QT Prolongation In Patients Research Articles

Psychotherapeutic drug-induced life-threatening arrhythmias: A retrospective analysis using the Japanese adverse drug eventreport database.

Drug-induced life-threatening ventricular arrhythmias including torsade de pointes (TdP), ventricular tachycardia (VT), and ventricular fibrillation (VF) are serious cardiac side effects. Psychotherapeutic drugs are known to be risk factors for arrhythmias. The aim of this study was to evaluate psychotherapeutic drugs associated with life-threatening ventricular arrhythmias using the Japanese Adverse Drug Event Report (JADER) database. From the JADER database (April 2004 to September 2022), cases of TdP, VT, VF, and QT prolongation in patients taking psychotherapeutic drugs as 'suspected drugs' were extracted. The adjusted reported odds ratio (aROR) was calculated to identify potential drugs involved in combined TdP/VF/VT or combined QT prolongation/TdP. Of the 4,530,772 cases reported, life-threatening arrhythmia-related adverse events were reported in 1760 cases (QT prolongation 1261, TdP 192, VF 108, VT 199) among 909 patients; 58.9% of patients were female, and the highest incidence was among patients aged 80-89 years (18.6%), followed by patients aged 70-79 years (15.4%). The highest aROR for TdP/VF/VT was found for trazodone (17.1), followed by sulpiride (10.8), haloperidol (9.8), donepezil (9.1), and fluvoxamine (7.9). The highest aROR for QT prolongation/TdP was found for guanfacine (87.8), followed by sultopride (60.1), escitalopram (21.0), trazodone (12.8), and donepezil (9.3). This study showed that typical antipsychotics, antidepressants, and antidementia drugs were associated with life-threatening arrhythmia-related adverse events in a Japanese clinical setting. These events were more frequent in women and elderly individuals.

THE EFFECTIVENESS AND SAFETY OF BEDAQUILINE-CONTAINING REGIMENS IN THE TREATMENT OF PATIENTS WITH MULTI-DRUG RESISTANT TUBERCULOSIS (MDR-TB): A SYSTEMATIC LITERATURE REVIEW

Objective: MDR-TB is a life-threatening infectious disease. In recent years, RR/MDR TB sufferers have increased by 10% from 186,883 patients in 2018 to 206,030 in 2019. The success rate of treatment for RR/MDR-TB patients only reaches 57% globally. WHO has recommended bedaquiline for treatment of MDR-TB as the first drug in an all-oral regimen designed to maximize treatment outcomes. Purpose: to describe the efficacy and safety of a bedaquiline-containing regimen for the treatment of MDR-TB. Methods: Pubmed, Science Direct, and Embase online databases were used to obtain data published in the last five years where literature searches were carried out independently by researchers. The keywords used in this search are combined with the Boolean operator "AND", namely (bedaquiline) AND (multidrug resistant) AND (effectiveness). Results: Eight studies met the inclusion criteria, demonstrating a higher conversion rate of sputum cultures on the bedaquiline containing regimen between 74%-95.8% with a mean time to culture conversion between 39 days-3 months. The majority of studies reported an adverse effect of QT prolongation in patients treated with bedaquiline. Conclusion: This systematic review showed that bedaquiline is effective and safe for use in the treatment of MDR-TB. However, serious side effects of QT prolongation occurred in some respondents who were treated with bedaquiline, so an effective and efficient monitoring and surveillance system is needed to ensure best practice in the treatment of MDR-TB.

Gefitinib Increases the Incidence of QT Prolongation in Patients with Non-Small Cell Lung Cancer.

