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The Definitive Thrombosis Update Pulmonary Embolism

The Definitive Thrombosis Update Pulmonary Embolism . Harry R. Büller, MD, PhD Professor of Medicine Department of Vascular Medicine Academic Medical Center Amsterdam, The Netherlands. Rivaroxaban. Specific, direct factor Xa inhibitor High, oral bioavailability Rapid onset of action

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The Definitive Thrombosis Update Pulmonary Embolism

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  1. The Definitive Thrombosis Update Pulmonary Embolism Harry R. Büller, MD, PhD Professor of Medicine Department of Vascular Medicine Academic Medical Center Amsterdam, The Netherlands

  2. Rivaroxaban Specific, direct factor Xa inhibitor High, oral bioavailability Rapid onset of action Half-life: 7 to 11 hours Dual mode of elimination One-third of drug is excreted unchanged by the kidneys Two-thirds of drug is metabolized by the liver: half excreted renally, half excreted via the hepatobiliary route Phase 2 dose-finding studies indicated that for VTE treatment, a regimen consisting of rivaroxaban 15 mg, twice daily for 3 weeks followed by rivaroxaban 20 mg, once daily for the subsequent period appeared most optimal

  3. EINSTEIN-PE Randomized, Open-Label, Event-Driven, Noninferiority Study Up to 48 hours of heparin/fondaparinux treatment permitted before study entry Confirmed PE without DVT N = 4833 Enoxaparin, 2x/d ≥ 5 days + VKA to target INR = 2.5 (range 2-3) Rivaroxaban 15 mg, 2x/d for 3 weeks then 20 mg, 1x/d Primary outcome: symptomatic recurrent VTE Secondary outcomes: clinically relevant bleeding (major bleeding + clinically relevant nonmajor bleeding); all deaths + other vascular events • 30 days posttreatment period, predefined treatment period of 3, 6, or 12 months • Noninferiority margin: 2.0 • 88 primary efficacy outcomes needed

  4. Patient Groups Total patients = 4833 EINSTEIN–PE Investigators, et al. N Engl J Med. 2012;366:1287-1297.

  5. Patient Characteristics ITT Population EINSTEIN–PE Investigators, et al. N Engl J Med. 2012;366:1287-1297.

  6. EINSTEIN-PE: Primary Efficacy Outcome Analysis HR 1.12 0.75 1.68* 0 1.00 2.00 Rivaroxaban superior Rivaroxaban noninferior Rivaroxaban inferior P = .57 for superiority (2 sided) P = .0026 for noninferiority (1 sided) *Potential relative risk increase < 68.4%; absolute risk difference 0.24% (-0.5 to 1.02). Büller HR. ACC 2012.

  7. EINSTEIN-PE: Primary Efficacy Outcome: Time to First Event 3.0 2.5 2.0 1.5 1.0 0.5 0.0 0 30 60 90 120 150 180 210 240 270 300 330 360 ITT Population Rivaroxaban n = 2419 Enoxaparin/VKA n = 2413 Cumulative Event Rate, % HR: 1.12; P < .0026 (noninferiority) TTR: 62.7% Time to Event, days From EINSTEIN–PE Investigators, et al. N Engl J Med. 2012;366:1287-1297.

  8. EINSTEIN-PE: Principal Safety Outcome: Major or Nonmajor Clinically Relevant Bleeding 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1 0 0 30 60 90 120 150 180 210 240 270 300 330 360 Safety Population Enoxaparin/VKA n = 2405 Rivaroxaban n = 2412 Cumulative Event Rate, % Time to Event, days From EINSTEIN–PE Investigators, et al. N Engl J Med. 2012;366:1287-1297.

  9. EINSTEIN-PE: Major Bleeding 3.0 2.5 2.0 1.5 1.0 0.5 0.0 0 30 60 90 120 150 180 210 240 270 300 330 360 Safety Population Enoxaparin/VKA n = 2405 Cumulative Event Rate, % Rivaroxaban n = 2412 Time to Event, days From EINSTEIN–PE Investigators, et al. N Engl J Med. 2012;366:1287-1297.

  10. EINSTEIN-PE: Key Secondary Outcomes *Primary efficacy outcome plus major bleeding. EINSTEIN–PE Investigators, et al. N Engl J Med. 2012;366:1287-1297.

  11. EINSTEIN-PE: Conclusions In patients with acute symptomatic PE with or without DVT, rivaroxaban showed Noninferiority to LMWH/VKA for efficacy: HR = 1.12 (95% CI, 0.75-1.69); P = .0026 for noninferiority margin of 2.0 Similar findings for principal safety outcome: HR = 0.90 (95% CI, 0.76-1.07); P = .23 Superiority for major bleeding: HR = 0.49 (95% CI, 0.31-0.79); P = .0032 Consistent efficacy and safety results irrespective of age, body weight, gender, kidney function, or cancer No evidence for liver toxicity

  12. The Definitive Thrombosis Update Venous Thromboembolism Professor the Lord Ajay K. Kakkar, MD, PhD Prevention of Atrial Fibrillation-Related Stroke Keith A. A. Fox, MB, ChB Secondary Prevention Following Acute Coronary Syndrome Freek W. A. Verheugt, MD Pulmonary Embolism Harry R. Büller, MD, PhD

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