Clinical Policy Title: Inhaled nitric oxide

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1 Clinical Policy Title: Inhaled nitric oxide Clinical Policy Number: Effective Date: June Initial Review Date: February 19, 2014 Most Recent Review Date: May 17, 2017 Next Review Date: March 2018 Policy contains: Inhaled nitric oxide. Respiratory distress. Pediatric pulmonary hypertension. Related policies: None. ABOUT THIS POLICY: AmeriHealth Caritas has developed clinical policies to assist with making coverage determinations. AmeriHealth Caritas clinical policies are based on guidelines from established industry sources, such as the Centers for Medicare & Medicaid Services (CMS), state regulatory agencies, the American Medical Association (AMA), medical specialty professional societies, and peer-reviewed professional literature. These clinical policies along with other sources, such as plan benefits and state and federal laws and regulatory requirements, including any state- or plan-specific definition of medically necessary, and the specific facts of the particular situation are considered by AmeriHealth Caritas when making coverage determinations. In the event of conflict between this clinical policy and plan benefits and/or state or federal laws and/or regulatory requirements, the plan benefits and/or state and federal laws and/or regulatory requirements shall control. AmeriHealth Caritas clinical policies are for informational purposes only and not intended as medical advice or to direct treatment. Physicians and other health care providers are solely responsible for the treatment decisions for their patients. AmeriHealth Caritas clinical policies are reflective of evidence-based medicine at the time of review. As medical science evolves, AmeriHealth Caritas will update its clinical policies as necessary. AmeriHealth Caritas clinical policies are not guarantees of payment.. Coverage policy AmeriHealth Caritas considers the use of inhaled nitric oxide (ino) for the management of at- or nearterm infants at risk for pulmonary hypertension to be clinically proven and, therefore, medically necessary when all of the following criteria are met: ino is a component treatment of respiratory failure associated with pulmonary hypertension. Infants are at 35 weeks of gestation. There is no presence of congenital diaphragmatic hernia. ino is performed in centers with Level 3 or Level 4 neonatal intensive care units and referral access to extracorporeal membrane oxygenation (ECMO). AmeriHealth Caritas considers the use of ino for respiratory distress in infants at <35 weeks of gestation to be investigational and, therefore, not medically necessary. Limitations: 1

2 All other uses of ino are not medically necessary. Alternative covered services: Standard medical care as found in the peer-reviewed medical journals for the treatment of asthma, respiratory distress, chronic lung disease, and pulmonary disease in infants and newborns. Background Nitric oxide (chemical designation NO) is a free radical serving as a signal for inflammatory processes and as a regulator serves as a vasodilator. Nitric oxide is formed from the actions of nitric oxide synthease (NOS) catalyzing the abduction of guanidine nitrogen from arginine raising intracellular levels of cyclic-guanosine 3, 5 -monophosphate and yielding NO and water. Three isozymes of NOS exist with a similar final common pathway. However, the NOS isoenzymes are expressed in the epithelium of the airways in both normal and asthmatic subjects. NO has several potential functions in airway physiology and pathophysiology. Physiologically, NO causes vasodilatation and relaxation of airway smooth muscles. It inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. In the face of inflammatory processes, more NO is produced and, in turn, is reduced in the face of glucocorticosteroids. ino: ino has been proposed as a treatment option for pulmonary hypertension and hypoxemic respiratory failure. The U.S. Food and Drug Administration (FDA) approved ino (marketed as INOmax gas, Mallinckrodt Hospital Products IP Limited, Hampton, New Jersey) as a vasodilator to improve oxygenation and reduce the need for ECMO in term and near-term (> 34 weeks of gestation) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, in conjunction with ventilatory support and other appropriate agents (FDA 1999). FDA warns of rebound pulmonary hypertension syndrome following abrupt discontinuation from ino, methemoglobinemia, airway injury, and heart failure as a result of nitric oxide (FDA, 2004). Off-label use is widespread (Keszler, 2012). Searches AmeriHealth Caritas searched PubMed and the databases of: UK National Health Services Centre for Reviews and Dissemination. Agency for Healthcare Research and Quality s (AHRQ s) National Guideline Clearinghouse and other evidence-based practice centers. The Centers for Medicare & Medicaid Services (CMS). 2

