–Test of stored blood may help answer troubling questions about the trial.
A new analysis of stored blood by the ROCKET AF trial investigators may help resolve lingering questions about the trial.
The questions about ROCKET AF, which compared rivaroxaban (Xarelto, Johnson & Johnson) to warfarin in patients with atrial fibrillation, emerged last November, when it was revealed that the portable device used to monitor and calibrate warfarin usage in the trial had been defective and had been the subject of a serious FDA recall. Since then two separate investigations, one from the trial investigators and one from the European Medicines Agency [PDF], concluded that the problem with the device did not appear to have substantially altered the reliability of the t rial’s findings.
In the new report, published online in the New England Journal of Medicine, the investigators present a second effort to understand the impact of the defective device. In this case they compared INR scores of blood samples obtained from trial subjects at 12 and 24 weeks with INR scores obtained at the same time from the portable device used in the trial. However, they acknowledge that this method only allowed them to compare a small percentage– 6%– of all the point of care INR tests used in the trial.
13% of the samples were significantly different, according to international standards, at either week 12 or week 24. 4% of the samples were discordant at both time points. These discrepancies did not occur more often in people with the conditions, including inflammation, infections, and anemia, that were highlighted in the FDA recall notice. About 60% of the subjects would have had no change in their treatment criteria, which was based on INRs of below 2, 2-3, and over 3. More than one third of patients had a lower INR level in the stored sample while 4% had a higher level.
The investigators reported that bleeding and stroke rates were higher in subjects with discrepant values. But, they explained in a statement to the press, “if potentially underestimated INR values from the POC device testing led to clinical events, then more bleeding but not higher stroke rates would be expected in the warfarin-treated patients.” In addition, they found that rivaroxaban-treated patients with discrepant results also had higher bleeding rates.” This suggests that this discordance may be a marker for a different type of patient , said Manesh Patel (Duke University), a co-author of the NEJM letter and a member of the ROCKET AF executive committee, in an interview.
In another analysis the investigators compared the outcome of warfarin and rivaroxaban patients in only those with nondiscrepant values at both time points. The rate of stroke or systemic embolism was 1.46 per 100 patient-years for rivaroxaban compared with 1.37 for warfarin (HR 1.06, CI 0.78-1.45, p=0.70 for superiority, p=0.03 for noninferiority). For major and nonmajor clinically relevant bleeding there were 11.36 events per 100 patient-years in the rivaroxaban group compared with 12.42 in the warfarin group (HR 0.92, CI 0.82-1.03, p=0.13).
The investigators concluded that their results “are consistent with the originally reported overall trial results,” though they “acknowledge the limitations of these analyses.” In his interview Patel said that the trial investigators have no current plans to perform additional studies to address this issue.
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