ABSTRACT
Amidst the COVID-19 pandemic, hydroxychloroquine (HCQ) was widely administered despite limited data on its safety and efficacy. This study assesses the acute and chronic impacts of HCQ on electrocardiography (ECG) parameters alongside the effects of azithromycin and levofloxacin coadministration in patients with COVID-19. A comprehensive analysis was conducted on 109 COVID-19 patients receiving HCQ, with or without Azithromycin and/or Levofloxacin, and 51 long-term HCQ-treated Sjogren's syndrome (SS) patients. ECG parameters, including QTc interval, were meticulously evaluated against a control group of 109 COVID-19 patients without HCQ treatment. HCQ monotherapy, in combination with Levofloxacin, significantly prolonged the QTc interval in COVID-19 patients compared to controls. Notably, the combination of HCQ and Azithromycin demonstrated a mitigated impact on QTc prolongation. Long-term HCQ use in SS patients did not significantly affect QTc intervals, illustrating a distinct safety profile from short-term use in COVID-19 treatment. HCQ's impact on QTc prolongation is influenced by therapeutic context, coadministered drugs, and patient demographics. The findings underscore the necessity of cautious HCQ use, particularly in acute settings like COVID-19, where monitoring and consideration of drug interactions and patient-specific factors are critical.
Subject(s)
Azithromycin , COVID-19 Drug Treatment , Electrocardiography , Hydroxychloroquine , Long QT Syndrome , Humans , Hydroxychloroquine/adverse effects , Hydroxychloroquine/therapeutic use , Hydroxychloroquine/administration & dosage , Electrocardiography/drug effects , Female , Male , Middle Aged , Azithromycin/therapeutic use , Azithromycin/adverse effects , Azithromycin/administration & dosage , Long QT Syndrome/chemically induced , Aged , Sjogren's Syndrome/drug therapy , Drug Therapy, Combination , Levofloxacin/therapeutic use , Levofloxacin/administration & dosage , Levofloxacin/adverse effects , Adult , SARS-CoV-2 , COVID-19ABSTRACT
Heart failure (HF) with reduced ejection fraction (HFrEF) is a risk factor for drug-induced QT interval prolongation. It is unknown if HF with preserved ejection fraction (HFpEF) is also associated with an increased risk. Dofetilide and sotalol are potent QT interval-prolonging agents that are frequently used in patients with HFpEF, in whom atrial fibrillation is a common comorbidity. We tested the hypothesis that the risk of QT interval prolongation associated with dofetilide and sotalol is increased in patients with HFpEF. We conducted a retrospective cohort study conducted using electronic health records from the Indiana Network for Patient Care (January 31, 2010 -May 3, 2021). After removing patients with overlapping diagnoses of HFpEF and HFrEF, no diagnosis code, and absence of QT interval records, we identified patients taking dofetilide or sotalol among three groups: HFrEF (n = 138), HFpEF (n = 109), and no HF (n = 729). QT prolongation was defined as heart rate-corrected QT (QTc) > 500 ms during dofetilide/sotalol therapy. Unadjusted odds ratios (OR) for QT prolongation were determined by univariate analysis. Adjusted ORs were determined by generalized estimating equations (GEE) with logit link to account for an individual cluster with different times of hospitalization and covariates. QTc prolongation associated with dofetilide or sotalol occurred in 53.2%, 71.7% and 30.0% of patients with HFpEF, HFrEF, and patients with no HF, respectively. After adjusting for age, sex, race, serum potassium and magnesium concentrations, kidney function, concomitant drug therapy, and comorbid conditions, the adjusted odds of QTc prolongation were significantly higher in patients with HFpEF [OR = 1.98 (95% CI 1.17-3.33)], and in those with HFrEF [OR = 5.23, (3.15-8.67)], compared to those with no evidence of HF. The odds of QT prolongation among inpatients receiving dofetilide or sotalol were increased in patients with HFpEF and HFrEF compared to those who did not have HF.
