QT-prolonging Medications Research Articles

QTc prolongation during antiviral therapy in two COVID‐19 patients

What is known and objectiveAcquired long QT syndrome secondary to drug‐induced QT prolongation and torsades de pointes has been reported for antiviral drugs. However, no studies have reported an association between corrected QT (QTc) prolongation and antiviral therapy in patients with novel coronavirus disease (COVID‐19).Case descriptionWe present two cases from our institution in which patients with COVID‐19 experienced QTc prolongation during treatment with antiviral therapy. Lopinavir/ritonavir, together with gender and drug‐drug interactions, may have contributed to the induction of QTc prolongation in those patients.What is new and conclusionCo‐administration of QT‐prolonging medications and drugs interfering with the metabolism of those medications must be considered in patients with COVID‐19. Careful analysis of electrocardiograms for QTc duration should be performed at baseline and during antiviral therapy to identify individuals at high risk of arrhythmias.

Incidence and determinants of QT interval prolongation in COVID-19 patients treated with hydroxychloroquine and azithromycin.

Combined use of hydroxychloroquine and azithromycin was globally adopted, in part due to paucity and high cost of alternative therapies. However the utility of these medications has been questioned; and thus safety becomes a major concern given clinical equipoise regarding efficacy. Both hydroxychloroquine and azithromycin continue to be administered in US clinical trials examining their potential role in prevention of infection, treatment of mild infection in ambulatory patients, and in combination with other medical regimens in treatment of patients with severe disease. These drugs also continue to be clinically utilized in hospitalized patients around the globe, often without continuous telemetry due to lack of resources. Concern regarding use of hydroxychloroquine without adequate rhythm monitoring in clinical trials has been recently expressed.1 A review of clinicaltrials.gov at the time of submission of this correspondence reveals actively recruiting trials of combined hydroxychloroquine/azithromycin with or without additional COVID-19 therapies, for both ambulatory and hospitalized patients within and outside the US. The potential for hydroxychloroquine and azithromycin to cause QT prolongation is counterbalanced by very low risk of pro-arrhythmia in the general population, and emerging evidence of relatively low risk of Torsades de Pointes (TdP) in COVID-19 patients.2,3,4,5 Thus delineation of the determinants of significant QTc prolongation and pro-arrhythmic risk for hydroxychloroquine/azithromycin is very important, especially given mounting evidence of inefficacy in COVID-19 treatment.

Androgen Deprivation Therapy for Prostatic Cancer in Patients With Torsades de Pointes.

BackgroundMen normally have shorter heart rate-corrected QT interval (QTc) than women, at least in part due to accelerating effects of testosterone on ventricular repolarization. Accumulating data suggest that androgen-deprivation therapy (ADT) used for the treatment of prostatic cancer, may increase Torsades de Pointes (TdP) risk by prolonging QTc. However, the evidence for such an association is currently limited to few case reports, in most cases deriving from the analysis of uncontrolled sources such as pharmacovigilance databases.ObjectiveTo better determine the clinical impact of ADT on TdP development, we examined the prevalence of this therapy in a consecutive cohort of 66 TdP patients, prospectively collected over a ~10 years period.Methods and ResultsWe found and described four patients who were under ADT for prostatic cancer when TdP occurred, and in two cases degenerated to cardiac arrest. Notably, in this unselected population, ADTs unexpectedly represented the second most frequently administered QT-prolonging medication in males (4/24, 17%), after amiodarone. Moreover, in the ADT patients, a blood withdrawal was performed within 24 h from TdP/marked QTc prolongation occurrence and circulating concentration of androgens and gonadothropins were measured. As expected, all cases showed markedly reduced testosterone levels (total, free, and available).ConclusionWe provide evidence that a significant proportion of patients developing TdP were under treatment with ADT for prostatic cancer, thus confirming the clinical relevance of previous pharmacovigilance signals. An accurate assessment of the arrhythmic risk profile should be included in the standard of care of prostatic cancer patients before starting ADT.

