QTc Interval Prolongation In Patients Research Articles

The Effects of Cycle Ergometer Versus Treadmill Exercise Stress Testing on QTc Interval Prolongation in Patients With Long QT Syndrome: A Systematic Review and Meta-analysis.

The safest and most effective exercise stress tests (EST) modalities for long QT syndrome (LQTS) are currently unknown. The main objective was to explore the effects of EST on the corrected QT interval (QTc) in patients with LQTS, and to compare the effects of different EST modalities (cycle ergometer vs treadmill). Systematic searches were performed in September 2022 in accordance with the PRISMA statement through PubMed, Medline, EBM Reviews, Embase, and Web of Science. A total of 1728 patients with LQTS, whether congenital or acquired, without any age restrictions (pediatric age ≤18 years and adult age >19 years), and 2437 control subjects were included in the 49 studies. The QT interval data were available for 15 studies. Our analyses showed that the QT interval prolonged in a similar manner using either a cycle ergometer or a treadmill (standardized mean difference [SMD] = 1.89 [95% CI, 1.07-2.71] vs SMD = 1.46 [95% CI, 0.78-2.14], respectively). Therefore, it seems that either modality may be used to evaluate patients with LQTS. The methodology for the measurement of the QT interval was very heterogeneous between studies, which inevitably influenced the quality of the analyses. Hence, researchers should proceed with caution when exploring and interpreting data in the field of exercise and LQTS.

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.

Factors of QTc interval prolongation in patients with arterial hypertension

The relevance of determining the factors of the prolonged QTc interval development in patients with arterial hypertension is high, as it solves the issue of preliminary diagnosis among patients from risk groups and allows adjusting the diagnostic and therapeutic tactics of managing such patients. Aim: to determine factors for the development of prolonged average daily QTc interval in patients with arterial hypertension. Materials and methods. The study included 195 patients with arterial hypertension, who were divided into 2 subgroups: 175 individuals with a normal average daily duration of the QTc interval and 20 patients with a prolonged average daily duration of the QTc interval. All the patients underwent 24-hour heart rate monitoring and determination of blood pressure variability. At the stage of involving patients in the study, the following were performed: anamnesis collection and determination of physical data (estimation of systolic and diastolic blood pressure). Results. The study has revealed risk factors of daily QTc interval prolongation in hypertensive patients with further developing a prognostic model with high sensitivity (88.9 %) and specificity (70.6 %). Prolongation of QTc in patients with hypertension was associated with such parameters: male sex (OR = 4.292 [95.0 % CI 1.337–13.779], Р = 0.014), body mass index (OR = 1.107 [95.0 % CI 0.987–1.243], Р = 0.083), mean 24-hour diastolic (OR = 1.076 [95.0 % CI 1.017–1.139], Р = 0.011) and pulse blood pressure (OR = 1.075 [95.0 % CІ 1.012–1.141], Р = 0.018), time since hypertension was diagnosed (OR = 1.093 [95.0 % CI 0.997–1.197], Р = 0.057) and office pulse blood pressure (OR = 0.948 [95.0 % CІ 0.900–0.999], Р = 0.046). Conclusions. The study has determined risk factors of developing a prolonged average daily QTc interval in patients with hypertension, which will allow correcting diagnostic and treatment tactics of management for patients from risk groups.

Heart rate-corrected QT interval prolongation is associated with decreased heart rate variability in patients with type 2 diabetes.

