|The following Consensus Statement was adopted by the 6th Karolinska Stroke Update meeting on
November 13, 2006.
The consensus statement was proposed by the chairperson in the
session, Professor Anna Czlonkowska, Stockholm, the session secretary dr Mia von Euler, Stockholm, together with the speakers in the session. The statement was
then finally approved by the participants of the meeting, after
listening to the different presentations.
The speakers in this session
were Professor Ale Algra, Utrecht, Professor Natan Bornstein, Tel Aviv, Professor Gudrun Boysen, Copenhagen and Professor Werner Hacke, Heidelberg
Questions for the 2006 consensus session:
Is there sufficient evidence to support a recommendation of combined aspirin and dipyridamole as first choice antiplatelet therapy after stroke and TI
Which aspirin dose would be appropriate?
Which conclusion can be made on combined use of aspirin and clopidogrel as antiplatelet therapy after stroke and TIA?
Aspirin and dipyridamole
The evidence for the combination therapy of aspirin and dipyridamole is supported by the recently published ESPRIT trial (1) confirming the results of the ESPS 2 trial (2). A meta-analysis including all trials in patients with stroke and TIA, demonstrated a risk ratio of 0.82 (0.74 – 0.91) for the combination of aspirin and dipyridamole versus aspirin alone (1). ESPRIT was an open trial in which the dose of dipyridamole was 200 mg twice daily. The dose of aspirin varied from 30 to 325 mg daily with a median dose of 75 mg daily. The vast majority of the patients used extended release dipyridamole (only 17% was treated with regular dipyridamole) (1). Based on the studies (1-2) there is grade A evidence for the combination therapy of aspirin and dipyridamole to be more efficacious than aspirin mono-therapy. We recommend it to be used as a first choice in patients with TIA or ischaemic stroke of arterial origin.
Cost-effectiveness has been shown for the population studied in the ESPS 2 study (i.e. TIA and not disabling stroke) (3). However, this is Grade B evidence and more studies of cost-effectiveness in the entire stroke population are needed.
Which aspirin dose would be appropriate?
For stroke prevention, aspirin doses of 50 mg and above, have been shown to be effective (4). (Grade A evidence) For patients with concomitant coronary disease a higher dose of at least 75 mg is recommended (4). (Grade A evidence)
Clopidogrel versus aspirin
Clopidogrel has been shown to have a modest but statistically significant better effect than aspirin in preventing vascular events. (Grade A evidence) Up to now, there is no direct comparison between clopidogrel and aspirin + dipyridamole in stroke patients. The PRoFESS trial will address this question.
Clopidogrel and aspirin
Based on the results from the MATCH and CHARISMA studies (5-6) the combination of clopidogrel and aspirin cannot be recommended for long-term use in patients with stroke or TIA due to lack of efficacy on primary end-points and the increased risk of bleeding. (Grade A evidence)
The combination seems to have a somewhat stronger antithrombotic effect than aspirin or clopidogrel alone, but the risk of severe bleeding is increased. There may be a period of about 3 months where the combination of clopidogrel and aspirin can be given safely especially in conditions such as severe carotid stenosis with evidence of micro-emboli (CARESS) (7) and after carotid stenting (8). (Grade B evidence).
For patients who can tolerate neither aspirin nor clopidogrel, dipyridamole can be considered.
- The ESPRIT Study Group; Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet. 2006;367(9523):1665-73.
- Diener HC, Cunha I, Forbes C, Sivenius J, Smets P, Lowenthal A. European
Stroke prevention Study 2: dipyridamole and acetylsalicylic acid in the
secondary prevention of stroke. J Neurol Sci 1996;143:1-13.
- Jones L, Griffin S, Palmer S, Main C, Orton V, Sculpher M, Sudlow C, Henderson R, Hawkins N, Riemsma R. Clinical effectiveness and cost-effectiveness of clopidogrel and modified-release dipyridamole in the secondary prevention of occlusive vascular events: a systematic review and economic evaluation. Health Technol Assess. 2004;8(38): 1-196.
- 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(7329):71-86.
- Diener HC, Bogousslavsky J, Brass LM, Cimminiello C, Csiba L, Kaste M, Leys D, Matias-Guiu J, Rupprecht HJ; MATCH investigators. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364(9431):331-7.
- Bhatt DL, Fox KA, Hacke W, Berger PB, Black HR, Boden WE, Cacoub P, Cohen EA, Creager MA, Easton JD, Flather MD, Haffner SM, Hamm CW, Hankey GJ, Johnston SC, Mak KH, Mas JL, Montalescot G, Pearson TA, Steg PG, Steinhubl SR, Weber MA, Brennan DM, Fabry-Ribaudo L, Booth J, Topol EJ; CHARISMA Investigators. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354(16):1706-17.
- Markus HS, Droste DW, Kaps M, Larrue V, Lees KR, Siebler M, Ringelstein EB. Dual antiplatelet therapy with clopidogrel and aspirin in symptomatic carotid stenosis evaluated using Doppler embolic signal detection: the Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic Carotid Stenosis (CARESS) trial. Circulation. 2005;111(17):2233-40.
- McKevitt FM, Randall MS, Cleveland TJ, Gaines PA, Tan KT, Venables GS. The benefits of combined anti-platelet treatment in carotid artery stenting.
Eur J Vasc Endovasc Surg. 2005;29(5):522-7.