 0 0 m 8.507 -5.738 12.266 -8.31 v 16.026 -10.882 31.656 -13.85 y f Q 0 0 0 1 k /GS1 gs q 1 0 0 1 61.4719 516.3129 cm 0 0 m 4.244 -2.587 8.689 -5.606 12.854 -8.326 c 18.766 -11.101 25.35 -12.228 31.656 -13.85 c 25.2 -12.681 18.547 -11.665 12.563 -8.837 c 8.383 -6.056 4.031 -2.971 0 0 c f Q q 1 0 0 1 87.0466 587.3994 cm 0 0 m -4.56 -9.655 l -3.477 -10.168 l 1.083 -0.512 l f Q q 1 0 0 1 80.8613 572.8984 cm 0 0 m 0.411 7.715 l 2.328 4.932 l 5.697 5.219 l h f Q EMC Q BT 0 0 0 1 k /GS1 gs 0.028 Tw 8 0 0 8 45.5 605.9158 Tm [(Push plunger all the)-29.2 ( )]TJ 0 Tc 0 Tw 9.339 0 Td ( )Tj -0.029 Tc 0.028 Tw -9.339 -1.062 Td (way down.)Tj ET 0 0 0 0 k /GS0 gs 384.26 487.747 126 103.013 re f q 384.26 487.747 126 103.013 re W n q 0 Tc 0 Tw 0 g 0 G 10 M /GS2 gs 0 TL/Fm2 Do Q Q 335.3 597.42 241.2 47.52 re f BT 0 0 0 1 k /GS1 gs 8 0 0 8 344.3 633.7599 Tm [(W)8.8 (ith the child seated upright or slightly inclined)-28.8 ( )]TJ 0 Tc 0 Tw 21.852 0 Td ( )Tj -0.029 Tc 0.028 Tw -21.852 -1.062 Td [(\(tilted back\), place the oral syringe into the mouth)-28.9 ( )]TJ 0 Tc 0 Tw 22.667 0 Td ( )Tj -0.029 Tc 0.028 Tw -22.667 -1.062 Td (with the tip along either cheek.)Tj 0 -1.355 Td (Slowly push the plunger all the way down to give)Tj 0 Tc 0 Tw 22.172 0 Td ( )Tj -0.029 Tc 0.028 Tw -22.172 -1.062 Td (all medicine in the syringe.)Tj ET 10 M q 1 0 0 1 45.5 461.8308 cm 0 0 m 522 0 l S Q BT 0.056 Tw 10 0 0 10 45.5 465.9308 Tm [(Part )0.5 (2:)]TJ /Span< >> BDC [( )0.6 ( )]TJ EMC 3.6 0 Td (Repeat)Tj /C2_0 1 Tf 0.029 Tw [<0BD8>-0.6 <0003>-55.5 <003600570048005300560003>-55.5 <00180003>-55.5 <0057004B005500520058004A004B0003>-55.5 <001A0003>-55.5 <005700520003>-55.5 <004A004C005900480003>-55.5 <00440051005C0003>-55.5 <0055004800500044004C0051004C0051004A0003>-55.5 <005000480047004C0046004C005100480003>-55.5 <004C00510003>-55.6 <0057004B00480003>-55.6 <004600580053001D>]TJ ET 0 0 0 0 k /GS0 gs 253.22 264.42 98.28 104.4 re f /PlacedPDF /MC2 BDC q 253.22 264.42 98.28 104.4 re W n q 1 0 0 1 305.5529 327.2516 cm 0 0 m -3.296 0.879 -5.056 1.758 v f Q 0 0 0 1 k /GS1 gs q 1 0 0 1 305.5529 327.2516 cm 0 0 m -1.816 0.043 -3.655 0.588 -5.056 1.758 c -3.253 1.409 -1.598 0.917 0 0 c f Q 0 0 0 0 k /GS0 gs q 1 0 0 1 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PE.)37 ( )37.4 (All )0.5 (key safety )0.5 (and )0.5 (ef\037cac)20 (y )0.5 (endpoints )0.5 (were )0.5 (adjudica)-10 (ted )0.5 (in )0.5 (a )0.5 (blinded)-25 ( )]TJ 0.084 Tw 0 -1.062 Td (manner by an independent committee.)Tj /T1_2 1 Tf 0.025 Tw 0 -1.737 Td (AMPLIFY)Tj /T1_1 1 Tf 0.192 Tw 0 -1.288 Td [(The primar)-18 (y objective of )36.6 (AMPLIFY was to determine whether ELIQUIS was noninferior)-25 ( )]TJ 0.139 Tw 0 -1.062 Td [(to enoxa)-9.9 (parin/warfarin for the incidence of recurrent )36.8 (VTE \(venous thromboembolism\) or)-25 ( )]TJ 0.19 Tw 0 -1.062 Td [(VTE-rela)-10 (ted dea)-9.9 (th.)37 ( P)18.1 (a)-10 (tients with an objectively con\037rmed symptoma)-10 (tic DVT and/or PE)-25 ( )]TJ 0.09 Tw 0 -1.062 Td [(were randomized to trea)-10 (tment with ELIQUIS 10)]TJ /Span< >> BDC ( )Tj EMC 16.985 0 Td [(mg twice daily orally for 7 days follo)-9.9 (wed)-25 ( )]TJ 0.23 Tw -16.985 -1.062 Td (by ELIQUIS 5)Tj /Span< >> BDC ( )Tj EMC 5.092 0 Td [(mg twice daily orally for 6 months,)37 ( or enoxa)-10 (parin 1)]TJ /Span< >> BDC ( )Tj EMC 19.795 0 Td [(mg/kg twice daily)-25 ( )]TJ 0.123 Tw -24.888 -1.062 Td [(subcutaneously for a)-9.9 (t least 5 days \(until INR \0362\) follo)-10 (wed by warfarin \(target INR range)-25 ( )]TJ 0.164 Tw 0 -1.062 Td [(2.0-3.0\) orally for 6 months.)37 ( P)18 (a)-10 (tients who required thrombectomy)55 (,)37 ( insertion of a ca)-10 (val)-25 ( )]TJ 0.132 Tw 0 -1.062 Td [(\037lter)74.1 (,)37 ( or use of a \037brinolytic a)-10 (gent,)37 ( and pa)-9.9 (tients with crea)-10 (tinine c)20 (learance <25 mL/min,)12 ( )]TJ 0.2 Tw 0 -1.062 Td [(signi\037cant liver disease,)37 ( an existing heart valve or a)-10 (trial \037brilla)-10 (tion,)37 ( or active bleeding)-25 ( )]TJ 0.082 Tw 0 -1.062 Td [(were exc)20 (luded from the )36.7 (AMPLIFY stud)-10 (y)55 (.)37 ( P)18 (a)-10 (tients were allo)-10 (wed to enter the stud)-10 (y with or)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(without prior parenteral anticoa)-10 (gula)-9.9 (tion \(up to 48 hours\).)]TJ 0.169 Tw 0 -1.512 Td [(A total )0.5 (of 5244 pa)-9.9 (tients )0.5 (were )0.5 (evaluable )0.5 (for ef\037cac)20 (y )0.5 (and )0.5 (were follo)-10 (wed for a )0.5 (mean )0.5 (of)-25 ( )]TJ 0.051 Tw 0 -1.062 Td [(154 days in the ELIQUIS group and 152 days in the enoxa)-10 (parin/warfarin group.)37 ( )37 (The mean)-25 ( )]TJ 0 Tc 0 Tw 31.5 0 Td ( )Tj -0.025 Tc 0.28 Tw -31.5 -1.062 Td [(a)-10 (ge was 57)]TJ /Span< >> BDC ( )Tj EMC 4.822 0 Td [(years.)37 ( )37.2 (The )37.3 (AMPLIFY stud)-9.9 (y popula)-10 (tion was 59% male,)37 ( 83% Caucasian,)12 ( )]TJ 0 Tc 0 Tw 26.678 0 Td ( )Tj -0.025 Tc 0.127 Tw -31.5 -1.062 Td [(8% )37 (Asian,)37 ( and 4% Black.)37.1 ( F)20 (or pa)-9.9 (tients randomized to warfarin,)37 ( the mean percenta)-9.9 (ge of)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(time in thera)-10 (peutic range \(INR 2.0-3.0\) was 60.9%.)]TJ 0.184 Tw 0 -1.512 Td [(A)-10 (pproxima)-10 (tely 90% of pa)-10 (tients enrolled in )37.2 (AMPLIFY had an unprovoked DVT or PE a)-9.9 (t)-25 ( )]TJ 0.163 Tw 0 -1.062 Td [(baseline.)37 ( )36.9 (The remaining 10% of pa)-10 (tients with a provoked DVT or PE were required to)-25 ( )]TJ 0.054 Tw 0 -1.062 Td [(ha)-10 (ve )0.5 (an )0.5 (additional )0.5 (ongoing )0.5 (risk )0.5 (factor )0.5 (in )0.5 (order )0.5 (to )0.5 (be )0.5 (randomized,)37 ( )0.5 (which )0.5 (inc)20 (luded )0.6 (previous)-25.1 ( )]TJ 0.301 Tw 0 -1.062 Td [(episode of DVT or PE,)37 ( immobiliza)-10 (tion,)37.1 ( histor)-18 (y of cancer)73.9 (,)37.1 ( active cancer)74 (,)37 ( and kno)-10 (wn)-25 ( )]TJ 0.084 Tw 0 -1.062 Td (prothrombotic genotype.)Tj 0.175 Tw 0 -1.512 Td [(ELIQUIS was sho)-10 (wn to be noninferior to enoxa)-10 (parin/warfarin in the )37.2 (AMPLIFY stud)-10 (y for)-25 ( )]TJ 0.238 Tw 0 -1.062 Td [(the primar)-17.9 (y endpoint of recurrent symptoma)-10 (tic )37.2 (VTE \(nonfa)-10 (tal DVT or nonfa)-10 (tal PE\) or)-25 ( )]TJ 0 Tc 0 Tw 31.5 0 Td ( )Tj -0.025 Tc 0.084 Tw -31.5 -1.062 Td [(VTE-rela)-10 (ted dea)-10 (th over 6 months of thera)-9.9 (py \(T)74 (able 17\).)]TJ ET 0 0 0 1 K /GS2 gs q 1 0 0 1 36 404.5363 cm 0 0 m 78.12 0 l S Q q 1 0 0 1 114.12 404.5363 cm 0 0 m 47.88 0 l S Q q 1 0 0 1 162 404.5363 cm 0 0 m 69.34 0 l S Q q 1 0 0 1 231.34 404.5363 cm 0 0 m 56.66 0 l S Q 0.5 w q 1 0 0 1 36 376.0643 cm 0 0 m 78.12 0 l S Q q 1 0 0 1 114.12 376.0643 cm 0 0 m 47.88 0 l S Q q 1 0 0 1 162 376.0643 cm 0 0 m 69.34 0 l S Q q 1 0 0 1 231.34 376.0643 cm 0 0 m 56.66 0 l S Q 1 w q 1 0 0 1 36 311.5529 cm 0 0 m 78.12 0 l S Q q 1 0 0 1 114.12 311.5529 cm 0 0 m 47.88 0 l S Q q 1 0 0 1 162 311.5529 cm 0 0 m 69.34 0 l S Q q 1 0 0 1 231.34 311.5529 cm 0 0 m 56.66 0 l S Q 0.5 w q 1 0 0 1 36 281.2809 cm 0 0 m 78.12 0 l S Q q 1 0 0 1 114.12 281.2809 cm 0 0 m 47.88 0 l S Q q 1 0 0 1 162 281.2809 cm 0 0 m 69.34 0 l S Q q 1 0 0 1 231.34 281.2809 cm 0 0 m 56.66 0 l S Q BT /GS1 gs /T1_0 1 Tf -0.022 Tc 8 0 0 8 36 408.1362 Tm (Table 17:)Tj /Span< >> BDC ( )Tj EMC 5.4 0 Td [(Efficacy Results in the AMPLIFY Study)-22 ( )]TJ 0.022 Tw 7.6 0 0 8 126.8843 395.9443 Tm (ELIQUIS)Tj 0 Tc 0 Tw 7.6 0 0 8 149.2357 395.9443 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 126.7209 387.4443 Tm (N=2609)Tj 0 Tc 0 Tw 7.6 0 0 8 149.399 387.4443 Tm ( )Tj 7.6 0 0 8 136.16 378.9443 Tm (n)Tj -0.022 Tc 0.022 Tw 4.053 2.125 Td (Enoxaparin/Warfarin)Tj 0 Tc 0 Tw 7.6 0 0 8 226.3778 395.9443 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 185.3309 387.4443 Tm (N=2635)Tj 0 Tc 0 Tw 7.6 0 0 8 208.009 387.4443 Tm ( )Tj 7.6 0 0 8 194.77 378.9443 Tm (n)Tj -0.022 Tc 0.024 Tw 6.078 2.125 Td (Relative Risk)Tj 0.844 -1.062 Td (\(95% CI\))Tj /T1_1 1 Tf -0.014 Tc -27.813 -2.451 Td [(VTE or )37 (VTE-rela)-10 (ted dea)-9.9 (th*)]TJ -0.022 Tc 11.684 0 Td (59 \(2.3%\))Tj 7.712 0 Td (71 \(2.7%\))Tj 7.083 0 Td [(0.84 \(0.60,)37 ( 1.18\))]TJ -0.014 Tc 0.366 Tw /Span< >> BDC -26.48 -1.344 Td ( )Tj EMC (DVT)Tj 0 Tc 0 Tw 4.94 0 0 5.2 51.4363 359.4805 Tm (\206)Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 124.802 357.0805 Tm (22 \(0.8%\))Tj 7.712 0 Td (35 \(1.3%\))Tj -0.014 Tc 0.366 Tw /Span< >> BDC -19.396 -1.344 Td ( )Tj EMC (PE)Tj 0 Tc 0 Tw 4.94 0 0 5.2 47.4615 348.7286 Tm (\206)Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 124.802 346.3286 Tm (27 \(1.0%\))Tj 7.712 0 Td (25 \(0.9%\))Tj -0.014 Tc /Span< >> BDC -19.396 -1.344 Td ( )Tj EMC 0.592 0 Td [(VTE-rela)-10 (ted dea)-9.9 (th)]TJ 0 Tc 0 Tw 4.94 0 0 5.2 89.2374 337.9767 Tm (\206)Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 124.802 335.5767 Tm (12 \(0.4%\))Tj 7.712 0 Td (16 \(0.6%\))Tj -0.014 Tc -19.396 -1.344 Td [(VTE or all-cause dea)-10 (th)]TJ -0.022 Tc 11.684 0 Td (84 \(3.2%\))Tj 7.483 0 Td (104 \(4.0%\))Tj 7.312 0 Td [(0.82 \(0.61,)37 ( 1.08\))]TJ -0.014 Tc -26.48 -1.344 Td [(VTE or CV)18 (-rela)-10 (ted dea)-9.9 (th)]TJ -0.022 Tc 11.684 0 Td (61 \(2.3%\))Tj 7.712 0 Td (77 \(2.9%\))Tj 7.083 0 Td [(0.80 \(0.57,)37 ( 1.11\))]TJ -0.025 Tc 0.084 Tw -26.457 -1.479 Td (*)Tj /Span< >> BDC ( )Tj EMC 0.527 0 Td [(Noninferior compared to enoxa)-10 (parin/warfarin \(P-value <0.0001\).)]TJ 0 Tc 0 Tw 5.98 0 0 5.98 36.176 294.8909 Tm (\206)Tj -0.025 Tc 0.199 Tw /Span< >> BDC 7.6 0 0 8 38.9088 293.3809 Tm ( )Tj EMC 0.167 0 Td [(Events associa)-10 (ted with )0.5 (each )0.5 (endpoint were counted once per subject,)37 ( but )0.5 (subjects may)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(ha)-10 (ve contributed events to multiple endpoints.)]TJ 0.117 Tw 8 0 0 8 36 257.231 Tm [(In the )37.3 (AMPLIFY stud)-10 (y)55 (,)37 ( pa)-9.9 (tients were stra)-10 (ti\037ed according to their index event of PE \(with)-25 ( )]TJ 0.05 Tw 0 -1.062 Td [(or without DVT\) or DVT \(without PE\).)37 ( Ef\037cac)20 (y in the initial trea)-10 (tment of )37.2 (VTE was consistent)-25 ( )]TJ 0.084 Tw 0 -1.062 Td (between the two subgroups.)Tj /T1_3 1 Tf 0.025 Tw 0 -1.58 Td [(AMPLIFY)74 (-EXT)]TJ /T1_1 1 Tf 0.094 Tw 0 -1.512 Td [(P)18 (a)-10 (tients who had been trea)-9.9 (ted for DVT and/or PE for 6 to 12 months with anticoa)-9.9 (gulant)-25 ( )]TJ 0.194 Tw 0 -1.062 Td [(thera)-10 (py without ha)-10 (ving a recurrent event were randomized to trea)-10 (tment with ELIQUIS)-25 ( )]TJ 0.217 Tw 0 -1.062 Td (2.5)Tj /Span< >> BDC ( )Tj EMC 1.338 0 Td [(mg orally twice daily)55 (,)37 ( ELIQUIS 5)]TJ /Span< >> BDC ( )Tj EMC 12.101 0 Td [(mg orally twice daily)55 (,)37 ( or placebo for 12 months.)12 ( )]TJ 0.088 Tw -13.439 -1.062 Td [(A)-10 (pproxima)-10 (tely one-third of pa)-10 (tients participa)-9.9 (ted in the )36.7 (AMPLIFY stud)-9.9 (y prior to enrollment)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(in the )37 (AMPLIFY)74 (-EXT stud)-10 (y)55 (.)]TJ 0.162 Tw 0 -1.512 Td [(A total of 2482 pa)-10 (tients were randomized to stud)-10 (y trea)-10 (tment and were follo)-10 (wed for a)-25 ( )]TJ 0.202 Tw 0 -1.062 Td [(mean of a)-10 (pproxima)-10 (tely 330 days in the ELIQUIS group and 312 days in the placebo)-25 ( )]TJ 0.077 Tw 0 -1.062 Td [(group.)37 ( )36.6 (The mean a)-9.9 (ge in the )36.6 (AMPLIFY)74 (-EXT stud)-10 (y was 57)]TJ /Span< >> BDC ( )Tj EMC 20.08 0 Td [(years.)37 ( )36.6 (The stud)-10 (y popula)-10 (tion was)-25 ( )]TJ 0.084 Tw -20.08 -1.062 Td [(57% male,)37 ( 85% Caucasian,)37 ( 5% )37 (Asian,)37 ( and 3% Black.)]TJ 0.037 Tw 0 -1.512 Td [(The )37.2 (AMPLIFY)74 (-EXT stud)-10 (y enrolled pa)-9.9 (tients with either an unprovoked DVT or PE a)-10 (t baseline)-24.9 ( )]TJ 0.266 Tw 0 -1.062 Td [(\(a)-10 (pproxima)-9.9 (tely 92%\) or pa)-10 (tients with a provoked baseline event and one additional)-25 ( )]TJ 0.182 Tw 0 -1.062 Td [(risk factor for recurrence \(a)-10 (pproxima)-10 (tely 8%\).)37 ( Ho)-9.9 (wever)74 (,)37 ( pa)-10 (tients who had experienced)-25 ( )]TJ 0.098 Tw 0 -1.062 Td [(multiple episodes of unprovoked DVT or PE were exc)20 (luded from the )36.8 (AMPLIFY)74 (-EXT stud)-10 (y)55 (.)12 ( )]TJ 0.065 Tw 0 -1.062 Td [(In the )37.3 (AMPLIFY)74 (-EXT stud)-10 (y)55 (,)37 ( both doses of ELIQUIS were superior to placebo in the primar)-18 (y)-24.9 ( )]TJ 0.095 Tw 0 -1.062 Td [(endpoint of symptoma)-10 (tic,)37 ( recurrent )36.8 (VTE \(nonfa)-10 (tal DVT or nonfa)-10 (tal PE\),)37 ( or all-cause dea)-10 (th)-25.1 ( )]TJ 0.084 Tw 0 -1.062 Td [(\(T)74 (able 18\).)]TJ ET 1 w /GS2 gs q 1 0 0 1 377.28 723.6481 cm 0 0 m 37.08 0 l S Q q 1 0 0 1 414.36 723.6481 cm 0 0 m 33.3 0 l S Q q 1 0 0 1 447.66 723.6481 cm 0 0 m 33.3 0 l S Q q 1 0 0 1 377.28 620.2247 cm 0 0 m 37.08 0 l S Q q 1 0 0 1 414.36 620.2247 cm 0 0 m 33.3 0 l S Q q 1 0 0 1 447.66 620.2247 cm 0 0 m 33.3 0 l S Q 0.5 w q 1 0 0 1 324 607.3128 cm 0 0 m 53.28 0 l S Q q 1 0 0 1 377.28 607.3128 cm 0 0 m 37.08 0 l S Q q 1 0 0 1 414.36 607.3128 cm 0 0 m 33.3 0 l S Q q 1 0 0 1 447.66 607.3128 cm 0 0 m 33.3 0 l S Q q 1 0 0 1 480.96 607.3128 cm 0 0 m 47.52 0 l S Q q 1 0 0 1 528.48 607.3128 cm 0 0 m 47.52 0 l S Q q 1 0 0 1 480.96 683.9543 cm 0 0 m 0 27.972 l S Q q 1 0 0 1 480.96 620.7247 cm 0 0 m 0 10.252 l S Q 1 w q 1 0 0 1 480.96 620.2247 cm 0 0 m 47.52 0 l S Q q 1 0 0 1 528.48 620.2247 cm 0 0 m 47.52 0 l S Q 0.5 w q 1 0 0 1 480.96 652.4805 cm 0 0 m 0 19.502 l S Q q 1 0 0 1 480.96 641.7285 cm 0 0 m 0 10.752 l S Q q 1 0 0 1 480.96 630.9766 cm 0 0 m 0 10.752 l S Q q 1 0 0 1 377.28 683.7043 cm 0 0 m 37.08 0 l S Q q 1 0 0 1 414.36 683.7043 cm 0 0 m 33.3 0 l S Q q 1 0 0 1 447.66 683.7043 cm 0 0 m 33.3 0 l S Q q 1 0 0 1 480.96 683.7043 cm 0 0 m 47.52 0 l S Q q 1 0 0 1 480.96 672.4824 cm 0 0 m 0 10.972 l S Q q 1 0 0 1 528.48 683.7043 cm 0 0 m 47.52 0 l S Q q 1 0 0 1 377.28 672.2324 cm 0 0 m 37.08 0 l S Q q 1 0 0 1 414.36 672.2324 cm 0 0 m 33.3 0 l S Q q 1 0 0 1 447.66 672.2324 cm 0 0 m 33.3 0 l S Q q 1 0 0 1 480.96 672.2324 cm 0 0 m 47.52 0 l S Q q 1 0 0 1 528.48 672.2324 cm 0 0 m 47.52 0 l S Q 1 w q 1 0 0 1 480.96 723.6481 cm 0 0 m 47.52 0 l S Q q 1 0 0 1 528.48 723.6481 cm 0 0 m 47.52 0 l S Q 0.5 w q 1 0 0 1 480.96 712.4262 cm 0 0 m 0 10.722 l S Q q 1 0 0 1 480.71 712.1762 cm 0 0 m 47.77 0 l S Q q 1 0 0 1 528.48 712.1762 cm 0 0 m 47.52 0 l S Q 1 w q 1 0 0 1 324 723.6481 cm 0 0 m 53.28 0 l S Q q 1 0 0 1 324 620.2247 cm 0 0 m 53.28 0 l S Q 0.5 w q 1 0 0 1 324 672.2324 cm 0 0 m 53.28 0 l S Q BT /GS1 gs /T1_0 1 Tf -0.022 Tc 8 0 0 8 324 727.2481 Tm (Table 18:)Tj /Span< >> BDC ( )Tj EMC 5.4 0 Td (Efficacy Results in the AMPLIFY-EXT Study)Tj 0.022 Tw 7.6 0 0 8 384.6443 703.5843 Tm (ELIQUIS)Tj 0 Tc 0 Tw 7.6 0 0 8 406.9957 703.5843 Tm ( )Tj -0.022 Tc -0.115 Tw 7.6 0 0 8 381.042 695.0843 Tm (2.5)Tj /Span< >> BDC ( )Tj EMC [(mg )-139 (bid)]TJ 0 Tc 0 Tw 7.6 0 0 8 410.598 695.0843 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 386.2213 686.5843 Tm (N=840)Tj 4.423 2.125 Td (ELIQUIS)Tj 0 Tc 0 Tw 7.6 0 0 8 442.1857 703.5843 Tm ( )Tj -0.022 Tc -0.115 Tw 7.6 0 0 8 418.8007 695.0843 Tm (5)Tj /Span< >> BDC ( )Tj EMC [(mg )-139 (bid)]TJ 0 Tc 0 Tw 7.6 0 0 8 443.2193 695.0843 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 421.4113 686.5843 Tm (N=813)Tj 4.121 2.125 Td (Placebo)Tj 0 Tc 0 Tw 7.6 0 0 8 475.6381 703.5843 Tm ( )Tj -1.616 -1.062 Td ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 454.5863 686.5843 Tm (N=829)Tj 0.024 Tw 5.55 3.559 Td (Relative Risk \(95% CI\))Tj 0.022 Tw -0.408 -1.434 Td (ELIQUIS)Tj 0 Tc 0 Tw 7.6 0 0 8 516.0207 703.5843 Tm ( )Tj -0.022 Tc -0.115 Tw 7.6 0 0 8 490.067 695.0843 Tm (2.5)Tj /Span< >> BDC ( )Tj EMC [(mg )-139 (bid)]TJ 0 Tc 0 Tw 7.6 0 0 8 519.623 695.0843 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 489.2653 686.5843 Tm (vs Placebo)Tj 0.022 Tw 6.816 2.125 Td (ELIQUIS)Tj 0 Tc 0 Tw 7.6 0 0 8 563.4156 703.5843 Tm ( )Tj -0.022 Tc -0.115 Tw 7.6 0 0 8 540.0307 695.0843 Tm (5)Tj /Span< >> BDC ( )Tj EMC [(mg )-139 (bid)]TJ 0 Tc 0 Tw 7.6 0 0 8 564.4493 695.0843 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 536.6603 686.5843 Tm (vs Placebo)Tj /T1_1 1 Tf -15.106 -1.434 Td (n \(%\))Tj -0.014 Tc -0.013 Tw -12.875 -1.389 Td [(Recurrent VTE )-37 (or)-14 ( )]TJ 0.024 Tw 0 -1.125 Td [(all-cause dea)-10 (th)]TJ -0.022 Tc 8.074 0.562 Td (32 \(3.8\))Tj 4.63 0 Td (34 \(4.2\))Tj 4.136 0 Td (96 \(11.6\))Tj -0.032 Tc 7.2 0 0 8 484.1779 663.7504 Tm [(0.33 \(0.22,)37 ( 0.48\))]TJ 0 Tc 0 Tw 7.2 0 0 8 525.5123 663.7504 Tm ( )Tj -0.032 Tc 0.032 Tw 7.2 0 0 8 492.3209 655.2504 Tm (p<0.0001)Tj 0.024 Tw 5.452 1.062 Td [(0.36 \(0.25,)37 ( 0.53\))]TJ 0 Tc 0 Tw 7.2 0 0 8 572.9073 663.7504 Tm ( )Tj -0.032 Tc 0.032 Tw 7.2 0 0 8 539.7158 655.2504 Tm (p<0.0001)Tj -0.014 Tc 0.695 Tw /Span< >> BDC 7.6 0 0 8 324.0001 644.2485 Tm ( )Tj EMC (DVT)Tj 0 Tc 0 Tw (*)Tj -0.022 Tc 0.024 Tw 8.074 0 Td (19 \(2.3\))Tj 4.63 0 Td (28 \(3.4\))Tj 4.365 0 Td (72 \(8.7\))Tj 0 Tc 0 Tw /Span< >> BDC 4.94 0 0 5.2 324.0001 635.8967 Tm ( )Tj EMC -0.014 Tc 0.014 Tw 7.6 0 0 8 331.0001 633.4966 Tm (PE)Tj 0 Tc 0 Tw (*)Tj -0.022 Tc 0.024 Tw 7.153 0 Td (23 \(2.7\))Tj 4.63 0 Td (25 \(3.1\))Tj 4.365 0 Td (37 \(4.5\))Tj 0 Tc 0 Tw /Span< >> BDC 4.94 0 0 5.2 324.0001 625.1447 Tm ( )Tj EMC -0.027 Tc 0.024 Tw 7.6 0 0 8 331.0001 622.7447 Tm [(All-cause dea)-10 (th)]TJ -0.022 Tc 7.153 0 Td (22 \(2.6\))Tj 4.63 0 Td (25 \(3.1\))Tj 4.365 0 Td (33 \(4.0\))Tj -0.025 Tc 0.084 Tw -17.046 -1.479 Td (*)Tj /Span< >> BDC ( )Tj EMC 0.427 0 Td [(P)18 (a)-10 (tients with more than one event are counted in multiple ro)-10 (ws.)]TJ /T1_0 1 Tf 0.025 Tw 8 0 0 8 324.0001 580.5628 Tm (14.4)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td [(T)74 (reatment of VTE and Prevention of Recurrent VTE in P)24 (ediatric P)24 (atients)-24.9 ( )]TJ 0 -1.062 Td (from birth and older)Tj /T1_2 1 Tf 0.084 Tw -3.375 -1.737 Td [(Stud)6 (y CV185325)]TJ /T1_1 1 Tf 0.175 Tw 0 -1.288 Td [(ELIQUIS for the trea)-10 (tment of venous thromboembolism \(VTE\) and reduction in the risk)-25 ( )]TJ 0.16 Tw 0 -1.062 Td [(of recurrent )37.4 (VTE was evalua)-10 (ted )0.5 (in Stud)-10 (y CV185325,)37.1 ( a multicenter)74 (,)37 ( randomized,)37 ( active-)]TJ 0.075 Tw 0 -1.062 Td [(controlled,)37 ( open-label,)37.1 ( multi-center stud)-9.9 (y in 229 pedia)-9.9 (tric pa)-10 (tients from birth to less than)-25 ( )]TJ 0.201 Tw 0 -1.062 Td [(18 years with con\037rmed )37.2 (VTE.)37 ( )37.1 (This was a descriptive stud)-10 (y and no formal inferences)-25 ( )]TJ 0.178 Tw 0 -1.062 Td [(were performed.)37 ( )37.3 (There were 137 pa)-10 (tients a)-10 (ged 12 to <18 years,)37 ( 44 pa)-10 (tients a)-10 (ged 2)-25 ( )]TJ 0.1 Tw 0 -1.062 Td [(to <12 years,)37 ( 32 pa)-9.9 (tients a)-9.9 (ged 28 days to less than 2 years and 16 pa)-10 (tients from birth)-25 ( )]TJ 0.142 Tw 0 -1.062 Td [(to )0.6 (less )0.5 (than )0.5 (27 )0.6 (days.)37 ( )0.5 (Overall,)37 ( )0.6 (the )0.6 (median )0.5 (a)-9.9 (ge )0.6 (was )0.6 (14.2 )0.6 (years )0.5 (with )0.5 (a )0.5 (range )0.5 (of )0.5 (0.04 )0.5 (to)-25 ( )]TJ 0.034 Tw 0 -1.062 Td [(18.0 years.)37 ( Neona)-10 (tes and infants were exc)20 (luded from enrollment if they were <34 weeks\222)-25 ( )]TJ 0.068 Tw 0 -1.062 Td [(gesta)-10 (tion \(until a)-9.9 (ge of >6 months\) or had a bod)-10 (y weight of <2.6 kg.)37 ( F)20.1 (or pre-term infants)-25 ( )]TJ 0.151 Tw 0 -1.062 Td [(born between 34 and <37 weeks gesta)-9.9 (tion,)37 ( neona)-10 (tes who reached 37 weeks starting)-25 ( )]TJ 0.234 Tw 0 -1.062 Td [(from actual da)-10 (te of birth \(postna)-10 (tal a)-10 (ge\),)37 ( from 27 day neona)-10 (tal period starting from)-25 ( )]TJ 0.074 Tw 0 -1.062 Td [(actual da)-9.9 (te of birth \(postna)-10 (tal a)-10 (ge\),)37.1 ( or from when the postmenstrual a)-9.9 (ge \(gesta)-10 (tional a)-10 (ge)-25 ( )]TJ 0.124 Tw 0 -1.062 Td [(de\037ned as time ela)-9.9 (psed between \037rst day of last normal menstrual period and the day)-25 ( )]TJ 0.064 Tw 0 -1.062 Td [(of )0.6 (deliver)-17.9 (y )0.5 (plus )0.6 (postna)-9.9 (tal )0.5 (a)-9.9 (ge\) )0.5 (and )0.5 (enrolled )0.5 (the )0.5 (neona)-10 (te )0.6 (no )0.5 (more )0.5 (than )0.5 (27 )0.5 (days )0.5 (thereafter)74 (.)12 ( )]TJ 0 Tc 0 Tw 31.5 0 Td ( )Tj -0.025 Tc 0.067 Tw -31.5 -1.062 Td [(There were )0.5 (101 )0.5 (\(44.1%\) )0.5 (males,)37 ( )0.5 (and )0.5 (128 )0.5 (\(55.9%\) )0.5 (females )0.5 (in )0.5 (the )0.5 (stud)-10 (y)55.1 (.)37 ( One hundred )0.5 (and)-25 ( )]TJ 0.112 Tw 0 -1.062 Td [(seventy-\037ve \(76.4%\) pa)-10 (tients were )36.7 (White,)37 ( 31 \(13.5%\) were Black,)37 ( 9 \(3.9%\) were )36.8 (Asian,)12 ( )]TJ 0 Tc 0 Tw 31.5 0 Td ( )Tj -0.025 Tc 0.173 Tw -31.5 -1.062 Td [(4 \(1.7%\) were Other)74 (,)37 ( 2 \(0.9%\) were Multiracial and 1 \(0.4%\) was )36.6 (American Indian or)-24.9 ( )]TJ 0.199 Tw 0 -1.062 Td [(Alaska Na)-9.9 (tive,)37 ( and 7 \(3.1%\) were missing this informa)-10 (tion.)37 ( )37.3 (T)74 (wenty-\037ve \(10.9%\) were)-24.9 ( )]TJ 0.084 Tw 0 -1.062 Td [(Hispanic or La)-10 (tino and 204 \(89.1%\) were not Hispanic or La)-9.9 (tino.)]TJ 0.169 Tw 0 -1.512 Td [(Index )36.9 (VTE was c)20 (lassi\037ed as deep venous thrombosis \(DVT\),)37 ( pulmonar)-18 (y embolism \(PE\),)12 ( )]TJ 0.054 Tw 0 -1.062 Td [(device-rela)-9.9 (ted thrombosis \(neona)-10 (tal popula)-10 (tion only\),)37 ( and other )36.7 (VTE \(i.e.)37 ( cerebral vein and)-25 ( )]TJ 0.153 Tw 0 -1.062 Td [(sinus thrombosis,)37 ( renal vein thrombosis,)37 ( intracardiac thrombus\).)37.1 ( Prior to randomiza)-9.9 (tion,)12 ( )]TJ 0.101 Tw 0 -1.062 Td [(pa)-10 (tients could be trea)-10 (ted with SOC anticoa)-10 (gula)-9.9 (tion for up to 14 days; overall mean \(SD\))-25 ( )]TJ 0.248 Tw 0 -1.062 Td [(dura)-10 (tion of trea)-10 (tment with SOC anticoa)-9.9 (gula)-10 (tion prior to randomiza)-10 (tion was 4.9 \(2.6\))-25 ( )]TJ 0.112 Tw 0 -1.062 Td [(days,)37 ( and for 92.9% of pa)-10 (tients the dura)-9.9 (tion was between 0 and 7 days.)37 ( P)18 (a)-10 (tients were)-25 ( )]TJ 0.076 Tw 0 -1.062 Td [(randomized according to a 2:1 ra)-9.9 (tio to receive either an a)-10 (ge-a)-9.9 (ppropria)-9.9 (te formula)-9.9 (tion and)-25 ( )]TJ 0.059 Tw 0 -1.062 Td [(bod)-10 (y weight-adjusted doses of ELIQUIS or SOC.)37 ( F)20 (or pa)-10 (tients 2 to less than 18 years,)37 ( SOC)-25 ( )]TJ 0.089 Tw 0 -1.062 Td [(was comprised of lo)-10 (w molecular weight heparins \(LMWH\),)37 ( unfractiona)-10 (ted heparins \(UFH\))-24.9 ( )]TJ 0.156 Tw 0 -1.062 Td [(or vitamin K anta)-10 (gonists \(VKA\).)37 ( F)20 (or pa)-9.9 (tients 28 days to less than 2 years of a)-9.9 (ge,)37 ( SOC)-25 ( )]TJ 0.068 Tw 0 -1.062 Td [(was limited to heparins \(UFH or LMWH\).)37 ( )37 (The main trea)-9.9 (tment phase lasted 6 to 12 weeks)-25 ( )]TJ 0.072 Tw 0 -1.062 Td [(for pa)-10 (tients a)-9.9 (ged birth to less than 2 years,)37 ( and 12 weeks for pa)-9.9 (tients a)-9.9 (ged grea)-9.9 (ter than)-25 ( )]TJ 0.132 Tw 0 -1.062 Td [(2 years.)37 ( P)18 (a)-10 (tients a)-9.9 (ged 28 days to less than 18 years who were randomized to receive)-24.9 ( )]TJ 0.108 Tw 0 -1.062 Td [(a)-10 (pixaban had the option to continue a)-10 (pixaban trea)-9.9 (tment for 6 to 12 additional weeks in)-25 ( )]TJ 0.084 Tw 0 -1.062 Td (the extension phase.)Tj 0.177 Tw 0 -1.512 Td [(A )0.5 (dia)-10 (gnostic )0.5 (ima)-9.9 (ging )0.5 (test )0.6 (was )0.5 (obtained )0.6 (a)-10 (t )0.6 (baseline,)37 ( )0.5 (a)-10 (t )0.5 (week )0.5 (6,)37 ( )0.6 (and )0.5 (end )0.5 (of )0.6 (trea)-10 (tment)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(for pa)-10 (tients \0362 years of a)-10 (ge and a)-9.9 (t baseline and end of trea)-10 (tment for <2 years of a)-9.9 (ge.)]TJ ET 1 w /GS2 gs q 1 0 0 1 324.0001 214.0509 cm 0 0 m 156.24 0 l S Q q 1 0 0 1 480.2401 214.0509 cm 0 0 m 42.3 0 l S Q q 1 0 0 1 522.54 214.0509 cm 0 0 m 53.82 0 l S Q 0.5 w q 1 0 0 1 324.0001 194.079 cm 0 0 m 156.24 0 l S Q q 1 0 0 1 480.2401 194.079 cm 0 0 m 42.3 0 l S Q q 1 0 0 1 522.54 194.079 cm 0 0 m 53.82 0 l S Q 1 w q 1 0 0 1 324.0001 153.3232 cm 0 0 m 156.24 0 l S Q q 1 0 0 1 480.2401 153.3232 cm 0 0 m 42.3 0 l S Q q 1 0 0 1 522.54 153.3232 cm 0 0 m 53.82 0 l S Q 0.5 w q 1 0 0 1 324.0001 96.8313 cm 0 0 m 156.24 0 l S Q q 1 0 0 1 480.2401 96.8313 cm 0 0 m 42.3 0 l S Q q 1 0 0 1 522.54 96.8313 cm 0 0 m 53.82 0 l S Q BT /GS1 gs /T1_0 1 Tf -0.022 Tc 8 0 0 8 324.0001 217.6509 Tm (Table 19:)Tj /Span< >> BDC ( )Tj EMC 5.4 0 Td (Primary efficacy results from Study CV185325)Tj 0.022 Tw 7.6 0 0 8 490.2144 205.459 Tm (ELIQUIS)Tj 0 Tc 0 Tw 7.6 0 0 8 512.5657 205.459 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 491.7914 196.959 Tm (N=155)Tj 0.024 Tw 4.057 1.062 Td (Standard of care**)Tj 0 Tc 0 Tw 7.6 0 0 8 576.2776 205.459 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 541.5917 196.959 Tm (N=74)Tj /T1_1 1 Tf -0.014 Tc 0.024 Tw -28.63 -1.389 Td [(Symptoma)-10 (tic and asymptoma)-10 (tic recurrent )37 (VTE*)]TJ 0 Tc 0 Tw 7.6 0 0 8 453.174 185.847 Tm ( )Tj -0.014 Tc 0.024 Tw 7.6 0 0 8 324.0001 177.347 Tm [(and )37 (VTE* rela)-10 (ted mortality***)]TJ /Span< >> BDC 0 -1.344 Td ( )Tj EMC 0.592 0 Td (Number \(%\) Subjects with Event)Tj -0.022 Tc 21.602 0 Td (4 \(2.6\))Tj 6.324 0 Td (2 \(2.7\))Tj -0.014 Tc /Span< >> BDC -28.517 -1.344 Td ( )Tj EMC 0.592 0 Td [(95% Confidence Inter)-18 (val \(1\))]TJ -0.022 Tc 21.173 0 Td [(\(0.7,)37 ( 6.5\))]TJ 6.324 0 Td [(\(0.3,)37 ( 9.4\))]TJ -0.025 Tc 0.149 Tw /Span< >> BDC -28.089 -1.479 Td ( )Tj EMC 0.3 0 Td (*)Tj /Span< >> BDC [( )347.3 ( )]TJ EMC 0.344 0 Td [(Recurrent )37.5 (VTE,)37 ( )0.5 (defined )0.5 (as either )0.5 (contiguous )0.5 (progression )0.5 (or )0.5 (non-contiguous )0.5 (new )0.5 (thrombus)-24.9 ( )]TJ 0.084 Tw 0 -1.062 Td [(and inc)20 (luding,)37.1 ( but not limited to DVT)92 (,)37 ( PE and paradoxical embolism.)]TJ -0.644 -1.107 Td [(\(1\) 95% Confidence Inter)-17.9 (val calcula)-10 (ted using the Clopper)37 (-P)18 (earson exact method.)]TJ /Span< >> BDC 0 -1.107 Td ( )Tj EMC 0.348 0 Td (**)Tj /Span< >> BDC ( )Tj EMC 0.654 0 Td [(UFH/LMWH for pa)-9.9 (tients less than 2 years of a)-9.9 (ge and UFH/LMWH/VKA for those equal to)-24.9 ( )]TJ 0 -1.062 Td [(or grea)-10 (ter than 2 years of a)-10 (ge.)]TJ -1.002 -1.107 Td (***)Tj /Span< >> BDC ( )Tj EMC 1.021 0 Td [(no )37 (VTE rela)-9.9 (ted mortality was obser)-18 (ved in either trea)-10 (tment arms during the stud)-10 (y)55 (.)]TJ ET endstream endobj 265 0 obj <>/Font<>/ProcSet[/PDF/Text]>>/Subtype/Form>>stream 0 0 0 1 K 0.75 w /GS0 gs q 1 0 0 1 36 747.3931 cm 0 0 m 252 0 l S Q BT 0 0 0 1 k /T1_0 1 Tf -0.027 Tc 0.027 Tw 0 Ts 100 Tz 0 Tr 8 0 0 8 36 750.2881 Tm (ELIQUIS)Tj 0 Tc 0 Tw 5.98 0 0 5.98 66.4853 751.7981 Tm (\256)Tj -0.027 Tc 0.097 Tw 8 0 0 8 71.1084 750.2881 Tm ( \(apixaban\))Tj ET q 1 0 0 1 324 747.3931 cm 0 0 m 252 0 l S Q BT 0.027 Tw 8 0 0 8 500.65 750.2881 Tm (ELIQUIS)Tj 0 Tc 0 Tw 5.98 0 0 5.98 531.1353 751.7981 Tm 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(ADV)37 (ANCE-3 and )37.4 (ADV)37 (ANCE-2,)37 ( )0.5 (the )0.5 (primar)-17.9 (y endpoint )0.5 (was)-25 ( )]TJ 0.197 Tw 0 -1.062 Td [(tested for noninferiority)55 (,)37 ( then superiority)55 (,)37 ( of ELIQUIS to enoxa)-10 (parin.)37 ( In )36.7 (ADV)37 (ANCE-1,)36.9 ( the)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(primar)-18 (y endpoint was tested for noninferiority of ELIQUIS to enoxa)-10 (parin.)]TJ 0 -1.512 Td [(The ef\037cac)20 (y da)-10 (ta are provided in )37 (T)74 (ables 15 and 16.)]TJ ET 1 w /GS2 gs q 1 0 0 1 324 706.6481 cm 0 0 m 81.4 0 l S Q q 1 0 0 1 519.1333 706.6481 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 324 501.8452 cm 0 0 m 81.4 0 l S Q 0.5 w q 1 0 0 1 324 696.6162 cm 0 0 m 81.4 0 l S Q q 1 0 0 1 519.1333 696.6162 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 324 668.8643 cm 0 0 m 81.4 0 l S Q q 1 0 0 1 519.1333 668.8643 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 324 658.1124 cm 0 0 m 81.4 0 l S Q q 1 0 0 1 519.1333 658.1124 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 324 630.3605 cm 0 0 m 81.4 0 l S Q q 1 0 0 1 519.1333 630.3605 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 324 551.1009 cm 0 0 m 81.4 0 l S Q q 1 0 0 1 519.1333 551.1009 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 324 531.849 cm 0 0 m 81.4 0 l S Q q 1 0 0 1 519.1333 531.849 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 324 521.097 cm 0 0 m 81.4 0 l S Q q 1 0 0 1 519.1333 521.097 cm 0 0 m 56.867 0 l S Q 1 w q 1 0 0 1 519.1333 501.8452 cm 0 0 m 56.867 0 l S Q 0.5 w q 1 0 0 1 324 462.7132 cm 0 0 m 81.4 0 l S Q q 1 0 0 1 405.4 462.7132 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 462.2667 462.7132 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 519.1333 462.7132 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 324 619.6085 cm 0 0 m 81.4 0 l S Q q 1 0 0 1 519.1333 619.6085 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 324 561.8528 cm 0 0 m 81.4 0 l S Q q 1 0 0 1 519.1333 561.8528 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 405.4 668.8643 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 462.2667 668.8643 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 405.4 658.1124 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 462.2667 658.1124 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 405.4 630.3605 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 462.2667 630.3605 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 405.4 619.6085 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 462.2667 619.6085 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 405.4 561.8528 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 462.2667 561.8528 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 405.4 551.1009 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 462.2667 551.1009 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 405.4 531.849 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 462.2667 531.849 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 405.4 521.097 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 462.2667 521.097 cm 0 0 m 56.867 0 l S Q 1 w q 1 0 0 1 405.4 501.8452 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 462.2667 501.8452 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 405.4 706.6481 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 462.2667 706.6481 cm 0 0 m 56.867 0 l S Q 0.5 w q 1 0 0 1 405.4 696.6162 cm 0 0 m 56.867 0 l S Q q 1 0 0 1 462.2667 696.6162 cm 0 0 m 56.867 0 l S Q BT /GS1 gs /T1_3 1 Tf -0.022 Tc 8 0 0 8 324 727.248 Tm (Table 15:)Tj /Span< >> BDC ( )Tj EMC 5.4 0 Td [(Summary of Key Efficacy Analysis Results During the)-22 ( )]TJ 0 Tc 0 Tw 20.823 0 Td ( )Tj -0.022 Tc 0.084 Tw -20.823 -1.062 Td [(Intended Treatment Period for Patients Undergoing Elective)-22 ( )]TJ 0 Tc 0 Tw 23.047 0 Td ( )Tj -0.022 Tc 0.084 Tw -23.047 -1.062 Td (Hip Replacement Surgery*)Tj 0.024 Tw 7.6 0 0 8 444.3575 698.7761 Tm ( ADVANCE-3)Tj /T1_0 1 Tf -15.837 -2.361 Td [(Events During 35-Day)-22 ( )]TJ 0 -1.062 Td [(T)74 (rea)-10 (tment P)18 (eriod)]TJ 0.022 Tw 13.073 2.125 Td (ELIQUIS)Tj 0 Tc 0 Tw 7.6 0 0 8 444.3136 688.3842 Tm ( )Tj -0.022 Tc -0.005 Tw 7.6 0 0 8 424.2954 679.8842 Tm (2.5)Tj /Span< >> BDC ( )Tj EMC (mg)Tj 0 Tc 0 Tw 7.6 0 0 8 443.3712 679.8842 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 425.5077 671.3842 Tm (po bid)Tj 0.022 Tw 6.627 2.125 Td [(Enoxa)-10 (parin)]TJ 0 Tc 0 Tw 7.6 0 0 8 505.5272 688.3842 Tm ( )Tj -0.022 Tc -0.005 Tw 7.6 0 0 8 481.9905 679.8842 Tm (40)Tj /Span< >> BDC ( )Tj EMC (mg)Tj 0 Tc 0 Tw 7.6 0 0 8 499.4095 679.8842 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 483.3471 671.3842 Tm (sc qd)Tj 6.196 2.125 Td [(Rela)-10 (tive Risk)]TJ 0 Tc 0 Tw 7.6 0 0 8 564.6966 688.3842 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 536.0376 679.8842 Tm (\(95% CI\))Tj 0 Tc 0 Tw 7.6 0 0 8 559.0956 679.8842 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 537.4513 671.3842 Tm (P-value)Tj /T1_3 1 Tf 0.024 Tw -28.086 -1.344 Td [(Number of P)24 (atients)]TJ 0.022 Tw 12.96 0 Td (N=1949)Tj 7.482 0 Td (N=1917)Tj /T1_0 1 Tf -0.013 Tw -20.442 -2.406 Td [(T)74 (otal VTE)]TJ 0 Tc 0 Tw 4.94 0 0 5.2 347.9927 643.7804 Tm (\206)Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 350.2651 641.3804 Tm [(/All-cause dea)-9.9 (th)]TJ 9.022 0.531 Td (27 \(1.39%\))Tj 0 Tc 0 Tw 7.6 0 0 8 448.8317 645.6304 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 418.3789 637.1304 Tm [(\(0.95,)37 ( 2.02\))]TJ 7.542 1.062 Td (74 \(3.86%\))Tj 0 Tc 0 Tw 7.6 0 0 8 505.6983 645.6304 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 475.2456 637.1304 Tm [(\(3.08,)37 ( 4.83\))]TJ 0.022 Tw 8.709 1.594 Td (0.36)Tj 0 Tc 0 Tw 7.6 0 0 8 553.6998 649.8804 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 532.1122 641.3804 Tm [(\(0.22,)37 ( 0.54\))]TJ 0 Tc 0 Tw 7.6 0 0 8 563.021 641.3804 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 534.0806 632.8804 Tm (p<0.0001)Tj /T1_3 1 Tf 0.024 Tw -27.642 -1.344 Td [(Number of P)24 (atients)]TJ 0.022 Tw 12.96 0 Td (N=2708)Tj 7.482 0 Td (N=2699)Tj /T1_0 1 Tf 0.024 Tw /Span< >> BDC -20.442 -1.875 Td ( )Tj EMC 0.592 0 Td [(All-cause dea)-9.9 (th)]TJ 12.115 0.531 Td (3 \(0.11%\))Tj 0 Tc 0 Tw 7.6 0 0 8 447.0913 611.3766 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 418.3789 602.8766 Tm [(\(0.02,)37 ( 0.35\))]TJ 7.771 1.062 Td (1 \(0.04%\))Tj 0 Tc 0 Tw 7.6 0 0 8 503.9579 611.3766 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 475.2456 602.8766 Tm [(\(0.00,)37 ( 0.24\))]TJ 0.374 Tw /Span< >> BDC -19.901 -1.875 Td ( )Tj EMC (PE)Tj 0.024 Tw 12.707 0.531 Td (3 \(0.11%\))Tj 0 Tc 0 Tw 7.6 0 0 8 447.0913 592.1246 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 418.3789 583.6246 Tm [(\(0.02,)37 ( 0.35\))]TJ 7.771 1.062 Td (5 \(0.19%\))Tj 0 Tc 0 Tw 7.6 0 0 8 503.9579 592.1246 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 475.2456 583.6246 Tm [(\(0.07,)37 ( 0.45\))]TJ /Span< >> BDC -19.901 -1.875 Td ( )Tj EMC 0.592 0 Td [(Symptoma)-9.9 (tic DVT)]TJ 12.115 0.531 Td (1 \(0.04%\))Tj 0 Tc 0 Tw 7.6 0 0 8 447.0913 572.8727 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 418.3789 564.3727 Tm [(\(0.00,)37 ( 0.24\))]TJ 7.771 1.062 Td (5 \(0.19%\))Tj 0 Tc 0 Tw 7.6 0 0 8 503.9579 572.8727 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 475.2456 564.3727 Tm [(\(0.07,)37 ( 0.45\))]TJ /T1_3 1 Tf -19.901 -1.344 Td [(Number of P)24 (atients)]TJ 0.022 Tw 12.96 0 Td (N=2196)Tj 7.482 0 Td (N=2190)Tj /T1_0 1 Tf 0.024 Tw /Span< >> BDC -20.442 -1.875 Td ( )Tj EMC 0.592 0 Td (Proximal DVT)Tj 0 Tc 0 Tw 4.94 0 0 5.2 364.0823 541.0189 Tm (\207)Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 420.5753 542.8689 Tm (7 \(0.32%\))Tj 0 Tc 0 Tw 7.6 0 0 8 447.0913 542.8689 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 418.3789 534.3689 Tm [(\(0.14,)37 ( 0.68\))]TJ 7.542 1.062 Td (20 \(0.91%\))Tj 0 Tc 0 Tw 7.6 0 0 8 505.6983 542.8689 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 475.2456 534.3689 Tm [(\(0.59,)37 ( 1.42\))]TJ /T1_3 1 Tf -19.901 -1.344 Td [(Number of P)24 (atients)]TJ 0.022 Tw 12.96 0 Td (N=1951)Tj 7.482 0 Td (N=1908)Tj /T1_0 1 Tf 0.024 Tw /Span< >> BDC -20.442 -1.875 Td ( )Tj EMC 0.592 0 Td (Distal DVT)Tj 0 Tc 0 Tw 4.94 0 0 5.2 355.8519 511.0151 Tm (\207)Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 418.8349 512.8651 Tm (20 \(1.03%\))Tj 0 Tc 0 Tw 7.6 0 0 8 448.8317 512.8651 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 418.3789 504.3651 Tm [(\(0.66,)37 ( 1.59\))]TJ 7.542 1.062 Td (57 \(2.99%\))Tj 0 Tc 0 Tw 7.6 0 0 8 505.6983 512.8651 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 475.2456 504.3651 Tm [(\(2.31,)37 ( 3.86\))]TJ -0.025 Tc 0.052 Tw -19.878 -1.479 Td (*)Tj /Span< >> BDC ( )Tj EMC 0.527 0 Td [(Events associa)-10 (ted with each endpoint were counted once per subject but subjects may ha\ )-10 (ve)-25 ( )]TJ 0.084 Tw -0.001 -1.062 Td (contributed events to multiple endpoints.)Tj 0 Tc 0 Tw 5.98 0 0 5.98 324.176 476.6832 Tm (\206)Tj -0.025 Tc 0.084 Tw /Span< >> BDC 7.6 0 0 8 326.9088 475.1732 Tm ( )Tj EMC 0.167 0 Td [(T)74 (otal )37 (VTE inc)20.1 (ludes symptoma)-10 (tic and asymptoma)-9.9 (tic DVT and PE.)]TJ 0 Tc 0 Tw 5.98 0 0 5.98 324.176 467.8232 Tm (\207)Tj -0.025 Tc 0.084 Tw /Span< >> BDC 7.6 0 0 8 326.9088 466.3131 Tm ( )Tj EMC 0.167 0 Td [(Inc)20 (ludes symptoma)-10 (tic and asymptoma)-10 (tic DVT)92 (.)]TJ ET 1 w /GS2 gs q 1 0 0 1 324 409.6512 cm 0 0 m 41.86 0 l S Q q 1 0 0 1 470.5103 409.6512 cm 0 0 m 37.255 0 l S Q q 1 0 0 1 507.7657 409.6512 cm 0 0 m 37.994 0 l S Q q 1 0 0 1 545.76 409.6512 cm 0 0 m 30.24 0 l S Q 0.5 w q 1 0 0 1 324 398.1793 cm 0 0 m 41.86 0 l S Q q 1 0 0 1 324 361.9274 cm 0 0 m 41.86 0 l S Q q 1 0 0 1 324 342.6755 cm 0 0 m 41.86 0 l S Q q 1 0 0 1 324 314.9236 cm 0 0 m 41.86 0 l S Q q 1 0 0 1 324 180.1602 cm 0 0 m 41.86 0 l S Q q 1 0 0 1 470.5103 398.1793 cm 0 0 m 37.255 0 l S Q q 1 0 0 1 507.7657 398.1793 cm 0 0 m 37.994 0 l S Q q 1 0 0 1 545.76 398.1793 cm 0 0 m 30.24 0 l S Q q 1 0 0 1 470.5103 361.9274 cm 0 0 m 37.255 0 l S Q q 1 0 0 1 507.7657 361.9274 cm 0 0 m 37.994 0 l S Q q 1 0 0 1 545.76 361.9274 cm 0 0 m 30.24 0 l S Q q 1 0 0 1 470.5103 342.6755 cm 0 0 m 37.255 0 l S Q q 1 0 0 1 507.7657 342.6755 