A new first line choice? Has clopidogrel superseded aspirin for secondary prevention following selected minor ischaemic strokes?

Following minor ischaemic stroke, current guidelines offer both aspirin and clopidogrel as acceptable first‐line options for secondary stroke prevention after a short course of dual antiplatelet therapy, leaving clinicians to choose based on individual patient factors. ¹ This flexibility has resulted in considerable practice variation and ongoing debate about optimal selection. While aspirin has traditionally been favoured, recent data have prompted renewed interest in whether clopidogrel should be preferentially considered as first‐line therapy.

Pooled analyses show clopidogrel provides modestly stronger protection against recurrent ischaemic events compared with aspirin. ² , ³ A 2019 meta‐analysis of five studies (n ≈ 29 357) reported that clopidogrel reduced recurrent ischaemic stroke (RR 0.72, 95% CI 0.56–0.92) and had a lower bleeding risk than aspirin. ² A retrospective cohort study of 1228 stroke patients found improved 5‐year survival with clopidogrel compared to aspirin (log‐rank 16.4; p < 0.0001), and a Korean study (n ≈ 494 patients) demonstrated significantly fewer net adverse clinical and cerebral events with clopidogrel compared with aspirin (HR 0.47, 95% CI 0.23–0.95). ⁴ However, a large Taiwanese registry reported a similar stroke recurrence but higher all‐cause mortality with clopidogrel (HR 1.30, 95% CI 1.07–1.58), potentially reflecting residual confounding inherent in observational datasets. ⁴ , ⁵

Aspirin carries well‐established, dose‐dependent gastrointestinal toxicity, while clopidogrel shows variable bleeding rates across studies depending on population and endpoint definitions. Though pooled analyses report lower overall bleeding with clopidogrel, a similar bleeding risk between the two drugs was observed in the CAPRIE trial. ⁶

Universal clopidogrel adoption faces pharmacogenomic hurdles. Clopidogrel is a prodrug requiring CYP2C19‐mediated bioactivation; however, loss‐of‐function alleles present in up to 30%–60% of patients (most commonly among Asians) create significant pharmacogenomic variability. ⁷ Meta‐analyses show stroke patients carrying these variants have over double the recurrence risk compared with genetic responders. ⁸ However, cost‐effectiveness studies indicate that CYP2C19 genotype testing is both cost‐saving and increases quality‐adjusted life‐years (QALYs). ⁹ Hence, UK clinical guidelines endorse routine genotype testing. ¹⁰ Australia, however, lacks economic modelling and access to genetic testing, leaving guidelines without recommendations for routine testing despite international evidence and Australia's growing Asian population. ¹¹

In Australia, both aspirin and clopidogrel are subsidised under the Pharmaceutical Benefits Scheme (PBS), so patient costs are comparable. However, meaningful economic impact arises from downstream healthcare costs from recurrent vascular events and long‐term disability. ¹² A cost‐effectiveness analysis based on CAPRIE data showed clopidogrel provided an additional 0.17 QALYs at an incremental cost of about US$31200 per QALY, largely due to fewer recurrent events. ¹³ Although Australian‐specific economic evaluations in secondary stroke prevention are limited, even modest reductions in recurrence are likely to translate into meaningful long‐term health‐system savings.

Overall, clopidogrel shows superior efficacy over aspirin in pooled analysis and observational studies, yet CYP2C19 loss‐of‐function alleles present a barrier to these benefits. In other countries, genotype testing has been shown to be cost‐effective and may offer a solution. Future trials should implement randomised trials directly comparing clopidogrel and aspirin for secondary stroke prevention, incorporating CYP2C19‐guided therapy versus standard care and integrating economic modelling to evaluate long‐term cost‐effectiveness.

Data availability statement

Data sharing not applicable to this article as no datasets were generated or analysed during the current study.