- Email: [email protected]
Palivizumab Utilization and Compliance: Trends in Respiratory Syncytial Virus Prophylaxis in Florida
Palivizumab Utilization and Compliance: Trends in Respiratory Syncytial Virus Prophylaxis in Florida Christian Hampp, PhD, Arwa S. Saidi, MBBCh, and Almut G. Winterstein, PhD Objectives To analyze adherence to guidelines to prevent respiratory syncytial virus hospitalization and to a monthly immunoprophylaxis schedule in the absence of prior authorization requirements.
Study design Among Florida Medicaid fee-for-service recipients 0 to 2 years of age from the 1998/1999 season through the 2004/2005 season with available birth certificates, we identified indications for palivizumab prophylaxis based on claims data. At least 4 doses of palivizumab in the 5 core season-months were considered full season coverage. Results Of 302 101 children-seasons, 6089 were associated with 24 469 doses of palivizumab. In the 2004/2005 season, 73.6% of children with chronic lung disease received immunoprophylaxis, 67.6% children with gestational age <32 weeks, 37% with congenital heart disease, 26.4% with cystic fibrosis, and 19.4% with severe immunodeficiency. Multiple indications increased the likelihood for prophylaxis from 34.9% to 80.4%. Full season coverage was consistent across indications at approximately 70%. From the 1998/1999 season through the 2004/2005 season, 8038 doses were administered during 2051 children-seasons without any indication; mostly (69.6%) where premature children had exceeded the recommended age range for prophylaxis. Conclusions High utilization rates were found in children with multiple indications, and compliance with a monthly schedule was consistently high. One third of doses were administered outside of guidelines, suggesting suboptimal utilization of resources in the absence of prior authorization. (J Pediatr 2010;156:953-9).
R
espiratory syncytial virus (RSV) is the most frequent cause of lower respiratory tract infections among infants and children. According to one estimate for the United States, RSV causes up to 120 000 hospitalizations annually for pneumonia or bronchiolitis among infants younger than 1 year of age,1 whereas a more recent study reports an annual RSV hospitalization rate of 57 275 for children under the age of 5 years.2 The same study estimated that 2.1 million children under the age of 5 years seek medical attention for RSV infections each year—3% of whom are hospitalized, 25% visit emergency departments, and 73% are treated in pediatric practices. Although no vaccination is available for RSV, palivizumab (Synagis, MedImmune Inc., Gaithersburg, Maryland), a humanized monoclonal antibody, has been shown to prevent RSV-related hospitalizations,3,4 albeit at significant cost. Five doses of palivizumab are necessary to protect 1 child throughout a 5-month RSV season at an average total wholesale price that can exceed $8000, depending on body weight.5 These costs limit prophylaxis to children at greatest risk for infection, such as children with chronic lung disease (CLD), congenital heart disease (CHD), and certain preterm infants as recommended by the American Academy of Pediatrics (AAP) RSV prevention guideline from 2003.6 Among the listed indications, strength of evidence for the effectiveness of palivizumab ranges from expert opinion to data from randomized clinical trials. Accordingly, the guideline’s recommendations for indications that are not based on randomized clinical trials data are phrased more carefully (Table I; available at www.jpeds.com). Even though the strength of evidence is considered in guidelines development, it is unclear whether this is reflected in prescriber decision-making and palivizumab utilization rates. Information about underutilization in children who should receive prophylaxis and overutilization in those not included in the guidelines is critical for third-party payers to target policy interventions. Knowledge about palivizumab utilization in the absence of prior authorization programs can help health plans to develop or refine their own reimbursement policies to ensure access for children who might benefit from immunoprophylaxis and restrict access where the RSV hospitalization risk is low. Furthermore, because gaps in palivizumab administration may lead to suboptimal effectiveness, knowledge about adherence to the monthly dosing schedule during the core season is important to ensure optimal protection. We sought to analyze
AAP CF CHD CI CLD GA OR RSV
American Academy of Pediatrics Cystic fibrosis Congenital heart disease Confidence interval Chronic lung disease Gestational age Odds ratio Respiratory syncytial virus
From the Department Pharmaceutical Outcomes and Policy (C.H., A.W.), College of Pharmacy, the Department of Pediatrics (A.S.), College of Medicine; and the Department of Epidemiology and Biostatistics (A.W.), College of Public Health and Health Professions, University of Florida, Gainesville, FL Supported in part by a grant from the Florida Agency of Healthcare Administration, AHCA. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright Ó 2010 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2009.12.016
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longitudinal compliance with the 2003 AAP guidelines for RSV immunoprophylaxis with palivizumab in the Florida Medicaid population. We report the proportion of patients who recieved any palivizumab prophylaxis and the proportion with full compliance broken down by indication for prophylaxis during a single season. Further objectives were to investigate sociodemographic patient factors as determinants for immunoprophylaxis and to present the proportion of palivizumab recipients without indications according to guideline.
Methods Our sample consisted of Florida Medicaid fee-for-service recipients under 2 years of age. This analysis concentrated on the core months of the RSV season from October through February and covered 7 seasons from 1998/1999 through 2004/2005. To ensure that every subject had the chance to receive a full course of palivizumab, participants had to be continuously eligible between September and February to be included in the respective season. We restricted age to a minimum of 30 days on October 1 and a maximum of 2 years at the end of February. Subjects had to be in ambulatory care during September because inpatient claims data provide no information about medication utilization, which was necessary for the identification of guideline-supported indications for palivizumab prophylaxis. The unit of analysis was children-season, and 1 child could contribute up to 2 childrenseasons. To achieve valid estimates on gestational age, we matched Medicaid recipient data to birth certificates. Season Definition RSV seasons in Florida differ from the rest of the country, resulting in earlier onset and longer duration.7 As a consequence, seasonal palivizumab utilization can exceed the 5 doses per child, as are generally recommended for the northern hemisphere.6 Seasons differ even within the state, with longer seasons in the south compared with the north.8 To use a time period that is applicable to the whole state, we defined a core season from October through February to include months that consistently have shown high infection rates across the study period according to the Centers for Disease Control and Prevention’s National Respiratory and Enteric Virus Surveillance System and the Florida Department of Heath RSV Surveillance System.9,10 Indications We grouped risk factors for RSV infections according to AAP guidelines into 6 palivizumab indications, which are detailed in Table I (available at www.jpeds.com). This classification considered age restrictions for immunoprophylaxis such as a maximum age at season onset of 12 months for infants born before or during 28 weeks’ gestational age (GA). As a consequence, a prematurely born child with CLD would have multiple indications in the first year of life but only 1 indication, CLD, in the second year. 954
Vol. 156, No. 6 The guideline from 2003 added the CHD indication as a modification from the previous guideline published in 1998.11 To facilitate longitudinal comparisons, we applied the definitions from the 2003 guideline to the entire time period. International Classification of Diseases–Clinical Modification Version 9 codes of inpatient and outpatient claims were used in conjunction with drug claims (for CLD and CHD) to identify children with current indications for palivizumab. Utilization and Compliance Using National Drug Codes and procedure codes, we identified palivizumab claims for each season and assigned recipients into categories according to their number of claims in 1 season. Two claims had to be at least 20 days apart to ensure that single doses that were associated with multiple claims (for more than 1 vial) only were counted once. Because the nature of our data set did not allow for assessment of drug utilization during hospital stays, we imputed 1 dose of palivizumab for each hospital stay if the patient had another claim for palivizumab at some point in the season but not between admission and 30 days after discharge. We calculated the proportion of fully compliant users as the proportion of patients with at least 4 doses during 1 season divided by the number of palivizumab users, that is, children who received at least 1 dose. Although a 5-month season would require 5 doses of palivizumab for a high-risk patient, we accepted 4 doses as full coverage to allow for minor delays in palivizumab administration. For the most recent season in our study period, the 2004/ 2005 season, we calculated unadjusted exposure odds ratios for subjects with indication to determine predictors for immunoprophylaxis. Also for 2004/2005, we provide additional detail on the level of single indications. Within indications, we used conditional logistic regression to calculate the likelihood of receiving immunoprophylaxis associated with the presence of a second indication, adjusting for patient demographics (sex, age, race, Medicaid district, type of eligibility, and rural versus urban location). Data were analyzed using SAS 9.1.3 (SAS Institute, Cary, North Carolina), graphs were created in Microsoft Office Excel 2003 (Microsoft Corporation, Redmond, Washington), and Epi Info 3.3.2 (Centers for Disease Control and Prevention, Atlanta, Georgia) was used to calculate odds ratios and 95% confidence intervals. The institutional review boards of the University of Florida and the Florida Department of Health approved the study protocol.
