Weight-adjusted aspirin for cardiovascular prevention
Authors: Katherine N Theken, Tilo Grosser
Journal: The Lancet (2018)

Understanding the sources of variability in patients' responses to medicines has the potential to improve efficacy and safety through personalisation of treatment. Individual factors—ie, a patient's risk of cardiovascular events—are already considered when deciding who is prescribed low-dose aspirin for cardiovascular prevention. However, aspirin inhibits just one of several pathways of platelet activation, so it is not surprising that many patients still experience cardiovascular events.1Antithrombotic Trialists' (ATT) CollaborationAspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials.Lancet. 2009; 373: 1849-1860Summary Full Text Full Text PDF PubMed Scopus (2792) Google Scholar Factors that potentially contribute to these treatment failures, sometimes named as aspirin resistance, have been studied extensively, and several plausible mechanisms have been suggested, including non-adherence,2Hennekens CH Schneider WR Hebert PR Tantry US Gurbel PA Hypothesis formulation from subgroup analyses: nonadherence or nonsteroidal anti-inflammatory drug use explains the lack of clinical benefit of aspirin on first myocardial infarction attributed to "aspirin resistance".Am Heart J. 2010; 159: 744-748Crossref PubMed Scopus (28) Google Scholar accelerated platelet turnover in patients with diabetes,3Pascale S Petrucci G Dragani A et al.Aspirin-insensitive thromboxane biosynthesis in essential thrombocythemia is explained by accelerated renewal of the drug target.Blood. 2012; 119: 3595-3603Crossref PubMed Scopus (173) Google Scholar drug interactions with non-steroidal anti-inflammatory drugs,4Li X Fries S Li R et al.Differential impairment of aspirin-dependent platelet cyclooxygenase acetylation by nonsteroidal antiinflammatory drugs.Proc Natl Acad Sci USA. 2014; 111: 16830-16835Crossref PubMed Scopus (59) Google Scholar reduced bioavailability due to enteric coating,5Maree AO Curtin RJ Dooley M et al.Platelet response to low-dose enteric-coated aspirin in patients with stable cardiovascular disease.J Am Coll Cardiol. 2005; 46: 1258-1263Crossref PubMed Scopus (187) Google Scholar, 6Grosser T Fries S Lawson JA Kapoor SC Grant GR FitzGerald GA Drug resistance and pseudoresistance: an unintended consequence of enteric coating aspirin.Circulation. 2013; 127: 377-385Crossref PubMed Scopus (157) Google Scholar and bodyweight.7Peace A McCall M Tedesco T et al.The role of weight and enteric coating on aspirin response in cardiovascular patients.J Thromb Haemost. 2010; 8: 2323-2325Crossref PubMed Scopus (54) Google Scholar Considering these factors when tailoring dose, dosing frequency, and perhaps even time of dosing to individual patients might have substantial public health effects. In The Lancet, Peter Rothwell and colleagues8Rothwell PM Cook NR Gaziano JM 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; (published online July 12.)http://dx.doi.org/10.1016/S0140-6736(18)31133-4Summary Full Text Full Text PDF Scopus (227) Google Scholar report their investigation of the effects of the interaction between bodyweight and aspirin dose on the risk of vascular events, bleeding, and cancer by combining individual patient data from randomised controlled trials. Their analysis included nine trials of aspirin in primary prevention of cardiovascular events and major bleeding (including roughly 103 000 patients) and four of aspirin in secondary prevention of stroke (including roughly 13 000 patients). The authors found that low-dose aspirin (≤100 mg/day) prevented cardiovascular events only in individuals with low bodyweight (<70 kg), whereas higher doses of aspirin (≥300 mg/day) were effective only in individuals weighing 70 kg or more. A similar interaction was observed for colorectal cancer and bleeding, albeit with an apparently higher weight cutoff (≥80 kg for colorectal cancer and ≥90 kg for major bleeds). Notably, the analysis implies that weight-adjusted aspirin dosing might substantially improve the effectiveness of aspirin. Low-dose aspirin reduced cardiovascular events by 23% (hazard ratio [HR] 0·77, 95% CI 0·68–0·87; p<0·0001) in individuals weighing less than 70 kg, compared with a reduction of only 12% (0·88, 0·81–0·95; p=0·0008) in the overall primary prevention population when weight was not considered. Also, the authors suggest that sex differences in bodyweight—eg, more men than women weighed more than 70 kg—might explain aspirin's long recognised lack of efficacy in preventing stroke in men. The difference in stroke risk between men and women was no longer detectable when bodyweight was accounted for. Weight can affect drug distribution and clearance, and is known to modulate platelet inhibition by clopidogrel and prasugrel.9Angiolillo DJ Fernandez-Ortiz A Bernardo E et al.Platelet aggregation according to body mass index in patients undergoing coronary stenting: should clopidogrel loading-dose be weight adjusted?.J Invasive Cardiol. 