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Drug-induced QT prolongation (DI-QTP) is a clinical entity in which administration of a human ether-à-go-go–related gene/rapid delayed rectifier potassium current blocker such as dofetilide prolongs the cardiac action potential duration (APD) and the QT interval on the electrocardiogram. Inhibition of serum and glucocorticoid regulated kinase-1 (SGK1) reduces the APD at 90% repolarization (APD90) in induced pluripotent stem cell–derived cardiomyocytes (iPSC-CMs) derived from patients with congenital long QT syndrome. Here, we test the efficacy of 2 novel SGK1 inhibitors—SGK1-I1 and SGK1-I2—in iPSC-CM models of dofetilide-induced APD prolongation. Normal iPSC-CMs were treated with dofetilide to produce a DI-QTP iPSC-CM model. SGK1-I1's and SGK1-I2's therapeutic efficacy for shortening the dofetilide-induced APD90 prolongation was compared to mexiletine. The APD90 values were recorded 4 hours after treatment using a voltage-sensing dye. The APD90 was prolonged in normal iPSC-CMs treated with dofetilide (673 ± 8 ms vs 436 ± 4 ms; P <.0001). While 10 mM mexiletine shortened the APD90 of dofetilide-treated iPSC-CMs from 673 ± 4 to 563 ± 8 ms (46% attenuation; P <.0001), 30 nM of SGK1-I1 shortened the APD90 from 673 ± 8 to 502 ± 7 ms (72% attenuation; P <.0001). Additionally, 300 nM SGK1-I2 shortened the APD90 of dofetilide-treated iPSC-CMs from 673 ± 8 to 460 ± 7 ms (90% attenuation; P <.0001). These novel SGK1-Is substantially attenuated the pathological APD prolongation in a human heart cell model of DI-QTP. These preclinical data support the development of this therapeutic strategy to counter and neutralize DI-QTP, thereby increasing the safety profile for patients receiving drugs with torsadogenic potential. [ABSTRACT FROM AUTHOR]

Presently, acute pharmacological termination of paroxysmal supraventricular tachycardia (PSVT) unresponsive to patient-initiated vagal maneuvers requires in-hospital intervention. Etripamil, a fast-acting, nondihydropyridine, L-type calcium channel blocker, is formulated as an intranasal spray to rapidly terminate atrioventricular (AV) nodal-dependent PSVT in a medically unsupervised setting. The NODE-301 study did not meet its prespecified primary end point of PSVT conversion over 5 hours following a single dose of etripamil 70 mg. However, analysis at earlier time points demonstrated etripamil treatment effect during the first 30 minutes, consistent with its expected rapid onset and short duration of action. This led to the design of the RAPID study, which includes a new dosing regimen (up to 2 etripamil 70 mg doses separated by 10 minutes) to increase the exposure and pharmacodynamic effect of etripamil. The primary objective of RAPID (NCT03464019) is to determine if etripamil self-administered by patients is superior to placebo in terminating PSVT in an at-home setting. The secondary objective is to evaluate the safety of etripamil when self-administered by patients without medical supervision. Additional efficacy end points include the proportion of patients requiring additional medical intervention in an emergency department to terminate PSVT and patient-reported outcomes. After successfully completing a test dose to assess the safety of 2 70 mg doses of etripamil during sinus rhythm, approximately 500 patients will be randomized 1:1 to etripamil or placebo to accrue 180 positively adjudicated AV nodal-dependent PSVT events for treatment with the study drug. Etripamil may offer a new alternative to the current in-hospital treatment modality, providing for safe and effective at-home termination of PSVT. [ABSTRACT FROM AUTHOR]

