Pharmacoeconomics

Cost-Effectiveness of Prophylactic Indomethacin

in Very-Low-Birth-Weight Infants

Martin P Moya and Ronald N Goldberg

OBJECTIVE: To perform cost-effectiveness analysis to facilitate the decision-making process surrounding use of indomethacin in
preterm infants to lower the incidence of patent ductus arteriosus (PDA), intraventricular hemorrhage (IVH), and death.
METHODS: A MEDLINE literature search from 1966 to July 2000 was performed to identify relevant randomized, controlled trials
(RCTs), as well as cohort and retrospective case–control studies. A decision tree was built representing the choice to use or not use
indomethacin, and the potential outcome costs. Probabilities of being in each chance node were obtained from this search. Where
data probabilities were not clear, a sensitivity analysis was conducted.
RESULTS: There was no difference in the expected survival per year; however, there was a significant difference when effectiveness
was measured as quality-adjusted life years (QALYs), resulting in 11 and 10 years for the indomethacin and control groups,
respectively. The indomethacin treatment cost was $95 157 and that of the control groups was $99 955. The cost effectiveness per
life expectancy of being in the indomethacin and control groups was $7142 and $7727, respectively. The sensitivity analysis for
PDA closure and prevention of IVH for infants eventually developing PDA versus those without PDA showed no difference. The
cost-effectiveness analysis per QALY was $8443 for the indomethacin treatment and $9168 for the control group.
CONCLUSIONS: The prophylactic use of indomethacin is less costly and more effective within an important range of certainty.
However, this analysis does not include several potentially confounding factors, such as antenatal steroid use or indomethacin-
induced renal toxicity. Depending on the frequency with which these factors arise, economic projections may be considerably
altered against the early use of indomethacin.
KEY WORDS: indomethacin, low-birth-weight infants, patent ductus arteriosus.

Ann Pharmacother 2002;36:218-24.

rematurity is by far the most important problem in
P modern perinatal medicine in terms of morbidity and
mortality. Very-low-birth-weight (VLBW) infants (<1500
g) account for only 1.2% of all births, but represent 46% of
infant deaths.1 Advances in neonatal technology have sig-
nificantly improved survival for VLBW infants, but at a
high cost. Pomerance et al.2 first reported the cost of caring
for infants weighing ≥1000 g. In subsequent years, re-
ports3-19 showed increasing awareness of the rising cost of
health care for the sick newborn.
Preterm infants with parenchymal central nervous sys-
tem injury and intraventricular hemorrhage (IVH) are be-
Author information provided at the end of the text.
lieved to be at significant risk for neurodevelopmental hand-
icap, mental retardation, and cerebral palsy.20-24 Concern,
therefore, about the neurodevelopmental outcome of VLBW
infants has prompted multiple pharmacologic intervention
trials to prevent IVH.25-28 Some animal and human studies,
as well as a meta-analysis done by Fowlie29 suggest that in-
domethacin lowers the incidence of IVH.30-36 In addition, it
is used for pharmacologic closure of the ductus.37 In-
domethacin may improve cerebral outcome by lowering
baseline cerebral blood flow and modulating changes in re-
sponse to hypercarbic insult, decreasing serum prostaglandin
concentrations, and promoting germinal matrix microvas-
cular maturation.38-41
The purpose of this study was to use a cost-effectiveness
analysis methodology to facilitate decision making sur-

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rounding the use of prophylactic indomethacin in preterm
infants to lower the incidence of patent ductus arteriosus
(PDA), IVH, and death. The use of this type of analysis of-
fers the practitioner another tool to assess the utility of con-
troversial therapies and their impact in the nursery.
