Alon Marmor

Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial

BACKGROUND Serelaxin, recombinant human relaxin-2, is a vasoactive peptide hormone with many biological and haemodynamic effects. In a pilot study, serelaxin was safe and well tolerated with positive clinical outcome signals in patients with acute heart failure. The RELAX-AHF trial tested the hypothesis that serelaxin-treated patients would have greater dyspnoea relief compared with patients treated with standard care and placebo. METHODS RELAX-AHF was an international, double-blind, placebo-controlled trial, enrolling patients admitted to hospital for acute heart failure who were randomly assigned (1:1) via a central randomisation scheme blocked by study centre to standard care plus 48-h intravenous infusions of placebo or serelaxin (30 μg/kg per day) within 16 h from presentation. All patients had dyspnoea, congestion on chest radiograph, increased brain natriuretic peptide (BNP) or N-terminal prohormone of BNP, mild-to-moderate renal insufficiency, and systolic blood pressure greater than 125 mm Hg. Patients, personnel administering study drug, and those undertaking study-related assessments were masked to treatment assignment. The primary endpoints evaluating dyspnoea improvement were change from baseline in the visual analogue scale area under the curve (VAS AUC) to day 5 and the proportion of patients with moderate or marked dyspnoea improvement measured by Likert scale during the first 24 h, both analysed by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00520806. FINDINGS 1161 patients were randomly assigned to serelaxin (n=581) or placebo (n=580). Serelaxin improved the VAS AUC primary dyspnoea endpoint (448 mm × h, 95% CI 120-775; p=0·007) compared with placebo, but had no significant effect on the other primary endpoint (Likert scale; placebo, 150 patients [26%]; serelaxin, 156 [27%]; p=0·70). No significant effects were recorded for the secondary endpoints of cardiovascular death or readmission to hospital for heart failure or renal failure (placebo, 75 events [60-day Kaplan-Meier estimate, 13·0%]; serelaxin, 76 events [13·2%]; hazard ratio [HR] 1·02 [0·74-1·41], p=0·89] or days alive out of the hospital up to day 60 (placebo, 47·7 [SD 12·1] days; serelaxin, 48·3 [11·6]; p=0·37). Serelaxin treatment was associated with significant reductions of other prespecified additional endpoints, including fewer deaths at day 180 (placebo, 65 deaths; serelaxin, 42; HR 0·63, 95% CI 0·42-0·93; p=0·019). INTERPRETATION Treatment of acute heart failure with serelaxin was associated with dyspnoea relief and improvement in other clinical outcomes, but had no effect on readmission to hospital. Serelaxin treatment was well tolerated and safe, supported by the reduced 180-day mortality. FUNDING Corthera, a Novartis affiliate company.

Relaxin for the treatment of patients with acute heart failure (Pre-RELAX-AHF): a multicentre, randomised, placebo-controlled, parallel-group, dose-finding phase IIb study

