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* AccessCare, Morrisville, North Carolina
Department of Pediatrics, School of Medicine
Pharmaceutical Policy and Evaluative Sciences, School of Pharmacy
|| Department of Medicine, School of Medicine
¶ Department of Health Policy and Administration, School of Public Health, University of North Carolina, Chapel Hill, North Carolina
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Methods. A cohort study was performed of infants who were younger than 1 year and were enrolled in an enhanced primary care case management model within the North Carolina Medicaid Program. Comparisons were made between infants who received (Synagis prophylaxis group) and did not receive palivizumab (nonprophylaxis group) during the study period. Cost was examined using the sum of Medicaid paid services for prophylaxis with palivizumab and treatment for RSV infections that occurred between October 1, 2002, and May 31, 2003. The Anderson framework was used to specify the regression cost models to compare the participants who received (Synagis prophylaxis) and did not receive (nonprophylaxis group) palivizumab. The primary outcomes were actual 7-month seasonal costs and standardized seasonal costs adjusting for the varied months of infant participation.
Results. The study sample included 185 Synagis prophylaxis and 182 nonprophylaxis participants who met the inclusion criteria. The average per-person total cost of RSV care and prophylaxis was $5117 for the Synagis prophylaxis group and $371 for the nonprophylaxis group. Five hospitalizations occurred in the prophylaxis group, and 12 occurred in the nonprophylaxis group (odds ratio: 0.27). No deaths occurred in either group.
Conclusions. Palivizumab administered to infants who were born at 32 to 35 weeks' EGA did not provide direct cost savings related to hospitalization or ambulatory care in a Medicaid population. The primary difference in cost between the groups was attributable to the palivizumab prophylaxis.
Key Words: respiratory syncytial virus • bronchiolitis • prophylaxis • palivizumab • cost analysis • Synagis
Abbreviations: RSV, respiratory syncytial virus • EGA, estimated gestational age • CLD, chronic lung disease • AAP, American Academy of Pediatrics • PA, prior authorization
Respiratory syncytial virus (RSV) is the leading cause of serious lower respiratory tract infections in children.1–7 Serious RSV disease, often measured by the need for hospitalization, is predominantly manifested as bronchiolitis in infants yet may occur as pneumonia.5 In the United States, >90 000 hospitalizations are attributed to RSV per year.6,8,9
The efficacy of palivizumab, a humanized monoclonal antibody, was investigated during the 1996–1997 RSV season in the Impact-RSV randomized, double-blind, placebo-controlled trial.6 Participants who received palivizumab experienced a 55% reduction in RSV hospitalizations compared with nontreated control subjects for all risk groups in the study sample. In this same randomized trial, an 80% reduction in RSV hospitalizations was observed in the 32- to 35-week estimated gestational age (EGA) subgroup. In contrast, an observational study that examined children who were 10 months or younger at the start of the season and had a diagnosis of prematurity or chronic lung disease (CLD) and were enrolled in the Kansas Medicaid Program reported that the impact of palivizumab on hospitalization reduction was smaller (50%).10
In 1998, the Food and Drug Administration approved the drug palivizumab for preventing serious lower respiratory tract disease caused by RSV in pediatric patients who are at high risk for RSV disease.4,11 That same year, the American Academy of Pediatrics (AAP) recommended consideration of palivizumab use for infants (1) who are younger than 2 years with CLD requiring medical therapy for this condition within 6 months of the RSV season; (2) who were born at 28 weeks' EGA or earlier up to 12 months of age; (3) who were born at 29 to 32 weeks' EGA for up to 6 months of age; and (4) who were born between 32 and 35 weeks' EGA only with additional risk factors defined as "underlying conditions that predispose to respiratory complications (eg, neurologic disease in very low birth weight infants), number of young siblings, child care center attendance, exposure to tobacco smoke in the home, anticipated cardiac surgery, and distance to and availability of hospital care for severe respiratory disease."11 The AAP published revised recommendations for RSV prophylaxis with palivizumab in 2003. The 2003 recommendations for infants in the 32- to 35-week EGA risk group reserve palivizumab prophylaxis for those with 
2 of the following risk factors: child care attendance, school-aged siblings, exposure to environmental air pollutants, congenital abnormalities of the airways, and severe neuromuscular disease.12
The North Carolina Medicaid program has used a series of measures to encourage compliance with the 1998 AAP published recommendations, including implementation of a prior authorization (PA) program for palivizumab use. During the 2002–2003 RSV season, the North Carolina PA criteria closely matched the 1998 AAP published recommendations. Participants who met the following guidelines were automatically approved for palivizumab administration: (1) infants who were <24 months with CLD that has necessitated treatment in the last 6 months, (2) infants who were born at 28 to 32 weeks' EGA without CLD and were younger than 6 months at the start of the RSV season, (3) infants who were born at 
28 weeks' EGA without CLD and were younger than 12 months at the start of the RSV season, and (4) infants who were born at 32 to 35 weeks' EGA without CLD and were younger than 6 months at the start of the RSV season with 2 illnesses or risk factors that predispose the infant to respiratory complications. Any requests that were sent back to the primary care physician requested missing or additional information. All requests that were resubmitted were ultimately approved.
