Maria Dorobantu

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.

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.

Ischaemic heart disease in women: are there sex differences in pathophysiology and risk factors?Position Paper from the Working Group on Coronary Pathophysiology and Microcirculation of the European Society of Cardiology

Cardiovascular disease (CVD) is the leading cause of death in women, and knowledge of the clinical consequences of atherosclerosis and CVD in women has grown tremendously over the past 20 years. Research efforts have increased and many reports on various aspects of ischaemic heart disease (IHD) in women have been published highlighting sex differences in pathophysiology, presentation, and treatment of IHD. Data, however, remain limited. A description of the state of the science, with recognition of the shortcomings of current data, is necessary to guide future research and move the field forward. In this report, we identify gaps in existing literature and make recommendations for future research. Women largely share similar cardiovascular risk factors for IHD with men; however, women with suspected or confirmed IHD have less coronary atherosclerosis than men, even though they are older and have more cardiovascular risk factors than men. Coronary endothelial dysfunction and microvascular disease have been proposed as important determinants in the aetiology and prognosis of IHD in women, but research is limited on whether sex differences in these mechanisms truly exist. Differences in the epidemiology of IHD between women and men remain largely unexplained, as we are still unable to explain why women are protected towards IHD until older age compared with men. Eventually, a better understanding of these processes and mechanisms may improve the prevention and the clinical management of IHD in women.

Presentation, management, and outcomes of ischaemic heart disease in women

Scientific interest in ischaemic heart disease (IHD) in women has grown considerably over the past 2 decades. A substantial amount of the literature on this subject is centred on sex differences in clinical aspects of IHD. Many reports have documented sex-related differences in presentation, risk profiles, and outcomes among patients with IHD, particularly acute myocardial infarction. Such differences have often been attributed to inequalities between men and women in the referral and treatment of IHD, but data are insufficient to support this assessment. The determinants of sex differences in presentation are unclear, and few clues are available as to why young, premenopausal women paradoxically have a greater incidence of adverse outcomes after acute myocardial infarction than men, despite having less-severe coronary artery disease. Although differential treatment on the basis of patient sex continues to be described, the extent to which such inequalities persist and whether they reflect true disparity is unclear. Additionally, much uncertainty surrounds possible sex-related differences in response to cardiovascular therapies, partly because of a persistent lack of female-specific data from cardiovascular clinical trials. In this Review, we assess the evidence for sex-related differences in the clinical presentation, treatment, and outcome of IHD, and identify gaps in the literature that need to be addressed in future research efforts.

Prognostic value of ventricular arrhythmias in systemic hypertension.

Objective Hypertensive left ventricular hypertrophy is associated with an increased risk of arrhythmias and mortality. However, no clinical study has demonstrated a significant relationship between ventricular arrhythmias and mortality in systemic hypertension. Design and methods To evaluate the prognostic value of arrhythmogenic markers, we included, prospectively, 214 hypertensive patients aged (mean ± SD) 59.1 ± 12.8 years, without symptomatic coronary disease, myocardial infarction, systolic dysfunction or electrolyte disturbances. At inclusion, a 12-lead electrocardiogram (ECG) with QT dispersion calculation, a 24 h Holter ECG (204 patients) with Lown classification of ventricular arrhythmias, echocardiography (reliable in 187 patients) and a signal-averaged ECG (125 patients) with ventricular late potentials were recorded. Results At baseline, echocardiographic left ventricular hypertrophy was found in 63 patients (33.7%). Non-sustained ventricular tachycardia (Lown class IVb) was recorded in 33 patients (16.2%) and late potentials in 27 patients (21.6%). After a mean follow-up of 42.4 ± 26.8 months, all-cause mortality was 11.2% (24 patients); 17 patients died of cardiac causes (7.9%); of these, nine (4.2%) died suddenly. In univariate analysis, age, Lown class IVb and a QT dispersion > 80 ms were significantly related to global, cardiac and sudden death (P< 0.01). The left ventricular mass index was related to cardiac mortality (P = 0.002). In multivariate analysis, only Lown class IVb was an independent predictor of global and cardiac mortality, increasing the risk of global death 2.6-fold (95% confidence interval 1.2–6.0) and cardiac death 3.5-fold (95% confidence interval 1.2–9.7). Conclusion In hypertensive patients the presence of non-sustained ventricular tachycardia has prognostic value.

