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• W2920844186 abstract "Aspirin is one of the most universally recognized and commonly prescribed medications worldwide. It is estimated that 48.7 million US adults are taking aspirin for cardiovascular disease (CVD) prevention; the majority (~73%) for primary prevention.1Stuntz M. Bernstein B. Recent trends in the prevalence of low-dose aspirin use for primary and secondary prevention of cardiovascular disease in the United States, 2012-2015.Prev Med Rep. 2016; 5: 183-186Crossref PubMed Scopus (72) Google Scholar The benefit of aspirin for secondary prevention of CVD is well-established, with meta-analysis results favoring low-dose (75-150 mg/d) over high-dose (>150 mg/d) aspirin given similar efficacy but lower bleeding risk. In contrast, the role of aspirin in primary CVD prevention is more controversial; historical trials found benefit,2Capodanno D. Angiolillo D.J. Aspirin for primary cardiovascular risk prevention and beyond in diabetes mellitus.Circulation. 2016; 134: 1579-1594Crossref PubMed Scopus (91) Google Scholar but trials since 2008 have shown either null effects on all-cause and CVD mortality2Capodanno D. Angiolillo D.J. Aspirin for primary cardiovascular risk prevention and beyond in diabetes mellitus.Circulation. 2016; 134: 1579-1594Crossref PubMed Scopus (91) Google Scholar, 3Bowman L. Mafham M. Wallendszus K. et al.Effects of aspirin for primary prevention in persons with diabetes mellitus.N Engl J Med. 2018; 379: 1529-1539Crossref PubMed Scopus (599) Google Scholar, 4Gaziano J.M. Brotons C. Coppolecchia R. et al.Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial.Lancet. 2018; 392: 1036-1046Abstract Full Text Full Text PDF PubMed Scopus (464) Google Scholar or a signal for increased mortality in the context of excess bleeding.5McNeil J.J. Wolfe R. Woods R.L. et al.Effect of aspirin on cardiovascular events and bleeding in the healthy elderly.N Engl J Med. 2018; 379: 1509-1518Crossref PubMed Scopus (577) Google Scholar Many theories have been put forward as to why low-dose aspirin no longer appears efficacious in primary prevention. These include a diminishing return on efficacy in the context of contemporary care (eg, smoking cessation, statins, and control of A1c) and the possibility that one aspirin dose may not fit all patients (eg, dosing primary prevention aspirin according to weight might improve safety and efficacy6Rothwell P.M. Cook N.R. Gaziano J.M. et al.Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: analysis of individual patient data from randomised trials.Lancet. 2018; 392: 387-399Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar). In this commentary, we summarize evidence for and against weight-based aspirin dosing in primary prevention, place this evidence in the context of recently published aspirin trials, and offer updated clinical advice for aspirin use in the primary prevention of CVD in the year 2019 and beyond. The need to adjust aspirin dose according to weight has physiological plausibility. For example, aspirin requires deacetylation to become active, and pharmacokinetic studies have found that obesity is associated with inadequate treatment response to aspirin, as assessed by thromboxane inhibition. A 2018 meta-analysis by Rothwell et al6Rothwell P.M. Cook N.R. Gaziano J.M. et al.Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: analysis of individual patient data from randomised trials.Lancet. 2018; 392: 387-399Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar, which included 9 trials of aspirin in primary prevention (including 103,000 participants) and 4 trials of secondary prevention of stroke (17,000 participants), reported that the effectiveness of aspirin at a dose of ≤100 mg in reducing cardiovascular events decreased with increasing weight, with benefit seen in patients weighing 50–69 kg (hazard ratio [HR] 0:75; 95% confidence interval [CI], 0.65-0.85) but not in those weighing 70 kg or more (HR 0:95 [95% CI, 0.93-1.29]).6Rothwell P.M. Cook N.R. Gaziano J.M. et al.Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: analysis of individual patient data from randomised trials.Lancet. 2018; 392: 387-399Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar Consistent with this, low-dose aspirin only increased risk of bleeding when bodyweight was <90 kg. Conversely, aspirin (≥325 mg) had the opposite interaction with body weight, reducing cardiovascular events solely among those >70 kg.6Rothwell P.M. Cook N.R. Gaziano J.M. et al.Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: analysis of individual patient data from randomised trials.Lancet. 2018; 392: 387-399Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar Although the analysis by Rothwell et al6Rothwell P.M. Cook N.R. Gaziano J.M. et al.Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: analysis of individual patient data from randomised trials.Lancet. 2018; 392: 387-399Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar raises concerns that aspirin should be dosed according to weight, their results also raise some questions. For instance, although higher doses of aspirin appeared more effective in reducing cardiovascular events in those with higher body weight, the same was not found for high-dose aspirin in patients weighing ≤70 kg. Among this group, ≥300 mg aspirin daily did not reduce cardiovascular events alone or in combination with death.6Rothwell P.M. Cook N.R. Gaziano J.M. et al.Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: analysis of individual patient data from randomised trials.Lancet. 2018; 392: 387-399Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar If the benefit of increased aspirin does correlates with body weight, one would expect this higher dose to also be efficacious among the low-weight cohort, which was not observed. Similarly, 75-100 mg aspirin did not reduce cardiovascular events among those ≤50 kg, even though it did between 50 and 69 kg.6Rothwell P.M. Cook N.R. Gaziano J.M. et al.Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: analysis of individual patient data from randomised trials.Lancet. 2018; 392: 387-399Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar Since the publication of the Rothwell et al6Rothwell P.M. Cook N.R. Gaziano J.M. et al.Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: analysis of individual patient data from randomised trials.Lancet. 