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.

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.

Presence of coronary plaques in patients with nonalcoholic fatty liver disease.

PURPOSE: To evaluate the relationship between nonalcoholic fatty liver disease (NAFLD) and coronary artery disease (CAD) and to define determinants of CAD in patients with or without metabolic syndrome. MATERIALS AND METHODS: This study was approved by the local ethics committee; informed consent was obtained. Twenty-nine subjects (mean age, 53 years +/- 7 [standard deviation]) with low to intermediate risk for CAD and with fatty liver were included. Thirty-two sex- and age-matched individuals without NAFLD served as controls. CAD was defined as a stenosis of more than 50% in at least one major coronary artery. Fatty liver was assessed by means of an attenuation of -10 HU or higher (calculated as liver attenuation minus spleen attenuation) by using computed tomography (CT), coronary plaques and stenosis by using CT coronary angiography, and biomarkers of insulin resistance, lipotoxicity, systemic inflammation, and oxidant and antioxidant status. A logistic regression analysis was performed to study multivariable associations. RESULTS: When compared with controls, NAFLD patients showed a higher prevalence of calcified and noncalcified coronary plaques (67% vs 34% and 52% vs 29%, respectively; both P < .001), higher prevalence of nonobstructive coronary stenosis (34% vs 14%; P < .008), higher homeostasis model assessment of insulin resistance (3.8 epsilonU/mL +/- 3.6 vs 2.6 epsilonU/mL +/- 3.2; P < .005) and higher triglyceride levels (208 mg/dL +/- 87 vs 148 mg/dL +/- 70; P < .005). Fatty liver proved to be a strong predictor of coronary atherosclerosis (odds ratio [OR], 2; P < .04), independent of indicators for metabolic syndrome (OR, 1.2; P > .2) and C-reactive protein levels (OR, 0.7; P > .4). CONCLUSION: Patients with NAFLD, even without metabolic syndrome, are at high risk for atherosclerosis. Assessment of NAFLD may be helpful for cardiovascular risk stratification.

Unilateral presentation of postpartum cardiomyopathy misdiagnosed as pneumonia.

A 34-year-old woman presented to the emergency department with severe dyspnoea 10 days following a normal-course caesarean delivery. She had been experiencing shortness of breath throughout the third trimester of pregnancy accompanied by tachycardia (110 bpm); however, her evaluation did not include ECG or chest radiography to elucidate the cause. Following delivery, chest radiography was performed demonstrating predominantly unilateral findings interpreted as pneumonia. ECG revealed T-wave inversion in leads V(4)-V(6), which was unaddressed. Overnight she deteriorated and a chest CT angiography was performed demonstrating heart enlargement and pulmonary oedema. An echocardiogram established a diminished ejection fraction (EF) of 15-20%, suggesting the diagnosis of peripartum cardiomyopathy. She was treated with angiotensin-converting enzyme inhibitors, spirinolactone and furosemide, and was free of symptoms the following month with an EF of 40-45%. Though uncommon, heart failure is a potentially fatal cause of peripartum dyspnoea, often misdiagnosed, meriting further attention.

A new noninvasive device for measuring central ejection dP/dt mathematical foundation of cardiac dP/dt measurement using a model for a collapsible artery.

We have developed a novel non-invasive device for the measurement of one of the most sensitive indices of myocardial contractility as represented by the rate of increase of intraventricular pressure (left ventricular dP/dt and arterial dP/dt performance index (dP/dt(ejc)). Up till now, these parameters could be obtained only by invasive catheterization methods. The new technique is based on the concept of applying multiple successive occlusive pressures on the brachial artery from peak systole to diastole using a inflatable cuff and plotting the values against time intervals that leads to the reconstruction of the central aortic pressure noninvasively. The following describes the computer simulator developed for providing a mathematical foundation of the new sensor. At the core of the simulator lies a hemodynamic model of the blood flow on an artery under externally applied pressure. The purpose of the model is to reproduce the experimental results obtained in studies on patients (Gorenberg et al. in Cardiovasc Eng: 305-311, 2004; Gorenberg et al. in Emerg med J 22 (7): 486-489, 2005) and a animal model where ischemia resulted from balloon inflation during coronary catheterization (Gorenberg and Marmor in J Med Eng Technol, 2006) and to describe correlations between the dP/dt(ejc) and other hemodynamic variables. The model has successfully reproduced the trends observed experimentally, providing a solid in-depth understanding of the hemodynamics involved in the new measurement. A high correlation between the dP/dt(ejc) and the rate of pressure rise in the aorta during the ejection phase was observed. dP/dt(ejc) dependence on other hemodynamic parameters was also investigated.

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 relaxin's 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.

Hemoptysis--a rare complication of pacemaker implantation.

We describe a case of hemoptysis as a rare complication of pacemaker lead insertion via the axillary approach in a patient with difficult chest anatomy.

Assessment of a new non-invasive index of cardiac performance for detection of dobutamine-induced myocardial ischemia.

