1. Statins In COPD: A Systematic Review Surinder J, Kirly P et al. Chest 2009; 136: 734-743. Divya Bappanad March 11, 2010 Journal Club

2. Background COPD is a systemic inflammatory disease not limited to the lung Increased recruitment and activation of inflammatory cells( neutrophils, eosinophils, lymphocytes and alveolar macrophages) Increased levels of IL-6, IL-8, CRP, fibrinogen, TNF, and leukocytes Chronic inflammation persists even after cessation of smoking

3. Background Statins pleiotropic anti-inflammatory effects Decrease neutrophil numbers, T cell activation and differentiation, and increase apoptosis of eosinophils Also regulate inflammation by increased phagocytosis of apoptotic cells Murine and rat models demonstrate slowed progression of emphysema with statin use

4. Methods Study Sources – Medline, Cochrane, PapersFirst and Excerpta Medical Database as well as bibliographies of found papers Design of studies included – randomized, single or double blinded, placebo controlled, observational cohort( prospective or restrospective), population based analysis Study exclusion criteria – laboratory or experimental based studies Number of studies screened vs. accepted – 264 vs 9 Outcomes – All cause mortality, COPD related mortality, COPD, the time to and number of COPD exacerbations, the time to an number of COPD intubations, exercise capacity, and pulmonary function FEV1 and FVC

5. Validity Focused clinical question addressed Appropriate study inclusion criteria No important studies excluded Significant degree of heterogeneity between studies

6. Results 4 retrospective cohort 1 nested case control of a retrospective cohort 1 combination retrospective cohort 2 case control 1 randominized controlled trial

7. Results All cause mortality ◦ Mancini et al nested case control  OR 0.53(95% CI 0.43 -0.65) vs OR 0.49(95% CI0.41-0.58)  In both high risk CV and low risk CV group ◦ Soyseth et al retrospective cohort  HR 0.57(95% CI 0.38-0.87) ◦ Van Gestel et al retrospective cohort  short term( 30 day) OR 0.48(95% CI 0.23-1)  long term(10 year) OR (95% CI 0.52-0.86)

8. Results COPD related mortality ◦ Frost et al retrospective cohort and case control  Low dose statin OR 0.58(95% CI 0.17-0.92)  Moderate dose statin OR 0.17(95% CI 0.07-0.42)  Dose dependant effect ◦ Ishida et al population based  Annual sales with negative correlation  Correlation coefficient 0.574(p<0.001)

9. Results COPD hospitalizations ◦ Keddissi et al retrospective cohort  *0.17+/- 0.31 patients per year vs 0.11 +/-0.26 patients per year  But rate decrease FEV1 and FVC slowed with statin use ◦ Mancini et al  High risk CV OR 0.71(95% CI 0.56 -0.91)  Low risk CV OR 0.71(95% CI 0.64-0.77) COPD exacerbations ◦ Blamoun et al retrospective cohort  OR 2.35(95% CI 1.01-5.5)

10. Results Exercise capacity and CRP ◦ Lee et al RCT ◦ Pravastatin vs placebo ◦ Increased exercise time on treadmill  599 +/- 323 to 922 +/- 328 s p<0.0001 ◦ Decreased CRP  3.94 +/- 3.54 to 2.66 +/- 2.49 p<0.0005

11. Comments All studies showed benefit in range of COPD related outcomes Clinical finding correlate to findings in pulmonary systems of animal models Lack of RCTs mean that confounding variables and bias present Definitions of COPD varied as did dose and duration of statins

12. Next steps Atorvastatin vs placebo for change in peak flow Simvastatin vs placebo for changes in CRP Lovastatin vs placebo for changes in apoptosis and efferocytosis in pulmonary macrophages