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NIHR Signal The best dose of aspirin for cardiovascular protection may depend on body weight

Published on 18 December 2018

doi: 10.3310/signal-000699

Low dose aspirin only appears to be effective at preventing stroke or heart attack for people weighing less than 70kg, while higher doses are better for people who weigh over 70kg.

Researchers analysed data from 13 trials of aspirin for primary or secondary prevention of cardiovascular events, totalling over 115,000 participants. They found that 75 to 100mg aspirin only benefitted people who weighed less than 70kg, while only those who weighed 70kg or more benefited from doses of 325mg or above.

This NIHR-funded trial suggests that prescribing the same dose to people of all weights is unlikely to be ideal and, if aspirin is indicated, dose adjustments by weight are required.

UK guidelines do not recommend routine treatment with aspirin for people who do not have cardiovascular disease because of the increased risk of bleeding. However, for people at high risk of heart attack or stroke, the benefits may outweigh this increased risk. This study suggests that the dose may also need to be adjusted according to a person’s weight.

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Why was this study needed?

Around 45% of men and 34% of women aged 65 and over in the UK take aspirin to prevent cardiovascular events. Aspirin is recommended as secondary prevention after a heart attack or ischaemic stroke, but its place in primary prevention of cardiovascular disease is less certain and recent large studies have questioned this role.

Studies have shown that an antiplatelet effect may help reduce risk of a first cardiovascular event. However, the effect size is modest and varies in different groups (such as men and women). Aspirin also raises the risk of bleeding and gastrointestinal problems.

The researchers wanted to find out whether overall body weight (not body mass index) affected how much benefit people got from aspirin.

What did this study do?

Researchers carried out a systematic review of individual patient data from randomised trials of aspirin for prevention of cardiovascular disease. Nine trials were aimed at primary prevention, and four looked at secondary prevention after a stroke.

The researchers calculated the effect of different doses of aspirin for people who weigh 70kg or above, or less than 70kg.

The figures were adjusted to take account of factors including people’s age, sex, smoking status, body mass index and whether they used enteric coated or delayed release aspirin.

Some analyses were based on small numbers, and the trials were not set up to compare aspirin effectiveness for people of different weights, but the trends found are plausible.

What did it find?

For primary prevention of any cardiovascular event:

  • Low dose aspirin (75 to 100mg) reduced the risk by 23% in men and women weighing less than 70kg (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.68 to 0.87). People weighing 70kg or more did not get any reduction in risk from taking low dose aspirin (HR 0.95, 95% CI 0.86 to 1.04).
  • Higher dose aspirin (300 to 325mg) did not reduce the risk for people weighing less than 70kg (HR 1.01, 95% CI 0.79 to 1.30) but reduced the risk by 17% in men and women weighing 70kg or more (HR 0.83, 95% CI 0.70 to 0.98).

For secondary prevention of any cardiovascular event:

  • Low dose aspirin was effective for people weighing less than 70kg, reducing the risk by 33% (HR 0.67, 95% CI 0.54 to 0.84) but not for people weighing 70kg or more (HR 1.01, 95% CI 0.75 to 1.37).
  • Higher doses of aspirin did not reduce the risk for people weighing less than 70kg (HR 0.95, 95% CI 0.76 to 1.18) but reduced the risk by 27% for people weighing 70 to 79kg (HR 0.73, 95% CI 0.58 to 0.93).

Bleeding risk:

  • Both low and high dose aspirin increased the risk of a major bleed at any weight except low dose for people over 90kg.

What does current guidance say on this issue?

NHS guidance does not recommend antiplatelet treatment for the primary prevention of cardiovascular disease because the benefits do not outweigh the risk of intestinal bleeding. However, it does recommend considering aspirin for people at high risk of stroke or myocardial infarction.

Antiplatelet treatment is recommended for secondary prevention of cardiovascular events in people with angina and peripheral arterial disease, acute coronary syndrome and after heart attack, stroke or a stent implant. The recommended dose for aspirin is 75mg a day, and the guidance does not suggest varying this by body weight.

What are the implications?

The findings challenge current guidance and clinical practice in the way aspirin is used to protect against cardiovascular disease. These results suggest that current practice may not be effective for the majority of people, those over 70kg, taking standard low dose aspirin to prevent heart attacks and strokes.

Although the authors of the study propose a weight-based dosing schedule based on their results, this needs to be validated with further research. The results imply that antiplatelet treatment could be improved with weight-based dosing.

Citation and Funding

Rothwell 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;392(10145):387-99.

