Abstract
Nesiritide is a recombinant form of human B-type natriuretic peptide, a naturally occurring endogenous hormone released by cardiac ventricles in response to an increase in ventricular wall stress. Its use in the treatment of acute decompensated heart failure (ADHF) has been evaluated in a series of randomised controlled clinical trials. It is currently approved in the US for the treatment of ADHF. Nesiritide induces a balanced vasodilation and an indirect increase in cardiac output, but has no actual inotropic effects and exerts a neutral effect on heart rate. In addition, it inhibits adverse neurohormonal activation and, in some individuals, promotes natriuresis and diuresis. In adults with ADHF, nesiritide reduces pulmonary capillary wedge pressure, right atrial pressure and systemic vascular resistance; decreases symptoms of heart failure; and enhances global clinical status. Important questions regarding the risks of nesiritide therapy have recently been raised, and resolution of the safety of nesiritide is a process that remains in evolution. The most frequently reported adverse effect is dose-related hypotension. In addition, nesiritide may cause an acute increase in serum creatinine concentration. This increase seems to be a haemodynamic response to a combination of volume depletion, vasodilation and neurohormonal inhibition. Nesiritide-induced changes in renal function have not been definitively shown to negatively affect mortality. The effect of nesiritide on all-cause mortality is currently unresolved. Recent meta-analyses of existing databases have raised concerns regarding adverse effects of the drug on 30-day mortality. However, reviews of large, observational, registry databases do not suggest an adverse inpatient mortality effect compared with other vasodilator therapies. Further resolution of the mortality question awaits completion of pending randomised controlled clinical trials.
When used for approved indications and according to recommended dosage and administration regimens, nesiritide represents a reasonable treatment adjunct for ADHF.
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References
Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics—2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee [published erratum appears in Circulation 2007; 115: e172]. Circulation 2007; 115(5): e69–e171
Kozak LJ, Owings MF, Hall MJ. National hospital discharge survey: 2002 annual summary with detailed diagnosis and procedure data. National Center for Health Statistics. Vital Health Stat 2005; 13(158): 1–199
Nieminen MS, Böhm M, Cowie MR, et al. Executive summary of the guidelines on the diagnosis and treatment of acute heart failure: the Task Force on Acute Heart Failure of the European Society of Cardiology. Eur Heart J 2005; 26(4): 384–416
Rich MW, Beckham V, Wittenberg C, et al. A multidisciplinary intervention to prevent the readmission of elderly patients with congestive heart failure. N Engl J Med 1995; 333(18): 1190–5
Krumholz HM, Chen YT, Vaccarino V, et al. Correlates and impact on outcomes of worsening renal function in patients ≥65 years of age with heart failure. Am J Cardiol 2000; 85(9): 1110–3
Fonarow GC, Adams Jr KF, Abraham WT, et al., for the ADHERE Scientific Advisory Committee, Study Group, and Investigators. Risk stratification for in-hospital mortality in acutely decompensated heart failure: classification and regression tree analysis. JAMA 2005; 293(5): 572–80
Akhter MW, Aronson D, Bitar F, et al. Effect of elevated admission serum creatinine and its worsening on outcome in hospitalized patients with decompensated heart failure. Am J Cardiol 2004; 94(7): 957–60
