Stroke Prevention – are two agents better than one?

15th August 2018, Dr Chee L Khoo

Following an acute coronary event we know that two anti-platelets are better than aspirin alone in preventing further coronary events. What about a cerebro-vascular events? Following a mild CVA or a TIA, we would normally commenced aspirin to prevent another stroke especially in the first 90 days. Would adding another agent to aspirin be better in preventing further strokes? I had a patient just in that scenario this week. She had neurological symptoms suggestive of either a TIA or a complex migraine. She was not commenced on aspirin on discharge from hospital and I ponder whether she should be aspirin while the diagnosis was unsettled. Or maybe two agents?

The risk of another ischaemic stroke after a minor CVA or TIA in the first 90 days ranges between 3-15%. Aspirin has been shown to reduce that risk by 20%. Clopidogrel blocks platelet aggregation synergistically with aspirin. Thus, adding clopidogrel to aspirin theoretically, should reduce that risk further. In theory, at least. Does it?

The Clopidogrel in High Risk Patients with Acute Nondisabiling Cerebro-Vascular Events (CHANCE) trial reported a 32% further reduction in stroke recurrence in Chinese patients when clopidogrel was added to aspirin2. Because of the restricted ethnic population in the study, dual anti-platelet therapy has not been recommended routinely in stroke prevention guidelines yet.

A recent trial added to the findings from the CHANCE trial. The Platelet Oriented Inhibition in New TIA and Minor Ischaemic Stroke (POINT) trial was published in the New England Journal of Medicine a few weeks ago1. 4881 patients from 269 international sites with minor ischaemic stroke or high-risk TIA were enrolled to receive either aspirin alone or aspirin with clopidogrel from Day 1 of the event. A loading dose of 600mg clopidogrel was initiated followed by 75mg daily in the clopidogrel arm. Aspirin doses differ at different sites and ranged from 50-325 mg.

At 90 days, major ischaemic events occurred in 5% of patients in the clopidogrel + aspirin arm and 6.5% of patients in the aspirin alone arm suffered major ischaemic events. This represents a 25% reduction between the groups. Most of the events occurred within the first week of the initial neurological event. Major haemorrhage occurred in 0.9% of the combination arm and in 0.4% of the aspirin alone arm (Hazard Ratio of 2.32, p= 0.02). The authors estimated that for every 1000 patients who are treated with clopidogrel plus aspirin during a period of 90 days, such treatment would prevent approximately 15 ischemic events and would cause 5 major haemorrhages.

In the CHANCE trial, the clopidogrel regimen as slightly different to the POINT trial. The loading dose of clopidogrel was 300mg and clopidogrel was only added to aspirin in the first 21 days. This could have explained a lower risk of haemorrhage in the CHANCE trial. In both trials, the maximum benefit for stroke prevention was in the first month whereas the risk of bleeding was constant throughout the trial. I guess the longer one is on a double agent, the higher the risk of haemorrhage.

These two trials come after previous trials which did not show benefit adding another anti-platelet agent for stroke prevention. The SOCRATES (Acute Stroke or Transient Ischemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes) trial compared ticagrelor with aspirin in an international population and found no difference in the risk of major vascular events3. In the TARDIS (Triple Antiplatelets for Reducing Dependency after Ischemic Stroke) trial, investigators compared a combination of clopidogrel, aspirin, and dipyridamole with either clopidogrel alone or aspirin plus dipyridamole administered within 48 hours after the onset of ischemic stroke or TIA4. They found that patients who received the triple combination had no benefit with regard to the incidence and severity of recurrent stroke but had a higher rate of haemorrhage than those who received fewer medications.

The combination of ticagrelor and aspirin is being tested in the THALES (Acute Stroke or Transient Ischemic Attack Treated with Ticagrelor and ASA [acetylsalicylic acid] for Prevention of Stroke and Death) trial. It is expected to complete in December 2019 and report shortly after that.

Access the abstract for the POINT trial here.

Reference

  1. Claiborne Johnston, J. Donald Easton, Mary Farrant, William Barsan. Clopidogrel and Aspirin in Acute Ischemic Stroke. and High-Risk TIA. N Engl J Med 2018;379:215-25.
  2. Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med 2013; 369: 11-9.
  3. Johnston SC, Amarenco P, Albers GW, et al. Ticagrelor versus aspirin in acute stroke or transient ischemic attack. N Engl J Med 2016; 375: 35-43.
  4. Bath PM, Woodhouse LJ, Appleton JP, et al. Antiplatelet therapy with aspirin, clopidogrel, and dipyridamole versus clopidogrel alone or aspirin and dipyridamole in patients with acute cerebral ischaemia (TARDIS): a randomised, open-label, phase 3 superiority trial. Lancet 2018; 391: 850-9.