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Macrolide Therapy for Pneumonia: Balancing Benefits with Cardiovascular Risks Eric Mortensen, MD, MSc, FACP
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Faculty Disclosure I have no relevant conflicts of interest nor will discuss “off label” use of any medications
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Community-Acquired Pneumonia (CAP) Leading infectious cause of death Since 1950 mortality has been stable or increasing Increased incidence with aging of the population
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CAP Clinical Practice Guidelines ATS- 1993 and 2001 IDSA- 1998, 2000, and 2003 BTS- 1993 and 2001 CIDS/CTS- 1993 and 2000 CDC- 2000 ERS- 2005 and 2011 IDSA/ATS- 2007 Mandell et al.,Clin Infect Dis, 2007. 44 Suppl 2: p. S27 Woodhead et al. Clin Micro Infect 2011. 17 Suppl. 6, 1–24
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IDSA/ATS Outpatient Antibiotic Recommendations No risk factors for drug resistant S. pneumoniae (DRSP) Macrolide or doxycycline Has risk factors for DRSP or significant comorbid conditions Anti-pneumococcal fluoroquinolone -lactam + macrolide or doxycycline
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IDSA/ATS Inpatient Antibiotic Recommendations Wards – -lactam + macrolide or doxycycline –Anti-pneumococcal fluoroquinolone alone ICU – -lactam + azithromycin or fluoroquinolone
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Beneficial Effects of Macrolides on the Inflamed Airway Kanoh S, and Rubin B K Clin. Microbiol. Rev. 2010;23:590-615
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Macrolides for Pneumonia Erythromycin Clarithromycin Azithromycin
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Factors Associated With Mortality And Lengthy Of Stay In Elderly Patients With CAP- Azithromycin vs. Clarithromycin Sánchez F et al. Clin Infect Dis. 2003;36:1239-1245
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Macrolide versus non-macrolide therapy and mortality in critically ill patients with community-acquired pneumonia: primary analysis (n=27) Sligl, W, et al. Critical Care Medicine. 42(2):420-432
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Ray WA, et al. NEJM. May 17 2012; 366(20):1881-1890
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Cumulative Incidence of Cardiovascular Death and Death from Any Cause for Patients Who Took Azithromycin vs Amoxicillin Ray WA et al. N Engl J Med 2012;366:1881-1890.
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Cardiovascular Death and Death from Any Cause among Patients Who Took Azithromycin vs. no Antibiotics Ray WA et al. N Engl J Med 2012;366:1881-1890.
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Svanström H et al. N Engl J Med 2013;368:1704-1712
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Risk of Death from Cardiovascular Causes with Azithromycin Use as Compared with No Antibiotic Use or Use of Penicillin V Svanström H et al. N Engl J Med 2013;368:1704-1712
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Subgroup Analyses of the Risk of Death from Cardiovascular Causes with Current Use of Azithromycin as Compared with Penicillin V Svanström H et al. N Engl J Med 2013;368:1704-1712
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jamanetwork.com Available at jama.com and on The JAMA Network Reader at mobile.jamanetwork.com EM Mortensen and coauthors Association of Azithromycin With Mortality and Cardiovascular Events Among Older Patients Hospitalized With Pneumonia
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Aim: To examine the association of azithromycin use with all-cause mortality and cardiovascular events for older patients hospitalized with pneumonia Mortensen et al. JAMA 2014
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Inclusion Criteria Hospitalized with pneumonia in VA health care system between FY 2002 and 2012 > 65 years old >3 outpatient visits in year prior & received outpatient medications Received guideline-concordant antibiotic therapy and first dose given within 48 hours of admission
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Guideline-Concordant Antibiotic Regimes Wards –Beta-lactam + azithromycin –Antipneumococcal fluoroquinolone alone ICU –Beta-lactam + azithromycin –Beta-lactam + fluoroquinolone Mandell LA, et al. Clin Infect Dis. Mar 1 2007;44 Suppl 2:S27-72
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Primary Outcomes Mortality within 90-days Cardiovascular events within 90-days –MI –Heart failure –Arrhythmia –Any
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Statistical Analyses Propensity matching with score created using 59 variables including: –Demographics (age, race, marital status) –Comorbid conditions –Severity of illness (ICU, vasopressors) –Outpatient medications (statins, anti-diabetic) Instrumental variable analysis –Chosen IV was proportion of patients receiving azithromycin in each hospital
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Results Overall 73,690 patients from 118 hospitals meet inclusion criteria Propensity-matched group composed of 63,726 patients
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After matching no significant differences (all p >0.3) Variable Azithromycin N=31,863 No Azithromycin N=31,863 Age, mean (SD)77.8 (7.4) Men98.2% Married52.5%52.4% ICU admission15.6%15.5% Mechanical ventilation5.2%5.3% Tobacco use39.7% Alcohol abuse4.5% Myocardial infarction7.1%7.0% Heart failure25.7%25.6% COPD51.8%51.7% Prior antibiotic therapy31.3%31.1%
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Survival Curves by Azithromycin Use vs Nonuse
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Time to First Cardiac Event by Azithromycin Use vs Nonuse
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Outcomes after Propensity Matching OutcomeOdds Ratio95% CI 90-day mortality0.730.70-0.76 MI1.171.08-1.25 Arrhythmia0.990.95-1.02 Heart failure1.01 0.97-1.04 Any CV event1.010.98-1.05
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Instrumental Variable Analysis Outcome Average Marginal Effect of Azithromycin Bootstrapped 95% CI Mortality-0.08-0.10 to -0.07 Any CV Event-0.004-0.02 to 0.02 Heart Failure-0.04-0.06 to -0.02 MI0.030.02 to 0.04 Arrhythmia0.01-0.01 to 0.03 Azithromycin users had 8% lower probability of mortality 4% lower probability of HF 3% higher probability of MI
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Secondary Analyses No prior outpatient antibiotics –90-day mortality OR 0.74 (0.71-0.78) –Any CV event OR 1.02 (0.97-1.06) Prior cardiac disease –90-day mortality OR 0.72 (0.67-0.77) –Any CV event OR 1.04 (0.97-1.11) Invasive mechanical ventilation –90- day mortality OR 0.81 (0.70-0.93) –Any CV event OR 1.24 (1.08-1.43)
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Conclusions- Azithromycin and CAP Azithromycin use associated with lower mortality but higher rate of MI –NNT to prevent 1 death- 21 –NNH to cause 1 MI- 144 –Net benefit: 7 deaths averted for each non-fatal MI
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Summary Macrolides are part of guideline- concordant pneumonia therapy Azithromycin is associated with some increased cardiac risks, but… For pneumonia, benefits of azithromycin outweigh risks
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Questions? Eric.Mortensen@UTSouthwestern.edu
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