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2. Macrolide Therapy for Pneumonia: Balancing Benefits with Cardiovascular Risks Eric Mortensen, MD, MSc, FACP

3. Faculty Disclosure I have no relevant conflicts of interest nor will discuss “off label” use of any medications

4. Community-Acquired Pneumonia (CAP) Leading infectious cause of death Since 1950 mortality has been stable or increasing Increased incidence with aging of the population

5. 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

6. 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

7. IDSA/ATS Inpatient Antibiotic Recommendations Wards –  -lactam + macrolide or doxycycline –Anti-pneumococcal fluoroquinolone alone ICU –  -lactam + azithromycin or fluoroquinolone

8. Beneficial Effects of Macrolides on the Inflamed Airway Kanoh S, and Rubin B K Clin. Microbiol. Rev. 2010;23:590-615

9. Macrolides for Pneumonia Erythromycin Clarithromycin Azithromycin

10. 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

11. 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

12. Ray WA, et al. NEJM. May 17 2012; 366(20):1881-1890

13. 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.

14. 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.

15. Svanström H et al. N Engl J Med 2013;368:1704-1712

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. Primary Outcomes Mortality within 90-days Cardiovascular events within 90-days –MI –Heart failure –Arrhythmia –Any

23. 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

24. Results Overall 73,690 patients from 118 hospitals meet inclusion criteria Propensity-matched group composed of 63,726 patients

25. 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%

26. Survival Curves by Azithromycin Use vs Nonuse

27. Time to First Cardiac Event by Azithromycin Use vs Nonuse

28. 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

29. 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

30. 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)

31. 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

32. 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

33. Questions? Eric.Mortensen@UTSouthwestern.edu