Clinical UM Guideline


Subject:Nesiritide (Natrecor®)
Guideline #:  CG-DRUG-18Current Effective Date:  01/14/2014
Status:ReviewedLast Review Date:  11/14/2013

Description

Nesiritide (Natrecor®, Scios Inc., Mountain View, CA) is a sterile, purified preparation of a new drug class, human B-type natriuretic peptide (hBNP), and is manufactured from E. coli using recombinant DNA technology. Nesiritide is indicated for the intravenous (IV) treatment of individuals with acutely decompensated congestive heart failure who have dyspnea at rest or with minimal activity.

Clinical Indications

Medically Necessary:
Nesiritide is considered medically necessary when administered intravenously in an inpatient clinical setting where blood pressure can be closely monitored, for the treatment of individuals with acutely decompensated congestive heart failure who have dyspnea at rest or with minimal activity. 

Not Medically Necessary:
Nesiritide is considered not medically necessary when administered in any route except intravenously, all settings except inpatient, and for all indications other than for the treatment of individuals with acutely decompensated congestive heart failure who have dyspnea at rest or with minimal activity.

Coding

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member.

HCPCS 
J2325Injection, nesiritide, 0.1 mg
  
ICD-9 Procedure[For dates of service prior to 10/01/2014]
00.13Injection or infusion of nesiritide
  
ICD-9 Diagnosis[For dates of service prior to 10/01/2014]
 All diagnoses
  
ICD-10 Procedure[For dates of service on or after 10/01/2014]
3E030VHIntroduction of human B-type natriuretic peptide into peripheral vein, open approach
3E033VHIntroduction of human B-type natriuretic peptide into peripheral vein, percutaneous approach
3E040VHIntroduction of human B-type natriuretic peptide into central vein, open approach
3E043VHIntroduction of human B-type natriuretic peptide into central vein, percutaneous approach
3E050VHIntroduction of human B-type natriuretic peptide into peripheral artery, open approach
3E053VHIntroduction of human B-type natriuretic peptide into peripheral artery, percutaneous approach
3E060VHIntroduction of human B-type natriuretic peptide into central artery, open approach
3E063VHIntroduction of human B-type natriuretic peptide into central artery, percutaneous approach
  
ICD-10 Diagnosis[For dates of service on or after 10/01/2014]
 All diagnoses
  
Discussion/General Information

According to the American College of Cardiology/American Heart Association (ACC/AHA) 2009 Practice Guideline Update for the Diagnosis and Management of Heart Failure in Adults (Hunt, 2009), approximately 5 million individuals in this country have heart failure and over 550,000 are diagnosed with heart failure for the first time each year.

Nesiritide has venous, arterial, and coronary vasodilatory affects which reduce preload and afterload resulting in increased cardiac output without direct inotropic effects. Nesiritide has also been shown to increase glomerular filtration rate, suppress renin-angiotensin, and stimulate natriuresis in those with advanced heart failure (VMAC, 2002). Nesiritide (Natrecor, Scios Inc., Mountain View, CA) was approved by the U.S. Food and Drug Administration (FDA) on August 10, 2001 for the intravenous treatment of individuals with acutely decompensated congestive heart failure who have dyspnea at rest or with minimal activity.

The VMAC (Vasodilation in the Management of Acute Congestive Heart Failure 2002) trial was a randomized, double-blind study of 489 individuals (246 subjects requiring a right heart catheter, 243 subjects without a right heart catheter) who required hospitalization for management of shortness of breath at rest due to acutely decompensated CHF. The study compared the effects of nesiritide, placebo, and IV nitroglycerin (NTG) when added to background therapy (IV and oral diuretics, non-IV cardiac medications, dobutamine, and dopamine). Individuals with acute coronary syndrome, preserved systolic function, arrhythmia, and renal insufficiency were not excluded. The primary endpoints of the study were the change from baseline in pulmonary capillary wedge pressure (PCWP) and the change from baseline in the subject's dyspnea, evaluated after three hours. In this study, individuals receiving nesiritide reported greater improvement in their dyspnea at 3 hours than those receiving placebo (p = 0.034). VMAC (2002) concluded: when added to standard care, fixed-dose administration of nesiritide produced a more rapid and greater improvement in hemodynamics than NTG titration or standard care alone. Nesiritide, but not NTG, was associated with significant improvements in dyspnea, compared to standard care alone. Compared to NTG, nesiritide was better tolerated by these acutely ill CHF individuals. These data from the VMAC Trial suggested an important role for nesiritide in the treatment of acutely decompensated CHF, with or without invasive monitoring and without the need for dose titration.

