The Consensus Statement includes two parts, the Consensus Statement itself, and the Recommendation to the European Stroke Organisation (ESO) on revision of ESO Guidelines. Please note that the final text of the Guidelines, is decided by ESO and that the recommendation in this document may not be the final guidelines version. As soon as the guidelines are confirmed, they will appear on this website as well as on the ESO website www.eso-stroke.org

A. Karolinska Stroke Update Consensus Statement

Antithrombotic therapy

The following Consensus Statement was adopted by the 7th Karolinska Stroke Update meeting on November 17, 2008.
The consensus statement was proposed by the chairman of the session, Professor Didier Leys, Lille, the co-chair Professor Anna Czlonkowska and the session secretary dr Mia von Euler, Stockholm, together with the speakers of 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 Hans-Christoph Diener, Essen, Professor Ale Algra, Utrecht and Professor Pierre Amarenco, Paris. 

Controversy to be discussed at the 2008 Consensus Session:

Position: the combination of aspirin and dipyridamole is the first choice antiplatelet therapy for secondary prevention after ischaemic stroke or transient ischaemic attacks (TIA)

Contra-position: clopidogrel is the first choice antiplatelet therapy for secondary prevention after ischaemic stroke or TIA

Alternative position: either of combined aspirin and dipyridamole or clopidogrel are first choice antiplatelet therapies for secondary prevention after ischaemic stroke or TIA, depending on availability and cost. 

Background

In the acute state of cerebral ischemia aspirin is at present the only antiplatelet agent studied and shown effective in a larger population [1-3] . A loading dose of at least 160-300 mg should be used.Antiplatelet therapy reduces the occurrence of new vascular events, including non-fatal myocardial infarction, nonfatal stroke and vascular death, in patients with previous ischaemic stroke or TIA (RR 0.78; 95% CI 0.76-0.80) [4]. Aspirin reduces the risk of recurrent ischaemic events irrespective of its dose (50 to 1300 mg/d) [5-10], although high doses (>150mg/day) increase adverse events. In patients with symptomatic intracranial atherosclerosis, aspirin is as effective as oral anticoagulation and has fewer complications [11].

Clopidogrel is slightly more effective than aspirin in preventing new vascular events (RR 0.91; 95% CI 0.84-0.97) [9]. In the subgroup of patients recruited after an ischaemic stroke, there was a non-significant tendency for superiority of clopidogrel over aspirin in preventing new vascular events (RR 0.93; 95% CI 0.81-1.06) [9]. It may be more effective in high-risk patients (e.g. those with previous stroke, peripheral artery disease, symptomatic coronary disease, or diabetes) [12].

Dipyridamole reduces stroke recurrence with similar efficacy to aspirin [13].Triflusal reduces stroke recurrence with similar efficacy to aspirin but with fewer adverse events [14].

Compared with clopidogrel alone, the combination of aspirin and clopidogrel did not reduce the risk of ischaemic stroke, myocardial infarction, vascular death, or re-hospitalisation [19]; however, life-threatening or major bleeding were increased with the combination. Similarly, in the CHARISMA study, the combination of aspirin and clopidogrel did not reduce the risk of myocardial infarction, stroke, or death from cardiovascular causes, compared with aspirin alone [20]. In patients who have had an acute coronary event within 12 months, or coronary stenting, the combination of clopidogrel and aspirin reduces the risk of new vascular events [21].

Indirect comparisons suggested that aspirin plus extended-release dipyridamole was superior to clopidogrel in the prevention of recurrent stroke [22]. In the PRoFESS trial [23], patients were randomly assigned to receive 25 mg of aspirin plus 200 mg of extended-release dipyridamole twice daily, or 75 mg of clopidogrel. The primary outcome was first recurrence of stroke. Sequential statistical testing of non-inferiority (margin of 1.075) was planned. A total of 20,332 patients were followed for a mean of 2.5 years. Recurrent stroke occurred in 916 patients (9.0%) receiving combination of aspirin and dipyridamole and in 898 patients (8.8%) receiving clopidogrel (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11). There was no difference between the two arms for secondary outcomes. Major hemorrhagic events were more frequent in patients under combination of aspirin and dipyridamole (419 [4.1%]) than in those under clopidogrel (365 [3.6%]) (hazard ratio, 1.15; 95% CI, 1.00 to 1.32), including intracranial haemorrhage (hazard ratio, 1.42; 95% CI, 1.11 to 1.83). The net risk of recurrent stroke or major hemorrhagic event was similar in the two groups. This trial did not meet the predefined criteria for non-inferiority but showed similar rates of recurrent stroke with combination of aspirin and dipyridamole and with clopidogrel [23]. There is no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke, and this was true for all pre-specified subgroups of patients [23].Final secondary prevention should be started before the patient is discharged from the stroke unit [24].

