Was FDA’s Pradaxa® Analysis Flawed?

Despite a growing number of serious gastrointestinal bleed reports linked to Pradaxa®, the U.S. Food & Drug Administration (FDA) argues that the blood thinner, manufactured by Behringer Ingelheim, is safe when used as directed.

Pradaxa® was approved two years ago and has been associated with a large number of post-marketing incidences of gastrointestinal bleeding, said Forbes. Yet, the FDA states that it has concluded that Pradaxa® bleeding rates are no higher that what is reported in patients taking Coumadin (warfarin), a decades-old and traditional blood thinner treatment. Pradaxa® is typically used to minimize stroke and blood clot risks in atrial fibrillation patients.

Pradaxa® has been linked to over 500 deaths and even more side effect reports than any other drug, noted Forbes, citing the Institute for Safe Medicine Practices (ISMP). One major problem with Pradaxa®–unlike warfarin—there is no antidote for a Pradaxa® bleed.

Forbes suggests a review of how the FDA analyzed Pradaxa®, saying the agency used a so-called “unadjusted incidence rate ratios” method which the Observational Medical Outcomes Project (OMOP) found to be lacking. The OMOP is a non-profit formed by the FDA, PhRMA, and the Foundation for the NIH, said Forbes, and was created to identify the most reliable methods of data analysis.

In reaching its more positive conclusions regarding Pradaxa®, the agency relied on its Mini-Sentinel Pilot, a program that relied on insurance claims and administrative data for its assessment, said Forbes. The Mini-Sentinel Pilot is part of the larger, Sentinel Initiative created to monitor safety issues. Meanwhile, data presented at an OMOP symposium this June suggested that the Sentinel Pradaxa® analysis might be “problematic,” said Forbes. In fact, the OMOP suggests that issues with this methodology might extend beyond Pradaxa® and may call the entire Mini-Sentinel effort into question.

It seems that the data utilized to review gastrointestinal bleeding reports revealed that the unadjusted incidence rate ratios methodology used actually does not perform well, according to OMOP report, which relied on an array of databases such as the Commercial Claims and Encounters (CCAE), which is similar to what is used by the Mini-Sentinel, said Forbes. In other words, explained Forbes, the agency used measurements where no causal relationship exists, which is “tantamount to a guess,” it explained, or used analysis methods known to be less reliable. The OMOP suggests the FDA rethink its analysis.

Meanwhile, much current research has found that Pradaxa® carries a more significant risk of severe bleeding episodes—namely gastrointestinal and cerebral hemorrhaging—than drugs like Coumadin that had been available for years on the market. Yet, the FDA maintains that “the results of this assessment indicate that bleeding rates associated with new use of Pradaxa® do not appear to be higher than bleeding rates associated with new use of warfarin, which is consistent with observations from the large clinical trial used to approve Pradaxa® (the RE-LY trial).”

We recently wrote that a study of new blood thinners, including Pradaxa®, found that these novel drugs pose an elevated bleeding risk that cancels out their benefits in patients with Acute Coronary Syndrome (ACS). The study was published in the Archives of Internal Medicine.

As we’ve written, the FDA launched a review of Pradaxa® this past December over reports of bleeding-related side effects, while regulators in Europe and Japan have directed Boehringer Ingelheim to strengthen warnings for the drug. According to the ISMP’s latest QuarterWatch report, the FDA received 3,781 adverse event reports associated with Pradaxa® in 2011. These included 541 deaths, 2,367 reports of hemorrhage, 291 reports of kidney failure and 644 reports of stroke. Pradaxa® was also a suspect in more than 15 cases of liver failure reported to the FDA.

Both Pradaxa® and warfarin can cause internal bleeding, but there are readily available antidotes for warfarin bleeding. A growing number of Pradaxa® bleeding lawsuits allege the drug caused serious, uncontrollable bleeding side effects, including gastrointestinal bleeding and cerebral hemorrhaging for which there is no reversal agent.

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