Results After excluding patients without available birth certificates and applying our seasonal eligibility criteria, our sample consisted of 302 101 children-seasons. Among these, 6089 were associated with 24 469 doses of palivizumab during the seasons 1998/1999 through 2004/2005. Hampp, Saidi, and Winterstein
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Table II. Demographics of children with any indication for palivizumab prophylaxis, season 2004/2005 Palivizumab recipients n = 973 (children-seasons)
Sex Male Female Race White Black Hispanic Other/Unknown Age at season onset 0-6 mo 7-12 13-18 19-24 County Urban Rural Medicaid eligibility AFDC-TANF SSI OBRA Other
No palivizumab n = 1422
Odds ratio of receiving palivizumab
(%)
Frequency
(%)
Frequency
(95% CI)
53.2 46.8
518 455
51.4 48.2
737 685
Reference 0.95 (0.80 - 1.12)
22.3 19.3 13.0 45.4
217 188 126 442
26.7 28.7 23.6 21.1
379 408 335 300
Reference 0.80 (0.63 - 1.03) 0.66 (0.50 - 0.86) 2.57 (2.05 - 3.23)
55.2 27.7 13.6 3.60
537 269 132 35
55.2 21.9 17.4 5.49
785 311 248 78
Reference 1.26 (1.03 - 1.55) 0.78 (0.61 - 0.99) 0.66 (0.42 - 1.01)
87.5 12.5
851 122
89.7 10.3
1275 147
Reference 1.24 (0.96 - 1.62)
28.6 51.4 15.4 4.62
278 500 150 45
46.3 19.0 28.1 6.61
658 270 400 94
Reference 4.38 (3.56 - 5.40) 0.89 (0.70 - 1.13) 0.26 (0.17 - 0.39)
AFDC-TANF, Aid to Families with Dependent Children/Temporary Assistance for Needy Families; SSI, Supplemental Security Income; OBRA, Omnibus Budget Reconciliation Act.
Table II summarizes demographics of children with indication for palivizumab for the season 2004/2005. Girls show a similar likelihood of receiving palivizumab as boys (odds ratio [OR], 0.95; 95% confidence interval, 0.80 to 1.12). Our numbers indicate racial disparity, with blacks (OR, 0.80; 0.63 to 1.03) trending toward lower likelihood and Hispanics (OR, 0.66; 0.50 to 0.86) being less likely than whites to receive prophylaxis. The other/unknown race category is mainly (90.4%) composed of children with missing race information. Missing race information is associated with poorer health status in our data set, as 21.9% of these children are eligible for Medicaid through Supplemental Security Income status as aid for disability compared with approximately 1% in the general population. Likewise, a larger proportion of children with missing race were prematurely born (5.84%) compared with the general population (0.92%). Children in rural areas experience a trend toward higher likelihood for immunoprophylaxis compared with those in urban locations (OR, 1.24; 0.96 to 1.62). Children eligible for Medicaid through Supplemental Security Income showed increased odds of prophylaxis (OR, 4.38; 3.56 to 5.40). Utilization and Compliance Figure 1 depicts a longitudinal view of palivizumab utilization rates. The number of recipients increased steadily from 282 in the season 1998/1999 to 1486 in 2004/2005. In the last season, 3.27% of all infants in their first year of life received immunoprophylaxis compared with 1.70% of children in their second year. Proportions of full compliance increased during the first 2 RSV seasons when palivizumab became available (1998/1999 and 1999/2000), to reach a plateau at approximately 70% during the subsequent seasons (data not shown).
Children Without Indication Figure 2 contrasts the number of palivizumab doses administered to children with and without indications. In 1998/ 1999, 18.5% of doses were administered to children without indication. This proportion increased throughout the observation period to 36.3% in 2001/2002 and remained at a similar level thereafter. Across the seasons 1998/1999 through 2004/2005, 8038 doses of palivizumab were administered during 2051 children-seasons, in which recipients did not meet any guideline-recommended indication. Because the prematurity indications limit recommended prophylaxis to an age at season onset of 6 or 12 months depending on gestational age, we investigated the number of prematurely born children who received palivizumab despite exceeding the recommended age range before season onset. We identified 1405 prematurely born children who received 5597 doses after their recommended age. Of note, these children did not have any other indication for RSV prophylaxis. This group of palivizumab recipients accounts for 69.6% of the total 8038 doses received without indication. Utilization and Compliance by Indication, Season 2004/2005 Table III provides results of utilization within indications for the season 2004/2005. Among 55 082 children, 1486 (2.70%) received palivizumab, 973 with indication (65.5%) and 513 (34.5%) without indication for prophylaxis. Only 12.6% of children with indication and 0.54% of the whole sample had multiple indications. Compared with children with only 1 indication, multiple indications increased the likelihood for prophylaxis from 34.9% to 80.4% (OR, 4.37; 95% confidence interval [CI], 3.12 to 6.12, adjusted for sex, age, race, Medicaid district, type of eligibility, and rural versus urban location).
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Vol. 156, No. 6 Larger deviations are observable only in subgroups in which the count of palivizumab recipients was small.
Discussion
Figure 1. Palivizumab utilization comparison, first versus second year of life.
Overall, 73.6% of children with CLD received immunoprophylaxis; however, only 55.5% did so when no other indication was present. Compared with CLD only, the likelihood for receiving palivizumab increased to 83.3% (OR, 3.42 [1.76, 6.66]) with the presence of a second indication. Although more than two thirds of infants born at <32 weeks’ GA received palivizumab (67.6%) and 85.9% did so when additional indications were present, we observed a utilization rate of only 22.7% in children born at 32 to 35 weeks’ GA. Thirty-seven percent of children with CHD who met guideline criteria for prophylaxis received palivizumab but only 22.6% did so when CHD was the only indication. With additional indications, utilization increased to 79.1% (OR, 9.50 [6.09, 14.8]). Finally, of the 38 children with cystic fibrosis (CF) in our sample, 26.4% received prophylaxis, as well as 19.4% of 93 children with severe combined or acquired immunodeficiency. Complete Season Coverage Among all palivizumab recipients, 67.9% were considered fully compliant with at least 4 doses and 41.3% received at least 5 doses. Full compliance was achieved in 63.7% of cases without any indication and in 72.0% in which at least 1 indication were observed. Within indications, the proportion of full compliance was generally consistent at around 70%.
