Intracellular uptake of agents that block the hERG channel can confound the assessment of QT interval prolongation and arrhythmic risk.

BACKGROUND: Oliceridine is a biased ligand at the µ-opioid receptor recently approved for the treatment of acute pain. In a thorough QT study, corrected QT (QTc) prolongation displayed peaks at 2.5 and 60 minutes after a supratherapeutic dose. The mean plasma concentration peaked at 5 minutes, declining rapidly thereafter. OBJECTIVE: The purpose of this study was to examine the basis for the delayed effect of oliceridine to prolong the QTc interval. METHODS: Repolarization parameters and tissue accumulation of oliceridine were evaluated in rabbit left ventricular wedge preparations over a period of 5 hours. The effects of oliceridine on ion channel currents were evaluated in human embryonic kidney and Chinese hamster ovary cells. Quinidine was used as a control. RESULTS: Oliceridine and quinidine produced a progressive prolongation of the QTc interval and action potential duration over a period of 5 hours, paralleling slow progressive tissue uptake of the drugs. Oliceridine caused modest prolongation of these parameters, whereas quinidine produced a prominent prolongation of action potential duration and QTc interval as well as development of early afterdepolarization (after 2 hours), resulting in a high torsades de pointes score. The 50% inhibitory concentration values for the oliceridine inhibition of the rapidly activating delayed rectifier current (human ether a-go-go current) and late sodium channel current were 2.2 and 3.45 µM when assessed after traditional acute exposure but much lower after 3 hours of drug exposure. CONCLUSION: Our findings suggest that a gradual increase of intracellular access of drugs to the hERG channels as a result of their intracellular uptake and accumulation can significantly delay effects on repolarization, thus confounding the assessment of QT interval prolongation and arrhythmic risk when studied acutely. The multi-ion channel effects of oliceridine, late sodium channel current inhibition in particular, point to a low risk of devloping torsades de pointes.

Large-Scale Assessment of a Smartwatch to Identify Atrial Fibrillation.

BACKGROUND: Optical sensors on wearable devices can detect irregular pulses. The ability of a smartwatch application (app) to identify atrial fibrillation during typical use is unknown. METHODS: Participants without atrial fibrillation (as reported by the participants themselves) used a smartphone (Apple iPhone) app to consent to monitoring. If a smartwatch-based irregular pulse notification algorithm identified possible atrial fibrillation, a telemedicine visit was initiated and an electrocardiography (ECG) patch was mailed to the participant, to be worn for up to 7 days. Surveys were administered 90 days after notification of the irregular pulse and at the end of the study. The main objectives were to estimate the proportion of notified participants with atrial fibrillation shown on an ECG patch and the positive predictive value of irregular pulse intervals with a targeted confidence interval width of 0.10. RESULTS: We recruited 419,297 participants over 8 months. Over a median of 117 days of monitoring, 2161 participants (0.52%) received notifications of irregular pulse. Among the 450 participants who returned ECG patches containing data that could be analyzed - which had been applied, on average, 13 days after notification - atrial fibrillation was present in 34% (97.5% confidence interval [CI], 29 to 39) overall and in 35% (97.5% CI, 27 to 43) of participants 65 years of age or older. Among participants who were notified of an irregular pulse, the positive predictive value was 0.84 (95% CI, 0.76 to 0.92) for observing atrial fibrillation on the ECG simultaneously with a subsequent irregular pulse notification and 0.71 (97.5% CI, 0.69 to 0.74) for observing atrial fibrillation on the ECG simultaneously with a subsequent irregular tachogram. Of 1376 notified participants who returned a 90-day survey, 57% contacted health care providers outside the study. There were no reports of serious app-related adverse events. CONCLUSIONS: The probability of receiving an irregular pulse notification was low. Among participants who received notification of an irregular pulse, 34% had atrial fibrillation on subsequent ECG patch readings and 84% of notifications were concordant with atrial fibrillation. This siteless (no on-site visits were required for the participants), pragmatic study design provides a foundation for large-scale pragmatic studies in which outcomes or adherence can be reliably assessed with user-owned devices. (Funded by Apple; Apple Heart Study ClinicalTrials.gov number, NCT03335800.).

Defining Clinically Important Difference in the Atrial Fibrillation Effect on Quality-of-Life Score.