In-hospital case fatality rates for acute myocardial infarction in Romania

Background: We describe the clinical characteristics, treatments and in-hospital case-fatality rates in an unselected population of patients admitted for acute myocardial infarction. Methods: From January 2000 to June 2007, we tracked consecutive patients who were admitted to 7 tertiary referral and 21 county hospitals in Romania for medical treatment of ST-segment elevation acute myocardial infarction. These patients were enrolled in the Romanian Registry for ST-segment Elevation Myocardial Infarction. For this prospective study, we collected data on demographic characteristics, cardiovascular risk factors, various aspects of treatment for myocardial infarction, and in-hospital death. Results: The 9186 patients in the study group had a mean age of 63.8 years. The median time from onset of symptoms to thrombolysis was 230 (interquartile range 120–510) minutes. Of the 9186 patients, 4986 (54.3%) had hypertension, 1974 (21.5%) had diabetes mellitus, 3545 (38.6%) had lipid disorders and 4653 (50.7%) were smokers. The in-hospital mortality rate was 12.7% (1170 deaths). The study group consisted of 2893 women and 6293 men. The women were older than the men and had higher rates of hypertension and diabetes mellitus but were less likely to be smokers. A smaller proportion of women than men presented within 2 hours after onset of symptoms (23.1% v. 34.4%, p < 0.001). Smaller proportions of women received thrombolytics (40.8% v. 53.5%, p < 0.001), anticoagulants (93.4% v. 95.2%; p = 0.001), antiplatelet agents (88.3% v. 91.2%, p < 0.001) and primary percutaneous coronary interventions (1.5% v. 2.2%, p = 0.030). The risk of in-hospital death was greater for women, even after adjustment for confounders (odds ratio 1.33, 95% confidence interval 1.13–1.56; p < 0.001). Interpretation: The rates of reperfusion therapy for patients with acute myocardial infarction were low, and in-hospital case-fatality rates were high in this study. Excess in-hospital mortality was more pronounced among women.

The Romanian Acute Heart Failure Syndromes (RO-AHFS) Registry

AIMS The objective of the RO-AHFS registry was to evaluate the epidemiology, clinical presentation, inpatient management, and hospital course in a population hospitalized for acute heart failure syndromes. METHODS During a 12-month period, 13 Romanian medical centers enrolled all consecutive patients hospitalized with a primary diagnosis of AHFS. Patients were classified into the following 5 clinical profiles at admission: acute decompensated heart failure, cardiogenic shock, pulmonary edema, right heart failure, and hypertensive heart failure. Statistical significance was assessed using Fisher exact test or the χ(2) test for categorical variables and a 1-way analysis of variance for continuous variables. Independent predictors of in-hospital all-cause mortality (ACM) were identified using a multivariate logistic regression model. RESULTS A total of 3,224 consecutive patients hospitalized with AHFS were enrolled. The cohort had a mean age of 69.2 ± 11.8 years and 56% were men. The mean left ventricular ejection fraction was 37.7% ± 12.5%. The percentage of patients treated with evidence-based heart failure therapies increased from admission to discharge, but even at discharge, only 56%, 66%, and 54% of patients were on a β-blocker, an angiotensin-converting enzyme inhibitors or an angiotensin receptor blocker, and a mineralocorticoid receptor antagonist, respectively. In-hospital ACM was 7.7% with substantial variation between sites (4.1%-11.0%). Increasing age, inotrope therapy, the presence of life-threatening ventricular arrhythmias, and elevated baseline blood urea nitrogen were all found to be independent risk factors for in-hospital ACM, whereas elevated systolic blood pressure and baseline treatment with a β-blocker had a protective effect. CONCLUSIONS The RO-AHFS study found substantial variation both among sites and between Romania and other European countries. National and regional registries have important clinical implications for patient care and the design and conduct of global clinical trials.

Blood pressure and low-density lipoprotein-cholesterol lowering for prevention of strokes and cognitive decline: a review of available trial evidence.