Figure 2. Palivizumab utilization outside of recommendations. 956
This large observational study provides comprehensive detail on palivizumab utilization and compliance. Two smaller studies relied on parental recollection of immunoprophylaxis: Mansbach et al12 found that 17 children of 35 who were eligible for prophylaxis received palivizumab (49%) and another study reports an adherence to guideline in only 14 of 40 children (35%).13 The latter study found that neither age, race, nor insurance status affected immunoprophylaxis, but this may be a result of limited statistical power. Compliance with a monthly prophylaxis schedule was investigated by a group in Italy who found a compliance rate with all recommended doses of 87%.14 This compliance rate is somewhat higher than the one observed in our study despite their stricter requirement that full compliance equals the receipt of all recommended doses. High compliance also was found in a Canadian study in which 77% of doses were given within 30 5 days of the previous injection and only 11.5% of children experienced an interruption in their dosing schedule.15 Our results indicate large variations in the proportion of palivizumab recipients by guideline-recommended indications. With some exceptions, the utilization rate corresponds to the strength of the available evidence for a given indication. We observed high utilization rates for CLD and premature birth <32 weeks’ GA, indications that are supported by grade I evidence according to guidelines. Evidence for palivizumab effectiveness in CF and severe combined or acquired immunodeficiency is weak at grade III and is reflected in low prophylaxis rates. A lack of consensus for the need of immunoprophylaxis for infants with CF has been described in a survey,16 and our results confirm that palivizumab prophylaxis is not standard of care in this group of patients. CF also may have manifested after infants had completed the RSV season and thus they may have not been identified as candidates for prophylaxis. While this study was under review, AAP updated their recommendations for infants born at 32 to 35 weeks’ GA in the 2009 Red Book.17 The guidelines recommend a maximum of 3 doses for these infants until they turn 3 months of age, even if that results in cessation of immunoprophylaxis during the RSV season. If prior authorization programs adopt this recommendation, savings on prophylaxis may be substantial, considering the size of this group of infants. Importantly, palivizumab utilization is low for children with CHD despite the strength of evidence for effectiveness. Before 2003, the recommendation was restricted to children with asymptomatic acyanotic CHD who had other indications for prophylaxis, presumably because a similar agent, RSV-IGIV, was contraindicated in children with cyanotic CHD due to safety concerns. These safety concerns were ruled out for palivizumab4 and subsequently led to immunoprophylaxis recommendations for children with hemodynamically significant cyanotic or acyanotic CHD. Hampp, Saidi, and Winterstein
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Table III. Palivizumab utilization by indication in season 2004/2005
All children Total Without indication With 1 indication With $2 indications By indication: CLD Total No other indication At least 1 other indication Prematurity <32 weeks GA Prematurity, 33-35 weeks GA CHD CF SCID/AIDS Prematurity <32 weeks GA Total No other indication At least 1 other indication CLD CHD CF SCID/AIDS Prematurity 32 through 35 weeks GA Total No other indication At least 1 other indication CLD CHD CF SCID/AIDS CHD Total No other indication At least 1 other indication CLD Prematurity <32 weeks GA Prematurity, 33-35 weeks GA CF SCID/AIDS CF Total No other indication At least 1 other indication CLD Prematurity <32 weeks GA Prematurity, 33-35 weeks GA CHD SCID/AIDS SCID/AIDS Total No other indication At least 1 other indication CLD Prematurity <32 weeks GA Prematurity, 33-35 weeks GA CHD CF
No. of children-seasons
% of total
No. of palivizumab recipients
% palivizumab recipients
% with full season coverage
55 082 52 687 2094 301
100 95.7 3.80 0.55
1486 513 731 242
2.70 0.97 34.9 80.4
67.9 63.7 71.8 72.7
341 119 222 128 2 138 0 4
100 34.9 65.1 37.5 0.59 40.5 0 1.17
251 66 185 112 1 114 0 4
73.6 55.5 83.3 87.5 50.0 82.6 0 100
76.1 75.8 76.2 78.6 0 73.7 0 75.0
771 601 170 128 89 0 1
100 78.0 22.0 16.6 11.5 0 0.13
521 375 146 112 77 0 1
67.6 62.4 85.9 87.5 86.5 0 100
72.7 72.3 74.0 72.3 68.8 0 100
150 133 17
22.7 21.0 65.4
69.3 70.7 58.8
660 634 26
100 96.1 3.9
2 23 0 2
0.30 3.48 0 0.30
1 16 0 1
50.0 69.6 0 50.0
0 62.5 0 0
844 629 215 138 89 23 3 13
100 74.5 25.5 16.4 10.5 2.73 0.36 1.54
312 142 170 114 77 16 1 9
37.0 22.6 79.1 82.6 86.5 69.6 33.3 69.2
70.8 71.8 70.0 73.7 68.8 62.5 100 66.7
38 35 3 0 0 0 3 0
100 92.1 7.9 0 0 0 7.89 0
10 9 1 0 0 0 1 0
26.4 25.7 33.3 0 0 0 33.3 0
40.0 33.3 100.0 0 0 0 100 0
93 76 17 4 1 2 13 0
100 81.7 18.30 4.30 1.08 2.15 14.0 0
18 6 12 4 1 1 9 0
19.4 7.9 70.6 100 100 50.0 69.2 0
72.2 83.3 66.6 75.0 100 0 66.7 0
Odds Ratio for receiving palivizumab [95% CI]*
0.03 [0.03 - 0.04] reference 4.37 [3.12 - 6.12]
reference 3.42 [1.76 - 6.66]
reference 4.13 [2.53 - 6.76]
reference 6.66 [2.73 - 16.2]
reference 9.50 [6.09 - 14.8]
reference n/a
reference n/a
AIDS, Acquired immunodeficiency syndrome; SCID, severe combined immunodeficiency. *Odds ratio adjusted for sex, age, race, Medicaid district, type of eligibility, and rural versus urban location.
Nevertheless, we observed high utilization rates for children with CHD only if they had additional risk factors. A reason might be that according to the guideline, children who had surgery for CHD are only considered at high risk for RSV
hospitalization if they still require medication for congestive heart failure. This recommendation may be somewhat confusing because even after palliative surgery, children with single ventricles may remain cyanotic but not be receiving
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medication for congestive heart failure, yet still be eligible for palivizumab due to their cyanotic state. Conversely, Bellavance et al18 found in a cohort of Canadian children with CHD in 2003/2004 that 20% received palivizumab outside of guidelines; half of these children (52%) had no residual lesions after surgical correction. These findings, together with ours, may indicate variation in how prescribers interpret the guidelines for children with CHD. We found a different utilization rate between the children’s first (3.27% in 04/05) and second seasons (1.70%). Although the guidelines recommend prophylaxis for most indications during the first 2 years of life, the evidence for effectiveness is stronger for the first versus the second year. Palivizumab approval is based on 2 randomized clinical trials that enrolled children up to 2 years of age,3,4 but the low average age at study entry (approximately 6 months) leaves uncertainty about effectiveness during the second year of life.17 Furthermore, the incidence of RSV hospitalization decreases with increasing age,19 which results in a higher number needed to treat in the second year of life compared with the first year, making it more difficult to achieve acceptable cost-effectiveness ratios. Our data suggest that clinicians take this into account by preferentially protecting children in their first year of life. The prospect of the need for monthly physician office visits may be another factor to explain the lower rate of prophylaxis if parents perceive their children as stronger in their second year of life. We observed that the proportion of full compliance with at least 4 doses in 1 season increased between the 1998/1999 and 1999/2000 seasons and plateaued thereafter. One hypothesis is that this early increase is related to the market introduction of palivizumab in June 1998 and a delay in the inclusion of the drug into clinical practice in the first season. With few exceptions, the proportion of full compliance remained consistently around 70%. Hence, once treatment was initiated, the full course was given to most children; however, a considerable portion remained with only partial coverage. The impact of partial coverage on the risk of RSV-related hospitalizations should be addressed in further research. One third of palivizumab recipients did not have any indication according to AAP guidelines. More than 8000 doses translate into cost exceeding $1 000 000 for a single Medicaid agency, with questionable benefit. During our study period, Florida Medicaid did not have a prior authorization system in place for palivizumab (personal communication with Anne C. Wells, Bureau Chief, Florida Medicaid Pharmacy Services, 02/02/2009). Consequently, our observed palivizumab utilization rates reflect practitioners’ decisions on immunoprophylaxis without restraints by payers. We expect that our observations regarding palivizumab utilization outside of guidelines reflect utilization patterns in other states and health plans where prior authorization requirements are not in place, suggesting opportunities to optimize utilization. A limitation to our study is the lack of available data regarding additional risk factors to establish the indication 958
Vol. 156, No. 6 for prophylaxis for infants born between 32 and 35 weeks’ GA. We estimated the maximum number of children who could have met the indication based on gestational age only. Thus, our analysis included subjects who did not have additional risk factors such as daycare attendance or smoking parents and would not have met criteria to receive palivizumab. We therefore caution that the seemingly low percentage of utilization (22.7% in 2004/2005) does not necessarily represent underutilization but rather the fact that our denominator overestimated the number of patients who met the indication. We report utilization based on prescription drug claims as proxies for administered doses. A study on accuracy of palivizumab claims in the North Carolina Medicaid program found 87% agreement for infants with any palivizumab injection claim compared with medical records, but agreement was only reached in 46.1% of infants regarding the number of injections.20 The second finding may be related to injections during inpatient stays that would have been identified in the medical records but not in the Medicaid claims data set due to the aggregate nature of a Medicaid hospitalization claim. We tried to overcome this inaccuracy by imputing a dose for a hospital stay under conditions as described above. We investigated palivizumab utilization only in children 0 to 2 years of age, not in older children, adolescents, or adults. Because palivizumab dose is based on body weight, the amount and thus the cost per administered dose are significantly higher in these populations compared with young children. The extent of palivizumab use and its effectiveness in non-infant populations deserve attention in future studies. The analysis of palivizumab utilization and compliance revealed both overutilization and underutilization. Immunoprophylaxis was infrequent in children with hemodynamically significant acyanotic or cyanotic CHD, whereas the substantial proportion of palivizumab recipients without any indication according to guideline indicates room for resource optimization. An encouraging observation is the high utilization rate for children with more than 1 indication and also the consistently high proportion of palivizumab recipients with a full course of RSV prophylaxis. n The study was conducted in collaboration with the University of Florida Center for Medicaid and the Uninsured. We are grateful to the Office of Vital Statistics, Florida Department of Health, for the provision of birth certificates and the Florida Agency for Healthcare Administration for provision of Medicaid claims data. Submitted for publication Jul 13, 2009; last revision received Nov 13, 2009; accepted Dec 9, 2009. Reprint requests: Dr Christian Hampp, 101 Newell Drive, Room 3334, Gainesville, FL, 32610. E-mail: [email protected].