BACKGROUND Most patients admitted for acute heart failure have normal or increase blood pressure. Relaxin is a natural human peptide that affects multiple vascular control pathways, suggesting potential mechanisms of benefit for such patients. We assessed the dose response of relaxins effect on symptom relief, other clinical outcomes, and safety. METHODS In a placebo-controlled, parallel-group, dose-ranging study, 234 patients with acute heart failure, dyspnoea, congestion on chest radiograph, and increased brain natriuretic peptide (BNP) or N-terminal prohormone of BNP, mild-to-moderate renal insufficiency, and systolic blood pressure greater than 125 mm Hg were recruited from 54 sites in eight countries and enrolled within 16 h of presentation. Patients were randomly assigned, in a double-blind manner via a telephone-based interactive voice response system, to standard care plus 48-h intravenous infusion of placebo (n=62) or relaxin 10 microg/kg (n=40), 30 microg/kg (n=43), 100 microg/kg (n=39), or 250 microg/kg (n=50) per day. Several clinical endpoints were explored to assess whether intravenous relaxin should be pursued in larger studies of acute heart failure, to identify an optimum dose, and to help to assess endpoint selection and power calculations. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT00520806. FINDINGS In the modified intention-to-treat population, 61 patients were assessed in the placebo group, 40 in the relaxin 10 microg/kg per day group, 42 in the relaxin 30 microg/kg per day group, 37 in the relaxin 100 microg/kg per day group, and 49 in the relaxin 250 microg/kg per day group. Dyspnoea improved with relaxin 30 microg/kg compared with placebo, as assessed by Likert scale (17 of 42 patients [40%] moderately or markedly improved at 6 h, 12 h, and 24 h vs 14 of 61 [23%]; p=0.044) and visual analogue scale through day 14 (8214 mm x h [SD 8712] vs 4622 mm x h [9003]; p=0.053). Length of stay was 10.2 days (SD 6.1) for relaxin-treated patients versus 12.0 days (7.3) for those given placebo, and days alive out of hospital were 47.9 (10.1) versus 44.2 (14.2). Cardiovascular death or readmission due to heart or renal failure at day 60 was reduced with relaxin (2.6% [95% CI 0.4-16.8] vs 17.2% [9.6-29.6]; p=0.053). The number of serious adverse events was similar between groups. INTERPRETATION When given to patients with acute heart failure and normal-to-increased blood pressure, relaxin was associated with favourable relief of dyspnoea and other clinical outcomes, with acceptable safety.

Effect of Serelaxin on Cardiac, Renal, and Hepatic Biomarkers in the Relaxin in Acute Heart Failure (RELAX-AHF) Development Program Correlation With Outcomes

OBJECTIVES The aim of this study was to assess the effects of serelaxin on short-term changes in markers of organ damage and congestion and relate them to 180-day mortality in patients with acute heart failure. BACKGROUND Hospitalization for acute heart failure is associated with high post-discharge mortality, and this may be related to organ damage. METHODS The Pre-RELAX-AHF (Relaxin in Acute Heart Failure) phase II study and RELAX-AHF phase III study were international, multicenter, double-blind, placebo-controlled trials in which patients hospitalized for acute heart failure were randomized within 16 h to intravenous placebo or serelaxin. Each patient was followed daily to day 5 or discharge and at days 5, 14, and 60 after enrollment. Vital status was assessed through 180 days. In RELAX-AHF, laboratory evaluations were performed daily to day 5 and at day 14. Plasma levels of biomarkers were measured at baseline and days 2, 5, and 14. All-cause mortality was assessed as a safety endpoint in both studies. RESULTS Serelaxin reduced 180-day mortality, with similar effects in the phase II and phase III studies (combined studies: N = 1,395; hazard ratio: 0.62; 95% confidence interval: 0.43 to 0.88; p = 0.0076). In RELAX-AHF, changes in markers of cardiac (high-sensitivity cardiac troponin T), renal (creatinine and cystatin-C), and hepatic (aspartate transaminase and alanine transaminase) damage and of decongestion (N-terminal pro-brain natriuretic peptide) at day 2 and worsening heart failure during admission were associated with 180-day mortality. Serelaxin administration improved these markers, consistent with the prevention of organ damage and faster decongestion. CONCLUSIONS Early administration of serelaxin was associated with a reduction of 180-day mortality, and this occurred with fewer signs of organ damage and more rapid relief of congestion during the first days after admission.