Gefitinib (GEF) may increase the risk of corrected QT prolongation (QTc). We aimed to evaluate whether gefitinib increases the risk of corrected QT interval (QTc) prolongation and analyze the associated risk factors.A total of 122 cases of advanced EGFR-mutated non-small cell lung cancer (NSCLC) who received gefitinib therapy from January 2015 to December 2020 were evaluated. The results of at least two resting 12-lead electrocardiogram before and after gefitinib treatment were obtained. The Bazett and Fridericia formulas were used to calculate the QTc interval, and the changes of QTc interval values before and after treatment were evaluated. The correlation between gefitinib and QTc interval prolongation and related risk factors were analyzed.After gefitinib-targeted therapy, 23 patients (18.9%) had a prolonged QTc interval, which increased from a mean of 446 ± 25 ms at baseline to 478 ± 18 ms (P < 0.001). Three of the patients met criteria for Grade 3 QTc prolongation in the common term V5.0 for clinical adverse events. Univariate analysis showed that age (ORR, 1.054; 95% confidence interval [CI], 1.003-1.107; P = 0.038), history of hypertension (ORR, 3.409; 95% CI, 1.334-8.713; P = 0.01), CCB medication history (ORR, 0.259; 95% CI, 0.094-0.712; P = 0.009), history of lung cancer surgery (ORR, 0.231; 95% CI, 0.064-0.829; P = 0.025), and baseline QT interval (ORR, 0.978; 95% CI, 0.964-0.993; P = 0.004) were important predictors of QTc interval prolongation in patients treated with gefitinib. The results of multivariate analysis showed that the history of lung cancer surgery and the baseline QT interval were important factors affecting QTc interval prolongation in patients treated with gefitinib.Gefitinib increases the risk of QTc prolongation in NSCLC patients, which may be more pronounced in patients with advanced age, hypertension, CCB therapy, lung cancer surgery, and a long QT interval at baseline.

Dostarlimab, an anti-programmed death-1 monoclonal antibody, does not cause QT prolongation in patients with solid tumours: A concentration-QT analysis.

Patients with solid tumours were treated with the anti-PD-1 antibody dostarlimab in the Phase I GARNET trial. This study aimed to examine dostarlimab's effect on corrected QT (QTc) interval and the systemic concentration-QTc interval relationship. In GARNET Part 2B, patients received 500 mg dostarlimab every 3weeks (Q3W) for four cycles, then 1000 mg Q6W. Triplicate 12-lead ECGs were recorded and time-matched pharmacokinetic (PK) samples collected at screening, on Day 1 of Cycles 1, 4, 5, 8, 12 (pre-dose and 0.5h after infusion end), and at treatment end. Concentration-change from baseline QTcF (ΔQTcF) analysis using a linear mixed effects model, summary statistics, incidence of clinically noteworthy ECG values and rhythm abnormalities were evaluated. A total of 377 patients were considered for evaluation (n = 15 excluded from concentration-ΔQTcF). There was a non-significant concentration-ΔQTcF relationship (0.001589 ms/μg/mL; P = .5906). Mean ΔQTcF increase was <6ms (upper-bound two-sided 90% confidence interval [CI], <10ms at all post-dose timepoints). Highest geometric mean concentration was 414.1μg/mL (Cycle 5 Day 1, 0.5h) with predicted mean ∆QTcF of 3.064 ms (upper-bound two-sided 90% CI: 5.071). Mean QTcF prolongation (all concentrations) was 2.4ms. QTcF prolongation ≥500 ms occurred in five patients (1.3%); 51 (13.6%) and nine patients (2.4%) had ΔQTcF ≥30 ms and ≥60 ms, respectively. Ten patients (2.7%) reported rhythm abnormalities. No U-wave abnormalities, torsades de pointes, ventricular tachycardia or ventricular fibrillation/flutter were observed. Dostarlimab does not cause clinically significant QTcF prolongation exceeding the regulatory concern threshold.

Prevalence of QT prolongation and its risk factors in patients with type 2 diabetes

BackgroundQT prolongation increases cardiovascular mortality in diabetes. The risk factors for QT prolongation vary across different studies. There is no data on the QT prolongation in patients with diabetes from the Arab region, where diabetes is highly prevalent. Here we aimed to assess the prevalence of QT prolongation and its associated risk factors in patients with type 2 diabetes from Saudi Arabia.MethodThis was a retrospective, cross-sectional, hospital-based file review study. Data were collected from the medical records of patients with type 2 diabetes aged above 14 years and underwent ECG examination, and laboratory investigations were done within one month of ECG.ResultsThe study included 782 patients with a prevalence of QTc prolongation of 13%. Patients with prolonged QTc interval were characterized by older age, higher BMI, longer diabetes duration, lower total cholesterol and LDL-C, and more diabetic nephropathy, hypertension, and CVD cases. They were also more in insulin treatment, antihypertensive medications, loop diuretics, and potassium-sparring diuretics. Logistic regression analysis revealed the odds of prolonged QTc interval increased significantly with CVD (OR = 1.761, 95% CI:1.021–3.036, p = 0.042), and usage of loop diuretics (OR = 2.245, 95% CI:1.023–4.923, p = 0.044) after adjusting for age, gender, and duration of diabetes.ConclusionThe risk factors associated with QTc prolongation in patients with type 2 diabetes are CVD, and loop diuretics. Age, BMI, and diabetes duration were more in people with QTc prolongation, whereas total cholesterol and LDL-C levels were lower. More patients had diabetic nephropathy, hypertension, and CVD with prolonged QTc.

