Abstract
Background/Aim: Torsade de pointes (TdP)/QT prolongation (QTP) is one of the most life-threatening adverse effects of antifungal triazoles. The aim of the present study was to evaluate the association of antifungal triazoles with TdP/QTP by age group and the profile of the time of TdP/QTP onset by analyzing the spontaneous adverse event database for Japan. Patients and Methods: Data registered in the Japanese Adverse Drug Event Report database (JADER) from April 2004 to March 2022 were analyzed. The association between the administration of antifungal triazoles and TdP/QTP according to age was evaluated using an adjusted reporting odds ratio (aROR). In addition, the time-to-onset of TdP/QTP after antifungal triazole treatment was analyzed using the Weibull distribution according to the route of administration. Results: Antifungal triazole treatment was associated with TdP/QTP (aROR=1.77, 95% confidence interval=1.52-2.07). In the subgroup analyses by age group, antifungal triazole treatments in patients ≤29 years old and ≥50 (except ≥90) years old were associated with TdP/QTP. The medians (quartiles) of time-to-onset for intravenous and oral antifungal triazole treatment were 8 (6-12) and 23 (8-86) days, respectively. In addition, the shape parameter in the Weibull distribution analysis of oral triazole treatment revealed that the hazard exhibited an early failure profile. Conclusion: TdP/QTP is associated with antifungal triazoles even in young patients, and patients should be monitored for the development of TdP/QTP, especially early after the initiation of treatment.
- Torsade de pointes
- QT prolongation
- antifungal triazole
- disproportionality analysis
- Japanese Adverse Drug Event Report database
Torsade de pointes (TdP) is a potentially fatal polymorphic ventricular tachycardia characterized by gradual changes in the amplitude and twisting of the QRS complexes around the isoelectric line on an electrocardiogram (1). TdP is associated with QT prolongation (QTP) and can lead to sudden cardiac death (2, 3). QTP may be genetic or acquired. Several factors increase the risk of QTP; baseline and unmodified predisposing risk factors include female sex, advanced age, and bradycardia, whilst acquired risk factors include structural and functional heart problems, hypokalemia, and HIV infection (4, 5). The risk of QTP may also be increased by exposure to some drugs. The approximate rate of drug-induced QTP is 2.0-8.8% among patients treated with antiarrhythmics, and one in a thousand to one in a million patients prescribed non-cardiac drugs (6), including antidepressants, antipsychotics, and antibiotics (7-9). Some antifungal triazoles prolong the QT interval and are associated with TdP (7, 8, 10, 11); most reports of TdP induced by drug interactions involve ketoconazole and itraconazole (11-14). However, TdP/QTP developed in young patients after taking recently launched drugs, such as posaconazole, including in monotherapy (15, 16).
Epidemiological studies on the risk factors of TdP/QTP are difficult because TdP/QTP is a rare adverse event (AE). Databases were used to examine drug-associated TdP/QTP in several reports (6, 17, 18). However, the association between antifungal triazoles and TdP/QTP in Japan has not been fully investigated. Furthermore, information on the time-to-onset of fatal AEs, such as TdP/QTP, is extremely limited. Therefore, the objective of the present study was to evaluate the association between the use of antifungal triazoles and TdP/QTP and the time of TdP/QTP onset using the Japanese Adverse Drug Event Report database (JADER).
Patients and Methods
Data source. JADER data from April 2004 to March 2022 were downloaded from the Pharmaceuticals and Medical Devices Agency website (https://www.pmda.go.jp/safety/info-services/drugs/adr-info/suspected-adr/0003.html). The JADER consists of four datasets: Patient demographic information (DEMO), drug information (DRUG), AEs (REAC), and primary disease (HIST). The DEMO table contains basic patient information, such as age, sex, and reporting year. The age description is provided as a decade (i.e. 10s, 20s, etc.), not the exact age. The DRUG table contains information on the drug name, route of administration, date of beginning administration, date of ending administration, and drug involvement. The REAC table contains information on AEs, including names, onset dates, and outcomes. The HIST table contains information about the patient’s underlying disease. Patients with missing, unclear, or vague age categories (such as adult, child, aged, and newborn) were excluded from the analysis.
Drugs of interest. The drugs of interest included all antifungal triazoles on the market in Japan and comprised the following triazoles registered in the JADER: itraconazole, fluconazole, fosfluconazole, fosravuconazole, posaconazole, and voriconazole.
Definition of AEs. The AEs in the REAC table are coded using preferred terms (PTs) from the Medical Dictionary for Regulatory Activities (MedDRA). We defined the AE by the narrow scope of torsade de pointes/QT prolongation (coded SMQ 20000001) with six PTs, including abnormal electrocardiogram QT interval (PT: 10063748), prolonged electrocardiogram QT (PT: 10014387), long QT syndrome (PT: 10024803), congenital long QT syndrome (PT: 10057926), torsade de pointes (PT: 10044066), and ventricular tachycardia (PT: 10047302) in MedDRA/J v25.1 (https://www.jmo.gr.jp/jmo/servlet/mdrLoginTop).