cm 0 0 m 37.994 0 l S Q q 1 0 0 1 545.76 342.6755 cm 0 0 m 30.24 0 l S Q q 1 0 0 1 470.5103 314.9236 cm 0 0 m 37.255 0 l S Q q 1 0 0 1 507.7657 314.9236 cm 0 0 m 37.994 0 l S Q q 1 0 0 1 545.76 314.9236 cm 0 0 m 30.24 0 l S Q q 1 0 0 1 470.5103 180.1602 cm 0 0 m 37.255 0 l S Q q 1 0 0 1 507.7657 180.1602 cm 0 0 m 37.994 0 l S Q q 1 0 0 1 545.76 180.1602 cm 0 0 m 30.24 0 l S Q 1 w q 1 0 0 1 470.5103 160.9083 cm 0 0 m 37.255 0 l S Q q 1 0 0 1 507.7657 160.9083 cm 0 0 m 37.994 0 l S Q q 1 0 0 1 545.76 160.9083 cm 0 0 m 30.24 0 l S Q 0.5 w q 1 0 0 1 324 295.6717 cm 0 0 m 41.86 0 l S Q q 1 0 0 1 470.5103 295.6717 cm 0 0 m 37.255 0 l S Q q 1 0 0 1 507.7657 295.6717 cm 0 0 m 37.994 0 l S Q q 1 0 0 1 545.76 295.6717 cm 0 0 m 30.24 0 l S Q q 1 0 0 1 324 199.4121 cm 0 0 m 41.86 0 l S Q q 1 0 0 1 470.5103 199.4121 cm 0 0 m 37.255 0 l S Q q 1 0 0 1 507.7657 199.4121 cm 0 0 m 37.994 0 l S Q q 1 0 0 1 545.76 199.4121 cm 0 0 m 30.24 0 l S Q q 1 0 0 1 324 121.7764 cm 0 0 m 41.86 0 l S Q q 1 0 0 1 365.8601 121.7764 cm 0 0 m 36.837 0 l S Q q 1 0 0 1 402.6969 121.7764 cm 0 0 m 36.837 0 l S Q q 1 0 0 1 439.5338 121.7764 cm 0 0 m 30.976 0 l S Q q 1 0 0 1 470.5103 121.7764 cm 0 0 m 37.255 0 l S Q q 1 0 0 1 507.7657 121.7764 cm 0 0 m 37.994 0 l S Q q 1 0 0 1 545.76 121.7764 cm 0 0 m 30.24 0 l S Q 1 w q 1 0 0 1 324 160.9083 cm 0 0 m 41.86 0 l S Q q 1 0 0 1 365.8601 409.6512 cm 0 0 m 36.837 0 l S Q q 1 0 0 1 402.6969 409.6512 cm 0 0 m 36.837 0 l S Q q 1 0 0 1 439.5338 409.6512 cm 0 0 m 30.976 0 l S Q q 1 0 0 1 365.8601 160.9083 cm 0 0 m 36.837 0 l S Q q 1 0 0 1 402.6969 160.9083 cm 0 0 m 36.837 0 l S Q q 1 0 0 1 439.5338 160.9083 cm 0 0 m 30.976 0 l S Q 0.5 w q 1 0 0 1 365.8601 398.1793 cm 0 0 m 36.837 0 l S Q q 1 0 0 1 402.6969 398.1793 cm 0 0 m 36.837 0 l S Q q 1 0 0 1 439.5338 398.1793 cm 0 0 m 30.976 0 l S Q q 1 0 0 1 365.8601 361.9274 cm 0 0 m 36.837 0 l S Q q 1 0 0 1 402.6969 361.9274 cm 0 0 m 36.837 0 l S Q q 1 0 0 1 439.5338 361.9274 cm 0 0 m 30.976 0 l S Q q 1 0 0 1 365.8601 342.6755 cm 0 0 m 36.837 0 l S Q q 1 0 0 1 402.6969 342.6755 cm 0 0 m 36.837 0 l S Q q 1 0 0 1 439.5338 342.6755 cm 0 0 m 30.976 0 l S Q q 1 0 0 1 365.8601 314.9236 cm 0 0 m 36.837 0 l S Q q 1 0 0 1 402.6969 314.9236 cm 0 0 m 36.837 0 l S Q q 1 0 0 1 439.5338 314.9236 cm 0 0 m 30.976 0 l S Q q 1 0 0 1 365.8601 295.6717 cm 0 0 m 36.837 0 l S Q q 1 0 0 1 402.6969 295.6717 cm 0 0 m 36.837 0 l S Q q 1 0 0 1 439.5338 295.6717 cm 0 0 m 30.976 0 l S Q q 1 0 0 1 365.8601 199.4121 cm 0 0 m 36.837 0 l S Q q 1 0 0 1 402.6969 199.4121 cm 0 0 m 36.837 0 l S Q q 1 0 0 1 439.5338 199.4121 cm 0 0 m 30.976 0 l S Q q 1 0 0 1 365.8601 180.1602 cm 0 0 m 36.837 0 l S Q q 1 0 0 1 402.6969 180.1602 cm 0 0 m 36.837 0 l S Q q 1 0 0 1 439.5338 180.1602 cm 0 0 m 30.976 0 l S Q BT /GS1 gs /T1_3 1 Tf -0.022 Tc 8 0 0 8 324 430.2512 Tm (Table 16:)Tj /Span< >> BDC ( )Tj EMC 5.4 0 Td [(Summary of Key Efficacy Analysis Results During the)-22 ( )]TJ 0 Tc 0 Tw 20.823 0 Td ( )Tj -0.022 Tc 0.084 Tw -20.823 -1.062 Td [(Intended Treatment Period for Patients Undergoing Elective)-22 ( )]TJ 0 Tc 0 Tw 23.047 0 Td ( )Tj -0.022 Tc 0.084 Tw -23.047 -1.062 Td (Knee Replacement Surgery*)Tj 0.022 Tw 7.6 0 0 8 401.1956 401.0593 Tm (ADVANCE-1)Tj 13.825 0 Td (ADVANCE-2)Tj /T1_0 1 Tf 0.024 Tw 7.2 0 0 8 323.9999 389.9474 Tm (Events during)Tj 0 Tc 0 Tw 7.2 0 0 8 358.5161 389.9474 Tm ( )Tj -0.022 Tc 0.022 Tw 7.2 0 0 8 323.9999 381.4474 Tm (12-day)Tj 0 Tc 0 Tw 7.2 0 0 8 342.1076 381.4474 Tm ( )Tj -0.022 Tc 0.022 Tw 7.2 0 0 8 323.9999 372.9474 Tm [(trea)-10 (tment)]TJ 0 Tc 0 Tw 7.2 0 0 8 348.6519 372.9474 Tm ( )Tj -0.022 Tc 0.022 Tw 7.2 0 0 8 323.9999 364.4474 Tm (period)Tj 6.993 2.125 Td (ELIQUIS)Tj 0 Tc 0 Tw 7.2 0 0 8 394.2071 381.4474 Tm ( )Tj -0.022 Tc -0.005 Tw 7.2 0 0 8 375.2426 372.9474 Tm (2.5)Tj /Span< >> BDC ( )Tj EMC (mg)Tj 0 Tc 0 Tw 7.2 0 0 8 393.3143 372.9474 Tm ( )Tj -0.022 Tc 0.024 Tw 7.2 0 0 8 376.391 364.4474 Tm (po bid)Tj 0.022 Tw 4.261 2.125 Td [(Enoxa)-10 (parin)]TJ 0 Tc 0 Tw 7.2 0 0 8 435.1622 381.4474 Tm ( )Tj -0.022 Tc -0.005 Tw 7.2 0 0 8 412.8642 372.9474 Tm (30)Tj /Span< >> BDC ( )Tj EMC (mg)Tj 0 Tc 0 Tw 7.2 0 0 8 429.3664 372.9474 Tm ( )Tj -0.022 Tc 0.024 Tw 7.2 0 0 8 410.8518 364.4474 Tm (sc q12h)Tj 0.022 Tw 4.745 3.188 Td [(Rela)-10 (tive)]TJ 0 Tc 0 Tw 7.2 0 0 8 465.0296 389.9474 Tm ( )Tj -0.022 Tc 0.022 Tw 7.2 0 0 8 449.5933 381.4474 Tm (Risk)Tj 0 Tc 0 Tw 7.2 0 0 8 460.4507 381.4474 Tm ( )Tj -0.022 Tc 0.024 Tw 7.2 0 0 8 444.0997 372.9474 Tm (\(95% CI\))Tj 0 Tc 0 Tw 7.2 0 0 8 465.9442 372.9474 Tm ( )Tj -0.022 Tc 0.022 Tw 7.2 0 0 8 445.439 364.4474 Tm (P-value)Tj 4.69 2.125 Td (ELIQUIS)Tj 0 Tc 0 Tw 7.2 0 0 8 499.0666 381.4474 Tm ( )Tj -0.027 Tc -0.115 Tw 7.2 0 0 8 480.5881 372.9474 Tm (2.5)Tj /Span< >> BDC ( )Tj EMC (mg)Tj 0 Tc 0 Tw 7.2 0 0 8 497.6878 372.9474 Tm ( )Tj -0.027 Tc 0.024 Tw 7.2 0 0 8 481.3405 364.4474 Tm (po bid)Tj -0.022 Tc 0.022 Tw 4.358 2.125 Td [(Enoxa)-10 (parin)]TJ 0 Tc 0 Tw 7.2 0 0 8 540.8097 381.4474 Tm ( )Tj -0.022 Tc -0.005 Tw 7.2 0 0 8 518.5117 372.9474 Tm (40)Tj /Span< >> BDC ( )Tj EMC [(mg)-22 ( )]TJ 0 Tc 0 Tw 7.2 0 0 8 536.5978 372.9474 Tm ( )Tj -0.022 Tc 0.024 Tw 7.2 0 0 8 519.7969 364.4474 Tm (sc qd)Tj 0.022 Tw 4.316 3.188 Td [(Rela)-10 (tive)]TJ 0 Tc 0 Tw 7.2 0 0 8 570.8876 389.9474 Tm ( )Tj -0.022 Tc 0.022 Tw 7.2 0 0 8 555.4512 381.4474 Tm (Risk)Tj 0 Tc 0 Tw 7.2 0 0 8 566.3087 381.4474 Tm ( )Tj -0.022 Tc 0.024 Tw 7.2 0 0 8 549.9578 372.9474 Tm (\(95% CI\))Tj 0 Tc 0 Tw 7.2 0 0 8 571.8022 372.9474 Tm ( )Tj -0.022 Tc 0.022 Tw 7.2 0 0 8 551.297 364.4474 Tm (P-value)Tj /T1_3 1 Tf 0.024 Tw -31.569 -1.344 Td (Number of)Tj 0 Tc 0 Tw 7.2 0 0 8 352.7419 353.6955 Tm ( )Tj -0.022 Tc 0.022 Tw 7.2 0 0 8 323.9999 345.1955 Tm [(P)24 (atients)]TJ 6.88 0.531 Td (N=1157)Tj 5.116 0 Td (N=1130)Tj 9.677 0 Td (N=976)Tj 5.226 0 Td (N=997)Tj /T1_0 1 Tf -0.013 Tw -26.899 -2.406 Td [(T)74 (otal VTE)]TJ 0 Tc 0 Tw 4.68 0 0 5.2 346.7299 332.5936 Tm (\206)Tj 7.2 0 0 8 348.8827 330.1936 Tm (/)Tj 7.2 0 0 8 350.8843 330.1936 Tm ( )Tj -0.022 Tc 0.024 Tw 7.2 0 0 8 323.9999 321.6936 Tm [(All-cause dea)-10 (th)]TJ 6.26 1.062 Td [(1)100 (04 \(8)40 (.)40 (99%\))]TJ 0 Tc 0 Tw 7.2 0 0 8 399.4882 330.1936 Tm ( )Tj -0.022 Tc 0.024 Tw 7.2 0 0 8 369.4287 321.6936 Tm [(\(7)100 (.)80 (4)40 (7,)37 ( 1)80 (0)20 (.)80 (79\))]TJ 4.996 1.062 Td [(1)40 (00 \(8.85%\))]TJ 0 Tc 0 Tw 7.2 0 0 8 436.829 330.1936 Tm ( )Tj -0.022 Tc 0.024 Tw 7.2 0 0 8 405.9055 321.6936 Tm [(\(7)100 (.)80 (3)40 (3,)37 ( 1)80 (0.66\))]TJ 0.022 Tw 6.055 1.594 Td [(1)80 (.02)]TJ 0 Tc 0 Tw 7.2 0 0 8 460.5443 334.4436 Tm ( )Tj -0.022 Tc 0.024 Tw 7.2 0 0 8 441.317 325.9436 Tm [(\(0.)80 (7)40 (8,)37 ( 1)80 (.)60 (32\))]TJ 0 Tc 0 Tw 7.2 0 0 8 468.7269 325.9436 Tm ( )Tj -0.022 Tc 0.022 Tw 7.2 0 0 8 451.2996 317.4436 Tm (NS)Tj 0.024 Tw 2.824 1.594 Td (147 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(Fibrillation in ARISTOTLE \(Intent-to-Treat Analysis\))Tj 0.022 Tw 7.6 0 0 8 136.4243 563.8444 Tm (ELIQUIS)Tj 0 Tc 0 Tw 7.6 0 0 8 158.7757 563.8444 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 136.2609 554.8444 Tm (N=9120)Tj 0 Tc 0 Tw 7.6 0 0 8 158.9391 554.8444 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 132.4421 545.8444 Tm (n \(%/year\))Tj 0.022 Tw 5.594 2.25 Td (Warfarin)Tj 0 Tc 0 Tw 7.6 0 0 8 199.8058 563.8444 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 176.041 554.8444 Tm (N=9081)Tj 0 Tc 0 Tw 7.6 0 0 8 198.7191 554.8444 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 172.2221 545.8444 Tm (n \(%/year\))Tj 5.797 2.25 Td (Hazard Ratio)Tj 0 Tc 0 Tw 7.6 0 0 8 253.1573 563.8444 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 222.4272 554.8444 Tm (\(95% CI\))Tj 0.022 Tw 5.486 1.125 Td (P-value)Tj /T1_0 1 Tf 0.024 Tw -30.015 -3.639 Td (Stroke or systemic embolism)Tj 12.85 0 Td (212 \(1.27\))Tj 5.234 0 Td (265 \(1.60\))Tj 5.112 0 Td [(0.79 \(0.66,)37 ( 0.95\))]TJ 0.022 Tw 7.454 0 Td (0.01)Tj -0.014 Tc 0.958 Tw /Span< >> BDC -30.651 -1.344 Td ( )Tj EMC (Stroke)Tj -0.022 Tc 0.024 Tw 12.85 0 Td (199 \(1.19\))Tj 5.234 0 Td (250 \(1.51\))Tj 5.112 0 Td [(0.79 \(0.65,)37 ( 0.95\))]TJ -0.014 Tc /Span< >> BDC -23.197 -1.344 Td [( )-934.2 ( )]TJ EMC 1.842 0 Td (Ischemic without)Tj 0 Tc 0 Tw 7.6 0 0 8 96.283 513.2286 Tm ( )Tj -0.014 Tc 0.432 Tw /Span< >> BDC 7.6 0 0 8 36 504.7286 Tm [( )-526.2 ( )]TJ EMC [(hemorrha)-10 (ge)]TJ -0.022 Tc 0.024 Tw 12.85 0.531 Td (140 \(0.83\))Tj 5.234 0 Td (136 \(0.82\))Tj 5.112 0 Td [(1.02 \(0.81,)37 ( 1.29\))]TJ -0.014 Tc /Span< >> BDC -23.197 -1.875 Td [( )-934.2 ( )]TJ EMC 1.842 0 Td [(Ischemic with)-14 ( )]TJ 0 Tc 0 Tw 7.6 0 0 8 89.5343 493.9767 Tm ( )Tj -0.014 Tc 0.432 Tw /Span< >> BDC 7.6 0 0 8 36 485.4767 Tm [( )-526.2 ( )]TJ EMC [(hemorrha)-10 (gic )408 (conversion)]TJ -0.022 Tc 0.024 Tw 13.079 0.531 Td (12 \(0.07\))Tj 5.234 0 Td (20 \(0.12\))Tj 4.883 0 Td [(0.60 \(0.29,)37 ( 1.23\))]TJ -0.014 Tc 0.432 Tw /Span< >> BDC -23.197 -1.875 Td [( )-526.2 ( )]TJ EMC [(Hemorrha)-10 (gic)]TJ -0.022 Tc 0.024 Tw 13.079 0 Td (40 \(0.24\))Tj 5.234 0 Td (78 \(0.47\))Tj 4.883 0 Td [(0.51 \(0.35,)37 ( 0.75\))]TJ -0.014 Tc 0.432 Tw /Span< >> BDC -23.197 -1.344 Td [( )-526.2 ( )]TJ EMC [(Unkno)-10 (wn)]TJ -0.022 Tc 0.024 Tw 13.079 0 Td (14 \(0.08\))Tj 5.234 0 Td (21 \(0.13\))Tj 4.883 0 Td [(0.65 \(0.33,)37 ( 1.29\))]TJ /Span< >> BDC -23.197 -1.344 Td ( )Tj EMC 1.184 0 Td (Systemic embolism)Tj 11.895 0 Td (15 \(0.09\))Tj 5.234 0 Td (17 \(0.10\))Tj 4.883 0 Td [(0.87 \(0.44,)37 ( 1.75\))]TJ -0.012 Tc 0.119 Tw -23.197 -1.479 Td [(The primar)-18 (y endpoint was based on the time to first event \(one per subject\).)37 ( Component)-11.9 ( )]TJ 0.084 Tw 0 -1.05 Td [(counts are for subjects with an)-10 (y event,)37 ( not necessarily the first.)]TJ /T1_2 1 Tf -0.022 Tc 8 0 0 8 324 727.248 Tm (Figure 4:)Tj /Span< >> BDC ( )Tj EMC 5.4 0 Td [(Kaplan-Meier Estimate of Time to First Stroke or Systemic)-22.1 ( )]TJ 0 -1.062 Td (Embolism in ARISTOTLE \(Intent-to-Treat Population\))Tj ET /PlacedGraphic /MC0 BDC EMC q 324 561.271 246.626 149.317 re W n /GS0 gs q 1 0 0 1 363.1143 612.4759 cm 0 0 m 0 -1.514 l 16.691 0 m 16.691 -1.514 l 33.384 0 m 33.384 -1.514 l 50.345 0 m 50.345 -1.514 l 67.029 0 m 67.029 -1.514 l 83.73 0 m 83.73 -1.514 l 100.69 0 m 100.69 -1.514 l 117.375 0 m 117.375 -1.514 l 134.059 0 m 134.059 -1.514 l 151.029 0 m 151.029 -1.514 l 167.713 0 m 167.713 -1.514 l 184.405 0 m 184.405 -1.514 l 201.366 0 m 201.366 -1.514 l -7.646 76.714 m -6.279 76.714 l -7.646 59.053 m -6.279 59.053 l -7.646 41.096 m -6.279 41.096 l -7.646 23.139 m -6.279 23.139 l -7.646 5.183 m -6.279 5.183 l -7.646 94.679 m -6.279 94.679 l 207.262 0.012 -213.485 97.419 re S Q Q /GS0 gs q 1 0 0 1 482.016 650.1063 cm 0 0 m 2.359 0 l 2.359 -0.624 l 0.563 -0.624 l 0.563 -2.415 l 2.257 -2.415 l 2.257 -3.039 l 0.563 -3.039 l 0.563 -5.086 l 2.436 -5.086 l 2.436 -5.709 l 0 -5.709 l h f Q q 1 0 0 1 485.037 650.1063 cm 0 0 m 0.563 0 l 0.563 -5.086 l 2.417 -5.086 l 2.417 -5.709 l 0 -5.709 l h f Q 487.936 644.397 0.563 5.709 re f q 324 556.817 252 153.77 re W n q 1 0 0 1 490.681 645.4926 cm 0 0 m 0.313 0.432 l 0.735 -0.048 l 0.876 0.384 0.907 1.032 0.907 1.759 c 0.907 3.079 0.805 4.15 0.025 4.15 c -0.755 4.15 -0.857 3.079 -0.857 1.759 c -0.857 0.44 -0.755 -0.631 0.025 -0.631 c 0.191 -0.631 0.332 -0.584 0.441 -0.496 c h 0.812 -0.919 m 0.613 -1.103 0.351 -1.207 0.025 -1.207 c -1.234 -1.207 -1.446 0.32 -1.446 1.759 c -1.446 3.198 -1.234 4.726 0.025 4.726 c 1.285 4.726 1.496 3.198 1.496 1.759 c 1.496 0.935 1.425 0.08 1.125 -0.496 c 1.585 -1.024 l 1.272 -1.439 l h f Q q 1 0 0 1 492.865 650.1063 cm 0 0 m 0.562 0 l 0.562 -4.014 l 0.562 -4.854 0.78 -5.245 1.336 -5.245 c 1.937 -5.245 2.116 -4.814 2.116 -4.014 c 2.116 0 l 2.678 0 l 2.678 -4.014 l 2.678 -5.109 2.231 -5.821 1.336 -5.821 c 0.422 -5.821 0 -5.19 0 -4.014 c h f Q 496.295 650.106 0.563 -5.709 re f q 1 0 0 1 499.596 648.6268 cm 0 0 m 0 0.6 -0.173 1.016 -0.71 1.016 c -1.183 1.016 -1.465 0.696 -1.465 0.088 c -1.465 -1.519 0.69 -0.56 0.69 -2.646 c 0.69 -3.966 -0.083 -4.341 -0.729 -4.341 c -1.797 -4.341 -2.11 -3.654 -2.11 -2.438 c -1.548 -2.438 l -1.548 -3.078 -1.515 -3.766 -0.691 -3.766 c -0.243 -3.766 0.102 -3.366 0.102 -2.758 c 0.102 -1.143 -2.053 -2.079 -2.053 0.016 c -2.053 0.544 -1.874 1.591 -0.717 1.591 c 0.153 1.591 0.55 1.048 0.562 0 c h f Q q 1 0 0 1 503.654 650.1063 cm 0 0 m -0.517 -1.064 -0.703 -2.351 -0.703 -3.59 c -0.703 -4.885 -0.473 -6.037 0 -7.18 c -0.306 -7.18 l -0.907 -6.149 -1.24 -4.854 -1.24 -3.59 c -1.24 -2.319 -0.914 -1.04 -0.306 0 c h f Q q 1 0 0 1 505.779 646.9882 cm 0 0 m 0 0.231 l 0 0.711 -0.122 1.279 -0.595 1.279 c -1.157 1.279 -1.221 0.415 -1.221 0.16 c -1.221 0 l h -1.24 -0.528 m -1.24 -1.184 -1.24 -2.175 -0.582 -2.175 c -0.071 -2.175 0 -1.503 0 -1.184 c 0.537 -1.184 l 0.537 -1.639 0.32 -2.703 -0.614 -2.703 c -1.451 -2.703 -1.803 -1.975 -1.803 -0.504 c -1.803 0.567 -1.637 1.807 -0.582 1.807 c 0.467 1.807 0.562 0.664 0.562 -0.256 c 0.562 -0.528 l h f Q q 1 0 0 1 506.702 648.6829 cm 0 0 m 0.589 0 l 1.228 -3.438 l 1.24 -3.438 l 1.88 0 l 2.468 0 l 1.541 -4.286 l 0.927 -4.286 l h f Q q 1 0 0 1 511.333 646.9882 cm 0 0 m 0 0.231 l 0 0.711 -0.121 1.279 -0.594 1.279 c -1.157 1.279 -1.221 0.415 -1.221 0.16 c -1.221 0 l h -1.24 -0.528 m -1.24 -1.184 -1.24 -2.175 -0.582 -2.175 c -0.07 -2.175 0 -1.503 0 -1.184 c 0.538 -1.184 l 0.538 -1.639 0.32 -2.703 -0.613 -2.703 c -1.451 -2.703 -1.803 -1.975 -1.803 -0.504 c -1.803 0.567 -1.636 1.807 -0.582 1.807 c 0.467 1.807 0.563 0.664 0.563 -0.256 c 0.563 -0.528 l h f Q q 1 0 0 1 512.544 648.6829 cm 0 0 m 0.512 0 l 0.512 -0.504 l 0.525 -0.504 l 0.665 -0.112 1.023 0.112 1.356 0.112 c 2.257 0.112 2.257 -0.744 2.257 -1.247 c 2.257 -4.286 l 1.72 -4.286 l 1.72 -1.327 l 1.72 -1 1.701 -0.464 1.215 -0.464 c 0.928 -0.464 0.538 -0.704 0.538 -1.327 c 0.538 -4.286 l 0 -4.286 l h f Q q 1 0 0 1 515.726 649.9305 cm 0 0 m 0.536 0 l 0.536 -1.248 l 1.131 -1.248 l 1.131 -1.775 l 0.536 -1.775 l 0.536 -4.526 l 0.536 -4.87 0.607 -5.005 0.888 -5.005 c 1.003 -5.005 1.067 -4.989 1.125 -4.982 c 1.125 -5.533 l 1.054 -5.549 0.914 -5.581 0.69 -5.581 c 0.133 -5.581 0 -5.294 0 -4.733 c 0 -1.775 l -0.499 -1.775 l -0.499 -1.248 l 0 -1.248 l h f Q q 1 0 0 1 518.751 647.4275 cm 0 0 m 0 0.544 -0.115 0.84 -0.505 0.84 c -0.677 0.84 -1.061 0.784 -1.061 0.184 c -1.061 -0.32 -0.639 -0.416 -0.217 -0.592 c 0.199 -0.767 0.621 -0.951 0.621 -1.799 c 0.621 -2.703 0.154 -3.142 -0.485 -3.142 c -1.649 -3.142 -1.662 -2.063 -1.662 -1.623 c -1.125 -1.623 l -1.125 -2.142 -1.01 -2.614 -0.485 -2.614 c -0.313 -2.614 0.083 -2.511 0.083 -1.903 c 0.083 -1.327 -0.338 -1.207 -0.754 -1.031 c -1.169 -0.855 -1.598 -0.704 -1.598 0.184 c -1.598 0.983 -1.099 1.367 -0.505 1.367 c 0.493 1.367 0.531 0.504 0.538 0 c h f Q 520.064 645.245 0.589 -0.848 re 520.064 648.443 0.589 -0.848 re f q 1 0 0 1 525.579 644.3973 cm 0 0 m -2.532 0 l -2.532 1.056 -2.058 1.775 -1.554 2.319 c -1.183 2.71 l -0.818 3.102 -0.581 3.446 -0.581 4.07 c -0.581 4.558 -0.754 5.085 -1.24 5.085 c -1.937 5.085 -1.956 4.182 -1.956 3.862 c -2.519 3.862 l -2.519 4.933 -2.161 5.661 -1.234 5.661 c -0.185 5.661 -0.019 4.645 -0.019 4.15 c -0.019 3.286 -0.307 2.83 -0.812 2.287 c -1.451 1.591 l -1.701 1.327 -1.88 0.999 -1.943 0.623 c 0 0.623 l h f Q q 1 0 0 1 526.336 649.1307 cm 0 0 m 0.57 0.04 1.094 0.128 1.12 0.928 c 1.503 0.928 l 1.503 -4.733 l 0.966 -4.733 l 0.966 -0.479 l 0 -0.479 l h f Q q 1 0 0 1 531.838 644.3973 cm 0 0 m -2.532 0 l -2.532 1.056 -2.059 1.775 -1.554 2.319 c -1.183 2.71 l -0.818 3.102 -0.582 3.446 -0.582 4.07 c -0.582 4.558 -0.755 5.085 -1.24 5.085 c -1.937 5.085 -1.957 4.182 -1.957 3.862 c -2.519 3.862 l -2.519 4.933 -2.161 5.661 -1.234 5.661 c -0.186 5.661 -0.019 4.645 -0.019 4.15 c -0.019 3.286 -0.307 2.83 -0.812 2.287 c -1.451 1.591 l -1.701 1.327 -1.88 0.999 -1.943 0.623 c 0 0.623 l h f Q q 1 0 0 1 533.586 650.2181 cm 0 0 m 0.422 0 l -1.061 -5.933 l -1.483 -5.933 l h f Q q 1 0 0 1 535.506 649.5306 cm 0 0 m -0.562 0 -0.715 -0.712 -0.715 -1.312 c -0.715 -1.911 -0.601 -2.623 0 -2.623 c 0.601 -2.623 0.717 -1.911 0.717 -1.312 c 0.717 -0.712 0.563 0 0 0 c -0.613 -3.886 m -0.613 -4.35 -0.402 -4.717 -0.019 -4.717 c 0.736 -4.717 0.78 -3.302 0.78 -3.015 c 0.78 -2.567 l 0.767 -2.567 l 0.678 -2.774 0.403 -3.198 -0.095 -3.198 c -0.882 -3.198 -1.278 -2.471 -1.278 -1.407 c -1.278 -0.312 -0.843 0.528 0 0.528 c 1.253 0.528 1.343 -0.992 1.343 -2.159 c 1.343 -3.454 1.279 -5.245 -0.031 -5.245 c -1.087 -5.245 -1.176 -4.15 -1.176 -3.886 c h f Q q 1 0 0 1 537.562 649.1307 cm 0 0 m 0.569 0.04 1.093 0.128 1.119 0.928 c 1.502 0.928 l 1.502 -4.733 l 0.965 -4.733 l 0.965 -0.479 l 0 -0.479 l h f Q q 1 0 0 1 543.063 644.3973 cm 0 0 m -2.532 0 l -2.532 1.056 -2.059 1.775 -1.554 2.319 c -1.183 2.71 l -0.818 3.102 -0.582 3.446 -0.582 4.07 c -0.582 4.558 -0.754 5.085 -1.24 5.085 c -1.937 5.085 -1.957 4.182 -1.957 3.862 c -2.519 3.862 l -2.519 4.933 -2.161 5.661 -1.234 5.661 c -0.186 5.661 -0.019 4.645 -0.019 4.15 c -0.019 3.286 -0.307 2.83 -0.812 2.287 c -1.451 1.591 l -1.701 1.327 -1.879 0.999 -1.943 0.623 c 0 0.623 l h f Q q 1 0 0 1 544.927 644.8134 cm 0 0 m 0.69 0 0.728 1.143 0.728 2.334 c 0.728 3.582 0.69 4.717 0 4.717 c -0.691 4.717 -0.729 3.582 -0.729 2.334 c -0.729 1.143 -0.691 0 0 0 c -1.292 2.334 m -1.292 3.582 -1.221 5.245 0 5.245 c 1.22 5.245 1.291 3.726 1.291 2.334 c 1.291 1.135 1.22 -0.528 0 -0.528 c -1.221 -0.528 -1.292 0.991 -1.292 2.334 c f Q q 1 0 0 1 546.547 642.9261 cm 0 0 m 0.518 1.063 0.703 2.351 0.703 3.59 c 0.703 4.885 0.473 6.037 0 7.18 c 0.307 7.18 l 0.908 6.148 1.241 4.853 1.241 3.59 c 1.241 2.319 0.914 1.039 0.307 0 c h f Q q 1 0 0 1 408.9814 683.1023 cm 0 0 m 0.562 0 l 1.259 -4.669 l 1.272 -4.669 l 1.918 0 l 2.596 0 l 3.241 -4.669 l 3.254 -4.669 l 3.951 0 l 4.514 0 l 3.574 -5.709 l 2.89 -5.709 l 2.263 -1.087 l 2.25 -1.087 l 1.592 -5.709 l 0.908 -5.709 l h f Q q 1 0 0 1 415.3662 679.7283 cm 0 0 m -0.198 -0.264 -0.671 -0.32 -0.914 -0.504 c -1.087 -0.64 -1.176 -0.808 -1.176 -1.184 c -1.176 -1.615 -1.055 -1.919 -0.69 -1.919 c -0.339 -1.919 0 -1.543 0 -1.104 c h -1.656 0.655 m -1.656 1.631 -1.323 2.063 -0.505 2.063 c 0.537 2.063 0.537 1.279 0.537 0.831 c 0.537 -1.56 l 0.537 -1.735 0.537 -1.903 0.704 -1.903 c 0.774 -1.903 0.806 -1.887 0.831 -1.863 c 0.831 -2.343 l 0.793 -2.351 0.652 -2.383 0.518 -2.383 c 0.313 -2.383 0.058 -2.383 0.032 -1.831 c 0.019 -1.831 l -0.153 -2.215 -0.486 -2.447 -0.806 -2.447 c -1.445 -2.447 -1.739 -1.967 -1.739 -1.2 c -1.739 -0.6 -1.534 -0.184 -1.093 -0.016 c -0.371 0.256 l 0.019 0.408 0.019 0.543 0.019 0.903 c 0.019 1.303 -0.172 1.535 -0.531 1.535 c -1.119 1.535 -1.119 0.847 -1.119 0.695 c -1.119 0.655 l h f Q q 1 0 0 1 416.6348 681.679 cm 0 0 m 0.537 0 l 0.537 -0.64 l 0.55 -0.64 l 0.703 -0.232 0.908 0.112 1.291 0.112 c 1.4 0.112 1.477 0.096 1.528 0.064 c 1.528 -0.592 l 1.477 -0.583 1.413 -0.56 1.24 -0.56 c 0.972 -0.56 0.537 -0.864 0.537 -1.575 c 0.537 -4.286 l 0 -4.286 l h f Q q 1 0 0 1 418.689 681.1512 cm 0 0 m -0.499 0 l -0.499 0.528 l 0 0.528 l 0 1.032 l 0 1.679 0.224 2.015 0.742 2.015 c 1.132 2.015 l 1.132 1.439 l 0.882 1.439 l 0.652 1.439 0.537 1.327 0.537 1.032 c 0.537 0.528 l 1.126 0.528 l 1.126 0 l 0.537 0 l 0.537 -3.758 l 0 -3.758 l h f Q q 1 0 0 1 421.7598 679.7283 cm 0 0 m -0.198 -0.264 -0.671 -0.32 -0.914 -0.504 c -1.087 -0.64 -1.176 -0.808 -1.176 -1.184 c -1.176 -1.615 -1.055 -1.919 -0.691 -1.919 c -0.339 -1.919 0 -1.543 0 -1.104 c h -1.656 0.655 m -1.656 1.631 -1.323 2.063 -0.505 2.063 c 0.537 2.063 0.537 1.279 0.537 0.831 c 0.537 -1.56 l 0.537 -1.735 0.537 -1.903 0.704 -1.903 c 0.774 -1.903 0.806 -1.887 0.831 -1.863 c 0.831 -2.343 l 0.793 -2.351 0.652 -2.383 0.518 -2.383 c 0.313 -2.383 0.058 -2.383 0.032 -1.831 c 0.019 -1.831 l -0.153 -2.215 -0.486 -2.447 -0.806 -2.447 c -1.445 -2.447 -1.739 -1.967 -1.739 -1.2 c -1.739 -0.6 -1.534 -0.184 -1.093 -0.016 c -0.371 0.256 l 0.019 0.408 0.019 0.543 0.019 0.903 c 0.019 1.303 -0.172 1.535 -0.531 1.535 c -1.119 1.535 -1.119 0.847 -1.119 0.695 c -1.119 0.655 l h f Q q 1 0 0 1 423.0283 681.679 cm 0 0 m 0.537 0 l 0.537 -0.64 l 0.55 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0 -1.062 Td [(were similar in the trea)-10 (tment arms.)]TJ 0.209 Tw 0 -1.512 Td [(In )36.6 (ARISTOTLE,)37 ( the results for the primar)-18 (y ef\037cac)20 (y endpoint were generally consistent)-25 ( )]TJ 0.241 Tw 0 -1.062 Td [(across most major subgroups inc)20 (luding weight,)37.1 ( CHADS)]TJ 0 Tc 0 Tw 5.2 0 0 5.2 487.8042 469.8771 Tm (2)Tj -0.025 Tc 0.241 Tw 8 0 0 8 490.1702 470.4771 Tm [( score \(a scale from 0 to 6)-25 ( )]TJ 0.15 Tw -20.771 -1.062 Td [(used )0.6 (to )0.6 (predict )0.6 (risk )0.5 (of )0.5 (stroke )0.6 (in )0.5 (pa)-9.9 (tients )0.6 (with )37.5 (AF)111 (,)37.1 ( )0.5 (with )0.6 (higher )0.6 (scores )0.6 (predicting )0.5 (grea)-10 (ter)-24.9 ( )]TJ 0.105 Tw 0 -1.062 Td [(risk\),)37 ( prior warfarin use,)37 ( level of renal impairment,)37 ( geogra)-10 (phic region,)37 ( and aspirin use a)-10 (t)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(randomiza)-10 (tion \(F)18 (igure 5\).)]TJ /T1_2 1 Tf -0.022 Tc -36 -6.026 Td (Figure 5:)Tj /Span< >> BDC ( )Tj EMC 5.4 0 Td (Stroke and 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-3.277 c -5.087 -3.277 -6.554 -1.81 -6.554 0 c -6.554 1.81 -5.087 3.277 -3.277 3.277 c -1.467 3.277 0 1.81 0 0 c h S Q /CS0 CS 1 SCN 0.42 w /GS1 gs q 1 0 0 1 423.8386 276.2293 cm 0 0 m 30.58 0 l S Q 423.637 274.921 0.402 2.615 re B 454.62 274.921 -0.402 2.615 re f 454.62 274.921 -0.402 2.615 re 434.954 254.651 m 456.552 254.651 l S 434.753 253.343 0.402 2.615 re B 456.753 253.343 -0.402 2.615 re B q 1 0 0 1 447.4896 254.6506 cm 0 0 m 0 -0.898 -0.728 -1.625 -1.625 -1.625 c -2.523 -1.625 -3.251 -0.898 -3.251 0 c -3.251 0.898 -2.523 1.625 -1.625 1.625 c -0.728 1.625 0 0.898 0 0 c f Q 1 G 0.21 w /GS0 gs q 1 0 0 1 447.4896 254.6506 cm 0 0 m 0 -0.898 -0.728 -1.625 -1.625 -1.625 c -2.523 -1.625 -3.251 -0.898 -3.251 0 c -3.251 0.898 -2.523 1.625 -1.625 1.625 c -0.728 1.625 0 0.898 0 0 c h S Q /GS1 gs q 1 0 0 1 447.3589 233.0189 cm 0 0 m 0 -1.119 -0.907 -2.026 -2.026 -2.026 c -3.145 -2.026 -4.052 -1.119 -4.052 0 c -4.052 1.119 -3.145 2.026 -2.026 2.026 c -0.907 2.026 0 1.119 0 0 c f Q /GS0 gs q 1 0 0 1 447.3589 233.0189 cm 0 0 m 0 -1.119 -0.907 -2.026 -2.026 -2.026 c -3.145 -2.026 -4.052 -1.119 -4.052 0 c -4.052 1.119 -3.145 2.026 -2.026 2.026 c -0.907 2.026 0 1.119 0 0 c h S Q /CS0 CS 1 SCN 0.42 w /GS1 gs q 1 0 0 1 433.0311 233.0189 cm 0 0 m 24.401 0 l S Q 432.83 231.711 0.402 2.616 re B 457.633 231.711 -0.402 2.616 re f 457.633 231.711 -0.402 2.616 re 435.458 211.444 m 464.14 211.444 l S 435.257 210.136 0.403 2.615 re B 464.341 210.136 -0.402 2.615 re B q 1 0 0 1 452.0869 211.4439 cm 0 0 m 0 -1.287 -1.044 -2.331 -2.331 -2.331 c -3.619 -2.331 -4.662 -1.287 -4.662 0 c -4.662 1.288 -3.619 2.331 -2.331 2.331 c -1.044 2.331 0 1.288 0 0 c f Q 1 G 0.21 w /GS0 gs q 1 0 0 1 452.0869 211.4439 cm 0 0 m 0 -1.287 -1.044 -2.331 -2.331 -2.331 c -3.619 -2.331 -4.662 -1.287 -4.662 0 c -4.662 1.288 -3.619 2.331 -2.331 2.331 c -1.044 2.331 0 1.288 0 0 c h S Q /CS0 CS 1 SCN 0.42 w /GS1 gs q 1 0 0 1 440.7436 204.1514 cm 0 0 m 22.313 0 l S Q 440.542 202.844 0.402 2.615 re B 463.258 202.844 -0.402 2.615 re B q 1 0 0 1 454.2327 204.1514 cm 0 0 m 0 -1.288 -1.044 -2.331 -2.331 -2.331 c -3.619 -2.331 -4.663 -1.288 -4.663 0 c -4.663 1.287 -3.619 2.331 -2.331 2.331 c -1.044 2.331 0 1.287 0 0 c f Q 1 G 0.21 w /GS0 gs q 1 0 0 1 454.2327 204.1514 cm 0 0 m 0 -1.288 -1.044 -2.331 -2.331 -2.331 c -3.619 -2.331 -4.663 -1.288 -4.663 0 c -4.663 1.287 -3.619 2.331 -2.331 2.331 c -1.044 2.331 0 1.287 0 0 c h S Q /CS0 CS 1 SCN 0.42 w /GS1 gs q 1 0 0 1 432.6825 125.0067 cm 0 0 m 21.995 0 l S Q 432.481 123.699 0.402 2.615 re B 454.879 123.699 -0.402 2.615 re B q 1 0 0 1 446.0146 125.0067 cm 0 0 m 0 -1.223 -0.992 -2.215 -2.215 -2.215 c -3.438 -2.215 -4.429 -1.223 -4.429 0 c -4.429 1.223 -3.438 2.215 -2.215 2.215 c -0.992 2.215 0 1.223 0 0 c f Q 1 G 0.21 w /GS0 gs q 1 0 0 1 446.0146 125.0067 cm 0 0 m 0 -1.223 -0.992 -2.215 -2.215 -2.215 c -3.438 -2.215 -4.429 -1.223 -4.429 0 c -4.429 1.223 -3.438 2.215 -2.215 2.215 c -0.992 2.215 0 1.223 0 0 c h S Q /CS0 CS 1 SCN 0.42 w /GS1 gs q 1 0 0 1 433.5809 197.0039 cm 0 0 m 18.638 0 l S Q 433.38 195.696 0.402 2.615 re B 452.42 195.696 -0.402 2.615 re B q 1 0 0 1 445.1048 197.0039 cm 0 0 m 0 -1.223 -0.992 -2.215 -2.215 -2.215 c -3.438 -2.215 -4.429 -1.223 -4.429 0 c -4.429 1.223 -3.438 2.215 -2.215 2.215 c -0.992 2.215 0 1.223 0 0 c f Q 1 G 0.21 w /GS0 gs q 1 0 0 1 445.1048 197.0039 cm 0 0 m 0 -1.223 -0.992 -2.215 -2.215 -2.215 c -3.438 -2.215 -4.429 -1.223 -4.429 0 c -4.429 1.223 -3.438 2.215 -2.215 2.215 c -0.992 2.215 0 1.223 0 0 c h S Q /GS1 gs q 1 0 0 1 440.3584 276.2293 cm 0 0 m 0 -0.674 -0.546 -1.221 -1.221 -1.221 c -1.895 -1.221 -2.442 -0.674 -2.442 0 c -2.442 0.674 -1.895 1.221 -1.221 1.221 c -0.546 1.221 0 0.674 0 0 c f Q /GS0 gs q 1 0 0 1 440.3584 276.2293 cm 0 0 m 0 -0.674 -0.546 -1.221 -1.221 -1.221 c -1.895 -1.221 -2.442 -0.674 -2.442 0 c -2.442 0.674 -1.895 1.221 -1.221 1.221 c -0.546 1.221 0 0.674 0 0 c h S Q /GS1 gs q 1 0 0 1 462.7717 326.6625 cm 0 0 m 0 -1.104 -0.895 -1.999 -1.999 -1.999 c -3.103 -1.999 -3.998 -1.104 -3.998 0 c -3.998 1.104 -3.103 1.999 -1.999 1.999 c -0.895 1.999 0 1.104 0 0 c f Q /GS0 gs q 1 0 0 1 462.7717 326.6625 cm 0 0 m 0 -1.104 -0.895 -1.999 -1.999 -1.999 c -3.103 -1.999 -3.998 -1.104 -3.998 0 c -3.998 1.104 -3.103 1.999 -1.999 1.999 c -0.895 1.999 0 1.104 0 0 c h S Q /CS0 CS 1 SCN 0.42 w /GS1 gs q 1 0 0 1 435.4079 175.3815 cm 0 0 m 26.989 0 l S Q 435.207 174.074 0.402 2.615 re B 462.598 174.074 -0.402 2.615 re B q 1 0 0 1 450.6182 175.3815 cm 0 0 m 0 -0.857 -0.694 -1.552 -1.551 -1.552 c -2.408 -1.552 -3.103 -0.857 -3.103 0 c -3.103 0.857 -2.408 1.551 -1.551 1.551 c -0.694 1.551 0 0.857 0 0 c f Q 1 G 0.21 w /GS0 gs q 1 0 0 1 450.6182 175.3815 cm 0 0 m 0 -0.857 -0.694 -1.552 -1.551 -1.552 c -2.408 -1.552 -3.103 -0.857 -3.103 0 c -3.103 0.857 -2.408 1.551 -1.551 1.551 c -0.694 1.551 0 0.857 0 0 c h S Q /CS0 CS 1 SCN 0.42 w /GS1 gs q 1 0 0 1 398.4995 182.6298 cm 0 0 m 72.046 0 l S Q 398.298 181.322 0.402 2.615 re B 470.747 181.322 -0.402 2.615 re B q 1 0 0 1 434.7745 182.6298 cm 0 0 m 0 -0.214 -0.174 -0.388 -0.388 -0.388 c -0.602 -0.388 -0.776 -0.214 -0.776 0 c -0.776 0.214 -0.602 0.388 -0.388 0.388 c -0.174 0.388 0 0.214 0 0 c f Q 1 G 0.21 w /GS0 gs q 1 0 0 1 434.7745 182.6298 cm 0 0 m 0 -0.214 -0.174 -0.388 -0.388 -0.388 c -0.602 -0.388 -0.776 -0.214 -0.776 0 c -0.776 0.214 -0.602 0.388 -0.388 0.388 c -0.174 0.388 0 0.214 0 0 c h S Q /CS0 CS 1 SCN 0.42 w /GS1 gs q 1 0 0 1 439.5785 160.9326 cm 0 0 m 22.818 0 l S Q 439.377 159.625 0.402 2.616 re B 462.598 159.625 -0.402 2.616 re B q 1 0 0 1 453.522 160.9326 cm 0 0 m 0 -1.428 -1.158 -2.586 -2.586 -2.586 c -4.014 -2.586 -5.171 -1.428 -5.171 0 c -5.171 1.428 -4.014 2.586 -2.586 2.586 c -1.158 2.586 0 1.428 0 0 c f Q 1 G 0.21 w /GS0 gs q 1 0 0 1 453.522 160.9326 cm 0 0 m 0 -1.428 -1.158 -2.586 -2.586 -2.586 c -4.014 -2.586 -5.171 -1.428 -5.171 0 c -5.171 1.428 -4.014 2.586 -2.586 2.586 c -1.158 2.586 0 1.428 0 0 c h S Q /CS0 CS 1 SCN 0.42 w /GS1 gs q 1 0 0 1 430.7186 146.5505 cm 0 0 m 33.18 0 l S Q 430.517 145.243 0.402 2.615 re B 464.1 145.243 -0.402 2.615 re B q 1 0 0 1 448.8895 146.5505 cm 0 0 m 0 -0.909 -0.737 -1.646 -1.646 -1.646 c -2.555 -1.646 -3.292 -0.909 -3.292 0 c -3.292 0.909 -2.555 1.646 -1.646 1.646 c -0.737 1.646 0 0.909 0 0 c f Q 1 G 0.21 w /GS0 gs q 1 0 0 1 448.8895 146.5505 cm 0 0 m 0 -0.909 -0.737 -1.646 -1.646 -1.646 c -2.555 -1.646 -3.292 -0.909 -3.292 0 c -3.292 0.909 -2.555 1.646 -1.646 1.646 c -0.737 1.646 0 0.909 0 0 c h S Q /GS1 gs q 1 0 0 1 447.5954 168.1767 cm 0 0 m 0 -1.415 -1.147 -2.563 -2.563 -2.563 c -3.978 -2.563 -5.126 -1.415 -5.126 0 c -5.126 1.416 -3.978 2.563 -2.563 2.563 c -1.147 2.563 0 1.416 0 0 c f Q /GS0 gs q 1 0 0 1 447.5954 168.1767 cm 0 0 m 0 -1.415 -1.147 -2.563 -2.563 -2.563 c -3.978 -2.563 -5.126 -1.415 -5.126 0 c -5.126 1.416 -3.978 2.563 -2.563 2.563 c -1.147 2.563 0 1.416 0 0 c h S Q /CS0 CS 1 SCN 0.42 w /GS1 gs q 1 0 0 1 434.9757 168.1772 cm 0 0 m 19.639 0 l S Q 434.775 166.869 0.402 2.615 re B 454.816 166.869 -0.402 2.615 re B 0.604 w q 1 0 0 1 452.4654 96.6554 cm 0 0 m -48.374 0 l S Q q 1 0 0 1 399.8301 96.6554 cm 0 0 m 6.005 2.454 l 4.58 0 l 6.005 -2.453 l h f Q q 1 0 0 1 458.5226 96.6554 cm 0 0 m 22.056 0 l S Q q 1 0 0 1 484.8402 96.6554 cm 0 0 m -6.005 -2.454 l -4.58 0 l -6.005 2.453 l h f Q Q BT /T1_3 1 Tf 0 Tc 0 Tw 6.72 0 0 6.72 397.3248 101.2326 Tm ( )Tj -0.03 Tc 0.03 Tw 0.595 0 Td (0.)Tj -0.01 Tc 0.01 Tw 0.62 0 Td (25 )Tj 3.263 0 Td (0.5 )Tj 3.912 0 Td (1 )Tj 0 Tc 0 Tw 3.683 0 Td (2)Tj -0.01 Tc 0.01 Tw -8.774 -1.803 Td (Apixaban)Tj 0.578 -1.125 Td (Better)Tj 0 Tc 0 Tw 5.406 1.125 Td (W)Tj -0.01 Tc 0.01 Tw 0.694 0 Td (arfarin)Tj -0.26 -1.125 Td (Better)Tj ET q 36 63.888 540 324.72 re W n q 1 0 0 1 202.5792 377.4567 cm 0 0 m 135.072 0 l S Q Q BT /T1_4 1 Tf 0 Tw 6.72 0 0 6.72 219.8572 380.0859 Tm (n of Events / N of P)Tj 7.321 0 Td (atients \(% per year\))Tj 0.01 Tw -21.592 -1.609 Td (Subgroup)Tj 14.9 0 Td (Apixaban)Tj 0 Tc 0 Tw 10.217 0 Td (W)Tj -0.01 Tc 0.01 Tw 0.732 0 Td (arf)Tj 1.06 0 Td (arin)Tj 0 Tw 5.679 0 Td (Hazard Ratio \(95% CI\))Tj /T1_3 1 Tf 0.01 Tw -32.588 -1.175 Td (All )Tj -0.028 Tc 0.028 Tw 1.108 0 Td (Pa)Tj -0.01 Tc 0.01 Tw 0.897 0 Td (tients)Tj 0 Tw 11.775 0 Td (212 / 9120 \(1.3\))Tj 10.05 0 Td (265 / 9081 \(1.6\))Tj 9.973 0 Td (0.79 \(0.66,)Tj 3.934 0 Td ( 0.95\))Tj 0.01 Tw -37.737 -1.074 Td (Prior )Tj 0 Tc 0 Tw 1.864 0 Td (W)Tj -0.01 Tc 0.01 Tw 0.694 0 Td (arfarin/V)Tj 0.055 Tc -0.055 Tw 3.071 0 Td (KA)Tj -0.01 Tc 0 Tw 1.045 0 Td ( Status)Tj 0 Tc -6.674 -1.074 Td ( )Tj -0.01 Tc 1.125 0 Td (Experienced \(57%\))Tj 12.655 0 Td (102 / 5208 \(1.1\))Tj 10.05 0 Td (138 / 5193 \(1.5\))Tj 9.973 0 Td (0.73 \(0.57,)Tj 3.934 0 Td ( 0.95\))Tj 0 Tc -37.737 -1.074 Td ( )Tj -0.01 Tc 1.125 0 Td (Naive \(43%\))Tj 12.655 0 Td (110 / 3912 \(1.5\))Tj 10.05 0 Td (127 / 3888 \(1.8\))Tj 9.973 0 Td (0.86 \(0.66,)Tj 3.934 0 Td ( 1.11\))Tj 0.01 Tw -37.737 -1.074 Td (Age)Tj 0 Tc 0 Tw 0 -1.074 Td ( )Tj -0.01 Tc 1.125 0 Td (<65 \(30%\))Tj 12.89 0 Td (51 / 2731 \(1.0\))Tj 10.05 0 Td (44 / 2740 \(0.9\))Tj 9.738 0 Td (1.16 \(0.77,)Tj 3.934 0 Td ( 1.73\))Tj 0 Tc -37.737 -1.074 Td ( )Tj -0.01 Tc 1.125 0 Td (\03765 and <75 \(39%\))Tj 12.89 0 Td (82 / 3539 \(1.3\))Tj 9.815 0 Td (112 / 3513 \(1.7\))Tj 9.973 0 Td (0.72 \(0.54,)Tj 3.934 0 Td ( 0.96\))Tj 0 Tc -37.737 -1.074 Td ( )Tj -0.01 Tc 1.125 0 Td (\03775 \(31%\))Tj 12.89 0 Td (79 / 2850 \(1.6\))Tj 9.815 0 Td (109 / 2828 \(2.2\))Tj 9.973 0 Td (0.71 \(0.53,)Tj 3.934 0 Td ( 0.95\))Tj 0.01 Tw -37.737 -1.074 Td (Sex)Tj 0 Tc 0 Tw 0 -1.074 Td ( )Tj -0.01 Tc 1.125 0 Td (Male \(65%\))Tj 12.655 0 Td (132 / 5886 \(1.2\))Tj 10.05 0 Td (160 / 5899 \(1.5\))Tj 9.973 0 Td (0.82 \(0.65,)Tj 3.934 0 Td ( 1.04\))Tj 0 Tc 0.885 Tw -37.737 -1.074 Td ( F)Tj -0.01 Tc 0 Tw 1.535 0 Td (emale \(35%\))Tj 12.48 0 Td (80 / 3234 \(1.3\))Tj 9.815 0 Td (105 / 3182 \(1.8\))Tj 9.973 0 Td (0.74 \(0.56,)Tj 3.934 0 Td ( 1.00\))Tj 0 Tc -37.737 -1.074 Td (W)Tj -0.01 Tc 0.01 Tw 0.694 0 Td (eight)Tj 0 Tc 0 Tw -0.694 -1.074 Td ( )Tj -0.01 Tc 1.125 0 Td (\03660 kg \(11%\))Tj 12.89 0 Td (34 / 1018 \(2.0\))Tj 10.285 0 Td (52 / 967 \(3.2\))Tj 9.503 0 Td (0.63 \(0.41,)Tj 3.934 0 Td ( 0.97\))Tj 0 Tc -37.737 -1.074 Td ( )Tj -0.01 Tc 1.125 0 Td (>60 kg \(89%\))Tj 12.655 0 Td (177 / 8070 \(1.2\))Tj 10.05 0 Td (212 / 8084 \(1.4\))Tj 9.973 0 Td (0.83 \(0.68,)Tj 3.934 0 Td ( 1.01\))Tj -37.737 -1.074 Td (Prior Stroke or )Tj 0.015 Tc -0.015 Tw 5.371 0 Td (TI)Tj 0 Tc 0 Tw 0.692 0 Td (A)Tj 0.885 Tw -6.063 -1.074 Td ( Y)Tj -0.01 Tc 0 Tw 1.502 0 Td (es \(19%\))Tj 12.513 0 Td (73 / 1694 \(2.5\))Tj 10.05 0 Td (98 / 1742 \(3.2\))Tj 9.738 0 Td (0.76 \(0.56,)Tj 3.934 0 Td ( 1.03\))Tj 0 Tc -37.737 -1.074 Td ( )Tj -0.01 Tc 1.125 0 Td (No \(81%\))Tj 12.655 0 Td (139 / 7426 \(1.0\))Tj 10.05 0 Td (167 / 7339 \(1.2\))Tj 9.973 0 Td (0.82 \(0.65,)Tj 3.934 0 Td ( 1.03\))Tj -37.737 -1.074 Td (Diabetes Mellitus)Tj 0 Tc 0.885 Tw 0 -1.074 Td ( Y)Tj -0.01 Tc 0 Tw 1.502 0 Td (es \(25%\))Tj 12.513 0 Td (57 / 2284 \(1.4\))Tj 10.05 0 Td (75 / 2263 \(1.9\))Tj 9.738 0 Td (0.75 \(0.53,)Tj 3.934 0 Td ( 1.05\))Tj 0 Tc -37.737 -1.074 Td ( )Tj -0.01 Tc 1.125 0 Td (No \(75%\))Tj 12.655 0 Td (155 / 6836 \(1.2\) )Tj 10.05 0 Td (190 / 6818 \(1.5\))Tj 9.973 0 Td (0.81 \(0.65,)Tj 3.934 0 Td ( 1.00\))Tj 0.01 Tw -37.737 -1.074 Td (CHADS)Tj 0 Tc 0 Tw 4.8972 0 0 4.8972 141.3398 215.7061 Tm (2)Tj -0.01 Tc 6.72 0 0 6.72 143.6414 217.0332 Tm ( Score)Tj 0 Tc -2.929 -1.074 Td ( )Tj -0.01 Tc 0.01 Tw 0.918 0 Td (\0361 )Tj 1.394 0 Td (\(34%\))Tj 0 Tw 11.703 0 Td (44 / 3100 \(0.7\))Tj 10.05 0 Td (51 / 3083 \(0.9\))Tj 9.738 0 Td (0.85 \(0.57,)Tj 3.934 0 Td ( 1.27\))Tj 0 Tc -37.737 -1.074 Td ( )Tj -0.01 Tc 0.01 Tw 1.405 0 Td (2 )Tj 0.907 0 Td (\(36%\))Tj 0 Tw 11.703 0 Td (74 / 3262 \(1.2\))Tj 10.05 0 Td (82 / 3254 \(1.4\))Tj 9.738 0 Td (0.90 \(0.66,)Tj 3.934 0 Td ( 1.23\))Tj 0 Tc -37.737 -1.074 Td ( )Tj -0.01 Tc 0.01 Tw 0.918 0 Td (\0373 )Tj 1.394 0 Td (\(30%\))Tj 0 Tw 11.703 0 Td (94 / 2758 \(2.0\))Tj 9.815 0 Td (132 / 2744 \(2.8\))Tj 9.973 0 Td (0.70 \(0.54,)Tj 3.934 0 Td ( 0.91\))Tj -37.737 -1.074 Td (Creatinine Clearance)Tj 0 Tc 0 -1.074 Td ( )Tj -0.01 Tc 1.842 0 Td (<30 mL/min )Tj 0.01 Tw 5.345 0 Td (\(1%\))Tj 0 Tw 7.298 0 Td (6 / 137 \(2.8\))Tj 9.815 0 Td (10 / 133 \(5.1\))Tj 9.503 0 Td (0.55 \(0.20,)Tj 3.934 0 Td ( 1.53\))Tj 0 Tc -37.737 -1.074 Td ( )Tj -0.01 Tc 1.15 0 Td (30-50 mL/min )Tj 0.01 Tw 6.037 0 Td (\(15%\))Tj 0 Tw 6.828 0 Td (48 / 1365 \(2.0\))Tj 10.05 0 Td (59 / 1382 \(2.5\))Tj 9.738 0 Td (0.83 \(0.57,)Tj 3.934 0 Td ( 1.21\))Tj 0 Tc -37.737 -1.074 Td ( )Tj -0.01 Tc 0.56 0 Td (>50-80 mL/min )Tj 0.01 Tw 6.627 0 Td (\(42%\))Tj 0 Tw 6.828 0 Td (87 / 3817 \(1.2\))Tj 9.815 0 Td (116 / 3770 \(1.7\))Tj 9.973 0 Td (0.74 \(0.56,)Tj 3.934 0 Td ( 0.97\))Tj 0 Tc -37.737 -1.074 Td ( )Tj -0.005 Tc 1.792 0 Td (>80 mL/min )Tj 0.005 Tw 5.395 0 Td (\(41%\))Tj 0 Tw 6.793 0 Td (70 / 3761 \(1.0\))Tj 10.05 0 Td (79 / 3757 \(1.1\))Tj 9.733 0 Td (0.88 \(0.64,)Tj 3.989 0 Td ( 1.21\))Tj -37.752 -1.074 Td (Geographic Region)Tj 0 Tc 0 -1.074 Td ( )Tj -0.005 Tc 1.125 0 Td (US \(19%\))Tj 12.855 0 Td (31 / 1720 \(0.9\))Tj 10.05 0 Td (39 / 1697 \(1.2\))Tj 9.733 0 Td (0.79 \(0.50,)Tj 3.989 0 Td ( 1.27\))Tj 0 Tc -37.752 -1.074 Td ( )Tj -0.005 Tc 1.125 0 Td (Non-US \(81%\))Tj 12.618 0 Td (181 / 7400 \(1.3\))Tj 10.05 0 Td (226 / 7384 \(1.7\))Tj 9.97 0 Td (0.79 \(0.65,)Tj 3.989 0 Td ( 0.96\))Tj -0.004 Tc -37.752 -1.074 Td (Aspirin at Randomization)Tj 0 Tc 0.885 Tw 0 -1.074 Td ( Y)Tj -0.005 Tc 0 Tw 1.507 0 Td (es \(31%\))Tj 12.473 0 Td (70 / 2859 \(1.3\))Tj 10.05 0 Td (94 / 2773 \(1.9\))Tj 9.733 0 Td (0.72 \(0.53,)Tj 3.989 0 Td ( 0.98\))Tj 0 Tc -37.752 -1.074 Td ( )Tj -0.005 Tc 1.125 0 Td (No \(69%\))Tj 12.618 0 Td (142 / 6261 \(1.2\))Tj 10.05 0 Td (171 / 6308 \(1.5\))Tj 9.97 0 Td (0.83 \(0.67,)Tj 3.989 0 Td ( 1.04\))Tj 0 0 0 1 k /T1_0 1 Tf -0.025 Tc 0.067 Tw 7.6 0 0 8 36 65.2937 Tm [(Note:)37 ( )36.9 (The figure above presents effects in various subgroups,)37 ( all of which are baseline characteristics and all of which were prespec\ ified,)37 ( if not the groupings.)37 ( )37 (The 95% confidence limits tha)-10 (t are sho)-10 (wn)-25 ( )]TJ 0.118 Tw 0 -1.062 Td [(do not take into account ho)-10 (w man)-10 (y comparisons were made,)37 ( nor do they reflect the effect of a particular factor after adjustment \ for all other factors.)37 ( )36.9 (A)-10 (pparent homogeneity or heterogeneity among)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(groups should not be over)37 (-interpreted.)]TJ ET endstream endobj 316 0 obj <> endobj 317 0 obj <> endobj 319 0 obj <>stream Adobe InDesign CC 2014 (Macintosh) 2015-09-16T23:46Z burgoss Figure 5_ARISTOTLE Stroke Study 0815_v2.indd endstream endobj 318 0 obj <>stream application/postscript Fig4_Clin_KM_Aristotle_3in_v4 Mercer, Barton 2012-12-19T16:07:04-05:00 2012-12-19T16:07:04-05:00 2012-12-19T16:07:04-05:00 Adobe Illustrator CS5.1 xmp.iid:32B042902F2068118083D0FBAF454DE4 xmp.did:32B042902F2068118083D0FBAF454DE4 uuid:5D20892493BFDB11914A8590D31508C8 proof:pdf uuid:149bf22e-d993-874a-8e34-af874a56b451 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)0.5 (a)-10 (pixaban )0.5 (is )0.5 (a)-10 (pproxima)-10 (tely )0.5 (18 )0.5 (mL/min.)10 ( )]TJ 0.125 Tw 0 -1.068 Td [(The systemic exposure of a)-9.9 (pixaban is 14% lo)-10 (wer on dialysis when compared to not on)-27 ( )]TJ 0.027 Tw 0 -1.068 Td (dialysis.)Tj -0.025 Tc 0.224 Tw 0 -1.518 Td [(Protein binding was similar \(92%-94%\) between healthy controls and ESR\ D subjects)-25 ( )]TJ 0.084 Tw 0 -1.068 Td (during the on-dialysis and off-dialysis periods.)Tj /T1_0 1 Tf 0.124 Tw 0 -1.608 Td [(P)18 (edia)-9.9 (tric P)18 (a)-9.9 (tient)]TJ 0 Tc 0 Tw (s)Tj 6.08 0 Td (:)Tj /T1_1 1 Tf -0.025 Tc 0.124 Tw /Span< >> BDC 0.215 0 Td ( )Tj EMC 0.017 0 Td [( )36.8 (A)-10 (pixaban reached maximum concentra)-10 (tion \(C)]TJ 0.025 Tw 5.2 0 0 5.2 507.2839 574.1431 Tm (max)Tj 