Enhanced electrocardiographic monitoring of patients with Coronavirus Disease 2019

BackgroundMany of the drugs being used in the treatment of the ongoing pandemic coronavirus disease 2019 (COVID-19) are associated with QT prolongation. Expert guidance supports electrocardiographic (ECG) monitoring to optimize patient safety.ObjectiveThe purpose of this study was to establish an enhanced process for ECG monitoring of patients being treated for COVID-19.MethodsWe created a Situation Background Assessment Recommendation tool identifying the indication for ECGs in patients with COVID-19 and tagged these ECGs to ensure prompt over reading and identification of those with QT prolongation (corrected QT interval > 470 ms for QRS duration ≤ 120 ms; corrected QT interval > 500 ms for QRS duration > 120 ms). This triggered a phone call from the electrophysiology service to the primary team to provide management guidance and a formal consultation if requested.ResultsDuring a 2-week period, we reviewed 2006 ECGs, corresponding to 524 unique patients, of whom 103 (19.7%) met the Situation Background Assessment Recommendation tool–defined criteria for QT prolongation. Compared with those without QT prolongation, these patients were more often in the intensive care unit (60 [58.3%] vs 149 [35.4%]) and more likely to be intubated (32 [31.1%] vs 76 [18.1%]). Fifty patients with QT prolongation (48.5%) had electrolyte abnormalities, 98 (95.1%) were on COVID-19–related QT-prolonging medications, and 62 (60.2%) were on 1–4 additional non-COVID-19–related QT-prolonging drugs. Electrophysiology recommendations were given to limit modifiable risk factors. No patient developed torsades de pointes.ConclusionThis process functioned efficiently, identified a high percentage of patients with QT prolongation, and led to relevant interventions. Arrhythmias were rare. No patient developed torsades de pointes.

Chloroquine-induced torsades de pointes in a patient with coronavirus disease 2019

Chloroquine-induced torsades de pointes in a patient with coronavirus disease 2019

Association of QT-Prolonging Medications With Risk of Autopsy-Defined Causes of Sudden Death

QT-prolonging medications (QTPMs) are a reported risk factor for sudden cardiac death (SCD) when defined by consensus criteria that presume an arrhythmic cause. The effect of QTPM on autopsy-defined sudden arrhythmic death (SAD) is unknown. To evaluate the association between QTPM and autopsy-defined SAD vs nonarrhythmic cause of sudden death. This prospective countywide case-control study included World Health Organization-defined (presumed) SCD cases who underwent autopsy as part of the San Francisco Postmortem Systematic Investigation of Sudden Cardiac Death Study (POST SCD) to determine arrhythmic or nonarrhythmic cause, and control deaths due to trauma (hereinafter referred to as trauma controls) in San Francisco County, California, from February 1, 2011, to March 1, 2014. Multivariate regression was used to evaluate the association of QTPM with the risk of presumed SCD, autopsy-defined SAD, and non-SAD compared with trauma controls. Medication exposure, determined by prescription lists and postmortem toxicologic findings, was used to calculate a summative QTPM exposure score (range, 0-20). Data were analyzed from September 1, 2018, to June 15, 2019. QT-prolonging medication exposure, as measured by QTPM score (1 indicated low; 2-4, moderate; and >4, high). Death due to trauma, presumed SCD, and autopsy-defined non-SAD and SAD with no postmortem findings of extracardiac cause. A total of 629 patients (mean [SD] age, 61.4 [15.7] years; 439 men [69.8%]) were included, 525 with presumed SCDs and 104 traumatic death controls. Individuals with presumed SCDs had higher exposure and were more likely to be taking any QTPM (291 [55.4%] vs 28 [26.9%]; P < .001) than trauma controls. Use of QTPMs was associated with increased risk of presumed SCD in low (odds ratio [OR], 2.25 [95% CI, 1.03-4.96]; P = .04) and high (OR, 6.70 [95% CI, 1.47-30.67]; P = .01) exposure groups. After autopsy adjudication, use of QTPMs was associated with increased risk of non-SAD (low-risk OR, 2.88 [95% CI, 1.18-6.99; P = .02]; moderate-risk OR, 2.62 [95% CI, 1.20-5.73; P = .02]; and high-risk OR, 14.22 [95% CI, 2.91-69.30; P = .001]) but not SAD in all exposure groups. This association was attenuated by the exclusion of occult overdose non-SADs in the highest exposure group. These findings confirm the association between QTPMs and presumed SCD; however, after autopsy, this risk was specific for nonarrhythmic causes of sudden death. Studies using consensus SCD criteria may overestimate the association of QTPMs with the risk of SAD.