The cost benefit of palivizumab use in infants who were born at 32 to 35 weeks' EGA and are younger than 1 year has been studied with mixed results.8,10,13–16 Joffe et al13 reported cost estimates of $38 000 to $420 000 per hospitalization averted for RSV infection in infants who were born at 32 to 35 weeks' EGA, taking into consideration the duration of perinatal oxygen use and month of neonatal intensive care unit discharge. Shireman et al15 reported that in all patients, costs of prophylaxis with palivizumab were 6.67 times higher than RSV treatment costs in the Kansas Medicaid program. A number of published cost analyses used hypothetical cohorts with published costs and hospitalization rates from efficacy trials, and several applied hospitalization costs or charges that were not specific to the 32- to 35-week EGA subgroup.13–16
Concern exists over the high costs associated with palivizumab prophylaxis and the absence of definitive peer-reviewed economic evaluations of palivizumab use in the 32- to 35-week EGA subgroup.11,13 The cost of palivizumab prophylaxis (drug only) to the North Carolina state Medicaid program was $12.3 million in 2003. The aim of this investigation was to determine whether the costs of palivizumab use in the 32- to 35-week EGA subgroup outweigh the direct health care costs associated with serious RSV infection in a cohort of North Carolina Medicaid recipients who qualify for palivizumab treatment under current guidelines. Costs and impact on participants' health after the study period were not examined.
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METHODS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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The Anderson model for access to health care services was selected as the theoretical framework to guide identification of covariates that have the potential to influence patients' access to and utilization of health care services. This model categorizes characteristics of the population at risk into 3 groups: predisposing, enabling, and need (risk) variables.18,19 The predisposing variables are those that "describe the propensity of individuals to use services," such as gender, race, religion, and values regarding health.18 The variables race, gender, and age of participant's mother at the infant's date of birth were selected as predisposing variables to be used in our models. The enabling variables refer to resources that the patients and families have to use services, such as income, insurance, and geographic region.18 The enabling variables incorporated into our models include the highest educational level attained by the infant participant's mother and the number of miles the infant lived from a hospital that cares for infants or children or has an emergency department.11,12 Because all study participants were covered by Medicaid during the study period, income and insurance status were not selected for statistical modeling. The need variables refer to one's illness level or perceived need for care as evaluated by the individual or the health care delivery system.18 The need variables were selected for this study on the basis of the North Carolina PA guidelines for palivizumab use in 2002–2003 and include whether an infant participant (1) had a sibling in school, (2) attended day care during the study period, (3) is exposed to cigarette smoke in the home, or (4) was part of a multiple birth.11,12 Risk variables identified from the North Carolina PA program were supplemented with the number of people living in the infant participant's home during the study period (as a proxy for crowding), the infant's estimated gestational age in weeks, and the infant participant's birth weight in kilograms.11
Patients for the study were selected from all 28 widely dispersed pediatric practices that serve North Carolina Medicaid patients within the AccessCare/Community Care Program, an enhanced primary care case management program. Study participant recruitment began in late January 2003, independent of the physicians' decisions to recommend palivizumab and of the North Carolina PA program. Potential study participants, those having received or not received palivizumab, in any of the North Carolina PA risk categories were identified by local care managers at participating practices through review of palivizumab PA forms, Medicaid claims, birth lists and medical records, and meetings with Synagis nurses. Potential participants were screened for eligibility using date of birth, EGA, Medicaid and Carolina Access enrollment, and comorbidities. Patients were eligible for this economic study when they were born between March 1, 2002, and February 28, 2003, at 32 to 35 weeks' EGA and enrolled in the AccessCare Medicaid program during the study period. Patients were excluded from this 32- to 35-week EGA subgroup when they had a diagnosis of CLD and/or hemodynamically unstable congenital heart disease to study a relatively homogeneous risk group. CLD was defined as patients "with CLD who have required medical therapy (supplemental oxygen, bronchodilator, diuretic, or corticosteroid therapy) for CLD within 6 months before the anticipated start of the RSV season."7 A physician and nurse team reviewed patient diagnoses and treatments listed in medical records and Medicaid claims data to identify patient exclusions, as defined in the Red Book, 2003.7
Data Collection
Study data for Synagis prophylaxis and nonprophylaxis participants were collected from parental survey, medical record abstraction, and North Carolina Medicaid claims and demographic files. Local care managers provided names of eligible children and contact information to research personnel. Parents or guardians were contacted by research staff at the end of the season by telephone to perform a 21-question survey to identify risk factors for RSV hospitalization, respiratory-related hospitalizations, and demographic data. When families were not reached by telephone, data were collected by home or clinic visit or chart review. Survey data were entered into a SQL server database.
