Epidemiological evidence for a protective role for statins in Community Acquired Pneumonia British Thoracic Society Winter Meeting 2012, London Yana Vinogradova

Background Statins – common medications, 24% in 45+ age group. CAP – common infection, 230 per 100,000 person-years, 670 for 60+ age group. Evidence from lab data that statins may benefit in cases of infectious diseases

Figure Legend: Pleiotropic effects of statins. eNOS = endothelial nitric oxide synthase; PAI-1 = plasminogen activator inhibitor-1; NADPH = nicotinamide adenine dinucleotide phosphate hydrogen; MCP1 = monocytic chemoattractant protein 1; TNF = tumor necrosis factor; LFA-1 = lymphocyte function-associated antigen-1. From: Does Statin Use Improve Pneumonia Outcomes? Chopra, Flanders, CHEST. 2009;136(5): doi: /chest

Pharmacoepidemiology and Prescription Kwok et al. Eur J Clin Pharmacol (2012) 68, Fig. 3 Meta-analysis of adjusted risk of pneumonia with statin therapy From: Statins and associated risk of pneumonia: a systematic review and meta-analysis of observational studies

QResearch –660 GP practices Currently largest database in the UK 537 UK practices > 6 practices in every SHA > 9 million patients including those who died, left and still registered > 30 million person years of observation Patient level data from GP clinical records Anonymised Longitudinal data for 20+ years Validated externally and internally Industry independent

Methods: Study design and analysis Nested case control study Study period Jan 1996-Dec 2005 Cases were incident CAP patients 5 controls matched by age, sex, practice analysis restricted to subjects with at least 2 years of prescribing data Conditional logistic regression, odds ratios 95%CI

Methods: Assessment of Exposure use: at least 2 scripts in 12 months prior to the index date different types of statins atorvastatinpravastatincerivastatin simvastatinfluvastatinrosuvastatin time before the index date: 28 days days days

Methods: Confounding factors Socio-economic status Townsend quintiles Smoking status Non-smoker Smoker not recorded Vaccinations Influenza pneumococcal Morbidities List of co-morbidities recommended for pneumococcal vaccination Additional co- morbidities limiting mobility or suppressing immune system Medications Acid-lowering drugs

Results: Sample and statin use in the last year 17,757 cases with 2 years of medical records 2231 cases (12.6%) statin users 80,484 controls with 2 years of medical records 8759 controls (10.9%) statin users

Crude OR, 95%CI 1.23, 1.13 – 1.33 Crude OR, 95%CI 1.25, 1.16 – 1.34

Crude OR, 95%CI 1.27, 1.20 – , 1.08 – , 0.98 – % 55% 11% 9% 37% 30% 62% 7%

69% 63% 48% 70% 60% 38%

CHD and stroke Crude OR, 95%CI 2.18, 2.10 – 2.27 Statin use, OR, 95%CI Crude 1.24, 1.18 – 1.31 Adjusted 0.81, 0.77 – % 23% 26% 31%

Limitations Residual confounding as no information –on X-ray –on microbiological tests –on severity of pneumonia Information on prescriptions only Over-the-counter statin use Missing data Strengths Large sample size and representative population Data electronically collected – unlikely misclassification bias Data collected before diagnosis – no recall bias All cases used – no selection bias

Further research RCT in 26 countries Randomisation in , last visit in participants with no history of CVD and diabetes Rosuvastatin 20mg or placebo Incidence of infections during the trial

Figure 2: Kaplan–Meier estimates from intention-to-treat analysis showing cumulative incidence of first pneumonia adjusted for competing risk of cardiovascular events. Participants were censored at the time of a cardiovascular event. HR (95%CI) 1 st CAP 0.81 (0.67 – 1.97)

Further research Danish National Registry , additional analysis for ,914 patients hospitalised with pneumonia Matched to up to 10 controls Current statin use: at least 1 prescription in last 125 days Adjusted for co-morbidities, medications, smoking, demographics...

Conclusions There is an association between use of statins and decreased risk of pneumonia, more pronounced for patients having recent statin use. It may be due to anti-inflammatory and immunomodulatory properties of statins It may also be due to reduced rate of CVD events and rates of associated complication such as pneumonia

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