Correspondence
Warfarin or Aspirin for Recurrent Ischemic Stroke
N Engl J Med 2002; 346:1169-1171April 11, 2002
- Article
To the Editor:
The conclusions in the Abstract of the article by Mohr et al. (Nov. 15 issue)1 overstate the benefits of anticoagulation. They state that the authors “found no difference between aspirin and warfarin in the prevention of recurrent ischemic stroke or death or in the rate of major hemorrhage. Consequently, [the authors] regard both warfarin and aspirin as reasonable therapeutic alternatives.” Mohr et al. do not clearly distinguish between absence of evidence of an effect and evidence of absence of an effect. The primary null hypothesis was that there would be no difference between the treatments (as in an equivalence trial), yet the sample size was calculated according to a 30 percent difference between treatments (as in a nonequivalence trial). Equivalence trials are usually much larger than nonequivalence trials, and we believe that the study was underpowered.
The point estimate of the hazard ratio for the primary end point was 1.13, equivalent to an absolute excess of 21 recurrent ischemic strokes and deaths per 1000 patients treated with warfarin as compared with aspirin (95 percent confidence limits, 13 fewer to 61 more events per 1000 patients treated). Thus, the Warfarin–Aspirin Recurrent Stroke Study (WARSS) does not rule out the possibility of a clinically important disadvantage with warfarin as compared with aspirin. The conclusions in the Discussion section are fair and balanced and are in line with two recent systematic reviews.2,3 The final sentence reads, “Aspirin, either alone or in combination with some other antiplatelet agents, appears to be a well-justified choice for the prevention of recurrent ischemic stroke.” Aspirin is noted to be cheaper than warfarin and easier to administer. However, the conclusions drawn in the Abstract (the only ones many readers will read) are potentially misleading.
3 ReferencesStephanie C. Lewis, Ph.D.
Peter A.G. Sandercock, D.M.
University of Edinburgh, Edinburgh EH4 2XU, United Kingdom
steff.lewis@ed. ac. uk 1
Mohr JP ,Thompson JLP ,Lazar RM , et al. A comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. N Engl J Med 2001;345:1444-1451
Full Text | Web of Science | Medline2
Liu M, Counsell C, Sandercock P. Anticoagulants for preventing recurrence following ischaemic stroke or transient ischaemic attack. In: Cochrane database of systematic reviews. Issue 3. Oxford, England: Update Software, 2001 (computer data base).
3
Algra A, De Schryver ELLM, van Gijn J, Kappelle LJ, Koudstaal PJ. Oral anticoagulants versus antiplatelet therapy for preventing further vascular events after transient ischaemic attack or minor stroke of presumed arterial origin. In: Cochrane database of systematic reviews. Issue 4. Oxford, England: Update Software, 2001 (computer data base).
To the Editor:
The WARSS investigators should be commended for performing a well-organized, multicenter trial in the search for more efficacious drugs than those currently available for secondary prevention after cerebral ischemia of presumed arterial origin. The investigators may be disappointed that low-intensity anticoagulation (target international normalized ratio [INR], 1.4 to 2.8; achieved median, 1.9) tended not to be better than the current touchstone, aspirin (325 mg daily), in reducing the incidence of the primary outcome (ischemic stroke or death from any cause). We were disappointed when high-intensity anticoagulation (target INR, 3.0 to 4.5) turned out to cause major bleeding complications at an unacceptably high rate in the Stroke Prevention in Reversible Ischemia Trial (SPIRIT).1 Recently, we sought to determine the optimal level of anticoagulation in an observational study of 356 patients similar to those in WARSS and SPIRIT who were referred to the Red Cross Anticoagulation Clinic, Leiden, the Netherlands.2 During a two-year follow-up, 19 ischemic and 25 hemorrhagic events occurred. The optimal achieved INR was between 2.5 and 3.5. We therefore think that the interpretation offered by Powers in his editorial — that it is “unlikely” that “oral anticoagulant therapy at some target INR level intermediate between these two levels [those of WARSS and SPIRIT] will be superior to aspirin”3 — is premature.
