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Abstract The aim of this study was to investigate the association between baseline resting heart rate (RHR) and all‐cause death in the China Stroke Primary Prevention Trial (CSPPT). A post hoc analysis was conducted using data from 20,648 hypertensive adults without cardiovascular disease in the CSPPT and with baseline RHR data available. Over a median follow‐up duration of 4.5 years, the baseline RHR and risk for all‐cause death had a nonlinear relationship. The risk of all‐cause death was higher in participants with an RHR ≥85 bpm (hazard ratio 1.42; 95% confidence interval 1.03–1.96, p = .031) than in those with a baseline RHR of 75–80 bpm. The effect of RHR on all‐cause death during the treatment period was modified by the folate level (p = .020) and systolic blood pressure (SBP) during treatment(p = .056). The effect of RHR on the risk of all‐cause death was stronger when the folate level was low than when it was high; the risk was higher when the RHR was

Background and Purpose: DT-678 is a novel antiplatelet prodrug, capable of releasing the antiplatelet active metabolite of clopidogrel (AM) upon exposure to glutathione. In this study, we investigated factors responsible for clopidogrel high on-treatment platelet reactivity (HTPR) in acute coronary syndrome (ACS) patients and evaluated the capacity of DT-678 to overcome HTPR., Experimental Approach: A total of 300 consecutive ACS patients naive to P2Y 12 receptor inhibitors were recruited and genotyped for CYP2C19 alleles. Blood samples were drawn before and after administration of 600-mg clopidogrel. Platelet reactivity index (PRI) and plasma AM concentrations were determined and grouped according to their CYP2C19 genotypes. DT-678 was applied ex vivo to whole blood samples to examine its inhibitory effects. To further examine the antiplatelet effectiveness of DT-678 in vivo, 20 healthy human subjects were recruited in a Phase I clinical trial, and each received a single dose of either 3-mg DT-678 or 75-mg clopidogrel. The pharmacokinetics and pharmacodynamics in different CYP2C19 genotype groups were compared., Key Results: Statistical analyses revealed that CYP2C19 genotype, body mass index, hyperuricaemia, and baseline PRI were significantly associated with a higher risk of clopidogrel HTPR in ACS patients. The addition of DT-678 ex vivo decreased baseline PRI regardless of CYP2C19 genotypes, overcoming clopidogrel HTPR. This observation was further confirmed in healthy volunteers receiving 3 mg of DT-678., Conclusion and Implications: These results suggest that DT-678 effectively overcomes clopidogrel HTPR resulting from genetic and/or clinical factors in Chinese ACS patients, demonstrating its potential to improve antiplatelet therapy., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)