In large trials comparing direct oral anticoagulants (DOACs) to warfarin in patients with atrial fibrillation (AF), most deaths are not due to stroke or bleeding. Instead, they're cardiac-related, suggesting that new interventions, beyond anticoagulation, are needed to reduce mortality in this population, researchers say.
Overall, DOACs have conferred only a modest reduction in mortality, according to a paper released December 5 by the Journal of the American College of Cardiology.
As Dr. Antonio Gomez-Outes told Reuters Health by email, "Contemporary atrial fibrillation trials have focused on the potential improvement of anticoagulation management with the DOACS compared with warfarin. These trials have shown that the DOACs may confer some benefit over warfarin in reducing bleeding rates with at least similar efficacy."
"Our systematic review," he added, "shows that overall rates of fatal strokes and fatal bleeding in anticoagulated patients are currently below 1% per year with either DOACs or warfarin. Therefore, we are reaching the point of diminishing returns with contemporary anticoagulation."
Dr. Gomez-Outes of the Agencia Espanola de Medicamentos y Productos Sanitarios (AEMPS), Madrid, and colleagues studied data on more than 71,000 patients in four trials of these agents for prevention of stroke and systemic embolism.
Over follow-up ranging from 1.9 to 2.8 years, 6,206 patients (9%) died. The adjusted mortality rate was 4.72% per year. Cardiac events accounted for 46% of deaths. Nonhemorrhagic stroke and systemic embolism caused 5.7% of deaths and hemorrhage-related deaths were seen in 5.6%.
Compared to patients who survived, those who died were more likely to have a history of heart failure (odds ratio, 1.75), permanent/persistent AF (OR, 1.38) and diabetes (OR, 1.37). They were also more likely to be men (OR, 1.24).
There was a small but significant reduction in all-cause mortality with DOAC versus warfarin which amounted to 0.42% per year. This was due mainly to a reduction in fatal bleedings.
Thus, concluded Dr. Gomez-Outes, "There is still a need to improve current management of comorbidities and associated cardiovascular risk factors (i.e., heart failure, diabetes, hypertension) in order to reduce mortality rates in AF beyond anticoagulation."
Commenting by email, Dr. Stuart J. Connolly, author of an accompanying editorial, told Reuters Health, "One of the major benefits of novel oral anticoagulants over warfarin is a reduction in major bleeding. Some of these bleeds are acutely fatal. However the reduction in acute fatal bleeding only explains part of the mortality benefit that is documented by the meta-analysis. The rest of the benefit is likely due to late effect of bleeds that are not immediately fatal."
In his editorial, Dr. Connolly of Hamilton Health Sciences, Ontario, pointed out, "The common idea that strokes and myocardial infarctions leave permanent damage, but patients recover without long-term consequences from major bleeding, is an intuition that is not supported by current data.