Anticoagulation and Thrombosis Management - PowerPoint Presentation

Anticoagulation and Thrombosis Management A Review of Non-Vitamin K Oral Anticoagulants: Other Uses

Dabigatran Rivaroxaban Apixaban Edoxaban TargetIIa (thrombin)XaXaXaHours to maximum concentration1-32-43-41-2Half-life, h12-175-13129-11Renal clearance, % 8033*2550TransportersP-gpP-gpP-gpP-gpCytochrome P450 metabolism, %None<32~50<4 *33% renally cleared; 33% excreted unchanged in urine. Comparative PK/PD of NOACs Heidbuchel H, et al. Europace. 2013;15:625-651 [1] ; Hellwig T, et al. Ann Pharmacother. 2013;47:1478-1487. [2]

Rationale for the Use of Oral Anticoagulation Post MI WARISa Warfarin, n = 607 Placebo, n = 607PDeath, %15.5 20.3.0267Reinfarction, %13.520.4.0007Major bleeding1.3----WARIS-IIbWarfarin,n = 1216 Aspirin, n = 1206 W + A, n = 1208 PW vs APW vs W + APA vs W + ADeath, nonfatal reinfarction or stroke, %16.72015.03NS.001Major bleeding, %/y0.680.170.57------ Smith P, et al. N Engl J Med. 1990;323:147-152 [3] ; b. Hurlen M, et al. N Engl J Med. 2002;347:969-974. [4]

Outcome Apixaban 5 mg twice daily, % Placebo, % HR (95% CI) P Efficacy n = 3705n = 3687Cardiovascular death, myocardial infarction, or ischemic stroke7.57.90.95 (0.80-1.11).51Death4.23.91.08 (0.86-1.35).51Cardiovascular death2.83.00.96 (0.73-1.25).76Safety: bleedingn = 3673n = 3642 TIMI criteria: major bleeding1.3 0.5 2.59 (1.50-4.46) .001 Fatal bleeding0.10NANAIntracranial bleeding0.30.14.06 (1.15-14.38).03Any bleeding18.58.42.36 (2.06-2.70)< .001APPRAISE-2 Efficacy and Safety Results Alexander JH, et al. N Engl J Med. 2011;365:699-708.[5]Trial terminated November 2011 because of excess clinically important bleeding events in the apixaban group without counterbalancing reduction in ischemic events

Rivaroxaban in ACS: ATLAS ACS 2—TIMI 51 Mega JL, et al. N Engl J Med. 2012;366:9-19.[6]Trial dose of rivaroxaban was 2.5 mg and 5 mg twice daily vs 20 mg daily in patients with atrial fibrillation P = .002P = .02P = .03P = .66%Rivaroxaban 2.5 mg twice dailyRivaroxaban 5 mg twice daily Placebo

ATLAS-2 Reduction in Stent Thrombosis (Definite/Probable ) Gibson CM, et al. J Am Coll Cardiol. 2013;62:286-290.[7]Kaplan-Meier Event Rate, %P values = mITTP = .023P = .089Rivaroxaban 2.5 mg twice dailyRivaroxaban 5 mg twice daily Placebo

Mega JL, et al. J Am Coll Cardiol. 2013;61:1853-1859.[8] P = .008 P = .007P = .006P = .006N = 7727ATLAS-2Mortality Benefit With Very Low-dose Rivaroxaban in Patients With STEMI

NOAC Trials Outcomes in Patients With Cancer: Prespecified Subgroup AnalysesBauersachs R, et al. N Engl J Med . 2010;363:2499-2510 [9] ; Büller HR, et al. N Engl J Med. 2012;366:1287-1297[10]; Agnelli G, et al. N Engl J Med. 2013;369:799-808[11]; Agnelli G, et al. N Engl J Med. 2013;368:699-708[12]; Schulman S, et al. N Engl J Med. 2009;361:2342-2352[13]; Schulman S, et al. N Engl J Med. 2013;368:709-718[14]; Büller HR, et al. N Engl J Med. 2013;369:1406-1415[15]; Raskob GE, et al. ASH 2013. Abstract 211.[16]NOAC TrialPatients With Active CancerRecurrent VTEClinically Relevant BleedingEINSTEIN-DVTRivaroxaban = 6.8%VKA = 5.2%Rivaroxaban = 3.4%VKA = 5.6%Rivaroxaban = 14.4%VKA =15.9%EINSTEIN-PERivaroxaban = 4.7%VKA = 4.5%Rivaroxaban = 1.8% VKA = 2.8%Rivaroxaban = 12.3% VKA = 9.3%EINSTEIN-ExtensionRivaroxaban = 4.5%Placebo = 4.4% NR NR AMPLIFY Apixaban = 2.5%VKA = 2.8%NRNRAMPLIFY-EXTPlacebo = 2.2%2.5 mg apixaban =1.8%5 mg apixaban =1.1%NRNRRE-COVERDabigatran = 5%VKA =4.5%Dabigatran = 3.1%VKA = 5.3%NRRE-MEDYDabigatran = 4.2%VKA = 4.1%Dabigatran = 3.3%VKA = 1.7%NRHokusai-VTEEdoxaban = 2.6%VKA = 2.4%Edoxaban = 3.7%VKA = 7.1%Edoxaban = 18.3%VKA = 25.3%

