Dabigatran, bleeding, and the regulators Thomas J Moore and colleagues highlight the differences in how US and European regulators managed the safety problems of the new anticoagulant dabigatran and ask both to think again and mandate plasma monitoring of dabigatran Thomas J Moore senior scientist 1 , Michael R Cohen president 1 , Donald R Mattison chief medical officer 23 1 Institute for Safe Medication Practices, 200 Lakeside Drive, Suite 200, Horsham, PA 19044, USA; 2 Risk Sciences International, Ottawa, ON, Canada ; 3 University of Ottawa, Ottawa Dabigatran was the first drug across the finish line in the global race to develop a new and better replacement for the five decade old anticoagulant warfarin. An important indication was long term treatment to reduce the risk of stroke in patients with non-valvular atrial fibrillation. This vulnerable older group, mostly over age 75, number many millions worldwide. The main risk of treating atrial fibrillation with warfarin is that inhibiting coagulation can also result in bleeding in the brain, eyes, intestines, and elsewhere. A major bleed after warfarin treatment could result in patients losing 20-30% of their blood supply before the bleeding was halted. However, the objective of treatment was also important: blood could pool and form clots in the fibrillating atrial primer pumps, and these clots could travel to the brain, lungs, or elsewhere, causing irreversible damage. As regulators at the European Medicines Agency (EMA) and US Food and Drug Administration (FDA) considered the benefits and risks of dabigatran in 2010, they knew, or should have known, that reducing risk of bleeding with anticoagulants deserved to be ranked as a patient safety issue of the first order. A study of cases of drug adverse effects seen in 58 emergency departments across the United States 1 showed that warfarin accounted for more emergency hospital admissions in patients aged 65 or older than any other drug. Warfarin accounted for 33.3% of all hospital admissions from the emergency department for adverse drug effects; insulins were next with 13.9%. The two agencies’ evaluation of dabigatran was a study in contrasts. The FDA pursued a policy making the new drug easier to use with just one primary dose, even though it would increase the risk of haemorrhage in older patients. But the FDA also believed its actions might slightly improve the efficacy of dabigatran in preventing stroke. The EMA, by contrast, showed continuing concerns about reducing the risk of bleeding and pursued multiple risk reduction policies. But neither agency insisted on the most effective step to reduce bleeding risk—optimising the drug’s anticoagulant effect in each patient. Single pivotal clinical trial Most data supporting the US and European approval of dabigatran for non-valvular atrial fibrillation came from a single non-inferiority trial (n=18 113) comparing dabigatran with warfarin. 2 Known as RE-LY and published in 2009, it compared two fixed doses of dabigatran, 110 mg twice daily and 150 mg twice daily, with warfarin at a dose adjusted for each patient to optimise anticoagulation. The study had 18 different endpoints or combinations of endpoints, divided roughly equally between efficacy (primarily stroke and other thromboembolic events) and safety (mainly various definitions of bleeding). Most absolute differences between dabigatran and warfarin were less than 1% a year. For example, compared with warfarin 150 mg dabigatran reduced ischaemic strokes by 0.28% (1.2% v 0.92%) and major bleeds by 0.25% (3.36% v 3.11%) but increased the number of myocardial infarctions by 0.21% (0.53% v 0.74%). Because of the large sample size most of these small differences were statistically significant. However, with a largely unblinded trial in 951 centres spread across 44 countries, it was not clear whether differences of a fraction of 1% a year were clinically relevant. If the differences between dabigatran 150 mg twice daily and warfarin were quite small, the absolute bleeding risks of both drugs in this patient population were quite large (table 1⇓). In the published, corrected, adjudicated version, major bleeding rates ranged from 2.87% a year with dabigatran 110 mg to 3.57% with warfarin. 3 The definitions for “major bleeds”—set years earlier for testing drugs with haematological effects—were limited to the most severe bleeds and could exclude emergency room visits, symptomatic gastrointestinal bleeding that didn’t require a two unit transfusion, and some emergency admissions. 4 In the RE-LY trial, major and minor bleeds occurred in 18.5% of warfarin patients each year and 16.4% of patients taking dabigatran 150 mg twice daily. Correspondence to: T J Moore tmoore@ismp.org For personal use only: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe BMJ 2014;349:g4517 doi: 10.1136/bmj.g4517 (Published 23 July 2014) Page 1 of 7 Analysis ANALYSIS