This project was funded by the National Institute for Health Research Oxford Biomedical Research Centre and the Wellcome Trust.

Bibliography

K N Theken and T Grosser. Weight-adjusted aspirin for cardiovascular prevention. Lancet. 2018; 392:361-62.

NICE. Antiplatelet treatment. Clinical Knowledge Summary. London: National Institute for Health and Care Excellence; updated June 2018.

P Elwood, G Morgan, J White et al. Aspirin taking in a south Wales county. Br J Cardiol. 2011;18;101-72.

Why was this study needed?

Around 45% of men and 34% of women aged 65 and over in the UK take aspirin to prevent cardiovascular events. Aspirin is recommended as secondary prevention after a heart attack or ischaemic stroke, but its place in primary prevention of cardiovascular disease is less certain and recent large studies have questioned this role.

Studies have shown that an antiplatelet effect may help reduce risk of a first cardiovascular event. However, the effect size is modest and varies in different groups (such as men and women). Aspirin also raises the risk of bleeding and gastrointestinal problems.

The researchers wanted to find out whether overall body weight (not body mass index) affected how much benefit people got from aspirin.

What did this study do?

Researchers carried out a systematic review of individual patient data from randomised trials of aspirin for prevention of cardiovascular disease. Nine trials were aimed at primary prevention, and four looked at secondary prevention after a stroke.

The researchers calculated the effect of different doses of aspirin for people who weigh 70kg or above, or less than 70kg.

The figures were adjusted to take account of factors including people’s age, sex, smoking status, body mass index and whether they used enteric coated or delayed release aspirin.

Some analyses were based on small numbers, and the trials were not set up to compare aspirin effectiveness for people of different weights, but the trends found are plausible.

What did it find?

For primary prevention of any cardiovascular event:

  • Low dose aspirin (75 to 100mg) reduced the risk by 23% in men and women weighing less than 70kg (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.68 to 0.87). People weighing 70kg or more did not get any reduction in risk from taking low dose aspirin (HR 0.95, 95% CI 0.86 to 1.04).
  • Higher dose aspirin (300 to 325mg) did not reduce the risk for people weighing less than 70kg (HR 1.01, 95% CI 0.79 to 1.30) but reduced the risk by 17% in men and women weighing 70kg or more (HR 0.83, 95% CI 0.70 to 0.98).

For secondary prevention of any cardiovascular event:

  • Low dose aspirin was effective for people weighing less than 70kg, reducing the risk by 33% (HR 0.67, 95% CI 0.54 to 0.84) but not for people weighing 70kg or more (HR 1.01, 95% CI 0.75 to 1.37).
  • Higher doses of aspirin did not reduce the risk for people weighing less than 70kg (HR 0.95, 95% CI 0.76 to 1.18) but reduced the risk by 27% for people weighing 70 to 79kg (HR 0.73, 95% CI 0.58 to 0.93).

Bleeding risk:

  • Both low and high dose aspirin increased the risk of a major bleed at any weight except low dose for people over 90kg.

What does current guidance say on this issue?

NHS guidance does not recommend antiplatelet treatment for the primary prevention of cardiovascular disease because the benefits do not outweigh the risk of intestinal bleeding. However, it does recommend considering aspirin for people at high risk of stroke or myocardial infarction.

Antiplatelet treatment is recommended for secondary prevention of cardiovascular events in people with angina and peripheral arterial disease, acute coronary syndrome and after heart attack, stroke or a stent implant. The recommended dose for aspirin is 75mg a day, and the guidance does not suggest varying this by body weight.

What are the implications?

The findings challenge current guidance and clinical practice in the way aspirin is used to protect against cardiovascular disease. These results suggest that current practice may not be effective for the majority of people, those over 70kg, taking standard low dose aspirin to prevent heart attacks and strokes.

Although the authors of the study propose a weight-based dosing schedule based on their results, this needs to be validated with further research. The results imply that antiplatelet treatment could be improved with weight-based dosing.

Citation and Funding

Rothwell 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;392(10145):387-99.

This project was funded by the National Institute for Health Research Oxford Biomedical Research Centre and the Wellcome Trust.

Bibliography

K N Theken and T Grosser. Weight-adjusted aspirin for cardiovascular prevention. Lancet. 2018; 392:361-62.

NICE. Antiplatelet treatment. Clinical Knowledge Summary. London: National Institute for Health and Care Excellence; updated June 2018.

P Elwood, G Morgan, J White et al. Aspirin taking in a south Wales county. Br J Cardiol. 2011;18;101-72.

