Azithromycin Use and Cardiovascular Mortality
abstract
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Access this abstract nowImportance
Azithromycin is one of the most commonly prescribed antibiotics in the US. It has been associated with an increased risk of cardiovascular death in some observational studies.
Objective
To estimate the relative and absolute risks of cardiovascular and sudden cardiac death after an outpatient azithromycin prescription compared with amoxicillin, an antibiotic not known to increase cardiovascular events.
Design, Setting, and Participants
This retrospective cohort study included 2 large, diverse, community-based integrated care delivery systems with comprehensive capture of encounters and prescriptions from January 1, 1998, to December 31, 2014. The cohort included patients aged 30 to 74 years who had at least 12 months of health-plan enrollment prior to antibiotic exposure. The exclusion criteria were absence of prescription benefits, prescription for more than 1 type of study antibiotic within 10 days, hospitalization or nursing home residence, and serious medical conditions. Risk of cardiovascular death associated with azithromycin vs amoxicillin exposure was calculated after controlling for confounding factors using a propensity score. Data were analyzed from December 1, 2016, to March 30, 2020.
Exposures
Outpatient prescription of azithromycin or amoxicillin.
Main Outcomes and Measures
The primary outcomes were cardiovascular death and sudden cardiac death. An a priori subgroup analysis quantified the effects of azithromycin exposure among patients with increased baseline cardiovascular risk. The secondary outcomes were noncardiovascular death and all-cause mortality.
Results
The study included 7 824 681 antibiotic exposures, including 1 736 976 azithromycin exposures (22.2%) and 6 087 705 amoxicillin exposures (77.8%), among 2 929 008 unique individuals (mean [SD] age, 50.7 [12.3] years; 1 810 127 [61.8%] women). Azithromycin was associated with a significantly increased hazard of cardiovascular death (hazard ratio [HR], 1.82; 95% CI, 1.23-2.67) but not sudden cardiac death (HR, 1.59; 95% CI, 0.90-2.81) within 5 days of exposure. No increases in risk were found 6 to 10 days after exposure. Similar results were observed in patients within the top decile of cardiovascular risk (HR, 1.71; 95% CI, 1.06-2.76). Azithromycin was also associated with an increased risk of noncardiovascular death (HR, 2.17; 95% CI, 1.44-3.26) and all-cause mortality (HR, 2.00; 95% CI, 1.51-2.63) within 5 days of exposure.
Conclusions and Relevance
These findings suggest that outpatient azithromycin use was associated with an increased risk of cardiovascular death and noncardiovascular death. Causality cannot be established, particularly for noncardiovascular death, owing to the likelihood of residual confounding.
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Additional Info
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Azithromycin and Increase in Death?
In the past, azithromycin, like erythromycin, was shown to prolong the QT interval. The T wave is where your heart resets itself after the contraction so that it is ready for the next contraction. But if the T wave is delayed, then the heart is not ready. So if the signal for the next beat comes in, the heart might not give a normal beat, which can then lead to arrhythmias like torsade de pointes. Hence, there was a warning about QT prolongation and azithromycin.
In this study, the authors wanted to see if there is associated increase death with azithromycin use. Now to make sure that the patients had similar conditions, they compared azithromycin patients with patients taking amoxicillin. The death event rates will be low, so you need large numbers to be able to detect any difference.
This study used the Kaiser Permanente database of 7,824,681 antibiotic exposures, which included 1,736,976 azithromycin exposures (22.2%) and 6,087,705 amoxicillin exposures. There were 2,929,008 unique patients in that database. After propensity score matching, they looked at the death rates during two periods: day 0-5 and day 6-10.
Azithromycin is taken for 5 days, so blood levels would be highest in the first 5 days. If there was toxicity from serum levels, then that would show up during the day 0-5 period. However, azithromycin concentrates inside phagocytes and they in turn carry the azithromycin to the tissues, and that is why there are such high tissue concentrations. So the Day 6-10 period would capture if this were the mechanism of harm. That is why death events were assessed separately during these two periods.
During the first 5 days, cardiovascular death was increased by 82% (HR, 1.82; 95% CI, 1.23-2.67) but not sudden cardiac death (HR, 1.59; 95% CI, 0.90-2.81). So the effect may not be due to QT prolongation or arrhythmias. For the day 6-10 period, there were no significant increases in death; therefore, the tissue concentration may not be the culprit.
Interestingly, all-cause death within the first 5 days was doubled (HR, 2.17; 95% CI, 1.44-3.26) and non-cardiovascular death within that first 5 days was also doubled (HR, 2.00; 95% CI, 1.51-2.63). Again the day 6-10 window had no increase. So the mechanism is not clear as to why there is this increase.