Subject(s)
Heart Failure , Long QT Syndrome , Phenethylamines , Sotalol , Stroke Volume , Sulfonamides , Humans , Heart Failure/physiopathology , Heart Failure/drug therapy , Female , Male , Aged , Phenethylamines/adverse effects , Sotalol/adverse effects , Stroke Volume/drug effects , Retrospective Studies , Sulfonamides/adverse effects , Long QT Syndrome/chemically induced , Long QT Syndrome/physiopathology , Long QT Syndrome/epidemiology , Middle Aged , Aged, 80 and over , Electrocardiography , Anti-Arrhythmia Agents/adverse effects , Risk FactorsSubject(s)
Action Potentials , Induced Pluripotent Stem Cells , Long QT Syndrome , Myocytes, Cardiac , Humans , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Myocytes, Cardiac/pathology , Induced Pluripotent Stem Cells/drug effects , Induced Pluripotent Stem Cells/metabolism , Long QT Syndrome/chemically induced , Long QT Syndrome/physiopathology , Action Potentials/drug effects , Phenotype , Heart Rate/drug effects , Pharmacogenomic VariantsABSTRACT
Islatravir is a deoxynucleoside analog being developed for the treatment of HIV-1 infection. Clinical studies are being conducted to evaluate islatravir, administered in combination with other antiretroviral therapies, at doses of 0.25 mg once daily and 2 mg once weekly. In multiple previous clinical studies, islatravir was generally well tolerated, with no clear trend in cardiac adverse events. A trial was conducted to evaluate the effect of islatravir on cardiac repolarization. A randomized, double-blind, active- and placebo-controlled phase 1 trial was conducted, in which a single dose of islatravir 0.75 mg, islatravir 240 mg (supratherapeutic dose), moxifloxacin 400 mg (active control), or placebo was administered. Continuous 12-lead electrocardiogram monitoring was performed before dosing through 24 hours after dosing. QT interval measurements were collected, and safety and pharmacokinetics were evaluated. Sixty-three participants were enrolled, and 59 completed the study. Fridericia's QT correction for heart rate was inadequate; therefore, a population-specific correction was applied (QTcP). The placebo-corrected change from baseline in QTcP (ΔΔQTcP) interval at the observed geometric mean maximum plasma concentration associated with islatravir 0.75 mg and islatravir 240 mg was <10 ms at all time points. Assay sensitivity was confirmed because the use of moxifloxacin 400 mg led to a ΔΔQTcP >10 ms. The pharmacokinetic profile of islatravir was consistent with that of previous studies, and islatravir was generally well tolerated. Results from the current trial suggest that single doses of islatravir as high as 240 mg do not lead to QTc interval prolongation.
Subject(s)
Electrocardiography , Fluoroquinolones , Moxifloxacin , Humans , Adult , Male , Electrocardiography/drug effects , Double-Blind Method , Female , Middle Aged , Fluoroquinolones/adverse effects , Fluoroquinolones/pharmacokinetics , Moxifloxacin/adverse effects , Moxifloxacin/pharmacokinetics , Heart Rate/drug effects , Long QT Syndrome/chemically induced , Young Adult , Anti-HIV Agents/pharmacokinetics , Anti-HIV Agents/adverse effects , Anti-HIV Agents/therapeutic use , Aza Compounds/adverse effects , Aza Compounds/pharmacokinetics , DeoxyadenosinesABSTRACT
BACKGROUND: Heart failure (HF) is a pervasive global health concern, with acute decompensated heart failure (ADHF) contributing significantly to morbidity and mortality. Medications used in patients with HF may exacerbate HF or prolong the QT interval, posing additional risks. OBJECTIVE: The objective is to assess the prevalence and utilization patterns of medications known to cause or exacerbate HF and prolong the QT interval among patients with ADHF. Understanding these patterns is crucial for optimizing patient care and minimizing potential risks. METHODS: A retrospective chart review was conducted at Huntsville Hospital, Huntsville, USA, covering 602 patients with ADHF over a 40-month period. Inclusion criteria involved age ≥ 18 years, a history of HF, and ADHF admission. The 2016 American Heart Association Scientific Statement was used to identify drugs that may cause or exacerbate HF and those that could prolong the QT interval RESULTS: Among the 602 patients, 57.3% received medications causing or exacerbating HF, notably albuterol (34.9%) and diabetes medications (20.4%), primarily metformin, followed by urologic agents (14.3%), mostly tamsulosin, and nonsteroidal anti-inflammatory drugs (NSAIDs) (6.1%). Moreover, 82.9% were on medications prolonging the QT interval, with loop diuretics, amiodarone, ondansetron, and famotidine most prevalent. Furthermore, 42.1% of the patients received more than two concomitant medications that prolong the QT interval, which can further exacerbate the risk of torsades de pointes. CONCLUSION: This study underscores the high prevalence of HF-causing or HF-exacerbating medications and QT-prolonging drugs in patients with ADHF. Healthcare professionals must be cognizant of these patterns, advocating for safer prescribing practices to optimize patient outcomes and reduce the burden of HF-related hospitalizations.
