Mitchell T. Saltzberg

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.

Ultrafiltration is Associated With Fewer Rehospitalizations than Continuous Diuretic Infusion in Patients With Decompensated Heart Failure: Results From UNLOAD

BACKGROUND Compare outcomes of ultrafiltration (UF) versus standard intravenous (IV) diuretics by continuous infusion or bolus injection in volume overloaded heart failure (HF) patients. In the Ultrafiltration versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated heart Failure (UNLOAD) study, UF produced greater fluid reduction and fewer HF rehospitalizations than IV diuretics in 200 hospitalized HF patients. Outcomes may be due to greater fluid removal, but UF removes more sodium/unit volume than diuretics. METHODS AND RESULTS Outcomes of 100 patients randomized to UF were compared with those of patients randomized to standard IV diuretic therapy with continuous infusion (32) or bolus injections (68). Choice of diuretic therapy was by the treating physician. Forty-eight hour weight loss (kg): 5.0 +/- 3.1 UF, 3.6 +/- 3.5 continuous infusion, and 2.9 +/- 3.5 bolus diuretics (P = .001 UF versus bolus diuretic; P > .05 for the other comparisons). Net fluid loss (L): 4.6 +/- 2.6 UF, 3.9 +/- 2.7 continuous infusion, and 3.1 +/- 2.6 bolus diuretics (P < .001 UF versus bolus diuretic; P > .05 for the other comparisons). At 90 days, rehospitalizations plus unscheduled visits for HF/patient (rehospitalization equivalents) were fewer in UF group (0.65 +/- 1.36) than in continuous infusion (2.29 +/- 3.23; P = .016 versus UF) and bolus diuretics (1.31 +/- 1.87; P = .050 versus UF) groups. No serum creatinine differences occurred between groups up to 90 days. CONCLUSIONS Despite similar fluid loss with UF and continuous diuretic infusion, fewer HF rehospitalizations equivalents occurred only with UF. Removal of isotonic fluid by UF compared with hypotonic urine by diuretics more effectively reduces total body sodium in congested HF patients.

Effects of Xanthine Oxidase Inhibition in Hyperuricemic Heart Failure Patients: The Xanthine Oxidase Inhibition for Hyperuricemic Heart Failure Patients (exact-hf) Study

Background— Oxidative stress may contribute to heart failure (HF) progression. Inhibiting xanthine oxidase in hyperuricemic HF patients may improve outcomes. Methods and Results— We randomly assigned 253 patients with symptomatic HF, left ventricular ejection fraction ⩽40%, and serum uric acid levels ≥9.5 mg/dL to receive allopurinol (target dose, 600 mg daily) or placebo in a double-blind, multicenter trial. The primary composite end point at 24 weeks was based on survival, worsening HF, and patient global assessment. Secondary end points included change in quality of life, submaximal exercise capacity, and left ventricular ejection fraction. Uric acid levels were significantly reduced with allopurinol in comparison with placebo (treatment difference, –4.2 [–4.9, –3.5] mg/dL and –3.5 [–4.2, –2.7] mg/dL at 12 and 24 weeks, respectively, both P<0.0001). At 24 weeks, there was no significant difference in clinical status between the allopurinol- and placebo-treated patients (worsened 45% versus 46%, unchanged 42% versus 34%, improved 13% versus 19%, respectively; P=0.68). At 12 and 24 weeks, there was no significant difference in change in Kansas City Cardiomyopathy Questionnaire scores or 6-minute walk distances between the 2 groups. At 24 weeks, left ventricular ejection fraction did not change in either group or between groups. Rash occurred more frequently with allopurinol (10% versus 2%, P=0.01), but there was no difference in serious adverse event rates between the groups (20% versus 15%, P=0.36). Conclusions— In high-risk HF patients with reduced ejection fraction and elevated uric acid levels, xanthine oxidase inhibition with allopurinol failed to improve clinical status, exercise capacity, quality of life, or left ventricular ejection fraction at 24 weeks. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00987415.Despite guideline-recommended therapy for patients with heart failure (HF), morbidity and mortality rates remain unacceptably high.1 Given the public health burden of HF, there is a clear need for improved therapies. A growing body of evidence suggests that increased oxidative stress contributes to ventricular and vascular remodeling and disease progression in HF.2 Xanthine oxidase (XO) is a potential source of oxidative stress, and may be an important target for therapy.3 During purine metabolism, increased XO activity leads to the production of superoxide and uric acid (UA). Significant hyperuricemia is present in about 25% of patients with HF and reduced ejection fraction,4, 5 and is associated with worsening symptoms, exercise intolerance and reduced survival.6–8 Serum UA levels are included in HF risk scores,8, 9 and may help to select high-risk patients for XO inhibition. Allopurinol is a potent inhibitor of XO that may reverse several pathophysiological processes in HF, including decreased calcium sensitivity, mechanoenergetic uncoupling, increased anaerobic metabolism, and energy depletion.10 Studies in animals and humans with HF have shown that allopurinol can increase myocardial efficiency and reduce oxygen consumption.11, 12 Magnetic resonance spectroscopy has demonstrated that allopurinol increases myocardial high-energy phosphates and adenosine triphosphate flux, thereby improving mechanoenergetic coupling.13 Impaired endothelial function improves in a dose-dependent fashion with chronic XO inhibition in HF,14, 15 and observational studies in HF patients with gout suggest that treatment with allopurinol is associated with improved survival.16–18 Notably, allopurinol use is treated as a marker of improved survival in the Seattle Heart Failure Model.8 Hare et al.19 randomized 405 patients with moderate to severe HF and reduced ejection fraction to 6 months of treatment with oxypurinol (the active metabolite of allopurinol) or placebo. Although oxypurinol had no clinical benefit in the overall study population, a sub-group of patients with hyperuricemia (UA level ≥9.5 mg/dL) responded favorably with improved clinical status and trends towards decreased all-cause and cardiovascular death. Based on these findings, we hypothesized that in patients with symptomatic HF and reduced LVEF, who have elevated serum UA levels, treatment with high-dose allopurinol for 24 weeks would improve a composite clinical outcome of survival, worsening HF and patient global assessment.

