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The Relationship between ACE Inhibitors, Statins
and Pneumonia
Mark Woodhead
Honorary Clinical Professor of Respiratory MedicineUniversity of Manchester & Manchester Royal Infirmary
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Mark Woodhead
Honorary Clinical Professor of Respiratory MedicineUniversity of Manchester & Manchester Royal Infirmary
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PneumoniaPathogenesis
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ANTIBIOTIC
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ACE inhibitors
Substance P
Dysphagia
Arai T, Yasuda Y, Takaya T, et al. ACEinhibitors and symptomless dysphagia.Lancet 1998; 352: 115–16.
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ACE inhibitors
Substance P
CoughDysphagia
Arai T, Yasuda Y, Takaya T, et al. ACEinhibitors and symptomless dysphagia.Lancet 1998; 352: 115–16.
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ACE inhibitors
Substance P
Pneumonia
CoughDysphagia
Arai T, Yasuda Y, Takaya T, et al. ACEinhibitors and symptomless dysphagia.Lancet 1998; 352: 115–16.
?
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N = 516 with hypertension
247 Calcium channel blocker
3 year follow up
Pneumonia 22 (8.9%)
60 controls
Pneumonia 5 (8.3%)
Arai et al Lancet 1998;352:1937-1938
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N = 516 with hypertension
269 ACEI (imidrapil) 247 Calcium channel blocker
3 year follow up
Pneumonia 9 (3.3%) Pneumonia 22 (8.9%)
60 controls
Pneumonia 5 (8.3%)
P=0.025
Arai et al Lancet 1998;352:1937-1938
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OddsRatio
Favours Treatment A
Favours Treatment B
Forest Plot
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OddsRatio
Favours Treatment A
Favours Treatment B
Forest PlotReasons for Reduced Confidence
Confidence Interval crossing unity line
WideConfidence
Interval
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OddsRatio
Favours Treatment A
Favours Treatment B
Forest PlotReasons for Reduced Confidence
OddsRatio
Favours Treatment A
Favours Treatment B
Confidence Interval crossing unity line
WideConfidence
Interval Discordant results
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Caldeira et al BMJ 2012;345:e4260 doi: 10.1136/bmj.e4260 (Published 11 July 2012)
ACEIs and Pneumonia riskSystematic Review and Meta-analysis
Favours ACEI
Favours control
Oddsratio
1
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Caldeira et al BMJ 2012;345:e4260 doi: 10.1136/bmj.e4260 (Published 11 July 2012)
ACEIs and Pneumonia riskSystematic Review and Meta-analysis
Favours ACEI
Favours control
Oddsratio
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Caldeira et al BMJ 2012;345:e4260 doi: 10.1136/bmj.e4260 (Published 11 July 2012)
ACEIs and Pneumonia riskSystematic Review and Meta-analysis
Oddsratio
+ cohort + case-control studies
Favours ACEI
Favours control
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Caldeira et al BMJ 2012;345:e4260 doi: 10.1136/bmj.e4260 (Published 11 July 2012)
ARBs and Pneumonia riskSystematic Review and Meta-analysis
Favours ARB
Favours control
Oddsratio
1
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Caldeira et al BMJ 2012;345:e4260 doi: 10.1136/bmj.e4260 (Published 11 July 2012)
ARBs and Pneumonia riskSystematic Review and Meta-analysis
Oddsratio
Favours ARB
Favours control
+ case-control studies
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Caldeira et al BMJ 2012;345:e4260 doi: 10.1136/bmj.e4260 (Published 11 July 2012)
ACEIs and ARBs and Pneumonia riskSystematic Review and Meta-analysis
Favours ACEI/ARB
Favours control
Oddsratio
1
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Caldeira et al BMJ 2012;345:e4260 doi: 10.1136/bmj.e4260 (Published 11 July 2012)
ACEIs and Pneumonia riskSystematic Review and Meta-analysis
Favours ACEI
Favours control
Oddsratio
1
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Caldeira et al BMJ 2012;345:e4260 doi: 10.1136/bmj.e4260 (Published 11 July 2012)
ACEIs and ARBs and Pneumonia MortalitySystematic Review and Meta-analysis
Oddsratio
1
Favours ACEI/ARB
Favours control
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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
