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ARTICLE: Derek C. Angus, Gilles Clermont, R. Scott Watson, Walter T. Linde-Zwirble, Reese H. Clark, and Mark S. Roberts Cost-Effectiveness of Inhaled Nitric Oxide in the Treatment of Neonatal Respiratory Failure in the United States Pediatrics 2003; 112: 1351-1360 [Abstract] [Full text] [PDF]

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Cost-effectiveness of inhaled nitric oxide

Ronald W. Day   (13 January 2004)

In Response to Dr. Day

Derek C Angus, Mark S. Roberts, MD, MPP and Reese H. Clark, MD   (15 March 2004)

Cost-effectiveness of inhaled nitric oxide 13 January 2004
Ronald W. Day, Pediatric Cardiologist University of Utah Send letter to journal: Re: Cost-effectiveness of inhaled nitric oxide pcrday{at}ihc.com Ronald W. Day	To the Editor.- I read with concern an article reporting the cost-effectiveness of inhaled nitric oxide by Dr. Angus and associates.1 I appreciate the editorial comments of Dr. Field and associates.2 Dr. Angus and associates performed a superb analysis. Unfortunately, the study is based upon an inappropriate assumption, which limits the scientific merit and credibility of the results. I believe at least 2 additional comments should supplement the remarks of Dr. Field and associates. First, the authors used a cost of $125.00 per hour for inhaled nitric oxide. This is currently the cost that INO Therapeutics charges hospitals for the use of inhaled nitric oxide. It is not the cost that is billed to patients or their insurance providers. In the United States, hospitals frequently charge an additional cost. At Primary Children’s Medical Center, inhaled nitric oxide is billed at $179.95 per hour. This cost does not include the additional charges of respiratory therapists and neonatologists who modify charges according to the complexity of care. The actual cost of inhaled nitric oxide is much different than the authors reported. As a result, the actual profile of cost-effectiveness is considerably less favorable than reported. This oversight is inconsistent with the authors’ otherwise meticulous attention to detail in the statistical analysis. It is disappointing that an obvious flaw was overlooked during the review process of a company-sponsored manuscript. Second, nitric oxide is frequently being used inappropriately. The authors claim that the profile of cost-effectiveness would be more favorable if patients with congenital diaphragmatic hernia were excluded from the analysis. This is probably true. In the United States however, it is not uncommon for inhaled nitric oxide to be used in newborns with lung hypoplasia and older children with acute respiratory failure even though previous studies have failed to show a sustained beneficial effect of therapy.3,4 The empiric use of inhaled nitric oxide following surgery for congenital heart disease is also unnecessary for many patients.5 I have witnessed a dramatic improvement in the clinical condition of many patients who have been treated with inhaled nitric oxide. I know it is an effective therapy for selected patients. However, I believe the cost of inhaled nitric oxide is excessive. Ronald W. Day, MD Division of Pediatric Cardiology Primary Children’s Medical Center 100 North Medical Drive Salt Lake City, UT 84113 References 1. Angus DC, Clermont G, Watson RS, Linde-Zwirble WT, Clark RH, Roberts MS. Cost-effectiveness of inhaled nitric oxide in the treatment of neonatal respiratory failure in the United States. Pediatrics. 2003;112:1351-1360 2. Field D, Normand C, Elbourne D. Cost-effectiveness of inhaled nitric oxide in the treatment of neonatal respiratory failure in the US. Pediatrics. 2003;112:1422-1423 3. The Neonatal Inhaled Nitric Oxide Study Group (NINOS). Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital diaphragmatic hernia. Pediatrics. 1997;99:838-845. 4. Day RW, Allen EM, Witte MK. A randomized, controlled study of the 1-hour and 24-hour effects of inhaled nitric oxide therapy in children with acute hypoxemic respiratory failure. Chest. 1997;112:1324-1331. 5. Day RW, Hawkins JA, McGough EC, Crezeé KL, Orsmond GS. Randomized controlled study of inhaled nitric oxide after operation for congenital heart disease. Ann Thorac Surg. 2000;69:1907-1913.
In Response to Dr. Day 15 March 2004