People who recover from cardiac arrest are at risk of suffering a recurrent episode. A subset of this group (60 to 80 percent) exhibits abnormalities in heart function during electrocardiogram (ECG) testing; these patients respond well to medication that alleviates the abnormalities. This improvement appears to prevent recurrence of cardiac arrest. The remaining 20 to 40 percent of patients show no abnormalities during ECG testing; this group is thought to be at a particularly high risk for sudden cardiac death. Seventy-one survivors of a single episode of cardiac arrest were evaluated. During testing, 26 of these patients had no inducible ECG abnormalities, such as ventricular tachycardia (abnormally rapid patterns of contraction of the ventricle). After a 16-month follow-up, 11 of the 26 patients suffered recurrent cardiac arrest, and 10 of these patients died. Analysis of the clinical data pertaining to these patients revealed that several variables were more likely to be associated with recurrent cardiac arrest. Among the 11 patients who suffered a recurrence, 55 percent had dilated cardiomyopathy (a defect in the functioning of the heart muscle), and 64 percent experienced premature ventricular contractions. Twenty-four-hour ambulatory ECG-guided therapy (wearing a portable ECG machine) did not improve the survival rate for these patients. Further studies are needed to determine the optimal treatment strategy for this high-risk group of patients. (Consumer Summary produced by Reliance Medical Information, Inc.)

Ventricular aneurysms (ballooning of the walls of the lower heart chamber) have many causes, with coronary artery disease being the cause in 75 percent of cases. Infrequently, no cause can be found; these are idiopathic cases. A case is reported of a 56-year-old woman with three idiopathic left ventricular aneurysms. For four years, prior to hospitalization, the patient had dyspnea (shortness of breath) on exertion, which was diagnosed as mild congestive heart failure. She had no other history of disorders which could contribute to ventricular tachycardia (rapid heartbeat), the symptom for which she was hospitalized. Her heart rate was 200 beats per minute (bpm), while the normal rate is 72 bpm. The initial chest X-ray showed no abnormal bulges indicative of aneurysms. Invasive imaging techniques were needed to reveal the aneurysms. Ventricular tachycardia was not responsive to drugs, and a device was implanted to restore normal heart rhythm. All previously reported cases of ventricular aneurysms were of single aneurysms, all of which were associated with arrhythmias. The study suggests this is a case of true idiopathic disease, as little or no evidence was found for known causes such as coronary artery disease, thrombi (clots), Chagas disease (a parasitic infection), or syphilis. (Consumer Summary produced by Reliance Medical Information, Inc.)

The novel direct oral anticoagulants (NOACs) represent a major advance in oral anticoagulant therapy and are replacing vitamin K antagonists as the preferred options for many indications. Given in fixed doses without routine laboratory monitoring, they have been shown to be at least as effective in reducing thromboembolic stroke as dose-adjusted warfarin in phase 3 randomized trials and less likely to cause hemorrhagic stroke. Pharmacokinetic and/or pharmacodynamic subanalyses of the major NOAC trials in patients with atrial fibrillation have established relationships between clinical characteristics, and drug levels and/or pharmacodynamic responses with both efficacy and safety. Based on these analyses, pharmaceutical manufacturers and regulatory authorities have provided contraindications and dosing recommendations based on clinical characteristics that are associated with drug levels and/or pharmacodynamic responses, stroke reduction, and bleeding risk to optimize the risk-benefit profile of the NOACs in the real world. The current fixed-dosing strategy of NOACs has triggered discussions about the potential value of laboratory monitoring and dose adjustment in customizing drug exposure to further improve the safety and efficacy of the NOACs in patients with atrial fibrillation. As there is neither high-quality evidence nor consensus about the potential role of laboratory monitoring and dose adjustment for the NOACs, a Cardiac Research Safety Consortium "Think Tank" meeting was held at the American College of Cardiology Heart House in December 2015 to discussions these issues. This manuscript reports on the deliberations and the conclusions reached at that meeting. [ABSTRACT FROM AUTHOR]

The Cardiac Safety Research Consortium (CSRC), a transparent, public-private partnership established in 2005 as a Critical Path Program and formalized in 2006 under a Memorandum of Understanding between the United States Food and Drug Administration and Duke University, is entering its second decade. Our continuing goal is to advance paradigms for more efficient regulatory science related to the cardiovascular safety of new therapeutics, both in the United States and globally, particularly where such safety questions add burden to innovative research and development. Operationally, CSRC brings together a broad base of stakeholders from academia, industry, and government agencies in a collaborative forum focused on identifying barriers and then creating novel solutions through shared data, expertise, and collaborative research. This white paper provides a brief overview of the Consortium's activities in its first decade and a context for some of our current activities and future directions. The growth and success of the CSRC have been primarily driven by members' active participation and the development of goodwill and trust throughout our membership, which have facilitated novel collaborations across traditionally competitive or contentious stakeholder boundaries. The continued expansion of our base of participating academicians, industry experts, and regulators will define the Consortium's success in our second decade. It is our hope that sharing our endeavors to date will stimulate additional participation in the CSRC and also provide a model for other groups starting to develop similar collaborative forums. [ABSTRACT FROM AUTHOR]