Electrocardiographic features at rest and during exercise in young adults born preterm below 30 weeks of gestation.

Preterm birth has adverse consequences on the cardiovascular system. Whether premature birth is associated with conduction and repolarisation abnormalities past childhood and into adulthood still needs to be demonstrated. We analyzed the ECG of young adults (23.9 ± 3.1 years) born term (≥37 weeks, n = 53) and preterm (<30 weeks, n = 49) at rest, peak exercise and 3 min into recovery during an exercise test on a cycle ergometer. We measured PR, QRS and QT intervals, calculated the corrected QT (QTc), and determined blood calcium, magnesium, potassium and fasting glucose. Mean gestational age was 39.7 ± 1.1 and 27.3 ± 1.3 weeks for the term and the preterm groups, respectively. Apart from an increased heart rate at rest in individuals born preterm, no significant difference was found between both groups for any other ECG parameters at rest. None of the participants had a severely prolonged QTc (>500 ms) at rest; exercise revealed severely prolonged QTc in two participants including one in the preterm group. The use of QT-prolonging medications did not influence ECG parameters in either groups. We observed no significant difference in electrocardiographic measurements between young adults born preterm and term. Current results do not support avoidance of QT-prolonging medications in individuals born preterm. Preterm birth is associated with adverse cardiovascular consequences in early adulthood, but controversial evidence exists regarding differences in electrocardiographic features between young individuals born term and preterm.This study aims to assess the differences in electrocardiographic features between young adults born term and preterm, at rest and during exercise training.In contrast with previously published data, we observed no significant difference in electrocardiographic measurements between young adults born preterm and term.Our study does not support that preterm birth itself exposes young adults to a higher risk of QT prolongation.Current results do not support avoidance of QT-prolonging medications in individuals born preterm.

QTc Prolongation and Risk of Torsades de Pointes in Hospitalized Pediatric Oncology Patients

To evaluate the prevalence of torsades de pointes and to identify risk factors associated with QTc prolongation of ≥500milliseconds in hospitalized pediatric oncology patients. A QTc prolongation of ≥500milliseconds is associated with higher mortality in hospitalized adults but has not been demonstrated in pediatrics. A single-center, retrospective review of all hospitalized oncology patients ≤21years of age was performed from 2014 to 2016. Patients with long/short QT syndrome or a QRS interval of ≥120ms were excluded. Rapid response events were reviewed to determine the prevalence of torsades. In patients with ECGs for review, data were compared between patients with a QTc of <500 and≥500ms via logistic regression. There were 1934 hospitalized patients included. Rapid response events occurred in 90 patients (4.7%) with 2 torsades events (0.1%). There were 1412 electrocardiograms performed in 287 unique patients (10.6±6.3years of age; 43% female). The mean QTc was 448±31ms; 25 patients (8.7%) had ≥1 ECG with a QTc of ≥500ms. The prevalence of torsades was greater in patients with a QTc of ≥500ms (8% vs 0%; P<.01). In multivariate analysis, factors associated with a QTc of ≥500ms included female sex, (OR 2.95) and ≥2 QT-prolonging medications (OR, 2.95). The prevalence of torsades in hospitalized pediatric oncology patients was low (0.1%), although the risk was significantly greater in patients with a QTc of ≥500ms. Routine monitoring of electrocardiograms and electrolytes is essential in patients with risk factors predisposing to QTc prolongation.

Prevalence and risk factors of prolonged QT interval and electrocardiographic abnormalities in persons living with HIV.

