Peptide education
Nesiritide
Natrecor · Recombinant human B-type natriuretic peptide · rhBNP
Nesiritide is a laboratory-produced version of B-type natriuretic peptide, a hormone made by the heart. The former US product Natrecor was an intravenous medicine for patients hospitalized with acute heart failure and shortness of breath at rest or with little activity. FDA withdrew Natrecor's approval after its manufacturer stopped marketing it.
In ASCEND-HF, 9.4% of patients receiving nesiritide and 10.1% receiving placebo died or were rehospitalized for heart failure within 30 days, a difference that was not statistically significant. Hypotension was more frequent with nesiritide.
Overview
Quick answer
Lower heart-filling pressure is not the same outcome as living longer or avoiding another hospitalization. VMAC measured early pressure and breathing changes; the larger ASCEND-HF trial also measured death and rehospitalization.
What is nesiritide?
It is a recombinant form of human B-type natriuretic peptide. It relaxes blood vessels and can lower the pressure at which blood fills the heart.
What was Natrecor used for?
Its former US label covered acutely decompensated heart failure with shortness of breath at rest or with minimal activity. It was given intravenously in a setting where blood pressure could be monitored.
Is Natrecor still approved in the United States?
FDA withdrew Natrecor's approval after the applicant reported that it was no longer marketed. FDA later determined that the product had not been withdrawn from sale for safety or effectiveness reasons.
Did it improve survival or prevent rehospitalization?
ASCEND-HF did not find a statistically significant difference in the combined 30-day outcome of death or heart-failure rehospitalization. Small differences in breathing scores also did not meet the trial's prespecified significance threshold.
What were the main risks?
Low blood pressure could be symptomatic or prolonged. The historical label also warned about worsening kidney function and serious hypersensitivity, and listed cardiogenic shock and persistently low systolic blood pressure as contraindications.
Evidence
Evidence snapshot
Natrecor was no longer marketed when its applicant requested withdrawal of the approval. FDA separately found it was not withdrawn from sale for safety or effectiveness reasons.
Among 7,141 randomized patients, death or heart-failure rehospitalization occurred in 9.4% on nesiritide and 10.1% on placebo. The prespecified dyspnea significance threshold was not met.
At 3 hours, mean pulmonary capillary wedge pressure fell by 5.8 mm Hg with nesiritide, 3.8 with nitroglycerin and 2.0 with placebo. Breathing improvement differed from placebo but not significantly from nitroglycerin.
The historical label reports symptomatic hypotension in 7.1% of nesiritide-treated patients versus 4.0% of placebo patients in ASCEND-HF.
Claims
Common claims vs evidence
| Claim | Human evidence | Mechanistic evidence | Verdict |
|---|---|---|---|
| Nesiritide lowers cardiac filling pressure in acute heart failure. | VMAC found a larger fall in pulmonary capillary wedge pressure at 3 hours with nesiritide than with either placebo or nitroglycerin in the study comparison. | Natriuretic peptide receptor signaling increases cyclic GMP and relaxes blood vessels. | Supported for the measured short-term hemodynamic endpoint. This result does not by itself establish better survival or fewer hospitalizations. |
| Nesiritide prevents death or repeat hospitalization. | ASCEND-HF compared nesiritide with placebo alongside standard care and found no significant difference in the combined 30-day outcome. | The large trial did not demonstrate that benefit in the studied population. | |
| Natrecor remains an approved US product. | The historical label documents its former indication. FDA later withdrew the product application after the applicant reported that it was no longer marketed. | The Natrecor approval was withdrawn. FDA's later sale determination said the withdrawal from sale was not for safety or effectiveness reasons. |
Bottom line
Main takeaway
Nesiritide was a hospital heart-failure medicine. Its former US approval was withdrawn, and a large trial found little evidence of clinical benefit over standard care.
VMAC showed a short-term filling-pressure effect. ASCEND-HF tested more patients and did not meet its prespecified breathing or 30-day composite endpoints.
The dyspnea differences in ASCEND-HF did not cross the prespecified significance threshold. Renal and mortality comparisons should be read with their confidence intervals, alongside the higher hypotension rate.
Identity
What it is
Nesiritide has the same 32-amino-acid sequence as human B-type natriuretic peptide. Natrecor was made using recombinant technology and supplied for intravenous administration.
The hormone pathway relaxes arteries and veins. VMAC measured a reduction in heart-filling pressure, while ASCEND-HF assessed whether adding nesiritide to standard hospital care changed breathing, death or rehospitalization outcomes.
Use context
Routes, doses, and cycle patterns
Natrecor's historical label described an intravenous bolus followed by a continuous infusion. ASCEND-HF used the same infusion rate, with an optional initial bolus.
Human studies and product labels
Former Natrecor label
- Purpose
- Acute decompensated heart failure with shortness of breath
- Context
- Historical US prescribing information
- Route
- Intravenous bolus followed by continuous infusion
- Amount
- 2 mcg/kg bolus followed by 0.01 mcg/kg/min
- Frequency
- Continuous infusion after the bolus
- Duration
- Adjusted according to hospital monitoring and response
The historical label warned that the bolus might not be appropriate with systolic blood pressure below 110 mm Hg or recent afterload-reducing drugs. This differs from the contraindication for persistent systolic pressure below 100 mm Hg. Natrecor's US approval was subsequently withdrawn.