Subject(s)
Heart Failure , Hospitalization , Humans , Heart Failure/drug therapy , Heart Failure/epidemiology , Retrospective Studies , Male , Female , Aged , Hospitalization/statistics & numerical data , Middle Aged , Aged, 80 and over , Acute Disease , Long QT Syndrome/chemically induced , Long QT Syndrome/epidemiologyABSTRACT
Some anti-mycobacterial drugs are known to cause QT interval prolongation, potentially leading to life-threatening ventricular arrhythmia. However, the highest leprosy and tuberculosis burden occurs in settings where electrocardiographic monitoring is challenging. The feasibility and accuracy of alternative strategies, such as the use of automated measurements or a mobile electrocardiogram (mECG) device, have not been evaluated in this context. As part of the phase II randomized controlled BE-PEOPLE trial evaluating the safety of bedaquiline-enhanced post-exposure prophylaxis (bedaquiline and rifampicin, BE-PEP, versus rifampicin, SDR-PEP) for leprosy, all participants had corrected QT intervals (QTc) measured at baseline and on the day after receiving post-exposure prophylaxis. The accuracy of mECG measurements as well as automated 12L-ECG measurements was evaluated. In total, 635 mECGs from 323 participants were recorded, of which 616 (97%) were of sufficient quality for QTc measurement. Mean manually read QTc on 12L-ECG and mECG were 394 ± 19 and 385 ± 18 ms, respectively (p < 0.001), with a strong correlation (r = 0.793). The mean absolute QTc difference between both modalities was 11 ± 10 ms. Mean manual and automated 12L-ECG QTc were 394 ± 19 and 409 ± 19 ms, respectively (n = 636; p < 0.001), corresponding to moderate agreement (r = 0.655). The use of a mECG device for QT interval monitoring was feasible and yielded a median absolute QTc error of 8 ms. Automated QTc measurements were less accurate, yielding longer QTc intervals.
Subject(s)
Diarylquinolines , Electrocardiography , Feasibility Studies , Leprosy , Rifampin , Humans , Diarylquinolines/administration & dosage , Diarylquinolines/adverse effects , Male , Adult , Female , Leprosy/drug therapy , Leprosy/diagnosis , Rifampin/administration & dosage , Rifampin/adverse effects , Middle Aged , Leprostatic Agents/adverse effects , Leprostatic Agents/administration & dosage , Long QT Syndrome/chemically induced , Long QT Syndrome/diagnosis , Young Adult , Drug Therapy, Combination/methodsABSTRACT
BACKGROUND: Energy drinks potentially can trigger life-threatening cardiac arrhythmias. It has been postulated that the highly stimulating and unregulated ingredients alter heart rate, blood pressure, cardiac contractility, and cardiac repolarization in a potentially proarrhythmic manner. OBJECTIVE: The purpose of this study was to describe our experience regarding sudden cardiac arrest (SCA) occurring in proximity to energy drink consumption in patients with underlying genetic heart diseases. METHODS: The electronic medical records of all SCA survivors with proven arrhythmias referred to the Mayo Clinic Windland Smith Rice Genetic Heart Rhythm Clinic for evaluation were reviewed to identify those who consumed an energy drink before their event. Patient demographics, clinical characteristics, documented energy drink consumption, and temporal relationship of energy drink consumption to SCA were obtained. RESULTS: Among 144 SCA survivors, 7 (5%; 6 female; mean age at SCA 29 ± 8 years) experienced an unexplained SCA associated temporally with energy drink consumption. Of these individuals, 2 had long QT syndrome and 2 had catecholaminergic polymorphic ventricular tachycardia; the remaining 3 were diagnosed with idiopathic ventricular fibrillation. Three patients (43%) consumed energy drinks regularly. Six patients (86%) required a rescue shock, and 1 (14%) was resuscitated manually. All SCA survivors have quit consuming energy drinks and have been event-free since. CONCLUSION: Overall, 5% of SCA survivors experienced SCA in proximity to consuming an energy drink. Although larger cohort studies are needed to elucidate the incidence/prevalence and quantify its precise risk, it seems prudent to sound an early warning on this potential risk.
