Dr Amelia Carro Hevia, Medical Director, Instituto Corvilud, Spain

Heart failure (HF) is a major public health problem with increasing incidence1,2. Current goals of treatment include symptom relief, reducing hospital admission, and prolonging life. Pharmacological agents, devices, heart transplantation and lifestyle changes are currently the main strategies used for management.

Angiotensin converting-enzyme inhibitors (ACEI) have been shown to be beneficial in large trials, i.e. CONSENSUS3, SOLVD-Treatment4, and V-HeFT II5. These drugs have been shown to reduce hospitalizations with HF. The Val-HeFT trial5 suggested that angiotensin-receptor blockers (ARB) can be also useful for HF therapy, particularly as an alternative to ACEI.

As chronic activation of the sympathetic nervous system has a key role in HF progression and events, beta blockers (BB) were used and found to be of therapeutic value. Mortality benefit was documented for three BB (bisoprolol, carvedilol, and extended-release metoprolol) in patients with stable systolic HF across a broad range of disease severities6-10. Currently ACEI and BB represent the cornerstone of HF treatment.

More recently, the mineralocorticoid-receptor antagonist (MRA) spironolactone, yielded clear-cut survival benefits, which were additional to those of ACEI, in patients with advanced disease (class III or IV systolic HF) (RALES trial)11.  Trials testing the MRA eplerenone confirmed and extended this finding in individuals with systolic HF early after myocardial infarction (EPHESUS)12 and those with systolic HF and mild symptoms (EMPHASIS-HF trial)13.

Cardiac glycosides are inotropic agents and one of the oldest therapies for HF. The DIG trial14 however showed unequivocally that digoxin has no beneficial effect on mortality in HF but reduces hospitalization for HF by 28%. Cardiac glycosides are no longer first line therapy, but can be used to mitigate symptoms and reduce HF hospitalizations.

Nesiritide, a recombinant B-type natriuretic peptide with vasodilator properties, was shown to reduce dyspnoea when added to conventional treatment for HF. However, the ASCEND-HF trial15 demonstrated no benefit of nesiritide on the coprimary end point of death or rehospitalization with HF and no significant improvement in dyspnoea.

Cardio Debate expert, Dr X Garcia-Moll, and Dr Robin Ray, Consultant Cardiologist and HF specialist, have been asked to comment on the role of nesiritide in the management of HF, if any.

Cardio Debate Expert Comments

Nesiritide (human BNP) is a vasodilator agent that reduces left ventricular (LV) filling pressure but has variable effects on cardiac output, urinary output, and sodium excretion. An initial study in patients with acute decompensated (AD) heart failure (HF) (1) reported that nesiritide, added to standard treatment, reduced the severity of dyspnea more rapidly, compared with diuretics.  The VMAC study (Vasodilation in the Management of Acute Congestive Heart Failure) later on established the superiority of nesiritide over placebo or nitroglycerin to reduce pulmonary capillary wedge pressure and dyspnea in patients with ADHF. (2) Of interest, VMAC study was the basis for the FDA to approve the use of nesiritide for treatment of ADHF.

There has been controversy regarding the effect of nesiritide in patients with HF, as after the publication of VMAC (2), two meta-analyses suggested that nesiritide was associated with a higher risk of death (3) and also with the possibility of worsening renal function, respectively. (4) Later meta-analyses, however, reported no increase in the risk of immediate or delayed mortality or worsening of renal function with the use of nesiritide. (5) The ADHERE registry reported similar results. (6) An opinion paper in 2008 stated that several issues issues with nesiritide required consideration such as appropriate dosing, i.e. low doses appeared not to have a hypotensive effect and would therefore be ‘renoprotective’, and identifying which patients would truly benefit from nesiritide. (7) The first study to assess clinical endpoints in patients receiving nesiritide was the ASCEND-HF trial. (8) This large randomized trial in 7141 patients hospitalized with ADHF showed that nesiritide had no impact on mortality, rehospitalization or renal function. The rate of rehospitalization for HF or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (p=ns). Rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate, were higher (although not statistically different) in the nesiritide group (31.4% vs. 29.5%). There was a small but statistically significant impact on dyspnea, and an increased risk of hypotension. Interestingly. The authors in ASCEND-HF did not recommend a broad use of nesiritide in HF. From a clinical perspective, it has to be taken into account that nesiritide has a longer half life than intravenous sodium nitroprusside and nitroglycerine, and this may result in its main secondary effect, hypotension, to persist longer. All in all there has been no convincing beneficial effect on prognosis, and the use of this agent is mainly limited to the relief of dyspnea in the hospitalized HF patient with normal blood pressure.