3 Searches were conducted on January 13, Search terms were: "nitric oxide" (MeSH), inhaled nitric oxide, and respiratory distress. We included: Systematic reviews, which pool results from multiple studies to achieve larger sample sizes and greater precision of effect estimation than in smaller primary studies. Systematic reviews use predetermined transparent methods to minimize bias, effectively treating the review as a scientific endeavor, and are thus rated highest in evidence-grading hierarchies. Guidelines based on systematic reviews. Economic analyses, such as cost-effectiveness, and benefit or utility studies (but not simple cost studies), reporting both costs and outcomes sometimes referred to as efficiency studies which also rank near the top of evidence hierarchies. Findings: An AHRQ-funded evidence report on ino in preterm infants found a 7 percent reduction in the composite outcome of death or bronchopulmonary dysplasia (BPD) at 36 weeks compared to control; however, there was insufficient evidence to support the use of ino outside of rigorous randomized controlled trials (RCTs) (Allen, 2010). A consensus panel from the American Association for Respiratory Care (AARC) made recommendations for: (1) a trial of ino in newborns 34 weeks of gestation with oxygen tension < 100 mm Hg on 100 percent oxygen; (2) using ino starting early to reduce duration of mechanical ventilation; and (3) not using ino in infants with congenital diaphragmatic hernia, cardiac anomalies with right-to-left shunts, or heart failure (DiBlasi, 2010). The AARC relied on evidence compiled by the Cochrane Neonatal Group, which failed to find evidence to support ino as rescue therapy, but did find that early use of ino in preterm infants with respiratory conditions did not affect brain injury or mortality (Barrington, 2010). A National Institutes of Health (NIH) panel did not find evidence supporting the use of ino for rescue and care of infants with <34 weeks of gestation (Cole, 2011). Another meta-analysis of 14 published trials found significant differences in the design of published trials that precluded a determination of the salutary impact of ino (Askie, 2011). The American Academy of Pediatrics literature review found insufficient evidence to support treating preterm infants who have respiratory failure with ino and no evidence of a salutary impact on neurodevelopmental processes for infants who received ino compared to controls (Kumar, 2014). As a summary of the findings of the studies, the following points may be made: There is evidence to support the use of ino in term or late preterm infants with respiratory distress and pulmonary hypertension for its acute favorable impacts as a smooth muscle relaxant on pulmonary vascular system and bronchiolar tree. 3

4 ino should not be used for more than four days because of toxicity, nor is it effective in treatment of hypoxemia related to congenital diaphragmatic hernia. The use of ino for treatment of preterm infants with respiratory distress, BPD, or pulmonary hypertension has not been standardized and its impact is not known. The effectiveness of ino in adults with acute respiratory distress syndrome (ARDS) has not been demonstrated. The above recommendations for the use of ino are based on controlled clinical trials, except as mentioned in the first bullet. Policy updates: We found three Cochrane reviews (Barrington, 2017a; Barrington 2017b [updated 2010]; Gebistorf, 2016) and two consensus statements (Hansmann, 2016; Kaestner, 2016) for this policy update. The new evidence found that ino is effective at an initial concentration of 20 ppm for term and near-term infants with hypoxic respiratory failure who do not have a diaphragmatic hernia, but it is not an effective treatment for preterm infants (Barrington, 2017a and 2017b). For adults with ARDS, ino results in a transient improvement in oxygenation but not a reduction in mortality, and may increase renal impairment (Gebistorf, 2016). The European Paediatric Pulmonary Vascular Disease Network (EPPVDN) strongly supports ino for treating acute pulmonary vascular crisis and/or acute exacerbation of pediatric pulmonary hypertension, but only weakly supports ino for treating post-operative pediatric pulmonary hypertension in the intensive care unit (Hansmann, 2016; Kaestner, 2016). These results do not change previous findings. Therefore, no policy changes are warranted. Summary of clinical evidence: Citation Barrington (2017a) Content, Methods, Recommendations Cochrane review ino for respiratory failure in infants born at or near term Systematic review and meta-analysis of 17 RCTs that compared ino versus control (placebo or standard care without ino) in infants with moderate or severe illness. Overall quality: moderate to high. ino reduced the incidence of the combined endpoint of death or use of ECMO and improved oxygenation in the short term. Earlier ino reduced disease progression, but did not further decrease mortality, nor the need for ECMO. ino did not affect mortality, incidence of disability, incidence of deafness, or infant development scores. No clear correlation between echocardiographic evidence of persistent pulmonary hypertension of the newborn and response to ino. Outcomes of infants with diaphragmatic hernia were not improved (moderate-quality evidence). 4