Gheorghiade M, Gattis WA, O’Connor CM, et al., for the Acute and Chronic Therapeutic Impact of a Vasopressin Antagonist in Congestive Heart Failure (ACTIV in CHF) Investigators. Effects of tolvaptan, a vasopressin antagonist, in patients hospitalized with worsening heart failure: a randomized controlled trial. JAMA 2004; 291(16): 1963–71
Publication Committee for the VMAC Investigators. Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA 2002; 287(12): 1531–40
Follath F, Cleland JG, Just H, et al., for the Steering Committee and Investigators of the Levosimendan infusion versus Dobutamine (LIDO) Study. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet 2002; 360(9328): 196–202
Shahar E, Lee S, Kim J, et al. Hospitalized heart failure: rates and long-term mortality. J Card Fail 2004; 10(5): 374–9
Southworth MR. Treatment options for acute decompensated heart failure. Am J Health Syst Pharm 2003; 60 ( Suppl.): S7–S15
Adams Jr KF, Fonarow GC, Emerman CL, et al., for the ADHERE Scientific Advisory Committee and Investigators. Characteristics and outcomes of patients hospitalized for heart failure in the United States: rationale, design, and preliminary observations from the first 100,000 cases in the Acute Decompensated Failure National Registry (ADHERE). Am Heart J 2005; 149(2): 209–16
National Kidney Foundation. K/DOQI Clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Guideline 1. National Kidney Foundation [online]. Available from URL: http://www.kidney.org/professionals/kdoqi/guidelines_ckd/p4_class_g1.htm [Accessed 2007 Jan 23]
Cleland JGF, Swedberg K, Follath F, et al. The EuroHeart Failure survey programme: a survey on the quality of care among patients with heart failure in Europe. Part 1: patient characteristics and diagnosis. Eur Heart J 2003; 24(5): 442–63
Heart Failure Society of America. Executive summary: HFSA 2006 comprehensive heart failure practice guideline. J Card Fail 2006; 12(1): 10–38
DiDomenico RJ, Park HY, Southworth MR, et al. Guidelines for acute decompensated heart failure treatment. Ann Pharmacother 2004; 38(4): 649–60
Francis GS, Benedict C, Johnstone DE, et al. Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure: a substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation 1990; 82(5): 1724–9
Cotter G, Weissgarten J, Metzkor E, et al. Increased toxicity of high-dose furosemide versus low-dose dopamine in the treatment of refractory congestive heart failure. Clin Pharmacol Ther 1997; 62(2): 187–93
Ikram H, Chan W, Espiner EA, et al. Haemodynamic and hormone responses to acute and chronic furosemide therapy in congestive heart failure. Clin Sci 1980; 59(6): 443–9
Francis GS, Siegel RM, Goldsmith SR, et al. Acute vasoconstrictor response to intravenous furosemide in patients with chronic congestive heart failure: activation of the neurohumoral axis. Ann Intern Med 1985; 103(1): 1–6
Gottlieb SS, Brater DC, Thomas I, et al. BG9719 (CVT-124), an A1 adenosine receptor antagonist, protects against the decline in renal function observed with diuretic therapy. Circulation 2002; 105(11): 1348–53
Kubo SH, Clark M, Laragh JH, et al. Identification of normal neurohormonal activity in mild congestive heart failure and stimulating effect of upright posture and diuretics. Am J Cardiol 1987; 60(16): 1322–8
Mehta RL, Pascual MT, Soroko S, et al., for the PICARD Study Group. Diuretics, mortality, and nonrecovery of renal function in acute renal failure. JAMA 2002; 288(20): 2547–53
Domanski M, Norman J, Pitt B, et al. Diuretic use, progressive heart failure, and death in patients in the studies of left ventricular dysfunction (SOLVD). J Am Coll Cardiol 2003; 42(4): 705–8
