Treatment Of Acute Heart Failure Syndromes Research Articles

Nitrates for acute heart failure syndromes

Current drug therapy for acute heart failure syndromes (AHFS) consists mainly of diuretics supplemented by vasodilators or inotropes. Nitrates have been used as vasodilators in AHFS for many years and have been shown to improve some aspects of AHFS in some small studies. The aim of this review was to determine the clinical efficacy and safety of nitrate vasodilators in AHFS. To quantify the effect of different nitrate preparations (isosorbide dinitrate and nitroglycerin) and the effect of route of administration of nitrates on clinical outcome, and to evaluate the safety and tolerability of nitrates in the management of AHFS. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 3), MEDLINE (1950 to July week 2 2011) and EMBASE (1980 to week 28 2011). We searched the Current Controlled Trials MetaRegister of Clinical Trials (compiled by Current Science) (July 2011). We checked the reference lists of trials and contacted trial authors. We imposed no language restriction. Randomised controlled trials comparing nitrates (isosorbide dinitrate and nitroglycerin) with alternative interventions (frusemide and morphine, frusemide alone, hydralazine, prenalterol, intravenous nesiritide and placebo) in the management of AHFS in adults aged 18 and over. Two authors independently performed data extraction. Two authors performed trial quality assessment. We used mean difference (MD), odds ratio (OR) and 95% confidence intervals (CI) to measure effect sizes. Two authors independently assessed and rated the methodological quality of each trial using the Cochrane Collaboration tool for assessing risk of bias. Four studies (634 participants) met the inclusion criteria. Two of the included studies included only patients with AHFS following acute myocardial infarction (AMI); one study excluded patients with overt AMI; and one study included participants with AHFS with and without acute coronary syndromes.Based on a single study, there was no significant difference in the rapidity of symptom relief between intravenous nitroglycerin/N-acetylcysteine and intravenous frusemide/morphine after 30 minutes (fixed-effect MD -0.30, 95% CI -0.65 to 0.05), 60 minutes (fixed-effect MD -0.20, 95% CI -0.65 to 0.25), three hours (fixed-effect MD 0.20, 95% CI -0.27 to 0.67) and 24 hours (fixed-effect MD 0.00, 95% CI -0.31 to 0.31). There is no evidence to support a difference in AHFS patients receiving intravenous nitrate vasodilator therapy or alternative interventions with regard to the following outcome measures: requirement for mechanical ventilation, systolic blood pressure (SBP) change after three hours and 24 hours, diastolic blood pressure (DBP) change after 30, 60 and 90 minutes, heart rate change at 30 minutes, 60 minutes, three hours and 24 hours, pulmonary artery occlusion pressure (PAOP) change after three hours and 18 hours, cardiac output (CO) change at 90 minutes and three hours and progression to myocardial infarction. There is a significantly higher incidence of adverse events after three hours with nitroglycerin compared with placebo (odds ratio 2.29, 95% CI 1.26 to 4.16) based on a single study. There was no consistent evidence to support a difference in AHFS patients receiving intravenous nitrate vasodilator therapy or alternative interventions with regard to the following secondary outcome measures: SBP change after 30 and 60 minutes, heart rate change after 90 minutes, and PAOP change after 90 minutes. None of the included studies reported healthcare costs as an outcome measure. There were no data reported by any of the studies relating to the acceptability of the treatment to the patients (patient satisfaction scores).Overall there was a paucity of relevant quality data in the included studies. Assessment of overall risk of bias in these studies was limited as three of the studies did not give sufficient detail to allow assessment of potential risk of bias. There appears to be no significant difference between nitrate vasodilator therapy and alternative interventions in the treatment of AHFS, with regard to symptom relief and haemodynamic variables. Nitrates may be associated with a lower incidence of adverse effects after three hours compared with placebo. However, there is a lack of data to draw any firm conclusions concerning the use of nitrates in AHFS because current evidence is based on few low-quality studies.

Acute Intravenous Infusion of an Adenosine Regulating Agent Improves Left Ventricular Function in Dogs with Advanced Heart Failure