We investigated the association between the heart rate-corrected QT interval (QTc interval) measured by standard electrocardiography and heart rate variability (HRV) in patients with type 2 diabetes mellitus (T2DM). From March 1, 2009, to December 12, 2009, 411 patients with T2DM who underwent resting 12-lead electrocardiography and cardiovascular autonomic function testing concurrently without the exclusion criteria were consecutively recruited in this cross-sectional study. Time- and frequency-domain HRV variables were assessed for 5 minutes by beat-to-beat HRV recording. The QT interval was corrected for the heart rate using Bazett's formula. QTc interval measurements of >440 ms were considered abnormally prolonged. The mean age and diabetes duration were 56.3 ± 10.6 years and 9.6 ± 7.3 years, respectively. A total of 90 patients had QTc interval prolongation (21.9%). The participants with a prolonged QTc interval were older (59.4 ± 10.1 years vs 55.5 ± 10.6 years, P = .002), were more likely to be a woman (72.2% vs 51.7%, P = .001), had a higher prevalence of hypertension (46.7% vs 33.4%, P = .022), had a higher hemoglobin A1c level (8.8% ± 2.2% vs 8.2% ± 1.8%, P = .045), and had decreased values for the variables measuring HRV, except for the low frequency (LF)/high frequency (HF) ratio (total power [TP], 147.7 [74.1-335.9] ms vs 328.7 [185.7-721.7] ms, P = .002). After adjusting for multiple confounders, QTc interval prolongation was associated with the lowest quartile of the HRV parameters of TP (odds ratio [OR] = 3.99; 95% confidence interval [CI]: 2.29-6.96), HF (OR = 3.20; 95% CI: 1.84-5.58), LF (OR = 3.68; 95% CI: 2.10-6.43), standard deviation of the normal-to-normal interval (OR = 3.31; 95% CI: 1.89-5.77), and root-mean-square of the successive differences (OR = 1.98; 95% CI: 1.13-3.47) in patients with T2DM. Decreased values for the variables measuring HRV, except for the LF/HF ratio, might be associated with QTc interval prolongation in patients with T2DM.

C-reactive Protein Elevation Is Associated With QTc Interval Prolongation in Patients Hospitalized With COVID-19.

BackgroundThe relationship between inflammation and corrected QT (QTc) interval prolongation is currently not well defined in patients with COVID-19.ObjectiveThis study aimed to assess the effect of marked interval changes in the inflammatory marker C-reactive protein (CRP) on QTc interval in patients hospitalized with COVID-19.MethodsIn this retrospective cohort study of hospitalized adult patients admitted with COVID-19 infection, we identified 85 patients who had markedly elevated CRP levels and serial measurements of an ECG and CRP during the same admission. We compared mean QTc interval duration, and other clinical and ECG characteristics between times when CRP values were high and low. We performed mixed-effects linear regression analysis to identify associations between CRP levels and QTc interval in univariable and adjusted models.ResultsMean age was 58 ± 16 years, of which 39% were women, 41% were Black, and 25% were White. On average, the QTc interval calculated via the Bazett formula was 15 ms higher when the CRP values were “high” vs. “low” [447 ms (IQR 427–472 ms) and 432 ms (IQR 412–452 ms), respectively]. A 100 mg/L increase in CRP was associated with a 1.5 ms increase in QTc interval [β coefficient 0.15, 95% CI (0.06–0.24). In a fully adjusted model for sociodemographic, ECG, and clinical factors, the association remained significant (β coefficient 0.14, 95% CI 0.05–0.23).ConclusionAn interval QTc interval prolongation is observed with a marked elevation in CRP levels in patients with COVID-19.

QTc interval prolongation in patients infected with SARS-CoV-2 and treated with antiviral drugs