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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
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Mevalonate Pathway
Statins
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Mevalonate Pathway
Immunomodulatory
Anti-inflammatory
Anti-thromobotic
Anti-microbial
Acetyl-CoA
HMG-CoA
Mevalonate
Cholesterol
HMG-CoA reductaseStatins
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Boyd et al BMC Microbiology 2012;12:73
Survival of Simvastatin-fed Mice with S pneumoniae Infection
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Boyd et al BMC Microbiology 2012;12:73
Survival of Simvastatin-fed Mice with S pneumoniae Infection
Bacterial numbers
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Boyd et al BMC Microbiology 2012;12:73
Survival of Simvastatin-fed Mice with S pneumoniae Infection
Bacterial numbers Lung neutrophils
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Statins in CAP1007 admitted to hospital 2005-2007, mortality 9.6%
257 (26%) were receiving statins
Predictor Adjusted 95% CIs pOdds Ratio
Statin 0.46 0.25 – 0.85 0.01Aspirin 0.63 0.36 – 1.11 0.11ACEI 1.16 0.64 – 2.11 0.62ß-agonist 1.97 1.03 – 3.78 0.04
Chalmers et al Am J Med 2008;121:1002-1007
? Healthy usereffect
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UK GP database, adults age > 45 years17, 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)
Risk of Pneumonia in those taking StatinsPopulation-based Nested case-control Study
Vinogradova et al Br J Gen Pract 2011;DOI:10.3399/bjgp11X606654.
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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.
No association – unadjustedAssociation - adjusted
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.
Beneficial effect of statins
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].
Apparent benefit ? due to unmeasured confounders
Meta-analyses of Statin Treatment and Pneumonia
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Meta-analysis of Statins in Pneumonia - Prevention
Khan et al (2013) PLoS ONE 8(1): e52929. doi:10.1371/journal.pone.0052929
Favours Statin Favours No-Statin
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Khan et al (2013) PLoS ONE 8(1): e52929. doi:10.1371/journal.pone.0052929
Meta-analysis of Statins in Pneumonia - Treatment
Favours Statin Favours No-Statin
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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 – unadjustedAssociation - adjusted
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.
Beneficial effect of statins
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].
Apparent benefit ? due to unmeasured confounders
Meta-analyses of Statin Treatment and Pneumonia
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
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Conclusions
Has the ball crossed the line?
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Conclusions
Has the ball crossed the line?
Do ACEIs, ARBs or Statins prevent/alter outcome in pneumonia?
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Conclusions
• ACEIS and ARBs may reduce pneumonia frequency
• Statins may reduce pneumonia frequency
• Statins may reduce pneumonia mortality
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RCT of Atorvastatin in Severe Sepsis in ICU
Kruger et al Am J Respir Crit Care Med Vol 187, Iss. 7, pp 743–750, Apr 1, 2013
250 critically ill patients (123 statins, 127 placebo) withsevere sepsis were administrated either atorvastatin (20mgdaily) or
matched placebo
Favours statin
Favours placebo
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Conclusions
• ACEIS and ARBs may reduce pneumonia frequency
• Statins may reduce pneumonia frequency
• Statins may reduce pneumonia mortality
Only Randomised Controlled
Trials will answer these
questions!
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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
Atorvastatin in Bronchiectasis in Patients With Pseudomonas Aeruginosa
Statins for the Early Treatment of Sepsis (SETS)
Effect of Atorvastatin on the Frequency of Ventilator-associated Pneumonia in Patients With Ischemic Stroke
Pravastatin and Ventilatory Associated Pneumonia (EPRAVAP)
www.clinicaltrials.gov
Clinical Trials in Progress……..