Does a “One-Size-Fits-All” Aspirin Dosing Approach Still Hold WEIGHT?

Podcast Case: Weight-based Aspirin Dosing

Personalized medicine is at the forefront of health care today, focusing on how best to tailor the treatment approach to each person. But should we be thinking about personalizing the approach for prevention as well? A 42-year old male who weighs 116 kilograms (kg) and a 63-year old female who weighs 54 kg may both have the same indication for aspirin for the primary prevention of cardiovascular (CV) events … but should they take the same dose?

Aspirin has long been used in the primary prevention of CV disease due to its potent and long-lasting antiplatelet effects. Randomized trials have used doses ranging from 75 to 500 mg/day.^1-9 A modest CV benefit has been demonstrated in most clinical trials at doses as low as 75 mg daily. Aspirin has also been used for cancer prevention, specifically colorectal cancer. Despite the potential beneficial effects of aspirin in these populations, it is not benign and may cause major, sometimes fatal bleeding. What is poorly understood is the optimal dose and the influence of body weight.

The one-dose-fits-all approach has been used in nearly all aspirin studies.  The reason why aspirin has resulted in only modest benefits in clinical trials might be related to under (and over) dosing in patients based on body weight. Potential explanations why weight might be an important factor that should influence the dose of aspirin include diminished inhibition of cyclooxygenase-1 in obese patients and reduced systemic absorption in patients with high lean body mass.^10-11

Rothwell and colleagues sought to evaluate the impact of weight on the effects of high and low doses of aspirin for primary prevention of CV events and cancer. The study analyzed individual patient data as well as pooled data from the included trials. Trials were included in the analysis if they were randomized controlled trials comparing daily or alternate-day aspirin versus no aspirin for primary prevention of CV events, reported individual patient data on baseline characteristics, and reported major CV events. There were nine trials included in the analysis with 117,279 participants.  Seven studies evaluated lower doses of aspirin (75-100 mg) and two evaluated higher doses of aspirin (≥ 300 mg).^1-9 The study investigators also evaluated four trials of aspirin for secondary stroke prevention to validate findings from the primary prevention trials.^12-15

The outcomes evaluated included the incidence of all CV events (composite), stroke, myocardial infarction (MI), vascular death, major bleeding, and cancer. Participants were categorized initially into two groups (weight <70 kg versus weight ≥70 kg) and hazard ratios (HRs) for these outcomes were determined for aspirin versus control in a pooled analysis. The characteristics of the seven trials evaluating low-dose aspirin for primary prevention can be found in Table 1.  The pooled HR for aspirin on the risk of all CV events was 0.77 (95% CI 0.68-0.87, p<0.0001) in patients weighing <70 kg and 0.94 (95% CI 0.86-1.04, p=0.24) in patients weighing ≥ 70 kg. See Table 2. Results were similar for risk of stroke, MI, and vascular death in which patients weighing <70 kg had a significant reduction in risk with low-dose aspirin and patients weighing ≥70 kg did not (See Table 2). When evaluating the effect of low-dose aspirin in 10 kg increments of weight, the investigators found that the effect of low-dose daily aspirin on CV risk reduction was greatest in patients weighing 50-69 kg (HR 0.68; 95% CI 0.56-0.83; p=0.0001). This finding did not hold true for patients weighing <50 kg (HR 1.25, 95% CI 0.74-2.09; p=0.40) and in patients weighing ≥70 kg, low-dose aspirin was associated with an increase in fatal CV events (HR 1.33, 95% CI 1.08-1.64; p=0.0082). To validate the findings, secondary prevention trials were evaluated and effect modification by weight was similar in the ESPS-2 secondary prevention of stroke trial when compared to the primary prevention trials.¹²  The risk of major bleeding was lost in participants weighing ≥ 90 kg (p_interaction=0.024).

Table 1: Characteristics of the seven trials of low-dose aspirin (75-100 mg) vs. control in primary prevention

Table 2: Pooled analysis of the effects of low-dose aspirin versus control in primary prevention of vascular events

_{Abbreviations: ASA, aspirin; HR, hazard ratio; CI, confidence interval}

In contrast, the primary prevention trials comparing higher doses of aspirin (≥300 mg/day) versus control found a reduction in CV events in patients weighing ≥ 70 kg. In one trial, the 325 mg dose of aspirin reduced CV events in patients weighing ≥ 70 kg (HR 0.83, 95% CI 0.70-0.98; p=0.028). In the other trial, the 500 mg dose of aspirin reduced CV events or death in patients weighing ≥ 90 kg (HR 0.52, 95% CI 0.30-0.89, p=0.017). The results were consistent in the pooled analysis as well. The risk of major bleeding was not lost, however, in patients weighing ≥ 90 kg.

Among the primary prevention trials included in the study, five studies (n = 73,372 participants) had follow-up data on cancer. Results for colorectal cancer risk reduction parallel the findings from the CV analysis. Low-dose aspirin was associated with a reduced risk of colorectal cancer in patients weighing <70 kg (HR 0.64, 95% CI 0.50-0.82; p=0.0004) but not in patients weighing ≥ 70 kg (HR 0.87, 95% CI 0.71-1.07, p=0.32). In the analysis by 10 kg weight increments, the benefit of aspirin for colorectal cancer risk reduction extended to patients weighing up to 80 kg. However, higher doses of aspirin (≥325mg/day) were not associated with a reduction in risk in patients with higher body weight ≥80 kg (HR 1.08, 95% CI 0.83-1.39). This finding is in contrast to the CV analysis in which higher doses were associated with a reduction in CV events in patients at higher weight (≥70 kg).  

This study suggests that patient body weight is an important variable to consider when using aspirin to reduce CV and colorectal cancer risk. Lower aspirin doses (75-100 mg/day) were not effective in patients with higher body weights (>70 kg) while higher aspirin doses (>300 mg/day) prevented CV events. Additionally, based on these study findings, ‘under dosing’ or ‘overdosing’ was associated with harm. Strengths of this study include the large number of patients included, low heterogeneity among the studies included, consistency in trends seen for CV outcomes and cancer-risk, and validation with secondary prevention studies for stroke.

From a practice standpoint, there are a couple of things to consider.  Given that patient weight often changes over time, especially over the long duration that aspirin therapy is typically used, it remains unknown whether aspirin doses need to be adjusted over time based on changes in weight. Additionally, the risk of bleeding with low-dose aspirin did not diminish until patients were >90 kg and risk of bleeding with high-dose aspirin remained even in patients weighing >90 kg.  In other words, an effective dose of aspirin is likely accompanied by a higher risk of bleeding.  Whether there is a sweet spot where the benefits are maximized and the risks minimized is unclear.

A one-dose-fits-all approach appears to be suboptimal based on these study findings. But how much WEIGHT will this study hold in your clinical practice? Will you recommend higher doses (325mg daily or every other day) of aspirin to all of your patients who weigh > 70 kg?  Should clinical practice guidelines recommend weight-adjusted doses of aspirin?