0.124 Tw 8 0 0 8 515.0681 574.7431 Tm [(\) in pedia)-9.9 (tric pa)-10 (tients)-25 ( )]TJ 0.04 Tw -23.884 -1.068 Td [(a)-10 (pproxima)-9.9 (tely 2 hours after single-dose administra)-10 (tion.)37 ( In pedia)-9.9 (tric pa)-10 (tients,)37 ( a)-10 (pixaban has)-25 ( )]TJ 0.084 Tw 0 -1.068 Td [(a total a)-9.9 (pparent c)20 (learance of about 3.0 L/h.)]TJ 0.033 Tw 0 -1.608 Td [(An explora)-9.9 (tor)-18 (y analysis in pedia)-10 (tric pa)-10 (tients did not reveal relevant differences in a)-10 (pixaban)-25 ( )]TJ 0.084 Tw 0 -1.068 Td (exposure based on gender or race.)Tj /T1_2 1 Tf 0.025 Tw 0 -1.945 Td (13)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td [(NONCLINIC)18 (AL TOXICOLOGY)]TJ 0.025 Tw -3.375 -1.923 Td (13.1)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td [(Carcinogenesis,)37 ( Mutagenesis,)37.1 ( Impairment of F)19.9 (ertility)]TJ /T1_0 1 Tf 0.025 Tw -3.375 -1.518 Td (Carcinogene)Tj 0 Tc 0 Tw (s)Tj 4.717 0 Td (i)Tj 0.179 0 Td (s)Tj 0.382 0 Td (:)Tj /T1_1 1 Tf -0.025 Tc 0.11 Tw /Span< >> BDC 0.215 0 Td ( )Tj EMC 0.017 0 Td [( )37.2 (A)-10 (pixaban was not carcinogenic when administered to mice and ra)-10 (ts for)-25 ( )]TJ 0.111 Tw -5.51 -1.068 Td (up to 2)Tj /Span< >> BDC ( )Tj EMC 2.849 0 Td [(years.)37 ( )37.2 (The systemic exposures \(AUCs\) of unbound a)-9.9 (pixaban in male and female)-25 ( )]TJ 0.211 Tw -2.849 -1.068 Td [(mice a)-9.9 (t the highest doses tested \(1500 and 3000)]TJ /Span< >> BDC ( )Tj EMC 18.914 0 Td [(mg/kg/day\) were 9 and 20 times,)12 ( )]TJ 0.086 Tw -18.914 -1.068 Td [(respectively)55 (,)37 ( the human exposure of unbound drug a)-10 (t the MRHD of 10)]TJ /Span< >> BDC ( )Tj EMC 25.257 0 Td [(mg/day)55 (.)37 ( Systemic)-24.9 ( )]TJ 0.224 Tw -25.257 -1.068 Td [(exposures of unbound a)-9.9 (pixaban in male and female ra)-9.9 (ts a)-9.9 (t the highest dose tested)-25 ( )]TJ 0.084 Tw 0 -1.068 Td (\(600)Tj /Span< >> BDC ( )Tj EMC 1.794 0 Td [(mg/kg/day\) were 2 and 4 times,)37 ( respectively)55 (,)37 ( the human exposure.)]TJ /T1_0 1 Tf 0.025 Tw -1.794 -1.518 Td [(Muta)-9.9 (gene)]TJ 0 Tc 0 Tw (s)Tj 3.876 0 Td (i)Tj 0.179 0 Td (s)Tj 0.382 0 Td (:)Tj /T1_1 1 Tf -0.025 Tc 0.13 Tw /Span< >> BDC 0.215 0 Td ( )Tj EMC 0.017 0 Td [( )37 (A)-10 (pixaban was neither muta)-9.9 (genic in the bacterial reverse muta)-10 (tion \(Ames\))-24.9 ( )]TJ 0.051 Tw -4.669 -1.068 Td [(assay)55 (,)37 ( nor c)20 (lastogenic in Chinese hamster ovar)-18 (y cells\034)]TJ /T1_0 1 Tf 18.944 0 Td (in vitro)Tj /T1_1 1 Tf /Span< >> BDC ( )Tj EMC 2.383 0 Td [(,)37 ( in a 1-month\034)]TJ /T1_0 1 Tf 5.285 0 Td (in vivo/)Tj (in vitro)Tj /T1_1 1 Tf 0 Tc -0.248 Tw /Span< >> BDC 4.887 0 Td ( )Tj EMC ( )Tj 0 Tw T* ( )Tj -0.025 Tc 0.172 Tw -31.5 -1.068 Td [(c)20 (ytogenetics stud)-10 (y in ra)-9.9 (t peripheral blood lymphoc)20 (ytes,)37 ( or in a ra)-10 (t micronuc)20 (leus stud)-10 (y)]TJ 0 Tc 0 Tw 31.5 0 Td ( )Tj /T1_0 1 Tf -0.025 Tc 0.084 Tw -31.5 -1.068 Td (in vivo)Tj /T1_1 1 Tf 0 Tc 0 Tw (.)Tj /T1_0 1 Tf -0.025 Tc 0.15 Tw 0 -1.518 Td [(Impairment of F)24 (ertility:)]TJ /T1_1 1 Tf /Span< >> BDC ( )Tj EMC 8.056 0 Td [( )37.2 (A)-10 (pixaban had no effect on fertility in male or female ra)-9.9 (ts when)-25 ( )]TJ 0.195 Tw -8.056 -1.068 Td [(given a)-10 (t doses up to 600)]TJ /Span< >> BDC ( )Tj EMC 9.717 0 Td [(mg/kg/day)55 (,)37 ( a dose resulting in unbound a)-9.9 (pixaban exposure)-25 ( )]TJ 0.084 Tw -9.717 -1.068 Td [(levels tha)-9.9 (t are 3 and 4 times,)37 ( respectively)55 (,)37.1 ( the human exposure.)]TJ 0.105 Tw 0 -1.608 Td [(A)-10 (pixaban administered to female ra)-10 (ts a)-10 (t doses up to 1000)]TJ /Span< >> BDC ( )Tj EMC 21.194 0 Td [(mg/kg/day from implanta)-9.9 (tion)-25 ( )]TJ 0.5 Tw -21.194 -1.068 Td [(through the end of lacta)-9.9 (tion produced no adverse \037ndings in male offspring)-25.1 ( )]TJ 0.079 Tw 0 -1.068 Td [(\(F1 genera)-10 (tion\) a)-9.9 (t doses up to 1000)]TJ /Span< >> BDC ( )Tj EMC 13.019 0 Td [(mg/kg/day)55 (,)37 ( a dose resulting in exposure to unbound)-25 ( )]TJ 0.257 Tw -13.019 -1.068 Td [(a)-10 (pixaban tha)-10 (t is 5 times the human exposure.)37 ( )37.1 (Adverse effects in the F1)120 (-genera)-10 (tion)-25 ( )]TJ 0.045 Tw 0 -1.068 Td [(female )0.5 (offspring )0.5 (were )0.5 (limited )0.5 (to )0.5 (decreased )0.5 (ma)-10 (ting )0.5 (and )0.5 (fertility )0.5 (indices )0.5 (a)-9.9 (t )0.5 (\036200)]TJ /Span< >> BDC ( )Tj EMC 27.739 0 Td [(mg/kg/day)-25 ( )]TJ 0 Tc 0 Tw 3.761 0 Td ( )Tj -0.025 Tc 0.054 Tw -31.5 -1.068 Td [(\(a dose resulting in exposure to unbound a)-10 (pixaban tha)-9.9 (t is \0365 times the human exposure\).)]TJ /T1_2 1 Tf 0.025 Tw 0 -1.855 Td (14)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td [(CLINIC)18 (AL STUDIES)]TJ 0.025 Tw -3.375 -1.923 Td (14.1)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td [(Reduction of Risk of Stroke and Systemic Embolism in Nonv)16 (alvular)-25 ( )]TJ 0 Tc 0 Tw 25.586 0 Td ( )Tj -0.025 Tc 0.048 Tw -25.586 -1.068 Td (Atrial Fibrillation)Tj /T1_3 1 Tf 0.025 Tw -3.375 -1.743 Td [(ARIST)30 (O)30 (TLE)]TJ /T1_1 1 Tf 0.158 Tw 0 -1.293 Td [(Evidence for the ef\037cac)20 (y and safety of ELIQUIS was derived from )36.8 (ARISTOTLE,)37 ( a multi-)]TJ 0.342 Tw 0 -1.068 Td [(na)-10 (tional,)37 ( double-blind stud)-10 (y in pa)-9.9 (tients with nonvalvular )36.7 (AF comparing the effects)-25.1 ( )]TJ 0.207 Tw 0 -1.068 Td [(of ELIQUIS and warfarin on the risk of stroke and non-central ner)-17.9 (vous system \(CNS\))-25 ( )]TJ 0.033 Tw 0 -1.068 Td [(systemic embolism.)37 ( In )37.3 (ARISTOTLE,)37 ( pa)-10 (tients were randomized to ELIQUIS 5)]TJ /Span< >> BDC ( )Tj EMC 26.141 0 Td [(mg orally twice)-24.9 ( )]TJ 0.161 Tw -26.141 -1.068 Td (daily \(or 2.5)Tj /Span< >> BDC ( )Tj EMC 4.592 0 Td [(mg twice daily in subjects with a)-10 (t least 2 of the follo)-10 (wing characteristics:)12 ( )]TJ 0 Tc 0 Tw 26.908 0 Td ( )Tj -0.025 Tc 0.237 Tw -31.5 -1.068 Td [(a)-10 (ge grea)-10 (ter than or equal to 80)]TJ /Span< >> BDC ( )Tj EMC 12.366 0 Td [(years,)37 ( bod)-10 (y weight less than or equal to 60)]TJ /Span< >> BDC ( )Tj EMC 16.932 0 Td [(kg,)37 ( or)-24.9 ( )]TJ 0.129 Tw -29.298 -1.068 Td [(serum crea)-10 (tinine grea)-9.9 (ter than or equal to 1.5)]TJ /Span< >> BDC ( )Tj EMC 16.606 0 Td [(mg/dL\) or to warfarin \(targeted to an INR)-25 ( )]TJ 0 Tc 0 Tw 14.894 0 Td ( )Tj -0.025 Tc 0.046 Tw -31.5 -1.068 Td [(range of 2.0-3.0\).)37 ( P)18 (a)-10 (tients had to ha)-10 (ve one or more of the follo)-10 (wing additional risk factors)-25 ( )]TJ 0.084 Tw 0 -1.068 Td (for stroke:)Tj 0.025 Tw 0 -1.518 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.625 0 Td [(prior stroke or transient ischemic a)-9.9 (ttack \(TIA\))]TJ 0.025 Tw -1.625 -1.518 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.625 0 Td (prior systemic embolism)Tj 0.025 Tw -1.625 -1.518 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.625 0 Td [(a)-10 (ge grea)-10 (ter than or equal to 75)]TJ /Span< >> BDC ( )Tj EMC 11.449 0 Td (years)Tj 0.025 Tw -13.074 -1.518 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.625 0 Td [(arterial hypertension requiring trea)-9.9 (tment)]TJ 0.025 Tw -1.625 -1.518 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.625 0 Td (diabetes mellitus)Tj 0.025 Tw -1.625 -1.518 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.625 0 Td [(heart failure \036New )37 (Y)75 (ork Heart )37 (Associa)-9.9 (tion Class 2)]TJ 0.025 Tw -1.625 -1.518 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.625 0 Td (left ventricular ejection fraction \03340%)Tj 0.079 Tw -1.625 -1.518 Td [(The primar)-18 (y objective of )36.7 (ARISTOTLE was to determine whether ELIQUIS 5)]TJ /Span< >> BDC ( )Tj EMC 26.299 0 Td [(mg twice daily)-25 ( )]TJ 0.047 Tw -26.299 -1.068 Td (\(or 2.5)Tj /Span< >> BDC ( )Tj EMC 2.506 0 Td [(mg twice daily\) was effective \(noninferior to warfarin\) in reducing t\ he risk of stroke)-24.9 ( )]TJ 0.048 Tw -2.506 -1.068 Td [(\(ischemic or hemorrha)-9.9 (gic\) and systemic embolism.)37 ( Superiority of ELIQUIS to warfarin was)-25 ( )]TJ 0.158 Tw 0 -1.068 Td [(also )0.5 (examined )0.6 (for )0.6 (the )0.6 (primar)-17.9 (y )0.5 (endpoint )0.6 (\(ra)-10 (te )0.6 (of )0.6 (stroke )0.5 (and )0.6 (systemic )0.5 (embolism\),)37.1 ( )0.5 (major)-24.9 ( )]TJ 0.084 Tw 0 -1.068 Td [(bleeding,)37 ( and dea)-10 (th from an)-10 (y cause.)]TJ 0.257 Tw 0 -1.518 Td [(A total of 18,201 pa)-10 (tients were randomized and follo)-10 (wed on stud)-10 (y trea)-10 (tment for a)-25 ( )]TJ 0.192 Tw 0 -1.068 Td [(median of 89 weeks.)37.1 ( F)20 (orty-three percent of pa)-10 (tients were vitamin K anta)-10 (gonist \(VKA\))-25 ( )]TJ 0.207 Tw 0 -1.068 Td [(\223naive,)37 (\224)37 ( de\037ned as ha)-9.9 (ving received \03330 consecutive days of trea)-10 (tment with warfarin)-25 ( )]TJ 0.084 Tw -36 86.406 Td [(A)-10 (pixaban is a substra)-10 (te of transport proteins:)37 ( P-gp and breast cancer resistance protein.)]TJ /T1_3 1 Tf 0 -1.751 Td [(Drug Inter)6.1 (action Studies)]TJ /T1_1 1 Tf 0.025 Tw 0 -1.301 Td (In\034)Tj /T1_0 1 Tf 0.32 Tw 1.152 0 Td (in vitro)Tj /T1_1 1 Tf /Span< >> BDC ( )Tj EMC 2.652 0 Td [( a)-10 (pixaban studies a)-10 (t concentra)-9.9 (tions signi\037cantly grea)-10 (ter than thera)-10 (peutic)-25 ( )]TJ 0.233 Tw -3.804 -1.076 Td [(exposures,)37 ( no inhibitor)-18 (y effect on the activity of CYP1A2,)37 ( CYP2A6,)37 ( CYP2B6,)37 ( CYP2C8,)12 ( )]TJ 0.08 Tw 0 -1.076 Td [(CYP2C9,)37 ( CYP2D6,)37 ( CYP3A4/5,)37 ( or CYP2C19,)37 ( nor induction effect on the activity of CYP1A2,)12 ( )]TJ 0.165 Tw 0 -1.076 Td [(CYP2B6,)37 ( or CYP3A4/5 were obser)-18 (ved.)37 ( )36.6 (Therefore,)37 ( a)-9.9 (pixaban is not expected to alter the)-25 ( )]TJ 0.2 Tw 0 -1.076 Td [(metabolic c)20 (learance of coadministered drugs tha)-10 (t are metabolized by these enzymes.)12 ( )]TJ 0.084 Tw 0 -1.076 Td [(A)-10 (pixaban is not a signi\037cant inhibitor of P-gp.)]TJ -0.032 Tc 0.075 Tw 0 -1.526 Td [(The effects of coadministered drugs on the pharmacokinetics of a)-9.9 (pixaban are summarized)-32 ( )]TJ -0.025 Tc 0.084 Tw 0 -1.076 Td [(in F)18.1 (igure 2 )]TJ /T1_0 1 Tf 0 Tc 0 Tw ([)Tj 4.349 0 Td (s)Tj -0.025 Tc 0.084 Tw 0.382 0 Td (ee al)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.047 Tw 2.117 0 Td [(o W)18 (arning)]TJ 0 Tc 0 Tw (s)Tj -0.025 Tc 0.084 Tw 3.925 0 Td ( and Precaution)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.084 Tw 5.949 0 Td ( \(5.2\) and Drug Interaction)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.084 Tw 9.739 0 Td ( \(7\)])Tj /T1_1 1 Tf 0 Tc 0 Tw (.)Tj /T1_2 1 Tf -0.022 Tc 0.084 Tw -26.46 -2.426 Td (Figure 2:)Tj /Span< >> BDC ( )Tj EMC 5.4 0 Td [(Effect of Coadministered Drugs on the Pharmacokinetics of)-22 ( )]TJ 0.022 Tw 0 -1.076 Td (Apixaban)Tj ET /PlacedGraphic /MC0 BDC EMC BT /GS0 gs /T1_4 1 Tf -0.005 Tc 0 Tw 6.8 0 0 6.8 50.4399 595.0303 Tm (Interacting Drug)Tj 0.005 Tw 15.307 0 Td (PK)Tj 0 Tw 4.448 0 Td (Fold Change and 90% CI)Tj -19.755 -2.016 Td (Combined P)Tj 4.667 0 Td (-gp and Strong CYP3A4 Inhibitors)Tj /T1_5 1 Tf -3.678 -1.299 Td (Ketoconazole 400 mg)Tj 0 Tc 13.99 -0.057 Td (C)Tj -0.005 Tc 0.005 Tw 5.1 0 0 5.1 155.7885 571.2527 Tm (max)Tj 6.8 0 0 6.8 152.2933 565.2936 Tm (AUC)Tj /T1_4 1 Tf -0.01 Tc 0 Tw -14.979 -5.154 Td (Other CYP3A4 and P)Tj 7.74 0 Td (-gp Inhibitor)Tj 0 Tc (s)Tj /T1_5 1 Tf -0.005 Tc -6.751 -1.367 Td (Diltiazem 360 mg)Tj 0 Tc 13.99 -0.004 Td (C)Tj -0.005 Tc 0.005 Tw 5.1 0 0 5.1 155.7885 520.0834 Tm (max)Tj 6.8 0 0 6.8 152.2933 514.124 Tm (AUC)Tj 0 Tw -13.99 -2.138 Td (Naproxen 500 mg)Tj 0 Tc 13.99 -0.066 Td (C)Tj -0.005 Tc 0.005 Tw 5.1 0 0 5.1 155.7885 498.297 Tm (max)Tj 6.8 0 0 6.8 152.2933 492.3376 Tm (AUC)Tj /T1_4 1 Tf -0.01 Tc 0 Tw -14.978 -1.969 Td (Combined P)Tj 4.617 0 Td (-gp and Strong CYP3A4 Inducer)Tj /T1_5 1 Tf -0.005 Tc -3.628 -1.284 Td (Rifampin 600 mg)Tj 0 Tc 13.99 -0.055 Td (C)Tj -0.005 Tc 0.005 Tw 5.1 0 0 5.1 155.7885 469.0026 Tm (max)Tj 6.8 0 0 6.8 152.2933 463.0432 Tm (AUC)Tj /T1_4 1 Tf 0 Tw 4.832 -4.576 Td (Change Relative to Reference)Tj /T1_5 1 Tf -0.01 Tc 0.01 Tw 9.479 1.774 Td (2.0 )Tj ET 0 0 0 1 K 0.639 w q 1 0 0 1 203.4667 451.1662 cm 0 0 m 0 134.83 l S Q q 50.44 430.402 221.143 170.273 re W n 0.656 w q 1 0 0 1 174.0329 452.8492 cm 0 0 m 97.549 0 l S Q Q BT 6.8 0 0 6.8 176.0168 443.9879 Tm (0.5 )Tj 3.607 0 Td (1.0 )Tj 3.607 0 Td (1.5 )Tj ET q 1 0 0 1 229.86 573.0104 cm 0 0 m 13.637 0 l S Q q 48.6 428.513 226.8 174.149 re W n q 1 0 0 1 234.8283 573.0104 cm 0 0 m 0 -0.898 0.656 -1.625 1.467 -1.625 c 2.276 -1.625 2.934 -0.898 2.934 0 c 2.934 0.898 2.276 1.626 1.467 1.626 c 0.656 1.626 0 0.898 0 0 c f Q 230.114 572.121 -1.721 1.906 re f 245.224 572.121 -1.721 1.906 re f q 1 0 0 1 245.8103 565.9137 cm 0 0 m 18.093 0 l S Q q 1 0 0 1 253.1228 565.9137 cm 0 0 m 0 -0.898 0.657 -1.625 1.467 -1.625 c 2.278 -1.625 2.934 -0.898 2.934 0 c 2.934 0.898 2.278 1.625 1.467 1.625 c 0.657 1.625 0 0.898 0 0 c f Q 246.67 565.024 -1.72 1.906 re f 264.764 565.024 -1.72 1.906 re f Q BT -0.005 Tc 0 Tw 6.8 0 0 6.8 57.1635 552.1721 Tm (Clarithromycin 500 mg)Tj 0 Tc 13.99 -0.057 Td (C)Tj -0.005 Tc 0.005 Tw 5.1 0 0 5.1 155.7885 550.9411 Tm (max)Tj 6.8 0 0 6.8 152.2933 544.982 Tm (AUC)Tj ET q 48.6 428.513 226.8 174.149 re W n q 1 0 0 1 217.11 552.6984 cm 0 0 m 7.687 0 l S Q q 1 0 0 1 219.5283 552.6984 cm 0 0 m 0 -0.898 0.656 -1.625 1.467 -1.625 c 2.276 -1.625 2.934 -0.898 2.934 0 c 2.934 0.898 2.276 1.626 1.467 1.626 c 0.656 1.626 0 0.898 0 0 c f Q 217.364 551.809 -1.721 1.906 re f 226.524 551.809 -1.721 1.906 re f q 1 0 0 1 229.6603 545.6016 cm 0 0 m 9.593 0 l S Q q 1 0 0 1 231.8728 545.6016 cm 0 0 m 0 -0.898 0.657 -1.625 1.467 -1.625 c 2.278 -1.625 2.934 -0.898 2.934 0 c 2.934 0.898 2.278 1.625 1.467 1.625 c 0.657 1.625 0 0.898 0 0 c f Q 230.52 544.712 -1.72 1.906 re f 240.114 544.712 -1.72 1.906 re f q 1 0 0 1 212.9994 525.5731 cm 0 0 m 15.109 0 l S Q q 1 0 0 1 218.5729 525.5731 cm 0 0 m 0 -0.897 0.657 -1.626 1.467 -1.626 c 2.278 -1.626 2.934 -0.897 2.934 0 c 2.934 0.897 2.278 1.626 1.467 1.626 c 0.657 1.626 0 0.897 0 0 c f Q 212.976 524.649 -1.721 1.906 re f 228.692 524.649 -1.72 1.906 re f q 1 0 0 1 216.4054 518.3115 cm 0 0 m 16.507 0 l S Q q 1 0 0 1 222.0358 518.3115 cm 0 0 m 0 -0.898 0.656 -1.625 1.466 -1.625 c 2.277 -1.625 2.934 -0.898 2.934 0 c 2.934 0.897 2.277 1.626 1.466 1.626 c 0.656 1.626 0 0.897 0 0 c f Q 216.714 517.342 -1.72 1.907 re f 233.644 517.342 -1.72 1.907 re f q 1 0 0 1 226.035 502.6652 cm 0 0 m 19.899 -0.013 l S Q q 1 0 0 1 233.8474 502.6592 cm 0 0 m 0 -0.898 0.658 -1.625 1.468 -1.625 c 2.279 -1.625 2.934 -0.898 2.934 0 c 2.934 0.898 2.279 1.625 1.468 1.625 c 0.658 1.625 0 0.898 0 0 c f Q 226.895 501.833 -1.721 1.907 re f 246.794 501.833 -1.721 1.907 re f q 1 0 0 1 225.4044 494.9259 cm 0 0 m 13.637 0 l S Q q 1 0 0 1 230.3726 494.9259 cm 0 0 m 0 -0.898 0.656 -1.626 1.466 -1.626 c 2.276 -1.626 2.933 -0.898 2.933 0 c 2.933 0.898 2.276 1.624 1.466 1.624 c 0.656 1.624 0 0.898 0 0 c f Q 225.658 494.056 -1.721 1.907 re f 240.161 494.056 -1.721 1.907 re f q 1 0 0 1 179.693 470.2445 cm 0 0 m 6.463 0 l S Q q 1 0 0 1 181.1737 470.4417 cm 0 0 m 0 -0.898 0.656 -1.625 1.466 -1.625 c 2.276 -1.625 2.934 -0.898 2.934 0 c 2.934 0.898 2.276 1.625 1.466 1.625 c 0.656 1.625 0 0.898 0 0 c f Q 180.7 469.355 -1.721 1.907 re f 186.87 469.355 -1.722 1.907 re f q 1 0 0 1 174.9798 462.3123 cm 0 0 m 3.595 0 l S Q q 1 0 0 1 175.2773 462.3123 cm 0 0 m 0 -0.899 0.656 -1.625 1.467 -1.625 c 2.277 -1.625 2.934 -0.899 2.934 0 c 2.934 0.897 2.277 1.625 1.467 1.625 c 0.656 1.625 0 0.897 0 0 c f Q 176.066 461.423 -1.72 1.907 re f 179.219 461.423 -1.72 1.907 re f q 1 0 0 1 179.6488 454.528 cm 0 0 m 0 -3.362 l 73.597 0 m 73.597 -3.362 l 49.184 0 m 49.184 -3.362 l S Q Q BT /GS1 gs /T1_1 1 Tf -0.025 Tc 0.158 Tw 8 0 0 8 36 412.7228 Tm [(In dedica)-9.9 (ted studies conducted in healthy subjects,)37 ( famotidine,)37 ( a)-10 (tenolol,)37 ( prasugrel,)37 ( and)-25 ( )]TJ 0.084 Tw 0 -1.076 Td [(enoxa)-10 (parin did not meaningfully alter the pharmacokinetics of a)-9.9 (pixaban.)]TJ 0.353 Tw 0 -1.526 Td [(In studies conducted in healthy subjects,)37 ( a)-10 (pixaban did not meaningfully alter the)-24.9 ( )]TJ 0.084 Tw 0 -1.076 Td [(pharmacokinetics of digoxin,)37 ( na)-9.9 (proxen,)37 ( a)-10 (tenolol,)37 ( prasugrel,)37 ( or acetylsalic)20 (ylic acid.)]TJ /T1_3 1 Tf 0 -1.751 Td (Speci\037c Populations)Tj /T1_1 1 Tf 0.028 Tw 0 -1.301 Td [(The effects of level of renal impairment,)37 ( a)-9.9 (ge,)37 ( bod)-10 (y weight,)37 ( and level of hepa)-10 (tic impairment)-25 ( )]TJ 0.084 Tw 0 -1.076 Td [(on the pharmacokinetics of a)-9.9 (pixaban are summarized in F)18 (igure 3.)]TJ /T1_2 1 Tf 0 -2.426 Td (Figure 3: )Tj /Span< >> BDC ( )Tj EMC 4.5 0 Td (Effect of Specific Populations on the Pharmacokinetics of Apixaban)Tj ET /PlacedGraphic /MC1 BDC EMC /GS0 gs q 1 0 0 1 217.5771 289.9279 cm 0 0 m 0.62 0 l 1.902 -4.051 l 1.913 -4.051 l 1.913 0 l 2.391 0 l 2.391 -4.853 l 1.733 -4.853 l 0.489 -0.924 l 0.479 -0.924 l 0.479 -4.853 l 0 -4.853 l h f Q q 48.6 117.255 226.8 205.324 re W n q 1 0 0 1 222.0643 286.8968 cm 0 0 m 0 0.788 -0.093 1.468 -0.582 1.468 c -1.044 1.468 -1.142 0.788 -1.142 0 c -1.142 -0.789 -1.05 -1.468 -0.582 -1.468 c -0.099 -1.468 0 -0.789 0 0 c -0.571 1.916 m 0.271 1.916 0.478 1.026 0.478 0 c 0.478 -1.026 0.266 -1.917 -0.571 -1.917 c -1.414 -1.917 -1.62 -1.026 -1.62 0 c -1.62 1.026 -1.408 1.916 -0.571 1.916 c f Q q 1 0 0 1 225.2084 285.4694 cm 0 0 m 0.506 0 0.587 0.598 0.587 1.427 c 0.587 2.134 0.489 2.854 0 2.854 c -0.424 2.854 -0.533 2.297 -0.533 1.427 c -0.533 0.557 -0.424 0 0 0 c 1.016 -0.394 m 0.581 -0.394 l 0.581 0.054 l 0.57 0.054 l 0.51 -0.217 0.256 -0.489 -0.06 -0.489 c -0.751 -0.489 -1.012 0.279 -1.012 1.427 c -1.012 2.189 -0.913 3.344 -0.093 3.344 c 0.168 3.344 0.445 3.147 0.548 2.834 c 0.559 2.834 l 0.559 4.459 l 1.016 4.459 l h f Q q 1 0 0 1 228.3033 286.8968 cm 0 0 m 0 0.788 -0.092 1.468 -0.581 1.468 c -1.043 1.468 -1.141 0.788 -1.141 0 c -1.141 -0.789 -1.049 -1.468 -0.581 -1.468 c -0.098 -1.468 0 -0.789 0 0 c -0.57 1.916 m 0.272 1.916 0.479 1.026 0.479 0 c 0.479 -1.026 0.267 -1.917 -0.57 -1.917 c -1.413 -1.917 -1.619 -1.026 -1.619 0 c -1.619 1.026 -1.408 1.916 -0.57 1.916 c f Q q 1 0 0 1 230.4903 287.6509 cm 0 0 m 0 0.462 -0.099 0.713 -0.429 0.713 c -0.576 0.713 -0.903 0.666 -0.903 0.156 c -0.903 -0.272 -0.544 -0.353 -0.185 -0.503 c 0.168 -0.652 0.527 -0.809 0.527 -1.529 c 0.527 -2.297 0.13 -2.671 -0.414 -2.671 c -1.402 -2.671 -1.413 -1.753 -1.413 -1.38 c -0.956 -1.38 l -0.956 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0 1.272 0.938 c 1.272 1.414 1.016 1.713 0.571 1.713 c 0 1.713 l h -0.479 2.202 m 0.777 2.202 l 1.386 2.202 1.771 1.754 1.771 0.986 c 1.771 0.455 1.625 -0.102 1.174 -0.238 c 1.174 -0.252 l 1.511 -0.299 1.701 -0.645 1.722 -1.06 c 1.755 -1.889 l 1.777 -2.426 1.848 -2.562 1.962 -2.65 c 1.386 -2.65 l 1.304 -2.548 1.266 -2.188 1.255 -1.95 c 1.223 -1.196 l 1.184 -0.53 0.891 -0.489 0.647 -0.489 c 0 -0.489 l 0 -2.65 l -0.479 -2.65 l h f Q q 1 0 0 1 59.5446 268.298 cm 0 0 m 0 0.197 l 0 0.605 -0.103 1.087 -0.505 1.087 c -0.984 1.087 -1.038 0.353 -1.038 0.136 c -1.038 0 l h -1.054 -0.449 m -1.054 -1.006 -1.054 -1.849 -0.495 -1.849 c -0.06 -1.849 0 -1.278 0 -1.006 c 0.457 -1.006 l 0.457 -1.393 0.272 -2.297 -0.522 -2.297 c -1.234 -2.297 -1.533 -1.679 -1.533 -0.428 c -1.533 0.482 -1.391 1.536 -0.495 1.536 c 0.397 1.536 0.478 0.564 0.478 -0.217 c 0.478 -0.449 l h f Q q 1 0 0 1 60.5249 269.7387 cm 0 0 m 0.435 0 l 0.435 -0.428 l 0.446 -0.428 l 0.565 -0.095 0.87 0.095 1.152 0.095 c 1.918 0.095 1.918 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0.68 -1.486 l 0.301 -2.457 l -0.037 -2.457 l 0.503 -1.179 l h f Q Q BT /GS1 gs /T1_1 1 Tf 0.221 Tw 7.6 0 0 8 36.176 105.9638 Tm (*)Tj /Span< >> BDC ( )Tj EMC 0.527 0 Td [(ESRD subjects trea)-10 (ted with intermittent hemodialysis; reported PK findings are follo)-10 (wing)-25 ( )]TJ 0.084 Tw -0.001 -1.076 Td [(single dose of a)-9.9 (pixaban posthemodialysis.)]TJ 0 Tc 0 Tw 5.98 0 0 5.98 36.176 89.8929 Tm (\206)Tj -0.025 Tc 0.084 Tw /Span< >> BDC 7.6 0 0 8 38.9088 88.3829 Tm ( )Tj EMC 0.167 0 Td (Results reflect CrCl of 15 mL/min based on regression analysis.)Tj 0 Tc 0 Tw 5.98 0 0 5.98 36.176 80.9224 Tm (\207)Tj -0.025 Tc 0.176 Tw /Span< >> BDC 7.6 0 0 8 38.9088 79.4124 Tm ( )Tj EMC 0.167 0 Td [(Dashed vertical lines illustra)-9.9 (te pharmacokinetic changes tha)-10 (t were used to inform dosing)-24.9 ( )]TJ 0.025 Tw 0 -1.076 Td [(recommenda)-9.9 (tions.)]TJ 0 Tc 0 Tw 5.98 0 0 5.98 36.176 63.3414 Tm (\247)Tj -0.025 Tc 0.055 Tw /Span< >> BDC 7.6 0 0 8 38.9088 61.8314 Tm ( )Tj EMC 0.167 0 Td [(No dose adjustment is recommended for nonvalvular a)-10 (trial fibrilla)-10 (tion pa)-9.9 (tients unless a)-10 (t least)-24.9 ( )]TJ 0.066 Tw 0 -1.076 Td [(2 of the follo)-10 (wing pa)-10 (tient characteristics \(a)-10 (ge grea)-10 (ter than or equal to 80)]TJ /Span< >> BDC ( )Tj EMC 25.955 0 Td [(years,)37 ( bod)-9.9 (y weight)-24.9 ( )]TJ 0.174 Tw -25.955 -1.076 Td (less than or equal to 60)Tj /Span< >> BDC ( )Tj EMC 9.197 0 Td [(kg,)37 ( or serum crea)-10 (tinine grea)-9.9 (ter than or equal to 1.5)]TJ /Span< >> BDC ( )Tj EMC 19.427 0 Td [(mg/dL\) are)-25 ( )]TJ 0.025 Tw -28.624 -1.076 Td (present.)Tj ET endstream endobj 306 0 obj <>/Filter/FlateDecode/Height 11/Intent/RelativeColorimetric/Length 98/Name/X/Subtype/Image/Type/XObject/Width 23>>stream HÚóå?&ÈÉÙ³°In.¦èFF!¡÷hÿþW0A ºâG a¦Í¨¢ßÍÀÅÖ/¾ PÀÒù.zA¦>ýÚÍÄÕݼ-øÐ0@G¯ endstream endobj 307 0 obj <>/Filter/FlateDecode/Height 11/Intent/RelativeColorimetric/Length 17/Name/X/Subtype/Image/Type/XObject/Width 3>>stream Hb``øÏ0À ÀY à 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0.382 0 Td [(ee W)18 (arning)]TJ 0 Tc 0 Tw (s)Tj -0.025 Tc 0.26 Tw 4.52 0 Td [( and)-25 ( )]TJ 0.025 Tw -29.705 -1.066 Td (Precaution)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.26 Tw 4.056 0 Td ( \(5.2\)])Tj /T1_1 1 Tf [(.)37 ( )37 (A 50% to 60% increase in anti-FXa activity was obser)-18 (ved when)-25 ( )]TJ 0.084 Tw -4.056 -1.066 Td [(ELIQUIS was coadministered with enoxa)-10 (parin or na)-10 (proxen.)]TJ /T1_2 1 Tf 0 -1.696 Td (Speci\037c Populations)Tj /T1_3 1 Tf 0.073 Tw 0 -1.291 Td (Renal impairment:)Tj /T1_1 1 Tf /Span< >> BDC ( )Tj EMC 6.44 0 Td [( )36.8 (Anti-FXa activity adjusted for exposure to a)-10 (pixaban was similar across)-25 ( )]TJ 0.084 Tw -6.44 -1.066 Td [(renal function ca)-9.9 (tegories.)]TJ /T1_3 1 Tf 0.152 Tw 0 -1.516 Td [(Hepa)-9.9 (tic impairment:)]TJ /T1_1 1 Tf /Span< >> BDC ( )Tj EMC 7.181 0 Td [( Changes in anti-FXa activity were similar in pa)-10 (tients with mild-to-)]TJ 0.131 Tw -7.181 -1.066 Td [(modera)-10 (te hepa)-10 (tic impairment and healthy subjects.)37 ( Ho)-10 (wever)74 (,)37 ( in pa)-10 (tients with modera)-10 (te)-24.9 ( )]TJ 0.239 Tw 0 -1.066 Td [(hepa)-9.9 (tic )0.5 (impairment,)37 ( )0.5 (there )0.5 (is )0.5 (no )0.5 (c)20 (lear )0.6 (understanding )0.5 (of )0.5 (the )0.5 (impact )0.5 (of )0.5 (this degree )0.5 (of)-25 ( )]TJ 0.143 Tw 0 -1.066 Td [(hepa)-9.9 (tic function impairment on the coa)-10 (gula)-10 (tion cascade and its rela)-10 (tionship to ef\037cac)20 (y)-25 ( )]TJ 0.084 Tw 0 -1.066 Td [(and bleeding.)37 ( P)18 (a)-10 (tients with severe hepa)-9.9 (tic impairment were not studied.)]TJ /T1_3 1 Tf 0.202 Tw 0 -1.516 Td [(P)18 (edia)-9.9 (tric pa)-9.9 (tient)]TJ 0 Tc 0 Tw (s)Tj 6.158 0 Td (:)Tj /T1_1 1 Tf -0.025 Tc 0.202 Tw /Span< >> BDC 0.215 0 Td ( )Tj EMC 0.017 0 Td [( In pedia)-10 (tric pa)-10 (tients trea)-9.9 (ted with a)-9.9 (pixaban,)37 ( the correla)-10 (tion between)-25 ( )]TJ 0.084 Tw -6.389 -1.066 Td [(anti-FXa activity and plasma concentra)-10 (tion is linear with a slope c)20 (lose to 1.)]TJ /T1_2 1 Tf 0 -1.741 Td [(Car)6 (diac Electroph)6.1 (ysiology)]TJ /T1_1 1 Tf 0 -1.291 Td [(A)-10 (pixaban has no effect on the QTc inter)-18 (val in humans a)-10 (t doses up to 50)]TJ /Span< >> BDC ( )Tj EMC 26.059 0 Td (mg.)Tj /T1_0 1 Tf 0.025 Tw -26.059 -1.854 Td (12.3)Tj /Span< >> BDC ( )Tj EMC 3.375 0 Td (Pharmacokinetics)Tj /T1_1 1 Tf 0.349 Tw -3.375 -1.516 Td [(A)-10 (pixaban demonstra)-9.9 (tes linear pharmacokinetics with dose-proportional increases in)-25 ( )]TJ 0.084 Tw 0 -1.066 Td (exposure for oral doses up to 10)Tj /Span< >> BDC ( )Tj EMC 11.865 0 Td (mg.)Tj /T1_2 1 Tf 0.025 Tw -11.865 -1.696 Td (Absorption)Tj /T1_1 1 Tf 0.118 Tw 0 -1.291 Td [(The )0.5 (absolute bioa)-9.9 (vailability of a)-10 (pixaban is a)-9.9 (pproxima)-10 (tely 50% for doses up to 10)]TJ /Span< >> BDC ( )Tj EMC 29.354 0 Td [(mg of)-25 ( )]TJ 0.178 Tw -29.354 -1.066 Td [(ELIQUIS.)37 ( F)20 (ood does not affect the bioa)-10 (vailability of a)-9.9 (pixaban.)37 ( Maximum concentra)-10 (tions)-25 ( )]TJ 0.025 Tw 0 -1.066 Td (\(C)Tj 5.2 0 0 5.2 329.6799 276.373 Tm (max)Tj 0.199 Tw 8 0 0 8 337.4641 276.973 Tm [(\) of a)-10 (pixaban a)-10 (ppear 3 to 4 hours after oral administra)-10 (tion of ELIQUIS.)37 ( )36.9 (At doses)-25 ( )]TJ 0.188 Tw -1.683 -1.066 Td (\03625)Tj /Span< >> BDC ( )Tj EMC 1.595 0 Td [(mg,)37 ( )0.5 (a)-10 (pixaban displays dissolution-limited )0.5 (absorption )0.5 (with )0.5 (decreased )0.5 (bioa)-9.9 (vailability)55 (.)12 ( )]TJ 0.062 Tw -1.595 -1.066 Td [(F)20 (ollo)-10 (wing oral administra)-10 (tion of 10)]TJ /Span< >> BDC ( )Tj EMC 12.39 0 Td [(mg of a)-9.9 (pixaban as 2 crushed 5)]TJ /Span< >> BDC ( )Tj EMC 11.3 0 Td [(mg tablets suspended)-25 ( )]TJ 0.072 Tw -23.69 -1.066 Td [(in 30 mL of wa)-10 (ter)74 (,)37 ( exposure was similar to tha)-9.9 (t after oral administra)-10 (tion of 2 intact 5)]TJ /Span< >> BDC ( )Tj EMC 30.34 0 Td [(mg)-25 ( )]TJ 0.171 Tw -30.34 -1.066 Td [(tablets.)37 ( F)20 (ollo)-10 (wing oral administra)-10 (tion of 10)]TJ /Span< >> BDC ( )Tj EMC 15.695 0 Td [(mg of a)-10 (pixaban as 2 crushed 5)]TJ /Span< >> BDC ( )Tj EMC 11.955 0 Td [(mg tablets)-25 ( )]TJ 0.045 Tw -27.649 -1.066 Td [(mixed with 30 g of a)-9.9 (pplesauce,)37 ( the C)]TJ 0.025 Tw 5.2 0 0 5.2 429.0756 233.7224 Tm (max)Tj 0.045 Tw 8 0 0 8 436.8598 234.3224 Tm [( and )36.8 (AUC were 20% and 16% lo)-10 (wer)74 (,)37 ( respectively)55 (,)12 ( )]TJ 0.108 Tw -14.107 -1.066 Td [(when compared to administra)-10 (tion of 2 intact 5)]TJ /Span< >> BDC ( )Tj EMC 16.951 0 Td [(mg tablets.)37 ( F)20 (ollo)-10 (wing administra)-9.9 (tion of a)-25 ( )]TJ 0.112 Tw -16.951 -1.066 Td (crushed 5)Tj /Span< >> BDC ( )Tj EMC 3.782 0 Td [(mg ELIQUIS tablet tha)-10 (t was suspended in 60 mL D5W and delivered through)-25 ( )]TJ 0.199 Tw -3.782 -1.066 Td [(a )0.5 (nasogastric )0.5 (tube,)37 ( )0.5 (exposure )0.5 (was )0.5 (similar )0.5 (to )0.5 (tha)-10 (t )0.5 (seen )0.5 (in )0.5 (other )0.5 (c)20 (linical )0.5 (trials )0.5 (involving)-25 ( )]TJ 0.084 Tw 0 -1.066 Td (healthy volunteers receiving a single oral 5)Tj /Span< >> BDC ( )Tj EMC 15.417 0 Td (mg tablet dose.)Tj /T1_2 1 Tf 0.025 Tw -15.417 -1.696 Td (Distribution)Tj /T1_1 1 Tf 0.066 Tw 0 -1.291 Td [(Plasma )0.5 (protein )0.6 (binding )0.6 (in )0.5 (humans )0.6 (is )0.5 (a)-10 (pproxima)-9.9 (tely )0.6 (87%.)37 ( )37.5 (The )0.5 (volume )0.6 (of )0.5 (distribution )0.5 (\(Vss\))-25 ( )]TJ 0.084 Tw 0 -1.066 Td [(is a)-9.9 (pproxima)-10 (tely 21 liters.)]TJ /T1_2 1 Tf 0.025 Tw 0 -1.696 Td (Metabolism)Tj /T1_1 1 Tf 0.165 Tw 0 -1.291 Td [(A)-10 (pproxima)-10 (tely 25% of an orally administered a)-10 (pixaban dose is recovered in urine and)-25 ( )]TJ 0 Tc 0 Tw 31.5 0 Td ( )Tj -0.025 Tc 0.031 Tw -31.5 -1.066 Td [(feces as metabolites.)37 ( )37.1 (A)-10 (pixaban is metabolized mainly via CYP3A4 with minor contributions)-25 ( )]TJ 0.287 Tw 0 -1.066 Td [(from CYP1A2,)37 ( 2C8,)37 ( 2C9,)37 ( 2C19,)37 ( and 2J2.)37 ( O-demethyla)-10 (tion and hydroxyla)-10 (tion a)-10 (t the)-25 ( )]TJ 0.084 Tw 0 -1.066 Td [(3-oxopiperidin)-10 (yl moiety are the major sites of biotransforma)-9.9 (tion.)]TJ 0.138 Tw 0 -1.516 Td [(Unchanged a)-10 (pixaban is the major drug-rela)-10 (ted component in human plasma; there are)-25 ( )]TJ 0.084 Tw 0 -1.066 Td [(no active circula)-9.9 (ting metabolites.)]TJ /T1_2 1 Tf 0.025 Tw 0 -1.696 Td (Elimination)Tj /T1_1 1 Tf 0.103 Tw 0 -1.291 Td [(A)-10 (pixaban is elimina)-10 (ted in both urine and feces.)37 ( Renal excretion accounts for about 27%)-25 ( )]TJ 0.262 Tw 0 -1.066 Td [(of total c)20 (learance.)37 ( Biliar)-18 (y and direct intestinal excretion contributes to elimina)-9.9 (tion of)-25 ( )]TJ 0.084 Tw 0 -1.066 Td [(a)-10 (pixaban in the feces.)]TJ 0.122 Tw 0 -1.516 Td [(A)-10 (pixaban has a total c)20.1 (learance of a)-10 (pproxima)-10 (tely 3.3 L/hour and an a)-10 (pparent half-life of)-25 ( )]TJ 0.084 Tw 0 -1.066 Td [(a)-10 (pproxima)-10 (tely 12 hours follo)-10 (wing oral administra)-10 (tion.)]TJ ET 0 0 0 1 K 0.5 w /GS2 gs q 1 0 0 1 36 686.6762 cm 0 0 m 126 0 l S Q q 1 0 0 1 162 686.6762 cm 0 0 m 126 0 l S Q 1 w q 1 0 0 1 36 706.6481 cm 0 0 m 126 0 l S Q q 1 0 0 1 162 706.6481 cm 0 0 m 126 0 l S Q q 1 0 0 1 36 650.1005 cm 0 0 m 126 0 l S Q q 1 0 0 1 162 650.1005 cm 0 0 m 126 0 l S Q BT /GS1 gs /T1_0 1 Tf -0.022 Tc 8 0 0 8 36 727.2481 Tm (Table 12:)Tj /Span< >> BDC ( )Tj EMC 5.4 0 Td [(Inadequate renal function by sex and post-natal age in pediatric)-22 ( )]TJ 0 -1.062 Td (patients <2)Tj /Span< >> BDC ( )Tj EMC 4.595 0 Td [(years of age as defined in the pediatric VTE trial for)-22 ( )]TJ 0.022 Tw -4.595 -1.062 Td (ELIQUIS)Tj 0.024 Tw 7.6 0 0 8 66.3282 693.8062 Tm (Postnatal age \(gender\))Tj 12.752 0.531 Td [( Threshold eGFR used to define inadequate)-22 ( )]TJ 2.016 -1.062 Td (renal function \(mL/min/1.73 m)Tj 0 Tc 0 Tw 5.98 0 0 5.98 266.4445 691.0662 Tm (2)Tj 7.6 0 0 8 269.1833 689.5562 Tm (\))Tj /T1_1 1 Tf -0.022 Tc 0.024 Tw -30.682 -1.479 Td (1 week \(males and females\))Tj 0.022 Tw 24.339 0 Td (<8)Tj 0.024 Tw -24.339 -1.524 Td (2\2268 weeks \(males and females\))Tj 0.022 Tw 24.11 0 Td (<12)Tj 0.024 Tw -24.11 -1.524 Td (>8 weeks to <2)Tj /Span< >> BDC ( )Tj EMC 5.947 0 Td (years \(males and females\))Tj 0.022 Tw 18.164 0 Td (<22)Tj -0.025 Tc 0.226 Tw 8 0 0 8 36 630.2853 Tm [(Inadequa)-10 (te renal function was de\037ned as <30% of 1 standard devia)-10 (tion \(SD\) belo)-10 (w)-24.9 ( )]TJ 0.128 Tw 0 -1.064 Td [(normal GFR for a)-9.9 (ge and size as determined by the upda)-9.9 (ted Schwartz formula for a)-9.9 (ges)-25 ( )]TJ 0.078 Tw 0 -1.064 Td [(up to 2 years.)37 ( Beyond 2 years of a)-9.9 (ge,)37 ( the qualifying GFR for the pedia)-10 (tric )36.8 (VTE stud)-10 (y was)-25 ( )]TJ 0.084 Tw 0 -1.064 Td (\03630 mL/min/1.73m)Tj 0 Tc 0 Tw 5.98 0 0 5.98 91.1511 606.2498 Tm (2)Tj -0.223 Tw /Span< >> BDC 8 0 0 8 93.872 604.7397 Tm ( )Tj EMC (.)Tj /T1_0 1 Tf -0.025 Tc 0.025 Tw -7.234 -1.852 Td (8.7)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td (Hepatic Impairment)Tj /T1_1 1 Tf 0.209 Tw -3.375 -1.514 Td [(No dose adjustment is required in pa)-9.9 (tients with mild hepa)-10 (tic impairment \(Child-Pugh)-25 ( )]TJ 0.047 Tw 0 -1.064 Td [(c)20 (lass A\).)]TJ -0.026 Tw 0 -1.514 Td [(Because pa)-10 (tients with modera)-10 (te hepa)-10 (tic impairment \(Child-Pugh c)20 (lass B\) may ha)-10 (ve intrinsic)-25 ( )]TJ 0 Tc 0 Tw 31.5 0 Td ( )Tj -0.025 Tc 0.149 Tw -31.5 -1.064 Td [(coa)-9.9 (gula)-10 (tion abnormalities and there is limited c)20 (linical experience with ELIQUIS in these)-24.9 ( )]TJ 0.062 Tw 0 -1.064 Td [(pa)-10 (tients,)37 ( )0.5 (dosing )0.5 (recommenda)-10 (tions )0.5 (cannot )0.5 (be )0.5 (provided )]TJ /T1_3 1 Tf 0 Tc 0 Tw 19.353 0 Td ([)Tj 0.234 0 Td (s)Tj -0.025 Tc 0.062 Tw 0.382 0 Td [(ee )0.5 (Clinical)]TJ [( )0.5 (Pharmacolog)-10 (y )0.5 (\(12.2\)])]TJ /T1_1 1 Tf 0 Tc 0 Tw (.)Tj -0.025 Tc 0.222 Tw -19.969 -1.514 Td [(ELIQUIS is not recommended in pa)-10 (tients with severe hepa)-10 (tic impairment \(Child-Pugh)-25 ( )]TJ 0.084 Tw 0 -1.064 Td [(c)20 (lass C\) )]TJ /T1_3 1 Tf 0 Tc 0 Tw ([)Tj 3.285 0 Td (s)Tj -0.025 Tc 0.084 Tw 0.382 0 Td (ee Clinical)Tj [( Pharmacolog)-9.9 (y \(12.2\)])]TJ /T1_1 1 Tf 0 Tc 0 Tw (.)Tj -0.025 Tc 0.084 Tw -3.667 -1.514 Td [(ELIQUIS has not been studied in pedia)-10 (tric pa)-10 (tients with hepa)-10 (tic impairment.)]TJ /T1_0 1 Tf 0.025 Tw 0 -1.852 Td (10)Tj /Span< >> BDC ( )Tj EMC 3.375 0 Td (OVERDOSAGE)Tj /T1_1 1 Tf 0.084 Tw -3.375 -1.582 Td (Overdose of ELIQUIS increases the risk of bleeding )Tj /T1_3 1 Tf 0 Tc 0 Tw ([)Tj 18.507 0 Td (s)Tj -0.025 Tc 0.047 Tw 0.382 0 Td [(ee W)18 (arning)]TJ 0 Tc 0 Tw (s)Tj -0.025 Tc 0.084 Tw 4.344 0 Td ( and Precaution)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.084 Tw 5.949 0 Td ( \(5.2\)])Tj /T1_1 1 Tf 0 Tc 0 Tw (.)Tj -0.025 Tc 0.102 Tw -29.181 -1.514 Td [(In healthy subjects,)37 ( administra)-10 (tion of activa)-9.9 (ted charcoal 2 and 6 hours after ingestion of)-25 ( )]TJ 0.098 Tw 0 -1.064 Td [(a )0.5 (20-mg )0.5 (dose )0.5 (of )0.5 (a)-9.9 (pixaban )0.5 (reduced )0.5 (mean )0.5 (a)-9.9 (pixaban )37.5 (AUC )0.5 (by )0.6 (50% )0.5 (and )0.6 (27%,)37 ( )0.5 (respectively)55 (.)12 ( )]TJ 0.1 Tw 0 -1.064 Td [(Thus,)37 ( administra)-10 (tion of activa)-10 (ted charcoal may be useful in the mana)-9.9 (gement of ELIQUIS)-25 ( )]TJ 0.298 Tw 0 -1.064 Td [(overdose or accidental ingestion.)37 ( )37.1 (An a)-10 (gent to reverse the anti-factor Xa activity of)-24.9 ( )]TJ 0.084 Tw 0 -1.064 Td [(a)-10 (pixaban is a)-10 (vailable.)]TJ 0.134 Tw 0 -1.514 Td [(Consider contacting the P)18 (oison Help line \(1)80 (-800-222-)60 (1)40 (222\) or a medical toxicologist for)-24.9 ( )]TJ 0.084 Tw 0 -1.064 Td [(additional overdose mana)-9.9 (gement recommenda)-9.9 (tions.)]TJ /T1_0 1 Tf 0.025 Tw 0 -1.852 Td (11)Tj /Span< >> BDC ( )Tj EMC 3.375 0 Td (DESCRIPTION)Tj /T1_1 1 Tf 0.654 Tw -3.375 -1.582 Td [(ELIQUIS \(a)-9.9 (pixaban\),)37 ( a factor Xa \(FXa\) inhibitor)74 (,)37.1 ( is chemically described as)-25 ( )]TJ 0.016 Tc -0.016 Tw 0 -1.064 Td [(1-\(4)0.5 (-metho)0.5 (xyphe)0.5 (n)-9.6 (yl\)-7-)0.5 (oxo-6)0.5 (-[4-\(2-)0.5 (oxop)0.5 (ip)0.5 (eridi)0.5 (n-1-yl\)p)0.5 (hen)-9.6 (yl])0.5 (-4,5,6)0.5 (,7-te)0.5 (trahydr)0.5 (o-)]TJ 0 Tc 0 Tw 0 -1.064 Td (1)Tj /T1_3 1 Tf 0.455 0 Td (H)Tj /T1_1 1 Tf -0.025 Tc 0.025 Tw 0.512 0 Td (-pyrazolo[3,4-)Tj /T1_3 1 Tf 0 Tc 0 Tw (c)Tj /T1_1 1 Tf -0.025 Tc 0.786 Tw 5.304 0 Td [(]pyridine-3-carboxamide.)37 ( Its molecular formula is C)]TJ 0.025 Tw 5.2 0 0 5.2 259.5882 368.0258 Tm (25)Tj 0 Tc 0 Tw 8 0 0 8 264.3201 368.6259 Tm (H)Tj -0.025 Tc 0.025 Tw 5.2 0 0 5.2 268.416 368.0258 Tm (25)Tj 0 Tc 0 Tw 8 0 0 8 273.148 368.6259 Tm (N)Tj 5.2 0 0 5.2 277.396 368.0258 Tm (5)Tj 8 0 0 8 279.762 368.6259 Tm (O)Tj 5.2 0 0 5.2 284.0099 368.0258 Tm (4)Tj -0.037 Tc 0.037 Tw 8 0 0 8 286.3759 368.6259 Tm (, )Tj 0 Tc 0 Tw 0.203 0 Td ( )Tj -0.025 Tc 0.405 Tw -31.5 -1.064 Td [(which corresponds to a molecular weight of 459.5.)37 ( )37.1 (A)-10 (pixaban has the follo)-10 (wing)-25 ( )]TJ 0 Tc 0 Tw 31.5 0 Td ( )Tj -0.025 Tc 0.084 Tw -31.5 -1.064 Td (structural formula:)Tj ET /PlacedGraphic /MC0 BDC EMC /GS0 gs q 1 0 0 1 159.7011 308.2305 cm 0 0 m 1.063 0 l 3.092 -3.234 l 3.105 -3.234 l 3.105 0 l 4.106 0 l 4.106 -4.821 l 3.037 -4.821 l 1.015 -1.593 l 1.001 -1.593 l 1.001 -4.821 l 0 -4.821 l h f Q 0.75 w 1 j q 1 0 0 1 140.6406 318.0933 cm 0 0 m 0 -12.097 l -1.704 -1.154 m -1.704 -10.831 l 0 -12.097 m 10.504 -18.089 l 10.504 -18.089 m 16.887 -14.423 l 21.007 -8.952 m 21.007 0 l 21.007 0 m 10.504 6.104 l 10.504 6.104 m 0 0 l S Q q 1 0 0 1 119.9914 314.2225 cm 0 0 m 1.062 0 l 3.092 -3.234 l 3.105 -3.234 l 3.105 0 l 4.106 0 l 4.106 -4.821 l 3.037 -4.821 l 1.014 -1.593 l 1.001 -1.593 l 1.001 -4.821 l 0 -4.821 l h f Q q 1 0 0 1 127.0868 304.4527 cm 0 0 m 1.062 0 l 3.092 -3.234 l 3.105 -3.234 l 3.105 0 l 4.106 0 l 4.106 -4.821 l 3.037 -4.821 l 1.014 -1.593 l 1.001 -1.593 l 1.001 -4.821 l 0 -4.821 l h f Q q 1 0 0 1 140.6406 318.0933 cm 0 0 m -11.59 3.778 l -11.59 3.778 m -16.345 -2.774 l -10.878 1.805 m -14.903 -3.76 l -16.083 -9.584 m -14.024 -12.45 l -7.826 -14.61 m 0 -12.097 l 24.53 -14.07 m 31.526 -18.089 l 31.526 -18.089 m 42.032 -12.004 l 33.142 -19.076 m 42.032 -13.884 l 31.526 -18.089 m 31.526 -30.186 l 31.526 -30.186 m 41.942 -36.29 l 33.142 -29.219 m 41.942 -34.318 l 41.942 -36.29 m 52.463 -30.186 l 52.463 -30.186 m 52.463 -18.089 l 50.832 -29.219 m 50.832 -19.076 l 52.463 -18.089 m 41.942 -12.097 l -30.817 -26.967 m -18.685 -26.967 l -29.825 -28.679 m -19.678 -28.679 l -18.685 -26.967 m -14.192 -19.895 l -30.817 -26.967 m -36.828 -37.463 l -36.828 -37.463 m -30.817 -47.941 l -34.936 -37.463 m -29.825 -46.228 l -30.817 -47.941 m -18.685 -47.941 l -18.685 -47.941 m -12.582 -37.463 l -19.678 -46.228 m -14.547 -37.463 l -12.582 -37.463 m -18.685 -26.967 l S Q q 1 0 0 1 89.9955 261.8907 cm 0 0 m 1.069 0 l 1.069 -1.85 l 3.037 -1.85 l 3.037 0 l 4.106 0 l 4.106 -4.82 l 3.037 -4.82 l 3.037 -2.741 l 1.069 -2.741 l 1.069 -4.82 l 0 -4.82 l h f Q q 36 253.499 252 95.502 re W n q 1 0 0 1 95.4751 256.4637 cm 0 0 m 0.242 -0.02 0.592 0.028 0.592 0.343 c 0.592 0.575 0.405 0.709 0.199 0.709 c -0.083 0.709 -0.234 0.5 -0.23 0.217 c -0.766 0.217 l -0.746 0.78 -0.377 1.17 0.195 1.17 c 0.639 1.17 1.128 0.898 1.128 0.406 c 1.128 0.146 0.997 -0.086 0.739 -0.158 c 0.739 -0.165 l 1.044 -0.233 1.231 -0.484 1.231 -0.791 c 1.231 -1.37 0.743 -1.697 0.199 -1.697 c -0.425 -1.697 -0.846 -1.327 -0.834 -0.693 c -0.298 -0.693 l -0.286 -0.992 -0.135 -1.236 0.191 -1.236 c 0.445 -1.236 0.643 -1.063 0.643 -0.803 c 0.643 -0.385 0.274 -0.393 0 -0.393 c h f Q q 1 0 0 1 100.4877 260.2708 cm 0 0 m -0.068 0.479 -0.531 0.844 -1.062 0.844 c -2.023 0.844 -2.383 0.034 -2.383 -0.811 c -2.383 -1.614 -2.023 -2.424 -1.062 -2.424 c -0.409 -2.424 -0.041 -1.979 0.041 -1.344 c 1.076 -1.344 l 0.967 -2.546 0.129 -3.316 -1.062 -3.316 c -2.567 -3.316 -3.452 -2.201 -3.452 -0.811 c -3.452 0.621 -2.567 1.735 -1.062 1.735 c 0.007 1.735 0.906 1.114 1.035 0 c h f Q q 1 0 0 1 104.4695 257.8467 cm 0 0 m 0.96 0 1.321 0.81 1.321 1.613 c 1.321 2.458 0.96 3.268 0 3.268 c -0.96 3.268 -1.321 2.458 -1.321 1.613 c -1.321 0.81 -0.96 0 0 0 c 0 4.159 m 1.505 4.159 2.39 3.045 2.39 1.613 c 2.39 0.223 1.505 -0.892 0 -0.892 c -1.505 -0.892 -2.39 0.223 -2.39 1.613 c -2.39 3.045 -1.505 4.159 0 4.159 c f Q q 1 0 0 1 109.8236 270.1526 cm 0 0 m -4.4 -7.519 l S Q q 1 0 0 1 103.4225 336.368 cm 0 0 m 1.069 0 l 1.069 -1.85 l 3.037 -1.85 l 3.037 0 l 4.106 0 l 4.106 -4.821 l 3.037 -4.821 l 3.037 -2.741 l 1.069 -2.741 l 1.069 -4.821 l 0 -4.821 l h f Q q 1 0 0 1 108.1438 330.9964 cm 0 0 m -0.02 0.63 0.342 1.114 1.009 1.114 c 1.517 1.114 1.962 0.791 1.962 0.252 c 1.962 -0.162 1.739 -0.39 1.466 -0.583 c 1.191 -0.776 0.866 -0.933 0.663 -1.217 c 1.978 -1.217 l 1.978 -1.697 l -0.063 -1.697 l -0.059 -1.059 0.334 -0.787 0.814 -0.465 c 1.06 -0.3 1.394 -0.13 1.398 0.209 c 1.398 0.468 1.223 0.634 0.981 0.634 c 0.647 0.634 0.54 0.291 0.54 0 c h f Q q 1 0 0 1 110.6735 336.368 cm 0 0 m 1.062 0 l 3.092 -3.234 l 3.105 -3.234 l 3.105 0 l 4.106 0 l 4.106 -4.821 l 3.037 -4.821 l 1.014 -1.593 l 1.001 -1.593 l 1.001 -4.821 l 0 -4.821 l h f Q q 1 0 0 1 129.0511 321.8712 cm 0 0 m -4.849 11.017 l -4.849 11.017 m -13.48 12.261 l S Q q 1 0 0 1 131.2505 340.8336 cm 0 0 m 0.96 0 1.321 0.81 1.321 1.614 c 1.321 2.458 0.96 3.268 0 3.268 c -0.96 3.268 -1.321 2.458 -1.321 1.614 c -1.321 0.81 -0.96 0 0 0 c 0 4.159 m 1.505 4.159 2.39 3.045 2.39 1.614 c 2.39 0.223 1.505 -0.891 0 -0.891 c -1.505 -0.891 -2.39 0.223 -2.39 1.614 c -2.39 3.045 -1.505 4.159 0 4.159 c f Q q 1 0 0 1 123.2097 332.985 cm 0 0 m 5.037 6.885 l 1.348 -0.991 m 6.385 5.895 l S Q q 1 0 0 1 151.0967 285.9854 cm 0 0 m 0.96 0 1.321 0.81 1.321 1.614 c 1.321 2.458 0.96 3.268 0 3.268 c -0.96 3.268 -1.321 2.458 -1.321 1.614 c -1.321 0.81 -0.96 0 0 0 c 0 4.159 m 1.505 4.159 2.39 3.045 2.39 1.614 c 2.39 0.223 1.505 -0.891 0 -0.891 c -1.505 -0.891 -2.39 0.223 -2.39 1.614 c -2.39 3.045 -1.505 4.159 0 4.159 c f Q q 1 0 0 1 151.9492 300.4508 cm 0 0 m 0 -9.324 l -1.704 0 m -1.704 -9.324 l S Q q 1 0 0 1 201.6367 284.0189 cm 0 0 m 1.063 0 l 3.092 -3.234 l 3.106 -3.234 l 3.106 0 l 4.106 0 l 4.106 -4.821 l 3.038 -4.821 l 1.015 -1.593 l 1.001 -1.593 l 1.001 -4.821 l 0 -4.821 l h f Q q 1 0 0 1 193.1039 287.9073 cm 0 0 m 6.816 -3.946 l S Q q 1 0 0 1 214.0582 298.0821 cm 0 0 m 0.961 0 1.322 0.81 1.322 1.614 c 1.322 2.458 0.961 3.268 0 3.268 c -0.959 3.268 -1.32 2.458 -1.32 1.614 c -1.32 0.81 -0.959 0 0 0 c 0 4.159 m 1.505 4.159 2.391 3.045 2.391 1.614 c 2.391 0.223 1.505 -0.891 0 -0.891 c -1.504 -0.891 -2.389 0.223 -2.389 1.614 c -2.389 3.045 -1.504 4.159 0 4.159 c f Q Q q 89.995 254.768 135.008 90.226 re W n q 1 0 0 1 207.2017 283.8687 cm 0 0 m 6.906 4.039 l 6.103 3.499 m 6.103 12.097 l 7.808 3.499 m 7.808 12.097 l 6.906 4.039 m 17.502 -2.159 l -3.6 -6.104 m -3.6 -14.162 l -3.6 -14.162 m 6.906 -20.173 l 6.906 -20.173 m 17.427 -14.162 l 17.427 -14.162 m 17.427 -2.065 l S Q Q BT /GS1 gs 0.12 Tw 8 0 0 8 35.704 242.3586 Tm [(A)-10 (pixaban is a white to pale-yello)-9.9 (w po)-10 (wder)74 (.)37.1 ( )37.2 (At physiological pH \(1.2-6.8\),)37 ( a)-10 (pixaban does)-25 ( 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tablets\).)Tj 0.053 Tw -14.984 -1.514 Td [(ELIQUIS 0.5 mg \037lm coa)-9.9 (ted tablets for oral suspension are supplied in packets containing)-25 ( )]TJ 0.019 Tw 0 -1.064 Td [(1 )0.5 (\(0.5 )0.5 (mg\),)37 ( )0.5 (3 )0.5 (\(1.5 )0.5 (mg\) )0.5 (or 4 )0.5 (\(2 )0.5 (mg\) )0.5 (a)-10 (pixaban )0.5 (tablets.)37 ( )37.5 (The )0.5 (inactive )0.5 (ingredients )0.5 (are )0.5 (anhydrous)-25 ( )]TJ 0.281 Tw 0 -1.064 Td [(lactose,)37 ( microcr)-18 (ystalline cellulose,)37 ( croscarmellose sodium,)37 ( sodium laur)-17.9 (yl sulfa)-10 (te,)37 ( and)-25 ( )]TJ 0.325 Tw 0 -1.064 Td [(ma)-10 (gnesium steara)-9.9 (te.)37 ( )36.9 (The \037lm coa)-10 (ting contains lactose monohydra)-10 (te,)37.1 ( hypromellose,)12 ( )]TJ 0.084 Tw 0 -1.064 Td [(titanium dioxide,)37 ( triacetin,)37 ( and red iron oxide.)]TJ 0.034 Tw 0 -1.514 Td [(ELIQUIS SPRINKLE 0.15 mg for oral suspension is supplied as a white to o\ ff-white po)-10 (wder)-25 ( )]TJ 0.238 Tw 0 -1.064 Td [(in ca)-10 (psules,)37 ( which contain 0.15 mg 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thrombin genera)-10 (tion and)-25 ( )]TJ 0.084 Tw 0 -1.064 Td (thrombus development.)Tj ET endstream endobj 299 0 obj <> endobj 334 0 obj <>stream 2012-12-27T23:12:02-05:00 2012-12-27T23:12:02-05:00 2012-12-27T23:12:02-05:00 Adobe Illustrator CS5.1 application/postscript Illus Deluca, Donna xmp.did:F77F1174072068118083DC136F68E070 xmp.iid:F77F1174072068118083DC136F68E070 uuid:6e7a437c-6b89-854f-946b-1a074cee0d85 proof:pdf uuid:7c782396-3dc8-ad4c-aa02-021f484fddd9 xmp.did:FA7F1174072068118083C5125A16E0BC uuid:6e7a437c-6b89-854f-946b-1a074cee0d85 proof:pdf saved xmp.iid:F77F1174072068118083C5125A16E0BC 2012-12-27T22:56:46-05:00 Adobe Illustrator CS5.1 / saved xmp.iid:F87F1174072068118083C5125A16E0BC 2012-12-27T22:57:39-05:00 Adobe Illustrator CS5.1 / saved xmp.iid:F97F1174072068118083C5125A16E0BC 2012-12-27T22:57:48-05:00 Adobe Illustrator CS5.1 / saved xmp.iid:FA7F1174072068118083C5125A16E0BC 2012-12-27T23:00:57-05:00 Adobe Illustrator CS5.1 / saved 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indica)-10 (ting tha)-9.9 (t)-25 ( )]TJ 0.049 Tw 0 -1.062 Td [(a)-10 (pixaban can accumula)-9.9 (te in milk.)37.1 ( )37.3 (The concentra)-10 (tions of a)-10 (pixaban in animal milk does not)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(necessarily predict the concentra)-9.9 (tion of drug in human milk.)]TJ /T1_2 1 Tf 0.025 Tw 0 -1.58 Td (8.3)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td [(F)20 (emales and Males of Reproductive P)24 (otential)]TJ /T1_0 1 Tf 0.258 Tw -3.375 -1.512 Td [(F)24 (emales of reproductive potential requiring anticoa)-10 (gula)-10 (tion should discuss pregnanc)20 (y)-25 ( )]TJ 0.084 Tw 0 -1.062 Td (planning with their physician.)Tj 0.339 Tw 0 -1.513 Td [(The )0.6 (risk )0.5 (of )0.6 (c)19.9 (linically )0.5 (signi\037cant )0.5 (uterine )0.5 (bleeding,)37 ( )0.5 (potentially )0.5 (requiring )0.5 (g)-10 (ynecological)-25 ( )]TJ 0.249 Tw 0 -1.062 Td [(surgical inter)-18 (ventions,)37 ( identi\037ed with oral anticoa)-9.9 (gulants inc)20 (luding ELIQUIS should be)-24.9 ( )]TJ 0.084 Tw 0 -1.062 Td (assessed in females of reproductive potential and those with abnormal ut\ erine bleeding.)Tj /T1_2 1 Tf 0.025 Tw 0 -1.85 Td (8.4)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td [(P)24 (ediatric Use)]TJ /T1_0 1 Tf 0.167 Tw -3.375 -1.512 Td [(The safety and effectiveness of ELIQUIS for the trea)-10 (tment of )37 (VTE and the reduction in)-25 ( )]TJ 0.068 Tw 0 -1.062 Td [(the risk of recurrent )36.6 (VTE ha)-10 (ve been established in pedia)-9.9 (tric pa)-9.9 (tients a)-9.9 (ged birth and older)74 (.)12.1 ( )]TJ 0 Tc 0 Tw 31.5 0 Td ( )Tj -0.025 Tc 0.387 Tw -31.5 -1.062 Td [(Use of ELIQUIS for this indica)-9.9 (tion is supported by evidence from adequa)-10 (te and)-25 ( )]TJ 0 Tc 0 Tw 31.5 0 Td ( )Tj -0.025 Tc 0.058 Tw -31.5 -1.062 Td [(well-controlled studies in adults with additional pharmacokinetic,)37 ( safety)55 (,)37 ( and ef\037cac)20 (y da)-10 (ta)-25 ( )]TJ 0.12 Tw 0 -1.062 Td [(in pedia)-10 (tric pa)-10 (tients.)37 ( )36.9 (These studies inc)20 (luded a randomized,)37 ( active controlled,)37 ( open label,)12 ( )]TJ 0.084 Tw 0 -1.062 Td [(multi-center stud)-10 (y of ELIQUIS )]TJ /T1_1 1 Tf 0 Tc 0 Tw ([)Tj 10.917 0 Td (s)Tj -0.025 Tc 0.047 Tw 0.382 0 Td (ee Adver)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.084 Tw 3.466 0 Td (e Reaction)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.084 Tw 4.103 0 Td ( \(6.1\) and Clinical Studie)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.084 Tw 9.081 0 Td ( \(14.4\)])Tj /T1_0 1 Tf 0 Tc 0 Tw (.)Tj /T1_2 1 Tf -0.025 Tc 0.025 Tw -27.948 -1.58 Td (8.5)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td (Geriatric Use)Tj /T1_0 1 Tf 0.262 Tw -3.375 -1.512 Td [(Of the total subjects in the )36.7 (ARISTOTLE and )36.7 (A)20 (VERROES c)19.9 (linical studies,)37 ( >69% were)-25 ( )]TJ 0.061 Tw 0 -1.062 Td (65)Tj /Span< >> BDC ( )Tj EMC 1.123 0 Td [(years of a)-10 (ge and older)74 (,)37 ( and >31% were 75)]TJ /Span< >> BDC ( )Tj EMC 15.511 0 Td [(years of a)-10 (ge and older)74 (.)37 ( In the )37.3 (ADV)37 (ANCE-1,)12 ( )]TJ 0.235 Tw -16.634 -1.062 Td [(ADV)37 (ANCE-2,)37 ( and )37.4 (ADV)37 (ANCE-3 c)20 (linical studies,)37 ( 50% of subjects were 65)]TJ /Span< >> BDC ( )Tj EMC 26.765 0 Td [(years of a)-10 (ge)-24.9 ( )]TJ 0.102 Tw -26.765 -1.062 Td [(and older)74 (,)37 ( while 16% were 75)]TJ /Span< >> BDC ( )Tj EMC 11.046 0 Td [(years of a)-10 (ge and older)74 (.)37 ( In the )37.2 (AMPLIFY and )37.2 (AMPLIFY)74 (-EXT)-25 ( )]TJ 0.231 Tw -11.046 -1.062 Td [(c)20 (linical studies,)37 ( >32% of subjects were 65)]TJ /Span< >> BDC ( )Tj EMC 16.278 0 Td [(years of )0.5 (a)-10 (ge )0.5 (and older )0.5 (and >13% were)-24.9 ( )]TJ 0.14 Tw -16.278 -1.062 Td (75)Tj /Span< >> BDC ( )Tj EMC 1.123 0 Td [(years of a)-9.9 (ge and older)74 (.)37 ( )0.5 (No c)20.1 (linically )0.5 (signi\037cant )0.5 (differences )0.5 (in )0.5 (safety or effectiveness)-25 ( )]TJ 0.084 Tw -1.123 -1.062 Td [(were obser)-17.9 (ved when comparing subjects in different a)-9.9 (ge groups.)]TJ /T1_2 1 Tf 0.025 Tw 0 -1.85 Td (8.6)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td (Renal Impairment)Tj /T1_3 1 Tf 0.045 Tw -3.375 -1.737 Td [(Reduction of Risk of Strok)6 (e and Systemic Embolism in Patients with Nonv)12 (alvular )36.8 (Atrial)-25 ( )]TJ 0.025 Tw 0 -1.062 Td (Fibrillation)Tj /T1_0 1 Tf 0.032 Tw 0 -1.288 Td (The recommended dose is 2.5)Tj /Span< >> BDC ( )Tj EMC 10.895 0 Td [(mg twice daily in pa)-9.9 (tients with a)-9.9 (t least two of the follo)-10 (wing)-25 ( )]TJ 0 Tc 0 Tw 20.605 0 Td ( )Tj -0.025 Tc 0.025 Tw -31.5 -1.062 Td (characteristics )Tj /T1_1 1 Tf 0 Tc 0 Tw 5.329 0 Td ([)Tj 0.234 0 Td (s)Tj -0.025 Tc 0.084 Tw 0.382 0 Td (ee Do)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.047 Tw 2.469 0 Td [(a)-10 (ge )-37 (and Admini)]TJ 0 Tc 0 Tw (s)Tj -0.025 Tc 0.084 Tw 5.93 0 Td [(tra)-9.9 (tion \(2.1\)])]TJ /T1_0 1 Tf 0 Tc 0 Tw (:)Tj -0.025 Tc 0.025 Tw -14.344 -1.512 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.625 0 Td [(a)-10 (ge grea)-10 (ter than or equal to 80)]TJ /Span< >> BDC ( )Tj EMC 11.449 0 Td (years)Tj 0.025 Tw -13.074 -1.512 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.625 0 Td [(bod)-10 (y weight less than or equal to 60)]TJ /Span< >> BDC ( )Tj EMC 13.36 0 Td (kg)Tj 0.025 Tw -14.985 -1.512 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.625 0 Td [(serum crea)-9.9 (tinine grea)-10 (ter than or equal to 1.5)]TJ /Span< >> BDC ( )Tj EMC 16.291 0 Td (mg/dL)Tj /T1_4 1 Tf -17.916 -1.737 Td (Patients with End-Stage Renal Disease on Dialysis)Tj /T1_0 1 Tf 0.161 Tw 0 -1.288 Td [(Clinical ef\037cac)20.1 (y and safety studies with ELIQUIS did not enroll pa)-9.9 (tients with end-sta)-10 (ge)-25 ( )]TJ 0.303 Tw 0 -1.062 Td [(renal )0.5 (disease )0.5 (\(ESRD\) )0.5 (on )0.6 (dialysis.)37.1 ( )0.5 (In )0.5 (pa)-10 (tients )0.5 (with )0.5 (ESRD )0.5 (maintained )0.5 (on )0.5 (intermittent)-25 ( )]TJ 0.138 Tw 0 -1.062 Td [(hemodialysis,)37 ( administra)-9.9 (tion )0.5 (of )0.5 (ELIQUIS )0.5 (a)-10 (t )0.5 (the )0.5 (usually )0.5 (recommended dose )]TJ /T1_1 1 Tf 0 Tc 0 Tw ([)Tj 27.285 0 Td (s)Tj -0.025 Tc 0.138 Tw 0.382 0 Td [(ee )0.5 (Do)]TJ 0 Tc 0 Tw (s)Tj -0.025 Tc 0.025 Tw 2.523 0 Td [(a)-10 (ge)-24.9 ( )]TJ 0.056 Tw -30.189 -1.062 Td (and Admini)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.093 Tw 4.354 0 Td [(tra)-9.9 (tion \(2.1\)])]TJ /T1_0 1 Tf [( will result in concentra)-10 (tions of a)-9.9 (pixaban and pharmacod)-10 (ynamic)-25 ( )]TJ 0.214 Tw -4.354 -1.062 Td [(activity similar to those obser)-18 (ved in the )36.8 (ARISTOTLE stud)-10 (y )]TJ /T1_1 1 Tf 0 Tc 0 Tw ([)Tj 21.982 0 Td (s)Tj -0.025 Tc 0.214 Tw 0.382 0 Td (ee Clinical)Tj [( Pharmacolog)-9.9 (y)-25 ( )]TJ 0.025 Tw -22.364 -1.062 Td (\(12.3\)])Tj /T1_0 1 Tf 0.081 Tw [(.)37 ( It is not kno)-10 (wn whether these concentra)-10 (tions will lead to similar stroke reduction)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(and bleeding risk in pa)-10 (tients with ESRD on dialysis as was seen in )37 (ARISTOTLE.)]TJ /T1_3 1 Tf 0.203 Tw 0 -1.737 Td [(Proph)6.1 (ylaxis of Deep )36.8 (V)18 (ein )36.8 (Thrombosis Follo)6 (wing Hip or Knee Replacement Sur)6 (ger)-18 (y)74 (,)12 ( )]TJ 0.07 Tw 0 -1.062 Td [(and )36.6 (T)74 (r)6 (eatment of DVT and PE and Reduction in the Risk of Recurr)6 (ence of DVT and PE)]TJ /T1_0 1 Tf 0.089 Tw 0 -1.288 Td [(No dose adjustment is recommended for pa)-9.9 (tients with renal impairment,)37 ( inc)20 (luding those)-24.9 ( )]TJ 0.108 Tw 0 -1.062 Td (with ESRD on dialysis )Tj /T1_1 1 Tf 0 Tc 0 Tw ([)Tj 8.332 0 Td (s)Tj -0.025 Tc 0.108 Tw 0.382 0 Td (ee Do)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.071 Tw 2.493 0 Td [(a)-10 (ge )-36.7 (and Admini)]TJ 0 Tc 0 Tw (s)Tj -0.025 Tc 0.108 Tw 5.977 0 Td [(tra)-9.9 (tion \(2.1\)])]TJ /T1_0 1 Tf [(.)37 ( Clinical ef\037cac)20 (y and safety)-25 ( )]TJ 0.204 Tw -17.184 -1.062 Td [(studies with ELIQUIS did not enroll pa)-10 (tients with ESRD on dialysis or pa)-9.9 (tients with a)-25 ( )]TJ 0.05 Tw 0 -1.062 Td [(CrCl <15 mL/min; therefore,)37 ( dosing recommenda)-10 (tions are based on pharmacokinetic and)-25 ( )]TJ 0.145 Tw 0 -1.062 Td [(pharmacod)-10 (ynamic \(anti-FXa activity\) da)-10 (ta in subjects with ESRD maintained on dialysis)-25 ( )]TJ /T1_1 1 Tf 0 Tc 0 Tw 0 -1.062 Td ([)Tj 0.234 0 Td (s)Tj -0.025 Tc 0.084 Tw 0.382 0 Td (ee Clinical)Tj [( Pharmacolog)-9.9 (y \(12.3\)])]TJ /T1_0 1 Tf 0 Tc 0 Tw (.)Tj /T1_3 1 Tf -0.025 Tc 0.097 Tw -0.616 -1.737 Td [(T)74 (r)6 (eatment )0.5 (of )37.5 (V)18 (enous )37.5 (Thromboembolism )0.5 (\(VTE\) )0.5 (and )0.5 (Reduction )0.5 (in )0.5 (the )0.5 (Risk )0.5 (of )0.5 (Recurr)6 (ent)-25 ( )]TJ 0.084 Tw 0 -1.062 Td (VTE in Pediatric Patients)Tj /T1_0 1 Tf 0.052 Tw 0 -1.288 Td [(In pedia)-10 (tric pa)-9.9 (tients equal to or grea)-9.9 (ter than 2 years of a)-10 (ge,)37 ( ELIQUIS is not recommended)-25 ( )]TJ 0.072 Tw 0 -1.062 Td [(in pa)-10 (tients with an estima)-9.9 (ted glomerular \037ltra)-10 (tion ra)-10 (te \(eGFR\) <30 mL/min/1.73 m)]TJ 0 Tc 0 Tw 5.98 0 0 5.98 557.2985 178.2781 Tm (2)Tj -0.025 Tc 0.072 Tw 8 0 0 8 560.0193 176.7681 Tm [( bod)-10 (y)-25 ( )]TJ 0.084 Tw -29.502 -1.062 Td (surface area \(BSA\).)Tj 0.25 Tw 0 -1.512 Td [(In )0.5 (pa)-10 (tients )0.5 (less )0.5 (than )0.5 (2 )0.5 (years of )0.5 (a)-10 (ge,)37 ( )0.5 (ELIQUIS )0.5 (is )0.5 (not recommended )0.5 (in )0.5 (pa)-10 (tients with)-25 ( )]TJ 0.094 Tw 0 -1.062 Td [(inadequa)-10 (te renal function de\037ned by sex and postna)-10 (tal a)-9.9 (ge as used in the pedia)-10 (tric )37.2 (VTE)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(trial for ELIQUIS \(see )37 (T)74 (able 12 belo)-10 (w\).)]TJ 0.105 Tw 0 -1.512 Td [(T)74 (o estima)-10 (te GFR,)37 ( the pedia)-10 (tric )37.1 (VTE trial for ELIQUIS used the upda)-10 (ted Schwartz formula,)12 ( )]TJ 0.032 Tw 0 -1.062 Td (eGFR \(ml/min/1.73m)Tj 0 Tc 0 Tw 5.98 0 0 5.98 382.2379 120.0781 Tm (2)Tj -0.025 Tc 0.032 Tw /Span< >> BDC 8 0 0 8 384.9587 118.5681 Tm ( )Tj EMC 0.017 0 Td (\))Tj /Span< >> BDC ( )Tj EMC 0.316 0 Td (=)Tj /Span< >> BDC ( )Tj EMC 0.675 0 Td [(0.413* height \(cm\)/serum crea)-10 (tinine \(mg/dL\) for serum crea)-10 (tinine)-25 ( )]TJ 0 Tc 0 Tw 22.872 0 Td ( )Tj -0.025 Tc 0.282 Tw -31.5 -1.062 Td [(measured by an enzyma)-10 (tic crea)-10 (tinine method calibra)-10 (ted to be traceable to isotope)-24.9 ( )]TJ 0.084 Tw 0 -1.062 Td [(dilution mass spectrometr)-18 (y \(IDMS\).)]TJ ET q 1 0 0 1 36 486.8281 cm 0 0 m 41.551 0 l S Q q 1 0 0 1 36 355.2281 cm 0 0 m 63.303 0 l S Q q 1 0 0 1 36 342.2581 cm 0 0 m 151.692 0 l S Q q 1 0 0 1 36 289.8581 cm 0 0 m 92.046 0 l S Q q 1 0 0 1 36 254.4581 cm 0 0 m 47.911 0 l S Q q 1 0 0 1 36 203.288 cm 0 0 m 13.104 0 l S Q q 1 0 0 1 36 190.3181 cm 0 0 m 34.791 0 l S Q q 1 0 0 1 36 74.608 cm 0 0 m 41.551 0 l S Q BT /T1_2 1 Tf 0.025 Tw 8 0 0 8 36 727.2481 Tm (7.2)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td (Combined P-gp and Strong CYP3A4 Inducers)Tj /T1_0 1 Tf 0.232 Tw -3.375 -1.512 Td [(Avoid concomitant use of ELIQUIS with combined P-gp and strong CYP3A4 in\ ducers)-25 ( )]TJ 0 Tc 0 Tw 31.5 0 Td ( )Tj -0.025 Tc 0.295 Tw -31.5 -1.062 Td [(\(e.g.,)37 ( rifampin,)37 ( carbamazepine,)37 ( phen)-10 (ytoin,)37 ( St.)37 ( John\222)55 (s wort\) because such drugs will)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(decrease exposure to a)-9.9 (pixaban )]TJ /T1_1 1 Tf 0 Tc 0 Tw ([)Tj 11.559 0 Td (s)Tj -0.025 Tc 0.084 Tw 0.382 0 Td (ee Clinical)Tj [( Pharmacolog)-9.9 (y \(12.3\)])]TJ /T1_0 1 Tf 0 Tc 0 Tw (.)Tj -0.025 Tc 0.106 Tw -11.941 -1.512 Td [(A)-10 (pixaban is a substra)-10 (te of both CYP3A4 and P-gp.)37 ( Concomitant use with drugs tha)-9.9 (t are)-25 ( )]TJ 0.034 Tw 0 -1.062 Td [(combined P-gp and strong CYP3A4 inducers decreases exposure to a)-10 (pixaban )]TJ /T1_1 1 Tf 0 Tc 0 Tw ([)Tj 27.538 0 Td (s)Tj -0.025 Tc 0.034 Tw 0.382 0 Td (ee Clinical)Tj 0 Tc 0 Tw 3.58 0 Td ( )Tj -0.025 Tc 0.261 Tw -31.5 -1.062 Td [(Pharmacolog)-10 (y \(12.3\)])]TJ /T1_0 1 Tf [( which increases the risk for stroke and other thromboembolic)-25 ( )]TJ 0.025 Tw 0 -1.062 Td (events.)Tj /T1_2 1 Tf 0 -1.85 Td (7.3)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td (Anticoagulants and Antiplatelet Agents)Tj /T1_0 1 Tf 0.145 Tw -3.375 -1.512 Td [(Coadministra)-10 (tion of antipla)-9.9 (telet a)-10 (gents,)37 ( \037brinolytics,)37 ( heparin,)37 ( aspirin,)37 ( and chronic NSAID)-25 ( )]TJ 0.084 Tw 0 -1.062 Td (use increases the risk of bleeding.)Tj 0.044 Tw 0 -1.512 Td [(APPRAISE-2,)37 ( a placebo-controlled c)20 (linical trial of ELIQUIS in high-risk,)37 ( post-acute coronar)-18 (y)-25 ( )]TJ 0.067 Tw 0 -1.062 Td [(syndrome pa)-10 (tients trea)-9.9 (ted with aspirin or the combina)-10 (tion of aspirin and c)20 (lopidogrel,)37 ( was)-25 ( )]TJ 0.193 Tw 0 -1.062 Td [(termina)-10 (ted early due to a higher ra)-9.9 (te of bleeding with ELIQUIS compared to placebo.)12 ( )]TJ 0.105 Tw 0 -1.062 Td [(The ra)-10 (te of ISTH major bleeding was 2.8% per year with ELIQUIS versus 0.6% per\ year)-25 ( )]TJ 0.068 Tw 0 -1.062 Td [(with placebo in pa)-10 (tients receiving single antipla)-10 (telet thera)-10 (py and was 5.9% per year with)-25.1 ( )]TJ 0.084 Tw 0 -1.062 Td [(ELIQUIS versus 2.5% per year with placebo in those receiving dual antipl\ a)-10 (telet thera)-10 (py)55 (.)]TJ 0.16 Tw 0 -1.512 Td [(In )36.6 (ARISTOTLE,)37 ( concomitant use of aspirin increased the bleeding risk on ELIQUIS from)-24.9 ( )]TJ 0.112 Tw 0 -1.062 Td [(1.8% per year to 3.4% per year and concomitant use of aspirin and warfar\ in increased)-25 ( )]TJ 0.159 Tw 0 -1.062 Td [(the bleeding risk from 2.7% per year to 4.6% per year)74 (.)37 ( In this c)20 (linical trial,)37 ( there was)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(limited \(2.3%\) use of dual antipla)-10 (telet thera)-10 (py with ELIQUIS.)]TJ /T1_2 1 Tf 0.025 Tw 0 -2.413 Td (8)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td [(USE IN SPECIFIC POPULA)55 (TIONS)]TJ 0.025 Tw -3.375 -1.648 Td (8.1)Tj /Span< >> BDC ( )Tj EMC 3.375 0 Td [(Pregnanc)10 (y)]TJ /T1_0 1 Tf 0.084 Tw -3.375 -1.58 Td [(Risk Summar)-17.9 (y)]TJ 0.123 Tw 0 -1.512 Td [(The limited a)-10 (vailable da)-10 (ta on ELIQUIS use in pregnant women are insuf\037cient to inform)-25 ( )]TJ 0.292 Tw 0 -1.062 Td [(drug-associa)-9.9 (ted risks of major birth defects,)37 ( miscarria)-10 (ge,)37 ( or adverse developmental)-25 ( )]TJ 0.16 Tw 0 -1.062 Td [(outcomes.)37 ( )37.1 (T)74 (rea)-10 (tment may increase the risk of bleeding during pregnanc)20 (y and deliver)-18 (y)55 (.)12 ( )]TJ 0.307 Tw 0 -1.062 Td [(In animal reproduction studies,)37 ( no adverse developmental effects were seen when)-25 ( )]TJ 0.068 Tw 0 -1.062 Td [(a)-10 (pixaban was administered to ra)-10 (ts \(orally\),)37 ( rabbits \(intra)-10 (venously\) and mice \(orally\) during)-25 ( )]TJ 0.039 Tw 0 -1.062 Td [(organogenesis a)-10 (t unbound a)-10 (pixaban exposure levels up to 4,)37 ( 1 and 19 times,)37 ( respectively)55 (,)12.1 ( )]TJ 0.086 Tw 0 -1.062 Td [(the human exposure based on area under plasma-concentra)-10 (tion time cur)-18 (ve \(AUC\) a)-10 (t the)-25 ( )]TJ 0.084 Tw 0 -1.062 Td (Maximum Recommended Human Dose \(MRHD\) of 5)Tj /Span< >> BDC ( )Tj EMC 18.787 0 Td [(mg twice daily)55 (.)]TJ 0.127 Tw -18.787 -1.512 Td [(The estima)-10 (ted background risk of major birth defects and miscarria)-10 (ge for the indica)-9.9 (ted)-25 ( )]TJ 0.113 Tw 0 -1.062 Td [(popula)-10 (tions is unkno)-10 (wn.)37 ( )37.3 (All pregnancies ha)-9.9 (ve a background risk of birth defect,)37 ( loss,)37 ( or)-25 ( )]TJ 0.153 Tw 0 -1.062 Td [(other adverse outcomes.)37 ( In the U.S.)37 ( general popula)-10 (tion,)37 ( the estima)-9.9 (ted background risk)-25 ( )]TJ 0.11 Tw 0 -1.062 Td [(of )0.5 (major )0.5 (birth )0.5 (defects )0.5 (and )0.5 (miscarria)-10 (ge )0.5 (in )0.5 (c)20 (linically )0.5 (recognized )0.5 (pregnancies )0.5 (is )0.6 (2% )0.5 (to )0.5 (4%)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(and 15% to 20%,)37 ( respectively)55 (.)]TJ 0 -1.737 Td [(Clinical Considera)-10 (tions)]TJ /T1_1 1 Tf 0 -1.58 Td [(Disease-associa)-10 (ted ma)-10 (ternal and/or embr)-18 (yo/fetal risk)]TJ /T1_0 1 Tf 0.097 Tw 0 -1.512 Td [(Pregnanc)20 (y confers an increased risk of thromboembolism tha)-10 (t is higher for women with)-25 ( )]TJ 0.054 Tw 0 -1.062 Td [(underlying )0.5 (thromboembolic disease )0.5 (and certain )0.5 (high-risk pregnanc)20 (y )0.5 (conditions.)37 ( Published)-25 ( )]TJ 0.102 Tw 0 -1.062 Td [(da)-10 (ta )0.5 (describe )0.6 (tha)-10 (t )0.6 (women )0.6 (with )0.6 (a )0.5 (previous )0.6 (histor)-17.9 (y )0.5 (of )0.5 (venous )0.5 (thrombosis )0.6 (are )0.5 (a)-10 (t )0.6 (high )0.5 (risk)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(for recurrence during pregnanc)20 (y)55 (.)]TJ /T1_1 1 Tf 0 -1.85 Td [(F)24 (etal/Neona)-9.9 (tal adverse reactions)]TJ /T1_0 1 Tf 0.133 Tw 0 -1.512 Td [(Use )0.5 (of anticoa)-10 (gulants,)37 ( )0.5 (inc)20 (luding ELIQUIS,)37 ( may increase )0.5 (the risk of )0.5 (bleeding in the fetus)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(and neona)-10 (te.)]TJ /T1_1 1 Tf 0 -1.85 Td [(Labor or deliver)-17.9 (y)]TJ /T1_0 1 Tf 0.102 Tw 0 -1.512 Td [(All pa)-10 (tients receiving anticoa)-10 (gulants,)37 ( inc)20 (luding pregnant women,)37 ( are a)-9.9 (t risk for bleeding.)12 ( )]TJ 0.153 Tw 0 -1.062 Td [(ELIQUIS use during labor or deliver)-18 (y in women who are receiving neuraxial anesthesia)-25 ( )]TJ 0.021 Tw 0 -1.062 Td [(may )0.5 (result )0.5 (in )0.5 (epidural )0.5 (or )0.5 (spinal )0.5 (hema)-10 (tomas.)37 ( )0.5 (Consider )0.5 (use )0.5 (of )0.5 (a )0.6 (shorter acting )0.5 (anticoa)-10 (gulant)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(as deliver)-17.9 (y a)-10 (pproaches )]TJ /T1_1 1 Tf 0 Tc 0 Tw ([)Tj 8.671 0 Td (s)Tj -0.025 Tc 0.047 Tw 0.382 0 Td [(ee W)18 (arning)]TJ 0 Tc 0 Tw (s)Tj -0.025 Tc 0.084 Tw 4.344 0 Td ( and Precaution)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.084 Tw 5.949 0 Td ( \(5.3\)])Tj /T1_0 1 Tf 0 Tc 0 Tw (.)Tj -0.025 Tc 0.025 Tw -19.346 -1.737 Td [(Da)-10 (ta)]TJ /T1_1 1 Tf 0.084 Tw 0 -1.58 Td [(Animal Da)-10 (ta)]TJ /T1_0 1 Tf 0.266 Tw 0 -1.513 Td [(No )0.5 (developmental )0.5 (toxicities )0.5 (were )0.6 (obser)-18 (ved )0.5 (when )0.6 (a)-10 (pixaban )0.5 (was )0.5 (administered )0.5 (during)-25 ( )]TJ 0.348 Tw 0 -1.062 Td [(organogenesis to ra)-9.9 (ts )0.5 (\(orally\),)37 ( rabbits )0.5 (\(intra)-9.9 (venously\) and mice \(orally\) a)-10 (t unbound)-25 ( )]TJ 0.259 Tw 0 -1.062 Td [(a)-10 (pixaban exposure levels 4,)37 ( 1,)37 ( and 19 times,)37 ( respectively)55 (,)37 ( the human exposures a)-10 (t)-25 ( )]TJ 0.138 Tw 0 -1.062 Td [(the MRHD.)37 ( )36.7 (There was no evidence of fetal bleeding,)37 ( although conceptus exposure was)-25 ( )]TJ 0.073 Tw 0 -1.062 Td [(con\037rmed in ra)-10 (ts and rabbits.)37 ( Oral administra)-10 (tion of a)-10 (pixaban to ra)-9.9 (t dams from gesta)-9.9 (tion)-25 ( )]TJ 0.143 Tw 0 -1.062 Td [(day 6 through lacta)-10 (tion day 21 a)-9.9 (t ma)-10 (ternal unbound a)-10 (pixaban exposures ranging from)-24.9 ( )]TJ 0.198 Tw 0 -1.062 Td [(1.4 to 5 times the human exposures a)-10 (t the MRHD was not associa)-9.9 (ted with reduced)-25 ( )]TJ 0.074 Tw 0 -1.062 Td [(ma)-10 (ternal mortality or reduced conceptus/neona)-9.9 (tal viability)55 (,)37 ( although increased incidences)-25 ( )]TJ 0.119 Tw 0 -1.062 Td [(of peri-va)-10 (ginal bleeding were obser)-18 (ved in dams a)-9.9 (t all doses.)37 ( )37.2 (There was no evidence of)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(neona)-10 (tal bleeding.)]TJ /T1_2 1 Tf 0.025 Tw 0 -1.85 Td (8.2)Tj /Span< >> BDC ( )Tj EMC 3.375 0 Td (Lactation)Tj /T1_0 1 Tf 0.084 Tw -3.375 -1.58 Td [(Risk Summar)-17.9 (y)]TJ 0.171 Tw 0 -1.512 Td [(There )0.5 (are )0.6 (no )0.6 (da)-10 (ta )0.6 (on )0.6 (the )0.5 (presence )0.6 (of )0.5 (a)-9.9 (pixaban )0.6 (or )0.5 (its )0.5 (metabolites )0.6 (in )0.6 (human )0.6 (milk,)37 ( )0.5 (the)-25 ( )]TJ 0.22 Tw 0 -1.062 Td [(effects on the breastfed child,)37 ( or the effects on milk production.)37 ( )36.8 (A)-9.9 (pixaban and/or its)-25 ( )]TJ 0.043 Tw 0 -1.062 Td [(metabolites were present in the milk of ra)-9.9 (ts)]TJ /Span< >> BDC ( )Tj EMC /T1_1 1 Tf 0 Tc 0 Tw 15.479 0 Td (\()Tj 0.216 0 Td (s)Tj -0.025 Tc 0.043 Tw 0.382 0 Td [(ee Da)-10 (ta\))]TJ /T1_0 1 Tf /Span< >> BDC ( )Tj EMC 2.942 0 Td [(.)37 ( Because human exposure through)-25 ( )]TJ 0.084 Tw -19.019 -1.062 Td [(milk is unkno)-10 (wn,)37 ( breastfeeding is not recommended during trea)-10 (tment with ELIQUIS.)]TJ ET endstream endobj 296 0 obj <> endobj 335 0 obj <> endobj 336 0 obj <>stream H\Ýn@
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Ôµ0¾ËuÅ+RÄWvBêv¤8Sy{Áàää´(¦A± ÝÆ /¾Ñæ endstream endobj 295 0 obj <>stream q /GS0 gs 0 TL/Fm0 Do Q BT 0 0 0 1 k /GS1 gs /T1_0 1 Tf -0.025 Tc 0.084 Tw 8 0 0 8 324 727.2256 Tm (Pediatric Patients)Tj /T1_1 1 Tf 0.097 Tw 0 -1.202 Td [(T)74 (r)6 (eatment )0.5 (of )37.5 (V)18 (enous )37.5 (Thromboembolism )0.5 (\(VTE\) )0.5 (and )0.5 (Reduction )0.5 (in )0.5 (the )0.5 (Risk )0.5 (of )0.6 (Recurr)6 (ent)-25 ( )]TJ 0.084 Tw 0 -1.067 Td (VTE in Pediatric Patients)Tj /T1_2 1 Tf 0.093 Tw 0 -1.292 Td [(The safety assessment of ELIQUIS is based on da)-9.9 (ta from CV185325,)37.1 ( a phase 3 stud)-10 (y in)-25 ( )]TJ 0.083 Tw 0 -1.067 Td [(225 pa)-10 (tients from birth and older)74 (.)37 ( P)18 (a)-10 (tients were randomized 2:1 to receive bod)-10 (y weight-)]TJ 0.182 Tw 0 -1.067 Td [(adjusted doses of an a)-10 (ge-a)-10 (ppropria)-10 (te formula)-9.9 (tion of ELIQUIS or standard of care.)37 ( )36.7 (The)-25 ( )]TJ 0.085 Tw 0 -1.067 Td [(standard )0.6 (of )0.5 (care )0.6 (trea)-10 (tments )0.6 (inc)20 (luded )0.5 (unfractiona)-9.9 (ted )0.6 (heparin )0.5 (\(UFH\),)37 ( )0.5 (lo)-9.9 (w )0.5 (molecular )0.5 (weight)-25 ( )]TJ 0.084 Tw 0 -1.067 Td [(heparin \(LMWH\),)37 ( or vitamin K anta)-10 (gonist \(VKA\).)]TJ 0.265 Tw 0 -1.517 Td [(Overall,)37 ( the safety pro\037le of ELIQUIS in pedia)-10 (tric pa)-10 (tients from birth and older was)-25 ( )]TJ 0.163 Tw 0 -1.067 Td [(generally similar to tha)-9.9 (t in adults and consistent across different pedia)-10 (tric a)-10 (ge groups.)12 ( )]TJ 0.121 Tw 0 -1.067 Td [(In pedia)-10 (tric pa)-10 (tients,)37 ( excessive menstrual bleeding occurred in 17 \(11%\) pa)-10 (tients in the)-24.9 ( )]TJ 0.047 Tw 0 -1.067 Td [(ELIQUIS group and )0.5 (3 \(4%\) pa)-10 (tients )0.5 (in the standard )0.5 (of care group.)37 ( Epistaxis )0.5 (occurred in )0.5 (24)-25 ( )]TJ 0.058 Tw 0 -1.067 Td [(\(16%\) pa)-10 (tients in the ELIQUIS group and 14 \(19%\) pa)-9.9 (tients in the standard of care group.)]TJ 0.184 Tw 0 -1.517 Td [(Bleeding results from Stud)-9.9 (y CV185325 in pedia)-9.9 (tric pa)-10 (tients with )37.1 (VTE are summarized)-25 ( )]TJ 0.047 Tw 0 -1.067 Td [(in T)74 (able )-37 (10.)]TJ ET 0 0 0 1 K 0.5 w /GS2 gs q 1 0 0 1 324 544.5436 cm 0 0 m 95.04 0 l S Q q 1 0 0 1 419.04 544.5436 cm 0 0 m 78.23 0 l S Q q 1 0 0 1 497.27 544.5436 cm 0 0 m 78.23 0 l S Q 1 w q 1 0 0 1 324 564.5155 cm 0 0 m 95.04 0 l S Q q 1 0 0 1 419.04 564.5155 cm 0 0 m 78.23 0 l S Q q 1 0 0 1 497.27 564.5155 cm 0 0 m 78.23 0 l S Q 0.5 w q 1 0 0 1 324 482.284 cm 0 0 m 95.04 0 l S Q q 1 0 0 1 419.04 482.284 cm 0 0 m 78.23 0 l S Q q 1 0 0 1 497.27 482.284 cm 0 0 m 78.23 0 l S Q 1 w q 1 0 0 1 324 417.7725 cm 0 0 m 95.04 0 l S Q q 1 0 0 1 419.04 417.7725 cm 0 0 m 78.23 0 l S Q q 1 0 0 1 497.27 417.7725 cm 0 0 m 78.23 0 l S Q 0.5 w q 1 0 0 1 324 361.2806 cm 0 0 m 95.04 0 l S Q q 1 0 0 1 419.04 361.2806 cm 0 0 m 78.23 0 l S Q q 1 0 0 1 497.27 361.2806 cm 0 0 m 78.23 0 l S Q q 1 0 0 1 324 450.0283 cm 0 0 m 95.04 0 l S Q q 1 0 0 1 419.04 450.0283 cm 0 0 m 78.23 0 l S Q q 1 0 0 1 497.27 450.0283 cm 0 0 m 78.23 0 l S Q q 1 0 0 1 324 514.5397 cm 0 0 m 95.04 0 l S Q q 1 0 0 1 419.04 514.5397 cm 0 0 m 78.23 0 l S Q q 1 0 0 1 497.27 514.5397 cm 0 0 m 78.23 0 l S Q BT /GS1 gs /T1_3 1 Tf -0.022 Tc 0.084 Tw 8 0 0 8 324 576.6155 Tm (Table 10:)Tj /Span< >> BDC ( )Tj EMC 5.4 0 Td [(Bleeding Results in Study CV185325 \226 Safety Analysis Set \226)-22 ( )]TJ 0 Tc 0 Tw 23.408 0 Td ( )Tj -0.022 Tc 0.084 Tw -23.408 -1.062 Td [(Main Phase)-22 ( )]TJ 0.022 Tw 7.6 0 0 8 446.9793 555.9236 Tm (ELIQUIS)Tj 0 Tc 0 Tw 7.6 0 0 8 469.3307 555.9236 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 448.5563 547.4236 Tm (N=152)Tj 0.024 Tw 8.026 1.062 Td (Standard of care**)Tj 0 Tc 0 Tw 7.6 0 0 8 563.2126 555.9236 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 528.5267 547.4236 Tm (N=73)Tj /T1_2 1 Tf 0.024 Tw -26.911 -1.389 Td (Major Bleeding)Tj 0 -1.344 Td [(Number \(%\) Subjects with Event)-22 ( )]TJ 0 -1.062 Td [(95% Confidence Inter)-18 (val \(1\))]TJ 0 Tc 0 Tw 17.412 0.531 Td (0)Tj 10.293 0 Td (0)Tj -0.022 Tc 0.022 Tw 8 0 0 8 324 506.3078 Tm (CRNM*)Tj 0.084 Tw 0 -1.344 Td (Number \(%\) Subjects with Event)Tj 0.024 Tw 7.6 0 0 8 449.438 495.5559 Tm (2 \(1.3\))Tj 10.293 0 Td (1 \(1.4\))Tj 0.084 Tw 8 0 0 8 324 484.804 Tm (95% Confidence Interval \(1\))Tj 0.024 Tw 7.6 0 0 8 446.1814 484.804 Tm [(\(0.2,)37 ( 4.7\))]TJ 10.293 0 Td [(\(0.0,)37 ( 7.4\))]TJ 0.084 Tw 8 0 0 8 323.9999 474.0521 Tm (Minor Bleeding)Tj 0 -1.344 Td (Number \(%\) Subjects with Event)Tj 0.024 Tw 7.6 0 0 8 445.9571 463.3002 Tm (54 \(35.5\))Tj 10.293 0 Td (21 \(28.8\))Tj 0.084 Tw 8 0 0 8 323.9999 452.5482 Tm (95% Confidence Interval \(1\))Tj 0.024 Tw 7.6 0 0 8 442.7006 452.5482 Tm [(\(27.9,)37 ( 43.7\))]TJ 10.293 0 Td [(\(18.8,)37 ( 40.6\))]TJ 0.022 Tw 8 0 0 8 323.9999 441.7963 Tm (All)Tj 0.084 Tw 0 -1.344 Td (Number \(%\) Subjects with Event)Tj 0.024 Tw 7.6 0 0 8 445.9571 431.0444 Tm (55 \(36.2\))Tj 10.293 0 Td (21 \(28.8\))Tj 0.084 Tw 8 0 0 8 323.9999 420.2925 Tm (95% Confidence Interval \(1\))Tj 0.024 Tw 7.6 0 0 8 442.7006 420.2925 Tm [(\(28.6,)37 ( 44.4\))]TJ 10.293 0 Td [(\(18.8,)37 ( 40.6\))]TJ -0.025 Tc 0.084 Tw -25.889 -1.479 Td (*)Tj /Span< >> BDC ( )Tj EMC 0.527 0 Td (CRNM)Tj /Span< >> BDC ( )Tj EMC 2.298 0 Td (=)Tj /Span< >> BDC ( )Tj EMC 0.675 0 Td [(c)20 (linically relevant nonmajor bleeding.)]TJ -3.523 -1.107 Td [(\(1\) 95% Confidence Inter)-17.9 (val calcula)-10 (ted using the Clopper)37 (-P)17.9 (earson exact method)]TJ 0.076 Tw 0 -1.107 Td [(Events associa)-9.9 (ted with each endpoint were counted once per subject,)37 ( but subjects may ha)-10 (ve)-25 ( )]TJ 0.084 Tw 0 -1.062 Td (contributed events to multiple endpoints.)Tj 0.098 Tw 0.023 -1.107 Td [(**UFH/LMWH for pa)-10 (tients less than 2)]TJ /Span< >> BDC ( )Tj EMC 13.441 0 Td [(years of a)-10 (ge and UFH/LMWH/VKA for those equal to or)-25 ( )]TJ 0.084 Tw -12.915 -1.062 Td [(grea)-10 (ter than 2)]TJ /Span< >> BDC ( )Tj EMC 5.276 0 Td [(years of a)-10 (ge.)12 ( )]TJ 0.172 Tw 8 0 0 8 323.9999 332.6961 Tm [(Non-bleeding adverse reactions occurring in \03610% of pa)-9.9 (tients in stud)-10 (y CV185325 are)-24.9 ( )]TJ 0.084 Tw 0 -1.067 Td [(listed in )37 (T)74 (able 11.)]TJ ET /GS2 gs q 1 0 0 1 323.9999 258.0432 cm 0 0 m 95.04 0 l S Q q 1 0 0 1 419.0399 258.0432 cm 0 0 m 78.23 0 l S Q q 1 0 0 1 497.27 258.0432 cm 0 0 m 78.23 0 l S Q 1 w q 1 0 0 1 323.9999 236.5393 cm 0 0 m 95.04 0 l S Q q 1 0 0 1 419.0399 236.5393 cm 0 0 m 78.23 0 l S Q q 1 0 0 1 497.27 236.5393 cm 0 0 m 78.23 0 l S Q q 1 0 0 1 323.9999 286.515 cm 0 0 m 95.04 0 l S Q q 1 0 0 1 419.0399 286.515 cm 0 0 m 78.23 0 l S Q q 1 0 0 1 497.27 286.515 cm 0 0 m 78.23 0 l S Q BT /GS1 gs /T1_3 1 Tf -0.022 Tc 8 0 0 8 323.9999 298.6151 Tm (Table 11:)Tj /Span< >> BDC ( )Tj EMC 5.4 0 Td [(Other Adverse Reactions Occurring in \03610% of Patients in)-22 ( )]TJ 0 Tc 0 Tw 22.544 0 Td ( )Tj -0.022 Tc 0.084 Tw -22.544 -1.062 Td [(Study CV185325)-22 ( )]TJ 0.024 Tw 7.6 0 0 8 323.9999 273.6731 Tm [(Number of Subjects Ev)16 (aluable)-22 ( )]TJ 0 -1.062 Td (for Adverse Reaction)Tj 0.022 Tw 16.181 1.594 Td (ELIQUIS)Tj 0 Tc 0 Tw 7.6 0 0 8 469.3306 277.9231 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 448.5563 269.4231 Tm (N=152)Tj 0 Tc 0 Tw 7.6 0 0 8 467.7536 269.4231 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 450.3803 260.9231 Tm (n \(%\))Tj 8.117 2.125 Td (Standard of Care)Tj 0 Tc 0 Tw 7.6 0 0 8 560.6969 277.9231 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 528.5267 269.4231 Tm (N=73)Tj 0 Tc 0 Tw 7.6 0 0 8 544.2432 269.4231 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 528.6103 260.9231 Tm (n \(%\))Tj /T1_2 1 Tf 0.022 Tw 8 0 0 8 323.9999 249.8112 Tm (Headache)Tj 0.024 Tw 7.6 0 0 8 445.0376 249.8112 Tm ( 25 \(16.4\))Tj 10.414 0 Td (11 \(15.1\))Tj 0.022 Tw 8 0 0 8 323.9999 239.0593 Tm (Vomiting)Tj 0.024 Tw 7.6 0 0 8 445.9571 239.0593 Tm (21 \(13.8\))Tj 10.751 0 Td (5 \(6.8\))Tj /T1_3 1 Tf -0.025 Tc 0.025 Tw 8 0 0 8 323.9999 209.5048 Tm (7)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td [(DR)-10 (UG INTERACTIONS)]TJ 0.025 Tw -3.375 -1.922 Td (7.1)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td (Combined P-gp and Strong CYP3A4 Inhibitors)Tj /T1_2 1 Tf 0.174 Tw -3.375 -1.517 Td [(F)20 (or pa)-10 (tients receiving ELIQUIS 5)]TJ /Span< >> BDC ( )Tj EMC 11.906 0 Td (mg or 10)Tj /Span< >> BDC ( )Tj EMC 3.726 0 Td [(mg twice daily)55 (,)37 ( the dose of ELIQUIS should)-25 ( )]TJ 0.204 Tw -15.632 -1.067 Td [(be decreased by 50% when coadministered with drugs tha)-9.9 (t are combined P-gp and)-25 ( )]TJ 0.255 Tw 0 -1.067 Td [(strong CYP3A4 inhibitors \(e.g.,)37 ( ketoconazole,)37 ( itraconazole,)37 ( ritona)-10 (vir\) )]TJ /T1_4 1 Tf 0 Tc 0 Tw ([)Tj 25.401 0 Td (s)Tj -0.025 Tc 0.255 Tw 0.382 0 Td (ee Do)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.255 Tw 2.64 0 Td [(a)-10 (ge and)-25 ( )]TJ 0.025 Tw -28.424 -1.067 Td (Admini)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.084 Tw 2.788 0 Td [(tra)-9.9 (tion \(2.6\) and Clinical Pharmacolog)-9.9 (y \(12.3\)])]TJ /T1_2 1 Tf 0 Tc 0 Tw (.)Tj -0.025 Tc 0.181 Tw -2.788 -1.517 Td [(F)20 (or pa)-10 (tients receiving ELIQUIS a)-9.9 (t a dose of 2.5)]TJ /Span< >> BDC ( )Tj EMC 17.58 0 Td [(mg twice daily)55 (,)37 ( a)-9.9 (void coadministra)-10 (tion)-25 ( )]TJ 0.115 Tw -17.58 -1.067 Td (with combined P-gp and strong CYP3A4 inhibitors )Tj /T1_4 1 Tf 0 Tc 0 Tw ([)Tj 18.511 0 Td (s)Tj -0.025 Tc 0.115 Tw 0.382 0 Td (ee Do)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.078 Tw 2.5 0 Td [(a)-10 (ge )-36.8 (and Admini)]TJ 0 Tc 0 Tw (s)Tj -0.025 Tc 0.115 Tw 5.992 0 Td [(tra)-9.9 (tion \(2.6\))-25 ( )]TJ 0.084 Tw -27.384 -1.067 Td [(and Clinical Pharmacolog)-9.9 (y \(12.3\)])]TJ /T1_2 1 Tf 0 Tc 0 Tw (.)Tj -0.025 Tc 0.056 Tw 0 -1.517 Td [(Concomitant administra)-10 (tion of combined )0.5 (P-gp and strong )0.5 (CYP3A4 inhibitors has not been)-25 ( )]TJ 0.084 Tw 0 -1.067 Td [(studied in pedia)-10 (tric pa)-10 (tients.)]TJ 0.216 Tw 0 -1.517 Td [(A)-10 (pixaban is a substra)-10 (te of both CYP3A4 and P-gp.)37 ( Concomitant use with drugs tha)-10 (t)-25 ( )]TJ 0.162 Tw 0 -1.067 Td [(are combined P-gp and strong CYP3A4 inhibitors increases exposure to a)-10 (pixaban )]TJ /T1_4 1 Tf 0 Tc 0 Tw ([)Tj 30.255 0 Td (s)Tj -0.025 Tc 0.025 Tw 0.382 0 Td [(ee)-25 ( )]TJ -30.637 -1.067 Td (Clinical)Tj 