Risk Of QTc Prolongation Research Articles

Assessment of the risk of QT-interval prolongation associated with potential drug-drug interactions in patients admitted to Intensive Care Units

ObjectivesTo evaluate the relationship between drug interactions and QT-interval prolongation in patients admitted to a general intensive care unit (ICU). MethodsThis study was approved by the Institutional Review Board and written informed consent was obtained from all patients. From May 2015 to July 2016, all patients over 18 years-old admitted to the ICU for more than 24 h and in whom the QT-interval on the ECG could be read were prospectively included in this observational, cross-sectional study. All medications administered in the 24 h prior to admission were recorded and the QT-interval was measured upon ICU admission and corrected with Bazzet’s formula (QTc). Drug-drug interactions involving drugs potentially associated with QTc prolongation (DDIQT) were searched and QTc increase associated with pharmacokinetic (PK-DDIQT) and pharmacodynamic (PD-DDIQT) interactions was assessed with multiple regression adjusted by patient varibles. ResultsThe study population consisted of 283 patients, 54.4% males, mean age 57.6 ± 16.7 years-old. Forty five (15.9%) patients presented 65 DDIQT with predominance of pharmacodynamic (66.1%). The risk of DDIQT prescription increased with lower systolic blood pressure, in hypokalemia, in non-diabetics and with the number of medications. PK-DDIQT alone did not affect the QTc interval (7.75 ms, 95%CI: –22.4 to 37.9 ms, p = 0.61), but PD-DDIQT increased QTc by 28.4 ms (95%CI: 9.67 to 47.4 ms, p = 0.003). Most PD-DDIQT involved metoclopramide with ondansetron or amiodarone, and ondansetron with ciprofloxacin. ConclusionsIn patients exposed to drugs associated with prolonged QTc in the 24 h prior to ICU admission, pharmacodynamic DDIQT are associated with increased risk of QTc prolongation.

A smart algorithm for the prevention and risk management of QTc prolongation based on the optimized RISQ-PATH model.

QTc prolongation is a complex problem linked with multiple risk factors. The RISQ-PATH score was previously developed to identify high-risk patients for QTc prolongation. The aim of this study was to optimize and validate this risk score in a large patient cohort, and to propose an algorithm to generate smart QT signals in the electronic medical record. A retrospective study was performed in the Nexus hospital network (n=17) in Belgium. All electrocardiograms performed in 2015 in both ambulatory and hospitalized patients were collected together with risk factors for QTc prolongation (training database). Multiple logistic regression was performed to obtain the optimal prediction (RISQ-PATH) model. The model was tested in a validation database (electrocardiograms between January and April 2016). In total, 60 208 patients (52.8% males, mean age 63±18 years) were included; 3543 patients (5.9%) had a QTc≥450(♂)/470(♀)ms and 453 (0.8%) a QTc≥500ms. The optimized RISQ-PATH model has an area under the ROC-curve of 0.772 [95% CI 0.763-0.780] to predict QTc≥450(♂)/470(♀)ms. A predicted probability of ≥0.035 was set as cutoff for a high risk of QTc prolongation. This cutoff resulted in a sensitivity of 87.4% [95% CI 86.2-88.5] and a specificity of 46.2% [95% CI 45.8-46.6]. These results could be confirmed for QTc≥500ms and in the validation database (n=28 400). The RISQ-PATH model, with a cutoff probability of 0.035, predicted a prolonged QTc interval ≥ 450/470ms or ≥500ms with a sensitivity of ±87% and a specificity of ±45%. This RISQ-PATH model can be used in clinical decision support systems to create smart QT alerts.

Lurasidone is not associated with risk of QTc prolongation

Lurasidone is not associated with risk of QTc prolongation

Effect of serum electrolytes within normal ranges on QTc prolongation: a cross-sectional study in a Chinese rural general population