References 1. Shay DK, Holman RC, Newman RD, Liu LL, Stout JW, Anderson LJ. Bronchiolitis-associated hospitalizations among US children, 19801996. JAMA 1999;282:1440-6.
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June 2010 2. Hall CB, Weinberg GA, Iwane MK, Blumkin AK, Edwards KM, Staat MA, et al. The burden of respiratory syncytial virus infection in young children. N Engl J Med 2009;360:588-98. 3. The IMpact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 1998; 102(3 Pt 1):531-7. 4. Feltes TF, Cabalka AK, Meissner HC, Piazza FM, Carlin DA, Top FH Jr., et al. Palivizumab prophylaxis reduces hospitalization due to respiratory syncytial virus in young children with hemodynamically significant congenital heart disease. J Pediatr 2003;143:532-40. 5. Drug Topics Red Book. Pharmacy’s Fundamental Reference. Montvale, NJ: Thomson PDR December 2006. 6. Committee on Infectious Diseases and Committee on Fetus and Newborn. Revised indications for the use of palivizumab and respiratory syncytial virus immune globulin intravenous for the prevention of respiratory syncytial virus infections. Pediatrics 2003;112(6 Pt 1):1442-6. 7. Brief report. respiratory syncytial virus activity–United States, July 2006November 2007. MMWR 2007;56:1263-5. 8. Bauman J, Eggleston M, Oquist N, Malinoski F. Respiratory syncytial virus: seasonal data for regions of Florida and implications for palivizumab. South Med J 2007;100:669-76. 9. http://www.doh.state.fl.us/Disease_ctrl/epi/RSV/rsv_trends.htm. Accessed 07/09/2009. 10. http://www.cdc.gov/surveillance/nrevss/rsv/default.html. Accessed 02/ 23/2009. 11. Committee on Infectious Diseases and Committee on Fetus and Newborn. Prevention of Respiratory Syncytial Virus Infections: Indications
12.
13.
14.
15.
16. 17. 18.
19.
20.
for the Use of Palivizumab and Update on the Use of RSV-IGIV. Pediatrics 1998;102:1211-6. Mansbach J, Kunz S, Acholonu U, Clark S, Camargo CA Jr. Evaluation of compliance with palivizumab recommendations in a multicenter study of young children presenting to the emergency department with bronchiolitis. Pediatr Emerg Care 2007;23:362-7. Moynihan JA, Kim TY, Young T, Checchia PA. Rate of palivizumab administration in accordance with current recommendations among hospitalized children. J Pediatr Health Care 2004;18:224-7. Pignotti MS, Catarzi S, Donzelli GA. 4-year survey on palivizumab respiratory syncytial virus (RSV)-prophylaxis: how can compliance be improved? J Matern Fetal Neonatal Med 2006;19:221-4. Oh PI, Lanctjt KL, Yoon A, Lee DS, Paes BA, Simmons BS, et al. Palivizumab prophylaxis for respiratory syncytial virus in Canada: utilization and outcomes. Pediatr Infect Dis J 2002;21:512-8. Giusti R. North American synagis prophylaxis survey. Pediatr Pulmonol 2009;44:96-8. Respiratory Syncytial Virus. Red Book 2009;1:560–569. Bellavance M, Rohlicek CV, Bigras JL, Cote JM, Paquet M, Lebel MH, et al. Palivizumab use among children with congenital heart disease in Quebec: impact of Canadian guidelines on clinical practice. Paediatr Child Health 2006;11:19-23. Hampp C, Winterstein AG, Saidi A. Role of Age in Respiratory Syncytial Virus Infection Risk: Recommendations for Palivizumab Utilization, presented at 24th International Conference on Pharmacoepidemiology and Therapeutic Risk Management. Pharmacoepidemiol Drug Safety 2008;17:186. Jacobson Vann J, Feaganes J, Wegner S. Reliability of medicaid claims versus medical record data: in a cost analysis of palivizumab. Pharmacoeconomics 2007;25:793-800.
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Table I. Indications for RSV prophylaxis with palivizumab*,† Indication CLD
Premature I Premature II
Age at season onset (mo) 0-24
a) 0-12 b) 0-6 0-6
CHD
0-24
CF
0-24
Severe combined immunodeficiency /acquired immunodeficiency syndrome
0-24
Condition Chronic lung disease with medical therapy (steroids, oxygen, bronchodilators, diuretics) within 6 months before season onset a) Born # 28 weeks of gestation b) Born 29 to # 32 weeks of gestation Born >32 to 35 weeks of gestation with $2 additional risk factors: child care attendance, school-aged siblings, and exposure to environmental air pollutants such as tobacco smoke. Because exposure to these risk factors cannot be assessed from Medicaid claims data, we attempted to calculate the maximum possible number of children treated for this indication by using only gestational age as a criterion. a) Hemodynamically significant cyanotic CHD b) Acyanotic CHD with claim for oxygen, diuretics, digoxin or angiotensin converting enzyme inhibitors during season CF Severe combined immunodeficiency or severe acquired immunodeficiency syndrome
Evidence
References
Grade I, RCT
3, 4
Grade I, RCT
3
Grade I, RCT
3
Grade I, RCT
4
AAP guideline: ‘‘insufficient data’’(Reference 6) Grade III, ‘‘children [.] may benefit from prophylaxis’’(Reference 6)
N/A N/A
Evidence grade I: evidence obtained from at least 1 properly designed, randomized, controlled trial. Evidence grade III: opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees. *According to AAP guideline6 and AAP Red Book.5 †The indications are not mutually exclusive. One child can have multiple indications and would subsequently be assigned to multiple categories.