Subject(s)
Death, Sudden, Cardiac , Energy Drinks , Humans , Female , Male , Energy Drinks/adverse effects , Adult , Death, Sudden, Cardiac/etiology , Death, Sudden, Cardiac/epidemiology , Retrospective Studies , Young Adult , Incidence , Electrocardiography , Risk Factors , Tachycardia, Ventricular/etiology , Tachycardia, Ventricular/physiopathology , Tachycardia, Ventricular/epidemiology , Long QT Syndrome/physiopathology , Long QT Syndrome/chemically inducedABSTRACT
Drug-induced QT prolongation increases the risk of Torsade de Pointes (TdP). Drug-induced QT prolongation is a complex and unpredictable system due to many uncertainties. Risk factors such as electrolyte disturbances, heart failure and genetics play an important role in estimating the effect on QT prolongation. Moreover, the degree of QT prolongation is not always directly related to the risk of TdP and the assessment of the QT-interval is variable depending on the type and timing of QT measurement. Therefore, the variation in QT measurement may be larger than the effect of certain drugs on the QT interval. Because of the potentially lethal risk, several measures are undertaken to reduce the risk of QT prolongation and TdP, while their effect and proportionality are unclear. We suggest we should be less stringent in certain settings when risk of TdP is extremely low given the limited availability of our resources.
Subject(s)
Long QT Syndrome , Risk Management , Torsades de Pointes , Humans , Drug-Related Side Effects and Adverse Reactions/prevention & control , Electrocardiography , Long QT Syndrome/chemically induced , Long QT Syndrome/prevention & control , Risk Factors , Torsades de Pointes/chemically induced , Torsades de Pointes/prevention & controlABSTRACT
INTRODUCTION: Nonclinical evaluation of the cardiovascular effects of novel chemical or biological entities (NCE, NBEs) is crucial for supporting first-in-human clinical trials. One important aspect of these evaluations is the assessment of potential QT/QTc prolongation risk, as drug-induced QT prolongation can have catastrophic effects. The recent publication of E14/S7B Q&As allows for the situational incorporation of nonclinical QTc data as part of an integrated risk assessment for a Thorough QT (TQT) waiver application provided certain best practice criteria are met. Recent publications provided detailed characterization of nonclinical QTc telemetry data collected from the commonly used Latin square study design. METHODS: To understand whether data from alternate telemetry study designs were sufficient to serve as part of the E14/S7B integrated risk assessment, we report the performance and translational sensitivity to identify clinical risk of QTc prolongation risk for an ascending dose telemetry design. RESULTS: The data demonstrated low variability in QTci interval within animals from day to day, indicating a well-controlled study environment and limited concern for uncontrolled effects across dosing days. Historical study variances of the ascending dose design with n = 4 subjects, measured by least significant difference (LSD) and root mean square error (RMSE) values, were low enough to detect a + 10 ms QTci interval change, and the median minimum detectable difference (MDD) for QTci interval changes was <10 ms. Furthermore, concentration-QTci (C-QTci) assessments to determine +10 ms QTci increases for known hERG inhibitors were comparable to clinical CC values listed in the E14/S7B training materials, supporting the use of the ascending dose design in an E14/S7B integrated risk assessment. DISCUSSION: These findings suggest that the ascending dose design can be a valuable tool in nonclinical evaluation of QT/QTc prolongation risk and the support of TQT waiver applications.
