Concomitant Risk Factors in Reports of Torsades de Pointes Associated with Macrolide Use: Review of the United States Food and Drug Administration Adverse Event Reporting System

Shaffer, Douglas; Singer, Sarah J.; Korvick, Joyce A.; Honig, Peter K.

doi:10.1086/340861

Cited by 137 publications

(105 citation statements)

References 6 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This is in line with literature data and information from the Arizona CERT, which considers azithromycin, clarithromycin and erythromycin as having a risk of TdP [17,10].…”

Section: Discussionsupporting

confidence: 87%

Macrolides and Torsadogenic Risk: Emerging Issues from the FDA Pharmacovigilance Database

Poluzzi¹

2013

J Pharmacovigilance

View full text Add to dashboard Cite

Introduction: Concern exists on the pro-arrhythmic potential of macrolides, namely Torsade de Pointes (TdP). Recent evidence has challenged the common opinion of considering azithromycin a safer therapeutic option, causing emerging regulatory and clinical interest. Materials and Methods:We analyzed cases of drug-induced TdP (2004TdP ( -2011 submitted to the publicly available FDA Adverse Event Reporting System (FAERS). Four groups of mutually exclusive events were identified in decreasing order of drug-attributable risk: 1) TdP; 2) QT interval abnormalities; 3) ventricular arrhythmia (VA); 4) Sudden Cardiac Death (SCD). They were combined into case definition A (TdP/QT abnormalities) and case definition B (VA/SCD). Both case-by-case analysis (information on concomitant drugs, especially QT-prolonging agents listed by Arizona CERT, and disproportionality approach (Reporting Odds Ratio, ROR, with 95%CI) were carried out.Results: Over the 8-year period, macrolides were associated with 183 and 419 cases of interest (case definition A and B, respectively). Clarithromycin was the most frequently reported (84 and 162 cases), followed by azithromycin (63 and 140). Only 27% of cases of TdP/QT abnormalities with azithromycin occurred in patients >65 years of age (63, 47 and 44% for clari-, ery-and telithromycin, respectively). In cases of TdP/QT abnormalities, concomitant QT-prolonging drugs (Arizona CERT lists 1 or 2) were recorded with a proportion very different among macrolides (11 to 89%). The highest percentage of fatal outcome was recorded for azithromycin (17%). Disproportionality was found for azithromycin, clarithromycin and telithromycin for both events of interest, whereas erithromycin showed disproportion only for TdP/QT abnormalities. Conclusions:Despite inherent limitations of spontaneous reporting analyses, the remarkable proportion of fatal cases and the occurrence of TdP-related events in middle-aged patients strengthen the view that caution is needed before considering azithromycin as a safer therapeutic option among macrolides. Before performing the analysis, several technical issues were handled with. This is the case for the drug mapping, duplicate removal and management of missing data [13]. Data of interest for the 2004-2011 period were collected from "DEMO" (demographic information), "DRUG", "REACTION" (adverse events coded according to the Medical Dictionary for Regulatory Activities terminology, MedDRA version 13.0) and "OUTCOME" files [14]. Macrolides and Torsadogenic Data analysisIn the light of the peculiar clinical setting in which TdP usually occurs (i.e., multi-factorial causative roles with different risk factors), a case listing was first generated in order to describe demographic information (e.g., age and sex) and concomitant drugs, which may act as potential confounders of the drug-event association by reducing the so-called "repolarization reserve" [15]. Specifically, each event of interest was assessed for co-administration of drugs with cardiovascular indications (i.e., Cla...

show abstract

“…This is in line with literature data and information from the Arizona CERT, which considers azithromycin, clarithromycin and erythromycin as having a risk of TdP [17,10].…”

Section: Discussionsupporting

confidence: 87%

Macrolides and Torsadogenic Risk: Emerging Issues from the FDA Pharmacovigilance Database

