Pradaxa to replace Coumadin as the drug of choice for stroke-prevention for patients with atrial fibrillation.
In the summer of 2009 the RE-LY trial was completed. The trial compared two doses of Dabigatran (marketed name Pradaxa) to Warfarin (marketed name Coumadin) for prevention of stroke for patients with atrial fibrillation. The two primary endpoints that were compared were the rate of strokes over time and the occurrence of major bleeding. There were several secondary endpoints. The trial was a non-inferiority trial meaning that Dabigatran only had to show that it was acceptably effective at reducing stroke and having acceptable major bleeding rates compared to Coumadin. It did not have to show superiority because Coumadin has many drawbacks to its use that Dabigatran does not have including need to monitor patients international normalized ratio (INR) and to have an adverse interaction with certain foods and other drugs. For Coumadin the INR must be kept in the range of 2.0 to 3.0 and must be checked at least monthly. The trial was a global trial with over 6,000 patients randomized to each of the three groups (Dabigatran 110 mg twice daily dose, Dabigatran 150 mg twice daily dose and standard dose of Coumadin). Patients and investigators knew whether the patient was randomized to Dabigatran or Coumadin but if they got Dabigatran the dose was not told to them.
Because of the drawbacks of Coumadin and the high number of elderly patients with atrial fibrillation, several pharmaceutical companies entered a race to find a drug that would replace Coumadin. Some products failed to meet their trial objectives. The results of the RE-LY trial were reported in the New England Journal of Medicine in August 2009. Both doses of the drug met the non-inferiority criteria for major bleeding and stroke risk compared to Coumadin. Furthermore the two doses did better than expected. The 150 mg dose was superior to Coumadin with respect to stroke risk and the 110 mg dose was superior to Coumadin with respect to major bleeding. Superiority is demonstrated if the upper bound of the 95% confidence interval (two-sided equivalent to 97.5% one-sided upper confidence bound) for relative risk (hazard ratio) is less than 1. Noninferiority is shown if the upper bound is below 1.46. These relative risk ratios are estimated from a Cox proportional hazards model that is fit to the trial data. Further details can be found in article.
The FDA has reviewed the data and audited a sample of the trial sites for over a year and additional medical research papers showing other benefits of Dabigatran have been published. On September 20, 2010, an advisory committee of medical experts met and by a vote of 9 to 0 recommended that the FDA approve Dabigatran and the FDA approved the drug on October 19, 2010. The sponsor, Boehringer Ingelheim, recommended that the FDA approve both doses of the drug so that physicians will have the option to prescribe the 110 mg dose for patients who have a high risk for bleeding. In spite of this the FDA has said that they are inclined to only approve the 150 mg dose. The committee is of mixed opinion on this as they voted 6-4 in favor of accepting both doses. Regardless of how the FDA decided on the dosing issue a new drug will be available as an alternative to Coumadin and is likely to take over the market for patients with atrial fibrillation (estimated at $10 billion annually).