FDA can help reduce dabigatran (PRADAXA) bleeding

Two recently published studies of one of the newer blood thinners, Pradaxa, point the way to reducing the risk of its major drawback—high rates of bleeding of 16% a year.

Pradaxa was approved in October 2010 as an alternative to the standby blood thinner Coumadin (warfarin). Both are effective in reducing the risk of disabling strokes in people with a condition known as atrial fibrillation, a heart disorder affecting about 2.5 million mostly older patients in the U.S.

Pradaxa's marketing advantage was that it was easier to use than Coumadin, which requires careful monitoring of its blood clotting effects and often a dose adjustment.  The FDA approved Pradaxa with only a single standard therapeutic dose of 150 mg, taken twice a day. The laboratory test for Coumadin, called INR, was not useful or accurate with Pradaxa for determining whether blood clotting was inhibited too much—leading to bleeding—or not enough, which might increase stroke risk. However, unlike Coumadin, no antidote exists for Pradaxa to halt bleeding quickly should it occur.

For many clinicians, Pradaxa-associated bleeding has been of major concern. In January 2012, our QuarterWatch™ publication detected a strong signal of a safety problem while monitoring serious adverse drug events reported to the FDA in first months after the drug's approval in 2010. There were an unexpectedly large number of serious and fatal bleeding reports, particularly in older patients with a median age of 80. In a clinical study of Pradaxa, which has the generic name of dabigatran, from 3-7% suffered a major bleed requiring a transfusion in one year's time, depending on age and other risk factors, and 16% experienced some bleeding.

By the end of 2012, FDA had received 7,387 domestic reports serious injury associated with Pradaxa, including 1,158 patient deaths. We ranked anticoagulants as the leading drug safety risks of both 2011 and 2012, and we urged that a 110 mg dose of Pradaxa be reconsidered by FDA and called for monitoring improvements to identify high-risk older patients.

Even if a patient appears at higher risk of bleeding with Pradaxa, clinicians currently have no option for reducing the dose. In most advanced countries, in addition to the available 150 mg strength, there's a 110 mg dose available, and recommended for use in patients age 80 and over and those with risk factors. But the FDA disallowed this lower dose here. A 75 mg dose has been approved, but only for use in patients with severe kidney disease.

An additional perspective on this safety problem recently emerged with two studies published in the American Journal of Cardiology and documents reported in the news media. These found that in many older patients, the lower 110 mg dose of Pradaxa is just as effective as the higher dose, but lowered the bleeding risk. The new studies also show the risk of severe bleeding in older patients can be substantially reduced if a laboratory monitoring test were available to identify patients at highest bleeding risk. This is because the newly published data showed that the very same 150 mg dose could produce a five-fold or more difference in the critical blood clotting function.

The blood test, called the Hemoclot thrombin inhibitor kit assay, is only available in the U.S. for research purposes. The test would be a valuable asset to healthcare practitioners because it can help identify the 10% of patients with extremely high blood levels of Pradaxa that are at greatest risk.

Given the risk of bleeding, these options are extremely important. They are both already available to healthcare providers in Canada, Australia, Europe and elsewhere. While the publications are new, the data were collected in 2009 prior to the approval of Pradaxa and were available to the FDA. The Agency should reevaluate the need for making these two therapeutic options available in the United States.

Thomas J. Moore, ISMP senior scientist, contributed editorial review and research.

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