Background The Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire has recently been validated to measure the impact of atrial fibrillation on quality of life, but a clinically important difference in AFEQT score has not been well defined. Methods and Results To determine the clinically important difference in overall AFEQT (score range= 0 [worst] to 100 [best]) and selected subscales, we analyzed data in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) registry, a United States-based outpatient atrial fibrillation registry. AFEQT was assessed at baseline and 1 year in a subset of 1347 ORBIT-AF patients from 80 US sites participating in ORBIT-AF from June 2010 to August 2011. The mean change method was used to relate changes in 1-year AFEQT scores to clinically important changes in the physician assessment of European Heart Rhythm Association functional status (1 class improvement and separately 1 class deterioration). Clinically important differences and 95% CI corresponding to either a 1 European Heart Rhythm Association class improvement or deterioration were 5.4 (3.6-7.2) and -4.2 (-6.9 to -1.5) AFEQT points, respectively. Similarly, clinically important difference values were seen for a 1 European Heart Rhythm Association class improvement for the AFEQT subscales Activities of Daily Living and Symptoms: 5.1 (2.5-7.6) and 7.1 (5.3-9.0) AFEQT points, respectively. Conclusions Based on the anchor of 1 European Heart Rhythm Association class change, changes in AFEQT score of + or -5 points are clinically important changes in patients' health. Clinical Trial Registration URL: https://clinicaltrials.gov . Unique identifier: NCT01165710.

How well does physician risk assessment predict stroke and bleeding in atrial fibrillation? Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF).

BACKGROUND: Assessments of stroke and bleeding risks are essential to selecting oral anticoagulation in patients with atrial fibrillation (AF). We aimed to assess outcomes according to physician assessed risk, with comparison to empirical risk scores. METHODS: This was a prospective, observational study of 9,715 outpatients with AF enrolled in ORBIT-AF, a US national registry. Stroke and bleeding risks were quantified by physician assignment, CHADS2 and CHA2DS2-VASc stroke scores, and ATRIA and HAS-BLED bleeding scores. Outcomes were stroke or systemic embolism and major bleeding during a median follow-up of 28 months. RESULTS: Physician-assigned risk was associated with thromboembolic events: low risk (0.71 per 100 patient-years [95% CI 0.56-0.91], n=3,991), intermediate risk (0.98 [95% CI 0.79-1.20], n=4,148), and high risk (1.84 [95% CI 1.43-2.37], n=1,576, P<.0001), and major bleeding: low (3.43 [95% CI 3.07-3.82], n=4,250), intermediate (4.55 [95% CI 4.03-5.15], n=2,702), and high (5.76 [95% CI 4.42-7.50], n=468; P<.0001). Discrimination of stroke risk was similar with CHADS2 (c=0.59, 95% CI 0.57-0.61) vs physician assessment (c=0.58, 95% CI 0.55-0.62). Among patients on oral anticoagulation, bleeding risk discrimination was higher with ATRIA (c=0.63, 95% CI 0.61-0.65) and HAS-BLED (c=0.60, 95% CI 0.59-0.62) than with physician assessment (0.55, 95% CI 0.53-0.57). Physician-assessed risk categories did not add significantly to empirical risk scores, in Cox models for outcomes (Padjusted>.05 for all physician assessments vs Padjusted<.05 for empirical scores). CONCLUSION: Physician-assigned risk showed a graded relationship with outcomes, and both physician-based and empirical scores yielded only moderate discrimination. Although empirical scores provided valuable risk stratification information (with or without physician judgment), physician assessment added little to existing scores. These data support the use of empirical scores for stroke and bleeding risk stratification, and the need for novel approaches to risk stratification in this population.

Clinical Characteristics, Oral Anticoagulation Patterns, and Outcomes of Medicaid Patients With Atrial Fibrillation: Insights From the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF I) Registry.

BACKGROUND: Whereas insurance status has been previously associated with care patterns, little is currently known about the association between Medicaid insurance and the clinical characteristics, treatment, or outcomes of patients with atrial fibrillation (AF). METHODS AND RESULTS: We used data from adults with AF enrolled in the Outcomes Registry for Better Informed Treatment of AF (ORBIT-AF), a national outpatient registry conducted at 176 community, multispecialty sites. The primary outcome of interest was the proportion of patients prescribed any oral anticoagulation (OAC; warfarin or novel oral anticoagulants [NOAC]). Secondary outcomes of interest included the proportion of patients prescribed NOACs (dabigatran or rivaroxaban); time in therapeutic range (TTR) for warfarin users, all-cause mortality, stroke/systemic embolism, and major bleed. Of 10 133 patients, N=470 (4.6%) had Medicaid insurance. Medicaid patients were similarly likely to receive OAC at baseline (72.8% vs 76.3%; unadjusted P=0.079), but less likely to receive NOAC at baseline or follow-up (12.1% vs 16.3%; unadjusted P=0.019). After risk adjustment, Medicaid status was associated with lower use of OAC at baseline among patients with high stroke risk (odds ratio [OR]=0.68; 95% CI=0.49, 0.94), but was not associated with OAC use overall (OR=0.82; 95% CI=0.61, 1.09). Among warfarin users, median TTR was lower among Medicaid patients (60% vs 68%; P<0.0001; adjusted TTR difference, -2.9; 95% CI=-5.7, -0.2; P=0.04). Use of an NOAC over 2 years of follow-up was not statistically different by insurance. Compared with non-Medicaid patients, Medicaid patients had higher unadjusted rates of mortality, stroke/systemic embolism, and major bleeding; however, these differences were attenuated following adjustment for clinical characteristics. CONCLUSIONS: In a contemporary AF cohort, use of OAC overall and use of NOACs were not significantly lower among Medicaid patients relative to others. However, among warfarin users, Medicaid patients spent less time in therapeutic range compared with those with other forms of insurance.

