Aspirin to Prevent Cardiovascular Events: Not a ‘One-Dose-Fits-All’

Wednesday, January 2, 2019
Author: 

R.L. Wynn

Dosing of aspirin for the long-term prevention of cardiovascular events has traditionally taken the “one-dose-fits-all” approach. This has yielded only modest benefits in the prevention of cardiovascular events, possibly due to under dosing in patients of large body size and excess dosing in patients of small body size.

A study by the University of Oxford, Harvard, and other collaborators reviewed randomized trials of aspirin in primary prevention of cardiovascular events. The investigators found that low doses of aspirin, defined as 75-100 mg, were 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 more than 70 kg. In contrast, higher doses of aspirin, defined as 325 mg or greater, were only effective in patients weighing 70 kg or more.

In addition, the study authors noted that aspirin’s effects on other outcomes, including cancer, also showed dose variance with body size, and the current “one-dose-fits-all” approach to aspirin is unlikely to be optimal and requires a more tailored strategy. 

Aspirin Study Details

The study was published in Lancet and completed by investigators from multiple institutions. The lead author was from the Department of Clinical Neuroscience, University of Oxford, UK. Other authors hailed from Harvard Medical School, Boston, MA, USA; University of Edinburgh, Edinburgh, UK; Ninewells Hospital and Medical School, Dundee, UK; Institute of Research Pharmacology Mario Negri, Milan, Italy; and Hyogo College of Medicine, Nishinomiya, Japan.

Methods

A literature search strategy reviewed trials of aspirin versus control in primary prevention of vascular events as identified from the Antithrombotic Trialists (ATT) Collaboration, from other previous systemic reviews of trials of aspirin, and from the Cochrane Collaboration Database of Systemic Reviews. Trials were eligible if they randomly assigned participants to daily or alternate-day aspirin versus no aspirin. Trials of aspirin versus control in secondary prevention of stroke that randomized at least 1,000 participants were identified, along with any trials comparing different doses of aspirin in the secondary prevention of stroke. 

Using individual patient data, the authors analyzed the modifying effects of bodyweight (10-kg segments) and height (10-cm segments) on the effects of low doses (100 mg or less) and higher doses (300-325 mg or equal to or greater than 500 mg) of aspirin in the primary prevention and cardiovascular events trials. They stratified the findings by age, sex, and vascular risk factors and validated them in trials of aspirin in secondary prevention of stroke.

In addition, they assessed whether any weight or height dependence was evident for the effect of aspirin on 20-year risk of colorectal cancer or any in-trial higher doses of aspirin versus control.

Findings

The authors identified 10 eligible trials of aspirin versus control in primary prevention of cardiovascular events. All but one trial had collected data on weight or height. Individual patient data on baseline characteristics and all major cardiovascular events were available from nine trials.

Seven trials investigated low-dose aspirin (75-100 mg) versus controls, and two trials investigated higher doses of aspirin versus controls.

The authors identified five eligible trials of aspirin in secondary prevention of stroke and obtained individual patient data from the four largest trials. Bodyweight varied four-fold in each of the trials, with the median weight ranging from 60.0 kg to 81.2 kg. Trials also differed in age of participants and in number of participants who smoked.

Low-dose aspirin:

