Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Warfarin was not more effective than aspirin and increased adverse events in symptomatic intracranial arterial stenosis

PDF

ACP J Club. 2005 Sep-Oct;143:32. doi:10.7326/ACPJC-2005-143-2-032

Related Content in this Issue
• Companion Abstract and Commentary: Low-dose aspirin lowered stroke risk but not risks for MI or cardiovascular deaths in women


Clinical Impact Ratings

GIM/FP/GP: 6 stars

Hematol/Thrombo: 6 stars

Neurology: 6 stars


Source Citation

Chimowitz MI, Lynn MJ, Howlett-Smith H, et al. Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med. 2005;352:1305-16. [PubMed ID: 15800226]


Abstract

Question

In patients with symptomatic intracranial arterial stenosis, how does aspirin compare with warfarin?

Methods

Design: Randomized controlled trial (Warfarin-Aspirin Symptomatic Intracranial Disease [WASID] Trial).

Allocation: Concealed.*

Blinding: Blinded (patients and outcome assessors).*

Follow-up period: Mean 1.8 years.

Setting: 59 sites in North America.

Patients: 569 patients ≥ 40 years of age (mean age 64 y, 61.5% men) with transient ischemic attack or nondisabling stroke in the previous 90 days caused by angiographically verified 50% to 99% stenosis of a major intracranial artery and a modified Rankin score ≤ 3. Exclusion criteria included tandem 50% to 99% stenosis of the extracranial carotid artery, nonatherosclerotic stenosis of an intracranial artery, and a cardiac source of embolism.

Intervention: Aspirin, 1300 mg/d (n = 280), or warfarin, 5 mg/d initial dose, which was adjusted to achieve an international normalized ratio (INR) target range of 2.0 to 3.0 (n = 289).

Outcomes: Primary composite endpoint of ischemic stroke, brain hemorrhage, and death from vascular causes other than stroke; and adverse events.

Patient follow-up: 98% (intention-to-treat analysis).

Main results

Aspirin and warfarin did not differ for the primary composite endpoint or for death from vascular or nonvascular causes (Table). Warfarin was associated with higher rates of all-cause death, major hemorrhage, and myocardial infarction or sudden death than aspirin (Table).

Conclusion

In patients with symptomatic intracranial arterial stenosis, warfarin was not more effective than aspirin and increased the rates of all-cause death, major hemorrhage, and myocardial infarction or sudden death.

*See Glossary.

Sources of funding: National Institutes of Health; Bristol-Myers Squibb; Bayer.

For correspondence: Dr. M.I. Chimowitz, Emory University, Atlanta, GA, USA. E-mail mchimow@emory.edu.


Table. Aspirin vs warfarin for symptomatic intracranial arterial stenosis at mean 1.8 years†

Outcomes Aspirin Warfarin HR (95% CI) RRI (CI) NNH
Primary composite endpoint‡ 22.1% 21.8% 1.04 (0.73 to 1.48) 4% (−25 to 40) Not significant
RRR (CI) NNT (CI)
All-cause death 4.3% 9.7% 0.46 (0.23 to 0.90) 53% (10 to 76) 20 (14 to 108)
Death from vascular causes 3.2% 5.9% 0.56 (0.25 to 1.26) 43% (−25 to 74) Not significant
Death from nonvascular causes 1.1% 3.8% 0.30 (0.08 to 1.07) 70% (−7 to 92) Not significant
Major hemorrhage 3.2% 8.3% 0.39 (0.18 to 0.84) 60% (15 to 81) 18 (13 to 67)
Myocardial infarction or sudden death 2.9% 7.3% 0.40 (0.18 to 0.91) 59% (9 to 81) 24 (17 to 158)

†HR = hazard ratio. Other abbreviations defined in Glossary; NNT and CI calculated from data in article.
‡Primary composite endpoint = ischemic stroke, brain hemorrhage, and death from vascular causes other than stroke.


Commentary

Uncertainty has existed on whether aspirin or warfarin should be the preferred antithrombotic in selected patients at high risk for noncardioembolic stroke, and whether aspirin is effective and safe for primary prevention of cardiovascular disease in women.

