Discontinuation of statins in older patients with polypharmacy associated with increased cardiovascular events

1. Older patients with polypharmacy who discontinued statins had increased rates of admissions for heart failure, all-cause emergency hospital admissions, cardiovascular outcomes, and all-cause death versus those that did not.

Evidence Rating Level: 2 (Good)

Study Rundown: With advanced age, patients have multiple comorbidities and are commonly treated with multiple drugs, each of which can cause side effects, adverse drug reactions, and drug-drug interactions. Generally, older adults with so-called “polypharmacy” are managed with the practice of deprescribing, which is the systematic and careful removal of drugs that do not lead to significant clinical benefits or avoidance of detriment. This retrospective cohort study sought to identify if there was clinical detriment to deprescribing statins in elderly patients on multiple drugs. The study objective was to assess the cardiovascular and non-cardiovascular clinical implications of discontinuing statins, including hospital admissions, emergency department visits, and death. Senior patients with polypharmacy, defined as those using a statin (discontinued) and blood pressure-lowering, anti-diabetic, and antiplatelet agents, were matched to those who maintained their statin use, from the Lombardy, Italy National Health Service database on prescriptions and clinical outcomes. Those patients who discontinued statins showed increased incidence and increased hazard ratio of hospital admissions risk for heart failure, any-cause emergency department admissions, and all-cause death. Demographic data could not explain these effects. A strength of this study is the large sample size and accuracy of database information, as the National Health Service database legally mandates hospitals and pharmacies update the database. Additionally, inclusion of an active matched group with similar polypharmacy and adherence reduced the potential for confounding error. Finally, a similar analysis on the discontinuation of proton pump inhibitors successfully showed to not affect mortality, providing negative control that suggests there was no confounding error. However, the potential for confounding error cannot be eliminated as this study design did not feature randomization, but instead a retrospective cohort. This study was limited by a few different types of exposure misclassification because of the assumptions that: 1) the “discontinuing group” did not restart statins and the “maintaining group” did not discontinue statins outside the time of interest, 2) medication use reflected that of pharmacy ordering and was not affected by non-compliance, 3) private healthcare did not play a large role. Only the first of these assumptions was addressed by an analysis where statin exposure was a time-dependent covariate.

Click to read the study in JAMA Network Open

Relevant Reading: Recommendations for (Discontinuation of) Statin Treatment in Older Adults: Review of Guidelines

In-Depth [retrospective cohort]: This study identified patients who were 65 years or older from Lombardy, Italy in the National Health Service database who were being treated with a statin, and blood pressure-lowering, anti-diabetic, and antiplatelet agents (polypharmacy) (n= 95,040 of 2.3 million). Of these, 29,047 met inclusion criteria of lacking discontinuation (defined as not filling a prescription for 90 days after completion) in a 3-year pre-follow up period. Patients who discontinued a statin while continuing other drug therapies in a 2-year follow-up window formed the discontinuing group (n=5819) and were 1:1 matched by nearest-neighbor on propensity score (PS) to patients who had maintained statin use and other drug use for at least 180 days past the date of their pair’s statin discontinuation (n=4203). Logistic regression of baseline covariates (sex, age at follow-up start, comorbidities and adherence to medications) determined exposure PS. Patients discontinuing statins were more often older (76.5±6.5 vs 75.3±6.3 years) women (59.7% men vs 64.6% men) without heart failure (8.1% vs 8.5% with heart failure) than those maintaining statins, corrected by the matching. Person-years (PYs) starting 180 days after the discontinuation of the exposed member were calculated until clinical end-point or emigration, end of data availability, or study conclusion (35 months). For polypharmacy patients who discontinued statins vs maintained statins, hazard ratios showed increased hospital admissions risk for heart failure (1.24; 95% Confidence Interval [CI], 1.07-1.43), any-cardiovascular event (1.14; 95%CI, 1.03-1.26), increased risk of any-cause emergency department admissions (1.12; 95%CI, 1.05-1.19), and increased risk of all-cause death (1.15; 95%CI, 1.02-1.30). Using a liberal time-fixed assumption or as-treated design did not change these effects. Sex, age, clinical profile, nor primary vs secondary prevention of CV events setting could not explain these effects. A negative control assessment of discontinuations of proton pump inhibitors was successfully shown to not affect mortality (1.08; 95%CI, 0.95-1.22).

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