IntroductionMany antiviral agents, such as hydroxychloroquine, have been used to treat COVID-19, without being broadly accepted. QTc prolongation is a worrisome adverse effect, scarcely studied in pediatrics. Patients and methodsPaediatric patients affected from COVID-19 who received antivirals were matched (1:2) with controls not infected nor exposed. Electrocardiograms were prospectively analyzed at baseline, during the first 72 h of treatment and after 72 h. ResultsEleven (22.9%) out of 48 patients admitted due to COVID-19 (March–July 2020) received antiviral therapy. All had underlying diseases: congenital heart disease (4/11; 36.4%) and immunosuppression (3/11; 27.3%) stand out. 5/11 (45.5%) received treatment at baseline with a potential effect on QTc. There where no differences observed in the baseline QTc between cases and controls: 414.8 ms (49.2) vs 416.5 ms (29.4), (P = .716). Baseline long QT was observed in 2/11 cases and 2/22. Among cases, 10/11 (90.9%) received hydroxychloroquine, mainly associated with azithromycin (8/11; 72.7%), 3 received lopinavir/ritonavir and one remdesivir. The median increase in QTc after 72 h under treatment was 28.9 ms [IQR 48.7] (P = .062). 4/11 (36.4%) patients had a long QTc at 72 h, resulting in 3 patients ≥500 ms; treatment was stopped in one (QTc 510 ms) but ventricular arrhythmias were not documented. ConclusionsThe use of antivirals caused an increase on the QTc interval after 72 h of treatment, being the QTc long in 36.3% of the patients, although no arrhythmic events were observed. The use of hydroxychloroquine and antivirals requires active QTc monitoring and it is recommended to discontinue treatment if QTc > 500 ms.

QTc interval prolongation in the patients with primary biliary cholangitis.

BackgroundThe QT interval prolongation was associated with fatal arrhythmias and cardiac death. However, there were not adequate data to clarify the situation of QT interval prolongation in primary biliary cholangitis (PBC) patients. The aim of this study was to clarify the rate and the associated risk factors of corrected QT (QTc) interval prolongation in PBC patients.MethodsFrom January 2016 to December 2020, PBC patients were retrospectively enrolled. The rate of QTc interval prolongation was surveyed and the associated risk factors were clarified by univariate and multivariate analyses.ResultsAmong the 189 PBC patients, 24.3% (46/189) had the QTc interval prolongation. The univariate analysis showed that age, Child‐Pugh classification, creatinine, international normalized ratio (INR), and platelet (PLT) were associated with QTc interval prolongation in the PBC patients. The multivariate analysis further showed only age (p = .028) and Child‐Pugh classification (p = .035) were the associated risk factors. It had the highest risk of QTc interval prolongation (as high as 64.3%) in the patients who were more than 62.5 years old and with Child‐Pugh C.ConclusionThe QTc interval prolongation was frequent in PBC patients, especially in the patients with decompensated cirrhosis. The rate of QTc interval prolongation was as high as 64.3% in the PBC patients who were more than 62.5 years old and classified as Child‐Pugh C.

Suppression of Electrographic Seizures Is Associated with Amelioration of QTc Interval Prolongation in Patients with Traumatic Brain Injury.

Introduction: Disorders in electroencephalography (EEG) are commonly noted in patients with traumatic brain injury (TBI) and may be associated with electrocardiographic disturbances. Electrographic seizures (ESz) are the most common features in these patients. This study aimed to explore the relationship between ESz and possible changes in QTc interval and spatial QRS-T angle both during ESz and after ESz resolution. Methods: Adult patients with TBI were studied. Surface 12-lead ECGs were recorded using a Cardiax device during ESz events and 15 min after their effective suppression using barbiturate infusion. The ESz events were diagnosed using Masimo Root or bispectral index (BIS) devices. Results: Of the 348 patients considered for possible inclusion, ESz were noted in 72, with ECG being recorded in 21. Prolonged QTc was noted during ESz but significantly ameliorated after ESz suppression (540.19 ± 60.68 ms vs. 478.67 ± 38.52 ms, p < 0.001). The spatial QRS-T angle was comparable during ESz and after treatment. Regional cerebral oximetry increased following ESz suppression (from 58.4% ± 6.2 to 60.5% ± 4.2 (p < 0.01) and from 58.2% ± 7.2 to 60.8% ± 4.8 (p < 0.05) in the left and right hemispheres, respectively). Conclusion: QTc interval prolongation occurs during ESz events in TBI patients but both it and regional cerebral oximetry are improved after suppression of seizures.