Incidence and predictors of QT prolongation in patients on amiodarone

Incidence and predictors of QT prolongation in patients on amiodarone

An overview of the role of selpercatinib and pralsetinib in RET-fusion-positive non-small cell lung cancer (NSCLC)

Selpercatinib and pralsetinib are new targeted therapies used to treat patients with non-small cell lung cancer (NSCLC) due to RET gene rearrangements. The objective of this article is to review selpercatinib and pralsetinib in the context of RET-fusion-positive NSCLC. The pivotal LIBRETTO-001 and ARROW trials were evaluated regarding the use of selpercatinib and pralsetinib as treatment for RET-fusion-positive NSCLC. Comparative studies, review articles and current studies on selpercatinib and pralsetinib in RET-fusion-positive NSCLC were searched on pubmed.org and scholar.google.com using "selpercatinib," "pralsetinib," and "NSCLC" as keywords. Product monographs were searched on google.ca and uptodate.com using the keywords "selpercatinib," "pralsetinib," and/or "monograph." Selpercatinib and pralsetinib are orally administered highly selective RET inhibitors approved by the FDA following the accelerated approvals granted due to the pivotal LIBRETTO-001 and ARROW trials which evaluated selpercatinib and pralsetinib, respectively. Both drugs have shown efficacy for brain metastases and are primarily metabolized by CYP3A4 through hepatic metabolism. The most common grade 3 or 4 adverse effects of selpercatinib were hypertension, increased ALT level, and increased AST level while for pralsetinib, it was neutropenia, hypertension, and anemia. The safety profile shows similarities in severity and tolerability but additional monitoring for QT prolongation in patients on selpercatinib is recommended, compared to the risks of interstitial lung disease or pneumonitis for patients on pralsetinib. Overall, the increased use of selpercatinib and pralsetinib has led to the implementation of these drugs in the clinical practice of healthcare professionals such as pharmacists.

Risk Factors for QT Prolongation in Patients with Chronic Hydroxychloroquine Use.

Hydroxychloroquine is used as an antimalarial and immunomodulator, however it can induce QT prolongation that could potentially lead to fatal arrhythmia. We investigated changes in QT interval in long-term hydroxychloroquine users, and identified possible risk factors associated with significant QTc prolongation. We retrospectively enrolled 3603 patients who received long-term hydroxychloroquine treatment from 2009 to 2019, of whom 167 had electrocardiography (ECG) results before and during hydroxychloroquine therapy. Baseline characteristics, laboratory data, comorbidities, concurrent medications, and related clinical outcomes were reviewed. Overall, 225 patients (6.2%) died within the study period, with 50 patients (1.4%) continuously receiving hydroxychloroquine treatment until death. Three patients had fatal ventricular arrhythmia. No significant change in corrected QT interval (QTc) was noted before and during hydroxychloroquine treatment (451.1 ± 39.9 ms vs. 456.0 ± 37.3 ms, P = 0.140) in the ECG cohort. Multivariable logistic regression showed that diabetes mellitus [odds ratio (OR): 9.55, 95% confidence interval (CI): 2.02-45.22; P = 0.005] and use of additional QT-prolonging drugs (OR: 2.89, 95% CI: 1.40-5.94; P = 0.004) were independent risk factors for significant QTc prolongation. Multiple linear regression, with the number of QT-prolonging drugs and comorbidities including diabetes mellitus, hypertension, and atrial fibrillation as explanatory variables, predicted QTc response (adjusted R2 = 0.385) in the long-term hydroxychloroquine users. In the long-term users of hydroxychloroquine, those with diabetes mellitus and concurrent use of additional QT-prolonging drugs were at a higher risk of significant QTc prolongation. Baseline QTc interval, concurrent medications, and comorbidities predicted QTc response.