Materials and Methods
DECISION ANALYSIS MODEL
A decision analytic model was constructed employing a simple deci-
sion tree comparing the use of prophylactic indomethacin with the stan-
dard of treatment for premature infants (Figure 1). The probabilities of
events in the decision tree (Tables 113,15,24,29,36,42-51 and 213,15,24,29,36,42-51)
were derived primarily from the work of Fowlie29 and Ment et al.36
With prophylaxis, an infant subgroup-specific probability of PDA (P)
was assumed equal to that found in a meta-analysis,36 and an infant’s
probability of not having PDA was assumed to be equal to 1-(P). The
same procedure was performed with the control group, and for all other
possible outcomes. The probability of ductal closure by indomethacin or
control was derived from the work of Zerella et al.42
The probabilities of developing an IVH in groups with and without
PDA for both indomethacin and control groups were obtained after dis-
Figure 1. Decision tree with expected cost.
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cussion with experts and from evidence that PDA is a dependent factor
in the occurrence of IVH.52,53
Survival rates in the indomethacin and control groups were obtained
from the meta-analysis,29 because those numbers match more closely
with the overall data for the VLBW infant.
The analysis took the societal perspective and included both direct
medical and nonmedical (specifically work-loss cost). The primary out-
come was cost. Secondary outcomes included effectiveness in terms of
years and quality-adjusted life years (QALYs), cost per discounted years
of life saved, and cost per discounted QALYs saved. When considerable
uncertainty existed about costs or probabilities, we chose base-case as-
sumptions favorable to standard of treatment to bias the analysis against
our findings. The analysis was done using a standard computer program
(Decision Maker54,55) to analyze decision trees and perform sensitivity
analyses.
COSTS
Costs are summarized in Tables 1 and 2. We estimated the cost of in-
domethacin at $23, based on a published wholesale pharmaceutical cata-
log. Thus, the cost of three doses of indomethacin treatment was estimat-
ed to be $69.
The cost of treating PDA surgically was $11 108 based on the North
Carolina Department of Medical Assistance diagnosis-related group
weight table.18 A major cardiovascular procedure with complication is
The Annals of Pharmacotherapy ■ 2002 February, Volume 36 ■ 219
MP Moya and RN Goldberg

4.7907 and accounts for 20% of the procedures. A major

cardiovascular procedure without complication is 2.3518, Table 1. Costs of Prophylactic Indomethacin
accounting for 80% of procedures. The cost of care in the Parameter Baseline Range Reference
first year of life for a patient <1500 g with no IVH was
$93 800.50 The estimation of cost in the first year for a Probability
VLBW infant with IVH was the cost of the one without PDA 0.10 0.05–0.20 29,36
IVH plus $68 453. This cost was obtained from Pikus et medical treatment 0.585 0.50–0.90 42-45
al.,24 who calculated the treatment cost of a VLBW infant IVH grade III, IV 0.526 0.40–0.60 29,36,46
in the first year of life. For every year these patients sur- survival 0.50 29,36,46
no IVH 0.474 29,36,46
vived, $40 406 was added based on an estimate from Mc-
survival 0.80 46
Callum and Turbeville.44 The cost in the first year if the
surgical ligation 0.415 42-45
child died was $29 700 (Tables 1 and 2).50 IVH grade III, IV 0.742 29,36,46
survival 0.50 29,36,46
no IVH 0.258 29,36,46
OTHER ASSUMPTIONS survival 0.80 44,46
No PDA 0.90 29,36
The time horizon was set at 15 years for a premature
IVH grade III, IV 0.017 0.008–0.03 29,36
infant in both groups. Fifteen years of life were used to survival 0.50 46
avoid increasing uncertainties including calculating how no IVH 0.983 46
much the individual would return to the state after being survival 0.96 0.90–1.0 46
able to work. This model did not incorporate the cost of
Utility
lost productivity resulting from the death of a child. This
IVH grade III, IV survival (y) 3.2 47
also decreased the uncertainties introduced into this type No IVH survival (y) 15 13
of study. Cost-effectiveness was also represented as an in- Death (y) 0
cremental cost-effectiveness ratio over the best option
(Table 3). Cost ($)
Indomethacin 23 (× 3 doses) 51
Surgical ligation 11 108 48
USE OF EXPERT JUDGMENT ICN first year 93 800 23,49
ICN first year + IVH 162 253 24,50
A quality-of-life value was assigned after consultation IVH per year of life 40 406 24,50
Death 29 700 15
with experts in the developmental follow-up of infants.