RITZ-5: randomized intravenous TeZosentan (an endothelin-A/B antagonist) for the treatment of pulmonary edema. A prospective, multicenter, double-blind, placebo-controlled study ☆

OBJECTIVES The objective of this study was to evaluate the addition of intravenous (IV) tezosentan to standard therapy for patients with pulmonary edema. BACKGROUND Tezosentan is an IV nonselective endothelin (ET)-1 antagonist that yields favorable hemodynamic effects in patients with acute congestive heart failure (CHF). METHODS Pulmonary edema was defined as acute CHF leading to respiratory failure, as evidenced by an oxygen saturation (SO(2)) <90% by pulse oxymeter despite oxygen treatment. All patients received oxygen 8 l/min through a face mask, 3 mg of IV morphine, 80 mg of furosemide, and 1 to 3 mg/h continuous drip isosorbide-dinitrate according to their blood pressure level and were randomized to receive a placebo or tezosentan (50 or 100 mg/h) for up to 24 h. RESULTS Eighty-four patients were randomized. The primary end point, the change in SO(2) from baseline to 1 h, was 9.1 +/- 6.3% in the placebo arm versus 7.6 +/- 10% in the tezosentan group (p = NS). The incidence of death, recurrent pulmonary edema, mechanical ventilation, and myocardial infarction during the first 24 h of treatment was 19% in both groups. Reduced baseline SO(2), lower echocardiographic ejection fraction, high baseline mean arterial blood pressure (MAP), and inappropriate vasodilation (MAP reduction at 30 min of <5% or >30%) correlated with worse outcomes. A post-hoc analysis revealed that the outcome of patients who received only 50 mg/h tezosentan was better than patients in the placebo group whereas patients receiving 100 mg/h had the worst outcomes. CONCLUSIONS In the present study, tezosentan (an ET-1 antagonist) did not affect the outcome of pulmonary edema, possibly because of the high dose used.

Recurrent myocardial infarction: clinical predictors and prognostic implications.

Based on a prospective study in 200 consecutive patients with myocardial infarction, we reported previously that early recurrent myocardial infarction is more frequent after nontransmural than transmural infarction. Multiple logistic regression analysis using 14 clinical variables identified, in addition to type of infarction (nontransmural), three other risk factors for early recurrent infarction: obesity, female gender and recurrent chest pain. Early recurrent infarction was documented by reelevation in plasma MB CK activity. The present study was performed to assess the accuracy of these variables as prospective predictors of early recurrent infarction. Studies were performed in a new population of 150 patients admitted consecutively with acute myocardial infarction (test set). The regression coefficients derived by multiple logistic analysis from the training set population were applied by comparable analysis to the test set population and the presence or absence of recurrent infarction was predicted correctly for 80% of the patients. Patients were followed prospectively for 9 months (range 3–18 months) and life‐table analysis was performed to assess the impact of recurrent infarction on short and long term survival. During the first 21 days after infarction, mortality was 23% for patients with transmural and 10% for nontransmural infarction (p < 0.01). However, among patients with nontransmural infarction, hospital mortality was 23% among those with early recurrent infarction and 8% for those without recurrence (p < 0.05). At the conclusion of follow‐up, mortality was 34% among patients with nontransmural infarction and recurrence, compared with 23% among patients with nontransmural infarction and no recurrence. Thus, early recurrent infarction has a distinct deleterious effect on survival, and a subset of patients more likely to experience recurrent infarction can be prospectively identified.

Effect of Mibefradil, a T-Type Calcium Channel Blocker, on Morbidity and Mortality in Moderate to Severe Congestive Heart Failure The MACH-1 Study

