Clinical UM Guideline
|Guideline #:||CG-DRUG-18||Current Effective Date:||01/05/2016|
|Status:||Reviewed||Last Review Date:||11/05/2015|
This document addresses nesiritide (Natrecor, Scios Inc., Mountain View, CA), a sterile, purified preparation of the drug class, human B-type natriuretic peptide (hBNP). Nesiritide is manufactured from E. coli using recombinant DNA technology and is used for the intravenous (IV) treatment of individuals with acutely decompensated congestive heart failure who have dyspnea at rest or with minimal activity.
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.
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.
|J2325||Injection, nesiritide, 0.1 mg|
|3E030VH||Introduction of human B-type natriuretic peptide into peripheral vein, open approach|
|3E033VH||Introduction of human B-type natriuretic peptide into peripheral vein, percutaneous approach|
|3E040VH||Introduction of human B-type natriuretic peptide into central vein, open approach|
|3E043VH||Introduction of human B-type natriuretic peptide into central vein, percutaneous approach|
|3E050VH||Introduction of human B-type natriuretic peptide into peripheral artery, open approach|
|3E053VH||Introduction of human B-type natriuretic peptide into peripheral artery, percutaneous approach|
|3E060VH||Introduction of human B-type natriuretic peptide into central artery, open approach|
|3E063VH||Introduction of human B-type natriuretic peptide into central artery, percutaneous approach|
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. 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).
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 3 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% and 67% of the subjects (as compared with 14% of those receiving placebo, P<0.001), reduced dyspnea in 57% and 53% of the subjects (as compared with 12% of those receiving placebo, P<0.001), and reduced fatigue in 32% and 38% of the subjects (as compared with 5% 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 (dobutamine, milrinone, nitroglycerin, or nitroprusside) for 7 days without hemodynamic monitoring. The improvements in global clinical status, dyspnea, and fatigue were sustained with nesiritide therapy for up to the 7 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 and concluded:
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.
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:
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 4 to 6 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 4 to 6 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 4 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."
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 endpoint 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 endpoint 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 2 co-primary endpoints which consisted of the change in self-reported dyspnea at 6 and 24 hours after the initiation of the study drug and the composite endpoint of re-hospitalization 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.
A sub-study of the ASCEND-HF clinical trial (Ezekowitz, 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. 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.
In 2014, several additional sub-studies of the ASCEND-HF trial were published. Patel and colleagues (2014) used data from the ASCEND-HF trial and assessed factors associated with in-hospital hypotension and 30-day mortality. From the 7141 study subjects initially randomized to nesiritide or placebo, 1555 (21.8%) had an episode of hypotension. Of these, 1136 (73.1%) were asymptomatic, 302 (19.4%) were symptomatic and 117 (7.5%) had both asymptomatic and symptomatic hypotension. Those with an episode of hypotension during their hospitalization had a higher 30-day mortality risk (7.1% versus 2.9% for no hypotension). Additionally, risk of 30-day mortality or all cause hospitalization was higher in the group with symptomatic hypotension (11.6% versus 5.6% for no hypotension). Death among those with symptomatic and asymptomatic hypotension was generally due to worsening heart failure. There was no statistical interaction found between assignment to nesiritide and hypotension for 30-day outcomes, indicating that nesiritide did not change the relationship between 30-day outcomes and hypotension. However, results did demonstrate that in-hospital hypotension is associated with increased 30 day hospitalization and mortality regardless of the study drug assigned. The authors concluded that hypotension is common during hospitalization for ADHF and is an independent predictor of adverse 30-day outcomes.
Van Deursen and colleagues (2014) performed a retrospective analysis of the ASCEND-HF trial and examined the clinical predictors of changes in creatinine, the relationship between changes in renal function and outcomes and the effects of nesiritide on renal function. Of the 7141 subjects randomized to receive either placebo or nesiritide, a total of 5702 subjects had a recorded baseline creatinine. The frequency of worsening renal function at any time from randomization to discharge occurred in 13.5% of subjects, and the frequency was similar in both the nesiritide and placebo groups (14.1% and 12.8%, respectively). The authors concluded that in this renal retrospective analysis, nesiritide did not affect renal function in those hospitalized with ADHF. Also noted was that "baseline, discharge and change in renal dysfunction were associated with higher 30 day mortality and re-hospitalization for heart failure."
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.
The American College of Cardiology Foundation; American Heart Association Task Force on Practice Guidelines. 2013 ACCF/AHA guideline for the management of heart failure includes the following class IIb* recommendation addressing the use of nesiritide:
If symptomatic hypotension is absent, intravenous nitroglycerin, nitroprusside, or nesiritide may be considered an adjuvant to diuretic therapy for relief of dyspnea in patients admitted with acutely decompensated HF (760-763). (Level of Evidence: A**)
*Class IIb-Benefit is greater or equal to the risk.
**Level of evidence A-multiple populations evaluated. Data derived from multiple randomized clinical trials or meta-analyses.
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 (2013) advises of the following contraindications, warnings and precautions:
WARNINGS AND PRECAUTIONS:
Peer Reviewed Publications:
Government Agency, Medical Society, and Other Authoritative Publications:
Acutely Decompensated Congestive Heart Failure
Congestive Heart Failure
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.
|Reviewed||11/05/2015||Medical Policy & Technology Assessment Committee (MPTAC) review. Discussion and Reference sections updated. Removed ICD-9 codes from Coding section.|
|Reviewed||11/13/2014||MPTAC review. Description, Discussion and Reference sections updated.|
|Reviewed||11/14/2013||MPTAC review. References updated.|
|Reviewed||11/08/2012||MPTAC review. Discussion and Reference sections updated.|
|Reviewed||11/17/2011||MPTAC review. Discussion, Coding and Reference sections updated.|
|Reviewed||11/18/2010||MPTAC review. Description, Discussion and References updated.|
|Reviewed||11/19/2009||MPTAC review. Discussion and references updated. Dosage recommendations and place of service section removed. No changes made to position stance.|
|Revised||11/20/2008||MPTAC 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.|
|04/01/2008||References updated to reflect change from USP DI to new DrugPoints compendia.|
|Reviewed||11/29/2007||MPTAC review. Rationale and references updated.|
|New||12/07/2006||MPTAC initial document development.|