Atrial fibrillation (AF) is the most common cardiac arrhythmia, and is associated with a five-fold increase in the risk of stroke and embolism.1 Oral anticoagulation (OAC) with warfarin reduces stroke by two-thirds compared with no treatment.1–3 Compared with aspirin, OAC reduces the risk of stroke by 45% and reduces cardiovascular events by 29%.4 However, it increases the risk of major bleeding by about 70% compared with aspirin. In addition, the response to OAC is influenced by variations in hepatic function, gut flora, and interactions with numerous drugs and diet, requiring regular monitoring of the level of anticoagulation. Despite the fact that OAC is at present the treatment of choice for patients at higher risk of stroke,5 only about half of potentially eligible patients currently receive OAC.6 An effective, simple, and safe alternative to OAC could be of great potential clinical value.
Recently, new data in AF thromboprophylaxis for potential alternative approaches to anticoagulation have emerged from several large, randomized clinical trials. These studies have compared the efficacy of a new class of oral anticoagulants—the oral direct thrombin inhibitors—and that of the combination of two antiplatelet agents—aspirin plus clopidogrel—with standard warfarin therapy. This brief summary will review the results of these trials.
Trials with Direct Thrombin Inhibitors
Oral direct thrombin inhibitors are a new class of anticoagulants currently developed for stroke prevention in AF. Ximelagratan has been the first such compound that has been thoroughly evaluated in clinical trials. The compound has a predictable pharmacokinetic profile that is stable over time. With a rapid onset of action and metabolism independent of the hepatic cytochrome P450 enzyme system, ximelagratan has a low potential for drug interactions and no known food interactions, making coagulation monitoring and dose adjustments unnecessary. Two large pivotal trials have been carried out comparing the efficacy and safety of ximelagratan with that of warfarin. The Stroke Prevention using an Oral Thrombin Inhibitor in Atrial Fibrillation (SPORTIF) III7 study was a European long-term phase III study, and similar to the North American SPORTIF V study.8 The major difference between the trials was that SPORTIF III was an open-label, randomized trial whereas anticoagulation was administered in a double-blind fashion in SPORTIF V.
The trials randomized 3,410 and 3,922 patients, respectively, to ximelagratan 36mg twice-daily or adjusted-dose warfarin (international normalized ratio (INR) 2–3) with the primary end-point of stroke and peripheral embolism. Both trials followed a non-inferiority design. In SPORTIF III, the primary event rate was 2.3% per year with warfarin and 1.6% with ximelagratan. In the sister trial, these numbers were 1.2% for warfarin and 1.6% for ximelagratan. Accordingly, both trials established non-inferiority against warfarin. The rates of major bleedings were comparable for both treatments, but minor bleedings occurred less frequently with the direct thrombin inhibitor.
However, more abnormal liver function tests were observed during ximelagratan therapy. In patients receiving ximelagratan, serum alanine aminotransferase levels more than three times the upper limit of normal occurred in 6% in SPORTIF III and V, which was significantly more common than in the warfarin group. Most of these abnormalities cleared, even when therapy was continued. However, regulatory agencies became so concerned about the issue of liver toxicity that ximelagratan was not approved for the indication of anticoagulation in AF. The manufacturer thus decided to stop its development program. Currently, several other oral direct thrombin inhibitors are tested in similar large study programs for anticoagulation of patients with AF, with particular emphasis given to potential signs of liver toxicity.
Trials with Combined Antiplatelet Therapy
Both aspirin and clopidogrel are antiplatelet agents that act through different mechanisms. Aspirin reduces the risk of stroke in patients with AF by approximately 20%.1–3 The additive benefits of combining a thienopyridine with aspirin have been clearly demonstrated in patients undergoing percutaneous coronary intervention and in those with acute coronary syndrome or acute myocardial infarction.9,10 Based on the documented protective effect of aspirin in AF, it was therefore reasonable to expect that the addition of clopidogrel to aspirin would provide incremental benefits so that clopidogrel plus aspirin would be of similar efficacy as warfarin in patients with AF. Accordingly, a prospective randomized trial was designed to test this hypothesis. The purpose of The Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE W) was to determine whether clopidogrel plus aspirin was statistically non-inferior to warfarin for prevention of vascular events in patients with AF at higher risk of stroke and eligible for oral anticoagulation.11
Patients were randomly assigned to receive OAC (target INR of 2–3) or clopidogrel (75mg per day) plus aspirin (75–100mg per day recommended). The primary outcome was the first occurrence of stroke, non-central nervous system (CNS) systemic embolus, myocardial infarction, or vascular death. In total, 3,335 patients were treated by combined antiplatelet therapy and 3,371 received OAC. Median follow-up duration was 1.3 years. After that time, the data safety and monitoring board recommended to stop the study due to clear evidence of the superiority of OAC.
There were 164 primary events on OAC (annual risk of 3.90%) and 234 on clopidogrel plus aspirin (annual risk of 5.60%) (relative risk (RR) 1.45, 95% confidence interval (CI) 1.19–1.77; p<0.001). There was no difference in total mortality (RR 1.01, 95% CI 0.81–1.26; p=0.91) or in major hemorrhage (RR 1.10, 95% CI 0.83–1.45; p=0.53). However, the predominant advantage with OAC was seen in stroke. The combined antiplatelet therapy carried a significantly larger risk for stroke (RR 1.75, 95% CI 1.26–2.41; p<0.001) and for non-CNS systemic embolism (RR 4.66, 95% CI 1.58–13.8; p=0.005) compared with OAC.
There was an important difference between patients who had previously received warfarin before entering ACTIVE and those who had not. At the time of study entry, 77% of patients were already receiving OAC. They had a trend to greater reduction in vascular events with OAC (RR 1.51, 95% CI 1.20–1.91) and a significantly (p interaction=0.028) lower risk of major bleeding with OAC (RR 1.30, 95% CI 0.94–1.79) compared with patients not on OAC at study entry (RR 1.27, 95% CI 0.85–1.89 and RR 0.59, 95% CI 0.32–1.08, respectively).
In summary, therefore, ACTIVE W demonstrated that OAC with warfarin is superior to combined antiplatelet therapy in patients with non-valvular AF and high risk for stroke. This was particularly true for patients already taking OAC at study entry. Of note, the ACTIVE program is currently continued within the ACTIVE A trial, which randomizes patients with contraindications to warfarin or who are unwilling to undergo OAC. This trial is expected to end in the summer of 2008. At the same time, trials evaluating other new antithrombotic agents such as direct thrombin inhibitors or factor X inhibitors are underway. There is hope that within the next few years, clinically useful alternatives to OAC using warfarin will be available, but at the present time warfarin continues to be the therapy of choice in patients with AF at risk of stroke. However, the risks of stroke, death, and major bleeding are closely related to INR control in these patients, and only good INR control is associated with improved outcome.12