Potential QT-prolonging drug-drug interactions in cardiovascular disease patientsAbstract
The study aimed to assess the prevalence and characteristics of potential drug-drug interactions (pDDIs) that increase the risk of QT prolongation, in a population of cardiovascular disease patients. An observational retrospective study was conducted at a cardiology ward. A total of 351 patients were included in the analysis, with almost equal gender distribution (female 48.4%) and mean age 70±10 years. In the total set of tested drug pairs (5620), QT-prolonging pDDIs were identified in 13 drug pairs on admission. The highest frequency was observed for ciprofloxacin (involved in 5 pDDIs), followed by propafenone (4 pDDIs) and beta2-agonists (4 pDDIs). The pharmacodynamic mechanism was involved in all pDDIs. The study revealed a low prevalence of QT-prolonging pDDIs on admission to the cardiology ward, about 3% in the studied population. However, given that underlying heart disease is a significant risk factor for the occurrence of QTc prolongation, the additional risk for acquired QT prolongation should not be neglected. Due to serious consequences caused by QT prolongation and TdP, the key role of health professionals is to identify predisposed patients and to recognize pDDIs involving QT-prolonging agents. Hence, patients’ modifiable risk factors for QT prolongation should be minimized, if not eliminated.
Keywords:
QT interval; QT prolongation; Drug-induced; Drug-drug interactions; Cardiac patients; Patient safety
INTRODUCTION
The QT interval denotes the duration from the beginning of the QRS complex to the end of the T-wave on the electrocardiogram. That interval represents the duration of ventricular electrical systole, which includes ventricular activation and recovery. The length of QT interval is dependent on the heart rate, being shorter in tachycardia, and longer in bradycardia (Ambhore et al., 2014). Therefore, it is more accurate to use the term corrected QT interval (QTc), which is the heart rate adjusted lengthening of the QT interval. QTc values up to 440 ms are considered normal, whereas values from 440 to 460 ms in males and 440−470 ms in females are considered to be prolonged (Surawicz, Knilans, 2001). QTc values >500 ms are associated with an increased risk of Torsade de Pointes (TdP), a rare but lethal form of cardiac arrhythmia (Isbister, Page, 2013). QTc prolongation does not necessarily mean the occurrence of TdP; however, a 2- to 3-fold increased risk of TdP was observed (Cohagan, Brandis, 2022). On the other hand, QTc prolongation was found in every TdP case; hence, QTc interval represents one of the diagnostic criteria for TdP occurrence. (Roden, 2004; Savić, Gojković-Bikarica, 2008). QTc prolongation can be either congenital or acquired. Congenital forms are usually related to inherited cardiac channelopathies, whereas acquired QTc prolongation is usually caused by heart disease, electrolyte abnormalities, and/or exposure to precipitating drugs (Ambhore et al., 2014; Cohagan, Brandis, 2022; Thomas, Behr, 2016). Nevertheless, acquired long QTc syndrome is most often drug-related (Ambhore et al., 2014). At the moment, the AZCERT (the Arizona Center for Education and Research on Therapeutics) list of QTc-prolonging drugs comprises about 255 drugs marketed in the USA, associated with QTc prolongation and TdP. The list includes well-known antiarrhythmic agents, as well as an increasing number of non-cardiac drugs (Letsas et al., 2009; Thomas, Behr, 2016; Woosley et al., 2018). Drug-drug interactions (DDIs) have been identified as an important contributor to QT prolongation, either by a pharmacokinetic or pharmacodynamic mechanism (Armahizer et al., 2013). Pharmacokinetic DDIs may result in high concentrations of a QTc-prolonging drug, mostly due to metabolism inhibition (Fernandes et al., 2019). In pharmacodynamic DDIs, there is concomitant use of two or more drugs known to independently cause QTc prolongation (Smithburger et al., 2012). Another example of a pharmacodynamic DDI is the administration of a QTc-prolonging drug with a