QTc interval prolongation in patients with systemic lupus erythematosus treated with hydroxychloroquine

Objectives The primary objective is to reveal the effect of hydroxychloroquine (HCQ) treatment on corrected QT (QTc) interval in patients with systemic lupus erythematosus (SLE). The secondary objective is to investigate factors that affect QTc prolongation. Methods SLE patients who had electrocardiograms between 2015 and 2020 were recruited and assigned to two groups based on whether they were treated with HCQ (HCQ group) or not (control group). Change of QTc before and after HCQ administration in the HCQ group was measured and compared with the control group. Patients treated with HCQ were further divided into two groups based on presence or absence of QTc prolongation and the characteristics were compared. Results In total, 126 patients were recruited, of whom 42 were treated with HCQ. In the HCQ group, the mean QTc significantly increased (p < .001), while there was no significant difference of mean QTc in the control group. Moreover, those in the HCQ group with QTc prolongation showed a significantly higher proportion of hypertension and longer SLE duration compared to those without QTc prolongation. However, the multiple logistic regression analysis showed that there were no significant differences among them. Conclusion HCQ could induce QTc prolongation in SLE patients. It might be better that the possibility of QTc prolongation was taken into consideration when HCQ was administered in the patients with longer disease duration of SLE and coincidence of hypertension.

Corrected QT interval in hospitalized patients with coronavirus disease 2019: Focus on drugs therapy.

Corrected QT (QTc) interval prolongation has been associated with poor patient prognosis. In this study, we assessed the effects of different drugs and cardiac injury on QTc interval prolongation in patients with coronavirus disease 2019 (COVID-19).The study cohort consisted of 395 confirmed COVID-19 cases from the Wuhan Union Hospital West Campus. All hospitalized patients were treated with chloroquine/hydroxychloroquine (CQ/HCQ), lopinavir/ritonavir (LPV/r), quinolones, interferon, Arbidol, or Qingfei Paidu decoction (QPD) and received at least 1 electrocardiogram after drug administration.Fifty one (12.9%) patients exhibited QTc prolongation (QTc ≥ 470 ms). QTc interval prolongation was associated with COVID-19 severity and mortality (both P < .001). Administration of CQ/HCQ (odds ratio [OR], 2.759; 95% confidence interval [CI], 1.318–5.775; P = .007), LPV/r (OR, 2.342; 95% CI, 1.152–4.760; P = .019), and quinolones (OR, 2.268; 95% CI, 1.171–4.392; P = .015) increased the risk of QTc prolongation. In contrast, the administration of Arbidol, interferon, or QPD did not increase the risk of QTc prolongation. Notably, patients treated with QPD had a shorter QTc duration than those without QPD treatment (412.10 [384.39–433.77] vs 420.86 [388.19–459.58]; P = .042). The QTc interval was positively correlated with the levels of cardiac biomarkers (creatine kinase-MB fraction [rho = 0.14, P = .016], high-sensitivity troponin I [rho = .22, P < .001], and B-type natriuretic peptide [rho = 0.27, P < .001]).In conclusion, QTc prolongation was associated with COVID-19 severity and mortality. The risk of QTc prolongation was higher in patients receiving CQ/HCQ, LPV/r, and quinolones. QPD had less significant effects on QTc prolongation than other antiviral agents.

Qtc interval prolongation during targeted therapy with tyrosine kinase inhibitors for patients with chronic myeloid leukemia

