Clarithromycin, QTc interval prolongation and torsades de pointes: the need to study case reports

Abstract

Abstract:Background: The manufacturers of clarithromycin sought a drug similar in efficacy to erythromycin but with a superior side-effect profile. They generally achieved this outcome, but postmarketing findings identified a series of reports linking clarithromycin to QTc interval prolongation and torsades de pointes (TdP) ultimately leading to a Black Box Warning. We sought to clarify risk factors associated with TdP among case reports of patients receiving clarithromycin linked to QTc interval prolongation and TdP. Methods and results: In a detailed literature search, we found 15 women, five men, and one boy meeting our search criteria. Among the 17 adults with reported clarithromycin dose and concurrent QTc interval measurement, we found no statistically significant relationship between clarithromycin dose and QTc interval duration. This did not change for the adults who developed TdP. Among adults, major risk factors were female sex (15), old age (11) and heart disease (17). A total of eight adult subjects had all three major risk factors and 14 of the 20 adults had at least two major risk factors. All adult subjects had at least two risk factors besides clarithromycin. A total of four of the 20 adults received cisapride and three received disopyramide. Three adults were considered to suffer from some aspect of the congenital long QT syndrome. Conclusions: We believe that the risk factor description for this drug should be refined to emphasize the major risk factors of (1) female sex, (2) old age and (3) heart disease.

Erythromycin, QTc interval prolongation, and torsade de pointes: Case reports, major risk factors and illness severity

“…Comparison with clarithromycin and azithromycin Whilst the present study is limited to the evaluation of 29 case reports with erythromycin, there is good concordance between its findings and the results of recent analyses of case reports with other macrolide agents (azithromycin and clarithromycin) that we have conducted Vieweg et al 2013a;Gysel et al 2013]. For both azithromycin and clarithromycin there was no significant correlation between administered drug dose and QTc interval of the cases examined, whilst female sex, old age and heart disease were identified as major risk factors Vieweg et al 2013a].…”

“…For both azithromycin and clarithromycin there was no significant correlation between administered drug dose and QTc interval of the cases examined, whilst female sex, old age and heart disease were identified as major risk factors Vieweg et al 2013a]. The present evaluation of erythromycin complements well these recent studies, whilst further identifying illness severity as a factor in the case of erythromycin.…”

“…In the ICU, independent and dependent characterization may change from moment to moment. We believe that risk factors associated with druginduced QTc interval prolongation and TdP may change dynamically and interact in a nonlinear fashion [Vieweg et al 2012[Vieweg et al , 2013a[Vieweg et al , 2013bKogut et al 2013;Hancox et al 2013]. We therefore suspect that nonlinear dynamics may best describe the interaction of drug-linked QTc interval prolongation and attendant risk factors to produce TdP.…”

“…We therefore suspect that nonlinear dynamics may best describe the interaction of drug-linked QTc interval prolongation and attendant risk factors to produce TdP. At present, we do not have a mathematical approximation of this linkage and must struggle with the clinical setting and risk factors identified from case reports to best understand the potentially fatal cardiac arrhythmia TdP [Vieweg et al 2012[Vieweg et al , 2013a[Vieweg et al , 2013bKogut et al 2013;Hancox et al 2013]. The use of case reports is, however, subject to some limitations.…”

A novel genetic modifier for clarithromycin-related cardiac arrhythmia risk?

“…Clarithromycin is one such drug [e.g. Gysel et al 2013;Vieweg et al 2013]. A recent paper in this journal reported major risk factors from the evaluation of 21 case reports of TdP associated with clarithromycin use .…”