Disproportionality analysis. The association between the administration of antifungal triazoles and TdP/QTP was estimated using the reporting odds ratio (ROR) (19-21). Signal scores were calculated using a case/non-case method (22, 23). Cases were defined as individuals who received the drug of interest and experienced an AE (defined as TdP/QTP), and all other reports comprised the non-cases. The causality of each drug was assigned a code in the DRUG table according to its association with adverse drug reactions, including “suspected drug”, “concomitant drug”, or “interacting drug”. The ROR for each drug was calculated using all data without subjective judgment of certainty, and subset data using only with high certainty (classified as a suspected drug).
RORs can be adjusted through logistic regression analysis and covariates can be controlled (24-26). Adjusted RORs (aRORs) were calculated according to previous reports (27, 28). aRORs were calculated using only database entries with complete information about year, sex and age. The reports were stratified by age as follows: <10, 10s, 20s, 30s, 40s, 50s, 60s, 70s, 80s, and ≥90s. An association was defined when the lower limit of the 95% confidence interval (CI) of the aROR was greater than 1, and the p-value of the Fisher’s exact test or chi-square test was less than 0.05.
Time-to-onset of TdP/QTP. The time of TdP/QTP onset was calculated as the number of days from the initiation of administration of the drug of interest until the onset of TdP/QTP using the time information record. Therefore, only reports with time-to-onset data were analyzed. The median time in days and interquartile range (IQR) to TdP/QTP onset were calculated according to administration route. The Wilcoxon rank-sum test was used for comparisons.
Outcome after the onset of TdP/QTP. There are six outcome descriptors in the REAC table of the JADER: “recovery”, “remission”, “not recovered”, “with sequelae”, “death”, and “unclear”. Using all of these descriptors except “unclear,” an analysis of outcomes after the onset of TdP/QTP was conducted.
Weibull distribution. The Weibull parameters of the Weibull distribution were used to evaluate the AE profile (29-31). The Weibull distribution is expressed using the scale parameter α, which represents the scale of the distribution function, and the shape parameter β, which represents the change in a hazard without a reference population over time. A β value with a 95% CI <1 indicates that the hazard increases at an early stage but subsequently decreases (early failure type). A β value equal to or nearly 1 and a 95% CI including 1 indicate that the hazard is constant during the exposure period (random failure type). A β value with a 95% CI of >1 indicates that the hazard increases over time (wear-out failure type).
All statistical analyses and data visualizations were performed using JMP Pro ver. 13.2.1 (SAS Institute, Cary, NC, USA).
Results
Data analyzed. A total of 777,555 reports were extracted from the JADER. After missing, unknown, and inadequate data were excluded, 688,457 reports were used for the analysis, including 4,580 reports of TdP/QTP.
Association between antifungal triazoles and TdP/QTP. The statistical analysis of the association between antifungal triazoles and TdP/QTP is presented in Table I. When analyzing the whole dataset, an association was detected between the administration of antifungal triazoles and TdP/QTP, both in the analysis of all registered antifungal triazoles and of individual suspected drugs (Table I).
Association of torsade de pointes and QT prolongation as an adverse event of treatment with each antifungal triazole.
Association between antifungal triazoles and TdP/QTP stratifying patients by age. The statistical analysis of the association between antifungal triazoles and TdP/QTP when patients were stratified by age is presented in Table II. In the analysis of all registered antifungal triazoles, antifungal triazole use was associated with TdP/QTP in the 10s, 20s, 50s, 60s, 70s, and 80s subgroups (Table II). In the analysis of registered antifungal triazoles with suspicion of causing TdP/QTP, the association between antifungal triazoles and TdP/QTP was also found in the <10 subgroup (Table II).
Association of torsade de pointes and QT prolongation as an adverse event of treatment with each antifungal triazole when patients were stratified by age.
Time to onset of TdP/QTP. For the time-to-onset of TdP/QTP, 38 out of 49 reports of AEs after intravenous use of antifungal triazole and 67 out of 114 reports of use of oral antifungal triazoles were calculatable and used for the analyses. Box plots with the median times of TdP/QTP onset are shown in Figure 1. The median time (IQR) for TdP/QTP onset was 12 (6-38) days. In the analysis based on formulations, the median time-to-onset was 8 (6-12) days for treatment with intravenous antifungal triazoles and 23 (8-86) days for that with oral antifungal triazoles. The time to onset of TdP/QTP was significantly shorter for use of intravenous antifungal triazoles compared with oral antifungal triazoles (p<0.001).
The box plot of the time to torsade de pointes and QT prolongation onset associated with the administration of antifungal triazoles. It was not possible to calculate values for fosfluconazole and posaconazole. Lines in boxes indicate the median, boxes indicate the interquartile range, and whiskers indicate the minimum and maximum values.
Outcome after the onset of TdP/QTP. As shown in Figure 2, all outcomes for antifungal triazole-associated TdP/QTP events were poor and included death, especially for intravenous administration. Regardless of the route of administration, deaths were reported for use of all antifungal triazoles except itraconazole (Figure 2).
