Oral rivaroxaban alone for the treatment of symptomatic pulmonary embolism: the EINSTEIN PE study Harry R Büller on behalf of the EINSTEIN Investigators.

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Oral rivaroxaban alone for the treatment of symptomatic pulmonary embolism: the EINSTEIN PE study Harry R Büller on behalf of the EINSTEIN Investigators

Disclosures for Harry R Büller Research Support/P.I.Sanofi-aventis, Bayer HealthCare, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Pfizer, Roche, Isis, Thrombogenics EmployeeNo relevant conflicts of interest to declare ConsultantSanofi-aventis, Bayer HealthCare, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Pfizer, Roche, Isis, Thrombogenics Major StockholderNo relevant conflicts of interest to declare Speakers BureauNo relevant conflicts of interest to declare Scientific Advisory BoardSanofi-aventis, Bayer HealthCare, Bristol-Myers Squibb, Daiichi-Sankyo, GlaxoSmithKline, Pfizer, Roche, Isis, Thrombogenics

EINSTEIN PE: study design Randomized, open-label, event-driven, non-inferiority study  Up to 48 hours’ heparins/fondaparinux treatment permitted before study entry  88 primary efficacy outcomes needed  Non-inferiority margin: 2.0 Predefined treatment period of 3, 6, or 12 months 15 mg bid Rivaroxaban Day 1Day 21 Enoxaparin bid for at least 5 days, plus VKA INR 2.5 (range 2.0–3.0) 20 mg od N=4833 Rivaroxaban R Objectively confirmed PE ± DVT 30-day post-study treatment period  Primary efficacy outcome: first recurrent VTE  Principal safety outcome: first major or nonmajor clinically relevant bleeding

Patient flow *As treated Withdrawal of consent Lost to follow-up Safety population* ITT population Randomized (N=4833) Per-protocol population Rivaroxaban Enoxaparin/VKA

EINSTEIN PE: primary efficacy outcome analysis Rivaroxaban (N=2419) Enoxaparin/VKA (N=2413) n (%)n First symptomatic recurrent VTE50(2.1)44(1.8) Recurrent DVT18(0.7)17(0.7) Recurrent DVT + PE02(<0.1) Non-fatal PE22(0.9)19(0.8) Fatal PE/unexplained death where PE cannot be ruled out 10(0.4)6(0.2) Rivaroxaban superior Rivaroxaban non-inferior Rivaroxaban inferior P= for non-inferiority (one-sided) p=0.57 for superiority (two-sided) * *Potential relative risk increase <68.4%; absolute risk difference 0.24% (–0.5 to 1.02) HR

EINSTEIN PE: principal safety outcome – major or non-major clinically relevant bleeding Rivaroxaban n/N (%) Enoxaparin/VKA n/N (%) HR (95% CI) p-value 249/2412 (10.3) 274/2405 (11.4) 0.90 (0.76–1.07) p=0.23 Safety population Number of patients at risk Rivaroxaban Enoxaparin/VKA Time to event (days) Rivaroxaban N=2412 Enoxaparin/VKA N=2405 Cumulative event rate (%)

Safety population Cumulative event rate (%) Time to event (days) Rivaroxaban N=2412 Enoxaparin/VKA N=2405 Number of patients at risk Rivaroxaban Enoxaparin/VKA EINSTEIN PE: major bleeding Rivaroxaban n/N (%) Enoxaparin/VKA n/N (%) HR (95% CI) p-value 26/2412 (1.1) 52/2405 (2.2) 0.49 (0.31–0.79) p=0.0032

EINSTEIN PE: conclusions  In patients with acute symptomatic PE with or without DVT, rivaroxaban showed:  Non-inferiority to LMWH/VKA for efficacy: HR=1.12 (0.75–1.69); p non-inferiority = for non-inferiority margin of 2.0  Similar findings for principal safety outcome: HR=0.90 (0.76–1.07); p=0.23  Superiority for major bleeding: HR=0.49 (0.31–0.79) p=  Consistent efficacy and safety results irrespective of age, body weight, gender, kidney function and cancer  No evidence for liver toxicity