QTc Changes Research Articles

Electrocardiogram Changes Following the Treatment with Gonadotropin-Releasing Hormone Agonists in Patients with Precocious Puberty

Background: GnRH agonists are the standard treatment for precocious puberty. Studies on the side effects of these drugs in adults have shown that these drugs may cause changes in ECG and some cardiovascular effects; however, few studies have evaluated these effects in children. This study aims to investigate the effect of these drugs on ECG intervals in children with precocious puberty.Methods: In this study with a pre-post design 50 children with precocious puberty referred to the endocrinology clinic of Tabriz Children's Hospital in 2019 for receiving GnRH agonists were included. From all patients, ECGs were obtained before starting the treatment and then 6, 12, and 18 weeks later and PR, QRS, and QTc intervals were extracted from ECG records.Results: The mean age of the participants was 91±9 months including 48 (96%) girls and 2 (4%) boys. Triptorelin (GnRH agonist) was administered for all patients with the standard protocol. Comparison of pre- and post-treatment ECG intervals showed that the drug did not cause a significant change in PR (p = 0.535) and QTc (p = 0.250) intervals, whilst there was a significant increase in QRS interval after the treatment (p = 0.001).Conclusion: The use of GnRH agonists in children can lead to some changes in ECG records by increasing in QRS intervals; and ECG could be used as a tool to detect these changes. Further studies are also needed to identify ECG changes in larger sample sizes and longer intervals.

Characterization of a high throughput human stem cell cardiomyocyte assay to predict drug-induced changes in clinical electrocardiogram parameters

Human induced pluripotent stem cell derived cardiomyocytes (hIPSC-CM's) play an increasingly important role in the safety profiling of candidate drugs. For such models to have utility a clear understanding of clinical translation is required. In the present study we examined the ability of our hIPSC-CM model to predict the clinically observed effects of a diverse set of compounds on several electrocardiogram endpoints, including changes in QT and QRS intervals. To achieve this, compounds were profiled in a novel high throughput voltage-sensitive dye platform. Measurements were taken acutely (30 min) and chronically (24 h) to ensure that responses from compounds with slow onset kinetics or that affected surface ion channel expression would be captured. In addition, to avoid issues associated with changes in free drug levels due to protein binding, assays were run in serum free conditions. Changes in hIPSC-CM threshold APD90 values correlated with compound plasma exposures that produced a +10 ms change in clinical QTc (Pearson r2 = 0.80). In addition, randomForest modeling showed high predictivity in defining TdP risk (AUROC value = 0.938). Risk associated with QRS prolongation correlated with an increase in action potential rise-time (AUROC value = 0.982). The in-depth understanding of the clinical translatability of our hIPSC-CM model positions this assay to play a key role in defining cardiac risk early in drug development. Moreover, the ability to perform longer term studies enables the detection of compounds that may not be highlighted by more acute assay formats, such as inhibitors of hERG trafficking.

Prolongation of QTc interval at the beginning and during dialysis is associated with hypervolemia and calcium and magnesium change in the first 2h.

High rates of sudden cardiac death are mostly attributed to ventricular arrhythmias including QTc prolongation in hemodialysis patients. We aimed to investigate the correlation of electrolyte and volume changes with QTc interval prolongation in hemodialysis patients. The present study is designed as a cross-sectional study. The study was conducted at the hemodialysis unit of a training and research hospital and its' satellite dialysis unit. Patients were divided into three groups. Group-1: with normal QTc interval both at the beginning and during dialysis session; group-2: with prolonged QTc interval at the beginning and remained prolonged during dialysis session; group-3: with normal QTc interval at the beginning but prolonged during the dialysis session. In addition, patients were evaluated in terms of QTc change between the beginning and 2nd hour (delta-QTc-1) and between 2nd hour and 4th hour (delta-QTc-2), respectively, and defined as 'patients with increased QTc interval' and 'patients without increased QTc interval'. A total of 45 prevalent hemodialysis patients were enrolled in the study. 14 patients (31.1%) had normal QTc interval (group-1), 13 patients (28.9%) had prolonged QTc interval at the beginning and remained prolonged during dialysis session (group-2) and 18 patients (40%) had normal QTc interval at the beginning but prolonged during dialysis session (group-3). There was no statistically significant difference between groups in terms of baseline electrolyte levels. Calcium change in the first 2h was lower in patients with QTc prolongation from the start or during the dialysis session (group-2 and group-3). In addition, systolic blood pressure (SBP) levels at the beginning of the session (118 ± 15mmHg vs 124 ± 28mmHg vs138 ± 24mmHg; p = 0.04) and intradialytic ultrafiltration (UF) rate were higher (1.96 ± 0.6 L/4h vs 2.6 ± 1.0 L/4h vs 2.8 ± 0.9 L/4h; p = 0.03) in group-2 and group-3 compared to patients in group-1. Increase in QTc interval was found higher in patients with less calcium increase (Rho: -0.36; p = 0.01) and with greater magnesium decrease in the first 2h (Rho: 0.31; p = 0.04). QTc interval prolongation is common among hemodialysis patients. High intradialytic UF rates, change in serum magnesium and calcium levels in the first 2h were found associated with QTc prolongation. However, QTc prolongation was found independently associated only with UF volume and calcium change in the first 2h.