Patients who were alive without complications were as- ICN = intensive care nursery; IVH = intraventricular hemorrhage; PDA = patent duc-
signed a value of 0.85. A sensitivity analysis was done, tus arteriosus.
with a sensitivity analysis ranging from 0.70 to 1. A qual-
ity-of-life value was also assigned to patients who had
IVH. This value was 0.4, with a sensitivity analysis rang-
ing from 0.25 to 0.6. For these patients, cost-effectiveness
is also represented as an incremental cost-effectiveness
ratio over the best option. Table 2. Costs of Standard Indomethacin Treatment
Parameter Baseline Range Reference
SENSITIVITY ANALYSIS Probability
PDA 0.32 0.20–0.45 29,36
We evaluated the sensitivity of the model to variations medical treatment 0.585 0.50–0.70 42-45
in key assumptions over plausible ranges (Figure 2). We IVH grade III, IV 0.278 0.20–0.40 29,36,46
varied the following: survival 0.50 29,36,46
1. the occurrence of PDA: 5–20% for the prophylac- no IVH 0.722 29,36,46
tic group and 20 – 45% in the standard treatment survival 0.90 46
group; surgical ligation 0.415 42-45
2. medical treatment for PDA: 50 –90% for the pro- IVH grade III, IV 0.391 29,36,46
phylactic group and 50–70% in the standard treat- survival 0.50 29,36,46
ment group; no IVH 0.609 29,36,46
survival 0.90 44,46
3. grade III and IV IVH in the babies who had had
No PDA 0.680 29,36
PDA and received medical treatment: 40–60% for
IVH grade III, IV 0.038 0.019–0.067 29,36
the prophylactic group and 20 – 40% in the stan- survival 0.50 46
dard treatment group; no IVH 0.962 46
4. grade III and IV IVH in babies who had had no survival 1 0.9–1.0 46
PDA: 0.8–3% for the prophylactic group and 1.9–
Utility
6% in the standard treatment group; and
IVH grade III, IV live (y) 3.2 47
5. the likelihood of survival in babies without PDA No IVH live (y) 15 13
and IVH: 90–100% for both groups. Death (y) 0
Cost ($)
STATISTICS Indomethacin 23 (× 3 doses) 51
Surgical ligation 11 108 48
No statistics were used. This was all expected value ICN first year 93 800 23,49
calculation, “folding or rolling down the tree,” and con- ICN first year + IVH 162 253 24,50
sisted of multiplying the utilities by the probabilities of IVH per year of life 40 406 24,50
their occurrence, and summing them for each chance Death 29 700 15
node. Two-way sensitivity analysis enabled us to test the ICN = intensive care nursery; IVH = intraventricular hemorrhage; NC DMA DRG =
sensitivity of a proposed decision to simultaneous changes North Carolina Department of Medical Assistance Diagnosis-Related Group; PDA =
in the values of two variables. Results are presented in a patent ductus arteriosus.
region graph.

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Results
Prophylactic indomethacin prevented the occurrence of
IVH, incurred less cost than the standard treatment group,
and thus was the dominant strategy. Prophylactic in-
domethacin was estimated to cost $95 157 (Table 3) in com-
parison with standard treatment cost ($99 955). We also per-
formed the analysis with cost and effectiveness, quantity
(years of life gained), and quality (QALY expectancy). Us-
ing these assumptions, prophylactic indomethacin resulted
in 13 expected survival years and 11 QALYs, and the stan-
dard treatment resulted in 13 expected survival years and 10
QALYs. The cost-effectiveness in years of life was $7142
for the prophylactic group and $7727 in the standard treat-
ment group. We also performed the same cost-effectiveness
analysis, but instead of using the number of years gained as
effectiveness, we used QALYs as effectiveness. This analy-
sis gave us $9168 for the prophylactic group and $8443 for
standard treatment.
