Editor's Note: Commentary based on Orkaby AR, Driver JA, Ho YL, et al. Association of statin use with all-cause and cardiovascular mortality in US veterans 75 years and older. JAMA 2020;324:68-78.

Rationale for study:  Despite being at the highest risk, older adults have been excluded from most randomized trials evaluating statin treatment for the primary prevention of atherosclerotic cardiovascular disease (ASCVD) and practice guidelines reflect this evidence gap.^2,3 Robust observational data is urgently needed to inform these frequent clinical decisions pending randomized trial evidence.

Funding: VA CSR&D CDA-2 award IK2-CX001800, National Institute on Aging R03-AG060169, and VA Merit AwardI01 CX001025.

Study Cohort:  US Veterans ≥75 years old and free of ASCVD with no prior statin prescription and with a clinical visit at a Veterans Health Administration (VHA) site between 2002-2012. VHA data were linked to CMS data.

Inclusion criteria:

1. Age 75 years and older
2. Free of statin use at index visit
3. Regular use of VHA with 2 years of utilization prior to entry into the cohort

Exclusion criteria:

• Death within 150 days of entry into the cohort
• Veterans with only visits where medications could not be prescribed (i.e. for prosthetics or hearing aids)
• Veterans with invalid death dates (i.e. death before the clinical encounter) or unlikely birth dates (age >109 years)
• Prevalent ASCVD (history of myocardial infarction (MI), transient ischemic attack, stroke, peripheral vascular disease, or coronary revascularization)
• Veterans with questionable demographic information (missing sex, race, or BMI)

*Of note, individuals with cancer, dementia, and/or paralysis were NOT excluded.

Study Design: A new-user design was utilized with date of first statin prescription used as index date. VHA data were linked to CMS medication data for completeness. Any statin nonuser was included in the cohort after 2 years of utilization without being prescribed a statin, with those started on a statin being assigned to the statin exposure group.

Outcomes: The co-primary outcomes were all-cause and cardiovascular mortality, ascertained from the National Death Index (NDI). Secondary outcomes identified using VHA and CMS claims data included MI, ischemic stroke, revascularization, and a composite of those three.

Statistical Analysis
Demographics and clinical characteristics were assessed for the cohort both before and after propensity score overlap weighting. The association between statin use and the outcomes of interest was assessed using Cox proportional hazards models using overlap weighting. A generalized linear model with time to event as offset and repeated measurements was used to estimate event rates in statin users versus non-users. Prespecified sub-group analyses were conducted by age groups, sex, race, prevalent diabetes, dementia, and arthritis, with interaction tests run for each group.

Results

Overview of the cohort

• Of the 326,981 eligible veterans, the mean age was 81.1 years, 97% men, and 91% white.
• 17.5% of subjects were started on statin treatment during the study period (N=57,178).

Event rates

• Over a mean follow-up of 6.8 years, death rates were higher in statin nonusers (98.2 total deaths/1000 person-years) compared with statin users (78.7 deaths/1000 person-years) (weighted incidence rate difference(IRD)/1000 person-years = -19.5, 95% CI -20.4 to -18.5).
• Cardiovascular death rates were also higher in statin nonusers versus statin users (weighted IRD/1000 person-years = -3.1, 95% CI -3.6 to -2.6).
• ASCVD (MI, ischemic stroke, revascularization) event rates were also lower among statin users versus nonusers (weighted IRD/1000 person-years = -4.1, 95% CI -5.1 to -3.0).

Outcomes

• Statin use was associated with lower all-cause mortality (HR 0.75, 95% CI 0.74-0.76), cardiovascular mortality (HR 0.80, 95% CI 0.78-0.81), and the composite of ASCVD events (HR 0.92, 95% CI 0.91-0.94) after propensity score overlap weighting.

Limitations:

• Cohort limited to largely white male population, thus limiting generalizability outside of that population.
• Unmeasured confounding in this retrospective cohort study may bias results.
• Potential adverse effects from statins were not assessed.

References

1. Orkaby AR, Driver JA, Ho YL, et al. Association of statin use with all-cause and cardiovascular mortality in US veterans 75 years and older. JAMA 2020;324:68-78.
2. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;73:3168:3209.
3. Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;74:e177-e232.

Clinical Topics: Cardiovascular Care Team, Dyslipidemia, Geriatric Cardiology, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Nonstatins, Novel Agents, Statins, Sleep Apnea

Keywords: Geriatrics, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Ischemic Attack, Transient, Proportional Hazards Models, Propensity Score, Retrospective Studies, Linear Models, Cardiovascular Diseases, Veterans, Hearing Aids, National Institute on Aging (U.S.), Body Mass Index, Brain Ischemia, Centers for Medicare and Medicaid Services, U.S., Follow-Up Studies, Veterans Health, Stroke, Cohort Studies, Diabetes Mellitus, Primary Prevention, Myocardial Infarction, Neoplasms, Peripheral Vascular Diseases, Paralysis, Arthritis, Prescriptions, Dementia

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