Antiplatelet Therapy Evidence Tables and Reference List
Substantial evidence from randomized trials and meta-analyses supports the use of antithrombotic agents in patients who have experienced an ischemic stroke or TIA to reduce the risk of future events. The most commonly recommended antiplatelet agents for secondary stroke prevention in North America and Europe are acetylsalicylic acid (ASA, 75 to 325 mg/day), clopidogrel, and the combination of ASA and extended-release dipyridamole.
A meta-analysis conducted by The Antithrombotic Trialists’ Collaboration (2002) included the results of 287 RCTs (n=135,000) examining any antiplatelet therapy for the prevention of vascular events in high-risk patients. In 9 of these trials, long-term aspirin monotherapy was examined in patients who had experienced a previous stroke or TIA. In these trials, fewer patients receiving aspirin therapy experienced a vascular event (8.2% vs. 9.1%) representing an 11% odds reduction. In 65 trials examining aspirin monotherapy across doses ranging from <75mg to 1.500 mg, the mean percentage odds reduction of any vascular event was 23%. ASA and other forms of antiplatelet drugs reduced the incidence of nonfatal stroke by one-quarter. The Antithrombotic Trialists’ Collaborative (ATTC) included the results of 18 RCTs examining aspirin therapy for primary (n=6 with 95,456 subjects) and secondary (n=16) prevention of vascular events (Baigent et al. 2009). In the primary prevention trials, there was a significant reduction in risk of any serious vascular event, but no significant reduction in the risk of stroke (RR=0.95, 95% CI 0.85-1.06, p=0.40), fatal stroke (RR=1.21, 95% CI 0.84-1.74) or nonfatal stroke (RR=0.92, 95% CI 0.79-1.07). Secondary prevention trials were associated with a reduced risk of stroke of unknown cause (RR=0.77, 95% CI 0.62-0.96), but no reduction in the risk of ischemic stroke (RR=0.78, 95% CI 0.57-1.06) or fatal stroke (RR=1.08, 95% CI 0.73-1.62).
While aspirin at varying doses is the most widely-used antiplatelet agent, the risk of hemorrhagic events, particularly gastrointestinal bleeding, remains substantial. The use of another agent, ticagrelor, a P2Y12 receptor inhibitor, has recently been studied as a potentially safer alternative to aspirin. In the Acute Stroke or Transient Ischemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial (Johnston et al. 2016), 13,199 patients who had experienced a minor stroke or high-risk TIA within the previous 24 hours were randomized to receive either ticagrelor or aspirin. At the end of 90 days, there were no significant differences between groups on the primary, secondary or safety outcomes between groups, indicating that ticagrelor was not superior to aspirin.
Dual vs. Monotherapy with Clopidogrel
Several large clinical trials have examined the combination of clopidogrel + aspirin vs. aspirin alone. While the results from some of these trials failed to demonstrate a significant further reduction in risk of recurrent stroke associated with dual therapy among patients who had already sustained a minor stroke or TIA, most reported an increased risk of bleeding events. The Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial randomly assigned 15,603 patients with clinically evident cardiovascular disease or multiple risk factors to receive clopidogrel (75 mg/day) plus low-dose ASA (75 to 162 mg/day) or placebo plus low-dose ASA, with a median follow-up of 28 months (Bhatt et al. 2006). There was a non-significant reduction in the risk of the primary outcome (a composite of nonfatal stroke, nonfatal myocardial infarction or vascular death) associated with dual therapy (6.8% vs. 7.3%, RR=0.93, 95% CI 0.83-1.05, p=0.22). There were also non-significant reductions in death from any cause, death from cardiovascular causes and non-fatal MI associated with dual therapy. There was a significant reduction in the risk of all nonfatal stroke (1.9% vs. 2.4%, RR=0.79, 95% CI 0.64-0.98, p=0.03), but not nonfatal ischemic stroke (1.7% vs. 2.1%, RR=0.81, RR=0.64-1.02, p=0.07). More patients in the dual therapy group experienced moderate bleeding (2.1% vs. 1.3%, p<0.001) but there was no difference between groups in other adverse events (severe and fatal bleeding and ICH). The investigators concluded that, clopidogrel plus ASA was not significantly more effective than ASA alone in reducing the rate of myocardial infarction, stroke or vascular death. Similar results were reported in the Fast Assessment of Stroke and TIA to prevent Stroke Recurrence (FASTER) trial (Kennedy et al. 2007) where there was a non-significant reduction in the risk of stroke associated with clopidogrel use (7.1% vs. 10.8%, RR=0.7, 95% CI 0.3-1.2, p=0.19) and a significant 3% increase in risk (p=0.03) for symptomatic bleeding events in the groups allocated to clopidogrel. In the Secondary Prevention of Small Subcortical Strokes (SPS3) trial, patients were randomized to receive 325 mg of enteric coated aspirin + 75 mg clopidogrel daily or aspirin + placebo (Benavente et al. 2012). After a mean follow-up period of 3.4 years, the addition of clopidogrel was not associated with reductions in stroke, MI or death from vascular causes, but it was associated with an increased risk of all-cause mortality. A subgroup analysis that included patients who were on aspirin therapy at the time of the qualifying stroke demonstrated that the addition of 75 mg clopidogrel was not associated with reductions in the risk of stroke or MI, but was associated with a significant increase in death from any cause and vascular death (Cote et al. 2014). One recent major trial that did report a benefit of the addition of clopidogrel was the Clopidogrel in High-Risk Patients with Acute Nondisabling Cerebrovascular Events (CHANCE) trial, in which investigators randomized 5,170 patients with minor ischemic stroke within 24 hours or high-risk TIA to receive clopidogrel (75 mg/day) plus low-dose ASA (75 mg/day) or clopidogrel placebo plus aspirin for 90 days (Wang et al. 2013). Significantly fewer patients in the clopidogrel + aspirin group experienced a stroke within 90 days (Any stroke: 8.2% vs. 11.7%, HR=0.68, 95% CI 0.0.57-0.81, p<0.001) or an MI, stroke or vascular death stroke (8.4% vs. 11.9%, HR=0.69, 95% CI 0.58- 0.82, p<0.001). There was no difference in (any) bleeding events between groups (2.3% vs. 1.6%, p=0.09). A recently published meta-analysis included the results from 13 RCTs (Palacio et al. 2015). Overall, the use of clopidogrel+ aspirin was associated with significantly reduced odds of any stroke (OR=0.81, 95% CI 0.74-0.89). The odds were reduced for patients with stable vascular disease (OR=0.82, 95% CI 0.69-0.97) and for patients with a recent vascular event (OR=0.84, 95% CI 0.72-0.98). However, the use of dual therapy was associated with a significant increase in the odds of major hemorrhage (OR=1.40, 95% CI 1.26-1.55). Among the 4 RCTs that included patients with recent ischemic stroke (CARESS, CHARISMA, CLAIR, FASTER), the odds of all stroke were significantly reduced (OR=0.67, 95% CI 0.46-0.97), while the odds of major hemorrhage were not significantly increased (OR=0.91, 95% CI 0.40-2.07).