BackgroundMany previous clinical studies have reported that prolongation of the QT interval corrected for heart rate (QTc) is associated with an increased risk of sudden cardiac death and all-cause mortality. This study aimed to explore associations between serum electrolytes and QTc prolongation in the north-eastern Chinese rural general population.MethodsWe performed a cross-sectional study including 10,334 (4820 men and 5514 women) from the general population aged ≥35 years in the Liaoning Province from 2012 to 2013. Anthropometric measurements, laboratory examinations and self-reported lifestyle factor information, echocardiography and electrocardiogram were collected by trained personnel. The associations between serum electrolytes and QTc prolongation were tested using multiple linear regression and logistic regression analyses.ResultsThe mean QTc interval were 415.6 ± 18.8 and 470.1 ± 23.1 ms in normal group and QTc prolongation group respectively. The prevalence of QTc prolongation increased significantly with a decrease in serum potassium and an increase in magnesium. Stepwise multiple linear regression showed that age, hypertension, waist circumference were prominently positive associated with QTc interval both in male and female population. But serum potassium was significantly inversely associated with QTc interval. Serum magnesium and calcium also showed a positive relationship with QTc interval. Furthermore, multiple logistic regression found that lower quartile of serum potassium had higher risk for QTc prolongation, especially in female population (Q2 vs. Q4: OR: 1.54, 95%CI: 1.01–2.35; Q1 vs. Q4: OR: 2.02, 95%CI: 1.36–3.01). In addition, the higher serum magnesium increased the risk of QTc prolongation, which was significantly only in male population.ConclusionsIn present Chinese rural general population, even with normal range, a decrease in serum potassium and an increase in serum magnesium are important risk factors for QTc prolongation.

Evaluation of dependent variable, time effect, covariates, and covariation structure in concentration-QTc modeling: A simulation study.

The revised ICH E14 Question and Answer (R3) document issued in December 2015 enables pharmaceutical companies to use concentration-QTc (C-QTc) modeling as the primary analysis for assessing QTc prolongation risk of new drugs. A new approach by including the time effect into the current C-QTc model is introduced. Through a simulation study, we evaluated performances of different C-QTc modeling with different dependent variables, covariates, and covariance structures. This simulation study shows that C-QTc models with ΔQTc being dependent variable without time effect inflate false negative rate and that fitting C-QTc models with different dependent variables, covariates, and covariance structures impacts the control of false negative and false positive rates. Appropriate C-QTc modeling strategies with good control of false negative rate and false positive rate are recommended.

Pretransplant increases in left ventricular volume and mass are associated with QT prolongation during pediatric liver transplantation.

Structural alterations in the cirrhotic heart may contribute to electromechanical abnormalities, represented by QT prolongation. The aim of this study was to investigate the changes in QTc according to the operative stage during pediatric LT and to identify which baseline echocardiographic parameters were associated with intraoperative QTc prolongation. Data were evaluated from 39 children undergoing LT for chronic liver disease (median age 9months). In 19 patients (48.7%), baseline QTc was prolonged ≥440ms (462±19ms). Through the period of post-reperfusion, QTI, QTc, and JTI progressively increased, although values partially recovered toward the end of surgery. High LVMI (≥82.51g/m2 ) was associated with baseline QTc≥440ms (OR=1.034, P=.032). In the 5minutes post-reperfusion stage, marked QTc prolongation (defined as QTc≥500ms; n=24, 61.5%) was significantly associated with high EDVI (OR=1.060, P=.027) and SVI (OR=1.075, P=.026). In children with chronic liver disease, increased ventricular volumes and mass may increase the risk of QTc prolongation during LT, suggesting that repolarization abnormalities might be contributed by structural changes characteristic of cirrhotic cardiomyopathy.

Low dose oral haloperidol does not prolong QTc interval in older acutely hospitalised adults: a subanalysis of a randomised double-blind placebo-controlled study.

BackgroundHaloperidol is the most frequently prescribed antipsychotic for delirium symptoms. The risk of QTc prolongation often raises concerns, although the effect of haloperidol on QTc interval has not yet been investigated in a randomised placebo-controlled fixed-dose study.MethodsA subanalysis of a randomised double-blind placebo-controlled study was conducted to evaluate the effect of prophylactic haloperidol 1 mg or placebo 1 mg orally twice-daily (maximum of 14 doses) on QTc interval in patients aged 70 years and over. Bedside, 12-lead ECGs were recorded before, during and after the one-week intervention period. Automatic QTc measurements were obtained in addition to manual measurements of QT and RR intervals, blinded for treatment status. Manual measurements were corrected (QTc) using Bazett (QTc-B), Framingham (QTc-Fa), Fridericia (QTc-Fi) and Hodges (QTc-H) methods. Mixed model analyses were used to test for differences in longitudinal course of QTc between patients receiving haloperidol and placebo.ResultsECG recordings of 72 patients (haloperidol n = 38) were analysed, 45.8% male. Median (range) haloperidol serum concentration on day 4 was 0.71 (0.32–1.82) µg/L (n = 23). Longitudinal course of mean QTc did not significantly differ between treatment arms for any of the automatic or manually derived QTc values.ConclusionsLow dose oral haloperidol did not result in QTc prolongation in older acutely hospitalised patients. Results may not be generalizable to patients with existing ECG abnormalities such as atrial fibrillation.

