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Aspirin inhibits platelet aggregation by irreversible acetylation of the cyclo-oxygenase-1 (COX-1) enzyme, resulting in almost complete inhibition of thromboxane production by platelets. However, aspirin yields only modest long-term reductions in vascular events, which has led investigators to develop alternative antiplatelet drugs and to study the effects of their combination with aspirin and of dual treatment with anticoagulant drugs. Yet the disparity between the effect of aspirin on thromboxane production and its clinical benefits might be due, at least in part, to the one-dose-fits-all approach used in trials and clinical practice, particularly the use of low doses in individuals with higher bodyweight. Obesity and increased body-mass index (BMI) are associated with reduced inhibition of COX-1 by low doses of aspirin, probably due to increased platelet activation or turnover, but high lean body mass could also reduce the systemic bioavailability of aspirin. Aspirin is rapidly de-acetylated by esterases in the intestinal wall, plasma, red blood cells, and liver, and so the proportion of a fixed dose that reaches the systemic circulation will depend on the mass of these tissues, which is correlated with lean body size. Given that aspirin acetylates several highly abundant proteins such as albumin, haemoglobin, and fibrinogen, their masses might also affect the systemic bioavailability of aspirin. Although about 50% of an oral dose of aspirin reaches the portal circulation6—and can therefore inhibit circulating platelets—reduced systemic bioavailability could restrict inhibition of COX-1 in megakariocytes and, hence, in the 10–15% of new platelets that are released daily. Thus, reduced systemic bioavailability of once-daily, low-dose aspirin at higher lean body mass could reduce clinical effectiveness, especially if doses are missed. Total bodyweight could be a particularly powerful determinant of clinical effects if obesity also increases platelet turnover.
EVIDENCE BEFORE THIS STUDY
A one-dose-fits-all approach to use of aspirin has yielded only modest benefits in the long-term prevention of cardiovascular events, possibly due to underdosing in patients of high body size and excess dosing in those of low body size. Randomised trials of aspirin in primary prevention of cardiovascular events have all tested a single dose against a control, but have differed in the dose(s) chosen. We identified ten randomised trials of aspirin in primary prevention (involving 117 279 participants) from the Antithrombotic Trialists' Collaboration, the Cochrane Collaboration Database of Systematic Reviews, and previous systematic reviews.
ADDED VALUE OF THIS STUDY
We found that the ability of low-dose aspirin (75–100 mg) to reduce cardiovascular events declined with increasing weight, with substantial benefit at 50–69 kg but no benefit at 70 kg or more, and with increased case fatality of first cardiovascular events in people weighing 70 kg or more. Higher doses (≥325 mg) of aspirin showed a reverse interaction with weight and height, reducing cardiovascular events only at larger body size. Findings were consistent in men and women, in participants with diabetes, and in trials of aspirin in secondary prevention of stroke. Reductions in long-term risk of colorectal cancer by aspirin were both height and weight dependent. However, stratification by body size revealed harms due to excess dosing, with an increase in sudden deaths at lower weight and an increase in the short-term risk of cancer at lower weight and shorter height in participants aged 70 years or older.
IMPLICATIONS OF ALL THE AVAILABLE EVIDENCE
The optimal dose of aspirin to prevent cardiovascular events depends on bodyweight, driven more by lean body mass and height than by body-mass index. Once-daily low doses (75–100 mg) of aspirin were ineffective in people weighing 70 kg or more, particularly in those who smoke or were treated with enteric-coated formulations, whereas higher doses became more effective with increasing weight. We also found that the effects of aspirin on sudden cardiac death and cancer showed dose–weight interactions. The substantial reductions in cardiovascular events and death at optimal doses for weight highlight the potential to improve effectiveness and argue for a more tailored dosing strategy. Higher doses of aspirin should overcome any reduced bioavailability with increasing body size, but might be excessive in patients with low bodyweight because of reduced endothelial prostacyclin production due to high systemic levels of aspirin or possibly because of increased salicylate levels. If the effectiveness of lower doses decreases, and the effectiveness of higher doses increases, with increasing body size, then weight–dose interactions could explain why low-dose aspirin appears to prevent stroke only in women, and high doses only in men despite them having similar BMIs.
CONCLUSIONS FROM THIS STUDY
In conclusion, the optimal dose of aspirin to prevent cardiovascular events depends on bodyweight, driven more by lean body mass and height than by BMI. Low-dose (75–100 mg) aspirin once a day was ineffective in people weighing 70 kg or more, particularly in those who smoked or were treated with enteric-coated formulations, whereas higher doses became more effective with increasing weight. Given that the effects on sudden cardiac death and cancer also showed dose–weight interactions, the one-dose-fits-all strategy for daily aspirin use is unlikely to be optimal. The substantial reductions in cardiovascular events and death at optimal doses for weight highlight the potential to improve effectiveness and argue for a more tailored dosing strategy.
Reprinted from THE LANCET 8-4-20-18 This is a condensed version of the article.
The educational pieces I stick on the web site are primarily things I was looking up to better understand issues I’m dealing with in my practice. Some of it might be pretty boring for you, but I thought it wouldn’t hurt for you to see how we sort out stuff rather than to just lecture at you. Watch out for the occasional cuss word.
Low 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.
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SHOULD YOU TAKE ASPIRIN?
EFFECTS OF ASPIRIN ON RISKS OF VASCULAR EVENTS AND CANCER ACCORDING TO BODYWEIGHT AND DOSE: ANALYSIS OF INDIVIDUAL PATIENT DATA FROM RANDOMISED TRIALS