Boehringer Ingelheim is accusing The British Medical Journal (BMJ) of making “misleading statements” after the journal published an article and an editorial critical of the company’s pursuit of approvals for the stroke risk-reduction anticoagulant drug Pradaxa® (dabigatran etexilate mesylate), stating that the pharma giant “withheld from the regulators important analyses regarding how to use the drug as safely and effectively as possible.”

In a 5,381-word article and two “sidebar” related briefs by the journal’s investigations editor Deborah Cohen, as well as an editorial, The BMJ yesterday concluded that recommendations for use of Pradaxa and other new-generation oral anticoagulants “may be flawed because regulators did not see evidence showing that monitoring drug plasma levels could improve safety.”

The BMJ cited data in previously-confidential internal Boehringer documents, released as part of the court case that the pharma giant settled when it agreed in May to pay $650 million to resolve about 4,000 lawsuits—a majority of the litigation—that linked Pradaxa to 500 patient deaths and serious bleeding.

Those documents, according to The BMJ, included “extensive” analyses that found that if the plasma levels of Pradaxa were measured, and the dose was adjusted accordingly, major bleeds could be reduced by 30-40% compared with well controlled warfarin. The analyses also identified the plasma levels at which the dose adjustment should occur to reduce the risk of a major bleed – though the adjustment would have little or no effect on the risk of ischaemic stroke, the journal reported.

“Optimally used (=titrated) dabigatran has the potential to provide patients an even better efficacy and safety profile than fixed dose dabigatran and also a better safety and efficacy profile than a matched warfarin group,” according to one document quoted in the article.

The BMJ also cited internal emails not shared with regulators. One email, written by a Boehringer employee whose name was redacted, hinted that further study of dosage adjustment may complicate efforts to market Pradaxa: “This may not be a onetime test and could result in a more complex message (regular monitoring) and a weaker value proposition.”

Boehringer has positioned Pradaxa as an anticoagulant that not require regular blood-testing and adjustments in dosage to ensure that patients are receiving the dosage they need—unlike the half-century-old blood thinner warfarin.

One factor in the bleeding reports associated with the drug suggested by the journal: More Pradaxa users were elderly  (45% were 76 years or older, 30% 80 or older), according to Boehringer marketing data, compared with the Phase III study that resulted in the drug’s initial approval (40% were over 75 and 17% over 80).

Earlier this year, the company highlighted favorable results published by the FDA from a study of 134,000 Medicare patients aged 65 or older who were diagnosed with atrial fibrillation. The study found that among new users of blood-thinning drugs, Pradaxa was associated with a lower risk of clot-related strokes, bleeding in the brain and death compared to warfarin.

Boehringer countered The BMJ article yesterday with a press release and a video. In the release, the company stated that in 2012, its scientists performed what it called “preliminary, exploratory simulations with mathematical models” to understand whether dose adjustments based on plasma concentrations might further improve Pradaxa’s benefits and safety.

“Because the simulations did not offer reliable predictions of actual patient outcomes, they were not provided to regulators. However, all of the data that was used for the simulations had already been provided,” Boehringer stated. “It is inappropriate to provide regulators simulations that are unreliable and have limitations.”

The company called the preliminary simulations post-hoc exploratory analyses that are generally not shared with regulators because they require testing in a clinical trial.

“Boehringer Ingelheim made a robust effort to find ways to utilize plasma levels to further improve the risk/benefit profile of Pradaxa and it is irrational to suggest otherwise,” Sabine Luik, M.D., the company’s svp, Medicine & Regulatory Affairs, stated in the press release. “The truth is the totality of scientific evidence does not support dosing decisions for Pradaxa based on blood levels. The research shows that individual patient characteristics, such as kidney function and certain medications, are critical factors in contributing to the risk of bleeding.”

Boehringer added: “We are deeply concerned that the BMJ’s biased reports could compromise the health and safety of people who may benefit from Pradaxa to reduce their risk of thrombotic events.”

The video featured John Smith, M.D., Ph.D., regional medical director for Boehringer, who insisted that Pradaxa was safe when used as directed, and contended: “Specifically hand-picked fragments of our robust internal discussions were made available to the media by external parties, which resulted in a gross distortion of the facts about Pradaxa and Boehringer Ingelheim.

“Ethical behavior and patient safety are at the core of everything we do,” Dr. Smith declared.

Pradaxa first won FDA approval in 2010 for reducing the risk of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF), based on a single Phase III trial, RE-LY, that Dr. Smith said involved more than 18,000 patients. Two postmarket studies showed a favorable risk-benefit profile for the drug, he added in the video.

In April, Pradaxa won approval for a new indication, prevention of deep venous thrombosis (DVT) and pulmonary embolism (PE). Last year, Pradaxa racked up €1.206 billion ($1.6 billion) in 2013 sales, up 16.2% over 2012. 

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