Aspirin Continues to Attract Research and Debate, 115 Years After Its Synthesis

Figure 1. The absolute risk of vascular complications is the major determinant of the absolute benefit of antiplatelet prophylaxis. Data are plotted from placebo-controlled aspirin trials in different clinical settings. For each category of patients, the abscissa denotes the absolute risk of experiencing a major vascular event as recorded in the placebo arm of the trial(s). The absolute benefit of antiplatelet treatment is reported on the ordinate as the number of subjects in whom an important vascular event (nonfatal myocardial infarction, nonfatal stroke, or vascular death) is prevented by treating 1000 subjects with Acetylsalicylic acid, synthesized in an industrial environment in 1897, was introduced to the market as Aspirin in 1899. For about 70 years it represented the mainstay of analgesic/antiinflammatory drug therapy and its pharmacologic actions provided the template for the synthesis of novel nonsteroidal antiinflammatory drugs. Following several fundamental discoveries on its mechanism of action as an antiplatelet drug in the seventies, aspirin has lived a second life as an antithrombotic agent, becoming a fundamental component of cardiovascular prevention and treatment. Making the jump from a largely over-the-counter analgesic remedy to a life-saving prescription drug represents a success story of independent translational research. Key components of success were: a) mechanistic insight into the way in which aspirin inhibits platelet function; b) careful studies of the clinical pharmacology of its antiplatelet effect, establishing the unusual requirements of low dose and long dosing interval for optimal platelet inhibition; and c) a large number of adequately sized, placebo-controlled clinical trials to demonstrate its efficacy and safety in a variety of clinical settings characterized by high cardiovascular risk. As with other cardiovascular prevention strategies (eg, blood pressureor lipid-lowering drugs), low-dose aspirin can only reduce a fraction (about one quarter) of all major vascular events, not because of ‘‘resistance’’ to its antiplatelet effect, but because of the multifactorial nature of atherothrombosis. As with statins or antihypertensive drugs, the absolute benefits of aspirin (how many vascular events can be prevented by treating 1000 patients for one year) are linearly related to the underlying cardiovascular risk of the patients (Fig. 1). An extensive literature has described lower-than-expected inhibition of platelet function (often referred to as ‘‘resistance’’) in a variable proportion of aspirin-treated patients. However, neither the mechanism(s) of response variability nor its reversibility have been established. Major limitations of previous studies are related to: a) inadequate ascertainment of compliance; b) largely undefined time interval between aspirin dosing and measurement of platelet inhibition; c) dichotomous definition of responder vs nonresponder status based on a single determination of platelet function using arbitrary thresholds of response; and d) lack of intervention studies to clarify the underlying mechanism(s) of variability in aspirin responsiveness.