BACKGROUND Calcium antagonists have proved disappointing in long-term congestive heart failure (CHF) studies. Mibefradil, a new calcium antagonist that selectively blocks T-type calcium channels, has been shown to be an effective antihypertensive, antianginal, and anti-ischemic agent, and because of its different mechanism of action, it may be beneficial as adjunct therapy in CHF patients. METHODS AND RESULTS This multicenter, randomized, double-blind study compared mibefradil with placebo as adjunct to usual therapy in 2590 CHF patients (NYHA class II to IV; left ventricular fraction <35%). The initial 50-mg daily dose of mibefradil was uptitrated to 100 mg after 1 month and continued up to 3 years. Patients were monitored at 1 week; 1, 2, and 3 months; and every 3 months thereafter. All-cause mortality, cardiovascular mortality, and cardiovascular morbidity/mortality were analyzed by use of the log-rank test (alpha=0.05). Substudies included exercise tolerance, plasma hormone and cytokines, echocardiography, and quality of life. Total mortality was similar between mibefradil- and placebo-treated patients (P=0.151). The 14% increased risk of mortality with mibefradil in the first 3 months was not statistically significant (P=0.093). Treatment groups had similar cardiovascular mortality (P=0.246), cardiovascular morbidity/mortality (P=0.783), and reasons for death or hospitalization. Patients comedicated with mibefradil and antiarrhythmics (class I or III), including amiodarone, had a significantly increased risk of death. Substudies demonstrated no significant differences between treatments. CONCLUSIONS When used as adjunct therapy, mibefradil did not affect the usual outcome of CHF. The potential interaction with antiarrhythmic drugs, especially amiodarone, and drugs associated with torsade de pointes may have contributed to poor outcomes early in the study.

Functional response of the right ventricle to myocardial infarction: dependence of the site of left ventricular infarction.

We previously showed that the extent of infarction is virtually identical in patients with anterior and inferior infarction despite the more favorable prognosis associated with the latter. We postulated that the damage associated with inferior infarction is shared by both ventricles, thereby causing less hemodynamic impairment than anterior infarction, which involves only the left ventricle. To further explore this hypothesis, global and regional function of both right and left ventricles was assessed by gated radionuclide ventriculography in 50 patients with infarction within 48 hours after admission and again on the tenth day. Radionuclide ventriculography was also performed in 10 normal subjects. In 22 patients who had anterior infarction, the mean global left ventricular ejection fraction was decreased (27 ± 15% [± SD] vs 64 ± 10% in normal subjects, p < 0.05), reflecting regional abnormalities, and increased only slightly by the tenth day (33 ± 11%, p < 0.05). The global right ventricular ejection fraction was decreased (28 ± 11% vs 43 ± 9% in normal subjects, p < 0.05), reflecting a uniform depression of function without localized abnormalities, and returned to normal by the tenth day (43 ± 12, p < 0.05). In 20 patients who had inferior infarction, global left ventricular ejection fraction was only slightly decreased (51 ± 11%), reflecting inferoapical dysfunction, and did not change (55 ± 10). In contrast, global right ventricular ejection fraction was severely and persistently decreased (23 ± 9 vs 28 ± 9, p > 0.05), reflecting abnormalities primarily of the inferior region. The decreased right ventricular ejection fraction after inferior infarction correlated inversely with enzymatic estimates of infarct size (r −0.85, p < 0.01), although there was no correlation between left ventricular ejection fraction and infarct size. Thus, the functional responses of the ventricles to myocardial infarction are markedly influenced by the site of damage. In patients with anterior infarction there was persistent regional and global impairment of left ventricular function but only transient impairment of the right ventricle, whereas inferior infarction was associated with severe, persistent regional and global impairment of the right ventricle. These results indicate that the site of infarction is a major determinant of ventricular function and its recovery and that right ventriclular infarction is much more common with inferior infarction than is generally appreciated.

Ventricular systolic assessment in patients with dilated cardiomyopathy by preload-adjusted maximal power. Validation and noninvasive application.

