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Published byCurtis Baldwin Modified over 8 years ago
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Oral Rivaroxaban for Symptomatic Venous Thromboembolism
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Background Tx ↓ risk of recurrence from 25% to 3% during first 6-12 months of therapy Risk after tx ends: 5-10% during first year Standard: Parenteral heparin initially + Vit K antagonist Annual risk of major bleeding after first year 1-2%
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Background Monitoring challenging for outpatients Solution: oral anticoagulant without monitoring Rivaroxaban: Direct factor Xa inhibitor
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Methods: Acute DVT Design: Randomized, open label, event driven, non-inferiority study P: Pts with acute, symptomatic DVT I: Rivaroxaban C: Enoxaparin + Vit K antagonist O: Symptomatic, recurrent VT
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Acute DVT: Inclusion Criteria Legal age for consent Acute, symptomatic objectively confirmed proximal DVT, without symptomatic PE
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Acute DVT: Exclusion Criteria If therapeutic doses of LMWH, fondaparinux or UFH received for >48 hours or >1 dose of a VKA before randomization Treated with thrombectomy, vena cava filter or a fibrinolytic agent for the current episode of thrombosis Any CIs
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Methods: Acute DVT Duration of tx: determined by the treating physician 15 mg BID X 3 wks 20 mg OD for 3,6 or 12 months Standard: SC enoxaparin ( 1mg/kg BID) Warfarin or acenocoumarol started within 48 hrs of randomization
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Methods: Continued Tx Study Design: Randomized, double-blind (subject, caregiver,investigator, outcomes assessor), event-driven superiority study P: Pts with DVT or PE treated x 6-12 months with a Vit K antagonist or rivaroxaban I: Rivaroxaban 20 mg OD C: Placebo O: Symptomatic, Recurrent VT
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Continued Tx Study: Inclusion Criteria Objectively confirmed symptomatic DVT or PE Treated X 6-12 months with acenocoumarol or warfarin or rivaroxaban If there was equipoise with respect to the need for continued anticoagulation
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Exclusion criteria for both studies Another indication for Vit K antagonist CrCl< 30ml/min Clinically significant liver disease (acute hepatitis, chronic active hepatitis, or cirrhosis) or an ALT>3 ULN Bacterial endocarditis Active bleeding or a high risk of bleeding
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Exclusion Criteria for both studies CI anticoagulant treatment SBP >180 mm Hg or DBP>110 mm Hg Childbearing potential without proper contraception measures Pregnancy or breast feeding Concomitant use of strong P-450 3A4 inhibitors or inducers Participation in another experimental pharmacotherapeutic program within 30 days before screening Life expectancy <3 months
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Methods Continued Tx: Rivaroxaban 20 mg OD or matching placebo for 6 or 12 months Both studies: NSAID & antiplatelet use discouraged If indicated ASA (up to 100 mg), clopidogrel (75 mg) or both allowed
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Outcome assessments 1 ⁰ efficacy outcome: Symptomatic, recurrent VT Acute DVT Study: Principal safety outcome: Clinically relevant bleeding = composite of major or clinically relevant nonmajor bleeding Continued Treatment Study: Major bleeding
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Outcome assessments Predefined 2 ⁰ outcome: All-cause mortality Vascular events (ACS, ischemic stroke, TIA or SE) Net clinical benefit (composite of primary efficacy outcome +major bleeding)
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Statistical Analysis: Acute DVT Event driven, Non-inferiority Study Assumption: equal efficacy in 2 study groups A total of 88 events would provide a power of 90% to demonstrate that rivaroxaban is non inferior to standard therapy Margin = 2.0, corresponds to maintenance of at least 50% of the proven efficacy of standard tx
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Statistical Analysis: Continued Tx Event driven, superiority study Assumption: 70% RR with rivaroxaban 30 events, power of 90%
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Results: Acute DVT Efficacy Rivaroxaban (1731 ) Enoxaparin- VKA (1718) HR (95% CI)P value Recurrent VTE 36(2.1)51(3.0)0.68(0.44- 1.04) <0.001 Net clinical benefit 51(2.9)73(4.2)0.67(0.47- 0.95) 0.03 Principal safety outcome: 8.1% in each group No difference in safety outcomes and total deaths
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Results: Continued Treatment Nonfatal major bleed 0.7% in rivaroxaban group vs. none (P=0.11) EfficacyRivaroxaban (602) Placebo (594) HR (95% CI)P value Recurrent VTE 8(1.3)42(7.1)0.18(0.09- 0.39) <0.00 1 Net clinical benefit 12(2.0)42(7.1) 0.28 (0.15- 0.53) <0.0 01
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CASP SR Checklist Did the study ask a clearly focused question? Yes Was this a randomized controlled trial (RCT) and was it appropriately so? The first study is open label but the second one is RCT. Yes Were participants appropriately allocated to intervention and control groups? Yes Were participants, staff and study personnel ‘blind’ to participants’ study group? Outcomes Assessor blinded Were all of the participants who entered the trial accounted for at its conclusion? Yes
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CASP SR Checklist Were the participants in all groups followed up and data collected in the same way? Yes Did the study have enough participants to minimize the play of chance? Yes How are the results presented and what is the main result? How precise are these results? Were all important outcomes considered so the results can be applied?
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Limitations Blinding: no protection from bias Suspected cases higher in rivaroxaban group Margin of 2.0 = at least 50% of proven efficacy of standard therapy. Acceptable? On-treatment & per-protocol analyses similar to ITT but data not shown
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Limitations Safety: Bleeding events included in the analyses if occurred during tx or within 2 days after d/c Compliance Serious events not defined Results of non-inferiority trial not as credible as a superiority trial
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Implications to practice Dose needs to be studied more Single-drug approach to short-term & continued tx of VT Option in patients not willing to do INR monitoring Reversal of bleeding: no specific antidote, general hemostatic measures Activated charcoal within 2 hours of dose Highly protein bound not dialyzable
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