Company Fretted Over Dabigatran Report, Documents Show

February 07, 2014

NEW YORK, NY (updated) — Legal documents unsealed this week in court reveal that employees at Boehringer Ingelheim were so concerned about a research paper suggesting patients taking dabigatran (Pradaxa) might require blood monitoring, authored by one of their own, that they questioned whether the paper should be published, according to the New York Times[1].

The emails, memos, and internal presentations were released this week in a US district court in St Louis, MO, as part of a lawsuit filed by patients taking dabigatran in which they claim they were not properly warned about its potential risks.

The paper in question, with first author Dr Paul Reilly, a researcher at Boehringer Ingelheim, found ischemic stroke and bleeding risks were correlated with plasma concentrations of the drug in 9183 patients treated with dabigatran 110 mg or 150 mg twice daily (the available European doses). In their logistic regression analysis, the risk of ischemic stroke was inversely associated with trough concentrations of dabigatran.

The researchers concluded that "the magnitude of the effect of dabigatran plasma concentrations on outcomes in atrial-fibrillation patients in RE-LY depends strongly on demographic factors, most importantly increasing age." However, the results also confirmed a wide therapeutic range among those treated with dabigatran, with a more than fivefold variation in plasma concentrations. The researchers concluded there might be a subset of patients who could improve their risk/benefit profile by tailoring the dose of dabigatran.

The analysis was published online September 27, 2013 in the Journal of the American College of Cardiology and eventually appeared this week in the journal's print version[2].

Company Concerned About "Messaging"

The New York Times reports that as draft versions of the research paper circulated throughout Boehringer Ingelheim, employees worried about its marketing implications. One employee, Dr Jutta Heinrich-Nols, sent an email stating the Reilly et al analysis would undermine the company's message that patients taking dabigatran don't require blood monitoring. If blood testing were needed, it would undo the company's efforts to compete with rivaroxaban (Xarelto, Bayer/Janssen Pharmaceuticals) and apixaban (Eliquis, Bristol-Myers Squibb/Pfizer), two other anticoagulants approved for use in atrial fibrillation that don't require monitoring.

In addition, employees were concerned about the legal consequences of the research paper if it suggested the drug worked best in a specific therapeutic window. Dr Andreas Clemens, one of those employees, is quoted in emails saying "the world is crying out for this information—but the tricky part is that we have to tailor the messages smart."

In the paper, there are no references to the optimal plasma concentration of dabigatran, although such statements were in various drafts that circulated throughout the company, according to the New York Times. When the paper was published online in October, Reilly told Reuters news[3] that the "there is no single plasma concentration range that provides optimal benefit-risk for all patients" and that "no monitoring is necessary."

Dr Lisa Schwartz (Dartmouth Institute for Health Policy and Clinical Practice, Hanover, NH) told the New York Times the emails reveal how much information and messaging lay with people with a financial stake in the outcome. "In these situations, where the stakes are really high, how crazy is it that it's in the hands of people who are so conflicted?" she said.

Just Part of the Scientific Process, Says Boehringer

Boehringer Ingelheim said the unsealed documents "represent small fragments of the robust discussion and debate that is a vital component in all scientific inquiry and in the research and development of any important medication such as Pradaxa." All the eventual changes to the Reilly et al paper were made as thinking evolved. The researchers themselves concluded that there was no range of dabigatran plasma concentration ideal for all patients.

To heartwire , a spokesperson for Boehringer Ingelheim said the company "has never placed commercial priorities above patient safety and never would." In a statement, the company called the New York Times article "a simplistic characterization" and that the "truth of the matter is our research found that patient characteristics like age, renal function, etc, are more important considerations in evaluating an individual's bleeding risk.

"We remain confident that Boehringer Ingelheim and its employees, including those mentioned in the New York Times article, acted appropriately and responsibly in the clinical development and marketing of Pradaxa," the statement continues. "We stand behind the safety and efficacy of Pradaxa and will vigorously defend all associated product-liability lawsuits."

The New York Times quotes Dr Hugo ten Cate (Maastricht University Medical Center, the Netherlands), who believes the company has "come back a little bit" from its initial stance that no blood monitoring is needed. Dr Thomas Moore (Institute for Safe Medication Practices, Horsham, PA) is also quoted saying that "the one-size-fits-all was a mistake for a drug with this kind of risk."

As reported by heartwire , dabigatran is now under the watchful eye of the US Food and Drug Administration. The agency is planning to conduct a study that will assess safety outcomes in adults with atrial fibrillation who recently started treatment with dabigatran or warfarin. Of particular concern with the one-time safety assessment is the risk of ischemic stroke, intracranial hemorrhage, and major extracranial hemorrhage in patients taking dabigatran when compared with warfarin-treated patients.




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