June 7th, 2012

Growing Popularity of Dabigatran Leads to Increased Complications

Since its approval in the United States in October 2010, dabigatran (Pradaxa) has been prescribed 3.2 million times to more than 600,000 patients with nonvalvular atrial fibrillation (AF), according to its manufacturer, Boehringer Ingelheim. The company also announced that, based on the pivotal RE-LY trial, the “Clinical Studies” section of the drug’s prescribing information now includes the statement that 150 mg twice daily of dabigatran “was superior in reducing ischemic and hemorrhagic strokes relative to warfarin.”

But the news about dabigatran is not entirely upbeat. According to new data compiled by QuarterWatch (PDF), in 2011 the FDA received more safety reports about dabigatran than any other drug. The data are not entirely unexpected, since the bleeding complications of dabigatran are well known and physicians are more likely to report adverse events associated with new drugs. The drug that dabigatran was designed to replace, warfarin (Coumadin), was the second most reported drug, and has been high on the FDA list for many years.

Dabigatran was the subject of  3781 serious adverse events reported to the FDA in 2011. This included 542 patient deaths and 2367 hemorrhages. Warfarin was the subject of 1106 serious adverse events, including 72 deaths.

QuarterWatch noted that the difference between the two anticoagulants “could be at least partly explained by differences in the reporting rate for an older generic drug with many manufacturers, and a newly launched brand name drug being promoted by a large sales force.” But, according to QuarterWatch:

What is clear, however, is that the FDA’s system is receiving a strong signal about this safety issue. A large share of dabigatran reports (79%) come from health professionals, suggesting that despite this well-known drug risk the bleeding was unexpected or unusually severe.

QuarterWatch notes that the rapid uptake of dabigatran is probably due to its ease of use — no frequent INR tests are required — and the lack of drug interactions. One likely source of complications is the use of the standard 150-mg dose in older patients or those with renal dysfunction. The label now recommends that physicians “assess renal function during therapy as clinically indicated” but QuarterWatch wonders “whether this modest language will lead to safer use.”

12 Responses to “Growing Popularity of Dabigatran Leads to Increased Complications”

  1. It would be discouraging if physicians continue use the higher (“standard” dose) of dibigatran depite the FDA approval of a lower dose specifically for patients with renal disease. For this, physicians must take the blame and possibly be held responsible. Further, noting this Boehringer Ingelheim should be required to do a better job of educating physicians. Indeed a substantially lower dose was approved specifically for this reason.

    • Joel Wolkowicz, MDCM says:

      Unfortunately 110 mg tablets are not available. Do you have any recommendations?

  2. Walter Keyes, MD says:

    Of the 3781 serious adverse events,2367 were hemorrhages.What were the other 1414 serious adverse events?

    • Andrew Rees, BMBS FRACGP says:

      hemorrhage (2,367 cases), acute renal failure (291), and stroke (644). It was also suspect in 15 cases of liver failure.

  3. Edgar Abovich, MD says:

    I suspect that most of the reported 542 deaths from dabigatran are due to fatal hemorrhage and can be added to 2367 cases of nonfatal hemorrhage. The chance of dying from major hemorrhage(approx.542/2909) is much higher than the same from warfarin reporting which makes sense.

  4. David Kaufman, MD says:

    Ironically, I think one of the problems here is precisely what is considered a “strength” of dabigatran and weakness of coumadin: the lack of vs need for measuring therapeutic level, ie INR. Yes, it is a pain (pun intended) for patients and docs, yes it varies, yes it is frustrating, but at least we can measure INR, adjust dose, and perhaps control adverse events a little better. AND we can reverse it. With dabigatran, we can only cross our fingers. I have started only using the lower dose with older patients, but sad truth is, I have no idea if this is effective. Will it reduce clots/strokes??????
    Newer is not always better, tho usually always better advertised and more expensive.

  5. Luciene Borowik, MD says:

    I am still waiting for more studies, before starting to offer dabigatran to my patients.

  6. Joseph Wildman, MD says:

    With regard to Dr. Massie’s comments:
    1. Do we have evidence that the high rate of adverse events is attributable to “overdosing”?
    2. The FDA approved lower dose is a very strange animal, having NEVER BEEN TESTED! What is the basis of that recommendation?

    • Amichai Perlman, PharmD says:

      Regarding point #2: While the lack of testing is indeed unfortunate this is the case when dosing just about every single other drug in renal failure – at best you have a kinetic profile of the drug in humans, often not even that.

  7. How do we reconcile this with the report from European Medicines Agency released two weeks ago which stated that “the frequency of reported fatal bleeding with dabigatran since the drug has been approved has been significantly lower than that observed in clinical trials”? Also when the high incidence of bleeding with dabigatran was analysed in Japan and New Zealand, the increased risk seemed to be associated with prescribing the drug to high-risk patients.

  8. Paul Kempen, MD, PhD says:

    What was the rate of trauma patient “hemorrhages” in the FDA reports-that is surely one BIG disadvantage to patients on Pradaxa-no reversal ability! Hardly want to dialyse someone to control life threatening bleeding!

  9. Mark Scott, MBBS FACEM says:

    I wonder if doctors are more likely to report bleeding that they have no easy fix to control and possibly feel guilty or frustrated about as opposed to bleeding that has a clear treatment pathway which is relatively safe and effective.
    I would not tend to report a warfarin related epistaxis that I could reverse in ED and send home as opposed to a dabigatran related epistaxis that I had to pack, admit, consult haematology and load with factor VII.