Andrew D. Mosholder, M.D., M.P.H., Justin Mathew,
Pharm.D., John J. Alexander, M.D., M.P.H., Harry Smith, Ph.D., and
Sumathi Nambiar, M.D., M.P.H.
N Engl J Med 2013; 368:1665-1668
In 2011, approximately 40.3 million people in
the United States (roughly one eighth of the population) received an
outpatient prescription for the
macrolide azithromycin, according to
IMS
Health. During that year, we at the
Food and Drug Administration (FDA)
reviewed the labels of azithromycin and other approved macrolide
antibacterials in view of cardiovascular risks that had become evident
from published studies and reports emerging through postmarketing
surveillance. On the basis of its review, the FDA approved revisions to
azithromycin
product labels
regarding risks of QT-interval prolongation and the associated
ventricular arrhythmia torsades de pointes. The revised labels advise
against using azithromycin in patients with known risk factors such as
QT-interval prolongation, hypokalemia, hypomagnesemia, bradycardia, or
use of certain antiarrhythmic agents, including class IA (e.g.,
quinidine and procainamide) and
class III (e.g., dofetilide, amiodarone,
and sotalol) — drugs that can prolong the QT interval. In March 2013,
the FDA announced that azithromycin labels had been further revised to
reflect the results of a clinical study showing that azithromycin can
prolong the
corrected QT interval.
In a 2012
observational study involving Tennessee
Medicaid patients, Ray et al.
1
quantified the risk of death from cardiovascular causes associated with
azithromycin as compared with other antibacterial drugs or nonuse. The
study showed that the risks of death, both from any cause and from
cardiovascular causes, associated with azithromycin were greater than
those associated with amoxicillin. For every 21,000 outpatient
prescriptions written for azithromycin, one cardiovascular death
occurred in excess of those observed with the same number of amoxicillin
prescriptions. The excess risk over amoxicillin varied considerably
according to cardiovascular risk factors; the researchers estimated that
there was one excess cardiovascular death per 4100 prescriptions among
patients at high cardiovascular risk but less than one per 100,000 among
patients with lower cardiovascular risk.
The study by Ray et al.
has limitations that are intrinsic to observational, nonrandomized
clinical studies. In particular, nonrandomized studies cannot exclude
the possibility that patients receiving a drug under evaluation differ
from control patients in some important but undetected way, causing bias
in the results. Such confounding may bias comparisons not only between
patients receiving antibacterial drugs and those receiving no
antibacterials but also between patients receiving different
antibacterials. Although Ray et al. used appropriate analytic methods to
address potential confounding, we cannot know for certain whether these
methods were fully successful. Replication of the authors' results,
through analysis of a distinct data set, would provide more confidence
in the finding of increased cardiovascular mortality among patients
receiving azithromycin.
Despite such caveats, the results
presented by Ray et al. warrant serious attention. A chief strength of
the results is the time-limited pattern of the risk: the
azithromycin-associated increase in the rates of death from any cause
and from cardiovascular causes spanned days 1 through 5, reflecting the
typical 5-day duration of azithromycin administration (e.g., Zithromax
Z-Pak). On days 6 through 10, an elevated risk of death from
cardiovascular causes was no longer detected. This pattern is consistent
with the timing of peak plasma azithromycin concentrations and the
concomitant risk of QT-interval prolongation. The elevated risk was
statistically significant, regardless of whether azithromycin treatment
was compared with amoxicillin or with nonuse of an antibacterial drug.
Furthermore, the observed excess mortality was attributable solely to
cardiovascular deaths and, in particular, to sudden cardiac death;
although sudden cardiac death can result from causes other than
arrhythmias, an increase in deaths in this category would be the pattern
expected from an arrhythmogenic, QT-interval–prolonging drug. Also, the
azithromycin-associated risk was higher among patients with
cardiovascular disorders, which is consistent with a drug-related
arrhythmia.
A new study by Svanström and colleagues (pages
1704–1712), using Danish national health care data, found no difference
between azithromycin and penicillin V in the 5-day risk of
cardiovascular death (relative risk, 0.93; 95% confidence interval [CI],
0.56 to 1.55). However, the upper bound of the 95% confidence interval
does not exclude an increased risk of as much as 55%. As Svanström et
al. point out, the population they studied differed from that studied by
Ray et al. with respect to the baseline risk of death and
cardiovascular risk factors. Overall, the Danish patients had better
cardiovascular health than the Tennessee Medicaid patients. In a
subgroup analysis of patients with a history of cardiovascular disease,
the
risk ratio for azithromycin versus penicillin V was greater than 1,
though the difference was not statistically significant (relative risk,
1.35;
95% CI, 0.69 to 2.64). Svanström et al. conclude that their
results do not conflict with those of Ray et al. Rather, the effect on
cardiovascular mortality may be limited to patients with cardiovascular
disease.