This white paper provides a summary of presentations and discussions that were held at an Anticoagulant-Induced Bleeding and Reversal Agents Think Tank co-sponsored by the Cardiac Safety Research Consortium and the US Food and Drug Administration (FDA) at the FDA's White Oak Headquarters on April 22, 2014. Attention focused on a development pathway for reversal agents for the novel oral anticoagulants (NOACs). This is important because anticoagulation is still widely underused for stroke prevention in patients with atrial fibrillation. Undertreatment persists, although NOACs, in general, overcome some of the difficulties associated with anticoagulation provided by vitamin K antagonists. One reason for the lack of a wider uptake is the absence of NOAC reversal agents. As there are neither widely accepted academic and industry standards nor a definitive regulatory policy on the development of such reversal agents, this meeting provided a forum for leaders in the fields of cardiovascular clinical trials and cardiovascular safety to discuss the issues and develop recommendations. Attendees included representatives from pharmaceutical companies; regulatory agencies; end point adjudication specialist groups; contract research organizations; and active, academically based physicians. There was wide and solid consensus that NOACs overall offer improvements in convenience, efficacy, and safety compared with warfarin, even without reversal agents. Still, it was broadly accepted that it would be helpful to have reversal agents available for clinicians to use. Because it is not feasible to do definitive outcomes studies demonstrating a reversal agent's clinical benefits, it was felt that these agents could be approved for use in life-threatening bleeding situations if the molecules were well characterized preclinically, their pharmacodynamic and pharmacokinetic profiles were well understood, and showed no harmful adverse events in early human testing. There was also consensus that after such approval, efforts should be made to augment the available clinical information until such time as there is a body of evidence to demonstrate real-world clinical outcomes with the reversal agents. No recommendations were made for more generalized use of these agents in the setting of non–life-threatening situations. This article reflects the views of the authors and should not be construed to represent FDA's views or policies. [ABSTRACT FROM AUTHOR]

This White Paper provides a summary of presentations and discussions at a Cardiovascular Safety Outcome Trials Think Tank cosponsored by the Cardiac Safety Research Consortium, the US Food and Drug Administration, and the American College of Cardiology, held at American College of Cardiology's Heart House, Washington, DC, on February 19, 2014. Studies to assess cardiovascular (CV) risk of a new drug are sometimes requested by regulators to resolve ambiguous safety signals seen during its development or among other members of its class. Think Tank participants thought that important considerations in undertaking such studies were as follows: (1) plausibility —how likely it is that a possible signal indicating risk is real, based on strength of evidence, and/or whether a plausible mechanism of action for potential CV harm has been identified; (2) relevance —what relative and absolute CV risk would need to be excluded to determine that the drug had an acceptable benefit-to-risk balance for its use in the intended patient population; and (3) how plausibility and relevance influence the timing and approach to further safety assessment. [ABSTRACT FROM AUTHOR]

This white paper provides a summary of presentations and discussions at a cardiovascular (CV) end point adjudication think tank cosponsored by the Cardiac Safety Research Committee and the US Food and Drug Administration (FDA) that was convened at the FDA's White Oak headquarters on November 6, 2013. Attention was focused on the lack of clarity concerning the need for end point adjudication in both CV and non-CV trials: there is currently an absence of widely accepted academic or industry standards and a definitive regulatory policy on how best to structure and use clinical end point committees (CECs). This meeting therefore provided a forum for leaders in the fields of CV clinical trials and CV safety to develop a foundation of initial best practice recommendations for use in future CEC charters. Attendees included representatives from pharmaceutical companies, regulatory agencies, end point adjudication specialist groups, clinical research organizations, and active, academically based adjudicators. The manuscript presents recommendations from the think tank regarding when CV end point adjudication should be considered in trials conducted by cardiologists and by noncardiologists as well as detailing key issues in the composition of a CEC and its charter. In addition, it presents several recommended best practices for the establishment and operation of CECs. The science underlying CV event adjudication is evolving, and suggestions for additional areas of research will be needed to continue to advance this science. This manuscript does not constitute regulatory guidance. [ABSTRACT FROM AUTHOR]

