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BACKGROUND

Although several macrolide antibiotics are proarrhythmic and associated with an increased risk of sudden cardiac death, azithromycin is thought to have minimal cardiotoxicity. However, published reports of arrhythmias suggest that azithromycin may increase the risk of cardiovascular death.
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METHODS

We studied a Tennessee Medicaid cohort designed to detect an increased risk of death related to short-term cardiac effects of medication, excluding patients with serious noncardiovascular illness and person-time during and shortly after hospitalization. The cohort included patients who took azithromycin (347,795 prescriptions), propensity-score–matched persons who took no antibiotics (1,391,180 control periods), and patients who took amoxicillin (1,348,672 prescriptions), ciprofloxacin (264,626 prescriptions), or levofloxacin (193,906 prescriptions).
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RESULTS

During 5 days of therapy, patients taking azithromycin, as compared with those who took no antibiotics, had an increased risk of cardiovascular death (hazard ratio, 2.88; 95% confidence interval [CI], 1.79 to 4.63; P<0.001) and death from any cause (hazard ratio, 1.85; 95% CI, 1.25 to 2.75; P=0.002). Patients who took amoxicillin had no increase in the risk of death during this period. Relative to amoxicillin, azithromycin was associated with an increased risk of cardiovascular death (hazard ratio, 2.49; 95% CI, 1.38 to 4.50; P=0.002) and death from any cause (hazard ratio, 2.02; 95% CI, 1.24 to 3.30; P=0.005), with an estimated 47 additional cardiovascular deaths per 1 million courses; patients in the highest decile of risk for cardiovascular disease had an estimated 245 additional cardiovascular deaths per 1 million courses. The risk of cardiovascular death was significantly greater with azithromycin than with ciprofloxacin but did not differ significantly from that with levofloxacin.
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CONCLUSIONS

During 5 days of azithromycin therapy, there was a small absolute increase in cardiovascular deaths, which was most pronounced among patients with a high baseline risk of cardiovascular disease. (Funded by the National Heart, Lung, and Blood Institute and the Agency for Healthcare Quality and Research Centers for Education and Research on Therapeutics.)

Azithromycin, a broad-spectrum macrolide antibiotic, has been reported to be relatively free of cardiotoxic effects.[size=11]1 However, the closely related drugs erythromycin and clarithromycin can increase the risk of serious ventricular arrhythmias2-7 and are associated with an increased risk of sudden cardiac death.8-10 Furthermore, accumulating evidence suggests that azithromycin also may have proarrhythmic effects. There are at least seven published reports of patients with normal baseline QT intervals in whom azithromycin had arrhythmia-related adverse cardiac effects, including pronounced QT-interval prolongation,11-13 torsades de pointes,14-16 and polymorphic ventricular tachycardia in the absence of QT-interval prolongation.17 The Food and Drug Administration's Adverse Event Reporting System includes at least 20 reports of torsades de pointes associated with azithromycin.18[/size]

METHODS

Study Oversight

Study Cohort

The study cohort consisted of persons enrolled in the Tennessee Medicaid program[size=11]19,20; all data on patients in the study were appropriately deidentified. Computerized Medicaid data, which were linked to death certificates and to a statewide hospital-discharge database, provided information on Medicaid enrollment, medical care encounters, and dates and causes of death. Antibiotics and other medications that patients had taken were identified from Medicaid pharmacy files.19,21-23[/size]

The study also included matched control periods (of similar length to the courses of antibiotic therapy) during which there was no use of study antibiotics. For each qualifying azithromycin prescription, we identified four such control periods, which were frequency-matched[size=11]24 according to a propensity score that was calculated from 153 covariates (Table 3 in the Supplementary Appendix). The persons in the control group had to satisfy the eligibility criteria on the day that the control period began and could not have used any study antibiotics during the prior 30 days.[/size]

To attempt to control for confounding by indication, we also included as additional control groups patients who took three other antibiotics: amoxicillin (including amoxicillin with clavulanate potassium), ciprofloxacin, and levofloxacin. Amoxicillin, the primary control antibiotic, has indications that are similar to those of azithromycin and has not been shown to have adverse cardiac effects.[size=11]8The indications for ciprofloxacin and levofloxacin overlap those of azithromycin. Ciprofloxacin is thought to have minimal adverse electrophysiological effects, although there are case reports of torsades de pointes.1,25 Levofloxacin, which is considered to have greater proarrhythmic potential than ciprofloxacin,1,25 has been implicated in numerous case reports of torsades de pointes.18[/size]

