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Three Part Question

In [patients with acute heart failure] does treatment with [nesiritide] improve [outcome] compared to standard therapy?

Clinical Scenario

A 75 y/o gentleman presents at 5am with a 2h history of sudden onset of shortness of breath. It is difficult to obtain a clear history as the patient is too breathless to speak. He is tachypnoeic, tachycardic, cold, clammy and is sweating profusely. Chest auscultation and CXR are consistent with pulmonary oedema and you start treatment for this, giving high flow oxygen, diuretics and a GTN infusion. The patient improves vastly over the next 30 minutes. You have heard of a new treatment for heart failure called nesiritide and wonder if it would have been useful in this situation.

Search Strategy

Medline through OVID interface 1966 to Week 1 April 2006.
Cochrane database searched under heart failure, natrecor, nesiritide and bnp.
[exp Heart Failure, Congestive/ OR exp Atrial Natriuretic Factor/ or heart failure.mp. OR congestive cardiac failure.mp. OR ccf.mp. OR exp Ventricular Dysfunction, Left/ or lvf.mp. OR exp Dyspnea/ OR exp Echocardiography/ OR acute dyspnoea.mp. OR exp Natriuretic Peptide, Brain/ OR cardiac insufficiency.mp. OR failing heart.mp.OR left ventricular failure.mp. OR exp Pulmonary Edema/ OR pulmonary oedema.mp.] AND [nesiritide.mp. OR natrecor.mp. OR exp Natriuretic Peptide, Brain/ ] LIMIT to humans and English language and "all adult (19 plus years)") LIMIT to randomized controlled trial