This white paper provides a summary of a scientific proposal presented at a Cardiac Safety Research Consortium/Health and Environmental Sciences Institute/Food and Drug Administration–sponsored Think Tank, held at Food and Drug Administration's White Oak facilities, Silver Spring, MD, on July 23, 2013, with the intention of moving toward consensus on defining a new paradigm in the field of cardiac safety in which proarrhythmic risk would be primarily assessed using nonclinical in vitro human models based on solid mechanistic considerations of torsades de pointes proarrhythmia. This new paradigm would shift the emphasis from the present approach that strongly relies on QTc prolongation (a surrogate marker of proarrhythmia) and could obviate the clinical Thorough QT study during later drug development. These discussions represent current thinking and suggestions for furthering our knowledge and understanding of the public health case for adopting a new, integrated nonclinical in vitro/in silico paradigm, the Comprehensive In Vitro Proarrhythmia Assay, for the assessment of a candidate drug's proarrhythmic liability, and for developing a public-private collaborative program to characterize the data content, quality, and approaches required to assess proarrhythmic risk in the absence of a Thorough QT study. This paper seeks to encourage multistakeholder input regarding this initiative and does not represent regulatory guidance. [Copyright &y& Elsevier]

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. [ABSTRACT FROM AUTHOR]

The ability to make informed benefit-risk assessments for potentially cardiotoxic new compounds is of considerable interest and importance at the public health, drug development, and individual patient levels. Cardiac imaging approaches in the evaluation of drug-induced myocardial dysfunction will likely play an increasing role. However, the optimal choice of myocardial imaging modality and the recommended frequency of monitoring are undefined. These decisions are complicated by the array of imaging techniques, which have varying sensitivities, specificities, availabilities, local expertise, safety, and costs, and by the variable time-course of tissue damage, functional myocardial depression, or recovery of function. This White Paper summarizes scientific discussions of members of the Cardiac Safety Research Consortium on the main factors to consider when selecting nonclinical and clinical cardiac function imaging techniques in drug development. We focus on 3 commonly used imaging modalities in the evaluation of cardiac function: echocardiography, magnetic resonance imaging, and radionuclide (nuclear) imaging and highlight areas for future research. [ABSTRACT FROM AUTHOR]

Electrocardiographic monitoring is an integral component of the clinical assessment of cardiac safety of all compounds in development. The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use E14 guideline recommends a dedicated study to evaluate drug-induced effects on cardiac repolarization (“thorough QT/QTc study”). There has been limited published information on QT interval changes secondary to therapeutic proteins; however, in theory, biologic therapies may affect cardiac electrical activity either directly or indirectly. This article summarizes scientific discussions of members of the Cardiac Safety Research Consortium and includes possible approaches to consider for the clinical evaluation of drug-induced QT prolongation in development programs of therapeutic proteins. [ABSTRACT FROM AUTHOR]

Abstract: Objective:: This study assessed the effect of coadministration of ezetimibe and simvastatin on high sensitivity C-reactive protein (hs-CRP) in a large subject cohort (N =1089). Methods:: Data were combined from two nearly identical prospective trials. After dietary stabilization, washout period, and placebo lead-in period, patients with baseline low-density lipoprotein cholesterol (LDL-C)≥3.75–6.50mmol/l and triglycerides (TG)≤4.0mmol/l were randomized to one of the following daily treatments for 12 weeks: ezetimibe 10mg; simvastatin monotherapy (10, 20, 40, or 80mg); ezetimibe 10mg plus simvastatin (10, 20, 40, or 80mg); or placebo. The primary analysis was the percent change in hs-CRP for the pooled ezetimibe plus simvastatin versus simvastatin monotherapy cohorts. Results:: Ezetimibe coadministered with simvastatin more than doubled the hs-CRP reduction compared to simvastatin monotherapy (−33.3% versus −14.3%, p &#60;0.01). At each individual simvastatin dose level, coadministration therapy exerted significant further incremental hs-CRP reductions compared to simvastatin monotherapy. Similar hs-CRP reductions with coadministered ezetimibe and simvastatin were observed in the major subgroups examined (coronary heart disease, gender, age, baseline LDL-C, and body mass index). Conclusion:: In this large subject cohort, ezetimibe coadministered with simvastatin significantly reduced hs-CRP, suggesting a possible additional anti-inflammatory/anti-atherosclerotic action of combination therapy compared to simvastatin monotherapy. [Copyright &y& Elsevier]