Study End Points

The primary study end points were cardiovascular death (see the Supplementary Appendix) and death from any cause. We hypothesized that the incidence of cardiovascular death should be increased if azithromycin is proarrhythmic, particularly in a cohort chosen to reduce the likelihood of out-of-hospital deaths from serious illnesses. We included an analysis of death from any cause to guard against differential misclassification of deaths related to use of a study antibiotic. Given the study hypothesis, we also analyzed sudden cardiac deaths, identified with an independently validated computerized definition that is based on multiple sources of data (see the Supplementary Appendix) and that has a positive predictive value of 88%.[size=11]26[/size]

Statistical Analysis

The study unit of analysis was the course of antibiotic therapy, which was defined as a fixed period, beginning with the date on which the prescription was filled, during which patients would have been advised to take the antibiotic. This should correspond to the period of greatest risk of adverse cardiac effects, given that the case reports for azithromycin suggest an acute mechanism.[size=11]11-17Because the usual duration of treatment varies according to the specific study antibiotic, we analyzed two periods: the 5-day period that is generally recommended for azithromycin and the 10-day period most commonly suggested for the other study antibiotics. The 10-day analyses for azithromycin included an interval during which patients were unlikely to be taking the drug (days 6 through 10); these days were considered separately in several analyses. Although these periods usually had a fixed duration (5 or 10 days), the data were censored if the patient filled a subsequent prescription for a study antibiotic or ceased to meet the eligibility criteria.[/size]

Each study comparison was adjusted for an extensive set of covariates (reflecting status on the date on which the prescription was filled) that were possibly associated with both the use of the study antibiotic and the risk of death (Table 3 in the Supplementary Appendix). This adjustment used the propensity score[size=11]27 (the conditional probability of having a prescription for a study antibiotic, given the covariates). Specific propensity scores were estimated for each pairwise comparison (Tables 4 and 5 in the Supplementary Appendix). The propensity scores for comparisons between study antibiotics included the recorded antibiotic indication (see the Supplementary Appendix).[/size]

To check for misspecification of the propensity-score regression models, we evaluated whether the covariate distributions were balanced across the study groups. For the azithromycin group and the control group of persons not taking antibiotics, this distribution was unadjusted, because the propensity-score matching should ensure balance. For amoxicillin, the distribution was adjusted for the propensity score, with the use of a modified method for weighting by inverse probability of treatment[size=11]28 that standardized the distribution to that for azithromycin (Table 6 in the Supplementary Appendix).29 We also checked for overlap of the distribution of propensity scores (Tables 4 and 5 in the Supplementary Appendix).[/size]

To provide a summary measure of the risk of cardiovascular death, we calculated a risk score for cardiovascular disease.[size=11]30 This score estimated the probability of cardiovascular death (in the absence of use of a study antibiotic) as a function of the indicators of coexisting conditions (see the Supplementary Appendix).[/size]

RESULTS

Characteristics of the Study Cohort

, and Table 7 in the Supplementary Appendix). The characteristics of patients receiving azithromycin prescriptions and the propensity-score matched controls were very similar. In contrast, patients who were prescribed ciprofloxacin or levofloxacin were generally more likely to have complications of diabetes, incontinence, and wheelchair or walker use. The mean summary cardiovascular risk scores for patients taking amoxicillin (9.5), ciprofloxacin (10.3), and levofloxacin (10.6) were higher than the scores for those taking azithromycin (9.3) (Table 1).

