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The Relationship between ACE Inhibitors, Statins and Pneumonia

The Relationship between ACE Inhibitors, Statins and Pneumonia. Mark Woodhead Honorary Clinical Professor of Respiratory Medicine University of Manchester & Manchester Royal Infirmary. Mark Woodhead Honorary Clinical Professor of Respiratory Medicine

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The Relationship between ACE Inhibitors, Statins and Pneumonia

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  1. The Relationship between ACE Inhibitors, Statins and Pneumonia Mark Woodhead Honorary Clinical Professor of Respiratory Medicine University of Manchester & Manchester Royal Infirmary

  2. Mark Woodhead Honorary Clinical Professor of Respiratory Medicine University of Manchester & Manchester Royal Infirmary

  3. Pneumonia Pathogenesis

  4. ANTIBIOTIC

  5. ACE inhibitors Arai T, Yasuda Y, Takaya T, et al. ACE inhibitors and symptomless dysphagia. Lancet 1998; 352: 115–16. Substance P Dysphagia

  6. ACE inhibitors Arai T, Yasuda Y, Takaya T, et al. ACE inhibitors and symptomless dysphagia. Lancet 1998; 352: 115–16. Substance P Dysphagia Cough

  7. ACE inhibitors Arai T, Yasuda Y, Takaya T, et al. ACE inhibitors and symptomless dysphagia. Lancet 1998; 352: 115–16. Substance P Dysphagia Cough ? Pneumonia

  8. N = 516 with hypertension 247 Calcium channel blocker 60 controls 3 year follow up Pneumonia 22 (8.9%) Pneumonia 5 (8.3%) Arai et al Lancet 1998;352:1937-1938

  9. N = 516 with hypertension 269 ACEI (imidrapil) 247 Calcium channel blocker 60 controls 3 year follow up Pneumonia 9 (3.3%) Pneumonia 22 (8.9%) Pneumonia 5 (8.3%) P=0.025 Arai et al Lancet 1998;352:1937-1938

  10. Forest Plot Odds Ratio Favours Treatment A Favours Treatment B

  11. Forest Plot Reasons for Reduced Confidence Odds Ratio Wide Confidence Interval Confidence Interval crossing unity line Favours Treatment A Favours Treatment B

  12. Forest Plot Reasons for Reduced Confidence Odds Ratio Odds Ratio Wide Confidence Interval Discordant results Confidence Interval crossing unity line Favours Treatment A Favours Treatment B Favours Treatment A Favours Treatment B

  13. ACEIs and Pneumonia risk Systematic Review and Meta-analysis Odds ratio Favours ACEI 1 Favours control Caldeira et al BMJ 2012;345:e4260 doi: 10.1136/bmj.e4260 (Published 11 July 2012)

  14. ACEIs and Pneumonia risk Systematic Review and Meta-analysis Odds ratio Favours ACEI Favours control Caldeira et al BMJ 2012;345:e4260 doi: 10.1136/bmj.e4260 (Published 11 July 2012)

  15. ACEIs and Pneumonia risk Systematic Review and Meta-analysis Odds ratio + cohort + case-control studies Favours ACEI Favours control Caldeira et al BMJ 2012;345:e4260 doi: 10.1136/bmj.e4260 (Published 11 July 2012)

  16. ARBs and Pneumonia risk Systematic Review and Meta-analysis Odds ratio Favours ARB 1 Favours control Caldeira et al BMJ 2012;345:e4260 doi: 10.1136/bmj.e4260 (Published 11 July 2012)

  17. ARBs and Pneumonia risk Systematic Review and Meta-analysis Odds ratio + case-control studies Favours ARB Favours control Caldeira et al BMJ 2012;345:e4260 doi: 10.1136/bmj.e4260 (Published 11 July 2012)

  18. ACEIs and ARBs and Pneumonia risk Systematic Review and Meta-analysis Odds ratio Favours ACEI/ARB 1 Favours control Caldeira et al BMJ 2012;345:e4260 doi: 10.1136/bmj.e4260 (Published 11 July 2012)

  19. ACEIs and Pneumonia risk Systematic Review and Meta-analysis Odds ratio Favours ACEI 1 Favours control Caldeira et al BMJ 2012;345:e4260 doi: 10.1136/bmj.e4260 (Published 11 July 2012)

  20. ACEIs and ARBs and Pneumonia Mortality Systematic Review and Meta-analysis Odds ratio 1 Favours ACEI/ARB Favours control Caldeira et al BMJ 2012;345:e4260 doi: 10.1136/bmj.e4260 (Published 11 July 2012)

  21. ACEIs and ARBs and Pneumonia risk • ACEIS and ARBs may reduce pneumonia risk in those with hypertension • ACEI effect greater than ARB effect • Effect on mortality small

  22. ACEIs and ARBs and Pneumonia risk • ACEIS and ARBs may reduce pneumonia risk in those with hypertension • ACEI effect greater than ARB effect • Effect on mortality small • No RCTs designed with pneumonia endpoint • ? Effect in those without hypertension • ? Effect in non-Asians

  23. Mevalonate Pathway Statins

  24. Mevalonate Pathway Acetyl-CoA Statins Immunomodulatory Anti-inflammatory Anti-thromobotic Anti-microbial HMG-CoA HMG-CoA reductase Mevalonate Cholesterol