Colucci and colleagues (2000) studied the acute benefit of nesiritide in the short-term treatment of decompensated heart failure in a study of 432 individuals. Nesiritide infusion at rates of 0.015 and 0.030 microg per kilogram per minute decreased pulmonary-capillary wedge pressure by 6.0 and 9.6 mm Hg, respectively (as compared with an increase of 2.0 mm Hg with placebo, P<0.001), resulted in improvements in global clinical status in 60 percent and 67 percent of the subjects (as compared with 14 percent of those receiving placebo, P<0.001), reduced dyspnea in 57 percent and 53 percent of the subjects (as compared with 12 percent of those receiving placebo, P<0.001), and reduced fatigue in 32 percent and 38 percent of the subjects (as compared with 5 percent of those receiving placebo, P<0.001). In the comparative phase of this trial, 305 individuals were randomly assigned to nesiritide or standard vasoactive agents (e.g., dobutamine, milrinone, nitroglycerin, or nitroprusside) for seven days without hemodynamic monitoring. The improvements in global clinical status, dyspnea, and fatigue were sustained with nesiritide therapy for up to the seven days of the entire infusion period and were similar to those observed with standard intravenous therapy for heart failure. The most common side effect was dose-related hypotension, which was usually asymptomatic. Colucci concluded in those hospitalized with decompensated congestive heart failure, nesiritide improves hemodynamic function and clinical status. Based on trials such as this, nesiritide was approved for the intravenous treatment of individuals with acutely decompensated congestive heart failure who have dyspnea at rest or with minimal activity.

Subsequently, questions were raised regarding the effects of nesiritide on renal function and survival. Sackner-Bernstein and colleagues (2005) investigated the renal effects of nesiritide as treatment for acutely decompensated congestive heart failure (ADHF) and concluded: "Nesiritide significantly increases the risk of worsening renal function in patients with ADHF. Whether worsening renal function reflects hemodynamic effect or renal injury is unknown, but the prognostic importance of worsening renal function suggests the need for further investigation in appropriately powered clinical trials."

Sackner-Bernstein and colleagues (2005) also investigated the safety of nesiritide relative to noninotrope-based control therapies, primarily consisting of diuretics or vasodilators, concluding "Compared with noninotrope-based control therapy, nesiritide may be associated with an increased risk of death after treatment for acutely decompensated heart failure. The possibility of an increased risk of death should be investigated in a large-scale, adequately powered, controlled trial before routine use of nesiritide for acutely decompensated heart failure." It should be noted death within 30 days tended to occur more often among individuals randomized to nesiritide therapy.

Concerns regarding nesiritide's safety as well as its appropriate use with respect to worsening renal function and death as raised by these studies caused Scios/Johnson & Johnson (J&J), the manufacturer, to establish an expert panel of cardiologists and heart failure specialists to review use and safety data. The panel convened in June 2005 at the request of the manufacturer to evaluate data associated with the treatment of acute heart failure by means of nesiritide. The panel provided the following three recommendations on the use of nesiritide:

  1. The use of nesiritide should be strictly limited to patients presenting to the hospital with acutely decompensated CHF who have dyspnea at rest, as were the patients in the largest trial that led to approval of the drug (VMAC). Physicians considering the use of nesiritide should consider its efficacy in reducing dyspnea, the possible risks of the drug, and the availability of alternate therapies to relieve the symptoms of CHF (emphasis added).
  2. Nesiritide should not be used to replace diuretics. Furthermore, because sufficient evidence is not currently available to demonstrate benefit for the applications listed below, nesiritide should not be used for: intermittent outpatient infusion, scheduled repetitive use, improvement of renal function, or enhancement of diuresis.
  3. The manufacturer should immediately undertake a pro-active educational program to inform physicians regarding the conditions and circumstances in which nesiritide should and should not be used. Sponsor supported communications, including review articles of nesiritide, should reflect the above recommendations. Scios should ensure that current and future marketing and sales activities related to nesiritide are consistent with this educational program.

