March 15, 2013

A new analysis of the US Food and Drug Administration's (FDA's) Mini-Sentinel database has given reassuring results on the rates of gastrointestinal (GI) and intracranial bleeding with dabigatran (Pradaxa, Boehringer Ingelheim).

However, a separate analysis of dabigatran bleeding reports submitted to the FDA, presented at the recent American College of Cardiology (ACC) meeting in San Francisco, California, has suggested a much higher case fatality rate than that reported in the major clinical trials of the drug.

Mini-Sentinel Analysis

The Mini-Sentinel analysis, published online in the New England Journal of Medicine on March 13, was conducted by 3 FDA employees in response to the high numbers of bleeding reports with dabigatran when it was first approved in the United States.

The researchers, with first author Mary Ross Southworth, PharmD, from FDA's Center for Drug Evaluation and Research, examined the Mini-Sentinel database, which monitors routinely collected electronic healthcare data, for the period from October 19, 2010 (the date of dabigatran approval), to December 31, 2011. The authors sought to identify inpatient diagnosis codes for intracranial and GI hemorrhages associated with new use of dabigatran or warfarin.

Results showed that bleeding rates associated with dabigatran use during that period did not appear to be higher than those associated with warfarin.

Table 1. Intracranial and GI Bleeding in New Users of Dabigatran and Warfarin for Atrial Fibrillation

Endpoint Patients (n) Events (n) Events per 100,000 Days at Risk
GI hemorrhage 10,599 16 1.6
Intracranial hemorrhage 10,587 8 0.8
GI hemorrhage 43,541 160 3.5
Intracranial hemorrhage 43,594 109 2.4


Noting the limitations to the Mini-Sentinel analysis, including lack of adjustment for confounding variables and lack of a detailed medical record review, the authors nevertheless say they believe these data are reassuring.

They conclude that the large number of reported cases of bleeding associated with dabigatran was probably an example of stimulated reporting due to publicity surrounding the launch of the drug, as well as a tendency to preferentially report adverse events with new drugs.

They add that further analysis of the Mini-Sentinel and other claims databases is ongoing, as is routine postmarketing surveillance.

Adverse Events Reported to FDA

The other analysis, presented at the ACC meeting by Kevin W. McConeghy, PharmD, BCPS, University of Illinois at Chicago, examined publicly available data from adverse event reports submitted to the FDA on dabigatran.

They found that such reports relate to patients who are older and more often female than in the RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial that established the efficacy of the drug. And of the dabigatran bleeding reports submitted to the FDA, the case fatality rate was 16%, almost double that reported in the major clinical trials of the drug.

Dr. McConeghy stated that the aims of his study were to describe the population of dabigatran users experiencing adverse events, estimate the risk for death among FDA bleeding reports associated with dabigatran, and determine a lower-bound estimate of dabigatran-related bleeding deaths in the United States.

For the study, the researchers examined reports of bleeding with dabigatran or warfarin submitted to the FDA between January 1, 2010, and June 30, 2012.


Table 2. Adverse Drug Reactions Relating to Warfarin or Dabigatran Reported to the FDA

Endpoint Warfarin Dabigatran
Total adverse events reported (n) 4524 12,581
Bleeding events, n (%) 590 (13) 2453 (19)
Women (%) 54 48
Age (y) 68.5 75
Weight (kg) 85 82


Dr. McConeghy pointed out that the mean age of patients who had an adverse event with dabigatran reported to the FDA (75 years) was greater than that in the RE-LY trial (71 years), and more patients with FDA-reported events were female (48%) than those included in RELY (36.7%).

"This suggests the drug is being used in a different profile of patients as that in the RE-LY trial," he said.

16% Case Fatality Rate

Of the 2453 dabigatran bleeding adverse events reported to the FDA, 393 (16%) were fatal, almost double the case fatality rate of patients who bled in the 5 phase 3 trials of the drug, he noted.

Table 3. Bleeding Events Reported to the FDA

Event Warfarin Dabigatran
Total bleeding events (n) 590 2453
GI bleeding events, n (%) 162 (27) 1352 (55)
Intracranial bleeding events, n (%) 69 (12) 280 (11)
Bleeding-related deaths, n (%) 47 (8) 393 (16)


Table 4. 30-day Mortality After First Major Bleeding Event in 5 Phase 3 Trials

Variable Warfarin Dabigatran
Mortality, n/n (%) 53/407 (13) 57/627 (9)


Using the FDA adverse event report data and a previously published estimate that in 2011 there were 232,000 patient-years of exposure to dabigatran in the United States, the researchers calculated a fatal event rate of 95.3 per 100,000 person-years. Dr. McConeghy said this could be considered a lower-bound estimate because not all adverse events are reported. He worked out that if fewer than 1 in 3 adverse bleeding events were reported to the FDA, this fatality rate may signal an increased risk for bleeding death compared with that seen in RE-LY.

But he cautioned that the figures used in this analysis suffered from reporting bias and accuracy and duplication problems, so they should not be used to draw any definite conclusions.

N Engl J Med. Published online March 13, 2013. Abstract

American College of Cardiology (ACC) 2013 Scientific Sessions. Abstract 914-8. Presented March 10, 2013.