Search Outcome

146 papers of which 8 were relevant. Some papers were discarded if they used subgroups from studies already listed.
A protocol for a Cochrane review exists but has not been completed at this time.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Yoshimura, M; Morita, E; Sakaino, N; et al 1991 Japan	7 patients with clinical heart failure (NYHA II, III or IV) and 8 control patients. Control group consisted of patients who had undergone investigation for chest pain but were found not to have cardiac disease. Of the heart failure patients 5 had dilated cardiomyopathy, 1 had previous MI and 1 had mitral regurgitation.	The patients all underwent invasive monitoring and were given a 30 minute infusion of nesiritide at the rate of 1µg/kg/min	Change in mean arterial pressure	No significant change in the heart failure patients, decreased from 87±6 mmHg to 79±6 mmHg (P<0.05) in the control group.	Small study measuring physiological parameters rather than clinical outcomes. Control patients not representative of population at large, heart failure patients treated electively and not typical of those that present as an emergency
			Change in pulmonary capillary wedge pressure.	Decreased from 21±3 to 14±4mmHg in the heart failure group (P<0.05) and decreased from 5±1 to 2±1mmHg (P<0.01) in the control group.
			Change in cardiac index	Increased from 2.4±0.2 to 3.2±0.3l/min/sq.m (P<0.05) and in the control group it increased from 3.4±0.2 to 4.3±0.3l/min/sq.m.(P<0.01).
Hobbs, RE; et al 1996 USA	27 patients with heart failure- 14 had ischaemic cardiomyopathy and 13 had idiopathic dilated cardiomyopathy. Patients with systolic BP <85mmHg or PCWP<16mmHg were excluded.	21 patients received either 0.3, 1.0, 3.0, 10, 15 or 20µg/kg intravenous injection of nesiritide and 6 patients received placebo. Not clear from text how many patients received each dose, 4 patients received 20µg/kg and 6 patients received 10 or 15µg/kg doses. Monitored for 4h.	Decrease in PCWP	In the group receiving 10 or 15 µg/kg there was a decrease of 71%, P<0.001.	Little demographic data provided and limited data available of results. Results mainly provided in graph form, in the data that is provided the patients have been grouped together to provide significant results. No clinical outcomes provided.
			Change in mean arterial pressure	Decreased by 28% in the group receiving 10 or 15µg/kg (P=0.001)
			Change in cardiac index	Increased by 28% in the group receiving 10 or 15µg/kg (p=0.001)
			Adverse events	No adverse events noted, specifically no symptomatic hypotension or reflex tachycardia
Marcus, L; Hart, D; Packer, M; et al 1996 USA	20 patients with heart failure diagnosed at least 2 months previously, (NHYA II-IV). All patients underwent right heart catheterisation for monitoring.	Randomised, double-blind cross-over study. Patients received a 6h infusion of either placebo or nesiritide and then received the alternative drug on the following day. The nesiritide infusion consisted of 4 consecutive 90 minute infusions of 0.003, 0.01, 0.03 and 0.1µg/kg/minute. The study protocol was altered after the 14th patient had an episode of prolonged hypotension after receiving the highest dose and the 6 remaining patients did not receive the highest dose. 2 other patients did not receive the higher doses due to symptomatic hypotension. The 14th patient who had prolonged hypotension withdrew from the study and the data was not included in the analysis. Data analysed at highest completed dose.	Change in mean pulmonary artery pressure	Decreased by 32% (P<0.01)	Small study in stable patients. Does not examine clinical outcomes.
			Change in pulmonary capillary wedge pressure.	Decreased by 47% (P<0.01)
			Change in mean arterial pressure	Decreased by 12% (P<0.01)
			Adverse events	6 patients had symptomatic hypotension. 3 responded to normal saline infusion, 2 recovered on stopping the infusion and 1 patient required normal saline and a dopamine infusion for 6h after cessation of the infusion.
Abraham, W; Lowes, B; Ferguson, D; et al 1998 USA	16 patients with Class III NYHA heart failure. The patients are described as clinically decompensated but all of the patients had their heart failure medications withdrawn at least one day before the study. All of the patients had a pulmonary artery catheter inserted for monitoring. 1 patient developed staphylococcal septicaemia and was withdrawn from the study. 1 patient developed symptomatic hypotension which responded to discontinuing the infusion and replacement of fluids. This patient completed the study but was not included in the analyses.	Randomised, double-blind, placebo-controlled, ascending dose trial. Patients randomised in groups of 8 so that 6 received nesiritide and 2 received placebo. The first 6 patients receiving nesiritide were given an infusion of 0.025µg/kg/min, the second 6 patients received 0.05µg/kg/min. The patients were observed for 4h, received the infusion for 4h and then were observed for a further 4h.	Change in mean arterial pressure	Unchanged in the placebo group, decreased from 88±4 to 73±4mmHg in the treatment group (P<0.001).	Small study. Little demographic data provided. No information on clinical outcomes.
			Change in PCWP	Decreased by 40% in the treatment group, (P<0.01).
Mills, R; LeJemtel, T; Horton, D; et al 1999 USA	103 patients with heart failure (NYHA class II-IV) were recruited from 16 study sites. Patients had their normal cardiac medications stopped at least 12h before commencing with the study. 5 patients in the placebo group did not complete the study due to worsening heart failure, 1 patient in the treatment group withdrew due to worsening heart failure, 4 withdrew due to hypotension and 4 withdrew due to decreased PCWP.	Patients were randomised to one of 4 groups. Group 1 received a placebo bolus followed by a placebo infusion. Group 2 received a bolus of 0.25µg/kg nesiritide followed by an 0.015µg/kg/min infusion. Group 3 received a bolus of 0.5µg/kg followed by an infusion of 0.03µg/kg/min. Group 4 received a bolus of 1mg/kg followed by an infusion of 0.06µg/kg/min. Infusion continued for 24h and the patient had observations continued for a further 4h. In the event of hypotension, defined as a systolic BP<85mmHg or a PCWP <10mmHg, the infusion rate was to be halved.	Change from baseline PCWP at 24h	The decreases in PCWP were 1.8±6.4, 8.3±6.4, 3.7±6.4 and 8.4±6.4mmHg in the placebo group and each of the respective treatment groups (P<0.05 for all groups).	No assessment of clinical symptoms or outcome.
			Change in cardiac index at 24h	The increases in CI were 0.1±0.3, 0.2±0.5*, 0.0±0.7 and 0.4±0.4* l/min/sq.m in the placebo group and each of the treatment groups (in groups marked * P<0.05).
			Reduction in dose due to low PCWP	0(0%), 4(18%),7(27%) and 9(35%) in the placebo and nesiritide groups respectively
			Reduction in dose due to low BP	1(3%), 1(5%), 1(4%) and 3(12%) of placebo and nesiritide groups respectively.