Neuberg GW, Miller AB, O’Connor CM, et al., for the PRAISE Investigators. Diuretic resistance predicts mortality in patients with advanced heart failure. Am Heart J 2002; 144(1): 31–8
Cooper HA, Dries DL, Davis CE, et al. Diuretics and risk of arrhythmic death in patients with left ventricular dysfunction. Circulation 1999; 100(12): 1311–5
Emerman CL, DeMarco T, Costanzo MR, et al., for the ADHERE® Scientific Advisory Committee. Impact of intravenous diuretics on the outcomes of patients hospitalized with acute decompensated heart failure: insights from the ADHERE® Registry [abstract 368]. J Card Fail 2004; 10 Suppl. 4: S116
Packer M, Lee WH, Kessler PD, et al. Prevention and reversal of nitrate tolerance in patients with congestive heart failure. N Engl J Med 1987; 317(13): 799–804
Ferreira A, Bettencourt P, Dias P, et al. Neurohormonal activation, the renal dopaminergic system and sodium handling in patients with severe heart failure under vasodilator therapy. Clin Sci 2001; 100(5): 557–66
Abraham WT, Adams KF, Fonarow GC, et al., the ADHERE Scientific Advisory Committee and Investigators and the ADHERE Study Group. In-hospital mortality in patients with acute decompensated heart failure treated with intravenous vasoactive medications: an analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). J Am Coll Cardiol 2005; 46(1): 57–64
Arnold LM, Carroll NV, Oinonen M, et al. Mortality and length of hospital stay in patients receiving dobutamine, milrinone, or nesiritide for acute decompensated heart failure [abstract 317]. J Card Fail 2004; 10 Suppl. 4: S103
Aronson D, Horton DP, Burger AJ. The effect of dobutamine on neurohormonal and cytokine profiles in patients with decompensated congestive heart failure [abstract 095]. J Card Fail 2001; 7 (3 Suppl. 2): 28
Burger AJ, Horton DP, LeJemtel T, et al. Effect of nesiritide (B-type natriuretic peptide) and dobutamine on ventricular arrhythmias in the treatment of patients with acutely decompensated congestive heart failure: The PRECEDENT Study. Am Heart J 2002; 144(6): 1102–8
Elkayam U, Tasissa G, Binanay C, et al. Use and impact of inotropes and vasodilator therapy during heart failure hospitalization in the ESCAPE Trial [abstract 2415]. Circulation 2004; 110 (17Suppl. III): III-515
Ewy GA. Inotropic infusions for chronic congestive heart failure. Medical miracles or misguided medicinals? J Am Coll Cardiol 1999; 33(2): 572–5
Nieminen MS, Akkila J, Hasenfuss G, et al., on behalf of the Study Group. Hemodynamic and neurohumoral effects of continuous infusion of levosimendan in patients with congestive heart failure. J Am Coll Cardiol 2000; 36(6): 1903–12
Stiles S. SURVIVE: no levosimendan survival benefit over dobutamine in acute HF [online]. Available from URL: www.theheart.org/article/606501.do [Accessed 2007 Jan 23]
Stiles S. REVIVE-2: levosimendan improves five-day clinical status in acute HF [online]. Available from URL: http://www.theheart.org/article/600671.do [Accessed 2007 Jan 23]
Coletta AP, Cleland JG, Freemantle N, et al. Clinical trials update from the European Society of Cardiology Heart Failure meeting: SHAPE, BRING-UP 2 VAS, COLA II, FOSIDIAL, BETACAR, CASINO and meta-analysis of cardiac resynchronisation therapy. Eur J Heart Fail 2004; 6(5): 673–6
Keating GM, Goa KL. Nesiritide: a review of its use in acute decompensated heart failure. Drugs 2003; 63(1): 47–70
Boerrigter G, Burnett Jr JC. Recent advances in natriuretic peptides in congestive heart failure. Expert Opin Investig Drugs 2004; 13(6): 643–52
Marcus LS, Hart D, Packer M, et al. Hemodynamic and renal excretory effects of human brain natriuretic peptide infusion in patients with congestive heart failure: a double-blind, placebo-controlled, randomized crossover trial. Circulation 1996; 94(12): 3184–9
