FDA Evaluation of Warfarin and Pradaxa Bleeding Risks Raises Questions

Federal drug regulators have indicated that the bleeding risks of Pradaxa and warfarin are comparable, despite a spike in the number of reports involving severe and often fatal hemorrhages among users of the new anticoagulant. However, some are now criticizing the methodology used by the agency and indicate that the findings do not take into account the lack of an antidote to reverse the bleeding side effects of Pradaxa when they do occur.

Pradaxa (dabigitran) was introduced by Boehrnger Ingelheim in October 2010 as a new alternative for prevention of strokes among patients with atrial fibrillation. It quickly grew in popularity, with more than 750,000 patients in the United States receiving a prescription for the drug during the first two years on the market.

The medication has been promoted as superior to the decades-old treatment warfarin, which is more commonly known by the brand name Coumadin. However, doctors soon discovered that, unlike warfarin, there is no quick fix to reverse the blood thinning effects of Pradaxa, which left doctors unable to control many of the bleeding problems that do develop among users of the medication.

Amid increasing concerns within the medical community and a spike of adverse event reports during the first full year Pradaxa was on the market, the FDA announced in December 2011 that it was evaluating the bleeding risks with Pradaxa.

In a drug safety communication issued on November 2, the FDA provided an update for this ongoing review, indicating that data suggests the bleeding rates with Pradaxa and warfarin are comparable.

FDA Report Compares Bleeding Rates with Pradaxa and Warfarin

The FDA findings came after an evaluation of insurance claims and administrative data from an FDA drug safety pilot program known as Mini-Sentinel.

The agency compared the actual rates of gastrointestinal bleeding, which occur in the stomach and intestines, and intracranial hemorrhage, which is a type of brain bleed, among new users of Pradaxa and new users of Warfarin.

Reviewers found that the Pradaxa bleeding rates do not appear to be higher than warfarin, which they indicate is also consistent with the findings of the large clinical trial conducted by Boehrnger Ingelheim to gain approval for the medication.

Questions have been raised about the methodology used by the FDA, which did not take into account the lack of an antidote or reversal agent for Pradaxa. While users of warfarin who develop a bleed can be given a dose of vitamin K to reverse the blood thinning effects of the older medication, no such quick fix is available for users of Pradaxa.

Although Boehringer Ingelheim has issued a press release, heralding the findings and suggesting that the agency’s determination reaffirms the safety of Pradaxa, many have complained that it is not the rate of bleeding events with Pradaxa that cause concern, but rather stopping them that is the problem.

With no reversal agent handy, Pradaxa bleeding events, though no more common than warfarin, can result in more severe outcomes because they are difficult to stop.

In addition, the FDA’s methodology, using unadjusted incidence rate ratios, has come under fire by the Observational Medical Outcomes Project (OMOP), a non-profit group formed to determine the best means of analyzing drug data. The group includes FDA experts. OMOP has questioned the method’s accuracy, saying that some of the techniques the FDA used in its analysis are little better than guessing.

According to a report issued earlier this year by the Institute for Safe Medication Practices (ISMP), which analyzed all adverse event reports submitted to the FDA during 2011, there were 2,367 reports of Pradaxa bleeding problems, and 542 reports of death among Pradaxa users. By comparison, warfarin was linked to 1,106 adverse event reports, including 72 patient deaths.

Pradaxa Lawsuits Allege Failure to Warn About Lack of Reversal Agent

Boehringer Ingelheim faces a growing number of Pradaxa lawsuits filed on behalf of individuals throughout the United States who suffered uncontrollable bleeding while using the medication, including a number of wrongful death lawsuits that allege the inability to reverse the effects of Pradaxa led to fatal complications.

At least 120 complaints have been filed in the federal court system, which are consolidated for pretrial proceedings as part of an MDL, or multidistrict litigation. The cases have been centralized before U.S. District Judge David R. Herndon in the Southern District of Illinois.

All of the complaints involve similar allegations that Boehringer Ingelheim failed to fully research Pradaxa before introducing it and aggressively marketing the drug as a superior alternative to warfarin. In addition to allegations that the drug may actually increase the risk of certain types of bleeds, most of the complaints focus on the failure to warn consumers and the medical community about the lack of a reversal agent to stop hemorrhages that may develop while using the medication.

Although the cases were just recently centralized as part of the Pradaxa MDL in August 2012, Judge Herndon has set an aggressive pretrial schedule, indicating that the first cases will be ready for trial to begin by August 2014.

Judge Herndon has indicated that the “expeditious resolution to the factual allegations made” in these claims will not only serve the interests the plaintiffs and defendants in the cases, but will also provide benefit for the medical community and doctors making daily prescription decisions.