Subject(s)
Dose-Response Relationship, Drug , Electrocardiography , Long QT Syndrome , Telemetry , Animals , Telemetry/methods , Risk Assessment/methods , Long QT Syndrome/chemically induced , Dogs , Electrocardiography/methods , Electrocardiography/drug effects , Male , Drug Evaluation, Preclinical/methods , Heart Rate/drug effects , FemaleABSTRACT
INTRODUCTION: In preclinical cardiovascular safety pharmacology studies, statistical analysis of the rate corrected QT interval (QTc) is the focus for predicting QTc interval changes in the clinic. Modeling of a concentration/QTc relationship, common clinically, is limited due to minimal pharmacokinetic (PK) data in nonclinical testing. It is possible, however, to relate the average drug plasma concentration from sparse PK samples over specific times to the mean corrected QTc. We hypothesize that averaging drug plasma concentration and the QTc-rate relationship over time provides a simple, accurate concentration-QTc relationship bridging statistical and concentration/QTc modeling. METHODS: Cardiovascular telemetry studies were conducted in non-human primates (NHP; n = 48) and canines (n = 8). Pharmacokinetic samples were collected on separate study days in both species. Average plasma concentrations for specific intervals (CAverage0-X) were calculated for moxifloxacin in canines and NHP using times corresponding to super-intervals for the QTc data statistical analysis. The QTc effect was calculated for each super-interval using a linear regression correction incorporating QT and HR data from the whole super-interval. The concentration QTc effects were then modeled. RESULTS: In NHP, a 10.9 ± 0.06 ms (mean ± 95% CI) change in QTc was detected at approximately 1.5× the moxifloxacin plasma concentration that causes a 10 ms QTc change in humans, based on a 0-24 h super-interval. When simulating a drug without QT effects, mock, no effect on QTc was detected at up to 3× the clinical concentration. Similarly, in canines, a 16.6 ± 0.1 ms change was detected at 1.7× critical clinical moxifloxacin concentration, and a 0.04 ± 0.1 ms change was seen for mock. CONCLUSIONS: While simultaneous PK and QTc data points are preferred, practical constraints and the need for QTc averaging did not prevent concentration-QTc analyses. Utilizing a 0-24 h super-interval method illustrates a simple and effective method to address cardiovascular questions when preclinical drug exposures exceed clinical concentrations.
Subject(s)
Electrocardiography , Long QT Syndrome , Moxifloxacin , Telemetry , Animals , Dogs , Moxifloxacin/pharmacokinetics , Moxifloxacin/administration & dosage , Electrocardiography/drug effects , Electrocardiography/methods , Telemetry/methods , Long QT Syndrome/chemically induced , Drug Evaluation, Preclinical/methods , Fluoroquinolones/pharmacokinetics , Fluoroquinolones/administration & dosage , Heart Rate/drug effects , Male , Models, Animal , Dose-Response Relationship, Drug , FemaleABSTRACT
INTRODUCTION: Cardiovascular safety and the risk of developing the potentially fatal ventricular tachyarrhythmia, Torsades de Pointes (TdP), have long been major concerns of drug development. TdP is associated with a delayed ventricular repolarization represented by QT interval prolongation in the electrocardiogram (ECG), typically due to block of the potassium channel encoded by the human ether-a-go-go related gene (hERG). Importantly however, not all drugs that prolong the QT interval are torsadagenic and not all hERG blockers prolong the QT interval. Recent clinical reports suggest that partitioning the QT interval into early (J to T peak; JTp) and late repolarization (T peak to T end; TpTe) components may be valuable for distinguishing low-risk mixed ion channel blockers (hERG plus calcium and/or late sodium currents) from high-risk pure hERG channel blockers. This strategy, if true for nonclinical animal models, could be used to de-risk QT prolonging compounds earlier in the drug development process. METHODS: To explore this, we investigated JTp and TpTe in ECG data collected from telemetered dogs and/or monkeys administered moxifloxacin or amiodarone at doses targeting relevant clinical exposures. An optimized placement of the Tpeak fiducial mark was utilized, and all intervals were corrected for heart rate (QTc, JTpc, TpTec). RESULTS: Increases in QTc and JTpc intervals with administration of the pure hERG blocker moxifloxacin and an initial QTc and JTpc shortening followed by prolongation with the mixed ion channel blocker amiodarone were detected as expected, aligning with clinical data. However, anticipated increases in TpTec by both standard agents were not detected. DISCUSSION: The inability to detect changes in TpTec reduces the utility of these subintervals for prediction of arrhythmias using continuous singlelead ECGs collected from freely moving dogs and monkeys.