3 ReferencesAle Algra, M.D.
University Medical Center Utrecht, 3508 GA Utrecht, the Netherlands
a.algra@neuro. azu. nl for the European–Australian Stroke Prevention in Reversible Ischemia Trial Study Group
1
The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group
CrossRef | Web of Science | Medline2
Torn M ,Algra A ,Rosendaal FR . Oral anticoagulation for cerebral ischemia of arterial origin: high initial bleeding risk. Neurology 2001;57:1993-1999
Web of Science | Medline3
Powers WJ . Oral anticoagulant therapy for the prevention of stroke. N Engl J Med 2001;345:1493-1495
Full Text | Web of Science | Medline
To the Editor:
Mohr and colleagues address an important clinical issue in their comparison of warfarin and aspirin for the prevention of recurrent ischemic stroke. The authors conclude that the efficacy and safety of warfarin and aspirin are similar in patients with inferred noncardioembolic ischemic stroke. However, they do not provide details about the status of the aorta on noninvasive imaging such as transesophageal echocardiography. Amarenco et al.1 used transesophageal echocardiography in their study of the prevalence of ulcerated aortic plaques in large numbers of patients with stroke. Ulcerated aortic plaques were present in 28 percent of the patients with a brain infarct and in 61 percent of those with no known cause of cerebral infarction. Cohen et al.2 pointed out that in patients with ischemic stroke, the risk of vascular events associated with an aortic-plaque thickness of 4 mm or more is markedly increased by the absence of plaque calcification. In another study, transesophageal echocardiography identified ulcerated atherosclerotic plaques in the thoracic aorta in 39 percent of patients with unexplained ischemic strokes.3 The mobility of the protruding plaques may have important therapeutic implications. Vaduganathan et al.4 compared findings of aortic plaques on transesophageal echocardiography with the results of pathological examination and showed that thrombi were present in all the samples with mobile aortic plaques. Antiplatelet and statin therapy should be advised as a first-line therapy in the majority of patients with stroke.
Transesophageal echocardiography, by identifying mobile aortic plaques, intracardiac thrombi, or certain intracardiac shunts, can help guide the choice of anticoagulation treatment in patients with cryptogenic ischemic stroke.
4 ReferencesDavid H. Hsi, M.D.
Darrick J. Alaimo, M.D.
Park Ridge Hospital, Rochester, NY 14626
dhsi@hospitals-doctors.com 1
Amarenco P ,Duyckaerts C ,Tzourio C ,Henin D ,Bousser M-G ,Hauw J-J . The prevalence of ulcerated plaques in the aortic arch in patients with stroke. N Engl J Med 1992;326:221-225
Full Text | Web of Science | Medline2
Cohen A ,Tzourio C ,Bertrand B , et al. Aortic plaque morphology and vascular events: a follow-up study in patients with ischemic stroke. Circulation 1997;96:3838-3841
Web of Science | Medline3
Stone DA ,Hawke MW ,LaMonte M , et al. Ulcerated atherosclerotic plaques in the thoracic aorta are associated with cryptogenic stroke: a multiplane transesophageal echocardiographic study. Am Heart J 1995;130:105-108
CrossRef | Web of Science | Medline4
Vaduganathan P ,Ewton A ,Nagueh SF ,Weilbaecher DG ,Safi HJ ,Zoghbi WA . Pathologic correlates of aortic plaques, thrombi and mobile “aortic debris“ imaged in vivo with transesophageal echocardiography. J Am Coll Cardiol 1997;30:357-363
CrossRef | Web of Science | Medline
To the Editor:
The WARSS investigators provide data about five groups defined according to the clinically inferred mechanism of stroke. Among these five groups, there was a group of 576 patients with cryptogenic stroke. In many patients (up to 50 percent) with cryptogenic stroke who are less than 55 years of age, the role of patent foramen ovale in the recurrence of thromboembolic events has been shown.1,2 It would be interesting to have information about the presence of patent foramen ovale in the patients with cryptogenic stroke in WARSS. In our series of patients with cryptogenic stroke who underwent percutaneous closure of patent foramen ovale and were followed for a median of 15 months (range, 1 to 50), 2 of 86 patients (2.3 percent) had recurrent ischemic stroke.3 This rate of recurrence is quite low when compared with rates of 15.0 percent and 16.5 percent — the rates in the patients in WARSS who had cryptogenic stroke (those who were given warfarin and those who were given aspirin, respectively).
3 ReferencesGianfranco Butera, M.D., Ph.D.
Massimo Chessa, M.D., Ph.D.
Mario Carminati, M.D.
Istituto Policlinico San Donato, 20097 San Donato Milanese, Italy
gianfra.but@lycos. com 1
Lechat P ,Mas JL ,Lascault G , et al. Prevalence of patent foramen ovale in patients with stroke. N Engl J Med 1988;318:1148-1152
Full Text | Web of Science | Medline2
Webster MW ,Chancellor AM ,Smith HJ , et al. Patent foramen ovale in young stroke patients. Lancet 1988;2:11-12
CrossRef | Web of Science | Medline3
Butera G ,Bini MR ,Chessa M ,Bedogni F ,Onofri M ,Carminati M . Transcatheter closure of patent foramen ovale in patients with cryptogenic stroke. Ital Heart J 2001;2:115-118
Medline
Author/Editor Response
The authors reply:
To the Editor: Algra's comments suggest that a test of higher INR ranges than those examined in our study might have shown a greater benefit with warfarin than with aspirin. Apart from our support of Powers's carefully chosen words in his editorial, we cite again concern about safety at this and higher ranges.1 Nonetheless, we would welcome the results of a randomized, double-blind trial in a sample of adequate size.
