Verinurad does not prolong QTc interval: a thorough QT study using concentration-QTc modelling.

AIM: This thorough QT/QTc (TQT) study was conducted to evaluate the risk of QT prolongation for verinurad when combined with allopurinol. Verinurad is a novel, urate anion exchanger 1 inhibitor that reduces serum urate levels by promoting urinary excretion of uric acid. It is co-administered with a xanthine oxidase inhibitor. METHODS: The TQT study (NCT04256629) was a randomized, placebo-controlled, double-blind, three-period, crossover study, conducted in healthy volunteers. A total of 24 participants received single doses of verinurad 24 mg extended release, 40 mg immediate release formulation (both co-administered with allopurinol 300 mg), and matching placebos. The primary endpoint was baseline- and placebo-adjusted Fridericia-corrected QTcF interval (ΔΔQTcF) at the concentration of interest. A prespecified linear mixed-effects concentration-QTc model was used to estimate the primary endpoint. Time-matched 12-lead digital electrocardiograms and plasma concentrations were measured at baseline and up to 48 h after dose in each participant. RESULTS: Estimated ΔΔQTcF at the highest clinically relevant scenario (76 ng/mL) was -2.7 msec (90% confidence interval [CI]: -4.6, -0.8). Furthermore, the upper 90% ΔΔQTcF CI was estimated to be below 10 msec at all observed verinurad concentrations. Supratherapeutic verinurad dose was used to achieve exposures eightfold higher than the highest clinically relevant exposure, thus waiving the need for positive control. CONCLUSIONS: As the effect on ΔΔQTcF was below the threshold for regulatory concern (10 msec) at the supratherapeutic exposure, it can be concluded that verinurad and allopurinol treatment does not induce QTcF prolongation at the highest clinically relevant exposures.

The U-wave: A remaining enigma of the electrocardiogram.

The U-wave's electrophysiological origin remains unknown and is subject to debate. It is rarely used for diagnosis in clinical practice. The aim of this study was to review new information regarding the U-wave. Further to present the proposed theories behind the U-wave's origin along with potential pathophysiologic and prognostic implications related to its presence, polarity and morphology. METHOD: Literature searches were conducted to retrieve publications related to the electrocardiogram U-wave in the literature database Embase. RESULTS: The review of the literature revealed the following major theories that will be discussed; late depolarisation, delayed or prolonged repolarisation, electro-mechanical stretch and IK1 dependent intrinsic potential differences in the terminal part of the action potential. Various pathologic conditions were found to correlate with the presence and properties of the U-wave, such as its amplitude and polarity. Abnormal U-waves can, for example, be observed in coronary artery disease with ongoing myocardial ischemia or infarction, ventricular hypertrophy, congenital heart disease, primary cardiomyopathy and valvular defects. Negative U-waves are highly specific for the presence of heart diseases. Concordantly negative T- and U-waves are especially associated with cardiac disease. Patients with negative U-waves tend to have higher blood pressure and history of hypertension, higher heart rate, cardiac disease and left ventricular hypertrophy compared to subjects with normal U-waves. Negative U-waves have been found to be associated with increased risk of all-cause mortality, cardiac death and cardiac hospitalisation in men. CONCLUSIONS: The origin of the U-wave is still not established. U-wave diagnostics may reveal cardiac disorders and the cardiovascular prognosis. Including the U-wave characteristics in the clinical ECG assessment may be useful.

Ticagrelor does not impact patient-reported pain in young adults with sickle cell disease: a multicentre, randomised phase IIb study.

Ticagrelor is an antiplatelet agent for adults with coronary artery disease. The inhibition of platelet activation may decrease the frequency of vaso-occlusion crisis (VOC) in sickle cell disease (SCD). The HESTIA2 study (NCT02482298) randomised 87 adults with SCD (aged 18-30 years) 1:1:1 to twice-daily ticagrelor 10, 45 mg or placebo for 12 weeks. Numerical decreases from baseline in mean proportion of days with patient-reported pain (primary endpoint) were seen in all three groups, as well as in pain intensity and analgesic use, with no significant differences between placebo and ticagrelor treatment groups. Plasma ticagrelor concentrations and platelet inhibition increased with dose. Adverse events were distributed evenly across groups and two non-major bleeding events occurred per group. Ticagrelor was well tolerated with a low bleeding risk, but no effect on diary-reported pain was detected. Potential effects on frequency of VOCs will need to be evaluated in a larger and longer study.