Evaluating the risk of QTc prolongation associated with antidepressant use in older adults: a review of the evidence.

Antidepressants are widely used medications for a range of medical conditions such as mood disorders and chronic pain in older adults. A vast body of evidence exists concerning the risks of QT interval prolongation associated with these agents and healthcare providers should critically evaluate the potential for QT prolongation when selecting antidepressant agents. Long QT syndrome is a disorder of myocardial repolarization that manifests as a prolonged QT interval on an electrocardiogram (ECG) and has been demonstrated to increase with age. The objective of this review is to present and evaluate existing literature regarding the risk of QT prolongation in older adults, age 60 years and older, and discuss the implications for clinical practice. A PubMed search was conducted to identify studies evaluating the QT prolonging effects of antidepressant medications and publications were chosen based on pertinent criteria. Depending on the antidepressant agent and patient-specific factors, clinicians should assess and monitor electrolytes and EGCs to evaluate the risks and benefits for older adults receiving agents known to prolong the QT interval.

Association between a frailty index based on common laboratory tests and QTc prolongation in older adults: the Rugao Longevity and Ageing Study.

BackgroundRisk factors for heart rate-corrected QT interval (QTc) proglongation should be explored to stratify high-risk individuals to aid the prevention of incident cardiovascular events and mortality. The diversity of risk factors for QTc prolongation suggests that use of the frailty index (FI), indicating general health deficits, may be an effective approach, especially in the elderly, to identify the risk of QTc prolongation.MethodsWe used the data of 1,780 individuals aged 70–87 years from the Rugao Longevity and Ageing Study (RuLAS), a community-based longitudinal study. The FI was constructed using 20 routine laboratory tests, plus the body mass index and measures of systolic and diastolic blood pressures (FI-Lab).ResultsThe mean FI-Lab value was 0.24±0.09. The mean heart rate-corrected QT interval (QTc) was 407±38 ms. The prevalence of QTc prolongation was 5.2% in elderly community populations aged 70–87 years. A higher FI-Lab value was associated with a higher risk for QTc prolongation. Each 10% increase in the FI-Lab value increased the odds ratio (OR) by 33% (OR: 1.33; 95% CI: 1.07–1.64). Compared with the lowest quartile, the top quartile FI-Lab score was associated with a 2.50-fold QTc prolongation risk in elderly individuals (95% CI: 1.21–5.19).ConclusionAn FI based on routine laboratory data can identify older adults at increased risk for QTc prolongation. The FI approach may therefore be useful for the risk stratification of QTc prolongation.

Hepatitis C (HCV) and the Risk of QTC Prolongation - An Exploratory Cohort Study Among Opiate Users in Substitution

Background: Prolongation of the QT interval is a known adverse event associated with certain pharmacotherapies, stress sensitivity, female gender, and low potassium level. It can potentially lead to fatal outcomes by inducing Torsade de pointes arrhythmia. Patients with opiate dependence are highly vulnerable to this condition due to the side effects of opioids and other accumulated risk factors. Methods: A convenience sample of 99 patients with opiate dependence receiving substitution treatment was recruited in an Inner-city substitution clinic in Germany. All patients were assessed with an ECG before and after taking opiate-agonist medication. Additional sociodemographic information and medical history were also collected. To determine the impact of different variables on QTc interval, a multiple variables linear regression with a stepwise selection was fitted. Findings: A concerning high prevalence of QT prolongation was observed among participants (32·3% before and 17·2% after medication intake). A significant finding in this study was the identification of Hepatitis C infection as an important risk factor in addition to baseline QTc prolongation, female gender, tobacco - dependence and QT-prolonging medications. Interpretation: The accumulation of risk factors for QT prolongation can have serious adverse consequences in patients with substance use disorder receiving opiate-agonist medications. Addressing these factors for example treatment of HCV infection needs to be considered as part of an integrated treatment program to prevent such consequences. Further research is required to explore the association of various factors with QTc prolongation, evaluate the impact of potential interventions on cardiac adverse events and also unravel the underlying mechanisms of QTc prolongation in this population. Funding: No grant funding. Declaration of Interest: Authors do not have any conflict of interests in regards to this study to disclose. Ethical Approval: The study design was approved by the ethics committee of the Ludwig Maximillian University (LMU) in Munich.

