Simvastatin Does Not Affect Exacerbation Rates in High-Risk Patients with COPD

Some studies have shown that treatment with statins may decrease the frequency and severity of exacerbations in patients with chronic obstructive pulmonary disease (COPD), as well as decrease rehospitalizations and mortality.

To test whether simvastatin can prevent exacerbations and other related poor outcomes in patients with COPD, researchers conducted a large, multicenter trial of adult patients with COPD who received treatment with daily simvastatin 40 mg for up to three years.

In a presentation at the 2014 American Thoracic Society International Conference announcing results from the study, Gerard J. Criner, MD, Professor of Medicine, Director of the Medical Intensive Care Unit and Ventilator Rehabilitation Unit, and Co-Director of the Center for Inflammation, Translational and Clinical Lung Research, at Temple University School of Medicine, noted that effective treatments for COPD are urgently needed as the condition is the third leading cause of death in the United States and is hallmarked by acute exacerbations. Although there are established treatments for prevention and therapy of COPD, none of these are fully effective.

He said that in addition to the lipid-lowering effects of the statins, the anti-inflammatory and immunomodulatory pleiotropic effects of these agents have been postulated to be beneficial in COPD for more than 10 years.

Until very recently, the evidence to support this was largely from multiple retrospective studies with only one small, single-center, randomized trial of 6 months duration being carried out.

Criner and his fellow investigators, at 45 sites in the US and Canada, conducted a prospective, randomized, placebo controlled study of simvastatin (at a daily dose of 40 mg) versus placebo with annual exacerbation rates as the primary outcome. The original enrollment totaled 885 randomized patients (44% women) age 40 to 80 years. More than 80% of patients had been on steroids or antibiotics during the 12 months prior to enrollment.

The results of this study presented at this meeting were simultaneously published online by the New England Journal of Medicine.

After the STATCOPE trial commenced in March 2010, the FDA issued a warning on June 8, 2011, against the concomitant use of amlodipine or high doses of verapamil with simvastatin. Consequently, the study drug was discontinued in those participants receiving either amlodipine or high-dose verapamil (16 subjects in the simvastatin group and 20 in the placebo).

Criner mentioned that the STATCOPE Data Safety Monitoring Board (DSMB) subsequently recommended the exclusion of patients with diabetes, which resulted in the termination of 28 participants (14 in each group) from the study. Following these exclusions, it was projected that an additional 75 patients would need to be enrolled to attain a final study population of 1,200 subjects.

On October 11, 2013, the DSMB reviewed the clinical data for about 800 patients and made a determination of futility and the study was terminated at that point.

It was concluded that simvastatin at a daily dose of 40 mg did not affect exacerbation rates or the time to a first exacerbation in patients with COPD who were at high risk for exacerbations. The lack of treatment effects was consistent across the spectrum of disease severity and there was no effect regardless of variations in respiratory and QOL parameters.

Following the talk, there was discussion about the possible explanations for this prospective, randomized trial not supporting the observations from the previous studies.

Another questioner pointed out that the study criteria carefully excluded subjects who were already taking statins. Criner confirmed that this was the case. This prompted some discussion about the interrelationship between cardiovascular changes and COPD and whether the failure to show a treatment effect was partly due to patient selection criteria.