Sent 7/3/07      R Saxena, PJ Koudstaal. Anticoagulants for preventing stroke in patients with nonrheumatic atrial fibrillation and a history of stroke or transient ischaemic attack. Cochrane Database of Systematic Reviews 2004, Issue 2. Art. No.: CD000185.pub2. DOI: 10.1002/14651858. (Stroke)

 

The authors’ concluded, “The evidence suggests that anticoagulants are beneficial, without serious adverse effects, for people with NRAF and recent cerebral ischaemia.” These conclusions are not justified by the evidence. The two randomized controlled trials (RCTs) of warfarin as secondary stroke prevention for patients with non rheumatic atrial fibrillation (NRAF) are too small and follow-up times are too short to prove safety or efficacy of vitamin K inhibitors for this indication for patients in general clinical practice.

 

Safety of vitamin k inhibitors for NRAF patients with a history of stroke or TIA

 

The frequency of anticoagulant associated intracerebral haemorrhage (AAICH) has increased by seven fold in UK between 1981 and 2006.1 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).2 Using the data to extrapolate to 2004, Flaherty estimated the rate of AAICH at 5.1 – 6.5 / 100,000. From 1988 to 1999, the dispensation of warfarin in the USA increased 4.4-fold. In 1999 of those with AAICH in Cincinnatti, 48% had atrial fibrillation.3 In the USA, this translates into over 6,300 patients with AF who suffered AAICH in 1999 and at least 7,300 in 2004.

 

Compared with observational studies, RCTs tend to report lower risks of complications because of selection of patients entering the trials and closer monitoring by research investigators. In the EAFT (90.5% of the patients in this review), age limits for entry into the trial were left to the discretion of each randomising physician, and age was the most common reason for not entering a patient into the trial (55% of those excluded). In contrast, a series of consecutive patients over 65 years old started on warfarin for atrial fibrillation (32% of patients over 80 years old) reported higher rates of bleeding complications: 7.2% / year major bleeding, 2.5% / year of intracerebral bleeding and 0.8% / year of fatal bleeding.4

 

In the two trials in this Cochrane Review, 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.5 Accordingly, although neither of these trials with careful patient selection had an intracerebral bleed (i.e., for the 500+ subject-years of follow-up on anticoagulants), about 12 such bleeds would be expected in a in general practice setting with similar number of patient-years on anticoagulants.4 

 

Vitamin k inhibitors in this patient population do have serious adverse effects.

 

Efficacy of vitamin k inhibitors

 

These trials involved far too few subjects to determine whether the efficacy of warfarin for secondary prevention of stroke and arterial emboli depends on the age of the patient. However, in a meta-analysis of 4,052 NRAF subjects receiving oral anticoagulants (primary prevention), age was a factor in the efficacy in preventing vascular events (patients < 75 years old: 62% reduction versus patients >/= 75 years old: 37% reduction, P< 0.08).

 

Strokes and arterial emboli due to rebound hypercoagulability from discontinuing warfarin6, 7 was not taken into consideration in these short-term trials (2.3 years and 1.7 year duration). Comparing the venous thromboembolism recurrence incidences in the first two months after discontinuing warfarin with the subsequent recurrence rate per two months,7 previous studies have documented rates of 7.0% dropping to 1.0%,8 8.6% dropping to 0.73%,9 and 4.3% falling to 0.47%.10

 

In people at high risk for stroke, rebound hypercoagulability causing more strokes after discontinuing vitamin k inhibitors has not been ruled out. Since warfarin will probably be stopped at some point for most people with NRAF and previous cerebral ischemia, a true measurement of prevention of strokes and other thromboses must include data on at least the first two months after discontinuation of anticoagulation for most of the subjects in the study. With an average of about 2 years on study, RCTs involving vitamin k inhibitors for NRAF patients report rates of permanent discontinuation from warfarin of 38%,11 10%,12 26%,13 32%,14 and 25%.15 The very high rate of warfarin discontinuation in patients with atrial fibrillation makes evaluating rebound hypercoagulation require studies with at least 4-6 years of follow up. Until a longer study is done, it should be assumed that rebound hypercoagulability will reduce the long-term efficacy of vitamin k inhibitors in preventing strokes and arterial emboli.

 

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. The trials in this review did not document the number of TIA and mild stroke patients with NRAF evaluated in the participating institutions while these two trials were accruing their 485 subjects. The study patient accrual rate would probably be no more than the low rate of accrual of subjects to the primary stroke prevention RCTs of NRAF patients (3-40%).11-13, 16, 17

 

Accordingly, the net benefit in recurrent stroke and arterial emboli reduction in these RCTs, run by experienced researchers with carefully selected relatively young subjects, probably will not translate into significant benefit in general medical practice. Vitamin k antagonists are not evidence-based to be safe or effective in unselected patients with AF and a history of cerebral ischemia. In general medical practice, their high risk of intracerebral and extracerebral bleeding is not offset by any proof of efficacy in reducing mortality or dependency. 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.18, 19

 

Peter J. Koudstaal, MD also participated in the International Stroke Trial.19

 

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2.         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.

3.         Flaherty ML, Haverbusch M, Sekar P, et al. Location and Outcome of Anticoagulant-Associated Intracerebral Hemorrhage. Neurocrit. Care. 2006;5:197–201.

4.         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.

5.         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.

6.         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.

7.         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.

8.         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.

9.         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.

10.       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.

11.       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.

12.       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.

13.       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.

14.       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.

15.       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.

16.       Stroke Prevention in Atrial Fibrillation Study. Final results. Circulation. 1991;84(2):527-539.

17.       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.

18.       UK Stroke Association. Available at: http://www.stroke.org.uk/fundraising/company_support/corporate_2.html. Accessed January 17, 2007.

19.       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.