Derek C Angus, Professor and Vice Chair Department of Critical Care Medicine, The CRISMA Laboratory, University of Pittsburgh, Pittsburgh,PA, Mark S. Roberts, MD, MPP and Reese H. Clark, MD Send letter to journal: Re: In Response to Dr. Day angusdc{at}ccm.upmc.edu Derek C Angus, et al.	We thank Dr. Day for complimenting the quality of our analysis and for raising several important issues. We offer the following in consideration of his concerns. First, he cites the fact that the hospital acquisition cost for iNO is less than that charged to patients. However, when conducting a cost- effectiveness assessment from the societal perspective, one models the likely cost to society. Even though hospitals “up-charge” medications, insurers rarely pay these upcharges. Instead, they pay based on an estimate of hospital costs. Indeed, hospital charges can often be considerably higher than the 50% or so increase cited by Dr. Day. Typically, charges are 100 to 200% higher than actual costs. These charges, though unpleasant for an individual without insurance, are essentially irrelevant for anyone with insurance, including the large proportion of neonates managed under Medicaid. They are even somewhat irrelevant for many patients without insurance, because of charity care and default on payment. Thus, they are deliberately ignored in this analysis. One additional point regarding this issue: if we were to consider the hospital charge, we would need to consider all hospital charges at face value, which would massively increase all hospital costs, including costs of ECMO, mechanical ventilation, etc. Many of the savings associated with iNO are due to reduced hospital costs. Therefore, if these costs were larger (i.e., calculated from the reduction in charges), the savings with iNO might paradoxically increase under Dr. Day’s recommendation. Second, he raises the fact that there are hidden costs to iNO administration, which includes the cost of respiratory therapists and neonatologists who modify charges according to complexity of care. We were very aware of the potential change in ancillary hospital costs, resulting either in increased costs on particular hospital days or increased costs due to a prolongation of hospital stay. We therefore modeled this in our sensitivity analysis. Using hospital length of stay as a proxy for hospital costs, we artificially prolonged or shortened hospital length of stay up to a change of 4 days outside the observed effect on length of stay in the CINRGI trial.(1) Treatment with iNO was still cost saving even if length of stay increased by almost 2 days, and was still under the $100,000 per QALY willingness-to-pay threshold if length of stay increased by almost 3 days (see Table 3 in Angus, et al.(2)). Given that such prolongation of length of stay is the equivalent of several thousand dollars in expense, it is unlikely that modifications in respiratory therapist or neonatologist care during the time iNO is infused would be more than this. Therefore, although an important theoretical concern, as demonstrated in our sensitivity analysis, it does not meaningfully impact our results. It follows from the above that we do not believe there was ‘an obvious flaw’, and consequently do not believe anything was overlooked in the peer review process. Dr. Day also alludes to the fact that our manuscript was company-sponsored. While it is true that our study was sponsored by iNO Therapeutics, iNO Therapeutics had no editorial input to this work and did not explicitly fund this manuscript. The study was executed under a grant from INO Therapeutics, Inc. to the University of Pittsburgh. As part of the financial contract for this grant, iNO Therapeutics signed and abided by the University of Pittsburgh Office of Research Publications Agreement, which protects the authors from company interference. We do not minimize the potential for conflict of interest, and we have attempted to be forthright in our disclosure of such potential, but believe we have felt ‘free to operate’ in all aspects of this work. In response to Dr. Day’s second concern, we agree that there is considerable inappropriate use of iNO and that the FDA labeled indications do not cover many of the patients currently being treated. The "off label" use of any product is experimental. While common in neonatology, the off label use of any product must be considered unsafe and without credible (or at least FDA approvable) evidence of efficacy. The FDA mandates that pharmaceutical companies and device manufactures discourage the off label use of their products. Insurance companies and other third party payers do not have to pay for experimental practices and therefore it would be inappropriate to try to include the off label use of iNO in a cost effective analysis. As other indications develop and are approved based on credible science then it would be appropriate to redo our analysis to include these new types of patients. Sincerely, Derek C. Angus, MB, ChB, MPH Mark S. Roberts, MD, MPP University of Pittsburgh Pittsburgh, PA 15213 Reese H. Clark, MD Pediatrix Medical Group, Inc Sunrise, FL 33223 References 1. Clark RH, Kueser TJ, Walker MW, et al: Low-dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. N Engl J Med 2000; 342:469-474 2. Angus DC, Clermont G, Watson RS, et al: Cost-effectiveness of inhaled nitric oxide in the treatment of neonatal respiratory failure in the United States. Pediatrics 2003; 112:1351-1360