Oral Rivaroxaban for Symptomatic Venous Thromboembolism
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Transcript of Oral Rivaroxaban for Symptomatic Venous Thromboembolism
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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 1⁰ 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 2⁰ 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 DVTEfficacy 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)
Efficacy Rivaroxaban (602)
Placebo (594)
HR (95% CI) P value
Recurrent VTE
8(1.3) 42(7.1) 0.18(0.09-0.39)
<0.001
Net clinical benefit
12(2.0) 42(7.1) 0.28 (0.15-0.53)
<0.001
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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