A single, large trial has examined the treatment contrast of clopidogrel + aspirin vs. clopidogrel alone (Deiner et al. 2004). The Management of Atherothrombosis with Clopidogrel in High-risk patients with recent TIA or ischemic stroke (MATCH) trial included 7,599 high-risk patients with recent ischemic stroke or transient ischemic attack and at least one additional vascular risk factor. All patients received 75 mg of clopidogrel daily; In addition, patients were randomized to receive 75 mg aspirin daily or placebo, daily for 18 months. The addition of aspirin did not reduce the occurrence of the primary outcome (a composite of ischemic stroke, myocardial infarction, vascular death or rehospitalization for acute ischemia:16% vs. 17%, Absolute Risk Reduction=6.4%, 95% CI -4.6%-16.3%, p=0.244), or the incidence of fatal/nonfatal stroke and vascular death (11% vs. 11%, ARR=0.75%, 95% CI -0.7%-2.2%, p=0.324) or any stroke (9% vs. 9%, ARR=0.20%, 95% CI -1.1%-1.55, p=0.79). The investigators concluded that the addition of ASA was associated with a nonsignificant reduction in major vascular events and a significant increase in the risk of life-threatening or major bleeding.
The use of clopidogrel among children for the prevention of stroke recurrence has not been well-studied. Soman et al. (2006) followed 17 children, aged 1 month to 17 years, for up to 4 years after arterial ischemic stroke. Children were started on clopidogrel after demonstrating failure or intolerance to aspirin. There were no cases of stroke recurrence during a mean follow-up of 1.8 years. No patient receiving monotherapy with clopidogrel reported any major complications, while two patients reported minor complications (hand numbness and headache) that were not thought to be medication related. Among 9 patients who received aspirin in addition to clopidogrel, there were 2 cases of intracranial bleeding.
Dual vs. Monotherapy with Dipyridamole
Dipyridamole is another antiplatelet agent that can be combined with aspirin for the prevention of stroke. The European/Australasian Stroke Prevention in Reversible Ischaemia Trial (ESPRIT) randomized 2,763 patients who had experienced a TIA or minor stroke within the previous 6 months to receive extended-release dipyridamole (200 mg bid) + aspirin (30 to 325 mg/d-mean dose, 75 mg, n=1,363) or aspirin (as above) alone for 3.5 years. Significantly fewer patients in the dual therapy group experienced the primary outcome (composite of vascular death, nonfatal stroke, nonfatal MI or major bleeding complication: 12.7% vs. 15.7%, HR=0.80, 95% CI 0.66-0.98, NNT=104), all-cause mortality or nonfatal stroke. Patients taking ASA and dipyridamole discontinued trial medication more often than those on ASA alone (34% vs. 26%), mainly because of headache. A recent systematic review and meta-analysis (Wong et al. 2013) included the results of 3 RCTs (ESP-2, ESPRIT & EARLY) examining the risk of stroke recurrence associated with dipyridamole + aspirin vs. aspirin alone. There was a non-significant reduction in the risk of stroke recurrence associated with dual therapy (RR=0.64, 95% CI 0.37-1.10, p=0.80).
A single trial has examined the effectiveness of an non-aspirin comparator as the single agent in a dual agent trial (Sacco et al. 2008). The Prevention Regimen for Effectively avoiding Second Stroke (PRoFESS) trial, randomized 20,332 patients, who had experienced an ischemic stroke within the previous 90 days to receive 25 mg aspirin + 200 mg extended release dipyridamole (ERDP) twice daily or 75 mg clopidogrel daily, for 4 years. There was no difference in the number of patients who experienced stroke, MI or vascular death between group (13.1% in each group, HR=0.99, 95% CI 0.92-1.07). Stroke recurrence rates were similar in both arms of the trial (9.0% among patients assigned to receive ASA plus extended-release dipyridamole and 8.8% among patients assigned to receive clopidogrel; HR 1.01, 95% CI 0.92–1.11). More patients in the ERDP group experienced a major hemorrhagic event (4.1% vs. 3.6%, HR=1.15, 95% CI 1.00-1.32) or an intracranial hemorrhage (0.9% vs. 0.5%, HR=1.08, 95% CI 1.11-1.83).