Dose-dependent augmentation of cardiac systolic function with the selective cardiac myosin activator, omecamtiv mecarbil: a first-in-man study.

BACKGROUND: Decreased systolic function is central to the pathogenesis of heart failure in millions of patients worldwide, but mechanism-related adverse effects restrict existing inotropic treatments. This study tested the hypothesis that omecamtiv mecarbil, a selective cardiac myosin activator, will augment cardiac function in human beings. METHODS: In this dose-escalating, crossover study, 34 healthy men received a 6-h double-blind intravenous infusion of omecamtiv mecarbil or placebo once a week for 4 weeks. Each sequence consisted of three ascending omecamtiv mecarbil doses (ranging from 0·005 to 1·0 mg/kg per h) with a placebo infusion randomised into the sequence. Vital signs, blood samples, electrocardiographs (ECGs), and echocardiograms were obtained before, during, and after each infusion. The primary aim was to establish maximum tolerated dose (the highest infusion rate tolerated by at least eight participants) and plasma concentrations of omecamtiv mecarbil; secondary aims were evaluation of pharmacodynamic and pharmacokinetic characteristics, safety, and tolerability. This study is registered at ClinicalTrials.gov, number NCT01380223. FINDINGS: The maximum tolerated dose of omecamtiv mecarbil was 0·5 mg/kg per h. Omecamtiv mecarbil infusion resulted in dose-related and concentration-related increases in systolic ejection time (mean increase from baseline at maximum tolerated dose, 85 [SD 5] ms), the most sensitive indicator of drug effect (r(2)=0·99 by dose), associated with increases in stroke volume (15 [2] mL), fractional shortening (8% [1]), and ejection fraction (7% [1]; all p<0·0001). Omecamtiv mecarbil increased atrial contractile function, and there were no clinically relevant changes in diastolic function. There were no clinically significant dose-related adverse effects on vital signs, serum chemistries, ECGs, or adverse events up to a dose of 0·625 mg/kg per h. The dose-limiting toxic effect was myocardial ischaemia due to excessive prolongation of systolic ejection time. INTERPRETATION: These first-in-man data show highly dose-dependent augmentation of left ventricular systolic function in response to omecamtiv mecarbil and support potential clinical use of the drug in patients with heart failure. FUNDING: Cytokinetics Inc.

The effects of the cardiac myosin activator, omecamtiv mecarbil, on cardiac function in systolic heart failure: a double-blind, placebo-controlled, crossover, dose-ranging phase 2 trial.

BACKGROUND: Many patients with heart failure remain symptomatic and have a poor prognosis despite existing treatments. Decreases in myocardial contractility and shortening of ventricular systole are characteristic of systolic heart failure and might be improved by a new therapeutic class, cardiac myosin activators. We report the first study of the cardiac myosin activator, omecamtiv mecarbil, in patients with systolic heart failure. METHODS: We undertook a double-blind, placebo-controlled, crossover, dose-ranging, phase 2 trial investigating the effects of omecamtiv mecarbil (formerly CK-1827452), given intravenously for 2, 24, or 72 h to patients with stable heart failure and left ventricular systolic dysfunction receiving guideline-indicated treatment. Clinical assessment (including vital signs, echocardiograms, and electrocardiographs) and testing of plasma drug concentrations took place during and after completion of each infusion. The primary aim was to assess safety and tolerability of omecamtiv mecarbil. This study is registered at ClinicalTrials.gov, NCT00624442. FINDINGS: 45 patients received 151 infusions of active drug or placebo. Placebo-corrected, concentration-dependent increases in left ventricular ejection time (up to an 80 ms increase from baseline) and stroke volume (up to 9·7 mL) were recorded, associated with a small reduction in heart rate (up to 2·7 beats per min; p<0·0001 for all three measures). Higher plasma concentrations were also associated with reductions in end-systolic (decrease of 15 mL at >500 ng/mL, p=0·0026) and end-diastolic volumes (16 mL, p=0·0096) that might have been more pronounced with increased duration of infusion. Cardiac ischaemia emerged at high plasma concentrations (two patients, plasma concentrations roughly 1750 ng/mL and 1350 ng/mL). For patients tolerant of all study drug infusions, no consistent pattern of adverse events with either dose or duration emerged. INTERPRETATION: Omecamtiv mecarbil improved cardiac function in patients with heart failure caused by left ventricular dysfunction and could be the first in class of a new therapeutic agent. FUNDING: Cytokinetics Inc.

Cardiac toxicity screening by echocardiography in healthy volunteers: a study of the effects of diurnal variation and use of a core laboratory on the reproducibility of left ventricular function measurement.

