Factors associated with non-vitamin K antagonist oral anticoagulants for stroke prevention in patients with new-onset atrial fibrillation: Results from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation II (ORBIT-AF II).

BACKGROUND: Several non-vitamin K antagonist oral anticoagulant (NOAC) alternatives to warfarin are available for stroke prevention in atrial fibrillation (AF). We aimed to describe the factors associated with selection of NOACs versus warfarin in patients with new onset AF. METHODS: The ORBIT-AF II study is a national, US, prospective, observational, cohort study of anticoagulation treatment in patients with AF receiving NOACs or warfarin in the United States from 2013 to 2016. We measured factors associated with oral anticoagulant selection in 4,670 patients recently diagnosed with AF. RESULTS: At baseline, 1,169 (25%) patients were started on warfarin and 3,501 (75%) on NOACs: of these latter, 259 (6%) were started on dabigatran, 1858 (40%) on rivaroxaban, and 1384 (30%) on apixaban. Those receiving NOACs were slightly younger patients (median age 71 vs 72, P<.0001); were less likely to have prior stroke (5.3% vs 8.6%; P<.0001) or prior bleeding (2.7% vs 4.4%; P=.005); had better kidney function (mean estimated glomerular filtration rate 91 mL/min vs 80 mL/min, P<.0001); and had fewer patients at high stroke risk (CHA2DS2-VASc score [Congestive heart failure, Hypertension, Age ≥75years, Diabetes mellitus, Prior stroke, transient ischemic attack {TIA}, or thromboembolism,Vascular disease, Age 65-74years, Sex category {female}] ≥2 in 86% vs 93%; P<.0001). In multivariable analysis, factors associated with NOAC selection versus warfarin included renal function, prior stroke or valve replacement, rhythm control AF management strategy, treatment by a cardiologist, and higher patient education level. CONCLUSIONS: In contemporary clinical practice, up to three-fourths of patients with new-onset AF are now initially treated with a NOAC for stroke prevention. Those selected for NOAC treatment had lower stroke and bleeding risk profiles, were more likely treated by cardiologists, and had higher socioeconomic status. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01701817.

Practical Considerations for the Nonvitamin K Antagonist Oral Anticoagulants.

OBJECTIVES: Dabigatran, rivaroxaban, apixaban, and edoxaban are nonvitamin K antagonist oral anticoagulants (NOACs) approved for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). Phase-3 clinical trials demonstrated NOACs were as effective as warfarin in the prevention of stroke or systemic embolism and associated with decreased incidences of intracranial bleeding. Additionally, NOACs provide quicker onset of action, simpler dosing, more predictable pharmacokinetic profiles, and decreased food and drug interactions compared with warfarin. Despite the advantages of NOACs, the lack of knowledge may limit their use in clinical practice. METHODS: A search was performed on the terms 'atrial fibrillation' and 'dabigatran', 'apixaban', 'edoxaban', or 'rivaroxaban' to identify relevant papers; large randomized clinical trials, meta-analyses, and treatment guideline recommendations were given preference. Searches to identify registries, treatment guidelines, and meta-analyses relevant to patient subgroups were also employed. RESULTS: Dosing recommendations, initiation of treatment, and applications in patients who undergo NVAF procedures, have mechanical heart valves, or experience other cardiovascular conditions such as myocardial infarction, previous stroke, and valvular heart disease are summarized. The NOAC-specific reversal approaches are also discussed. CONCLUSIONS: Several important factors should be considered regarding the adequate use of NOACs, especially in patients with renal impairment or cardiovascular conditions other than NVAF.

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.

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.

Differentiating electrophysiological effects and cardiac safety of drugs based on the electrocardiogram: a blinded validation.

BACKGROUND: The ventricular components (QRS and QT) on the electrocardiogram (ECG) depend on the properties of ventricular action potentials that can be modulated by drugs via specific ion channels. However, the correlation of ECG ventricular waveforms with underlying ion actions is not well established and has been extensively debated. OBJECTIVE: To conduct a blinded in vitro assessment of the ionic mechanisms for drug-induced ECG changes. METHODS AND RESULTS: Fourteen cardiac and noncardiac drugs with known effects on cardiac ion channels were selected by the study sponsor, and were tested in the rabbit left ventricular wedge preparation with recording of the ECG and contractility. The investigators who performed the experiments and analyzed the data were blinded to names, concentrations, and molecular weights of the drugs. The compounds were prepared by the sponsor and sent to the investigators as 56 stock solutions. The effects of I(Kr), I(Ks), I(Ca,L), I(Na) blocker, and I(KATP) opener on QRS, QT, and T(p-e), were evaluated. Disclosure of the names and concentrations after completion of the study revealed that there were highly correlated ECG changes with underlying ionic mechanisms and proarrhythmic potential of drugs that, respectively, target I(Kr), I(Ks), I(Ca,L), I(Na), and I(KATP). Among ECG parameters, T(p-e) was more useful in differentiating drugs' actions. CONCLUSIONS: Specific electrophysiological action and the consequent proarrhythmic potential of a drug can be accurately determined by analysis of drug-induced changes in ECG in the rabbit left ventricular wedge preparation. Change in T(p-e) provides the most relevant information.