Subject(s)
Amiodarone , Electrocardiography , Long QT Syndrome , Moxifloxacin , Torsades de Pointes , Animals , Moxifloxacin/administration & dosage , Moxifloxacin/pharmacology , Dogs , Amiodarone/administration & dosage , Amiodarone/pharmacology , Electrocardiography/drug effects , Electrocardiography/methods , Torsades de Pointes/chemically induced , Long QT Syndrome/chemically induced , Long QT Syndrome/physiopathology , Male , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Ether-A-Go-Go Potassium Channels/metabolism , Female , Macaca fascicularis , Fluoroquinolones/administration & dosage , Fluoroquinolones/pharmacology , Heart Rate/drug effects , Potassium Channel Blockers/administration & dosage , Potassium Channel Blockers/pharmacology , ERG1 Potassium Channel/antagonists & inhibitors , ERG1 Potassium Channel/metabolismABSTRACT
BACKGROUND: Determination of a drug's potency in blocking the hERG channel is an established safety pharmacology study. Best practice guidelines have been published for reliable assessment of hERG potency. In addition, a set of plasma concentration and plasma protein binding fraction data were provided as denominators for margin calculations. The aims of the current analysis were five-fold: provide data allowing creation of consistent denominators for the hERG margin distributions of the key reference agents, explore the variation in hERG margins within and across laboratories, provide a hERG margin to 10 ms QTc prolongation based on several newer studies, provide information to use these analyses for reference purposes, and provide recommended hERG margin 'cut-off' values. METHODS: The analyses used 12 hERG IC50 'best practice' data sets (for the 3 reference agents). A group of 5 data sets came from a single laboratory. The other 7 data sets were collected by 6 different laboratories. RESULTS: The denominator exposure distributions were consistent with the ICH E14/S7B Training Materials. The inter-occasion and inter-laboratory variability in hERG IC50 values were comparable. Inter-drug differences were most important in determining the pooled margin variability. The combined data provided a robust hERG margin reference based on best practice guidelines and consistent exposure denominators. The sensitivity of hERG margin thresholds were consistent with the sensitivity described over the course of the last two decades. CONCLUSION: The current data provide further insight into the sensitivity of the 30-fold hERG margin 'cut-off' used for two decades. Using similar hERG assessments and these analyses, a future researcher can use a hERG margin threshold to support a negative QTc integrated risk assessment.
Subject(s)
Ether-A-Go-Go Potassium Channels , Long QT Syndrome , Humans , Risk Assessment/methods , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Long QT Syndrome/chemically induced , ERG1 Potassium Channel/antagonists & inhibitors , ERG1 Potassium Channel/metabolism , Laboratories/standards , Animals , Potassium Channel Blockers/pharmacology , Potassium Channel Blockers/adverse effects , Inhibitory Concentration 50ABSTRACT
OBJECTIVE: To evaluate the effect of favipiravir administered to diabetic and non-diabetic COVID-19 patients on the QT/QTc interval. STUDY DESIGN: Analytical study. Place and Duration of the Study: Republic of Turkey, Ministry of Health, State Hospital, Corlu, Tekirdag, Turkiye, from March to September 2021. METHODOLOGY: Electrocardiogram (ECG) analysis was performed on all participants (n=180) divided into four groups. Group 1 included only healthy volunteers. Group 2 included only cases diagnosed with T2DM. Group 3 included only severe acute respiratory syndrome coronavirus-2 (SARS-Cov-2) cases. Group 4 included cases diagnosed with both SARS and T2DM. Favipiravir was administered only to the cases in Group 3 and Group 4. In the cases that were administered favipiravir, the QT/QTc interval was calculated and recorded at different time intervals on the first and fifth days of the therapy. The difference between groups was determined by Tukeye's test after ANOVA. Pearson's correlation test was used to determine whether there was a linear relationship between two numericals. The alpha significance value was determined to be <0.05 in all statistical analyses. RESULTS: When all groups were compared, it was seen that both QT and QTc values ââincreased in Groups 3 and 4, which were administered favipiravir (p <0.05). Favipiravir may cause an increased risk of ventricular and atrial arrhythmias. CONCLUSION: Favipiravir may cause QT interval prolongation, particularly in SARS-Cov-2 patients diagnosed with T2DM. KEY WORDS: COVID-19, Drug-induced long QT syndrome, Intra-infarct haemorrhage; Favipiravir, Type 2 diabetes mellitus.
