SAN DIEGO – The novel oral anticoagulants clearly outperformed warfarin for stroke prevention and safety endpoints in patients with atrial fibrillation and comorbid heart failure in a meta-analysis of four recent landmark Phase 3 clinical trials.
Collectively the four novel oral anticoagulants (NOACs) approved for stroke prophylaxis in nonvalvular atrial fibrillation (AF) reduced the risk of stroke and systemic embolism by 14%, compared with patients randomized to warfarin. Moreover, the NOACs decreased the risks of major bleeding and intracranial bleeding by 23% and 45%, respectively, Dr. Gianluigi Savarese reported at the annual meeting of the American College of Cardiology.
Bruce Jancin/Frontline Medical News
“NOACs represent a valuable therapeutic option in patients with nonvalvular atrial fibrillation and heart failure,” concluded Dr. Savarese of Federico II University, Naples.
There has never been a randomized trial comparing a NOAC to warfarin specifically in patients with these dual diagnoses. In the absence of such a definitive study, the next best thing is a meta-analysis of the pivotal Phase 3 trials in which warfarin was compared to dabigatran (Pradaxa, the RE-LY study), apixaban (Eliquis, ARISTOTLE), rivaroxaban (Xarelto, ROCKET AF), and edoxaban (Savaysa, ENGAGE AF-TIMI 48).
The meta-analysis focused on a subset population of 26,384 randomized patients with AF and heart failure. It’s important to know how the NOACs stack up against warfarin in this population because symptomatic heart failure is common: indeed, it’s present in 30% of patients with AF. Patients with AF and comorbid heart failure are generally older, frailer, have more comorbidities, and are at higher risk of both stroke and bleeding, compared with AF patients without heart failure. Since heart failure is a recognized risk factor for reduced time in the therapeutic international normalized ratio (INR) range for patients on warfarin, it’s likely that warfarin-treated dual diagnosis patients would be exposed to further increased risks of stroke and bleeding, according to Dr. Savarese.
In the meta-analysis, in addition to the NOAC-treated patients’ significantly reduced risks of stroke, major bleeding, and intracranial bleeding, they showed a 12% decrease in total bleeding and an 8% reduction in cardiovascular death, compared with warfarin-treated controls, although neither of those latter two favorable trends achieved statistical significance.
The four NOACs didn’t differ significantly on any of the prespecified outcomes in the meta-analysis.
One audience member noted that while the relative risk reductions for stroke and major bleeding seen with the NOACs in the meta-analysis were large and impressive, the absolute risk reductions were actually quite small. For example, warfarin-treated controls in RE-LY, the first of the major trials, had a stroke/systemic embolism rate of 1.69%/year and a major bleeding rate of 3.4%/year (N. Engl. J. Med. 2009;361:1139-51), while controls in ENGAGE AF-TIMI 48 had annualized stroke and major bleeding rates of 1.5% and 3.4%, respectively (N. Engl. J. Med. 2013;369:2093-2104).
Dr. Savarese replied that he and his coinvestigators consider those absolute risk reductions to be clinically meaningful, especially in light of the enormous and rapidly growing number of patients with both AF and heart failure.
He reported having no financial conflicts regarding this meta-analysis, which was carried out free of commercial support.