Temporary prolongation of corrected QT interval after cardioneuroablation for functional bradyarrhythmias

Abstract Background There are controversial reports on QT interval response to ganglionic plexi ablation that are selectively targeted during cardioneuroablation (CNA) or occurs as collateral lesion during left atrial ablation procedures. Both shortening or prolongation of the heart-rate corrected QT interval (QTc) with therapeutic or safety implications were described. Purpose In this retrospective study, we investigated longitudinal changes of QTc after CNA. Methods The study included 108 patients (age: 39±12 years, 60% males) who underwent biatrial cardioneuroablation (radiofrequency time: 15.5±6.7 min) for symptomatic functional bradyarrhythmias. Surface ECG examinations were performed on the day before the CNA (N=108), 1 hour after the CNA (N=106), on the 1st post-ablation day (N=50), at the 3-month (N=99), and 1-year (N=63) follow-up visits. Automated measurements of QT interval were employed for the analysis. Four formulas (Bazett, Framingham, Fridericia, and Hodges) were used for the correction of QT interval to instant heart rate. Results QTc significantly prolonged immediately after the CNA with rapid return to baseline values (Figure and Table). This was particularly valid for QT correction by Framingham formula (and similarly for Fridericia and Hodges formulas). The QTc by Bazett formula, which is known to overestimate QT at higher heart rates, returned to baseline more slowly and incompletely. Several mechanisms may contribute to observed QTc dynamics: (1) direct effect of autonomic denervation with recovery phenomenon; (2) QT hysteresis with an extremely long time constant; or (3) artifact due to suboptimum QT correction to a substantial change of heart rate. Conclusions The study suggests that CNA produces acute prolongation of QTc interval with rapid decay and virtual normalization in 3 months. CNA in otherwise healthy subjects is not likely associated with substantial long-term risk of long-QT-associated arrhythmias. In the same way, we cannot confirm earlier observations of clinically significant QTc shortening effect of ganglionated plexi ablation. Funding Acknowledgement Type of funding sources: None. Figure 1Table 1

Effects of cardiac toxicity of combination therapy with hydroxychloroquine and azithromycin in COVID-19 patients

Coronavirus disease 2019 (COVID-19), which began in China, caused a global pandemic. Few studies have shown the benefit of hydroxychloroquine (HY) ± azithromycin (AZ) for treating COVID-19. Concerns of QT prolongation and increased risks of torsade’s de pointes (TdP) with this combination have been raised since each agent can individually prolong the QT interval. This retrospective, observational study included hospitalized patients treated with HY and AZ from March 2020 to May 2020 at a large community hospital. Serial assessments of the QT interval were performed. Our aim is to evaluate the safety and characterize the change in QTc interval and arrhythmic events in COVID-19 patients treated with HY/AZ. A total of 21 COVID patients who received at least four days of HY and AZ were included in this study. Mean baseline was QTc 403 ms, mean maximum QTc was 440 ms, mean change in QTc was 36 ms. Only one patient (4.8%) developed prolonged QTc > 500 ms. No patient had a change in QTc of 60 ms or more. No patient developed TdP. Fifteen patients (71.4%) had hypoxia on admission, with only two patients (9.5%) required oxygen of 1−2 L at discharge. 80.9% of patients have been discharged home or inpatient rehabilitation.