diuretic that causes hypokalemia and therefore increases the risk of QTc prolongation (Smithburger et al., 2010). Besides the known risk, studies have found a high prevalence of DDIs that increase the risk of QTc prolongation. Most of the research was conducted in intensive care units, where the prevalence rates of DDIs with the risk of QTc prolongation were between 15.9% and 32.7% (Armahizer et al., 2013; Fernandes et al., 2019; Khan et al., 2018). The results were similar in cancer patients (21.8%) (Khan et al., 2017b), as well as in psychiatric patients (20%) (Meid et al., 2017). However, the studies have demonstrated a high burden of DDIs with the expected adverse outcome on QTc prolongation at all levels of healthcare. In the discharge medication lists of a large geriatric cohort with more than 130,000 patients, the prevalence of pharmacodynamic DDIs that increased the risk of QTc prolongation was calculated to be 22% (Schachtele et al., 2016). Cardiovascular patients are under increased risk of QTc prolongation due to: (i) increased risk of DDIs, due to the presence of multiple medications in therapy; (ii) age; (iii) administration of cardiac drugs known to cause long QTc intervals, such as antiarrhythmics and beta-blockers; (iv) administration of diuretics and ACE inhibitors, which may cause electrolyte disturbances; and (v) underlying heart disease as an inherent risk factor for TdP occurrence (Khan et al., 2018; Tisdale et al., 2012). Nevertheless, the burden of DDIs with the potential to increase the risk of QTc prolongation in the vulnerable population of cardiovascular disease patients has not been thoroughly investigated. Therefore, the main aim of the study was to assess the prevalence and characteristics of potential DDIs that increase the risk of QTc prolongation in a population of cardiovascular disease patients. The secondary aim was to assess the association between the presence of potential QTc-prolonging DDIs in patients’ therapy and irregular heart rhythm observed at the moment of hospital admission.
MATERIAL AND METHODS
An observational retrospective study was conducted at the cardiology ward of the University Clinical Hospital Center Bezanijska Kosa. The data were collected for all the patients with cardiovascular disease who were consecutively admitted to the cardiology ward from June 2015 to January 2015. Demographic and clinical data were obtained from medical charts, at the time of admission. Patients with complete data including age, gender, medical history, the reason for admission, and the therapy used at least one month before hospitalisation were included in the study. At the time of admission, the patients underwent complete clinical examination, including the electrocardiogram (ECG) test. The Ethics committee of the University Clinical Hospital Center Bezanijska Kosa (Date 30-01-2014; Approval Number 222/3) and the Ethics committee of the University of Belgrade - Faculty of Pharmacy (Date 09-06-2017; Approval Number 1027/2) approved this study.
The LexiInteract electronic database (Lexi-Comp, Inc., Hudson, Ohio) was used for screening for potential DDIs with an expected adverse outcome on QTc prolongation. Potential DDI (pDDI) is defined as the co-prescription of two drugs known to interact, and a manifestation could occur in the exposed patient (Hines, Murphy, 2011; Scheife et al., 2015). Characteristics of the identified pDDIs were presented as follows: risk rating (X - avoid combination; D - modify regimen; C - monitor therapy; B - no action needed; A - no known interaction); severity (major; moderate; minor); reliability (excellent; good; fair; poor); mechanism (pharmacokinetic; pharmacodynamic). The QTc-prolonging potential of the drugs involved in pDDIs was additionally assessed using the CredibleMeds electronic database (www.crediblemeds.org). CredibleMeds lists drugs according to the risk of QTc prolongation and occurrence of TdP, placing them into three main categories: known risk, possible risk, and conditional risk of TdP. The fourth category denotes drugs to avoid in Congenital Long QT Syndrome.
