AF, Aspirin, and Additional Antiplatelet Agents

Atrial fibrillation (AF) is a common problem—prevalence is about 10% in persons age 80 years or older—and treating AF is a challenge. For most patients, warfarin is the most effective option, but it is an agent which is subject to drug interactions, sometimes requires onerous monitoring, and causes hemorrhages. Also, it is high on the top ten list of drugs causing problematic events in inpatients. Aspirin, while rather less effective, has been used as an alternative for some time. An ongoing conundrum has been whether the addition of clopidogrel to aspirin for AF confers additional protection against strokes, thrombotic events, and so forth, without undue additional adverse effect risk. The results of previous studies have been somewhat mixed, especially with regard to stroke prevention, and the largest study pertained to acute coronary syndrome, not stroke.

But, new data are at hand. The ACTIVE study evaluated the effects of adding clopidogrel to aspirin on the risk of vascular events in patients with AF. Eligible patients had AF and were at increased risk for stroke, based on the presence of at least one of several pre-defined risk factors. AF eligibility requirements were either the presence of AF at enrollment or at least two episodes of intermittent AF in the previous 6 months. Eligible patients were judged not candidates for warfarin, and patients at increased risk for hemorrhage were excluded.

An interesting aside - The reasons given for not taking warfarin were: A specific risk of bleeding (22.9%), a physician's judgment that warfarin treatment was not appropriate for the patient (49.7%), and patient preference (26.0%). Thus, the largest group of patients not taking warfarin were due to physician decision, in the absence of a clear specific hemorrhage risk. As warfarin is clearly more effective than antiplatelet agents, the rationale for this decision in so many patients is curious.

At any rate, enrolled patients (n=7554) were randomly assigned to receive clopidogrel 75 mg./day or placebo, in addition to aspirin (with the dose recommended being 75-100 mg./day). The primary outcome measure was a composite of stroke, non—CNS embolism, myocardial infarction, or vascular causes of death. The primary secondary outcome measure was stroke. Average age was about 71-years-old. This was a long term study: The mean duration of follow-up was 3.6 years.

Results: At the time of follow-up, major vascular events had occurred in 832 clopidogrel patients (6.8%/year) v. 924 patients receiving placebo (7.6%/year) (relative risk with clopidogrel, 0.89; 0.81-0.98; p = 0.01). Stroke reduction was the primary driver of the difference: 296 clopidogrel patients (2.4%/year) v. 408 placebo patients (3.3%/year) (relative risk, 0.72; 0.62-0.83; p<0.001) had strokes. 0.9%, although a small figure on the surface, is actually a material absolute risk reduction. MI reduction was not statistically significant. Treatment adherence was equivalent between groups, but nearly 40% were not adherent by 4 years. Also, at baseline, 96% of patients were taking between 75 and 100 mg. aspirin per day. Thus, almost all the patients were taking aspirin within the recommended narrow dose range.

Needless to say, adverse effects did occur: Major bleeding in 251 clopidogrel patients (2.0%/year) v. 162 placebo patients (1.3% per year) (relative risk, 1.57; 1.29-1.92; p<0.001). There were 42 fatal hemorrhages in the clopidogrel group, compared with 27 in the placebo group, but this was not statistically significant. The most common hemorrhage site, not surprisingly, was gastrointestinal.

So, these data are of value in making treatment decisions. This was a large, long term, randomized study, where stroke was an important and carefully monitored outcome. In this trial, the addition of clopidogrel to aspirin in patients with AF significantly reduced stroke risk, but at a cost of significantly increased hemorrhage rates. And, even with clopidogrel added, antiplatelet therapy still lags far behind warfarin therapy in efficacy for this indication. In patients who absolutely cannot or will not take warfarin, adding clopidogrel to aspirin reduces stroke risk.