Incidence, Diagnosis, and Management of QT Prolongation Induced by Cancer Therapies: A Systematic Review.

BackgroundThe cardiovascular complications of cancer therapeutics are the focus of the burgeoning field of cardio‐oncology. A common challenge in this field is the impact of cancer drugs on cardiac repolarization (ie, QT prolongation) and the potential risk for the life‐threatening arrhythmia torsades de pointes. Although QT prolongation is not a perfect marker of arrhythmia risk, this has become a primary safety metric among oncologists. Cardiologists caring for patients receiving cancer treatment should become familiar with the drugs associated with QT prolongation, its incidence, and appropriate management strategies to provide meaningful consultation in this complex clinical scenario.Methods and ResultsIn this article, we performed a systematic review (using Preferred Reporting Items of Systematic Reviews and Meta‐Analyses (PRISMA) guidelines) of commonly used cancer drugs to determine the incidence of QT prolongation and clinically relevant arrhythmias. We calculated summary estimates of the incidence of all and clinically relevant QT prolongation as well as arrhythmias and sudden cardiac death. We then describe strategies to prevent, identify, and manage QT prolongation in patients receiving cancer therapy. We identified a total of 173 relevant publications. The weighted incidence of any corrected QT (QTc) prolongation in our systematic review in patients treated with conventional therapies (eg, anthracyclines) ranged from 0% to 22%, although QTc >500 ms, arrhythmias, or sudden cardiac death was extremely rare. The risk of QTc prolongation with targeted therapies (eg, small molecular tyrosine kinase inhibitors) ranged between 0% and 22.7% with severe prolongation (QTc >500 ms) reported in 0% to 5.2% of the patients. Arrhythmias and sudden cardiac death were rare.ConclusionsOur systematic review demonstrates that there is variability in the incidence of QTc prolongation of various cancer drugs; however, the clinical consequence, as defined by arrhythmias or sudden cardiac death, remains rare.

What Is Old Is New Again: Delafloxacin, a Modern Fluoroquinolone.

Delafloxacin is a new fluoroquinolone antimicrobial approved for the treatment of acute bacterial skin and skin structure infections (ABSSSIs) in adults using dosage regimens of 300mg intravenously every 12hours, 450mg orally every 12hours, or switching from intravenous to oral regimens for a 5- to 14-day treatment duration. Dosage adjustments in patients with severe renal dysfunction (estimated glomerular filtration rate [eGFR]=15-29ml/min/1.73m2 ) are not required for oral doses but should be decreased to 200mg intravenously every 12hours in patients requiring parenteral therapy. Due to insufficient data, use of delafloxacin is not recommended for patients on hemodialysis or with end-stage renal disease (eGFR <15ml/min/1.73m2 ). Delafloxacin works through inhibition of DNA gyrase (topoisomerase II) and topoisomerase IV, which are essential enzymes for bacterial DNA transcription, replication, repair, and recombination and exhibits bactericidal activity against gram-positive and gram-negative organisms through a concentration-dependent matter. Delafloxacin has a very broad spectrum of activity against atypical, anaerobic, and resistant gram-negative and gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa. During phase 3 trials, the most common side effects associated with delafloxacin were gastrointestinal (nausea, diarrhea). Unlike other fluoroquinolones, there does not seem to be a risk of QTc prolongation or phototoxicity with delafloxacin. The availability of both parenteral and oral formulations for delafloxacin distinguishes it from many of the currently available agents approved for ABSSSIs. Phase 3 studies for the treatment of respiratory infections are currently under way, and future results of these studies will further help delineate the role of delafloxacin.