Comparison of the effect of citalopram, bupropion, sertraline, and tricyclic antidepressants on QTc: A cross-sectional study

BackgroundSome data suggests that citalopram has more risk of corrected QT interval (QTc) prolongation than other selective serotonin reuptake inhibitors. Consequently the U.S. Food and Drug Administration distributed a safety warning limiting the maximum dose for citalopram.There is also a suggestion that bupropion may decrease QTc in patients on drugs that increase QTc. The goals of this cross-sectional study were to examine (1) effects on QTc of citalopram compared to sertraline, bupropion, and tricyclic antidepressants; (2) dose dependent effects of citalopram; and (3) effects of bupropion on citalopram-mediated changes in QTc. MethodsRecords of subjects who received an EKG while taking one of the specified antidepressants were reviewed to collect demographic information, antidepressant history, and information about other confounders. Linear regression was used to examine the relationship between QTc and antidepressants. Results487 subjects provided 798 EKG records. The sample was 95% male with an average age of 61 years. No differences were found in QTc between citalopram and other antidepressants. No dose relationship was detected between citalopram and QTc. Bupropion did not affect the relationship between citalopram and QTc (coefficient = -3.4; 95%CI = -14.2, 7.5; p = 0.54). LimitationsObservational study designs are prone to biases from retrospective data collection. Some data subsets had small numbers of subjects. ConclusionsNo effect of citalopram on QTc was found at therapeutic doses. Neither was there evidence of a “QTc-sparing” effect of bupropion. The risk of adverse cardiovascular effects from citalopram at doses of 60 mg per day or less appears minimal.

B-PO02-163 ELECTROCARDIOGRAPHIC FINDINGS ASSOCIATED WITH INCREASED MORTALITY IN HOSPITALIZED COVID-19 PATIENTS

COVID-19 infection may trigger acute cardiovascular events in patients with stable disease or may present with other cardiac complaints including acute coronary syndrome, myocarditis, myopericarditis, acute heart failure, arrhythmia, and sudden cardiac death. Various newly diagnosed ECG changes reported in patients with COVID-19 include sinus tachycardia, atrial fibrillation, AV block, abnormal axis, LBBB, RBBB, IVCD, QTc changes, ST-T changes, and Brugada pattern.

Safety and Efficacy of Ibutilide for Acute Pharmacological Cardioversion of Rheumatic Atrial Fibrillation

Introduction: Ibutilide is indicated for acute cardioversion of nonvalvular atrial fibrillation (AF). However, its efficacy and safety in the pharmacological cardioversion of rheumatic AF are unknown. Methods: Patients with mild-to-moderate rheumatic mitral valve (MV) disease with symptomatic, paroxysmal, or persistent AF were included in the analysis. Intravenous ibutilide was administered at doses tailored to body weight (0.5–2.0 mg) for over 10 min. The primary end point was efficacy, assessed as the rate of conversion of AF to sinus rhythm. The secondary end point was safety, including arrhythmic events and death within 24 h of drug initiation. Results: From June 2016 to October 2018, 165 patients (94 with mitral stenosis, 23 with mitral regurgitation, 11 with mixed MV disease, and 37 with MV replacement) received ibutilide (mean dose 0.90 ± 0.54 mg). Ibutilide successfully converted AF to sinus rhythm in 127/165 (76.9%) patients, with a conversion time of 7.9 ± 4.1 min. The QTc increased from 419.9 ± 15.8 to 487.5 ± 34 ms after ibutilide administration (p < 0.001). The mean change in QTc after ibutilide administration (∆QTc) was 72.01 ± 36.03. There were no deaths, but 3 patients (1.8%) developed torsades de pointes (TdP) requiring defibrillation 55 ± 37 min after infusion. Conclusion: Ibutilide cardioverted 77% of rheumatic AF to sinus rhythm, indicating its potential as a clinically useful option for pharmacological cardioversion of rheumatic AF. TdP is a potentially serious adverse event that requires careful monitoring.

The impact of hydroxychloroquine and azithromycin on the corrected qt interval in patients with the novel Coronavirus disease 2019.

