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Cardiovascular Risks Associated With Azithromycin: Worth the Hype?
Cardiovascular Risks Associated With Azithromycin: Worth the Hype? Azithromycin (AZI) is a macrolide antibiotic and, until recently, was generally considered safe and effective for outpatient management of conditions such as upper respiratory tract and sexually transmitted infections. Compared with clarithromycin, erythromycin, and other agents within the same class, AZI offers several advantages, such as tolerability, convenient dosing, and fewer drug-drug interactions. In spite of those advantages, a widely read article published in 2012 in The New England Journal of Medicine (NEJM)1 suggested the potential for AZI to induce sudden cardiac death secondary to life-threatening arrhythmias.2,3 This led the United States Food and Drug Administration to issue safety warnings related to the use of the drug. The NEJM study was a retrospective analysis of adult patients who had AZI outcomes of cardiovascular (CV) death and all-cause mortality. The patients were compared with propensity-score‒matched cohorts of patients who received no antimicrobial or other antimicrobial agents, including amoxicillin and fluoroquinolones (FQs). The investigators observed a small increase in the risk of CV-related death with AZI relative to both placebo (hazard ratio 2.88; 95% confidence interval 1.79-4.63; P < .001) and amoxicillin (hazard ratio 2.49; 95% CI 1.38-4.50; P ¼ .002). The results should be interpreted cautiously due to some limitations, including the retrospective nature of the study and lack of similar findings in a sufficient number of previous randomized studies and metaanalyses.4,5 In addition, data were collected from health care records of Medicaid patients’ billing information, which may be incomplete and/or inaccurate. Furthermore, comparing the incidence of CV-related death associated with www.npjournal.org
the use of AZI relative to FQs may have been a more clinically relevant approach, as these agents have a greater association with QT prolongation, particularly in patients with underlying risk factors, such as concomitant
PRESCRIPTION PAD Nadia I. Awad, PharmD, BCPS medications that induce prolongation of the QT interval, and electrolyte abnormalities, such as hypokalemia and hypomagnesemia. The investigators found that AZI did not demonstrate an increased risk of CV-related death relative to either of the FQs evaluated in the study. In a retrospective, observational cohort study in NEJM published a full year later,6 the investigators evaluated the incidence of CVrelated death in Danish adults in 2 different comparator groups: no antibiotics versus AZI and AZI versus penicillin V. The investigators found no increased risk of CV-related death with AZI relative to penicillin V (rate ratio 0.93; 95% confidence interval 0.56-1.55). The authors noted that the patients evaluated were relatively young and healthy without any major comorbidities, including CV disease. The baseline demographics contrasted starkly with those of the 2012 study1; patients were approximately 10 years older and a higher percentage of them were on therapy for CV disease. The authors noted that patients with a history of CV disease The Journal for Nurse Practitioners - JNP
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were at greater risk of death, and the greater incidence of CV-related death in the AZI group relative to no antibiotics could be attributed to the acute infectious process and not the treatment itself. Another recently published observational study also forces us to re-evaluate the idea linking AZI to CV-related morbidity and mortality.7 In a retrospective cohort study of over 73,000 inpatients with a diagnosis of community-acquired pneumonia, investigators compared the incidence of 30- and 90-day allcause mortality and 90-day cardiac arrhythmias, heart failure, myocardial infarction, and any CV event in patients who received guidelineconcordant therapy, which included a combination of b-lactam and AZI or monotherapy with a respiratory FQ. In the AZI group, 1,948 patients had myocardial infarction within 90 days compared with 1,523 patients in the nonAZI group (odds ratio 1.11; 95% confidence interval 1.03-1.20). However, AZI was associated with a lower incidence of all-cause mortality at 90 days, and there were no differences in cardiac arrhythmias during this same time frame relative to the non-AZI group. The decision to prescribe AZI should be made on an individual basis. It is generally safe in patients who are otherwise healthy and with no underlying CV risk factors. Due to the CV risk associated with AZI, alternative therapies may need to be considered in those with CV comorbidities or risk factors for cardiac dysrhythmias and those on concomitant therapies that may increase the risk for prolongation of the QT interval, especially in the outpatient setting. For inpatients, one may consider
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The Journal for Nurse Practitioners - JNP
obtaining a baseline electrocardiogram and serum electrolytes to minimize the risk for developing cardiac dysrhythmias after initiation of AZI. The studies highlighted herein have raised several questions related to the CV risk associated with AZI. Additional prospective studies are needed, particularly in adult patients with risk factors for CV arrhythmias, to establish appropriate treatment strategies in these patient populations. References 1. Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012;366(20): 1881-1890. 2. US Food and Drug Administration. FDA statement regarding azithromycin (Zithromax) and the risk of cardiovascular death. http:// www.fda.gov/Drugs/DrugSafety/ucm304372.htm/. Accessed September 20, 2014. 3. US Food and Drug Administration. FDA drug safety communication: azithromycin (Zithromax or Zmax) and the risk of potentially fatal heart rhythms. http://www.fda.gov/Drugs/DrugSafety/ucm341822.htm/. Accessed September 20, 2014. 4. Grayston JT, Kronmal RA, Jackson LA, et al. Azithromycin for the secondary prevention of coronary events. N Engl J Med. 2005;352(16):1637-1645. 5. Baker WL, Couch KA. Azithromycin for the secondary prevention of coronary artery disease: a meta-analysis. Am J Health Syst Pharm. 2007;64(8):830-836. 6. Svanström H, Pasternak B, Hviid A. Use of azithromycin and death from cardiovascular causes. N Engl J Med. 2013;368(18):1704-1712. 7. Mortensen EM, Halm EA, Pugh MJ, et al. Association of azithromycin with mortality and cardiovascular events among older patients hospitalized with pneumonia. JAMA. 2014;311(21):2199-2208.
