Nesiritide: new hope for acute heart failure syndromes?

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1 European Heart Journal Supplements (2005) 7 (Supplement B), B25 B30 doi: /eurheartj/sui010 Nesiritide: new hope for acute heart failure syndromes? John C. Burnett* Department of Medicine, Mayo Clinic and Foundation, Rochester, MN 55905, USA KEYWORDS Acute disease; B-type natriuretic peptide; Congestive heart failure; pathophysiology/prevention and control/therapy; Pharmacotherapy Natriuretic peptides: a physiological rescue mechanism in heart failure The function of the heart as an endocrine organ was first demonstrated in the 1960s, with the observation of cardiac synthesis and release of noradrenaline. 1 About 20 years later, the heart was also identified as the source of the natriuretic peptides (NPs). Four members of the NP family structurally similar, yet distinct, gene products have been discovered to date. 2 Atrial and B-type natriuretic peptide (ANP and BNP) are of myocardial origin, whereas C-type natriuretic peptide is synthesized in endothelial cells. The most recently discovered member Dendroaspis natriuretic peptide has been reported to be present in human plasma and atrial myocardium. BNP is a polypeptide hormone comprising 32 amino acids. 3 It is synthesized as pro-bnp, which is enzymatically cleaved to form BNP and non-biologically active N-terminal pro-bnp. BNP in common with ANP activates membrane-bound NP receptors, leading to the stimulation of particulate guanylate cyclases located in multiple organs, and mediation of natriuresis, inhibition of hormonal systems, vasodilation, and anti-fibrosis through the cyclic GMP (cgmp) second messenger system. Nitrates * Corresponding author. address: burnett.john@mayo.edu B-type natriuretic peptide (BNP) is a peptide hormone that exerts cardiac, renal, and hormonal effects, and is produced by the myocardium as part of the compensatory response of the failing heart. The therapeutic benefits of exogenous BNP administration to patients with acute heart failure syndromes have been demonstrated, and recombinant human BNP (nesiritide) was licensed in the USA for the treatment of this condition in Recent studies have also found that the beneficial effects of BNP in patients with heart failure extend beyond haemodynamics, to include natriuretic, renoprotective, and anti-remodelling properties. New therapeutic opportunities for BNP are also under investigation, including the possibility of long-term use in patients with chronic congestive heart failure. also stimulate cgmp, but through a soluble guanylate cyclase that activates a primarily dilating pathway. As the heart fails, and volume and pressure rise, NPs along with other mediators are released in response to myocardial overload and stretch. The beneficial compensatory cardiac, renal and neurohormonal effects of the NPs combine to counteract the deleterious effects of other hormones, including noradrenaline, angiotensin II, aldosterone, endothelin-1, and vasopressin, unloading the failing heart. During early chronic heart failure, the body s natural compensatory mechanisms are so successful that 50% of individuals with left ventricular dysfunction are asymptomatic. 4 BNP as a therapy for acute heart failure syndromes NP release in acute heart failure can be interpreted as an attempt by the heart to rescue itself. Although NPs play key protective roles in myocardial dysfunction, it appears that during later stages of congestive heart failure (CHF), and the acute, decompensated episodes described as acute heart failure syndromes (AHFS), the failing heart may be unable to maintain sufficiently high levels of compensatory hormones. The balance of adaptive neurohormonal activation tips towards deleteriously high levels of mediators that lead to congestion and reduced perfusion. This raises the possibility of & The European Society of Cardiology All rights reserved. For Permissions, please journals.permissions@oupjournals.org

2 B26 J.C. Burnett therapeutic opportunities for exogenous natriuretic peptides and other compensatory mediators. Two pivotal trials by Colucci et al. 5 paved the way for the use of NPs as a therapeutic intervention for patients with AHFS. These studies collectively showed nesiritide to provide significant haemodynamic and symptomatic improvement compared with placebo, and similar symptomatic improvements to those obtained with standard intravenous therapy, which were sustained for up to 7 days. The positive results from this study led to the design and execution of the larger, definitive FDA-approval study of BNP in acute human heart failure Vasodilation in the Management of Acute CHF (VMAC). This Phase III trial investigated the effects of administering standard care plus nesiritide, nitroglycerin or placebo in a broad AHFS population of 489 patients, including those with acute coronary syndromes, acute decompensated heart failure, and preserved systolic function. The primary endpoints were changes from baseline in pulmonary capillary wedge pressure (PCWP) and patient-evaluated dyspnoea after 3 h of study treatment. PCWP is an important outcome predictor in AHFS: elevated PCWP is predictive of an increased risk of fatal decompensation and sudden death. 