Descriptive and inferential statistics were performed using PASW 22 (SPSS Inc., Chicago, IL, USA). Categorical variables were reported as the number of patients with percentage, ordinal as the median value with interquartile and total range, and continuous as the mean value ± standard deviation with total range. Chi-square (or Fisher’s exact test, where appropriate), Mann Whitney and t-test were used to assess the difference in patients’ characteristics between groups with and without QTc-prolonging pDDI. Binary logistic regression was used to test the predictive ability of QTc-prolonging pDDIs on irregular heart rhythm (method: Enter). The dependent variable “irregular heart rhythm” included all types of arrhythmia, determined on the admission (atrial fibrillation; atrial fibrillation and flutter; atrial premature depolarization; atrioventricular and left bundle-branch block; atrioventricular block, first degree; bradycardia, unspecified; left bundle-branch block, unspecified; paroxysmal tachycardia; re-entry ventricular arrhythmia; right fascicular block; ventricular premature depolarization; other cardiac arrhythmias). Odds ratios (OR), crude and adjusted for patients’ characteristics, with 95% confidence intervals, were reported. A two-tailed p-value <0.05 was considered statistically significant.
RESULTS
Characteristics of the study population
A total of 351 patients were included in the analysis, with almost equal gender distribution (female, 170, 48.4%). The patients were mainly elderly (≥65 years; 254, 72.4%), with the mean age of 70.0 ± 10.1 years. Hypertension was the most common cardiac diagnosis (236, 67.2%), followed by arrhythmia (168, 47.9%), heart failure (147, 41.9%), and angina pectoris (108, 30.8%). The patients had 6 drugs in their therapy on average, expressed by the median value. Polypharmacy (≥5 drugs) was present in 242 patients (68.9%), whereas 10 or more drugs were present in 31 patients (8.8%). The demographic and clinical characteristics are presented in Table I.
Prevalence and characteristics of QT-prolonging pDDIs on admission
The prevalence of pDDIs with an expected adverse outcome on QT prolongation was calculated at 3.1% (11 patients) on admission. Table II presents the distribution of additional risk factors for TdP, relative to the presence of QT-prolonging pDDIs. Patients with the pDDIs present on admission were older (72.5 vs 69.9 years), but the difference was not statistically significant (p=0.420). The length of stay was calculated at 10.7 ± 4.3 in patients with QT-prolonging pDDIs present on admission, compared to 9.5 ± 6.3 in patients without pDDIs on admission, which was not statistically significant (p = 0.513). Polypharmacy (≥5 drugs in therapy) was highly prevalent in the total investigated population (N=242, 68.9%). The median number of drugs in patients with pDDIs was 7 [IQR 4−12], compared to 6 [IQR 4−8] in patients without this type of pDDIs (p=0.129). When comparing the morbidity burden between groups, the mean Charlson Comorbidity Index was somewhat higher in patients having QT-prolonging pDDIs: 3.3 ± 1.7 compared to 3.0 ± 1.6 (p=0.564).
In the total set of tested drug pairs (5620), QT-prolonging pDDIs were identified in 13 drug pairs. Among them, there were 11 unique combinations involving 14 different drugs (international nonproprietary name, INN). The highest frequency was observed for ciprofloxacin (involved in 5 pDDIs), followed by propafenone (4 pDDIs) and beta2-agonists (4 pDDIs). Besides propafenone, other antiarrhythmics were much less involved - amiodarone and sotalol in only 1 pDDI each. The identified pDDIs are presented in Table III. The pharmacodynamic mechanism was involved in all pDDIs. Among them, one pDDI was attributed the X risk rating (ciprofloxacin + sotalol). This drug combination should be avoided in patients in general, since both of the drugs independently have a known risk of QT prolongation and TdP occurrence. Four pDDIs involved ciprofloxacin coadministered with ACE inhibitors (ACEI) or Angiotensin II receptor blockers (ARB). Although the risk classification was the same for both types of pDDIs (C class: monitor therapy), the severity was marked as major for ciprofloxacin + valsartan, whereas ciprofloxacin coadministration with enalapril or ramipril was considered to be of moderate severity. LexiInteract database states that ACEI or ARB may enhance the arrhythmogenic effect of quinolones. If ACEI/ARB and fluoroquinolones are used concomitantly in patients with other risk factors for either acute kidney injury or arrhythmias, more frequent monitoring of renal function or cardiac rhythm may be appropriate.