The WASID trial did not show any difference in efficacy between warfarin (target INR 2.0 to 3.0) and aspirin for preventing stroke or nonstroke vascular death in patients with symptomatic major intracranial artery stenosis. However, the study had to be stopped early because of evidence of harm with warfarin.

The high incidence of bleeding in patients treated with warfarin (5/100 patient-y) is surprising. This may be due to the broad definition of major bleeding. The high dose of aspirin used in this study (1300 mg/d) may have selectively increased bleeding in patients treated with aspirin (1), reducing the difference between the 2 treatments. Nevertheless, a clear excess of bleeding with warfarin remained evident. The increased all-cause mortality with warfarin compared with aspirin is unexplained. Previous randomized trials suggest that moderate-intensity warfarin (INR 2.0 to 3.0) is at least as effective as aspirin for preventing major vascular events (2). Yet, warfarin in the WASID trial was associated with a consistent pattern of excess deaths from both vascular and nonvascular causes, including myocardial infarction, sudden death, and cancer. This is unlikely to be explained by the efficacy of high-dose aspirin because, unlike safety, no convincing evidence exists to suggest that the efficacy of aspirin is dose-related (1, 3). The optimal dose of aspirin is less clear from these data but, when considered in the context of what we already know, a strong argument can be made to use the lowest proven effective dose (75 to 150 mg/d), thereby minimizing the risk for bleeding complications.

In 2002, the U.S. Preventive Services Task Force concluded that good evidence existed to suggest that aspirin lowers the incidence of coronary artery disease in adults without previous symptomatic cardiovascular disease (4). This conclusion was based on a review of 5 randomized trials involving > 50 000 persons. However, aspirin did not reduce stroke and the evidence was less clear for women because only 20% of trial participants were women.

The Women's Health Study randomized almost 40 000 initially healthy women. In contrast to previous trials, aspirin did not reduce myocardial infarction or death but lowered the incidence for ischemic stroke and transient ischemic attack. These benefits were partly counterbalanced by an increase in gastrointestinal ulcers and bleeding, highlighting the potential for toxicity even if low doses of aspirin are taken every other day, and the importance of balancing risks and benefits when making decisions about the use of aspirin for primary prevention of cardiovascular disease.

Controversy concerning apparent sex differences in the antiplatelet effects of aspirin is not new. Subgroup analyses from early randomized aspirin trials suggested that men, but not women, benefited from aspirin (5, 6); later, large trials and systematic reviews (3) confirmed a benefit for both. In the Women's Health Study, the low event rates and use of a potentially suboptimal aspirin dose may have contributed to the apparent lack of benefit of aspirin for preventing myocardial infarction. However, lack of evidence of benefit is not the same as evidence of lack of benefit; the 95% CI of the risk estimates do not exclude a 16% reduction in myocardial infarction or a 20% reduction in major cardiovascular events with aspirin treatment. Nevertheless, if a benefit exists, it is small in absolute terms.

John W. Eikelboom, MD
McMaster University
Hamilton, Ontario, Canada


References

1. Patrono C, Coller B, FitzGerald GA, Hirsh J, Roth G. Platelet-active drugs: the relationships among dose, effectiveness, and side effects: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest. 2004;126:234S-64S. [PubMed ID: 15383474]

2. Anand SS, Yusuf S. Oral anticoagulant therapy in patients with coronary artery disease: a meta-analysis. JAMA. 1999;282:2058-67. [PubMed ID: 10591389]

3. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324:71-86. [PubMed ID: 11786451]

4. U.S. Preventive Services Task Force. Aspirin for the primary prevention of cardiovascular events: recommendation and rationale. Ann Intern Med. 2002;136:157-60. [PubMed ID: 11790071]

5. The Canadian Cooperative Study Group. A randomized trial of aspirin and sulfinpyrazone in threatened stroke. N Engl J Med. 1978;299:53-9. [PubMed ID: 351394]

6. Harris WH, Salzman EW, Athanasoulis CA, Waltman AC, DeSanctis RW. Aspirin prophylaxis of venous thromboembolism after total hip replacement. N Engl J Med. 1977;297:1246-9. [PubMed ID: 335247]