Burden of Sodium Abnormalities in Patients Hospitalized for Heart Failure

Hyponatremia presumably is associated with adverse clinical outcomes in patients with congestive heart failure (CHF), but risk thresholds and economic burden are less studied. The authors analyzed 115,969 patients hospitalized for CHF and grouped them by serum sodium levels (severe hyponatremia, ≤130 mEq/L; hyponatremia, 131-135 mEq/L; normonatremia, 136-145 mEq/L; hypernatremia, >145 mEq/L). Univariable and multivariable analyses on the associated clinical and economic outcomes were performed. The most common abnormality was hyponatremia (15.9%), followed by severe hyponatremia (5.3%) and hypernatremia (3.2%). Hospital mortality was highest for severe hyponatremia (7.6%), followed by hypernatremia (6.7%) and hyponatremia (4.9%) (P<.0001). Compared with normonatremia, risk-adjusted mortality was highest for severe hyponatremia (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.59-1.99), followed by hypernatremia (OR, 1.55; 95% CI, 1.34-1.80) and hyponatremia (OR, 1.29; 95% CI, 1.19-1.40; all P<.0001). Risk-adjusted hospital prolongation was greater for each level of sodium abnormality than for normonatremia, ranging from 0.42 (CI, 0.26-0.60) days for hypernatremia to 1.28 (CI, 1.11-1.47) days for severe hyponatremia. Risk-adjusted attributable hospital cost increase was highest for severe hyponatremia (

Destination mechanical circulatory support: proposal for clinical standards

1132; CI,

Effects of Xanthine Oxidase Inhibition in Hyperuricemic Heart Failure Patients: The EXACT-HF Study

856-

Effects of Xanthine Oxidase Inhibition in Hyperuricemic Heart Failure PatientsCLINICAL PERSPECTIVE

1425; all (P<.0001). Sodium abnormalities were common in patients hospitalized for CHF. Adverse outcomes resulted not only from severe hyponatremia, but also from mild hyponatremia and hypernatremia.

ENHANCED BIOACTIVE TGF- LEVELS IN THE MYOCARDIUM SUGGESTS EARLY PATHOLOGICAL TRANSITION IN ASYMPTOMATIC SEVERE MITRAL REGURGITATION

