August 4, 2011 (Paris, France) — New reports of two elderly women faring badly when taking the novel anticoagulant dabigatran (Pradaxa, Boehringer Ingelheim) for stroke prevention in atrial fibrillation (AF) have prompted more discussion about the caution needed with this drug when treating the very old or those with renal impairment [1].

In an accompanying commentary [2], Dr Jeremy M Jacobs (Hadassah Medical Center, Jerusalem, Israel) and Dr Jochanan Stessman (Hebrew University-Hadassah Medical School, Jerusalem, Israel) say: “These cases require careful attention and serve to highlight a unique problem associated with oldest-old patients and novel drug therapy.

“It is of concern that those most likely to need anticoagulation are potentially those most at risk of its adverse effects—ie, frail, oldest-old patients among whom poorly diagnosed renal impairment, sarcopenia, and altered body composition are common. The lack of a specific antidote for dabigatran further renders this vulnerable group at risk,” they state.

One of the investigators of the RE-LY study— the pivotal trial on which approval of dabigatran for the prevention of stroke in AF was based—Dr Lars Wallentin (Uppsala Clinical Research Centre, Sweden), told heartwire that while it could not be proven that individuals who have fared badly on dabigatran would not also have done poorly on the alternative, traditional treatment of warfarin, he agrees that caution should be exercised with the new drug in the very elderly and frail. “Both the case reports and the commentary are relevant and appropriate,” he observes.

Two Very Elderly, Frail Women Fare Badly on Dabigatran

In most countries in which dabigatran is approved, the choices of dose are 150 mg twice daily, which was shown to be more effective than warfarin in RE-LY but carries a higher risk of bleeding, or 110 mg twice daily, which was shown to be equivalent to warfarin. In Canada, the EU, and other countries, dabigatran was approved for the stroke/AF indication in both the 110-mg and 150-mg doses, but the US made the controversial decision to approve only the 150-mg dose and an untested 75-mg dose for patients with severe renal impairment, stating that the data in favor of a 110-mg dose “were suggestive but not entirely convincing.”

Dabigatran is primarily eliminated via the kidneys, so the patient prescribing information advises “dose adjustment” for renal impairment and notes an increased bleeding risk among those older than 75.

In one of the case reports just published, an 84-year-old woman taking 75 mg of dabigatran twice daily for AF, who weighed just 40 kg, developed massive rectal bleeding, had a cardiac arrest, and died, Dr Matthieu Legrand (Lariboisière Hospital, Paris, France) and colleagues report in the July 25, 2011 issue of the Archives of Internal Medicine. In the other case, an 89-year-old woman weighing 45 kg who had been taking 110-mg twice-daily dabigatran for AF for five months was found to have increased bleeding times and an elevated plasma level of dabigatran when tested prior to cochlear implant surgery. She had suffered recurrent nosebleeds for a week prior to this. Treatment with dabigatran was stopped, and the outcome was favorable.

110 Mg Twice Daily a “Good Choice” for the Over-75s

Jacobs and Stessman state in their editorial that they would like to see a subanalysis of the RE-LY data by age group. Another RE-LY investigator, Dr Salim Yusuf (McMaster University, Hamilton, ON), told heartwire that a “detailed analysis of RE-LY by age” is at an advanced stage.

“In the meantime, increased vigilance is warranted for bleeding events among elderly patients, particularly those with renal impairment, as dabigatran enters the market and gains popularity and we accumulate more data via clinical trials, registries, and case reports [such as these],” the editorialists conclude.

Many of us in the RE-LY group believe that for those aged >75 years, 110 mg twice daily seems to be a good choice.

Wallentin says: “Based on RE-LY, we have evidence that 110 mg twice daily is as effective as warfarin with a lower risk of bleeding, and some doctors might prefer that dose because usually physicians like to stay on a safety course, especially for elderly patients with many other medications. Many of us in the RE-LY group believe that for those aged >75 years, 110 mg twice daily seems to be a good choice.”

He and his coinvestigators believe the decision not to approve the 110-mg twice-daily dose of dabigatran in the US is thus leading to a reluctance to use the drug among doctors there, and they have repeatedly called for the FDA to reconsider its decision.

Monitoring With Dabigatran May Even Be Required in High-Risk Groups

Wallentin also told heartwire that a pharmacokinetic analysis, which is in press, shows that the 75-mg dose “might be recommended for those with a creatinine clearance at or below 30 mL/min,” as per the recommendation made by the FDA for those with impaired renal function.

And he says that, in the future, “there might even be a reason to tailor the dabigatran dose based on measurements of dabigatran plasma concentrations or eventually thrombin time in patients at high risk of bleeding or risk of exposure to too-high dabigatran plasma concentrations.”

Asked by heartwire whether this would not negate one of the big advantages of dabigatran over warfarin—no monitoring required—he stressed that, if agreed—”and it still needs further discussion”—this would be necessary only in certain select groups, rather than in everyone, as is the case with warfarin.

Case report authors and editorialists report no conflicts of interest. Wallentin and Yusuf are investigators for RE-LY, a collaboration between Boehringer Ingelheim; McMaster University and Hamilton Health Sciences; the Uppsala Clinical Research Centre, Sweden; and Lankenau Institute for Medical Research

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