BACKGROUND Noninvasive cardiac-specific analysis of contractile function in patients with dilated heart failure remains problematic. This study tests whether maximal power divided by the square of end-diastolic volume (PWRmx/EDV2, or preload-adjusted PWRmx) can provide such assessment. METHODS AND RESULTS To validate the load insensitivity of the PWRmx index and determine its response to contractile change, 24 subjects with chronic dilated cardiomyopathy underwent invasive pressure-volume catheterization study using the conductance catheter technique. Preload was transiently reduced by 30% using balloon occlusion of the inferior vena cava, and afterload impedance was lowered by 50%, induced by a bolus injection of nitroglycerin. Contractile state was varied by intravenous dobutamine, verapamil, or esmolol. PWRmx was calculated from the simultaneous product of ventricular pressure and rate of volume change (dV/dt), the latter derived from the volume catheter signal. PWRmx varied directly with preload but was minimally influenced by afterload. However, PWRmx/EDV2 was not significantly altered by either loading change. PWRmx/EDV2 did vary with contractility, correlating closely with changes in the end-systolic pressure-volume relation (r = .91, P < .001). To test the noninvasive application of this index, 12 additional patients were studied, with PWRmx/EDV2 derived from nuclear ventriculography combined with a novel method to measure central arterial pressures. Subjects received intravenous nitroprusside or dobutamine in random order. Ejection fraction increased similarly with both agents (+42.9 +/- 8.9% for dobutamine and +29.4 +/- 5.3% for nitroprusside, both P < .01). In contrast, PWRmx/EDV2 did not significantly change with nitroprusside but increased by 126 +/- 16.1% with dobutamine (P < .01). CONCLUSIONS Preload-adjusted PWRmx is a steady-state index of ventricular systolic function that is sensitive to inotropic state and minimally influenced by physiological changes in afterload impedance or volume load. It appears useful for noninvasive cardiac-specific analysis of acute drug effects.

Validation of a method for noninvasive measurement of central arterial pressure

The goal of this study was to validate a newly improved noninvasive method for calibrated measurement of the ascending portion of the central arterial pressure wave in humans. Noninvasive pressure waveforms were generated by measuring the time delay between the R wave of the electrocardiogram and onset of brachial artery flow (by Doppler) during computer-controlled upper arm cuff deflation. This delay shortens with falling cuff pressure (becoming near constant at and below diastolic pressure), so that a plot of pressure versus time delay yields the ascending portion of the arterial waveform. These waveforms were compared with simultaneous invasive ascending aortic pressures in 57 adult patients (31 by fluid manometer [group A] and 26 by catheter-tipped micromanometer [group B]) during routine cardiac catheterization. Patient age ranged from 26 to 77 years. Eighty percent of group A patients and 40% of group B had coronary artery disease. Noninvasive systolic and diastolic pressures were very similar to invasive values in both groups (Pni = 0.98 x Pi, r = 0.99, p < 0.0001). Instantaneous pressure differences between waveforms were also similar in both groups, averaging between 4.5 and 5.5 mm Hg. Micromanometer and noninvasive pressure data were also obtained before and after intravenous nitroglycerin (n = 5) and isometric handgrip (n = 8) and demonstrated good agreement. A potential application of these pressures is for estimating maximal ventricular power to assess systolic function. This was tested using invasive pressure-volume data from four patients under a variety of conditions (exercise, pacing, etc.).(ABSTRACT TRUNCATED AT 250 WORDS)

A Single Dose of Cilazapril Improves Diastolic Function in Hypertensive Patients

We studied the effect of a single dose of cilazapril, 5.0 mg orally, on systolic and diastolic cardiac function in eight hypertensive patients using a double-blind crossover placebo-controlled design. All patients had concentric left ventricular hypertrophy (measured by echocardiography), unimpaired systolic function (measured by radionuclide ventriculography), and long-standing hypertension treated by a combination of beta-blockers and diuretics. Radionuclide scintigraphy was performed with cilazapril and placebo, given one week apart. A two-week washout period of all cardioactive drugs preceded the study. Within three hours after oral administration of cilazapril, the time to peak filling rate of the left ventricle, expressed as a percentage of diastole, was reduced from 44.5 +/- 13.2 percent to 31.2 +/- 7.2 percent (p less than 0.05). Systolic blood pressure was also significantly reduced by cilazapril. Heart rate was slightly reduced. Left ventricular ejection fraction, peak filling rate, and the absolute time to peak filling rate were not significantly altered. Cilazapril improves a sensitive index of diastolic cardiac function in hypertensive patients.