Colucci, W; Elkayam, U; Horton, D; et al 2000 USA	432 patients who required hospitalisation and intravenous therapy for decompensated heart failure were recruited from 66 centres. Patients were recruited into one of two separate trials. The first trial was a double-blind, placebo-controlled trial examining the short-term efficacy of nesiritide. The second trial compared nesiritide with standard intravenous agents. The majority of centres only recruited into one or the other trial, 3 centres recruited patients for both trials and it is not clear how it was decided which trial patients entered. In the first trial patients were required to have a Swan-Ganz pulmonary artery catheter in place. Patients were required to stop dopamine, dobutamine or intravenous vasodilators at least 30 minutes before beginning the study.	Trial 1: patients were randomised in blocks of 12 to receive placebo as an intravenous bolus and then an infusion, nesiritide as 0.3µg/kg bolus then 0.015µg/kg/min infusion or nesiritide as a 0.6µg/kg bolus and then 0.03µg/kg/min infusion. The infusion was continued for at least 6h and the patient oral vasoactive drugs and intravenous diuretics were withheld from 4h before starting the trial until after the 6h period. Trial 2: Patients were randomly assigned to "standard therapy" ( a single intravenous vasoactive agent decided by the attending physician), nesiritide given as a 0.3µg/kg bolus then a 0.015µg/kg/min infusion or nesiritide as a 0.6µg/kg bolus followed by a 0.03µg/kg/min infusion. At the discretion of the investigator the doses of all medications could be increased and a second intravenous vasoactive agent could be added to or substituted for the first drug. Intravenous diuretics and oral medications could be added at any time.	Change in PCWP in trial 1	Placebo +2.0±7.2mmHg, Low dose -6.0±7.2mmHg, high dose -9.6±6.2mmHg, P<0.001	Two separate trials are combined in this paper with the data from both trials often provided in the same table or diagram. It is not clear how it was decided which trial some of these patients would be recruited into. 57% of patients in the "standard therapy" group received dobutamine as the single intravenous vasoactive agent while only 18% of patients received nitroglycerin. There is no data provided regarding any additional drugs that these patients received apart from the statement that patients in the nesiritide groups received significantly less diuretics than patients in the "standard therapy" group.
			Change in cardiac index in trial 1	Placebo -0.1±0.47, low dose +0.2±0.49, high dose +0.4±0.69 l/min/sq.m, P<0.001.
			Global clinical status in trial 2 - judged by patient and investigator	All patients felt to have improved at 6h, 24h and on finishing therapy. No significant difference between the groups at any time.
			Symptomatic hypotension in trial 2	Standard therapy 4%, low dose 11%, high dose 17%, P=0.008.
Publication Committee for the VMAC Investigators 2002 USA	Multicentre trial involving 498 patients with decompensated heart failure.	Patients were stratified according to the attending physician's decision as to whether or not the patient required a right heart catheter. Non-catheterised patients were randomised to placebo, nitroglycerin that could be titrated or fixed dose nesiritide for the first 3h. Catheterised patients were randomised to these three choices plus the option of adjustable dose nesiritide. After 3h the patients receiving placebo in both groups were randomised again to receive either titratable nitroglycerin or fixed dose nesiritide in a double-blind fashion. All patients received at least 24h treatment.	Change in PCWP at 3h	Placebo -2±4.2, nitroglycerin -3.8±5.3, nesiritide -5.8±6.5mmHg. P<0.05 for nesiritide against placebo or nitroglycerin.	Protocol allowed down-titration of nesiritide/placebo infusion at any point, no information provided as to whether or not this occurred. Table 4 provides information on the adverse events within 24h but only provides data on 143 of 146 patients in the nitroglycerin group who had an adverse event and 99 of the 140 patients in the nesiritide group who had an adverse event. Although the dose of nitroglycerin could be increased at the investigator's discretion the dose received by patients in the non-catheterised group remained low (~1.7mg/h) while it was titrated up to ~3.3mg/h in patients with a catheter.
			Change in cardiac index at 3h	Placebo 0.0±0.6, nitroglycerin +0.2±0.5, nesiritide 0.1±0.5 l/min/sq.m. Not significant.
			Pt's assessment of dyspnoea (7 point scale from markedly worsened to markedly improved)	At 3h nesiritide group showed significant improvement compared to placebo group (P=0.03) but no significant difference compared to the nitroglycerin group.
			Pt's assessment of dyspnoea at 24h	No significant difference between nesiritide and nitroglycerin groups
			7 day mortality rates	1 death in nitroglycerin group (0.5%) and 4 deaths in nesiritide group (1.5%). No death attributed to study drug.
			6 month mortality rates	Nitroglycerin group 20.8%, nesiritide group 25.1%, not statistically significant.
Peacock, W; Holland, R; Gyarmathy, R; et al 2005 USA	Multicentre trial recruited 250 patients with a history consistent with acute decompensated heart failure who were felt to require at least 12h of intravenous therapy. Patients were excluded if "their condition was estimated to prohibit discharge from the ED or observation unit in less than 24h." (Peacock et al, AJEM 2005). Patients were excluded if it was felt that the patient would require intravenous vasodilators within 3h. 237 patients received the appropriate drugs and were analysed.	Recruited patients were randomised to receive either "standard therapy" plus placebo or "standard therapy" and nesiritide. "Standard therapy" was at the investigator's discretion but included diuretics, oxygen and one or more agents to decrease systemic vascular resistance and increase cardiac contractility. Intravenous nitroglycerin was not used "due to the requirement for frequent monitoring and dose adjustment."	Termination of study due to adverse events	Nesiritide group 12%, placebo group 4%, P=0.036	The "standard care" group excluded the use of intravenous nitrates. Not clear how it was decided which patients would require 12h of intravenous therapy but not require admission after 24h.
			Termination of study due to inadequate response	Nesiritide group 12%, placebo group 15%, P=0.513.
			Patients requiring admission to hospital from ED observation unit	49% nesiritide group, 55% placebo group, P=0.436.
			Mean length of stay in hospital	5.5 +/- 4.9 days, placebo group 5.1+/- 5.0 days, P=0.6178.
			Change in dyspnoea score (7 point scale from markedly worse to markedly improved)	Both groups had a mean improvement of 2 points at 12h.
			30 day mortality rate	5 patients in the nesiritide group had died, 1 patient in the placebo group had died.