SENSITIVITY ANALYSES
Under what circumstances might prophylactic indo-
methacin therapy be more effective than the standard treat-
ment, and how would this improvement influence effec-
tiveness of prophylactic indomethacin? We answered these
questions by performing a two-way sensitivity analysis for
all major parameters in the model in which information
was not conclusive. After the sensitivity analyses, prophy-
lactic indomethacin remained the preferred strategy. The
only sensitivity analysis that could change our strategy was
one in which probabilities of PDA were changed (Figure
2). In this case scenario, when the occurrence of PDA was
at the extremes for both groups, the option may change.
Discussion
In neonatology, the limits set for aggressive manage-
ment of the VLBW infant have gradually been lowered by
virtue of the increasing successful survival at each birth
weight. What is not always encouraging is that the inci-
dence of IVH has decreased at a slower rate than that of
survival.56 As a result, the increase in number of children
with cerebral palsy and cognitive impairment has risen.
In view of the increasing number of patients with IVH
but limited healthcare resources, there is a need to optimize
management. Prophylactic indomethacin is one of a num-
ber of therapies that have been employed, although its effi-
cacy has been disputed. Evaluation of the usefulness of in-
Table 3. Incremental Cost-Effectiveness Ratio Over the Best Option
Strategy Expected Cost ($) Expected Survival (y)
Standard treatment 99 955
Prophylactic indomethacin 95 157
ICER = incremental cost-effectiveness ratio; QALY = quality-adjusted life year.
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domethacin therapy has been hindered by its use in only a
limited number of nurseries with random geographic dis-
tribution. Our study facilitates decision making concerning
the use of indomethacin in preterm infants.
Cost-effectiveness analysis is a method used to assess
the outcomes and cost of interventions designed to im-
prove health. The results of the analyses are usually sum-
marized in a series of cost-effectiveness ratios that show
the cost of achieving a type of healthcare outcome. Cost-ef-
fectiveness analysis shows the trade-offs involved in
choosing among interventions or variants of an interven-
tion. Thus, decision makers in diverse settings (physicians,
health maintenance organizations, state or federal pro-
grams) obtain important data for making informed judg-
ments about interventions, especially when the clinical
usefulness is controversial.
The findings of this study would suggest that indometh-
acin for infants weighing <1500 g is less costly than conven-
tional management, and if indomethacin is used as prophy-
laxis for IVH, the cost of neonatal health care may decrease.
Since the results, which are based on published data,
showed that indomethacin is also more clinically effective,
it is necessary to consider the cost-effectiveness before de-
ciding whether to introduce it prophylactically.
Figure 2. Two-way sensitivity analysis allows testing for the sensitivity of a
proposed decision to simultaneous changes in the values of two variables.
Results are presented in a region graph. pIndPDA = prophylactic indomethacin
for patent ductus arteriosus; pNoIndPDA = no prophylactic indomethacin for
patent ductus arteriosus.
Expected QALYs (y) ICER ($/y) ICER ($/QALY)
13 10 585 (7727) 725 (9168)
13 11 (7142) (8443)
The Annals of Pharmacotherapy ■ 2002 February, Volume 36 ■ 221
MP Moya and RN Goldberg
The benefits in terms of effectiveness are in the hypo-
thetical number of years gained by the person, which can
be seen in Table 3. However, when QALYs gained are tak-
en into account, a difference is noted. The cost without the
potential benefits or effectiveness of the treatment is also
represented in Table 3, where again the indomethacin
choice is the more economical.
In considering cost-effectiveness of the results, it is nec-
essary to look at the incremental cost-effectiveness ratio
(ICER; defined as the ratio of the mean difference in aver-
age cost to the mean difference in average effectiveness).
The ICER for the conventional management was $4798.
When the cost-effectiveness of the two options was ana-
lyzed, the results showed that indomethacin was the option
for improved effectiveness in years of life and QALYs.
