I have posted on aspirin & PCa a half-dozen times over the past two years. This post is not about PCa.
The last study I read (not cited) found that while low-dose aspirin did lower the risk of a secondary cardiovascular event, it was ineffective against a first. The new study discredits the idea of one-dose-fits-all, & may throw into doubt the conclusions of some earlier studies.
Aspirin is a COX-1 inhibitor. As such, it inhibits the production of thromboxane in platelets. This prevents the aggregation (clumping) of platelets which is the first step in clot formation. The attraction of aspirin for coagulation inhibition is that a low dose is sufficient to achieve that. The downside is that even a low dose, when used chronically, can cause serious bleeding. For those at high risk for blood clots, the bleeding risk is considered to be an acceptable trade-off.
But, in the U.S., there are many who self-medicate, assuming that a low-dose aspirin must be safe. Although usage has been dropping, 30% of adults use aspirin to avert a cardiovascular event - 22% for initial prevention & 8% for a repeat event. [2] Assuming that interest in aspirin as a CVD prophylactic increases with age, those numbers should be much higher for this group.
Because of the publicity surrounding positive PCa studies (they are actually a mixed bag), usage might be even higher for this group.
The new study "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. ...
"... 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."
"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, suggesting that the one-dose-fits-all strategy for daily aspirin 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."
"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."
"Our findings ... have implications for practice. First, given that low-dose aspirin reduces cardiovascular events to a greater extent than previously thought in individuals weighing 50–69 kg, comparisons with other antiplatelet or antithrombotic regimens should be stratified by body size. Second, interactions between dose and weight probably explain previously reported sex differences in the effects of aspirin on risks of stroke and myocardial infarction,9, 10 which might not be explained by overweight or obesity alone. Third, that 75–100 mg aspirin was ineffective in primary prevention of cardiovascular events in the 80% of men and nearly 50% of women who weighed 70 kg or more in our study, even increasing the case fatality of first events, questions the use of once-daily low doses of aspirin irrespective of weight, particularly in people who smoke or are taking enteric-coated aspirin. More data on the weight dependence of the effects of standard-release, low-dose aspirin would be helpful, but in larger individuals, any advantage of enteric coating in reducing upper-gastrointestinal tract side-effects must be weighed against the loss of effect on cardiovascular events. Fourth, no trial of 75–100 mg aspirin versus placebo was available in the setting of secondary prevention of stroke or myocardial infarction (records were destroyed37 or weight or height were not recorded32). However because loss of effectiveness in primary prevention of stroke or myocardial infarction in participants weighing 70 kg or more was most evident at older ages, in people who smoked, and in people with diabetes (appendix p 5), similar findings are likely in long-term secondary prevention. Moreover, analyses of trials comparing antiplatelet regimens in secondary prevention of stroke show that dual antiplatelet treatment is more effective than low-dose aspirin alone in people weighing 70 kg or more (Rothwell, unpublished), further implying that platelet inhibition is suboptimal at higher weight. Inadequate inhibition might explain the paradoxically increased case fatality of cardiovascular events in people of higher weight who are on low-dose aspirin, particularly if COX-independent pathways are upregulated. Fifth, guidelines to target individuals at high predicted risk of vascular events (eg, people who are overweight and smoke) for primary prevention with low-dose aspirin might not yield benefits. Sixth, widespread use of 325 mg aspirin once a day in the USA, and elsewhere, is questionable in low-weight individuals given the effectiveness of lower doses and the apparent hazards of excess dosing. Seventh, the possible harm of 75–100 mg aspirin in individuals weighing less than 50 kg will be most relevant in Japan and in parts of Asia where bodyweight is often less than 50 kg in women. The effects of 25–30 mg aspirin twice a day in the ESPS-2 trial (figure 2) suggest that lower doses might be preferable for such women. The mechanism of harm from aspirin at very low bodyweight is uncertain, but systemic effects on underlying non-vascular disease might be relevant, particularly in those who are underweight. Finally, our findings might inform interpretation of trials of dual therapy with aspirin and P2Y12 inhibitors after coronary events. Previous trials38, 39 investigating this combination reported that the effects of irreversible inhibitors, such as clopidogrel and prasugrel, appeared to be more weight dependent than those of the reversible P2Y12 inhibitor (ticagrelor), possibly because of twice-daily dosing, and that the efficacy of clopidogrel versus ticagrelor when added to aspirin might depend on both aspirin dose and bodyweight."
"We found that the effect of 75–100 mg aspirin on major bleeding was not lost until weight exceeded 90 kg. A 90 kg threshold was also found for reduced major bleeding on long-term treatment with 75 mg aspirin in a population-based cohort (OR for people weighing ≥90 kg was 0·58 [95% CI 0·36–0·84, p=0·002; Rothwell, unpublished). By contrast, we found that excess bleeding on high-dose aspirin did not diminish above 90 kg (appendix p 18), but appeared to increase with weight, similar to the effect on vascular events."
-Patrick
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