Medicaid health care claims were obtained in December 2003 for health care services that were provided during the study period. Inpatient claims were screened using diagnoses: acute bronchiolitis due to RSV, acute bronchiolitis due to other infectious organism, acute bronchitis, RSV pneumonia, pneumonia organism not otherwise specified, and viral pneumonia. For inpatient stays identified by claims and/or survey, care managers abstracted medical records to determine RSV test results (rapid antigen tests). Hospitalizations and related costs were included in the analyses when RSV tests were positive or when RSV tests were not performed but RSV was listed in the final diagnoses. When RSV tests were negative, hospitalizations were excluded.
Ambulatory care claims, including outpatient, emergency department, and office visits, were included for all RSV-related and/or bronchiolitis diagnoses or wheezing because RSV testing is not routinely performed by providers in this study for ambulatory care services. Ambulatory care claims were not adjusted for lack of RSV testing because previous cost studies of palivizumab have found cost modeling to be insensitive to changes in the number of emergency department and physician office visits.14
Palivizumab injection dates and doses were abstracted from medical records, including injections that were given during hospitalizations. Palivizumab was not provided to study participants during home visits. Palivizumab injection data (medical records) were compared with Medicaid palivizumab drug claims. Medical records data were selected as the source for dates of administration and doses because palivizumab is provided to the physician practice and billed by a pharmacy provider that is a wholesale distributor within the North Carolina Medicaid program. In this program, the palivizumab drug claim service dates frequently precede the injection dates in the medical records. The costs of injections were assigned to injections on the basis of doses and North Carolina Medicaid reimbursement rates. When only the injection date was abstracted from the medical record, the cost was assigned from the claims database. Palivizumab costs were adjusted for (1) the manufacturer's discount to the state Medicaid programs according to the federal rebate program, (2) drug handling fees, and (3) nurse visits (in lieu of physician office visits billed for some injections) for conservative cost estimates.
Participants were assigned to the nonprophylaxis study group in the absence of documented evidence of palivizumab injections and to the Synagis prophylaxis group when there was documented evidence of receipt of at least 1 palivizumab injection during the study period. RSV-attributed hospitalizations were reviewed for temporal relationships to palivizumab injections to identify prophylaxis status at the time of admission. The 4 participants who were identified as having RSV-attributed hospitalizations occurring before receipt of palivizumab were assigned to the nonprophylaxis study group as this was their prophylaxis status as of the time of admission. All eligible health care costs and utilization for these 4 participants were assigned to the nonprophylaxis study group for conservative cost estimates. This included the costs of 1 participant who was hospitalized with an RSV infection both before and after palivizumab prophylaxis, whose costs were not allocated between the 2 study groups because this report does not include person-time analytic methods.
Statistical Methods
In these analyses, 2 primary outcome variables were defined: hospitalizations for RSV-related conditions and the total RSV-related health care costs per individual for the 7-month study period. Taking the payer perspective, in this case North Carolina Medicaid, the total RSV-related cost was defined to include expenditures on all RSV-related health care services including hospitalization, emergency department, ambulatory care (outpatient and office visit), and palivizumab prophylaxis costs. Total seasonal costs were measured in both actual value and standardized value. The latter was used to account for the fact that some infants were born after the beginning of the study period and therefore did not complete the full 7-month study period. The total seasonal cost variable was standardized by dividing the total individual costs by the actual number of months that a child was in the study and multiplying by 7 months. Because the rapid antigen tests used to detect RSV have sensitivities that are 80% to 90% effective,20 it is likely that all RSV-attributed hospitalizations were not captured using the inclusion criteria. Therefore, sensitivity analyses of total costs were performed by including hospitalization costs for non-RSV bronchiolitis for comparison.
Power calculations estimated that a sample size of 16 in each study group was needed to detect an effect size of 1.92 or greater using projected average monthly costs (outcome) with 90% power (.05 level of significance, 1-sided).21 For detecting differences in hospitalization proportions with a relative risk of 0.2, at least 114 patients per study group were required.22
Using the Anderson framework,18,19 a descriptive analysis was conducted to compare predisposing, enabling, and need factors between the Synagis prophylaxis and nonprophylaxis study groups, with differences tested using the 
2 test for dichotomous and categorical variables and the t test for continuous variables.23,24 The pooled t test was selected for equal variances, and Satterthwaite t test was chosen for unequal variances, based on the F test. The descriptive statistics provide information on possible confounding of palivizumab's protective effect as a result of potential sample selection bias. Unadjusted per-participant average seasonal costs and utilization were compared between the study groups for RSV-attributed hospitalizations, ambulatory care visits, emergency department visits, and palivizumab injections. In addition, to assess the similarity of health status between the 2 study groups, the overall health care costs for the duration of the study period, net of the costs of RSV treatment and palivizumab prophylaxis were compared.
