By Michael H. Crawford, MD

Professor of Medicine, Chief of Clinical Cardiology, University of California, San Francisco

Dr. Crawford reports no financial relationships relevant to this field of study.

SYNOPSIS: A large observational study showed that the primary prevention of myocardial infarction and stroke in patients with atrial fibrillation is better with vitamin K antagonists alone as compared to aspirin alone and dual therapy.

SOURCES: Lee CJ, Pallisgaard JL, Olesen JB, et al. Antithrombotic therapy and first myocardial infarction in patients with atrial fibrillation. J Am Coll Cardiol 2017;69:2901-2909.

Halperin JL. Preventing myocardial infarction in patients with atrial fibrillation: Another piece of the puzzle. J Am Coll Cardiol 2017;69:2910-2912.

Although thromboprophylaxis is the preferred treatment for the prevention of stroke in atrial fibrillation (AF) patients, the ideal treatment to prevent myocardial infarction (MI) in AF patients is unclear despite the increased risk of MI in AF patients. Thus, investigators from Denmark assessed their national database to determine the incidence of first MI in AF patients treated with different antithrombic regimens, and estimated the risk of stroke and bleeding. All adult Danes hospitalized for first episode of AF without a history of coronary artery disease (CAD) between 1997 and 2012 were considered, and only those taking aspirin or vitamin K antagonists (VKA) were included. Also excluded were those > 100 years of age, with prior stroke, ablation, cardioversion, vascular disease, or clopidogrel prior therapy. The primary outcome was first MI. Secondary outcomes included stroke and bleeding requiring hospitalization. Of the 175,118 patients meeting the primary criteria for the study, 103,159 (59%) were excluded for the reasons stated above. The study cohort consisted of 71,959 patients; of them, 37,539 were treated with VKA, 25,458 with aspirin, and 8,962 with both. The aspirin monotherapy group was older, more often female, and had higher stroke risk scores. The dual therapy group had more heart failure, hypertension, and diabetes. During a median follow-up of four years, 2,275 had an MI (3%). Compared to VKA alone, the risk of MI was higher in the aspirin-alone group (hazard ratio [HR], 1.54; 95% confidence interval [CI], 1.40-1.68) and the dual therapy group (HR, 1.22; 95% CI, 1.06-1.40). Also, 8% developed stroke and 8% developed bleeding requiring hospitalization. The risk of stroke was greatest with aspirin alone (HR, 3.21; 95% CI, 3.10-3.32) and was also higher compared to VKA alone in the dual therapy group (HR, 1.3; 95% CI, 1.18-1.43). Dual therapy had the greatest risk of bleeding (HR, 4.52; 95% CI, 4.28-4.78). The authors concluded that in patients with AF, VKA therapy alone was associated with a lower risk of MI and stroke than aspirin alone. Dual therapy did not reduce the risk of MI, but increased bleeding risk.

COMMENTARY

Patients with AF often have risk factors for atherosclerosis and are at higher risk for MI. In this observational study of AF patients over four years, 3% experienced MI, 8% suffered strokes, and 8% demonstrated major bleeding events. Preventing stroke is important, but the primary prevention of MI also is a consideration, since the rate of MI among AF patients is about twice that of non-AF patients. Consequently, there is a potential rationale for adding low-dose aspirin to oral anticoagulants in AF patients without known atherosclerosis. In this study, that approach did not reduce first MI rates compared to a VKA alone, but did increase major bleeding. In fact, aspirin monotherapy was inferior to VKA alone for preventing MIs and stroke in this study. Other smaller studies have shown similar results. In the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W), aspirin plus clopidogrel was less effective than VKA alone.

Why these results? Recent studies have questioned the benefit of aspirin for the primary prevention of MI compared to the risk of bleeding. Perhaps aspirin is inadequate in the prevention of MI? On the other hand, this was an observational study, and perhaps the dual therapy group may have included high-risk patients. The group did feature more hypertension, heart failure, and diabetes patients. Even more interesting is the concept that in AF patients, MIs may be more likely caused by thromboembolism rather than plaque rupture, but there are little data to support this theory.

There are limitations to this study. Residual confounding cannot be excluded since this large database study lacked detailed clinical information such as the international normalized ratio on VKA therapy, blood pressure, or body mass index. Also, adherence to the drug therapy is unknown. Although in Denmark, other studies have shown this is quite high. Additionally, aspirin can be obtained without a prescription in Denmark, and we do not know if it was taken without their physician’s knowledge.

Today, many patients with AF take direct-acting oral anticoagulants (DOACs), which were not included in this study. However, in the studies comparing VKA to DOACs, the observed MI rates were the same. So, it was very reasonable to assume that the results would be similar with the DOACs. There are more data on patients with known vascular disease. It has been known for a long time that VKAs are effective as secondary prevention post-MI. So the results of this study are not completely surprising. Many investigators have studied post-coronary stenting patients and shown that if they have AF, VKA plus clopidogrel is safer as compared to triple therapy or VKA plus aspirin.

It appears that one should not add aspirin to anticoagulant therapy in patients with AF but no evidence of vascular disease. In post-coronary stenting patients, oral anticoagulants plus clopidogrel or other P2Y12 inhibitors are best. The real issue remaining concerns chronic stable coronary artery disease patients with AF.