Added value of patient- and drug-related factors to stratify drug-drug interaction alerts for risk of QT prolongation: Development and validation of a risk prediction model.

AIMS: Many clinical decision support systems trigger warning alerts for drug-drug interactions potentially leading to QT prolongation and torsades de pointes (QT-DDIs). Unfortunately, there is overalerting and underalerting because stratification is only based on a fixed QT-DDI severity level. We aimed to improve QT-DDI alerting by developing and validating a risk prediction model considering patient- and drug-related factors. METHODS: We fitted 31 predictor candidates to a stepwise linear regression for 1000 bootstrap samples and selected the predictors present in 95% of the 1000 models. A final linear regression model with those variables was fitted on the original development sample (350 QT-DDIs). This model was validated on an external dataset (143 QT-DDIs). Both true QTc and predicted QTc were stratified into three risk levels (low, moderate and high). Stratification of QT-DDIs could be appropriate (predicted risk = true risk), acceptable (one risk level difference) or inappropriate (two risk levels difference). RESULTS: The final model included 11 predictors with the three most important being use of antiarrhythmics, age and baseline QTc. Comparing current practice to the prediction model, appropriate stratification increased significantly from 37% to 54% appropriate QT-DDIs (increase of 17.5% on average [95% CI +5.4% to +29.6%], padj = 0.006) and inappropriate stratification decreased significantly from 13% to 1% inappropriate QT-DDIs (decrease of 11.2% on average [95% CI -17.7% to -4.7%], padj ≤ 0.001). CONCLUSION: The prediction model including patient- and drug-related factors outperformed QT alerting based on QT-DDI severity alone and therefore is a promising strategy to improve DDI alerting.

Clinician Satisfaction With Advanced Clinical Decision Support to Reduce the Risk of Torsades de Pointes.

OBJECTIVES: Clinical decision support (CDS) can potentially help clinicians identify and manage patients who are at risk for torsades de pointes (TdP). However, computer alerts are often ignored and might contribute to alert fatigue. The goals of this project were to create an advanced TdP CDS advisory that presents patient-specific, relevant information, including 1-click management options, and to determine clinician satisfaction with the CDS. METHODS: The advanced TdP CDS was developed and implemented across a health system comprising 29 hospitals. The advisory presents patient-specific information including relevant risk factors, laboratory values, and 1-click options to help manage the condition in high-risk patients. A short electronic survey was created to gather clinician feedback on the advisory. RESULTS: After implementation, an email invitation to complete the anonymous advisory-related survey was sent to 442 clinicians who received the advisory. Among the 38 respondents, feedback was generally positive, with 79% of respondents reporting that the advisory helps them care for their patients and 87% responding that alternative actions for them to consider were clearly specified. However, 46% of respondents indicated the alert appeared too frequently. CONCLUSIONS: Advanced TdP risk CDS that provides relevant, patient-specific information and 1-click management options can be generally viewed favorably by clinicians who receive the advisory.

Walk the Line-The Importance of Well-Informed Interpretation of QT Prolongation.

Acute care pharmacists play an integral role in identifying drug-drug interactions that may predispose patients to QT prolongation. Although most pharmacists are equipped with a baseline understanding of drug interactions and the risks of QTc prolongation, few understand the limitations of QTc calculation and interpretation. In this commentary, we put forth the notion that at times health care providers, including pharmacists, place an overemphasis on the QTc interval. In the context of using the QTc to guide pharmacotherapy decisions, unintended consequences may include a cascade of effects leading to delays in treatment, suboptimal medication selection, alert fatigue, and overutilization of resources.

Managing drug-induced QT prolongation in clinical practice.

Many drug therapies are associated with prolongation of the QT interval. This may increase the risk of Torsades de Pointes (TdP), a potentially life-threatening cardiac arrhythmia. As the QT interval varies with a change in heart rate, various formulae can adjust for this, producing a 'corrected QT' (QTc) value. Normal QTc intervals are typically <450 ms for men and <460 ms for women. For every 10 ms increase, there is a ~5% increase in the risk of arrhythmic events. When prescribing drugs associated with QT prolongation, three key factors should be considered: patient-related risk factors (eg, female sex, age >65 years, uncorrected electrolyte disturbances); the potential risk and degree of QT prolongation associated with the proposed drug; and co-prescribed medicines that could increase the risk of QT prolongation. To support clinicians, who are likely to prescribe such medicines in their daily practice, we developed a simple algorithm to help guide clinical management in patients who are at risk of QT prolongation/TdP, those exposed to QT-prolonging medication or have QT prolongation.

QT Interval Prolongation Under Hydroxychloroquine/Azithromycin Association for Inpatients With SARS-CoV-2 Lower Respiratory Tract Infection.