With the coronavirus disease 2019 (COVID-19) continuing to spread all over the world, although there is no specific treatment until now, hydroxychloroquine and azithromycin have been reported to be effective in recent studies. Although long-term use of hydroxychloroquine and azithromycin has been reported to cause QT prolongation and malign arrhythmia, there is not enough data about the effect of short-term use on arrhythmia. Therefore, this study aims to assess the effect of hydroxychloroquine alone and hydroxychloroquine + azithromycin on corrected QT (QTc). A baseline electrocardiogram and on-treatment baseline electrocardiogram were retrospectively collected in COVID-19 patients who received hydroxychloroquine and/or azithromycin. The QTc interval was calculated, and the baseline and peak QTc intervals were compared. In addition, the peak QTc intervals of monotherapy and combination therapy were compared. Of the 155 patients included, 102 (65.8%) patients were using hydroxychloroquine, and 53 (34.2%) patients were using hydroxychloroquine + azithromycin combination. The use of both hydroxychloroquine alone and hydroxychloroquine + azithromycin combined therapy significantly prolonged the QTc, and the QTc interval was significantly longer in patients receiving combination therapy. QTc prolongation caused early termination in both groups, 5 (4.9%) patients in the monotherapy group and 6 (11.3%) patients in the combination therapy group. In this study, patients who received hydroxychloroquine for the treatment of COVID-19 were at high risk of QTc prolongation, and concurrent treatment with azithromycin was associated with greater changes in QTc.

The impact of hydroxychloroquine and azithromycin on the corrected qt interval in patients with the novel coronavirus disease 2019

Funding AcknowledgementsType of funding sources: None.BackgroundAlthough long-term use of HCQ and AZT has been reported to cause QT prolongation and malign arrhythmia, there is not enough data about the effect of short-term use on arrhythmia. Purpose: The aim of this study was to assess the effect of HCQ alone and HCQ + AZT on corrected QT (QTc).Methods: A baseline ECG and on-treatment ECGs were retrospectively collected in COVID-19 patients who received HCQ and/or AZT. Also peak QTc intervals of monotherapy and combination therapy was compared. Results: Of the 155 patients included, 102 (65.8%) were using HCQ, 53 (34.2%) were using HCQ + AZT combination. The use of both HCQ alone and HCQ + AZT combined therapy significantly prolonged the QTc and the QTc interval was significantly longer in patients received combination therapy. QTc prolongation caused early termination in both groups, 5 (4.9%) patients in the monotherapy group and in 6 (11.3%) patients in the combined therapy group.Conclusion: Patients who received HCQ for COVID-19 were at high risk of QTc prolongation, and concurrent treatment with AZT was associated with greater changes in QTc. Comparison of baseline characteristics aCharacteristicTotal (n = 155)Hydroxychloroquine (n = 102)Hydroxychloroquine /Azithromycin (n = 53)P valueLength of stay at ward, SD9.54 ± 4.289.64 ± 4.319.31 ± 4.250.88Length of stay Intensive care unite,SD7.92 ± 3.767.18 ± 3.188.46 ± 4.150.29Radiographic findings of pneumonia118(76.1%)76(74.5%)42(49.2%)0.32Mechanically ventilation16(10.3%)7(6.9%)9(17.0%)0.049In hospital death19(12.3%)10(9.8%)9(17.0%)0.15ECG findings median(IQR) (ms)Baseline QRS duration91.0(80.0-103.0)92.5(80.75-105.50)90.0(80.0-102.5)0.5Posttreatment QRS peak97.0(86.0-109.0)97.5(88.0-109.25)95.0(85.5-109)0.68ΔQRS4.0(0.0-9.0)2.0(0.0-8.25)5.0(1.0-9.5)0.14Baseline QTc duration407.0(385.0-426.0)408.0(389.25-427.50)404.0(384.0-420.0)0.1Posttreatment QTc peak437.0(414.0-460.0)428.0(412.75-449.25)456.0(422.0-467.5)<0.001ΔQTc27.0(13.0-45.0)18.0(11.0-30.0)46.0(40.5-54.5)<0.001Baseline PR duration145.50(128.7-160.0)147.0(135.0-160.0)144.0(120.0-160.0)0.53Posttreatment PR peak159.0(140.0-170.0)159.0(141.0-168.50)156.0(139.5-171.0)0.97ΔPR7.0(1.0-13.0)5.0(0.0-12.25)10.0(5.0-15.0)0.022QTc peak day5.0(4.0-5.0)5.0(4.0-6.0)4.0(3.0-5.0)0.022Drug withdrawl due to QRS prolongation11(7.1%)5(4.9%)6(11.3%)0.12

Initial real life experience with ribociclib in breast cancer: Outcome with focus on tolerance and cardiac toxicity.

