Antiplatelet therapy - Karolinska Stroke Update

Consensus Statement 2004


The following Consensus Statement was adopted by the 5th Karolinska Stroke Update meeting on November 15, 2004.

The consensus statement  was proposed by the chairpersons in the session, Professor Bo Norrving, Lund, and Professor Juhani Sivenius, Kuopio, 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 Christoph Diener, Essen, Professor Bo Norrving, Lund, Professor Lazslo Csiba, Debrecen and Professor Natan Bornstein, Tel Aviv



Consensus statement: Antiplatelet therapy

Since the last statement 2002, there have been major advances in delineating the early risk of recurrent ischemic events, as well as the role of combined antiplatelet therapy with clopidogrel and aspirin after TIA or ischemic stroke. 


1 Early risk of recurrent ischemic events

Several observational studies have shown that the early risk for recurrent ischemic events after TIA and minor stroke is much higher than previously thought: about 5 % within the first few days, and circa 10 % within 1-3 months. The prognosis appears to depend on the underlying disease processes. Thus, the early risk is up to eight times higher in patients with large artery disease than in those with small artery disease. Patients with TIA who have acute ischemic abnormalities on dw-MRI, as well as stroke-patients with multiple acute ischemic areas, may be other subsets at increased risk for early recurrence.

Consequently, patients with symptoms of TIA or stroke should seek urgent medical attention. Diagnostic procedures and start of secondary preventive measures, according to established principles (see previous consensus statements), should not be delayed. The issue of more aggressive preventive therapies in the acute phase is currently a field for research (see below). The benefit of carotid endarterectomy decreases rapidly with delay to treatment after a TIA or ischemic stroke (see section on “Carotid Endarterectomy”).

Today, one third or more of all TIA and ischemic stroke occur in patients who are already on treatment with a single antiplatelet agent. There are no firm trial data on the usefulness to modify the antiplatelet regimen in such patients.


2 Cost effectiveness

A recent systematic review of clinical effectiveness and cost-effectiveness of clopidogrel and extended-release (ER) dipyridamole in the secondary prevention of occlusive vascular events (Jones L et al. Health Technol Assess 2004 Oct;8(38):1-210) showed that for the stroke and TIA subgroups, aspirin-ER dipyridamole would be the most cost-effective therapy given a 2-year treatment duration as long as all patients were not left disabled by their initial (qualifying) stroke. In patients left disabled by their initial stroke, aspirin would be the most cost-effective therapy. Clopidogrel and ER-dipyridamole alone would not be cost effective under any scenario. The analysis was based on the assumption that a cost of ₤20 000 – 40 000 per additional QALY was acceptable.

Cost-effectiveness analyses are very sensitive to changes in back-ground variables and treatment duration. Cost-effectiveness may thus be different in selected patients with higher risks and benefits, such as the early period following an acute ischemic event.


3 Combination of clopidogrel and aspirin

The first large randomised clinical trial (MATCH) on adding aspirin to clopidogrel in high-risk patients with recent ischemic stroke or TIA showed that combination therapy was associated with a non-significant difference in reducing major vascular events, but the risk of life-threatening or major bleeding was increased by the addition of aspirin. 

However, the patient population studied in MATCH deviated from unselected patients in clinical practice in several aspects: 70% of the patients were diabetics, 50 % had small vessel disease, only 30 % had large vessel disease, and there were few patients with coronary heart disease. Furthermore, MATCH recruited most patients several weeks after the presenting event, i.e. after the acute phase when the risk of recurrent events is highest.

Thus, the over-all negative findings in the MATCH trial does not exclude the possibility that the combination of clopidogrel and aspirin may be of benefit in other types of patients with different clinical characteristics, risk factors and underlying disease processes.

More aggressive antiplatelet therapy may also provide particular benefit in situations when the risk of new ischemic events is very high. The recent CARESS trial, in which the combined use of clopidogrel and aspirin was significantly more effective than aspirin alone in reducing silent cerebral microemboli in patients with recently symptomatic moderate-to-severe carotid stenosis, provides support for this concept. The effect of a short period of combined clopidogrel-aspirin treatment, with or without a statin, initiated soon after the event is evaluated in a large, randomised controlled trial which is currently ongoing (FASTER). The effectiveness of the combination of aspirin and ER-dipyridamole versus clopidogrel is currently tested in the ongoing PRoFESS-trial.

At present, there are no trial data to support the use of combined antiplatelet therapy with clopidogrel and aspirin in patients with first or recurrent TIA or ischemic stroke in clinical practice.


4 Antiplatelet therapies in conjunction with carotid surgery or stenting

Patients with symptomatic stenosis of brain supplying arteries should receive antiplatelet treatment in the interval between the event and intervention. This can be done with aspirin, but pending further trial evidence the combination of 75 mg clopidogrel plus 75 mg aspirin may also be used because the benefit in terms of reduced ischemic events is likely to be higher than the risk of bleeding complications.

Clopidogrel should be stopped at least 3 days before surgery, whereas aspirin should be given throughout surgery. After stenting patients should be treated for 3 to 6 months with the combination of clopidogrel plus aspirin. After that period antiplatelet monotherapy can be used.