Nadia I. Awad, PharmD, BCPS, is a clinical assistant professor of emergency medicine in the Ernest Mario School of Pharmacy at Rutgers, The State University of New Jersey in Piscataway. She practices as an emergency medicine pharmacist at Robert Wood Johnson University Hospital Somerset in Somerville, NJ. She can be reached at nadia@ pharmacy.rutgers.edu. Timothy Nguyen, PharmD, BCPS, CCP, FASCP, is the Prescription Pad department editor and can be reached at [email protected].
1555-4155/14/$ see front matter © 2015 Elsevier, Inc. All rights reserved. http://dx.doi.org/10.1016/j.nurpra.2014.10.028
Volume 11, Issue 1, January 2015
the use of AZI relative to FQs may have been a more clinically relevant approach, as these agents have a greater association with QT prolongation, particularly in patients with underlying risk factors, such as concomitant
PRESCRIPTION PAD Nadia I. Awad, PharmD, BCPS medications that induce prolongation of the QT interval, and electrolyte abnormalities, such as hypokalemia and hypomagnesemia. The investigators found that AZI did not demonstrate an increased risk of CV-related death relative to either of the FQs evaluated in the study. In a retrospective, observational cohort study in NEJM published a full year later,6 the investigators evaluated the incidence of CVrelated death in Danish adults in 2 different comparator groups: no antibiotics versus AZI and AZI versus penicillin V. The investigators found no increased risk of CV-related death with AZI relative to penicillin V (rate ratio 0.93; 95% confidence interval 0.56-1.55). The authors noted that the patients evaluated were relatively young and healthy without any major comorbidities, including CV disease. The baseline demographics contrasted starkly with those of the 2012 study1; patients were approximately 10 years older and a higher percentage of them were on therapy for CV disease. The authors noted that patients with a history of CV disease The Journal for Nurse Practitioners - JNP
149
JNP
were at greater risk of death, and the greater incidence of CV-related death in the AZI group relative to no antibiotics could be attributed to the acute infectious process and not the treatment itself. Another recently published observational study also forces us to re-evaluate the idea linking AZI to CV-related morbidity and mortality.7 In a retrospective cohort study of over 73,000 inpatients with a diagnosis of community-acquired pneumonia, investigators compared the incidence of 30- and 90-day allcause mortality and 90-day cardiac arrhythmias, heart failure, myocardial infarction, and any CV event in patients who received guidelineconcordant therapy, which included a combination of b-lactam and AZI or monotherapy with a respiratory FQ. In the AZI group, 1,948 patients had myocardial infarction within 90 days compared with 1,523 patients in the nonAZI group (odds ratio 1.11; 95% confidence interval 1.03-1.20). However, AZI was associated with a lower incidence of all-cause mortality at 90 days, and there were no differences in cardiac arrhythmias during this same time frame relative to the non-AZI group. The decision to prescribe AZI should be made on an individual basis. It is generally safe in patients who are otherwise healthy and with no underlying CV risk factors. Due to the CV risk associated with AZI, alternative therapies may need to be considered in those with CV comorbidities or risk factors for cardiac dysrhythmias and those on concomitant therapies that may increase the risk for prolongation of the QT interval, especially in the outpatient setting. For inpatients, one may consider
150
The Journal for Nurse Practitioners - JNP
obtaining a baseline electrocardiogram and serum electrolytes to minimize the risk for developing cardiac dysrhythmias after initiation of AZI. The studies highlighted herein have raised several questions related to the CV risk associated with AZI. Additional prospective studies are needed, particularly in adult patients with risk factors for CV arrhythmias, to establish appropriate treatment strategies in these patient populations. References 1. Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death. N Engl J Med. 2012;366(20): 1881-1890. 2. US Food and Drug Administration. FDA statement regarding azithromycin (Zithromax) and the risk of cardiovascular death. http:// www.fda.gov/Drugs/DrugSafety/ucm304372.htm/. Accessed September 20, 2014. 3. US Food and Drug Administration. FDA drug safety communication: azithromycin (Zithromax or Zmax) and the risk of potentially fatal heart rhythms. http://www.fda.gov/Drugs/DrugSafety/ucm341822.htm/. Accessed September 20, 2014. 4. Grayston JT, Kronmal RA, Jackson LA, et al. Azithromycin for the secondary prevention of coronary events. N Engl J Med. 2005;352(16):1637-1645. 5. Baker WL, Couch KA. Azithromycin for the secondary prevention of coronary artery disease: a meta-analysis. Am J Health Syst Pharm. 2007;64(8):830-836. 6. Svanström H, Pasternak B, Hviid A. Use of azithromycin and death from cardiovascular causes. N Engl J Med. 2013;368(18):1704-1712. 7. Mortensen EM, Halm EA, Pugh MJ, et al. Association of azithromycin with mortality and cardiovascular events among older patients hospitalized with pneumonia. JAMA. 2014;311(21):2199-2208.
Nadia I. Awad, PharmD, BCPS, is a clinical assistant professor of emergency medicine in the Ernest Mario School of Pharmacy at Rutgers, The State University of New Jersey in Piscataway. She practices as an emergency medicine pharmacist at Robert Wood Johnson University Hospital Somerset in Somerville, NJ. She can be reached at nadia@ pharmacy.rutgers.edu. Timothy Nguyen, PharmD, BCPS, CCP, FASCP, is the Prescription Pad department editor and can be reached at [email protected].
1555-4155/14/$ see front matter © 2015 Elsevier, Inc. All rights reserved. http://dx.doi.org/10.1016/j.nurpra.2014.10.028
Volume 11, Issue 1, January 2015