Background and objectives: It is well established by a large number of randomized controlled trials that lowering blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) by drugs are powerful means to reduce stroke incidence, but the optimal BP and LDL-C levels to be achieved are largely uncertain. Concerning BP targets, two hypotheses are being confronted: first, the lower the BP, the better the treatment outcome, and second, the hypothesis that too low BP values are accompanied by a lower benefit and even higher risk. It is also unknown whether BP lowering and LDL-C lowering have additive beneficial effects for the primary and secondary prevention of stroke, and whether these treatments can prevent cognitive decline after stroke. Results: A review of existing data from randomized controlled trials confirms that solid evidence on optimal BP and LDL-C targets is missing, possible interactions between BP and LDL-C lowering treatments have never been directly investigated, and evidence in favour of a beneficial effect of BP or LDL-C lowering on cognitive decline is, at best, very weak. Conclusion: A new, large randomized controlled trial is needed to determine the optimal level of BP and LDL-C for the prevention of recurrent stroke and cognitive decline.

Cardiac resynchronization therapy in patients with chronic heart failure is associated with anti-inflammatory and anti-remodeling effects

OBJECTIVES Proinflammatory cytokines, matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play a role in left ventricular (LV) structural remodeling. We aimed to investigate the effects of cardiac resynchronization therapy (CRT) on serum levels of amino-terminal prohormone B-type natriuretic peptide (NT-proBNP), some interleukins (IL-1β, IL-6, IL-8), MMP-2 and TIMP-2 in patients with chronic heart failure (CHF). DESIGN AND METHODS We studied 27 patients (15 M/12 F) with CHF, III-IV NYHA class, implanted with a biventricular pacemaker/defibrillator and 40 healthy subjects (23 M/17 F). Blood samples were collected at baseline and 1 week, 3, 6, and 12 months after CRT device implantation. Cardiac function was assessed echocardiographically. RESULTS CRT induced significant improvement in the NYHA class (baseline 3.2±0.5 vs. 1.0 at 12 months, P=0.0002) and significant LV reverse remodeling, with a 41% (P=0.001) reduction in LV end-systolic volume (LVESV). This was associated with a significant reduction in serum NT-proBNP, IL-6 and IL-8. Positive extracellular matrix remodeling was illustrated by decreasing levels of MMP-2 and increasing TIMP-2. MMP-2/TIMP-2 ratio decreased with 55% (P=0.003) from baseline value at 12 months and the correlation with LVESV reduction was 0.41 (P=0.001). CONCLUSIONS Structural response to CRT is associated with reduced immune activation and positive extracellular matrix remodeling.

Continuation of the ESH-CHL-SHOT trial after publication of the SPRINT: rationale for further study on blood pressure targets of antihypertensive treatment after stroke.

Alberto Zanchetti, Lisheng Liu, Giuseppe Mancia, Gianfranco Parati, Guido Grassi, Marco Stramba-Badiale, Vincenzo Silani, Grzegorz Bilo, Giovanni Corrao, Antonella Zambon, Lorenza Scotti, Xinhua Zhang, Ting Rui Guan, Yuqing Zhang, Xuezhong Zhang, Eivind Berge, Josep Redon, Krzysztof Narkiewicz, Anna Dominiczak, Peter Nilsson, Margus Viigimaa, Stéphane Laurent, Enrico Agabiti-Rosei, Zhaosu Wu, Dingliang Zhu, José Luis Rodicio, Luis Miguel Ruilope, Nieves Martell-Claros, Fernando Pinto Roland E. Schmieder, Michel Burnier, Maciej Banach, Renata Cifkova, Csaba Farsang, Alexandra Konradi, Irina Lazareva, Yuriy Sirenko, Maria Dorobantu, Arman Postadzhiyan, Rok Accetto, Bojan Jelakovic, Dragan Lovic, Athanasios J. Manolis, Philippos Stylianou, Dror Dicker, Gangzhi Wei, Chengbin Xu, Hengge Xie, Antonio Coca, John O’Brien, Gary Ford, on behalf of the ESH-CHL-SHOT trial investigators