This expert group, referred to as the "Nesiritide Advisory Panel," considered renal insufficiency, mortality, and the effectiveness of nesiritide. The panel suggested Scios immediately conduct an educational campaign to inform physicians about the circumstances in which nesiritide should and should not be used and should ensure current and future marketing and sales activities are consistent with the educational program. The Panel's conclusions above were sent out as a "Dear Healthcare Provider Letter" on July 13, 2005. The other recommendation of this Scios sponsored Natrecor Advisory Panel was for the FUSION trial to study the safety/efficacy of Natrecor in an outpatient setting.

The FUSION I study was one of the first large-scale clinical trials to test the safety and feasibility of using serial infusions of nesiritide for heart failure in an outpatient setting (Yancy, 2004). In this open label (researchers and subjects were aware of the treatment regimen, and thus susceptible to bias) study, 210 individuals suffering from acutely decompensated congestive heart failure (ADHF) were assigned to one of three treatment groups: (1) usual care as determined by the investigating physician (n=69); (2) usual care plus 0.005 µg/kg/min of nesiritide given for four to six hours, preceded by a 1.0 µg/kg bolus (n=72); or (3) usual care plus 0.01 µg/kg/min of nesiritide given for four to six hours, preceded by a 2.0 µg/kg bolus (n=69). Primary endpoints included adverse events, serious adverse events (including all-cause death and hospitalization), vital signs, and laboratory assessment. The study treatment period was 12 weeks, with an additional four weeks of follow-up. No statistically significant differences could be found between treatment groups when evaluating deaths or hospitalizations, though individuals receiving nesiritide showed trends for more days alive and out of the hospital compared with those receiving usual care. A prospective analysis defining higher risk subgroups noted a significant decrease in cardiovascular events (Yancy, 2004).

The purpose of the Second Follow-Up Serial Infusions of Natrecor (nesiritide) for the Management of Patients With Heart Failure (FUSION II) trial was to further evaluate the efficacy, safety, and optimal dosing frequency of Natrecor administered as serial infusions to individuals with American College of Cardiology/American Heart Association (ACC/AHA) stage C/D heart failure in the outpatient setting (Yancy 2007). Individuals with persistently symptomatic heart failure despite the use of guideline-driven, evidence-based pharmacological and device therapy are classified as having ACC/AHA stage C or stage D heart failure (Yancy 2008). Fusion II was a randomized, double-blind, placebo control, single group assignment, safety/efficacy study using mortality and cardio-renal hospitalization as a composite end point. This multi-center study randomly assigned approximately 900 subjects to either treatment with usual care plus nesiritide or usual care plus placebo. Yancy and colleagues (2008) noted subjects in Fusion II receiving nesiritide experienced a higher incidence of hypotension but less predefined worsening renal function. The authors also concluded on the basis of study results there is no indication for intermittent outpatient nesiritide infusions in individuals with ACC/AHA stage C/D heart failure.

Chung and colleagues (2006) studied the safety and tolerability of serial infusions of nesiritide for advanced heart failure in the home setting. This small, non-randomized, open-label pilot concluded: "the safety and tolerability demonstrated in the present study may serve to facilitate the design of future studies in which efficacy measures of serial home nesiritide infusions are assessed."

The American College of Emergency Physician's 2007 Clinical Policy: Critical Issues in the Evaluation and Management of Adult Patients Presenting to the Emergency Department with Acute Heart Failure Syndromes recommends that nesiritide not be considered as first line therapy for acute heart failure syndromes due to the lack of clear superiority of nesiritide over nitrates and uncertainty regarding its safety.

Arora and colleagues (2006) studied short and long-term mortality with nesiritide and concluded that nesiritide may not be associated with increased risk of mortality but further trials to evaluate mortality are required to conclusively address findings.

Witteles and colleagues (2007) evaluated the impact of nesiritide on renal function in individuals with acute decompensated heart failure (ADHF) and baseline renal dysfunction. Seventy-five consecutive subjects (39 nesiritide, 36 placebo) were enrolled in a randomized, double-blind, placebo-controlled clinical trial. Individuals were randomized to receive nesiritide or placebo (5% dextrose in water) for 48 hours in addition to their typical care. The first predefined primary end point of the trial was a significant decline in renal function (defined as a peak serum creatinine increase of greater or equal to 20% at any time during the first 7 days of hospitalization as compared to the creatinine on admission). The second predefined primary end point was a change in serum creatinine from the value on admission to discharge or the 7th day of hospitalization, whichever was sooner Results indicated there were no significant differences in the incidence of a 20% creatinine rise (23% for the nesiritide group vs. 25% for the placebo group) or in the change in serum creatinine from the admission value (-0.05 for the nesiritide group vs. +0.05 mg/dl for the placebo group). There were no significant differences in the secondary end points of change in weight (-2.19 vs. -1.58 kg), intravenous furosemide (125 vs. 107 mg), discontinuation of the infusion due to hypotension (13% vs. 6%), or 30-day death/hospital readmission (33% vs. 25%). The authors concluded, based on the results of this study, that nesiritide therapy does not cause or prevent worsened renal function in individuals with ADHF and pre-existing renal dysfunction.