Exacerbation of Gastroparesis After Ablation for Atrial Fibrillation

A 54 year old woman with a history of paroxysmal atrial fibrillation (afib) and myasthenia gravis (MG) was referred to our clinic for a gastroparesis (GP) exacerbation. Her medications included cellcept, mestinon, prednisone and IV immunoglobulin. She was diagnosed with GP on a prior gastric emptying study, but had been asymptomatic on diet alone. She had failed two prior radiofrequency ablations (RFA) for afib, and therefore underwent a third cardiac cryoablation (CRYO) of all four pulmonary veins. The procedure was done with general anesthesia and was uncomplicated. The day after the ablation, she developed epigastric abdominal pain, nausea, vomiting, and post-prandial fullness lasting 5-6 hours. These symptoms prompted an emergency department visit, during which they ruled out an acute coronary syndrome. She was referred for urgently to our clinic where she reported ongoing symptoms. Upper endoscopy revealed mild gastric antral erythema without other significant findings, similar to her prior endoscopies. Thus her symptoms were thought to be secondary to an exacerbation of her GP. Due to her MG medications and risk for QTc prolongation with antiemetics such as ondansetron, metoclopramide and phenergan, a scopolamine patch was started, which somewhat improved her nausea. Numerous causes of GP are known including diabetes, scleroderma, neuromuscular diseases, hypothyroidism, and post gastrointestinal surgery. GP is a known risk of cardiac ablation secondary to vagus nerve injury, due to its proximity to the cardiac ablation site. While this complication is well established in cardiology literature, this case represents only the second instance of post-ablation GP discussed in gastroenterology literature and the first in which CRYO was utilized. The prevalence of post ablation GP is unknown, but thought to occur in 7-17% of patients. Further study is needed to determine if there is a difference in risk for GP between RFA vs. CRYO. Some have suggested the use of CRYO or microwaves instead of RFA as a potential means of reducing rates of post-ablation GP, but a clinical trial has yet to be performed. Most cases of post-ablation GP occur within the first 96 hours post-ablation and eventually resolve within 12 months. Extra consideration and planning should be considered in patients with a prior diagnosis of GP prior to afib ablation. This case demonstrates a noteworthy risk factor for GP, which is often unrecognized by gastroenterology providers.

Risk Management of Hospitalized Psychiatric Patients Taking Multiple QTc-Prolonging Drugs.

Drug-related QTc prolongation has been linked with Torsade de Pointes and sudden cardiac death. The objective of this study was to investigate the impact of starting an additional QTc-prolonging drug on the QTc interval of psychiatric inpatients. An observational study was performed between May 2011 and December 2014 in 6 Belgian psychiatric hospitals. Inpatients who were already taking 1 QTc-prolonging drug or more could be included in the study when an additional QTc-prolonging drug was started. Electrocardiograms were performed at baseline and follow-up. Demographic, medical, medication, and laboratory data were collected. A risk score was used to estimate the risk of QTc prolongation based on patient-specific risk factors. A cutoff value of 8 points was set as high risk for QTc prolongation. One hundred fifty-two patients (44.7% women; mean age, 44 [SD, 17] years) were included who received a prescription for an additional QTc-prolonging drug. There was a small but significant difference (P = 0.032) in mean QTc interval between baseline (409.1 [SD, 21.8] milliseconds) and follow-up (411.8 [SD, 21.7] milliseconds). Three patients developed a prolonged QTc interval in the follow-up electrocardiogram (QTc, ≥450 [men]/470 [women] milliseconds); 8 patients had a delta QTc of 30 milliseconds or longer. No cases of torsade de pointes or sudden cardiac death were identified. Fifty-eight patients (38.2%) had a risk score of 8 or higher; these patients had a significantly longer QTc interval at follow-up than did patients with a risk score of lower than 8 (P < 0.001). Only a limited number of patients developed a prolonged QTc interval after the start of an additional QTc-prolonging drug. Nevertheless, it is still important to screen for high-risk patients at baseline. A risk score can help to select high-risk patients and to stimulate an appropriate and feasible risk management of QTc prolongation in psychiatry.

Analysis of the QT interval prolongation and pharmaceuticals in elderly patients in ambulatory care

OBJECTIVES: The objective of this study was to evaluate the frequency of long QT syndrome (LQTS) in the electrocardiographic tracing of elderly people and the concomitant use of drugs that can aggravate this condition. METHODS: This is a crosssectional, observational study of elderly patients in outpatient services at Hospital Santa Casa de Misericórdia de Vitória, over a six-month period. RESULTS: A total of 163 patients with 75 ± 8 (60–94) years of age, 60.7% (n = 99) of whom were female, participated in the study. Of the total number of patients, 33.1% (n = 54) were regularly taking at least one pharmaceutical that increased the risk of QTc prolongation; 34 patients (20.9%) had prolonged QTc and 15 (9,2%) had at-risk QTc. Of these patients with at-risk QTc, 4 (23.4%) were using at least 1 1 pharmaceutical that increases the risk of QT prolongation (p = 0.07). CONCLUSION: In this sample, a high frequency of LQTS was observed, as well as the use of pharmaceuticals that potentially cause LQTS and arrhythmias.