BACKGROUND: Electrocardiography has a very low sensitivity in detecting dobutamine-induced myocardial ischemia. OBJECTIVES: To assess the added diagnostic value of a new cardiac performance index (dP/dtejc) measurement, based on brachial artery flow changes, as compared to standard 12-lead ECG, for detecting dobutamine-induced myocardial ischemia, using Tc99m-Sestamibi single-photon emission computed tomography as the gold standard of comparison to assess the presence or absence of ischemia. METHODS: The study group comprised 40 patients undergoing Sestamibi-SPECT/dobutamine stress test. Simultaneous measurements of ECG and brachial artery dP/dtejc were performed at each dobutamine level. In 19 of the 40 patients perfusion defects compatible with ischemia were detected on SPECT. The increase in dP/dtejc during infusion of dobutamine in this group was severely impaired as compared to the non-ischemic group. dP/dtejc outcome was combined with the ECG results, giving an ECG-enhanced value, and compared to ECG alone. RESULTS: The sensitivity improved dramatically from 16% to 79%, positive predictive value increased from 60% to 68% and negative predictive value from 54% to 78%, and specificity decreased from 90% to 67%. CONCLUSIONS: If ECG alone is used for specificity, the combination with dP/dtejc improved the sensitivity of the test and could be a cost-savings alternative to cardiac imaging or perfusion studies to detect myocardial ischemia, especially in patients unable to exercise.

Buddy wire, buddy balloon or better together!

The inability to cross tortuous, calcified or previously stented segments with an angioplasty balloon or coronary stent remains one of the frequent causes of the procedural failure. Numerous techniques have been developed to facilitate stent delivery in this situation: buddy wire, balloon deflection and use of specially designed guidewires. We report a case in which an ACE(R) fixed-wire balloon dilatation catheter was used as a "buddy", combining the best properties of different techniques in one device.

Effect of nutritional composition of meals on exercise tests in patients with ischaemic heart disease.

BACKGROUND: Patients with ischaemic heart disease have to perform exercise tests repeatedly. It is not clear if a small meal eaten before the test might influence it and if the meal's composition is important. DESIGN AND METHOD: We performed a double blind, randomised, crossover study on 20 volunteers with documented ischaemic heart disease known to have positive exercise tests. Each had three symptom limited exercise tests done one hour after a 200 ml meal, rich in either fat, carbohydrate or protein. Each postprandial test was compared to a fasting exercise test performed just before the meal. RESULTS: Postprandial blood pressure, time to angina and to peak exercise and double product at onset of ST-depression were not significantly altered by any of the meals. Heart rate was slightly increased only after the fat meal. CONCLUSIONS: The nutritional composition of a small meal eaten an hour before an exercise test has no clinically important impact on the results of the test in patients with stable angina pectoris.

Mild sedation before transesophageal echo induces significant hemodynamic and respiratory depression.

AIMS: Midazolam is often used for conscious sedation before transesophageal echo (TEE) studies. It is not clear to what extent midazolam administration or the insertion of the TEE probe itself is responsible for the respiratory and hemodynamic depression during TEE examinations. We compared the performance of TEE with versus without midazolam to elucidate the effects of each. METHODS: Patients were given the choice of having midazolam prior to their TEE. Thirty-one patients preferred to have sedation (Sed+) and 31 others declined sedation (Sed-). Both groups had SaO(2) and blood pressure measured before the study, following sedation (in Sed+) and at the end of the TEE study. RESULTS: Increase in HR was greater in Sed+ than in Sed- (12 +/- 19% vs 6 +/- 11%, both P < 0.05). There was a greater decrease in saturation of O(2) in Sed+ than in Sed- (3 +/- 3% vs 2 +/- 3%, both P < 0.05). Systolic blood pressure (SBP) increased in Sed- by 6 +/- 11% (P< 0.05) but dropped in Sed+ immediately after sedation (16 +/- 8%, P < 0.000001). Diastolic blood pressure decreased in Sed+ after sedation by 11 +/- 9% (P < 0.05). CONCLUSIONS: Midazolam sedation before TEE examinations causes more prominent tachycardia and depression of SaO(2)than insertion of the TEE probe alone. It also causes a substantial drop in SBP. Midazolam should be offered only to hemodynamically stable patients without preceding respiratory depression.

Prior peripheral arterial disease and cerebrovascular disease are independent predictors of adverse outcome in patients with acute coronary syndromes: are we doing enough? Results from the Orbofiban in Patients with Unstable Coronary Syndromes-Thrombolysis In Myocardial Infarction (OPUS-TIMI) 16 study.

BACKGROUND: Cerebrovascular accidents (CVAs), transient ischemic attacks (TIAs), and peripheral arterial disease (PAD) frequently coexist with coronary artery disease (CAD) and were previously reported to adversely affect the prognosis of patients with chronic CAD. METHODS: We examined the effect of prior CVA/TIA or PAD (extra-cardiac vascular disease [EVD]) on the outcome of 10,281 patients with acute coronary syndromes enrolled in the Orbofiban in Patients with Unstable Coronary Syndromes-Thrombolysis in Myocardial Infarction (OPUS-TIMI) 16 trial of the oral glycoprotein IIb/IIIa antagonist orbofiban plus aspirin versus aspirin alone. We evaluated mortality, recurrent cardiac events, and stroke and used multivariate analysis to control for differences in baseline characteristics. RESULTS: Patients with EVD were older, had more coronary risk factors, had a history of CAD, and received more intensive medical treatment at baseline. The acute event in these patients was more often unstable angina pectoris and less commonly Q-wave myocardial infarction. With coronary angiography, patients with prior EVD more often had multivessel disease. During the 10 months of follow-up, the presence of EVD was predictive of an increased hazard of death, reinfarction, recurrent ischemia, stroke, and a composite of these events. Despite the increased severity of the CAD and increased risk of events, patients with EVD were treated less frequently with beta-blockers and more frequently with calcium blockers. Despite patients with EVD having a 45% higher incidence of hypercholesterolemia, lipid-lowering agents were prescribed in a similar percentage of patients as patients without EVD. CONCLUSION: In patients with acute coronary syndromes, the presence of prior CVA, TIA, or PAD is associated with more extensive CAD and worse outcome. These patients appear to receive less aggressive treatment, which may explain, at least in part, their worse outcome.

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.