Coverage Policy Manual
Policy #: 2005024
Category: Pharmacy
Initiated: August 2005
Last Review: September 2018
  Nesiritide (Natrecor) for Use in the Outpatient Setting

Description:
Nesiritide is a biosynthetic (recombinant DNA origin) form of human B-type natriuretic peptide vasodilator.  It is FDA approved for the intravenous treatment of patients with acutely decompensated congestive heart failure who have dyspnea at rest or with minimal activity.

Policy/
Coverage:
Effective September 2012
The use of nesiritide in the outpatient setting for acute heart failure or any other indication does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
 
For members with contracts without primary coverage criteria, the use of nesiritide in the outpatient setting for acute heart failure or any other indication is considered investigational.  Investigational services are specific contract exclusions in most member benefit certificates of coverage.
 
Effective August 2010 to August 2012
Nesiritide (HCPCS J2325) meets primary coverage criteria for effectiveness that there be scientific evidence of effectiveness in improving health outcomes in the hospital setting for patients with acutely decompensated congestive heart failure who have dyspnea at rest or with minimal activity, are not hypotensive, and remain symptomatic despite administration of intravenous loop diuretics.
  
The use of nesiritide for any indication not listed in the preceding paragraph including, but not limited to the following is not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes:
    • Its use as a replacement for diuretics
    • By intermittent out-patient infusion
    • Scheduled repetitive use
    • Its use to improve renal function
    • Its use to enhance diuresis in the absence of decompensated congestive heart failure.
  
For members with contracts without Primary Coverage Criteria, any other use of nesiritide, including but not limited to the above-mentioned indications, is considered investigational and is not covered.  Investigational services are an exclusion in the member benefit certificate.
 
Effective August 2005 to July 2010
 
Nesiritide (HCPCS J2325) meets primary coverage criteria for effectiveness and is covered in hospital setting for patients with acutely decompensated congestive heart failure who have dyspnea at rest or with minimal activity, are not hypotensive, and remain symptomatic despite administration of intravenous loop diuretics.
 
The use of nesiritide for any indication not listed in the preceding paragraph including, but not limited to the following is not covered based on benefit certificate primary coverage criteria that there be scientific evidence of effectiveness:
    • Its use as a replacement for diuretics
    • By intermittent out-patient infusion
    • Scheduled repetitive use
    • Its use to improve renal function
    • Its use to enhance diuresis in the absence of decompensated congestive heart failure.
 
For members with contracts without Primary Coverage Criteria, any other use of nesiritide, including but not limited to the above-mentioned indications, is considered investigational and is not covered.  Investigational services are an exclusion in the member benefit certificate.

Rationale:
Nesiritide is a biosynthetic (recombinant DNA origin) form of human B-type natriuretic peptide vasodilator.  It is FDA approved for the intravenous treatment of patients with acutely decompensated congestive heart failure who have dyspnea at rest or with minimal activity.
 
According to the AHFS drug compendium (2005), “nesiritide’s ability to improve overall clinical status and symptoms o decompensated heart failure has been shown to be comparable to that of standard IV therapy (principally dobutamine, milrinone, or nitroglycerin).  In addition, although the VMAC [Vasodilation in the Management of Acute Congestive Heart Failure] study does not permit a reliable comparison of the efficacy of nesiritide with that of nitroglycerin, the reduction in pulmonary capillary wedge pressure produced by nesiritide appeared to be faster in onset (within 15 minutes) and more pronounced through 24 hours than that produced by nitroglycerin; however, some clinicians have stated that the nitroglycerin dosage in this study appeared to be lower than dosages generally used in clinical practice.  No difference in duration of hospitalization has been reported between patients receiving nesiritide and those receiving dobutamine.  Data comparing the effects of nesiritide and nitroglycerin on duration of hospitalization are not available to date.  Some clinicians suggest that, until more data are available, nesiritide probably should be reserved for use in patients who do not respond to nitroglycerin or who cannot be treated with sodium nitroprusside.”  
 