  25. Survival of Simvastatin-fed Mice with S pneumoniae Infection Boyd et al BMC Microbiology 2012;12:73

  26. Survival of Simvastatin-fed Mice with S pneumoniae Infection Bacterial numbers Boyd et al BMC Microbiology 2012;12:73

  27. Survival of Simvastatin-fed Mice with S pneumoniae Infection Bacterial numbers Lung neutrophils Boyd et al BMC Microbiology 2012;12:73

  28. ? Healthy user effect Statins in CAP 1007 admitted to hospital 2005-2007, mortality 9.6% 257 (26%) were receiving statins Predictor Adjusted 95% CIs p Odds Ratio Statin 0.46 0.25 – 0.85 0.01 Aspirin 0.63 0.36 – 1.11 0.11 ACEI 1.16 0.64 – 2.11 0.62 ß-agonist 1.97 1.03 – 3.78 0.04 Chalmers et al Am J Med 2008;121:1002-1007

  29. Risk of Pneumonia in those taking Statins Population-based Nested case-control Study UK GP database, adults age > 45 years 17, 775 pneumonias vs 80,484 with no pneumonia Adjusted Odds Ratio Exposure in last year 0.78 (0.74-0.83) Atorvastatin 0.79 (0.72-0.86) Simvastatin 0.82 (0.76-0.88) Pravastatin 0.80 (0.68-0.94) Vinogradova et al Br J Gen Pract 2011;DOI:10.3399/bjgp11X606654.

  30. Meta-analyses of Statin Treatment and Pneumonia No association – unadjusted Association - adjusted Kwok CS, Yeong JK, Turner RM, Cavallazzi R, Singh S, et al. (2012) Statins and associated risk of pneumonia: a systematic review and meta-analysis of observational studies. Eur J Clin Pharmacol. 68(5): 747–55. Epub 2011 Nov 15. Beneficial effect of statins Chopra V, Rogers MA, Buist M, Govindan S, Lindenauer PK, et al. (2012)Is Statin Use Associated with Reduced Mortality After Pneumonia? A Systematic Review and Meta-analysis Am J Med. 125(11):1111-23. Apparent benefit ? due to unmeasured confounders Van den Hoek HL, Bos WJ, de Boer A, van de Garde EM (2011) Statins and prevention of infections: systematic review and meta-analysis of data from large randomised placebo controlled trials BMJ. 29; 343: d7281. [PMID: 22127443].

  31. Meta-analysis of Statins in Pneumonia - Prevention Favours Statin Favours No-Statin Khan et al (2013) PLoS ONE 8(1): e52929. doi:10.1371/journal.pone.0052929

  32. Meta-analysis of Statins in Pneumonia - Treatment Favours Statin Favours No-Statin Khan et al (2013) PLoS ONE 8(1): e52929. doi:10.1371/journal.pone.0052929

  33. Meta-analyses of Statin Treatment and Pneumonia Kwok CS, et al. (2012) Statins and associated risk of pneumonia: a systematic review and meta-analysis of observational studies. Eur J Clin Pharmacol. 68(5): 747–55. Epub 2011 Nov 15. No association – unadjusted Association - adjusted Beneficial effect of statins Chopra V, et al. (2012)Is Statin Use Associated with Reduced Mortality After Pneumonia? A Systematic Review and Meta-analysis Am J Med. 125(11):1111-23. Apparent benefit ? due to unmeasured confounders Van den Hoek HL, et al (2011) Statins and prevention of infections: systematic review and meta-analysis of data from large randomised placebo controlled trials BMJ. 29; 343: d7281. [PMID: 22127443]. Khan et al (2013) The Role of Statins in Prevention and Treatment of Community Acquired Pneumonia: A Systematic Review and Meta-Analysis PLoS ONE 8(1): e52929. doi:10.1371/journal.pone.0052929 Benefit against development and mortality But Very low quality data

  34. Conclusions Has the ball crossed the line?

  35. Conclusions Has the ball crossed the line? Do ACEIs, ARBs or Statins prevent/alter outcome in pneumonia?

  36. Conclusions • ACEIS and ARBsmay reduce pneumonia frequency • Statins may reduce pneumonia frequency • Statins may reduce pneumonia mortality

  37. RCT of Atorvastatin in Severe Sepsis in ICU 250 critically ill patients (123 statins, 127 placebo) with severe sepsis were administrated either atorvastatin (20mgdaily) or matched placebo Favours statin Favours placebo Kruger et al Am J Respir Crit Care Med Vol 187, Iss. 7, pp 743–750, Apr 1, 2013

  38. Conclusions • ACEIS and ARBsmay reduce pneumonia frequency • Statins may reduce pneumonia frequency • Statins may reduce pneumonia mortality Only Randomised Controlled Trials will answer these questions!

  39. Clinical Trials in Progress…….. STATIN-VAP STATIN-VAP - STATINs and Ventilator-Associated Pneumonia Effect of Atorvastatin on the Frequency of Ventilator-associated Pneumonia in Patients With Ischemic Stroke Effect of Simvastatin on Pneumonia Prognosis in Elderly Patients Effect of Atorvastatin on the Frequency of Ventilator-associated Pneumonia in Patients With Ischemic Stroke Pravastatin and Ventilatory Associated Pneumonia (EPRAVAP) Atorvastatin in Bronchiectasis in Patients With Pseudomonas Aeruginosa Statins for the Early Treatment of Sepsis (SETS) www.clinicaltrials.gov

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