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Study design Among Florida Medicaid fee-for-service recipients 0 to 2 years of age from the 1998/1999 season through the 2004/2005 season with available birth certificates, we identified indications for palivizumab prophylaxis based on claims data. At least 4 doses of palivizumab in the 5 core season-months were considered full season coverage. Results Of 302 101 children-seasons, 6089 were associated with 24 469 doses of palivizumab. In the 2004/2005 season, 73.6% of children with chronic lung disease received immunoprophylaxis, 67.6% children with gestational age <32 weeks, 37% with congenital heart disease, 26.4% with cystic fibrosis, and 19.4% with severe immunodeficiency. Multiple indications increased the likelihood for prophylaxis from 34.9% to 80.4%. Full season coverage was consistent across indications at approximately 70%. From the 1998/1999 season through the 2004/2005 season, 8038 doses were administered during 2051 children-seasons without any indication; mostly (69.6%) where premature children had exceeded the recommended age range for prophylaxis. Conclusions High utilization rates were found in children with multiple indications, and compliance with a monthly schedule was consistently high. One third of doses were administered outside of guidelines, suggesting suboptimal utilization of resources in the absence of prior authorization. (J Pediatr 2010;156:953-9).
R
espiratory syncytial virus (RSV) is the most frequent cause of lower respiratory tract infections among infants and children. According to one estimate for the United States, RSV causes up to 120 000 hospitalizations annually for pneumonia or bronchiolitis among infants younger than 1 year of age,1 whereas a more recent study reports an annual RSV hospitalization rate of 57 275 for children under the age of 5 years.2 The same study estimated that 2.1 million children under the age of 5 years seek medical attention for RSV infections each year—3% of whom are hospitalized, 25% visit emergency departments, and 73% are treated in pediatric practices. Although no vaccination is available for RSV, palivizumab (Synagis, MedImmune Inc., Gaithersburg, Maryland), a humanized monoclonal antibody, has been shown to prevent RSV-related hospitalizations,3,4 albeit at significant cost. Five doses of palivizumab are necessary to protect 1 child throughout a 5-month RSV season at an average total wholesale price that can exceed $8000, depending on body weight.5 These costs limit prophylaxis to children at greatest risk for infection, such as children with chronic lung disease (CLD), congenital heart disease (CHD), and certain preterm infants as recommended by the American Academy of Pediatrics (AAP) RSV prevention guideline from 2003.6 Among the listed indications, strength of evidence for the effectiveness of palivizumab ranges from expert opinion to data from randomized clinical trials. Accordingly, the guideline’s recommendations for indications that are not based on randomized clinical trials data are phrased more carefully (Table I; available at www.jpeds.com). Even though the strength of evidence is considered in guidelines development, it is unclear whether this is reflected in prescriber decision-making and palivizumab utilization rates. Information about underutilization in children who should receive prophylaxis and overutilization in those not included in the guidelines is critical for third-party payers to target policy interventions. Knowledge about palivizumab utilization in the absence of prior authorization programs can help health plans to develop or refine their own reimbursement policies to ensure access for children who might benefit from immunoprophylaxis and restrict access where the RSV hospitalization risk is low. Furthermore, because gaps in palivizumab administration may lead to suboptimal effectiveness, knowledge about adherence to the monthly dosing schedule during the core season is important to ensure optimal protection. We sought to analyze
AAP CF CHD CI CLD GA OR RSV
American Academy of Pediatrics Cystic fibrosis Congenital heart disease Confidence interval Chronic lung disease Gestational age Odds ratio Respiratory syncytial virus
From the Department Pharmaceutical Outcomes and Policy (C.H., A.W.), College of Pharmacy, the Department of Pediatrics (A.S.), College of Medicine; and the Department of Epidemiology and Biostatistics (A.W.), College of Public Health and Health Professions, University of Florida, Gainesville, FL Supported in part by a grant from the Florida Agency of Healthcare Administration, AHCA. The authors declare no conflicts of interest. 0022-3476/$ - see front matter. Copyright Ó 2010 Mosby Inc. All rights reserved. 10.1016/j.jpeds.2009.12.016
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longitudinal compliance with the 2003 AAP guidelines for RSV immunoprophylaxis with palivizumab in the Florida Medicaid population. We report the proportion of patients who recieved any palivizumab prophylaxis and the proportion with full compliance broken down by indication for prophylaxis during a single season. Further objectives were to investigate sociodemographic patient factors as determinants for immunoprophylaxis and to present the proportion of palivizumab recipients without indications according to guideline.
Methods Our sample consisted of Florida Medicaid fee-for-service recipients under 2 years of age. This analysis concentrated on the core months of the RSV season from October through February and covered 7 seasons from 1998/1999 through 2004/2005. To ensure that every subject had the chance to receive a full course of palivizumab, participants had to be continuously eligible between September and February to be included in the respective season. We restricted age to a minimum of 30 days on October 1 and a maximum of 2 years at the end of February. Subjects had to be in ambulatory care during September because inpatient claims data provide no information about medication utilization, which was necessary for the identification of guideline-supported indications for palivizumab prophylaxis. The unit of analysis was children-season, and 1 child could contribute up to 2 childrenseasons. To achieve valid estimates on gestational age, we matched Medicaid recipient data to birth certificates. Season Definition RSV seasons in Florida differ from the rest of the country, resulting in earlier onset and longer duration.7 As a consequence, seasonal palivizumab utilization can exceed the 5 doses per child, as are generally recommended for the northern hemisphere.6 Seasons differ even within the state, with longer seasons in the south compared with the north.8 To use a time period that is applicable to the whole state, we defined a core season from October through February to include months that consistently have shown high infection rates across the study period according to the Centers for Disease Control and Prevention’s National Respiratory and Enteric Virus Surveillance System and the Florida Department of Heath RSV Surveillance System.9,10 Indications We grouped risk factors for RSV infections according to AAP guidelines into 6 palivizumab indications, which are detailed in Table I (available at www.jpeds.com). This classification considered age restrictions for immunoprophylaxis such as a maximum age at season onset of 12 months for infants born before or during 28 weeks’ gestational age (GA). As a consequence, a prematurely born child with CLD would have multiple indications in the first year of life but only 1 indication, CLD, in the second year. 954
Vol. 156, No. 6 The guideline from 2003 added the CHD indication as a modification from the previous guideline published in 1998.11 To facilitate longitudinal comparisons, we applied the definitions from the 2003 guideline to the entire time period. International Classification of Diseases–Clinical Modification Version 9 codes of inpatient and outpatient claims were used in conjunction with drug claims (for CLD and CHD) to identify children with current indications for palivizumab. Utilization and Compliance Using National Drug Codes and procedure codes, we identified palivizumab claims for each season and assigned recipients into categories according to their number of claims in 1 season. Two claims had to be at least 20 days apart to ensure that single doses that were associated with multiple claims (for more than 1 vial) only were counted once. Because the nature of our data set did not allow for assessment of drug utilization during hospital stays, we imputed 1 dose of palivizumab for each hospital stay if the patient had another claim for palivizumab at some point in the season but not between admission and 30 days after discharge. We calculated the proportion of fully compliant users as the proportion of patients with at least 4 doses during 1 season divided by the number of palivizumab users, that is, children who received at least 1 dose. Although a 5-month season would require 5 doses of palivizumab for a high-risk patient, we accepted 4 doses as full coverage to allow for minor delays in palivizumab administration. For the most recent season in our study period, the 2004/ 2005 season, we calculated unadjusted exposure odds ratios for subjects with indication to determine predictors for immunoprophylaxis. Also for 2004/2005, we provide additional detail on the level of single indications. Within indications, we used conditional logistic regression to calculate the likelihood of receiving immunoprophylaxis associated with the presence of a second indication, adjusting for patient demographics (sex, age, race, Medicaid district, type of eligibility, and rural versus urban location). Data were analyzed using SAS 9.1.3 (SAS Institute, Cary, North Carolina), graphs were created in Microsoft Office Excel 2003 (Microsoft Corporation, Redmond, Washington), and Epi Info 3.3.2 (Centers for Disease Control and Prevention, Atlanta, Georgia) was used to calculate odds ratios and 95% confidence intervals. The institutional review boards of the University of Florida and the Florida Department of Health approved the study protocol.