Effects of aspirin on risks of vascular events and cancer according to bodyweight and dose: analysis of individual patient data from randomised trials

Published on 19 July 2018

Rothwell, P. M.,Cook, N. R.,Gaziano, J. M.,Price, J. F.,Belch, J. F. F.,Roncaglioni, M. C.,Morimoto, T.,Mehta, Z.

Lancet , 2018

BACKGROUND: A one-dose-fits-all approach to use of aspirin has yielded only modest benefits in long-term prevention of cardiovascular events, possibly due to underdosing in patients of large body size and excess dosing in patients of small body size, which might also affect other outcomes. METHODS: Using individual patient data, we analysed the modifying effects of bodyweight (10 kg bands) and height (10 cm bands) on the effects of low doses (</=100 mg) and higher doses (300-325 mg or >/=500 mg) of aspirin in randomised trials of aspirin in primary prevention of cardiovascular events. We stratified the findings by age, sex, and vascular risk factors, and validated them in trials of aspirin in secondary prevention of stroke. Additionally, we 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 cancer. RESULTS: Among ten eligible trials of aspirin in primary prevention (including 117 279 participants), bodyweight varied four-fold and trial median weight ranged from 60.0 kg to 81.2 kg (p<0.0001). The ability of 75-100 mg aspirin to reduce cardiovascular events decreased with increasing weight (pinteraction=0.0072), with benefit seen in people weighing 50-69 kg (hazard ratio [HR] 0.75 [95% CI 0.65-0.85]) but not in those weighing 70 kg or more (0.95 [0.86-1.04]; 1.09 [0.93-1.29] for vascular death). Furthermore, the case fatality of a first cardiovascular event was increased by low-dose aspirin in people weighing 70 kg or more (odds ratio 1.33 [95% CI 1.08-1.64], p=0.0082). Higher doses of aspirin (>/=325 mg) had the opposite interaction with bodyweight (difference pinteraction=0.0013), reducing cardiovascular events only at higher weight (pinteraction=0.017). Findings were similar in men and women, in people with diabetes, in trials of aspirin in secondary prevention, and in relation to height (pinteraction=0.0025 for cardiovascular events). Aspirin-mediated reductions in long-term risk of colorectal cancer were also weight dependent (pinteraction=0.038). Stratification by body size also revealed harms due to excess dosing: risk of sudden death was increased by aspirin in people at low weight for dose (pinteraction=0.0018) and risk of all-cause death was increased in people weighing less than 50 kg who were receiving 75-100 mg aspirin (HR 1.52 [95% CI 1.04-2.21], p=0.031). In participants aged 70 years or older, the 3-year risk of cancer was also increased by aspirin (1.20 [1.03-1.47], p=0.02), particularly in those weighing less than 70 kg (1.31 [1.07-1.61], p=0.009) and consequently in women (1.44 [1.11-1.87], p=0.0069). INTERPRETATION: 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. FUNDING: Wellcome Trust and National Institute for Health Research Oxford Biomedical Research Centre.

Expert commentary

Aspirin is sometimes recommended by physicians for the primary prevention of cardiovascular disease. However, the ideal dose of aspirin and its effectiveness are both unclear.

In this study, which used individual patient data from randomised trials, Rothwell and colleagues aimed to address these questions. They found that low doses of aspirin (75–100mg) were only effective in preventing cardiovascular events in patients weighing less than 70kg. In contrast, higher doses of aspirin were only effective in patients weighing 70kg or more.

The findings of the study reinforce the importance of not adopting a “one-dose-fits-all” strategy to using aspirin for the primary prevention of cardiovascular disease; but rather, tailoring the dose of aspirin to a patient’s characteristics, including their weight.

Azeem Majeed, Professor of Primary Care and Head of the Department of Primary Care & Public Health, Imperial College London

Expert commentary

In the UK, the commonest dose of aspirin used for cardiovascular prevention is 75mg daily.

Rothwell and colleagues show that this dose is ineffective for most people, and that choice of dose needs to be tailored to the individual based on weight. They provide a plausible explanation for anomalous past findings with regard to differential efficacy of aspirin by sex (women tend to weigh less than men, so are likely to benefit from a lower dose). This research will lead to a re-think in how aspirin is prescribed in the future.

The paper is an elegant illustration of the value of individual patient data analysis that sheds new light on old research.

Jonathan Mant, Professor of Primary Care Research and Head of the Primary Care Unit, University of Cambridge