After the descriptive analysis, multivariate regression analyses were conducted to assess the protective effect of palivizumab on the risk of hospitalization and costs while controlling for possible confounding factors, such as previously identified risk factors. Specifically, 3 multivariable regression models were estimated. Model 1 is a logistic regression model that estimated the between-group difference in the likelihood of RSV hospitalization during the study period. Model 2 is a linear regression of individual seasonal total costs as a function of palivizumab intervention and other covariates, using both actual and standardized costs. Model 3 is a log-transformed regression of the seasonal costs in an attempt to minimize the highly skewed distribution of the cost data. In each regression model, the potential influence of risk factors and other covariates on costs and hospitalizations, individually, as index variables, and as dichotomized index variables, was assessed. Index risk factor variables were created by counting the number of positive risk factors identified for each study participant, first using 2002–2003 PA criteria and second using 2003–2004 PA criteria. Dichotomous risk factor variables then were created by identifying participants with 2 positive risk factors versus <2.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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2 positive risk factors) were not statistically significant in any of the regression models.
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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With >4 million live births in the United States each year27 and 
5.6% occurring at 32 to 35 weeks' EGA,28 RSV prophylaxis in this relatively large population subgroup has major economic implications for payers. The absence of significant differences in direct costs of hospitalization and ambulatory care for RSV infection between the study groups without addition of the palivizumab expense presents an interesting dilemma for payers, such as North Carolina Medicaid, in the absence of long-term health outcome data for RSV-infected infants in this gestational age group. In the absence of information on long-term health outcomes and costs and with limited resources available for publicly funded health care, it seems prudent to consider cost of palivizumab as 1 factor in developing policies and practice guidelines for treatment of patients who are at risk for serious RSV infections. Focusing effort on preventive measures to reduce risk of severe RSV infection in higher risk groups, if these can be defined, seems appropriate. Currently, the 2 risk factor approach to identifying at-risk infants seems to be a conservative approach to this issue but was not supported by analyses of our data. Public health efforts to reduce prematurity and low birth weight should be the highest priority.29 Development of an effective vaccine is also viewed as a high priority.2,8,20 Promotion of continued breastfeeding throughout infancy has been suggested.29 Health care providers have a role in counseling caregivers on the importance of not exposing infants to tobacco smoke (including prenatal), good handwashing, and limiting infant exposure to crowds and children with respiratory infections.7,12 These public health initiatives will likely provide a means to reduce infection but have not been widely implemented.
In the past few years, many states have suffered with deficit budgets and ballooning Medicaid costs.30 As a result, many states have cut enrollment, eliminated services, and decreased reimbursement.30,31 Drug costs have continued to rise as a percentage of the total expenditures and in total dollars. Palivizumab costs were the highest for any single drug within the AccessCare/Community Care Program in 2001. With costs of RSV prophylaxis in our 32- to 35-week EGA study group far exceeding the costs of treatment for RSV-attributed infections, and in the absence of clear data to support long-term outcome differences in this gestational age group with or without palivizumab treatment, consideration must be given to the continued use of this drug in 32- to 35-week EGA infants. When Medicaid programs are faced with decisions concerning cutting enrollment versus reducing drug use that is not cost-effective, we feel certain that the choice is obvious.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Of particular importance was the observation that there were no deaths reported in our cohort during the study period, the same as observed in the IMpact RSV placebo group.6 Death was not a factor in our cost analysis.
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ACKNOWLEDGMENTS |
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We are indebted to the study participants; practice site staff and physicians; and patient support coordinators, local care managers, regional project managers, and data support staff at AccessCare for dedication and involvement in data collection. We are also grateful to Dr Charles Willson, East Carolina University, and Dr Marian Earls, at Guilford Child Health, for support and assistance in study planning and implementation.
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FOOTNOTES |
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Reprint requests to (S.W.) AccessCare, 3500 Gateway Centre Blvd, Suite 130, Morrisville, NC 27560-8501. E-mail: sew{at}ncaccesscare.org
No conflict of interest declared.
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REFERENCES |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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This article has been cited by other articles:
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  J. Gooding, A. Millage, A.-K. Rye, and R. Lacroix The Cost and Safety of Multidose Use of Palivizumab Vials Clinical Pediatrics, March 1, 2008; 47(2): 160 - 163. [Abstract] [PDF]
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