Discussion

Arguments in favour of position: In two large trials combined aspirin plus dipyridamole proved to be clearly more effective than aspirin alone in the prevention of new vascular events: the relative risk reduction from the updated meta-analysis was 18%. Thienopyridines (ticlopidine and clopidogrel) are somewhat more effective than aspirin alone in the prevention of new vascular events: the relative risk reduction from the Cochrane review is 8%. PRoFESS in a direct comparison of combined aspirin plus dipyridamole and clopidogrel showed a relative risk reduction of 1% (95% CI -7 to +8) for vascular events. The direct comparison from PRoFESS does not show much of a difference between the two antiplatelet regimens. However, if all evidence is taken together, thus including that from the indirect comparison, the overall balance tends to tip in favour of combined aspirin plus dipyridamole.

Arguments in favour of contraposition: Clopidogrel has been shown superior to aspirin (i.e. more effective and better tolerated) in the CAPRIE trial in reducing stroke, MI and vascular death. Its antithrombotic effect with a significant reduction of major vascular events has been demonstrated against placebo on a background of aspirin in patients with myocardial infarction, unstable angina or PCI in three large randomised trials (CURE, COMMIT and CLARITY). In CAPRIE, myocardial infarction was the most prevented vascular event in patients randomised in the clopidogrel arm. Direct comparison with combined aspirin plus dipyridamole in the PRoFESS trial showed similar overall efficacy on the reduction of stroke, myocardial infarction and vascular death with clopidogrel, and a better safety profile for clopidogrel with less intracranial haemorrhage and less headache. The combination of a better safety profile (less major bleeding complications), a proven superiority over aspirin alone in reducing myocardial infarction in patients with symptomatic coronary heart disease (which is not the case for combined aspirin plus dipyridamole), and the once-daily prescription compared to twice daily for combined aspirin plus dipyridamole, make clopidogrel a first choice for a prescription after brain infarction or TIA, provided the health care system can afford it.

Conclusion

Ischaemic stroke patients not requiring anticoagulation should receive antiplatelet therapy. Aspirin monotherapy with a loading-dose of 160-300 mg should be given at the acute stage. Before discharge, long term prevention should be installed. When possible combined aspirin and dipyridamole, or clopidogrel alone, should be given. The two strategies being similar, the choice between combined aspirin plus dipyridamole, and clopidogrel is based on the presence of coexistent disorders, tolerability and cost. Alternatively, aspirin alone, dipyridamole alone, or trifusal alone, may be used.

B. Recommendation by Karolinska Stroke Update participants to ESO Guidelines Committee to revise ESO guidelines:

New text marked red

Specific treatment:

Recommendations

• Ischaemic stroke patients not requiring anticoagulation or thrombolysis in the acute phase should receive antiplatelet therapy. Aspirin monotherapy with a loading-dose of 160-300 mg should be given in the acute phase or, if intravenous thrombolysis is given, after 24 h (Class I, Level A)

Non cardio-embolic ischaemic stroke/TIA:

• It is recommended that patients receive antithrombotic therapy (Class I, Level A) 
• Before discharge, long term prevention should be installed (Class IV, GCP).   
• It is recommended that patients not requiring anticoagulation should receive antiplatelet therapy (Class I, Level A). Where possible, combined aspirin and dipyridamole, or clopidogrel alone, should be given (Class I, Level A). The two strategies being similar, the choice between combined aspirin plus dipyridamole, and clopidogrel is based on the presence of coexistent disorders, tolerability and cost. Alternatively, aspirin alone, dipyridamole alone, or triflusal alone, may be used (Class I, Level A).
• The combination of aspirin and clopidogrel is not recommended in patients with recent ischaemic stroke, except in patients with specific indications (e.g. unstable angina or non-Q-wave MI, or recent cardiac vessels stenting, recent stenting of cerebral or pre-cerebral arteries); treatment should be given for up to 9 months after the event (Class I, Level A). Patients with carotid stenting combination therapy should be given up to 3 months (Class IV, GCP). There is no data supporting a specific duration of combined aspirin and clopidogrel, but the MATCH study showed increased risk of bleeding after 3 months.
• It is recommended that patients who have a stroke on antiplatelet therapy should be re-evaluated for pathophysiology and risk factors (Class IV, GCP)
• It is recommended that anticoagulation should not be used after non-cardio-embolic ischaemic stroke (Class I, Level A). In some specific situations, such as aortic atheromas, fusiform aneurysms of the basilar artery, cervical artery dissection, or PFO in the presence of proven deep vein thrombosis (DVT) or atrial septal aneurysm  anticoagulation may be considered (Class IV, GCP)