Abnormal ECGs are associated with increased risk of arrhythmias and sudden cardiac death. We aimed to investigate the prevalence and associated risk factors of prolonged QTc and major ECG abnormalities, in persons living with HIV (PLWH) and uninfected controls. PLWH aged at least 40 years were recruited from the Copenhagen comorbidity in HIV infection (COCOMO) study and matched on sex and age to uninfected controls from the Copenhagen General Population Study. ECGs were categorized according to Minnesota Code Manual of ECG Findings definition of major abnormalities. A QT interval corrected for heart rate (QTc) greater than 440 ms in men and greater than 460 ms in women was considered prolonged. Pathologic Q-waves were defined as presence of major Q-wave abnormalities. ECGs were available for 745 PLWH and 2977 controls. Prolonged QTc was prevalent in 9% of PLWH and 6% of controls, P = 0.052. Pathologic Q-waves were more common in PLWH (6%) than in controls (4%), P = 0.028. There was no difference in prevalence of major ECG abnormalities between PLWH and controls, P = 0.987.In adjusted analyses, HIV was associated with a 3.6 ms (1.8-5.4) longer QTc interval, P < 0.001, and HIV was independently associated with prolonged QTc [adjusted odds ratio: 1.59 (1.14-2.19)], P = 0.005. HIV was borderline associated to pathologic Q-waves after adjusting, P = 0.051. HIV was associated with higher odds ratio of prolonged QTc after adjustment for cardiovascular risk factors, but analyses were not adjusted for QT-prolonging medication. Although evidence indicated more pathologic Q-waves in PLWH, the risk seemed to be associated mainly with an adverse risk profile.

Identification of Risk of QT Prolongation by Pharmacists When Conducting Medication Reviews in Residential Aged Care Settings: A Missed Opportunity?

QT interval prolongation is associated with torsade de pointes and sudden cardiac death. QT prolongation can be caused by many drugs that are commonly prescribed in elderly residential aged care populations. The aim of this study was to investigate the prevalence of use of QT-prolonging drugs and to identify interventions made by pharmacists to reduce the risk of QT prolongation when conducting medication reviews in aged care. A retrospective analysis of 400 medication reviews undertaken by Australian pharmacists in aged care settings was conducted. The assessment included the risk of QT prolongation due to prescribed medications and other risk factors and the recommendations made by pharmacists to reduce the risk of QT prolongation. There was a high prevalence of the use of QT-prolonging medication, with 23% of residents (92 out of 400) taking at least one medication with a known risk of QT prolongation. Amongst the 945 prescribed drugs with any risk of QT prolongation, antipsychotics were the most common (n = 246, 26%), followed by antidepressants (19%) and proton pump inhibitors (13%). There appeared to be low awareness amongst the pharmacists regarding the risk of QT prolongation with drugs. Out of 400 reviews, 66 residents were categorised as high risk and were taking at least one medication associated with QT prolongation; yet pharmacists intervened in only six instances (9%), mostly when two QT-prolonging medications were prescribed. There is a need to increase awareness amongst pharmacists conducting medication reviews regarding the risk factors associated with QT prolongation, and further education is generally needed in this area.

1222 Co-Prescription of Ondansetron With Other QT-Prolonging Drugs: Data From a Large Community-Based Hospital System

INTRODUCTION: The Food and Drug Administration (FDA) has warned about the co-prescription of ondansetron with other QT-prolonging medications. Electronic medical records (EMR) with built-in warning systems for drug-drug interactions (DDIs) are designed to improve patient safety. However, overriding of warnings are common. Response to warnings for potentially life-threatening DDIs such as QT-prolongation has not been fully investigated. We studied outpatient co-prescription of ondansetron with other QT-prolonging medications in a large community-based health practice. METHODS: Data for all outpatient prescriptions for oral ondansetron from January 1 to March 31st, 2016 at NorthShore University HealthSystem was reviewed. A de-identified dataset was developed that included all outpatient prescriptions for oral ondansetron in patients receiving another QT-prolonging drug. Duplicate orders were removed. Interaction warnings, including the severity of the interactions are generated at the time of order placement. Prescriber response to DDI warnings and further analysis of the co-prescribed QT-prolonging drugs was performed. Demographic information was also studied. RESULTS: 11,935 cases of inpatient and outpatient co-prescriptions of ondansetron with and one or more QT-prolonging drug occurred during the study period. After filtering, there were 884 outpatient ondansetron and QT-prolonging co-prescription orders in 723 patients. All warnings were “severe interactions”. Only 93 (10.5%) prescriptions in outpatients were canceled, while 791 (89.5%) of the prescription orders were overridden. The most common classes of QT-prolonging medications taken by patients with overridden orders for ondansetron were selective serotonin reuptake inhibitors (SSRIs) (33%), macrolide antibiotics (29%), fluoroquinolone antibiotics (13%), and serotonin antagonist reuptake inhibitors (SARIs) (11%) (See Table 1). The most commonly co-prescribed QT prolonging drugs are listed in Table 2. Twelve patients receiving QT-prolonging antiarrhythmic agents had completed orders for ondansetron. 617 (78%) of overridden prescriptions occurred in women. CONCLUSION: Warnings for ondansetron co-prescription with other QT-prolonging drugs are usually ignored. Co-prescription of ondansetron with other QT-prolonging drugs is more common in female patients. This is of particular concern because women are more likely to develop serious arrhythmias related to ondansetron-induced QT-prolongation.

