Assessment of Vascular Event Prevention and Cognitive Function Among Older Adults With Preexisting Vascular Disease or Diabetes: A Secondary Analysis of 3 Randomized Clinical Trials

Abstract

Importance: Acquisition of reliable randomized clinical trial evidence of the effects of cardiovascular interventions on cognitive decline is a priority.

Objectives: To estimate the association of cognitive aging with the avoidance of vascular events in cardiovascular intervention trials and understand whether reports of nonsignificant results exclude worthwhile benefit.

Design, setting, and participants: This secondary analysis of 3 randomized clinical trials in participants with preexisting occlusive vascular disease or diabetes included survivors to final in-trial follow-up in the Heart Protection Study (HPS), Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH), and Treatment of HDL (High-Density Lipoprotein) to Reduce the Incidence of Vascular Events (HPS2-THRIVE) trials of lipid modification for prevention of cardiovascular events. Data were collected from February 1994 through January 2013 and analyzed from January 2015 through December 2018.

Exposures: Incident vascular events and diabetes and statin therapy.

Main outcomes and measures: Cognitive function was assessed at the end of a mean (SD) of 4.9 (1.5) years of follow-up using a 14-item verbal test. Associations of the incidence of vascular events and new-onset diabetes during the trials, with cognitive function at final in-trial follow-up were estimated and expressed as years of cognitive aging (using the association of the score with age >60 years). The benefit on cognitive aging mediated through the effects of lowering low-density lipoprotein cholesterol levels on events was estimated by applying these findings to nonfatal event differences observed with statin therapy in the HPS trial.

Results: Among 45 029 participants undergoing cognitive assessment, mean (SD) age was 67.9 (8.0) years; 80.7% were men. Incident stroke (n = 1197) was associated with 7.1 (95% CI, 5.7-8.5) years of cognitive aging; incident transient ischemic attack, myocardial infarction, heart failure, and new-onset diabetes were associated with 1 to 2 years of cognitive aging. In HPS, randomization to statin therapy for 5 years resulted in 2.0% of survivors avoiding a nonfatal stroke or transient ischemic attack and 2.4% avoiding a nonfatal cardiac event, which yielded an expected reduction in cognitive aging of 0.15 (95% CI, 0.11-0.19) years. With 15 926 participants undergoing cognitive assessment, HPS had 80% power to detect a 1-year (ie, 20% during the 5 years) difference in cognitive aging.

Conclusions and relevance: The expected cognitive benefits of the effects of preventive therapies on cardiovascular events during even the largest randomized clinical trials may have been too small to be detectable. Hence, nonsignificant findings may not provide good evidence of a lack of worthwhile benefit on cognitive function with prolonged use of such therapies.

Trial registration: isrctn.com and ClinicalTrials.gov Identifiers: ISRCTN48489393, ISRCTN74348595, and NCT00461630.

Conflict of interest statement

Conflict of Interest Disclosures: Drs Offer, Arnold, Bennett, Haynes, and Parish reported receiving grants from the Medical Research Council (MRC), the British Heart Foundation (BHF), Cancer Research UK (CRUK), Merck, and Roche during the conduct of the study. Dr Clarke reported receiving grants from the MRC, the BHF, Merck, and Roche during the conduct of the study. Dr Bowman reported receiving grants from the MRC and the BHF during the conduct of the study and grants from Merck outside the submitted work. Dr Bulbulia reported receiving grants from the MRC during the conduct of the study. Dr Hopewell reported receiving grants from the BHF, the MRC, CRUK, Merck, and Roche during the conduct of the study and grants from Merck and the Medicines Company (MEDCO) outside the submitted work. Dr Landray reported receiving grants from the MRC, the BHF, CRUK, Merck, Roche, and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre during the conduct of the study and grants from MEDCO, Boehringer Ingelheim, Novartis, and Pfizer outside the submitted work. Dr Armitage reported receiving grants from the MRC, the BHF, CRUK, and Merck during the conduct of the study and grants from Bayer, Solvay, Abbott, Alzheimers’ Research UK, MEDCO, the BHF, and the NIHR outside the submitted work. Dr Collins reported receiving grants and personal fees from the BHF and from UKBIOBANK during the conduct of the study and grants from CRUK, the MRC, Merck, the NIHR, Wellcome Trust, Pfizer, and MEDCO during the conduct of the study. In addition, Drs Collins and Parish reported having a patent for a statin-related myopathy genetic test issued and licensed, with royalties paid to University of Oxford and the MRC, from Boston Heart Diagnostics (Drs Collins and Parish have waived any personal reward). No other disclosures were reported.

Figures

Figure 1.. Mean Cognitive Function z Score by Age and Study Cohort

Analyses are adjusted for age, sex, and baseline disease. In participants older than 60 years, the overall mean cognitive function was 4.0% (SE, 0.1%) of an SD lower per year of age, as shown by the diagonal solid line. The corresponding percentages in the separate cohorts were 3.6% (SE, 0.2%) SD in the Heart Protection Study (HPS), 4.4% (SE, 0.2%) SD in the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH), 4.2% (SE, 0.2%) SD in the European cohort of the Treatment of HDL (High-Density Lipoprotein) to Reduce the Incidence of Vascular Events (HPS2-THRIVE), and 4.0% (SE, 0.1%) SD in the Chinese cohort of HPS2-THRIVE. Whiskers represent 95% CIs.

Figure 2.. Cognitive Aging Associated With Nonfatal Incident Events

Among 45 029 participants in the Heart Protection Study (HPS), Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH), and Treatment of HDL (High-Density Lipoprotein) to Reduce the Incidence of Vascular Events trials, analyses were adjusted for age, sex, baseline disease, randomized treatment allocation, duration in study, and the baseline risk factors associated with cognitive function in each trial.