O'Connor and colleagues (2011), in the ASCEND-HF trial, randomly assigned 7141 subjects hospitalized with acute heart failure to receive either nesiritide or placebo for 24 to 168 hours in addition to standard care. The study had two coprimary end points which consisted of the change in self-reported dyspnea at 6 and 24 hours after the initiation of the study drug and the composite end point of rehospitalization for heart failure or death from any cause within 30 days. The trial was conducted from May 2007 through August 2010 at 298 centers throughout the world. The study subjects randomly assigned to nesiritide, as compared with those assigned to placebo, more often reported improved dyspnea at 6 hours (44.5% vs. 42.1%, P=0.03) and 24 hours (68.2% vs. 66.1%, P=0.007), but the prespecified level for significance (P≤0.005 for both assessments or P≤0.0025 for either) was not met. The rate of rehospitalization for heart failure or death from any cause within 30 days was 9.4% in the nesiritide group versus 10.1% in the placebo group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.1 to 0.7; P=0.31). There were no significant differences in death rates from any cause at 30 days or rates of worsening renal function, defined by more than a 25% decrease in the estimated glomerular filtration rate (31.4% vs. 29.5%; odds ratio, 1.09; 95% CI, 0.98 to 1.21; P=0.11). The authors concluded that nesiritide was not associated with an increase or a decrease in the rate of death and rehospitalization and had a small, nonsignificant effect on dyspnea when used in combination with other therapies. Nesiritide was not associated with a worsening of renal function, but it was associated with an increase in rates of hypotension. On the basis of study results, the authors indicated that nesiritide cannot be recommended for routine use in the broad population of individuals with acute heart failure.

In a sub-study of the ASCEND-HF clinical trial, Ezekowitz and colleagues (2012) hypothesized that peak expiratory flow rate (PEFR) would increase with acute heart failure treatment over the first 24 hours, related to a Dyspnea Index (DI) change and treatment effect of nesiritide or placebo. A total of 421 individuals at 37 sites underwent PEFR testing at baseline, 1, 6, and 24 hours after randomization to nesiritide (208) or placebo (213). DI was collected at 6 and 24 hours. Study subjects had a median age 70 years, and 34% were female. There were no significant differences between the subjects in the nesiritide or placebo groups. A model incorporating time and treatment over 24 hours showed greater PEFR improvement after nesiritide compared with placebo (p = 0.048). At study conclusion, it was noted that nesiritide had a greater effect than placebo on PEFR, and this predicted those with moderate/marked improvement in dyspnea, thereby providing an objective metric for assessing AHF.

Based on clinical trial outcomes and FDA approved indications, nesiritide should be limited to use in the inpatient clinical (hospital) setting for the intravenous treatment of individuals with acutely decompensated congestive heart failure who have dyspnea at rest or with minimal activity. The FDA approved label (2012) advises of the following contraindications, warnings and precautions: 

CONTRAINDICATIONS:

WARNINGS AND PRECAUTIONS:

References

Peer Reviewed Publications:

