Multiple versus fewer antiplatelet agents for preventing early recurrence after ischaemic stroke or transient ischaemic attack

Imama A Naqvi, Ayeesha K Kamal, Hasan Rehman

Stroke is a leading cause of morbidity and mortality worldwide. Antiplatelet agents are considered to be the cornerstone for secondary prevention of stroke, but the role of using multiple antiplatelet agents early after stroke or transient ischaemic attack (TIA) to improve outcomes has not been established. To determine the effectiveness and safety of initiating, within 72 hours after an ischaemic stroke or TIA, multiple antiplatelet agents versus fewer antiplatelet agents to prevent stroke recurrence. The analysis explores the evidence for different drug combinations. We searched the Cochrane Stroke Group Trials Register (last searched 6 July 2020), the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 7 of 12, 2020) (last searched 6 July 2020), MEDLINE Ovid (from 1946 to 6 July 2020), Embase (1980 to 6 July 2020), ClinicalTrials.gov, and the WHO ICTRP. We also searched the reference lists of identified studies and reviews and used the Science Citation Index Cited Reference search for forward tracking of included studies. We selected all randomised controlled trials (RCTs) that compared the use of multiple versus fewer antiplatelet agents initiated within 72 hours after stroke or TIA. We extracted data from eligible studies for the primary outcomes of stroke recurrence and vascular death, and secondary outcomes of myocardial infarction; composite outcome of stroke, myocardial infarction, and vascular death; intracranial haemorrhage; extracranial haemorrhage; ischaemic stroke; death from all causes; and haemorrhagic stroke. We computed an estimate of treatment effect and performed a test for heterogeneity between trials. We analysed data on an intention-to-treat basis and assessed bias for all studies. We rated the certainty of the evidence using the GRADE approach. We included 15 RCTs with a total of 17,091 participants. Compared with fewer antiplatelet agents, multiple antiplatelet agents were associated with a significantly lower risk of stroke recurrence (5.78% versus 7.84%, risk ratio (RR) 0.73, 95% confidence interval (CI) 0.66 to 0.82; P < 0.001; moderate-certainty evidence) with no significant difference in vascular death (0.60% versus 0.66%, RR 0.98, 95% CI 0.66 to 1.45; P = 0.94; moderate-certainty evidence). There was a higher risk of intracranial haemorrhage (0.42% versus 0.21%, RR 1.92, 95% CI 1.05 to 3.50; P = 0.03; low-certainty evidence) and extracranial haemorrhage (6.38% versus 2.81%, RR 2.25, 95% CI 1.88 to 2.70; P < 0.001; high-certainty evidence) with multiple antiplatelet agents. On secondary analysis of dual versus single antiplatelet agent therapy, benefit for stroke recurrence (5.73% versus 8.06%, RR 0.71, 95% CI 0.62 to 0.80; P < 0.001; moderate-certainty evidence) was maintained as well as risk of extracranial haemorrhage (1.24% versus 0.40%, RR 3.08, 95% CI 1.74 to 5.46; P < 0.001; high-certainty evidence). The composite outcome of stroke, myocardial infarction, and vascular death (6.37% versus 8.77%, RR 0.72, 95% CI 0.64 to 0.82; P < 0.001; moderate-certainty evidence) and ischaemic stroke (6.30% versus 8.94%, RR 0.70, 95% CI 0.61 to 0.81; P < 0.001; high-certainty evidence) were significantly in favour of dual antiplatelet therapy, whilst the risk of intracranial haemorrhage became less significant (0.34% versus 0.21%, RR 1.53, 95% CI 0.76 to 3.06; P = 0.23; low-certainty evidence). Multiple antiplatelet agents are more effective in reducing stroke recurrence but increase the risk of haemorrhage compared to one antiplatelet agent. The benefit in reduction of stroke recurrence seems to outweigh the harm for dual antiplatelet agents initiated in the acute setting and continued for one month. There is lack of evidence regarding multiple versus multiple antiplatelet agents. Further studies are required in different populations to establish comprehensive safety profiles and long-term outcomes to establish duration of therapy.