0.084 Tw [( Pharmacolog)-10 (y \(12.3\)])]TJ /T1_2 1 Tf ( which increases the risk for bleeding.)Tj /T1_0 1 Tf 0.025 Tw 0 -1.742 Td (Clarithromycin)Tj /T1_2 1 Tf 0.041 Tw 0 -1.292 Td [(Although c)19.9 (larithromycin is a combined P-gp and strong CYP3A4 inhibitor)74 (,)37.1 ( pharmacokinetic)-25 ( )]TJ 0.08 Tw 0 -1.067 Td [(da)-10 (ta suggest tha)-9.9 (t no dose adjustment is necessar)-17.9 (y with concomitant administra)-10 (tion with)-25 ( )]TJ 0.025 Tw 0 -1.067 Td (ELIQUIS )Tj /T1_4 1 Tf 0 Tc 0 Tw 3.014 0 Td ([)Tj 0.234 0 Td (s)Tj -0.025 Tc 0.084 Tw 0.382 0 Td (ee Clinical)Tj [( Pharmacolog)-9.9 (y \(12.3\)])]TJ /T1_2 1 Tf 0 Tc 0 Tw (.)Tj ET 0.5 w q 1 0 0 1 36 564.3644 cm 0 0 m 55.591 0 l S Q q 1 0 0 1 36 212.0885 cm 0 0 m 69.191 0 l S Q BT -0.025 Tc 0.052 Tw 8 0 0 8 36 727.248 Tm [(Adverse reactions occurring )0.5 (in \0361% of )0.5 (pa)-10 (tients in the )37.5 (AMPLIFY stud)-9.9 (y are listed in )37.5 (T)74 (able\034)-51.5 (7.)]TJ ET /GS2 gs q 1 0 0 1 36 670.132 cm 0 0 m 69.84 0 l S Q q 1 0 0 1 105.84 670.132 cm 0 0 m 90.83 0 l S Q q 1 0 0 1 196.67 670.132 cm 0 0 m 90.83 0 l S Q 1 w q 1 0 0 1 36 586.9966 cm 0 0 m 69.84 0 l S Q q 1 0 0 1 105.84 586.9966 cm 0 0 m 90.83 0 l S Q q 1 0 0 1 196.67 586.9966 cm 0 0 m 90.83 0 l S Q q 1 0 0 1 36 698.6039 cm 0 0 m 69.84 0 l S Q q 1 0 0 1 105.84 698.6039 cm 0 0 m 90.83 0 l S Q q 1 0 0 1 196.67 698.6039 cm 0 0 m 90.83 0 l S Q BT /GS1 gs /T1_3 1 Tf -0.022 Tc 0.084 Tw 8 0 0 8 36 710.7039 Tm (Table 7:)Tj /Span< >> BDC ( )Tj EMC 5.4 0 Td [(Adverse Reactions Occurring in \0361% of Patients Treated for)-22 ( )]TJ 0 Tc 0 Tw 23.257 0 Td ( )Tj -0.022 Tc 0.084 Tw -23.257 -1.062 Td [(DVT and PE in the AMPLIFY Study)-22 ( )]TJ 0.022 Tw 7.6 0 0 8 140.0793 690.012 Tm (ELIQUIS)Tj 0 Tc 0 Tw 7.6 0 0 8 162.4307 690.012 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 139.9159 681.512 Tm (N=2676)Tj 0 Tc 0 Tw 7.6 0 0 8 162.594 681.512 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 143.4803 673.012 Tm (n \(%\))Tj 0.022 Tw 9.065 2.125 Td (Enoxaparin/Warfarin)Tj 0 Tc 0 Tw 7.6 0 0 8 271.7928 690.012 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 230.7459 681.512 Tm (N=2689)Tj 0 Tc 0 Tw 7.6 0 0 8 253.424 681.512 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 234.3103 673.012 Tm (n \(%\))Tj /T1_2 1 Tf 0.022 Tw 8 0 0 8 36 662.08 Tm (Epistaxis)Tj 0.024 Tw 7.6 0 0 8 140.7975 662.08 Tm (77 \(2.9\))Tj 11.722 0 Td (146 \(5.4\))Tj 0.022 Tw 8 0 0 8 36 651.6881 Tm (Contusion)Tj 0.024 Tw 7.6 0 0 8 140.7975 651.6881 Tm (49 \(1.8\))Tj 11.951 0 Td (97 \(3.6\))Tj 0.022 Tw 8 0 0 8 36 641.2962 Tm (Hematuria)Tj 0.024 Tw 7.6 0 0 8 140.7975 641.2962 Tm (46 \(1.7\))Tj 11.722 0 Td (102 \(3.8\))Tj 0.022 Tw 8 0 0 8 36 630.9043 Tm (Menorrhagia)Tj 0.024 Tw 7.6 0 0 8 140.7975 630.9043 Tm (38 \(1.4\))Tj 11.951 0 Td (30 \(1.1\))Tj 0.022 Tw 8 0 0 8 36 620.5124 Tm (Hematoma)Tj 0.024 Tw 7.6 0 0 8 140.7975 620.5124 Tm (35 \(1.3\))Tj 11.951 0 Td (76 \(2.8\))Tj 0.022 Tw 8 0 0 8 36 610.1205 Tm (Hemoptysis)Tj 0.024 Tw 7.6 0 0 8 140.7975 610.1205 Tm (32 \(1.2\))Tj 11.951 0 Td (31 \(1.2\))Tj 0.084 Tw 8 0 0 8 36 599.7285 Tm (Rectal hemorrhage)Tj 0.024 Tw 7.6 0 0 8 140.7975 599.7285 Tm (26 \(1.0\))Tj 11.951 0 Td (39 \(1.5\))Tj 0.084 Tw 8 0 0 8 36 589.3366 Tm (Gingival bleeding)Tj 0.024 Tw 7.6 0 0 8 140.7975 589.3366 Tm (26 \(1.0\))Tj 11.951 0 Td (50 \(1.9\))Tj -0.025 Tc 0.084 Tw 8 0 0 8 36 565.3644 Tm [(AMPLIFY)74 (-EXT Stud)-10 (y)]TJ 0.362 Tw 0 -1.427 Td [(The mean dura)-10 (tion of exposure to ELIQUIS was a)-10 (pproxima)-10 (tely 330 days and to)-25 ( )]TJ 0.129 Tw 0 -1.067 Td [(placebo was 312 days in the )37.1 (AMPLIFY)74 (-EXT stud)-10 (y)55 (.)37 ( )37 (Adverse reactions rela)-10 (ted to bleeding)-25 ( )]TJ 0 Tc 0 Tw 31.5 0 Td ( )Tj -0.025 Tc 0.046 Tw -31.5 -1.067 Td [(occurred in 219 \(13.3%\) ELIQUIS-trea)-10 (ted pa)-10 (tients compared to 72 \(8.7%\) placebo-trea)-10 (ted)-25 ( )]TJ 0.144 Tw 0 -1.067 Td [(pa)-10 (tients.)37 ( )37.3 (The discontinua)-9.9 (tion ra)-9.9 (te due to bleeding events was a)-10 (pproxima)-9.9 (tely 1% in the)-25 ( )]TJ 0.079 Tw 0 -1.067 Td [(ELIQUIS-trea)-9.9 (ted pa)-10 (tients compared to 0.4% in those pa)-9.9 (tients in the placebo group in the)-24.9 ( )]TJ 0.084 Tw 0 -1.067 Td [(AMPLIFY)74 (-EXT stud)-10 (y)55 (.)]TJ 0 -1.517 Td [(Bleeding results from the )37 (AMPLIFY)74.1 (-EXT stud)-10 (y are summarized in )37 (T)74 (able 8.)]TJ ET /GS2 gs q 1 0 0 1 36 480.8143 cm 0 0 m 58.32 0 l S Q q 1 0 0 1 94.32 480.8143 cm 0 0 m 64.56 0 l S Q q 1 0 0 1 158.88 480.8143 cm 0 0 m 64.56 0 l S Q q 1 0 0 1 223.44 480.8143 cm 0 0 m 64.56 0 l S Q 0.5 w q 1 0 0 1 36 452.3424 cm 0 0 m 58.32 0 l S Q q 1 0 0 1 94.32 452.3424 cm 0 0 m 64.56 0 l S Q q 1 0 0 1 158.88 452.3424 cm 0 0 m 64.56 0 l S Q q 1 0 0 1 223.44 452.3424 cm 0 0 m 64.56 0 l S Q 1 w q 1 0 0 1 36 400.3828 cm 0 0 m 58.32 0 l S Q q 1 0 0 1 94.32 400.3828 cm 0 0 m 64.56 0 l S Q q 1 0 0 1 158.88 400.3828 cm 0 0 m 64.56 0 l S Q q 1 0 0 1 223.44 400.3828 cm 0 0 m 64.56 0 l S Q 0.5 w q 1 0 0 1 36 370.1109 cm 0 0 m 58.32 0 l S Q q 1 0 0 1 94.32 370.1109 cm 0 0 m 64.56 0 l S Q q 1 0 0 1 158.88 370.1109 cm 0 0 m 64.56 0 l S Q q 1 0 0 1 223.44 370.1109 cm 0 0 m 64.56 0 l S Q BT /GS1 gs /T1_3 1 Tf -0.022 Tc 8 0 0 8 36 484.4143 Tm (Table 8:)Tj /Span< >> BDC ( )Tj EMC 5.4 0 Td [(Bleeding Results in the AMPLIFY-EXT Study)-22 ( )]TJ 0.024 Tw 7.6 0 0 8 99.8103 472.2224 Tm (ELIQUIS 2.5)Tj /Span< >> BDC ( )Tj EMC 4.398 0 Td (mg bid)Tj 0 Tc 0 Tw 7.6 0 0 8 153.3897 472.2224 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 117.0013 463.7224 Tm (N=840)Tj 0 Tc 0 Tw 7.6 0 0 8 136.1987 463.7224 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 118.8253 455.2224 Tm (n \(%\))Tj 6.331 2.125 Td (ELIQUIS 5)Tj /Span< >> BDC ( )Tj EMC 3.722 0 Td (mg bid)Tj 0 Tc 0 Tw 7.6 0 0 8 215.3809 472.2224 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 181.5613 463.7224 Tm (N=811)Tj 0 Tc 0 Tw 7.6 0 0 8 200.7587 463.7224 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 183.3853 455.2224 Tm (n \(%\))Tj 0.022 Tw 8.011 2.125 Td (Placebo)Tj 0.244 -1.062 Td (N=826)Tj 0 Tc 0 Tw 7.6 0 0 8 265.3187 463.7224 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 247.9453 455.2224 Tm (n \(%\))Tj /T1_2 1 Tf 0.022 Tw 8 0 0 8 36 444.2905 Tm (Major)Tj 0.024 Tw 7.6 0 0 8 117.883 444.2905 Tm (2 \(0.2\))Tj 8.495 0 Td (1 \(0.1\))Tj 8.495 0 Td (4 \(0.5\))Tj 0.022 Tw 8 0 0 8 36 433.8986 Tm (CRNM*)Tj 0.024 Tw 7.6 0 0 8 116.1426 433.8986 Tm (25 \(3.0\))Tj 8.495 0 Td (34 \(4.2\))Tj 8.495 0 Td (19 \(2.3\))Tj 0.084 Tw 8 0 0 8 36 423.5067 Tm (Major + CRNM)Tj 0.024 Tw 7.6 0 0 8 116.1426 423.5067 Tm (27 \(3.2\))Tj 8.495 0 Td (35 \(4.3\))Tj 8.495 0 Td (22 \(2.7\))Tj 0.022 Tw 8 0 0 8 36 413.1147 Tm (Minor)Tj 0.024 Tw 7.6 0 0 8 116.1426 413.1147 Tm (75 \(8.9\))Tj 8.266 0 Td (98 \(12.1\))Tj 8.724 0 Td (58 \(7.0\))Tj 0.022 Tw 8 0 0 8 36 402.7228 Tm (All)Tj 0.024 Tw 7.6 0 0 8 114.4022 402.7228 Tm (94 \(11.2\))Tj 8.266 0 Td (121 \(14.9\))Tj 8.953 0 Td (74 \(9.0\))Tj -0.025 Tc -0.115 Tw -27.511 -1.456 Td (*)Tj /Span< >> BDC ( )Tj EMC (CRNM)Tj /Span< >> BDC ( )Tj EMC (=)Tj /Span< >> BDC ( )Tj EMC [(c)20 (linically )-199 (relevant )-198.9 (nonmajor )-199 (bleeding.)]TJ 0.081 Tw -0.023 -1.107 Td [(Events associa)-9.9 (ted with each endpoint were counted once per subject,)37 ( but subjects may ha)-10 (ve)-24.9 ( )]TJ 0.084 Tw 0 -1.062 Td (contributed events to multiple endpoints.)Tj 0.156 Tw 8 0 0 8 36 352.3287 Tm [(Adverse reactions occurring in \0361% of pa)-10 (tients in the )36.6 (AMPLIFY)74 (-EXT stud)-9.9 (y are listed in)-25 ( )]TJ 0.084 Tw 0 -1.067 Td [(T)74 (able 9.)]TJ ET /GS2 gs q 1 0 0 1 36 288.4803 cm 0 0 m 59.4 0 l S Q q 1 0 0 1 95.4 288.4803 cm 0 0 m 64.2 0 l S Q q 1 0 0 1 159.6 288.4803 cm 0 0 m 64.2 0 l S Q q 1 0 0 1 223.8 288.4803 cm 0 0 m 64.2 0 l S Q 1 w q 1 0 0 1 36 234.7207 cm 0 0 m 59.4 0 l S Q q 1 0 0 1 95.4 234.7207 cm 0 0 m 64.2 0 l S Q q 1 0 0 1 159.6 234.7207 cm 0 0 m 64.2 0 l S Q q 1 0 0 1 223.8 234.7207 cm 0 0 m 64.2 0 l S Q q 1 0 0 1 36 316.9522 cm 0 0 m 59.4 0 l S Q q 1 0 0 1 95.4 316.9522 cm 0 0 m 64.2 0 l S Q q 1 0 0 1 159.6 316.9522 cm 0 0 m 64.2 0 l S Q q 1 0 0 1 223.8 316.9522 cm 0 0 m 64.2 0 l S Q BT /GS1 gs /T1_3 1 Tf -0.022 Tc 8 0 0 8 36 329.0522 Tm (Table 9:)Tj /Span< >> BDC ( )Tj EMC 5.4 0 Td [(Adverse Reactions Occurring in \0361% of Patients Undergoing)-22 ( )]TJ 0 -1.062 Td [(Extended Treatment for DVT and PE in the AMPLIFY-EXT Study)-22 ( )]TJ 0.024 Tw 7.6 0 0 8 100.7103 308.3603 Tm (ELIQUIS 2.5)Tj /Span< >> BDC ( )Tj EMC 4.398 0 Td (mg bid)Tj 0 Tc 0 Tw 7.6 0 0 8 154.2897 308.3603 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 117.9013 299.8603 Tm (N=840)Tj 0 Tc 0 Tw 7.6 0 0 8 137.0987 299.8603 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 119.7253 291.3603 Tm (n \(%\))Tj 6.283 2.125 Td (ELIQUIS 5)Tj /Span< >> BDC ( )Tj EMC 3.722 0 Td (mg bid)Tj 0 Tc 0 Tw 7.6 0 0 8 215.9209 308.3603 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 182.1013 299.8603 Tm (N=811)Tj 0 Tc 0 Tw 7.6 0 0 8 201.2987 299.8603 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 183.9253 291.3603 Tm (n \(%\))Tj 0.022 Tw 7.963 2.125 Td (Placebo)Tj 0 Tc 0 Tw 7.6 0 0 8 267.3531 308.3603 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 246.3013 299.8603 Tm (N=826)Tj 0 Tc 0 Tw 7.6 0 0 8 265.4987 299.8603 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 248.1254 291.3603 Tm (n \(%\))Tj /T1_2 1 Tf 0.022 Tw 8 0 0 8 36 280.2484 Tm (Epistaxis)Tj 0.024 Tw 7.6 0 0 8 117.0426 280.2484 Tm (13 \(1.5\))Tj 8.447 0 Td (29 \(3.6\))Tj 8.676 0 Td (9 \(1.1\))Tj 0.022 Tw 8 0 0 8 36 269.4965 Tm (Hematuria)Tj 0.024 Tw 7.6 0 0 8 117.0426 269.4965 Tm (12 \(1.4\))Tj 8.447 0 Td (17 \(2.1\))Tj 8.676 0 Td (9 \(1.1\))Tj 0.022 Tw 8 0 0 8 36 258.7445 Tm (Hematoma)Tj 0.024 Tw 7.6 0 0 8 117.0426 258.7445 Tm (13 \(1.5\))Tj 8.447 0 Td (16 \(2.0\))Tj 8.447 0 Td (10 \(1.2\))Tj 0.022 Tw 8 0 0 8 36 247.9926 Tm (Contusion)Tj 0.024 Tw 7.6 0 0 8 117.0426 247.9926 Tm (18 \(2.1\))Tj 8.447 0 Td (18 \(2.2\))Tj 8.447 0 Td (18 \(2.2\))Tj 0.084 Tw 8 0 0 8 36 237.2407 Tm (Gingival bleeding)Tj 0.024 Tw 7.6 0 0 8 117.0426 237.2407 Tm (12 \(1.4\))Tj 8.676 0 Td (9 \(1.1\))Tj 8.447 0 Td (3 \(0.4\))Tj -0.025 Tc 0.047 Tw 8 0 0 8 36 213.0885 Tm [(Other Adverse )-37 (Reactions)]TJ 0.448 Tw 0 -1.427 Td [(Less common adverse reactions in ELIQUIS-trea)-10 (ted pa)-9.9 (tients in the )37 (AMPLIFY or)-25 ( )]TJ 0 Tc 0 Tw 31.5 0 Td ( )Tj -0.025 Tc 0.084 Tw -31.5 -1.067 Td [(AMPLIFY)74 (-EXT studies occurring a)-10 (t a frequenc)20 (y of \0360.1% to <1%:)]TJ /T1_4 1 Tf 0 -1.472 Td [(Blood and lympha)-10 (tic )]TJ 0 Tc 0 Tw (s)Tj 7.899 0 Td (y)Tj 0.381 0 Td (s)Tj -0.025 Tc 0.084 Tw 0.382 0 Td (tem di)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.025 Tw 2.648 0 Td (order)Tj 0 Tc 0 Tw (s)Tj 2.2 0 Td (:)Tj /T1_2 1 Tf -0.025 Tc 0.084 Tw /Span< >> BDC 0.215 0 Td ( )Tj EMC 0.017 0 Td [( hemorrha)-9.9 (gic anemia)]TJ /T1_4 1 Tf 0.025 Tw -13.741 -1.427 Td (Ga)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.025 Tw 1.313 0 Td (trointe)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.466 Tw 2.576 0 Td (tinal di)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.025 Tw 3.129 0 Td (order)Tj 0 Tc 0 Tw (s)Tj 2.2 0 Td (:)Tj /T1_2 1 Tf -0.025 Tc 0.466 Tw /Span< >> BDC 0.215 0 Td ( )Tj EMC 0.017 0 Td [( hema)-10 (tochezia,)37 ( hemorrhoidal hemorrha)-10 (ge,)37 ( gastrointestinal)-25 ( )]TJ 0.084 Tw -9.449 -1.067 Td [(hemorrha)-10 (ge,)37 ( hema)-9.9 (temesis,)37 ( melena,)37 ( anal hemorrha)-10 (ge)]TJ /T1_4 1 Tf 0.355 Tw 0 -1.427 Td [(Injur)-17.9 (y)55 (,)37 ( poi)]TJ 0 Tc 0 Tw (s)Tj -0.025 Tc 0.355 Tw 4.014 0 Td [(oning,)37 ( and )0.5 (procedural )0.5 (complica)-10 (tion)]TJ 0 Tc 0 Tw (s)Tj 13.581 0 Td (:)Tj /T1_2 1 Tf -0.025 Tc 0.355 Tw /Span< >> BDC 0.215 0 Td ( )Tj EMC 0.017 0 Td [( wound hemorrha)-10 (ge,)37 ( )0.5 (postprocedural)-24.9 ( )]TJ 0.084 Tw -17.828 -1.067 Td [(hemorrha)-10 (ge,)37 ( trauma)-10 (tic hema)-10 (toma,)37 ( periorbital hema)-10 (toma)]TJ /T1_4 1 Tf 0.025 Tw 0 -1.427 Td (Mu)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.025 Tw 1.499 0 Td (culo)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.084 Tw 1.819 0 Td (keletal and connective ti)Tj 0.025 Tw (ss)Tj 0.084 Tw (ue di)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.025 Tw 11.521 0 Td (order)Tj 0 Tc 0 Tw (s)Tj 2.2 0 Td (:)Tj /T1_2 1 Tf -0.025 Tc 0.084 Tw /Span< >> BDC 0.215 0 Td ( )Tj EMC 0.017 0 Td [( musc)20.1 (le hemorrha)-10 (ge)]TJ /T1_4 1 Tf 0.025 Tw -17.27 -1.427 Td (Reproductive )Tj 0 Tc 0 Tw 5.391 0 Td (s)Tj 0.382 0 Td (y)Tj 0.381 0 Td (s)Tj -0.025 Tc 0.645 Tw 0.382 0 Td (tem and brea)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.645 Tw 6.293 0 Td (t di)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.025 Tw 2.093 0 Td (order)Tj 0 Tc 0 Tw (s)Tj 2.2 0 Td (:)Tj /T1_2 1 Tf -0.025 Tc 0.645 Tw /Span< >> BDC 0.215 0 Td ( )Tj EMC 0.017 0 Td [( va)-9.9 (ginal hemorrha)-9.9 (ge,)37 ( metrorrha)-9.9 (gia,)12 ( )]TJ 0.084 Tw -17.353 -1.067 Td [(menometrorrha)-10 (gia,)37 ( genital hemorrha)-10 (ge)]TJ /T1_4 1 Tf -0.043 Tc 0.043 Tw 0 -1.427 Td (Va)Tj 0 Tc 0 Tw 0.838 0 Td (s)Tj -0.025 Tc 0.084 Tw 0.382 0 Td (cular di)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.025 Tw 3.006 0 Td (order)Tj 0 Tc 0 Tw (s)Tj 2.2 0 Td (:)Tj /T1_2 1 Tf -0.025 Tc -0.198 Tw /Span< >> BDC 0.215 0 Td ( )Tj EMC [( )-281.9 (hemorrha)-10 (ge)]TJ /T1_4 1 Tf 0.084 Tw -6.641 -1.427 Td (Skin and )Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.025 Tw 3.786 0 Td (ubcutaneou)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.084 Tw 4.464 0 Td ( ti)Tj 0.025 Tw (ss)Tj 0.084 Tw (ue di)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.025 Tw 3.631 0 Td (order)Tj 0 Tc 0 Tw (s)Tj 2.2 0 Td (:)Tj /T1_2 1 Tf -0.025 Tc 0.084 Tw /Span< >> BDC 0.215 0 Td ( )Tj EMC 0.017 0 Td [( ecchymosis,)37 ( skin hemorrha)-9.9 (ge,)37 ( petechiae)]TJ /T1_4 1 Tf -14.312 -1.427 Td (Eye di)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.025 Tw 2.536 0 Td (order)Tj 0 Tc 0 Tw (s)Tj 2.2 0 Td (:)Tj /T1_2 1 Tf -0.025 Tc 0.084 Tw /Span< >> BDC 0.215 0 Td ( )Tj EMC 0.017 0 Td [( conjunctival hemorrha)-10 (ge,)37 ( retinal hemorrha)-10 (ge,)37 ( eye hemorrha)-10 (ge)]TJ /T1_4 1 Tf 0.025 Tw -4.968 -1.427 Td (Inve)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.025 Tw 1.799 0 Td [(tiga)-9.9 (tion)]TJ 0 Tc 0 Tw (s)Tj 2.932 0 Td (:)Tj /T1_2 1 Tf -0.025 Tc 0.203 Tw /Span< >> BDC 0.215 0 Td ( )Tj EMC 0.017 0 Td [( blood urine present,)37 ( occult blood positive,)37 ( occult 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0.5 w /GS1 gs q 1 0 0 1 36 605.6479 cm 0 0 m 69.191 0 l S Q 0.979 w /GS2 gs q 1 0 0 1 36 715.1481 cm 0 0 m 43.56 0 l S Q q 1 0 0 1 79.56 715.1481 cm 0 0 m 52.04 0 l S Q q 1 0 0 1 131.6 715.1481 cm 0 0 m 52.04 0 l S Q q 1 0 0 1 183.64 715.1481 cm 0 0 m 52.04 0 l S Q q 1 0 0 1 235.68 715.1481 cm 0 0 m 52.04 0 l S Q q 1 0 0 1 36 647.3574 cm 0 0 m 43.56 0 l S Q q 1 0 0 1 79.56 647.3574 cm 0 0 m 52.04 0 l S Q q 1 0 0 1 131.6 647.3574 cm 0 0 m 52.04 0 l S Q q 1 0 0 1 183.64 647.3574 cm 0 0 m 52.04 0 l S Q q 1 0 0 1 235.68 647.3574 cm 0 0 m 52.04 0 l S Q 0.489 w q 1 0 0 1 36 626.0975 cm 0 0 m 43.56 0 l S Q q 1 0 0 1 79.56 626.0975 cm 0 0 m 52.04 0 l S Q q 1 0 0 1 131.6 626.0975 cm 0 0 m 52.04 0 l S Q q 1 0 0 1 183.64 626.0975 cm 0 0 m 52.04 0 l S Q q 1 0 0 1 235.68 626.0975 cm 0 0 m 52.04 0 l S Q q 1 0 0 1 36 686.0931 cm 0 0 m 43.56 0 l S Q q 1 0 0 1 79.56 686.0931 cm 0 0 m 52.04 0 l S Q q 1 0 0 1 131.6 686.0931 cm 0 0 m 52.04 0 l S Q q 1 0 0 1 183.64 686.0931 cm 0 0 m 52.04 0 l S Q q 1 0 0 1 235.68 686.0931 cm 0 0 m 52.04 0 l S Q BT 0 0 0 1 k /GS1 gs /T1_0 1 Tf -0.022 Tc 0.084 Tw 8 0 0 8 36 727.2481 Tm (Table 3:)Tj /Span< >> BDC ( )Tj EMC 5.4 0 Td [(Bleeding Events in Patients with Nonvalvular Atrial Fibrillation)-22 ( )]TJ 0 -1.062 Td [(in AVERROES)-22 ( )]TJ 0.022 Tw 7.6 0 0 8 94.4043 706.6171 Tm (ELIQUIS)Tj -0.021 -1.062 Td (N=2798)Tj 0.024 Tw -0.502 -1.062 Td (n \(%/year\))Tj 0.022 Tw 7.501 2.125 Td (Aspirin)Tj -0.152 -1.062 Td (N=2780)Tj 0.024 Tw -0.502 -1.062 Td (n \(%/year\))Tj 6.416 2.125 Td (Hazard Ratio)Tj 0 Tc 0 Tw 7.6 0 0 8 228.0973 706.6171 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 197.3672 698.1171 Tm (\(95% CI\))Tj 0.022 Tw 7.022 1.062 Td (P-value)Tj /T1_1 1 Tf -28.255 -3.729 Td (Major)Tj 0.024 Tw 7.55 0 Td (45 \(1.41\))Tj 6.847 0 Td (29 \(0.92\))Tj 5.502 0 Td [(1.54 \(0.96,)37 ( 2.45\))]TJ 0.022 Tw 8.991 0 Td (0.07)Tj -0.014 Tc 0.958 Tw /Span< >> BDC -28.89 -1.614 Td ( )Tj EMC [(F)20 (a)-10 (tal)]TJ -0.022 Tc 0.024 Tw 7.779 0 Td (5 \(0.16\))Tj 6.847 0 Td (5 \(0.16\))Tj 5.273 0 Td [(0.99 \(0.23,)37 ( 4.29\))]TJ 0 Tc 0 Tw 9.622 0 Td (-)Tj -0.014 Tc 0.958 Tw /Span< >> BDC -29.521 -1.614 Td ( )Tj EMC (Intracranial)Tj -0.022 Tc 0.024 Tw 7.55 0 Td (11 \(0.34\))Tj 6.847 0 Td (11 \(0.35\))Tj 5.502 0 Td [(0.99 \(0.39,)37 ( 2.51\))]TJ 0 Tc 0 Tw 9.622 0 Td (-)Tj -0.025 Tc 0.078 Tw -29.521 -1.604 Td [(Events associa)-10 (ted with each endpoint were counted once per subject,)37 ( but subjects may ha)-10 (ve)-25 ( )]TJ 0.084 Tw 0 -1.062 Td (contributed events to multiple endpoints.)Tj 0.047 Tw 8 0 0 8 36 606.6479 Tm [(Other Adverse )-37 (Reactions)]TJ 0.416 Tw 0 -1.512 Td [(Hypersensitivity reactions \(inc)20 (luding drug hypersensitivity)55 (,)37.1 ( such as skin rash,)37 ( and)-25 ( )]TJ 0.15 Tw 0 -1.062 Td [(ana)-9.9 (phylactic reactions,)37 ( such as allergic edema\) and syncope were reported in <1% of)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(pa)-10 (tients receiving ELIQUIS.)]TJ /T1_2 1 Tf 0 -1.737 Td [(Proph)6.1 (ylaxis of Deep )37 (V)18.1 (ein )37 (Thrombosis Follo)6 (wing Hip or Knee Replacement Sur)6 (ger)-18 (y)]TJ /T1_1 1 Tf 0.092 Tw 0 -1.288 Td [(The safety of ELIQUIS has been evalua)-10 (ted in 1 Phase II and 3 Phase III studies inc)20 (luding)-25 ( )]TJ 0.301 Tw 0 -1.062 Td [(5924 pa)-10 (tients exposed to ELIQUIS 2.5)]TJ /Span< >> BDC ( )Tj EMC 14.753 0 Td [(mg twice daily undergoing major orthopedic)-25 ( )]TJ 0.041 Tw -14.753 -1.062 Td [(surger)-18 (y of the lo)-10 (wer limbs \(elective hip replacement or elective knee replacement\) trea\ )-10 (ted)-25.1 ( )]TJ 0.084 Tw 0 -1.062 Td (for up to 38 days.)Tj 0.058 Tw 0 -1.512 Td [(In total,)37 ( 11% of the pa)-10 (tients trea)-10 (ted with ELIQUIS 2.5)]TJ /Span< >> BDC ( )Tj EMC 18.846 0 Td [(mg twice daily experienced adverse)-25 ( )]TJ 0.025 Tw -18.846 -1.062 Td (reactions.)Tj 0.053 Tw 0 -1.512 Td [(Bleeding results during the trea)-10 (tment period in the Phase III studies are sho)-9.9 (wn in )36.9 (T)74 (able)]TJ /Span< >> BDC ( )Tj EMC 30.842 0 Td [(4.)12 ( )]TJ 0.261 Tw -30.842 -1.062 Td [(Bleeding was assessed in each stud)-10 (y beginning with the \037rst dose of double-blind)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(stud)-10 (y drug.)]TJ ET 0.5 w /GS2 gs q 1 0 0 1 36 80.173 cm 0 0 m 45.58 0 l S Q q 1 0 0 1 81.58 80.173 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 115.8166 80.173 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 150.0533 80.173 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 184.29 80.173 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 218.5266 80.173 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 252.7633 80.173 cm 0 0 m 35.237 0 l S Q 1 w q 1 0 0 1 36 443.736 cm 0 0 m 45.58 0 l S Q q 1 0 0 1 81.58 443.736 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 115.8166 443.736 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 150.0533 443.736 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 184.29 443.736 cm 0 0 m 34.237 0 l S Q 0.5 w q 1 0 0 1 150.0533 415.5141 cm 0 0 m 0 27.722 l S Q 1 w q 1 0 0 1 218.5266 443.736 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 252.7633 443.736 cm 0 0 m 35.237 0 l S Q 0.5 w q 1 0 0 1 218.5266 415.5141 cm 0 0 m 0 27.722 l S Q q 1 0 0 1 36 415.2641 cm 0 0 m 45.58 0 l S Q q 1 0 0 1 36 332.8203 cm 0 0 m 45.58 0 l S Q q 1 0 0 1 36 322.0684 cm 0 0 m 45.58 0 l S Q q 1 0 0 1 36 294.3164 cm 0 0 m 45.58 0 l S Q q 1 0 0 1 36 275.0645 cm 0 0 m 45.58 0 l S Q q 1 0 0 1 36 255.8126 cm 0 0 m 45.58 0 l S Q q 1 0 0 1 36 236.5607 cm 0 0 m 45.58 0 l S Q q 1 0 0 1 36 217.3088 cm 0 0 m 45.58 0 l S Q q 1 0 0 1 36 198.0569 cm 0 0 m 45.58 0 l S Q 1 w q 1 0 0 1 36 178.8049 cm 0 0 m 45.58 0 l S Q 0.5 w q 1 0 0 1 81.58 415.2641 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 115.8166 415.2641 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 81.58 378.2922 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 115.8166 378.2922 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 81.58 332.8203 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 115.8166 332.8203 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 81.58 322.0684 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 115.8166 322.0684 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 81.58 294.3164 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 115.8166 294.3164 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 81.58 275.0645 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 115.8166 275.0645 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 81.58 255.8126 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 115.8166 255.8126 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 81.58 236.5607 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 115.8166 236.5607 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 81.58 217.3088 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 115.8166 217.3088 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 81.58 198.0569 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 115.8166 198.0569 cm 0 0 m 34.237 0 l S Q 1 w q 1 0 0 1 81.58 178.8049 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 115.8166 178.8049 cm 0 0 m 34.237 0 l S Q 0.5 w q 1 0 0 1 150.0533 415.2641 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 150.0533 378.5422 cm 0 0 m 0 36.472 l S Q q 1 0 0 1 184.29 415.2641 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 150.0533 378.2922 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 150.0533 333.0703 cm 0 0 m 0 44.972 l S Q q 1 0 0 1 184.29 378.2922 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 150.0533 332.8203 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 150.0533 322.3184 cm 0 0 m 0 10.252 l S Q q 1 0 0 1 184.29 332.8203 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 150.0533 322.0684 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 150.0533 294.5664 cm 0 0 m 0 27.252 l S Q q 1 0 0 1 184.29 322.0684 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 150.0533 294.3164 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 150.0533 275.3145 cm 0 0 m 0 18.752 l S Q q 1 0 0 1 184.29 294.3164 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 150.0533 275.0645 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 150.0533 256.0626 cm 0 0 m 0 18.752 l S Q q 1 0 0 1 184.29 275.0645 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 150.0533 255.8126 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 150.0533 236.8107 cm 0 0 m 0 18.752 l S Q q 1 0 0 1 184.29 255.8126 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 150.0533 236.5607 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 150.0533 217.5588 cm 0 0 m 0 18.752 l S Q q 1 0 0 1 184.29 236.5607 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 150.0533 217.3088 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 150.0533 198.3069 cm 0 0 m 0 18.752 l S Q q 1 0 0 1 184.29 217.3088 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 150.0533 198.0569 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 150.0533 179.3049 cm 0 0 m 0 18.502 l S Q q 1 0 0 1 184.29 198.0569 cm 0 0 m 34.237 0 l S Q 1 w q 1 0 0 1 150.0533 178.8049 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 184.29 178.8049 cm 0 0 m 34.237 0 l S Q 0.5 w q 1 0 0 1 218.5266 415.2641 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 218.5266 378.5422 cm 0 0 m 0 36.472 l S Q q 1 0 0 1 252.7633 415.2641 cm 0 0 m 35.237 0 l S Q q 1 0 0 1 218.5266 378.2922 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 218.5266 333.0703 cm 0 0 m 0 44.972 l S Q q 1 0 0 1 252.7633 378.2922 cm 0 0 m 35.237 0 l S Q q 1 0 0 1 218.5266 332.8203 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 218.5266 322.3184 cm 0 0 m 0 10.252 l S Q q 1 0 0 1 252.7633 332.8203 cm 0 0 m 35.237 0 l S Q q 1 0 0 1 218.5266 322.0684 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 218.5266 294.5664 cm 0 0 m 0 27.252 l S Q q 1 0 0 1 252.7633 322.0684 cm 0 0 m 35.237 0 l S Q q 1 0 0 1 218.5266 294.3164 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 218.5266 275.3145 cm 0 0 m 0 18.752 l S Q q 1 0 0 1 252.7633 294.3164 cm 0 0 m 35.237 0 l S Q q 1 0 0 1 218.5266 275.0645 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 218.5266 256.0626 cm 0 0 m 0 18.752 l S Q q 1 0 0 1 252.7633 275.0645 cm 0 0 m 35.237 0 l S Q q 1 0 0 1 218.5266 255.8126 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 218.5266 236.8107 cm 0 0 m 0 18.752 l S Q q 1 0 0 1 252.7633 255.8126 cm 0 0 m 35.237 0 l S Q q 1 0 0 1 218.5266 236.5607 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 218.5266 217.5588 cm 0 0 m 0 18.752 l S Q q 1 0 0 1 252.7633 236.5607 cm 0 0 m 35.237 0 l S Q q 1 0 0 1 218.5266 217.3088 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 218.5266 198.3069 cm 0 0 m 0 18.752 l S Q q 1 0 0 1 252.7633 217.3088 cm 0 0 m 35.237 0 l S Q q 1 0 0 1 218.5266 198.0569 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 218.5266 179.3049 cm 0 0 m 0 18.502 l S Q q 1 0 0 1 252.7633 198.0569 cm 0 0 m 35.237 0 l S Q 1 w q 1 0 0 1 218.5266 178.8049 cm 0 0 m 34.237 0 l S Q q 1 0 0 1 252.7633 178.8049 cm 0 0 m 35.237 0 l S Q BT /GS1 gs /T1_0 1 Tf -0.022 Tc 8 0 0 8 36 455.836 Tm (Table 4: )Tj /Span< >> BDC ( )Tj EMC 5.4 0 Td [(Bleeding During the Treatment Period in Patients Undergoing)-22 ( )]TJ 0 -1.062 Td (Elective Hip or Knee Replacement Surgery)Tj 0.022 Tw 7.6 0 0 8 36 430.8941 Tm (Bleeding)Tj 0 Tc 0 Tw 7.6 0 0 8 61.1406 430.8941 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 36 422.3941 Tm (Endpoint*)Tj 8.25 1.594 Td (ADVANCE-3)Tj 0 Tc 0 Tw 7.6 0 0 8 132.6812 435.1441 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 91.2389 426.6441 Tm (Hip Replacement)Tj 0 Tc 0 Tw 7.6 0 0 8 140.1444 426.6441 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 104.4438 418.1441 Tm (Surgery)Tj 8.271 2.125 Td (ADVANCE-2)Tj 0 Tc 0 Tw 7.6 0 0 8 201.2796 435.1441 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 157.3863 426.6441 Tm (Knee Replacement)Tj 0 Tc 0 Tw 7.6 0 0 8 211.1937 426.6441 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 173.0421 418.1441 Tm (Surgery)Tj 8.336 2.125 Td (ADVANCE-1)Tj 0 Tc 0 Tw 7.6 0 0 8 270.3779 435.1441 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 226.4846 426.6441 Tm (Knee Replacement)Tj 0 Tc 0 Tw 7.6 0 0 8 280.292 426.6441 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 242.1404 418.1441 Tm (Surgery)Tj /T1_1 1 Tf -20.253 -1.434 Td (ELIQUIS)Tj 0 Tc 0 Tw 7.6 0 0 8 109.1786 406.6722 Tm ( )Tj -0.022 Tc -0.005 Tw 7.6 0 0 8 84.9616 398.1722 Tm (2.5)Tj /Span< >> BDC ( )Tj EMC [(mg )-29 (po)-22 ( )]TJ 0.022 Tw 1.264 -1.062 Td (bid)Tj 0 Tc 0 Tw 7.6 0 0 8 102.8251 389.6722 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 84.0762 381.1722 Tm (35\2613 days)Tj 0.022 Tw 4.478 3.188 Td [(Enoxa)-10 (parin)]TJ 0 Tc 0 Tw 7.6 0 0 8 147.7622 406.6722 Tm ( )Tj -0.022 Tc -0.005 Tw 7.6 0 0 8 124.2255 398.1722 Tm (40)Tj /Span< >> BDC ( )Tj EMC [(mg)-22 ( )]TJ 0.024 Tw 0.179 -1.062 Td (sc qd)Tj 0 Tc 0 Tw 7.6 0 0 8 140.2879 389.6722 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 118.3128 381.1722 Tm (35\2613 days)Tj 0.022 Tw 5.05 3.188 Td (ELIQUIS)Tj 0 Tc 0 Tw 7.6 0 0 8 177.6519 406.6722 Tm ( )Tj -0.022 Tc -0.005 Tw 7.6 0 0 8 153.4349 398.1722 Tm (2.5)Tj /Span< >> BDC ( )Tj EMC [(mg )-29 (po)-22 ( )]TJ 0.022 Tw 1.264 -1.062 Td (bid)Tj 0 Tc 0 Tw 7.6 0 0 8 171.2984 389.6722 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 152.5495 381.1722 Tm (12\2612 days)Tj 0.022 Tw 4.478 3.188 Td [(Enoxa)-10 (parin)]TJ 0 Tc 0 Tw 7.6 0 0 8 216.2356 406.6722 Tm ( )Tj -0.022 Tc -0.005 Tw 7.6 0 0 8 192.6988 398.1722 Tm (40)Tj /Span< >> BDC ( )Tj EMC [(mg)-22 ( )]TJ 0.024 Tw 0.179 -1.062 Td (sc qd)Tj 0 Tc 0 Tw 7.6 0 0 8 208.7612 389.6722 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 186.7862 381.1722 Tm (12\2612 days)Tj 0.022 Tw 5.05 3.188 Td (ELIQUIS)Tj 0 Tc 0 Tw 7.6 0 0 8 246.1253 406.6722 Tm ( )Tj -0.022 Tc -0.005 Tw 7.6 0 0 8 221.9082 398.1722 Tm (2.5)Tj /Span< >> BDC ( )Tj EMC [(mg )-29 (po)-22 ( )]TJ 0.022 Tw 1.264 -1.062 Td (bid)Tj 0 Tc 0 Tw 7.6 0 0 8 239.7717 389.6722 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 221.0229 381.1722 Tm (12\2612 days)Tj 0.022 Tw 4.544 3.188 Td [(Enoxa)-10 (parin)]TJ 0 Tc 0 Tw 7.6 0 0 8 285.2089 406.6722 Tm ( )Tj -0.022 Tc -0.005 Tw 7.6 0 0 8 257.7545 398.1722 Tm (30)Tj /Span< >> BDC ( )Tj EMC [(mg )-29 (sc)-22 ( )]TJ 0.022 Tw 0.751 -1.062 Td (q12h)Tj 0 Tc 0 Tw 7.6 0 0 8 277.2976 389.6722 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 255.7595 381.1722 Tm (12\2612 days)Tj -22.374 -1.434 Td [(F)18 (irst dose)]TJ 0 Tc 0 Tw 7.6 0 0 8 111.6788 369.7003 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 91.7103 361.2003 Tm [(12 to)-22 ( )]TJ -0.652 -1.062 Td (24)Tj /Span< >> BDC ( )Tj EMC [(hours)-22 ( )]TJ 0.022 Tw 0.818 -1.062 Td (post)Tj 0 Tc 0 Tw 7.6 0 0 8 104.4248 344.2003 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 88.5868 335.7003 Tm [(surger)-18 (y)]TJ 0.024 Tw 4.127 4.25 Td [(F)18 (irst dose)]TJ 0 Tc 0 Tw 7.6 0 0 8 145.9155 369.7003 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 127.6874 361.2003 Tm [(9 to)-22 ( )]TJ -0.881 -1.062 Td (15)Tj /Span< >> BDC ( )Tj EMC [(hours)-22 ( )]TJ 0.022 Tw 0.764 -1.062 Td (prior)Tj 0 Tc 0 Tw 7.6 0 0 8 139.0718 344.2003 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 119.3998 335.7003 Tm [(to surger)-18 (y)]TJ 4.578 4.25 Td [(F)18 (irst dose)]TJ 0 Tc 0 Tw 7.6 0 0 8 180.1521 369.7003 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 160.1837 361.2003 Tm [(12 to)-22 ( )]TJ -0.652 -1.062 Td (24)Tj /Span< >> BDC ( )Tj EMC [(hours)-22 ( )]TJ 0.022 Tw 0.818 -1.062 Td [(post)-22 ( )]TJ -0.577 -1.062 Td [(surger)-18 (y)]TJ 0.024 Tw 4.127 4.25 Td [(F)18 (irst dose)]TJ 0 Tc 0 Tw 7.6 0 0 8 214.3888 369.7003 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 196.1607 361.2003 Tm [(9 to)-22 ( )]TJ -0.881 -1.062 Td (15)Tj /Span< >> BDC ( )Tj EMC [(hours)-22 ( )]TJ 0.022 Tw 0.764 -1.062 Td (prior)Tj 0 Tc 0 Tw 7.6 0 0 8 207.5452 344.2003 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 187.8731 335.7003 Tm [(to surger)-18 (y)]TJ 4.578 4.25 Td [(F)18 (irst dose)]TJ 0 Tc 0 Tw 7.6 0 0 8 248.6255 369.7003 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 228.657 361.2003 Tm [(12 to)-22 ( )]TJ -0.652 -1.062 Td (24)Tj /Span< >> BDC ( )Tj EMC [(hours)-22 ( )]TJ 0.022 Tw 0.818 -1.062 Td [(post)-22 ( )]TJ -0.577 -1.062 Td [(surger)-18 (y)]TJ 0.024 Tw 4.193 4.25 Td [(F)18 (irst dose)]TJ 0 Tc 0 Tw 7.6 0 0 8 283.3622 369.7003 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 263.3937 361.2003 Tm [(12 to)-22 ( )]TJ -0.652 -1.062 Td (24)Tj /Span< >> BDC ( )Tj EMC [(hours)-22 ( )]TJ 0.022 Tw 0.818 -1.062 Td (post)Tj 0 Tc 0 Tw 7.6 0 0 8 276.1081 344.2003 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 260.2701 335.7003 Tm [(surger)-18 (y)]TJ 0.024 Tw -29.509 -1.389 Td [(All trea)-9.9 (ted)]TJ 0.022 Tw 6.767 0 Td (N=2673)Tj 4.505 0 Td (N=2659)Tj 4.505 0 Td (N=1501)Tj 4.505 0 Td (N=1508)Tj 4.505 0 Td (N=1596)Tj 4.618 0 Td (N=1588)Tj -29.404 -1.344 Td (Major)Tj 0 Tc 0 Tw 7.6 0 0 8 51.23 313.8364 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 36 305.3364 Tm [(\(inc)20 (luding)-22 ( )]TJ 0.024 Tw 0 -1.062 Td [(surgical site\))-22 ( )]TJ 0.022 Tw 7.781 1.594 Td (22)Tj 0 Tc 0 Tw 7.6 0 0 8 102.2627 309.5864 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 86.9934 301.0864 Tm (\(0.82%\))Tj 0 Tc 0 Tw 4.94 0 0 5.2 108.0223 303.4864 Tm (\206)Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 129.3707 309.5864 Tm (18)Tj 0 Tc 0 Tw 7.6 0 0 8 136.4994 309.5864 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 122.337 301.0864 Tm (\(0.68%\))Tj 0 Tc 0 Tw 5.659 1.062 Td (9)Tj 7.6 0 0 8 168.9957 309.5864 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 155.4668 301.0864 Tm (\(0.60%\))Tj 0 Tc 0 Tw 4.94 0 0 5.2 176.4956 303.4864 Tm (\207)Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 197.844 309.5864 Tm (14)Tj 0 Tc 0 Tw 7.6 0 0 8 204.9727 309.5864 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 190.8103 301.0864 Tm (\(0.93%\))Tj 5.43 1.062 Td (11)Tj 0 Tc 0 Tw 7.6 0 0 8 239.2094 309.5864 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 225.047 301.0864 Tm [(\(0.69%\))-22 ( )]TJ 5.543 1.062 Td (22)Tj 0 Tc 0 Tw 7.6 0 0 8 274.3061 309.5864 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 260.1437 301.0864 Tm (\(1.39%\))Tj 0.374 Tw /Span< >> BDC -29.493 -2.406 Td ( )Tj EMC [(F)20 (a)-10 (tal)]TJ 0 Tc 0 Tw 8.01 0 Td (0)Tj 4.505 0 Td (0)Tj 4.505 0 Td (0)Tj 4.505 0 Td (0)Tj 4.505 0 Td (0)Tj 4.618 0.531 Td (1)Tj 7.6 0 0 8 272.5657 286.0845 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 260.1437 277.5845 Tm (\(0.06%\))Tj -0.218 Tw /Span< >> BDC -29.493 -1.344 Td [( )-592.1 ( )]TJ EMC [(Hgb )-242 (decrease)]TJ 0 Tc 0 Tw 7.6 0 0 8 77.382 266.8326 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 40.5 258.3326 Tm (\0362 g/dL)Tj 0.022 Tw 7.189 1.062 Td (13)Tj 0 Tc 0 Tw 7.6 0 0 8 102.2627 266.8326 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 88.1003 258.3326 Tm (\(0.49%\))Tj 5.43 1.062 Td (10)Tj 0 Tc 0 Tw 7.6 0 0 8 136.4994 266.8326 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 122.337 258.3326 Tm (\(0.38%\))Tj 0 Tc 0 Tw 5.659 1.062 Td (8)Tj 7.6 0 0 8 168.9957 266.8326 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 156.5737 258.3326 Tm (\(0.53%\))Tj 0 Tc 0 Tw 5.659 1.062 Td (9)Tj 7.6 0 0 8 203.2324 266.8326 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 190.8103 258.3326 Tm (\(0.60%\))Tj 5.43 1.062 Td (10)Tj 0 Tc 0 Tw 7.6 0 0 8 239.2094 266.8326 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 225.047 258.3326 Tm (\(0.63%\))Tj 5.543 1.062 Td (16)Tj 0 Tc 0 Tw 7.6 0 0 8 274.3061 266.8326 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 260.1437 258.3326 Tm (\(1.01%\))Tj -0.218 Tw /Span< >> BDC -29.493 -1.344 Td [( )-592.1 ( )]TJ EMC [(T)74 (ransfusion )-242 (of)-22 ( )]TJ 0.024 Tw 0.592 -1.062 Td (\0362 units RBC)Tj 0.022 Tw 7.189 1.062 Td (16)Tj 0 Tc 0 Tw 7.6 0 0 8 102.2627 247.5807 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 88.1003 239.0807 Tm (\(0.60%\))Tj 5.43 1.062 Td (14)Tj 0 Tc 0 Tw 7.6 0 0 8 136.4994 247.5807 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 122.337 239.0807 Tm (\(0.53%\))Tj 0 Tc 0 Tw 5.659 1.062 Td (5)Tj 7.6 0 0 8 168.9957 247.5807 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 156.5737 239.0807 Tm (\(0.33%\))Tj 0 Tc 0 Tw 5.659 1.062 Td (9)Tj 7.6 0 0 8 203.2324 247.5807 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 190.8103 239.0807 Tm (\(0.60%\))Tj 0 Tc 0 Tw 5.659 1.062 Td (9)Tj 7.6 0 0 8 237.469 247.5807 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 225.047 239.0807 Tm (\(0.56%\))Tj 5.543 1.062 Td (18)Tj 0 Tc 0 Tw 7.6 0 0 8 274.3061 247.5807 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 260.1437 239.0807 Tm (\(1.13%\))Tj -0.218 Tw /Span< >> BDC -29.493 -1.344 Td [( )-592.1 ( )]TJ EMC [(Bleed )-242 (a)-10 (t)]TJ 0 Tc 0 Tw 7.6 0 0 8 62.5166 228.3288 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 40.5 219.8288 Tm (critical site)Tj 0 Tc 0 Tw 5.98 0 0 5.98 69.0372 221.3388 Tm (\247)Tj 7.6 0 0 8 96.8744 228.3288 Tm (1)Tj 7.6 0 0 8 100.5224 228.3288 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 88.1003 219.8288 Tm (\(0.04%\))Tj 0 Tc 0 Tw 5.659 1.062 Td (1)Tj 7.6 0 0 8 134.759 228.3288 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 121.4175 219.8288 Tm ( \(0.04%\))Tj 0 Tc 0 Tw 5.78 1.062 Td (1)Tj 7.6 0 0 8 168.9957 228.3288 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 155.6541 219.8288 Tm ( \(0.07%\))Tj 0 Tc 0 Tw 5.78 1.062 Td (2)Tj 7.6 0 0 8 203.2324 228.3288 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 190.8103 219.8288 Tm (\(0.13%\))Tj 0 Tc 0 Tw 5.659 1.062 Td (1)Tj 7.6 0 0 8 237.4691 228.3288 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 225.047 219.8288 Tm (\(0.06%\))Tj 0 Tc 0 Tw 5.772 1.062 Td (4)Tj 7.6 0 0 8 272.5657 228.3288 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 260.1437 219.8288 Tm (\(0.25%\))Tj -29.493 -1.344 Td (Major)Tj 0 Tc 0 Tw 7.6 0 0 8 51.2301 209.0769 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 36.0001 200.5769 Tm (+ CRNM)Tj 0 Tc 0 Tw 5.98 0 0 5.98 59.0279 202.0869 Tm (\266)Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 93.3937 209.0769 Tm (129)Tj 0 Tc 0 Tw 7.6 0 0 8 104.0032 209.0769 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 