e13024 Background: CDK4/6 inhibitors, such as ribociclib, are a new class of medications that are used in combination with hormonal therapy to treat advanced or metastatic hormone receptor-positive, HER2-negative breast cancer. The primary objective of this study is to evaluate the tolerance and cardiac toxicity of ribociclib in all patients at our institution. Secondary objectives include progression free survival and response rates. Methods: Patients who received ribociclib between December 2018 and August 2020 were included. Rates of dose reduction and discontinuation of ribociclib were used as surrogate markers for intolerance and were compared to those reported in land-mark trials. QTc changes and cardiac adverse events (AEs) were also collected. Results: Thirty one patients were included. Ribociclib was administered in the first-, second-, third-, and fourth-line palliative hormonal therapy settings in 5 (16%), 14 (45%), 11 (35%) and 1 (3%) patients respectively and 8/31 (26%) received prior 1-4 palliative chemotherapy lines. Ribociclib was combined with letrozole in 21 (68%) and with fulvestrant in 10 (32%) patients. QTc interval was ≤ 470 msec in all patients prior to treatment and 11 (35%) patients had preexisting cardio vascular (non electro-conductive) co-morbidities. AEs related dose reduction was reported in 12 (39%) patients [bone marrow toxicity 6 (19%), QTc prolongation 4 (13%), abnormal liver function tests 1 (3%) and abdominal pain 1 (3%)]. Ribociclib was permanently discontinued due to AEs in 5 (16%) patients (2: prolonged QTc, 2: coronary events and 1: suspected allergic reaction). The median duration of follow up was 14 months. Objective response was evaluable in 28 patients [CR: 1 (3.6%), PR: 1 (3.6%), SD: 20 (71.4%) and PD: 6 (21.4%)]. The median progression free survival was 18 months (95% CI: 12.3-23.7). Conclusions: Although objective response rates were low in this mixed cohort of heavily pretreated patients, ribociclib combined with letrozole or fulvestrant has shown a robust progression free survival in real life practice. Treatment discontinuation rate is higher than that reported in clinical trials with stringent inclusion criteria. Ribociclib associated cardiac toxicity can be appropriately managed with careful monitoring.[Table: see text]

Exposure–response modeling of the effect of glasdegib on cardiac repolarization in patients with cancer

ABSTRACT Purpose To characterize the effect of glasdegib on cardiac repolarization (QTc) in patients with advanced cancer. Methods A concentration–QTc model was developed using data from two glasdegib single-agent, dose-escalation trials. Triplicate electrocardiogram was performed at pre-specified timepoints paired with pharmacokinetic blood collections after a single dose and at steady-state. Changes in QTc from baseline were predicted by model-based simulations at the clinical dose (100 mg QD) and in a supratherapeutic setting. Results Glasdegib did not affect the heart rate, but had a positive effect on the corrected QT interval, described by a linear mixed-effects model with ΔQTcF (QTc using Fridericia’s formula) as the dependent variable with glasdegib plasma concentrations from doses of 5–640 mg QD. The predicted mean QTcF change (upper bound of the 95% CI) was 5.30 (6.24) msec for the therapeutic 100-mg QD dose; at supratherapeutic concentrations (40% and 100% increase over the therapeutic Cmax), it was 7.42 (8.74) and 12.09 (14.25) msec, respectively. Conclusions The relationship of glasdegib exposure and QTc was well characterized by the model. The effect of glasdegib on the QTc interval did not cross the threshold of clinical concern for an oncology drug. Trial registration ClinicalTrials.gov ID: NCT01286467 and NCT00953758.

478 The Relationship between Sleep Disordered Breathing, Markers of Ventricular Repolarization and Cardiovascular Mortality