2018; 392: 387-399Abstract Full Text Full Text PDF PubMed Scopus (227) Google Scholar meta-analysis, 3 landmark trials examining the utility of aspirin in primary prevention have been reported. The Aspirin in Reducing Events in the Elderly (ASPREE) trial randomized patients ages 70 years or older (or ≥65 years of age among blacks and Hispanics in the United States) to aspirin 100 mg daily and found a significantly increased risk of major hemorrhage but no reduction in cardiovascular events with aspirin.5McNeil J.J. Wolfe R. Woods R.L. et al.Effect of aspirin on cardiovascular events and bleeding in the healthy elderly.N Engl J Med. 2018; 379: 1509-1518Crossref PubMed Scopus (577) Google Scholar Interestingly, despite null effects overall, low-dose aspirin did demonstrate a signal for CVD benefit in the overweight subgroup of ASPREE (HR: 0.82 [95% CI, 0.68-1.00]) but not in those who were lower weight, though there was no formal evidence of statistical interaction by body-mass index.5McNeil J.J. Wolfe R. Woods R.L. et al.Effect of aspirin on cardiovascular events and bleeding in the healthy elderly.N Engl J Med. 2018; 379: 1509-1518Crossref PubMed Scopus (577) Google Scholar A Study of Cardiovascular Events in Diabetes (ASCEND) trial randomized patients with diabetes mellitus to aspirin 100 mg daily and found a reduction in nonfatal vascular events but at a cost of increased major bleeding risk (HR: 1.29) and no reduction in cardiovascular mortality.3Bowman L. Mafham M. Wallendszus K. et al.Effects of aspirin for primary prevention in persons with diabetes mellitus.N Engl J Med. 2018; 379: 1529-1539Crossref PubMed Scopus (599) Google Scholar As with ASPREE, and again contrary to the meta-analysis performed by Rothwell et al, low-dose aspirin actually had a greater reduction in nonfatal vascular events in patients weighing >70 kg (HR: 0.83, p = 0.02) and no benefit in patients weighing <70 kg, this time with some evidence of statistical heterogeneity (P-interaction = 0.02).3Bowman L. Mafham M. Wallendszus K. et al.Effects of aspirin for primary prevention in persons with diabetes mellitus.N Engl J Med. 2018; 379: 1529-1539Crossref PubMed Scopus (599) Google Scholar Finally, in the Aspirin to Reduce Risk of Initial Vascular Events (ARRIVE) trial, there was no evidence of CVD benefit for aspirin 100 mg/d in intention to treat analyses, even among those with a body-mass index ≤25 kg/m2 (p-interaction = 0.15). Indeed, the ASPREE and ASCEND studies also found that bleeding risk was consistently increased with low-dose aspirin without any evidence of heterogeneity by baseline weight (bleeding outcomes stratified by weight have not been published from ARRIVE yet), representing further evidence that the potency of aspirin’s antiplatelet action is not influenced significantly by weight. The totality of randomized evidence since 2008, and 3 trials in particular published in 2018, no longer demonstrates a reduction in cardiovascular mortality or all-cause death among primary prevention adults treated with low-dose aspirin. All of the studies for aspirin in primary prevention, whether before or after 2008, also demonstrate excess bleeding risk. In this context, it appears no longer justifiable to routinely recommend aspirin for the primary prevention of CVD. This is in keeping with current European guidelines recommendations but contradicts current US guidelines, where aspirin is still recommended if 10-year CVD risk is estimated to be >10%. Updated American Heart Association/American College of Cardiology guidelines for the primary prevention of CVD, just published in March 2019, have lowered the support for primary prevention aspirin from a Class 1 indication among those at elevated CVD risk to a class 2b recommendation among high risk adults aged 40–70 years (aspirin is no longer recommended for primary prevention among those >70 years). The guideline also emphasizes the need to first treat other CVD risk factors to target and then only that aspirin might be considered in the context of lower non-fatal MI risk, after discussing with the patient that the risk of benefit to harm from bleeding is approximately equal. In this context, it is worth noting that, even in ASCEND and ARRIVE, primary prevention aspirin continues to have some evidence for reduced risk of incident myocardial infarction/revascularization (notably though only in the per-protocol analysis of ARRIVE), and as such, one reason mortality benefits may not have been seen in recent trials is because of the drastically reduced case-fatality of type-1 myocardial infarction in contemporary practice.7Rosamond W.D. Chambless L.E. Heiss G. et al.Twenty-two-year trends in incidence of myocardial infarction, coronary heart disease mortality, and case fatality in 4 US communities, 1987-2008.Circulation. 2012; 125: 1848-1857Crossref PubMed Scopus (257) Google Scholar A resulting caveat is that some physicians and patients may still consider low-dose aspirin in certain high-risk primary prevention scenarios, choosing to decrease risk for nonfatal myocardial infarction (which can have long-term consequences like heart failure that are not well captured in clinical trials of 5 or so years duration) at the expense of increasing bleeding risk (which is usually minor). The results of ASPREE, ASCEND, and ARRIVE all contradict the suggestion that weight-based dosing might have utility in primary prevention, in that none of these trials found benefit for low-dose aspirin among persons at low weight. Whether high-dose aspirin might have a role in some primary prevention adults (eg, overweight) remains speculative and hard to justify based on current evidence. An ongoing trial using a novel design is the Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-term (ADAPTABLE) trial, which will compare high- versus low-dose aspirin in 15,000 secondary prevention patients. If ADAPTABLE finds no benefit for high-dose aspirin in secondary prevention, then the weight-based dosing of aspirin for primary prevention (whether it be low- or high-dose) will become even harder to justify." @default.
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• W2920844186 title "Aspirin for the Primary Prevention of Cardiovascular Disease: Weighing Up the Evidence" @default.
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