Bleeding Risk with Blood Thinner Cited

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A cluster of bleeding episodes in patients treated with dabigatran (Pradaxa) led a group of New Zealand hematologists to express concern and call for better prescriber education.

A two-month review identified 78 bleeding episodes, including a dozen major bleeds, one of which might have contributed to a patient's death, the hematologists wrote in a letter published in the March 1 issue of the New England Journal of Medicine.

Many of the bleeding incidents involved older patients and patients with impaired renal function. Prescriber error occurred in about a fourth of the complications, suggesting a lack of awareness of the potential risks associated with the drug.

"The serious consequences of the lack of an effective reversal agent should not be underestimated," Paul Harper, MD, of Palmerston North Hospital in Palmerston North, New Zealand, and colleagues wrote. "Prolonged bleeding increased morbidity and possibly contributed to the death of one patient.

"Bleeding is an expected complication of dabigatran, especially in the elderly, a risk that is not completely mitigated by a dose reduction: 22 of our patients had a bleeding episode while receiving a reduced dose."

According to the authors, hematologists expressed concern about a possible excess of bleeding incidents with dabigatran not long after the drug became available in New Zealand in July 2011. The concern led the Hematology Society of Australia and New Zealand to form a panel to investigate.

A two-month audit of medical records revealed 78 bleeding incidents, including 44 at the three hospitals where Harper and his co-authors work. The audit identified four factors associated with bleeding complications:

  • Prescriber error (including failure to allow the international normalized ratio [INR] to fall below 2.0 before starting dabigatran, and use of the drug in patients with severe renal impairment)
  • Impaired renal function
  • Patient age
  • Lack of an effective reversal agent for dabigatran

Summarizing clinical characteristics of their 44 patients, the authors noted that two-thirds were older than 80, a majority had moderate or severe renal impairment, and half had low body weight (<60 kg).

The patients differed substantially from those in the pivotal trial of dabigatran, whose study population had a median age of 71, median weight of 83 kg, and creatinine clearance that averaged 68 mL/min.

"Our audit illustrates the difficulty in extrapolating trial data into clinical practice and emphasizes the need for post-marketing surveillance and adverse-event reporting to detect groups whose risk factors may not be apparent in a clinical-trial setting," Harper and co-authors wrote.

"Our review of unselected cases has limitations but highlights the need for appropriate prescriber education. In all patients, especially those 80 years of age or older with impaired renal function or low body weight, there must be a careful evaluation of the risks and benefits of treatment before starting dabigatran."

When contacted for comment by MedPage Today, a spokesperson for drugmaker Boehringer-Ingelheim referenced dabigatran's prescribing information, which states that the pivotal clinical trial "showed a trend toward a higher risk of major bleeding with Pradaxa 150 mg compared to warfarin in patients age 75 or older. The risk of stroke and bleeding increases with age, but the risk-benefit profile with Pradaxa 150 mg is favorable in all age groups.

"In recent months, we have provided physicians with additional guidance on the appropriate use of Pradaxa, including formal recommendations to conduct renal function testing prior to initiation of therapy and periodically as clinically indicated.

"Global data collected to date on major bleeding are consistent with our expectations based on the [pivotal] trial and are in alignment with the U.S. PI, which clearly state the benefits and risks associated with Pradaxa. Overall, the positive benefit-risk ratio of Pradaxa in nonvalvular atrial fibrillation remains unchanged."

From the American Heart Association:

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    Charles Bankhead is senior editor for oncology and also covers urology, dermatology, and ophthalmology. He joined MedPage Today in 2007. Follow

Primary Source

New England Journal of Medicine

Source Reference: Harper P, et al "Bleeding risk with dabigatran in the frail elderly" N Engl J Med 2012; 366: 864-866.