SELECT-DStudy Design Young A, et al. ASCO 2014. Abstract TPS9661.[17] Rivaroxaban 15 mg orally twice daily × 3 weeks 20 mg once daily × 6 monthsDalteparin200 IU/kg daily subcutaneously × 1 month150 IU/kg months 2 to 6Primary efficacy: incidence of recurrent VTESecondary outcomes: safety, acceptability, biomarker identification, and health economicsResidual vein thrombosis-positive patientsRivaroxaban20 mg once daily6 months vs 12 monthsof treatmentPlaceboProspective, randomized, open-label, multicenter, pilot trial in selected patients with cancer at risk for VTE recurrenceEstimated enrollment: 530 patients

95% CI = 95% confidence interval ACS = acute coronary syndrome AMPLIFY = Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line TherapyAPPRAISE = Apixaban for Prevention of Acute Ischemic Safety EventsATLAS ACS 2—TIMI 51 = Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome–Thrombolysis in Myocardial Infarction 51 DVT = deep vein thrombosis EXT = extensionHR = hazard ratioITT = intention to treatMITT = modified intention to treatNOAC = non-vitamin K (novel) oral anticoagulantNR = not reportedAbbreviations

PE = pulmonary embolismP- gp = P-glycoproteinPK/PD = pharmacokinetics/pharmacodynamics RE-COVER = Dabigatran versus Warfarin in the Treatment of Acute Venous ThromboembolismRE-MEDY = Extended Use of Dabigatran, Warfarin, or Placebo in Venous Thromboembolism SELECT-D = Anticoagulation Therapy in Selected Cancer Patients at Risk of Recurrence of Venous Thromboembolism STEMI = ST-segment-elevation myocardial infarction VKA = vitamin K antagonistVTE = venous thromboembolismWARIS = Warfarin Re-Infarction StudyWARIS-II = Warfarin, Aspirin, Re-Infarction StudyAbbreviations (cont)

References 1. Heidbuchel H, Verhamme P, Alings M, et al; European Heart Rhythm Association. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non- valvular atrial fibrillation. Europace . 2013;15:625-651.2. Hellwig T, Gulseth M. Pharmacokinetic and pharmacodynamic drug interactions with new oral anticoagulants: what do they mean for patients with atrial fibrillation? Ann Pharmacother. 2013;47:1478-1487.3. Smith P, Arnesen H, Holme I. The effect of warfarin on mortality and reinfarction after myocardial infarction. N Engl J Med. 1990;323:147-152.4. Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med. 2002;347:969-974.5. Alexander JH, Lopes RD, James S, et al; APPRAISE-2 Investigators. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med. 2011;365:699-708.6. Mega JL, Braunwald E, Wiviott SD, et al; ATLAS-ACS 2 TIMI 51. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366:9-19.7. Gibson CM, Chakrabarti AK, Mega J, et al; ATLAS-ACS 2 TIMI 51 Investigators. Reduction of stent thrombosis in patients with acute coronary syndromes treated with rivaroxaban in ATLAS-ACS 2 TIMI 51. J Am Coll Cardiol. 2013;62:286-290.

References (cont) 8. Mega JL, Braunwald E, Murphy SA, et al. Rivaroxaban in patients stabilized after a ST-segment elevation myocardial infarction: results from the ATLAS ACS-2-TIMI-51 trial (Anti- Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction-51). J Am Coll Cardiol. 2013;61:1853-1859.9. Bauersachs R, Berkowitz SD, Brenner B, et al; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499-2510.10. Büller HR, Prins MH, Lensin AW, et al; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287-1297.11. Agnelli G, Büller HR, Cohen A, et al; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369:799-808.12. Agnelli G, Büller HR, Cohen A, et al; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013;368:699-708.13. Schulman S, Kearon C, Kakkar AK, et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361:2342-2352 14. Schulman S, Kearon C, Kakkar AK, et al; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368:709-718.

References (cont) 15. Büller HR, Décousus H, Grosso MA, et al; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med . 2013;369:1406-1415. 16. Raskob GE, Büller HR, Angchaisuksiri P, et al. Edoxaban for long-term treatment of venous thromboembolism in cancer patients. Presented at: 55th ASH Annual Meeting and Exposition; December 9; 2013; New Orleans, LA. Abstract 211.17. Young A, Dunn J, Chapman O, et al. SELECT-D: Anticoagulation therapy in selected cancer patients at risk of recurrence of venous thromboembolism. Presented at: 2014 ASCO Annual Meeting; May 30-June 3, 2014; Chicago, IL. Abstract TPS9661.