More recently, since publication of the pivotal paper ASCEND-HF there have been 42 publications of the study trying to redefine the role of nesiritide. Some of them have focused on renal function, showing that nesiritide did not increase urine output in patients with ADHF(9), although baseline, discharge, and change in renal function were associated with 30-day mortality or rehospitalization for heart failure. (9,10) A recent review paper concluded that most of the novel agents failed to show promise for treatment of acute HF. (11)

The ROSE-AHF trial, (12) a multicenter double-blind, placebo-controlled clinical trial that randomized 360 hospitalized patients with acute HF and renal dysfunction (estimated glomerular filtration rate, 15-60 mL/min/1.73m2) assessed whether the addition of low-dose dopamine (2 μg/kg/min) or low-dose nesiritide (0.005 μg/kg/min without bolus) to diuretic therapy would enhance decongestion and preserve renal function in these patients. All patients were randomized within 24 hours of admission.  Patients were allocated 1:1 to dopamine or nesiritide strategies, and within each strategy they were randomized to placebo or active treatment. The outcomes were non- clinical, and included 72-hour cumulative urine volume and change in serum cystatin C from enrollment to 72 hours. Of interest, neither low-dose dopamine administration nor low-dose nesiritide treatment had significant effects on either of these endpoints. Nesiritide, however, had better results among patients with low ejection fraction (<50%), albeit the interaction was not statistically significant when compared with patients with preserved ejection fraction. This result conflicts with a recent report where the long term administration of nesiritide improved diastolic function without tachyphylaxis in patients with preclinical diastolic dysfunction. (13)

Finally, a meta-analysis published last year, where fifteen randomized controlled trials in patients with ADHF were included, showed that treatment with nesiritide was associated with increased risk of worsening renal function, mainly in patients treated with high dose nesiritide. The groups receiving treatment with a standard dose or a low dose had no difference with placebo. The conclusion of this study was that nesiritide may have a dose-dependent effect on renal function in patients with ADHF. (14)

It is of some concern that clinical outcome studies with this agent have taken so long to be performed. The way nesiritide has been assessed over the years highlights the importance of clinical outcomes trials for drug approval in the clinical setting. All in all, nesiritide is currently not recommended for HF treatment in the European Guidelines on the management of Heart Failure and it is not available in Europe (15). The drug currently has a IIB- A recommendation in the AHA/ACC guidelines for the management of heart failure. (16)

References:

