Rivaroxaban FDA review of ROCKET AF data
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 between rivaroxaban and warfarin come near the non-inferiority margin. 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 (open label vs double blind), variation in patient risk (87% were CHADS2 and above in ROCKET vs a third in RELY and ARISTOTLE) and distribution of countries with the attendant variation in TTR by country.
Resumption of Events Following Discontinuation of Study Drug
In its briefing document, the FDA expressed concern regarding the excess number of primary endpoint events in the rivaroxaban arm when study drug was discontinued at the end of the trial. There was no excess unmber of events if the drug was disontinued during the course of the study. Dr. Califf argued that the excess number of events among rivaroxaban patients is what would be expected given their high CHADS2 score (87% had a CHADS2 score > 3) while patients who had been treated with rivaroxaban during the study were awaiting therapeutic anticoagulation with coumdadin. In other words, these events represented a resumption of events in high risk patients awaiting therapeutic levels of anticoagulation versus rebound.
Method of Transition at the End of the Trial
- In the rivaroxaban arm, the warfarin was started at a maintenance dose rather than using a loading dose
- There was no overlap with blinded study drug and warfarin
- 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 warfarin arm consistent with effective warfarin 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 warfarin. RELY, ARISTOTLE and ROCKET AF all showed no interaction between center TTR and the benefit of a novel anticoagulant over warfarin.
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 warfarin 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 the North America by Trial
The median TTR in North America in the ROCKET trial was similar to that observed in comparable trials:
- ROCKET: 64% (63% US, 66% Canada)
- RELY: 67%
- ACTIVE: 66%
- Sportif V: 68%
TTR in ROCKET vs RELY Adjusting for Imbalances in Countries
Adjusting for imbalances in the distribution of countries, the TTR in ROCKET was 61.2% and was 64.&% in RELY.
Conclusions by Dr. Califf
- TTR varies substantially by region
- Some regions were slower to adjust the warfarin dose in response to an INR value
- Center TTR was not associated with the relative magnitude of treatment effect of a novel anticoagulant over a vitamin K antagonist in any recent trial (RELY, ROCKET, ARISTOTLE).
- In ROCKET there was a constancy in the benefit across all TTRs in a large number of analyses
- The North American TTR was 64% and is similar to that in other comparable trials and better than the 55% observed in the registry experiences by Baker et al.
- The risk adjusted event rates for warfarin patients in ROCKET were similar to those observed in other recent comparable trials consistent with the skillful management of warfarin in ROCKET.
Comments by Dr. Califf on the FDA Briefing Book
In comparing trials, the FDA briefing book did not point out that RELY was an unblinded trial whereas ROCKET was blinded and double dummy. In RELY, the patients and Drs. knew the INRs, and that could have affected INR management. Dr. Califf stated that drugs should not be "ranked" as a second or third line drug by the FDA based upon inappropriate cross-trial comparisons. There is a grey zone in classifying a patient with hemorrhagic conversion. 18 patients could not be classified as hemorrhagic or ischemic strokes.
Why was Hemorrhagic Stroke Included in the Efficacy Endpoint?
Dr. Sanjay Kaul asked the above question. Dr. Califf indicated that when a patient dies of a stroke, caregivers often do not know whether it was a hemorrhagic or ischemic stroke, particularly if it happened soon after hospitalization before imaging could be obtained. Therefore the two were lumped together in the primary endpoint.
Is there a Benefit in Bleeding if Hemorrhagic Stroke is Excluded?
There were also subdural bleeds and subarrachnoid bleeds.
Is there a Difference in Disabling Stroke Exclusive of Hemorrhagic Stroke?
The HR for disabling stroke was 0.39 favoring Rivaroxaban. This HR did not exclude hemorrhagic stroke. For disabling ischemic stroke, there were numerically fewer events.
Were the Sites Educated on the Importance of INR?
Mahaffey said yes, there was education. There was, however, no algorithm as to how to manage drug dosing to achieve and INR. The importance of INR management was emphasized to the sites during meetings and in newsletters. Dr. Steve Nissen of Cleveland Clinic asked why "third world" sites were not given more guidance in adjusting the INR? "You left them on their own?" Nissen was criticized for using the word "third world" by Califf. Nissen: You could have instructed patients to come back quicker if the INR is < 1.5. Califf emphasized that this was a real world trial. Califf emphasized that the TTR per country was as good as in other trials.
How Did TTR Affect Ischemic and Hemorrhagic Stroke?
Dr. Temple of the FDA pointed out that the benefit was largely driven by a reduction in hemorrhagic stroke and asked how over and under anticoagulation affected the benefit of rivaroxaban. Califf showed that the patients with good TTRs with respect to over anticoagulation, (specifically those with fewer with excess anticoagulation) still had a reduction in ICH.
Twice a day Versus Once a Day Dosing of Rivaroxaban
The FDA argued that rivaroxaban should have been administered as a twice a day drug rather than a once a day drug based upon its half life. Dr. Califf argued that while the efficacy of twice a day dosing might be quite good, once a day dosing might achieve greater compliance than twice a day dosing in real world clinical practice.
Commentary on TTR by Dr. Rose of the FDA
Dr. Rose indicated that the opinions he expressed were his own and not those of the FDA as a whole.
Dr. Rose highlighted that there was no algorithm for adjusting the VKA dose in ROCKET to achieve a target INR. In RELY, he indicated there was an algorithm.
The TTR was 55%. 30% of the time time warfarin patients were underanticoagulated, and 15% of the time warfarin patients were excessively anticoagulated. This could be interpreted as indicating that rivaroxaban is safer than a population of patients who were, if anything, slightly under-anticoagulated with warfarin.
The ROCKET investigaotrs used an analysis that calculated TTR based upon all days all patients TTR was in the therapeutic range / divided by all days all the patient were in the trial. This method weights the contribution of patients based upon how long they were in the trial. The method of Connolly would average each patients TTR at each site, and patients who were in the trial a short period of time contributed equally to those patients who were in the trial a long time.
Dr. Rose argued that the goal should be to achieve a TTR of > 70% in clinical practice.
Dr. Rose acknowledged that the relatively low TTR in ROCKET was largely due to the fact that those parts of the world with lower TTRs enrolled the most patients. The FDA and the sponsor agree that this difference in site distribution drove the lower TTR observed in ROCKET.
Dr. Rose stated "The ROCKET study enrolled patients from parts of the world that did not use warfarin well, and that is our concern."