Jonathan H. Goldman

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.

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.

Comparison of usefulness of dipyridamole stress myocardial contrast echocardiography to technetium-99m sestamibi single-photon emission computed tomography for detection of coronary artery disease (PB127 multicenter phase 2 trial results)

We hypothesized that assessment of hyperemic myocardial blood flow (MBF) velocity using myocardial contrast echocardiography (MCE) can detect coronary artery disease (CAD). We also postulated that only a single MCE study during stress is required for the detection of CAD in patients with normal function at rest. Patients with known or suspected CAD referred for dipyridamole stress technetium-99m sestamibi single-photon emission computed tomographic (SPECT) studies were enrolled. MCE was performed concurrently with SPECT using continuous infusions of PB127 during intermittent harmonic power Doppler imaging at multiple pulsing intervals. MCE and SPECT were compared in 43 of 54 patients who had adequate studies using both techniques. In 15 of the 43 patients, coronary angiography was performed within 30 days of the MCE/SPECT tests. Overall concordance for classification of patients as normal versus abnormal was 84% (kappa = 0.63) between the 2 tests. When false-negative SPECT scans were corrected for results of angiography, concordance increased to 93% (kappa = 0.82). For territorial analysis, concordance between MCE and SPECT for location of perfusion defects was 65% (kappa = 0.41) and 74% (kappa = 0.61) after SPECT was corrected by angiography. In patients with normal function at rest, a single stress MCE perfusion study allowed identification of CAD with the same concordance as rest/stress perfusion studies. In conclusion, visual assessment of regional differences in MBF velocity using PB127 allows detection of CAD with good concordance compared with technetium-99m sestamibi SPECT. In patients with normal left ventricular function at rest, a single stress PB127 MCE perfusion study is adequate for the detection of CAD.

Transesophageal Echocardiographic (TEE) Evaluation of Intracardiac and Pericardial Masses

Transesophageal echocardiography has assisted the detection of intracardiac masses and, in certain cases, aided our ability to define the specific type of mass. This technique, when coupled with three-dimensional imaging, may help to define infiltration of the wall. TEE aids in the intraoperative management of cardiac tumors.

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 ∼ 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.

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 </= 1.0). A total of 71 patients (cohort A) were studied at rest and another 64 (cohort B, age 62 +/- 12.6 years) were allocated to stress. Continuous electrocardigraphy was recorded. The study evaluated premature ventricular complex frequency at baseline, during, and after infusion of PB127 (dose < 0.175 mg/kg, <60-minute duration). Proportions of triggered and nontriggered intervals associated with premature ventricular complex were determined. PVC frequency did not increase with PB127 infusion in either cohort (P =.572, P =.263). Proportion of triggered intervals after QRS associated with PVC was similar to proportion of untriggered intervals in cohort A (P >.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.

Usefulness of Stroke Distance by Echocardiography as a Surrogate Marker of Cardiac Output That Is Independent of Gender and Size in a Normal Population

Left ventricular outflow tract stroke distance (SD) can be measured using pulsed-wave Doppler echocardiography, and is independent of body size. Moreover, persons with structurally normal hearts (heart rate < 55 beats/min) had SD > 0.18 m, and those with a heart rate > 95 beats/min had SD < 0.22 m; outside of these parameters, low- and high-output states are likely to exist, and suspicion of these can be confirmed by calculation of minute distance (normal range 9.7 to 20.5 m/min).

Prognosis of idiopathic dilated cardiomyopathy.

Previous reports in referral populations have emphasized the poor prognosis of dilated cardiomyopathy. This study evaluated mortality and morbidity in patients presenting at a referral center between 1989 and 1993. One hundred seventy-two consecutive patients were studied. At presentation, 82 were in New York Heart Association functional class III/IV. Mean (+/- SD) left ventricular end-diastolic dimension was 69 +/- 11 mm, ejection fraction was 25 +/- 10%, VO2 max was 21 +/- 9 mL/min/kg, and sodium was 136 +/- 9 mM. Treatments included vasodilators (n = 157, 92%), anticoagulation (n = 50, 29%), amiodarone (n = 52, 30%), and cardiac defibrillator (n = 5, 3%). During the follow-up period (mean, 26 +/- 29 months), 16 patients died and 60 developed progressive heart failure; 46 (27%) required cardiac transplantation. The majority of the patients (102, 59%) were stable or improved. Established prognostic determinants (left ventricular end-diastolic dimension, ejection fraction, sodium, and arrhythmia) were of low predictive value for the development of progressive heart failure or sudden death. The 1- and 2-year probabilities of death or transplantation was 16 and 21%, respectively (death only 6 and 7%, respectively). These observations are subject to referral bias, but suggest that the majority of patients can remain stable. Any improvement in survival compared to earlier experience can be due to earlier diagnosis, availability of transplantation, and new heart failure management strategies.

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.