Interpreting cost-effectiveness data to make decisions
about resource allocation raises concerns since, as cost and
effects are measured with error, a point estimate of cost-ef-
fectiveness must be presented with a measure of disper-
sion. For this reason, sensitivity analysis has traditionally
been applied to decision models to quantify the stability of
a preferred alternative to parametric variation.
The decision-analysis model was robust when changes
were made in all variables over the range of their plausible
values. Cost savings with presumptive treatment persisted
in all variables. Even when one-way and two-way sensitiv-
ity analyses assumed the worst-case scenario, the cost-ef-
fectiveness ratio for presumptive treatment of indomethacin
compared favorably with that for the standard treatment.
The exception was the sensitivity analysis that was per-
formed to determine the probability of PDA (Figure 2).
This graphic can be interpreted if the investigators know
the incidence of PDA in their intensive care nursery and
the number of infants eligible for prophylactic or treatment
indomethacin. Hypothetically, if there is an incidence of
15% for PDA in the prophylactic group and an incidence
of 25% in the standard group, the choice suggested by the
analysis will be not to use prophylactic indomethacin. This
analysis may help neonatal intensive care units that accu-
rately and consistently record the incidence of PDA in in-
fants treated or not with prophylactic indomethacin to
make specific decisions concerning that therapy.
The limitations of this study include the use of therapies
that may positively impact the incidence of IVH such as
prenatal steroids.57,58 The use of prenatal steroids was not
evaluated and therefore not included in this model and
may confound the data. In the largest study evaluating pro-
phylactic indomethacin,36 the use of prenatal steroids was
not evaluated. This trial was performed prior to use of pre-
natal steroids for premature birth. In fact, all work evaluat-
ing the use of indomethacin had been performed without
this variable in place because prenatal steroids were not
widely used. Since all economic analyses were based on
studies prior to these guidelines, no data are available at
present that evaluate this confounding variable. Having
said this and knowing that the studies included in this
model did have a well-conducted randomized assignment,
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there is no reason to believe that patient distribution would
be skewed. Another problem that may impact these results
is the inclusion of patients with hydrocephalus; however,
this study was the only one available. Applying this bias in
cost to both groups minimized its effect on the results. In
addition, the literature does not discriminate among differ-
ent weight groups.
Necrotizing enterocolitis (NEC) or bowel perforation
has been associated with the use of indomethacin in ex-
tremely low-birth-weight infants. We did not include this
risk because of its uncertain association at this time. We
believe it is premature to assign a risk for NEC to the treat-
ment group. These points, however, highlight the limita-
tions of this type of statistical approach.
Summary
The data presented here suggest that prophylactic in-
domethacin is cost-effective when considering its ability to
decrease PDA and IVH in a very-low-birth-weight popula-
tion. These data also suggest that this analysis might be
useful in decision analysis in the nursery when strict crite-
ria are used to define clinical phenomena and the limita-
tions of the methodology are appreciated.
Martin P Moya MD, Fellow, Department of Pediatrics, Division of
Neonatology, Duke University Medical Center, Durham, NC
Ronald N Goldberg MD, Chief, Department of Pediatrics, Division
of Neonatology, Duke University Medical Center
Reprints: Martin P Moya MD, Hugo Wast 4690 Cerro, Córdoba
5009, Argentina, E-mail mmoya@vitametrix.com
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EXTRACTO
TRASFONDO: Indometacina (Indo) es la terapia más comunmente usada
para tratar ductus arteriosus patentes (DAP) en neonatos prematuros. La
administración profiláctica de Indo en los primeros días de vida ha sido
usada para disminuir la incidencia de DAP, hemorragia intraventricular
(HIV) y mortalidad.
