The manufacturer of the oral anticoagulant dabigatran "withheld analyses that calculate how many major bleeds dose adjustment could prevent," the BMJ charges in an article based on internal documents released during litigation in the United States and freedom of information act requests obtained by the journal.
Boehringer Ingelheim "found that if the plasma levels of the drug were measured and the dose was adjusted accordingly major bleeds could be reduced by 30%-40%, compared with well-controlled warfarin," according to the article (BMJ 2014;349:g4670), which was published along with an editorial and an analysis. The article further stated that the manufacturer "has failed to share with regulators information about the potential benefits of monitoring anticoagulant activity and adjusting the dose to make sure the drug is working as safely and effectively as possible."
In the analysis, Thomas Moore, senior scientist at the Institute for Safe Medication Practices, Horsham, Pa., and his coauthors said that "the bleeding risk of dabigatran can be reduced and efficacy improved by individualizing the dose in patients based on plasma level, age, and kidney function" (BMJ 2014;349:g4517[doi:10.1136/bmj.g4517]).
Dr. Rita Redberg and Dr. Blake Charlton of the University of California, San Francisco, wrote in an accompanying editorial that the analysis "illuminates a lack of transparency about the safety of unmonitored dabigatran, compounded by the drug’s fickle pharmacokinetics, which can cause a fivefold variation of plasma concentration." (BMJ 2014;349:g4681 [doi:10.1136/bmj.g4681]).
The BMJ article, written by Deborah Cohen, includes responses from the manufacturer of dabigatran (Pradaxa).
Boehringer Ingelheim officials have asserted that no data were withheld. Additionally, the company has released a statement calling the BMJ article "biased" and "misleading."
Dabigatran is a direct thrombin inhibitor that was approved in the United States in October 2010 for reducing the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation at a fixed dose of 150 mg or 75 mg twice a day, with the lower dose recommended for those with renal impairment. Since its initial approval, dabigatran has gained indications for treating and reducing the risk of recurrence of deep venous thrombosis and pulmonary embolism.
The drug’s approval was based on the results of the Randomized Evaluation of Long Term Anticoagulant Therapy (RE-LY) trial, which compared the drug to warfarin in 18,113 patients with nonvalvular atrial fibrillation and at least one other risk factor for stroke. The annual rate of stroke and systemic embolism in RE-LY was 1.5% in the patients on the 110-mg twice daily dose, 1.1% in those on the 150-mg twice daily dose, and 1.7% among those on warfarin. The risk reductions with dabigatran were 10% and 35% for the 110-mg and 150-mg doses, respectively, compared with warfarin.
"Our company has provided regulators with the complete data set and analyses of clinical evidence demonstrating Pradaxa’s benefits and safety," Boehringer Ingelheim said in its statement. "Contrary to the BMJ’s accusation that BI withheld analyses, here are the facts: In 2012, our scientists performed 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."
Dr. Sanjay Kaul, who was on the Food and Drug Administration’s advisory panel that recommended approval of dabigatran, said in an interview that the FDA reviewers raised questions at that meeting about the utility of using plasma concentrations to monitor individual subjects and adjust dose based on dabigatran concentrations. "But they also acknowledged an exposure-response relationship existed that demonstrated that going from the 10th to 90th percentile of dabigatran concentration (23 to 283 ng/mL) reduced the probability of having a stroke by 50% (from 1% to 0.5%) while increasing sixfold (from 0.3% to 1.8%) the probability of having major bleeding within 1 year."
It is well known that plasma concentration is one of the factors – among others, such as age, renal function, or history of stroke – that affect the benefit-risk balance, said Dr. Kaul, a cardiologist at Cedars-Sinai Medical Center, Los Angeles. Even in patients with moderate to severe renal dysfunction (up to creatinine clearance of 15-30 mL/min) and elevated plasma concentrations, benefit still exceeds risk.
"To what degree monitoring drug levels could potentially optimize benefit-risk balance remains an open question. For example, benefit-risk balance for dabigatran 150 mg vs 110 mg was not predicted by pharmacokinetic/pharmacodynamic modeling. Based on the PK/PD modeling, one stroke would be prevented at the cost of three extra major bleeds using 150 mg , compared with 110 mg. The RE-LY data indicate four strokes prevented and three major bleeding events incurred with the 150-mg dose as compared with the 110-mg dose," he said. "There is quite a discordance in predicted vs. observed benefit-risk balance."