BACKGROUND: In investigational medicinal products testing centers (IMP), reliable methods for monitoring early signs of cardiotoxicity of a potential new drug in healthy volunteers are essential. This study examines what levels of left ventricular ejection fraction (LVEF) variance can be achieved with two-dimensional echocardiography (2DE) in a core laboratory versus a site laboratory. Diurnal variability of LVEF and diastolic parameters were also reviewed. METHODS AND RESULTS: 64 healthy males, (age range 18-40 years), with optimal echo windows were recruited. Two-dimensional and tissue Doppler (TDI) echocardiography was performed by one dedicated sonographer using an Acuson Sequoia C256 machine. Heart rate and blood pressure were recorded simultaneously. Echocardiograms were performed at set time points (0, 1, 4, and 20 hours) on all subjects. The images were analyzed independently by one on-site, unblinded, sonographer reader (site lab) and one experienced off-site blinded physician over reader (core lab). The core lab showed significantly less variance in LVEF measurements than the site lab (5.5% vs. 19.9%). There was no significant diurnal variation in mean blood pressure, LVEF or E:A ratio measurements over 20 hours. CONCLUSIONS: The core lab had better reproducibility and significantly less variance in LVEF measurements by 2DE than the site lab. There was no diurnal variation in LV function measurement.

Myocardial contrast echocardiography (MCE) with triggered ultrasound does not cause premature ventricular complexes: evidence from PB127 MCE studies.

Previous studies suggest that myocardial contrast echocardiography using high mechanical index triggered ultrasound can be associated with increased frequency of the premature ventricular complex (PVC). However, this association has not been systematically examined. PB127 (Point Biomedical Corp, San Carlos, Calif) is a novel microsphere designed for evaluation of myocardial perfusion with ultrasound. PB127 myocardial contrast echocardiography was performed with triggered harmonic power Doppler in early/mid diastole (mechanical index .999) and was lower than untriggered intervals (P =.001) in B, suggesting that triggers do not cause PVC. PB127 does not cause increase PVC frequency during or after imaging with triggered ultrasound at mechanical index of 1.

Effect of Optison on pulmonary artery systolic pressure and pulmonary vascular resistance.

Ultrasound contrast agent safety has received recent attention based on reports of associated serious adverse events. The US Food and Drug Administration requested this postmarketing study of the effects of Optison on pulmonary hemodynamics. The aim of this study was to compare Optison and a placebo for effects on pulmonary artery systolic pressure (PASP) and pulmonary vascular resistance (PVR) during right-sided cardiac catheterization. This was a single-blind, crossover, placebo-controlled, multicenter study of Optison in subjects referred for clinically indicated cardiac catheterization. Based on screening echocardiographic PASP, subjects were assigned to 1 of 2 strata (1 = normal PASP [≤35 mm Hg] and 2 = elevated PASP [>35 mm Hg]), in which they were randomized to treatment arm A (intravenous 0.5 ml Optison and then intravenous 0.5 ml placebo [5% dextrose] 15 minutes later) or arm B (intravenous 0.5 ml placebo [5% dextrose] and then 0.5 ml Optison 15 minutes later). Baseline pulmonary hemodynamics were obtained within 60 minutes before the first injection and 2, 6, and 10 minutes after each injection. Thirty patients each received their assigned treatments. There were no clinically relevant increases from baseline in mean PASP or PVR (Wood units) in either stratum alone or the combined strata. There were no serious adverse events. In conclusion, there is no change in PASP or PVR after intravenous injection of Optison at a clinically relevant dose in patients with normal or elevated baseline PASP.

A retrospective comparison of mortality in critically ill hospitalized patients undergoing echocardiography with and without an ultrasound contrast agent.

OBJECTIVES: To compare acute mortality in critically ill hospitalized patients undergoing echocardiography with and without an ultrasound contrast agent (UCA). BACKGROUND: Because of serious cardiopulmonary reactions reported immediately after administration of perflutren-containing UCAs, the FDA required a black box safety warning for this class of agents, including perflutren protein-type A microspheres injectable suspension. METHODS: This study used the largest hospital service-level database in the U.S. All adult patients undergoing in-patient echocardiography between January 2003 and October 2005 were identified (n = 2,588,722, of which 22,499 received perflutren protein-type A microspheres injectable suspension). Of the 22,499 contrast echocardiography patients, 2,900 had diagnoses meeting criteria for critical illness (heart failure, acute myocardial infarction, arrhythmia, respiratory failure, pulmonary embolism, emphysema, and pulmonary hypertension). To control for the differences between the contrast and noncontrast patients, we used propensity score matching. Variables used in the construction of the propensity score included comorbidities, demographic factors, hospital-specific factors, level of care, and mechanical ventilation status. Patients receiving contrast echocardiography were matched to 4 control patients who received noncontrast echocardiography. Conditional logistic regression was used to estimate mortality effects. RESULTS: There were 167 deaths in the study among critically ill patients, 38 of 2,900 from the contrast group and 129 of 11,600 from the control group. The contrast agent was not associated with an increase in same-day mortality (odds ratio: 1.18; 95% confidence interval: 0.82 to 1.71; p = 0.37). Before matching, contrast patients showed greater morbidity than noncontrast patients (Deyo-Charlson comorbidity score 2.45 vs. 2.25, p < 0.0001). After propensity score matching, these differences were significantly reduced, showing that both groups were well balanced. CONCLUSIONS: There is no increase in mortality in critically ill patients undergoing echocardiography with the UCA compared with case-matched control patients.