Antiarrhythmic Drug Therapy for Atrial Fibrillation.

Atrial fibrillation (AF) is the most frequently encountered arrhythmia. Prevalence increases with advancing age and so as its associated comorbidities, like heart failure. Choice of pharmacologic therapy depends on whether the goal of treatment is maintaining sinus rhythm or tolerating AF with adequate control of ventricular rates. Antiarrhythmic therapy and conversion of AF into sinus rhythm comes with the side effect profile, and we should select best antiarrhythmic therapy, individualized to the patient. New antiarrhythmic drugs are being tested in clinical trials. Drugs that target remodeling and inflammation are being tested for their use as prevention of AF or as upstream therapy.

Triple vs Dual Antithrombotic Therapy in Patients with Atrial Fibrillation and Coronary Artery Disease.

BACKGROUND: The role of triple antithrombotic therapy vs dual antithrombotic therapy in patients with both atrial fibrillation and coronary artery disease remains unclear. This study explores the differences in treatment practices and outcomes between triple antithrombotic therapy and dual antithrombotic therapy in patients with atrial fibrillation and coronary artery disease. METHODS: Using the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (n = 10,135), we analyzed outcomes in patients with coronary artery disease (n = 1827) according to treatment with triple antithrombotic therapy (defined as concurrent therapy with an oral anticoagulant, a thienopyridine, and aspirin) or dual antithrombotic therapy (comprising either an oral anticoagulant and one antiplatelet agent [OAC plus AA] or 2 antiplatelet drugs and no anticoagulant [DAP]). RESULTS: The use of triple antithrombotic therapy, OAC plus AA, and DAP at baseline was 8.5% (n = 155), 80.4% (n = 1468), and 11.2% (n = 204), respectively. Among patients treated with OAC plus AA, aspirin was the most common antiplatelet agent used (90%), followed by clopidogrel (10%) and prasugrel (0.1%). The use of triple antithrombotic therapy was not affected by patient risk of either stroke or bleeding. Patients treated with triple antithrombotic therapy at baseline were hospitalized for all causes (including cardiovascular) more often than patients on OAC plus AA (adjusted hazard ratio 1.75; 95% confidence interval, 1.35-2.26; P <.0001) or DAP (hazard ratio 1.82; 95% confidence interval, 1.25-2.65; P = .0018). Rates of major bleeding or a combined cardiovascular outcome were not significantly different by treatment group. CONCLUSIONS: Choice of antithrombotic therapy in patients with atrial fibrillation and coronary artery disease was not affected by patient stroke or bleeding risks. Triple antithrombotic therapy-treated patients were more likely to be hospitalized for all causes than those on OAC plus AA or on DAP.

Antiarrhythmic drug therapy for atrial fibrillation.

Atrial fibrillation (AF) is the most frequently encountered arrhythmia. Prevalence increases with advancing age and so as its associated comorbidities, like heart failure. Choice of pharmacologic therapy depends on whether the goal of treatment is maintaining sinus rhythm or tolerating AF with adequate control of ventricular rates. Antiarrhythmic therapy and conversion of AF into sinus rhythm comes with the side effect profile, and we should select best antiarrhythmic therapy, individualized to the patient. New antiarrhythmic drugs are being tested in clinical trials. Drugs that target remodeling and inflammation are being tested for their use as prevention of AF or as upstream therapy.

Assessment of drug-induced increases in blood pressure during drug development: report from the Cardiac Safety Research Consortium.

This White Paper, prepared by members of the Cardiac Safety Research Consortium, discusses several important issues regarding the evaluation of blood pressure (BP) responses to drugs being developed for indications not of a direct cardiovascular (CV) nature. A wide range of drugs are associated with off-target BP increases, and both scientific attention and regulatory attention to this topic are increasing. The article provides a detailed summary of scientific discussions at a Cardiac Safety Research Consortium-sponsored Think Tank held on July 18, 2012, with the intention of moving toward consensus on how to most informatively collect and analyze BP data throughout clinical drug development to prospectively identify unacceptable CV risk and evaluate the benefit-risk relationship. The overall focus in on non-CV drugs, although many of the points also pertain to CV drugs. Brief consideration of how clinical assessment can be informed by nonclinical investigation is also outlined. These discussions present current thinking and suggestions for furthering our knowledge and understanding of off-target drug-induced BP increases and do not represent regulatory guidance.

