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Anticoagulants versus antiplatelet therapy for preventing stroke in patients with nonrheumatic atrial fibrillation and a history of stroke or transient ischemic attack
R Saxena, PJ Koudstaal
DOI:10.1002/14651858.CD000187.pub2
Date received: September 13, 2007
Cite this comment as: http://www.cochranefeedback.com/cf/cda/citation.do?id=9710#9710
These two randomized controlled trials (RCTs) of warfarin as secondary stroke prevention for patients with non rheumatic atrial fibrillation (NRAF) are too small (1,962 patient-years of follow-up) and follow-up times are too short (2.3 years and 1 year) to prove safety and efficacy of vitamin K inhibitors for this indication for patients in general clinical practice.
Risks of warfarin versus antiplatelet agents
The EAFT data showed that an age over 75 years was associated with a higher risk of major bleeding (RR: 3.6, 95 % CI 1.0 to 13) independently of the therapeutic intensity of anticoagulation.1 In these two small trials, less than 30% of the subjects were over 75 years old. However, in clinical practice, stroke patients will be significantly older, on average, than these research subjects. For instance, in the USA, about 20% of men and about 50% of women who die of stroke are > 85 years old.2
Accordingly, although the risk of all intracranial bleeding per year was 4/971 (0.4%) in these small trials with selected, relatively young subjects, it would be expected to be about 2.5% per year in a general clinical practice based on a large observational study3 (i.e., for the 971 subject-years of follow-up on anticoagulants for these two trials, about 24 intracranial bleeds expected in a general practice setting).
Population-based studies are in accordance with observational reports in confirming higher bleeding risks from vitamin k inhibitors that reflected in these eight RCTs. In the greater Cincinnatti, Ohio area from 1988 to 1999, Flaherty and colleagues found the annual incidence of AAICH increased 5.5-fold (from 0.8 / 100,000 to 4.4 / 100,000) while the incidence of cardioembolic ischemic stroke did not change (1993/1994 versus 1999: 31.1 / 100,000 vs 30.4 /100,000, p = 0.65).4 In the USA from 1988 to 1999, the dispensation of warfarin increased 4.4-fold4 and, from 1998 to 2004, the number of dispensed outpatient prescriptions for warfarin increased from 21 million to nearly 31 million.5 In 1999 of those afflicted with anticoagulation-associated intracerebral haemorrhage (AAICH) in Cincinnatti, 48% had atrial fibrillation.6 In the USA, this translates into over 6,300 patients with AF suffering AAICH in 1999 and about 8,600 in 2004. A similar increase in AAICH has been documented in the UK. In Oxfordshire between 1981 and 2002 – 2006, the frequency of anticoagulation associated intracerebral haemorrhage (AAICH) has increased from 0 / 87,861 to 7 / 91,108 (1.9 / 100,000 / year).7
Despite highly screened patients and close follow-up plans, the SIFA researchers lost 7/454 (1.5%) warfarin treated patients to follow-up after giving them the initial prescription for the anticoagulant. Some of these subjects may have also suffered serious bleeding. The EAFT investigators did not report those lost to follow-up after receiving the initial warfarin prescription. Landefeld and Goldman found that the major bleeding risk with warfarin falls is particularly high in the first month (3% of patients in the first month, dropping to 0.3% per month after the first year).8
Both trials excluded patients with “uncontrolled” hypertension, but only the EAFT gave a specific cut-off point (diastolic greater than 100 or systolic greater than 180 mmHg). This review did not document what proportion of potential subjects were rejected because of high blood pressure. However, particularly in the EAFT, it may have been very high, since the vast majority of 60 – 80 year old people who have had strokes would also have significant hypertension. In the “implications for practice” section, no mention was made about not treating people with diastolic BP > 100 or systolic BP > 180.
Efficacy of warfarin
These trials involved far too few subjects to determine whether the efficacy of warfarin depended on the age of the patient. However, in a meta-analysis of 4,052 NRAF subjects receiving oral anticoagulants, age was a factor in the efficacy in preventing vascular events (patients < 75 years old: 62% reduction versus patient >/= 75 years old: 37% reduction, P< 0.08). Accordingly, the reduction in strokes in these small RCTs run by experienced researchers with relatively young subjects probably will not translate into stroke reduction in general medical practice.