Results After excluding patients without available birth certificates and applying our seasonal eligibility criteria, our sample consisted of 302 101 children-seasons. Among these, 6089 were associated with 24 469 doses of palivizumab during the seasons 1998/1999 through 2004/2005. Hampp, Saidi, and Winterstein
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Table II. Demographics of children with any indication for palivizumab prophylaxis, season 2004/2005 Palivizumab recipients n = 973 (children-seasons)
Sex Male Female Race White Black Hispanic Other/Unknown Age at season onset 0-6 mo 7-12 13-18 19-24 County Urban Rural Medicaid eligibility AFDC-TANF SSI OBRA Other
No palivizumab n = 1422
Odds ratio of receiving palivizumab
(%)
Frequency
(%)
Frequency
(95% CI)
53.2 46.8
518 455
51.4 48.2
737 685
Reference 0.95 (0.80 - 1.12)
22.3 19.3 13.0 45.4
217 188 126 442
26.7 28.7 23.6 21.1
379 408 335 300
Reference 0.80 (0.63 - 1.03) 0.66 (0.50 - 0.86) 2.57 (2.05 - 3.23)
55.2 27.7 13.6 3.60
537 269 132 35
55.2 21.9 17.4 5.49
785 311 248 78
Reference 1.26 (1.03 - 1.55) 0.78 (0.61 - 0.99) 0.66 (0.42 - 1.01)
87.5 12.5
851 122
89.7 10.3
1275 147
Reference 1.24 (0.96 - 1.62)
28.6 51.4 15.4 4.62
278 500 150 45
46.3 19.0 28.1 6.61
658 270 400 94
Reference 4.38 (3.56 - 5.40) 0.89 (0.70 - 1.13) 0.26 (0.17 - 0.39)
AFDC-TANF, Aid to Families with Dependent Children/Temporary Assistance for Needy Families; SSI, Supplemental Security Income; OBRA, Omnibus Budget Reconciliation Act.
Table II summarizes demographics of children with indication for palivizumab for the season 2004/2005. Girls show a similar likelihood of receiving palivizumab as boys (odds ratio [OR], 0.95; 95% confidence interval, 0.80 to 1.12). Our numbers indicate racial disparity, with blacks (OR, 0.80; 0.63 to 1.03) trending toward lower likelihood and Hispanics (OR, 0.66; 0.50 to 0.86) being less likely than whites to receive prophylaxis. The other/unknown race category is mainly (90.4%) composed of children with missing race information. Missing race information is associated with poorer health status in our data set, as 21.9% of these children are eligible for Medicaid through Supplemental Security Income status as aid for disability compared with approximately 1% in the general population. Likewise, a larger proportion of children with missing race were prematurely born (5.84%) compared with the general population (0.92%). Children in rural areas experience a trend toward higher likelihood for immunoprophylaxis compared with those in urban locations (OR, 1.24; 0.96 to 1.62). Children eligible for Medicaid through Supplemental Security Income showed increased odds of prophylaxis (OR, 4.38; 3.56 to 5.40). Utilization and Compliance Figure 1 depicts a longitudinal view of palivizumab utilization rates. The number of recipients increased steadily from 282 in the season 1998/1999 to 1486 in 2004/2005. In the last season, 3.27% of all infants in their first year of life received immunoprophylaxis compared with 1.70% of children in their second year. Proportions of full compliance increased during the first 2 RSV seasons when palivizumab became available (1998/1999 and 1999/2000), to reach a plateau at approximately 70% during the subsequent seasons (data not shown).
Children Without Indication Figure 2 contrasts the number of palivizumab doses administered to children with and without indications. In 1998/ 1999, 18.5% of doses were administered to children without indication. This proportion increased throughout the observation period to 36.3% in 2001/2002 and remained at a similar level thereafter. Across the seasons 1998/1999 through 2004/2005, 8038 doses of palivizumab were administered during 2051 children-seasons, in which recipients did not meet any guideline-recommended indication. Because the prematurity indications limit recommended prophylaxis to an age at season onset of 6 or 12 months depending on gestational age, we investigated the number of prematurely born children who received palivizumab despite exceeding the recommended age range before season onset. We identified 1405 prematurely born children who received 5597 doses after their recommended age. Of note, these children did not have any other indication for RSV prophylaxis. This group of palivizumab recipients accounts for 69.6% of the total 8038 doses received without indication. Utilization and Compliance by Indication, Season 2004/2005 Table III provides results of utilization within indications for the season 2004/2005. Among 55 082 children, 1486 (2.70%) received palivizumab, 973 with indication (65.5%) and 513 (34.5%) without indication for prophylaxis. Only 12.6% of children with indication and 0.54% of the whole sample had multiple indications. Compared with children with only 1 indication, multiple indications increased the likelihood for prophylaxis from 34.9% to 80.4% (OR, 4.37; 95% confidence interval [CI], 3.12 to 6.12, adjusted for sex, age, race, Medicaid district, type of eligibility, and rural versus urban location).
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Vol. 156, No. 6 Larger deviations are observable only in subgroups in which the count of palivizumab recipients was small.
Discussion
Figure 1. Palivizumab utilization comparison, first versus second year of life.
Overall, 73.6% of children with CLD received immunoprophylaxis; however, only 55.5% did so when no other indication was present. Compared with CLD only, the likelihood for receiving palivizumab increased to 83.3% (OR, 3.42 [1.76, 6.66]) with the presence of a second indication. Although more than two thirds of infants born at <32 weeks’ GA received palivizumab (67.6%) and 85.9% did so when additional indications were present, we observed a utilization rate of only 22.7% in children born at 32 to 35 weeks’ GA. Thirty-seven percent of children with CHD who met guideline criteria for prophylaxis received palivizumab but only 22.6% did so when CHD was the only indication. With additional indications, utilization increased to 79.1% (OR, 9.50 [6.09, 14.8]). Finally, of the 38 children with cystic fibrosis (CF) in our sample, 26.4% received prophylaxis, as well as 19.4% of 93 children with severe combined or acquired immunodeficiency. Complete Season Coverage Among all palivizumab recipients, 67.9% were considered fully compliant with at least 4 doses and 41.3% received at least 5 doses. Full compliance was achieved in 63.7% of cases without any indication and in 72.0% in which at least 1 indication were observed. Within indications, the proportion of full compliance was generally consistent at around 70%.