Comment(s)

Nesiritide (tradename Natrecor) is a human form of B-type natriuretic peptide. This peptide is mainly produced by myocytes in the cardiac ventricles in response to stretch and higher levels are present in people with heart failure. It acts as a potent vasodilator, causes a diuresis and natriuresis and has an inhibitory effect on the renin-angiotensin system. There are obvious theoretical benefits to the administration of this drug in patients with decompensated heart failure and there is also an obvious response in terms of haemodynamic parameters. This treatment has been licensed for use in patients with decompensated heart failure in the USA by the FDA since 2001. None of the studies listed show any definite benefit of neseritide over nitroglycerin in the treatment of heart failure in terms of death or hospitalisation. Two studies that have pooled available data suggest that there may be an increase in mortality associated with nesiritide vs. placebo (Sackner-Bernstein et al, JAMA, 2005) and that there may be a risk of worsening renal function in patients treated with this (Sackner-Bernstein et al, Circulation, 2005). The European Agency for Evaluation of Medicinal Products has still not given approval for nesiritide (Topol, NEJM, 2005).

Clinical Bottom Line

There is no evidence of increased benefit in terms of clinical outcome and survival in acute decompensated heart failure using nesiritide over standard therapy including intravenous nitrates. There is a suggestion that the use of nesiritide may worsen outcome in terms of mortality and renal impairment.

Level of Evidence

Level 2 - Studies considered were neither 1 or 3.

References

1. Yoshimura, M; Morita, E; Sakaino, N; et al Hemodynamic, renal and hormonal responses to brain natriuretic peptide infusion in patients with congestive heart failure Circulation 1991; 84 p 1581-1588
2. Hobbs, R; Miller, L; Bott-Silverman, C; et al Hemodynamic Effects of a Single Intravenous Injection of Synthetic Human Brain Natriuretic Peptide in Patients With Heart Failure Secondary to Ischemic or Idiopathic Dilated Cardiomyopathy American Journal of Cardiology 1996; (78) p896-901
3. Marus, L; 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, randomised cross-over trial. Circulation 1996; (94) p3184-9
4. Abraham, W; Lowes, B; Ferguson, D; 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 Journal of Cardiac Failure 1998; 4(1) p37-44
5. Mills, R; LeJemtel, T; Horton, D; et al Sustained hemodynamic effects of an infusion of nesiritide (human b-type natriuretic peptide) in heart failure: a randomized, double-blind, placebo-controlled clinical trial. Natrecor Study Group. Journal of the American College of Cardiology 1999; 34(1) p155-62
6. Colucci, W; Elkayam, U; Horton, D; et al Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. Nesiritide Study Group. New England Journal of Medicine 2000; 343(4) p246-53
7. 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) p1531-40
8. Peacock, W; Holland, R; Gyarmathy, R; et al Observation Unit Treatment of Heart Failure with Nesiritide: Results from the PROACTION Trial The Journal of Emergency Medicine 2005; 29(3) p243-252
9. Peacock,W; Emerman, C; Silver, M; et al Nesiritide added to standard care favorably reduces systolic blood pressure compared with standard care alone in patients with acute decompensated heart failure American Journal of Emergency Medicine 2005; (23) 327-331
10. Topol, E Nesiritide - Not Verified NEJM 2005; 353(2) p113-116
11. Sackner-Bernstein J; Kowalkski, M; Fox, M, Aaronson, K Short-term risk of death after treatment with nesiritide for decompensated heart failure. JAMA 2005; (293) 1900-5
12. Sackner-Bernstein, J; Skopicki, H; Aaronson, K Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation 2005; (111) p1487-91