 Cardio-embolic stroke/TIA

• Oral anticoagulation (INR 2.0–3.0) is recommended after ischaemic stroke associated with AF (Class I, Level A). Oral anticoagulation is not recommended in patients with co-morbid conditions such as falls, poor compliance, uncontrolled epilepsy, or gastrointestinal bleeding (Class III, Level C). Increasing age alone is not a contraindication to oral anticoagulation (Class I, Level A) It is recommended that patients with cardioembolic stroke unrelated to AF should receive anticoagulants (INR 2.0–3.0) if the risk of recurrence is high (Class III, Level C)  
• It is recommended that aspirin 325 mg should be given if oral anticoagulation is contraindicated for secondary prevention after  stroke with atrial fibrillation (Class II, GCP)  

Antithrombotic therapy

(Please note that the numbered references are in agreement with the ESO Guidelines paper for ischaemic stroke and TIA 2008. New references are indicated by the first author and year of publication. Full details are given in the reference list. The new references will be included in the next revision of the paper, planned for 2013). 

Antiplatelet Therapy

Antiplatelet therapy reduces vascular events, including non-fatal MI, nonfatal stroke and vascular death in patients with previous stroke or TIA (RR 0.78; 95% CI 0.76-0.80) [313]. 

Aspirin

Aspirin reduces recurrence irrespective of dose (50-1,300 mg/day) [314,315,316,317], although high doses (>150 mg/day) increase adverse events. In patients with symptomatic intracranial atherosclerosis, aspirin is as effective as oral anticoagulation and has fewer complications [318].

Clopidogrel

Clopidogrel is slightly more effective than aspirin in preventing vascular events (RR 0.91; 95% CI 0.84-0.97) [319]. In the subgroup of patients recruited after an ischaemic stroke, there was a non-significant tendency for superiority of clopidogrel over aspirin in preventing new vascular events (RR 0.93; 95% CI 0.81-1.06). It may be more effective in high-risk patients (i.e. those with previous stroke, peripheral artery disease, symptomatic coronary disease, or diabetes) [269].

Dipyridamole

Dipyridamole reduces stroke recurrence with similar efficacy to aspirin [320].

Triflusal

Triflusal reduces stroke recurrence with similar efficacy to aspirin but with fewer adverse events [321]. 

Dipyridamole plus Aspirin

The combination of aspirin (38-300 mg/day) and dipyridamole (200 mg extended release twice daily) reduces the risk of vascular death, stroke or MI, compared with aspirin alone (RR 0.82; 95% CI 0.74-0.91) [320, 322]. An individual patient data analysis with data from 5 trials showed that the benefits of aspirin plus dipyridamole over aspirin applied to all subgroups of patients, including the ones according to baseline risk [Halkes 2008]. Dipyridamole may cause headache; the incidence of this may be reduced by increasing the dose gradually [323, 324].

Clopidogrel plus Aspirin Compared with clopidogrel alone, the combination of aspirin and clopidogrel did not reduce the risk of ischaemic stroke, MI, vascular death, or re-hospitalization [325]; however, life-threatening or major bleeding was increased with the combination. Similarly, in the CHARISMA study, the combination of aspirin and clopidogrel did not reduce the risk of MI, stroke, or death from CV causes, compared with aspirin alone [269]. In patients who have had an acute coronary event within 12 months, or coronary stenting, the combination of clopidogrel and aspirin reduces the risk of new vascular events [326].

Comparisons between Aspirin plus Dipyridamole and Clopidogrel

Indirect comparisons suggested that aspirin plus extended-release dipyridamole was superior to clopidogrel in the prevention of recurrent stroke [Thijs 2008]. In the PRoFESS trial [Sacco 2008], patients were randomly assigned to receive 25 mg of aspirin plus 200 mg of extended-release dipyridamole twice daily, or 75 mg of clopidogrel. The primary outcome was first recurrence of stroke. Sequential statistical testing of non-inferiority (margin of 1.075) was planned. A total of 20,332 patients were followed for a mean of 2.5 years. Recurrent stroke occurred in 916 patients (9.0%) receiving combination of aspirin and dipyridamole and in 898 patients (8.8%) receiving clopidogrel (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11). There was no difference between the two arms for secondary outcomes. Major hemorrhagic events were more frequent in patients under combination of aspirin and dipyridamole (419 [4.1%]) than in those under clopidogrel (365 [3.6%]) (hazard ratio, 1.15; 95% CI, 1.00 to 1.32), including intracranial haemorrhage (hazard ratio, 1.42; 95% CI, 1.11 to 1.83). The net risk of recurrent stroke or major hemorrhagic event was similar in the two groups. This trial did not meet the predefined criteria for non-inferiority but showed similar rates of recurrent stroke with combination of aspirin and dipyridamole and with clopidogrel [Sacco 2008]. There is no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke, and this was true for all pre-specified subgroups of patients [Sacco 2008].

