Atrial fibrillation (AF) is the most common sustained arrhythmia. While it occurs in less than 1% of the general population, its incidence rises to the 10% range in patients over 80 years of age. AF has an associated five-fold increase in risk of embolic stroke and may cause up to 15% of all strokes.1 Oral anticoagulant therapy (OAC) using warfarin or other agents, is commonly employed to reduce thromboembolic events. Warfarin has a proven track record of thromboembolic risk reduction in AF (~1/3). It and other vitamin K antagonists do carry a real risk of severe bleeding (~1%). Anti-platelet therapy with aspirin is an alternative for patients with low thromboembolic risk or high bleeding risk. While aspirin alone is not as effective at thromboembolic risk reduction, it does offer some risk reduction (~22%)2 in patients who are ineligible or intolerant of warfarin.
One area under current investigation concerns the role of dual anti-platelet therapy with clopidogrel and aspirin. In 2006 the investigators of the ACTIVE W trial (Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events) first reported a comparison of OAC to clopidogrel plus low-dose aspirin.3 This prospective open-label non-inferiority trial reported results from 526 centers in 15 countries. Patients were eligible if they had ECG evidence of AF and one additional risk factor. It had 3371 patients randomized to OAC and 3335 allocated to dual anti-platelet therapy. OAC with warfarin was the primary therapy, but other vitamin K antagonists were included also. Anti-platelet therapy consisted of daily clopidogrel 75 mg plus aspirin (75-100 mg recommended). Persistent or permanent AF was present in 82% of the patients. The authors concluded that OAC was “superior to clopidogrel plus aspirin,” for embolic stroke risk reduction in AF.
More recently, the ACTIVE investigators reported the results of a post-hoc analysis of these earlier data.4 In this analysis, mean time in therapeutic range (TTR) was computed for each center and country in the study. These results were stratified by mean TTR quartiles of their respective center. Interestingly, there was not a statistical difference in the occurrence of stroke, myocardial infarction, vascular death, systemic embolism or major hemorrhage between OAC and dual anti-platelet therapy in the bottom two quartiles, representing those centers with a mean TTR ≤ 65%. In addition to the stratification by center mentioned above, a population-average model was used to account for clustering of TTR at the various sites. This provided a model that showed a non-linear relationship between TTR and benefit of OAC. The investigators concluded that OAC when TTR was below 58% in this model offered no benefit over dual anti-platelet therapy and had virtually the same bleeding risk.
This post hoc analysis offers a provocative possibility: if clinicians cannot maintain a mean TTR greater than the 58-65% range, they should consider offering dual anti-platelet therapy in lieu of OAC for risk reduction in AF. There are problems with this ...