Role of Clinical Pharmacology in the Development of Antiplatelet Drugs

PurposeThis review discusses the role of clinical pharmacology in the development of low-dose aspirin and other antiplatelet agents during the past 30 years, emphasizing the main determinants of several success stories as well as of complete failures in the field.MethodsThe author employs personal appraisal of the literature, with emphasis on personal contributions to the field.FindingsLow-dose aspirin provides an interesting paradigm of the independent development of a “new” antiplatelet agent by the medical/scientific community. Aspirin “resistance,” improved dosing regimens for personalized therapy, and chemoprevention of colorectal cancer are thoroughly discussed. The industry-driven development paradigm includes 12 mechanism-based antiplatelet agents. Of those completing Phase 3, only 6 have been approved for the acute treatment or secondary prevention of atherothrombosis. Inadequate Phase 2 studies were largely involved in Phase 3 failures.ImplicationsThe design of mechanism-based pharmacodynamic biomarkers and sophisticated Phase 2 investigations appear as an important key to successful drug development in this field. Clinical pharmacology has an excellent track record in this endeavor, and its role needs to be expanded, as suggested by the case studies discussed in this review. Finally, the choice of appropriate platelet-dependent end points and homogeneous clinical settings for Phase 3 trials not only represent desirable objectives for an integrated scientific and regulatory discussion but also deserve proper ethical consideration by all stakeholders to avoid an unacceptable burden of drug toxicity and an unsustainable waste of financial resources.     

Aspirin in the prevention of cardiovascular events in patients with diabetes

Diabetes imparts a substantial increased risk for cardiovascular disease-related mortality and morbidity. Because of this, current medical guidelines recommend prophylactic treatment with once-daily, low-dose aspirin (acetylsalicylic acid) for primary and secondary prevention of cardiovascular (CV) events in high-risk patients. However, only modest reductions in CV events and mortality have been observed with once-daily aspirin treatment in patients with diabetes, including patients with a previous CV event, perhaps because of disparity between aspirin pharmacokinetics and diabetes-related platelet abnormalities. Once-daily aspirin irreversibly inactivates platelets for only a short duration (acetylsalicylic acid half-life, approximately 15–20 minutes), after which time newly generated, active platelets enter the circulation and weaken aspirin’s effect. Platelets from patients with diabetes are more reactive and are turned over more rapidly than platelets from normal individuals; the short inhibitory window provided by once-daily aspirin may therefore be insufficient to provide 24-h protection against CV events. Alternative conventional aspirin regimens (e.g. higher daily dose, twice-daily dosing, combination with clopidogrel) and newer formulations (e.g. 24-h, extended-release) have been proposed to overcome the apparent limited efficacy of conventional aspirin in patients with diabetes; however, tolerability concerns and limited clinical efficacy data need to be taken into account when considering the use of such regimens.     

氯吡格雷联合阿司匹林治疗心肌梗塞临床观察

目的:观察氯吡格雷联合阿司匹林治疗心肌梗塞的临床疗效和安全性。方法:78例心肌梗塞患者随机分为观察组和对照组,两组均给予常规内科治疗,在此基础上,观察组加用氯吡格雷首剂300mg,随后75mg,1次/d,口服;阿司匹林0.3g,1次/d,口服,连用3d后,改为0.1g,1次/d,口服。半年为1个疗程。观察2组临床疗效及治疗半年后的心脏事件发生情况。结果:观察组总有效率为90%,对照组总有效率为84.2%,2组比较差异有统计学意义(P0.05)。观察组发生休克病人1例,对照组发生2例。观察组心电图及血液流变学均较对照组有明显改善。结论:氯吡格雷联合阿司匹林治疗心肌梗塞优于单一使用阿司匹林。     

Risk factors for bleeding after dental extractions in patients over 60 years of age who are taking antiplatelet drugs

The aim of this retrospective, single-centre study was to identify the risk factors for bleeding after dental extractions in patients aged over 60 who were being treated with antiplatelet drugs. A total of 338 patients who fulfilled the inclusion criteria were enrolled, and their personal and clinical details, and complications with bleeding after extraction, were retrieved and recorded. There were 182 men and 156 women (mean (SD) age 72 (8) years). A total of 469 teeth were extracted, with a mean (SD) of 1.4 (0.6) teeth/patient. Seventy-seven patients (23%) developed mild, and 55 (16%) severe, bleeding postoperatively. No patient developed a major cardiovascular or cerebrovascular event. We calculated the significance of the association of different variables with the occurrence of postoperative haemorrhage using a multivariate stepwise logistic regression model. The presence of three or more coexisting conditions, a complicated tooth extraction, and the use of two antiplatelet drugs were independent risk factors, while discontinuation of antiplatelet treatment four or more days before the tooth was extracted was a protective factor. This suggests that clinicians should assess the thrombotic risk associated with the interruption of antiplatelet drugs as well as the risk of bleeding for each patient before dental extraction. Strong and effective measures for haemostasis may be preferred over blind discontinuation of antiplatelet drugs. This study is registered in the Chinese Clinical Trial Registry (No. ChiCTR1800014355).