Mechanical circulatory support device (MCSDs) have evolved during the past 2 decades to become accepted bridging therapy for patients with irreversible hemodynamic deterioration while awaiting cardiac transplantation. More recently, based on the results of the Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) study, MCSD therapy has become available as permanent or destination therapy for a restricted population of patients with advanced heart failure (AHF) not thought to be appropriate transplant candidates. The potential proliferation of new devices and the possible expansion of the target populations bring new responsibilities. Unlike pharmaceutical trials that have included thousands of patients, trials with MCSDs will continue to be performed on a relatively small scale because equipoise for randomization can be undermined by the unmasked nature of mechanical support, the logistics of study finances, and the continuous device improvements—all of which constrain trial size and duration. Currently, insufficient evidence beyond REMATCH criteria exists for refining potential long-term MCSD therapy candidate cohorts, and application of this challenging therapy is complicated further by the degree of institutional commitment, surgical expertise, multidisciplinary skills, available devices, and overall experience required for the successful application of mechanical circulatory support. The REMATCH trial was a landmark study that demonstrated the benefit of MCSDs in patients with AHF not eligible for transplantation. Patients supported with MCSDs had significantly better survival at 1 year than did patients with advanced end-stage heart failure who were treated medically (many with long-term parenteral inotropes). Although a survival benefit was clear, it was only over a 2-year time period, and morbidity was substantial, particularly with respect to infections, neurologic events, and pump malfunctions. These observations force us to consider carefully patient selection and the infrastructure of centers with strategies developed to provide this type of care. In the United States, the Food and Drug Administration (FDA) approval of the HeartMate From Columbia University, New York, New York; Cleveland Clinic Foundation, Cleveland, Ohio; Harvard University, Boston, Massachusetts; Stanford University, Stanford, California; University of Alabama at Birmingham, Birmingham, Alabama; University of California at Los Angeles, Los Angeles, California; University of Minneapolis, Minneapolis, Minnesota; Midwest Heart Specialists, Downers Grove, Illinois; Tufts–Northeast Medical Center, Boston, Massachusetts; University of Pittsburgh, Pittsburgh, Pennsylvania. Submitted February 7, 2002. Reprint requests: Mario C. Deng, MD, The Heart Failure Center and Division of Circulatory Physiology, Columbia University College of Physicians and Surgeons, New York Presbyterian Hospital, Milstein Hospital Building, Room 5-407, 177 Fort Washington Avenue, New York, New York 10032. Telephone: 212-305-0200. Fax: 212-305-7439. E-mail: md785@columbia. edu J Heart Lung Transplant 2003;22:365–369 Copyright

Variability in Measurement of BNP in Routine Evaluation of Heart Failure(VAMPIRE)

Background— Oxidative stress may contribute to heart failure (HF) progression. Inhibiting xanthine oxidase in hyperuricemic HF patients may improve outcomes. Methods and Results— We randomly assigned 253 patients with symptomatic HF, left ventricular ejection fraction ⩽40%, and serum uric acid levels ≥9.5 mg/dL to receive allopurinol (target dose, 600 mg daily) or placebo in a double-blind, multicenter trial. The primary composite end point at 24 weeks was based on survival, worsening HF, and patient global assessment. Secondary end points included change in quality of life, submaximal exercise capacity, and left ventricular ejection fraction. Uric acid levels were significantly reduced with allopurinol in comparison with placebo (treatment difference, –4.2 [–4.9, –3.5] mg/dL and –3.5 [–4.2, –2.7] mg/dL at 12 and 24 weeks, respectively, both P<0.0001). At 24 weeks, there was no significant difference in clinical status between the allopurinol- and placebo-treated patients (worsened 45% versus 46%, unchanged 42% versus 34%, improved 13% versus 19%, respectively; P=0.68). At 12 and 24 weeks, there was no significant difference in change in Kansas City Cardiomyopathy Questionnaire scores or 6-minute walk distances between the 2 groups. At 24 weeks, left ventricular ejection fraction did not change in either group or between groups. Rash occurred more frequently with allopurinol (10% versus 2%, P=0.01), but there was no difference in serious adverse event rates between the groups (20% versus 15%, P=0.36). Conclusions— In high-risk HF patients with reduced ejection fraction and elevated uric acid levels, xanthine oxidase inhibition with allopurinol failed to improve clinical status, exercise capacity, quality of life, or left ventricular ejection fraction at 24 weeks. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00987415.Despite guideline-recommended therapy for patients with heart failure (HF), morbidity and mortality rates remain unacceptably high.1 Given the public health burden of HF, there is a clear need for improved therapies. A growing body of evidence suggests that increased oxidative stress contributes to ventricular and vascular remodeling and disease progression in HF.2 Xanthine oxidase (XO) is a potential source of oxidative stress, and may be an important target for therapy.3 During purine metabolism, increased XO activity leads to the production of superoxide and uric acid (UA). Significant hyperuricemia is present in about 25% of patients with HF and reduced ejection fraction,4, 5 and is associated with worsening symptoms, exercise intolerance and reduced survival.6–8 Serum UA levels are included in HF risk scores,8, 9 and may help to select high-risk patients for XO inhibition. Allopurinol is a potent inhibitor of XO that may reverse several pathophysiological processes in HF, including decreased calcium sensitivity, mechanoenergetic uncoupling, increased anaerobic metabolism, and energy depletion.10 Studies in animals and humans with HF have shown that allopurinol can increase myocardial efficiency and reduce oxygen consumption.11, 12 Magnetic resonance spectroscopy has demonstrated that allopurinol increases myocardial high-energy phosphates and adenosine triphosphate flux, thereby improving mechanoenergetic coupling.13 Impaired endothelial function improves in a dose-dependent fashion with chronic XO inhibition in HF,14, 15 and observational studies in HF patients with gout suggest that treatment with allopurinol is associated with improved survival.16–18 Notably, allopurinol use is treated as a marker of improved survival in the Seattle Heart Failure Model.8 Hare et al.19 randomized 405 patients with moderate to severe HF and reduced ejection fraction to 6 months of treatment with oxypurinol (the active metabolite of allopurinol) or placebo. Although oxypurinol had no clinical benefit in the overall study population, a sub-group of patients with hyperuricemia (UA level ≥9.5 mg/dL) responded favorably with improved clinical status and trends towards decreased all-cause and cardiovascular death. Based on these findings, we hypothesized that in patients with symptomatic HF and reduced LVEF, who have elevated serum UA levels, treatment with high-dose allopurinol for 24 weeks would improve a composite clinical outcome of survival, worsening HF and patient global assessment.