Prevalence of Prolonged QT Interval In Patients With Chronic Liver Disease

The incidence of QT prolongation in CLD patients is greater than 45% compared to approximately 5% in the general population. Multiple researches have revealed that end-stage liver disease is related with a variety of changes in electrophysiological parameters; especially in our population, a higher incidence of QT interval prolongation is observed. Prolonged QT intervals in chronic liver disease patients are related with augmented mortality and morbidity. Objective: To determine the frequency of QT prolongation in patients with chronic liver disease. Methods: A cross-sectional and descriptive study. 96 total patients aged 20-85 years of both sexes with chronic liver disease (CLD) were included. Patients with a history of coronary artery disease and the use of any anti-arrhythmic medication were excluded from the study. The 12-lead ECG was performed and interpreted by an electrophysiologist with over five years of experience. The Bazett-based QT interval (QTc) was automatically obtained using a computerized electrocardiograph to avoid inter-observer variability. Results: 20 to 60 years was the patients age in this study, with 39.44 ± 9.91 years of mean age. The maximum patients, 86 (89.58%), were 20-40 years of age. Among the 96 patients, 17 (17.71%) were female and 79 (82.17%) were male, with a M: F ratio of 1.3: 1. While the incidence of QT prolongation was found in 47 (48.96%) patients, 49 (51.04%) patients did not have QT prolongation. Conclusions: In this study it was found that the frequency of QT prolongation is quite high in patients with chronic liver disease

QT prolongation in patients with index evaluation for seizure or epilepsy is predictive of all-cause mortality.

Refractory epilepsy confers a considerable lifetime risk of sudden unexplained death in epilepsy (SUDEP). Mechanisms may overlap with sudden cardiac death (SCD), particularly regarding QTc prolongation. Guidelines in the United States do not mandate the use of electrocardiography (ECG) in diagnostic evaluation of seizures or epilepsy. The purpose of this study was to determine the frequency of ECG use and of QT prolongation, and whether QT prolongation predicts mortality in patients with seizures. We performed a retrospective cohort study including all patients seen at Mayo Clinic in Rochester, Minnesota, from January 1, 2000, to July 31, 2015, with index evaluation for seizure or epilepsy. Patients with an ECG were categorized by the presence of a prolonged QT interval with a primary endpoint of all-cause mortality after the 15-year observation period. Optimal cutoff QT intervals most predictive of mortality were identified. Median age was 40.0 years. An ECG was obtained in 18,222 patients (57.4%). After patients with confounding ECG findings were excluded, primary prolonged QT intervals were seen in 223 cases (1.4%), similar to the general population. Kaplan-Meier analysis demonstrated a significant increase in mortality (Cox hazard ratio [HR] 1.90; 95% confidence interval [CI] 1.76-2.05) for prolonged optimal cutoff QT, maintained after adjustments for age, Charlson comorbidity index, and sex (HR 1.48; 95% CI 1.37-1.59). Use of ECG in diagnostic workup of patients with seizures is poor. A prolonged optimal cutoff QTc interval predicts all-cause mortality in patients evaluated for seizure and those diagnosed with epilepsy. We advocate the routine use of a 12-lead ECG at index evaluation in patients with seizure or epilepsy.

The effect of oral ondansetron on QT interval in children with acute gastroenteritis; a retrospective observational study

