A Canadian context for the Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure (ASCEND-HF) trial

Abstract

C ongestive cardiac failure comprises a major public health problem that appears destined to grow substantially over the next decade. This entity is the unhappy, but logical final path for a diverse group of cardiovascular conditions dominated by ischemic heart disease and hypertension, but also populated by valvular and cardiomyopathic disorders. It constitutes a major cause of morbidity and mortality, which in its acute form is associated with an annualized mortality of at least 21% and a high rehospitalization rate (1,2). Accordingly, heart failure accounts for not only a large burden to the health care system, but also one that has major economic repercussions; it is now the single largest expense for Medicare in the United States (3). The projected increase in heart failure morbidity, hospitalization and mortality represents a near exponential curve based on the success of contemporary medical therapy and the increased age of the population.Somewhat paradoxically, and in contrast to acute coronary disease, acute heart failure has been relatively understudied. The current standard therapies of intravenous diuretics and vasodilators have been in use for many years. Whereas inotropic agents were commonly used intravenously as a logical therapeutic additive, their potential to induce ventricular arrhythmias and augment mortality has largely restricted their use to in-hospital and dire circumstances.Hence, the emergence of recombinant human BNP -which, in its wild-type motif is secreted by the heart in response to increased wall tension -represents a novel and potentially important advance in the care of patients with acute heart failure (4). Because BNP promotes vasodilation, increases salt and water excretion, and improves left ventricular diastolic filling properties, it has the capacity to reduce pulmonary congestion with resultant symptomatic relief.As is often the case with the emergence of new and potentially exciting pharmaceuticals that fill unmet needs, when synthetic recombinant human BNP (nesiritide) became available for use in patients with acute heart failure in the United States, its application was quickly taken up and extended beyond the labelled indication, ie, for inpatient acute heart failure.Subsequent review of both published and Food and Drug Administration-sponsored documentation raised questions about harmful side effects of nesiritide, including renal dysfunction and increased mortality in patients with acute decompensated heart failure (5,6). In ACUTE DECOMPENSATED HEART FAILURE ©2008 Pulsus Group Inc. All rights reserved Congestive heart failure comprises a major public health problem destined to grow enormously over the next decade. Paradoxically, and in contrast to acute coronary disease, acute heart failure has been relatively understudied. Current standards of care involve the use of intravenous diuretics and vasodilators; inotropic agents have been restricted to in-hospital use because of concern about their potential harmful effects. The emergence of recombinant human B-type nat...

Pharmacogenomics in Heart Failure

“…As a result of genetic substudies of BEST that have provided a wealth of knowledge, bucindolol may be the most auspicious candidate to be approved as a heart failure therapy that incorporates a pharmacogenomic-guided strategy. While genetic information is now routinely being collected in clinical trials worldwide 81,82 , it is not always being actively utilized or opened for exploration, squandering many great opportunities.…”

Cardiorenal syndrome: still not a defined entity

“…Larger randomized, placebo-controlled trials, such as the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure (ASCEND-HF) [62], are required to further elucidate the effect of nesiritide on renal function in patients hospitalized for decompensated heart failure.…”

Cardiorenal syndrome and heart failure

“…Although two meta-analyses [42,43] have found that at various doses nesiritide can worsen renal function, many others studies [44][45][46] have found that at low doses it poses no risk to kidney function and in some cases is renal protective. Further analysis of this drug and its effects on promoting or preventing cardiorenal syndrome is being performed in several other studies such as the Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure [47]. At the moment, it seems safe to say that at doses between 0.005 and 0.01 mg/ kg/ml, there are no additional risks to renal function, whereas doses between 0.0025 and 0.005 mg/kg/ml without an initial bolus may be cardiorenal protective [25,46,48].…”