  1. Arora RR, Venkatesh PK, Molnar J. Short and long-term mortality with nesiritide. Am Heart J. 2006; 152(6):1084-1090.
  2. Chung ES, Menon SG, Daly KA, et al. Safety and tolerability of serial home infusions of nesiritide for advanced heart failure. Am J Cardiol. 2006; 97(9):1370-1373.
  3. Colucci WS, Elkayam U, Horton DP et al. Intravenous nesiritide, a natriuretic peptide, in the treatment of decompensated congestive heart failure. Nesiritide Study Group. N Engl J Med 2000; 343(4):246-253.
  4. Ezekowitz JA, Hernandez AF, O'Connor CM, et al. Assessment of dyspnea in acute decompensated heart failure: insights from ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) on the contributions of peak expiratory flow. J Am Coll Cardiol. 2012; 59(16):1441-1448.
  5. Josephson S, Barnett PP. Nesiritide: practical approach and benefits in the outpatient setting. J Cardiovasc Nurs. 2004; 19(5):358-363.
  6. O'Connor CM, Starling RC, Hernandez AF, et al. Effect of nesiritide in patients with acute decompensated heart failure. N Engl J Med. 2011; 365(1):32-43.
  7. 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(15):1900-1905.  
  8. 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.
  9. (VMAC) Publication Committee for the VMAC Investigators (Vasodilatation in the Management of Acute CHF). Intravenous nesiritide vs. nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA. 2002. 27; 287(12):1531-1540.
  10. Witteles RM, Kao D, Christopherson D, Matsuda K, et al. Impact of nesiritide on renal function in patients with acute decompensated heart failure and pre-existing renal dysfunction a randomized, double-blind, placebo-controlled clinical trial. J Am Coll Cardiol. 2007; 50(19):1835-1840.
  11. Yancy CW, Krum H, Massie BM, et al. FUSION II Investigators. The Second Follow-up Serial Infusions of Nesiritide (FUSION II) trial for advanced heart failure: study rationale and design. Am Heart J. 2007; 153(4):478-484.
  12. Yancy CW, Krum H, Massie BM, et al. Safety and efficacy of outpatient nesiritide in patients with advanced heart failure. Results of the second follow-up serial infusions of nesiritide (FUSION II) trial. Circ Heart Fail 2008; 1: 9-16.
  13. 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(5):595-601.
  14. 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):226-229.

Government Agency, Medical Society, and Other Authoritative Publications:

  1. American College of Emergency Physicians Clinical Policies Subcommittee (Writing Committee) on Acute Heart Failure Syndromes, Silvers SM, Howell JM, Kosowsky JM, et al. Clinical policy: Critical issues in the evaluation and management of adult patients presenting to the emergency department with acute heart failure syndromes. Ann Emerg Med. 2007; 49(5):627-669.
  2. American Hospital Formulary Service (AHFS). AHFS Drug Information 2013. Bethesda, MD: American Society of Health System-Pharmacists; 2013.
  3. Centers for Medicare and Medicaid Services. National Coverage Determination: Nesiritide for Treatment of Heart Failure Patients. NCD # 200.1. Implementation date: 05/22/2006. Available at: http://www.cms.gov/medicare-coverage-database/. Accessed on October 1, 2013.
  4. Hunt SA, Abraham WT, Chin MH, et al. 2009 focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines: developed in collaboration with the International Society for Heart and Lung Transplantation. Circulation. 2009; 119(14):e391-479.
  5. Natrecor® [Product Information], Mountain View, CA. Scios Inc; April 2013. Available at: http://www.accessdata.fda.gov/drugsatfda_docs/label/2013/20920s033lbl.pdf. Accessed on October 1, 2013.
  6. Nesiritide (systemic). In: DrugPoints System [electronic version]. Truven Health Analytics. Greenwood Village, CO. Last modified August 23, 2012. Available at: http://www.micromedexsolutions.com. Accessed on October 1, 2013.
  7. Scios Inc. Dear Health Care Provider letter. (Recommendations of Nesiritide Advisory Panel), July 13, 2005. Available at: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm151889.htm. Accessed on October 1, 2013.
Index

Acutely Decompensated Congestive Heart Failure
Congestive Heart Failure
Natrecor
Nesiritide

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available. 

History

Status

Date

Action

Reviewed11/14/2013Medical Policy & Technology Assessment Committee (MPTAC) review. References updated.
Reviewed11/08/2012MPTAC review. Discussion and Reference sections updated.
Reviewed11/17/2011MPTAC review. Discussion, Coding and Reference sections updated.
Reviewed11/18/2010MPTAC review. Description, Discussion and References updated.
Reviewed11/19/2009MPTAC review. Discussion and references updated. Dosage recommendations and place of service section removed. No changes made to position stance.
Revised11/20/2008MPTAC review. Added the wording "intravenously" to the medical necessary statement and "any route except intravenously" to the not medically necessary statement. Discussion, medical management information, and references updated.
 04/01/2008References updated to reflect change from USP DI to new DrugPoints compendia.
Reviewed11/29/2007MPTAC review. Rationale and references updated.
New12/07/2006MPTAC initial document development.