BackgroundIn mildly to moderately dehydrated patients with acute gastroenteritis (AGE), oral rehydration therapy (ORT) is the treatment of choice. Though ondansetron is a very effective antiemetics and leads to succeed ORT, there have been reports QT prolongation in patients using it. We investigated the effect of oral ondansetron on QT interval in mildly to moderately dehydrated children with AGE.MethodsThis retrospective observational study was conducted in a single pediatric emergency department (ED) of a tertiary university hospital. We collected the medical records of patients with a primary diagnosis of AGE who received oral ondansetron and underwent an electrocardiogram between January 2017 and June 2018. A pediatric emergency physician calculated the corrected QT interval (QTc) by Bazett’s method, and the calculations were reviewed by a pediatric cardiologist. QTc values before (preQTc) and after (postQTc) ondansetron administration were analyzed. ΔQTc was calculated as the change from preQTc to postQTc. We also investigated any cardiac complications from oral ondansetron.ResultsTotal 80 patients were included. The mean age of the patients was 53.31 ± 32.42 months, and 45% were male. The mean dose of oral ondansetron was 0.18 ± 0.04 mg/kg. The mean interval from administration of ondansetron to performance of the electrocardiogram was 65 ± 26 min. The mean preQTc was 403.3 ± 24.0 ms, and the mean postQTc was 407.2 ± 26.7 ms. Two patients had a preQTc ≥460 ms, and one patient had a postQTc ≥460 ms. ΔQTc was ≥30 ms in seven patients (8.8%). No ΔQTc was ≥60 ms. No pre- or postQTc was ≥500 ms. No patient had a fatal cardiac arrhythmia after taking ondansetron.ConclusionOral administration of a single dose of ondansetron in children with AGE did not cause high-risk QTc prolongation or fatal arrhythmia.

B-PO03-163 QTC INTERVAL PROLONGATION AND IN-HOSPITAL MORTALITY AMONG PATIENTS HOSPITALIZED WITH COVID-19

QT interval prolongation is linked to an increased risk of life-threatening ventricular arrhythmias. The risk factors contributing to QT prolongation in patients with COVID-19 remain poorly defined. To characterize risk factors associated with prolonged QTc interval among patients hospitalized with COVID-19. We performed a retrospective study examining the QTc on the admission ECG of 2,456 hospitalized adult patients admitted for treatment of acute COVID-19 infection to five hospitals in the Baltimore / Washington, DC metropolitan area. Patients with atrial fibrillation or QRS widening >120ms were excluded. QTc (Bazett) prolongation was defined as QTc>440ms in men and 450ms in women. A severely prolonged QTc interval was defined as QTc>500ms (men and women). A prolonged and severely prolonged QTc was found in 34.28% and 4.23% of patients, respectively. In-hospital mortality in patients with a normal, prolonged, and severely prolonged QTc interval was 7.48%, 11.28%, and 17.31%, respectively (p<0.001 for trend). Factors associated with QTc prolongation were older age (57 vs. 61 vs. 63 yrs, p<0.001), CRP levels (9.2 vs. 12.7 vs. 12.3; p= 0.002), ferritin levels (562 vs. 665 vs. 844, p = 0.006), pro-BNP levels (108 vs. 314 vs. 1064; p<0.001), female sex, presence of chronic lung or kidney disease, diabetes mellitus, heart failure, and hypertension. No statistically significant associations of QTc prolongation were found for race, body mass index, coronary artery disease, troponin I levels, TSH, and liver function. QTc prolongation on admission ECG is common and associated with an increase in-hospital mortality, older age, higher inflammatory cytokine levels, heart failure, and presence of renal and pulmonary disease. Future studies are required to determine the utility of QTc interval on the admission ECG for risk stratification of patients hospitalized with COVID-19.

Cardiac Safety of Hydroxychloroquine-Azithromycine for COVID-19 Patients: Pandemic Experience of Military Teaching Hospital of Rabat

Introduction: While recent studies are still arguing the efficacy of Hydroxychloroquine and Azithromycin to heal patients with SARS-CoV-2 infection, Moroccan’s ministry of health has decided to maintain the protocol using these drugs. The main objective of this study is to characterize the degree and risk of QT prolongation in patients with COVID-19 in association with their use. Methods: This study is a cohort performed at Mohammed V Military Hospital of Rabat, of patients hospitalized with at least 1 positive COVID-19 nasopharyngeal reverse transcriptase polymerase chain reaction (RT-PCR) test result, and who received 10 day of hydroxychloroquine with 7 days of azithromycin from May9 through May26, 2020. Hydroxychloroquine was given orally at 200 mg TID. Azithromycin was given at a dose of 500 mg the first day followed by 250 mg daily for 6 days. Electrocardiogram was performed before the prescription, 2 days after and at the end of treatment. Results: During this period, 327 ECGs were studied, representing 109 unique patients. Their median age was 30 [25.5-44] years and 100% were male. All patients developed a paucisymptomatic form of the virus. Tisdale score varied between 6 and 8 points (89.9%-10.1%). The difference ΔQTc was significant (p&lt;0.01) from day 0 to 10 with a ΔQTc of 16.15 ms. However, the maximal QTc hadn’t exceed 500 milliseconds. None of the patients developed torsades de pointes or any other ventricular arrhythmias. Conclusion: Moroccan experience can reassure the prescribers on the safety of use of this drug combination in the threatening epidemic context.