Evaluation of ventricular arrhythmias in early clinical pharmacology trials and potential consequences for later development.

This white paper, prepared by members of the Cardiac Safety Research Consortium, discusses several important issues regarding the evaluation of ventricular arrhythmias in early clinical pharmacology trials and their potential consequences for later clinical drug development. Ventricular arrhythmias are infrequent but potentially important medical events whose occurrence in early clinical pharmacology trials can dramatically increase safety concerns. Given the increasing concern with all potential safety signals and the resultant more extensive electrocardiographic monitoring of subjects participating in early phase trials, an important question must be addressed: Are relatively more frequent observations of ventricular arrhythmias related simply to more extensive monitoring, or are they genuinely related to the drug under development? The discussions in this paper provide current thinking and suggestions for addressing this question.

Blinded validation of the isolated arterially perfused rabbit ventricular wedge in preclinical assessment of drug-induced proarrhythmias.

BACKGROUND: The development of preclinical models with high predictive value for the identification of drugs with a proclivity to induce Torsade de Pointes (TdP) in the clinic has long been a pressing goal of academia, industry and regulatory agencies alike. The present study provides a blinded appraisal of drugs, in an isolated arterially-perfused rabbit ventricular wedge preparation, with and without the potential to produce TdP. METHODS AND RESULTS: Thirteen compounds were tested for their potential for TdP using the rabbit left ventricular wedges. All investigators were blinded to the names, concentrations and molecular weights of the drugs. The compounds were prepared by the study sponsor and sent to the investigator as 4 sets of 13 stock solutions with the order within each set being assigned by a random number generator. Each compound was scored semi-quantitatively for its relative potential for TdP based on its effect on ventricular repolarization measured as QT interval, dispersion of repolarization measured as T(p-e)/QT ratio and early afterdepolarizations. Disclosure of the names and concentrations after completion of the study revealed that all compounds known to be free of TdP risk received a score of less or equal to 0.25, whereas those with known TdP risk received a score ranging from 1.00 to 7.25 at concentrations less than 100X their free therapeutic plasma C(max). CONCLUSIONS: Our study provides a blinded evaluation of the isolated arterially-perfused rabbit wedge preparation demonstrating both a high sensitivity and specificity in the assessment of 13 agents with varying propensity for causing TdP.

Assessment of the proarrhythmic potential of the novel antiarrhythmic agent AZD7009 and dofetilide in experimental models of torsades de pointes.

BACKGROUND: This study examined the proarrhythmic potential of the novel antiarrhythmic agent AZD7009 and dofetilide. METHODS AND RESULTS: The electrophysiological and proarrhythmic effects of AZD7009 and dofetilide were assessed in the arterially perfused canine and rabbit left ventricular wedge preparation. The proarrhythmic potential of AZD7009, dofetilide, and azimilide was further assessed in the methoxamine-sensitized rabbit model of torsades de pointes (TdP) in vivo. AZD7009 lengthened the action potential duration (APD) and the QT interval in a bell-shaped manner (15.9 +/- 1.3% in canine wedge and 46.1 +/- 2.9% in rabbit wedge) occurring at 3 and 1 microM. In contrast, dofetilide did not show the bell-shaped concentration response and the QT interval was lengthened more extensively (27.7 +/- 1.6% and 100.8 +/- 10.0%). Furthermore, whereas dofetilide prolonged the midmyocardial and endocardial APD predominantly, resulting in an increased transmural dispersion of repolarization (TDR), AZD7009 prolonged the APD more homogenously in all cell layers. At 1 microM, AZD7009 produced phase 2 early afterdepolarizations (EADs) in 1/4 rabbit preparations but without ventricular R-on-T extrasystoles or TdP. In contrast, starting at 0.03 microM, dofetilide-induced EADs, R-on-T extrasystoles and TdP in 6/6, 5/6, and 4/6 preparations. Following intravenous infusion of AZD7009 (210 nmol/kg/minute), dofetilide (2 nmol/kg/minute) or azimilide (3.33 micromol/kg/minute), TdP was induced in 0/8, 5/8, and 5/8 rabbits (P = 0.026 vs AZD7009), respectively. In 5/5 rabbits, AZD7009 promptly suppressed TdP induced by dofetilide. CONCLUSIONS: In animal models of TdP, AZD7009 delays ventricular repolarization in a self-limited way associated with a low risk of repolarization-related proarrhythmia.