Weight-Based Aspirin: Is it here to Stay?

Aspirin has been used since the ancient Egyptians used willow bark as an anti-inflammatory and pain medicine.  The remarkable journey of aspirin spans from 3000-1500 BC, from determining that aspirin could reduce fever in 1763 to 1828 when Joseph Buchner at Munich University extracted the active ingredient from willow, naming it salicin and in 1853 when Charles Frédéric Gerhardt determined the chemical structure of acetylsalicyclic acid.¹ The first clinical trial was published in 1876, finding that salicin reduced fever and joint inflammation in patients with rheumatism.² In the last century-plus, clinical trials have shown benefits in cancer, ischemic stroke and secondary prevention of cardiovascular events, across patients of all ages.^3-7 Through all of these trials, a one-size fits all approach to aspirin dosing has been primarily studied.^7-8  However, we are in the age of personalized medicine.  Thereby, does low-dose aspirin really confer benefit across all persons?  Previous analyses have not found consistent effects, based on BMI,⁸ bringing into question the relationship between aspirin dosing and application in all patients.

A recent study from the Centre for Prevention of Stroke and Dementia in the UK investigated the effects of the interaction between bodyweight and aspirin dose on the risk of vascular events, bleeding, and cancer by combining patient data from randomized controlled trials.⁹ The authors included ten trials of aspirin in primary prevention including 117,279 participants.  median bodyweight varied between 60 to 81.2 kg and aspirin dosing between 75-100mg (low-dose) to 300-325mg or ≥500mg (high-dose).  Low-dose reduced cardiovascular events decreased with increasing weight (p =0.0072) with the most benefit seen in < 69 kg but not in those weighing 70g or more.  Higher doses of aspirin had the inverse effect, only reducing cardiovascular events at the higher weight.  The findings also were similar in reducing long-term risk of colorectal cancer, in particular, those who were > 70 years old and weighed < 70 kg.  Greater harm was associated with people at the lowest weight for dose, including risk of sudden death, all-cause death in those patients who were < 50kg and received 75-100mg. 

For nearly a half century, the optimum dosage of aspirin has been unsettled.  Studies from the 1970s have shown that salicylate dosing maybe more informed by using body surface area rather than body weight.¹⁰  It is also important to note that salicylate  steady-state concentrations produced by chronic dosing increase more than proportionately with increasing the daily dose and time required to reach steady state increases with increasing daily dose.¹¹  This is due to the saturation of the salicylurate and salicyl phenolic glucoronide pathways, and the increasingly important renal clearance saturation occurs.¹²  So the issues raised by the above study must be considered in the context of pharmacokinetic parameters and whether the patients were all taking aspirin chronically and adherently throughout the follow-up period. 

Nonetheless, these findings show that a standard recommendation of 75-100mg of aspirin to prevent cardiovascular disease is dependent on body weight.  This dose was ineffective in most men (80%) and approximately half of women who weighed over 70 kg for primary prevention of cardiovascular events. 

So what should we recommend as the standard aspirin dose for primary prevention?  To answer this question, aspirin interactions must be considered.  The prescribing of concomitant antithrombotic drugs with aspirin is considered to be a serious drug-drug interaction, often leading to excess bleeding. Doses > 165mg are associated with loss of effect of RAAS inhibitors in heart failure.¹³   Therefore, a weight-based dosing of aspirin should be considered.  In the absence of drug-aspirin interactions, a dose of 325-500mg (> 70kg: 325mg and > 90kg: 500mg) daily may be considered. For those patients who weigh < 50kg aspirin 50mg may be prescribed, but there is no firm data on this recommendation. Perhaps the safest dose recommendation is 165mg/day in patients who are being prescribed aspirin-drug interactions, but further study of this dose is certainly warranted in the near future.

Is it time to draw a salicylate level obtained 5-7 days after initiation of therapy (1-3 hours post-dose) to maximize aspirin therapy for critical outcomes?  An idea posed almost 50 years ago!

Mark A. Munger, PharmD, FCCP, FACC, is a professor of pharmacotherapy and adjunct professor of internal medicine, at the University of Utah, where he also serves as the associate dean of Academic Affairs for the College of Pharmacy.

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References:

1. History of Aspirin. https://www.pharmaceutical-journal.com/news-and-analysis/infographics/a-history-of-aspirin/20066661.article  Accessed 08/2018
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