A “Perspective” article by Eric Topol in the New Engl J Med, 2005; 353:113-116 provides the following information:
“There have been two different analyses of the effects of nesiritide treatment on mortality, the most important end point in a randomized trial of an intervention for heart failure.  In one of them, Sackner-Bernstein et al. pooled data from the three trials involving patients whose baseline treatment regimen was not required to include inotropes and for which 30-day mortality data were available.  According to this analysis, there was an 81 per-cent increase in the death rate with nesiritide as compared with placebo (JAMA, 2005; 293:1900-1905).  In contrast, Scios [the manufacturer] analyzed seven trials that had 30-day mortality data, including trials involving open-label and outpatient use, but did not take into consideration the baseline treatment regimen.  The company reported a 24 percent increase in mortality (P = 0.33), and this figure was incorporated into a revised package insert in April 2005…
 
“Notwithstanding the fact that only one small, open-label feasibility study has been conducted, outpatient nesiritide use has become widespread…”
 
According to a letter from Scios to physicians regarding articles questioning the safety of the use of nesiritide, dated 6 May 2005, Scios has requested Eugene Braunwald, Hershey Professor of Medicine, Harvard Medical School, to convene a panel of experts to review all available studies and advise the company on their clinical development program for nesiritide.
 
2008 Update
Following early enthusiasm for use of nesiritide, concerns about increased mortality (mentioned above) and adverse effects on renal function have severely reduced the use of this drug. On the other hand, nesiritide appears to be less likely than dobutamine to produce ventricular arrhythmias in patients with heart failure.  Analysis of over 1200 patients who had received nesiritide or other intravenous vasodilators or inotropes for acute heart failure (Sackner-Bernstein & Skopicki, 2005) found a significantly greater rise in serum creatinine > 0.5 mg/dl in the patients on nesiritide.  Whether this was related to hypoperfusion or a direct effect of nesiritide is unknown.  More recently, a double blind randomized clinical trial with nesiritide v. placebo showed no difference in renal function between these groups after a 48-hour infusion (Witteles, 2007).  The relative benefits of nesiritide compared with other intravenous agents for heart failure remains uncertain. In a subsequent retrospective analysis of CHF patients over a three-year period, there initially appeared to be increased mortality in the patients treated with nesiritide; however, after adjustment for multiple variables, nesiritide therapy was associated with increased length of stay and pharmacy cost, but not hospital mortality (Carroll, 2007).  In a study conducted in a county hospital emergency room (Miller, 2008), acutely decompensated heart failure patients were treated with an 8-hour nesiritide infusion v. standard therapy prior to discharge.  Diuresis was similar between the two groups, and there was no significant difference in return visits to the emergency department or hospitalization at 30 days. There is an ongoing phase 3 trial of nesiritide in acute decompensated heart failure (ClinicalTrials.gov identifier: NCT00475852).  A study of nesiritide in the management of acute diastolic heart failure (ClinicalTrials.gov identifier: NCT00083772) was terminated.
 
2010 Update
A review of the available literature pertaining to the use of Nesiritide for the treatment of heart failure identified a randomized, double-blind, placebo-controlled trial of outpatient serial nesiritide infusions for patients with ACC/AHA stage C/D heart failure (FUSION II).  Patients (N=911) were randomly selected to receive either nesiritide (2 µg/kg bolus plus 0.01 µg/kg per minute infusion for 4 to 6 hours) or matching placebo once or twice a week for 12 weeks. The primary endpoint of all-cause mortality or cardiovascular or renal hospitalization was not met and no statistically significant differences were seen in any of the secondary endpoints.   The authors conclude, “Serial outpatient nesiritide infusions do not provide a demonstrable clinical benefit over intensive outpatient management of patients with advanced ACC/AHA stage C/D heart failure” (Yancy, 2008).
 
2012 Update
O’Connor and colleagues published results (O’Connor, 2011) of the phase III randomized trial (NCT00475852) discussed in the 2008 policy update. Subjects hospitalized with acute heart failure were randomly selected to receive either nesiritide or placebo for 24 to 168 hours plus standard of care treatment. Primary endpoints included measuring the change of dyspnea at 6 and 24 hours and heart failure related rehospitalization or death within 30 days. Results of the trial indicated a non-significant improvement in dyspnea at 6 hours and 24 hours in subjects treated with nesiritide versus placebo.  There was no significant difference in the rate of rehospitalization or death related to acute heart failure. Although there was no difference in worsening renal failure in patients treated with nesiritide versus placebo; there was an associated increase in hypotension in those subjects treated with nesiritide. The authors conclude, “On the basis of these results, nesiritide cannot be recommended for routine use in the broad population of patients with acute heart failure” (O’Connor, 2011). In an accompanying editorial, Topol goes further to indicate the article (O’Connor, 2011) “does not identify any type of patient who would benefit from nesiritide” (Topol, 2011). Additionally he revisits his position that “nesiritide was approved on the basis of a single trial in which surrogate end points were assessed 3 hours after administration” (Topol, 2011) without meeting the “minimal criteria for safety and efficacy” (Topol, 2011). This approval led to aggressive marketing of the drug which eventually led to the use of the drug in off-label use in outpatient heart failure clinics. This off-label use was found to be ineffective over placebo in the FUSION II trial discussed above (Yancy, 2008).  Finally, Topol writes, “it has taken nearly a full decade to learn the truth about nesiritide’s lack of efficacy in acute heart failure” (Topol, 2011).
 
