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

By

Robert S. Helmer, PharmD, BCPS

Allison M. Helmer, PharmD, BCACP

Sean Smithgall, PharmD, BCACP

Here’s what the evidence tells us about the use of 2 regimens—clopidogrel + aspirin and ER dipyridamole + aspirin—to prevent secondary ischemic stroke.

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PRACTICE RECOMMENDATIONS

› Initiate combined clopidogrel plus aspirin within 24 hours of a minor stroke or TIA and continue for no longer than 1 month; then switch patients to aspirin or clopidogrel monotherapy. A

› Do not use combined clopidogrel plus aspirin for long-term secondary stroke prevention. A

› Limit use of aspirin plus extended-release dipyridamole as a first choice for secondary stroke prevention because of limitations in efficacy and poor tolerability. B

Strength of recommendation (SOR)

A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series

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.

16. Li Z, Wang Y, Zhao X, et al. Treatment effect of clopidogrel plus aspirin within 12 hours of acute minor stroke or transient ischemic attack. J Am Heart Assoc. 2016;5:e003038.

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.

22. Sacco RL, Diener HC, Yusuf S, et al. Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke. N Engl J Med. 2008;359:1238-1251.

23. Dengler R, Diener HC, Schwartz A, et al. Early treatment with aspirin plus extended-release dipyridamole for transient ischaemic attack or ischaemic stroke within 24 h of symptom onset (EARLY trial): a randomised, open-label, blinded-endpoint trial. Lancet Neurol. 2010;9:159-166.

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 incidence of ischemic stroke in the United States is estimated to be more than 795,000 events each year.¹ After an initial stroke, the rate of recurrence is 5% to 20% within the first year, with the greatest prevalence in the first 90 days following an event.^2-5 Although dual antiplatelet therapy, often with aspirin and a P2Y12 inhibitor such as clopidogrel, reduces the risk for recurrent cardiovascular events, cerebrovascular events, and death following acute coronary syndromes and percutaneous intervention, the role of combination antiplatelet therapy for secondary prevention of ischemic stroke continues to be debated.⁶ Reconciling currently available data can be challenging, as many studies vary considerably in both the time to antiplatelet initiation and duration of therapy.

For many years, aspirin alone was the drug of choice for secondary prevention of noncardioembolic ischemic stroke.⁷ Efficacy is similar at dosages anywhere between 50 and 1500 mg/d; higher doses incur a greater risk for gastrointestinal hemorrhage.⁷ Current secondary prevention guidelines recommend a dosage of aspirin somewhere between 50 and 325 mg/d.⁷

Alternative agents have also been evaluated for secondary stroke prevention, but only clopidogrel is currently considered an acceptable alternative for monotherapy based on a subgroup analysis of the CAPRIE (Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events) trial.^7,8 Other alternatives, including cilostazol, ticlopidine, and ticagrelor, are limited by a lack of data, adverse drug reactions, or unproven efficacy and are not recommended in current guidelines.^7,9 The ongoing THALES (Acute Stroke or Transient Ischaemic Attack Treated with Ticagrelor and Aspirin for Prevention of Stroke and Death) trial, assessing combination ticagrelor and aspirin, may identify an additional option for antiplatelet therapy following acute stroke.¹⁰

The current guidelines from the American Heart Association/American Stroke Association (AHA/ASA) support the combination of aspirin and extended-release dipyridamole (ASA-ERDP) as a long-term alternative to aspirin monotherapy.^7,11 Additionally, the combination of clopidogrel and aspirin (CLO-ASA) is now recommended for limited duration in the early management of ischemic stroke.¹¹

This review will explore the role of dual antiplatelet therapy for secondary prevention of noncardioembolic ischemic stroke or transient ischemic attack (TIA), with particular focus on acute use of CLO-ASA.

Clopidogrel and aspirin: When to initiate, when to stop

The combined use of clopidogrel and aspirin has been well-studied for secondary prevention of ischemic stroke and TIA. However, interpreting and applying the results of these trials can be challenging given key differences in both time to treatment initiation and the duration of combination therapy. Highlights of the major randomized controlled trials (RCTs) evaluating the safety and efficacy of CLO-ASA are detailed in TABLE 1.^4,5,12-15

Initial trials evaluating CLO-ASA for secondary stroke prevention, including the MATCH (Management of ATherothrombosis with Clopidogrel in High-risk patients),¹² SPS3 (Secondary Prevention of Small Subcortical Strokes),¹³ and CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischaemic Stabilization, Management and Avoidance)¹⁴ trials assessed the long-term benefits of combination therapy, with most patients initiating treatment a month or more following an initial stroke and continuing therapy for at least 18 months.^12-14 Results from these trials indicate that long-term use (> 18 months) of CLO-ASA does not reduce recurrent events but increases rates of clinically significant bleeding.^12-14

Continue to: A look at Tx timing