Cardiovascular safety profile of dapoxetine during the premarketing evaluation.

The cardiovascular safety profile of dapoxetine, a novel selective serotonin reuptake inhibitor (SSRI) developed as an on-demand oral treatment for premature ejaculation (PE) in men, is evaluated. The cardiovascular assessment of dapoxetine was conducted throughout all stages of drug development, with findings from preclinical safety pharmacology studies, phase I clinical pharmacology studies investigating the effect of dapoxetine on QT/corrected QT (QTc) intervals in healthy men, and phase III, randomized, placebo-controlled studies evaluating the safety (and efficacy) of the drug. Preclinical safety pharmacology studies did not suggest an adverse electrophysiologic or hemodynamic effect with concentrations of dapoxetine up to 2-fold greater than recommended doses. Phase I clinical pharmacology studies demonstrated that dapoxetine did not prolong the QT/QTc interval and had neither clinically significant electrocardiographic effects nor evidence of delayed repolarization or conduction effects, with dosing up to 4-fold greater than the maximum recommended dosage. Phase III clinical studies of dapoxetine in men with PE indicated that dapoxetine was generally safe and well tolerated with the dosing regimens used (30 mg and 60 mg as required). Events of syncope were reported during the clinical development program, with the majority occurring during study visits (on site) on day 1 following administration of the first dose when various procedures (e.g. orthostatic maneuvers, venipunctures) were performed, suggesting that the procedures contributed to the incidence of syncope. This was consistent with previous reports showing that these and similar factors contribute to or trigger vasovagal syncope. Findings of the dapoxetine development program demonstrate that dapoxetine is associated with vasovagal-mediated (neurocardiogenic) syncope. No other associated significant cardiovascular adverse events were identified.

Electrophysiological properties of HBI-3000: a new antiarrhythmic agent with multiple-channel blocking properties in human ventricular myocytes.

HBI-3000 (sulcardine sulfate) has been shown to suppress various ventricular arrhythmias in animal models. The electrophysiological properties of HBI-3000 were investigated using standard microelectrode and patch-clamp techniques in single human ventricular myocytes. HBI-3000 led to concentration-dependent suppression of dofetilide-induced early afterdepolarizations in single nonfailing human ventricular myocytes and early afterdepolarizations seen in failing ventricular myocytes. The concentration-dependent prolongation of action potential duration (APD) by HBI-3000 was bell shaped with maximum response occurring around 10 µM. Interestingly, HBI-3000 at the concentration of 10 µM modestly prolonged the APD at all 3 basic cycle lengths. The slope of APD-cycle length curve of HBI-3000 was only slightly steeper than that of control (88.8 ± 7.7 ms/s vs. 78.9 ± 5.2 ms/s in control, n = 8, P > 0.05). HBI-3000 only showed a minimal use-dependent prolongation of the APD in human ventricular myocytes. HBI-3000 inhibited fast sodium current (INa-F), late sodium channel (INa-L), L-type calcium current (ICa-L), and rapidly activating delayed rectifier K current (IKr) in single human ventricular myocytes. The estimated half-maximal inhibitory concentration values of INa-F, INa-L, ICa-L, and IKr were 48.3 ± 3.8, 16.5 ± 1.4, 32.2 ± 2.9, and 22.7 ± 2.5 µM, respectively. The ion channel profile and electrophysiological properties of HBI-3000 are similar to those of ranolazine and chronic amiodarone (reduced INa-F, INa-L, ICa-L, and IKr). HBI-3000 may be a promising antiarrhythmic agent with low proarrhythmic risk.

Efficacy and safety of prescription omega-3 fatty acids for the prevention of recurrent symptomatic atrial fibrillation: a randomized controlled trial.