5 Citation Barrington (2017b; updated 2010) Cochrane review ino for respiratory failure in preterm infants Gebistorf (2016) Cochrane review ino for acute ARDS Hansmann (2016) for the EPPVDN Expert consensus statement on the diagnosis and treatment of pediatric pulmonary hypertension Kaestner (2016) for the EPPVDN Pediatric pulmonary hypertension in the intensive care unit Hayes (2014) ino for ARDS in adults Kumar P (2014) for the American Academy of Pediatrics Guidance: ino in preterm infants Content, Methods, Recommendations Systematic review and meta-analysis of 17 RCTs (3,957 total patients). ino used as rescue therapy, early routine use in infants with pulmonary disease, or as later treatment based on risk of BPD has no significant effect on the risk of death, BPD, intraventricular hemorrhage, other serious brain injury, or adverse long-term neurodevelopmental outcomes. Systematic review and meta-analysis of 14 RCTs. Overall quality: moderate-to-high with low-to-moderate risk of bias. No statistically significant effects of ino on ventilator-free days (five RCTs, 804 participants) or any mortality measure in any age group. Statistically significant improvement at 24 hours in partial pressure of oxygen in arterial blood (PaO2)/fraction of inspired oxygen (FiO2) (11 trials, 614 participants) and in oxygenation index (five RCTs, 368 participants). Statistically significant increase in renal failure in the ino groups. ino is mainly used in the ICU setting and is useful in patients with acute pulmonary vascular crisis and/or acute exacerbation of pulmonary hypertension in the setting of an underlying parenchymal lung disease and/or pediatric pulmonary hypertension (strong recommendation; moderate-quality evidence). ino may be considered for treatment of postoperative PH in mechanically ventilated patients to improve oxygenation and reduce the risk of pulmonary hypertensive crisis (weak recommendation; moderate-quality evidence). Systematic review of three RCTs (549 total patients). Overall quality: high with low risk of bias. ino does not improve clinical outcomes for adult patients who have ARDS. There is a lack of a mortality benefit, a marginal benefit on arterial oxygenation, and the potential risk of renal impairment. The results of RCTs, traditional meta-analyses, and an individualized patient data metaanalysis indicate neither rescue nor routine use of ino improve survival in preterm infants with respiratory failure (evidence quality, A; grade of recommendation, strong). The preponderance of evidence does not support treating preterm infants who have respiratory failure with ino to prevent or ameliorate BPD, severe intraventricular hemorrhage, or other neonatal morbidities (evidence quality, A; grade of recommendation, strong). The incidence of cerebral palsy, neurodevelopmental impairment, or cognitive 5

6 Citation Askie (2011) ino in pre-term infants (< 37 weeks of gestation) Cole (2011) NIH Consensus Development Conference Statement: ino for premature infants ( 34 weeks of gestation) Allen (2010) for AHRQ ino in pre-term infants DiBlasi (2010) for the AARC Guideline: ino for neonates with acute hypoxic respiratory failure Content, Methods, Recommendations impairment in preterm infants treated with ino is similar to that of control infants (evidence quality, A). There are limited data and inconsistent results of the effects of ino on pulmonary outcomes of preterm infants in early childhood. Individual-patient data meta-analysis of 12 RCTs (3,298 infants). No statistically significant effect of ino on death, chronic lung disease, or severe neurologic events on imaging. No statistically significant differences in ino effect according to any of the patient-level characteristics tested (gestational age, race, oxygenation index, postnatal age at enrollment, evidence of pulmonary hypertension, and mode of ventilation). A starting ino dose of > 5 ppm versus 5 ppm showed evidence of improved outcome (interaction P =.02); effect of higher starting doses on outcomes is inconclusive. Conclusion: Routine use of ino for treatment of respiratory failure is not recommended. Evidence suggests biological plausibility. Combined evidence from 14 RCTs shows equivocal effects on pulmonary, survival, and neurodevelopmental outcomes. Systematic review and meta-analysis of 14 RCTs and eight cohort studies comparing ino versus standard therapy. Overall quality: moderate for survival outcomes and low for all other outcomes. No studies were powered adequately to detect meaningful differences in infant functional outcome or quality of life. Current evidence does not support routine use of ino to treat premature infants; ino may offer some benefit based on the following observations: - A small but statistically significant difference in death or BPD at 36 weeks of post-menstrual age, the common primary outcome variable of 73% of RCTs conducted to date. - A statistically significant reduction in chronic pulmonary medication use at one year of corrected age, suggesting less severe lung disease in those treated with ino. Further research is warranted. Recommends a short trial (30 to 60 minutes) of ino in newborns (> 34 weeks of gestation, < 14 days of age) with PaO2 < 100 mm Hg on FIO2 1.0 and/or an oxygenation index (OI) >_ 25 (Grade 1A). - ino should be judged by an improvement in PaO2 or oxygenation index (OI); if there is no response, ino should be discontinued (Grade 1A). Recommends ino therapy early in the disease course, which potentially reduces the length of mechanical ventilation, oxygen requirement, and stay within the intensive care 6