Evaluation of the Effects of Quetiapine on QTc Prolongation in Critically Ill Patients

Quetiapine, an atypical antipsychotic used in the intensive care unit (ICU) to manage delirium, has a possible adverse effect of corrected QT (QTc) interval prolongation. The objective of this analysis was to describe the impact of quetiapine on QTc interval prolongation in critically ill patients. This was a single-center, prospective cohort analysis of ICU patients who received quetiapine between October 2015 and February 2016. The major end point was the incidence of QTc prolongation greater than 60 milliseconds above baseline during therapy. Minor end points included median change in QTc interval and incidence of Torsades de Pointes (TdP). Univariate and multivariable analyses were performed to determine variables associated with higher risk of QTc prolongation. During the study period, 103 patients were enrolled in the analysis. QTc interval prolongation greater than 60 milliseconds occurred in 14 (13.6%) patients. The median change in QTc interval was 20 milliseconds. There were no cases of TdP. On multivariable analysis, the only variable associated with higher incidence of QTc prolongation was administration of a concomitant medication known to prolong the QTc interval (P = .046). QTc prolongation was relatively uncommon among critically ill patients utilizing quetiapine. Patients receiving concomitant medications known to prolong the QTc interval may be at an increased risk.

QTc Interval in psychiatric inpatients: A retrospective study

IntroductionSeveral psychotropic medications (i.e. antipsychotics, antidepressant) have been recently associated with QTc prolongation. Despite literature data report only mild prolongation of QTc following the use of antidepressants or typical antipsychotics, post-marketing studies have clearly evidenced an increased risk of QTc prolongation and potentially lethal arrhythmias (i.e. torsade de pointes) in psychiatric patients.ObjectivesWe aimed to evaluate the prevalence of prolonged QTc and to identify potential predictors influencing QTc in a psychiatric inpatient population.MethodsMedical records of 200 patients admitted to our psychiatric ward between 2007 and 2012 were retrospectively reviewed.ResultsPrevalence of prolonged QTc at admission was very low (0.1%). No significant differences in QTc interval were observed between patients taking or not antipsychotics (P = 0.66), mood stabilizers (P = 0.36), or antidepressants (P = 0.07). A statistically significant difference was observed between patients on depot formulation and patients who were taking oral antipsychotic (P = 0.02). However, the pharmaceutical class of the medications appeared not significant.ConclusionsWe observed a very low rate of QTc prolongation in psychiatric inpatients at admission. Surprisingly we did not find a significant effect of specific medications; however, in our sample intramuscular formulation was associated with lower QTc interval.Disclosure of interestThe authors have not supplied their declaration of competing interest.

Cases of drug-induced Torsade de Pointes: a review of Belgian cases in the EudraVigilance database

Objectives: Post-marketing surveillance is very important, especially for rare adverse drug reactions like QTc-prolongation and Torsade de Pointes (TdP). The objective of this study was to investigate the characteristics of Belgian cases of drug-related TdP reported in the EudraVigilance database.Methods: The EudraVigilance database was searched for Belgian post-marketing cases of TdP reported between December 2001–April 2015. These cases were identified with MedDRA preferred terms. Duplicate reports were excluded. Each included case report was reviewed to collect data about age, gender, seriousness, suspected drug, concomitant drugs, causality, and other known risk factors for QTc-prolongation.Results: Between 2001 and 2015, only 31 cases coded as TdP were identified; 16 cases were also coded as ‘prolonged QT’ and 2 patients died. In total, 21 suspected drugs were implicated and most of them (N = 11) were part of list 1 of CredibleMeds. The most common suspected drugs were citalopram (N = 4) and amiodarone (N = 3). In 18 cases, a pharmacodynamic drug-drug interaction with risk of QTc-prolongation was present. Most patients (N = 25) had ≥2 other risk factors for QTc-prolongation.Conclusion: Over 15 years, only a low number of Belgian cases of TdP were identified in the EudraVigilance database. In most case reports, multiple risk factors for QTc-prolongation could be detected. This illustrates that there is a clear underreporting of QTc-prolongation and TdP in Belgium. Initiatives are needed to improve the awareness and knowledge of health care professionals regarding the risk of QTc-prolongation and TdP, both to prevent cases of TdP and to stimulate the reporting of these cases.

