Current Prevention of Secondary Stroke
Ischaemic stroke is a major cause of morbidity and mortality in modern life, ranking as the third most common cause of death after cardiovascular disease and cancer,¹ and its prevalence is expected to rise in line with extended life expectancy.² Eight to 12% of ischaemic strokes result in death within 30 days,³ while surviving patients are at an increased risk of subsequent vascular events, the most common being a second stroke.^4,5 The risk of a recurrent stroke or transient ischaemic attack (TIA) is between 5 and 15% per year and is highest immediately after the primary episode.^6,7 This accounts for approximately threequarters of all secondary vascular events following stroke.⁴ Secondary prevention strategies focus on reducing cardiovascular risk factors such as cigarette smoking, diabetes mellitus (DM), obesity, high blood pressure and increased cholesterol levels.⁸ In addition, pharmacological antiplatelet therapy is indicated in such patients. ASA is the the most widely used treatment. Clinical trials have shown that treating stroke patients with ASA significantly reduces the risk of a recurrent episode compared with placebo.^9–11 However, the absolute risk reduction is low. The protective effect was found not to be dose-dependent, leading to the use of lower doses with a more favourable side effect profile.

To explore other treatment possibilities, later studies compared the efficacy and safety of alternativee antiplatelet drugs with ASA in secondary stroke prevention. The Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRIE) trial examined the efficacy of clopidogrel compared with ASA in preventing recurrent vascular events among patients suffering from stroke, myocardial infarction (MI) or peripheral arterial disease.¹² Although clopidogrel was found to be more effective among the general study population, this was not significant in the stroke subgroup, and clopidogrel was deemed to be only as good as an ASA in preventing stroke.

The next step towards improving antiplatelet therapy was examining combination treatments. In the Clopidogerl in Unstable Angina to Prevent Recurrent Events (CURE) trial, the combination of clopidogrel and ASA was compared with ASA alone in the prevention of vascular ischaemic events. No significant differences were found in stroke prevention between the treatment groups. Furthermore, patients receiving the combination therapy were at a significantly greater risk of major bleeding.^13,14 The later Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance (CHARISMA) trial also looked at the benefit of adding clopidogrel to ASA compared with ASA monotherapy in secondary vascular prevention among a high-risk population. Here, too, no significant differences were found in the rate of cardiovascular disease, but an increase in the risk of major bleeding was evident.

However, subgroup analysis indicated a possible benefit, specifically in recurrent stroke prevention, warranting further investigation. The Management of Atherothrombosis with Clopidogrel in High-risk Patients with Recent TIA or Ischaemic stroke (MATCH) study compared the combination of clopidogrel and ASA with clopidogrel monotherapy in high-risk patients who had suffered a recent TIA or ischaemic stroke. Once again, it was found that combination therapy failed to produce any significant difference in risk reduction,^15,16 but it did increase the risk of major bleeding compared with monotherapy. These studies revealed that, while both antiplatelet drugs were equally effective in preventing recurrent vascular events, no real benefit was acquired from their combined use. Moreover, the combination increased the risk of serious side effects, namely major bleeding.

Recent clinical studies have explored combining ASA with other antiplatelet drugs in an attempt to achieve further reduction in the rate of recurrent stroke. The European Stroke Prevention Study 2 (ESPS II) and the later European–Australian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) both explored the efficacy of combining ASA and dipyridamole in secondary stroke prevention. It was found that the combination therapy was more effective in preventing stroke than either treatment alone, and that the combined effect did not increase the risk of severe or fatal bleeding compared with ASA alone.^10,17

Thus far, clinical trials have examined the role of ASA as well as the comparative efficacy of other drugs and combinations with regard to secondary stroke prevention. While ASA and others have been shown to reduce the risk of a recurrent episode, it still remains unclear which is the preferable regime in the general patient population or any specific subpopulation.