COMMENTARY

Statins in COPD: Useful or Not?

Nicholas Gross, MD, PhD

Disclosures

August 15, 2014

Simvastatin for the Prevention of Exacerbations in Moderate-to-severe COPD

Criner GJ, Connett JE, Aaron SD, et al; COPD Clinical Research Network; Canadian Institutes of Health Research
N Engl J Med. 2014;370:2201-2210

Statin Disappointment

Statins were developed 3 decades ago to control blood cholesterol and its components, and thus reduce the risks for myocardial and other vascular events. That goal has been achieved successfully. With the widespread use of statins, it soon became clear that these drugs might have other actions, with anti-inflammatory action being one possibility.

Some benefit from the use of statins has been reported in other disorders with inflammatory features. The present trial was a prospective, randomized, double-blind, placebo-controlled trial in 885 patients with moderate to severe chronic obstructive pulmonary disease (COPD) who had experienced an acute exacerbation in the previous year and did not require statin therapy for another diagnosis. Study patients received either 40 mg of simvastatin per day or placebo. The number of exacerbations per person, per year was the primary outcome.

The study was terminated prematurely because interim analysis of the results showed that the frequency of acute exacerbations was almost identical in the 2 groups, as was the time to first exacerbation. Mortality and adverse events were also almost identical in the 2 groups. Blood lipid levels decreased by an average of 33 mg/dL in the statin group. This indicated the use of a statin and that it had the expected effect on blood lipid levels. The total study results were disappointing.

Viewpoint

Statins have indeed been found to inhibit the expression of many inflammatory mediators, including tumor necrosis factor alpha, C-reactive protein, and several others. Anti-inflammatory actions following statin use have been suggested for rheumatoid arthritis, diabetes, and some renal abnormalities. Studies of the effect of statins in airway disease have also been suggestive of benefit, although a definitive, prospective, double-blind, randomized trial in COPD has not been published until now.

An observational study in veterans found that those who had been prescribed a statin experienced less decline in lung function than those who had not received a statin.[1] Being an observational study, it may be subject to confounding factors and an imbalance between patients who received a treatment and those who did not.

A meta-analysis of 9 selected studies, all of which were retrospective, found that the number of acute exacerbations of COPD, intubations for exacerbations, pulmonary function, exercise capacity, and mortality were all significantly better in patients who received statins.[2] In addition, a very recent meta-analysis of 10 publications suggested that mortality among COPD patients was reduced by about 19% in those who used statins.[3] Again, the studies were mostly retrospective, and the authors detected evidence of publication bias. Regrettably, previous reports such as these are well known to be unreliable for a variety of reasons, publication selection bias being a major problem.

The present trial tells us 2 things. First, routine use of a statin is unlikely to reduce the number of acute exacerbations of COPD. It may be beneficial for COPD in other ways, but determining that would require an additional appropriately designed prospective trial. In addition, meta-analyses, retrospective data, and observational studies -- sometimes called "real-world trials" -- can provide quite misleading results. They are best regarded as hypothesis-generating studies, to be tested definitively by a subsequent prospective, randomized, placebo-controlled, double-blind trial before being accepted as reliable.

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