The evaluation and management of drug effects on cardiac conduction (PR and QRS intervals) in clinical development.

Recent advances in electrocardiographic monitoring and waveform analysis have significantly improved the ability to detect drug-induced changes in cardiac repolarization manifested as changes in the QT/corrected QT interval. These advances have also improved the ability to detect drug-induced changes in cardiac conduction. This White Paper summarizes current opinion, reached by consensus among experts at the Cardiac Safety Research Consortium, on the assessment of electrocardiogram-based safety measurements of the PR and QRS intervals, representing atrioventricular and ventricular conduction, respectively, during drug development.

The signal-averaged electrocardiogram before and after electrical cardioversion of persistent atrial fibrillation-implications of the sudden change in rhythm.

BACKGROUND: Atrial fibrillation (AF), electrical cardioversion (direct current, or DC) shock energy, and a sudden change to sinus rhythm (SR) might all influence the interpretation of the signal-averaged electrocardiogram (SAECG) as risk markers of ventricular tachyarrhythmia. METHODS: The SAECG was recorded in 82 patients with persistent AF before and 2 hours after DC and analyzed for ventricular late potentials (LPs) and spectral turbulence. RESULTS: Sixty-nine patients (84%) obtained SR. Their mean (SD) heart rate decreased by 22 (20) beats/min, and the QTcF interval was significantly prolonged, 17 (38) milliseconds, as was the filtered QRS duration, 1.1 (4.7) milliseconds (40 Hz). The proportion of LP positivity (20%) did not change with the change in rhythm. Eight of 60 spectral turbulence-negative patients before DC became positive after DC (P = .01). The change in SAECG variables did not correlate significantly with the amount of energy delivered at DC. CONCLUSION: The LP analysis provided similar results in AF and SR, whereas the spectral turbulence analysis was more abnormal in SR. The electrical shock itself did not seem to explain this phenomenon.

Drug-induced myocardial dysfunction - recommendations for assessment in clinical and pre-clinical studies.

Introduction: Drug-induced myocardial dysfunction is an important safety concern during drug development. Oncology compounds can cause myocardial dysfunction, leading to decreased left ventricular ejection fraction and heart failure via several mechanisms. Cardiovascular imaging has a major role in the early detection and monitoring of cardiotoxicity. Echocardiography is the method of choice because of its widespread availability, low cost, and absence of radiation exposure. Cardiac magnetic resonance imaging can provide better reliability, reproducibility, and accuracy in the detection of drug-induced myocardial dysfunction. In addition, it enables assessment of myocardial edema, fibrosis, and necrosis. Cardiac serologic biomarkers such as troponins and B-type natriuretic peptides are used in combination with imaging during drug development. This article provides a general overview of each imaging modality and practical guidance for early detection and monitoring of cardiotoxicity.Areas covered: Cardiovascular imaging modalities and cardiac biomarkers for monitoring of cardiac function and early detection of drug-induced myocardial dysfunction in drug development.Expert opinion: Some new drugs especially in the oncology field, can cause myocardial dysfunction. Depending on the strength of pre-clinical or clinical data, CV imaging modalities and cardiac biomarkers play an important role in the early detection and mitigation plans for such drugs during their development.

The cancer patient and cardiology.