6 Over 3 h, nesiritide (2 mg/kg bolus followed by a 0.01 mg/kg/min infusion) induced a more rapid and greater decrease in PCWP compared with nitroglycerin and placebo (P, 0.05). These positive effects of nesiritide on PCWP were sustained for at least 24 h, while treatment with nitroglycerin only resulted in a significant difference from placebo at 2 h. Only nesiritide was associated with a significant improvement in patient-rated dyspnoea at 3 h compared with placebo (P, 0.05), although the difference in dyspnoea scores between the nesiritide and nitroglycerin groups did not reach significance. Renal and hormonal effects of BNP In addition to the positive haemodynamic effects of nesiritide, other aspects of its activity merit attention: namely, its renal and hormonal effects. There is a close relationship between the heart and the kidney under both physiological and pathophysiological conditions. The heart s physiological response to overload includes the release of BNP and ANP, whose multifaceted effects comprise natriuresis, diuresis, and vasodilation together with inhibition of renin, aldosterone, and fibrosis. In turn, the kidney communicates with the heart under physiological conditions of underfilling or salt depletion through the renin angiotensin aldosterone system (RAAS), whose effects include sodium retention, antidiuresis, vasoconstriction, and fibrosis. In healthy humans, infusion of exogenous BNP results in dose-dependent increases in urinary flow and natriuresis, and inhibition of renin secretion. 7 The kidney also plays a pivotal role under pathological conditions of CHF. As renal function has been shown to be a robust predictor of survival in heart failure, 8 it is imperative to determine the positive, neutral or deleterious effects of therapeutic interventions on the kidney. Animal models with reduced renal function are being developed to further our understanding of the consequences of renal impairment the ultimate goal being the design of strategies to delay disease progression or improve patient outcomes. The natriuretic effect seen upon infusion of BNP in healthy subjects is also observed in patients with CHF. A comparison between healthy subjects and patients with CHF found that urinary sodium excretion increased significantly, and by the same relative amount, in both groups in response to BNP. 9 Several studies have provided clinical evidence for a beneficial renal effect of nesiritide in patients with AHFS. In the efficacy study by Colucci et al., 5 mean urine output over 6 h was also higher in patients randomized to nesiritide than those receiving placebo. In addition, Marcus et al. 10 found that a 90 min infusion of synthetic human BNP resulted in significantly increased urine volume and urinary sodium excretion compared with placebo in patients with severe CHF (P, 0.05). These natriuretic benefits do not appear to be gained at the expense of renal function: BNP had no effect on urinary potassium or creatinine excretion. 10 Similarly, in the VMAC trial, nesiritide had no effect on serum creatinine levels. 11,12 The renal effects of nesiritide are likely to be closely related to its effects on the RAAS. Colucci et al. observed that over a 6 h period, plasma aldosterone levels decreased in patients who received nesiritide, but increased in those assigned to placebo (P ¼ 0.03). 5 A second study reported reductions in plasma noradrenaline and aldosterone in patients with AHFS who received a 4 h infusion of BNP, compared with those who received placebo. 13 Reduced plasma endothelin-1 levels compared with baseline were also observed in patients with AHFS treated for 24 h with intravenous nesiritide. 14 Although nesiritide is associated with beneficial renal effects, several studies have shown that diuretic use may have detrimental effects on renal function, by reducing glomerular filtration rate (GFR) and activating the RAAS. A recent study of mortality in patients with acute renal failure in the intensive care unit found high-dose diuretic use to be associated with adverse outcomes. 15 As diuretic treatment is a mainstay of current therapy for AHFS, there is, therefore, a need to introduce therapeutic interventions that can potentiate or substitute for the beneficial action of diuretics, while minimizing side-effects. An interesting possibility recently tested in a canine model of CHF is that nesiritide may preserve renal function when administered concomitantly with loop diuretics. Cataliotti et al. 16 found that coadministration of highdose BNP plus furosemide approximately doubled the GFR compared with furosemide alone, in experimental heart failure (P, , Figure 1A ). Increases in urinary flow and urinary sodium excretion were also greater when BNP was added to furosemide (Figure 1B and C ). In addition, despite the increased GFR, only a small increase in plasma aldosterone levels was observed in animals who received furosemide plus BNP, compared with those who received furosemide alone (P ¼ ). Ongoing studies by Boerrigter et al. suggest that the beneficial actions of BNP compared with nitroglycerin