Background The advances in the treatment of chronic myeloid leukemia using tyrosine kinase inhibitors have led to unequivocal improvement in the survival of those patients. However, the effect of tyrosine kinase inhibitors on cardiac repolarization causing QT interval prolongation and the potential risk of life-threatening arrhythmia Torsade de pointes poses a challenging risk.Objective The objective of this study was to assess the prevalence of QTc interval prolongation in patients with chronic myeloid leukemia receiving imatinib or nilotinib therapy.Patients and methods A total of 43 patients were included in this cross-sectional study, where 22 patients were on nilotinib and 21 patients were on imatinib. Electrocardiogram was done for patients while on tyrosine kinase inhibitors (TKI) therapy. Corrected QTc interval was assessed using Bazett’s formula.Results The prevalence of QTc prolongation in the total cohort of patients was 46.5%. Moreover, 23.3% of patients had QTc more than or equal to 500 ms. The mean QTc in patients receiving imatinib was 467 ms, whereas the mean QTc in patients on nilotinib was 433.5 ms, with a statistically significant difference (P=0.033). Overall, 61.9% of patients on imatinib had prolonged QTc compared with 31.8% of patients on nilotinib, with a statistically significant difference (P=0.048). However, although nonstatistically significant, the median QTc percentage prolongation for patients on nilotinib is 10.8 compared with 5.1 for patients on imatinib. No statistically significant sex difference was found; however, the mean QTc was higher in females (455.93 ms) compared with males (439.69 ms) (P=0.327). No significant difference was found between QTc and duration of TKI use or correlation between QTc and age.Conclusion The prevalence of QTc prolongation is significantly increased in patients with chronic myeloid leukemia (CML) treated with either imatinib or nilotinib. ECG monitoring in those patients is strongly recommended to prevent life-threatening arrhythmias.

Prevalence of QTc Interval Prolongation in Patients with Chronic Myeloid Leukemia Treated with Tyrosine Kinase Inhibitors

Prevalence of QTc Interval Prolongation in Patients with Chronic Myeloid Leukemia Treated with Tyrosine Kinase Inhibitors

Protective effect of acquired long QT syndrome in Takotsubo syndrome.

Clinical variables that predict long-term mortality and recurrence of Takotsubo syndrome (TTS) are not completely understood as the role of acquired corrected QT interval (QTc) prolongation. To detect the prevalence of QTc interval prolongation in patients with TTS and to evaluate its long-term prognostic impact. QTc intervals were analysed in 105 patients presenting with symptoms of TTS. These patients were included in an ongoing retrospective cohort database. The cohort was subsequently subdivided into two groups based on the presence (long QT (LQT) group, n = 73, 69.52%) or absence (non-long QT (non-LQT) group, n = 32, 30.43%) of QTc interval prolongation. Patients were followed up over a mean period of 4.2 years. The rate of life-threatening arrhythmia during the first 30 days in the LQT group was comparable with the non-LQT group (10.9 vs 12.5%), whereas in-hospital mortality and 30-day mortality occurred less frequently in the LQT group (2.7 vs 18.75%, P < 0.01). During this time span, 17 (23.3%) patients with acquired LQT syndrome died, whereas 14 (43.7%) patients with non-LQT duration died. Kaplan-Meier survival rates were significantly higher in the LQT group than those in the non-LQT group (Log-rank-test, P = 0.02). On multivariate analysis, the QTc interval was an independent negative predictor of all-cause mortality (P = 0.02). The QTc interval at admission is an independent negative predictor of long-term adverse outcome in patients with TTS.

Frequency, characteristics and nature of risk factors associated with use of QT interval prolonging medications and related drug-drug interactions in a cohort of psychiatry patients