ASCEND-HF trial
- Purpose
- Dyspnea and death or heart-failure rehospitalization
- Context
- Randomized placebo-controlled study with standard care
- Route
- Continuous intravenous infusion
- Amount
- 0.01 mcg/kg/min, with an optional 2 mcg/kg bolus
- Frequency
- Continuous infusion
- Duration
- 24 to 168 hours when continued for clinical symptoms
The trial used the initial bolus at the treating clinician's discretion. The primary clinical outcomes did not meet the prespecified significance thresholds.
What varies
- Endpoint: pressure changes, perceived breathing and survival or rehospitalization are different outcomes.
- Blood pressure: the historical label contraindicated use with persistent systolic pressure below 100 mm Hg or cardiogenic shock.
Research
Research evidence
VMAC showed lower early cardiac filling pressure and improvement in dyspnea versus placebo. ASCEND-HF was much larger and did not demonstrate a significant benefit for its prespecified dyspnea or 30-day death-or-rehospitalization outcomes. It also found more hypotension with nesiritide.
| Study / evidence area | Population | Design | Product context | Main outcome | Limitations | Weight |
|---|---|---|---|---|---|---|
| VMAC | 489 inpatients with decompensated heart failure and dyspnea at rest | Randomized double-blind trial | Intravenous nesiritide, nitroglycerin or placebo with standard care | At 3 hours, mean wedge pressure fell by 5.8 mm Hg with nesiritide versus 3.8 with nitroglycerin and 2.0 with placebo. Dyspnea improved versus placebo. | The dyspnea comparison with nitroglycerin was not statistically significant. Early pressure changes are not a survival endpoint. | Randomized, short-term outcomes |
| ASCEND-HF | 7,141 randomized patients hospitalized with acute heart failure | Randomized double-blind placebo-controlled trial | Nesiritide or placebo added to standard care | Death or heart-failure rehospitalization by 30 days was 9.4% versus 10.1%. Dyspnea differences did not meet the prespecified significance threshold. | The trial evaluated treatment on top of usual hospital care; its results do not establish the effect of an untested product or setting. | Large randomized trial |
| Natrecor FDA documents | Former US product and patients covered by its label | Historical label and Federal Register notices | Former intravenous Natrecor product | The label specified the former indication and safety warnings. FDA later withdrew the product application after the applicant reported that it was no longer marketed. | FDA's finding that the product was not withdrawn from sale for safety or effectiveness reasons does not remove the adverse effects reported in trials. | Regulatory and safety context |
Use context
Reported use context
ASCEND-HF evaluated an intravenous infusion alongside standard hospital care.
Study and label context
0.01 mcg/kg/min for 24 to 168 hours, with an optional 2 mcg/kg initial bolus.
Hospitalized patients with acute heart failure received standard care in both groups.Cautions
Safety and unknowns
- Hypotension could persist for hours. The historical label reported symptomatic hypotension in 7.1% of treated patients versus 4.0% of placebo patients in ASCEND-HF.
- The historical label warned of worsening renal function and recommended creatinine monitoring. ASCEND-HF found no significant difference in its specified worsening-kidney-function measure.
- The former label listed cardiogenic shock, persistent systolic pressure below 100 mm Hg and known product hypersensitivity as contraindications.
- The historical label said the loading bolus might not be appropriate below 110 mm Hg systolic pressure or after recent afterload-reducing drugs. It also warned that ACE inhibitors, angiotensin receptor blockers and other afterload reducers could increase hypotension risk.
- The former label did not recommend Natrecor when vasodilators were inappropriate, including significant valvular stenosis or cardiac tamponade, or when low cardiac filling pressures were suspected.
Product quality
Product identity and quality
Natrecor was a defined recombinant intravenous product. Its application was withdrawn after the applicant reported that it was no longer marketed.
Product identity
Clinical trial findings apply to the tested intravenous preparation.
Mechanism
How it is proposed to work
Nesiritide activates a natriuretic peptide receptor and raises cyclic GMP, relaxing blood vessels. That can reduce the pressure at which the heart fills.
The vasodilating effect can also lower systemic blood pressure, explaining the emphasis on hypotension in the historical label.
Details
Technical details
Sources
References
- 1.
FDA: historical label. Natrecor historical prescribing information
Historical Natrecor indication, intravenous regimen, blood-pressure thresholds, contraindications and safety warnings; its approval was subsequently withdrawn.
- 2.
FDA: approval withdrawal. FDA withdrawal of approval of Natrecor and other applications
Federal Register notice withdrawing the Natrecor application after the applicant reported that the product was no longer marketed.
- 3.
FDA: sale determination. FDA determination concerning discontinued drug products including Natrecor
FDA determined the listed products, including Natrecor, were not withdrawn from sale for safety or effectiveness reasons.
- 4.
PubMed. Nesiritide in hospitalized patients with acute decompensated heart failure: ASCEND-HF
doi:10.1056/NEJMoa1100171 PMID:21732835
Randomized trial of dyspnea, death or heart-failure rehospitalization, renal function and hypotension.
- 5.
PubMed. Intravenous nesiritide versus nitroglycerin in decompensated heart failure: VMAC
doi:10.1001/jama.287.12.1531 PMID:11911755
Randomized trial comparing early filling-pressure and dyspnea measures with placebo and nitroglycerin.