Some patients with stroke and transient ischaemic attack (TIA) are at high risk for early recurrent stroke, usually due to arterial thromboembolism. Aspirin reduces the risk of early recurrent stroke by only 12%. Adding clopidogrel to aspirin in patients with acute coronary syndromes reduces the risk of recurrent vascular events by 20% but increases the risk of major bleeding by 38%. Among 731 patients with acute ischaemic stroke or TIA (onset within previous 3 days) enrolled in five small trials, the addition of clopidogrel to aspirin was associated with non-significant trends toward a reduction in recurrent stroke and an increase in major bleeding.
Researchers writing in the New England Journal of Medicine, report the findings of the ‘Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events’ (CHANCE) trial. This was a randomised, double-blind, placebo-controlled study conducted at 114 centres in China involving 5170 patients within 24 hours after the onset of minor ischaemic stroke or high-risk TIA. They were randomised to combination therapy with clopidogrel at an initial dose of 300mg, followed by 75mg per day for 90 days, plus aspirin at a dose of 75mg per day for the first 21 days or to placebo plus aspirin (75mg per day for 90 days). All received open-label aspirin at a clinician-determined dose of 75 to 300 mg on day 1. The primary outcome was stroke (ischaemic or haemorrhagic) during 90 days of follow-up in an intention-to treat analysis.
Stroke occurred in 8.2% of patients in the clopidogrel–aspirin group vs. 11.7% of those in the aspirin group (hazard ratio, 0.68; 95% CI, 0.57 to 0.81; p <0.001). Moderate or severe haemorrhage occurred in 7 patients (0.3%) in the clopidogrel–aspirin group and in 8 (0.3%) in the aspirin group (p= 0.73); the rate of hemorrhagic stroke was 0.3% in each group.
The researchers note that the results of their trial differ from those of other trials of combination therapy with clopidogrel and aspirin after cerebral ischaemic events, which did not show a reduction in risk of ischaemic events but did show an increased risk of haemorrhage. They suggest that this difference may possibly be due to their trial targeted a population at particularly high risk for recurrent ischaemia and at low risk for haemorrhage, whereas previous trials included patients with more severe strokes and did not enrol patients in the first hours after an index minor stroke or TIA when the risk of recurrent ischaemia is particularly high.
An accompanying editorial notes that this was a scientifically rigorous trial that proves the concept that dual antiplatelet therapy can be more effective than single antiplatelet therapy in preventing early recurrent stroke in patients with acute symptomatic atherothrombosis of the brain. It estimates that treating 29 patients for 90 days with clopidogrel plus aspirin for the first 21 days, followed by clopidogrel alone from day 22 to day 90, prevented one stroke, as compared with aspirin alone. In addition, most of the absolute benefit of clopidogrel plus aspirin is realised within the first few days after TIA and ischaemic stroke, when the underlying atherosclerotic plaque is most unstable and the risk of recurrence is highest.
Furthermore, the safety data show that dual antiplatelet therapy can be given without excess harm in patients with acute focal brain ischaemia, provided that patients have a low risk of haemorrhagic transformation or a very small volume of fresh brain infarction. It was noted that in this study, the researchers had to screen 41,561 patients with stroke or TIA to find 5170 appropriate patients (12.4%), hence, the results cannot be generalised to most patients; the study excluded patients with major ischaemic stroke, who are at risk for haemorrhagic transformation, and patients with TIA due to isolated sensory, visual, or vertiginous syndromes, who are at low risk for recurrence. The results may also not apply to non-Chinese patients with different forms of underlying arterial disease and different prevalences of genetic polymorphisms of liver cytochrome P-450 (CYP) isozymes, which metabolise clopidogrel to its active metabolites. It was also highlighted that the absolute benefits of clopidogrel plus aspirin observed in this trial may also not be realised in those at lower absolute risk for recurrent stroke, i.e. a low prevalence of risk factors for recurrent stroke and those with access to effective secondary stroke prevention. Finally, the results of this trial cannot be generalised beyond 90 days after ischaemic stroke, when the cumulative risks of bleeding with clopidogrel plus aspirin, as compared with aspirin or clopidogrel alone, offset the benefits.
NICE guidance recommends clopidogrel monotherapy as an option to prevent occlusive vascular events for people who have had an ischaemic stroke or who have peripheral arterial disease or multivascular disease or for people who have had a myocardial infarction only if aspirin is contraindicated or not tolerated. Modified-release dipyridamole in combination with aspirin is recommended as an option to prevent occlusive vascular events for people who have had a transient ischaemicattack or for people who have had an ischaemic stroke only if clopidogrel is contraindicated or not tolerated.
The RCP has also issued a national guideline for stroke (see link below).