88.1004 200.5769 Tm (\(4.83%\))Tj 5.201 1.062 Td (134)Tj 0 Tc 0 Tw 7.6 0 0 8 138.2398 209.0769 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 122.337 200.5769 Tm (\(5.04%\))Tj 5.43 1.062 Td (53)Tj 0 Tc 0 Tw 7.6 0 0 8 170.7361 209.0769 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 156.5737 200.5769 Tm (\(3.53%\))Tj 5.43 1.062 Td (72)Tj 0 Tc 0 Tw 7.6 0 0 8 204.9728 209.0769 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 190.8104 200.5769 Tm (\(4.77%\))Tj 5.43 1.062 Td (46)Tj 0 Tc 0 Tw 7.6 0 0 8 239.2095 209.0769 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 225.047 200.5769 Tm (\(2.88%\))Tj 5.543 1.062 Td (68)Tj 0 Tc 0 Tw 7.6 0 0 8 274.3061 209.0769 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 260.1437 200.5769 Tm (\(4.28%\))Tj -29.493 -1.875 Td (All)Tj 7.552 0.531 Td (313)Tj 0 Tc 0 Tw 7.6 0 0 8 104.0032 189.825 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 86.36 181.325 Tm (\(11.71%\))Tj 5.43 1.062 Td (334)Tj 0 Tc 0 Tw 7.6 0 0 8 138.2398 189.825 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 120.5967 181.325 Tm (\(12.56%\))Tj 5.43 1.062 Td (104)Tj 0 Tc 0 Tw 7.6 0 0 8 172.4765 189.825 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 156.5737 181.325 Tm (\(6.93%\))Tj 5.201 1.062 Td (126)Tj 0 Tc 0 Tw 7.6 0 0 8 206.7132 189.825 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 190.8104 181.325 Tm (\(8.36%\))Tj 5.43 1.062 Td (85)Tj 0 Tc 0 Tw 7.6 0 0 8 239.2095 189.825 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 225.047 181.325 Tm (\(5.33%\))Tj 5.314 1.062 Td (108)Tj 0 Tc 0 Tw 7.6 0 0 8 276.0465 189.825 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 260.1437 181.325 Tm [(\(6.80%\))-22 ( )]TJ -0.025 Tc 0.084 Tw -29.469 -1.389 Td (*)Tj /Span< >> BDC ( )Tj EMC 0.49 0 Td [(All bleeding criteria inc)20 (luded surgical site bleeding.)]TJ 0 Tc 0 Tw 5.98 0 0 5.98 36.1761 162.863 Tm (\206)Tj -0.025 Tc 0.244 Tw /Span< >> BDC 7.6 0 0 8 38.9089 161.353 Tm ( )Tj EMC 0.167 0 Td [(Inc)20 (ludes 13 subjects with major bleeding events tha)-10 (t occurred before the first dose of)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(ELIQUIS \(administered 12 to 24 hours post surger)-18 (y\).)]TJ 0 Tc 0 Tw 5.98 0 0 5.98 36.1761 145.503 Tm (\207)Tj -0.025 Tc 0.05 Tw /Span< >> BDC 7.6 0 0 8 38.9089 143.993 Tm ( )Tj EMC 0.167 0 Td [(Inc)20 (ludes 5 subjects with major bleeding events tha)-10 (t occurred before the first dose of ELIQUIS)-25 ( )]TJ 0.084 Tw 0 -1.062 Td (\(administered 12 to 24)Tj /Span< >> BDC ( )Tj EMC [(hours post surger)-18 (y\).)]TJ 0 Tc 0 Tw 5.98 0 0 5.98 36.1761 128.143 Tm (\247)Tj -0.025 Tc 0.212 Tw /Span< >> BDC 7.6 0 0 8 38.9089 126.633 Tm ( )Tj EMC 0.167 0 Td [(Intracranial,)37 ( intraspinal,)37 ( intraocular)74 (,)37 ( pericardial,)37 ( an opera)-10 (ted joint requiring re-opera)-10 (tion or)-25 ( )]TJ 0.094 Tw 0 -1.062 Td [(inter)-17.9 (vention,)37 ( intramuscular with compartment syndrome,)37 ( or retroperitoneal.)37.1 ( Bleeding into an)-25 ( )]TJ 0.21 Tw 0 -1.062 Td [(opera)-10 (ted joint requiring re-opera)-10 (tion or inter)-18 (vention was present in all pa)-10 (tients with this)-25 ( )]TJ 0.262 Tw 0 -1.062 Td [(ca)-10 (tegor)-18 (y of bleeding.)37 ( Events and event ra)-10 (tes inc)20 (lude one enoxa)-9.9 (parin-trea)-10 (ted pa)-9.9 (tient in)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(ADV)37 (ANCE-1 who also had intracranial hemorrha)-10 (ge.)]TJ 0 Tc 0 Tw 5.98 0 0 5.98 36.1761 85.283 Tm (\266)Tj -0.025 Tc 0.084 Tw /Span< >> BDC 7.6 0 0 8 39.3515 83.773 Tm ( )Tj EMC 0.109 0 Td [(CRNM = c)20 (linically relevant nonmajor)74 (.)]TJ 0.23 Tw 8 0 0 8 36.0001 62.823 Tm [(Adverse reactions occurring in \0361% of pa)-10 (tients undergoing hip or knee replacement)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(surger)-18 (y in the 1 Phase II stud)-10 (y and the 3 Phase III studies are listed in )37.1 (T)73.9 (able)]TJ /Span< >> BDC ( )Tj EMC (5.)Tj ET 0.5 w q 1 0 0 1 324 269.4523 cm 0 0 m 42.911 0 l S Q 1 w /GS2 gs q 1 0 0 1 324 715.1481 cm 0 0 m 141.84 0 l S Q 0.5 w q 1 0 0 1 324 665.9243 cm 0 0 m 141.84 0 l S Q q 1 0 0 1 324 646.6724 cm 0 0 m 141.84 0 l S Q q 1 0 0 1 324 635.9205 cm 0 0 m 141.84 0 l S Q q 1 0 0 1 324 616.6685 cm 0 0 m 141.84 0 l S Q q 1 0 0 1 324 580.4166 cm 0 0 m 141.84 0 l S Q q 1 0 0 1 324 552.6647 cm 0 0 m 141.84 0 l S Q q 1 0 0 1 324 541.9128 cm 0 0 m 141.84 0 l S Q q 1 0 0 1 324 676.6762 cm 0 0 m 141.84 0 l S Q 1 w q 1 0 0 1 324 531.1609 cm 0 0 m 141.84 0 l S Q 0.5 w q 1 0 0 1 465.84 665.9243 cm 0 0 m 50.76 0 l S Q q 1 0 0 1 516.6 665.9243 cm 0 0 m 59.4 0 l S Q q 1 0 0 1 465.84 646.6724 cm 0 0 m 50.76 0 l S Q q 1 0 0 1 516.6 646.6724 cm 0 0 m 59.4 0 l S Q q 1 0 0 1 465.84 635.9205 cm 0 0 m 50.76 0 l S Q q 1 0 0 1 516.6 635.9205 cm 0 0 m 59.4 0 l S Q q 1 0 0 1 465.84 616.6685 cm 0 0 m 50.76 0 l S Q q 1 0 0 1 516.6 616.6685 cm 0 0 m 59.4 0 l S Q q 1 0 0 1 465.84 580.4166 cm 0 0 m 50.76 0 l S Q q 1 0 0 1 516.6 580.4166 cm 0 0 m 59.4 0 l S Q q 1 0 0 1 465.84 552.6647 cm 0 0 m 50.76 0 l S Q q 1 0 0 1 516.6 552.6647 cm 0 0 m 59.4 0 l S Q q 1 0 0 1 465.84 541.9128 cm 0 0 m 50.76 0 l S Q q 1 0 0 1 516.6 541.9128 cm 0 0 m 59.4 0 l S Q 1 w q 1 0 0 1 465.84 531.1609 cm 0 0 m 50.76 0 l S Q q 1 0 0 1 516.6 531.1609 cm 0 0 m 59.4 0 l S Q q 1 0 0 1 465.84 715.1481 cm 0 0 m 50.76 0 l S Q q 1 0 0 1 516.6 715.1481 cm 0 0 m 59.4 0 l S Q 0.5 w q 1 0 0 1 465.84 676.6762 cm 0 0 m 50.76 0 l S Q q 1 0 0 1 516.6 676.6762 cm 0 0 m 59.4 0 l S Q BT /GS1 gs /T1_0 1 Tf -0.022 Tc 8 0 0 8 324 727.2482 Tm (Table 5:)Tj /Span< >> BDC ( )Tj EMC 5.4 0 Td [(Adverse Reactions Occurring in \0361% of Patients in Either Group)-22 ( )]TJ 0 -1.062 Td (Undergoing Hip or Knee Replacement Surgery)Tj 0.024 Tw 7.6 0 0 8 470.6053 706.5563 Tm (ELIQUIS, n \(%\))Tj 0 Tc 0 Tw 7.6 0 0 8 511.8346 706.5563 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 471.9656 697.5563 Tm (2.5)Tj /Span< >> BDC ( )Tj EMC 1.237 0 Td (mg po bid)Tj 0 Tc 0 Tw 7.6 0 0 8 510.4743 697.5563 Tm ( )Tj -2.642 -1.125 Td ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 479.8809 679.5563 Tm (N=5924)Tj -0.027 Tc 0.024 Tw 7.44 0 0 8 521.5104 706.5563 Tm (Enoxaparin, n \(%\))Tj 0 Tc 0 Tw 7.44 0 0 8 571.0897 706.5563 Tm ( )Tj -0.022 Tc 0.024 Tw 7.44 0 0 8 525.5836 697.5563 Tm (40)Tj /Span< >> BDC ( )Tj EMC 1.019 0 Td (mg sc qd or)Tj 0 Tc 0 Tw 7.44 0 0 8 567.0164 697.5563 Tm ( )Tj -0.022 Tc 0.024 Tw 7.44 0 0 8 525.9369 688.5563 Tm (30)Tj /Span< >> BDC ( )Tj EMC 1.019 0 Td (mg sc q12h)Tj 0 Tc 0 Tw 7.44 0 0 8 566.663 688.5563 Tm ( )Tj -0.022 Tc 0.022 Tw 7.44 0 0 8 535.1996 679.5563 Tm (N=5904)Tj /T1_1 1 Tf 7.6 0 0 8 324 668.4443 Tm (Nausea)Tj 0.024 Tw 20.398 0 Td (153 \(2.6\))Tj 7.247 0 Td (159 \(2.7\))Tj -27.645 -1.344 Td [(Anemia \(inc)20 (luding postopera)-10 (tive and hemorrha)-9.9 (gic)-22 ( )]TJ 0 -1.062 Td [(anemia,)37 ( and respective labora)-10 (tor)-18 (y parameters\))]TJ 20.398 0.531 Td (153 \(2.6\))Tj 7.247 0 Td (178 \(3.0\))Tj 0.022 Tw -27.645 -1.875 Td (Contusion)Tj 0.024 Tw 20.627 0 Td (83 \(1.4\))Tj 7.018 0 Td (115 \(1.9\))Tj -27.645 -1.344 Td [(Hemorrha)-10 (ge \(inc)20 (luding hema)-9.9 (toma,)37 ( and va)-9.9 (ginal)]TJ 0 Tc 0 Tw 7.6 0 0 8 448.8801 627.6886 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 324 619.1886 Tm [(and urethral hemorrha)-9.9 (ge\))]TJ 20.627 0.531 Td (67 \(1.1\))Tj 7.247 0 Td (81 \(1.4\))Tj -27.874 -1.875 Td [(P)18 (ostprocedural hemorrha)-9.9 (ge \(inc)20 (luding)-22 ( )]TJ 0 -1.062 Td [(postprocedural hema)-10 (toma,)37 ( wound hemorrha)-10 (ge,)15 ( )]TJ 0 -1.062 Td [(vessel puncture-site hema)-9.9 (toma,)37 ( and ca)-9.9 (theter)37 (-site)-22 ( )]TJ 0.022 Tw 0 -1.062 Td [(hemorrha)-9.9 (ge\))]TJ 0.024 Tw 20.627 1.594 Td (54 \(0.9\))Tj 7.247 0 Td (60 \(1.0\))Tj -27.874 -2.938 Td [(T)74 (ransaminases increased \(inc)20 (luding alanine)-22 ( )]TJ 0 -1.062 Td [(aminotransferase increased and alanine)-21.9 ( )]TJ 0 -1.062 Td (aminotransferase abnormal\))Tj 20.627 1.062 Td (50 \(0.8\))Tj 7.247 0 Td (71 \(1.2\))Tj -27.874 -2.406 Td [(Asparta)-9.9 (te aminotransferase increased)]TJ 20.627 0 Td (47 \(0.8\))Tj 7.247 0 Td (69 \(1.2\))Tj -27.874 -1.344 Td (Gamma-glutamyltransferase increased)Tj 20.627 0 Td (38 \(0.6\))Tj 7.247 0 Td (65 \(1.1\))Tj -0.025 Tc 0.255 Tw 8 0 0 8 324 510.7823 Tm [(Less common adverse reactions in ELIQUIS-trea)-9.9 (ted pa)-10 (tients undergoing hip or knee)-25 ( )]TJ 0.084 Tw 0 -1.072 Td [(replacement surger)-17.9 (y occurring a)-9.9 (t a frequenc)20 (y of \0360.1% to <1%:)]TJ /T1_3 1 Tf 0.4 Tw 0 -1.441 Td [(Blood and lympha)-9.9 (tic )]TJ 0 Tc 0 Tw (s)Tj 8.847 0 Td (y)Tj 0.381 0 Td (s)Tj -0.025 Tc 0.4 Tw 0.382 0 Td (tem di)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.025 Tw 2.964 0 Td (order)Tj 0 Tc 0 Tw (s)Tj 2.2 0 Td (:)Tj /T1_1 1 Tf -0.025 Tc 0.4 Tw /Span< >> BDC 0.215 0 Td ( )Tj EMC 0.017 0 Td [( thromboc)20 (ytopenia \(inc)20 (luding pla)-10 (telet count)-25 ( )]TJ 0.025 Tw -15.006 -1.072 Td (decreases\))Tj /T1_3 1 Tf -0.043 Tc 0.043 Tw 0 -1.441 Td (Va)Tj 0 Tc 0 Tw 0.838 0 Td (s)Tj -0.025 Tc 0.084 Tw 0.382 0 Td (cular di)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.025 Tw 3.006 0 Td (order)Tj 0 Tc 0 Tw (s)Tj -0.223 Tw /Span< >> BDC 2.2 0 Td ( )Tj EMC (:)Tj /T1_1 1 Tf -0.025 Tc 0.084 Tw /Span< >> BDC 0.232 0 Td ( )Tj EMC 0.017 0 Td [( hypotension \(inc)20 (luding procedural hypotension\))]TJ /T1_3 1 Tf 0.025 Tw -6.674 -1.441 Td (Re)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.084 Tw 1.295 0 Td [(pira)-9.9 (tor)-18 (y)55 (,)37 ( thoracic,)37 ( and media)]TJ 0 Tc 0 Tw (s)Tj -0.025 Tc 0.084 Tw 10.429 0 Td (tinal di)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.025 Tw 2.747 0 Td (order)Tj 0 Tc 0 Tw (s)Tj 2.2 0 Td (:)Tj /T1_1 1 Tf -0.025 Tc -0.198 Tw /Span< >> BDC 0.215 0 Td ( )Tj EMC [( )-281.9 (epistaxis)]TJ /T1_3 1 Tf 0.025 Tw -16.886 -1.441 Td (Ga)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.025 Tw 1.313 0 Td (trointe)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.433 Tw 2.576 0 Td (tinal di)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.025 Tw 3.096 0 Td (order)Tj 0 Tc 0 Tw (s)Tj 2.2 0 Td (:)Tj /T1_1 1 Tf -0.025 Tc 0.433 Tw /Span< >> BDC 0.215 0 Td ( )Tj EMC 0.017 0 Td [( gastrointestinal hemorrha)-10 (ge \(inc)20 (luding hema)-10 (temesis and)-25 ( )]TJ 0.084 Tw -9.417 -1.072 Td [(melena\),)37 ( hema)-10 (tochezia)]TJ /T1_3 1 Tf 0.487 Tw 0 -1.441 Td [(Hepa)-9.9 (tobiliar)-18 (y di)]TJ 0 Tc 0 Tw (s)Tj -0.025 Tc 0.025 Tw 6.215 0 Td (order)Tj 0 Tc 0 Tw (s)Tj 2.2 0 Td (:)Tj /T1_1 1 Tf -0.025 Tc 0.487 Tw /Span< >> BDC 0.215 0 Td ( )Tj EMC 0.017 0 Td [( liver function test abnormal,)37 ( blood alkaline phospha)-9.9 (tase)-25 ( )]TJ 0.084 Tw -8.647 -1.072 Td [(increased,)37 ( blood bilirubin increased)]TJ /T1_3 1 Tf 0 -1.441 Td [(Renal and urinar)-18 (y di)]TJ 0 Tc 0 Tw (s)Tj -0.025 Tc 0.025 Tw 7.555 0 Td (order)Tj 0 Tc 0 Tw (s)Tj 2.2 0 Td (:)Tj /T1_1 1 Tf -0.025 Tc 0.084 Tw /Span< >> BDC 0.215 0 Td ( )Tj EMC 0.017 0 Td [( hema)-10 (turia \(inc)20 (luding respective labora)-9.9 (tor)-18 (y parameters\))]TJ /T1_3 1 Tf 0.014 Tw -9.986 -1.441 Td [(Injur)-17.9 (y)55 (,)37 ( poi)]TJ 0 Tc 0 Tw (s)Tj -0.025 Tc 0.014 Tw 3.674 0 Td [(oning,)37 ( and procedural complica)-10 (tion)]TJ 0 Tc 0 Tw (s)Tj 12.561 0 Td (:)Tj /T1_1 1 Tf -0.025 Tc 0.014 Tw /Span< >> BDC 0.215 0 Td ( )Tj EMC 0.017 0 Td [( wound secretion,)37 ( incision-site hemorrha)-10 (ge)-25 ( )]TJ 0.084 Tw -16.467 -1.072 Td [(\(inc)20 (luding incision-site hema)-9.9 (toma\),)37 ( opera)-9.9 (tive hemorrha)-9.9 (ge)]TJ 0.255 Tw 0 -1.441 Td [(Less common adverse reactions in ELIQUIS-trea)-9.9 (ted pa)-10 (tients undergoing hip or knee)-25 ( )]TJ 0.084 Tw 0 -1.072 Td [(replacement surger)-17.9 (y occurring a)-9.9 (t a frequenc)20 (y of <0.1%:)]TJ 0.177 Tw 0 -1.441 Td [(Gingival )0.5 (bleeding,)37 ( )0.5 (hemoptysis,)37 ( )0.6 (hypersensitivity)55 (,)37.1 ( )0.5 (musc)20 (le )0.5 (hemorrha)-9.9 (ge,)37 ( )0.5 (ocular )0.5 (hemorrha)-10 (ge)-25 ( )]TJ 0.084 Tw 0 -1.072 Td [(\(inc)20 (luding conjunctival hemorrha)-10 (ge\),)37.1 ( rectal hemorrha)-10 (ge)]TJ /T1_2 1 Tf 0 -1.666 Td [(T)74 (r)6 (eatment of DVT and PE and Reduction in the Risk of Recurr)6 (ence of DVT or PE)]TJ /T1_1 1 Tf 0.214 Tw 0 -1.297 Td [(The )0.5 (safety )0.5 (of )0.5 (ELIQUIS has been )0.5 (evalua)-9.9 (ted )0.5 (in )0.5 (the )37.5 (AMPLIFY )0.5 (and )37.4 (AMPLIFY)74 (-EXT studies,)12 ( )]TJ 0.169 Tw 0 -1.072 Td [(inc)20 (luding 2676 pa)-9.9 (tients exposed to ELIQUIS 10)]TJ /Span< >> BDC ( )Tj EMC 17.374 0 Td [(mg twice daily)55 (,)37 ( 3359 pa)-9.9 (tients exposed)-24.9 ( )]TJ 0.084 Tw -17.374 -1.072 Td (to ELIQUIS 5)Tj /Span< >> BDC ( )Tj EMC 4.634 0 Td [(mg twice daily)55 (,)37 ( and 840 pa)-9.9 (tients exposed to ELIQUIS 2.5)]TJ /Span< >> BDC ( )Tj EMC 20.416 0 Td [(mg twice daily)55 (.)]TJ 0.052 Tw -25.049 -1.522 Td [(Common adverse reactions \(\0361%\) were gingival bleeding,)37 ( epistaxis,)37 ( contusion,)37 ( hema)-10 (turia,)12 ( )]TJ 0.084 Tw 0 -1.072 Td [(rectal hemorrha)-9.9 (ge,)37 ( hema)-9.9 (toma,)37.1 ( menorrha)-10 (gia,)37.1 ( and hemoptysis.)]TJ 0 -1.86 Td [(AMPLIFY Stud)-10 (y)]TJ 0.051 Tw 0 -1.522 Td [(The mean dura)-10 (tion of exposure to ELIQUIS was 154 days and to enoxa)-9.9 (parin/warfarin was)-25 ( )]TJ 0.155 Tw 0 -1.072 Td [(152 days in the )37 (AMPLIFY stud)-10 (y)55 (.)37 ( )37 (Adverse reactions rela)-10 (ted to bleeding occurred in 417)-25 ( )]TJ 0.144 Tw 0 -1.072 Td [(\(15.6%\) ELIQUIS-trea)-9.9 (ted pa)-10 (tients compared to 661 \(24.6%\) enoxa)-9.9 (parin/warfarin-trea)-10 (ted)-25 ( )]TJ 0.039 Tw 0 -1.072 Td [(pa)-10 (tients.)37 ( )37.5 (The )0.5 (discontinua)-10 (tion ra)-9.9 (te )0.5 (due )0.5 (to )0.5 (bleeding )0.5 (events )0.5 (was )0.5 (0.7% )0.5 (in the )0.5 (ELIQUIS-trea)-10 (ted)-25 ( )]TJ 0.074 Tw 0 -1.072 Td [(pa)-10 (tients compared to 1.7% in enoxa)-10 (parin/warfarin-trea)-9.9 (ted pa)-10 (tients in the )37.2 (AMPLIFY stud)-10 (y)55 (.)]TJ 0.209 Tw 0 -1.522 Td [(In the )36.6 (AMPLIFY stud)-9.9 (y)55 (,)37 ( ELIQUIS was sta)-9.9 (tistically superior to enoxa)-10 (parin/warfarin in the)-25 ( )]TJ 0.053 Tw 0 -1.072 Td [(primar)-18 (y safety endpoint of major bleeding \(rela)-9.9 (tive risk 0.31,)37 ( 95% CI [0.17,)37 ( 0.55],)37 ( P-value)-24.9 ( )]TJ 0.025 Tw 0 -1.072 Td (<0.0001\).)Tj 0.084 Tw 0 -1.522 Td [(Bleeding results from the )37 (AMPLIFY stud)-10 (y are summarized in )37 (T)74 (able 6.)]TJ ET 1 w /GS2 gs q 1 0 0 1 324 157.7534 cm 0 0 m 56.88 0 l S Q q 1 0 0 1 380.88 157.7534 cm 0 0 m 65.04 0 l S Q q 1 0 0 1 445.92 157.7534 cm 0 0 m 65.04 0 l S Q q 1 0 0 1 510.96 157.7534 cm 0 0 m 65.04 0 l S Q q 1 0 0 1 324 65.802 cm 0 0 m 56.88 0 l S Q q 1 0 0 1 380.88 65.802 cm 0 0 m 65.04 0 l S Q q 1 0 0 1 445.92 65.802 cm 0 0 m 65.04 0 l S Q q 1 0 0 1 510.96 65.802 cm 0 0 m 65.04 0 l S Q 0.5 w q 1 0 0 1 324 36.2501 cm 0 0 m 56.88 0 l S Q q 1 0 0 1 380.88 36.2501 cm 0 0 m 65.04 0 l S Q q 1 0 0 1 445.92 36.2501 cm 0 0 m 65.04 0 l S Q q 1 0 0 1 510.96 36.2501 cm 0 0 m 65.04 0 l S Q q 1 0 0 1 324 128.5615 cm 0 0 m 56.88 0 l S Q q 1 0 0 1 380.88 128.5615 cm 0 0 m 65.04 0 l S Q q 1 0 0 1 445.92 128.5615 cm 0 0 m 65.04 0 l S Q q 1 0 0 1 510.96 128.5615 cm 0 0 m 65.04 0 l S Q BT /GS1 gs /T1_0 1 Tf -0.022 Tc 8 0 0 8 324 161.3535 Tm (Table 6:)Tj /Span< >> BDC ( )Tj EMC 5.4 0 Td [(Bleeding Results in the AMPLIFY Study)-22 ( )]TJ 0.022 Tw 7.6 0 0 8 402.2243 149.1615 Tm (ELIQUIS)Tj 0 Tc 0 Tw 7.6 0 0 8 424.5757 149.1615 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 402.0609 140.6615 Tm (N=2676)Tj 0 Tc 0 Tw 7.6 0 0 8 424.7391 140.6615 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 405.6253 132.1615 Tm (n \(%\))Tj 0.022 Tw 5.672 2.125 Td (Enoxaparin/Warfarin)Tj 0 Tc 0 Tw 7.6 0 0 8 508.1478 149.1615 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 467.1009 140.6615 Tm (N=2689)Tj 0 Tc 0 Tw 7.6 0 0 8 489.7791 140.6615 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 470.6653 132.1615 Tm (n \(%\))Tj 7.119 2.125 Td [(Relative Risk)-22 ( )]TJ 0 Tc 0 Tw 7.6 0 0 8 563.8589 149.1615 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 531.1873 140.6615 Tm (\(95% CI\))Tj /T1_1 1 Tf 0.022 Tw -27.261 -3.104 Td (Major)Tj -0.065 Tw /Span< >> BDC 7.484 0 Td ( )Tj EMC 3.163 0 Td (15 )Tj /Span< >> BDC 1.158 0 Td ( )Tj EMC (\(0.6\))Tj /Span< >> BDC 4.237 0 Td ( )Tj EMC 3.163 0 Td (49 )Tj /Span< >> BDC 1.158 0 Td ( )Tj EMC (\(1.8\))Tj 0.024 Tw 5.565 0.562 Td [(0.31 \(0.17,)37 ( 0.55\))]TJ 0 Tc 0 Tw 7.6 0 0 8 565.9034 120.3296 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 529.994 111.3296 Tm (p<0.0001)Tj -27.104 -1.344 Td (CRNM)Tj 0 Tc 0 Tw 6.5 0 0 6.5 340.796 102.0777 Tm (*)Tj -0.022 Tc -0.065 Tw /Span< >> BDC 7.6 0 0 8 380.8801 100.5777 Tm ( )Tj EMC 2.705 0 Td (103 )Tj /Span< >> BDC 1.616 0 Td ( )Tj EMC (\(3.9\))Tj /Span< >> BDC 4.237 0 Td ( )Tj EMC 2.705 0 Td (215 )Tj /Span< >> BDC 1.616 0 Td ( )Tj EMC (\(8.0\))Tj 0.024 Tw -20.363 -1.344 Td (Major + CRNM)Tj -0.065 Tw /Span< >> BDC 7.484 0 Td ( )Tj EMC 2.705 0 Td (115 )Tj /Span< >> BDC 1.616 0 Td ( )Tj EMC (\(4.3\))Tj /Span< >> BDC 4.237 0 Td ( )Tj EMC 2.705 0 Td (261 )Tj /Span< >> BDC 1.616 0 Td ( )Tj EMC (\(9.7\))Tj 0.022 Tw -20.363 -1.344 Td (Minor)Tj -0.065 Tw /Span< >> BDC 7.484 0 Td ( )Tj EMC 2.705 0 Td (313 )Tj /Span< >> BDC 1.616 0 Td ( )Tj EMC (\(11.7\))Tj /Span< >> BDC 4.237 0 Td ( )Tj EMC 2.705 0 Td (505 )Tj /Span< >> BDC 1.616 0 Td ( )Tj EMC (\(18.8\))Tj 0.022 Tw -20.363 -1.344 Td (All)Tj -0.065 Tw /Span< >> BDC 7.484 0 Td ( )Tj EMC 2.705 0 Td (402 )Tj /Span< >> BDC 1.616 0 Td ( )Tj EMC (\(15.0\))Tj /Span< >> BDC 4.237 0 Td ( )Tj EMC 2.705 0 Td (676 )Tj /Span< >> BDC 1.616 0 Td ( )Tj EMC (\(25.1\))Tj -0.025 Tc 0.084 Tw -20.34 -1.479 Td (*)Tj /Span< >> BDC ( )Tj EMC 0.427 0 Td [(CRNM = c)20 (linically relevant nonmajor bleeding.)]TJ 0.081 Tw -0.45 -1.107 Td [(Events associa)-9.9 (ted with each endpoint were counted once per subject,)37 ( but subjects may ha)-10 (ve)-24.9 ( )]TJ 0.084 Tw 0 -1.062 Td (contributed events to multiple endpoints.)Tj ET endstream endobj 342 0 obj <>stream q /GS0 gs 0 TL/Fm0 Do Q 0 0 0 1 K 0.5 w /GS1 gs q 1 0 0 1 36 396.428 cm 0 0 m 237.196 0 l S Q BT 0 0 0 1 k /T1_0 1 Tf -0.025 Tc 0.025 Tw 8 0 0 8 36 727.248 Tm (5.6)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td [(Increased Risk of Thrombosis in P)24 (atients with T)74 (riple P)24 (ositive)-25 ( )]TJ 0 -1.062 Td (Antiphospholipid Syndrome)Tj /T1_1 1 Tf 0.17 Tw -3.375 -1.512 Td [(Direct-acting oral anticoa)-9.9 (gulants \(DOACs\),)37 ( inc)20 (luding ELIQUIS,)37 ( are not recommended for)-25 ( )]TJ 0.05 Tw 0 -1.062 Td [(use in pa)-9.9 (tients with triple-positive antiphospholipid syndrome \(APS\).)37 ( F)20 (or pa)-9.9 (tients with )37.2 (APS)-25 ( )]TJ 0.139 Tw 0 -1.062 Td [(\(especially those who are triple positive [positive for lupus anticoa)-10 (gulant,)37 ( anticardiolipin,)12 ( )]TJ 0.151 Tw 0 -1.062 Td [(and anti\226beta 2-glycoprotein I antibodies]\),)37 ( trea)-9.9 (tment with DOACs has been associa)-10 (ted)-25 ( )]TJ 0.103 Tw 0 -1.062 Td [(with increased ra)-10 (tes of recurrent thrombotic events compared with vitamin K anta)-10 (gonist)-25 ( )]TJ 0.025 Tw 0 -1.062 Td [(thera)-10 (py)55 (.)]TJ /T1_0 1 Tf 0 -1.85 Td (6)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td (ADVERSE REACTIONS)Tj /T1_1 1 Tf 0.2 Tw -3.375 -1.58 Td [(The )0.5 (follo)-10 (wing )0.5 (c)20 (linically )0.5 (signi\037cant )0.5 (adverse )0.5 (reactions )0.5 (are )0.5 (discussed )0.5 (in )0.5 (grea)-10 (ter )0.5 (detail )0.5 (in)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(other sections of the prescribing informa)-10 (tion.)]TJ 0.025 Tw 0 -1.423 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.112 Tw 1.625 0 Td [(Increased Risk of )37.4 (Thrombotic Events )37.4 (After Prema)-10 (ture Discontinua)-10 (tion )]TJ /T1_2 1 Tf 0.075 Tw [([see W)18 (arnings)-25 ( )]TJ 0.084 Tw 0 -1.062 Td (and Precautions \(5.1\)])Tj /T1_1 1 Tf 0.025 Tw -1.625 -1.332 Td (\225)Tj /Span< >> BDC ( )Tj EMC 1.625 0 Td (Bleeding )Tj /T1_2 1 Tf 0.084 Tw 3.303 0 Td [([see )37 (W)18 (arnings and Precautions \(5.2\)])]TJ /T1_1 1 Tf 0.025 Tw -4.928 -1.332 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.625 0 Td [(Spinal/Epidural )37 (Anesthesia or Puncture )]TJ /T1_2 1 Tf [([see )37 (W)18 (arnings and Precautions \(5.3\)])]TJ /T1_0 1 Tf 0.025 Tw -1.625 -1.76 Td (6.1)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td [(Clinical T)74 (rials Experience)]TJ /T1_3 1 Tf 0.084 Tw -3.375 -1.512 Td (Adult Patients)Tj /T1_1 1 Tf 0.164 Tw 0 -1.288 Td [(Because c)20 (linical trials are conducted under widely var)-18 (ying conditions,)37 ( adverse reaction)-25 ( )]TJ 0.089 Tw 0 -1.062 Td [(ra)-10 (tes obser)-18 (ved in the c)20 (linical trials of a drug cannot be directly compared to ra)-10 (tes in the)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(c)20 (linical trials of another drug and may not re\035ect the ra)-9.9 (tes obser)-18 (ved in practice.)]TJ /T1_4 1 Tf 0.045 Tw 0 -1.737 Td [(Reduction of Risk of Strok)6 (e and Systemic Embolism in Patients with Nonv)12 (alvular )36.8 (Atrial)-25 ( )]TJ 0.025 Tw 0 -1.062 Td (Fibrillation)Tj /T1_1 1 Tf 0.24 Tw 0 -1.288 Td [(The safety of ELIQUIS was evalua)-10 (ted in the )37.1 (ARISTOTLE and )37 (A)20 (VERROES studies )]TJ /T1_2 1 Tf 0 Tc 0 Tw ([)Tj 30.255 0 Td (s)Tj -0.025 Tc 0.025 Tw 0.382 0 Td [(ee)-25 ( )]TJ -30.637 -1.062 Td (Clinical)Tj 0.079 Tw ( Studie)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.079 Tw 5.327 0 Td ( \(14\)])Tj /T1_1 1 Tf [(,)37 ( inc)20 (luding 11,284 pa)-9.9 (tients exposed to ELIQUIS 5)]TJ /Span< >> BDC ( )Tj EMC 19.386 0 Td [(mg twice daily and)-25 ( )]TJ 0.152 Tw -24.712 -1.062 Td [(602 pa)-9.9 (tients exposed to ELIQUIS 2.5)]TJ /Span< >> BDC ( )Tj EMC 13.556 0 Td [(mg twice daily)55 (.)37 ( )36.8 (The dura)-10 (tion of ELIQUIS exposure)-25 ( )]TJ 0.062 Tw -13.556 -1.062 Td [(was )0.5 (\03612 months )0.5 (for 9375 pa)-9.9 (tients )0.5 (and )0.5 (\03624 months for 3369 pa)-10 (tients in the )0.5 (two )0.5 (studies.)12 ( )]TJ 0.172 Tw 0 -1.062 Td [(In )36.8 (ARISTOTLE,)37 ( the mean dura)-9.9 (tion of exposure was 89 weeks \(>15,000 pa)-9.9 (tient-years\).)12 ( )]TJ 0 Tc 0 Tw 31.5 0 Td ( )Tj -0.025 Tc 0.251 Tw -31.5 -1.062 Td [(In )37.2 (A)19.9 (VERROES,)37 ( the mean dura)-10 (tion of exposure was a)-10 (pproxima)-9.9 (tely 59 weeks \(>3000)-25 ( )]TJ 0.025 Tw 0 -1.062 Td [(pa)-10 (tient-years\).)]TJ 0.055 Tw 0 -1.512 Td [(The most common reason for trea)-10 (tment discontinua)-10 (tion in both studies was for bleeding-)]TJ 0.217 Tw 0 -1.062 Td [(rela)-9.9 (ted adverse reactions; in )36.7 (ARISTOTLE this occurred in 1.7% and 2.5% of pa)-9.9 (tients)-25 ( )]TJ 0.092 Tw 0 -1.062 Td [(trea)-9.9 (ted with ELIQUIS and warfarin,)37 ( respectively)55 (,)37.1 ( and in )37.2 (A)20 (VERROES,)37 ( in 1.5% and 1.3% on)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(ELIQUIS and aspirin,)37 ( respectively)55 (.)]TJ 0 -1.85 Td [(Bleeding in P)18.1 (a)-10 (tients with Nonvalvular )37 (Atrial F)18 (ibrilla)-10 (tion in )37 (ARISTOTLE and )37.1 (A)20 (VERROES)]TJ 0.197 Tw 0 -1.512 Td [(T)74 (ables 2 and 3 sho)-10 (w the number of pa)-10 (tients experiencing major bleeding during the)-24.9 ( )]TJ 0.063 Tw 0 -1.062 Td [(trea)-9.9 (tment period )0.5 (and )0.5 (the )0.5 (bleeding )0.5 (ra)-9.9 (te )0.5 (\(percenta)-10 (ge )0.5 (of )0.5 (subjects )0.5 (with )0.5 (a)-9.9 (t )0.5 (least )0.5 (one )0.5 (bleeding)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(event per 100 pa)-9.9 (tient-years\) in )37 (ARISTOTLE and )37 (A)20 (VERROES.)]TJ ET 1 w /GS2 gs q 1 0 0 1 324 715.1481 cm 0 0 m 72 0 l S Q q 1 0 0 1 396 715.1481 cm 0 0 m 47.88 0 l S Q q 1 0 0 1 443.88 715.1481 cm 0 0 m 47.88 0 l S Q q 1 0 0 1 491.76 715.1481 cm 0 0 m 54.72 0 l S Q q 1 0 0 1 546.48 715.1481 cm 0 0 m 29.24 0 l S Q q 1 0 0 1 324 590.7208 cm 0 0 m 72 0 l S Q q 1 0 0 1 396 590.7208 cm 0 0 m 47.88 0 l S Q q 1 0 0 1 443.88 590.7208 cm 0 0 m 47.88 0 l S Q q 1 0 0 1 491.76 590.7208 cm 0 0 m 54.72 0 l S Q q 1 0 0 1 546.48 590.7208 cm 0 0 m 29.24 0 l S Q 0.5 w q 1 0 0 1 324 465.5089 cm 0 0 m 72 0 l S Q q 1 0 0 1 396 465.5089 cm 0 0 m 47.88 0 l S Q q 1 0 0 1 443.88 465.5089 cm 0 0 m 47.88 0 l S Q q 1 0 0 1 491.76 465.5089 cm 0 0 m 54.72 0 l S Q q 1 0 0 1 546.48 465.5089 cm 0 0 m 29.24 0 l S Q q 1 0 0 1 324 676.7361 cm 0 0 m 72 0 l S Q q 1 0 0 1 396 676.7361 cm 0 0 m 47.88 0 l S Q q 1 0 0 1 443.88 676.7361 cm 0 0 m 47.88 0 l S Q q 1 0 0 1 491.76 676.7361 cm 0 0 m 54.72 0 l S Q q 1 0 0 1 546.48 676.7361 cm 0 0 m 29.24 0 l S Q BT /GS1 gs /T1_0 1 Tf -0.022 Tc 8 0 0 8 324 727.248 Tm (Table 2:)Tj /Span< >> BDC ( )Tj EMC 5.4 0 Td [(Bleeding Events in Patients with Nonvalvular Atrial Fibrillation)-22 ( )]TJ 0 -1.062 Td (in ARISTOTLE)Tj 0 Tc 0 Tw 6.5 0 0 6.5 408.3916 720.248 Tm (*)Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 408.7643 705.8361 Tm (ELIQUIS)Tj 0 Tc 0 Tw 7.6 0 0 8 431.1157 705.8361 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 408.601 697.3361 Tm (N=9088)Tj 0 Tc 0 Tw 7.6 0 0 8 431.2791 697.3361 Tm ( )Tj -0.022 Tc -0.056 Tw 7.6 0 0 8 411.7093 688.8361 Tm [(n \(per)-22 ( )]TJ 0 Tc 0 Tw 7.6 0 0 8 429.8426 688.8361 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 402.4413 680.3361 Tm [(1)40 (00 pt-year\))]TJ 0.022 Tw 6.967 3.188 Td (Warfarin)Tj 0 Tc 0 Tw 7.6 0 0 8 480.2457 705.8361 Tm ( )Tj -0.022 Tc 0.022 Tw 7.6 0 0 8 456.481 697.3361 Tm (N=9052)Tj 0 Tc 0 Tw 7.6 0 0 8 479.1591 697.3361 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 459.5893 688.8361 Tm [(n)80 ( \(per)-22 ( )]TJ 0 Tc 0 Tw 7.6 0 0 8 477.7226 688.8361 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 450.3214 680.3361 Tm [(1)40 (00 pt-year\))]TJ 6.626 3.188 Td (Hazard Ratio)Tj 0 Tc 0 Tw 7.6 0 0 8 537.5573 705.8361 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 506.8272 697.3361 Tm (\(95% CI\))Tj 0.022 Tw 5.699 1.062 Td (P-value)Tj /T1_1 1 Tf -29.755 -4.666 Td (Major)Tj 0 Tc 0 Tw 4.94 0 0 5.2 339.0628 670.9042 Tm (\206)Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 406.0018 668.5042 Tm (327 \(2.13\))Tj 6.3 0 Td (462 \(3.09\))Tj 5.634 0 Td [(0.69 \(0.60,)37 ( 0.80\))]TJ 0.022 Tw 6.92 0 Td (<0.0001)Tj 0.024 Tw /Span< >> BDC -29.643 -1.344 Td ( )Tj EMC 0.592 0 Td (Intracranial \(ICH\))Tj 0 Tc 0 Tw 4.94 0 0 5.2 372.2521 660.1523 Tm (\207)Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 407.7422 657.7523 Tm (52 \(0.33\))Tj 6.071 0 Td (125 \(0.82\))Tj 5.634 0 Td [(0.41 \(0.30,)37 ( 0.57\))]TJ 0 Tc 0 Tw 8.298 0 Td (-)Tj -0.022 Tc 0.024 Tw /Span< >> BDC -31.021 -1.344 Td ( )Tj EMC 0.592 0 Td [(Hemorrha)-10 (gic stroke)]TJ 0 Tc 0 Tw 4.94 0 0 5.2 381.0221 649.4004 Tm (\247)Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 407.7422 647.0004 Tm (38 \(0.24\))Tj 6.3 0 Td (74 \(0.49\))Tj 5.405 0 Td [(0.51 \(0.34,)37 ( 0.75\))]TJ 0 Tc 0 Tw 8.298 0 Td (-)Tj -0.022 Tc 0.024 Tw /Span< >> BDC -31.021 -1.344 Td ( )Tj EMC 0.592 0 Td (Other ICH)Tj 10.427 0 Td (15 \(0.10\))Tj 6.3 0 Td (51 \(0.34\))Tj 5.405 0 Td [(0.29 \(0.16,)37 ( 0.51\))]TJ 0 Tc 0 Tw 8.298 0 Td (-)Tj -0.022 Tc 0.024 Tw /Span< >> BDC -31.021 -1.344 Td ( )Tj EMC 0.592 0 Td (Gastrointestinal \(GI\))Tj 0 Tc 0 Tw 4.94 0 0 5.2 379.8974 627.8966 Tm (\266)Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 406.0018 625.4966 Tm (128 \(0.83\))Tj 6.3 0 Td (141 \(0.93\))Tj 5.634 0 Td [(0.89 \(0.70,)37 ( 1.14\))]TJ 0 Tc 0 Tw 8.298 0 Td (-)Tj -0.022 Tc 0.374 Tw /Span< >> BDC -31.021 -1.344 Td ( )Tj EMC [(F)20 (a)-10 (tal)]TJ 0.022 Tw 7.6 0 0 7.2 341.2296 614.7446 Tm (**)Tj 0.024 Tw 7.6 0 0 8 407.7422 614.7446 Tm (10 \(0.06\))Tj 6.3 0 Td (37 \(0.24\))Tj 5.405 0 Td [(0.27 \(0.13,)37 ( 0.53\))]TJ 0 Tc 0 Tw 8.298 0 Td (-)Tj -0.022 Tc 0.374 Tw /Span< >> BDC -31.021 -1.344 Td ( )Tj EMC (Intracranial)Tj 0.024 Tw 11.248 0 Td (4 \(0.03\))Tj 6.071 0 Td (30 \(0.20\))Tj 5.405 0 Td [(0.13 \(0.05,)37 ( 0.37\))]TJ 0 Tc 0 Tw 8.298 0 Td (-)Tj -0.022 Tc 0.374 Tw /Span< >> BDC -31.021 -1.344 Td ( )Tj EMC (Non-intracranial)Tj 0.024 Tw 11.248 0 Td (6 \(0.04\))Tj 6.3 0 Td (7 \(0.05\))Tj 5.176 0 Td [(0.84 \(0.28,)37 ( 2.15\))]TJ 0 Tc 0 Tw 8.298 0 Td (-)Tj -0.025 Tc 0.263 Tw -30.998 -1.479 Td (*)Tj /Span< >> BDC ( )Tj EMC 0.527 0 Td [(Bleeding events within each subca)-10 (tegor)-18 (y were counted once per subject,)37 ( but subjects)-25 ( )]TJ 0.169 Tw -0.001 -1.062 Td [(may ha)-10 (ve contributed events to multiple endpoints.)37 ( Bleeding events were counted during)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(trea)-10 (tment or within 2 days of stopping stud)-10 (y trea)-10 (tment \(on-trea)-9.9 (tment period\).)]TJ 0 Tc 0 Tw 5.98 0 0 5.98 324.176 557.059 Tm (\206)Tj -0.025 Tc 0.043 Tw /Span< >> BDC 7.6 0 0 8 326.9088 555.549 Tm ( )Tj EMC 0.167 0 Td [(Defined as c)20 (linically overt bleeding accompanied by one or more of the follo)-10 (wing:)37 ( a decrease)-25 ( )]TJ 0.228 Tw 0 -1.062 Td [(in hemoglobin of \0362 g/dL,)37 ( a transfusion of 2 or more units of packed red blood cells,)12 ( )]TJ 0 Tc 0 Tw 7.6 0 0 8 575.72 547.049 Tm ( )Tj -0.025 Tc 0.311 Tw 7.6 0 0 8 328.176 538.549 Tm [(bleeding a)-9.9 (t a critical site:)37 ( intracranial,)37 ( intraspinal,)37 ( intraocular)74 (,)37 ( pericardial,)37 ( intra-articular)73.9 (,)12.1 ( )]TJ 0.084 Tw 0 -1.062 Td [(intramuscular with compartment syndrome,)37 ( retroperitoneal or with fa)-10 (tal outcome.)]TJ 0 Tc 0 Tw 5.98 0 0 5.98 324.176 522.699 Tm (\207)Tj -0.025 Tc 0.016 Tw /Span< >> BDC 7.6 0 0 8 326.9088 521.189 Tm ( )Tj EMC 0.167 0 Td [(Intracranial bleed inc)20 (ludes intracerebral,)37.1 ( intra)-9.9 (ventricular)74 (,)37 ( subdural,)37 ( and subarachnoid bleeding.)12 ( )]TJ 0 Tc 0 Tw 7.6 0 0 8 575.72 521.189 Tm ( )Tj -0.025 Tc 0.054 Tw 7.6 0 0 8 328.176 512.689 Tm [(An)-10 (y type of hemorrha)-10 (gic stroke was adjudica)-10 (ted and counted as an intracranial major bleed.)]TJ 0 Tc 0 Tw 5.98 0 0 5.98 324.176 505.3389 Tm (\247)Tj -0.025 Tc 0.046 Tw /Span< >> BDC 7.6 0 0 8 326.9088 503.8289 Tm ( )Tj EMC 0.167 0 Td [(On-trea)-10 (tment analysis based on the safety popula)-10 (tion,)37 ( compared to ITT analysis presented in)-25 ( )]TJ 0.084 Tw 0 -1.062 Td (Section 14.)Tj 0 Tc 0 Tw 5.98 0 0 5.98 324.176 487.9789 Tm (\266)Tj -0.025 Tc 0.084 Tw /Span< >> BDC 7.6 0 0 8 327.3514 486.4689 Tm ( )Tj EMC 0.109 0 Td [(GI bleed inc)20 (ludes upper GI,)37 ( lo)-10 (wer GI,)37 ( and rectal bleeding.)]TJ 0.025 Tw 5.98 0 0 5.98 324.176 479.119 Tm (**)Tj 0.246 Tw /Span< >> BDC 7.6 0 0 8 328.0868 477.6089 Tm ( )Tj EMC 0.012 0 Td [(F)20 (a)-10 (tal bleeding is an adjudica)-10 (ted dea)-10 (th with the primar)-18 (y cause of dea)-10 (th as intracranial)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(bleeding or non-intracranial bleeding during the on-trea)-9.9 (tment period.)]TJ 0.051 Tw 8 0 0 8 324 444.1589 Tm [(In )37.5 (ARISTOTLE,)37 ( )0.6 (the )0.5 (results )0.6 (for )0.6 (major )0.5 (bleeding )0.5 (were )0.5 (generally )0.5 (consistent )0.6 (across )0.6 (most )0.6 (major)-25 ( )]TJ 0.152 Tw 0 -1.062 Td [(subgroups inc)20 (luding a)-10 (ge,)37 ( weight,)37 ( CHADS)]TJ 0 Tc 0 Tw 5.2 0 0 5.2 441.4291 435.0589 Tm (2)Tj -0.025 Tc 0.152 Tw 8 0 0 8 443.795 435.6589 Tm [( score \(a scale from 0 to 6 used to estima)-10 (te)-25 ( )]TJ 0.122 Tw -14.974 -1.062 Td [(risk of stroke,)37 ( with higher )0.5 (scores predicting )0.5 (grea)-10 (ter )0.5 (risk\),)37 ( )0.5 (prior )0.5 (warfarin )0.5 (use,)37 ( geogra)-9.9 (phic)-25 ( )]TJ 0.154 Tw 0 -1.062 Td [(region,)37 ( )0.5 (and )0.5 (aspirin use )0.5 (a)-9.9 (t randomiza)-10 (tion )0.5 (\(F)18 (igure )0.5 (1\).)37 ( )0.5 (Subjects trea)-10 (ted )0.5 (with ELIQUIS )0.5 (with)-25 ( )]TJ 0.084 Tw 0 -1.125 Td (diabetes bled more \(3% per year\) than did subjects without diabetes \(\ 1.9% per year\).)Tj /T1_0 1 Tf -0.022 Tc -36 -8.124 Td (Figure 1:)Tj /Span< >> BDC ( )Tj EMC 5.4 0 Td (Major Bleeding Hazard Ratios by Baseline Characteristics \226 ARISTOTLE \ Study)Tj ET /PlacedGraphic /MC0 BDC EMC BT /CS0 cs 1 scn /T1_5 1 Tf -0.01 Tc 0.01 Tw 6 0 0 6 407.394 71.8087 Tm (Apixaban)Tj ET q 36 64.54 540 275.388 re W n BT 6 0 0 6 410.8624 65.0587 Tm (Better)Tj ET Q BT 0 Tc 0 Tw 6 0 0 6 446.6115 71.8087 Tm (W)Tj -0.01 Tc 0.01 Tw 0.694 0 Td (arfarin)Tj ET q 36 64.54 540 275.388 re W n BT 6 0 0 6 449.2181 65.0587 Tm (Better)Tj ET Q /CS0 CS 1 SCN 0.375 w q 1 0 0 1 213.66 329.2569 cm 0 0 m 120.6 0 l S Q BT /T1_6 1 Tf 0 Tw 6 0 0 6 229.0868 331.6044 Tm (n of Events / N of P)Tj 7.321 0 Td (atients \(% per year\))Tj 0.01 Tw -21.592 -1.609 Td (Subgroup)Tj 14.9 0 Td (Apixaban)Tj 0 Tc 0 Tw 10.217 0 Td (W)Tj -0.01 Tc 0.01 Tw 0.732 0 Td (arf)Tj 1.06 0 Td (arin)Tj 0 Tw 5.679 0 Td (Hazard Ratio \(95% CI\))Tj /T1_5 1 Tf 0.01 Tw -32.588 -1.175 Td (All )Tj -0.028 Tc 0.028 Tw 1.108 0 Td (Pa)Tj -0.01 Tc 0.01 Tw 0.897 0 Td (tients)Tj 0 Tw 11.775 0 Td (327 / 9088 \(2.1\))Tj 10.05 0 Td (462 / 9052 \(3.1\))Tj 9.973 0 Td (0.69 \(0.60,)Tj 3.934 0 Td ( 0.80\))Tj 0.01 Tw -37.737 -1.074 Td (Prior )Tj 0 Tc 0 Tw 1.864 0 Td (W)Tj -0.01 Tc 0.01 Tw 0.694 0 Td (arfarin/V)Tj 0.055 Tc -0.055 Tw 3.071 0 Td (KA)Tj -0.01 Tc 0 Tw 1.045 0 Td ( Status)Tj 0 Tc -6.674 -1.074 Td ( )Tj -0.01 Tc 1.125 0 Td (Experienced \(57%\))Tj 12.655 0 Td (185 / 5196 \(2.1\))Tj 10.05 0 Td (274 / 5180 \(3.2\))Tj 9.973 0 Td (0.66 \(0.55,)Tj 3.934 0 Td ( 0.80\))Tj 0 Tc -37.737 -1.074 Td ( )Tj -0.01 Tc 1.125 0 Td (Naive \(43%\))Tj 12.655 0 Td (142 / 3892 \(2.2\))Tj 10.05 0 Td (188 / 3872 \(3.0\))Tj 9.973 0 Td (0.73 \(0.59,)Tj 3.934 0 Td ( 0.91\))Tj 0.01 Tw -37.737 -1.074 Td (Age)Tj 0 Tc 0 Tw 0 -1.074 Td ( )Tj -0.01 Tc 1.125 0 Td (<65 \(30%\))Tj 12.89 0 Td (56 / 2723 \(1.2\))Tj 10.05 0 Td (72 / 2732 \(1.5\))Tj 9.738 0 Td (0.78 \(0.55,)Tj 3.934 0 Td ( 1.11\))Tj 0 Tc -37.737 -1.074 Td ( )Tj -0.01 Tc 1.125 0 Td (\03765 and <75 \(39%\))Tj 12.655 0 Td (120 / 3529 \(2.0\))Tj 10.05 0 Td (166 / 3501 \(2.8\))Tj 9.973 0 Td (0.71 \(0.56,)Tj 3.934 0 Td ( 0.89\))Tj 0 Tc -37.737 -1.074 Td ( )Tj -0.01 Tc 1.125 0 Td (\03775 \(31%\))Tj 12.655 0 Td (151 / 2836 \(3.3\))Tj 10.05 0 Td (224 / 2819 \(5.2\))Tj 9.973 0 Td (0.64 \(0.52,)Tj 3.934 0 Td ( 0.79\))Tj 0.01 Tw -37.737 -1.074 Td (Sex)Tj 0 Tc 0 Tw 0 -1.074 Td ( )Tj -0.01 Tc 1.125 0 Td (Male \(65%\))Tj 12.655 0 Td (225 / 5868 \(2.3\))Tj 10.05 0 Td (294 / 5879 \(3.0\))Tj 9.973 0 Td (0.76 \(0.64,)Tj 3.934 0 Td ( 0.90\))Tj 0 Tc 0.885 Tw -37.737 -1.074 Td ( F)Tj -0.01 Tc 0 Tw 1.535 0 Td (emale \(35%\))Tj 12.245 0 Td (102 / 3220 \(1.9\))Tj 10.05 0 Td (168 / 3173 \(3.3\))Tj 9.973 0 Td (0.58 \(0.45,)Tj 3.934 0 Td ( 0.74\))Tj 0 Tc -37.737 -1.074 Td (W)Tj -0.01 Tc 0.01 Tw 0.694 0 Td (eight)Tj 0 Tc 0 Tw -0.694 -1.074 Td ( )Tj -0.01 Tc 1.125 0 Td (\03660 kg \(11%\))Tj 12.89 0 Td (36 / 1013 \(2.3\))Tj 10.285 0 Td (62 / 965 \(4.3\))Tj 9.503 0 Td (0.55 \(0.36,)Tj 3.934 0 Td ( 0.83\))Tj 0 Tc -37.737 -1.074 Td ( )Tj -0.01 Tc 1.125 0 Td (>60 kg \(89%\))Tj 12.655 0 Td (290 / 8043 \(2.1\))Tj 10.05 0 Td (398 / 8059 \(3.0\))Tj 9.973 0 Td (0.72 \(0.62,)Tj 3.934 0 Td ( 0.83\))Tj -37.737 -1.074 Td (Prior Stroke or )Tj 0.015 Tc -0.015 Tw 5.371 0 Td (TI)Tj 0 Tc 0 Tw 0.692 0 Td (A)Tj 0.885 Tw -6.063 -1.074 Td ( Y)Tj -0.01 Tc 0 Tw 1.502 0 Td (es \(19%\))Tj 12.513 0 Td (77 / 1687 \(2.8\))Tj 9.815 0 Td (106 / 1735 \(3.9\))Tj 9.973 0 Td (0.73 \(0.54,)Tj 3.934 0 Td ( 0.98\))Tj 0 Tc -37.737 -1.074 Td ( )Tj -0.01 Tc 1.125 0 Td (No \(81%\))Tj 12.655 0 Td (250 / 7401 \(2.0\))Tj 10.05 0 Td (356 / 7317 \(2.9\))Tj 9.973 0 Td (0.68 \(0.58,)Tj 3.934 0 Td ( 0.80\))Tj -37.737 -1.074 Td (Diabetes Mellitus)Tj 0 Tc 0.885 Tw 0 -1.074 Td ( Y)Tj -0.01 Tc 0 Tw 1.502 0 Td (es \(25%\))Tj 12.278 0 Td (112 / 2276 \(3.0\))Tj 10.05 0 Td (114 / 2250 \(3.1\))Tj 9.973 0 Td (0.96 \(0.74,)Tj 3.934 0 Td ( 1.25\))Tj 0 Tc -37.737 -1.074 Td ( )Tj -0.01 Tc 1.125 0 Td (No \(75%\))Tj 12.655 0 Td (215 / 6812 \(1.9\) )Tj 10.05 0 Td (348 / 6802 \(3.1\))Tj 9.973 0 Td (0.60 \(0.51,)Tj 3.934 0 Td ( 0.71\))Tj 0.01 Tw -37.737 -1.074 Td (CHADS)Tj 0 Tc 0 Tw 4.3725 0 0 4.3725 158.9819 184.8367 Tm (2)Tj -0.01 Tc 6 0 0 6 161.037 186.0217 Tm ( Score)Tj 0 Tc -2.929 -1.074 Td ( )Tj -0.01 Tc 0.01 Tw 0.918 0 Td (\0361 )Tj 1.394 0 Td (\(34%\))Tj 0 Tw 11.703 0 Td (76 / 3093 \(1.4\))Tj 9.815 0 Td (126 / 3076 \(2.3\))Tj 9.973 0 Td (0.59 \(0.44,)Tj 3.934 0 Td ( 0.78\))Tj 0 Tc -37.737 -1.074 Td ( )Tj -0.01 Tc 0.01 Tw 1.405 0 Td (2 )Tj 0.907 0 Td (\(36%\))Tj 0 Tw 11.468 0 Td (125 / 3246 \(2.3\))Tj 10.05 0 Td (163 / 3246 \(3.0\))Tj 9.973 0 Td (0.76 \(0.60,)Tj 3.934 0 Td ( 0.96\))Tj 0 Tc -37.737 -1.074 Td ( )Tj -0.01 Tc 0.01 Tw 0.918 0 Td (\0373 )Tj 1.394 0 Td (\(30%\))Tj 0 Tw 11.468 0 Td (126 / 2749 \(2.9\))Tj 10.05 0 Td (173 / 2730 \(4.1\))Tj 9.973 0 Td (0.70 \(0.56,)Tj 3.934 0 Td ( 0.88\))Tj -37.737 -1.074 Td (Creatinine Clearance)Tj 0 Tc 0 -1.074 Td ( )Tj -0.01 Tc 1.842 0 Td (<30 mL/min )Tj 0.01 Tw 5.345 0 Td (\(1%\))Tj 0 Tw 7.298 0 Td (7 / 136 \(3.7\))Tj 9.58 0 Td (19 / 132 \(11.9\))Tj 9.738 0 Td (0.32 \(0.13,)Tj 3.934 0 Td ( 0.78\))Tj 0 Tc -37.737 -1.074 Td ( )Tj -0.01 Tc 1.15 0 Td (30-50 mL/min )Tj 0.01 Tw 6.037 0 Td (\(15%\))Tj 0 Tw 6.828 0 Td (66 / 1357 \(3.2\))Tj 9.815 0 Td (123 / 1380 \(6.0\))Tj 9.973 