R01AG074989

Informing Optimal First-Line Antihypertensive Therapy: A Rigorous Comparative Effectiveness Analysis of ARBs vs. ACEIs on Long-Term Risk of Dementia, Cancer, Heart Disease, and Quality of Life - Project Summary

Hypertension (HTN) prevalence increases with aging and is a leading risk factor for several chronic illnesses including Alzheimer's disease and related dementias (ADRD), cardiovascular disease (CVD), and several cancers, as well as mortality.

Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) are two of the most commonly prescribed anti-HTN classes, used by approximately 40 million US adults. ARBs and ACEIs have distinctive beneficial downstream effects on physiologic abnormalities in HTN, including vasoconstriction, inflammation, fibrosis, and oxidative stress, which in turn may result in different long-term risks of ADRD and multimorbidity associated with aging.

However, current HTN guidelines recommend prescribing ARBs and ACEIs interchangeably due to presumed equivalent benefit and safety. Our goal is to optimize initial anti-HTN medication prescribing by clarifying the optimal first choice RAS-blocker between ARBs vs. ACEIs. Because approximately 23 million US adults are currently taking an ACEI and physiologic evidence supports differences in downstream effects of these medications, even if ARBs are only 15% more effective, the long-term population health impact of switching first-line RAS-blockade from ACEI to ARB would be enormous.

We will leverage data from the Veterans Health Administration (VHA) and Kaiser Permanente Southern California (KP SoCal) to evaluate the effects of ARBs vs. ACEIs on the risk of ADRD, multimorbidity, frailty, and health-adjusted life expectancy (HALE; the amount of time one can expect to live accounting for one's cumulative morbidity burden). The VHA and KP SoCal are ideal data sources to perform this research because they include comprehensive healthcare information for over 10 million patients, collect detailed information on medication use and health outcomes, and have high patient retention with over 10 years of follow-up.

The specific aims are to determine long-term comparative effects, including duration of use, of ARB- vs. ACEI-based anti-HTN medication regimens on (Aim 1) the incidence of ADRD, CVD (stroke, myocardial infarction, coronary revascularization, or heart failure), and cancers, separately and (Aim 2) the patient-centered outcome of frailty and the population-centered outcome of HALE. We will use an active comparator, new-user design accounting for medication adherence, as well as natural language processing to ascertain ADRD more accurately in the electronic health record over using administrative codes alone.

Our team is well-suited to perform the study given considerable prior experience analyzing VHA and KP data, including pharmacoepidemiologic analyses of anti-HTN medication use; assessment of ADRD, CVD incidence, cancer incidence, and multimorbidity; and application of causal inference methods. Our project could support a paradigm shift of first-choice RAS-blockade.

Current projections indicate that ADRD will affect over 115 million people by 2050 and cancer incidence will be 27 million per year by 2040. The potential public health benefit of addressing these knowledge gaps and, thereby, improving the quality and length of life is enormous.

Trustees Of The University Of Pennsylvania

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Pennsylvania United States

State-Wide

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 292% from $808,711 to $3,171,616.