Editorial Comment: Low-Dose or Moderate-Dose Anticoagulation: Dream or Hope for Stroke Prevention?
The preliminary contribution by the European/Australian Stroke Prevention in Reversible Ischemia Trial (ESPRIT) Study Group1 supports the idea that ESPRIT might settle the issue after Stroke Prevention in Reversible Ischemia Trial (SPIRIT)2 and Warfarin Aspirin Recurrent Stroke Study (WARSS)3 as to whether or not patients with noncardioembolic ischemic stroke benefit from oral anticoagulation versus platelet inhibition in secondary prevention of stroke. Ale Algra, on behalf of the ESPRIT Study Group, argues in favor of this hypothesis and claims that their study continues after WARSS so as not to miss the likelihood that moderate anticoagulation (international normalized ratio [INR] values, 2.0 to 3.0) is more effective than lower values (INR, 1.5 to 2.8 as reported in WARSS) but less dangerous than higher ones (INR, 3.0 to 4.5 as reported in SPIRIT). The data presented in this article suggest that the latter is true, ie, that major hemorrhages such as observed in SPIRIT in excess—which caused premature discontinuation of this study—are unlikely to occur in ESPRIT. Even if this observation is finally confirmed once ESPRIT is finished, however, the chances are small that oral anticoagulation will turn out to be more effective if achieved with slightly higher values than those gained in WARSS. However, limitations of the data available from the ESPRIT study at this stage prevent any scientifically reasonable prediction because ESPRIT is an open-labeled rather than a double-blind, randomized trial (like WARSS), yet it has unknown variability of target INR ranges in individual subjects. WARSS was very effective in this view, achieving only minor variations of INR values during follow-up. Furthermore, WARSS has nicely shown that despite constantly higher INR values ranging close to the upper border zone fixed in the trial (INR, 2.8) in a subgroup of patients, both risks of secondary strokes and final outcome did not differ from those observed in another subgroup of patients with lower INR values. Thus, WARSS confirmed previous studies with different ranges of anticoagulation documented, eg, in patients with nonvalvular atrial fibrillation (Stroke Prevention in Atrial Fibrillation [SPAF] I through III).4 These studies showed that efficacy of anticoagulation, although achieved once levels of INR >1.5 were maintained, did not improve with higher INR values; in contrast, outcome tended to be worse because of increasing associated risks. Another study by the authors of the present article5 also demonstrated the same risk-to-benefit ratios for INR values >1.5. Considering these data altogether, it does not seem very likely that ESPRIT will be more successful than WARSS in providing evidence of what many of us might have suspected and hoped for, ie, that anticoagulation could be more powerful.
- ↵Mohr JP, Thompson JL, Lazar RM, Levin B, Sacco RL, Furie KL, Kistler JP, Albers GW, Pettigrew LC, Adams HPJ, Jackson CM, Pullicino P, for the Warfarin-Aspirin Recurrent Stroke Study Group. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med. 2001; 345: 1444–1451.
- ↵Torn M, Algra A, Rosendaal FR. Oral anticoagulation for cerebral ischemia of arterial origin: high initial bleeding risk. Neurology. 2001; 57: 1993–1999.