What is the clinical evidence from this study?

Study design: Meta-Analysis. Population: Cardiovascular disease, recent TIA, or minor ischemic stroke (n=15141). Intervention: Clopidogrel plus Aspirin vs. Aspirin monotherapy (with or without placebo). Primary outcome: Major adverse cardiac events (MACE) (OR 0.84, 95% CI 0.70-1.02, p=0.13).

August 20, 2023Open Access

CYP2C19 and effect of clopidogrel for secondary prevention of major ischemic events: systematic review and meta-analysis

Key Result

Clopidogrel reduced major adverse cardiac events with an OR of 0.84 in CYP2C19 variant carriers compared to an OR of 0.70 in non-carriers, though the interaction was not statistically significant (p=0.13).

Study Design

Type

Meta-Analysis (n=15,141)

Structured PICO

Does clopidogrel combined with aspirin reduce ischemic stroke and MACE compared to aspirin alone in patients with cardiovascular disease or recent TIA/stroke, and is this effect modified by CYP2C19 LoF carrier status?

Population

15,141 patients with cardiovascular disease, recent TIA, or minor stroke from 6 randomized controlled trials, genotyped for CYP2C19 loss-of-function variants, followed for 90 days to 5 years.

Intervention

Clopidogrel (75 mg daily, with 300-600 mg loading dose in 3 studies) combined with aspirin (ASA)

Comparator

Aspirin (ASA) monotherapy (with matching placebo in 5 studies, without placebo in 1 study)

Outcome

1) Occurrence of fatal or non-fatal ischemic stroke; 2) Major cardiovascular event (MACE: composite of ischemic stroke, myocardial infarction, non-central nervous system embolism, or vascular death)composite

This meta-analysis could not definitively establish that clopidogrel is less effective for overall MACE prevention in CYP2C19 LoF carriers, though a significant interaction was observed in the TIA/minor stroke subgroup.

Main Result

Odds Ratio: 0.84 (95% CI 0.7–1.02)

p-value: p=0.13

Limitations

All included studies were performed as post-hoc analyses of genetic sub-studies.
Genotype was determined in only a small proportion of patients from the original trials.
In the TIA/minor stroke subgroup, 60% of all events were from a single trial (CHANCE).
The included studies consisted of heterogeneous patient populations with different manifestations of vascular disease.
Poor and intermediate metabolizers of CYP2C19 were not investigated separately.
The baseline NIHSS was low in the largest trials, limiting extrapolation to patients with more severe strokes.

Abstract

Abstract Background Carriers of the CYP2C19 Loss of Function (LoF) allele may experience decreased efficacy of clopidogrel in secondary prevention after cardiovascular events. Randomized clinical trials of clopidogrel in patients with known CYP2C19 carrier status provided inconsistent results. Our aim was to pool the evidence on the effect of clopidogrel on outcome, according to CYP2C19 LoF status, in a meta-analysis. Methods A systematic review and meta-analysis of randomized controlled trials (RCTs) on the effect of clopidogrel according to CYP2C19 LoF status in patients with cardiovascular disease and recent TIA or stroke was performed. The primary outcomes were 1) ischemic stroke and 2) major adverse cardiac events (MACE). We used random effects analysis to estimate the effect of clopidogrel as a pooled odds ratio (OR) in carriers and non-carriers of the LoF variant and tested for interaction between clopidogrel and CYP2C19. Results We included six RCTs with a total of 15,141 participants comparing combined clopidogrel and aspirin therapy to aspirin monotherapy. The effect of clopidogrel on MACE was OR=0.70 in CYP2C19 non-variant carriers compared to OR=0.84 in CYP2C19 variant carriers (pinteraction=0.13). In patients with a recent TIA or minor ischemic stroke, the OR for the effect of clopidogrel on MACE was OR=0.52 in CYP2C19 non-variant carriers compared to OR=0.84 in CYP2C19 variant carriers (pinteraction=0.02) while in patients with cardiovascular disease the difference in effect was not evident (non-variant carriers OR=0.76, variant carriers OR= 0.84, pinteraction=0.50). Conclusion Our meta-analysis could not establish that overall, clopidogrel is less effective in patients with a recent MI, minor stroke or TIA and a CYP2C19 LoF genotype. However, the size and direction of the difference in effect warrants further research. Registration - URL : https://www.crd.york.ac.uk/prospero/ ; Unique identifier: CRD42021242993.

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