More Choices of Antiplatelet Agents for the Secondary Prevention of Stroke

The New England Journal of Medicine recently published a large, randomized study (SOCRATES) comparing a relatively newer antiplatelet agent, ticagrelor, against aspirin in a prospective cohort of 13 199 patients with minor stroke or transient ischemic attack (TIA).¹ The primary composite end-point of stroke, myocardial infarction, or death occurred less frequently in the ticagrelor group, but these results were statistically insignificant (P=0.07). Safety end points also showed no difference in major bleeding between the 2 groups. The study concluded that ticagrelor was not superior to aspirin for the secondary prevention of vascular events when started within 24 hours of minor stroke or TIA.

To some, the results of this large trial may not be all that surprising. You may recall that the CAPRIE trial – a randomized, blinded trial of clopidogrel vs aspirin in patients at risk for ischemic events – looked at 19 185 patients and showed an absolute risk reduction of 0.51% in patients treated with clopidogrel for 1 year.² That translates roughly to a number needed to treat of 200 patients to prevent 1 stroke over aspirin. Ticagrelor is a direct acting reversible inhibitor of the P2Y12 receptor on platelets, the same receptor targeted by clopidogrel.¹ With such small absolute gains by clopidogrel, one could predict similar results from ticagrelor.

Granted, pharmacokinetic studies show a faster and more intense level of platelet inhibition with ticagrelor, which may be of significance in the secondary prevention of stroke within 24 hours of an ischemic event.¹ In that regard, a more recent Chinese trial demonstrated in patients with minor stroke or TIA (the group studied by SOCRATES) reduced recurrent events with the use of dual antiplatelet therapy with clopidogrel and aspirin for 21 days.³ Sub-group analysis looking at ticagrelor in patients who were already on aspirin (and for that matter, effectively on dual antiplatelet therapy for 7 days) did not show any difference, although this kind of analysis is strictly exploratory as the primary outcome was not significant.

The more interesting question arises when considering aspirin or clopidogrel failures (or suspected resistance to aspirin or clopidogrel). The incidence of resistance is somewhat difficult to ascertain as measurement of platelet reactivity has been the subject of controversy, although several studies and reviews suggest there is a benefit to testing.⁴ A study published in 2006 looked at 123 patients on aspirin with VerifyNow platelet assay and found an incidence of aspirin resistance at 12.1% defined as aspirin reaction units (ARU) >550.⁵ Clopidogrel resistance was recognized by the FDA in 2010 as a safety announcement warning providers that a portion of patients with certain genetic polymorphisms in the CYP2C19 liver enzyme may have no functional metabolism of clopidogrel.⁶ Estimates of clopidogrel resistance loom at 10%.⁴

The question of aspirin and other antiplatelet agent resistance and proper management is important as there is a growing body of literature that suggests that patients in this category are at risk for more severe strokes and larger core infarcts – and subsequently worse outcomes.⁷

In the event of recurrent ischemic stroke in patients already on aspirin or clopidogrel, ticagrelor may have an opportunity to shine. The use of platelet reactivity assays may help further stratify a cohort of patients who may benefit from a change in antiplatelet agent. Cardiac literature already supports the notion that stronger antiplatelet agents like ticagrelor and prasugrel reduce the recurrence of ischemic events.⁸ Evaluation of the use of other strong thienopyridines, such as prasugrel, in the prevention of ischemic stroke has been limited so far to sub-group analyses in larger trials studying cardiac disease, which were limited in power and with varying results.^8,9 There is still much work to be done to find the optimal role for newer antiplatelet agents in the prevention of stroke.

References

1. Johnston SC, Amarenco P, Albers GW, et al. Ticagrelor versus Aspirin in Acute Stroke or Transient Ischemic Attack. N Engl J Med. 2016; doi:10.1056/NEJMoa1603060.
2. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). The Lancet. 1996;348(9038):1329-1339.
3. 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(1):11-19.
4. Gurbel PA, Tantry US. Do platelet function testing and genotyping improve outcome in patients treated with antithrombotic agents?: Platelet function testing and genotyping improve outcome in patients treated with antithrombotic agents. Circulation. 2012;125(10):1276-87; discussion 1287.
5. Mirkhel A, Peyster E, Sundeen J, et al. Frequency of aspirin resistance in a community hospital. Am J Cardiol. 2006;98(5):577-579.
6. FDA drug safety communication. Reduced effectiveness of plavix (clopidogrel) in patients who are poor metabolizers of the drug. Published March 12, 2010. Updated March 24, 2016. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ ucm203888.htm.
7. Oh MS, Yu KH, Lee JH, et al. Aspirin resistance is associated with increased stroke severity and infarct volume. Neurology. 2016;86(19):1808-1817.
8. Chin CT, Neely B, Magnus Ohman E, et al. Time-varying effects of prasugrel versus clopidogrel on the long-term risks of stroke after acute coronary syndromes: Results from the TRILOGY ACS trial. Stroke. 2016;47(4):1135-1139.
9. Schomig A. Ticagrelor: Is there need for a new player in the antiplatelet-therapy field? N Engl J Med. 2009;361(11):1108-1111.