We doubt that “many” Journal devotees are mere slipshod scanners of abstracts, and we consider the usual reader already clear on the response we offer to Lewis and Sandercock: WARSS was designed as an efficacy trial, not an equivalency trial. It was designed to detect the same 30 percent difference that had been found in trials that compared warfarin and aspirin for atrial fibrillation, and it was not underpowered. The null hypothesis was not rejected (P=0.25). The overall result (hazard ratio, 1.13; 95 percent confidence interval, 0.92 to 1.38) favored aspirin somewhat, although there was only weak evidence (likelihood ratio, <2) in favor of the hypothesis that there actually is such a benefit, as compared with the hypothesis that there is no difference between aspirin and warfarin. In the Abstract we express our conclusion — that our equipoise remains undisturbed by the result (aspirin and warfarin are “reasonable therapeutic alternatives”). In the Discussion section we acknowledge, however, that “aspirin . . . appears to be a well-justified choice.” Both of these interpretations are legitimate, and there is room for debate over the clinical implications of the WARSS data. We did not, however, mistake “absence of evidence” for “evidence of absence.” This suggestion requires the ex post facto reinterpretation of WARSS as an equivalency trial, which is not a legitimate approach.
In response to Hsi and Alaimo and to Butera et al.: the Patent Cardiac Foramen Ovale in Cryptogenic Stroke Study (PICSS) is one of several substudies conducted in our cohort.2 The results of PICSS are currently under review for publication. PICSS may yield insights into the appropriate medical regimen for findings such as aortic-arch atheroma and valvular strands.
2 ReferencesJ.P. Mohr, M.D.
J.L.P. Thompson, Ph.D.
B. Levin, M.D.
Columbia Presbyterian Medical Center, New York, NY 10032
jpm10@columbia.edu for the Warfarin–Aspirin Recurrent Stroke Study Group
1
Yamaguchi T . Optimal intensity of warfarin therapy for secondary prevention of stroke in patients with nonvalvular atrial fibrillation: a multicenter, prospective, randomized trial. Stroke 2000;31:817-821
CrossRef | Web of Science | Medline2
The WARSS, APASS, PICSS, HAS, and GENESIS Study Groups
CrossRef | Web of Science
Author/Editor Response
The editorialist replies:
To the Editor: Algra disagrees with my conclusion that oral anticoagulation at an INR level between those studied in WARSS and SPIRIT1 is unlikely to be superior to aspirin for the prevention of recurrent noncardioembolic stroke. He cites as evidence a recent study of patients undergoing oral anticoagulation for cerebral ischemia in which an INR between 2.5 and 3.5 was “optimal.”2 This study analyzed the total occurrence of both hemorrhagic and thromboembolic events in these patients. The incidence of thromboembolism was actually lowest at an INR between 3.0 and 3.9, and the risk of hemorrhage was lowest within this INR range as well. It was not a randomized trial, so there was no control group receiving antiplatelet treatment for comparison. Thus, although it can be concluded from this study that an INR between 3.0 and 3.9 may be the optimal level of oral anticoagulation, no conclusion regarding the superiority of this approach over antiplatelet treatment can be made.
On the other hand, both WARSS and SPIRIT1 are randomized, controlled trials. Neither provides evidence that oral anticoagulation offers a benefit with respect to thromboembolic events. Given the lack of benefit in SPIRIT in the prevention of thromboembolic events with oral anticoagulation at an INR between 3.0 and 4.5, it is difficult to see how reducing the INR to a lower level would provide better protection, even if adverse hemorrhagic events are ignored. However, as I point out in my editorial, the confidence intervals in SPIRIT are too wide to rule out such a benefit. As long as the data are not definitive, it is ethical and proper to conduct a clinical trial such as the European–Australian Stroke Prevention in Reversible Ischemia Trial. In the meantime, extrapolations based on the available data, albeit less than perfect, must be made to guide patient care. It is my conclusion that the best available evidence at this time does not support the use of oral anticoagulation at any INR as a general strategy to prevent recurrent noncardioembolic stroke.
2 ReferencesWilliam J. Powers, M.D.
Washington University School of Medicine, St. Louis, MO 63110
wjp@npg.wustl. edu 1
The Stroke Prevention in Reversible Ischemia Trial (SPIRIT) Study Group
CrossRef | Web of Science | Medline2
Torn M ,Algra A ,Rosendaal FR . Oral anticoagulation for cerebral ischemia of arterial origin: high initial bleeding risk. Neurology 2001;57:1993-1999
Web of Science | Medline
- Citing Articles (1)
Citing Articles
1
Christine Lu-Emerson, David Likosky, Alpesh Amin, David Tirschwell. (2010) Management of ischemic stroke: Part 2. The inpatient stay. Journal of Hospital Medicine 5:2, 88-93
CrossRef