  1. Colucci WS, Elkayam U, Horton DP, et al., Nesiritide Study Group. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. N Engl J Med 2000;343:246–53. Errata in: N Engl J Med 2000;343:1504 and N Engl J Med 2000;343:896
  2. Publication Committee for the VMAC Investigators. Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA. 2002;287:1531–1540. Erratum in: JAMA 2002;288:577
  3. Sackner-Bernstein JD, Kowalski M, Fox M, Aaronson K. Short-term risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials. JAMA. 2005;293:1900–1905
  4. Sackner-Bernstein JD, Skopicki HA, Aaronson KD. Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation 2005;111:1487–1491
  5. Arora RR, Venkatesh PK, Molnar J. Short and long-term mortality with nesiritide. Am Heart J. 2006;152:1084 –1090
  6. Abraham WT, Adams KF, Fonarow GC, Costanzo MR, Berkowitz RL, LeJemtel TH, Cheng ML, Wynne J. In-hospital mortality in patients with acute decompensated heart failure requiring intravenous vasoactive medications: an analysis from the Acute Decompensated Heart Failure National Registry (ADHERE). J Am Coll Cardiol. 2005;46:57– 64
  7. Burnett JC, Korinek J. The Tumultuous Journey of Nesiritide: Past, Present, and Future. Circ Heart Fail 2008;1:6-8
  8. O’Connor CM, Starling RC, Hernandez AF, Armstrong PW, Dickstein K, Hasselblad V, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med 2011;365:32–43
  9. Gottlieb SS, Stebbins A, Voors AA, Hasselblad V, Ezekowitz JA, Califf RM, O’Connor CM, Starling RC, Hernandez AF. Effects of Nesiritide and Predictors of Urine Output in Acute Decompensated Heart Failure Results From ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure). J Am Coll Cardiol 2013;62:1177–83
  10. van Deursen VM, Hernandez AF, Stebbins A, Hasselblad V, Ezekowitz JA, Califf RM, Gottlieb SS, O’Connor CM, Starling RC, Tang WHW, McMurray JJ, Dickstein K, Voors AA. Nesiritide, Renal Function, and Associated Outcomes During Hospitalization for Acute Decompensated Heart Failure Results From the Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure (ASCEND-HF). Circulation. 2014;130:958-965
  11. Ertl G, Ruschitzka F. The Year in Cardiology 2013: heart failure. Eur Heart J 2014;35:470–473
  12. Chen HH, Anstrom KJ, Givertz MM, Stevenson LW, Semigran MJ, Goldsmith SR, et al, for the NHLBI Heart Failure Clinical Research Network. Low-Dose Dopamine or Low-Dose Nesiritide in Acute Heart Failure With Renal Dysfunction The ROSE Acute Heart Failure Randomized Trial. JAMA 2013;doi:10.1001/jama.2013.282190
  13. Wan SH, McKie PM, Schirger JA, Slusser JP, Hodge DO, Redfield MM, Burnett JR JC,, Chen HH. Chronic Peptide Therapy With B-Type Natriuretic Peptide in Patients With Preclinical Diastolic Dysfunction (Stage B Heart Failure). JACC: Heart Failure 2016; org/10.1016/j.jchf.2015.12.014
  14. Xiong B, Wang C, Yao Y, Huang Y, Tan J, Cao Y, et al. The Dose-Dependent Effect of Nesiritide on Renal Function in Patients with Acute Decompensated Heart Failure: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. PLoS ONE 2015;10(6): e0131326. doi:10.1371/journal.pone.0131326
  15. McMurray JJV, Adamopoulos S, Anker SD, Auricchio A, Böhm M, Dickstein K, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012. European Heart Journal 2012:33, 1787–1847
  16. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;62:e147–239

Acute heart failure (AHF) is the leading cause of hospital admission in people 65 years and older in the UK. After diuretic therapy, vasodilators are the most common intravenous treatment for AHF, however, there remains no robust evidence to demonstrate that they impart any meaningful effects on clinical outcomes other than early symptom relief. Nesiritide is an intravenous recombinant form of human BNP which functions as a balanced arterial and venous vasodilator and was approved by the Federal Drug Administration (FDA) for the management of AHF in 2001 following the multicentre Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) trial (1,2). Nesiritide was noted to acutely reduce pulmonary capillary wedge pressure and some self-reported symptoms such as dyspnoea in patients with ADHF compared to intravenous nitroglycerin.

However, in the ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide and Decompensated Heart Failure) trial, which randomised 7141 patients with AHF to nesiritide or placebo, nesiritide yielded only a modest improvement in dyspnoea with no reduction in either re-hospitalisation or death (3). In addition, there was no benefit in renal function but a significant increase in the rate of asymptomatic and symptomatic hypotension effecting about one quarter of patients. Nesiritide has a longer half-life than other vasodilators such as nitroglycerin, so side-effects such as hypotension persist for longer. As such, the evidence to date does not support the routine use of nesirtide in patients admitted with ADHF. There may very well be more promise in alternative novel vasodilators such as serelaxin or the natriuretic peptides, such as ularitide, the former of which has demonstrated favourable outcomes in preliminary studies with the results of larger trials awaited (4).

References

  1. Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. Publication Committee for the VMAC Investigators (Vasodilatation in the Management of Acute CHF). JAMA.2002;287:1531.
  2. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. Nesiritide Study Group. Colucci WS, Elkayam U, Horton DP et al. N Engl J Med. 2000;343(4):246.
  3. Effect of nesiritide in patients with acute decompensated heart failure. O'Connor CM, Starling RC, Hernandez AF et al. N Engl J Med. 2011;365(1):32.
  4. Serelaxin, recombinant human relaxin-2, for treatment of acute heart failure (RELAX-AHF): a randomised, placebo-controlled trial. Teerlink JR, Cotter G, Davison BA et al. Lancet. 2013 Jan;381(9860):29-39. 2012 Nov 7.