GP531 is a second generation adenosine regulating agent (ARA) that increases concentrations of endogenous adenosine, a natural cardioprotective agent, in ischemic/hypoxic tissue. This study examined the effects of acute intravenous infusions of GP531 on left ventricular (LV) systolic and diastolic function in dogs with advanced chronic heart failure (HF) (LV ejection fraction, EF <30%). Six dogs with intracoronary microembolization-induced HF received a constant intravenous infusion of GP531 (10μg/kg/min) or vehicle (normal saline) for 6h in random order 1week apart. Hemodynamic measurements were made at baseline and at 1, 2, 3, 4, 5 and 6h after initiating drug infusion. Myocardial oxygen consumption (MVO2) was measured at baseline and 4 and 6h. LV pressure-volume relationship (PVR) was measured at baseline and 6h. Vehicle infusions had no effect on indexes of LV systolic and diastolic function. GP531 infusion had no effect on heart rate or mean aortic pressure but significantly decreased LV end-diastolic pressure, end-diastolic volume, end-systolic volume and end-diastolic wall stress. GP531 significantly increased LV EF (27 ± 1 at baseline to 34 ± 1 after 6h of drug infusion, p < 0.05), deceleration time of early mitral inflow velocity and the slope of end-systolic PVR without increasing MVO2. Results of the study indicate that approaches which increase the local release of adenosine in failing LV myocardium, such as ARAs, have a favorable impact on LV performance. These observations support the continued development of ARA's for the treatment of acute HF syndromes.

New Investigational Drugs for the Management of Acute Heart Failure Syndromes

Acute heart failure syndromes (AHFS) enclose a broad spectrum of conditions with different clinical presentations, heart failure history, pathophysiology, prognosis and treatment. AHFS represent a major public health problem because of their high prevalence, high rates of mortality and readmissions and significant healthcare costs, and a therapeutic challenge for the clinicians because management strategies vary markedly. Traditionally used drugs for the treatment of AHFS, including diuretics, vasodilators and positive inotropics, improve clinical signs and symptoms as well as hemodynamics, but present important limitations, as they fail to reduce and may even increase in-hospital and postdischarge mortality, especially in patients with coronary artery disease. Thus, we need new pharmacological agents to not only improve signs and symptoms and cardiac performance, but also improve both short- and long-term outcomes (hospitalizations/survival). In the last decade, significant efforts have been made to identify new therapeutic targets involved in the genesis/progression of AHFS and to develop new therapeutic strategies that may safely improve outcomes. As a result, several new families of drugs have been developed and are currently studied in experimental models and in Phase II and III clinical trials, in an attempt to define their efficacy and safety profiles as well as their precise role in the treatment of AHFS patients. This review firstly analyzes the main clinical applications and limitations of conventional drugs, and then focuses on the mechanisms of action and effects of recently approved drugs and of new investigational agents on signs, symptoms, hemodynamics and outcomes in AHFS patients.

Istaroxime, a first in class new chemical entity exhibiting SERCA-2 activation and Na–K-ATPase inhibition: a new promising treatment for acute heart failure syndromes?

Acute heart failure syndromes (AHFS) are associated with the rapid onset of heart failure (HF) signs and symptoms. Hospitalizations for AHFS continue to rise and are associated with significant mortality and morbidity. Several pharmacological agents are currently approved for the treatment of AHFS, but their use is associated with an increase in short-term mortality. There is a need for new agents that can be given in the acute setting with increased efficacy and safety. Istaroxime is a unique agent with both inotropic and lusitropic properties which is currently being studied for the treatment of AHFS. Istaroxime inhibits the sodium-potassium adenosine triphosphatase (ATPase) and stimulates the sarcoplasmic reticulum calcium ATPase isoform 2 (SERCA-2) thereby improving contractility and diastolic relaxation. Early data from human studies reveal that istaroxime decreases pulmonary capillary wedge pressure (PCWP) and possibly improves diastolic function without causing a significant change in heart rate (HR), blood pressure, ischemic or arrhythmic events. Most commonly reported side effects were related to gastrointestinal intolerance and were dose related. In conclusion, istaroxime is a novel agent being investigated for the treatment of AHFS whose mechanism of action and cellular targets make it a promising therapy. Further studies with longer infusion times in patients with hypotension are required to confirm its efficacy and safety.

Multicenter Prospective Investigation on Efficacy and Safety of Carperitide as a First-Line Drug for Acute Heart Failure Syndrome With Preserved Blood Pressure COMPASS: Carperitide Effects Observed Through Monitoring Dyspnea in Acute Decompensated Heart Failure Study