Abstract Introduction Sleep disordered breathing (SDB) is associated with increased mortality. Obstructive apneas/hypopneas have been associated with an increase in both QTc duration and QT variability. These markers of ventricular repolarization are associated with arrhythmias and death. It is unknown whether SDB-related QTc changes are responsible for the relationship between QTc/QT variability and cardiovascular death (CVD). Methods From the Sleep Heart Health Study, we randomly selected 200 subjects in each of four groups based on overall apnea/hypopnea index: those with no SDB and those in either, mild, moderate or severe SDB at baseline, matched for gender, age and BMI. Respiratory-related channels and electrocardiograms (ECG) from each polysomnography were analyzed. QTc was calculated using Bazett’s heart rate correction. The following measures of QT variability were obtained: i) standard deviation of QT intervals (SDQT) at 1- and 5-minute intervals and ii) short-term interval QT variability (STVQT) at 5-minute intervals. Cox proportional hazards regression models were used to evaluate potential predictors of CVD. Results Twenty-nine subjects were excluded either due to missing data or low quality ECG. The 771 subjects included were 68±10 years of age, half were female. During follow-up, 220 subjects (28.5%) died of CVD among whom, 67 (30.5%) had comorbid severe SDB, 45 (20.5%) had no SDB, and the remaining CVD deaths had mild (47, 21.4%) and moderate 61 (27.7%) SDB. The CVD patients were more likely to be older(p&amp;lt;0.001), hypertensive (p&amp;lt;0.001), diabetic(p&amp;lt;0.001), and had increased SDQT(p&amp;lt;0.001), STVQT(p&amp;lt;0.001) and QTc (0.017). After adjusting for covariates, the presence of mild (p=0.562), moderate(p=0.439) and severe SDB (p=0.912) did not moderate the association between QTc prolongation and CVD. Additionally, mild (p=0.486), moderate(p=0.478) and severe SDB (p=0.849) did not moderate the association between SDQT and CVD. Similarly, mild (p=0.144), moderate(p=0.594) and severe SDB (p=0.508) did not moderate the association between STVQT and CVD. However, QTc, SDQT, STVQT, mild and severe SDB were individually associated with CVD (p=0.004, 0.000, 0.000, 0.014, 0.022, respectively). Conclusion SDB was not a factor in the relationship between QTc prolongation/QT variability and CVD. Support (if any) American Academy of Sleep Medicine Foundation (203-JF-18), National Institutes of Health (HL126140), University of Arizona Health Sciences Career and Development Award (5299903)

Resting electrocardiographic differences in ventricular repolarization between children and young adults with congenital heart disease and those with a structurally normal heart are diminished by exercise.

Exercise-induced repolarization changes have not been systematically evaluated in children and young adults with congenital heart disease (CHD). We carried out this study to assess the QTc responses during exercise in children and young adults (≤ 21 years) with CHD with comparison to those with structurally normal hearts. Baseline QRS duration, calculated baseline QTc, QTc at 4 min of recovery and delta QTc was measured in 360 exercise stress tests which were performed in 360 subjects (137 stress tests in patients with CHD [CHD group] and 223 stress tests in patients with structurally normal hearts). The effects of presence of CHD and potential confounders on primary outcome measure, change in QTc (delta QTc), and secondary outcome measures (QTc at baseline and QTc at 4 min of recovery) were determined using multiple linear regression analyses. The baseline QTc and the QTc at 4 min of recovery in the CHD group was longer than patients with structurally normal hearts (respective p values=.00 and .001). No significant difference was noted in delta QTc between the CHD and structurally normal heart groups. While patients with CHD had a longer QRS duration and QTc interval at baseline than those with structurally normal hearts, these differences did not persist or augment with exercise.

A clinical survey on the electrocardiogram after intravenous granisetron hydrochloride administration in clinically normal dogs

Cardiac side effect of 5-hydroxytryptamine-3 receptor antagonists has been a concern for clinicians. There is a substantial need for greater clarity about the safety of granisetron hydrochloride, an antiemetic agent of this class used in oncological and parvoviral gastroenteritis with acute vomiting in dogs. This study aimed to assess the electrocardiographic effects of a single dose of intravenous granisetron. We randomly assigned 16 adult crossbreed female healthy dogs into two groups of intervention and control and injected them intravenously with granisetron and normal saline, respectively, at a dose of 0.5 ml/kg over one minute. Standard electrocardiography (ECG) was recorded at the baseline, as well as 5, 15, 30, 60, 120, 360, and 720 minutes after the intervention. Heart rate and ECG parameters (PR intervals, QRS duration, ST-segment, T-wave amplitudes, QT, JT, QTc and JTc intervals) were evaluated in lead II.No significant difference was observed between the intervention and the control groups in any of the measured variables at any of the time-points. Mean values of measured parameters showed no significant difference compared with baseline values in the control group, while the granisetron group saw statistically significant but clinically asymptomatic changes in heart rate, PR, QRS, QT, JT, and QTc at different time-points, compared to the baseline values (P&lt;0.05). In conclusion, Granisetron administration was not associated with clinically significant adverse effects on ECG variables or heart rate. Thus, it can be regarded as a relatively safe drug.