Is outcome after heart transplantation influenced by ethnicity? A comparison of African Americans versus Caucasians.

Background— Oxidative stress may contribute to heart failure (HF) progression. Inhibiting xanthine oxidase in hyperuricemic HF patients may improve outcomes. Methods and Results— We randomly assigned 253 patients with symptomatic HF, left ventricular ejection fraction ⩽40%, and serum uric acid levels ≥9.5 mg/dL to receive allopurinol (target dose, 600 mg daily) or placebo in a double-blind, multicenter trial. The primary composite end point at 24 weeks was based on survival, worsening HF, and patient global assessment. Secondary end points included change in quality of life, submaximal exercise capacity, and left ventricular ejection fraction. Uric acid levels were significantly reduced with allopurinol in comparison with placebo (treatment difference, –4.2 [–4.9, –3.5] mg/dL and –3.5 [–4.2, –2.7] mg/dL at 12 and 24 weeks, respectively, both P<0.0001). At 24 weeks, there was no significant difference in clinical status between the allopurinol- and placebo-treated patients (worsened 45% versus 46%, unchanged 42% versus 34%, improved 13% versus 19%, respectively; P=0.68). At 12 and 24 weeks, there was no significant difference in change in Kansas City Cardiomyopathy Questionnaire scores or 6-minute walk distances between the 2 groups. At 24 weeks, left ventricular ejection fraction did not change in either group or between groups. Rash occurred more frequently with allopurinol (10% versus 2%, P=0.01), but there was no difference in serious adverse event rates between the groups (20% versus 15%, P=0.36). Conclusions— In high-risk HF patients with reduced ejection fraction and elevated uric acid levels, xanthine oxidase inhibition with allopurinol failed to improve clinical status, exercise capacity, quality of life, or left ventricular ejection fraction at 24 weeks. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00987415.Despite guideline-recommended therapy for patients with heart failure (HF), morbidity and mortality rates remain unacceptably high.1 Given the public health burden of HF, there is a clear need for improved therapies. A growing body of evidence suggests that increased oxidative stress contributes to ventricular and vascular remodeling and disease progression in HF.2 Xanthine oxidase (XO) is a potential source of oxidative stress, and may be an important target for therapy.3 During purine metabolism, increased XO activity leads to the production of superoxide and uric acid (UA). Significant hyperuricemia is present in about 25% of patients with HF and reduced ejection fraction,4, 5 and is associated with worsening symptoms, exercise intolerance and reduced survival.6–8 Serum UA levels are included in HF risk scores,8, 9 and may help to select high-risk patients for XO inhibition. Allopurinol is a potent inhibitor of XO that may reverse several pathophysiological processes in HF, including decreased calcium sensitivity, mechanoenergetic uncoupling, increased anaerobic metabolism, and energy depletion.10 Studies in animals and humans with HF have shown that allopurinol can increase myocardial efficiency and reduce oxygen consumption.11, 12 Magnetic resonance spectroscopy has demonstrated that allopurinol increases myocardial high-energy phosphates and adenosine triphosphate flux, thereby improving mechanoenergetic coupling.13 Impaired endothelial function improves in a dose-dependent fashion with chronic XO inhibition in HF,14, 15 and observational studies in HF patients with gout suggest that treatment with allopurinol is associated with improved survival.16–18 Notably, allopurinol use is treated as a marker of improved survival in the Seattle Heart Failure Model.8 Hare et al.19 randomized 405 patients with moderate to severe HF and reduced ejection fraction to 6 months of treatment with oxypurinol (the active metabolite of allopurinol) or placebo. Although oxypurinol had no clinical benefit in the overall study population, a sub-group of patients with hyperuricemia (UA level ≥9.5 mg/dL) responded favorably with improved clinical status and trends towards decreased all-cause and cardiovascular death. Based on these findings, we hypothesized that in patients with symptomatic HF and reduced LVEF, who have elevated serum UA levels, treatment with high-dose allopurinol for 24 weeks would improve a composite clinical outcome of survival, worsening HF and patient global assessment.