Oral Rivaroxaban for Symptomatic Venous Thromboembolism

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%

Background Monitoring challenging for outpatients

Solution: oral anticoagulant without monitoring

Rivaroxaban: Direct factor Xa inhibitor

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

Acute DVT: Inclusion Criteria Legal age for consent

Acute, symptomatic objectively confirmed proximal DVT, without symptomatic PE

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

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

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 

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

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

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

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

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

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)

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

Statistical Analysis: Continued Tx Event driven, superiority study

Assumption: 70% RR with rivaroxaban 30 events, power of 90%

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

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

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

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?

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

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

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