Agents with vasodilator properties in acute heart failure: how to design successful trials

Agents with vasodilator properties (AVDs) are frequently used in the treatment of acute heart failure (AHF). AVDs rapidly reduce preload and afterload, improve left ventricle to aorta and right ventricle to pulmonary artery coupling, and may improve symptoms. Early biomarker changes after AVD administration have suggested potentially beneficial effects on cardiac stretch, vascular tone, and renal function. AVDs that reduce haemodynamic congestion without causing hypoperfusion might be effective in preventing worsening organ dysfunction. Existing AVDs have been associated with different results on outcomes in randomized clinical trials, and observational studies have suggested that AVDs may be associated with a clinical outcome benefit. Lessons have been learned from past AVD trials in AHF regarding preventing hypotension, selecting the optimal endpoint, refining dyspnoea measurements, and achieving early randomization and treatment initiation. These lessons have been applied to the design of ongoing pivotal clinical trials, which aim to ascertain if AVDs improve clinical outcomes. The developing body of evidence suggests that AVDs may be a clinically effective therapy to reduce symptoms, but more importantly to prevent end‐organ damage and improve clinical outcomes for specific patients with AHF. The results of ongoing trials will provide more clarity on the role of AVDs in the treatment of AHF.     

急性心力衰竭综合病因评分预计死亡率研究

目的 探讨急性心力衰竭病因评分在急性心力衰竭疾病中的应用价值.方法 采用APACHEⅡ评分、心力衰竭基础病因及诱因综合评分,在此评分基础上对42 例急性心力衰竭患者预计死亡率进行评估并建立预计死亡率模型,分层计算群体预计死亡率.结果 根据急性心力衰竭病因评分分值进行分组,随着分值逐渐升高,实际病死率和预计死亡率也逐渐升高,死亡组评分均值显著高于生存组(P＜0.05).结论 急性心力衰竭病因评分系统简易实用,可用于院前急救及急诊急性心力衰竭患者初步评估.     

Decongestion in acute heart failure

Congestion is a major reason for hospitalization in acute heart failure (HF). Therapeutic strategies to manage congestion include diuretics, vasodilators, ultrafiltration, vasopressin antagonists, mineralocorticoid receptor antagonists, and potentially also novel therapies such as gut sequesterants and serelaxin. Uncertainty exists with respect to the appropriate decongestion strategy for an individual patient. In this review, we summarize the benefit and risk profiles for these decongestion strategies and provide guidance on selecting an appropriate approach for different patients. An evidence‐based initial approach to congestion management involves high‐dose i.v. diuretics with addition of vasodilators for dyspnoea relief if blood pressure allows. To enhance diuresis or overcome diuretic resistance, options include dual nephron blockade with thiazide diuretics or natriuretic doses of mineralocorticoid receptor antagonists. Vasopressin antagonists may improve aquaresis and relieve dyspnoea. If diuretic strategies are unsuccessful, then ultrafiltration may be considered. Ultrafiltration should be used with caution in the setting of worsening renal function. This review is based on discussions among scientists, clinical trialists, and regulatory representatives at the 9th Global Cardio Vascular Clinical Trialists Forum in Paris, France, from 30 November to 1 December 2012.     

奈西立肽治疗急性心力衰竭的研究进展

严重心力衰竭时,可能存在内源性脑钠肽相对不足和/或脑钠肽抵抗。奈西立肽是重组人脑钠肽。国内外多项前瞻性临床研究均证实,奈西立肽能迅速改善急性心力衰竭患者的血流动力学状况和临床症状,其有效性和安全性明显优于常规静脉制剂。但是汇总分析发现奈西立肽有引起肾脏损害和死亡率增加的风险。因此临床医师在使用此药时应严格掌握临床适应证,同时需要进一步的临床研究明确奈西立肽在急性心力衰竭中的治疗地位。     

