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Anything less than strict adherence to statin therapy was associated with greater mortality risk even in people who had regularly taken these medications for years, according to a study on patients in the Veterans Affairs Health System.

Lower adherence to statin therapy, as measured with medication possession ratio (MPR) was associated with more deaths -- even after adjustment for individual characteristics and adherence to other cardiac medications, according to Fatima Rodriguez, MD, MPH, of Stanford University in Palo Alto, California, and colleagues, writing in .

Relative to patients with MPRs of 90% or higher, hazard ratios for lower MPRs were as follows:

• MPR <50%: adjusted HR 1.30, 95% CI 1.27-1.34
• MPR 50-69%: adjusted HR 1.21, 95% CI 1.18-1.24
• MPR 70-89%: adjusted HR 1.08, 95% CI 1.06-1.09

Overall, adherence among patients with atherosclerotic cardiovascular disease (CVD) was very good -- 87.7% on average -- yet one-quarter of the nearly 350,000 patients included in the study nevertheless died during 3-year follow-up.

The graded association between statin low adherence and mortality "shows the benefit of strict statin adherence" and was strongest among patients taking high-intensity statins, Rodriguez's group said. "These findings suggest there is a substantial opportunity for improvement in the secondary prevention of atherosclerotic CVD through optimization of statin adherence."

VA patients who had no change to their statin prescription from 2013 to 2014 were included in the retrospective analysis. Medication adherence was derived from pharmacy records, MPR being the proportion of days with filled prescriptions. As is typical in VA studies, women were only 1.6% of the sample, which was also 81.9% white.

White race, ages 65-74, and moderate-intensity versus high-intensity statin therapy were each associated with higher MPRs.

Unlike previous studies, the work by Rodriguez and colleagues provides "evidence that the mortality benefit in this study was not purely due to a healthy adherer effect," according to an editor's note from Ann Marie Navar, MD, PhD, of Duke Clinical Research Institute in Durham, North Carolina.

Supporting this conclusion, Navar indicated were the persistence of the statin adherence-mortality relationship after adjustment for adherence to other cardiac medications; the particular strength of this link among those prescribed high-intensity statins; and the lack of an association between statin adherence and two negative controls (pneumonia and GI bleeding) shown by the investigators.

Yet Steven Nissen, MD, of the Cleveland Clinic, found the study "low in reliability," he told MedPage Today.

"Patients who are non-adherent to statins are probably also non-adherent to many other treatments, including dietary advice, other medications, etc. Accordingly, we don't know whether their less favorable outcomes were due to statin non-adherence or failure to receive other needed therapies," he said.

And given that statins don't reduce non-cardiovascular deaths, the study could have been strengthened by looking at MI and cardiovascular death rather than all-cause mortality, Nissen added.

Indeed, Rodriguez and colleagues acknowledged that causes of death were missing in their database. Their observational study was also subject to possible residual confounding, and the investigators could only assume that patients actually took the statins after picking them up from the pharmacy.

"This is a powerful reminder that even the most rigorously designed observational analyses cannot replace efficacy estimates from randomized clinical trials," Navar commented.

"Society has spent hundreds of millions of dollars on research to prove that statins save lives. The study by Rodriguez et al. reminds us that without improvements in medication adherence, the full benefit of this investment will never be realized," she emphasized.

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