This study assessed the effect of ezetimibe coadministered with simvastatin on high-sensitivity C-reactive protein (hs-CRP) in patients with primary hypercholesterolemia. After dietary stabilization, a 2- to 12-week washout period, and a 4-week, single-blind, placebo lead-in period, patients with baseline low-density lipoprotein cholesterol ≥145 and ≤250 mg/dl and triglycerides ≤350 mg/dl were randomized to one of these daily treatments for 12 consecutive weeks: ezetimibe 10 mg; simvastatin monotherapy (10, 20, 40, or 80 mg); ezetimibe 10 mg plus simvastatin (10, 20, 40, or 80 mg); or placebo. The primary analysis was the change in hs-CRP for the pooled ezetimibe plus simvastatin versus simvastatin monotherapy groups. Ezetimibe plus simvastatin significantly reduced median hs-CRP levels compared with simvastatin monotherapy (−34.8% vs −18.2%, p< 0.01), and incremental reductions were observed at each simvastatin dose level. Combination therapy-induced significant changes in individual lipid parameters did not explain the observed decreases in hs-CRP. Thus, ezetimibe coadministered with simvastatin resulted in significant incremental decreases in hs-CRP, possibly consistent with an additional anti-inflammatory effect compared with simvastatin monotherapy. [Copyright &y& Elsevier]

Focuses on the various treatment modalities for atrial fibrillation. Restoration of sinus rhythm after the patient's first episode; Use of prophylactic antiarrhythmic therapy in patients who remain symptomatic; Effectiveness of atrial-specific antiarrhythmic agents; Ablation therapy; Atrial implantable cardioverter-defibrillator.

Background: There is no nonparenteral medication for the rapid termination of paroxysmal supraventricular tachycardia.Objectives: The purpose of this study was to assess the efficacy and safety of etripamil nasal spray, a short-acting calcium-channel blocker, for the rapid termination of paroxysmal supraventricular tachycardia (SVT).Methods: This phase 2 study was performed during electrophysiological testing in patients with previously documented SVT who were induced into SVT prior to undergoing a catheter ablation. Patients in sustained SVT for 5 min received either placebo or 1 of 4 doses of active compound. The primary endpoint was the SVT conversion rate within 15 min of study drug administration. Secondary endpoints included time to conversion and adverse events.Results: One hundred four patients were dosed. Conversion rates from SVT to sinus rhythm were between 65% and 95% in the etripamil nasal spray groups and 35% in the placebo group; the differences were statistically significant (Pearson chi-square test) in the 3 highest active compound dose groups versus placebo. In patients who converted, the median time to conversion with etripamil was <3 min. Adverse events were mostly related to the intranasal route of administration or local irritation. Reductions in blood pressure occurred predominantly in the highest etripamil dose.Conclusions: Etripamil nasal spray rapidly terminated induced SVT with a high conversion rate. The safety and efficacy results of this study provide guidance for etripamil dose selection for future studies involving self-administration of this new intranasal calcium-channel blocker in a real-world setting for the termination of SVT. (Efficacy and Safety of Intranasal MSP-2017 [Etripamil] for the Conversion of PSVT to Sinus Rhythm [NODE-1]; NCT02296190). [ABSTRACT FROM AUTHOR]