Poluzzi¹

2013

J Pharmacovigilance

View full text Add to dashboard Cite

show abstract

“…The number of case reports cannot be used to estimate incidence rates even after adjusting for overall exposure rates because of inconsistent reporting and publication bias. Based on the FDA Adverse Event Reporting System (AERS) database, erythromycin was the most commonly reported torsadogenic macrolide between 1987 and 2000 [Shaffer et al 2002]. However between 2004 and 2011, torsade de pointes and QT/QTc interval abnormalities were most commonly reported with clarithromycin followed by azithromycin [Raschi et al 2013].…”

Section: Discussionmentioning

confidence: 99%

Azithromycin, cardiovascular risks, QTc interval prolongation, torsade de pointes, and regulatory issues: A narrative review based on the study of case reports

Hancox

Hasnain

Vieweg

et al. 2013

Therapeutic Advances in Infection

View full text Add to dashboard Cite

Over the past year, three articles have appeared in the New England Journal of Medicine describing conflicting findings about azithromycin and cardiac safety, particular azithromycin-induced QTc interval prolongation and torsade de pointes. The FDA wants healthcare providers to consider azithromycin-induced fatal cardiac arrhythmias for patients already at risk for cardiac death and other potentially arrhythmogenic cardiovascular conditions. In a systematic review of case reports we sought to determine factors that link to azithromycininduced/associated QTc interval prolongation and torsade de pointes. We found 12 cases: seven female and five male. Of the nine adults with reported azithromycin doses, concurrent QTc interval measurement, and without congenital long QT syndrome, we found no significant relationship between dose and QTc interval duration. Additional risk factors were female sex, older age, heart disease, QTc interval prolonging drugs and metabolic inhibitors, hypokalemia, and bradycardia. All 12 subjects had at least two additional risk factors. Elderly women with heart disease appear to be at particularly risk for drug-related QTc interval prolongation and torsade de pointes.

show abstract

“…It is also possible that this effect is under-reported since sudden death in patients with chronic respiratory diseases may well be assigned to the underlying respiratory condition as opposed to a cardiac arrhythmia. The risk related to a short course of macrolide for an acute infection in a young person might, therefore, be different to that related to prolonged use in an older patient with COPD or bronchiectasis, who is more likely to both have structural cardiac disease and be taking other commonly used drugs that prolong the QT interval [79].…”

Section: Discussionmentioning

confidence: 99%

Long-term macrolide therapy in chronic inflammatory airway diseases

Crosbie¹,

Woodhead²

2009

European Respiratory Journal

120

View full text Add to dashboard Cite

In addition to direct antibacterial actions, 14-and 15-member-ring macrolides have immune modulating effects that appear to be the reason for clinical benefit in diffuse panbronchiolitis.A literature search was conducted for studies of the clinical effectiveness of macrolides in other chronic lung conditions.A number of studies were identified that showed short-term beneficial outcomes or the potential for such outcomes in cystic fibrosis, bronchiectasis, chronic obstructive pulmonary disease, asthma and post-transplant obliterative bronchiolitis. The studies were limited by small patient numbers, different outcome measures and short-term follow-up, and were not designed to assess potentially harmful effects.Further large prospective and long-term studies are required in order to identify potential benefit and harm before these agents can be recommended routinely for these conditions.

show abstract

Concomitant Risk Factors in Reports of Torsades de Pointes Associated with Macrolide Use: Review of the United States Food and Drug Administration Adverse Event Reporting System

Cited by 137 publications

References 6 publications

Macrolides and Torsadogenic Risk: Emerging Issues from the FDA Pharmacovigilance Database

Macrolides and Torsadogenic Risk: Emerging Issues from the FDA Pharmacovigilance Database

Azithromycin, cardiovascular risks, QTc interval prolongation, torsade de pointes, and regulatory issues: A narrative review based on the study of case reports

Long-term macrolide therapy in chronic inflammatory airway diseases

Contact Info

Product

Resources

About