Effects of a Polypill, Aspirin, and the Combination of Both on Cognitive and Functional Outcomes: A Randomized Clinical Trial

Abstract

Importance: Vascular risk factors are associated with cognitive decline but studies addressing individual risk factors have not demonstrated an effect of risk factor management on the preservation of cognition. Few trials have examined the effect of vascular risk factor management on function.

Objective: To determine if a polypill could reduce cognitive and functional decline in people with risk factors but without manifest cardiovascular disease.

Design, setting, and participants: The International Polycap Study 3 (TIPS-3) was a 2 × 2 × 2 factorial randomized clinical trial. Hospital and community-based centers in 8 countries recruited and followed up participants between July 30, 2012, and September 30, 2020. A total of 5713 individuals were randomly assigned to treatment groups, and 2098 people 65 years or older at intermediate risk of cardiovascular disease completed a cognitive assessment and were included in the analyses.

Interventions: Polypill (antihypertensives and a statin), aspirin, or a combination of both treatments.

Main outcomes and measures: Cognitive and functional assessments completed at baseline, 2 years, and study end. The primary outcome was the effect of a polypill compared with placebo and a polypill plus aspirin compared with double placebo on the composite outcome of the proportion of participants in each group who experienced a substantive decrease (>1.5 SD change) in cognitive or functional abilities.

Results: Of the 2389 study participants older than 65 years, a total of 2098 (88%; mean [SD] age, 70.1 [4.5] years; 1266 female individuals [60%]) completed the baseline and follow-up assessment. A total of 1796 participants (86%) had hypertension, and 680 participants (32%) had impaired fasting plasma glucose levels. Mean (SD) baseline systolic blood pressure was 146.1 (17.7) mm Hg, and mean (SD) low-density lipoprotein cholesterol (LDL-C) level was 124.3 (40.7) mg/dL and decreased by 5.7 mm Hg and 24 mg/dL, respectively, among those assigned to the polypill group. During a 5-year follow-up, there were no significant differences between treatment groups in the number of participants who experienced substantive cognitive decline (356 assigned polypill, 328 assigned placebo) or dementia (2 assigned polypill, 4 assigned placebo). Functional decline was reduced during follow-up for those assigned to polypill compared with placebo (mean [SD] country-standardized adjusted follow-up Standard Assessment of Global Everyday Activities [SAGEA] scores, 0.06 [0.03] vs 0.15 [0.03]; P = .01) and polypill plus aspirin compared with double placebo (mean [SD] country-standardized adjusted follow-up SAGEA scores, 0.01 [0.04] vs 0.14 [0.04]; P = .01).

Conclusions and relevance: In this randomized clinical trial of patients 65 years or older with vascular risk factors, a polypill, with or without aspirin, was not associated with reduced cognitive outcomes but was associated with reduced functional decline.

Figure 1.. Disposition of Participants

DSST indicates Digit Symbol Substitution Test; MoCA, Montreal Cognitive Assessment; SAGEA, Standard Assessment of Global Everyday Activities; TMT-B, Trail Making Test Part B.

Figure 2.. Kaplan-Meier Plot: Primary Outcome Polypill vs Placebo

Kaplan-Meier plots of the primary outcome of the composite cognitive and functional deficit scores meeting the criteria for substantive decline in SAGEA subscores based on cohort location (A) and daily activities (B). Basic activities of daily living (bADL) score is of a total of 9, social ADL (sADL) score is of 9, mobility score is of 3, and instrumental ADL (iADL) score is of 3. SAGEA indicates Standard Assessment of Global Everyday Activities.