Predictive ability of QT-prolonging pDDIs
The presence of QT-prolonging pDDIs on admission was tested as the independent variable for the irregular heart rhythm obtained during medical examination on admission. The association between the expected adverse outcome and irregular cardiac function was presented as crude OR (Model 1: QT-prolonging pDDIs), as well as adjusted OR (Model 2: QT-prolonging pDDIs, adjusted for gender, age and Charlson Comorbidity Index), estimated by binary logistic regression analysis. The results are presented in Table IV. The crude OR for the presence of QT-prolonging pDDI (Model 1) was estimated at 1.707 (95% CI 0.445−6.553) but was not significant (p=0.436). In the next step, when adjusting for patients’ characteristics, the association between pDDI and irregular heart rhythm was calculated at OR=2.093 (95% CI 0.531−8.242), but the association remained non-significant (p=0.291). Among the patients’ characteristics, age and comorbidity burden showed significant association with irregular heart rhythm. With each increase of 1 unit in the Charlson Comorbidity Index, the chance of having irregular rhythm increased by 19.1% on average (95% CI 2.9%−37.9%).
DISCUSSION
Our study revealed a low prevalence of QT-prolonging pDDIs, about 3%, in a population of patients with cardiovascular disease, measured on admission to the cardiology ward. Previous studies on cardiac patients had been conducted on coronary or intensive care units and had reported much higher prevalence rates: 27.9%−32.7% (Armahizer et al., 2013; Khan et al., 2017a). The observed differences might be due to the characteristics of the studied population. Our study assessed the patients’ therapy that had been used before hospital admission, i.e., it reflects the prescriptions used in primary care. Patients hospitalised in coronary care units or intensive care units are more complex, requiring more drugs in therapy, which results in a higher number of QT-prolonging DDIs. In line with that, the average number of drugs administered in intensive care units or at the cardiology ward was reported to be 9.55−9.9 (Fernandes et al., 2019; Khan et al., 2017a), whereas in our study the median value was 6 (and mean 5.95; not reported in the tables). On the other hand, patients might be more exposed to pDDIs due to the possibility of vigilant monitoring of the patients’ cardiac function during the hospital stay. In clinical practice, it is often necessary to use a certain drug combination when a clinician perceives that the benefit of therapy outweighs the risk of a potential adverse event (Armahizer et al., 2013).
When analyzing concomitantly present additional risk factors for QTc prolongation in patients with pDDIs, we found a high frequency of unmodifiable risk factors, such as older age (10 out of 11 patients), whereas there were only 5 female patients (less than 50%). It was reported that almost 70% of cases of drug-induced TdP occur in females, due to sex hormones (Kaab et al., 2004; Zeltser et al., 2003). Among modifiable risk factors, bradycardia, renal disease nor hypokalemia were present in the group of patients exposed to QT-prolonging pDDIs. Four patients had diabetes (36.4%), which is a significant risk factor for sudden cardiac death, whereas little or no evidence was found for the diabetes impact on QTc prolongation (Vandael et al., 2017).