Advances in cancer treatments have improved clinical outcomes, leading to an increasing population of cancer survivors. However, this success is associated with high rates of short- and long-term cardiovascular (CV) toxicities. The number and variety of cancer drugs and CV toxicity types make long-term care a complex undertaking. This requires a multidisciplinary approach that includes expertise in oncology, cardiology and other related specialties, and has led to the development of the cardio-oncology subspecialty. This paper aims to provide an overview of the main adverse events, risk assessment and risk mitigation strategies, early diagnosis, medical and complementary strategies for prevention and management, and long-term follow-up strategies for patients at risk of cancer therapy-related cardiotoxicities. Research to better define strategies for early identification, follow-up and management is highly necessary. Although the academic cardio-oncology community may be the best vehicle to foster awareness and research in this field, additional stakeholders (industry, government agencies and patient organizations) must be involved to facilitate cross-discipline interactions and help in the design and funding of cardio-oncology trials. The overarching goals of cardio-oncology are to assist clinicians in providing optimal care for patients with cancer and cancer survivors, to provide insight into future areas of research and to search for collaborations with industry, funding bodies and patient advocates. However, many unmet needs remain. This document is the product of brainstorming presentations and active discussions held at the Cardiovascular Round Table workshop organized in January 2020 by the European Society of Cardiology.

Acute evaluation of transthoracic impedance vectors using ICD leads.

BACKGROUND: Minute ventilation (MV) has been proven to be very useful in rate responsive pacing. The aim of this study was to evaluate the feasibility of using implantable cardioverter-defibrillator (ICD) leads as part of the MV detection system. METHODS: At implant in 10 patients, the transthoracic impedance was measured from tripolar ICD, tetrapolar ICD, and atrial lead vectors during normal, deep, and shallow voluntary respiration. MV and respiration rate (RespR) were simultaneously measured through a facemask with a pneumotachometer (Korr), and the correlations with impedance-based measurements were calculated. Air sensitivity was the change in impedance per change in respiratory tidal volume, ohms (Omega)/liter (L), and the signal-to-noise ratio (SNR) was the ratio of the respiratory and cardiac contraction components. RESULTS: The air sensitivity and SNR in tripolar ICD vector were 2.70 +/- 2.73 ohm/L and 2.19 +/- 1.31, respectively, and were not different from tetrapolar. The difference in RespR between tripolar ICD and Korr was 0.2 +/- 1.91 breaths/minute. The regressed correlation coefficient between impedance MV and Korr MV was 0.86 +/- 0.07 in tripolar ICD. CONCLUSIONS: The air sensitivity and SNR in tripolar and tetrapolar ICD lead vectors did not differ significantly and were in the range of the values in pacemaker leads currently used as MV sensors. The good correlations between impedance-based and Korr-based RespR and MV measurements imply that ICD leads may be used in MV sensor systems.

Drug-induced blood pressure increase - recommendations for assessment in clinical and non-clinical studies.

INTRODUCTION: Changes in blood pressure (BP) are now proactively examined throughout the drug development process as an integral aspect of safety monitoring. This is because hypertension is a very strong risk factor for cardiovascular events and drug-induced increases in BP have attracted increased regulatory attention. However, there is currently no guidance from regulatory agencies on the minimum BP data required for submissions, and there are no specific criteria for what constitutes a safety signal for increased BP in non clinical studies. Areas covered: Evaluation of BP increases through the drug discovery and development process. Expert opinion: Research into the effects of drugs should begin before clinical development is initiated and continue throughout the clinical trial program. Non clinical studies should inform a benefit-risk analysis that will aid decision-making of whether to enter the drug into Phase I development. The degree of acceptable risk will vary according to the therapy area, treatment indication and intended population for the new drug, and the approach to BP assessment and risk mitigation should be tailored accordingly. However, BP monitoring should always be included in clinical trials, and data collected from multiple studies, to convincingly prove or refute a suspicion of BP effects.

Evaluation of the effect of Naloxegol on cardiac repolarization: a randomized, placebo- and positive-controlled crossover thorough QT/QTc study in healthy volunteers.

