Statins Versus Placebo for People with Chronic Obstructive Pulmonary Disease

Background: Chronic obstructive pulmonary disease (COPD) is a common, preventable, and treatable respiratory disease. COPD exacerbations are associated with worse quality of life, increased hospitalisations, and increased mortality. Currently available pharmacological interventions have variable impact on exacerbation frequency. The anti-inflammatory effects of statins may lead to decreased pulmonary and systemic inflammation, resulting in fewer exacerbations of COPD. Several observational studies have shown potential benefits of statins for patients with COPD.

Objectives: This review aims to evaluate available evidence on benefits and harms associated with statin therapy compared with placebo as adjunct therapy for patients with COPD. Primary objectives include the following.• To determine whether statins reduce mortality rates in COPD.• To determine whether statins reduce exacerbation frequency, improve quality of life, or improve lung function in COPD.• To determine whether statins are associated with adverse effects.

Search Methods: We identified trials from the Cochrane Airways Trials Register, which contains studies identified through multiple electronic searches and handsearches of other sources. We also searched trial registries and reference lists of primary studies. We conducted the most recent search on 20 May 2019.

Selection Criteria: Parallel, randomised controlled trials recruiting adults with COPD.

Data Collection And Analysis: We used standard methods as expected by Cochrane. Prespecified primary outcomes were number of exacerbations, all-cause mortality, and COPD-specific mortality.

Main Results: Eight studies including 1323 participants with COPD were included in the review. Participants had a mean age of 61.4 to 72 years, and most were male (median 73.4%). Mean baseline forced expiratory volume in one second (FEV₁) ranged from 41% to 90% predicted. All studies compared moderate- or high-intensity statin therapy versus placebo. The duration of treatment ranged from 12 weeks to 36 months.We found no statistically significant difference between statins and placebo in our primary outcome of number of exacerbations per person-year (mean difference (MD) -0.03, 95% confidence interval (CI) -0.25 to 0.19, 1 trial, 877 participants), including number of exacerbations requiring hospitalisation per person-year (MD 0.00, 95% CI -0.10 to 0.10, 1 trial, 877 exacerbations). This evidence was of moderate quality after downgrading for unclear risk of bias. Our primary outcomes of all-cause mortality (odds ratio (OR) 1.03, 95% CI 0.61 to 1.74, 2 trials, 952 participants) and COPD-specific mortality (OR 1.25, 95% CI 0.38 to 4.13, 1 trial, 877 participants) showed no significant difference between statins and placebo, with wide confidence intervals suggesting uncertainty about the precision of the results. This evidence was of low quality after downgrading for unclear risk of bias and imprecision.Results of the secondary outcomes analysis showed no clear differences between statins and placebo for FEV₁ (% predicted) (MD 1.18, 95% CI -2.6 to 4.97, 6 trials, 325 participants) but did show a statistically significant improvement in FEV₁/forced vital capacity (FVC) (MD 2.66, 95% CI 0.12 to 5.2; P = 0.04; 6 trials, 325 participants). A sensitivity analysis excluding two trials at high risk of bias showed no statistically significant difference in FEV₁/FVC (MD 2.05, 95% CI -0.87 to -4.97; P = 0.17; 4 trials, 255 participants). We also found no significant differences between the two groups in functional capacity measured by six-minute walk distance in metres (MD 1.79, 95% CI -52.51 to 56.09, 3 trials, 71 participants), with wide confidence intervals suggesting uncertainty about the precision of the results. Results show no clear difference in quality of life, which was reported in three trials, and a slight reduction in C-reactive protein (CRP) in the intervention group, which was statistically significant (MD -1.03, 95% CI -1.95 to -0.11; I² = 0%, P = 0.03; 3 trials, 142 participants). We noted a significant reduction in interleukin (IL)-6 in the intervention group (MD -2.11, 95% CI -2.65 to -1.56; I² = 0%, P ≤ 0.00001; 2 trials, 125 participants). All trials mentioned adverse events and indicated that statins were generally well tolerated. One study reported adverse events in detail and indicated that rates of all non-fatal adverse events (the number of serious adverse events per person-year) were similar in both groups (0.63 ± 1.56 events (intervention group) and 0.62 ± 1.48 events (control group); P > 0.20) for all comparisons, except for non-fatal serious adverse events involving the gastrointestinal tract, which were more frequent in the intervention group (in 30 patients (0.05 events per person-year) vs 17 patients (0.02 events per person-year); P = 0.02). Another trial lists the total numbers and percentages of adverse events in the intervention group (12 (26%)) and in the control group (21 (43%)) and of serious adverse events in the intervention group (4 (9%)) and in the control group (3 (6%)).The other trials stated that researchers found no significant adverse effects of statins but did not report adverse events in detail.

Authors' Conclusions: A small number of trials providing low- or moderate-quality evidence were suitable for inclusion in this review. They showed that use of statins resulted in a reduction in CRP and IL-6, but that this did not translate into clear clinical benefit for people with COPD. Further randomised controlled trials are needed to explore this topic.