Zhou HL, Fiscus RR. Brain natriuretic peptide (BNP) causes endothelium-independent relaxation and elevation of cyclic GMP in rat thoracic aorta. Neuropeptides 1989; 14(3): 161–9
Protter AA, Wallace AM, Ferraris VA, et al. Relaxant effect of human brain natriuretic peptide on human artery and vein tissue. Am J Hypertens 1996; 9(5): 432–6
Abraham WT, Lowes BD, Ferguson DA, et al. Systemic hemodynamic, neurohormonal, and renal effects of a steady-state infusion of human brain natriuretic peptide in patients with hemodynamically decompensated heart failure. J Card Fail 1998; 4(1): 37–44
Colucci WS, Elkayam U, Horton DP, et al., for the Nesiritide Study Group. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. N Engl J Med 2000; 343(4): 246–53
Mills RM, LeJemtel TH, Horton DP, et al., on behalf of the Natrecor Study Group. Sustained hemodynamic effects of an infusion of nesiritide (human B-type natriuretic peptide) in heart failure: a randomized, double-blind, placebo-controlled clinical trial. J Am Coll Cardiol 1999; 34(1): 155–62
Yoshimura M, Yasue H, Morita E, et al. Hemodynamic, renal, and hormonal responses to brain natriuretic peptide infusion in patients with congestive heart failure. Circulation 1991; 84(4): 1581–8
Michaels AD, Klein A, Madden JA, et al. Effects of intravenous nesiritide on human coronary vasomotor regulation and myocardial oxygen uptake. Circulation 2003; 107(21): 2697–701
Zellner C, Protter AA, Ko E, et al. Coronary vasodilator effects of BNP: mechanisms of action in coronary conductance and resistance arteries. Am J Physiol 1999; 276 (3 Pt 2): H1049–57
Roden RL, Asano K, Wichman S, et al. Inotropic effect of human B-type natriuretic peptide in the failing human heart [abstract 008]. J Card Fail 1998; 4 (3 Suppl.): 19
Burger AJ, Aronson D, Horton DP, et al. Comparison of the effects of dobutamine and nesiritide (B-type natriuretic peptide) on ventricular ectopy in acutely decompensated ischemic versus nonischemic cardiomyopathy. Am J Cardiol 2003; 91(11): 1370–2
Aronson D, Burger AJ. Effect of nesiritide (human B-type natriuretic peptide) and dobutamine on heart rate variability in decompensated heart failure. Am Heart J 2004; 148(5): 920–6
Swedberg K, Cleland J, Dargie H, et al. Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. Eur Heart J 2005; 26(11): 1115–40
Brunner-La Rocca HP, Kaye DM, Woods RL, et al. Effects of intravenous brain natriuretic peptide on regional sympathetic activity in patients with chronic heart failure as compared with healthy control subjects. J Am Coll Cardiol 2001; 37(5): 1221–7
Cataliotti A, Boerrigter G, Costello-Boerrigter LC, et al. Brain natriuretic peptide enhances renal actions of furosemide and suppresses furosemide-induced aldosterone activation in experimental heart failure. Circulation 2004; 109(13): 1680–5
Holmes SJ, Espiner EA, Richards AM, et al. Renal, endocrine, and hemodynamic effects of human brain natriuretic peptide in normal man. J Clin Endocrinol Metab 1993; 76(1): 91–6
Jensen KT, Carstens J, Pedersen EB. Effect of BNP on renal hemodynamics, tubular function and vasoactive hormones in humans. Am J Physiol 1998; 274 (1 Pt 2): F63–72
Jensen KT, Eiskjaer H, Carstens J, et al. Renal effects of brain natriuretic peptide in patients with congestive heart failure. Clin Sci (Lond) 1999; 96(1): 5–15
Yancy CW, Saltzberg MT, Berkowitz RL, et al. Safety and feasibility of using serial infusions of nesiritide for heart failure in an outpatient setting (from the FUSION I Trial). Am J Cardiol 2004; 94: 595–601
Yasue H, Yoshimura M. Natriuretic peptides in the treatment of heart failure. J Card Fail 1996; 2 (4 Suppl.): S277-85
