Oral rivaroxaban versus standard therapy for the acute and continued treatment of symptomatic deep vein thrombosis. The EINSTEIN DVT study.

Transcription

1 Oral rivaroxaban versus standard therapy for the acute and continued treatment of symptomatic deep vein thrombosis. The EINSTEIN DVT study Comments Harald Darius, Berlin

2 Disclosures for Harald Darius Research Support / P.I. Employee Consultant Major Stockholder Scientific Advisory Board or Speakers Bureau Bayer HealthCare, Boehringer Ingelheim, Bristol- Myers Squibb, Daiichi-Sankyo, Sanofi-Aventis No relevant conflicts of interest to declare No relevant conflicts of interest to declare Unfortunately, no conflicts of interest to declare Bayer HealthCare, Berlin-Chemie, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Sanofi-Aventis, The Medicines Company

3 3-day observation period EINSTEIN DVT: study design Randomized, open-label, event-driven, non-inferiority study 48 hours treatment with heparins/fondaparinux permitted before study entry 88 primary efficacy outcomes needed; non-inferiority margin 1.75; 9% power Treatment period: 3, 6 or 12 months Confirmed symptomatic DVT without symptomatic PE N=3,449 R Rivaroxaban Rivaroxaban 15 mg bid 2 mg od Enoxaparin 1. mg/kg bid 5 days, followed by VKA INR range 2 3 Day 1 Day 21 N = 3,449: 3429 safety population, 396 per protocol population 9.7% missing Mean age: 56 yrs Creatinin Clearance < 5/min: 7 % Pretreatment LMWH/Fonda: 73 and 71 % (clinical convenience for outpatients = no pretreatment) Statistics: very wide confidence margin for non-inferiority 1.75 Treatment regimen: 3 wks 15 mg bid continued 2 mg od: Really necessary?

4 Primary efficacy outcome analysis Rivaroxaban (n=1,731) Enoxaparin/VKA (n=1,718) n (%) n (%) First symptomatic recurrent VTE 36 (2.1) 51 (3.) Recurrent DVT 14 (.8) 28 (1.6) Recurrent DVT + PE 1 (<.1) () Non-fatal PE 2 (1.2) 18 (1.) Fatal PE/unexplained death where PE cannot be ruled out (.2) 6 (.3) 1 Hazard ratio 1.75 Rivaroxaban superior Rivaroxaban non-inferior Rivaroxaban inferior p=.76 for superiority (two-sided) p<.1 for non-inferiority (one-sided) ITT population Results of the per protocol cohort?

5 Cumulative event rate (%) Primary efficacy outcome: time to first event Quality of OAC: INR 57.7% in target range! Were I EP events associated with poor INR control? Enoxaparin / VKA (n=1,718) 2. Rivaroxaban (n=1,713) Time to event (days) Number of subjects at risk Rivaroxaban 1,731 1,668 1,648 1,621 1,424 1,412 1, Enox/VKA 1,718 1,616 1,581 1,553 1,368 1,358 1,

6 3-day follow-up period Study Design Randomised, double-blind, event driven (N=3), placebo-controled, superiority trial Confirmed symptomatic DVT or PE and 6- or 12-months pretreatment with rivaroxaban or a VKA in the EINSTEIN DVT / PE Trial ~ 53% N = R Treatment phase: 6 or 12 months Rivaroxaban 2 mg od Confirmed symptomatic DVT or PE and 6- or 12-months pretreatment with a VKA Day 1 Placebo ~ 47% DVT = deep vein thrombosis; PE = pulmonary embolism; VKA = vitamin-k-antagonist Buller, HR et al. Abstract Iba-2; ASH 29

7 Cumulated event rate (%) Results Time to primary efficacy endpoint event: Symptomatic, recurrent VTE (DVT, non-fatal PE and fatal PE NNT : 15 Days until event Placebo (N = 594*) HR =,184; p <,1 RRR = 82% Rivaroxaban (N = 62*) Buller, HR et al. Abstract Iba-2; ASH 29

8 Patients (n) Patients (n) Rivaroxaban 15 mg bid / 3wks 2 mg od for 3, 6, 12 mo Max. 2 days pretreatment LMWH/Fonda Dabigatran 15 mg bid / 6mo 5-1 days pretreatment LMWH/Fonda I EP: Sympt. rec. VTE = rec. DVT + non-fatal PE + fatal PE I EP: Rec. sympt. VTE + VTE assoc. death 5 HR.68; 95% CI: p <.1 for non-inferiority 51 (3,%) 4 HR 1.1; 95% CI: p <.1 for non-inferiority 4 36 (2,1%) 3 3 (2,4%) 27 (2,1%) Rivaroxaban VKA Dabigatran Warfarin N=3449 Pat. N=2539 Pat. Data from Schulman (29) N Engl J Med 361:

9 Patients (n) Patients (n) Rivaroxaban 15 mg bid / 3 wks 2 mg od for 3, 6, 12 mo Max. 2 days pretreatment LMWH/Fonda Dabigatran 15 mg bid / 6 mo 5-1 days pretreatment LMWH/Fonda I EP: Sympt. rec. VTE = rec. DVT + non-fatal PE + fatal PE I EP: Rec. sympt. VTE + VTE assoc. death HR.68; 95% CI: p <.1 for non-inferiority 36 (2,1%) Warning: 3 (2,4%) treatment duration, HR 1.1; 95% CI: p <.1 for non-inferiority Comparison 51 (3,%) may be influenced by 4 differences in: comparator therapy, endpoint and bleeding definitions 27 (2,1%) Rivaroxaban VKA Dabigatran Warfarin N=3449 Pat. N=2539 Pat. Data from Schulman (29) N Engl J Med 361:

10 Rivaroxaban 15 mg bid / 3wks 2 mg od for 3, 6, 12 mo Max. 2 days pretreatment LMWH/Fonda Dabigatran 15 mg bid / 6mo 5-1 days pretreatment LMWH/Fonda I Safety EP: Rivaroxaban VKA Dabigatran Warfarin First major or CRNMB % % HR.97; 95%CI ; P=.77 ISTH severe 2 24 HR.82; 95%CI ; n.s. II Safety EP: Major bleeding All bleedings 14.8 % % HR.71; 95%CI ; p<.1 CRNMB % % CRNMB: clinically relevant non-major bleeding Data from Schulman (29) N Engl J Med 361:

11 Rivaroxaban 15 mg bid / 3wks 2 mg od for 3, 6, 12 mo Max. 2 days pretreatment LMWH/Fonda Dabigatran 15 mg bid / 6mo 5-1 days pretreatment LMWH/Fonda I Safety EP: II Safety EP: Rivaroxaban VKA Dabigatran Warfarin First major or CRNMB % % HR.97; 95%CI ; P= % Major bleeding % ISTH severe 2 24 Warning: Comparison may be influenced by differences in: comparator therapy, treatment duration, endpoint and bleeding definitions HR.82; 95%CI ; n.s. All bleedings HR.71; 95%CI ; p<.1 CRNMB % % CRNMB: clinically relevant non-major bleeding Data from Schulman (29) N Engl J Med 361:

12 Conclusions Einstein DVT is a carefully designed and performed trial Some data are still missing or need to be interpreted (waiting for publication) e.g. late efficacy past 6 mo Rivaroxaban is of borderline superior efficacy (net benefit significant) without advantages in bleeding in the dose regimen chosen We are facing a new era of antithrombotic therapy for patients with DVT with some questions still to be resolved e.g. initial subcutaneous treatment really necessary or optimal duration of treatment or treatment of elderly patients with reduced renal function or performance of other F.Xa inhibitors or direct antithrombins in this indication