Subject(s)
Amides , Antiviral Agents , COVID-19 Drug Treatment , COVID-19 , Diabetes Mellitus, Type 2 , Electrocardiography , Long QT Syndrome , Pyrazines , SARS-CoV-2 , Humans , Pyrazines/therapeutic use , Pyrazines/adverse effects , Amides/therapeutic use , Amides/adverse effects , Male , Female , Middle Aged , Diabetes Mellitus, Type 2/drug therapy , Antiviral Agents/therapeutic use , Antiviral Agents/adverse effects , COVID-19/complications , Long QT Syndrome/chemically induced , Adult , Turkey , AgedABSTRACT
Regimens for the treatment of rifampicin-resistant tuberculosis currently rely on the use of QT-prolonging agents. Using data from the randomized controlled trial, TB-PRACTECAL, we investigated differences in QTcF among participants in the three interventional arms: BPaL (bedaquiline, pretomanid, and linezolid), BPaLC (BPaL with clofazimine), and BPaLM (BPaL with moxifloxacin). Additionally, we assessed whether age, body mass index, and country were causally associated with QTcF prolongation. The trial included participants from South Africa, Uzbekistan, and Belarus. A post hoc analysis of electrocardiogram data was undertaken. Random effects regression was used to model QTcF longitudinally over 24 weeks and causal frameworks guided the analysis of non-randomized independent variables. 328 participants were included in BPaL-based arms. The longitudinal analysis of investigational arms showed an initial QTcF steep increase in the first week. QTcF trajectories between weeks 2 and 24 differed slightly by regimen, with highest mean peak for BPaLC (QTcF 446.5 ms). Overall, there were 397 QTcF >450 ms (of 3,744) and only one QTcF >500 ms. The odds of QTcF >450 ms among participants in any investigational arm, was 8.33 times higher in Uzbekistan compared to Belarus (95% confidence interval: 3.25-21.33). No effect on QTcF prolongation was found for baseline age or body mass index (BMI). Clinically significant QTc prolongation was rare in this cohort of closely monitored participants. Across BPaL-based regimens, BPaLC showed a slightly longer and sustained effect on QTcF prolongation, but the differences (both in magnitude of change and trajectory over time) were clinically unimportant. The disparity in the risk of QTc prolongation across countries would be an important factor to further investigate when evaluating monitoring strategies. CLINICAL TRIALS: This study is registered with ClinicalTrials.gov as NCT02589782.
Subject(s)
Antitubercular Agents , Electrocardiography , Long QT Syndrome , Moxifloxacin , Rifampin , Humans , Rifampin/therapeutic use , Rifampin/adverse effects , Male , Adult , Female , Moxifloxacin/therapeutic use , Moxifloxacin/adverse effects , Antitubercular Agents/adverse effects , Antitubercular Agents/therapeutic use , Long QT Syndrome/chemically induced , Middle Aged , Tuberculosis, Multidrug-Resistant/drug therapy , South Africa , Clofazimine/therapeutic use , Clofazimine/adverse effects , Diarylquinolines/therapeutic use , Diarylquinolines/adverse effects , Republic of BelarusABSTRACT
BACKGROUND: Opioid Agonist Treatment (OAT) is the gold standard for managing Opioid Use Disorder (OUD). It is highly effective at reducing all-cause mortality and drug-related harms. Prescribing OAT, particularly methadone, is becoming increasingly complex as Scotland's OUD population ages. Older patients, with increased polypharmacy and multimorbidity, are more susceptible to QTc interval prolongation associated with methadone use. Therefore, adherence to ECG monitoring guidelines for patients prescribed methadone is crucial, though insights from substance use services indicate suboptimal compliance. Medically Assisted Treatment guidelines established by the Scottish Government advocate for shared care agreements, thus transferring OAT prescribing responsibilities to primary care. Understanding ECG monitoring guideline implementation in non-specialist services is vital for developing safe OAT services in primary care. AIM: This audit assessed adherence to NICE guidelines for ECG monitoring in OUD patients prescribed methadone in a Scottish primary care practice. METHOD: The notes of patients prescribed methadone were assessed using NICE criteria to determine eligibility for ECG monitoring. Eligible patients' medical records were reviewed to identify previous ECG investigations. RESULTS: Of 21 patients prescribed methadone, 16 qualified for ECG monitoring. Only 25% of eligible patients received ECG monitoring per NICE guideline, meaning 75% did not. CONCLUSION: These findings highlight that the issue of poor compliance with ECG monitoring guidelines is not limited to specialist services, but also affects primary care. Further exploration of barriers to guideline implementation is essential. Perhaps more resources are needed to integrate OAT services into primary care, which has taken on increased responsibilities without corresponding investment.