Figure 2. Palivizumab utilization outside of recommendations. 956
This large observational study provides comprehensive detail on palivizumab utilization and compliance. Two smaller studies relied on parental recollection of immunoprophylaxis: Mansbach et al12 found that 17 children of 35 who were eligible for prophylaxis received palivizumab (49%) and another study reports an adherence to guideline in only 14 of 40 children (35%).13 The latter study found that neither age, race, nor insurance status affected immunoprophylaxis, but this may be a result of limited statistical power. Compliance with a monthly prophylaxis schedule was investigated by a group in Italy who found a compliance rate with all recommended doses of 87%.14 This compliance rate is somewhat higher than the one observed in our study despite their stricter requirement that full compliance equals the receipt of all recommended doses. High compliance also was found in a Canadian study in which 77% of doses were given within 30 5 days of the previous injection and only 11.5% of children experienced an interruption in their dosing schedule.15 Our results indicate large variations in the proportion of palivizumab recipients by guideline-recommended indications. With some exceptions, the utilization rate corresponds to the strength of the available evidence for a given indication. We observed high utilization rates for CLD and premature birth <32 weeks’ GA, indications that are supported by grade I evidence according to guidelines. Evidence for palivizumab effectiveness in CF and severe combined or acquired immunodeficiency is weak at grade III and is reflected in low prophylaxis rates. A lack of consensus for the need of immunoprophylaxis for infants with CF has been described in a survey,16 and our results confirm that palivizumab prophylaxis is not standard of care in this group of patients. CF also may have manifested after infants had completed the RSV season and thus they may have not been identified as candidates for prophylaxis. While this study was under review, AAP updated their recommendations for infants born at 32 to 35 weeks’ GA in the 2009 Red Book.17 The guidelines recommend a maximum of 3 doses for these infants until they turn 3 months of age, even if that results in cessation of immunoprophylaxis during the RSV season. If prior authorization programs adopt this recommendation, savings on prophylaxis may be substantial, considering the size of this group of infants. Importantly, palivizumab utilization is low for children with CHD despite the strength of evidence for effectiveness. Before 2003, the recommendation was restricted to children with asymptomatic acyanotic CHD who had other indications for prophylaxis, presumably because a similar agent, RSV-IGIV, was contraindicated in children with cyanotic CHD due to safety concerns. These safety concerns were ruled out for palivizumab4 and subsequently led to immunoprophylaxis recommendations for children with hemodynamically significant cyanotic or acyanotic CHD. Hampp, Saidi, and Winterstein
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Table III. Palivizumab utilization by indication in season 2004/2005
All children Total Without indication With 1 indication With $2 indications By indication: CLD Total No other indication At least 1 other indication Prematurity <32 weeks GA Prematurity, 33-35 weeks GA CHD CF SCID/AIDS Prematurity <32 weeks GA Total No other indication At least 1 other indication CLD CHD CF SCID/AIDS Prematurity 32 through 35 weeks GA Total No other indication At least 1 other indication CLD CHD CF SCID/AIDS CHD Total No other indication At least 1 other indication CLD Prematurity <32 weeks GA Prematurity, 33-35 weeks GA CF SCID/AIDS CF Total No other indication At least 1 other indication CLD Prematurity <32 weeks GA Prematurity, 33-35 weeks GA CHD SCID/AIDS SCID/AIDS Total No other indication At least 1 other indication CLD Prematurity <32 weeks GA Prematurity, 33-35 weeks GA CHD CF
No. of children-seasons
% of total
No. of palivizumab recipients
% palivizumab recipients
% with full season coverage
55 082 52 687 2094 301
100 95.7 3.80 0.55
1486 513 731 242
2.70 0.97 34.9 80.4
67.9 63.7 71.8 72.7
341 119 222 128 2 138 0 4
100 34.9 65.1 37.5 0.59 40.5 0 1.17
251 66 185 112 1 114 0 4
73.6 55.5 83.3 87.5 50.0 82.6 0 100
76.1 75.8 76.2 78.6 0 73.7 0 75.0
771 601 170 128 89 0 1
100 78.0 22.0 16.6 11.5 0 0.13
521 375 146 112 77 0 1
67.6 62.4 85.9 87.5 86.5 0 100
72.7 72.3 74.0 72.3 68.8 0 100
150 133 17
22.7 21.0 65.4
69.3 70.7 58.8
660 634 26
100 96.1 3.9
2 23 0 2
0.30 3.48 0 0.30
1 16 0 1
50.0 69.6 0 50.0
0 62.5 0 0
844 629 215 138 89 23 3 13
100 74.5 25.5 16.4 10.5 2.73 0.36 1.54
312 142 170 114 77 16 1 9
37.0 22.6 79.1 82.6 86.5 69.6 33.3 69.2
70.8 71.8 70.0 73.7 68.8 62.5 100 66.7
38 35 3 0 0 0 3 0
100 92.1 7.9 0 0 0 7.89 0
10 9 1 0 0 0 1 0
26.4 25.7 33.3 0 0 0 33.3 0
40.0 33.3 100.0 0 0 0 100 0
93 76 17 4 1 2 13 0
100 81.7 18.30 4.30 1.08 2.15 14.0 0
18 6 12 4 1 1 9 0
19.4 7.9 70.6 100 100 50.0 69.2 0
72.2 83.3 66.6 75.0 100 0 66.7 0
Odds Ratio for receiving palivizumab [95% CI]*
0.03 [0.03 - 0.04] reference 4.37 [3.12 - 6.12]
reference 3.42 [1.76 - 6.66]
reference 4.13 [2.53 - 6.76]
reference 6.66 [2.73 - 16.2]
reference 9.50 [6.09 - 14.8]
reference n/a
reference n/a
AIDS, Acquired immunodeficiency syndrome; SCID, severe combined immunodeficiency. *Odds ratio adjusted for sex, age, race, Medicaid district, type of eligibility, and rural versus urban location.
Nevertheless, we observed high utilization rates for children with CHD only if they had additional risk factors. A reason might be that according to the guideline, children who had surgery for CHD are only considered at high risk for RSV
hospitalization if they still require medication for congestive heart failure. This recommendation may be somewhat confusing because even after palliative surgery, children with single ventricles may remain cyanotic but not be receiving
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medication for congestive heart failure, yet still be eligible for palivizumab due to their cyanotic state. Conversely, Bellavance et al18 found in a cohort of Canadian children with CHD in 2003/2004 that 20% received palivizumab outside of guidelines; half of these children (52%) had no residual lesions after surgical correction. These findings, together with ours, may indicate variation in how prescribers interpret the guidelines for children with CHD. We found a different utilization rate between the children’s first (3.27% in 04/05) and second seasons (1.70%). Although the guidelines recommend prophylaxis for most indications during the first 2 years of life, the evidence for effectiveness is stronger for the first versus the second year. Palivizumab approval is based on 2 randomized clinical trials that enrolled children up to 2 years of age,3,4 but the low average age at study entry (approximately 6 months) leaves uncertainty about effectiveness during the second year of life.17 Furthermore, the incidence of RSV hospitalization decreases with increasing age,19 which results in a higher number needed to treat in the second year of life compared with the first year, making it more difficult to achieve acceptable cost-effectiveness ratios. Our data suggest that clinicians take this into account by preferentially protecting children in their first year of life. The prospect of the need for monthly physician office visits may be another factor to explain the lower rate of prophylaxis if parents perceive their children as stronger in their second year of life. We observed that the proportion of full compliance with at least 4 doses in 1 season increased between the 1998/1999 and 1999/2000 seasons and plateaued thereafter. One hypothesis is that this early increase is related to the market introduction of palivizumab in June 1998 and a delay in the inclusion of the drug into clinical practice in the first season. With few exceptions, the proportion of full compliance remained consistently around 70%. Hence, once treatment was initiated, the full course was given to most children; however, a considerable portion remained with only partial coverage. The impact of partial coverage on the risk of RSV-related hospitalizations should be addressed in further research. One third of palivizumab recipients did not have any indication according to AAP guidelines. More than 8000 doses translate into cost exceeding $1 000 000 for a single Medicaid agency, with questionable benefit. During our study period, Florida Medicaid did not have a prior authorization system in place for palivizumab (personal communication with Anne C. Wells, Bureau Chief, Florida Medicaid Pharmacy Services, 02/02/2009). Consequently, our observed palivizumab utilization rates reflect practitioners’ decisions on immunoprophylaxis without restraints by payers. We expect that our observations regarding palivizumab utilization outside of guidelines reflect utilization patterns in other states and health plans where prior authorization requirements are not in place, suggesting opportunities to optimize utilization. A limitation to our study is the lack of available data regarding additional risk factors to establish the indication 958
Vol. 156, No. 6 for prophylaxis for infants born between 32 and 35 weeks’ GA. We estimated the maximum number of children who could have met the indication based on gestational age only. Thus, our analysis included subjects who did not have additional risk factors such as daycare attendance or smoking parents and would not have met criteria to receive palivizumab. We therefore caution that the seemingly low percentage of utilization (22.7% in 2004/2005) does not necessarily represent underutilization but rather the fact that our denominator overestimated the number of patients who met the indication. We report utilization based on prescription drug claims as proxies for administered doses. A study on accuracy of palivizumab claims in the North Carolina Medicaid program found 87% agreement for infants with any palivizumab injection claim compared with medical records, but agreement was only reached in 46.1% of infants regarding the number of injections.20 The second finding may be related to injections during inpatient stays that would have been identified in the medical records but not in the Medicaid claims data set due to the aggregate nature of a Medicaid hospitalization claim. We tried to overcome this inaccuracy by imputing a dose for a hospital stay under conditions as described above. We investigated palivizumab utilization only in children 0 to 2 years of age, not in older children, adolescents, or adults. Because palivizumab dose is based on body weight, the amount and thus the cost per administered dose are significantly higher in these populations compared with young children. The extent of palivizumab use and its effectiveness in non-infant populations deserve attention in future studies. The analysis of palivizumab utilization and compliance revealed both overutilization and underutilization. Immunoprophylaxis was infrequent in children with hemodynamically significant acyanotic or cyanotic CHD, whereas the substantial proportion of palivizumab recipients without any indication according to guideline indicates room for resource optimization. An encouraging observation is the high utilization rate for children with more than 1 indication and also the consistently high proportion of palivizumab recipients with a full course of RSV prophylaxis. n The study was conducted in collaboration with the University of Florida Center for Medicaid and the Uninsured. We are grateful to the Office of Vital Statistics, Florida Department of Health, for the provision of birth certificates and the Florida Agency for Healthcare Administration for provision of Medicaid claims data. Submitted for publication Jul 13, 2009; last revision received Nov 13, 2009; accepted Dec 9, 2009. Reprint requests: Dr Christian Hampp, 101 Newell Drive, Room 3334, Gainesville, FL, 32610. E-mail: [email protected].