Mosaic plot of outcomes of antifungal triazole-associated torsade de pointes and QT prolongation. Outcomes are presented as the proportion of all patients with TdP/QTP after therapy for each antifungal triazole.
Weibull distribution analysis. The results of the Weibull distribution analysis for the antifungal triazoles are shown in Table III. For all oral antifungal triazoles, the lower limit of the 95% CI for the shape parameter β was less than one, indicating an early failure type profile, whereas an analysis of intravenous antifungal triazoles indicated a random failure profile type, except for itraconazole.
Weibull parameters for torsade de pointes and QT prolongation as an adverse event of treatment with antifungal triazole.
Discussion
In the present study, the association of TdP/QTP with antifungal triazoles, and the time to TdP/QTP onset were evaluated using the Japanese pharmacovigilance database. All antifungal triazoles were associated with TdP/QTP. When we stratified the data according to age group, use of antifungal triazoles in those aged 50 to 89, and those aged 29 and younger were associated with TdP/QTP. The median time to TdP/QTP onset was significantly shorter for treatment with intravenous antifungal triazoles compared with oral antifungal triazoles. Moreover, Weibull distribution analysis indicated that oral antifungal triazoles exhibited an early failure type profile.
A previous study using the U.S. Food and Drug Administration Adverse Event Reporting System database also reported an association between TdP/QTP and use of antifungal triazoles (18), which our result support regarding commonly examined drugs. Other comprehensive studies using the JADER also reported an association between TdP/QTP or long QT syndrome and drug suspects (6, 17). However, these studies did not report an association between all or some antifungal triazoles and TdP/QTP. These differences may be explained by the relatively low ORs for antifungal triazoles in one study (17) and differences in the selected drug of interest and AE definition in the other (6).
Although older age is a risk factor for TdP/QTP (4), in the present study, even young patients were shown to have developed TdP/QTP associated with use of antifungal triazoles. In fact, some case reports describe young patients who develop TdP/QTP (15, 16), and QT prolongation in association with voriconazole has been reported in the pediatric population (32). Therefore, careful attention should be paid to both elderly and young patients when administering antifungal triazoles.
The most common cause of drug-induced QTP is blocking of the delayed rectifier potassium channel current (IKR), which is responsible for the regulation of action potential repolarization (33, 34). All known antifungal triazoles may cause QTP directly by blocking IKR channels, and by inhibiting cytochrome P450-dependent metabolism of other drugs that can cause QTP (15). Antifungal drugs are often co-administered with other drugs, and polypharmacy is a risk factor for drug interactions (35). Therefore, patients who are receiving multiple P450 isoform inhibitors or arrhythmia inducers should be monitored closely; the more concomitant medications used, the greater is the possibility of pharmacokinetic and pharmacodynamic interactions (36).
Studies that evaluated the time to onset of TdP/QTP for patients those with antifungal triazoles are rare. In previous studies using different AE-reporting databases, the median time to onset of TdP with use of antifungal triazole medications was up to 14 days (18, 37), which our results agree with despite the interethnic differences in sensitivity for QT prolongation (38, 39). In the present study, the time to TdP/QTP onset was significantly shorter for intravenous administration of antifungal triazole compared with oral administration (Figure 1). This difference may be due to the patient’s condition and the number of concomitant drugs administered.
The scale parameter α of the Weibull distribution represents the scale of the distribution function. In one quantile, 63.2% of AEs occur (29), and large-scale values stretch the distribution, whereas small-scale values shrink the distribution. Unlike oral antifungal triazole administration, intravenous antifungal triazoles are usually used for short-term treatment of severe cases, and the onset of AEs would accordingly be reflected in a shrunken distribution.
Although the analysis of data obtained from this study is informative, several potential limitations should be considered when interpreting the results. Firstly, the reported AEs may not be the result of treatment with a given drug, as some patients may have genetic causes of TdP/QTP. Secondly, not every AE that occurs with a drug is reported (reporting bias). Thirdly, as described above, some missing or inadequate data were excluded to calculate the time to TdP/QT onset. Additionally, concomitant conditions such as heart disease, hypokalemia, and HIV infection, as well as use of concomitant drugs, such as antiarrhythmics, antidepressants, antipsychotics and antibiotics, that increase the risk of TdP/QT were not considered.
Conclusion
The results of the present study indicate that TdP/QTP is associated with the administration of antifungal triazoles, not only in patients aged 50 to 89 years old, but also in patients aged 29 and younger. Consequently, patients receiving antifungal triazoles should be carefully monitored, especially early after the initiation of treatment. This information may be useful in preventing sudden cardiac death following TdP/QTP and in developing treatment plans.
Footnotes
Authors’ Contributions
KO and YH conceived and designed the study. KO, SA, and MI analyzed the data. KO drafted the article. All Authors critically reviewed the article and approved the final version of the article.
Conflicts of Interest
The Authors declare that they have no conflicts of interest.
- Received June 20, 2023.
- Revision received July 24, 2023.
- Accepted July 25, 2023.
- Copyright © 2023, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
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