Subject(s)
Electrocardiography , Guideline Adherence , Methadone , Opiate Substitution Treatment , Opioid-Related Disorders , Primary Health Care , Humans , Methadone/therapeutic use , Scotland , Opioid-Related Disorders/drug therapy , Opioid-Related Disorders/diagnosis , Female , Male , Opiate Substitution Treatment/methods , Adult , Middle Aged , Practice Guidelines as Topic , Long QT Syndrome/chemically induced , Long QT Syndrome/diagnosis , Analgesics, Opioid/therapeutic use , Analgesics, Opioid/adverse effectsABSTRACT
Drug-induced QT prolongation (diLQTS), and subsequent risk of torsade de pointes, is a major concern with use of many medications, including for non-cardiac conditions. The possibility that genetic risk, in the form of polygenic risk scores (PGS), could be integrated into prediction of risk of diLQTS has great potential, although it is unknown how genetic risk is related to clinical risk factors as might be applied in clinical decision-making. In this study, we examined the PGS for QT interval in 2500 subjects exposed to a known QT-prolonging drug on prolongation of the QT interval over 500ms on subsequent ECG using electronic health record data. We found that the normalized QT PGS was higher in cases than controls (0.212±0.954 vs. -0.0270±1.003, P = 0.0002), with an unadjusted odds ratio of 1.34 (95%CI 1.17-1.53, P<0.001) for association with diLQTS. When included with age and clinical predictors of QT prolongation, we found that the PGS for QT interval provided independent risk prediction for diLQTS, in which the interaction for high-risk diagnosis or with certain high-risk medications (amiodarone, sotalol, and dofetilide) was not significant, indicating that genetic risk did not modify the effect of other risk factors on risk of diLQTS. We found that a high-risk cutoff (QT PGS ≥ 2 standard deviations above mean), but not a low-risk cutoff, was associated with risk of diLQTS after adjustment for clinical factors, and provided one method of integration based on the decision-tree framework. In conclusion, we found that PGS for QT interval is an independent predictor of diLQTS, but that in contrast to existing theories about repolarization reserve as a mechanism of increasing risk, the effect is independent of other clinical risk factors. More work is needed for external validation in clinical decision-making, as well as defining the mechanism through which genes that increase QT interval are associated with risk of diLQTS.
Subject(s)
Electrocardiography , Long QT Syndrome , Multifactorial Inheritance , Humans , Male , Female , Long QT Syndrome/genetics , Long QT Syndrome/chemically induced , Middle Aged , Multifactorial Inheritance/genetics , Risk Factors , Aged , Adult , Torsades de Pointes/chemically induced , Torsades de Pointes/genetics , Case-Control Studies , Phenethylamines/adverse effects , Genetic Risk Score , SulfonamidesABSTRACT
INTRODUCTION: Guanfacine is a central α2-adrenergic receptor agonist that produces drowsiness, bradycardia, hypotension, and occasionally QT interval prolongation. We discuss giant T waves associated with guanfacine toxicity. CASE SUMMARIES: Three patients presented to the hospital with histories and physical findings compatible with guanfacine toxicity. Supratherapeutic concentrations were confirmed in two of them. All three developed QT interval prolongation and giant T waves on the electrocardiogram. Giant T waves occur commonly in patients with acute myocardial infarct and hyperkalemia, as well as rarely with a number of other cardiac and non-cardiac causes. CONCLUSION: Guanfacine toxicity may cause the novel electrocardiographic finding of 'giant T wave with QT interval prolongation'. Further studies are warranted to investigate the association between the novel electrocardiographic finding and guanfacine toxicity, as well as its diagnostic utility in such cases.