The primary efficacy endpoints, odds of recurrent strokes and odds of all vascular events, did not weigh the clinical significance of the events. An important missing comparison is the number of fatal or disabling vascular events, excluding the mild and reversible ischemic strokes. For instance in the SIFA RCT, the frequency of minor strokes differed (six with indobufen versus one with warfarin) but not the rate of major or fatal strokes (17 in each group).
Rebound hypercoagulability from discontinuing warfarin9-12 was not taken into consideration in these short-term trials. Comparing the venous thromboembolism recurrence rate in the first two months after discontinuing warfarin with the subsequent recurrence rate per two months,10 previous studies have documented 7.0% dropping to 1.0%,13 8.6% dropping to 0.73%,14 and 4.3% falling to 0.47%.15 Since warfarin will probably be stopped at some point for most people with NRAF and previous strokes, a true measurement of prevention of thrombosis must include data on at least the first two months after discontinuation of anticoagulation for thousands of subjects.
A conservative estimate of the frequency of discontinuation of warfarin in this patient population (secondary prevention of ischemic stroke) can be gleaned from the warfarin discontinuation rate in the much larger RCTs of oral anticoagulation for primary prevention of stroke in subjects with NRAF (follow up periods of 1.3-2.3 years, averaging about two years): 38%,16 26%,17 10%,18 32%,19 and 25%.20 At these rates of discontinuing warfarin, after 4-5 years most patient will discontinue and be subject to rebound hypercoagulation.
The generalizability of a RCT finding of efficacy of a treatment depends in considerable part on the proportion of the subjects in the participating institutions eligible for the trial who actually enroll in the study. This review does not document the number of eligible TIA and mild stroke patients treated in the participating institutions while these two trials were accruing their 1,371 subjects. The study patient accrual rate would probably be less than the rate of accrual of subjects to the primary stroke prevention RCTs of NRAF patients (3-40%).16-18, 21, 22
Summary
In these two small secondary prevention RCTs with short follow-up periods, given the unknown but presumably high rate of discontinuation of warfarin, the undocumented events due to rebound hypercoagulation after the discontinuation of the anticoagulant, the absence of data comparing frequencies of fatal and disabling strokes, and the unreported rate of exclusion of subjects due to hypertension, nothing is proven about the efficacy of warfarin as secondary prevention of stroke in patients with NRAF. The authors' conclusions in this review, “These data support the routine use of oral anticoagulants in patients with NRAF and a recent non-disabling stroke or TIA” are not justified. Vitamin K antagonists are not evidence-based to be safe or effective in this population. They should not be used.
Undisclosed Financial Conflict of Interest
Ritu Saxena, MD was on the Steering Committee of the International Stroke Trial. Its sponsors include the UK Stroke Foundation which is funded by Astra Zeneca, Boehringer, Bristol-Myers-Squibb, Ingleheim, Sanofi-Synthelabo, Merck Sharp Dohme, and Pfizer.23, 24
Peter J. Koudstaal, MD also participated in the International Stroke Trial.24
1. Optimal Oral Anticoagulant Therapy in Patients with Nonrheumatic Atrial Fibrillation and Recent Cerebral Ischemia. The European Atrial Fibrillation Trial Study Group. N Engl J Med. 1995;333(1):5-10.
2. Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics--2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2007;115(5):e69-171.
3. Hylek EM, Evans-Molina C, Shea C, Henault LE, Regan S. Major Hemorrhage and Tolerability of Warfarin in the First Year of Therapy Among Elderly Patients With Atrial Fibrillation. 10.1161/CIRCULATIONAHA.106.653048. Circulation. May 29, 2007;115(21):2689-2696.
4. Flaherty ML, Kissela B, Woo D, et al. The increasing incidence of anticoagulant-associated intracerebral hemorrhage. 10.1212/01.wnl.0000250340.05202.8b. Neurology. January 9, 2007;68(2):116-121.
5. Wysowski DK, Nourjah P, Swartz L. Bleeding Complications With Warfarin Use: A Prevalent Adverse Effect Resulting in Regulatory Action. 10.1001/archinte.167.13.1414. Arch Intern Med. July 9, 2007;167(13):1414-1419.