One must, of course, weigh any observed drug-associated
risk against clinical benefits, so it's appropriate to consider the
possibility that certain offsetting benefits of azithromycin may not
have been reflected in the risk data analyzed by Ray et al. For example,
other studies have suggested that macrolides have an advantage over
other antibacterial agents in terms of overall survival from
community-acquired pneumonia. In a recent Canadian observational study,
researchers followed 2973 outpatients with community-acquired pneumonia
and found significantly lower 30-day mortality among patients receiving
macrolides than among those receiving fluoroquinolones (adjusted odds
ratio, 0.28; 95% CI, 0.09 to 0.86).
2
A recent meta-analysis of observational studies showed a statistically
significant 25% difference in mortality among hospitalized patients with
community-acquired pneumonia favoring macrolides over nonmacrolide
antibacterials.
3
Such findings, which must be considered with due regard for the limits
of observational studies, do not necessarily contradict the results of
Ray et al. Past the 5-day period of risk of azithromycin-associated
cardiovascular death, the drug might reduce the longer-term (e.g.,
more-than-30-day) rate of death due to pneumonia. Pneumonia was an
uncommon indication among the Tennessee Medicaid patients treated with
azithromycin.
Clinicians must consider the arrhythmogenic
potential not only of azithromycin but also of potential alternative
antibacterial drugs. An earlier study showed an association between the
use of erythromycin and sudden cardiac death, augmented by concomitant
use of inhibitors of the cytochrome P-450 3A isozymes that metabolize
erythromycin.
4
Labels for erythromycin and clarithromycin include warnings regarding
QT-interval prolongation and arrhythmias. All labels for fluoroquinolone
products similarly have warnings regarding QT-interval prolongation,
and grepafloxacin was withdrawn from the market because of that risk. A
recent observational study of elderly residents of Quebec, Canada,
showed an association between outpatient fluoroquinolone use and serious
arrhythmias (as defined by hospital discharge diagnoses of ventricular
arrhythmia or sudden or unattended death).
5
And although Ray et al. found the risk of cardiovascular death to be
greater with azithromycin than with ciprofloxacin, they found the risk
with levofloxacin similar to that with azithromycin. The authors
interpreted this similarity as evidence that levofloxacin may be
proarrhythmic; however, levofloxacin was not implicated as proarrhythmic
in the Canadian study.
We investigated the most common
ambulatory indications for azithromycin by analyzing data from a survey
conducted by Encuity Research of approximately 3200 office-based
physicians for the decade from 2002 through 2011. Across all age groups
of patients, the two most common indications for azithromycin were
chronic sinusitis and bronchitis. The
table
Agents
Associated with Drug-Use Mentions for Chronic Sinusitis and Bronchitis,
According to U.S. Office-Based Physician Practices (January
2002–December 2011). shows the antibacterial drugs that
were used most commonly in the United States for these indications.
Azithromycin was the leading antibacterial drug for outpatient treatment
of bronchitis during this period (even if amoxicillin is combined with
amoxicillin–clavulanate). For chronic sinusitis, azithromycin ranked
second after amoxicillin. Because the indications are reported by the
prescribing physicians, these data don't allow us to assess the
diagnostic certainty regarding the infections being treated.
The
risks and benefits of antibacterial therapy should be considered in
prescribing decisions. Pharmacologic and epidemiologic data point to
lethal arrhythmias as a potential consequence of QT-interval
prolongation with use of azithromycin, other macrolides, and
fluoroquinolones. This possibility should give clinicians pause when
they're considering prescribing antibacterial drugs, especially for
patients with preexisting cardiovascular risk factors or clinical
conditions in which antibacterial drug therapy has limited benefits.
1
Ray WA, Murray KT, Hall K, Arbogast PG, Stein CM. Azithromycin and the risk of cardiovascular death.
N Engl J Med 2012;366:1881-1890
Free Full Text |
Web of Science |
Medline
2
Asadi L, Eurich DT, Gamble JM, Minhas-Sandhu JK, Marrie TJ, Majumdar SR. Guideline adherence and macrolides reduced mortality in outpatients with pneumonia.
Respir Med 2012;106:451-458
CrossRef |
Web of Science |
Medline
3
Asadi L, Sligl WI, Eurich DT,
et al. Macrolide-based regimens and mortality in hospitalized patients
with community-acquired pneumonia: a systematic review and
meta-analysis.
Clin Infect Dis 2012;55:371-380
CrossRef |
Web of Science |
Medline
4
Ray WA, Murray KT, Meredith S, Narasimhulu SS, Hall K, Stein CM. Oral erythromycin use and the risk of sudden cardiac death.
N Engl J Med 2004;351:1089-1096
Free Full Text |
Web of Science |
Medline
5
Lapi F, Wilchesky M, Kezouh A, Benisty JI, Ernst P, Suissa S. Fluoroquinolones and the risk of serious arrhythmia: a population-based study.
Clin Infect Dis 2012;55:1457-1465
CrossRef |
Web of Science |
Medline
