Polypill Tested for Cognitive, Functional Benefits

Reducing blood pressure and cholesterol in the TIPS-3 trial with a polypill, with or without aspirin, showed no protective effect on cognition in older adults with cardiovascular disease risk factors, a secondary analysis showed.

During a 5-year follow-up, about the same number of trial participants in TIPS-3 experienced substantive cognitive decline in both the treatment and placebo groups, according to Jacqueline Bosch, PhD, of McMaster University in Hamilton, Ontario, and colleagues.

The primary outcome — a composite of cognitive and functional deficit scores — occurred in 6.52 people per 100 patient-years in the polypill group and in 6.34 per 100 patient-years in the placebo group (HR 1.05, 95% CI 0.90-1.21, P=0.55), they reported in JAMA Neurology.

However, the polypill did show a benefit on functional decline. Adjusted Standard Assessment of Global Everyday Activities (SAGEA) scores for polypill versus placebo were 0.06 vs 0.15 at follow-up, and scores for polypill plus aspirin versus placebo were 0.01 vs 0.14 (P=0.01 for both).

“Larger studies with longer follow-up may be warranted to detect small changes in cognition that may still be relevant at a population level,” Bosch and colleagues wrote. “Use of functional assessments may be a more sensitive outcome measure in international studies.”

Meta-analyses have suggested antihypertensive treatment may have a small — 7% to 9% — effect on cognitive decline, the researchers noted. “The assessments we used are sensitive to change, but in a population without manifest vascular disease, change may be slow, at least initially,” they observed.

TIPS-3 reported that aspirin added to a polypill lowered the incidence of cardiovascular events in intermediate-risk population. The polypill contained atenolol 100 mg, ramipril 10 mg, hydrochlorothiazide 25 mg, and simvastatin 40 mg.

Bosch and colleagues evaluated cognitive deficit in TIPS-3 using a primary composite outcome of cognitive and functional assessment scores. The composite included the Montreal Cognitive Assessment; the Digit Symbol Substitution Test of speed, attention, and executive function; the Trail Making Test Part B to assess attention; and the SAGEA, a patient-reported outcome that gauged the ability to perform usual activities. A change of 1.5 standard deviations was considered a substantive decrease in cognitive or functional abilities.

The outcome was based on country-standardized scores. “These scores were used to account for the country-level differences in scores, likely due to unrecorded cultural or regional differences,” the researchers wrote.

Overall, 2,098 TIPS-3 participants with an average age of 70 (60% women) completed baseline and follow-up assessments. Participants were from eight countries, mostly the Philippines and India, and were followed from July 2012 through September 2020.

Most participants (86%) had hypertension and 32% had impaired fasting plasma glucose levels. Mean baseline systolic blood pressure was 146.1 mm Hg, which decreased by 5.7 mm Hg in the polypill group; mean LDL cholesterol level was 124.3 mg/dL and fell by 24 mg/dL.

A total of 1,076 people were randomized to polypill and 1,022 people received placebo. Within each group, participants were split between those receiving aspirin (75 mg/day) versus no aspirin.

Over 5 years of follow-up, there were no significant differences in the number of participants with substantive cognitive decline (356 in the polypill group and 328 in placebo) or dementia (two people in the polypill group and four in placebo). Results were similar for those who had daily aspirin plus the polypill.

Several reasons may account for this, Bosch and colleagues noted. “First, the effect of vascular modification on cognitive decline may be modest,” they wrote. “Second, traditional cognitive testing may be insensitive to detecting domains of vascular cognitive impairment and associated with increased random error in international studies involving different cultures and different educational backgrounds.”

It’s possible the study did not adequately assess cognitive decline, and also possible that functional changes were at least partly attributable to physical decline, the researchers pointed out. “We used measures that were developed in Western studies, and it is uncertain whether these measures are responsive to change in other populations,” they acknowledged.