Cardiovascular Death and Total Deaths

 and Table 2). For cardiovascular death, the hazard ratio was 2.88 (95% confidence interval [CI], 1.79 to 4.63; P<0.001); the risk was increased for both sudden cardiac death and other cardiovascular deaths. Although there was no increased risk of death from noncardiovascular causes, the risk of death from any cause was increased (hazard ratio, 1.85; 95% CI, 1.25 to 2.75; P=0.002). For the 10-day period after the prescription was filled, azithromycin use was associated with an increased risk of cardiovascular death (hazard ratio, 1.86; 95% CI, 1.27 to 2.73; P=0.002), but the risk of death from any cause was not significantly increased (hazard ratio, 1.27; 95% CI, 0.92 to 1.75; P=0.20). In contrast, amoxicillin use was not associated with a significantly increased risk of death from cardiovascular or noncardiovascular causes or of death from any cause during either the first 5 or all 10 days of therapy (Table 2, and Fig. 1 in the Supplementary Appendix).

, and Table 10 in the Supplementary Appendix). Thus, patients who took azithromycin had an estimated 47 additional cardiovascular deaths per 1 million 5-day courses of therapy. Alternative analyses, including a repeated-measures analysis, an analysis stratified by propensity score, and an analysis with a model that included terms for other proarrhythmic drugs, had similar results (Table 11 in the Supplementary Appendix). The risk of cardiovascular death was significantly higher for a 10-day period (hazard ratio, 1.87; 95% CI, 1.16 to 3.01; P=0.01) (Figure 2), although the risk was not increased for days 6 through 10. The risk of death from any cause was not significantly increased during the 10-day period.

, and Table 12 in the Supplementary Appendix). For patients in the highest decile of risk scores, who accounted for 59% of the cardiovascular deaths during azithromycin therapy, there were an estimated 245 additional cardiovascular deaths per 1 million 5-day courses of azithromycin therapy.

DISCUSSION

We included two distinct control groups in an effort to minimize confounding. One group comprised control periods that were propensity-score–matched with courses of azithromycin therapy. This balanced the prevalence of recorded cardiovascular disease and other coexisting conditions and probably provided some control for behavioral risk factors, given that their effects may be partially mediated through variables more readily identified in the database, such as diagnosed hyperlipidemia, hypertension, diabetes, heart failure, angina, or myocardial infarction. To minimize confounding by the short-term effects of infections, we included a second control group that comprised courses of amoxicillin therapy, which has indications similar to those for azithromycin. Patients who took amoxicillin had no increase in the risk of either cardiovascular death or death from any cause during the study period, which is consistent with our previous findings.[size=11]8 When azithromycin was directly compared with amoxicillin, in an analysis that also controlled for recorded antibiotic indication, the increased risk persisted for azithromycin.[/size]

Our study was prompted by evidence that azithromycin is proarrhythmic,[size=11]11-17 which led us to hypothesize that it would increase the risk of sudden cardiac death. Patients who took azithromycin did have an increased risk of sudden cardiac death, as identified from a previously developed computer definition.26 However, they also had a similarly increased risk of other, out-of-hospital cardiovascular deaths, although the numbers of these deaths were small. This finding could be due to misclassification, given that our definition of sudden cardiac death was designed to be specific; our prior study suggested that as many as 25% of patients would be misclassified as having died from other cardiovascular causes.26 Alternatively, a proarrhythmic effect of azithromycin might increase the risk of other types of cardiovascular death. Thus, although our data are consistent with an adverse cardiac effect of azithromycin, they cannot establish a specific causal mechanism.[/size]

The increased risk of cardiovascular death during the usual 5-day course of azithromycin therapy did not persist after the course of therapy ended. Although concentrations of azithromycin remain elevated in tissue for several days after cessation of oral therapy, serum concentrations decline more rapidly, falling to trough levels within 24 hours.[size=11]31 For many other drugs with proarrhythmic effects, an elevated serum concentration is a key determinant of increased risk,32 which is an important reason why rapid infusion of erythromycin is not recommended.25[/size]

The cohort also included patients who had taken ciprofloxacin and levofloxacin, which provided information on the relative safety of these broad-spectrum fluoroquinolones. For ciprofloxacin, the risks of both cardiovascular death and death from any cause during the study period were similar to those for amoxicillin, a finding that is consistent with the current opinion that ciprofloxacin has limited proarrhythmic liability.[size=11]1,25 In contrast, levofloxacin, which has recognized proarrhythmic potential,1,25 was associated with a trend toward an increased risk of cardiovascular death, although the point estimates were not significant. When azithromycin was compared directly with levofloxacin, there was no significant difference in the risk of either cardiovascular death or death from any cause.[/size]