Importance of initiation of final secondary prevention in the acute stroke unitFinal secondary prevention should be started before the patient is discharged from the stroke unit [Touze 1008].

References:
New:
[Halkes 2008] Halkes PH, Gray LJ, Bath PM, Diener HC, Guiraud-Chaumeil B, Yatsu FM, Algra A: Dipyridamole plus aspirin versus aspirin alone in secondary prevention after tia or stroke: A meta-analysis by risk. J Neurol Neurosurg Psychiatry 2008;79:1218-1223.

[Thijs] Thijs V, Lemmens R, Fieuws S: Network meta-analysis: Simultaneous meta-analysis of common antiplatelet regimens after transient ischaemic attack or stroke. Eur Heart J 2008;29:1086-1092.

[Sacco] Sacco RL, Diener HC, Yusuf S, Cotton D, Ounpuu S, Lawton WA, Palesch Y, Martin RH, Albers GW, Bath P, Bornstein N, Chan BP, Chen ST, Cunha L, Dahlof B, De Keyser J, Donnan GA, Estol C, Gorelick P, Gu V, Hermansson K, Hilbrich L, Kaste M, Lu C, Machnig T, Pais P, Roberts R, Skvortsova V, Teal P, Toni D, Vandermaelen C, Voigt T, Weber M, Yoon BW: Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med 2008;359:1238-1251.

[Touze] Touze E, Coste J, Voicu M, Kansao J, Masmoudi R, Doumenc B, Durieux P, Mas JL. Importance of in-hospital initiation of therapies and therapeutic inertia in secondary stroke prevention: Implementation of Prevention After a Cerebrovascular evenT (IMPACT) Study. Stroke 2008;39:1834-43.

Existing:

269. Bhatt D, Fox K, Hacke W, Berger P, Black H, Boden W, Cacoub P, Cohen E, Creager M, Easton J, Flather M, Haffner S, Hamm C, Hankey G, Johnston S, Mak K, Mas J, Montalescot G, Pearson T, Steg P, Steinhubl S, Weber M, Brennan D, Fabry-Ribaudo L, Booth J, Topol E: Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006;354:1706-1717.313. 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.

314. Algra A, van Gijn J: Aspirin at any dose above 30 mg offers only modest protection after cerebral ischaemia. J Neurol Neurosurg Psychiatry 1996;60:197-199.

315. The Dutch TIA Trial Study Group: A comparison of two doses of aspirin (30 mg vs. 283 mg a day) in patients after a transient ischemic attack or minor ischemic stroke. N Engl J Med 1991;325:1261-1266.

316. Farrell B, Godwin J, Richards S, Warlow C: The United Kingdom transient ischaemic attack (UK-TIA) aspirin trial: final results. J Neurol Neurosurg Psychiatry 1991;54:1044-1054.

317. Campbell C, Smyth S, Montalescot G, Steinhubl S: Aspirin dose for the prevention of cardiovascular disease: a systematic review. JAMA 2007;297:2018-2024.

318. Chimowitz M, Lynn M, Howlett-Smith H, Stern B, Hertzberg V, Frankel M, Levine S, Chaturvedi S, Kasner S, Benesch C, Sila C, Jovin T, Romano J: Comparison of warfarin and aspirin for symptomatic intracranial arterial stenosis. N Engl J Med 2005;352:1305-1316.


319. CAPRIE Steering Committee: A randomised, blinded trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996;348:1329-1339.

320. Diener HC, Cunha L, 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.

321. Costa J, Ferro JM, Matias-Guiu J, Alvarez-Sabin J, Torres F: Triflusal for preventing serious vascular events in people at high risk. Cochrane Database Syst Rev 2005:CD004296.

322. Halkes P, van Gijn J, Kappelle L, Koudstaal P, Algra A: Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): Randomised controlled trial. Lancet 2006;367:1665-1673.

323. Chang YJ, Ryu SJ, Lee TH: Dose titration to reduce dipyridamole-related headache. Cerebrovasc Dis 2006;22:258-262.

324. Diener H, Davidai G: Dipyridamole and headache. Future Neurol 2007;2:279-283.

325. Diener H, Bogousslavsky J, Brass L, Cimminiello C, Csiba L, Kaste M, Leys D, Matias-Guiu J, Rupprecht H: 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;364:331-337.

326. Yusuf S, Zhao F, Mehta S, Chrolavicius S, Tognoni G, Fox K, and the Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators: Effects of clopidogrel in addition to aspirin in patients with acute coronary syndroms without ST-segment elevation. N Engl J Med 2001;345:494-502.