Effect of Clofazimine Concentration on QT Prolongation in Patients Treated for Tuberculosis.

Clofazimine is classified as a WHO group B drug for the treatment of rifampin-resistant tuberculosis. QT prolongation, which is associated with fatal cardiac arrhythmias, is caused by several antitubercular drugs, including clofazimine, but there are no data quantifying the effect of clofazimine concentration on QT prolongation. Our objective was to describe the effect of clofazimine exposure on QT prolongation. Fifteen adults drug-susceptible tuberculosis patients received clofazimine monotherapy as 300 mg daily for 3 days, followed by 100 mg daily in one arm of a 2-week, multiarm early bactericidal activity trial in South Africa. Pretreatment Fridericia-corrected QT (QTcF) (105 patients, 524 electrocardiograms [ECGs]) and QTcFs from the clofazimine monotherapy arm matched with clofazimine plasma concentrations (199 ECGs) were interpreted with a nonlinear mixed-effects model. Clofazimine was associated with significant QT prolongation described by a maximum effect (Emax) function. We predicted clofazimine exposures using 100-mg daily doses and 2 weeks of loading with 200 and 300 mg daily, respectively. The expected proportions of patients with QTcF change from baseline above 30 ms (ΔQTcF > 30) were 2.52%, 11.6%, and 23.0% for 100-, 200-, and 300-mg daily doses, respectively. At steady state, the expected proportion with ΔQTcF of >30 ms was 23.7% and with absolute QTcF of >450 ms was 3.42% for all simulated regimens. The use of loading doses of 200 and 300 mg is not predicted to expose patients to an increased risk of QT prolongation, compared with the current standard treatment, and is, therefore, an alternative option for more quickly achieving therapeutic concentrations.

Effect of QT Prolongation in Patients Taking Cholinesterase Inhibitors (Donepezil) for Alzheimer's Disease.

Background: Cholinesterase inhibitors such as donepezil are used in the treatment of Alzheimer’s disease. Patients taking cholinesterase inhibitors can develop cholinergically mediated QT prolongation, which may lead to life-threatening arrhythmias. In this study we investigated the corrected QT interval (QTc) of patients taking donepezil.Methods and Results: This study enrolled 114 outpatients attending Tarumizu Chuo Hospital. Subjects were divided into a donepezil group (n=57) or an age- and sex-matched control group (n=57). Physical findings, laboratory data, and electrocardiographic parameters were compared between the groups. QTc was significantly prolonged (mean [±SD] 0.443±0.032 s vs. 0.426±0.026s; P<0.001) and the percentage of patients with prolonged QTc was significantly higher (30% vs. 9%; P<0.01) in the donepezil than control group. Furthermore, in the donepezil group, QTc was significantly prolonged after patients started taking donepezil compared with baseline (from 0.433±0.034 to 0.442±0.033s; n=46; P<0.05). On univariate analysis, QTc was significantly associated with taking donepezil, as well as with hemoglobin, serum calcium concentration, and estimated glomerular filtration rate (eGFR; all P<0.01). On multivariate analysis, QTc was significantly associated with taking donepezil (P<0.001), serum potassium concentration (P<0.05), and eGFR (P<0.05).Conclusions: The incidence of QTc prolongation was more frequent in patients taking donepezil than in the control group, and was difficult to predict. Periodic electrocardiogram examinations are recommended considering the possibility of adverse events, such as fatal arrhythmias.