The challenge of acute decompensated heart failure

Acute heart failure syndromes (AHFS) is a broad spectrum of heterogeneous conditions including pulmonary oedema, hypertensive crisis, worsening exacerbated CHF and cardiogenic shock. HF hospitalizations have steadily risen with more than one million in 2004 in the United States and a similar number has been reported in Europe. Each year heart failure accounts for 6.5 million days spent in hospital in the USA and 1.4 million days in France. Mortality data are derived from registries or clinical trials. Registry data in patients admitted to general or cardiology wards such as in Euroheart Failure Survey and ADHERE provide a far more optimistic picture compared with data from consecutive unselected patients in the most acute situation. such as in EFICA. Four-week mortality was higher than 25% in this case. A great pathophysiologic understanding of the different features of the various AHFS is needed in order to identify targets for therapy and research. This includes hemodynamics, the role of myocardial injury, neurohormonal and cytokine abnormalities and the cardiorenal syndromes. So far, very little progress has been made in developing new, effective therapies and implementing management guidelines in this patient population. Future clinical trial endpoints should be better designed and tailored to the various pathophysiological conditions of this complex syndrome. The goal of AHFS therapy is not only to prevent disease progression but also to have a beneficial effect on an acute event that exacerbates disease progression. A combined endpoint assessing survival and rehospitalisation rates is becoming increasingly popular for acute therapies. Specific trials may also need to be designed according to the time of access to the patient.     

Serelaxin in addition to standard therapy in acute heart failure: rationale and design of the RELAX‐AHF‐2 study

Patients admitted for acute heart failure (AHF) experience high rates of in‐hospital and post‐discharge morbidity and mortality despite current therapies. Serelaxin is recombinant human relaxin‐2, a hormone with vasodilatory and end‐organ protective effects believed to play a central role in the cardiovascular and renal adaptations of human pregnancy. In the phase 3 RELAX‐AHF trial, serelaxin met its primary endpoint of improving dyspnoea through day 5 in patients admitted for AHF. Compared to placebo, serelaxin also reduced worsening heart failure (WHF) by 47% through day 5 and both all‐cause and cardiovascular mortality by 37% through day 180. RELAX‐AHF‐2 ( ClinicalTrials.gov NCT01870778) is designed to confirm serelaxin's effect on these clinical outcomes. RELAX‐AHF‐2 is a multicentre, randomized, double‐blind, placebo‐controlled, event‐driven, phase 3 trial enrolling ～6800 patients hospitalized for AHF with dyspnoea, congestion on chest radiograph, increased natriuretic peptide levels, mild‐to‐moderate renal insufficiency, and systolic blood pressure ≥125 mmHg. Patients are randomized within 16 h of presentation to 48 h intravenous infusions of serelaxin (30 µg/kg/day) or placebo, both in addition to standard of care treatments. The primary objectives are to demonstrate that serelaxin is superior to placebo in reducing: (i) 180 day cardiovascular death, and (ii) occurrence of WHF through day 5. Key secondary endpoints include 180 day all‐cause mortality, composite of 180 day combined cardiovascular mortality or heart failure/renal failure rehospitalization, and in‐hospital length of stay during index AHF. The results from RELAX‐AHF‐2 will provide data on the potential beneficial effect of serelaxin on cardiovascular mortality and WHF in selected patients with AHF.     

双心室起搏治疗心力衰竭的有关临床试验

起博治疗充血性心力衰竭有了新的进展 ,试验证明多点起搏或单独左心室起搏比单独的右心 DDD起搏更有益于改善患者血流动力学功能及生活质量     

Newer mechanical devices in the management of acute heart failure

Heart Failure is the only cardiovascular disease diagnosis increasing in prevalence in the United States. Currently there are more than 5 million people diagnosed with heart failure in the United States and that population is increasing exponentially. Clinical trials in advanced pharmacological therapies have shown a significant value in reducing the morbidity and mortality of the disease process. Nevertheless, many patients who are optimally treated with drug therapy continue to progress from asymptomatic left ventricular dysfunction to symptomatic and then end-stage heart failure. Beyond drug therapy, devices have begun to make a significant impact on symptoms and clinical outcomes in patients, particularly those with more advanced forms of heart failure. New technologies being investigated include destination and bridge LV assist devices. Due to the invasive nature of these devices a new generation of “less invasive” percutaneous devices are now being studied. These new generation devices offer the promise of improved LV function and an enhanced neurohormonal profile for the failing ventricle, thus improving the quality of life in the ever-burgeoning heart failure population.