The incidence, predictors and outcomes of QTc prolongation in critically ill patients

PurposeTo study the incidence, predictors and outcomes of QTc prolongation (≥500 ms) during ICU admission. MethodsProspective observational study of patients admitted to a tertiary ICU during a two-month period. We obtained daily data on QTc intervals and arrhythmias from ICU monitors. We performed univariate and multivariable analyses to compare patients who did or did not experience QTc prolongation. ResultsOf the 257 patients, 93 (36.2%) developed ≥1 episode of QTc ≥500 ms. Such patients had higher APACHE II scores (p < .001), received more QT-prolonging medications (p = .002), and more frequently developed non-sustained (<8 beats, p = .007) and sustained ventricular tachycardia (≥8 beats; p < .001). However, after adjustment for confounders, there was no independent association between QTc duration and odds of ventricular tachyarrhythmia (OR = 0.921 [0.593–1.431], p = .715). Moreover, 98% of ventricular tachyarrhythmias resolved spontaneously. Patients with QTc prolongation had longer ICU (p < .001) and hospital length-of-stay (p = .002), and greater ICU (p = .030) and in-hospital mortality (p = .015). No patient experienced sustained Torsades de Pointes or died from ventricular arrhythmia. ConclusionsA QTc ≥500 ms likely represents a marker of illness severity modulated by several risk factors, and carries no independent association with clinically-significant ventricular tachyarrhythmias. Thus, cessation of QT-prolonging medications to prevent arrhythmias may lack clinical benefit.

Top New Drug Approvals of 2018

Top New Drug Approvals of 2018

Cochlear implantation in children with congenital long QT syndrome: Introduction of an evidence-based pathway of care

Congenital long QT syndrome (cLQTS) is an inherited cardiac ion channelopathy characterized by a long corrected-QT interval on the ECG, associated with a risk of syncope and sudden death as a result of arrhythmias. The archetypal arrhythmia associated with cLQTS is torsade de pointes which may degenerate into ventricular fibrillation. Children with Jervell and Lange-Neilsen syndrome have the combination of cLQTS and congenital sensorineural deafness and may present for cochlear implantation (CI). Sympathetic stimulation and administration of QT-prolonging medications may trigger arrhythmias in children with cLQTS and thus the perioperative period is a time of increased risk of adverse events, with deaths reported in the CI literature. Our Paediatric Cochlear Implant Programme had previously elected to discontinue offering CI to children with cLQTS following a perioperative death. However, subsequent demand for this service by parents led us to develop and introduce a multidisciplinary, evidence-based pathway of care. This pathway modifies the perioperative management of these children to reduce the associated risk. We present the cases of four children with cLQTS who underwent CI in our specialist children’s hospital.

Electrocardiogram Abnormalities Suggest Aberrant Cardiac Conduction in Huntington's Disease.