Association between Hydroxychloroquine (HCQ) and Azithromycin (AZT) is under evaluation for patients with lower respiratory tract infection (LRTI) caused by the Severe Acute Respiratory Syndrome (SARS-CoV-2). Both drugs have a known torsadogenic potential, but sparse data are available concerning QT prolongation induced by this association. Our objective was to assess for COVID-19 LRTI variations of QT interval under HCQ/AZT in patients hospitalized, and to compare manual versus automated QT measurements. Before therapy initiation, a baseline 12 lead-ECG was electronically sent to our cardiology department for automated and manual QT analysis (Bazett and Fridericia's correction), repeated 2 days after initiation. According to our institutional protocol (Pasteur University Hospital), HCQ/AZT was initiated only if baseline QTc ≤ 480ms and potassium level> 4.0 mmol/L. From March 24th to April 20th 2020, 73 patients were included (mean age 62 ± 14 years, male 67%). Two patients out of 73 (2.7%) were not eligible for drug initiation (QTc ≥ 500 ms). Baseline average automated QTc was 415 ± 29 ms and lengthened to 438 ± 40 ms after 48 hours of combined therapy. The treatment had to be stopped because of significant QTc prolongation in two out of 71 patients (2.8%). No drug-induced life-threatening arrhythmia, nor death was observed. Automated QTc measurements revealed accurate in comparison with manual QTc measurements. In this specific population of inpatients with COVID-19 LRTI, HCQ/AZT could not be initiated or had to be interrupted in less than 6% of the cases.

Drug-induced proarrhythmia: Discussion and considerations for clinical practice.

Clinical practice includes contributions from physicians, pharmacists, NPs, and physician assistants. Drug safety considerations are of considerable importance. This article discusses drug-induced proarrhythmia, with a specific focus on torsades de pointes, a polymorphic ventricular tachycardia that typically occurs in self-limiting bursts that can lead to dizziness, palpitations, syncope, and seizures, but on rare occasions can progress to ventricular fibrillation and sudden cardiac death. A dedicated clinical pharmacology study conducted during a drug's clinical development program has assessed its propensity to induce torsades using prolongation of the QT interval as seen on the ECG as a biomarker.Identification of QT-interval prolongation does not necessarily prevent a drug from receiving marketing approval if its overall benefit-risk balance is favorable, but, if approved, a warning is placed in its prescribing information. This article explains why drugs can have a proarrhythmic propensity.

Relationship of clinical adverse event reports to models of arrhythmia risk.

A vital aspect of the drug discovery and development process is the identification and filtering of drugs with high risk of dangerous adverse events. Torsade de Pointes (TdP) is one example of an adverse event that requires thorough in vitro and in vivo drug screening. This is because TdP, a tachycardic ventricular arrhythmia, can develop into fatal cardiac events if left unresolved and has been missed during drug development with profound consequences. These factors led to the development of pre-clinical screening guidelines based on the presence of drug induced QT prolongation (QTp), which has been linked to TdP. These guidelines have high sensitivity, but low specificity, as they tend to predict QTp, which precedes TdP events but does not always lead to TdP. Computational models have the potential to improve these prediction methods by bridging the gaps between preclinical and clinical data. This study proposes the use of adverse event reports obtained from the FDA Adverse Event Reporting System as a representation of clinical TdP risk. By incorporating these reports into computational models, a more accurate risk prediction may be developed.

Long-term proarrhythmic pharmacotherapy among patients with congenital long QT syndrome and risk of arrhythmia and mortality.

AIMS: It is Class I recommendation that congenital long QT syndrome (cLQTS) patients should avoid drugs that can cause torsades de pointes (TdP). We determined use of TdP risk drugs after cLQTS diagnosis and associated risk of ventricular arrhythmia and all-cause mortality. METHODS AND RESULTS: Congenital long QT syndrome patients (1995-2015) were identified from four inherited cardiac disease clinics in Denmark. Individual-level linkage of nation-wide registries was performed to determine TdP risk drugs usage (www.crediblemeds.org) and associated risk of ventricular arrhythmias and all-cause mortality. Risk analyses were performed using Cox-hazards analyses. During follow-up, 167/279 (60%) cLQTS patients were treated with a TdP risk drug after diagnosis. Most common TdP risk drugs were antibiotics (34.1%), proton-pump inhibitors (15.0%), antidepressants (12.0%), and antifungals (10.2%). Treatment with a TdP risk drug decreased 1 year after diagnosis compared with 1 year before (28.4% and 23.2%, respectively, P < 0.001). Five years after diagnosis, 33.5% were in treatment (P < 0.001). Risk factors for TdP risk drug treatment were age at diagnosis (5-year increment) [hazard ratio (HR) = 1.07, confidence interval (CI) 1.03-1.11] and previous TdP risk drug treatment (HR = 2.57, CI 1.83-3.61). During follow-up, nine patients were admitted with ventricular arrhythmia (three were in treatment with a TdP risk drug). Eight patients died (four were in treatment with a TdP risk drug). No significant association between TdP risk drug use and ventricular arrhythmias or all-cause mortality was found (P = 0.53 and P = 0.93, respectively), but events were few. CONCLUSION: Torsades de pointes risk drug usage was common among cLQTS patients after time of diagnosis and increased over time. A critical need for more awareness in prescribing patterns for this high-risk patient group is needed.