A total of 14 different drugs were involved in 13 QT-prolonging pDDIs. The highest frequency was found for ciprofloxacin (5 pDDIs), propafenone (4 pDDIs) and beta2-agonists (formoterol and salmeterol; 4 pDDIs). The total list included also antipsychotics (chlorpromazine, olanzapine), an antidepressant (sertraline), cardiovascular drugs excluding antiarrhythmics (enalapril, ramipril, valsartan, indapamide), amantadine and octreotide. Other studies reported different findings: diuretics, antiemetics, antimicrobials, proton pump inhibitors, antinausea and antiarrhythmic agents were involved in QT-prolonging DDIs, reported in the descending order (Khan et al., 2018). Nevertheless, this study was conducted in a coronary care unit. In contrast, studies which included patients with drug-induced QT prolongation as causative agents reported: antiarrhythmics, antipsychotics, antiemetics and antibiotics (Armahizer et al., 2013; Letsas et al., 2009). All of the pDDIs identified in our study had a proposed pharmacodynamic mechanism. Letsas et al. (2009) reported that pharmacokinetic DDIs involving the CYP450 metabolic pathway were present in 24% of cases with a drug-induced long QT interval. Another study conducted in patients with QT prolongation (QTc≥500 ms) found that 47% of patients had pharmacodynamic and 43% had pharmacokinetic DDIs. Similarly to the Letsas study, the pharmacokinetic mechanism involved metabolic inhibition of CYP450 isoenzymes (CYP1A2, CYP2D6, CYP3A4, CYP2C9) (Armahizer et al., 2013). However, both studies reported only CredibleMeds database for identification of pharmacodynamic DDIs, whereas no source for pharmacokinetic DDIs was reported. Fernandes and colleagues (2019) employed Micromedex and LexiInteract databases for DDIs screening in patients with at least one QT-prolonging drug prescribed in the intensive care unit. They identified DDIs in 15.9% of patients, where a pharmacodynamic mechanism had a dominant relative share among them, with 73.3%, compared to a pharmacokinetic one, found in 26.7% of patients exposed to DDIs (Fernandes et al., 2019). When analyzing the association between the present QT-prolonging pDDI and irregular heart rhythm, the estimated odds ratio was 1.707 (95% CI 0.445−6.553, p=0.436). When adjusting for age, gender and patients’ morbidity, the odds ratio was higher (2.093, 95% CI 0.531−8.242), although not significant. In contrast, a significant association was found between age or Charlson Comorbidity Index and irregular heart rhythm in our study. The body of evidence regarding the DDIs’ impact on QT prolongation is collative. While some studies showed an increased risk of QT prolongation and TdP when two or more drugs are used concomitantly (Heemskerk et al., 2018; Smithburger et al., 2010; van der Sijs et al., 2009), others reported no systematic correlation between the number of AZCERT drugs administered and the degree of QT prolongation (Meid et al., 2017; Niemeijer et al., 2015; Riad et al., 2017). However, the discrepancies in the abovementioned results serve mostly to explain the variability in DDIs effects (Wisniowska et al., 2016). Nevertheless, Wisniowska and colleagues (2016) concluded that DDIs are a significant element of cardiac safety, and that new methods are needed in the assessment of DDIs effects.
Our study estimated the prevalence of potential QT-prolonging DDIs in a population of patients with cardiovascular disease. The results reflect the state at the primary level of healthcare, since the therapy was evaluated at the moment of hospital admission. Drug combinations with a potential adverse effect were identified, giving an insight into potential risks for patients.
The main limitation of the study is the absence of data on the QT interval, as it was not routinely available in the collected medical documentation. Due to its retrospective design, it was not possible to determine the possible impact of DDIs on the patients’ hospitalisation. Additionally, this was a single-centre study; therefore, the results could not be extrapolated to a larger population of cardiovascular disease patients with different ethnic background. Nevertheless, due to the serious consequences caused by QT prolongation and TdP, the key role of health professionals is to identify predisposed patients and recognize pDDIs with QT-prolonging agents, reducing the patient’s risk as much as possible (Crouch et al., 2003). Three main reasons for prescribing potentially interacting drugs include the following: (i) a patient has obtained therapy from more than one prescriber practitioner; (ii) a practitioner is unaware of the DDI; or (iii) a practitioner has assessed the benefit/risk ratio and decided to proceed with therapy (Smithburger et al., 2010). Due to a long list of QT drugs and their potential interacting pairs and an increasing volume of knowledge, DDIs screening databases might be beneficial in assessing and preventing a patient’s risk (Roden, 2004). Studies have found that DDIs alerts are frequently overridden, due to a clinician’s assessment of a low risk of serious arrhythmia. However, these alerts raise the clinicians’ awareness, as it was found that electrocardiograms were subsequently more often recorded in patients with overridden alerts (van der Sijs et al., 2009).