BACKGROUND: Opioid-induced constipation (OIC) is a common adverse effect associated with opioid use. Naloxegol is a PEGylated derivative of naloxone in clinical development as a once-daily oral treatment of OIC. OBJECTIVES: A thorough QT/QTc study was conducted, according to International Conference on Harmonisation E14 guidelines, to characterize the effect of naloxegol on cardiac repolarization. METHODS: In this randomized, positive- and placebo-controlled crossover study, healthy men received a single dose of naloxegol 25 mg (therapeutic dose), naloxegol 150 mg (supratherapeutic dose), moxifloxacin 400 mg (positive control), or placebo in 1 of 4 sequences (Williams Latin square design). The washout time between treatment periods was at least 5 days. Digital 12-lead ECGs were recorded at baseline and at 10 time points over 24 hours after dosing in each treatment period. QT intervals were corrected for heart rate using the Fridericia formula (QTcF) and the Bazett formula (QTcB). RESULTS: A total of 52 subjects were enrolled (mean age, 28 years), and 45 received all 4 treatments. The placebo-corrected, baseline-adjusted, mean increases in QTcF with naloxegol 25 and 150 mg were both <5 msec at each time point, and all upper limits of the 2-sided 90% CI were <10 msec. Similar findings were observed using QTcB; the upper limits of the 2-sided 90% CI were <10 msec at all time points after dosing with naloxegol 25 or 150 mg. With moxifloxacin 400 mg, mean QTcF was increased by a maximum of 11.1 msec (90% CI, 9.3-12.9 msec), supporting assay sensitivity. CONCLUSION: Naloxegol at 25 and 150 mg was not associated with QT/QTc interval prolongation in these healthy men, and at the proposed therapeutic dose of 25 mg/d, naloxegol is not expected to have a clinically relevant effect on cardiac repolarization in patients with OIC. ClinicalTrials.gov identifier: NCT01325415.

Sex difference and factors associated with outcome in patients with sustained ventricular arrhythmias.

OBJECTIVE: To describe gender differences and factors of importance for outcome in patients referred for sustained ventricular arrhythmias. RESULTS: Two hundred and fifty three patients took part in the survey, 126 (20 women) had sustained monomorphic ventricular tachycardia (VT) and 127 (31 women) had polymorphic VT/ventricular fibrillation. Ischemic heart disease was less common in women than in men (47 vs. 80%). At discharge, an ICD implant was similarly common in women (33%) and men (29%). One hundred and twenty five (65%) men and 37 (79%) women were alive at follow-up, p =0.08 (median follow-up 53 months). Independent predictors of long-term mortality were: 1) PVT/VF as the presenting arrhythmia, 2) a low ejection fraction, 3) increased QRS duration and 4) diabetes mellitus. CONCLUSION: The lower proportion of women compared to men being referred for evaluation of sustained ventricular arrhythmias may contribute to the lower number of ICD implants in women. The long-term survival in women and men did not differ significantly.

Testing the implantable cardioverter-defibrillator after implantation--is it necessary?

The results of intraoperative and postoperative predischarge implantable cardioverter-defibrillator (ICD) testing of 211 consecutive patients, starting at 15 J and requiring two successful terminations of induced VT/VF with a relative defibrillation safety margin (DSM) of >10 J, were reviewed. The aim was to define the type of intraoperative response that would make postoperative predischarge testing unnecessary. The intraoperative responses were divided into three types: A, a DSM > or =10 J and an absolute energy level of < or =20 J; B, a DSM of > or =10 J and an absolute energy level of >20 J; and C, a DSM <10 J and an absolute energy level of >20 J. At operation, the responses to defibrillation were A, 88.6%; B, 7.1%; and C, 4.3%. Accepting an A response only would leave 11.4% of the patients for postoperative testing. The positive and negative predictive values for diagnosing a postoperative C response were 0.78 and 0.97, respectively. Similarly, the predictive values for diagnosing a postoperative B or C response were 0.71 and 0.97, respectively. The postoperative testing responses were A, 89.1%; B, 4.3%; and C, 6.6%. In summary, an intraoperative A response was sufficient to make a postoperative defibrillation testing unnecessary, while it was found that intraoperative B and C responders should undergo postoperative testing. Applying these criteria, approximately 90% of the patients could be discharged without any postoperative induction test.