The Relationship between ACE Inhibitors, Statins

and Pneumonia

Mark Woodhead

Honorary Clinical Professor of Respiratory MedicineUniversity of Manchester & Manchester Royal Infirmary

Mark Woodhead

Honorary Clinical Professor of Respiratory MedicineUniversity of Manchester & Manchester Royal Infirmary

PneumoniaPathogenesis

ANTIBIOTIC

ACE inhibitors

Substance P

Dysphagia

Arai T, Yasuda Y, Takaya T, et al. ACEinhibitors and symptomless dysphagia.Lancet 1998; 352: 115–16.

ACE inhibitors

Substance P

CoughDysphagia

Arai T, Yasuda Y, Takaya T, et al. ACEinhibitors and symptomless dysphagia.Lancet 1998; 352: 115–16.

ACE inhibitors

Substance P

Pneumonia

CoughDysphagia

Arai T, Yasuda Y, Takaya T, et al. ACEinhibitors and symptomless dysphagia.Lancet 1998; 352: 115–16.

?

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

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

OddsRatio

Favours Treatment A

Favours Treatment B

Forest Plot

OddsRatio

Favours Treatment A

Favours Treatment B

Forest PlotReasons for Reduced Confidence

Confidence Interval crossing unity line

WideConfidence

Interval

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

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

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

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

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

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

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

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

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

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

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

Mevalonate Pathway

Statins

Mevalonate Pathway

Immunomodulatory

Anti-inflammatory

Anti-thromobotic

Anti-microbial

Acetyl-CoA

HMG-CoA

Mevalonate

Cholesterol

HMG-CoA reductaseStatins

Boyd et al BMC Microbiology 2012;12:73

Survival of Simvastatin-fed Mice with S pneumoniae Infection

Boyd et al BMC Microbiology 2012;12:73

Survival of Simvastatin-fed Mice with S pneumoniae Infection

Bacterial numbers

Boyd et al BMC Microbiology 2012;12:73

Survival of Simvastatin-fed Mice with S pneumoniae Infection

Bacterial numbers Lung neutrophils

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

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.

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

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

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

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

Conclusions

Has the ball crossed the line?

Conclusions

Has the ball crossed the line?

Do ACEIs, ARBs or Statins prevent/alter outcome in pneumonia?

Conclusions

• ACEIS and ARBs may reduce pneumonia frequency

• Statins may reduce pneumonia frequency

• Statins may reduce pneumonia mortality

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

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!

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……..