When Should Aspirin Be Used for Prevention of Cardiovascular Events

Withmore than 100yearsofuse, aspirin is oneof themost extensively studied drugs in the history of medicine. In addition to its analgesic, anti-inflammatory, and antipyretic effects, acetylsalicylic acid is a potent irreversible inhibitor of platelet aggregation. In the late 19th century the acetylation of salicylic acid in an attempt tomake it less bitter and hence more palatable inadvertently gave this compound a unique property—the acetyl group can be transferred to the serine residue in theactive site of theenzymecyclooxygenase (COX), irreversibly inhibiting its function and therebypreventing the production of prostaglandins. In certain cells this property of aspirin is responsible for analgesic, anti-inflammatory, andantipyretic effects. Inplatelets, theCOX-1 isoformproduces thromboxaneA2,which aids in platelet aggregation. Thus, aspirin inhibits platelet aggregationandcan reduce thrombosis. In cellswithanucleus,COX canbe regenerated. Because platelets havenonucleus, COX-1 cannotbe reproducedand ispermanently inhibited.This leads to a prolonged antithrombotic effect lasting several days after a single dose until enough new platelets have been produced to restore normal function of the thrombotic system. With thisuniqueproperty, aspirinhasvaluable therapeutic effects inreducingtheriskofarterialvascularthromboticevents, suchasmyocardial infarctionandstroke,and, toa lesserextent, venous thrombotic events.However, this actionof aspirin also increases the risk of bleeding, leading to itsmost troubling adverseeffects: seriousgastrointestinalbleedingandhemorrhagic stroke.Overall, the balance betweenbenefit in preventingmajor vascular events and the risk of increasing serious bleeding events underlies the clinical decision ofwhen to use this inexpensivegenericdrug. Ingeneral, thehigher the riskof vascular events, themore advantageous it is to prescribe aspirin. A single trial, ISIS-2,1 demonstrated theutility of daily aspirin inthesettingofacutemyocardial infarctionreducingtherisk of vascular death by 23%.Aspirin also has been shown to be effectiveinthesettingofacuteischemicstroke.2Theacutebenefits of aspirin inaiding in thedissolutionof anacute thrombusover hourstodaysandthusrestoringbloodflowinthesettingofstroke ormyocardial infarctionvastlyoutweighanyshort-termbleedingrisks.For this reason,aspirin isamainstayofearly therapy in the acute settings of acute coronary syndromes and stroke. In pooled data from about 200 trials among patients with knownvascular disease, aspirinwas shown tohave long-term benefits inpreventingmajorvascularevents.2These trialsdemonstrated that among thosewithknownvasculardisease there isnetbenefit, reducingtheriskofmajorvasculareventsbymore than 20%exceeding themodest bleeding riskswhenaspirin is takenat a lowdosedaily.Higherdosesdonot increase thebeneficial effects but increase the risk of bleeding. Thus, aspirin is recommended at a dose of 75mg to 100mgper day for longertermsecondarypreventionofcardiovascularevents inpatients withknownvasculardisease.Aspirin alsohasutility in the settingof vascular procedures suchaspercutaneous coronary interventions,reducingtheriskofrestenosis,andisrecommended for several months up to a year after the procedure. Given thebeneficial effects of aspirinduring acute events, followingprocedures, and in the secondarypreventionofmajor vascular events among patients with cardiovascular disease (CVD), itwas logical to askwhether this inexpensivedrug could prevent the firstmyocardial infarction or stroke among persons who have yet to manifest vascular disease. Primary prevention trials for this question are especially challenging given the continued reduction in the incidence of important outcomes and require very large study populations followed up for many years. Beginning in the 1980s several large-scale trials were undertaken to address this question, startingwith 2 trials among male physicians, the British Doctors’ Trial3 and the Physicians’ Health Study.4 These studies, along with a handful of other primary prevention trials among more than 100 000 studyparticipants, havegenerally shownmoremodest reductions ofmajor vascular events comparedwith secondary prevention (12% for major vascular events vs 22% for secondary prevention5,6)andreductions inmyocardial infarctionandtransient ischemic attack risk, and some have demonstrated a reduced risk of ischemic stroke.5,6 In the vast majority of the primary prevention trials, the overall risk level of CVD events was very low.5 In the primary preventionsetting, thereare limiteddataamongthoseathigher risk. There is also a paucity of data in Asian populations, in which hemorrhagic stroke risk (one of the important adverse effects of aspirin) tends to be higher than inWestern populations, and thus this population is of particular interest. In this issue of JAMA, Ikeda and colleagues7 report the results of the Japanese Primary Prevention Project (JPPP). The JPPPclinical trial studiedtheeffectofonce-daily, low-dose (100 mg), enteric-coated aspirin comparedwith no aspirin for preventing atherosclerotic events in 14 658 Japanese patients 60 years or older with hypertension, dyslipidemia, or diabetes. The study,whichhadplanned to followupparticipants for 6.5 years,was stoppedearly due to futility. After amedian follow-upof5years, therewasnosignificantdifference in the rate of the composite primary end point of total number of major atherosclerotic events (nonfatal myocardial infarction, nonOpinion