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Table 5 Summary of work plan guidance for subpopulation considerations—example. Aspirin for prevention of cardiovascular events

From: An approach to addressing subpopulation considerations in systematic reviews: the experience of reviewers supporting the U.S. Preventive Services Task Force

Potential subpopulation Applicable to review updates only Applicable to new reviews and review updates
(A) Previous systematic review’s approach for this subpopulation (B) Previous separate subpopulation recommendation statement? (C) Importance of a priori designation (D) Rationale for importance determination for this review (E) Policy context (F) Proposed work plan approach
Age - Age not explicitly addressed in key questions
- Reported results of age-specific subgroup analyses from primary papers
- Recommendation statement cites substantial evidence for differential benefits by age in the form of risk assessment tables
Yes High Increasing potential benefit for aspirin as people get older due to increased baseline risk for cardiovascular disease (CVD); this is balanced against increasing potential harm as people get older and experience increased risk for gastrointestinal bleeding. - Addressed in recent meta-analyses
- Age is a principal component of CVD risk and risk assessment; there is wide availability of validated risk assessment tools including age in user-friendly formats
In 2009, the USPSTF recommended aspirin for men 45–79 and women 55–79 when the potential benefit of CVD event reduction outweighs the risk of gastrointestinal bleeding. There was insufficient evidence for adults 80 and older and a recommendation against aspirin for men younger than 45 and women younger than 55.
Continue to address age-specific subgroups. Establish age as an a priori subgroup; gather, analyze, and report evidence by age-specific subgroups. Attend to age 80 and older for evidence sufficiency and future research
Sex - Separate key questions for men and women for benefits and harms Yes Highest Epidemiology of CVD events is different for men and women; men have a higher risk for events and have events at younger ages. Men are also at higher risk for gastrointestinal bleeding. - Recently cited as most important subgroup by key informants
- Controversial: recent meta-analyses including new trial data suggest no differences in the benefit of aspirin by sex, which is different from the previous review that found a significant benefit in women for stroke (but not myocardial infarction (MI)) and a significant benefit for men in MI (but not stroke)
Continue to explicitly address sex-specific subgroups. Establish sex as an a priori subgroup; gather, analyze, and report evidence by sex-specific subgroups.
Race/ethnicity - Race/ethnicity not addressed in the previous review No Unknown due to lack of evidence
Perceived need for information
Due to disparities in incidence and mortality of CVD, particularly among Blacks, there is the potential for greater benefit from aspirin in this group. - Not addressed in recent meta-analyses
- Key informant indicates a lack of evidence for this subgroup
Based on the recent work of others and key informant input, evidence reported by race/ethnicity is not expected. However, if any subgroup data is reported in the literature, it should be captured, analyzed, and reported. Confirmed lack of subpopulation data should be reflected in Future Research section of the report.
Other risk-related subgroups - Not explicitly addressed in previous key questions
- Results of subgroup analyses from primary papers reported for the following groups:
• Diabetics
• Baseline blood pressure levels
• Smoking status
• Kidney function
No Moderate Possible biological plausibility for subgroup differences. Factors related to diabetes (e.g., hyperglycemia, hyperinsulinemia, increased oxidative stress, advanced glycosylation end products) may influence platelet activity. Patients with peripheral artery disease (PAD) or diabetes may have less response to aspirin due to high inflammatory burden and platelet activation. Concomitant medications (e.g., statins, angiotensin-converting enzyme inhibitors, fibrates, selective serotonin re-uptake inhibitors) influence platelet activity and bleeding risk. - 3 new RCTs since last review in higher risk populations (2/3 in diabetics and 2/3 in patients with PAD)
- Key informant identified patients with PAD as a priority
- Recent meta-analyses have addressed the following subgroup considerations: CVD risk, smoking, diabetes, and cholesterol and blood pressure
- Recent meta-analyses in diabetic and elevated blood pressure patients
- A public comment cited a subgroup analysis from the Women’s Health Study showing that aspirin use was associated with increased harm in current female smokers. Because smoking is associated with both increased cardiovascular risk and gastrointestinal complications, this reviewer called for a cautious approach to aspirin use in female smokers
Establish CVD risk groups a priori for consideration of benefits and harms, including diabetes, PAD, blood pressure, and smoking.