Clopidogrel and aspirin after ischemic stroke or transient ischemic attack: an updated systematic review and meta-analysis of randomized clinical trials

Kheiri, Babikir; Osman, Mohammed; Abdalla, Ahmed; Haykal, Tarek; Swaid, Bakr; Ahmed, Sahar; Chahine, Adam; Hassan, Mustafa; Bachuwa, Ghassan; Qasmi, Mohammed Al; Bhatt, Deepak L.

doi:10.1007/s11239-018-1786-z

Cited by 36 publications

(40 citation statements)

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“…A recent 2019 meta-analysis of 16 randomized clinical trials (30) found that dual antiplatelet therapy with aspirin was associated with significantly lower stroke rates (RR 0.80: 0.72 to 0.89), however some evidence of increased major bleeding was also observed (RR 1.90: 1.33 to 2.72). The authors noted that common CYP2C19 LoF variants may account for the effectiveness of dual therapy over clopidogrel monotherapy (30). In our study we found LoF carriers still had increased stroke or MI risk, even if co-prescribed aspirin.…”

Section: Discussionmentioning

confidence: 99%

Genetic variation in activating clopidogrel: longer-term outcomes in a large community cohort

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Türkmen

et al. 2021

Preprint

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Background The antiplatelet drug clopidogrel is commonly prescribed for stroke and myocardial infarction (MI) prevention. Clopidogrel prodrug is predominantly activated by liver enzyme CYP2C19. CYP2C19 Loss-of-function (LoF) genetic variants have been linked to excess morbidity mainly in patients hospitalized for acute ischemic events and related interventions. Little is known about the magnitude of impact of LoF variants in family practice, especially over long periods of exposure. We aimed to determine whether CYP2C19 LoF alleles increase risk of ischemic stroke and MI in primary care patients prescribed clopidogrel for up to 18 years. Methods Retrospective cohort analysis of 7,483 European-ancestry adults from the UK Biobank study with genetic and linked primary care data, aged 36 to 79 years at first clopidogrel prescription. We examined CYP2C19 LoF variant (*2-*8) associations with incident hospital-diagnosed ischemic stroke and MI in patients prescribed clopidogrel for at least 2 months using time-to-event models, with secondary analysis of the *17 gain of function variant. Results 28.7% (n=2,144/7,483) of included subjects (mean age 63 years at first clopidogrel prescription) carried at least one CYP2C19 intermediate or low metabolizer LoF variant. 1.9% of LoF variant carriers had an incident ischemic stroke whilst prescribed clopidogrel (mean 2.6 years, range 2 months to 18 years), versus 1.3% without the variants (0.6% absolute excess: Hazard Ratio 1.53: 95% CI 1.04 to 2.26, p=0.031). Additionally, 26.4% of CYP2C19 LoF variant carriers had an incident MI versus 24.1% (HR 1.14: 1.04 to 1.26, p=0.008). Adjustment for aspirin co-prescription produced similar estimates. In lifetables using observed incidence rates, 22.5% (95% CI 14.4% to 34.0%) of CYP2C19 LoF carriers on clopidogrel were projected to develop an ischemic stroke by age 79 (the oldest age in the study), compared with 15.4% (95% CI 11.4% to 20.5%) in non-carriers: the absolute excess stroke incidence with LoF variants was 7.1% by age 79. Conclusion In family practice patients on clopidogrel, CYP2C19 LoF variants are associated with substantially higher incidence of ischemic events. Genotype-guided (or routine) prescription of antiplatelet medications unaffected by CYP2C19 variants may improve outcomes in patients for whom clopidogrel is currently indicated.

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Section: Discussionmentioning

confidence: 99%

Genetic variation in activating clopidogrel: longer-term outcomes in a large community cohort

Pilling

Türkmen

et al. 2021

Preprint

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“…In conclusion, a long-term treatment with aspirin monotherapy is recommended in some systematic reviews (12,62) for a minor ischemic stroke event or small vessel disease presented as lacunar stroke or TIA; and as one the alternatives, is clopidogrel (as dual therapy) with a reduction of ischemic stroke of 25%, when installed for a short time (<1 month of the primary event occurred) and lower risk of bleeding compared to longterm therapy (63). Other systematic reviews also point out to the increased effect of dual therapy (28% reduction in the risk of ischemic stroke recurrence), but with moderate to severe bleeding events showed an increase of 64% (64).…”

