While dabigatran etexilate (Pradaxa, Boehringer Ingelheim) is a promising alternative for atrial fibrillation (AF) patients who cannot tolerate warfarin, much controversy remains over the FDA's approval of the higher 150 mg dose rather than the lower 110 mg dosage. The drug’s indication may very well extend to the elderly, a patient population that may be vulnerable to bleeding risk and overdose, researchers from France wrote in a clinical observation published in the July 25 issue of the Archives of Internal Medicine.

The FDA approved dabigatran to prevent stroke in AF patients in October 2010.

Two staff members from the FDA outlined the agency's decision not to approve dabigatran in the 110 mg dose in a recent New England Journal of Medicine perspective. Beasley and colleagues wrote that this decision was based on the fact that the drug increased bleeding events in elderly patients over the age of 75. While the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial found that patients administered a 150 mg dose of dabigatran had a reduced risk of stroke and embolism, patients over 75 saw increased incidence of major bleeding.

In the clinical observation, Matthieu Legrand, MD, of the Lariboisiere Hospital and Pharmacovigilance Center, Fernand Widal Hospital in Paris, and colleagues wrote that elderly patients often have renal impairment, a low body weight and drug interactions that are often not detected by a coagulation test, making overdose and major bleeding a potential risk.

In the paper, Legrand and colleagues highlighted two clinical case studies that outline the potential risk of bleeding events in elderly patients administered the drug. For the two cases—involving an 84-year-old woman and an 89-year-old woman—dabigatran plasma levels were measured using the diluted thrombin time method.

The 84-year-old patient was admitted to the ED for abdominal pain and a three-day history of rectal bleeding. The patient was being treated for four months with a 75 mg twice daily dose of dabigatran for AF, associated with a 200 mg dose of amiodarone. The patient was diagnosed with fecaloma and developed a massive rectal bleed within a few hours of evaluation. Soon after, she experienced a cardiac arrest and died from hemorrhagic shock. The researchers found that the plasma concentration of dabigatran was high (5,600 ng/mL) compared to the expected range of 31-225 ng/mL.

In the second case, the 89-year-old who was treated for five months with 110 mg twice daily dose of dabigatran, experienced recurrent episodes of epistaxis for one week and was treated with nasal cauterization. Dabigatran plasma concentrations were elevated to 2,670 ng/mL and cochlear implant removal was canceled and dabigatran treatment was halted.

“Dabigatran etexilate is a pro-drug converted into dabigatran by hydrolysis and eliminated predominantly (85 percent) by the kidneys,” the authors wrote. “Renal function impairment is likely to have caused drug overdose in both cases due to accumulation of the drug.”

Legrand and colleagues noted that the area under the curve (AUC) of dabigatran is 2.7-fold or six-fold higher in volunteers with moderate or severe renal insufficiency, with a two-times-longer half-life compared to patients with normal renal function. According to the researchers, AUC is increased 40 to 60 percent in elderly patients, and dabigatran AUC is increased by almost 60 percent when it is co-administered with a 600 mg dose of amiodarone.

While dabigatran is currently being used off-label in Europe, the researchers said that they expect widespread use of the drug in the elderly population following the new approval by the FDA. “The risk of overdose is, however, much increased in this population, with no way of detecting it with routine coagulation test and no antagonist available,” the authors concluded.

“We therefore call for great caution before administrating dabigatran etexilate in such patients and encourage physicians to declare bleeding events to drug regulatory agencies for close monitoring of adverse effects.”

“Clinicians and patients are often wary of anticoagulation, primarily owing to fear of bleeding, especially if the elderly patient is deemed to be at increased risk of falling,” Jeremy M. Jacobs, MBBS, and Jochanan Stessman, MD, of the Hadassah Hebrew-University Medical Center and Hebrew University Hadassah Medical School Mount Scopus in Jerusalem, wrote. “The pervasive underuse of anticoagulation is common, despite the lack of robust evidence to support withholding anticoagulation in these cases. Even if elderly patients with AF are frail and prone to falls and have associated comorbidity, the expert consensus supports long-term anticoagulation.

“Despite the consensus, the reluctance of some clinicians toinitiate anticoagulation is understandable,” Stessman and Jacobs noted. This, they stated, is due to the fact that prescribing warfarin also involves repeated blood monitoring, difficulty achieving optimal international normalized ratio (INR) and drug-drug interactions. “It is, however, the risk of bleeding that remainsthe most dominant and legitimate fear,” they noted.

“Dabigatran appears poised on the cusp of potentialmassive use, in particular among older people,” wrote Stessman and Jacobs, and this may be due to the fact that dabigatran does not require blood monitoring. The authors stated that a substudy of the RE-LY study evaluating separate age groups would be beneficial, particularly “because so many potential candidates for dabigatran treatment will be among the oldest old [patients].”

Stressman and Jacobs stressed that physicians should be vigilant with elderly patients as dabigatran continues to enter the market.