The Use of QT Prolongation Risk Factor Assessment Tool to Assess the Risk of QT Prolongation in Patients Taking Methadone: An Irish Experience

Currently, no tool exists to assist doctors in estimating their patients’ risk of QT prolongation. Methadone is one of many medications which is known to prolong a patient’s QT, and which can lead to Torsades de Pointes and sudden cardiac death. The aim of the study was to design a QT prolongation risk factor assessment tool, for patients taking methadone, which would allow physicians to objectively assess a patient’s risk of QT prolongation. Following a literature review a QT prolongation risk factor assessment tool was created. An audit was then carried out to see what risk factors for QT prolongation were identified prior to use of the tool, in our practice, and then after the tool had been introduced. The introduction of a dedicated QT risk factor assessment tool led to an 61% (39/100 to 100/100) increase in the documentation of individual QT prolongation risk factors in our patients. There was a 100% (4/4) increase in the documentation of risk of QT prolongation in the patient notes, of discussion that risk with patients (4/4), and of the frequency of repeat ECGS (4/4). The introduction of such a QT prolongation risk factor assessment tool in our practice led to an increased awareness of QT prolonging medications, an improvement in the documentation of QT prolonging risk factors and a change in the culture of the practice around medication prescribing and QT prolongation. In patients who are on methadone, a QT prolongation risk factor assessment tool allows for an objective assessment of each patient’s risk of QT prolongation which then allows for measures to be put in place to monitor and address this risk.

QT interval prolongation and risk of sudden death in patients with thalassemia or sickle cell disease

Sudden unexplained death is common in patients with hemoglobinopathies including sickle cell disease and thalassemia. The prolongation of the QTc interval is a risk factor for fatal arrhythmia in adults. To study the prevalence of QT prolongation in patients with sickle cell anemia or thalassemia followed at Ibn-Rochd CHU in Casablanca and to study the association between QT prolongation and the risk of sudden death. We examined electrocardiograms (ECG) of 52 consecutive patients (> 14 years) carrying hemoglobinopathies (sickle cell anemia or thalassemia) followed at the Ibn-Rochd university hospital in Casablanca between February 2017 and July 2018. The duration of the interval QTc was calculated using Bazett's formula and classified into three categories by sex (normal, long, short). The Chi-square test was used to study the association between prolonged QTc and sudden death. The statistical analysis was univariate and the significance level was set at (P < 0.05). Among the 52 ECGs examined, there were 3 cases of prolongation of the QT interval, including 2 patients with homozygous thalassemia and one patient with homozygous sickle cell disease, representing a percentage of 5.78% of all followed patients. The study of the association between prolonged QTc and the risk of mortality revealed a mortality rate of 66,7% with long QTc interval vs. 2% in normal QTc interval (P = 0.007). Prolonged QT in patients with sickle cell anemia or thalassemia is a risk factor for increased mortality.

Efficacy and Safety of Rociletinib Versus Chemotherapy in Patients With EGFR-Mutated NSCLC: The Results of TIGER-3, a Phase 3 Randomized Study

IntroductionThe TIGER-3 (NCT02322281) study was initiated to compare the efficacy and safety of rociletinib, a third-generation EGFR tyrosine kinase inhibitor (TKI) that targets EGFR T790M and common EGFR-activating mutations, versus chemotherapy in patients with NSCLC who progressed on first- or second-generation EGFR TKIs. MethodsPatients with advanced or metastatic EGFR-mutated NSCLC with disease progression on standard therapy (previous EGFR TKI and platinum-based chemotherapy) were randomized to oral rociletinib (500 or 625 mg twice daily) or single-agent chemotherapy (pemetrexed, gemcitabine, docetaxel, or paclitaxel). ResultsEnrollment was halted when rociletinib development was discontinued in 2016. Of 149 enrolled patients, 75 were randomized to rociletinib (n = 53: 500 mg twice daily; n = 22: 625 mg twice daily) and 74 to chemotherapy. The median investigator-assessed progression-free survival (PFS) was 4.1 months (95% confidence interval [CI]: 2.6–5.4) in the rociletinib 500-mg group and 5.5 months (95% CI: 1.8–8.1) in the 625-mg group versus 2.5 months (95% CI: 1.4–2.9) in the chemotherapy group. An improved PFS was observed in patients with T790M-positive NSCLC treated with rociletinib (n = 25; 500 mg and 625 mg twice daily) versus chemotherapy (n = 20; 6.8 versus 2.7 mo; hazard ratio = 0.55, 95% CI: 0.28–1.07, p = 0.074). Grade 3 or higher hyperglycemia (24.0%), corrected QT prolongation (6.7%), diarrhea (2.7%), and vomiting (1.3%) were more frequent with rociletinib than chemotherapy (0%, 0%, 1.4%, and 0%, respectively). ConclusionsRociletinib had a more favorable median PFS versus chemotherapy but had higher rates of hyperglycemia and corrected QT prolongation in patients with advanced EGFR-mutated NSCLC who progressed on previous EGFR TKI. Incomplete enrollment prevented evaluation of the primary efficacy end point.