Now before we completely abandon azithromycin, we need to look at the numbers more closely. In this whole study, there were only 485 deaths, with 211 deaths on the azithromycin side. So 1.7 million exposures to azithromycin and there were 211 total deaths on the azithromycin side, so it is not the case that every single patient who gets it will run the risk of death.
Also, when you look at the baseline characteristics of the patients, the azithromycin patients were “sicker.” In the year prior to the antibiotic exposure, the patients who received azithromycin had higher rates of pneumonia (14.0% vs 3.5%; P < .001), chronic obstructive pulmonary disease (20.6% vs 7.9%; P < .001), asthma (22.6% vs 10.4%; P < .001), and β-agonist use (40.7% vs 19.9%; P < .001). Effectively, the patients given azithromycin had more comorbidities even prior to the prescription. Now, propensity score matching can help blunt this, but the fact remains that the patients who received azithromycin compared with amoxicillin were sicker to begin with.
So what should be done with all this information? Let’s be frugal with our antibiotics. Let’s not give it unless required. It is not only antibiotic resistance that we have to worry about, also perhaps an increase in death. But on the other hand, we should not be so paralyzed with fear that we don’t use a good antibiotic when it is appropriate. So let’s be doctors again where we weigh the risks and benefits of every therapy for our patients and then choose the best path for them.
Azithromycin (AZ), a macrolide antibiotic, is one of the most commonly prescribed antibiotics in the US despite an increased risk of cardiovascular (CV) death noted in some studies, perhaps related to QT prolongation. The present study was a retrospective cohort study of almost 8 million antibiotic exposures (22% AZ; 78% amoxicillin) from January 1, 1998, to December 31, 2014, in patients with a mean age of 51 years, and 62% women. AZ was associated with a significantly increased hazard of CV death (HR, 1.82) but not sudden cardiac death within 5 days of exposure but not during 6 to 10 days of exposure. AZ was also associated with a significant increased risk of non-CV death (HR, 2.17) and all-cause mortality (HR, 2.00) within 5 days of exposure.
Other macrolide antibiotics such as clarithromycin and erythromycin have also been known to cause QT prolongation, probably all by blocking a potassium channel necessary for repolarization.1 Since this was a retrospective study, causality cannot be established due to confounders and other issues. In addition, if QT prolongation was the mechanism responsible for the increase in death, I would have expected the risk for sudden death to increase, which it did not, and non-CV death not to increase, which it did.
Nevertheless, the take-home message for clinicians is that AZ is associated with about a twofold increased risk of CV and non-CV death during the first 5-days of administration compared with amoxicillin and should be used with caution, particularly in patients who might be at increased risk, such as those with underlying heart disease or electrolyte abnormalities or those taking other drugs that might increase the QT interval.
Reference
In dentistry, antibiotics are prescribed for both therapeutic and prophylactic purposes, with clinical indications ranging from treating active odontogenic infections to utilizing them for preprocedural prophylaxis. General dentists and specialists contribute a great deal to the total outpatient antibiotic prescriptions in the Unites States.1 Antibiotics prescribed frequently by dentists include amoxicillin, clindamycin, penicillin, azithromycin, and cephalexin, with amoxicillin being the most commonly prescribed.1 Azithromycin is gaining significant momentum as an antibiotic of choice in penicillin-allergic patients.2 Azithromycin has several desirable pharmacological properties, such as stability in the acidic environment and better absorption/bioavailability.3 These properties, in turn, reduce the required number of medications to be taken in a day and therefore, can improve patient compliance as well.
In spite of the several advantages, azithromycin is not without adverse effects. Ever since an association between azithromycin and cardiac events (arrhythmia) was brought to light by an earlier investigation,4 several studies looked into the cardiac effects of azithromycin and ended up with conflicting results.5,6
In this retrospective cohort study, using a very large sample and addressing some of the limitations of earlier studies, the authors identified an approximately twofold increase in the risk for both cardiovascular and noncardiovascular deaths, within 5 days of azithromycin intake, compared with the intake of amoxicillin.
Results of this study corroborate with a previous investigation in dentistry that looked into adverse effects associated with antibiotics prescribed by dentists that showed increased cardiac events following azithromycin intake, compared with others.7 Results from the same report also confirmed the comparatively high level of safety with amoxicillin, indicating that amoxicillin can still be the go-to antibiotic for most of the clinical indications.7 In clinical scenarios that require an alternative antibiotic (eg, allergy to penicillin), being cognizant of the potential adverse effects of antibiotics such as azithromycin, along with careful history-taking, and risk–benefit assessment will allow the clinician to make appropriate selections.
References