ESPRIT: Safety and Efficacy of Oral Anticoagulation—a Rebuttal
To the Editor:
In his editorial comment on our article Prof Hennerici agrees with our conclusion that oral anticoagulation with a target and achieved INR of 2.0 to 3.0 is reasonably safe in patients with cerebral ischemia of arterial origin, based on observations in the European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT).1,2 He ends, however, by doubting that oral anticoagulation with such a target INR will be more effective than aspirin. Given the absence of reliable data, this is jumping to conclusions.
Hennerici writes that “limitations of the data available from ESPRIT at this stage prevent any scientifically reasonable prediction ….” Yes, true enough, because at this moment (June 2003) about 3000 of the planned 9000 patient-years for the anticoagulation-aspirin comparison have been accrued. But his sentence continues: “… because ESPRIT is an open-labeled rather than a double blind, randomized trial (like WARSS) ….” We cannot follow the logic of this reasoning: the size of the study has nothing to do with blinding. The sentence then continues: “… yet it has unknown variability of target INR ranges in individual subjects.” Indeed the achieved INR values vary (not, of course, the target values). These variations are described in the Figure of our research report, which is based on Rosendaal’s method for calculating the time spent within 0.5 U INR classes.3 The figure shows that about two thirds of the time INR values are within the target range and another quarter is spent in the adjacent 0.5 U INR classes. Hence we consider that the anticoagulation strategy in ESPRIT is on target. Moreover, these data are hardly different from those published for WARSS, in which 70.7% of all INR values 28 days or later after randomization were within the WARSS target range of INR of 1.4 to 2.8.4 It would be of interest to have the WARSS INR data presented as years spent in each INR class, but we are not aware that such data have been published.
One of the other sources for Hennerici’s doubt about the potential efficacy of anticoagulation with INR between 2.0 and 3.0 is based on an unpublished subgroup analysis from the WARSS study. Subgroup analyses should be viewed with utmost skepticism, in this case the more so because the WARSS trial as a whole has been considered as underpowered.5 Hennerici’s final argument is based on observations in patients with a cardiac source of cerebral ischemia. We think this is seriously misleading. All major guidelines recognize that secondary prevention in such patients is clearly different from those with an arterial source. The European Atrial Fibrillation Trial (EAFT) demonstrated that oral anticoagulation with target INR 2.5 to 4.0, was far superior to aspirin and safe,6 whereas the Stroke Prevention In Reversible Ischemia Trial (SPIRIT) showed that for patients in sinus rhythm, anticoagulant treatment with a similar intensity was unsafe.7 Hence we learned our lesson never again to extrapolate between these diseases!
In conclusion, we respect Prof Hennerici’s personal expectations but would like to underscore his initial statement that it is still too early for any scientifically reasonable prediction about the comparison between anticoagulation and aspirin.
European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) Study Group
Hennerici MG. Low-dose or moderate-dose anticoagulation: dream or hope for stroke prevention? Stroke. 2003; 34: e46–e47.Editorial comment.
ESPRIT. Oral anticoagulation in patients after cerebral ischemia of arterial origin and risk of intracranial hemorrhage. Stroke. 2003; 34: e45–e46.
Mohr JP, Thompson JL, Lazar RM, Levin B, Sacco RL, Furie KL, Kistler JP, Albers GW, Pettigrew LC, Adams HPJ, et al, 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.
Hankey GJ. Warfarin-Aspirin Recurrent Stroke Study (WARSS) trial: is warfarin really a reasonable therapeutic alternative to aspirin for preventing recurrent noncardioembolic ischemic stroke? Stroke. 2002; 33: 1723–1726.