3 Nesiritide for AHFS B27 Figure 1 Effect of adding BNP to furosemide treatment on (A) GFR, (B) urine flow, and (C) urinary sodium excretion in dogs with experimental CHF. BL, baseline; Rec, recovery; P, vs. baseline; P, vs. baseline; P, vs. furosemide. Reproduced from Cataliotti et al. 16 with permission. are not exclusively due to its favourable haemodynamic effects: whereas a marked natriuretic and diuretic response to BNP was reported by Cataliotti et al., urinary sodium excretion was unchanged in an experimental heart failure model in which nitroglycerin therapy was administered to reduce PCWP. 16,17 There is clinical evidence that these effects of nesiritide may result in a diuretic-sparing effect in a comparative trial, fewer patients with AHFS who received nesiritide required intravenous diuretics than those randomized to standard therapy. 5 Therefore, simultaneous administration of a loop diuretic and BNP may be an effective therapeutic strategy to preserve renal function and inhibit RAAS activation, while maximizing natriuresis and diuresis and unloading the failing heart. A subgroup analysis of the VMAC trial database found nesiritide to have a favourable safety and efficacy profile in patients with renal insufficiency (RI). 12 PCWP was significantly reduced at every timepoint from 15 min to 24 h in patients with RI who received nesiritide (n ¼ 60). In contrast, treatment with nitroglycerin resulted in a less robust decrease in PCWP, which did not reach significance at the 3 h primary endpoint. Addition of other standard therapies to placebo did not significantly reduce PCWP at any time point in this patient subgroup. Improvements in dyspnoea were also reported at 24 h by 84% of patients with RI who were treated with nesiritide, and global clinical status was improved in 83% of the subgroup. The authors concluded that nesiritide improves both haemodynamics and dyspnoea in individuals with RI, and should therefore be considered as a first-line agent for AHFS management in these patients. From acute to chronic disease: BNP as a long-term CHF therapy? Research into the therapeutic potential of BNP for CHF has so far focused on treatment of acute disease, but there is also a need for effective therapies to delay or prevent the progression of the condition. Two important questions would need to be resolved before BNP could be considered

4 B28 J.C. Burnett as a potential treatment for CHF: what are the therapeutic benefits, and is there a route of administration suitable for long-term outpatient therapy? Recent studies have begun to address some of these issues, and have given promising indications that BNP may indeed provide cardiovascular and humoral benefits in chronic CHF. A preclinical study by Chen et al. 18 examined the effects of subcutaneous (SQ) administration of BNP in dogs with experimental heart failure. Acute SQ BNP administration resulted in rapid, significant increases in plasma BNP and cgmp levels, urine flow, urinary sodium excretion and renal blood flow, and significant reductions in cardiac filling pressures. No significant activation of plasma renin activity occurred in the groups treated with SQ BNP. The increases in plasma BNP and cgmp were longer-lasting with SQ administration than previously reported for bolus intravenous injection, suggesting that this route of administration may be more suitable for chronic therapy. 19 Indeed, chronic administration of SQ BNP every 8 h for 10 days resulted in significantly increased cardiac output and decreased PCWP and systemic vascular resistance compared with dogs with untreated heart failure (P, 0.05). 18 A recent placebo-controlled, single-blind study examined the effect of SQ administration of nesiritide in patients with New York Heart Association Class II or III CHF (n ¼ 8). 20 SQ nesiritide administration every 12 h over 3 days increased cardiac output and decreased systolic blood pressure, with no concomitant change in heart rate. Natriuresis, diuresis, plasma BNP and cgmp levels, and urinary cgmp excretion also increased, whereas plasma renin activity and aldosterone decreased. The favourable response to nesiritide was sustained throughout the study period, with no evidence of the development of tolerance or significant adverse events. These initial indications that SQ nesiritide could be a useful long-term therapy for patients with chronic CHF are supported by a randomized, open-label pilot study (n ¼ 210) in which patients with CHF received serial outpatient infusions of nesiritide or standard care for 12 weeks. 