QTc prolongation in COVID-19 patients treated with hydroxychloroquine, chloroquine, azithromycin, or lopinavir/ritonavir: A systematic review and meta-analysis.

PurposeHydroxychloroquine, chloroquine, azithromycin, and lopinavir/ritonavir are drugs that were used for the treatment of coronavirus disease 2019 (COVID‐19) during the early pandemic period. It is well‐known that these agents can prolong the QTc interval and potentially induce Torsades de Pointes (TdP). We aim to assess the prevalence and risk of QTc prolongation and arrhythmic events in COVID‐19 patients treated with these drugs.MethodsWe searched electronic databases from inception to September 30, 2020 for studies reporting peak QTc ≥500 ms, peak QTc change ≥60 ms, peak QTc interval, peak change of QTc interval, ventricular arrhythmias, TdP, sudden cardiac death, or atrioventricular block (AVB). All meta‐analyses were conducted using a random‐effects model.ResultsForty‐seven studies (three case series, 35 cohorts, and nine randomized controlled trials [RCTs]) involving 13 087 patients were included. The pooled prevalence of peak QTc ≥500 ms was 9% (95% confidence interval [95%CI], 3%–18%) and 8% (95%CI, 3%–14%) in patients who received hydroxychloroquine/chloroquine alone or in combination with azithromycin, respectively. Likewise, the use of hydroxychloroquine (risk ratio [RR], 2.68; 95%CI, 1.56–4.60) and hydroxychloroquine + azithromycin (RR, 3.28; 95%CI, 1.16–9.30) was associated with an increased risk of QTc prolongation compared to no treatment. Ventricular arrhythmias, TdP, sudden cardiac death, and AVB were reported in <1% of patients across treatment groups. The only two studies that reported individual data of lopinavir/ritonavir found no cases of QTc prolongation.ConclusionsCOVID‐19 patients treated with hydroxychloroquine/chloroquine with or without azithromycin had a relatively high prevalence and risk of QTc prolongation. However, the prevalence of arrhythmic events was very low, probably due to underreporting. The limited information about lopinavir/ritonavir showed that it does not prolong the QTc interval.

Confirmation of the cardiac safety of nolasiban in a randomised cohort of healthy female volunteers

Nolasiban is an orally active oxytocin receptor antagonist being developed to increase the efficiency of assisted reproductive technologies. This study evaluated the pharmacokinetics, pharmacodynamics, and cardiac safety of nolasiban in 45 healthy women of child-bearing age. Nolasiban was administered in a fasted state with a standardised lunch served 4.5 h post-dose. Concentration-effect modelling was used to assess the effect of two dosages of nolasiban (900 mg and 1800 mg) on QTc following single-dose administration. We found no significant change in QTc at all tested dosages. Two-sided 90% confidence intervals of geometric mean Cmax for estimated QTc effects of nolasiban were below the threshold of regulatory concern. The sensitivity of the assay to detect small changes in QTc was confirmed by a significant shortening of QTc between 2 and 4 h after consumption of a meal, which served to validate the model. Independent of the nolasiban assessment, this study also explored the effects of sex hormones on ECG parameters, especially QT subintervals. We found a significant relationship between JTpc and oestradiol. Heart rate was negatively correlated with progesterone. This study confirms the cardiovascular safety of nolasiban and describes relationships of sex hormones and ECG parameters.

Parent and Metabolite Concentration-QT Modeling to Evaluate QT-Interval Prolongation at Savolitinib Therapeutic Doses.