MÉTODOS: Se realizó una búsqueda de la literatura a través de
MEDLINE de 1996 hasta el presente para identificar estudios aleatorios
controlados relevantes, así como estudios de cohorte y de casos
■ 2002 February, Volume 36 ■ 223
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controlados retrospectivos. Se construyó un modelo analítico de decisión
tipo árbol representado la selección o no selección de Indo y los
resultados de costos potenciales. Las probabilidades de estar en cada
nudo del árbol de decisión se obtuvieron de esta búsqueda. Si los datos
de probabilidades no estaban claros, se conducía un análisis de
sensitividad.
RESULTADOS: No hubo diferencia en la supervivencia esperada por año.
Sin embargo, hubo una diferencia significativa cuando se midió la
efectividad como años de vida ajustados a calidad resultando en 11 y 10
años para Indo y los grupos controles, respectivamente. El costo de
tratamiento con Indo fue $95 157 y, en los grupos controles, $99 955. La
costo efectividad por expectativa de vida de usar Indo y en los grupos
controles fue $7142 y $7727, respectivamente. El análisis de
sensitividad no demostró diferencia para el cierre de DAP y la
prevención de HIV en infantes que eventualmente desarrollaron DAP en
comparación con aquellos infantes sin DAP. El análisis de costo
efectividad por años de vida ajustados a calidad fue $8443 para el
tratamiento con Indo y $9168 para el grupo control.
DISCUSIÓN: El uso profiláctico de Indo es menos costoso y más efectivo
dentro de un alcance importante de certeza. Sin embargo, este análisis
no incluye varios factores potenciales de confusión como uso de
esteroides prenatales o toxicidad renal inducida por Indo. Dependiendo
de la frecuencia en que estos factores aparezcan, las proyecciones
económicas pueden ser alteradas considerablemente en contra del uso
temprano de Indo.
Juan F Feliu
RÉSUMÉ
RAPPEL: L’indométacine (Indo) est la thérapeutique la plus couramment
employée pour traiter la persistance du canal artériel (PDA) chez le
nouveau-né prématuré. L’administration prophylactique d’Indo dans les
premiers jours de la vie a été utilisée pour réduire l’incidence de la PDA,
l’hémorragie intraventriculaire (IVH), et la mortalité.
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MÉTHODES: Une recherche MEDLINE de la bibliographie datant de
1966 à nos jours a été effectuée pour identifier les essais contrôlés
randomisés pertinents, ainsi que les études cas-témoins de cohortes et
rétrospectives. Un arbre de décision a été construit indiquant
l’alternative entre Indo ou non, et les éléments potentiels en termes de
coûts. Les probabilités relatives à chaque nœud alternatif ont été
obtenues par cette recherche. Lorsque les données de probabilité
n’étaient pas claires, une analyse de sensibilité a été réalisée.
RÉSULTATS: Il n’a pas été trouvé de différence dans la survie attendue par
année, bien qu’une différence significative existe quand l’efficacité est
exprimée en QALY (Qualité ajustée aux années de vie), correspondant
respectivement à 11 et 10 ans pour les groupes Indo et contrôles. Le coût
de traitement Indo était de 95 157 dollars et de 99 955 dans les groupes
contrôles. Le rapport coût-efficacité en espérance de vie des groupes
Indo et contrôles était respectivement de 7142 et 7727 dollars. L’analyse
de sensibilité de l’obtention de la fermeture du canal artériel et de la
prévention de l’IVH pour les nouveau-nés développant par la suite une
PDA versus ceux sans PDA n’a pas montré de différence. Le rapport
coût-efficacité par QALY était de 8443 dollars dans le groupe Indo
contre 9168 dollars dans le groupe contrôle.
DISCUSSION: L’utilisation prophylactique d’Indo est moins coûteuse et
plus efficace avec un degré important de certitude. Cependant, cette
analyse ne tient pas compte de plusieurs facteurs pouvant
potentiellement jouer, tels que l’utilisation anténatale de stéroïdes et la
toxicité rénale induite par l’indométacine. En fonction de la fréquence
de survenue de tels facteurs, les projections économiques peuvent être
considérablement modifiées en défaveur d’un recours précoce à
l’indométacine.
Michel Le Duff
www.theannals.com