Section: Discussionmentioning

confidence: 99%

Secondary prevention in minor ischemic stroke with antiplatelet treatment. Systematic review and meta-analysis of comparative studies with aspirin under non-inferiority criteria

et al. 2020

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Minor ischemic stroke is the most frequent presentation of cerebral vascular disease and treatment with antiplatelet drugs can be used for the prevention of its recurrence. This systematic review and meta-analysis was aimed to assess non-inferiority criteria about the effect in the comparison of different antiplatelet schemes using aspirin as active control. Twelve randomized studies with a total of 52204 patients were chosen. All met the inclusion criteria with minor recurrent ischemic stroke as end point and any extracranial bleeding as safety event. The results showed a significant risk reduction of 22% [RR (95% CI) = 0.78 (0.72-0.84), p<0.0001, NNT: 67] in the recurrence of ischemic events with any antiplatelet drug (combined or not with aspirin) versus aspirin alone and there were no differences in the bleeding risk [RR (95% CI) = 1.02 (0.74- 1.41), p= 0.899, NNH: 500]. Dual antiplatelet therapy (DAPT) and cilostazol were more effective compared with aspirin alone (22% and 32% risk reduction respectively) but only cilostazol showed a higher reduction (52%) of bleeding events. In conclusion, although in some instances equivalence was demonstrated, a clinical superiority in the risk reduction for recurrent ischemic stroke of any antiplatelet treatment versus aspirin alone was observed. With the sole exception of the cilostazol trials there was an increase of the bleeding risk when the antiplatelet drugs treatments were compared with aspirin alone.

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“…Data from clinical use of antithrombotics show that over 25% of patients on antiplatelet drugs will experience treatment failure and suffer an ischemic event [75]. Attempts to improve clinical effectiveness by combining antiplatelet drugs, for example P2Y 12 blockers and thromboxanes inhibitor in single treatment regimens have precipitated increased bleeding as a side effect [76][77][78]. Clearly, this demonstrates the need for new drugs that are antithrombotics via mechanisms distinct from agents presently used in the clinics.…”

Section: Targeting Aquaporins For Arterial and Venous Antithrombosismentioning

confidence: 99%

Aquaporins in platelet function

Agbani

Poole

2021

Platelets

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Structurally, aquaporins (AQPs) are small channel proteins with monomers of ~ 30 kDa that are assembled as tetramers to form pores on cell membranes. Aquaporins mediate the conduction of water but at times also small solutes including glycerol across cell membranes and along osmotic gradients. Thirteen isoforms of AQPs have been reported in mammalian cells, and several of these are likely expressed in platelets. Osmotic swelling mediated by AQP1 sustains the calcium entry required for platelet phosphatidylserine exposure and microvesiculation, through calcium permeable stretch-activated or mechanosensitive cation channels. Notably, deletion of AQP1 diminishes platelet procoagulant membrane dynamics in vitro and arterial thrombosis in vivo, independent of platelet granule secretion and without affecting hemostasis. Water entry into platelets promotes procoagulant activity, and AQPs may also be critical for the initiation and progression of venous thrombosis. Platelet AQPs may therefore represent valuable targets for future development of a new class of antithrombotics, namely, antiprocoagulant antithrombotics, that are mechanistically distinct from current antithrombotics. However, the structure of AQPs does not make for easy targeting of these channels, hence they remain elusive drug targets. Nevertheless, thrombosis data in animal models provide compelling reasons to continue the pursuit of AQP-targeted antithrombotics. In this review, we discuss the role of aquaporins in platelet secretion, aggregation and procoagulation, the challenge of drugging AQPs, and the prospects of targeting AQPs for arterial and venous antithrombosis. History

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Clopidogrel and aspirin after ischemic stroke or transient ischemic attack: an updated systematic review and meta-analysis of randomized clinical trials

Cited by 36 publications

References 50 publications

Genetic variation in activating clopidogrel: longer-term outcomes in a large community cohort

Genetic variation in activating clopidogrel: longer-term outcomes in a large community cohort

Secondary prevention in minor ischemic stroke with antiplatelet treatment. Systematic review and meta-analysis of comparative studies with aspirin under non-inferiority criteria

Aquaporins in platelet function

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