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Epidemiological evidence for a protective role for statins in Community Acquired Pneumonia Yana Vinogradova British Thoracic Society Winter Meeting 2012 , London 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 From: Does Statin Use Improve Pneumonia Outcomes? Chopra, Flanders, CHEST. 2009;136(5):1381-1388. doi:10.1378/chest.09-0941 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. Pharmacoepidemiology and Prescription From: Statins and associated risk of pneumonia: a systematic review and meta-analysis of observational studies Kwok et al. Eur J Clin Pharmacol (2012) 68, 747-755 Fig. 3 Meta-analysis of adjusted risk of pneumonia with statin therapy • 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 atorvastatin simvastatin pravastatin fluvastatin • time before the index date: 28 days 29-89 days 90-365 days cerivastatin rosuvastatin 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 comorbidities 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 80,484 controls with 2 years of medical records 2231 cases (12.6%) statin users 8759 controls (10.9%) statin users Proportion of cases and controls exposed to statins by index year 25 controls any statin simvastatin atorvastatin pravastatin fluvastatin rosuvastatin 20 % 15 cases 10 5 0 1996 1997 ©RESEARCH 2006 version 11 1998 1999 2000 2001 Index year 2002 2003 2004 2005 Pneumonia episode rates by age and gender in 2005 1600 1400 1200 1000 800 600 400 200 0 45- 50- 55- 60- 6570Age groups Men ©QRESEARCH 2006 version 11 75Women 80- 85- 90+ Proportion of cases and controls exposed to statins by age and sex Women 25 Men Crude OR, 95%CI 1.23, 1.13 – 1.33 Crude OR, 95%CI 1.25, 1.16 – 1.34 20 % 15 10 5 0 45 50 55 60 65 70 75 80 85 90 95 45 50 55 60 65 70 75 80 85 90 95 Age at index date cases ©RESEARCH 2006 version 11 controls Last use of statin before the index date cases 20 % 15 controls 9% 13% 11% 37% 7% 30% 10 5 55% 62% 0 45 50 55 60 65 70 75 80 85 90 95 45 50 55 60 65 70 75 80 85 90 95 Age at index date 3 to 12 months 1 to 3 months up to 28 days ©QRESEARCH 2006 version 11 Crude OR, 95%CI 1.27, 1.20 – 1.34 1.14, 1.08 – 1.20 1.03, 0.98 – 1.09 Proportion of cases and controls and number of prescriptions by the last prescription time 8 7 6 % 5 4 70% 69% 3 Number of prescriptions 63% 2 60% 1 0 38% 48% 28days 90-365days 29-89days cases ©QRESEARCH 2006 version 11 29-89days 28days 90-365days controls 2-6 7-12 12+ Proportion of cases and controls with heart disease and stroke and their use of statin cases controls 60 50 % 40 30 23% 37% 20 10 26% 31% 0 45 50 55 60 65 70 75 80 85 90 95 CHD and stroke Crude OR, 95%CI 2.18, 2.10 – 2.27 ©QRESEARCH 2006 version 11 45 50 55 60 65 70 75 80 85 90 95 Age at index date not on statin on statin Statin use, OR, 95%CI Crude 1.24, 1.18 – 1.31 Adjusted 0.81, 0.77 – 0.86 Risk of pneumonia and use of statin in the last year OR and 95%CI Last year use (N of cases) OR (95%CI) overall use (2231) 0.78 (0.74 to 0.83) by time of use in 28 days (1222) 0.68 (0.63 to 0.73) 1 to 3 months (819) 0.97 (0.88 to 1.06) 3 months ago (190) 0.89 (0.75 to 1.06) .5 Odds ratios are adjusted for co-morbidities, deprivation, smoking status, acid lowering drugs and influenza and pneumococcal vaccinations ©QRESEARCH 2006 version 11 .75 1 1.25 Risk of pneumonia and use of different types of statins OR and 95%CI Types (N of cases) OR (95%CI) simvastatin (1222) 0.82 (0.76 to 0.88) atorvastatin (823) 0.79 (0.72 to 0.86) pravastatin (210) 0.80 (0.68 to 0.94) fluvastatin (79) 0.82 (0.63 to 1.07) rosuvastatin (26) 0.93 (0.58 to 1.48) .5 .75 Odds ratios are adjusted for co-morbidities, deprivation, smoking status, acid lowering drugs and influenza and pneumococcal vaccinations ©QRESEARCH 2006 version 11 1 1.25 1.5 Risk of pneumonia and use of most common types of statin OR and 95%CI Last use (N of cases) in 28 days (649) 1 to 3 months (442) 3 months ago (131) in 28 days (432) 1 to 3 months (292) 3 months ago (99) in 28 days (103) 1 to 3 months (70) 3 months ago (37) OR (95%CI) simvastatin 0.70 (0.63 to 0.77) 1.02 (0.91 to 1.15) 0.86 (0.70 to 1.06) atorvastatin 0.70 (0.62 to 0.78) 0.89 (0.77 to 1.02) 0.98 (0.78 to 1.25) pravastatin 0.65 (0.52 to 0.82) 1.06 (0.79 to 1.41) 0.88 (0.60 to 1.30) .5 .75 Odds ratios are adjusted for co-morbidities, deprivation, smoking status, acid lowering drugs and influenza and pneumococcal vaccinations ©QRESEARCH 2006 version 11 1 1.25 1.5 Limitations Strengths • Residual confounding as no information • 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 – on X-ray – on microbiological tests – on severity of pneumonia • Information on prescriptions only • Over-the-counter statin use • Missing data Further research • • • • • RCT in 26 countries Randomisation in 2003-2006, last visit in 2008 17802 participants with no history of CVD and diabetes Rosuvastatin 20mg or placebo Incidence of infections during the trial HR (95%CI) 1st CAP 0.81 (0.67 – 1.97) 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. Further research • • • • • • Danish National Registry 1997-2009, additional analysis for 2001-2009 70,914 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 Thank you Questions?