Progesterone pretreatment reduces the incidence of drug-induced torsades de pointes in atrioventricular node-ablated isolated perfused rabbit hearts.

INTRODUCTION: Higher progesterone concentrations are protective against drug-induced prolongation of ventricular repolarization. We tested the hypothesis that pretreatment with progesterone reduces the incidence of drug-induced torsades de pointes (TdP). METHODS AND RESULTS: Female New Zealand white rabbits (2.5-3.2 kg) underwent ovariectomy and were randomized to undergo implantation with subcutaneous 21-day sustained release pellets containing progesterone 50 mg (n = 22) or placebo (n = 23). After 20 days, hearts were excised, mounted, and perfused with modified Krebs-Henseleit solution. The atrioventricular (AV) node was destroyed manually. Following a 15-minute equilibration period, hearts were perfused with dofetilide 100 nM for 30 minutes, during which the electrocardiogram was recorded continuously. Incidences of spontaneous TdP, other ventricular arrhythmias and mean QTc intervals were compared. Median serum progesterone concentrations were higher in progesterone vs placebo-treated rabbits (3.8 [range, 2.8-5.1] vs 0.7 [0.4-1.7] ng/mL, P < 0.0001). Median serum estradiol concentrations were similar (58 [22-72] vs 53 [34-62] pg/mL), P = 0.79). The incidence of TdP was lower in hearts from progesterone-treated rabbits (27% vs 61%, P = 0.049). The incidences of bigeminy (36% vs 74%, P = 0.03) and trigeminy (18% vs 57%, P = 0.01) were also lower in hearts from progesterone-treated rabbits. There was no significant difference between groups in incidence of couplets (59% vs 74%, P = 0.54) or monomorphic ventricular tachycardia (14% vs 30%, P = 0.28). Maximum QT c interval and short-term beat-to-beat QT interval variability during dofetilide perfusion were significantly shorter in hearts from progesterone-treated rabbits. CONCLUSIONS: Pretreatment with progesterone reduces the incidence of drug-induced TdP, bigeminy, and trigeminy in isolated perfused AV node-ablated rabbit hearts.

Machine-Learning Prediction of Drug-Induced Cardiac Arrhythmia: Analysis of Gene Expression and Clustering.

A marked delay in the electrical repolarization of heart ventricles is characterized by prolongation of the Q-T wave (QT) interval on a surface electrocardiogram. Such a delay can lead to potentially life-threatening cardiac arrhythmia (torsades de pointes). Such prolongation is also a widely accepted cardiac safety biomarker in drug development. Current preclinical drug-safety assays include patch clamp analysis to evaluate drug-related blockade of cardiac repolarizing ion currents. Recently reported patch clamp assay results have shown predictive sensitivities and specificities in the ranges of 64%-82% and 75%-88%, respectively. In this project, we use a support vector machine classifier to find mean sensitivities and specificities of 85% and 90%, respectively, across 77 drug subclassifications. Clustering by gene expression profile similarities shows that drugs known to prolong the QT interval do not always form distinct groups, but the number of groups is limited. The most common biological network links associated with these groups involve genes linked with fatty acid metabolism, G proteins, intracellular glutathione, immune responses, apoptosis, mitochondrial function, electron transport, and mitogen-activated protein kinases. These results suggest that machine-learning analysis of gene expression and clustering may augment cardiac safety predictions for improving drug-safety assessments.

Domperidone for insufficient lactation in England 2002-2015: A drug utilization study with interrupted time series analysis.