In summary, there is a lack of scientific evidence that nesiritide improves health outcomes over standard of care treatment for acute heart failure.  The coverage statement has been changed in response to the new evidence discussed in this update.
 
2013 Update
A literature conducted through August 2013 did not reveal any new information that would prompt a change in the coverage statement.
 
2014 Update
A literature conducted through August 2014 did not reveal any new information that would prompt a change in the coverage statement.
 
2015 Update
A literature search conducted through August 2015 did not reveal any new information that would prompt a change in the coverage statement.  
 
2016 Update
A literature search conducted through August 2016 did not reveal any new information that would prompt a change in the coverage statement.
 
2017 Update
A literature search conducted through August 2017 did not reveal any new information that would prompt a change in the coverage statement.  The key identified literature is summarized below.
 
2018 Update
A literature search conducted through August 2018 did not reveal any new information that would prompt a change in the coverage statement.    

CPT/HCPCS:
J2325Injection, nesiritide, 0.1 mg

References: Aaronson D, Burger AJ.(2004) Effect of nesiritide (human b-type natriuretic peptide) and dobutamine on heart rate variability in decompensated heart failure. Am Heart J 2004; 148:e16.

Abraham WT, Adams KF, et al.(2005) 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). Am Coll Cardiol 2005; 46:57-64.

Braunwald E, et al.(2005) Panel of cardiology experts provides recommendations to Scios regarding Natrecor. http://www.natrecor.com/pdf/Braunwald_Panel_Release_&_Report, accessed 8/1/2005.

Carroll R, Mulla Z.(2007) Outcomes of patients hospitalized for acute decompensated heart failure: does nesiritide make a difference? BMC Cardiovasc Disord, 2007; 26:7.

Knox MA, Dancy T, et al.(2005) Intravenous nesiritide in acute heart failure. Am J Ther 2005; 12:233-7.

Miller A, Nazeer S.(2008) Acutely decompensated heart failure in a county emergency department; a double blne randomized controlled comparison of nesiritide versus placebo treatment. Emerg Med, 2008; 51:571.

O’Connor C.M., Starling R.C., Hernandez A.F., et al.(2011) Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med 2011;365:81-82.

Peacock WF, Emerman CL, Silver MA.(2005) 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; 23:327-31.

Sackner-Bernstein JD, Kowalski M, et al.(2005) Short-term risk of death after treatment with nesiritide for decompensated heart failure: a pooled analysis of randomized controlled trials. JAMA 2005; 293:1900-5.

Sackner-Bernstein JD, Skopicki HA, Aaronson KD.(2005) Risk of worsening renal function with nesiritide in patients with acutely decompensated heart failure. Circulation 2005; 111:1487-91.

Topal E.(2005) Nesiritide - not verified. NEJM 2005; 353:113-116.

Topol E.J.(2011) The lost decade of nesiritide. N Engl J Med 2011;365:32-43.

Witteles R, Kao D, Christopherson D.(2007) Impact of nesiritide on renal function in patients with acute decompensaed heart failure and pre-existing renal dysfunction: a randomized, double-blind, placebo-controlled clinical trial. J Am Coll Cardiol, 2007; 50:1841.

Yancy CW, Krum H, Massie BM, et al.(2008) Safety and Efficacy of Outpatient Nesiritide in Patients With Advanced Heart Failure (FUSION II). Circ Heart Fail. 2008;1:9-16.

Yancy CW.(2004) Treatment with B-type natriuretic peptide for chronic decompensated heart failure: insights learned from the follow-up serial infusion of nesiritide (FUSION) trial. Heart Fail Rev; 9:209-16.


Group specific policy will supersede this policy when applicable. This policy does not apply to the Wal-Mart Associates Group Health Plan participants or to the Tyson Group Health Plan participants.
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