Feedback from David K. Cundiff, MD

 

Sent 6/25/07 updated 8-19-07             E Berge, P Sandercock. Anticoagulants versus antiplatelet agents for acute ischaemic stroke. Cochrane Database of Systematic Reviews. 2002(Issue 4):Art. No.: CD003242. DOI: 003210.001002/14651858.CD14003242 (Stroke)

The justification for calling for further large-scale RCTs with low dose heparin and aspirin or low dose heparin alone versus aspirin comes from subgroup analyses of death at the end of the treatment: “Compared with aspirin alone, the combination of low-dose UFH and aspirin was associated with a marginally significant reduced risk of 'any recurrent stroke' and a marginally significant reduced risk of death at 14 days.” A possible cause for the favorable non-significant trend in these outcomes with low dose heparin and aspirin during treatment only is rebound hypercoagulability causing increased adverse events after the 14th day. Rebound hypercoagulability clearly occurs on withdrawal of warfarin1, 2 and has been considered with an heparinoid (Lomoparan (Org 10172).3 Clinically significant rebound hypercoagulability due to heparin or LMWHs has not been ruled out.

Given the absence of benefit with low dose heparin added to aspirin, the safety of this combination raises concerns about the recommendation of conducting further research with anticoagulants. The authors correctly point out that there was not a statistically significant increase in major extracranial or intracranial hemorrhage (OR: 1.82 (0.87-3.81) and 1.46 (0.72 – 2.97), respectively). However, when these two categories of major hemorrhage are combined, there is a borderline statistically significant increase in major bleeding (OR: 1.63 (0.98 – 2.72), P< 0.06), which represents 6.2 (95% CI: 0.1 – 16.8) additional major bleeds per 1000 patients by adding the low dose heparin. Risk of bleeding in clinical practice is probably greater than in closely monitored RCTs.

The review should be updated to reflect the status of the ongoing studies as of 2002. One of the co-authors of this review, Dr. Sandercock, was an author of the RAPID RCT, published in 2005.4 Asian stroke patients reported by Wong and colleagues had no benefit with LMWH over aspirin.5

 

Since adding low dose heparin to aspirin does not improve clinical outcomes at the end of followup and does add to the bleeding risk, the implications for research should say that further trials of any anticoagulants in acute ischemic stroke would be unethical and any ongoing such studies should be stopped.

1.       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.

2.       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.

3.       Hoek JA, Nurmohamed MT, Hamelynck KJ, et al. Prevention of deep vein thrombosis following total hip replacement by low molecular weight heparinoid. Thrombosis & Haemostasis. 1992;67(1):28-32.

4.       Chamorro A, Busse O, Obach V, et al. The rapid anticoagulation prevents ischemic damage study in acute stroke--final results from the writing committee. Cerebrovasc Dis. 2005;19(6):402-404.

5.       Wong KS, Chen C, Ng PW, et al. Low-molecular-weight heparin compared with aspirin for the treatment of acute ischaemic stroke in Asian patients with large artery occlusive disease: a randomised study. Lancet Neurol. 2007;6(5):407-413.