QT prolongation in patients with acute leukemia or high-risk myelodysplastic syndrome prescribed antifungal prophylaxis during chemotherapy-induced neutropenia

Benefits of serial electrocardiographic (ECG) monitoring to detect QT prolongation in patients with hematological malignancies remain unclear. This retrospective, single-center, study evaluated 316 adult acute leukemia and high-risk MDS patients who received 11,775 patient-days of voriconazole prophylaxis during induction chemotherapy. Of these, 37 patients (16.2%) experienced QTc prolongation. Medications associated with QTc prolongation included furosemide, haloperidol, metronidazole, mirtazapine, prochlorperazine, and venlafaxine. Hypokalemia and hypomagnesemia were also significantly associated with QTc prolongation (HR 3.15; p = .003 and HR 6.47, p = .007, respectively). Management modifications due to QTc prolongation included discontinuation of QT prolonging medications (n = 25), more aggressive electrolyte repletion (n = 5), and enhanced ECG monitoring (n = 3). One patient with multiple QT prolonging factors experienced possible Torsades de Pointes. Overall mortality was 15% with no cardiac-related deaths. Serial ECG monitoring during induction chemotherapy can be tailored proportionally to QT-prolonging risk factors. Management should include aggressive electrolyte repletion and avoidance of concurrent QT prolonging medications.

Adverse drug reactions in South African patients receiving bedaquiline-containing tuberculosis treatment: an evaluation of spontaneously reported cases

BackgroundBedaquiline was recently introduced into World Health Organization (WHO)-recommended regimens for treatment of drug resistant tuberculosis. There is limited data on the long-term safety of bedaquiline. Because bedaquiline prolongs the QT interval, there are concerns regarding cardiovascular safety. The Western Cape Province in South Africa has an established pharmacovigilance programme: a targeted spontaneous reporting system which solicits reports of suspected adverse drug reactions (ADRs) in patients with HIV-1 and/or tuberculosis infection. Since 2015, bedaquiline has been included in the treatment regimens recommended for resistant tuberculosis in South Africa. We describe ADRs in patients on bedaquiline-containing tuberculosis treatment that were reported to the Western Cape Pharmacovigilance programme.MethodsWe reviewed reports of suspected ADRs and deaths received between March 2015 and June 2016 involving patients receiving bedaquiline-containing tuberculosis treatment. A multidisciplinary panel assessed causality, and categorised suspected ADRs using World Health Organisation-Uppsala Monitoring Centre system categories. “Confirmed ADRs” included all ADRs categorised as definite, probable or possible. Preventability was assessed using Schumock and Thornton criteria. Where a confirmed ADR occurred in a patient who died, the panel categorised the extent to which the ADR contributed to the patient’s death as follows: major contributor, contributor or non-contributor.ResultsThirty-five suspected ADRs were reported in 32 patients, including 13 deaths. There were 30 confirmed ADRs, of which 23 were classified as “possible” and seven as “probable”. Bedaquiline was implicated in 22 confirmed ADRs in 22 patients. The most common confirmed ADR in patients receiving bedaquiline was QT prolongation (8 cases, 7 of which were severe). A fatal arrhythmia was suspected in 4 sudden deaths. These 4 patients were all taking bedaquiline together with other QT-prolonging drugs. There were 8 non-bedaquiline-associated ADRs, of which 7 contributed to deaths.ConclusionsConfirmed ADRs in patients receiving bedaquiline reflect the known safety profile of bedaquiline. Quantifying the incidence and clinical consequences of severe QT-prolongation in patients receiving bedaquiline-containing regimens is a research priority to inform recommendations for patient monitoring in treatment programmes for drug resistant tuberculosis. Pharmacovigilance systems within tuberculosis treatment programmes should be supported and encouraged, to provide ongoing monitoring of treatment-limiting drug toxicity.