Savolitinib is an oral, potent, and highly selective MET-tyrosine kinase inhibitor under investigation in various tumor types. A thorough QT study evaluated effects on QT interval after a 600-mg single savolitinib dose in healthy subjects. We report exposure-response (E-R) modeling from this study to characterize the effects of savolitinib and its metabolites, M2 and M3, on QTc changes. In a novel application, in vitro potencies against hERG current provided mechanistic support to model the metabolites' effects. The hERG IC50 estimates (95% CI) were 25.8 (22.2-29.9) and 22.6 (14.7-34.6) μM for parent and M2, respectively. The E-R was described by both linear and Emax models, with exposure captured by an active moiety that consisted of savolitinib and M2 concentrations, weighted by the hERG IC50 ratio (1.14). The maximal increase in ΔΔQTcF and EC50 estimates (95% CI) was 18.5 (9.2-27.7) ms and 5709 (2889-8529) nM, respectively. Ignoring M2 contribution resulted in under prediction of QTcF prolongation in the hypothetical case of inhibited M2 clearance; at 300 mg Cmax, the mean (90% CI) of ∆∆QTcF was 9.0 (5.7-12.6) and 5.9 (2.9-8.9) ms using the hERG-informed and parent-only linear models, respectively. Simulations in normal setting confirmed modest QTcF prolongation with 600 mg, but not 300 mg. Using the linear model, the mean (90% CI) maximum ΔΔQTcF were 12.3 (8.6-16.2) and 5.5 (2.6-8.5) ms for 600 and 300 mg, respectively. Further clinical studies will monitor cardiac safety to assess the clinical significance of QT-interval prolongation with savolitinib.

Pulmonary vein isolation in a real-world population does not influence QTc interval.

AimsWe aimed to examine whether routine pulmonary vein isolation (PVI) induces significant ventricular repolarization changes as suggested earlier.Methods and resultsFive-minute electrocardiograms were recorded at hospital’s admission (T−1d), 1 day after the PVI-procedure (T+1d) and at 3 months post-procedure (T+3m) from a registry of consecutive atrial fibrillation (AF) patients scheduled for routine PVI with different PVI modalities (radiofrequency, cryo-ablation, and hybrid). Only patients who were in sinus rhythm at all three recordings (n = 117) were included. QT-intervals and QT-dispersion were evaluated with custom-made software and QTc was calculated using Bazett’s, Fridericia’s, Framingham’s, and Hodges’ formulas. Both QT- and RR-intervals were significantly shorter at T+1d (399 ± 37 and 870 ± 141 ms) and T+3m (407 ± 36 and 950 ± 140 ms) compared with baseline (417 ± 36 and 1025 ± 164 ms). There was no statistically significant within-subject difference in QTc Fridericia (T−1d 416 ± 28 ms, T+1d 419 ± 33 ms, and T+3m 414 ± 25 ms) and QT-dispersion (T−1d 18 ± 12 ms, T+1d 21 ± 19 ms, and T+3m 17 ± 12 ms) between the recordings. A multiple linear regression model with age, sex, AF type, ablation technique, first/re-do ablation, and AF recurrence to predict the change in QTc at T+3m with respect to QTc at T−1d did not reach significance which indicates that the change in QTc does not differ between all subgroups (age, sex, AF type, ablation technique, first/re-do ablation, and AF recurrence).ConclusionBased on our data a routine PVI does not result in a prolongation of QTc in a real-world population. These findings, therefore, suggest that there is no need to intensify post-PVI QT-interval monitoring.

Sinus rhythm heart rate increase after atrial fibrillation ablation is associated with lower risk of arrhythmia recurrence.

Pulmonary vein isolation (PVI) with autonomic modulation may be more successful than PVI alone for atrial fibrillation (AF) ablation and may be signaled by changes in sinus rhythm heart rate (HR) post ablation. We sought to determine if a change in sinus rhythm HR predicted AF recurrence post PVI. Patients who underwent AF ablation from 2000 to 2011 were included if sinus rhythm was noted on ECG within 90 days pre and 7 days post ablation. Basic ECG interval and HR changes were analyzed and outcomes determined. A total of 1152 patients were identified (74.3% male, mean age 57 ± 11 years). Mean AF duration was 5.2 ± 5.3 years. Paroxysmal AF was noted in 712 (61.8%) of the patients. Mean EF was 61% ± 6%. Sinus rhythm HR was 61 ± 11 pre-ablation and 76 ± 13bpm post-ablation (27% ± 24% increase, p<.001). The ability of relative HR change post-ablation to predict AF recurrence was borderline (hazard ratio 0.65 [0.41-1.01], p=.067). With patients separated into quartiles based on the relative HR change, the upper quartile with the largest relative increase in HR had a significantly lower rate of AF recurrence compared to the lowest quartile following multi variable modeling (p=.038). There were significant changes in PR (171 ± 28 to 167 ± 30ms) and QTc (424 ± 25 to 434 ± 29ms) intervals (both p<.001) but these were not predictive of outcome. Relative changes in HR post AF ablation correlates with AF recurrence. Further prospective studies are needed to confirm this relationship.