Recently, vasodilators have been increasingly being recognized as useful for the treatment of acute heart failure syndromes (AHFS). Although carperitide (alpha-human atrial natriuretic peptide) has vasodilatory, diuretic and organ-protective effects, its efficacy and safety for the first-line drug treatment of AHFS have not been reported. A prospective observational study was performed in AHFS patients with preserved systolic blood pressure (SBP >or=120 mmHg), pulmonary congestion and dyspnea who were receiving carperitide monotherapy. The analysis was conducted in 1,832 patients (male: 52.7%; mean age: 75.1+/-12.7 years). The initial SBP was 151.1+/-25.7 mmHg; 62.0% were diagnosed as having acutely decompensated chronic heart failure and 78.8% were assessed as functional class III-IV according to New York Heart Association classification. Carperitide was administered at an initial dosage of 0.025-0.05 microg x kg(-1) x min(-1) in 50.4% of patients. In 1,524 patients (83.2%), carperitide monotherapy restored the acute phase and improved the degree of dyspnea as assessed using the modified Borg scale. The incidence of adverse drug reactions was 4.64%; the most frequently reported adverse reaction was hypotension (3.55%). In the present study, following carperitide monotherapy, 83.2% of AHFS patients recovered from the acute phase. Based on these findings, carperitide seems useful for the first-line drug treatment of AHFS in patients with pulmonary congestion and preserved blood pressure.

Assessment of quality of life in severe heart failure

Improvement of health-related quality of life (HRQL) is increasingly recognized as a priority in the management of heart failure (HF). In this review, we highlight the dramatic improvement in HRQL often observed in patients with severe HF and give particular emphasis to the nonpharmacologic therapy of cardiac resynchronization therapy, left ventricular assist devices, and cardiac rehabilitation. We juxtapose this to the less consistent improvement in HRQL seen with interventions aimed at treatment of acute HF syndromes. Conflicting data wherein HRQL improves in parallel to a detrimental or neutral effect on cardiovascular morbidity and mortality are also presented. We conclude with future directions and make the case for HF-specific instruments intended for the assessment of HRQL in hospitalized patients, longitudinal studies in which HRQL is followed over time, and continued attention to the preferences of those with severe and acute HF.

Review of Current and Investigational Pharmacologic Agents for Acute Heart Failure Syndromes

Acute heart failure syndromes (AHFS) are a major public health problem and present a therapeutic challenge to clinicians. Commonly used agents in the treatment of AHFS include diuretics, vasodilators (eg, nitroglycerin, nitroprusside, nesiritide), and inotropes (eg, dobutamine, dopamine, milrinone). Patients admitted to hospital with AHFS and low cardiac output state (AHFS/LO) represent a subgroup with very high inhospital and postdischarge mortality rates. Most of these patients require intravenous inotropic therapy. However, the use of current intravenous inotropes has been associated with risk for hypotension, atrial and ventricular arrhythmias, and possibly increased postdischarge mortality, particularly in those with coronary artery disease. Consequently, there is an unmet need for new agents to safely improve cardiac performance (contractility and/or active relaxation) in this patient population. This article reviews a selection of current and investigational agents for the treatment of AHFS, with a main focus on the high-risk patient population with AHFS/LO.

Beyond Diuretics: Management of Volume Overload in Acute Heart Failure Syndromes

Diuretics are an established foundation of therapy for patients with chronic heart failure (HF) as well as for those hospitalized for treatment of acute HF syndromes. Despite the accepted use of diuretics in acute HF syndromes, treatment patterns with diuretics vary widely, and there are no data from randomized studies on the benefit of diuretics on morbidity or mortality in patients hospitalized with acute HF syndromes. Additional pharmacologic therapies that complement or replace diuretics in this setting, especially in patients with diuretic resistance, include positive inotropes, nitrovasodilators, and natriuretic peptides, but data are likewise lacking on important clinical outcomes. Ultrafiltration has also been used as a nonpharmacologic strategy to treat patients with acute HF syndromes who exhibit resistance to diuretics. Effective monitoring of volume status with newer modalities may allow more selective use of diuretics and diuretic-like modalities, but additional randomized trial data are clearly needed to establish ideal strategies to promote volume removal in acute HF syndromes.

Reassessment of Dobutamine, Dopamine, and Milrinone in the Management of Acute Heart Failure Syndromes

The appropriate role of intravenous inodilator therapy (inotropic agents with vasodilator properties) in the management of acute heart failure syndromes (AHFS) has long been a subject of controversy, mainly because of the lack of prospective, placebo-controlled trials and a lack of alternative therapies. The use of intravenous inodilator infusions, however, remains common, but highly variable. As new options emerge for the treatment of AHFS, the available information should be reviewed to determine which approaches are supported by evidence, which are used empirically without evidence, and which should be considered inappropriate. For these purposes, we reviewed data available from randomized controlled trials on short-term, intermittent, and long-term use of intravenous inodilator agents (dobutamine, dopamine, and milrinone) in AHFS. Randomized controlled trials failed to show benefits with current medications and suggested that acute, intermittent, or continuous use of inodilator infusions may increase morbidity and mortality in patients with AHFS. Their use should be restricted to patients who are hypotensive as a result of low cardiac output despite a high left ventricular filling pressure.