I distrust small numbers. Still, a recent review published in the Journal of Neurosurgery warrants attention. The analysis tracked outcomes of patients on dabigatran who were admitted to a trauma center over a four-month period for closed head injuries after ground-level falls.
The sample size in the analysis is tiny: 55 patients, with five on dabigatran (Pradaxa, Boehringer Ingelheim), 15 on warfarin and 25 on no anticoagulants. Of the patients on dabigatran, CT scans during reversals of anticoagulation revealed new or expanded hemorrhage in four of the five patients compared with three of the warfarin patients. Two patients on dabigatran died while none in either the warfarin or no anticoagulant groups died.
The authors used the review to highlight not only the mortality rate but also the lack of protocol for treating patients on an anticoagulant that cannot be easily reversed. With no antidote and no specific protocol in place, physicians appeared to have to treat on the fly. After a literature review and armed with evidence from their institution, the authors developed a protocol that is being instituted at their center.
Earlier this year, FDA researchers published a study based on an analysis of the Mini-Sentinel program to evaluate postmarketing bleeding risks associated with dabigatran. The agency was concerned about the high number of adverse events associated with dabigatran that were submitted since the drug’s approval in October 2010. For instance, the Institute for Safe Medication Practices had placed dabigatran at the top of its list for reports of serious, disabling and fatal adverse drug events in the U.S. in 2011. Warfarin came in second.
The FDA review concluded that bleeding rates for dabigatran and warfarin were similar. Researchers attributed the high number of reports for dabigatran to “stimulated reporting,” that is, heightened awareness of dabigatran due to its novelty.
Closed head injuries in patients treated with dabigatran may present a particularly difficult situation for trauma physicians. Dabigatran was approved for the prevention of stroke in patients with nonvalular atrial fibrillation. Those patients tend to be older; the mean age of the dabigatran group in the closed head injury review was 82 years, for instance, and the mean age of the warfarin group was 84 years. This also is a population that is vulnerable to falls.
The authors of the Journal of Neurosurgery article recommended that prescribing physicians carefully weigh the benefits of dabigatran against potential risks. According to a 2011 analysis of PINNACLE-AF registry data, physicians caring for patients with atrial fibrillation have been slow to embrace dabigatran, perhaps preferring to stay with warfarin until more evidence becomes available.
The sample size in the study on closed head injuries is a significant limitation. PINNACLE-AF, on the other hand, is the opposite. It exists within the PINNACLE Registry, which held 4.7 million patient records (250,000 for atrial fibrillation) at the time of the analysis. The FDA’s postmarketing database also is a resource.
We will see more from PINNACLE-AF and the FDA reported plans to conduct more postmarketing assessments of dabigatran. In the meantime, observations from other specialists such as neurosurgeons and emergency care physicians may help inform cardiologists and FDA analysts of some questions to ask.
Candace Stuart
Cardiovascular Business, editor