Dual antiplatelet Tx for stroke prevention: Worth the risk?

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doi:10.12788/jfp.0020

Applied Evidence

Dual antiplatelet Tx for stroke prevention: Worth the risk?

J Fam Pract. 2020 July;69(6):272-279 | 10.12788/jfp.0020

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References

1. CDC. Stroke Facts. Last updated January 31, 2020. www.cdc.gov/stroke/facts.htm. Accessed June 29, 2020.

2. Amarenco P, Lavallee PC, Labreuche J, et al. One-year risk of stroke after transient ischemic attack or minor stroke. N Engl J Med. 2016;374:1533-1542.

3. Amarenco P, Lavallee PC, Monteiro Tavares L, et al. Five-year risk of stroke after TIA or minor ischemic stroke. N Engl J Med. 2018;378:2182-2190.

4. Johnston SC, Easton JD, Farrant M, et al. Clopidogrel and aspirin in acute ischemic stroke and high-risk TIA. N Engl J Med. 2018;379:215-225.

5. Wang Y, Wang Y, Zhao X, et al. Clopidogrel with aspirin in acute minor stroke or transient ischemic attack. N Engl J Med. 2013;369:11-19.

6. Bowry AD, Brookhart MA, Choudhry NK. Meta-analysis of the efficacy and safety of clopidogrel plus aspirin as compared to antiplatelet monotherapy for the prevention of vascular events. Am J Cardiol. 2008;101:960-966.

7. Kernan WN, Ovbiagele B, Black HR, et al. Guidelines for the prevention of stroke in patients with stroke and transient ischemic attack: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2014;45:2160-2236.

8. Gent M, Beaumont D, Blanchard J, et al. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348:1329-1339.

9. Lansberg MG, O’Donnell MJ, Khatri P, et al. Antithrombotic and thrombolytic therapy for ischemic stroke: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2 suppl):e601S-e636S.

10. Johnston SC, Amarenco P, Denison H, et al. The acute stroke or transient ischemic attack treated with ticagrelor and aspirin for prevention of stroke and death (THALES) trial: rationale and design. Int J Stroke. 2019;14:745‐751.

11. Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke. 2018;49:e46-e110.

12. Diener HC, Bogousslavsky J, Brass LM, et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet. 2004;364:331-337.

13. Benavente OR, Hart RG, McClure LA, et al. Effects of clopidogrel added to aspirin in patients with recent lacunar stroke. N Engl J Med. 2012;367:817-825.

14. Hankey GJ, Johnston SC, Easton JD, et al. Effect of clopidogrel plus ASA vs. ASA early after TIA and ischaemic stroke: a substudy of the CHARISMA trial. Int J Stroke. 2011;6:3-9.

15. Kennedy J, Hill MD, Ryckborst KJ, et al. Fast assessment of stroke and transient ischaemic attack to prevent early recurrence (FASTER): a randomised controlled pilot trial. Lancet Neurol. 2007;6:961-969.

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17. Scott SA, Sangkuhl K, Stein CM, et al. Clinical pharmacogenetics implementation consortium guidelines for CYP2C19 genotype and clopidogrel therapy: 2013 update. Clin Pharmacol Ther. 2013;94:317-323.

18. Wang Y, Zhao X, Lin J, et al. Association between CYP2C19 loss-of-function allele status and efficacy of clopidogrel for risk reduction among patients with minor stroke or transient ischemic attack. JAMA. 2016;316:70-78.

19. Diener HC, Cunha L, Forbes C, et al. European Stroke Prevention Study 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996;143:1-13.

20. Li X, Zhou G, Zhou X, et al. The efficacy and safety of aspirin plus dipyridamole versus aspirin in secondary prevention following TIA or stroke: a meta-analysis of randomized controlled trials. J Neurol Sci. 2013;332:92-96.

21. Halkes PH, van Gijn J, Kapelle IJ, et al. Aspirin plus dipyridamole versus aspirin alone after cerebral ischaemia of arterial origin (ESPRIT): randomised controlled trial. Lancet. 2006;367:1665-1673.

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24. 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;391:850-859.

The first trial to show benefit with ASA-ERDP was ESPS2 (European Stroke Prevention Study 2), which demonstrated superiority of the combination over placebo in reducing recurrent stroke when treatment was added within 3 months of an index stroke.¹⁹ A few studies have evaluated ASA-ERDP compared to aspirin monotherapy; however, most of these studies were small and did not show any difference in outcomes.²⁰ Only ESPRIT (European/Australasian Stroke Prevention in Reversible Ischaemia Trial)²¹ carried significant weight in a 2013 meta-analysis, which showed a significant reduction in recurrent events with the combination product compared to aspirin monotherapy.²⁰

Initiate clopidogrel + aspirin therapy within 24 hours of symptom onset and continue for no longer than 1 month; then switch to monotherapy with aspirin or clopidogrel.

Both the ESPS2 and ESPRIT trials had significant limitations.^19,21 Patients in both studies had vascular comorbidities including atherosclerotic cardiovascular disease (ASCVD); however, pharmacotherapies designated to treat these diseases were not mentioned in the demographic data, nor were these medications taken into consideration to limit potential bias.^19,21 Retrospectively, a significant proportion of aspirin doses utilized as a control in ESPRIT were inferior to the guideline-recommended dosing with 42% to 46% of patients receiving 30 mg/d.²¹ Despite these controversies, ASA-ERDP is still considered an alternative to aspirin monotherapy in the guidelines.⁷

The timing of ASA-ERDP initiation appears to be inversely related to the efficacy of the combination over therapeutic alternatives. Studies in which the therapy was initiated 3 to 6 months from the index stroke indicated favorable outcomes for the combination when compared to ASA or ERDP monotherapy.^19,21 Studies utilizing early initiation (ie, within 24 or 48 hours of the index event) or even within 3 weeks showed no difference in outcomes; however, this may be due in part to the use of clopidogrel or other combination antiplatelet therapy as active comparators.^22-24

Early initiation of ASA-ERDP also demonstrated a higher risk of major and intracranial bleeding compared to clopidogrel.²² Additionally, use of triple therapy with ASA-ERDP plus clopidogrel increased bleeding events without improving efficacy.²⁴ More recent studies of ASA-ERDP are focusing on earlier initiation of therapy; it is unknown whether the benefits of late initiation will be confirmed in future studies. Highlights of the major RCTs evaluating the safety and efficacy of ASA-ERDP are detailed in TABLE 2^19,21-24.

The takeaway. Methodological issues and potential confounding factors in many of the key trials for ASA-ERDP make it challenging to fully discern the role that ASA-ERDP may play in the secondary prevention of stroke. Further evidence utilizing appropriate controls, timing, and assessment of confounders is needed. Additionally, ASA-ERDP is plagued by tolerability issues such as headache, nausea, and vomiting, leading to higher rates of discontinuation than its comparators in clinical trials. Accordingly, the maintenance use of ASA-ERDP for secondary stroke prevention may be considered less preferred than other recommended alternatives such as aspirin or clopidogrel monotherapies.

CORRESPONDENCE
Robert S. Helmer, PharmD, BCPS, Department of Pharmacy Practice, Auburn University Harrison School of Pharmacy, 650 Clinic Drive, Suite 2100, Mobile, AL 36688; Rsh0011@auburn.edu.