CONTEXT: Atrial fibrillation (AF) is common, yet there remains an unmet medical need for additional treatment options. Current pharmacological treatments have limited efficacy and significant adverse events. Limited data from small trials suggest omega-3 polyunsaturated fatty acids may provide a safe, effective treatment option for AF patients. OBJECTIVE: To evaluate the safety and efficacy of prescription omega-3 fatty acids (prescription omega-3) for the prevention of recurrent symptomatic AF. DESIGN, SETTING, AND PARTICIPANTS: Prospective, randomized, double-blind, placebo-controlled, parallel-group multicenter trial involving 663 US outpatient participants with confirmed symptomatic paroxysmal (n = 542) or persistent (n = 121) AF, with no substantial structural heart disease, and in normal sinus rhythm at baseline were recruited from November 2006 to July 2009 (final follow-up was January 2010). INTERVENTIONS: Prescription omega-3 (8 g/d) or placebo for the first 7 days; prescription omega-3 (4 g/d) or placebo thereafter through week 24. MAIN OUTCOME MEASURES: The primary end point was symptomatic recurrence of AF (first recurrence) in participants with paroxysmal AF. Secondary analyses included first recurrence in the persistent stratum and both strata combined. Participants were followed up for 6 months. RESULTS: At 24 weeks, in the paroxysmal AF stratum, 129 of 269 participants (48%) in the placebo group and 135 of 258 participants (52%) in the prescription group had a recurrent symptomatic AF or flutter event. In the persistent AF stratum, 18 participants (33%) in the placebo group and 32 (50%) in the prescription group had documented symptomatic AF or flutter events. There was no difference between treatment groups for recurrence of symptomatic AF in the paroxysmal stratum (hazard ratio [HR], 1.15; 95% confidence interval [CI], 0.90-1.46; P = .26), in the persistent stratum (HR, 1.64; 95% CI, 0.92-2.92; P = .09), and both strata combined (HR, 1.22; 95% CI, 0.98-1.52; P = .08). Other, secondary end points were supportive of the primary result. A total of 5% of those receiving placebo and 4% of those receiving prescription omega-3 discontinued due to adverse events. Eicosapentaenoic and docosahexaenoic acid blood levels were significantly higher in the prescription group than in the placebo group at weeks 4 and 24. CONCLUSION: Among participants with paroxysmal AF, 24-week treatment with prescription omega-3 compared with placebo did not reduce recurrent AF over 6 months. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00402363.

Adjuvant therapy for atrial fibrillation.

Atrial fibrillation (AF) is the most common heart rhythm disorder, with increasing prevalence in the aging US population and affecting more than 2.3 million people. Current approaches for managing AF are rate- or rhythm-control strategies, both using anti-thrombotic therapy to prevent thromboembolism. While great advances have been made in understanding the pathophysiology of AF, few new strategies have shown promise in prevention or treatment of AF. Recent data suggest that non-antiarrhythmic medication may be useful in modifying the substrate that allows AF precipitation and perpetuation. This article reviews the data on the role of these agents in the prevention and management of AF as an adjunct to standard therapy.

Comparison of the cardiac electrophysiology and general toxicology of two formulations of intravenous amiodarone in dogs.

Intravenous amiodarone (AIV) must be administered slowly after dilution to avoid hypotension, which is due to the cosolvents polysorbate 80 and benzyl alcohol used in its formulation. PM101 is a formulation of amiodarone devoid of these cosolvents, which enables bolus administration. We evaluated any potential toxicity or exaggerated adverse cardiac electrophysiologic effects of PM101 compared with AIV and control. Beagle dogs were treated with the human-equivalent amiodarone loading dose (2.14 mg/kg) with PM101 (bolus push) or AIV (10 min infusion in the toxicology study and bolus push in the electrophysiology study) followed by maintenance infusion (0.014 mg kg(-1) min(-1) through 6 h followed by 0.007 mg kg(-1) min(-1) through 14 days) or a control. General toxicology was assessed in conscious dogs over 14 days. Cardiac electrophysiology was assessed in a separate cohort of anesthetized dogs during the first 20 min of dosing. In the toxicology study, dosing in all animals in the AIV group was terminated within 17 min of initiation due to a severe hypersensitivity reaction. There were no acute adverse clinical signs in the PM101 or control groups. There were no significant effects on body weight or ECG parameters, and no adverse histomorphologic changes were seen in dogs that received PM101 or AIV. No significant exaggerated cardiac electrophysiologic effects of the approved doses PM101 or AIV were observed. PM101 may represent a formulation of intravenous amiodarone that could be administered rapidly without dilution in the setting of life-threatening cardiac arrhythmias.

Assessing proarrhythmic potential of drugs when optimal studies are infeasible.

Assessing the potential for a new drug to cause life-threatening arrhythmias is now an integral component of premarketing safety assessment. International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use Guideline (ICH) E14 recommends the "Thorough QT Study" (TQT) to assess clinical QT risk. Such a study calls for careful evaluation of drug effects on the electrocardiographic QT interval at multiples of therapeutic exposure and with a positive control to confirm assay sensitivity. Yet for some drugs and diseases, elements of the TQT Study may be impractical or unethical. In these instances, alternative approaches to QT risk assessment must be considered. This article presents points to consider for evaluation of QT risk when alternative approaches are needed.