References 1. Shay DK, Holman RC, Newman RD, Liu LL, Stout JW, Anderson LJ. Bronchiolitis-associated hospitalizations among US children, 19801996. JAMA 1999;282:1440-6.
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June 2010 2. Hall CB, Weinberg GA, Iwane MK, Blumkin AK, Edwards KM, Staat MA, et al. The burden of respiratory syncytial virus infection in young children. N Engl J Med 2009;360:588-98. 3. The IMpact-RSV Study Group. Palivizumab, a humanized respiratory syncytial virus monoclonal antibody, reduces hospitalization from respiratory syncytial virus infection in high-risk infants. Pediatrics 1998; 102(3 Pt 1):531-7. 4. Feltes TF, Cabalka AK, Meissner HC, Piazza FM, Carlin DA, Top FH Jr., et al. Palivizumab prophylaxis reduces hospitalization due to respiratory syncytial virus in young children with hemodynamically significant congenital heart disease. J Pediatr 2003;143:532-40. 5. Drug Topics Red Book. Pharmacy’s Fundamental Reference. Montvale, NJ: Thomson PDR December 2006. 6. Committee on Infectious Diseases and Committee on Fetus and Newborn. Revised indications for the use of palivizumab and respiratory syncytial virus immune globulin intravenous for the prevention of respiratory syncytial virus infections. Pediatrics 2003;112(6 Pt 1):1442-6. 7. Brief report. respiratory syncytial virus activity–United States, July 2006November 2007. MMWR 2007;56:1263-5. 8. Bauman J, Eggleston M, Oquist N, Malinoski F. Respiratory syncytial virus: seasonal data for regions of Florida and implications for palivizumab. South Med J 2007;100:669-76. 9. http://www.doh.state.fl.us/Disease_ctrl/epi/RSV/rsv_trends.htm. Accessed 07/09/2009. 10. http://www.cdc.gov/surveillance/nrevss/rsv/default.html. Accessed 02/ 23/2009. 11. Committee on Infectious Diseases and Committee on Fetus and Newborn. Prevention of Respiratory Syncytial Virus Infections: Indications
12.
13.
14.
15.
16. 17. 18.
19.
20.
for the Use of Palivizumab and Update on the Use of RSV-IGIV. Pediatrics 1998;102:1211-6. Mansbach J, Kunz S, Acholonu U, Clark S, Camargo CA Jr. Evaluation of compliance with palivizumab recommendations in a multicenter study of young children presenting to the emergency department with bronchiolitis. Pediatr Emerg Care 2007;23:362-7. Moynihan JA, Kim TY, Young T, Checchia PA. Rate of palivizumab administration in accordance with current recommendations among hospitalized children. J Pediatr Health Care 2004;18:224-7. Pignotti MS, Catarzi S, Donzelli GA. 4-year survey on palivizumab respiratory syncytial virus (RSV)-prophylaxis: how can compliance be improved? J Matern Fetal Neonatal Med 2006;19:221-4. Oh PI, Lanctjt KL, Yoon A, Lee DS, Paes BA, Simmons BS, et al. Palivizumab prophylaxis for respiratory syncytial virus in Canada: utilization and outcomes. Pediatr Infect Dis J 2002;21:512-8. Giusti R. North American synagis prophylaxis survey. Pediatr Pulmonol 2009;44:96-8. Respiratory Syncytial Virus. Red Book 2009;1:560–569. Bellavance M, Rohlicek CV, Bigras JL, Cote JM, Paquet M, Lebel MH, et al. Palivizumab use among children with congenital heart disease in Quebec: impact of Canadian guidelines on clinical practice. Paediatr Child Health 2006;11:19-23. Hampp C, Winterstein AG, Saidi A. Role of Age in Respiratory Syncytial Virus Infection Risk: Recommendations for Palivizumab Utilization, presented at 24th International Conference on Pharmacoepidemiology and Therapeutic Risk Management. Pharmacoepidemiol Drug Safety 2008;17:186. Jacobson Vann J, Feaganes J, Wegner S. Reliability of medicaid claims versus medical record data: in a cost analysis of palivizumab. Pharmacoeconomics 2007;25:793-800.
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Table I. Indications for RSV prophylaxis with palivizumab*,† Indication CLD
Premature I Premature II
Age at season onset (mo) 0-24
a) 0-12 b) 0-6 0-6
CHD
0-24
CF
0-24
Severe combined immunodeficiency /acquired immunodeficiency syndrome
0-24
Condition Chronic lung disease with medical therapy (steroids, oxygen, bronchodilators, diuretics) within 6 months before season onset a) Born # 28 weeks of gestation b) Born 29 to # 32 weeks of gestation Born >32 to 35 weeks of gestation with $2 additional risk factors: child care attendance, school-aged siblings, and exposure to environmental air pollutants such as tobacco smoke. Because exposure to these risk factors cannot be assessed from Medicaid claims data, we attempted to calculate the maximum possible number of children treated for this indication by using only gestational age as a criterion. a) Hemodynamically significant cyanotic CHD b) Acyanotic CHD with claim for oxygen, diuretics, digoxin or angiotensin converting enzyme inhibitors during season CF Severe combined immunodeficiency or severe acquired immunodeficiency syndrome
Evidence
References
Grade I, RCT
3, 4
Grade I, RCT
3
Grade I, RCT
3
Grade I, RCT
4
AAP guideline: ‘‘insufficient data’’(Reference 6) Grade III, ‘‘children [.] may benefit from prophylaxis’’(Reference 6)
N/A N/A
Evidence grade I: evidence obtained from at least 1 properly designed, randomized, controlled trial. Evidence grade III: opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees. *According to AAP guideline6 and AAP Red Book.5 †The indications are not mutually exclusive. One child can have multiple indications and would subsequently be assigned to multiple categories.
959.e1
Hampp, Saidi, and Winterstein