Pitt B, Zannad F, Remme WJ, et al., for the Randomized Aldactone Evaluation Study Investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999; 341(10): 709–17
Pitt B, Williams G, Remme W, et al. The EPHESUS trial: eplerenone in patients with heart failure due to systolic dysfunction complicating acute myocardial infarction. Eplerenone Post-AMI Heart Failure Efficacy and Survival Study. Cardiovasc Drugs Ther 2001; 15(1): 79–87
Aronson D, Burger AJ. Intravenous nesiritide (human B-type natriuretic peptide) reduces plasma endothelin-1 levels in patients with decompensated congestive heart failure. Am J Cardiol 2002; 90(4): 435–8
Hunt PJ, Espiner EA, Nicholls MG, et al. Differing biological effects of equimolar atrial and brain natriuretic peptide infusions in normal man. J Clin Endocrinol Metab 1996; 81(11): 3871–6
La Villa G, Fronzaroli C, Lazzeri C, et al. Cardiovascular and renal effects of low dose brain natriuretic peptide infusion in man. J Clin Endocrinol Metab 1994; 78(5): 1166–71
van der Zander K, Houben AJHM, Hofstra L, et al. Hemodynamic and renal effects of low-dose brain natriuretic peptide infusion in humans: a randomized, placebo-controlled crossover study. Am J Physiol Heart Circ Physiol 2003; 285(3): H1206–12
Akabane S, Matsushima Y, Matsuo H, et al. Effects of brain natriuretic peptide on renin secretion in normal and hypertonic saline-infused kidney. Eur J Pharmacol 1991; 198(2–3): 143–8
Heywood JT. Combining nesiritide with high-dose diuretics may increase the risk of increased serum creatinine [abstract 950473]. J Card Fail 2005; 11 Suppl. 6: S154
Abraham WT. Serum creatinine elevations in patients receiving nesiritide are related to starting dose [abstract 2789]. Circulation 2005; 112 (17 Suppl. II): 589
Cheng JWM, Merl MY, Nguyen HM. Effect of nesiritide on renal function in patients with decompensated heart failure [abstract 11]. Pharmacotherapy 2005; 25(3): 4
Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation 2005; 111(12): 1487–91
Wang DJ, Dowling TC, Meadows D, et al. Nesiritide does not improve renal function in patients with chronic heart failure and worsening serum creatinine. Circulation 2004; 110(12): 1620–5
Elkayam U, Singh H, Akhter MW, et al. Effects of intravenous nesiritide on renal hemodynamics in patients with congestive heart failure [abstract 256]. J Card Fail 2004; 10: (4 Suppl.): S88
Natrecor® (nesiritide) for injection [package insert] [online]. Available from URL: http://www.sciosinc.com/pdf/natrecorpi_final.pdf [Accessed 2007 Jan 23]
Hobbs RE, Mills RM. Therapeutic potential of nesiritide (recombinant B-type natriuretic peptide) in the treatment of heart failure. Expert Opin Investig Drugs 1999; 8(7): 1063–72
Butler J, Emerman C, Peacock WF, et al. The efficacy and safety of B-type natriuretic peptide (nesiritide) in patients with renal insufficiency and acutely decompensated congestive heart failure. Nephrol Dial Transplant 2004; 19(2): 391–9
Yancy CW, Singh A. Potential applications of outpatient nesiritide infusions in patients with advanced heart failure and concomitant renal insufficiency (from the Follow-Up Serial Infusions of Nesiritide [FUSION I] trial). Am J Cardiol 2006; 98(2): 226–9
Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern? Arch Intern Med 2000; 160(5): 685–93
Palmer BF. Impaired renal autoregulation: implications for the genesis of hypertension and hypertension-induced renal injury. Am J Med Sci 2001; 321(6): 388–400
K/DOQI clinical practice guidelines on hypertension and antihypertensive agents in chronic kidney disease. Am J Kidney Dis 2004; 43 (5 Suppl. 1): S1–290
Abraham WT. Nesiritide and mortality risk: individual and pooled analyses of randomized controlled clinical trials. Rev Cardiovasc Med 2005; 6(2): 130