PURPOSE: Our aim was to describe trends in the prescription of domperidone for insufficient lactation in England, the characteristics of women prescribed it postpartum, and the impact of a 2014 European Medicines Agency (EMA) recommendation to restrict its use due to a potential increased risk of sudden cardiac death associated with its use. METHODS: We conducted a population-based cohort study with interrupted time series analysis using data from the Clinical Practice Research Datalink linked to Hospital Episode Statistics. We identified women with live births from 2002 to 2015, excluding those with nonlactation indications for domperidone (n = 247 349). We evaluated trends in the prescription rate of domperidone in the 6 months postpartum and differences in this rate before and after the EMA recommendation. RESULTS: Domperidone was prescribed among 1438 deliveries at a rate of 1.24 per 100 person-years. This rate increased from 0.56 to 2.1 per 100 person-years between 2002-2004 and 2011-2013 (rate ratio: 3.8; 95% confidence interval [CI], 3.2-4.6). Prescribing decreased in level by 0.35 (95% CI, -0.86 to 0.16) per 100 person-years immediately following the recommendation with little change in trend (0.003; 95% CI, -0.059 to 0.065 per 100 person-years). Following the recommendation, prescription of doses >30 mg and coprescription of drugs with a risk of torsade de pointes decreased. No arrhythmic events were observed among domperidone users. CONCLUSIONS: Although we observed an important increase in prescribing during the study period, domperidone remains infrequently prescribed postpartum in England. While overall prescribing changed little, some prescribing practices became more restricted following the EMA's recommendation.

Paradoxical Effects of Sodium-Calcium Exchanger Inhibition on Torsade de Pointes and Early Afterdepolarization in a Heart Failure Rabbit Model.

Calcium homeostasis plays an important role in development of early afterdepolarizations (EADs) and torsade de pointes (TdP). The role of sodium-calcium exchanger (NCX) inhibition in genesis of secondary Ca rise and EAD-TdP is still debated. Dual voltage and intracellular Ca optical mapping were conducted in 6 control and 9 failing rabbit hearts. After baseline electrophysiological and optical mapping studies, E4031 was given to simulate long QT syndrome. ORM-10103 was then administrated to examine the electrophysiological effects on EAD-TdP development. E4031 enhanced secondary Ca rise, EADs development, and TdP inducibility in both control and failing hearts. The results showed that ORM-10103 reduced premature ventricular beats but was unable to suppress the inducibility of TdP or EADs. The electrophysiological effects of ORM-10103 included prolongation of action potential duration (APD) and increased APD heterogeneity in failing hearts. ORM-10103 had a neutral effect on the amplitude of secondary Cai rise in control and heart failure groups. In this model, most EADs generated from long-short APD junction area. In conclusion, highly selective NCX inhibition with ORM-10103 reduced premature ventricular beat burden but was unable to suppress secondary Ca rise, EADs development, or inducibility of TdP. The possible electrophysiological mechanisms include APD prolongation and increased APD heterogeneity.

Ryanodine-receptor inhibition by dantrolene effectively suppresses ventricular arrhythmias in an ex vivo model of long-QT syndrome.

AIMS: A significant antiarrhythmic potential of ryanodine receptor inhibition was reported in experimental studies. The aim of the present study was to assess potential antiarrhythmic effects of dantrolene in an experimental whole-heart model of drug-induced long-QT syndrome (LQTS). METHODS: In 12 isolated rabbit hearts, long-QT-2-syndrome was simulated by infusion of erythromycin (300 µM). Twelve rabbit hearts were treated with veratridine (0.5 µM) to mimic long-QT-3-syndrome. RESULTS: Monophasic action potentials and ECG showed a significant prolongation of QT-interval (+71 ms, P < 0.01) and action potential duration (APD, +43 ms, P < 0.01) after infusion of erythromycin as compared with baseline. Similar results were obtained in veratridine-treated hearts (QT-interval: +43 ms, P < 0.01; APD: +36 ms, P < 0.01). Both erythromycin (+36 ms, P < 0.05) and veratridine (+38 ms) significantly increased dispersion of repolarization. Additional infusion of dantrolene (20 µM) did not significantly alter QT-interval and APD but resulted in a significant reduction of dispersion of repolarization (erythromycin group: -33 ms, P < 0.05; veratridine group: -29 ms, P < 0.05). Lowering of potassium concentration resulted in the occurrence of early afterdepolarizations (EAD) and polymorphic ventricular tachycardia (VT) in 9 of 12 erythromycin-treated hearts (175 episodes) and 8 of 12 veratridine-treated hearts (66 episodes). Additional infusion of dantrolene significantly reduced occurrence of polymorphic VT and resulted in occurrence of EAD and polymorphic VT in 1 of 12 erythromycin-treated hearts (18 episodes) and 1 of 12 veratridine-treated hearts (3 episodes). CONCLUSION: Inhibition of the ryanodine receptor by dantrolene significantly reduced occurrence of polymorphic VT in drug-induced LQTS. A significant reduction of spatial dispersion of repolarization represents a major antiarrhythmic mechanism. These results imply that dantrolene may represent a promising antiarrhythmic option in drug-induced LQTS.

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

PURPOSE/BACKGROUND: 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. METHODS: 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. RESULTS: 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). IMPLICATIONS/CONCLUSIONS: 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.