0 Td (0.53 \(0.39,)Tj 3.934 0 Td ( 0.71\))Tj 0 Tc -37.737 -1.074 Td ( )Tj -0.01 Tc 0.56 0 Td (>50-80 mL/min )Tj 0.01 Tw 6.627 0 Td (\(42%\))Tj 0 Tw 6.593 0 Td (157 / 3807 \(2.5\))Tj 10.05 0 Td (199 / 3758 \(3.2\))Tj 9.973 0 Td (0.76 \(0.62,)Tj 3.934 0 Td ( 0.94\))Tj 0 Tc -37.737 -1.074 Td ( )Tj -0.005 Tc 1.792 0 Td (>80 mL/min )Tj 0.005 Tw 5.395 0 Td (\(41%\))Tj 0 Tw 6.793 0 Td (96 / 3750 \(1.5\))Tj 9.813 0 Td (119 / 3746 \(1.8\))Tj 9.97 0 Td (0.79 \(0.61,)Tj 3.989 0 Td ( 1.04\))Tj -37.752 -1.074 Td (Geographic Region)Tj 0 Tc 0 -1.074 Td ( )Tj -0.005 Tc 1.125 0 Td (US \(19%\))Tj 12.855 0 Td (83 / 1716 \(2.8\))Tj 9.813 0 Td (109 / 1693 \(3.8\))Tj 9.97 0 Td (0.75 \(0.56,)Tj 3.989 0 Td ( 1.00\))Tj 0 Tc -37.752 -1.074 Td ( )Tj -0.005 Tc 1.125 0 Td (Non-US \(81%\))Tj 12.618 0 Td (244 / 7372 \(2.0\))Tj 10.05 0 Td (353 / 7359 \(2.9\))Tj 9.97 0 Td (0.68 \(0.57,)Tj 3.989 0 Td ( 0.80\))Tj -0.004 Tc -37.752 -1.074 Td (Aspirin at Randomization)Tj 0 Tc 0.885 Tw 0 -1.074 Td ( Y)Tj -0.005 Tc 0 Tw 1.507 0 Td (es \(31%\))Tj 12.236 0 Td (129 / 2846 \(2.7\))Tj 10.05 0 Td (164 / 2762 \(3.7\))Tj 9.97 0 Td (0.75 \(0.60,)Tj 3.989 0 Td ( 0.95\))Tj 0 Tc -37.752 -1.074 Td ( )Tj -0.005 Tc 1.125 0 Td (No \(69%\))Tj 12.618 0 Td (198 / 6242 \(1.9\))Tj 10.05 0 Td (298 / 6290 \(2.8\))Tj 9.97 0 Td (0.66 \(0.55,)Tj 3.989 0 Td ( 0.79\))Tj 0 Tc 0.4 Tw 0.993 -2.176 Td ( 0)Tj -0.07 Tc 0.07 Tw 1.09 0 Td (.1)Tj -0.01 Tc 0.01 Tw (25 )Tj -0.02 Tc 0.02 Tw 2.838 0 Td (0.)Tj 0 Tc 0 Tw 0.695 0 Td (25 )Tj -0.01 Tc 0.01 Tw 2.793 0 Td (0.5 )Tj 3.537 0 Td (1 )Tj 0 Tc 0 Tw 3.183 0 Td (2)Tj ET 0.717 w 1 j 1 J [0.242 1.461]0 d q 1 0 0 1 432.8768 318.851 cm 0 0 m 0 -228.436 l S Q 4 M []0 d q 1 0 0 1 443.0119 319.5804 cm 0 0 m 0 -228.436 l S Q 10 M q 1 0 0 1 384.3881 91.0563 cm 0 0 m 80.561 0 l 77.751 1.353 m 77.751 -1.329 l 58.618 1.353 m 58.618 -1.329 l 39.432 1.353 m 39.432 -1.329 l 20.138 1.353 m 20.138 -1.329 l 0.978 1.353 m 0.978 -1.329 l S Q 0.478 w 0 j 0 J q 1 0 0 1 426.3806 303.4222 cm 0 0 m 10.538 0 l S Q 426.2 302.305 0.36 2.337 re f 436.739 302.305 0.36 2.337 re f q 36 64.54 540 275.388 re W n q 1 0 0 1 434.0921 303.4732 cm 0 0 m 0 -1.365 -1.107 -2.472 -2.472 -2.472 c -3.837 -2.472 -4.944 -1.365 -4.944 0 c -4.944 1.365 -3.837 2.472 -2.472 2.472 c -1.107 2.472 0 1.365 0 0 c f Q 1 G 0.239 w /GS0 gs q 1 0 0 1 434.0921 303.4732 cm 0 0 m 0 -1.365 -1.107 -2.472 -2.472 -2.472 c -3.837 -2.472 -4.944 -1.365 -4.944 0 c -4.944 1.365 -3.837 2.472 -2.472 2.472 c -1.107 2.472 0 1.365 0 0 c h S Q /CS0 CS 1 SCN 0.478 w /GS1 gs q 1 0 0 1 430.4944 258.2973 cm 0 0 m 9.656 0 l S Q 430.314 257.158 0.36 2.338 re f 440.33 257.158 -0.36 2.338 re f q 1 0 0 1 438.0128 258.3266 cm 0 0 m 0 -1.421 -1.152 -2.573 -2.573 -2.573 c -3.994 -2.573 -5.145 -1.421 -5.145 0 c -5.145 1.421 -3.994 2.573 -2.573 2.573 c -1.152 2.573 0 1.421 0 0 c f Q 1 G 0.239 w /GS0 gs q 1 0 0 1 438.0128 258.3266 cm 0 0 m 0 -1.421 -1.152 -2.573 -2.573 -2.573 c -3.994 -2.573 -5.145 -1.421 -5.145 0 c -5.145 1.421 -3.994 2.573 -2.573 2.573 c -1.152 2.573 0 1.421 0 0 c h S Q /CS0 CS 1 SCN 0.478 w /GS1 gs q 1 0 0 1 428.8823 316.2596 cm 0 0 m 8.016 0 l S Q 428.702 315.148 0.36 2.338 re f 437.078 315.148 -0.36 2.338 re f q 1 0 0 1 436.2128 316.3169 cm 0 0 m 0 -1.835 -1.488 -3.322 -3.323 -3.322 c -5.157 -3.322 -6.645 -1.835 -6.645 0 c -6.645 1.835 -5.157 3.322 -3.323 3.322 c -1.488 3.322 0 1.835 0 0 c f Q 1 G 0.239 w /GS0 gs q 1 0 0 1 436.2128 316.3169 cm 0 0 m 0 -1.835 -1.488 -3.322 -3.323 -3.322 c -5.157 -3.322 -6.645 -1.835 -6.645 0 c -6.645 1.835 -5.157 3.322 -3.323 3.322 c -1.488 3.322 0 1.835 0 0 c h S Q /CS0 CS 1 SCN 0.478 w /GS1 gs q 1 0 0 1 428.3175 296.9606 cm 0 0 m 12.225 0 l S Q 428.138 295.84 0.36 2.338 re f 440.722 295.84 -0.36 2.338 re f q 1 0 0 1 436.377 297.0085 cm 0 0 m 0 -1.176 -0.953 -2.128 -2.128 -2.128 c -3.304 -2.128 -4.257 -1.176 -4.257 0 c -4.257 1.175 -3.304 2.128 -2.128 2.128 c -0.953 2.128 0 1.175 0 0 c f Q 1 G 0.239 w /GS0 gs q 1 0 0 1 436.377 297.0085 cm 0 0 m 0 -1.176 -0.953 -2.128 -2.128 -2.128 c -3.304 -2.128 -4.257 -1.176 -4.257 0 c -4.257 1.175 -3.304 2.128 -2.128 2.128 c -0.953 2.128 0 1.175 0 0 c h S Q /CS0 CS 1 SCN 0.478 w /GS1 gs q 1 0 0 1 426.4343 284.0958 cm 0 0 m 19.44 0 l S Q 426.254 282.969 0.36 2.338 re f 446.054 282.969 -0.36 2.338 re f q 1 0 0 1 425.0348 271.239 cm 0 0 m 11.617 0 l S Q 424.855 270.105 0.36 2.338 re f 436.832 270.105 -0.36 2.338 re f q 1 0 0 1 432.5917 271.2746 cm 0 0 m 0 -0.97 -0.787 -1.758 -1.757 -1.758 c -2.728 -1.758 -3.514 -0.97 -3.514 0 c -3.514 0.971 -2.728 1.757 -1.757 1.757 c -0.787 1.757 0 0.971 0 0 c f Q 1 G 0.239 w /GS0 gs q 1 0 0 1 432.5917 271.2746 cm 0 0 m 0 -0.97 -0.787 -1.758 -1.757 -1.758 c -2.728 -1.758 -3.514 -0.97 -3.514 0 c -3.514 0.971 -2.728 1.757 -1.757 1.757 c -0.787 1.757 0 0.971 0 0 c h S Q /GS1 gs q 1 0 0 1 435.3758 277.6818 cm 0 0 m 0 -1.095 -0.888 -1.983 -1.983 -1.983 c -3.078 -1.983 -3.965 -1.095 -3.965 0 c -3.965 1.095 -3.078 1.983 -1.983 1.983 c -0.888 1.983 0 1.095 0 0 c f Q /GS0 gs q 1 0 0 1 435.3758 277.6818 cm 0 0 m 0 -1.095 -0.888 -1.983 -1.983 -1.983 c -3.078 -1.983 -3.965 -1.095 -3.965 0 c -3.965 1.095 -3.078 1.983 -1.983 1.983 c -0.888 1.983 0 1.095 0 0 c h S Q /CS0 CS 1 SCN 0.478 w /GS1 gs q 1 0 0 1 426.8284 277.6432 cm 0 0 m 13.147 0 l S Q 426.649 276.513 0.36 2.338 re f 440.155 276.513 -0.36 2.338 re f q 1 0 0 1 421.1617 251.9636 cm 0 0 m 13.618 0 l S Q 420.982 250.821 0.36 2.338 re f 434.96 250.821 -0.36 2.338 re f q 1 0 0 1 429.9442 251.9894 cm 0 0 m 0 -1.095 -0.888 -1.983 -1.983 -1.983 c -3.078 -1.983 -3.965 -1.095 -3.965 0 c -3.965 1.095 -3.078 1.983 -1.983 1.983 c -0.888 1.983 0 1.095 0 0 c f Q 1 G 0.239 w /GS0 gs q 1 0 0 1 429.9442 251.9894 cm 0 0 m 0 -1.095 -0.888 -1.983 -1.983 -1.983 c -3.078 -1.983 -3.965 -1.095 -3.965 0 c -3.965 1.095 -3.078 1.983 -1.983 1.983 c -0.888 1.983 0 1.095 0 0 c h S Q /CS0 CS 1 SCN 0.478 w /GS1 gs q 1 0 0 1 429.495 232.6586 cm 0 0 m 8.585 0 l S Q 429.315 231.507 0.36 2.338 re f 438.26 231.507 -0.36 2.338 re f q 1 0 0 1 436.9106 232.6754 cm 0 0 m 0 -1.725 -1.398 -3.123 -3.123 -3.123 c -4.848 -3.123 -6.246 -1.725 -6.246 0 c -6.246 1.725 -4.848 3.123 -3.123 3.123 c -1.398 3.123 0 1.725 0 0 c f Q 1 G 0.239 w /GS0 gs q 1 0 0 1 436.9106 232.6754 cm 0 0 m 0 -1.725 -1.398 -3.123 -3.123 -3.123 c -4.848 -3.123 -6.246 -1.725 -6.246 0 c -6.246 1.725 -4.848 3.123 -3.123 3.123 c -1.398 3.123 0 1.725 0 0 c h S Q /CS0 CS 1 SCN 0.478 w /GS1 gs q 1 0 0 1 427.899 213.3378 cm 0 0 m 9.157 0 l S Q 427.719 212.176 0.36 2.338 re f 437.236 212.176 -0.36 2.338 re f q 1 0 0 1 435.4658 213.3449 cm 0 0 m 0 -1.656 -1.342 -2.998 -2.998 -2.998 c -4.654 -2.998 -5.996 -1.656 -5.996 0 c -5.996 1.656 -4.654 2.998 -2.998 2.998 c -1.342 2.998 0 1.656 0 0 c f Q 1 G 0.239 w /GS0 gs q 1 0 0 1 435.4658 213.3449 cm 0 0 m 0 -1.656 -1.342 -2.998 -2.998 -2.998 c -4.654 -2.998 -5.996 -1.656 -5.996 0 c -5.996 1.656 -4.654 2.998 -2.998 2.998 c -1.342 2.998 0 1.656 0 0 c h S Q /CS0 CS 1 SCN 0.478 w /GS1 gs q 1 0 0 1 424.2184 194.0647 cm 0 0 m 9.628 0 l S Q 424.039 192.894 0.36 2.338 re f 434.026 192.894 -0.36 2.338 re f q 1 0 0 1 431.9295 194.0625 cm 0 0 m 0 -1.605 -1.302 -2.907 -2.907 -2.907 c -4.513 -2.907 -5.814 -1.605 -5.814 0 c -5.814 1.606 -4.513 2.907 -2.907 2.907 c -1.302 2.907 0 1.606 0 0 c f Q 1 G 0.239 w /GS0 gs q 1 0 0 1 431.9295 194.0625 cm 0 0 m 0 -1.605 -1.302 -2.907 -2.907 -2.907 c -4.513 -2.907 -5.814 -1.605 -5.814 0 c -5.814 1.606 -4.513 2.907 -2.907 2.907 c -1.302 2.907 0 1.606 0 0 c h S Q /CS0 CS 1 SCN 0.478 w /GS1 gs q 1 0 0 1 427.5953 116.8342 cm 0 0 m 9.275 0 l S Q 427.415 115.626 0.36 2.338 re f 437.05 115.626 -0.36 2.338 re f q 1 0 0 1 435.2764 116.7944 cm 0 0 m 0 -1.686 -1.367 -3.054 -3.054 -3.054 c -4.74 -3.054 -6.108 -1.686 -6.108 0 c -6.108 1.687 -4.74 3.054 -3.054 3.054 c -1.367 3.054 0 1.687 0 0 c f Q 1 G 0.239 w /GS0 gs q 1 0 0 1 435.2764 116.7944 cm 0 0 m 0 -1.686 -1.367 -3.054 -3.054 -3.054 c -4.74 -3.054 -6.108 -1.686 -6.108 0 c -6.108 1.687 -4.74 3.054 -3.054 3.054 c -1.367 3.054 0 1.687 0 0 c h S Q /CS0 CS 1 SCN 0.478 w /GS1 gs q 1 0 0 1 426.4718 97.5907 cm 0 0 m 9.981 0 l S Q 426.292 96.373 0.36 2.338 re f 436.633 96.373 -0.36 2.338 re f q 1 0 0 1 434.352 97.5416 cm 0 0 m 0 -1.601 -1.298 -2.9 -2.9 -2.9 c -4.501 -2.9 -5.799 -1.601 -5.799 0 c -5.799 1.602 -4.501 2.9 -2.9 2.9 c -1.298 2.9 0 1.602 0 0 c f Q 1 G 0.239 w /GS0 gs q 1 0 0 1 434.352 97.5416 cm 0 0 m 0 -1.601 -1.298 -2.9 -2.9 -2.9 c -4.501 -2.9 -5.799 -1.601 -5.799 0 c -5.799 1.602 -4.501 2.9 -2.9 2.9 c -1.298 2.9 0 1.602 0 0 c h S Q /CS0 CS 1 SCN 0.478 w /GS1 gs q 1 0 0 1 414.7492 239.0752 cm 0 0 m 22.953 0 l S Q 414.569 237.926 0.36 2.338 re f 437.882 237.926 -0.36 2.338 re f q 1 0 0 1 426.0795 219.795 cm 0 0 m 16.717 0 l S Q 425.9 218.637 0.36 2.338 re f 442.976 218.637 -0.36 2.338 re f q 1 0 0 1 435.861 219.8055 cm 0 0 m 0 -0.786 -0.637 -1.423 -1.423 -1.423 c -2.209 -1.423 -2.847 -0.786 -2.847 0 c -2.847 0.786 -2.209 1.424 -1.423 1.424 c -0.637 1.424 0 0.786 0 0 c f Q 1 G 0.239 w /GS0 gs q 1 0 0 1 435.861 219.8055 cm 0 0 m 0 -0.786 -0.637 -1.423 -1.423 -1.423 c -2.209 -1.423 -2.847 -0.786 -2.847 0 c -2.847 0.786 -2.209 1.424 -1.423 1.424 c -0.637 1.424 0 0.786 0 0 c h S Q /GS1 gs q 1 0 0 1 443.8578 200.4689 cm 0 0 m 0 -0.984 -0.798 -1.781 -1.781 -1.781 c -2.765 -1.781 -3.563 -0.984 -3.563 0 c -3.563 0.984 -2.765 1.782 -1.781 1.782 c -0.798 1.782 0 0.984 0 0 c f Q /GS0 gs q 1 0 0 1 443.8578 200.4689 cm 0 0 m 0 -0.984 -0.798 -1.781 -1.781 -1.781 c -2.765 -1.781 -3.563 -0.984 -3.563 0 c -3.563 0.984 -2.765 1.782 -1.781 1.782 c -0.798 1.782 0 0.984 0 0 c h S Q /CS0 CS 1 SCN 0.478 w /GS1 gs q 1 0 0 1 434.8646 200.4678 cm 0 0 m 14.442 0 l S Q 434.685 199.3 0.36 2.338 re f 449.486 199.3 -0.36 2.338 re f q 1 0 0 1 420.5891 181.2314 cm 0 0 m 15.618 0 l S Q 420.41 180.054 0.36 2.338 re f 436.388 180.054 -0.36 2.338 re f q 1 0 0 1 430.4437 181.2232 cm 0 0 m 0 -1.135 -0.919 -2.055 -2.054 -2.055 c -3.189 -2.055 -4.109 -1.135 -4.109 0 c -4.109 1.134 -3.189 2.054 -2.054 2.054 c -0.919 2.054 0 1.134 0 0 c f Q 1 G 0.239 w /GS0 gs q 1 0 0 1 430.4437 181.2232 cm 0 0 m 0 -1.135 -0.919 -2.055 -2.054 -2.055 c -3.189 -2.055 -4.109 -1.135 -4.109 0 c -4.109 1.134 -3.189 2.054 -2.054 2.054 c -0.919 2.054 0 1.134 0 0 c h S Q /CS0 CS 1 SCN 0.478 w /GS1 gs q 1 0 0 1 429.141 174.7552 cm 0 0 m 12.794 0 l S Q 428.961 173.575 0.36 2.338 re f 442.115 173.575 -0.36 2.338 re f q 1 0 0 1 437.5837 174.7439 cm 0 0 m 0 -1.135 -0.92 -2.055 -2.055 -2.055 c -3.189 -2.055 -4.109 -1.135 -4.109 0 c -4.109 1.134 -3.189 2.054 -2.055 2.054 c -0.92 2.054 0 1.134 0 0 c f Q 1 G 0.239 w /GS0 gs q 1 0 0 1 437.5837 174.7439 cm 0 0 m 0 -1.135 -0.92 -2.055 -2.055 -2.055 c -3.189 -2.055 -4.109 -1.135 -4.109 0 c -4.109 1.134 -3.189 2.054 -2.055 2.054 c -0.92 2.054 0 1.134 0 0 c h S Q /CS0 CS 1 SCN 0.478 w /GS1 gs q 1 0 0 1 428.6351 104.0313 cm 0 0 m 12.912 0 l S Q 428.455 102.816 0.36 2.338 re f 441.727 102.816 -0.36 2.338 re f q 1 0 0 1 437.0325 103.9856 cm 0 0 m 0 -1.077 -0.873 -1.95 -1.95 -1.95 c -3.027 -1.95 -3.9 -1.077 -3.9 0 c -3.9 1.077 -3.027 1.95 -1.95 1.95 c -0.873 1.95 0 1.077 0 0 c f Q 1 G 0.239 w /GS0 gs q 1 0 0 1 437.0325 103.9856 cm 0 0 m 0 -1.077 -0.873 -1.95 -1.95 -1.95 c -3.027 -1.95 -3.9 -1.077 -3.9 0 c -3.9 1.077 -3.027 1.95 -1.95 1.95 c -0.873 1.95 0 1.077 0 0 c h S Q /CS0 CS 1 SCN 0.478 w /GS1 gs q 1 0 0 1 426.8411 168.2894 cm 0 0 m 12.677 0 l S Q 426.661 167.106 0.36 2.338 re f 439.698 167.106 -0.36 2.338 re f q 1 0 0 1 435.1208 168.2748 cm 0 0 m 0 -1.077 -0.873 -1.95 -1.95 -1.95 c -3.027 -1.95 -3.901 -1.077 -3.901 0 c -3.901 1.077 -3.027 1.95 -1.95 1.95 c -0.873 1.95 0 1.077 0 0 c f Q 1 G 0.239 w /GS0 gs q 1 0 0 1 435.1208 168.2748 cm 0 0 m 0 -1.077 -0.873 -1.95 -1.95 -1.95 c -3.027 -1.95 -3.901 -1.077 -3.901 0 c -3.901 1.077 -3.027 1.95 -1.95 1.95 c -0.873 1.95 0 1.077 0 0 c h S Q /GS1 gs q 1 0 0 1 427.2956 239.0947 cm 0 0 m 0 -0.586 -0.475 -1.062 -1.062 -1.062 c -1.649 -1.062 -2.124 -0.586 -2.124 0 c -2.124 0.587 -1.649 1.062 -1.062 1.062 c -0.475 1.062 0 0.587 0 0 c f Q /GS0 gs q 1 0 0 1 427.2956 239.0947 cm 0 0 m 0 -0.586 -0.475 -1.062 -1.062 -1.062 c -1.649 -1.062 -2.124 -0.586 -2.124 0 c -2.124 0.587 -1.649 1.062 -1.062 1.062 c -0.475 1.062 0 0.587 0 0 c h S Q /GS1 gs q 1 0 0 1 437.8905 284.1375 cm 0 0 m 0 -0.97 -0.787 -1.757 -1.757 -1.757 c -2.728 -1.757 -3.514 -0.97 -3.514 0 c -3.514 0.97 -2.728 1.757 -1.757 1.757 c -0.787 1.757 0 0.97 0 0 c f Q /GS0 gs q 1 0 0 1 437.8905 284.1375 cm 0 0 m 0 -0.97 -0.787 -1.757 -1.757 -1.757 c -2.728 -1.757 -3.514 -0.97 -3.514 0 c -3.514 0.97 -2.728 1.757 -1.757 1.757 c -0.787 1.757 0 0.97 0 0 c h S Q /CS0 CS 1 SCN 0.478 w /GS1 gs q 1 0 0 1 416.9884 149.0107 cm 0 0 m 16.835 0 l S Q 416.808 147.817 0.36 2.338 re f 434.003 147.817 -0.36 2.338 re f q 1 0 0 1 426.7706 148.9867 cm 0 0 m 0 -0.75 -0.607 -1.358 -1.357 -1.358 c -2.107 -1.358 -2.715 -0.75 -2.715 0 c -2.715 0.75 -2.107 1.357 -1.357 1.357 c -0.607 1.357 0 0.75 0 0 c f Q 1 G 0.239 w /GS0 gs q 1 0 0 1 426.7706 148.9867 cm 0 0 m 0 -0.75 -0.607 -1.358 -1.357 -1.358 c -2.107 -1.358 -2.715 -0.75 -2.715 0 c -2.715 0.75 -2.107 1.357 -1.357 1.357 c -0.607 1.357 0 0.75 0 0 c h S Q /CS0 CS 1 SCN 0.478 w /GS1 gs q 1 0 0 1 387.3577 155.4468 cm 0 0 m 48.605 0 l S Q 387.178 154.257 0.36 2.338 re f 436.142 154.257 -0.36 2.338 re f q 1 0 0 1 411.9852 155.4258 cm 0 0 m 0 -0.175 -0.142 -0.317 -0.317 -0.317 c -0.492 -0.317 -0.635 -0.175 -0.635 0 c -0.635 0.175 -0.492 0.317 -0.317 0.317 c -0.142 0.317 0 0.175 0 0 c f Q 1 G 0.239 w /GS0 gs q 1 0 0 1 411.9852 155.4258 cm 0 0 m 0 -0.175 -0.142 -0.317 -0.317 -0.317 c -0.492 -0.317 -0.635 -0.175 -0.635 0 c -0.635 0.175 -0.492 0.317 -0.317 0.317 c -0.142 0.317 0 0.175 0 0 c h S Q /CS0 CS 1 SCN 0.478 w /GS1 gs q 1 0 0 1 429.1076 136.1407 cm 0 0 m 15.03 0 l S Q 428.928 134.941 0.36 2.338 re f 444.318 134.941 -0.36 2.338 re f q 1 0 0 1 438.7781 136.1103 cm 0 0 m 0 -1.26 -1.022 -2.282 -2.282 -2.282 c -3.542 -2.282 -4.564 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0.359 Tw 15.736 0 Td ( other than warfarin \(oral or parenteral\):)Tj /T1_1 1 Tf 0 Tc -0.24 Tw /Span< >> BDC 15.764 0 Td ( )Tj EMC ( )Tj -0.025 Tc 0.136 Tw -31.5 -1.063 Td [(Discontinue ELIQUIS and begin taking the new anticoa)-10 (gulant other than warfarin a)-9.9 (t the)-25 ( )]TJ 0.084 Tw 0 -1.063 Td (usual time of the next dose of ELIQUIS.)Tj /T1_2 1 Tf 0.359 Tw 0 -1.513 Td [(Switching from anticoa)-9.9 (gulant)]TJ 0 Tc 0 Tw (s)Tj -0.025 Tc 0.359 Tw 11.221 0 Td ( other than warfarin \(oral or parenteral\) to ELIQUIS:)Tj /T1_1 1 Tf 0 Tc -0.24 Tw /Span< >> BDC 20.279 0 Td ( )Tj EMC ( )Tj -0.025 Tc 0.105 Tw -31.5 -1.063 Td [(Discontinue the anticoa)-10 (gulant other than warfarin and begin taking ELIQUIS a)-10 (t the usual)-25 ( )]TJ 0.084 Tw 0 -1.063 Td [(time of the next dose of the anticoa)-10 (gulant other than warfarin.)]TJ /T1_0 1 Tf 0.025 Tw 0 -1.85 Td (2.6)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td (Combined P-gp and Strong CYP3A4 Inhibitors)Tj /T1_1 1 Tf -0.007 Tw -3.375 -1.513 Td [(F)20 (or adult )0.5 (pa)-9.9 (tients )0.5 (receiving )0.5 (ELIQUIS )0.5 (doses )0.5 (of )0.5 (5)]TJ /Span< >> BDC ( )Tj EMC 16.203 0 Td [(mg )0.5 (or )0.5 (10)]TJ /Span< >> BDC ( )Tj EMC 3.363 0 Td [(mg )0.5 (twice )0.5 (daily)55 (,)37 ( )0.5 (reduce )0.5 (the )0.5 (dose )0.6 (by)-25 ( )]TJ 0.049 Tw -19.566 -1.063 Td [(50% when ELIQUIS is coadministered with drugs tha)-9.9 (t are combined P-glycoprotein \(P-gp\))-25 ( )]TJ 0 Tc 0 Tw 31.5 0 Td ( )Tj -0.025 Tc 0.188 Tw -31.5 -1.063 Td [(and strong c)20 (ytochrome P450 3A4 \(CYP3A4\) inhibitors \(e.g.,)37 ( ketoconazole,)37 ( itraconazole,)12 ( )]TJ 0.025 Tw 0 -1.063 Td [(ritona)-10 (vir\) )]TJ /T1_2 1 Tf 0 Tc 0 Tw 3.316 0 Td ([)Tj 0.234 0 Td (s)Tj -0.025 Tc 0.084 Tw 0.382 0 Td (ee Clinical)Tj [( Pharmacolog)-9.9 (y \(12.3\)])]TJ /T1_1 1 Tf 0 Tc 0 Tw (.)Tj -0.025 Tc 0.235 Tw -3.932 -1.513 Td [(In pa)-10 (tients alread)-9.9 (y taking 2.5)]TJ /Span< >> BDC ( )Tj EMC 11.171 0 Td [(mg twice daily)55 (,)37 ( a)-9.9 (void coadministra)-10 (tion of ELIQUIS with)-25 ( )]TJ 0.084 Tw -11.171 -1.063 Td (combined P-gp and strong CYP3A4 inhibitors )Tj /T1_2 1 Tf 0 Tc 0 Tw ([)Tj 16.522 0 Td (s)Tj -0.025 Tc 0.084 Tw 0.382 0 Td (ee Drug Interaction)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.084 Tw 7.127 0 Td ( \(7.1\)])Tj /T1_1 1 Tf 0 Tc 0 Tw (.)Tj /T1_0 1 Tf -0.025 Tc 0.025 Tw -24.031 -1.85 Td (2.7)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td (Administration Options)Tj /T1_2 1 Tf 0.084 Tw -3.375 -1.85 Td [( )37 (Adult and pedia)-10 (tric pa)-10 (tients weighing grea)-10 (ter than or equal to 35)]TJ /Span< >> BDC ( )Tj EMC 23.572 0 Td (kg.)Tj /T1_1 1 Tf -23.572 -1.513 Td [(F)20 (or pa)-10 (tients who are unable to s)-10 (wallo)-10 (w whole tablets,)37.1 ( 5 mg and 2.5 mg ELIQUIS tablets)-25 ( )]TJ 0.151 Tw 0 -1.063 Td [(may be crushed and suspended in wa)-9.9 (ter)74 (,)37 ( 5% dextrose in wa)-10 (ter \(D5W\),)37 ( or a)-10 (pple juice,)12 ( )]TJ 0.15 Tw 0 -1.063 Td [(or mixed with a)-10 (pplesauce and promptly administered orally )]TJ /T1_2 1 Tf 0 Tc 0 Tw ([)Tj 22.109 0 Td (s)Tj -0.025 Tc 0.15 Tw 0.382 0 Td (ee Clinical)Tj [( Pharmacolog)-10 (y)-25 ( )]TJ 0.025 Tw -22.491 -1.063 Td (\(12.3\)])Tj /T1_1 1 Tf 0.11 Tw [(.)37 ( )36.8 (Alterna)-10 (tively)55 (,)37 ( ELIQUIS tablets may be crushed and suspended in 60 mL of wa)-9.9 (ter)-25 ( )]TJ 0.269 Tw 0 -1.063 Td [(or D5W and promptly delivered through a 12 F)20 (rench nasogastric tube )]TJ /T1_2 1 Tf 0 Tc 0 Tw ([)Tj 27.303 0 Td (s)Tj -0.025 Tc 0.269 Tw 0.382 0 Td (ee Clinical)Tj 0 Tc 0 Tw 3.815 0 Td ( )Tj -0.025 Tc 0.084 Tw -31.5 -1.063 Td [(Pharmacolog)-10 (y \(12.3\)])]TJ /T1_1 1 Tf 0 Tc 0 Tw (.)Tj -0.025 Tc 0.205 Tw 0 -1.513 Td [(F)20 (ollo)-10 (wing administra)-10 (tion of the dose,)37 ( the nasogastric tube should be \035ushed with an)-25 ( )]TJ 0.084 Tw 0 -1.063 Td [(additional 20 mL of wa)-10 (ter or D5W)74 (.)]TJ 0.107 Tw 0 -1.513 Td [(Crushed ELIQUIS tablets are stable in wa)-9.9 (ter)74 (,)37 ( D5W)74 (,)37 ( a)-9.9 (pple juice,)37 ( and a)-10 (pplesauce for up to)-24.9 ( )]TJ 0.084 Tw 0 -1.063 Td (4 hours.)Tj /T1_2 1 Tf 0 -1.85 Td [(P)18 (edia)-9.9 (tric pa)-10 (tients weighing less than 35)]TJ /Span< >> BDC ( )Tj EMC 14.402 0 Td (kg.)Tj /T1_1 1 Tf 0.025 Tw -14.402 -1.85 Td [(Ca)-10 (psules)]TJ 0.279 Tw 0 -1.513 Td [(The 0.15 mg ELIQUIS SPRINKLE ca)-9.9 (psule must be opened,)37 ( and the entire contents)-25 ( )]TJ 0.307 Tw 0 -1.063 Td [(sprinkled )0.5 (in )0.5 (wa)-10 (ter or infant )0.5 (formula,)37 ( )0.5 (mixed,)37.1 ( and administered )0.5 (as )0.5 (described in the)-24.9 ( )]TJ 0.211 Tw 0 -1.063 Td [(Instructions for Use \(IFU\).)37.1 ( )36.8 (The liquid mixtures should be administered within 2 hours.)12 ( )]TJ 0 Tc 0 Tw 31.5 0 Td ( )Tj -0.025 Tc 0.084 Tw -31.5 -1.063 Td [(Do not s)-10 (wallo)-10 (w ca)-9.9 (psule.)]TJ 0 -1.85 Td [(T)74 (ablets for oral suspension)]TJ 0.125 Tw 0 -1.513 Td (The 0.5)Tj /Span< >> BDC ( )Tj EMC 2.973 0 Td [(mg ELIQUIS tablet in a packet for oral suspension should be mixed with w\ a)-10 (ter)74 (,)12.1 ( )]TJ 0.148 Tw -2.973 -1.063 Td [(infant )0.5 (formula,)37 ( a)-9.9 (pple )0.5 (juice,)37 ( )0.5 (or )0.5 (a)-10 (pple sauce )0.5 (as )0.5 (described in the IFU.)37 ( )37.4 (The liquid mixtures)-25 ( )]TJ 0.111 Tw 0 -1.063 Td [(with wa)-10 (ter)74 (,)37 ( infant formula or a)-10 (pple juice should be administered within 2 hours and the)-25 ( )]TJ 0.176 Tw 0 -1.063 Td [(mixture in a)-10 (pple sauce should be administered immedia)-9.9 (tely)55 (.)37 ( Each packet is for single)-25 ( )]TJ 0.096 Tw 0 -1.063 Td [(use only)55 (.)37 ( F)20 (or pedia)-9.9 (tric pa)-10 (tients who ha)-10 (ve dif\037culty s)-9.9 (wallo)-10 (wing,)37 ( the liquid mixture can be)-25 ( )]TJ 0.116 Tw 0 -1.063 Td [(delivered through a 5 F)20 (rench,)37 ( 6.5 F)20 (rench or 12 F)20.1 (rench nasogastric tube or gastrostomy)-25 ( )331 ( )]TJ 0.084 Tw 0 -1.063 Td [(tube.)37 ( See IFU.)]TJ /T1_0 1 Tf 0.025 Tw 0 -1.85 Td (3)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td (DOSAGE FORMS AND STRENGTHS)Tj /T1_1 1 Tf 0.025 Tw -3.375 -1.445 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.19 Tw 1.625 0 Td (0.5)Tj /Span< >> BDC ( )Tj EMC 1.338 0 Td [(mg,)37 ( )0.6 (pink,)37 ( )0.6 (round,)37 ( )0.5 (\037lm-coa)-10 (ted )0.5 (tablets )0.6 (for )0.6 (oral )0.5 (suspension )0.6 (packa)-10 (ged )0.6 (in )0.6 (packets.)]TJ 0 Tc 0 Tw 28.537 0 Td ( )Tj -0.025 Tc 0.084 Tw -29.875 -1.063 Td (1-count \(0.5)Tj /Span< >> BDC ( )Tj EMC 4.565 0 Td [(mg\),)37 ( 3-count \(1.5)]TJ /Span< >> BDC ( )Tj EMC 6.393 0 Td [(mg\),)37 ( and 4-count \(2)]TJ /Span< >> BDC ( )Tj EMC 7.317 0 Td (mg\).)Tj 0.025 Tw -19.9 -1.333 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.2 Tw 1.625 0 Td (2.5)Tj /Span< >> BDC ( )Tj EMC 1.338 0 Td [(mg,)37 ( yello)-9.9 (w)37 (,)37 ( round,)37 ( biconvex,)37 ( \037lm-coa)-10 (ted tablets with )37 (\223893\224)37 ( debossed on one)-25 ( )]TJ 0.084 Tw -1.338 -1.063 Td [(side and )37 (\2232\275\224)37 ( on the other side.)]TJ 0.025 Tw -1.625 -1.333 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.11 Tw 1.625 0 Td (5)Tj /Span< >> BDC ( )Tj EMC 0.668 0 Td [(mg,)37 ( pink,)37.1 ( oval-sha)-10 (ped,)37 ( biconvex,)37 ( \037lm-coa)-10 (ted tablets with )36.7 (\223894\224)37 ( debossed on one)-25 ( )]TJ 0.084 Tw -0.668 -1.063 Td [(side and )37 (\2235\224)37 ( on the other side.)]TJ 0.025 Tw -1.625 -1.333 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.024 Tw 1.625 0 Td (0.15)Tj /Span< >> BDC ( )Tj EMC 1.793 0 Td [(mg,)37 ( white to pale yello)-9.9 (w po)-9.9 (wder for oral suspension,)37 ( in a yello)-9.9 (w opaque ca)-10 (psule)-25 ( )]TJ 0 Tc 0 Tw 28.082 0 Td ( )Tj -0.025 Tc 0.047 Tw -29.875 -1.063 Td [(marked \223898\224)100.1 (.)]TJ ET 1 w 4 M q 1 0 0 1 29.948 376.6898 cm 0 0 m 0 -12.641 l S Q q 1 0 0 1 30.02 265.392 cm 0 0 m 0 -142.272 l S Q BT /T1_0 1 Tf 0.025 Tw 8 0 0 8 324 727.248 Tm (4)Tj /Span< >> BDC ( )Tj EMC 3.375 0 Td [(CONTRAINDIC)18 (A)55 (TIONS)]TJ /T1_1 1 Tf 0.084 Tw -3.375 -1.58 Td [(ELIQUIS is contraindica)-10 (ted in pa)-10 (tients with the follo)-9.9 (wing conditions:)]TJ 0.025 Tw 0 -1.558 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.344 Tw 1.625 0 Td [(Active pa)-10 (thological bleeding )]TJ /T1_2 1 Tf [([see )37.2 (W)18 (arnings and Precautions \(5.2\) and )37.1 (Adverse)-25 ( )]TJ 0.084 Tw 0 -1.062 Td (Reactions \(6.1\)])Tj /T1_1 1 Tf 0.025 Tw -1.625 -1.602 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 1.625 0 Td [(Severe hypersensitivity reaction to ELIQUIS \(e.g.,)37 ( ana)-10 (phylactic reactions\) )]TJ /T1_2 1 Tf 0.011 Tw [([see Adverse)-24.9 ( )]TJ 0.084 Tw 0 -1.062 Td (Reactions \(6.1\)])Tj /T1_0 1 Tf 0.025 Tw -1.625 -1.895 Td (5)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td [(W)18 (ARNINGS AND PREC)18 (AUTIONS)]TJ 0.025 Tw -3.375 -1.647 Td (5.1)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td (Increased Risk of Thrombotic Events after Premature Discontinuation)Tj /T1_1 1 Tf 0.084 Tw -3.375 -1.512 Td [(Prema)-10 (ture discontinua)-10 (tion of an)-10 (y oral anticoa)-9.9 (gulant,)37 ( inc)20 (luding ELIQUIS,)37 ( in the absence of)-25 ( )]TJ 0.049 Tw 0 -1.062 Td [(adequa)-10 (te alterna)-10 (tive anticoa)-10 (gula)-9.9 (tion increases the risk of thrombotic events.)37 ( )37.1 (An increased)-25 ( )]TJ 0 Tc 0 Tw 31.5 0 Td ( )Tj -0.025 Tc 0.202 Tw -31.5 -1.062 Td [(ra)-10 (te of )0.5 (stroke was obser)-18 (ved during the transition from )0.5 (ELIQUIS )0.5 (to warfarin )0.5 (in c)20 (linical)-25 ( )]TJ 0.252 Tw 0 -1.062 Td [(trials in a)-10 (trial \037brilla)-10 (tion pa)-10 (tients.)37 ( If ELIQUIS is discontinued for a reason other than)-25 ( )]TJ 0.281 Tw 0 -1.062 Td [(pa)-10 (thological bleeding or completion of a course of thera)-10 (py)55 (,)37 ( consider covera)-10 (ge with)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(another anticoa)-9.9 (gulant )]TJ /T1_2 1 Tf 0 Tc 0 Tw ([)Tj 8.135 0 Td (s)Tj -0.025 Tc 0.084 Tw 0.382 0 Td (ee Do)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.047 Tw 2.469 0 Td [(a)-10 (ge )-37 (and Admini)]TJ 0 Tc 0 Tw (s)Tj -0.025 Tc 0.084 Tw 5.93 0 Td [(tra)-9.9 (tion \(2.5\) and Clinical Studie)]TJ 0 Tc 0 Tw (s)Tj -0.025 Tc 0.084 Tw 11.285 0 Td ( \(14.1\)])Tj /T1_1 1 Tf 0 Tc 0 Tw (.)Tj /T1_0 1 Tf -0.025 Tc 0.025 Tw -28.2 -1.85 Td (5.2)Tj /Span< >> BDC ( )Tj EMC 3.375 0 Td (Bleeding)Tj /T1_1 1 Tf 0.126 Tw -3.375 -1.512 Td [(ELIQUIS increases the risk of bleeding and can cause serious,)37 ( potentially fa)-10 (tal,)37.1 ( bleeding)-25 ( )]TJ /T1_2 1 Tf 0 Tc 0 Tw 0 -1.062 Td ([)Tj 0.234 0 Td (s)Tj -0.025 Tc 0.084 Tw 0.382 0 Td (ee Do)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.047 Tw 2.469 0 Td [(a)-10 (ge )-37 (and Admini)]TJ 0 Tc 0 Tw (s)Tj -0.025 Tc 0.084 Tw 5.93 0 Td [(tra)-9.9 (tion \(2.1\) and )37 (Adver)]TJ 0 Tc 0 Tw (s)Tj -0.025 Tc 0.084 Tw 8.282 0 Td (e Reaction)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.084 Tw 4.103 0 Td ( \(6.1\)])Tj /T1_1 1 Tf 0 Tc 0 Tw (.)Tj -0.025 Tc 0.222 Tw -21.4 -1.512 Td [(Concomitant use of drugs affecting hemostasis increases the risk of blee\ ding.)37 ( )36.9 (These)-25 ( )]TJ 0.144 Tw 0 -1.062 Td [(inc)20 (lude )0.5 (aspirin )0.5 (and other )0.5 (antipla)-10 (telet )0.5 (a)-10 (gents,)37 ( )0.5 (other )0.5 (anticoa)-10 (gulants,)37 ( )0.5 (heparin,)37 ( )0.5 (thrombolytic)-25 ( )]TJ 0.484 Tw 0 -1.062 Td [(a)-10 (gents,)37 ( selective serotonin reuptake inhibitors,)37 ( serotonin norepinephrine reuptake)-24.9 ( )]TJ 0.041 Tw 0 -1.062 Td [(inhibitors,)37 ( and nonsteroidal anti-in\035amma)-9.9 (tor)-18 (y drugs \(NSAIDs\) )]TJ /T1_2 1 Tf 0 Tc 0 Tw ([)Tj 21.826 0 Td (s)Tj -0.025 Tc 0.041 Tw 0.382 0 Td (ee Drug Interaction)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.041 Tw 7.042 0 Td ( \(7.3\)])Tj /T1_1 1 Tf 0 Tc 0 Tw (.)Tj -0.025 Tc 0.178 Tw -29.25 -1.512 Td [(Advise pa)-10 (tients of signs and symptoms of blood loss and to report them immedia)-9.9 (tely)-25 ( )]TJ 0.181 Tw 0 -1.062 Td [(or go to an emergenc)20 (y room.)37 ( Discontinue ELIQUIS in pa)-10 (tients with active pa)-9.9 (thological)-25 ( )]TJ 0.025 Tw 0 -1.062 Td [(hemorrha)-10 (ge.)]TJ /T1_3 1 Tf 0.084 Tw 0 -1.737 Td [(Reversal of )37 (Anticoagulant Effect)]TJ /T1_1 1 Tf 0.168 Tw -0.037 -1.288 Td [(A speci\037c reversal a)-9.9 (gent \(andexanet alfa\) anta)-9.9 (gonizing the pharmacod)-10 (ynamic effect of)-25 ( )]TJ 0.027 Tw 0.037 -1.062 Td [(a)-10 (pixaban is a)-10 (vailable for adults.)37 ( Ho)-9.9 (wever)74 (,)37 ( its safety and ef\037cac)20 (y ha)-9.9 (ve not been established)-25 ( )]TJ 0.149 Tw 0 -1.062 Td [(in pedia)-10 (tric pa)-10 (tients \(refer to the USPI of andexanet alfa\).)37 ( )36.6 (The pharmacod)-10 (ynamic effect)-24.9 ( )]TJ 0.136 Tw 0 -1.062 Td [(of )0.5 (ELIQUIS )0.5 (can )0.5 (be )0.5 (expected to )0.5 (persist for a)-9.9 (t least 24 )0.5 (hours )0.5 (after the last dose,)37 ( i.e.,)37 ( for)-25 ( )]TJ 0.077 Tw 0 -1.062 Td [(about two drug half-lives.)37 ( Prothrombin complex concentra)-9.9 (te \(PCC\),)37 ( activa)-10 (ted prothrombin)-25 ( )]TJ 0.145 Tw 0 -1.062 Td [(complex concentra)-10 (te or recombinant factor )36.7 (VIIa may be considered,)37 ( but ha)-10 (ve not been)-25 ( )]TJ 0.207 Tw 0 -1.062 Td [(evalua)-10 (ted )0.5 (in c)20 (linical studies )]TJ /T1_2 1 Tf 0 Tc 0 Tw ([)Tj 10.72 0 Td (s)Tj -0.025 Tc 0.207 Tw 0.382 0 Td [(ee )0.5 (Clinical)]TJ [( )0.5 (Pharmacolog)-10 (y \(12.2\)])]TJ /T1_1 1 Tf [(.)37 ( )37.4 (When PCCs are )0.5 (used,)12 ( )]TJ 0.201 Tw -11.102 -1.062 Td [(monitoring for the anticoa)-9.9 (gula)-10 (tion effect of a)-10 (pixaban using a c)20 (lotting test \(PT)92.1 (,)36.9 ( INR,)37 ( or)-25 ( )]TJ 0.062 Tw 0 -1.062 Td [(aPTT\) )0.5 (or )0.6 (anti-factor )0.6 (Xa )0.5 (\(FXa\) )0.5 (activity )0.6 (is )0.5 (not )0.5 (useful )0.5 (and )0.6 (is )0.5 (not )0.5 (recommended.)37 ( )37.5 (Activa)-9.9 (ted )0.5 (oral)-25 ( )]TJ 0.027 Tw 0 -1.062 Td [(charcoal reduces absorption of a)-10 (pixaban,)37 ( thereby lo)-10 (wering a)-10 (pixaban plasma concentra)-10 (tion)-25 ( )]TJ /T1_2 1 Tf 0 Tc 0 Tw 0 -1.062 Td ([)Tj 0.234 0 Td (s)Tj -0.025 Tc 0.084 Tw 0.382 0 Td (ee Overdo)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.084 Tw 3.978 0 Td [(a)-10 (ge \(10\)])]TJ /T1_1 1 Tf 0 Tc 0 Tw (.)Tj -0.025 Tc 0.14 Tw -4.594 -1.512 Td [(Hemodialysis does not a)-9.9 (ppear to ha)-10 (ve a substantial impact on a)-10 (pixaban exposure )]TJ /T1_2 1 Tf 0 Tc 0 Tw ([)Tj 30.255 0 Td (s)Tj -0.025 Tc 0.025 Tw 0.382 0 Td [(ee)-25 ( )]TJ -30.637 -1.062 Td (Clinical)Tj 0.284 Tw [( Pharmacolog)-10 (y \(12.3\)])]TJ /T1_1 1 Tf [(.)37 ( Protamine sulfa)-10 (te and vitamin K are not expected to)-24.9 ( )]TJ 0.144 Tw 0 -1.062 Td [(affect the anticoa)-10 (gulant activity of a)-9.9 (pixaban.)37.1 ( )37.1 (There is no experience with anti\037brinolytic)-25 ( )]TJ 0.06 Tw 0 -1.062 Td [(a)-10 (gents \(tranexamic acid,)37 ( aminoca)-10 (proic acid\) in individuals receiving a)-10 (pixaban.)37 ( )36.9 (There is no)-25 ( )]TJ 0.204 Tw 0 -1.062 Td [(experience )0.6 (with )0.5 (systemic )0.6 (hemosta)-10 (tics )0.5 (\(desmopressin\) )0.6 (in )0.5 (individuals )0.5 (receiving )0.6 (ELIQUIS,)12 ( )]TJ 0.084 Tw 0 -1.062 Td [(and they are not expected to be effective as a reversal a)-9.9 (gent.)]TJ /T1_0 1 Tf 0.025 Tw 0 -1.85 Td (5.3)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td (Spinal/Epidural Anesthesia or Puncture)Tj /T1_1 1 Tf 0.283 Tw -3.375 -1.512 Td [(When neuraxial anesthesia \(spinal/epidural anesthesia\) or spinal/epidu\ ral puncture is)-25 ( )]TJ 0.121 Tw 0 -1.062 Td [(emplo)-10 (yed,)37 ( pa)-10 (tients trea)-9.9 (ted with antithrombotic a)-9.9 (gents for prevention of thromboembolic)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(complica)-10 (tions are a)-10 (t risk of developing an )0.5 (epidural or )0.5 (spinal hema)-10 (toma which can result)-25 ( )]TJ 0 -1.062 Td (in long-term or permanent paralysis.)Tj 0.045 Tw 0 -1.512 Td [(The risk of these events may be increased by the postopera)-10 (tive use of indwelling epidural)-25 ( )]TJ 0.114 Tw 0 -1.062 Td [(ca)-10 (theters or the concomitant use of medicinal products affecting hemostasi\ s.)37 ( Indwelling)-25 ( )]TJ 0.142 Tw 0 -1.062 Td [(epidural or intra)-10 (thecal ca)-10 (theters should not be removed earlier than 24 hours after the)-25 ( )]TJ 0.224 Tw 0 -1.062 Td [(last administra)-9.9 (tion of ELIQUIS.)37 ( )36.9 (The next dose of ELIQUIS should not be administered)-25 ( )]TJ 0.159 Tw 0 -1.062 Td [(earlier than 5 hours after the removal of the ca)-9.9 (theter)74 (.)37 ( )36.8 (The risk may also be increased)-25 ( )]TJ 0 Tc 0 Tw 31.5 0 Td ( )Tj -0.025 Tc 0.095 Tw -31.5 -1.062 Td [(by trauma)-9.9 (tic or repea)-9.9 (ted epidural or spinal puncture.)37 ( If trauma)-10 (tic puncture occurs,)37 ( delay)-24.9 ( )]TJ 0.084 Tw 0 -1.062 Td [(the administra)-10 (tion of ELIQUIS for 48 hours.)]TJ 0.467 Tw 0 -1.512 Td [(Monitor pa)-10 (tients frequently for signs and symptoms of neurological impairment)-25 ( )]TJ 0 Tc 0 Tw 31.5 0 Td ( )Tj -0.025 Tc 0.059 Tw -31.5 -1.062 Td [(\(e.g.,)37 ( numbness or weakness of the legs,)37 ( or bo)-9.9 (wel or bladder d)-10 (ysfunction\).)37 ( If neurological)-25 ( )]TJ 0.209 Tw 0 -1.062 Td [(compromise is noted,)37 ( urgent dia)-10 (gnosis and trea)-9.9 (tment is necessar)-18 (y)55 (.)37 ( Prior to neuraxial)-25 ( )]TJ 0.344 Tw 0 -1.062 Td [(inter)-17.9 (vention the physician should consider the potential bene\037t versus the\ risk in)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(anticoa)-10 (gula)-9.9 (ted pa)-9.9 (tients or in pa)-10 (tients to be anticoa)-10 (gula)-9.9 (ted for thromboprophylaxis.)]TJ 0.132 Tw 0 -1.512 Td [(No da)-10 (ta are a)-10 (vailable on the timing of the placement or removal of neuraxial ca)-9.9 (theters)-25 ( )]TJ 0.072 Tw 0 -1.062 Td [(in pedia)-9.9 (tric pa)-10 (tients while on ELIQUIS.)37 ( In such cases,)37 ( discontinue ELIQUIS and consider a)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(short acting parenteral anticoa)-9.9 (gulant.)]TJ /T1_0 1 Tf 0.025 Tw 0 -1.85 Td (5.4)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td [(P)24 (atients with Prosthetic Heart V)18 (alves)]TJ /T1_1 1 Tf 0.052 Tw -3.375 -1.512 Td [(The safety and ef\037cac)20 (y of ELIQUIS ha)-10 (ve not been studied in pa)-9.9 (tients with prosthetic heart)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(valves.)37 ( )37 (Therefore,)37 ( use of ELIQUIS is not recommended in these pa)-10 (tients.)]TJ /T1_0 1 Tf 0.025 Tw 0 -1.85 Td (5.5)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td [(Acute PE in Hemodynamically Unstable P)24 (atients or P)23.9 (atients who Require)-25 ( )]TJ 0 -1.062 Td [(Thrombolysis or Pulmonar)-18 (y Embolectomy)]TJ /T1_1 1 Tf 0.124 Tw -3.375 -1.512 Td [(Initia)-10 (tion )0.6 (of )0.5 (ELIQUIS )0.5 (is )0.6 (not )0.6 (recommended )0.6 (as )0.5 (an )0.6 (alterna)-10 (tive )0.6 (to )0.5 (unfractiona)-10 (ted )0.6 (heparin )0.5 (for)-25 ( )]TJ 0.056 Tw 0 -1.062 Td [(the initial trea)-10 (tment of pa)-10 (tients with PE who present with hemod)-10 (ynamic instability or who)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(may receive thrombolysis or pulmonar)-17.9 (y embolectomy)55 (.)]TJ ET q 1 0 0 1 318.524 470.2439 cm 0 0 m 0 -95.76 l S Q q 1 0 0 1 318.524 156.7559 cm 0 0 m 0 -29.088 l S Q endstream endobj 340 0 obj <>stream BT 0 0 0 1 k /GS0 gs /T1_0 1 Tf -0.025 Tc 0.048 Tw 8 0 0 8 36 582.9919 Tm [(FULL PRESCRIBING INFORMA)55 (TION)]TJ ET 0 0 0 1 K /GS1 gs q 1 0 0 1 36 573.9919 cm 0 0 m 252 0 l S Q q 1 0 0 1 36.5 289.52 cm 0 0 m 0 283.972 l S Q q 1 0 0 1 287.5 289.52 cm 0 0 m 0 283.972 l S Q q 1 0 0 1 36 289.02 cm 0 0 m 252 0 l S Q BT /GS0 gs -0.027 Tc 0.084 Tw 8 0 0 8 58.1093 562.52 Tm [(W)18 (ARNING: \(A\) PREMA)55 (TURE DISCONTINUA)55 (TION OF ELIQUIS \(apixaban\))-26.9 ( )]TJ 4.093 -1.062 Td [(INCREASES THE RISK OF THROMBO)24.1 (TIC EVENTS)]TJ 2.471 -1.288 Td [(\(B\) SPINAL/EPIDURAL HEMA)55 (TOMA)]TJ 0.431 Tw -8.546 -1.423 Td [(\(A\) PREMA)55 (TURE DISCONTINUA)55 (TION OF ELIQUIS INCREASES THE RISK OF)-27 ( )]TJ 0.084 Tw 0 -1.062 Td [(THROMBO)24 (TIC EVENTS)]TJ 0.499 Tw 0 -1.332 Td [(Premature discontinuation of an)-10 (y oral anticoagulant,)37 ( inc)20 (luding ELIQUIS,)9.9 ( )]TJ 0.276 Tw 0 -1.062 Td [(increases the risk of thrombotic events.)37 ( If anticoagulation with ELIQUIS is)-27 ( )]TJ 0.117 Tw 0 -1.062 Td [(discontinued for a reason other than pathological bleeding or completion\ of a)-27 ( )]TJ 0.135 Tw 0 -1.062 Td [(course of therapy)55 (,)37 ( consider co)-10 (verage with another anticoagulant )]TJ /T1_1 1 Tf 0 Tc 0 Tw ([)Tj 25.491 0 Td (s)Tj -0.027 Tc 0.135 Tw 0.417 0 Td (ee Do)Tj 0 Tc 0 Tw (s)Tj -0.027 Tc 0.027 Tw 2.637 0 Td [(age)-27 ( )]TJ 0.133 Tw -28.545 -1.062 Td (and Admini)Tj 0 Tc 0 Tw (s)Tj -0.027 Tc 0.133 Tw 4.795 0 Td [(tration \(2.5\),)37 ( W)17.9 (arning)]TJ 0 Tc 0 Tw (s)Tj -0.027 Tc 0.133 Tw 8.486 0 Td ( and Precaution)Tj 0 Tc 0 Tw (s)Tj -0.027 Tc 0.133 Tw 6.514 0 Td [( \(5.1\),)37 ( and Clinical Studie)]TJ 0 Tc 0 Tw (s)Tj ( )Tj -0.027 Tc 0.027 Tw -19.794 -1.062 Td (\(14.1\)])Tj 0 Tc 0 Tw (.)Tj /T1_0 1 Tf -0.027 Tc 0.084 Tw 0 -1.332 Td [(\(B\) SPINAL/EPIDURAL HEMA)55 (TOMA)]TJ 0.275 Tw 0 -1.332 Td [(Epidural )0.6 (or )0.6 (spinal )0.6 (hematomas )0.6 (may )0.5 (occur )0.5 (in )0.5 (patients )0.6 (treated )0.5 (with )0.6 (ELIQUIS)-26.9 ( )]TJ 0.146 Tw 0 -1.062 Td [(who are receiving neuraxial anesthesia or undergoing spinal puncture.)37.1 ( These)-27 ( )]TJ 0.201 Tw 0 -1.062 Td [(hematomas may result in long-term or permanent paralysis.)37 ( Consider these)-26.9 ( )]TJ 0.04 Tw 0 -1.062 Td [(risks when scheduling patients for spinal procedures.)37 ( F)20 (actors that can increase)-27 ( )]TJ 0.084 Tw 0 -1.062 Td [(the risk of developing epidural or spinal hematomas in these patients in\ c)20 (lude:)]TJ 0.027 Tw 0 -1.242 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.625 0 Td (use of indwelling epidural catheters)Tj 0.027 Tw -1.625 -1.153 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.001 Tw 1.625 0 Td [(concomitant use of other drugs that affect hemostasis,)37 ( such as nonsteroidal)-27 ( )]TJ 0.084 Tw 0 -1.062 Td [(anti-in\037)20 (ammator)-18 (y drugs \(NSAIDs\),)37.1 ( platelet inhibitors,)37 ( other anticoagulants)]TJ 0.027 Tw -1.625 -1.153 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.625 0 Td [(a histor)-18 (y of traumatic or repeated epidural or spinal punctures)]TJ 0.027 Tw -1.625 -1.153 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.625 0 Td [(a histor)-18 (y of spinal deformity or spinal surger)-18 (y)]TJ 0.027 Tw -1.625 -1.153 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.394 Tw 1.625 0 Td [(optimal timing between the administration of ELIQUIS and neuraxial)-26.9 ( )]TJ 0.084 Tw 0 -1.062 Td (procedures is not known)Tj /T1_1 1 Tf -1.625 -1.242 Td [([see W)18 (arnings and Precautions \(5.3\)])]TJ /T1_0 1 Tf 0.025 Tw 0 -1.332 Td [(Monitor )0.5 (patients )0.5 (frequently )0.6 (for )0.5 (signs )0.5 (and )0.6 (symptoms )0.5 (of )0.5 (neurological )0.5 (impairment.)10 ( )]TJ 0.361 Tw 0 -1.062 Td [(If neurological compromise is noted,)37 ( urgent treatment is necessar)-18 (y )]TJ /T1_1 1 Tf 0 Tc 0 Tw ([)Tj 28.619 0 Td (s)Tj -0.027 Tc 0.027 Tw 0.417 0 Td [(ee)-27 ( )]TJ -29.036 -1.062 Td [(W)18 (arning)]TJ 0 Tc 0 Tw (s)Tj -0.027 Tc 0.084 Tw 3.524 0 Td ( and Precaution)Tj 0 Tc 0 Tw (s)Tj -0.027 Tc 0.084 Tw 6.416 0 Td ( \(5.3\)])Tj 0 Tc 0 Tw (.)Tj /T1_0 1 Tf -0.027 Tc 0.372 Tw -9.94 -1.332 Td [(Consider the benefits and risks before neuraxial inter)-18 (vention in patients)-26.9 ( )]TJ 0.084 Tw 0 -1.062 Td (anticoagulated or to be anticoagulated )Tj /T1_1 1 Tf 0 Tc 0 Tw ([)Tj 15.249 0 Td (s)Tj -0.027 Tc 0.084 Tw 0.417 0 Td [(ee W)18.1 (arning)]TJ 0 Tc 0 Tw (s)Tj -0.027 Tc 0.084 Tw 4.693 0 Td ( and Precaution)Tj 0 Tc 0 Tw (s)Tj -0.027 Tc 0.084 Tw 6.416 0 Td ( \(5.3\)])Tj 0 Tc 0 Tw (.)Tj /T1_0 1 Tf -0.025 Tc 0.025 Tw -27.557 -2.74 Td (1)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td [(INDIC)18.1 (A)55 (TIONS AND USAGE)]TJ 0.025 Tw -3.375 -1.602 Td (1.1)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td [(Reduction of Risk of Stroke and Systemic Embolism in Nonv)16 (alvular)-25 ( )]TJ 0 -1.062 Td (Atrial Fibrillation)Tj /T1_2 1 Tf 0.071 Tw -3.375 -1.558 Td [(ELIQUIS is indica)-10 (ted to reduce the risk of stroke and systemic embolism in adult pa)-10 (tients)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(with nonvalvular a)-9.9 (trial \037brilla)-9.9 (tion.)]TJ /T1_0 1 Tf 0.025 Tw 0 -1.558 Td (1.2)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td [(Prophylaxis of Deep V)24 (ein Thrombosis Following Hip or Knee)-25 ( )]TJ 0 -1.062 Td [(Replacement Surger)-18 (y)]TJ /T1_2 1 Tf 0.054 Tw -3.375 -1.558 Td [(ELIQUIS is indica)-10 (ted for the prophylaxis of deep vein thrombosis \(DVT\),)37 ( which may lead to)-24.9 ( )]TJ 0.047 Tw 0 -1.062 Td [(pulmonar)-18 (y embolism \(PE\),)37 ( in adult pa)-9.9 (tients who ha)-10 (ve undergone hip or knee replacement)-25 ( )]TJ 0.025 Tw 0 -1.062 Td [(surger)-18 (y)55 (.)]TJ /T1_0 1 Tf 0 -1.558 Td (1.3)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td [(T)74 (reatment of Deep V)24 (ein Thrombosis)]TJ /T1_2 1 Tf 0.084 Tw -3.375 -1.558 Td [(ELIQUIS is indica)-10 (ted for the trea)-10 (tment of adults with deep vein thrombosis \(DVT\).)]TJ /T1_0 1 Tf 0.025 Tw 0 -1.558 Td (1.4)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td [(T)74 (reatment of Pulmonar)-17.9 (y Embolism)]TJ /T1_2 1 Tf 0.084 Tw -3.375 -1.558 Td [(ELIQUIS is indica)-10 (ted for the trea)-10 (tment of adults with pulmonar)-18 (y embolism \(PE\).)]TJ /T1_0 1 Tf 0.025 Tw 0 -1.558 Td (1.5)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td [(Reduction in the Risk of Recurrence of Deep V)24 (ein Thrombosis and)-25 ( )]TJ 0 -1.062 Td [(Pulmonar)-18 (y Embolism)]TJ /T1_2 1 Tf 0.225 Tw -3.375 -1.558 Td [(ELIQUIS is indica)-10 (ted to reduce the risk of recurrent deep vein thrombosis \(DVT\) and)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(pulmonar)-18 (y embolism \(PE\) in adult pa)-10 (tients follo)-10 (wing initial thera)-9.9 (py)55 (.)]TJ /T1_0 1 Tf 0.025 Tw 0 -1.85 Td (1.6)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td [(T)74 (reatment of V)24 (enous Thromboembolism and Reduction in the Risk of)-24.9 ( )]TJ 0 -1.062 Td [(Recurrent V)24 (enous Thromboembolism in P)24 (ediatric P)24 (atients)]TJ /T1_2 1 Tf 0.06 Tw -3.375 -1.512 Td [(ELIQUIS is indica)-10 (ted for the trea)-10 (tment of venous thromboembolism \(VTE\) and reduction in)-25 ( )]TJ 0.072 Tw 0 -1.062 Td [(the risk of recurrent )36.9 (VTE in pedia)-10 (tric pa)-9.9 (tients from birth and older after a)-9.9 (t least 5 days of)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(initial anticoa)-10 (gulant trea)-10 (tment.)]TJ ET 4 M q 1 0 0 1 30.024 80.496 cm 0 0 m 0 -48.996 l S Q BT /T1_0 1 Tf 0.025 Tw 8 0 0 8 324 582.9919 Tm (2)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td [(DOSAGE AND ADMINISTRA)55 (TION)]TJ 0.025 Tw -3.375 -1.608 Td (2.1)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td [(Recommended Dose in Adult P)24 (atients)]TJ /T1_3 1 Tf 0.235 Tw -3.375 -1.788 Td [(Reduction of Risk of Strok)6 (e and Systemic Embolism in Patients with Nonv)12 (alvular)-25 ( )]TJ 0.084 Tw 0 -1.068 Td (Atrial Fibrillation)Tj /T1_2 1 Tf 0.2 Tw 0 -1.293 Td [(The recommended dose of ELIQUIS \(a)-9.9 (pixaban\) for most pa)-10 (tients is 5)]TJ /Span< >> BDC ( )Tj EMC 25.734 0 Td [(mg taken orally)-24.9 ( )]TJ 0.084 Tw -25.734 -1.068 Td [(twice daily)55.1 (.)]TJ 0.088 Tw 0 -1.428 Td (The recommended dose of ELIQUIS is 2.5)Tj /Span< >> BDC ( )Tj EMC 15.093 0 Td [(mg twice daily in pa)-10 (tients with a)-9.9 (t least two of)-25 ( )]TJ 0.084 Tw -15.093 -1.068 Td [(the follo)-9.9 (wing characteristics:)]TJ 0.025 Tw 0 -1.518 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.625 0 Td [(a)-10 (ge grea)-10 (ter than or equal to 80)]TJ /Span< >> BDC ( )Tj EMC 11.449 0 Td (years)Tj 0.025 Tw -13.074 -1.518 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.625 0 Td [(bod)-10 (y weight less than or equal to 60)]TJ /Span< >> BDC ( )Tj EMC 13.36 0 Td (kg)Tj 0.025 Tw -14.985 -1.518 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.625 0 Td [(serum crea)-9.9 (tinine grea)-10 (ter than or equal to 1.5)]TJ /Span< >> BDC ( )Tj EMC 16.291 0 Td (mg/dL)Tj /T1_3 1 Tf -17.916 -1.743 Td [(Proph)6.1 (ylaxis of Deep )37 (V)18.1 (ein )37 (Thrombosis Follo)6 (wing Hip or Knee Replacement Sur)6 (ger)-18 (y)]TJ /T1_2 1 Tf 0.169 Tw 0 -1.293 Td (The recommended dose of ELIQUIS is 2.5)Tj /Span< >> BDC ( )Tj EMC 15.579 0 Td [(mg taken orally twice daily)55.1 (.)37 ( )37.2 (The initial dose)-25 ( )]TJ 0.084 Tw -15.579 -1.068 Td [(should be taken 12 to 24 hours after surger)-17.9 (y)55 (.)]TJ 0.025 Tw 0 -1.518 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.317 Tw 1.625 0 Td [(In pa)-10 (tients undergoing hip replacement surger)-18 (y)55 (,)37 ( the recommended dura)-10 (tion of)-25 ( )]TJ 0.084 Tw 0 -1.068 Td [(trea)-9.9 (tment is 35 days.)]TJ 0.025 Tw -1.625 -1.518 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.246 Tw 1.625 0 Td [(In pa)-10 (tients undergoing knee replacement surger)-17.9 (y)55 (,)37 ( the recommended dura)-10 (tion of)-25 ( )]TJ 0.084 Tw 0 -1.068 Td [(trea)-9.9 (tment is 12 days.)]TJ /T1_3 1 Tf -1.625 -1.743 Td [(T)74 (r)6 (eatment of DVT and PE)]TJ /T1_2 1 Tf 0.094 Tw 0 -1.293 Td (The recommended dose of ELIQUIS is 10)Tj /Span< >> BDC ( )Tj EMC 14.915 0 Td [(mg taken orally twice daily for the \037rst 7 days)-25 ( )]TJ 0.084 Tw -14.915 -1.068 Td [(of thera)-9.9 (py)55 (.)37 ( )37 (After 7 days,)37.1 ( the recommended dose is 5)]TJ /Span< >> BDC ( )Tj EMC 18.96 0 Td [(mg taken orally twice daily)55 (.)]TJ /T1_3 1 Tf -18.96 -1.743 Td [(Reduction in the Risk of Recurr)6.1 (ence of DVT and PE)]TJ /T1_2 1 Tf 0.244 Tw 0 -1.293 Td (The recommended dose of ELIQUIS is 2.5)Tj /Span< >> BDC ( )Tj EMC 16.028 0 Td [(mg taken orally twice daily after a)-9.9 (t least)-25 ( )]TJ 0.084 Tw -16.028 -1.068 Td [(6 months of trea)-9.9 (tment for DVT or PE )]TJ /T1_4 1 Tf 0 Tc 0 Tw ([)Tj 13.631 0 Td (s)Tj -0.025 Tc 0.084 Tw 0.382 0 Td (ee Clinical)Tj ( Studie)Tj 0 Tc 0 Tw (s)Tj -0.025 Tc 0.084 Tw 6.469 0 Td ( \(14.3\)])Tj /T1_2 1 Tf 0 Tc 0 Tw (.)Tj /T1_0 1 Tf -0.025 Tc 0.025 Tw -20.481 -1.856 Td (2.2)Tj /Span< >> BDC ( )Tj EMC 0.048 Tw 3.375 0 Td [(Recommended Dose in P)24 (ediatric P)24 (atients)]TJ /T1_4 1 Tf 0.064 Tw -3.375 -1.586 Td [(T)74 (rea)-9.9 (tment of )36.8 (V)18 (enous )36.8 (Thromboembolism \(VTE\) and Reduction in the Risk of Recurrent )36.7 (VTE)-25 ( )]TJ 0.084 Tw 0 -1.068 Td [(in P)18 (edia)-10 (tric P)18 (a)-10 (tients)]TJ /T1_2 1 Tf 0.28 Tw 0 -1.518 Td [(The recommended dose of ELIQUIS is based on the pa)-10 (tient\222)55 (s weight,)37 ( see )36.9 (T)74 (able 1.)12.1 ( )]TJ 0 Tc 0 Tw 31.5 0 Td ( )Tj -0.025 Tc 0.343 Tw -31.5 -1.068 Td [(Adjust the dose according to weight-tier as trea)-9.9 (tment progresses.)37 ( Initia)-9.9 (te ELIQUIS)-25 ( )]TJ 0.097 Tw 0 -1.068 Td [(trea)-9.9 (tment for pedia)-9.9 (tric pa)-10 (tients from birth to less than 18)]TJ /Span< >> BDC ( )Tj EMC 20.692 0 Td [(years of a)-10 (ge follo)-10 (wing a)-9.9 (t least)-25 ( )]TJ 0.217 Tw -20.692 -1.068 Td [(5 days of initial anticoa)-10 (gula)-10 (tion thera)-9.9 (py)55 (.)37 ( Individualize dura)-9.9 (tion of overall thera)-9.9 (py after)-25 ( )]TJ 0.084 Tw 0 -1.068 Td [(careful assessment of the trea)-10 (tment bene\037t and the risk for bleeding.)]TJ ET 10 M /GS1 gs q 1 0 0 1 324 208.5298 cm 0 0 m 54 0 l S Q q 1 0 0 1 378 208.5298 cm 0 0 m 63.36 0 l S Q 0.5 w q 1 0 0 1 324 195.6179 cm 0 0 m 54 0 l S Q q 1 0 0 1 378 195.6179 cm 0 0 m 63.36 0 l S Q q 1 0 0 1 378 182.956 cm 0 0 m 0 12.412 l S Q q 1 0 0 1 441.36 182.956 cm 0 0 m 0 12.412 l S Q q 1 0 0 1 324 182.706 cm 0 0 m 54 0 l S Q q 1 0 0 1 378 182.706 cm 0 0 m 63.36 0 l S Q q 1 0 0 1 378 146.2041 cm 0 0 m 0 36.252 l S Q q 1 0 0 1 441.36 182.706 cm 0 0 m 67.32 0 l S Q q 1 0 0 1 441.36 146.2041 cm 0 0 m 0 36.252 l S Q q 1 0 0 1 324 145.9541 cm 0 0 m 54 0 l S Q q 1 0 0 1 378 145.9541 cm 0 0 m 63.36 0 l S Q q 1 0 0 1 378 135.2022 cm 0 0 m 0 10.502 l S Q q 1 0 0 1 441.36 145.9541 cm 0 0 m 67.32 0 l S Q q 1 0 0 1 441.36 135.2022 cm 0 0 m 0 10.502 l S Q q 1 0 0 1 378 124.4503 cm 0 0 m 0 10.752 l S Q q 1 0 0 1 441.36 124.4503 cm 0 0 m 0 10.752 l S Q q 1 0 0 1 378 113.6983 cm 0 0 m 0 10.752 l S Q q 1 0 0 1 441.36 113.6983 cm 0 0 m 0 10.752 l S Q q 1 0 0 1 378 102.9464 cm 0 0 m 0 10.752 l S Q q 1 0 0 1 441.36 102.9464 cm 0 0 m 0 10.752 l S Q q 1 0 0 1 378 92.1945 cm 0 0 m 0 10.752 l S Q q 1 0 0 1 441.36 92.1945 cm 0 0 m 0 10.752 l S Q q 1 0 0 1 378 81.6926 cm 0 0 m 0 10.502 l S Q q 1 0 0 1 441.36 81.6926 cm 0 0 m 0 10.502 l S Q q 1 0 0 1 324 81.4426 cm 0 0 m 54 0 l S Q q 1 0 0 1 378 81.4426 cm 0 0 m 63.36 0 l S Q q 1 0 0 1 378 62.6907 cm 0 0 m 0 18.502 l S Q q 1 0 0 1 441.36 81.4426 cm 0 0 m 67.32 0 l S Q q 1 0 0 1 441.36 62.6907 cm 0 0 m 0 18.502 l S Q 1 w q 1 0 0 1 324 62.1907 cm 0 0 m 54 0 l S Q q 1 0 0 1 378 62.1907 cm 0 0 m 63.36 0 l S Q q 1 0 0 1 441.36 62.1907 cm 0 0 m 67.32 0 l S Q q 1 0 0 1 508.68 208.5298 cm 0 0 m 67.32 0 l S Q q 1 0 0 1 508.68 62.1907 cm 0 0 m 67.32 0 l S Q 0.5 w q 1 0 0 1 508.68 195.6179 cm 0 0 m 67.32 0 l S Q q 1 0 0 1 508.68 182.956 cm 0 0 m 0 12.412 l S Q q 1 0 0 1 508.68 182.706 cm 0 0 m 67.32 0 l S Q q 1 0 0 1 508.68 146.2041 cm 0 0 m 0 36.252 l S Q q 1 0 0 1 508.68 145.9541 cm 0 0 m 67.32 0 l S Q q 1 0 0 1 508.68 135.2022 cm 0 0 m 0 10.502 l S Q q 1 0 0 1 508.68 124.4503 cm 0 0 m 0 10.752 l S Q q 1 0 0 1 508.68 113.6983 cm 0 0 m 0 10.752 l S Q q 1 0 0 1 508.68 102.9464 cm 0 0 m 0 10.752 l S Q q 1 0 0 1 508.68 92.1945 cm 0 0 m 0 10.752 l S Q q 1 0 0 1 508.68 81.6926 cm 0 0 m 0 10.502 l S Q q 1 0 0 1 508.68 81.4426 cm 0 0 m 67.32 0 l S Q q 1 0 0 1 508.68 62.6907 cm 0 0 m 0 18.502 l S Q 1 w q 1 0 0 1 441.36 208.5298 cm 0 0 m 67.32 0 l S Q 0.5 w q 1 0 0 1 441.36 195.8679 cm 0 0 m 0 12.162 l S Q q 1 0 0 1 508.68 195.8679 cm 0 0 m 0 12.162 l S Q q 1 0 0 1 441.36 195.6179 cm 0 0 m 67.32 0 l S Q BT /GS0 gs /T1_0 1 Tf -0.022 Tc 8 0 0 8 324 229.1298 Tm (Table 1:)Tj /Span< >> BDC ( )Tj EMC 5.4 0 Td (Dose Recommendation in Pediatric Patients from Birth to less)Tj 0 Tc 0 Tw 23.866 0 Td ( )Tj -0.022 Tc 0.084 Tw -23.866 -1.062 Td [(than 18 Years of Age for the Treatment of VTE and Reduction in)-22 ( )]TJ 0 Tc 0 Tw 25.012 0 Td ( )Tj -0.022 Tc 0.084 Tw -25.012 -1.062 Td (the Risk of Recurrent VTE)Tj 0.024 Tw 7.6 0 0 8 462.1649 199.2179 Tm (Days 1-7)Tj 6.95 0 Td (Days 8 and beyond)Tj 0.022 Tw -23.98 -1.614 Td (Presentation)Tj 0.024 Tw 6.887 0 Td (Body weight \(kg\))Tj 8.7 0 Td (Dosing schedule)Tj 8.874 0 Td (Dosing schedule)Tj /T1_2 1 Tf -23.837 -1.479 Td [(P)18 (o)-10 (wder in)]TJ 0 Tc 0 Tw 7.6 0 0 8 364.2621 174.4741 Tm ( )Tj -0.022 Tc -0.005 Tw 7.6 0 0 8 328.0374 165.9741 Tm [(Ca)-10 (psule )-29 (0.15)]TJ /Span< >> BDC ( )Tj EMC (mg)Tj 0.024 Tw 0.072 -2.188 Td [(F)20 (or pedia)-9.9 (tric use)]TJ 7.593 1.625 Td (2.6 to less than 4)Tj 8.437 0 Td (0.3)Tj /Span< >> BDC ( )Tj EMC 1.347 0 Td (mg twice daily)Tj 7.298 0 Td (0.15)Tj /Span< >> BDC ( )Tj EMC 1.805 0 Td (mg twice daily)Tj -0.005 Tw -25.959 -5.235 Td [(T)74 (ablet )-29 (0.5)]TJ /Span< >> BDC ( )Tj EMC (mg)Tj 0.024 Tw -0.522 -2.188 Td [(F)20 (or pedia)-9.9 (tric use)]TJ 7.931 4.454 Td (4 to less than 6)Tj 8.437 0 Td (1)Tj /Span< >> BDC ( )Tj EMC 0.671 0 Td (mg twice daily)Tj 7.865 0 Td (0.5)Tj /Span< >> BDC ( )Tj EMC 1.347 0 Td (mg twice daily)Tj -18.321 -1.344 Td (6 to less than 9)Tj 8.437 0 Td (2)Tj /Span< >> BDC ( )Tj EMC 0.671 0 Td (mg twice daily)Tj 8.203 0 Td (1)Tj /Span< >> BDC ( )Tj EMC 0.671 0 Td (mg twice daily)Tj -18.212 -1.344 Td (9 to less than 12)Tj 8.666 0 Td (3)Tj /Span< >> BDC ( )Tj EMC 0.671 0 Td (mg twice daily)Tj 7.865 0 Td (1.5)Tj /Span< >> BDC ( )Tj EMC 1.347 0 Td (mg twice daily)Tj -18.779 -1.344 Td (12 to less than 18)Tj 8.895 0 Td (4)Tj /Span< >> BDC ( )Tj EMC 0.671 0 Td (mg twice daily)Tj 8.203 0 Td (2)Tj /Span< >> BDC ( )Tj EMC 0.671 0 Td (mg twice daily)Tj -18.441 -1.344 Td (18 to less than 25)Tj 8.895 0 Td (6)Tj /Span< >> BDC ( )Tj EMC 0.671 0 Td (mg twice daily)Tj 8.203 0 Td (3)Tj /Span< >> BDC ( )Tj EMC 0.671 0 Td (mg twice daily)Tj -18.441 -1.344 Td (25 to less than 35)Tj 8.895 0 Td (8)Tj /Span< >> BDC ( )Tj EMC 0.671 0 Td (mg twice daily)Tj 8.203 0 Td (4)Tj /Span< >> BDC ( )Tj EMC 0.671 0 Td (mg twice daily)Tj -0.005 Tw -25.584 -1.344 Td [(T)74 (ablets )-29 (2.5)]TJ /Span< >> BDC ( )Tj EMC (mg)Tj 0 Tc 0 Tw 7.6 0 0 8 370.665 73.2107 Tm ( )Tj -0.022 Tc -0.005 Tw 7.6 0 0 8 338.0312 64.7107 Tm [(and )-29 (5)]TJ /Span< >> BDC ( )Tj EMC (mg)Tj 0.024 Tw 6.805 1.062 Td [(grea)-10 (ter than or)-22 ( )]TJ 0 Tc 0 Tw 7.6 0 0 8 431.2822 73.2107 Tm ( )Tj -0.022 Tc 0.024 Tw 7.6 0 0 8 394.5222 64.7107 Tm (equal to 35)Tj 7.463 0.531 Td (10)Tj /Span< >> BDC ( )Tj EMC 1.129 0 Td (mg twice daily)Tj 7.974 0 Td (5)Tj /Span< >> BDC ( )Tj EMC 0.671 0 Td (mg twice daily)Tj -0.025 Tc 0.246 Tw 8 0 0 8 324 44.5453 Tm [(ELIQUIS is not recommended for use in pedia)-10 (tric pa)-10 (tients less than 2.6)]TJ /Span< >> BDC ( )Tj EMC 27.241 0 Td [(kg because)-25 ( )]TJ 0.084 Tw -27.241 -1.068 Td [(ELIQUIS was not studied in these pa)-10 (tients.)]TJ ET 1 w 4 M q 1 0 0 1 318.452 325.5322 cm 0 0 m 0 -80.836 l S Q BT /T1_0 1 Tf 8 0 0 8 36 750.2881 Tm [(FULL PRESCRIBING INFORMA)55 (TION: CONTENTS*)]TJ 0 -1.445 Td (12)Tj /Span< >> BDC ( )Tj EMC 2.375 0 Td [(CLINIC)18 (AL PHARMACOLOGY)]TJ /T1_2 1 Tf 0.047 Tw 0 -1.265 Td (12.1)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td [(Mechanism )-37 (of Action)]TJ 1.455 Tw -3.25 -1.288 Td (12.2)Tj /Span< >> BDC ( )Tj EMC [(Pharmacod)-10 (ynamics)]TJ 0 -1.288 Td (12.3)Tj /Span< >> BDC ( )Tj EMC (Pharmacokinetics)Tj /T1_0 1 Tf 0.084 Tw -2.375 -1.265 Td (13)Tj /Span< >> BDC ( )Tj EMC 2.375 0 Td [(NONCLINIC)18 (AL TOXICOLOGY)]TJ /T1_2 1 Tf 0 -1.265 Td (13.1)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td [(Carcinogenesis,)37 ( Muta)-9.9 (genesis,)37 ( Impairment of F)24 (ertility)]TJ /T1_0 1 Tf -5.625 -1.265 Td (14 )Tj /Span< >> BDC ( )Tj EMC 2.375 0 Td [(CLINIC)18 (AL STUDIES)]TJ /T1_2 1 Tf 0 -1.265 Td (14.1)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td (Reduction of Risk of Stroke and Systemic Embolism in)Tj 0 Tc 0 Tw 19.403 0 Td ( )Tj -0.025 Tc 0.047 Tw -19.403 -1.062 Td [(Nonvalvular Atrial )-37 (F)18.1 (ibrilla)-9.9 (tion)]TJ /T1_4 1 Tf 0 Tc 0 Tw 8.4081 0 0 8.4081 179.8425 750.257 Tm (\()Tj -0.02 Tc 0.02 Tw 0.221 0 Td (Continued\))Tj /T1_2 1 Tf -0.025 Tc 0.084 Tw 8 0 0 8 343 738.0481 Tm (14.2)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td [(Prophylaxis of Deep )37 (V)18 (ein )37 (Thrombosis F)20 (ollo)-9.9 (wing Hip or)]TJ 0 Tc 0 Tw 19.067 0 Td ( )Tj -0.025 Tc 0.084 Tw -19.067 -1.069 Td [(Knee Replacement Surger)-18 (y)]TJ -3.25 -1.294 Td (14.3)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td [(T)74 (rea)-9.9 (tment of DVT and PE and Reduction in the Risk of)]TJ 0 Tc 0 Tw 19.358 0 Td ( )Tj -0.025 Tc 0.084 Tw -19.358 -1.069 Td (Recurrence of DVT and PE)Tj -3.25 -1.294 Td (14.4)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td [(T)74 (rea)-9.9 (tment of )37 (VTE and Prevention of Recurrent )37 (VTE in P)18 (edia)-10 (tric)]TJ 0 Tc 0 Tw 22.017 0 Td ( )Tj -0.025 Tc 0.084 Tw -22.017 -1.069 Td [(P)18 (a)-10 (tients from birth and older)]TJ /T1_0 1 Tf -5.625 -1.271 Td (16)Tj /Span< >> BDC ( )Tj EMC 2.375 0 Td (HOW SUPPLIED/STORAGE AND HANDLING)Tj -2.375 -1.249 Td (17)Tj /Span< >> BDC ( )Tj EMC 2.375 0 Td [(P)54 (A)55 (TIENT COUNSELING INFORMA)55 (TION)]TJ /T1_2 1 Tf -2.375 -1.564 Td [(* Sections or subsections omitted from the full prescribing informa)-10 (tion are not listed.)]TJ ET q 1 0 0 1 36 643.9 cm 0 0 m 540 0 l S Q endstream endobj 339 0 obj <> endobj 353 0 obj <> endobj 354 0 obj <>stream H\ÝjÂ@
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O¼Ýý$[S¾ßËj¶q8S,QVR?íÒ@êÙoøqþØM-¨ILI CÎ[ÎX¸+µÁ-÷Ðj WV±eWZ$2w¹DQtªÕ+ø»DQý`§Zmëå'uÿ0 >stream 0 0 0 1 K 4 M /GS0 gs q 1 0 0 1 36 315.5181 cm 0 0 m 540 0 l S Q BT 0 0 0 1 k /T1_0 1 Tf -0.025 Tc 0.084 Tw 8 0 0 8 36 750.2881 Tm [(HIGHLIGHTS OF PRESCRIBING INFORMA)55 (TION)]TJ 0.15 Tw 0 -1.197 Td [(These highlights do not inc)20 (lude all )-0.6 (the )-0.6 (information )-0.6 (needed to use ELIQUIS )-0.6 (safely)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(and effectively)55 (.)37 ( See full prescribing information for ELIQUIS.)]TJ 0.025 Tw 0 -1.332 Td (ELIQUIS)Tj 0 Tc 0 Tw 5.98 0 0 5.98 59.1838 723.0581 Tm (\256)Tj -0.025 Tc 0.084 Tw 8 0 0 8 63.8182 721.5481 Tm [( \(apixaban\) tablets,)37 ( for oral use)]TJ 0.025 Tw -3.477 -1.197 Td (ELIQUIS)Tj 0 Tc 0 Tw 5.98 0 0 5.98 59.1838 713.4781 Tm (\256)Tj -0.025 Tc 0.084 Tw 8 0 0 8 63.8182 711.9681 Tm ( \(apixaban\) tablets for oral suspension)Tj 0.025 Tw -3.477 -1.197 Td (ELIQUIS)Tj 0 Tc 0 Tw 5.98 0 0 5.98 59.1838 703.8981 Tm (\256)Tj -0.025 Tc 0.084 Tw 8 0 0 8 63.8182 702.3881 Tm ( SPRINKLE \(apixaban\) for oral suspension)Tj -3.477 -1.197 Td [(Initial U.S.)37 ( Appro)-10 (v)16 (al: 2012)]TJ 4.848 -2.534 Td [(W)18 (ARNING: \(A\) PREMA)55 (TURE DISCONTINUA)55 (TION OF ELIQUIS)]TJ 0 Tc 0 Tw 21.805 0 Td ( )Tj -0.025 Tc 0.084 Tw -19.833 -1 Td [(INCREASES THE RISK OF THROMBO)24 (TIC EVENTS)]TJ 2.482 -1.27 Td [(\(B\) SPINAL/EPIDURAL HEMA)55 (TOMA)]TJ /T1_1 1 Tf -5.187 -1.27 Td (See full prescribing information for complete boxed warning.)Tj /T1_0 1 Tf 0.371 Tw -3.153 -1.27 Td [(\(A\) PREMA)55 (TURE DISCONTINUA)55 (TION OF ELIQUIS INCREASES THE RISK OF)-25 ( )]TJ 0.199 Tw 0 -1 Td [(THROMBO)24 (TIC EVENTS: Premature discontinuation of an)-9.9 (y oral anticoagulant,)12 ( )]TJ 0.057 Tw 0 -1 Td [(inc)20 (luding ELIQUIS,)37.1 ( increases the risk of thrombotic events.)37 ( T)73.9 (o reduce this risk,)11.9 ( )]TJ 0.076 Tw 0 -1 Td [(consider co)-10 (verage with another anticoagulant if ELIQUIS is discontinued for a)-25 ( )]TJ 0.079 Tw 0 -1 Td [(reason other than pathological bleeding or completion of a course of the\ rapy)55 (.)12 ( )]TJ 0.084 Tw 0 -1 Td [(\(2.5,)37.1 ( 5.1,)37 ( 14.1\))]TJ 0.137 Tw 0 -1.27 Td [(\(B\) SPINAL/EPIDURAL HEMA)55 (TOMA: Epidural or spinal hematomas )0.5 (may occur)-25.1 ( )]TJ 0.197 Tw 0 -1 Td [(in )0.5 (patients )0.5 (treated with ELIQUIS who )0.5 (are receiving )0.5 (neuraxial anesthesia or)-25 ( )]TJ 0.372 Tw 0 -1 Td [(undergoing spinal puncture.)37 ( These hematomas may result in long-term)-25 ( )]TJ 0.203 Tw 0 -1 Td [(or permanent paralysis.)37 ( Consider these risks when scheduling patients for)-25 ( )]TJ 0.084 Tw 0 -1 Td [(spinal procedures.)37 ( \(5.3\))]TJ ET 35.99 544.196 252.019 141.752 re S BT 0.025 Tw 8 0 0 8 36 529.4562 Tm (-------------------------------)Tj 0.084 Tw 10.797 0 Td (RECENT MAJOR CHANGES)Tj 0.025 Tw 9.903 0 Td (-------------------------------)Tj /T1_2 1 Tf 0.084 Tw -20.7 -1.332 Td [(Indica)-9.9 (tions and Usa)-9.9 (ge \(1.6\))]TJ /Span< >> BDC ( )Tj EMC 28.492 0 Td (04/2025)Tj -28.492 -1.242 Td [(Dosa)-9.9 (ge and )37.1 (Administra)-10 (tion \(2.2,)37 ( 2.6,)37 ( 2.7\))]TJ /Span< >> BDC ( )Tj EMC 28.492 0 Td (04/2025)Tj -28.492 -1.242 Td [(W)18 (arnings and Precautions \(5.2,)37 ( 5.3\))]TJ /Span< >> BDC ( )Tj EMC 28.492 0 Td (04/2025)Tj /T1_0 1 Tf 0.025 Tw -28.492 -1.602 Td (-------------------------------)Tj 0.084 Tw 10.976 0 Td [(INDIC)18.1 (A)55 (TIONS AND USAGE)]TJ -0.039 Tw /Span< >> BDC ( )Tj EMC (-------------------------------)Tj /T1_2 1 Tf 0.084 Tw -10.976 -1.332 Td [(ELIQUIS is a factor Xa inhibitor indica)-9.9 (ted:)]TJ 0.025 Tw 0 -1.242 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.083 Tw 1.125 0 Td [(to reduce the risk of stroke and systemic embolism in adult pa)-9.9 (tients with nonvalvular)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(a)-10 (trial \037brilla)-10 (tion.)37 ( \(1.1\))]TJ 0.025 Tw -1.125 -1.153 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.233 Tw 1.125 0 Td [(for )0.5 (the )0.6 (prophylaxis )0.6 (of )0.6 (deep )0.6 (vein )0.6 (thrombosis )0.6 (\(DVT\),)37 ( )0.6 (which )0.6 (may )0.6 (lead )0.6 (to )0.6 (pulmonar)-18 (y)-25 ( )]TJ 0.305 Tw 0 -1.062 Td [(embolism \(PE\),)37 ( in adult pa)-9.9 (tients who ha)-10 (ve undergone hip or knee replacement)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(surger)-18 (y)55 (.)37 ( \(1.2\))]TJ 0.025 Tw -1.125 -1.153 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.051 Tw 1.125 0 Td [(for )0.5 (the )0.5 (trea)-10 (tment )0.5 (of )0.5 (DVT )0.5 (and )0.6 (PE,)37 ( )0.6 (and )0.6 (for )0.6 (the )0.6 (reduction )0.6 (in )0.5 (the )0.5 (risk )0.5 (of )0.5 (recurrent )0.5 (DVT )0.6 (and)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(PE in adult pa)-10 (tients follo)-10 (wing initial thera)-9.9 (py)55 (.)37 ( \(1.3,)37 ( 1.4,)37 ( 1.5\))]TJ 0.025 Tw -1.125 -1.153 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.04 Tw 1.125 0 Td [(T)74 (rea)-9.9 (tment of venous thromboembolism \(VTE\) and reduction in the risk of rec\ urrent )36.8 (VTE)-25 ( )]TJ 0.122 Tw 0 -1.062 Td [(in pedia)-10 (tric pa)-10 (tients from birth and older after a)-10 (t least 5 days of initial anticoa)-10 (gulant)-24.9 ( )]TJ 0.084 Tw 0 -1.062 Td [(trea)-10 (tment.)37 ( \(1.6\))]TJ /T1_0 1 Tf 0.025 Tw -1.125 -1.512 Td (----------------------------)Tj 0.084 Tw 9.824 0 Td [(DOSAGE AND ADMINISTRA)55 (TION)]TJ -0.157 Tw /Span< >> BDC ( )Tj EMC (----------------------------)Tj /T1_2 1 Tf 0.025 Tw -9.824 -1.332 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.125 0 Td [(Reduction of risk of stroke and systemic embolism in nonvalvular a)-10 (trial \037brilla)-10 (tion:)]TJ 0.025 Tw 0 -1.153 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.305 0 Td (The recommended dose is 5)Tj /Span< >> BDC ( )Tj EMC 10.434 0 Td [(mg orally twice daily)55 (.)37 ( \(2.1\))]TJ 0.025 Tw -11.739 -1.153 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.035 Tw 1.305 0 Td [(In pa)-10 (tients with a)-10 (t least 2 of the follo)-10 (wing characteristics:)37 ( a)-10 (ge grea)-10 (ter than or equal)-25 ( )]TJ 0 Tc 0 Tw 29.07 0 Td ( )Tj -0.025 Tc -0.029 Tw -29.07 -1.062 Td (to 80)Tj /Span< >> BDC ( )Tj EMC 1.962 0 Td [(years,)37 ( bod)-10 (y weight less than or equal to 60)]TJ /Span< >> BDC ( )Tj EMC 14.804 0 Td [(kg,)37 ( or serum crea)-10 (tinine grea)-9.9 (ter than)-25 ( )]TJ 0 Tc 0 Tw 12.304 0 Td ( )Tj -0.025 Tc 0.084 Tw -29.07 -1.062 Td (or equal to 1.5)Tj /Span< >> BDC ( )Tj EMC 5.471 0 Td [(mg/dL,)37 ( the recommended dose is 2.5)]TJ /Span< >> BDC ( )Tj EMC 13.622 0 Td [(mg orally twice daily)55 (.)37 ( \(2.)75.1 (1\))]TJ 0.025 Tw 14.477 52.706 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.125 0 Td [(Prophylaxis of DVT follo)-9.9 (wing hip or knee replacement surger)-18 (y:)]TJ 0.025 Tw 0 -1.153 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.305 0 Td (The recommended dose is 2.5)Tj /Span< >> BDC ( )Tj EMC 11.104 0 Td [(mg orally twice daily)55 (.)37 ( \(2.1\))]TJ 0.025 Tw -13.534 -1.153 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.125 0 Td [(T)74 (rea)-9.9 (tment of DVT and PE:)]TJ 0.025 Tw 0 -1.153 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.098 Tw 1.305 0 Td (The recommended dose is 10)Tj /Span< >> BDC ( )Tj EMC 10.946 0 Td [(mg taken orally twice daily for 7 days,)37 ( follo)-10 (wed by)-25 ( )]TJ 0.084 Tw -10.946 -1.062 Td (5)Tj /Span< >> BDC ( )Tj EMC 0.668 0 Td [(mg taken orally twice daily)55 (.)37 ( \(2.1\))]TJ 0.025 Tw -3.098 -1.153 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.125 0 Td [(Reduction in the risk of recurrent DVT and PE follo)-9.9 (wing initial thera)-10 (py:)]TJ 0.025 Tw 0 -1.153 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.305 0 Td (The recommended dose is 2.5)Tj /Span< >> BDC ( )Tj EMC 11.104 0 Td [(mg taken orally twice daily)55 (.)37 ( \(2.1\))]TJ 0.025 Tw -13.534 -1.153 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.096 Tw 1.125 0 Td [(T)74 (rea)-9.9 (tment of )36.8 (VTE and reduction in the risk of recurrent )36.9 (VTE in pedia)-10 (tric pa)-10 (tients from)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(birth and older after a)-9.9 (t least 5 days of initial anticoa)-9.9 (gulant trea)-9.9 (tment:)]TJ 0.025 Tw 0 -1.153 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.305 0 Td [(See dosing recommenda)-10 (tions in the Full Prescribing Informa)-10 (tion.)37 ( \(2.2\))]TJ /T1_0 1 Tf 0.025 Tw -2.43 -1.512 Td (---------------------------)Tj 0.084 Tw 9.339 0 Td (DOSAGE FORMS AND STRENGTHS)Tj 0.048 Tw /Span< >> BDC ( )Tj EMC (--------------------------)Tj /T1_2 1 Tf 0.025 Tw -9.339 -1.332 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.125 0 Td [(T)74 (ablets:)37 ( 2.5)]TJ /Span< >> BDC ( )Tj EMC 4.25 0 Td (mg and 5)Tj /Span< >> BDC ( )Tj EMC 3.696 0 Td (mg \(3\))Tj 0.025 Tw -9.071 -1.153 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.125 0 Td [(T)74 (ablet F)20 (or Oral Suspension:)37 ( 0.5)]TJ /Span< >> BDC ( )Tj EMC 11.262 0 Td (mg \(3\))Tj 0.025 Tw -12.387 -1.153 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.125 0 Td [(F)20 (or Oral Suspension:)37 ( 0.15)]TJ /Span< >> BDC ( )Tj EMC 9.365 0 Td [(mg in a yello)-10 (w opaque ca)-10 (psule \(3\))]TJ /T1_0 1 Tf 0.025 Tw -10.49 -1.512 Td (----------------------------------)Tj 11.798 0 Td [(CONTRAINDIC)18 (A)55 (TIONS)]TJ 0.092 Tw /Span< >> BDC ( )Tj EMC (---------------------------------)Tj /T1_2 1 Tf 0.025 Tw -11.798 -1.332 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.125 0 Td [(Active pa)-10 (thological bleeding \(4\))]TJ 0.025 Tw -1.125 -1.153 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.125 0 Td [(Severe hypersensitivity to ELIQUIS \(a)-10 (pixaban\) \(4\))]TJ /T1_0 1 Tf 0.025 Tw -1.125 -1.512 Td (----------------------------)Tj 0.084 Tw 9.929 0 Td [(W)18 (ARNINGS AND PREC)18 (AUTIONS)]TJ -0.052 Tw /Span< >> BDC ( )Tj EMC (----------------------------)Tj /T1_2 1 Tf 0.025 Tw -9.929 -1.332 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.208 Tw 1.125 0 Td [(ELIQUIS can cause serious,)37 ( )0.5 (potentially )0.5 (fa)-10 (tal,)37.1 ( bleeding.)37 ( )0.5 (Promptly evalua)-10 (te signs and)-25 ( )]TJ 0.158 Tw 0 -1.062 Td [(symptoms )0.5 (of )0.5 (blood )0.5 (loss.)37 ( )37.5 (An )0.5 (a)-10 (gent )0.5 (to )0.5 (reverse )0.5 (the )0.5 (anti-factor )0.5 (Xa )0.5 (activity )0.5 (of )0.5 (a)-10 (pixaban)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(is a)-9.9 (vailable.)37 ( \(5.2\))]TJ 0.025 Tw -1.125 -1.153 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.084 Tw 1.125 0 Td [(Prosthetic heart valves:)37 ( ELIQUIS use not recommended.)37 ( \(5.4\))]TJ 0.025 Tw -1.125 -1.153 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.437 Tw 1.125 0 Td [(Increased Risk of )36.8 (Thrombosis in P)18 (a)-10 (tients with )36.8 (T)74 (riple P)18 (ositive )36.9 (Antiphospholipid)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(Syndrome:)37 ( ELIQUIS use not recommended.)37 ( \(5.6\))]TJ /T1_0 1 Tf 0.025 Tw -1.125 -1.512 Td (---------------------------------)Tj 0.084 Tw 11.699 0 Td (ADVERSE REACTIONS)Tj -0.006 Tw /Span< >> BDC ( )Tj EMC (---------------------------------)Tj /T1_2 1 Tf 0.025 Tw -11.699 -1.332 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.082 Tw 1.125 0 Td [(Most common adverse reactions \(>1%\) in adult pa)-10 (tients are rela)-10 (ted to bleeding.)37 ( \(6.1\))]TJ 0.025 Tw -1.125 -1.153 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.201 Tw 1.125 0 Td [(The )0.6 (most )0.5 (common )0.6 (adverse )0.5 (reactions )0.5 (\(\03610%\) )0.5 (in )0.5 (pedia)-10 (tric )0.6 (pa)-10 (tients )0.6 (were )0.6 (headache,)12 ( )]TJ 0.084 Tw 0 -1.062 Td [(vomiting,)37 ( and excessive menstrual bleeding.)37 ( \(6.1\))]TJ /T1_0 1 Tf 0.383 Tw -1.125 -1.445 Td [(T)74 (o report SUSPECTED ADVERSE REACTIONS,)37 ( contact Bristol-Myers Squibb at)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(1-800-721-5072 or FD)34 (A at 1-800-FD)34 (A-1088 or www)37 (.fda.go)-10 (v/medwatch.)]TJ /T1_2 1 Tf 0 Tc 0 Tw /Span< >> BDC 27.233 0 Td ( )Tj EMC /T1_0 1 Tf -0.025 Tc 0.025 Tw -27.233 -1.602 Td (----------------------------------)Tj 0.084 Tw 11.769 0 Td [(DR)-10 (UG INTERACTIONS)]TJ 0.064 Tw /Span< >> BDC ( )Tj EMC (---------------------------------)Tj /T1_2 1 Tf 0.025 Tw -11.769 -1.332 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.286 Tw 1.125 0 Td [(Combined P-gp and strong CYP3A4 inhibitors increase blood levels of a)-10 (pixaban.)12 ( )]TJ 0.084 Tw 0 -1.062 Td [(Reduce ELIQUIS dose or a)-10 (void coadministra)-10 (tion.)37 ( \(2.6,)37 ( 7.1,)37 ( 12.3\))]TJ 0.025 Tw -1.125 -1.153 Td (\225)Tj /Span< >> BDC ( )Tj EMC 0.041 Tw 1.125 0 Td [(Simultaneous use of combined P-gp and strong CYP3A4 inducers reduces blo\ od levels)-25 ( )]TJ 0.084 Tw 0 -1.062 Td [(of a)-10 (pixaban:)37 ( )37 (Avoid concomitant use.)37 ( \(7.2,)37 ( 12.3\))]TJ /T1_0 1 Tf 0.025 Tw -1.125 -1.512 Td (----------------------------)Tj 0.084 Tw 9.889 0 Td [(USE IN SPECIFIC POPULA)54.9 (TIONS)]TJ -0.091 Tw /Span< >> BDC ( )Tj EMC (----------------------------)Tj /T1_2 1 Tf 0.025 Tw -9.889 -1.332 Td (\225)Tj /Span< >> BDC ( )Tj EMC /T1_3 1 Tf 1.125 0 Td [(Pregnanc)20 (y:)]TJ /T1_2 1 Tf 0.084 Tw /Span< >> BDC ( )Tj EMC 3.873 0 Td [( Not recommended.)37 ( \(8.1\))]TJ 0.025 Tw -4.998 -1.153 Td (\225)Tj /Span< >> BDC ( )Tj EMC /T1_3 1 Tf 1.125 0 Td [(Lacta)-10 (tion:)]TJ /T1_2 1 Tf 0.084 Tw /Span< >> BDC ( )Tj EMC 3.404 0 Td [( )37 (Advise not to breastfeed.)37 ( \(8.2\))]TJ 0.025 Tw -4.529 -1.153 Td (\225)Tj /Span< >> BDC ( )Tj EMC /T1_3 1 Tf 0.084 Tw 1.125 0 Td [(Severe Hepa)-10 (tic Impairment:)]TJ /T1_2 1 Tf /Span< >> BDC ( )Tj EMC 9.796 0 Td [( Not recommended.)37 ( \(8.7,)37 ( 12.2\))]TJ /T1_0 1 Tf -10.921 -2.188 Td [(See 17 for P)54 (A)55 (TIENT COUNSELING INFORMA)55 (TION and Medication Guide.)]TJ 24.989 -1.355 Td (Revised: 04/2025)Tj -60.989 -7.086 Td [(FULL PRESCRIBING INFORMA)55 (TION: CONTENTS*)]TJ 0 -1.242 Td [(W)18 (ARNING: \(A\) PREMA)55 (TURE DISCONTINUA)55 (TION OF ELIQUIS INCREASES THE RISK)]TJ 0 Tc 0 Tw 30.17 0 Td ( )Tj -0.025 Tc 0.084 Tw -27.795 -1.062 Td [(OF THROMBO)24 (TIC EVENTS)]TJ 0 Tc 0 Tw 9.497 0 Td ( )Tj -0.025 Tc 0.084 Tw -9.497 -1.062 Td [(\(B\) SPINAL/EPIDURAL HEMA)55 (TOMA)]TJ -2.375 -1.242 Td (1)Tj /Span< >> BDC ( )Tj EMC 2.375 0 Td [(INDIC)18.1 (A)55 (TIONS AND USAGE)]TJ /T1_2 1 Tf 0 -1.265 Td (1.1)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td (Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular)Tj 0 Tc 0 Tw 23.756 0 Td ( )Tj -0.025 Tc 0.084 Tw -23.756 -1.062 Td [(Atrial F)18 (ibrilla)-10 (tion)]TJ -3.25 -1.287 Td (1.2)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td [(Prophylaxis of Deep )37 (V)18 (ein )37 (Thrombosis F)20 (ollo)-9.9 (wing Hip or Knee)]TJ 0 Tc 0 Tw 21.117 0 Td ( )Tj -0.025 Tc 0.084 Tw -21.117 -1.062 Td [(Replacement Surger)-17.9 (y)]TJ 0.047 Tw -3.25 -1.288 Td (1.3)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td [(T)74 (rea)-9.9 (tment )-36.9 (of )-37 (Deep V)18 (ein Thrombosis)]TJ 0.084 Tw -3.25 -1.287 Td (1.4)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td [(T)74 (rea)-9.9 (tment of Pulmonar)-17.9 (y Embolism)]TJ -3.25 -1.288 Td (1.5)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td (Reduction in the Risk of Recurrence of DVT and PE)Tj -3.25 -1.288 Td (1.6)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td [(T)74 (rea)-9.9 (tment of )37 (VTE and Reduction in the Risk of Recurrent )37 (VTE)]TJ 0 Tc 0 Tw 21.7 0 Td ( )Tj -0.025 Tc 0.084 Tw -21.7 -1.062 Td [(in P)18 (edia)-10 (tric P)18 (a)-10 (tients)]TJ /T1_0 1 Tf -5.625 -1.265 Td (2)Tj /Span< >> BDC ( )Tj EMC 2.375 0 Td [(DOSAGE AND ADMINISTRA)55 (TION)]TJ /T1_2 1 Tf 0 -1.265 Td (2.1)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td [(Recommended Dose in )37 (Adult P)18.1 (a)-10 (tients)]TJ -3.25 -1.288 Td (2.2)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td [(Recommended Dose in P)18 (edia)-9.9 (tric P)18.1 (a)-10 (tients)]TJ -3.25 -1.288 Td (2.3)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td (Missed Dose)Tj -3.25 -1.288 Td (2.4)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td [(T)74 (emporar)-18 (y Interruption for Surger)-18 (y and Other Inter)-17.9 (ventions)]TJ -3.25 -1.288 Td (2.5)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td (Converting from or to ELIQUIS)Tj -3.25 -1.287 Td (2.6)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td (Combined P-gp and Strong CYP3A4 Inhibitors)Tj -3.25 -1.288 Td (2.7)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td [(Administra)-10 (tion Options)]TJ /T1_0 1 Tf -5.625 -1.265 Td (3)Tj /Span< >> BDC ( )Tj EMC 2.375 0 Td (DOSAGE FORMS AND STRENGTHS)Tj 1.705 Tw -2.375 -1.242 Td (4)Tj /Span< >> BDC ( )Tj EMC [(CONTRAINDIC)18 (A)55 (TIONS)]TJ 0.084 Tw 0 -1.242 Td (5)Tj /Span< >> BDC ( )Tj EMC 2.375 0 Td [(W)18 (ARNINGS AND PREC)18 (AUTIONS)]TJ /T1_2 1 Tf 0 -1.265 Td (5.1)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td [(Increased Risk of )37.1 (Thrombotic Events after Prema)-10 (ture Discontinua)-10 (tion)]TJ 1.91 Tw -3.25 -1.287 Td (5.2)Tj /Span< >> BDC ( )Tj EMC (Bleeding)Tj 0.084 Tw 36 27.428 Td (5.3)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td [(Spinal/Epidural )37 (Anesthesia or Puncture)]TJ -3.25 -1.288 Td (5.4)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td [(P)18 (a)-10 (tients with Prosthetic Heart )37 (V)18 (alves)]TJ -3.25 -1.288 Td (5.5)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td [(Acute PE in Hemod)-9.9 (ynamically Unstable P)18 (a)-9.9 (tients or P)18 (a)-9.9 (tients)]TJ 0 Tc 0 Tw 20.962 0 Td ( )Tj -0.025 Tc 0.084 Tw -20.962 -1.062 Td [(who Require )37 (Thrombolysis or Pulmonar)-18 (y Embolectomy)]TJ -3.25 -1.288 Td (5.6)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td [(Increased Risk of )37.1 (Thrombosis in P)18 (a)-9.9 (tients with )37 (T)74 (riple P)18 (ositive)-25 ( )]TJ 0 -1.062 Td (Antiphospholipid Syndrome)Tj /T1_0 1 Tf -5.625 -1.265 Td (6)Tj /Span< >> BDC ( )Tj EMC 2.375 0 Td (ADVERSE REACTIONS)Tj /T1_2 1 Tf 0.047 Tw 0 -1.265 Td (6.1)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td [(Clinical T)74 (rials )-37 (Experience)]TJ /T1_0 1 Tf 0.084 Tw -5.625 -1.265 Td (7)Tj /Span< >> BDC ( )Tj EMC 2.375 0 Td [(DR)-10 (UG INTERACTIONS)]TJ /T1_2 1 Tf 0 -1.265 Td (7.1)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td (Combined P-gp and Strong CYP3A4 Inhibitors)Tj -3.25 -1.288 Td (7.2)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td (Combined P-gp and Strong CYP3A4 Inducers)Tj 0.047 Tw -3.25 -1.288 Td (7.3)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td [(Anticoa)-10 (gulants )-37 (and Antipla)-10 (telet Agents)]TJ /T1_0 1 Tf 0.084 Tw -5.625 -1.265 Td (8)Tj /Span< >> BDC ( )Tj EMC 2.375 0 Td [(USE IN SPECIFIC POPULA)55 (TIONS)]TJ /T1_2 1 Tf 1.91 Tw 0 -1.265 Td (8.1)Tj /Span< >> BDC ( )Tj EMC [(Pregnanc)20 (y)]TJ 0 -1.288 Td (8.2)Tj /Span< >> BDC ( )Tj EMC [(Lacta)-10 (tion)]TJ 0.084 Tw 0 -1.288 Td (8.3)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td [(F)24 (emales and Males of Reproductive P)18 (otential)]TJ -3.25 -1.288 Td (8.4)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td [(P)18 (edia)-9.9 (tric Use)]TJ -3.25 -1.288 Td (8.5)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td [(Geria)-10 (tric Use)]TJ -3.25 -1.288 Td (8.6)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td (Renal Impairment)Tj -3.25 -1.288 Td (8.7)Tj /Span< >> BDC ( )Tj EMC 3.25 0 Td [(Hepa)-9.9 (tic Impairment)]TJ /T1_0 1 Tf 1.25 Tw -5.625 -1.265 Td (10)Tj /Span< >> BDC ( )Tj EMC (OVERDOSAGE)Tj 0 -1.242 Td (11)Tj /Span< >> BDC ( )Tj EMC (DESCRIPTION)Tj /T1_3 1 Tf 0 Tc 0 Tw 8.4081 0 0 8.4081 542.3515 35.9375 Tm (\()Tj -0.02 Tc 0.02 Tw 0.221 0 Td (Continued\))Tj ET endstream endobj 356 0 obj <> endobj xref 0 357 0000000000 65535 f 0000000016 00000 n 0000000124 00000 n 0000011041 00000 n 0000000000 00000 f 0004414228 00000 n 0004415170 00000 n 0004416136 00000 n 0004417312 00000 n 0004418592 00000 n 0003880796 00000 n 0003881997 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