Peacock WF, Holland R, Gyarmathy R, et al. Observation unit treatment of heart failure with nesiritide: results from the PROACTION trial. J Emerg Med 2005; 29(3): 243–52
Velebit V, Podrid P, Lown B, et al. Aggravation and provocation of ventricular arrhythmias by antiarrhythmic drugs. Circulation 1982; 65(5): 886–94
The CAPS Investigators. The Cardiac Arrhythmia Pilot Study. Am J Cardiol 1986; 57(1): 91–5
Peacock IV WF, Emerman CL, et al. Nesiritide added to standard care favorably reduces systolic blood pressure compared with standard care alone in patients with acute decompensated heart failure. Am J Emerg Med 2005; 23(3): 327–31
Peacock WF. Initial results from the PROACTION study. J Emerg Med 2006; 31(4): 435–6
Butler J, Forman DE, Abraham WT, et al. Relationship between heart failure treatment and development of worsening renal function among hospitalized patients. Am Heart J 2004; 147(2): 331–8
Epstein BJ. Elevations in serum creatinine concentration: concerning or reassuring? Pharmacotherapy 2004; 24(5): 697–702
Palmer BF. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: what to do if the serum creatinine and/or serum potassium concentration rises. Nephrol Dial Transplant 2003; 18(10): 1973–5
Burger AJ. Risk of death with nesiritide [letter]. JAMA 2005; 294(8): 897
Heywood JT. Temporal characteristics of serum creatinine elevations in patients receiving nesiritide and nitroglycerin [abstract 255] [online]. Available from URL: http://www.hfsa.org [Accessed 2007 Jan 23]
Elkayam U. Nesiritide may diminish the increased acute mortality risk associated with worsening renal function [abstract 3168]. Circulation 2005; 112 (17 Suppl. II): 675–6
Sackner-Bernstein JD, Kowalski M, Fox M, et al. Short-term risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials. JAMA 2005; 293(15): 1900–5
Gortney JS, Porter KB. Risk of death with nesiritide. JAMA 2005; 294(8): 897–8
Abraham WT. Nesiritide does not increase 30-day or 6-month mortality risk [abstract 3169]. Circulation 2005; 112 (17 Suppl. II): II-676
Abraham WT. Effect of baseline covariates on mortality risk in the vasodilation in the management of acute congestive heart failure (VMAC) trial [abstract 2790]. Circulation 2005; 112 (17 Suppl. II): 589
Aaronson KD, Sackner-Bernstein J. Risk of death associated with nesiritide in patients with acutely decompensated heart failure. JAMA 2006; 296(12): 1465–6
Knox MA, Dancy T, Mook W, et al. Intravenous nesiritide in acute heart failure. Am J Ther 2005; 12(3): 233–7
Yancy CW. Treatment with B-type natriuretic peptide for chronic decompensated heart failure: insights learned for the Follow-up Serial Infusion of Nesiritide (FUSION) trial. Heart Fail Rev 2005; 9: 209–16
Panel of cardiology experts provides recommendations to Scios regarding Natrecor® [press release] [online]. Available from URL: http://www.sciosinc.com/scios/pr_1118721302 [Accessed 2007 Jan 23]
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This work was supported, in part, by an unrestricted educational grant from Scios Inc. No other sources of funding were used to assist in the preparation of this review. Editorial assistance from i3CME is acknowledged. The author has received research support and honoraria from Scios Inc., and has acted as a consultant to this company.
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Yancy, C.W. Benefit-Risk Assessment of Nesiritide in the Treatment of Acute Decompensated Heart Failure. Drug-Safety 30, 765–781 (2007). https://doi.org/10.2165/00002018-200730090-00004
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DOI: https://doi.org/10.2165/00002018-200730090-00004