1. Use of Azithromycin and Death from Cardiovascular Causes Whitney Shirley University of Georgia Pharm.D. Candidate 2014

2. Azithromycin: Background Information Macrolide antibiotic – Treats Lower and upper respiratory infections Skin and soft-tissue infections Sexually transmitted diseases – Adverse events Increased risk of death from cardiovascular causes seen in patients who are at a high baseline risk

3. Objectives Investigate the potential pro-arrhythmic effect of Azithromycin – Rational: Other macrolide antibiotics are known to prolong the QT interval Primary outcome – Cardiovascular death Secondary outcome – Death from other causes

4. Methods Inclusion Criteria – 18-64 years old – Denmark resident for the past 2 years Exclusion Criteria – hospitalizations/antibiotic use within the past 30 days – No prescription filled within 1 year before the index date – Received another antibiotic on index date

5. Methods Prospective study – 1997-2010 Azithromycin vs antibiotic use – N=2,204,100 – 1:1 ratio Azithromycin vs Penicillin use – N=1,102,419 (azithromycin) – N=7,364,292 (Penicillin) Current use: 1-5 days Recent use: 6-10 days Past use: 11-35 days

6. Results Primary outcomes – Significant increase in the risk of death from cardiovascular causes with current use of Azithromycin versus no antibiotic use Rate ratio: 2.85 – 95% confidence interval 1.13 to 7.24 – NO increased risk of cardiovascular death was seen in Azithromycin use over Penicillin Rate ratio: 0.93 – 95% confidence interval 0.56 to 1.55

7. Results Secondary outcomes – Azithromycin versus no antibiotic use Rate ratio: 1.60 95% confidence interval 1.00 to 2.54 – Azithromycin versus Penicillin use 46 deaths during current use of Azithromycin – Incidence rate: 3.1 per 1,000 person-years 410 deaths during current use of Penicillin – Incidence rate: 4.1 per 1,000 person-years

8. Results Subgroup Analyses of the Risk of Death from Cardiovascular Causes with Current Use of Azithromycin as Compared with Penicillin V Analysis Azithromycin (N=1,102,419) Penicillin V (N=7,364,292) Rate Ratio (95% CI) P Value no. of events no./1000 patient-yr no. of events no./1000 patient-yr Primary analysis171.11461.50.93 (0.56-1.55)0.79 Subgroup analysis Sex0.73 Male91.7872.30.86 (0.43-1.72) Female80.85911.03 (0.49-2.16) Age0.5 18-44 yr30.3170.31.42 (0.41-4.90) 45-64 yr142.51293.10.88 (0.51-1.53) History of cardiovascular disease0.16 Yes109.76281.35 (0.69-2.64) No70.5840.90.65 (0.30-1.41) Henrik Svanström, M.Sc., Björn Pasternak, M.D., Ph.D., and Anders Hviid, Dr.Med.Sci. N Engl J Med 2013; 368:1704-1712 May2,2013 DOI: 10.1056/NEJMoa1300799

9. Sensitivity Analysis Sensistivity Analysis of Risk of Death from Cardiovascular Causes with Azithromycin Use as Compared with Penicillin V Use Antibiotic Use Azithromycin (N=1,102,419) Penicillin V (N=1,102,419) Rate Ratio (95% CI) Current use No. of events 1716 No./1000 patient-yr 1.1 1.06 (0.54-2.10) Recent use No. of events78 No./1000 patient-yr0.50.60.86 (0.31-2.37) Past use No. of events2321 No./1000 patient-yr0.3 1.05 (0.58-1.89) Henrik Svanström, M.Sc., Björn Pasternak, M.D., Ph.D., and Anders Hviid, Dr.Med.Sci. N Engl J Med 2013; 368:1704-1712 May2,2013 DOI: 10.1056/NEJMoa1300799

10. Conclusions Significant increased risk of cardiovascular death was seen in Azithromycin use versus no antibiotic use, but was not seen when comparing Azithromycin use versus Penicillin use – The increased risk seen in the first group is contributed to the risk of death associated with acute infection rather than Azithromycin use NO association between azithromycin use and increased risk of death from cardiovascular causes in young and middle-aged adults

11. Seminarian’s Conclusions Azithromycin is a safe and effective antibiotic when used in the general population – Caution should be taken when prescribing azithromycin in elderly patients or in those patients who have extensive health care problems

12. References Svanström et al. Use of Azithromycin and Death from Cardiovascular Causese. N Engl J Med 2013; 368:1704-1712 May2,2013 DOI: 10.1056/NEJMoa1300799 Ray et al. Azithromycin and the Risk of Cardiovascular Death. N Engl J Med 2012; 366:1881-1890May 17, 2012DOI: 10.1056/NEJMoa1003833