Statins, systemic inflammation and risk of death in COPD: The Rotterdam study

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Abstract

Background

Studies suggest that statins decrease mortality in COPD patients but it is unknown which patients might benefit most.

Objectives

We investigated whether statins were associated with reduced mortality in COPD patients and whether effects differed according to baseline high-sensitivity C-reactive protein (hsCRP) concentration, a marker of systemic inflammation.

Methods

This nested case–control study was part of the Rotterdam Study, a prospective population-based cohort study among 7983 subjects ≥ 55 years. Using automated pharmacy records, we evaluated statin use of 363 cases (COPD patients who died during follow-up of 17 years) with 2345 age and sex matched controls (COPD patients who survived the follow-up period of the index case).

Results

Compared to never use, long-term statin use (>2 years) was associated with a 39% decreased risk of death in COPD patients. Stratified according to the level of systemic inflammation, long-term statin use was associated with a 78% reduced mortality if hsCRP level > 3 mg/L, versus a non significant 21% reduced mortality if hsCRP level ≤ 3 mg/L.

Conclusions

Statin use is associated with a beneficial effect on all-cause mortality in COPD, depending on the baseline level of systemic inflammation.

Introduction

Chronic obstructive pulmonary disease (COPD) is currently the fourth leading cause of morbidity and mortality worldwide. In industrialized countries about 400,000 COPD deaths occur each year and the mortality is expected to increase further [1]. The disease is characterized locally by a chronic inflammation of small airways and destruction of alveoli and systemically, in a subset of COPD patients, by increased markers of inflammation, including high-sensitivity C-reactive protein (hsCRP) and interleukin 6 (IL6) [2], [3], [4]. The subset of COPD patients with persistent systemic inflammation has recently been shown to be associated with poor clinical outcomes despite similar lung impairment [5]. The chronic low-grade inflammation might be the key link to the occurrence of various comorbidities in COPD including cardiovascular diseases and lung cancer. Moreover, these comorbidities are the main causes of death in mild to moderate COPD; therefore, with the increased recognition of the prognostic role of comorbidities in COPD, all-cause mortality has become one of the major endpoints in the evaluation of novel therapies [6].

Recent observational studies suggest that statins [3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors] may reduce morbidity and mortality in COPD patients [7], [8], [9]. Statins are a class of drugs mainly used to treat hypercholesterolemia and to prevent cardiovascular events. Statins reduce cholesterol synthesis by inhibition of HMG-CoA reductase in the liver and increase low density lipoprotein-cholesterol uptake from the circulation. In addition to their lipid-lowering effect, statins also possess pleiotropic anti-inflammatory and immunomodulating properties, and are able to reduce levels of inflammatory markers such as CRP [10]. CRP is a validated biomarker of systemic inflammation in COPD and increased CRP levels in patients with COPD are associated with increased mortality [11], [12]. Lee et al. recently showed in a randomized controlled trial with COPD patients, that pravastatin treatment significantly decreased CRP and IL6 levels compared to placebo and that the improvement of exercise tolerance was greater in those with a greater decrease of hsCRP levels and higher baseline CRP levels [13]. However, to our knowledge, studies exploring whether the beneficial effect of statins on all-cause mortality in COPD is greater in those with increased systemic inflammation, have not yet been published.

Therefore, the objective was to investigate whether statins have a beneficial effect on mortality in COPD patients with increased baseline hsCRP-levels in the Rotterdam Study, a large prospective population-based cohort study with long-term follow-up.

Section snippets

Study population and design

We performed a nested case–control analysis in all COPD cases within the Rotterdam Study, a population-based cohort study aimed at assessing the occurrence of and risk factors for chronic diseases in the elderly [14]. The Rotterdam study cohort includes 7983 participants aged ≥ 55 years, living in Ommoord, a well-defined suburb of Rotterdam, the Netherlands. Almost all participants (99.8%) are of Caucasian descent. Baseline data were collected from 1989 until 1993 and each participant visits

Baseline characteristics of the study population

Within the source population of 7983 subjects, hsCRP was successfully measured in 6658 participants at baseline (Fig. 1). Of these, 758 COPD patients were identified with a study start date after April 1st, 1991 to ensure at least three months of medication history. The vast majority (82.5%) of COPD patients was confirmed by an obstructive spirometry. Seventy-one patients with an incident COPD date after January 1st, 2006 were excluded from analyses because at least two years of follow-up

Discussion

This is the first prospective study in a general population showing that the beneficial effect of long-term statin use on the risk of mortality in COPD patients is modified by the baseline level of systemic inflammation. The results suggest that the subset of COPD patients characterized by increased markers of systemic inflammation might benefit most from long-term statin therapy. One in three COPD patients in our study died from cardiovascular causes – figures which have also been described by

Funding sources

This study was supported by the Fund for Scientific Research Flanders (FWO Vlaanderen) [Grant 019309] and the Netherlands Organization for Scientific Research (NWO) [Grants 904-61-093, 918-46-615]. Lies Lahousse is the recipient of a Belgian Respiratory Society Travel Fellowship. The funding sources had no involvement in study design, data collection, analysis, writing, interpretation, nor in the decision to submit the paper for publication.

Conflict of interest

None of the authors had any conflict of interest to declare with respect to this paper.

Acknowledgements

The authors thank the study participants, the staff from the Rotterdam Study and the participating general practitioners. An abstract of this study has been accepted for the American Thoracic Society congress 2012.

References (29)

  • D.D. Sin et al.

    Mortality in COPD: role of comorbidities

    Eur Respir J

    (2006)
  • C.C. Dobler et al.

    Associations between statins and COPD: a systematic review

    BMC Pulm Med

    (2009)
  • C.M. Lawes et al.

    Statin use in COPD patients is associated with a reduction in mortality: a national cohort study

    Prim Care Respir J

    (2012)
  • P.M. Ridker et al.

    C-reactive protein levels and outcomes after statin therapy

    N Engl J Med

    (2005)
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