Rivaroxaban FDA review of ROCKET AF data

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

The FDA conducted an advisory committee review regarding the approvability of rivaroxaban for reduction of stroke and systemic embolization in patients with non-valvular atrial fibrillation on September 8th, 2011.

Non-Inferiority Margin

An upper bound of the 95% CI of the hazard ratio was set at 1.38 by the FDA to establish non-inferiority. In no subgroup did the comparison come near the non-inferiority margin, and non-inferiority was clearly observed in all treatment subgroups and in all forms of analysis.

Primary Efficacy Endpoint

The primary efficacy endpoint was stroke and systemic embolization. The efficacy in the trial was driven by a reduction in hemorrhagic stroke and systemic embolization.

Secondary Efficacy Endpoints

There were fewer non-fatal myocardial infarctions in the Rivaroxaban group.

Safety Endpoint(s)

There were more major bleeding events in the rivaroxaban group, however, the risk of fatal bleeds (H.R.=0.61) and hemorrhagic strokes was reduced in the rivaroxaban group.

Cross Trial Comparisons

Dr. Califf emphasized that cross trial comparisons are inappropriate given the variation in design and patient risk.

Method of Transition at the End of the Trial

• In the rivaroxaban arm, the coumadin was started at a maintenance dose rather than using a loading dose
• There was no overlap with blinded study drug and coumading
• No INR was checked for three days
• Heparin bridging rarely used

IDMC indicated that there was no problem with the transition method. At the time the IDMC looked, there were more events in the warfarin arm. The excess number of events in the riva arm was due to an INR under 2 in the riva patients until they achieved anticoagulation. Following rug discontinuation there was a: 6.4% event rate per year in the rivaroxaban arm which is consistent with the rate in patients who are not anticoagulated 1.7 event rate per year in the coumadin arm consistent with effective coumadin therapy The efficacy of heparin bridging has not been established In the RELY trial, patients were rolled over into the RELIABLE study, and there was often not the opportunity to evaluate the patients for rebound. With drug discontinuation during the trial rather than at the end of the trial, there was no excess events.

Time in Therapeutic Range

Dr. Califf argued that:

• TTR is not a surrogate for anticoagulation risk benefit balance.
• TTR is associated with regional variations. The TTR in the US was 64%, and the treatment benefit in the US was greater than in countries with poor TTR such as in Eastern Europe.
• TTR has no effect on the benefit of a novel anticoagulant over coumadin. RELY, ARISTOTLE and ROCKET AF all showed no interaction between center TTR and the benefit of a novel anticoagulant over coumadin.

The events rates in ROCKET were similar to those in RELY and ARISTOTLE when stratified by CHADS 2 score.

How was TTR Calculated?

Any interruption in drug resulted in exclusion of the TTR during that period. In contrast, ROCKET included discontinuation < 7 days.

ROCKET included the total time on and off drug

Connolly method: Patient on drug for 1 week = patient on coumadin for 5 years

Is TTR a Surrogate Endpoint

Califf argued that TTR does not meet the criterion for a surrogate endpoint based upon the Fleming article form Annals of Internal Med 1997.

Predictors of Lower TTR in ROCKET

• Country is 3 to 4 times more important than all other factors combined
• Prior VKA
• Prior stroke
• CHF
• CHADS2 > 3
• Female gender
• Greater numbers of meds
• Poor socioeconomic status

==TTR in US++ ROCKET 64% RELY 67% ACTIVE 66% Sportif V 68%

TTR in ROCKET vs RELY Adjusting for Imbalances in Countries

Adjusting for imbalances in countries, the TTR in ROCKET was 61.2% and in RELY it was 64.7%.