  • For primary prevention, the odds ratio (OR) for the effect of aspirin (75-100 mg) on risk of cardiovascular events was 0.77, indicating less risk for those weighing less than 70 kg, versus 0.94, indicating no benefit for those weighing 70 kg or more
  • The ability of low-dose aspirin (75-100 mg) to reduce cardiovascular events decreased with increasing weight
  • Low-dose aspirin had the greatest effect on cardiovascular events in participants weighing 50-69 kg (383 events in 15,155 participants treated with aspirin versus 504 events in 15,145 treated with control)
  • For those participants who used aspirin every day, 172 of 4,432 experienced events with aspirin versus 245 of 4,400 treated with control in the 50-69 kg weight group. That equated to a hazard ratio (HR) of 0.68 aspirin effect (approximately 30% reduction in cardiovascular events)
  • In one trial of alternate-day dosing, 100 mg aspirin was effective in participants weighing 50-59 kg (72 of 4,325 vs 102 of 4,408; HR = 0.72)
  • The reduction in cardiovascular events with 75-100 mg aspirin in 50-59 kg weight group was not seen in those weighing less than 50 kg
  • Low-dose aspirin (75-100 mg) prevented stroke in women, but not men; no difference remained after accounting for weight
  • In those weighing 70 kg or more, low-dose aspirin (75 -100 mg) was associated with an increase in case fatality of first cardiovascular events (OR = 1.33), particularly for myocardial infarction (OR = 1.73)

High-dose aspirin:

  • In primary prevention, 325 mg of aspirin reduced cardiovascular events in participants weighing 70 kg or more (OR = 0.83), and a 500 mg dose reduced cardiovascular events (OR = 0.55) in participants weighing 90 kg or more. These results were consistent in a pooled analysis of all trials
  • Cardiovascular events were reduced in participants weighing 70 kg or more (OR = 0.79) with 300-325 mg aspirin and in those weighing 90 kg or more (OR = 0.45) with 500 mg or more
  • Findings were similar in men and women, in people with diabetes, in trials of aspirin in secondary prevention, and in relation to height
  • A dose of 325 mg or greater was shown to reduce cardiovascular events in trials in primary prevention with increasing height with the greatest effect on the tallest group (approximately 1.85 meters). A dose of 100 mg or less was associated with increased cardiovascular events with increasing height

Additional Results

Aspirin reduction in long-term risk of colorectal cancer also appeared to be weight-dependent. Low-dose aspirin (75-100 mg) reduced risk of colorectal cancer in participants weighing less the 70 kg (OR =0.64), but not in people weighing 70 kg or more.

The benefit from higher doses of aspirin (325 mg or greater) extended to participants weighing up to 80 kg (OR = 0.69) and for those weighing less than 80 kg, but not for those weighing greater than 80 kg.

The risk of all-cause death was increased in people weighing less than 50 kg and receiving 75-100 mg aspirin (HR = 1.52). In participants age 70 years or older, the 3-year risk of cancer was also increased by aspirin (HR = 1.2), particularly in those weighing less than 70 kg (HR = 1.31), and consequently in women (HR = 1.44).

Proposed Mechanism

Obesity and increased body mass index (BMI) are associated with reduced inhibition of cyclo-oxygenase by low-dose aspirin, probably due to increased platelet activation. However, loss of effect at larger body size, driven by weight and height, suggests insufficient systemic bioavailability of aspirin rather than increased platelet activation secondary to obesity. Aspirin is metabolized by esterases in the intestinal wall, plasma, red blood cells, and liver. The proportion of fixed dose that reaches the systemic circulation will depend on the mass of these tissues, which is correlated with lean body size. The higher the lean body mass, the more esterase may be present to further metabolize active aspirin. This will reduce the systemic bioavailability of non-metabolized active aspirin. In addition, bodyweight could be a useful determinant of clinical effects of aspirin if obesity also increases platelet activation.

Higher doses of aspirin should overcome any reduced bioavailability with increasing body size and the data supports this concept.

Summary and Conclusion

Aspirin dosing to prevent cardiovascular events depends on bodyweight, as defined by lean body mass and height rather than BMI. Low-dose aspirin (75-100 mg once a day) was ineffective in people weighing 70 kg or more. Higher doses were more effective with increasing weight. Effects on sudden cardiac death and cancer also showed dose-weight interactions.  A “one-dose-fits-all” strategy is therefore unlikely to be optimal for the population in general, and the results in this study argue for a more tailored dosing strategy.

Richard L. Wynn, BS Pharm, PhD, is professor of pharmacology at the Baltimore College of Dental Surgery, Dental School, University of Maryland Baltimore.

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