Controversies in stroke

The role of combination therapy, whether antiplatelet or antithrombotic, in secondary stroke prevention is controversial. The only widely accepted combination therapy is clopidogrel plus aspirin in patients with coronary, carotid, or intracranial artery stents. The duration of combination antiplatelet therapy in stent patients is, however, controversial, with a minimum of 3 months used in most patients. Permanent combination antiplatelet therapy is probably indicated in patient with drug eluting stents. The combination of extended release dipyridamole and low-dose aspirin was superior to either agent alone for secondary stroke prevention in the ESPS2 and ESPRIT trials. This is in contradistinction to combined clopidogrel and aspirin, which was not superior to either clopidogrel alone or aspirin alone in the MATCH and CHARISMA trials, respectively. Perhaps paradoxically, the combination of low-dose aspirin and extended release dipyridamole was not superior to clopidogrel alone in the PROFESS trial. In these trials, bleeding complications, including intracerebral hemorrhage, were significantly increased with combination antiplatelet therapy. The role of antiplatelet therapy combined with warfarin is even more controversial. Warfarin was not superior to aspirin for noncardioembolic stroke risk reduction in WARSS. In two substudies, there was no statistical benefit of warfarin compared to aspirin in patients with patent foramen ovale (PICSS) or antiphospholipid antibodies (APASS). Furthermore, warfarin was not superior to aspirin in patients with documented 50% intracranial atherostenosis in WASID. Warfarin is superior to either aspirin or clopidogrel plus aspirin for stroke prevention in patients with atrial fibrillation. Warfarin is also superior to antiplatelet therapy in patients with mechanical heart valves and probably in patients with severe left ventricular dysfunction (although this concept is being tested in WARCEF). It is well known that bleeding risks are higher with warfarin compared to antiplatelet therapy, and they are certainly further increased when warfarin is combined with aspirin or other antiplatelet agents. Given this data, are there any patient populations remaining where the bleeding risk associated with combined warfarin and antiplatelet therapy may be justified? Despite the studies cited above, this remains a surprisingly common clinical dilemma. The most common scenario involves patients at risk for both cardioembolic (“red clot”) and atherosclerotic (“white clot”) stroke. Another scenario involves defining “maximal medical therapy” in patients with recurrent or fluctuating ischemic events related to high grade atherostenosis. A third scenario consists of so-called aspirin or antiplatelet “failure” patients. A fourth scenario includes patients with very recent events. In a metaanalysis, Larson et al found that the combination of warfarin plus aspirin was beneficial only in patients with mechanical heart valves. In patients with mechanical heart valves, warfain plus aspirin significantly decreased thromboembolic events (relative risk [RR], 0.33; 95% confidence interval [CI], 0.19 to 0.58), increased major bleeding (RR,1.58; 95% CI, 1.02 to 2.44), and decreased all-cause mortality (RR, 0.43; 95% CI, 0.23 to 0.81) compared to warfarin alone. There was no evidence that adding aspirin to warfarin was beneficial in patients with recent myocardial infarction or atrial fibrillation. However, an increasingly common clinical scenario involves patients with atrial fibrillation (or other classic cardioembolic source such as left ventricular failure) who also require a coronary, carotid, or intracranial artery stent for symptomatic atherostenosis. In such patients warfarin alone is insufficient to prevent in stent thrombosis. These patients are often treated with aspirin plus clopidogrel plus warfarin for 3