6. Flaherty ML, Haverbusch M, Sekar P, et al. Location and Outcome of Anticoagulant-Associated Intracerebral Hemorrhage. Neurocrit. Care. 2006;5:197–201.
7. Lovelock CE, Molyneux AJ, Rothwell PM. Change in incidence and aetiology of intracerebral haemorrhage in Oxfordshire, UK, between 1981 and 2006: a population-based study. (the Oxford Vascular Study) DOI:10.1016/S1474-4422(07)70107-2. Lancet Neurology. May 1, 2007.
8. Landefeld CS, Goldman L. Major bleeding in outpatients treated with warfarin: incidence and prediction by factors known at the start of outpatient therapy. American Journal of Medicine. 1989;87(2):144-152.
9. Palareti G, Legnani C, Guazzaloca G, et al. Activation of blood coagulation after abrupt or stepwise withdrawal of oral anticoagulants--a prospective study. Thromb Haemost. 1994;72(2):222-226.
10. Cundiff DK. Commentary - Insufficient Evidence Supporting Low-Intensity Warfarin for Venous Thromboembolism (VTE) Prophylaxis. Medscape General Medicine™. 07/02/2003;http://www.medscape.com/viewarticle/457570.
11. Ascani A, Iorio A, Agnelli G. Withdrawal of warfarin after deep vein thrombosis: effects of a low fixed dose on rebound thrombin generation. Blood Coagul Fibrinolysis. 1999;10(5):291-295.
12. Sise HS, Moschos CB, Gauthier J, Becker R. The Risk of Interrupting Long-Term Anticoagulant Treatment: A Rebound Hypercoagulable State Following Hemorrhage. Circulation. November 1, 1961;24(5):1137-1142.
13. Schulman S, Rhedin AS, Lindmarker P, et al. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. Duration of Anticoagulation Trial Study Group. New Engl J Medicine. 1995;332(25):1661-1665.
14. Levine MN, Hirsh J, Gent M, et al. Optimal duration of oral anticoagulant therapy: a randomized trial comparing four weeks with three months of warfarin in patients with proximal deep vein thrombosis. Thrombosis & Haemostasis. 1995;74(2):606-611.
15. Ridker PM, Goldhaber SZ, Danielson E, et al. Long-Term, Low-Intensity Warfarin Therapy for the Prevention of Recurrent Venous Thromboembolism. N Engl J Med. February 24, 2003;348(15):1425-1434. Available at: http://content.nejm.org/cgi/content/abstract/1348/1415/1425.
16. Petersen P, Boysen G, Godtfredsen J, Andersen ED, Andersen B. Placebo-controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study. Lancet. 1989;1(8631):175-179.
17. Connolly SJ, Laupacis A, Gent M, Roberts RS, Cairns JA, Joyner C. Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. J Am Coll Cardiol. 1991;18(2):349-355.
18. The effect of low-dose warfarin on the risk of stroke in patients with non-rheumatic atrial fibrillation. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. N Engl J Med. 1990;323(22):1505-1511.
19. Hellemons BS, Langenberg M, Lodder J, et al. Primary prevention of arterial thromboembolism in non-rheumatic atrial fibrillation in primary care: randomised controlled trial comparing two intensities of coumarin with aspirin. BMJ. 1999;319(7215):958-964.
20. Gullov AL, Koefoed BG, Petersen P. Bleeding during warfarin and aspirin therapy in patients with atrial fibrillation: the AFASAK 2 study. Atrial Fibrillation Aspirin and Anticoagulation. Arch Intern Med. 1999;159(12):1322-1328.
21. Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation. 1991;84(2):527-539.
22. Ezekowitz MD, Bridgers SL, James KE, et al. Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. N Engl J Med. 1992;327(20):1406-1412.
23. UK Stroke Association. Available at: http://www.stroke.org.uk/fundraising/company_support/corporate_2.html. Accessed January 17, 2007.
24. Saxena R, Lewis S, Berge E, Sandercock PAG, Koudstaal PJ. Risk of Early Death and Recurrent Stroke and Effect of Heparin in 3169 Patients With Acute Ischemic Stroke and Atrial Fibrillation in the International Stroke Trial. 10.1161/hs1001.097093. Stroke. October 1, 2001;32(10):2333-2337.