Pragmatic Evaluation of Events And Benefits of Lipid-lowering in Older Adults

Study Overview
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Brief Summary
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PREVENTABLE is a multi-center, randomized, parallel group, placebo-controlled superiority study. Participants will be randomized 1:1 to atorvastatin 40 mg or placebo. This large study conducted in community-dwelling older adults without cardiovascular disease (CVD) or dementia will demonstrate the benefit of statins for reducing the primary composite of death, dementia, and persistent disability and secondary composites including mild cognitive impairment (MCI) and cardiovascular events.

Detailed Description
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PREVENTABLE will randomly assign atorvastatin 40 mg daily or matching placebo daily to 20,000 community-dwelling adults 75 years of age or older without clinically evident cardiovascular disease, significant disability, or dementia, and follow them for up to 5 years (estimated median of 3.8 years). The study will enroll participants from approximately 100 US sites. Community engagement efforts will leverage community groups and practices as collaborators for recruitment. We plan to partner with participants, caregivers, and clinicians in all aspects of the study. The enrolling sites are non-VA and VA sites. Each site will apply a study-specific cohort identification algorithm to their electronic health record to create a list of eligible participants based on study inclusion and exclusion criteria. The cohort identification will exclude individuals with clinically evident cardiovascular disease, significant disability, or dementia and other exclusions obtainable from data queries to define a potential cohort. Sites will screen potential participants to confirm eligibility and consent and randomize those interested in joining the study. Specifically related to dementia, the qualifying exclusion is a clinical diagnosis in the chart or clinician's assessment that dementia may be present. Sites will enter contact information, mailing address for study drug, demographic information, height, weight, statin history (if any), Social Security Number, and aspects of the medical history not obtainable from EHR. In addition, a Short Physical Performance Battery (SPPB) and Activities of Daily Living (ADL) screen will be site-performed at baseline. SPPB will provide an objective assessment of function for understanding frailty and physical function of the enrolled population. Baseline lipid panel (core lab) and biospecimen samples will be obtained using the same blood draw for 20cc of blood. Blinded lipid testing will be performed at baseline on all participants (n=20,000) and repeated at 3 months in a random subset (n=2,000). Lipid panels will be sent to the PREVENTABLE Core Lab to maintain study blind. Future testing of lipid panels during routine clinical care will be actively discouraged, but other laboratory testing as indicated by clinical care is permitted.Sites will have the option for telehealth enrollment. Baseline SPPB and Biorepository Labs are not required, but encouraged. As part of the study operations, with the rationale of providing patient centricity, ease of participation, and access for vulnerable and at risk participants, follow up will be performed by a combination of central and distributed research teams. This includes a call center as well as a nationwide system of decentralized research staff trained on the protocol able to meet the patient in their home or other desired location. The baseline and annual assessments performed centrally will include a phone screen for cognitive function (TICS-M) and physical function (Patient-reported Outcome Measurement Information System-Physical Function [PROMIS-PF]). After year 1, If baseline calls indicated by crossing pre-specified cutpoints, in-person assessments will be completed by trained and certified research staff at a mutually agreed upon time and a standardized interview of a knowledgeable informant. Cardiovascular event ascertainment will be via a systematic approach to data curation from the EHR, Medicare, and National Death Index. For convenience and compliance, the study pharmacy will mail a supply of study drug, sufficient for 90 days, directly to participants. This will start immediately after randomization and continue as long as the participant is on study drug.

Official Title
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PRagmatic EValuation of evENTs And Benefits of Lipid-lowering in oldEr Adults (PREVENTABLE)

Conditions
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Cognitive Impairment, Mild, Dementia, Cardiovascular Diseases

Intervention / Treatment
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* Drug: Atorvastatin 40 Mg Oral Tablet
* Drug: Placebo oral tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Community-dwelling adults Age ≥75 years English or Spanish as primary language Exclusion Criteria: Clinically evident cardiovascular disease defined as prior myocardial Infarction (MI), prior stroke, prior revascularization procedure, or a secondary prevention indication for a statin (clinician determined) Hospitalization for a primary diagnosis of heart failure in the prior 12 months (Note: History of heart failure in the absence of recent hospitalization or clinically evident cardiovascular disease is not an exclusion) Dementia (clinically evident or previously diagnosed) Dependence in any Katz Basic Activities of Daily Living [ADL] (with the exception of urinary or bowel continence) Severe hearing impairment (preventing phone follow up) Unable to talk (preventing phone follow up) Severe visual impairment (preventing cognitive testing) Statin use in the past year or for longer than 5 years previously (participant reported) Ineligible to take atorvastatin 40 mg (clinician determined) Documented intolerance to statins Active Liver Disease Long-term use of daily colchicine, verapamil at any dose, or diltiazem at a dose >240mg/day.

Ages Eligible for Study
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Minimum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Randomized 1:1 atorvastatin 40mg vs. placebo
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: atorvastatin 40mg<br>40mg atorvastatin po qd from consent to study end | Drug: Atorvastatin 40 Mg Oral Tablet<br>* To generate knowledge about the role of statins in older adults in whom risk/benefit for primary prevention is understudied,<br>* Other names: Lipitor;|
| Placebo Comparator: Placebo<br>matching placebo po qd from consent to study end | Drug: Placebo oral tablet<br>* To generate knowledge about the role of statins in older adults in whom risk/benefit for primary prevention is understudied,<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients without diagnosis of new dementia | Number of patients without diagnosis of new dementia in each group (placebo vs. atorvastatin) | 4 years | 
| Number of patients without of persistent disability | Number of patients without chronic disability in each group | 4 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiovascular mortality measured as a composite of CV death, hospitalization for myocardial infarction/unstable angina, heart failure, stroke/TIA, or coronary revascularization | Cardiovascular mortality is measured by a composite measure of multiple CV conditions. | 4 years | 
| Cognitive disability as measured as a composite of MCI or probable dementia | Cognitive disability is measured by a composite of having mild cognitive impairment or probable dementia. | 4 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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statin, older adults