Quite a number of antipsychotic and antidepressant drugs are known to cause significant QT-prolongation. Psychiatric patients constitute a population at notable risk of drug-induced QT-prolongation. The aims were to explore frequency of use of QTc-interval prolonging agents and QT-prolonging drug-drug interactions, and prevalence of risk factors for QTc-interval prolongation in patients reporting to psychiatry out-patient department (OPD) in a tertiary care hospital in India. This prospective cross-sectional study was carried out in the psychiatry OPD at All India Institute of Medical Sciences (AIIMS), Rishikesh, Uttarakhand, India from October 1, 2017 to September 30, 2018 using the relevant prescriptions (i.e., the OPD case record forms and treatment sheets). For each patient, the entire medication list was analyzed for the possibility of interactions, with particular attention on the high-risk QT prolonging ones. Arizona Center for Education and Research on Therapeutics (AZCERT) QT drug lists were used to classify TdP risks of psychotropic and other medications. One thousand three hundred twenty-six (1326) patients attending the psychiatry OPD during the study period were scrutinized. Seven hundred fifty-one 751 patients (56.6%) were males whereas 575 (43.4%) were females in our study. Of the 1326 patients, 636 patients (47.9%) were identified as receiving interacting medications with the ability to induce torsades de pointe (TdP). Nine hundred seventeen (917) interacting medication pairs with torsadogenic risk were encountered. The most frequently interacting medications were from antipsychotic (794), antidepressant (519), antimicrobial (84), proton pump inhibitor (80), anticonvulsant (66), and anti-nausea (25) therapeutic categories. As per AZCERT classification (CredibleMeds TdP risk-stratification lists), 597 (36.8%), 443 (27.3%) and 432 (26.7%) of the interacting medications were associated with known, possible, and conditional risk of TdP, respectively. Concurrent prescriptions of QT-prolonging drugs is frequent in psychiatry OPD setting. Appropriate precautions should be instituted to obviate undesirable outcomes arising out of these interactions. This highlights the pressing need for clear protocols & strategies for implementation to motivate careproviders with clarity in the context of drug use guidelines for rational and safe prescribing in psychiatry.

Clinical Factors associated with QTc interval prolongation in patients treated with beta-lactam antibiotics plus inhibitors of beta-lactamase

Clinical Factors associated with QTc interval prolongation in patients treated with beta-lactam antibiotics plus inhibitors of beta-lactamase

Arterial Stiffness Is Associated With QTc Interval Prolongation in Patients With Heart Failure.

A prolonged corrected QT (QTc) interval is a known risk factor for adverse cardiac events. Understanding the determinants and physiologic correlates of QTc is necessary for selecting proper strategies to reduce the risk of adverse events in high-risk patients. We sought to evaluate the role of arterial stiffness in heart failure as a determinant of QTc prolongation. This was an observational study that recruited ambulatory heart failure patients (New York Heart Association Classes I-II) from an outpatient heart failure clinic. In the supine resting position, consented patients underwent noninvasive 12-lead electrocardiograph (ECG) and hemodynamic monitoring using BioZ Dx impedance cardiography. ECGs were evaluated by a reviewer blinded to clinical data, and QTc interval was automatically computed. Patients with pacing or bundle branch block (BBB) were analyzed separately. Strengths of associations were evaluated using Pearson's r coefficients and multivariate linear regression. The final sample ( N = 44) was 62 ± 13 years of age and 64% male with ejection fraction of 34% ± 12%. At univariate level, QTc interval moderately ( r > .50) correlated with cardiac output, left cardiac work index, systemic vascular resistance, and total arterial compliance in patients with intrinsically narrow QRS complexes. At the multivariate level, increasing systemic vascular resistance and decreasing total arterial compliance remained independent predictors of widening QTc interval in this group ( R2 = .54). No significant correlations were seen in patients with pacing or BBB. In the absence of conduction abnormalities, magnitude of arterial stiffness, an indirect measure of endothelial dysfunction, is associated with QTc interval prolongation.

Prospective evaluation of QTc-interval prolongation in patients with advanced ovarian cancer after treatment with carboplatin, paclitaxel and bevacizumab

Prospective evaluation of QTc-interval prolongation in patients with advanced ovarian cancer after treatment with carboplatin, paclitaxel and bevacizumab

Hyperbaric oxygen therapy reduces the risk of QTc interval prolongation in patients with diabetes and hard-to-heal foot ulcers