Ultrasound contrast agents: balancing safety versus efficacy.

In October, 2007, the FDA issued a new 'black box' warning, several new disease state contraindications and a mandated 30-min post-procedure monitoring period for the ultrasound contrast agents Definity (perflutren lipid microsphere injectable suspension, Lantheus Medical Imaging, North Billerica, MA, USA) and Optison (perflutren protein type A microspheres for injectable suspension, GE Healthcare, Buckinghamshire, UK). These labeling changes were largely secondary to reports of 4 patient deaths, and approximately 190 other 'serious cardiopulmonary reactions' that were temporally related but not clearly causally attributable to Definity administration. Contrast agent use in the US plummeted in the immediate aftermath of this FDA action, with many hospitals, physician offices and outpatient imaging centers suspending contrast echocardiography altogether. This review will focus on the immediate response from the international physician community, new contrast agent safety data published within the past year, results of a special meeting of the FDA Cardio-Renal panel devoted to contrast agent safety in June 2008, recently issued revised product labeling for both agents and future prospects for contrast echocardiography.

Thinking outside the "box"-the ultrasound contrast controversy.

On October 10, 2007, the U.S. Food and Drug Administration (FDA) announced a new "black box" warning for the perflutren-containing ultrasound contrast agents, contraindicating their use in patients with acute coronary syndromes, acute myocardial infarction, and worsening or clinically unstable heart failure. These warnings ignore the proven efficacy of ultrasound contrast agents, the previously established safety of these compounds, the potential risks of alternative procedures, and the likely confounding effect of pseudocomplication. We suggest that the FDA Medical Imaging Division convene a panel of cardiologists experienced in a variety of imaging modalities to fully assess the adverse events that have been attributed to these agents and that any future FDA warnings acknowledge the possible influence of pseudocomplication, the proven efficacy of the modality in question for early and accurate diagnosis of cardiovascular disease, and the known and theoretical risks of alternative testing that may be necessary.

Left atrial size is a poor predictor of pathology in the older patient: preliminary observations.

OBJECTIVE: The goal of this study was to determine the relationship between left atrial (LA) size and pathology in humans. METHODS: We evaluated 14 patients (age 60 +/- 14 years, range 25-77, 9 males) who had died at our hospital. Eight patients were in sinus rhythm, 3 had paroxysmal atrial fibrillation (PAF), and 3 were in established atrial fibrillation (AF). LA size was calculated at transthoracic echocardiography (TTE) prior to death. At autopsy, histology of the dissected LA was examined at the appendage (APP), transverse sinus (TS), oblique sinus (OS), crux, and oval fossa. The severity of hypertrophy (HTY) and fibrosis (FIB) was determined by histochemistry. RESULTS: Mean LA weight was 37 +/- 11 g. One patient with PAF had amyloid. LA size by TTE was associated with LA weight (R = 0.6, P = 0.029). Increased age was associated with less severe APP FIB (P = 0.04). Younger patients tended to have less severe APP HTY (P = 0.09), and TS FIB (P = 0.12). Severity of atrial HTY and FIB was similar in APP and TS (P = NS). There was no relationship between abnormal atrial histology with LA volume or cardiac rhythm. Five patients had LA dilatation (LA end systolic volume index >30 ml/m(2)). Of those patients with normal LA size, 6 (75%) had APP FIB, 8 (100%) had APP HTY, 7 (88%) had TS FIB, 8 (100%) had TS HTY, and 7 (88%) had OS HTY. CONCLUSIONS: Abnormal LA histology is common in patients who have normal LA size by TTE. Microscopic atrial disease is associated with aging, and may represent a precursor state for LA dilatation or AF.

Pulmonary hemodynamic effects of dipyridamole infusion in patients with normal and elevated pulmonary artery systolic pressure receiving PB127.

BACKGROUND: Intravenous administration of microspheres used as ultrasound contrast agents may potentially alter pulmonary hemodynamics. PB127 (POINT Biomedical Corp., San Carlos, CA) is an investigational ultrasound perfusion-imaging agent used in conjunction with dipyridamole to diagnose coronary artery disease. The effects of PB127 alone or in combination with dipyridamole on pulmonary hemodynamics have not been described. METHODS: We studied 20 patients, including 10 with elevated screening pulmonary artery systolic pressure (>35 mm Hg). Doppler-derived pulmonary hemodynamics were determined before and after continuous infusion of PB127 (0.175 mg/kg diluted in 5% dextrose) or 5% dextrose. Patients then received dipyridamole (0.56 mg/kg) and hemodynamics were again assessed. RESULTS: During PB127/dextrose infusion, there were no significant changes in pulmonary hemodynamics compared with baseline. After dipyridamole, there were small increases in pulmonary artery systolic pressure and in pulmonary flow and a reduction in pulmonary vascular resistance. These changes occurred in patients with normal and elevated pulmonary artery systolic pressure. CONCLUSION: PB127 infusion does not alter pulmonary hemodynamics. Mild alterations of pulmonary hemodynamics occur after dipyridamole administration.