7 Citation Content, Methods, Recommendations unit (Grade 1A). No routine use of ino in newborns with: - Congenital diaphragmatic hernia (Grade 1A). - Cardiac anomalies dependent on right-to-left shunts, congestive heart failure, and lethal congenital anomalies (Grade 2C). - Congenital heart disease for postoperative management of hypoxia (grade 2C). The recommended starting dose for ino is 20 ppm (Grade 1A). References Professional society guidelines/other: Cole FS, Alleyne C, Barks JD, et al. NIH Consensus Development Conference statement: Inhaled nitricoxide therapy for premature infants. Pediatrics Feb; 127(2): Hansmann G, Apitz C. Treatment of children with pulmonary hypertension. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK. Heart. 2016; 102 Suppl 2: ii67 ii85. Kaestner M, Schranz D, Warnecke G, et al. Pulmonary hypertension in the intensive care unit. Expert consensus statement on the diagnosis and treatment of paediatric pulmonary hypertension. The European Paediatric Pulmonary Vascular Disease Network, endorsed by ISHLT and DGPK. Heart. 2016; 102 Suppl 2: ii57 ii66. Kumar P; Committee on Fetus and Newborn. Use of inhaled nitric oxide in preterm infants. Pediatrics Jan; 133(1): Peer-reviewed references: Allen MC, Donohue P, Gilmore M, et al. Inhaled Nitric Oxide in Preterm Infants. Evidence Report/Technology Assessment No (Prepared by Johns Hopkins University Evidence-based Practice Center under Contract No ). AHRQ Publication No. 11-E001. Rockville, MD: Agency for Healthcare Research and Quality. October AHRQ website: Accessed January 13, Askie LM, Ballard RA, Cutter GR, et al. Meta-analysis of Preterm Patients on Inhaled Nitric Oxide Collaboration. Inhaled nitric oxide in preterm infants: An individual-patient data meta-analysis of randomized trials. Pediatrics Oct; 128(4):

8 Barrington KJ, Finer N, Pennaforte T, Altit G. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev. 2017; 1: Cd (a) Barrington KJ, Finer N, Pennaforte T. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database Syst Rev. 2017; 1: Cd (b) Gebistorf F, Karam O, Wetterslev J, Afshari A. Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in children and adults. Cochrane Database Syst Rev. 2016; (6): Cd Hayes Inc., Hayes Medical Technology Report. Inhaled Nitric Oxide for Acute Respiratory Distress Syndrome (ARDS) in Adults. Lansdale, Pa. Hayes Inc.; 2016 (Updated 2016). DiBlasi RM, Myers TR, Hess DR. Evidence-based clinical practice guideline: inhaled nitric oxide for neonates with acute hypoxic respiratory failure. Respir Care Dec; 55(12): Hayes, Inc. Hayes Medical Technology Directory Report. Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in adults. Lansdale, Pa.: Hayes, Inc. October 26, INOmax (Nitric oxide). Approval letter. December 23, FDA website. Accessed January 13, INOmax (Nitric oxide). Supplemental approval letter. June 15, FDA website. Accessed January 13, Keszler M. Guidelines for Rational and Cost-Effective Use of ino Therapy in Term and Preterm Infants. J Clin Neonatol Apr; 1(2): Soll RF. Inhaled nitric oxide for respiratory failure in preterm infants. Neonatology. 2012; 102(4): CMS National Coverage Determinations (NCDs): No NCDs identified as of the writing of this policy. Local Coverage Determinations (LCDs): No LCDs identified as of the writing of this policy. Commonly submitted codes 8

9 Below are the most commonly submitted codes for the service(s)/item(s) subject to this policy. This is not an exhaustive list of codes. Providers are expected to consult the appropriate coding manuals and bill in accordance with those manuals. CPT Code Description Comments Pharmacologic agent administration (eg, inhaled nitric oxide, intravenous infusion of nitroprusside, dobutamine, milrinone, or other agent) including assessing hemodynamic measurements before, during, after and repeat pharmacologic agent administration, when performed (List separately in addition to code for primary procedure) Ventilation assist and management, initiation of pressure or volume preset ventilators for assisted or controlled breathing; hospital inpatient/observation, initial day Ventilation assist and management, initiation of pressure or volume preset ventilators for assisted or controlled breathing; hospital inpatient/observation, each subsequent day ICD-10 Code Description Comments P07.38 Preterm newborn, gestational age 35 completed weeks P07.39 Preterm newborn, gestational age 36 completed weeks P29.3 (Persistent)primary pulmonary hypertension of newborn HCPCS Level II Code N/A Description Comments 9