21 Treatment with nesiritide was well-tolerated, and patients who received this therapy showed significantly improved global clinical status (P, 0.05) and a trend towards improved survival. These preclinical and clinical studies support the further investigation of BNP in larger-scale, long-term trials, in patients with CHF. Other strategies to increase the availability or activity of BNP in the body could also be useful in the management of CHF patients. For example, a recent Phase III study reported significant reductions in deaths or hospitalizations due to cardiovascular causes, deaths or hospitalizations due to any cause, and sudden death from cardiac causes in patients with acute myocardial infarction, left ventricular dysfunction and heart failure treated daily for up to 16 months with the selective aldosterone blocker eplerenone compared with placebo. 22 It would be interesting to determine whether a combination of BNP and eplerenone, or other agents that may enhance the physiological effects of BNP, could act synergistically to provide effective chronic therapy. Anti-remodelling activity of BNP: could BNP prevent the progression from risk factors to heart failure? Heart failure is a disease with a destructive course, progressing from the presence of risk factors alone to the development of ventricular dysfunction and onto symptomatic ventricular dysfunction (Figure 2). In view of the substantial morbidity, mortality, and cost associated with both the chronic and acute phases of this disease, an important future goal for effective heart failure management is the development of preventive strategies. To prevent the development of CHF, interventions need to be targeted upstream, to halt remodelling and ventricular enlargement. Is there a potential role for BNP in this aspect of heart failure management? There is a rationale for believing that NPs could prevent development of CHF by providing cardiovascular protection. One aspect in which NPs could have a role is in prevention of cardiac remodelling after trauma, such as myocardial infarction, by inhibiting collagen deposition. The anti-fibrotic properties of NPs in the heart are well established: they have been shown to inhibit DNA synthesis by, and proliferation of, cardiac fibroblasts, and mice lacking BNP develop multifocal fibrotic lesions in the ventricles. 26 In cardiac fibroblasts in vitro, BNP significantly inhibited de novo collagen synthesis and stimulated the expression of matrix metalloproteinases enzymes that degrade collagen and may play an important role in ventricular remodelling (Figure 3). 27 In addition, treatment of human umbilical vein endothelial cells with ANP attenuated the effects of the inflammatory mediator tumour necrosis factor-a on macromolecule permeability and stress fibre formation, indicating that ANP at least may have antiinflammatory and anti-atherogenic effects. 28 Therefore, at least three possible anti-remodelling mechanisms can be envisaged for BNP: cardiac unloading via cardiorenal Figure 2 From risk factors to overt heart failure.

5 Nesiritide for AHFS B29 Figure 3 Effect of 10 min BNP stimulation on collagen synthesis (A ) and matrix metalloproteinase-2 abundance (B ) in cardiac fibroblasts. P, 0.01; P, 0.05 vs. untreated controls. MMP-2, matrix metalloproteinase-2. Reproduced from Tsuruda et al. 27 with permission. actions, anti-aldosterone mechanisms, and direct actions on endothelial cells and cardiac fibroblasts. The ongoing BELIEVE (B-type Natriuretic Peptide and Post-myocardial Infarction Left Ventricular Remodeling) study is the first clinical trial to examine the use of NPs as acute hormonal cardioprotective agents. The aim of the trial is to prevent cardiac remodelling by prescribing BNP to patients at the onset of acute myocardial infarction. Patients with first-time acute anterior myocardial infarction without heart failure are randomized to 3 days infusion of BNP vs. standard therapy. The trial has a projected completion date of late 2006, and the results are awaited with interest. Conclusions Nesiritide is a promising emergent therapy for AHFS, due to its multifaceted mode of action and absence of serious adverse effects. The safety and efficacy of nesiritide for treatment of AHFS have been demonstrated in a number of Phase III studies. Along with its haemodynamic benefits, nesiritide has diuretic-sparing properties and may preserve renal function. It may also provide advantages for specific high-risk patient groups, such as those with RI. Nesiritide therefore represents a valuable addition to currently available therapeutic options for AHFS. Further studies are required to establish the potential role of nesiritide in the prevention of disease progression in patients with CHF. Acknowledgements Meeting session and publication supported by an unrestricted educational grant from GlaxoSmithKline Ltd. J.C.B. currently holds a research grant from Scios Inc. References 1. Braunwald E, Harrison DC, Chidsey CA. The heart as an endocrine organ. 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