Decreasing C-reactive protein (CRP) in addition to decreasing low-density lipoprotein (LDL) cholesterol may further decrease coronary heart disease risk. The effects of rosuvastatin compared with atorvastatin in achieving a combined target of LDL cholesterol <70 mg/dl and CRP <2 mg/L in 509 patients with type 2 diabetes mellitus was evaluated. CRP decreased significantly versus baseline in both treatment groups. Significantly more patients treated with rosuvastatin achieved the combined end point of LDL cholesterol <70 mg/dl and CRP <2 mg/L compared with atorvastatin by the end of the study period (58% vs 37%; p <0.001 vs atorvastatin). In conclusion, CRP was effectively decreased in patients with type 2 diabetes receiving rosuvastatin or atorvastatin, whereas rosuvastatin decreased LDL cholesterol significantly more than atorvastatin. [Copyright &y& Elsevier]

To define the effect of short-term rosuvastatin treatment on the estimated glomerular filtration rate (eGFR), the database of controlled clinical trials in the Rosuvastatin Clinical Development Program was reviewed. Thirteen studies comprising 3,956 rosuvastatin-treated patients were selected based on a serum creatinine measurement at 6 or 8 weeks after initiation of rosuvastatin treatment, randomization to approved and marketed rosuvastatin doses (5 to 40 mg), and unchanged rosuvastatin dose from treatment initiation (baseline) through 6 to 8 weeks of treatment. eGFR was determined with the Modification of Diet in Renal Disease formula. eGFR significantly increased for each dose of rosuvastatin individually and for all doses combined compared with baseline (range +0.9 to +3.2 ml/min/1.73 m2). Further analysis of 5 blinded, placebo-controlled trials comprising 525 patients showed an increase in eGFR of +0.8 ml/min/1.73 m2 (95% confidence interval +0.1 to +1.5) for all rosuvastatin-treated patients, which was significantly different from baseline (p <0.04) and from a change of −1.5 ml/min/1.73 m2 in the placebo-treated patients (95% confidence interval −2.5 to −0.5, p <0.001). The increase in eGFR for rosuvastatin-treated patients was consistent across all major demographic and clinical subgroups of interest, including patients with baseline proteinuria, baseline eGFR <60 ml/min/1.73 m2, and in patients with hypertension and/or diabetes. In conclusion, these results are consistent with previous rosuvastatin studies that showed an upward trend in eGFR with long-term treatment (≥96 weeks) and with the hypothesis that statins may have pleiotropic mechanisms of action that include beneficial renal effects. [Copyright &y& Elsevier]

The lipid-modifying effects of statin therapy in hypercholesterolemic African-Americans have not been well characterized. This study compared the efficacy and safety of rosuvastatin and atorvastatin treatment for 6 weeks in hypercholesterolemic African-American adults. In the African American Rosuvastatin Investigation of Efficacy and Safety (ARIES) trial (4522US/0002), 774 adult African-Americans with low-density lipoprotein cholesterol ≥160 and ≤300 mg/dl and triglycerides <400 mg/dl were randomized to receive open-label rosuvastatin 10 or 20 mg or atorvastatin 10 or 20 mg for 6 weeks. At week 6, significantly greater reductions in low-density lipoprotein cholesterol, total cholesterol, non–high-density lipoprotein cholesterol, and apolipoprotein B concentrations, as well as lipoprotein and apolipoprotein ratios, were seen with rosuvastatin versus milligram-equivalent atorvastatin doses (analysis of variance with Bonferroni-adjusted critical p <0.017 for all comparisons). Rosuvastatin 10 mg also increased high-density lipoprotein cholesterol significantly more than atorvastatin 20 mg (p <0.017). Although statistical comparisons were not performed, larger proportions of rosuvastatin-treated patients than atorvastatin-treated patients achieved National Cholesterol Education Program Adult Treatment Panel III low-density lipoprotein cholesterol goals. The median high-sensitivity C-reactive protein levels were significantly reduced statistically from baseline with rosuvastatin 20 mg and atorvastatin 20 mg among all patients and with rosuvastatin 10 and 20 mg and atorvastatin 20 mg in those patients with a baseline C-reactive protein level >2.0 mg/L. The 2 study medications were well tolerated during the 6-week study period. In conclusion, rosuvastatin 10 and 20 mg improved the overall lipid profile of hypercholesterolemic African-Americans better than did milligram-equivalent doses of atorvastatin. [Copyright &y& Elsevier]