AimsHeart rate corrected QT (QTc) interval prolongation is a risk factor associated with increased mortality. Hyperbaric oxygen therapy (HBO) has previously been shown to have acute beneficial effects on QTc dispersion. The aim of this study was to evaluate long-term effects of HBO on QTc time in diabetic patients with hard-to-heal foot ulcers. MethodsIn a prospective, double-blinded placebo-controlled study, patients were randomized to 40 treatment sessions with either HBO or air (placebo), at 2.5 ATA. Patients fulfilling >35 completed treatment sessions were included in the evaluation. ResultsOf the initial 75 patients (38 HBO/37 placebo), two were excluded due to pacemaker use. Baseline characteristics were similar between groups. At the 2-year follow-up, QTc time was significantly shorter in the HBO compared to the placebo group (438 vs. 453ms, p<0.05). Further, fewer HBO treated patients had a QTc time >450ms (22 vs. 53 %, p<0.02). This difference seemed to be caused by a significant prolongation of the QTc interval in the placebo group (427 (419–459) at baseline vs. 456ms (424–469) after 2years), whereas no significant change was seen in HBO treated patients. ConclusionsHBO treatment might protect against QTc prolongation in this high-risk diabetic population.

The role of concentration-effect relationships in the assessment of QTc interval prolongation.

Population pharmacokinetic and pharmacokinetic-pharmacodynamic (PKPD) modelling has been widely used in clinical research. Yet, its application in the evaluation of cardiovascular safety remains limited, particularly in the evaluation of pro-arrhythmic effects. Here we discuss the advantages of disadvantages of population PKPD modelling and simulation, a paradigm built around the knowledge of the concentration-effect relationship as the basis for decision making in drug development and its utility as a guide to drug safety. A wide-ranging review of the literature was performed on the experimental protocols currently used to characterize the potential for QT interval prolongation, both pre-clinically and clinically. Focus was given to the role of modelling and simulation for design optimization and subsequent analysis and interpretation of the data, discriminating drug from system specific properties. Cardiovascular safety remains one of the major sources of attrition in drug development with stringent regulatory requirements. However, despite the myriad of tests, data are not integrated systematically to ensure accurate translation of the observed drug effects in clinically relevant conditions. The thorough QT study addresses a critical regulatory question but does not necessarily reflect knowledge of the underlying pharmacology and has limitations in its ability to address fundamental clinical questions. It is also prone to issues of multiplicity. Population approaches offer a paradigm for the evaluation of drug safety built around the knowledge of the concentration-effect relationship. It enables quantitative assessment of the probability of QTc interval prolongation in patients, providing better guidance to regulatory labelling and understanding of benefit/risk in specific populations.

Brentuximab vedotin does not cause clinically relevant QTc interval prolongation in patients with CD30-positive hematologic malignancies

Brentuximab vedotin (ADCETRIS®), an antibody-drug conjugate, comprises an anti-CD30 antibody conjugated by a protease-cleavable linker to a microtubule-disrupting agent, monomethyl auristatin E (MMAE). In vitro studies showed that MMAE does not interfere with hERG K+ channels at clinically relevant concentrations. In pivotal phase 2 clinical trials in patients with relapsed or refractory Hodgkin lymphoma and systemic anaplastic large cell lymphoma, brentuximab vedotin has shown substantial efficacy and an acceptable safety profile. This phase 1 open-label study was designed to evaluate the effect of brentuximab vedotin on the duration of cardiac ventricular repolarization. Patients with CD30-positive hematologic malignancies were treated with 1.8 mg/kg brentuximab vedotin by intravenous infusion every 3 weeks for up to 16 cycles. The primary endpoint was the change from baseline to Cycle 1 Days 2, 3, and 4 in the duration of ventricular repolarization using Fridericia's corrected QT interval (QTcF). There was no clinically meaningful change from baseline in the duration of ventricular repolarization as measured by QTcF in the 46 evaluable patients out of 52 total patients treated with brentuximab vedotin. There was no evidence of treatment-emergent cardiac safety abnormalities. Brentuximab vedotin was generally well tolerated with a response rate and an adverse event profile consistent with prior studies. There is no significant prolongation of the QT/QTc interval with brentuximab vedotin in patients with CD30-positive hematologic malignancies.