2004; 16: 169-174PubMed Google Scholar, 10Erlinge D Ten Berg J Foley D et al.Reduction in platelet reactivity with prasugrel 5 mg in low-body-weight patients is noninferior to prasugrel 10 mg in higher-body-weight patients: results from the FEATHER trial.J Am Coll Cardiol. 2012; 60: 2032-2040Crossref PubMed Scopus (68) Google Scholar Moreover, weight-adjusted dosing is common for intravenous platelet inhibitors (glycoprotein IIb/IIIa antagonists and cangrelor). With regard to aspirin, extensive clearance by esterases in the intestine, plasma, blood cells, and the liver results in a systemic bioavailability of just 50%. It seems plausible that individuals with a larger body mass would have a greater quantity of these esterases than would smaller individuals, resulting in reduced aspirin bioavailability. This hypothesis is supported by the observation that the interaction between weight and risk of cardiovascular events was accentuated with enteric-coated aspirin, which has about 40% lower systemic bioavailability than does non-coated aspirin.11Bochner F Somogyi AA Wilson KM Bioinequivalence of four 100 mg oral aspirin formulations in healthy volunteers.Clin Pharmacokinet. 1991; 21: 394-399Crossref PubMed Scopus (29) Google Scholar The purpose of using low doses of aspirin is to limit systemic aspirin exposure and the consequent depression of homoeostatic cyclo-oxygenase (COX) products in vasculature and the stomach. Aspirin irreversibly acetylates COX-1 in platelets that are unable to synthesise new enzyme. Thus, low doses of aspirin can inhibit platelet function as long as more platelets are inhibited than are newly released from megakaryocytes. This inhibition can occur presystemically before inactivation by liver esterases.12Pedersen AK FitzGerald GA Dose-related kinetics of aspirin. Presystemic acetylation of platelet cyclooxygenase.N Engl J Med. 1984; 311: 1206-1211Crossref PubMed Scopus (468) Google Scholar Prostacyclin, the vascular COX product intended to be spared by use of low doses of aspirin, is a potent platelet inhibitor and a central molecule in the important negative feedback mechanism that limits the growth of thrombi at sites of vascular injury.13Grosser T Ricciotti E FitzGerald GA The cardiovascular pharmacology of nonsteroidal anti-inflammatory drugs.Trends Pharmacol Sci. 2017; 38: 733-748Summary Full Text Full Text PDF PubMed Scopus (82) Google Scholar The apparent lack of efficacy of intermediate-dose and high-dose aspirin in individuals weighing less than 70 kg raises the question of whether these treatment failures might reflect inhibition of vascular prostacyclin because of the increased systemic bioavailability of aspirin in this subgroup. How might weight-adjusted dosing of aspirin affect bleeding risk? In the trials included in the analysis, 80% of men and nearly 50% of women weighed 70 kg or more. Thus, weight-adjusted dosing would result in increased daily doses of aspirin in the majority of patients, which would be expected to affect bleeding risk. However, this association might not be linear because the authors observed that the bleeding risk on low-dose aspirin was elevated in patients weighing 70–90 kg despite the failure to prevent cardiovascular events. As the authors note, bodyweight should be considered in ongoing and future randomised clinical trials that address aspirin dosing in cardiovascular prevention to clarify how weight-adjusted dosing will affect both benefit and risk. Rothwell and colleagues present provocative results with the potential to substantially affect public health. Clearly, further research is warranted to establish whether weight-adjusted dosing of aspirin should be incorporated into clinical care. We declare no competing interests. Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: analysis of individual patient data from randomised trialsLow doses of aspirin (75–100 mg) were only effective in preventing vascular events in patients weighing less than 70 kg, and had no benefit in the 80% of men and nearly 50% of all women weighing 70 kg or more. By contrast, higher doses of aspirin were only effective in patients weighing 70 kg or more. Given that aspirin's effects on other outcomes, including cancer, also showed interactions with body size, a one-dose-fits-all approach to aspirin is unlikely to be optimal, and a more tailored strategy is required. Full-Text PDF Open Access