Although the study reported a relatively low prevalence of QT-prolonging drug combinations, given that underlying heart disease is a significant risk factor for the occurrence of QTc prolongation, the additional risk for acquired QT prolongation should not be neglected. Due to the serious consequences caused by QT prolongation and TdP, the key role of health professionals is to identify predisposed patients and recognize the pDDIs involving QT-prolonging agents. The patient’s modifiable risk factors for QT prolongation, such as pDDIs-related burden, should be minimized, if not eliminated.
ACKNOWLEDGEMENT
This research was funded by the Ministry of Science, Technological Development and Innovation, Republic of Serbia through two Grant Agreements with the University of Belgrade - Faculty of Pharmacy No 451-03-65/2024-03/200161 and No 451-03-66/2024-03/200161.
SR and PS were affiliated with the University Clinical Hospital Center Bezanijska Kosa, Belgrade, Serbia at the time of the trial, and are currently affiliated with the University Clinical Hospital Center “Dr Dragisa Misovic - Dedinje”, Belgrade, Serbia.
REFERENCES
- Ambhore A, Teo SG, Bin Omar AR, Poh KK. Importance of QT interval in clinical practice. Singapore Med J. 2014;55(12):607-11; quiz 12.
- Armahizer MJ, Seybert AL, Smithburger PL, Kane-Gill SL. Drug-drug interactions contributing to QT prolongation in cardiac intensive care units. J Crit Care. 2013;28(3):243-9.
- Cohagan B, Brandis D 2022. Torsade de Pointes. StatPearls Publishing LLC.
- Crouch MA, Limon L, Cassano AT. Clinical relevance and management of drug-related QT interval prolongation. Pharmacotherapy. 2003;23(7):881-908.
- Fernandes FM, Da Silva Paulino AM, Sedda BC, Da Silva EP, Martins RR, Oliveira AG. Assessment of the risk of QT-interval prolongation associated with potential drug-drug interactions in patients admitted to Intensive Care Units. Saudi Pharm J. 2019;27(2):229-34.
- Heemskerk CPM, Pereboom M, Van Stralen K, Berger FA, Van Den Bemt P, Kuijper AFM, et al. Risk factors for QTc interval prolongation. Eur J Clin Pharmacol. 2018;74(2):183-91.
- Hines LE, Murphy JE. Potentially harmful drug-drug interactions in the elderly: a review. Am J Geriatr Pharmacother. 2011;9(6):364-77.
- Isbister GK, Page CB. Drug induced QT prolongation: the measurement and assessment of the QT interval in clinical practice. Br J Clin Pharmacol. 2013;76(1):48-57.
- Kaab S, Pfeufer A, Hinterseer M, Nabauer M, Schulze-Bahr E. Long QT syndrome. Why does sex matter? Z Kardiol. 2004;93(9):641-5.
- Khan Q, Ismail M, Haider I. High prevalence of the risk factors for QT interval prolongation and associated drug-drug interactions in coronary care units. Postgrad Med. 2018;130(8):660-65.
- Khan Q, Ismail M, Haider I, Haq IU, Noor S. QT interval prolongation in hospitalized patients on cardiology wards: a prospective observational study. Eur J Clin Pharmacol . 2017a;73(11):1511-18.
- Khan Q, Ismail M, Khan S. Frequency, characteristics and risk factors of QT interval prolonging drugs and drug-drug interactions in cancer patients: a multicenter study. BMC Pharmacol Toxicol. 2017b;18(1):75.
- Letsas KP, Efremidis M, Kounas SP, Pappas LK, Gavrielatos G, Alexanian IP, et al. Clinical characteristics of patients with drug-induced QT interval prolongation and torsade de pointes: identification of risk factors. Clin Res Cardiol. 2009;98(4):208-12.
- Meid AD, Bighelli I, Machler S, Mikus G, Carra G, Castellazzi M, et al. Combinations of QTc-prolonging drugs: towards disentangling pharmacokinetic and pharmacodynamic effects in their potentially additive nature. Ther Adv Psychopharmacol. 2017;7(12):251-64.