There is increasing evidence that the effects of Huntington's disease (HD) extend beyond the central nervous system. In particular, significant cardiac dysfunction has been described in transgenic mouse models and suggested in symptomatic patients, in whom cardiac involvement could provide an independent risk for sudden cardiac death. Standard 12-lead electrocardiograms (ECGs) obtained at screening from 590 early symptomatic (Stage 1 and 2) HD patients participating in a multi-site Phase III study were analyzed. Evaluating only those ECGs in individuals not on medications or with potentially contributing medical conditions, the prevalence of bradycardia was 28.3% (marked in 5.8%), prolonged QRS 4.9%, intraventricular conduction delay 3.4%, right bundle branch block 1.3%, and QTc prolongation 3.7%. Significant cardiac abnormalities, characterized primarily by conduction abnormalities, were found in a larger than expected number of patients. Abnormal intraventricular conduction may lead to increased risk for arrhythmia and may be compounded by prescription of QT-prolonging medications.

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.

Outpatient Co-prescription of Ondansetron With Other QT-Prolonging Drugs in a Large Community-Based Health System: A Warning Ignored

Introduction: Ondansetron is a 5HT-3 serotonin receptor antagonist that is commonly used to treat nausea and vomiting. The FDA has warned of QT-prolonging effects of ondansetron, especially when combined with other QT-prolonging drugs, or in patients with known cardiac disease. Electronic medical records with warning systems for drug-drug interactions have been promoted for patient safety. We present a review of de-identified data from a large community-based health system to determine how providers responded to electronic warnings when prescribing ondansetron combined with other QT-prolonging drugs. Methods: All prescriptions for ondansetron in combination with QT-prolonging drugs at NorthShore University HealthSystem between January and March 2016 were included in the initial database as part of a quality improvement project. Inpatient orders and IV ondansetron orders were removed. The name and class of co-prescribed QT-prolonging drugs, warning severity, response to the warning by prescribing practitioner (over-ride warning and prescribe, or cancel order), reason for the warning over-ride, patient age and gender were evaluated. Results: There were a total of 9203 episodes of co-prescription of ondansetron and another QT-prolonging drug in 2739 adult patients during the study time period. After filtering, there were 770 outpatient co-prescriptions in 500 patients. Mean patient age was 46.2 years (range 18 to 90 years). Orders were for 592 females (76.8%) and 178 males (33.2%). All warnings were considered “major interactions”. Most orders, 651 (84.5%) prescriptions were administered, while only 119 (15.5%) orders were canceled. The most common classes of co-prescribed QT-prolonging drugs were macrolide antibiotics (40.0%), flouroquinolone antibiotics (17.0%), SARI antidepressants (13.4%), and SSRI antidepressants (9.9%), (Table 1). There were nine (1.4%) cases of co-prescriptions with antiarrhythmic drugs (amioderone and flecainide). The most commonly co-prescribed QT-prolonging medications were azithromycin, levofloxacin, and trazadone (Table 2). Reasons for warning overrides were “benefit outweighs risk” in 266 (40.8%) and “not clinically significant” in 116 cases (17.7%).Table: Table. Classes of Drugs Co-Prescribed with OndansentronTable: Table. List of Drugs Co-Prescribed with OndansetronConclusion: After viewing warnings, practitioners still prescribed ondansetron with other QT-prolonging drugs 85% of the time. This form of co-prescription with ondansetron neglects FDA recommendations and could put patients at risk for cardiac arrhythmias.

Association of QT-Prolonging Medication Use in CKD with Electrocardiographic Manifestations.

Several drugs used in CKD can prolong electrocardiographic conduction. We examined the use of electrocardiogram QT-prolonging medications in predialysis CKD and their association with QT duration. In total, 3252 Chronic Renal Insufficiency Cohort participants with at least one study electrocardiogram between 2003 and 2011 were included. QT-prolonging medications used in 100 or more visits (n=16,451 visits) along with diuretics and proton pump inhibitors, given their potential for electrolyte disturbances, were examined for QT interval prolongation. Mean QT interval corrected for heart rate was at 414±21 (±SD) milliseconds and prolonged (≥450 milliseconds) in 4.6% of electrocardiograms. QT interval corrected for heart rate was inversely related to serum potassium and calcium. Medications classified as QT prolonging were taken at 76% of visits, with two or more of these taken at 33% of visits. Of 30 medications examined, eight were associated with statistically significant QT interval corrected for heart rate prolongation after adjustment for comorbidities, potassium, and calcium, including amiodarone (+10±2 milliseconds), metolazone (+7±2 milliseconds), fluoxetine (+4±1 milliseconds), citalopram (+4±1 milliseconds), hydroxyzine (+4±1 milliseconds), escitalopram (+3±2 milliseconds), venlafaxine (+3±1 milliseconds), and furosemide (+3±0 milliseconds). Potassium-depleting diuretics were associated with minimal decrements in potassium (between 0.1 and 0.3 mEq/L) and smaller changes in calcium. Diuretics associated with a change in QT interval corrected for heart rate before adjustment for potassium and calcium were metolazone (+8±3 milliseconds), furosemide (+4±1 milliseconds), and spironolactone (-3±3 milliseconds). Most of the QT prolongation associated with metolazone and furosemide, but not spironolactone, remained after adjustment for potassium and calcium. Proton pump inhibitors were not associated with QT prolongation. Use of medications associated with QT prolongation is common in CKD; the safety implications of these findings should be considered in these high-risk patients. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2017_08_09_CJASNPodcast_17_09_b.mp3.