Development of a risk score for QTc-prolongation: the RISQ-PATH study.

Background More than 170 drugs are linked with QTc-prolongation, which in extreme cases can lead to Torsade de Pointes. Monitoring of this potential side effect is an important challenge in clinical practice. Objective To investigate the risk of QTc-prolongation in hospital patients who started a QTc-prolonging drug, and to develop a risk score to identify patients at high/low risk for QTc-prolongation. Setting University Hospitals Leuven, Belgium. Method All patients starting with haloperidol or a QTc-prolonging antibiotic/antimycotic were eligible for this observational study. Twelve-lead electrocardiograms were recorded at baseline and follow-up (steady state). Demographic, medical and drug data were collected. The obtained data were used to calculate the performance characteristics of a preliminary risk score (RISQ-PATH score), based on a systematic review of risk factors. ROC analysis determined a score of <10 points as a low risk for QTc-prolongation. Main outcome measure QTc-interval in a baseline and follow-up electrocardiogram. Results 178 patients (46.6% female; mean age 69±14years) were included (levofloxacin: N=80; haloperidol: N=41; fluconazole: N=41). Overall, no significant difference between the mean QTc-values at baseline (425.7±31.7ms) and follow-up (428.0±30.7ms) was found (p=0.328). However, 26 patients (14.6%) did develop a prolonged QTc-interval (≥450(♂)/470(♀)ms) of whom 25 with a RISQ-PATH score ≥10. This score had a sensitivity of 96.2% (95% CI 78.4-99.8%) and a negative predictive value of 98.0% (95% CI 88.2-99.9%). Conclusion This RISQ-PATH score is able to rule out low-risk patients with a negative predictive value of 98.0% and is promising to exclude patients from further follow-up when starting QTc-prolonging drugs. Clinicaltrials.gov Registration Number: NCT02068170.

Methadone and Corrected QT Prolongation in Pain and Palliative Care Patients: A Case-Control Study.

Methadone (ME) is commonly used in pain and palliative care (PPC) patients with refractory pain or intolerable opioid adverse effects (AEs). A unique ME AE is its corrected QT (QTc) interval prolongation risk, but most evidence exists in methadone maintenance therapy patients. Our goal was to identify QTc interval prolongation risk factors in PPC patients receiving ME and other medications known to prolong the QTc interval and develop a risk stratification tool. We performed a case-control study of adult inpatients receiving ME for pain management. Settings/Subjects: Adult inpatients receiving ME with a QTc >470 msec (males) and >480 msec (females) were matched 1:2 according to age, history of QTc prolongation, and gender with ME patients who did not have a prolonged QTc interval. QTc prolongation risk factors were collected for both groups. Covariates were analyzed using conditional logistic regression. Classification and regression tree analysis was used to identify the ME dose associated with QTc prolongation. Predictors of QTc prolongation included congestive heart failure (CHF) (OR: 11.9; 95% CI: 3.7-38.2; p < 0.00), peptic ulcer disease (PUD) (odds ratio [OR]: 8.3; 95% confidence interval [95% CI]: 2.4-28.9; p < 0.00), hypokalemia (OR: 6.5; 95% CI: 1.5-28.2; p < 0.01), rheumatologic diseases (OR: 4.7; 95% CI: 1.6-13.9; p < 0.00), taking medications with a known torsades de pointes (TdP) risk (OR: 4.4; 95% CI: 1.8-10.7; p < 0.01), malignancy (OR: 3.3; 95% CI: 1.2-9.3; p < 0.03), hypocalcemia (OR: 2.1; 95% CI: 0.9-4.8; p < 0.07), and ME doses >45 mg per day (OR: 1.9; 95% CI: 0.8-4.8; p < 0.16). Mild liver disease was protective against QTc prolongation (OR: 0.05; 95% CI: 0.0-0.46; p < 0.01). Predictors of QTc prolongation in our multivariate conditional logistic regression model included CHF, PUD, hypokalemia, rheumatologic disorders, use of medications with a known TdP risk, malignancy, hypocalcemia, and ME doses >45 mg per day.