- Niemeijer MN, Van Den Berg ME, Leening MJ, Hofman A, Franco OH, Deckers JW, et al. Declining incidence of sudden cardiac death from 1990-2010 in a general middle-aged and elderly population: The Rotterdam Study. Heart Rhythm. 2015;12(1):123-9.
- Riad FS, Davis AM, Moranville MP, Beshai JF. Drug-Induced QTc Prolongation. Am J Cardiol. 2017;119(2):280-83.
- Roden DM. Drug-induced prolongation of the QT interval. N Engl J Med. 2004;350(10):1013-22.
- Savić N, Gojković-Bukarica L. Long QT syndrome: genetic implications and drug influence. Vojnosanit Pregl. 2008;65(4):308-12.
- Schachtele S, Tumena T, Gassmann KG, Fromm MF, Maas R. Co-Prescription of QT-Interval Prolonging Drugs: An Analysis in a Large Cohort of Geriatric Patients. PLoS One. 2016;11(5):e0155649.
- Scheife RT, Hines LE, Boyce RD, Chung SP, Momper JD, Sommer CD, et al. Consensus recommendations for systematic evaluation of drug-drug interaction evidence for clinical decision support. Drug Saf. 2015;38(2):197-206.
- Smithburger PL, Kane-Gill SL, Seybert AL. Drug-drug interactions in the medical intensive care unit: an assessment of frequency, severity and the medications involved. Int J Pharm Pract. 2012;20(6):402-8.
- Smithburger PL, Seybert AL, Armahizer MJ, Kane-Gill SL. QT prolongation in the intensive care unit: commonly used medications and the impact of drug-drug interactions. Expert Opin Drug Saf . 2010;9(5):699-712.
- Surawicz B, Knilans T 2001. Chou’s Electrocardiography in Clinical Practice: Adult and Pediatric, Saunders.
- Thomas SH, Behr ER. Pharmacological treatment of acquired QT prolongation and torsades de pointes. Br J Clin Pharmacol . 2016;81(3):420-7.
- Tisdale JE, Wroblewski HA, Overholser BR, Kingery JR, Trujillo TN, Kovacs RJ. Prevalence of QT interval prolongation in patients admitted to cardiac care units and frequency of subsequent administration of QT interval-prolonging drugs: a prospective, observational study in a large urban academic medical center in the US. Drug Saf . 2012;35(6):459-70.
- Van Der Sijs H, Kowlesar R, Klootwijk AP, Nelwan SP, Vulto AG, Van Gelder T. Clinically relevant QTc prolongation due to overridden drug-drug interaction alerts: a retrospective cohort study. Br J Clin Pharmacol . 2009;67(3):347-54.
- Vandael E, Vandenberk B, Vandenberghe J, Willems R, Foulon V. Risk factors for QTc-prolongation: systematic review of the evidence. Int J Clin Pharm. 2017;39(1):16-25.
- Wisniowska B, Tylutki Z, Wyszogrodzka G, Polak S. Drug-drug interactions and QT prolongation as a commonly assessed cardiac effect - comprehensive overview of clinical trials. BMC Pharmacol Toxicol . 2016;17:12.
- Woosley RL, Black K, Heise CW, Romero K. CredibleMeds.org: What does it offer? Trends Cardiovasc Med. 2018;28(2):94-9.
- Zeltser D, Justo D, Halkin A, Prokhorov V, Heller K, Viskin S. Torsade de pointes due to noncardiac drugs: most patients have easily identifiable risk factors. Medicine (Baltimore). 2003;82(4):282-90.
Data Availability Statement
Data availability
The data that support the findings of this study are available from the corresponding author MĆ upon reasonable request.
Publication Dates
-
Publication in this collection
20 Jan 2025 -
Date of issue
2025
History
-
Received
22 Jan 2024 -
Accepted
05 May 2024