The possible role of propofol in drug-induced torsades de pointes: A real-world single-center analysis

BackgroundTorsades de pointes (TdP) is a polymorphic ventricular tachycardia associated with QT prolongation. Propofol is a sedative-anesthetic with proarrhythmic effects on cardiac myocytes. We performed a retrospective study to determine the incidence of TdP following propofol exposure at Mayo Clinic (Rochester, MN) from 08/11/1998–11/20/2015. MethodsWe queried our database using key search terms to identify patients exposed to propofol who developed TdP perioperatively or during non-surgical sedation. QT intervals were obtained from electrocardiograms (ECGs) performed before propofol exposure and after documented TdP and were corrected using Fridericia and Framingham methods. T wave peak-to-end (Tp-e)/QT ratios were also calculated. ResultsA total of 628,784 patients received propofol over 17.3years. Of these patients, 21 developed TdP (12, postoperatively; 3, intraoperatively; 6, during sedation). There were 17 patients who were exposed to at least one factor associated with QT-prolongation, including QT-prolonging medications in 8 patients, heart rate <60 beats per minute in 8 patients, potassium <3.5mmol/L in 4 patients, magnesium <1.8mg/dL in 2 patients, and subarachnoid hemorrhage in 2 patients. The number of patients with QTc>500ms using Fridericia correction was significantly higher from baseline following exposure to propofol (1 patient vs 6 patients, P=0.04); however no significant difference was observed with Framingham correction. ConclusionIn our study, TdP after propofol administration occurred with an annual incidence of 1.93 per million and was often associated with other risk factors. Nevertheless, propofol should be administered with caution in patients at risk of developing TdP.

Clinical pharmacists' opportunities to reduce inappropriate prescription of QT-prolonging medications: calls to action.

All biologically active agents carry the potential to lead to adverse reactions in certain individuals, including serious cardiac adverse reactions. Since 2005, there has been an international regulatory landscape governing the investigation of a new drug's propensity to lead to the polymorphic ventricular tachycardia Torsades de Pointes (Torsades), a rare but potentially fatal occurrence. When a regulatory agency considers it appropriate, warning information is placed in a medicine's patient information leaflet (label) concerning drug-induced QT interval prolongation, a phenomenon associated with Torsades. In busy hospital settings, however, prescribers, including cardiologists, make injudicious prescribing decisions that put patients at risk. The science of cardiac safety, including the clinical trials that generate the information about QT prolongation in patient information leaflets, is frequently not part of the curriculum at Schools of Pharmacy. Given that medication-induced cardiotoxicity is extremely serious, we advocate that schools integrate the science of cardiac safety into existing therapeutics/therapeutic medication monitoring courses. Given their expert knowledge of pharmacology, pharmacists working as part of a hospital's clinical team would then be even better placed to review prescribing decisions concerning medications that prolong the QT interval, and alert prescribers in cases where reassessing their decisions seems prudent. National pharmacy societies or other pertinent professional societies could create practice guidelines to support graduates once employed as clinical pharmacists. Clinical pharmacists are well placed to be influential arbiters of safer prescribing decisions. Cardiac safety education during their pharmacy training and practice guideline support from professional societies during their careers can optimize this role.