Sudden death secondary to cardiac arrhythmias: mechanisms and treatment strategies.

PURPOSE OF REVIEW: This article reviews mechanisms and available therapeutic options for arrhythmias leading to sudden cardiac death in patients with coronary artery disease. RECENT FINDINGS: Intensive efforts have led to a better understanding of the pathophysiology and various treatments of sudden cardiac death. Antiarrhythmic medications have not demonstrated a survival benefit. Beta-adrenergic blocking agents have been revalidated in recent studies to improve survival and reduce risk of sudden cardiac death in patients with myocardial infarction. Angiotensin-converting enzyme inhibitors and aldosterone antagonists should also be used in these patients. Data from randomized trials demonstrate significant survival benefit with an implantable cardioverter-defibrillator and indications have expanded. Patients with established ischemic cardiomyopathy do not require electrophysiologic studies for induction of tachyarrhythmias based on these trials. One recent trial did not demonstrate mortality reduction with implantable defibrillators in patients with recent myocardial infarction. Devices may not provide survival benefit in patients with advanced New York Heart Association class IV heart failure. SUMMARY: The incidence of arrhythmia-related sudden death in the general population remains relatively high. Better risk stratification tools are needed to identify high-risk patients in the general population and in those with known coronary disease and to exclude low-risk patients.

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.

Electrophysiologic effects of SB-237376: a new antiarrhythmic compound with dual potassium and calcium channel blocking action.

Combined potassium and calcium channel blocking activities are suggested to be the basis for antiarrhythmic efficacy with low proarrhythmic risk. The electrophysiologic effects of SB-237376 were investigated in single myocytes and arterially perfused wedge preparations of canine or rabbit left ventricles. The concentration-dependent prolongation of action potential duration (APD) and QT interval by SB-237376 was bell-shaped and the maximum response occurred at 1-3 microM SB-237376 inhibited rapidly activating delayed rectifier K current (I(Kr) ) with an IC50 of 0.42 microM and use-dependently blocked L-type Ca current (I (Ca,L) ) at high concentrations. The SB-237376 (3 microM) induced phase-2 early afterdepolarizations (EADs) in five of six rabbit wedge preparations but none of six canine wedge preparations. This is probably due to larger increases of APD, QT interval, and transmural dispersion of repolarization (TDR) in rabbits than dogs. Based on the drug effects on QT interval, TDR, and EAD in rabbit ventricular wedge preparations, a scoring system predicted lower proarrhythmic risk for SB-237376 than for dl-sotalol, a specific I blocker. In conclusion, SB-237376 increases APD, QT interval, and TDR mainly by I (Kr) inhibition. These effects are self-limited due to SB-237376-induced I(Ca,L) blockade at high concentrations, which may explain its lower proarrhythmic risk than dl-sotalol.

Effect of epicardial or biventricular pacing to prolong QT interval and increase transmural dispersion of repolarization: does resynchronization therapy pose a risk for patients predisposed to long QT or torsade de pointes?

BACKGROUND: The present study examined pacing site-dependent changes in QT interval and transmural dispersion of repolarization (TDR) and their potential role in the development of torsade de pointes (TdP). METHODS AND RESULTS: In humans, the QT interval, JT interval, and TDR were measured in 29 patients with heart failure during right ventricular endocardial pacing (RVEndoP), biventricular pacing (BiVP), and left ventricular epicardial pacing (LVEpiP). In animal experiments, pacing site--dependent changes in ventricular repolarization were examined with a rabbit left ventricular wedge preparation in which action potentials from endocardium and epicardium could be simultaneously recorded with a transmural ECG. In humans, LVEpiP and BiVP led to significant QT and JT prolongation. LVEpiP also enhanced TDR. Frequent R-on-T extrasystoles generated by BiVP and LVEpiP but completely inhibited by RVEndoP occurred in 4 patients, of whom 1 developed multiple episodes of nonsustained polymorphic ventricular tachycardia and another suffered incessant TdP. In rabbit experiments, switching from endocardial to epicardial pacing produced a net increase in QT interval and TDR by 17+/-5 and 22+/-5 ms, respectively (n=6, P<0.01), without parallel increases in ventricular transmembrane action potential durations. Epicardial pacing facilitated transmural propagation of early afterdepolarization, leading to the development of R-on-T extrasystoles and TdP in the presence of action potential duration-prolonging agents. CONCLUSIONS: LVEpiP and BiVP increase QT, JT, and TDR by altering the transmural sequence of activation of the intrinsically heterogeneous ventricular myocardium. Our data suggest that the resultant exaggeration of arrhythmic substrates can lead to the development of TdP in a subset of patients.