The New England Journal of Medicine

Original Article

Volume 347:322-329

August 1, 2002

Number 5



Inhaled Iloprost for Severe Pulmonary Hypertension
Horst Olschewski, M.D., Gerald Simonneau, M.D., Nazzareno Galiè, M.D.,
Timothy Higenbottam, M.D., Robert Naeije, M.D., Lewis J. Rubin, M.D., Sylvia
Nikkho, M.D., Rudolf Speich, M.D., Marius M. Hoeper, M.D., Jürgen Behr,
M.D., Jörg Winkler, M.D., Olivier Sitbon, M.D., Wladimir Popov, M.D., H.
Ardeschir Ghofrani, M.D., Alessandra Manes, M.D., David G. Kiely, M.D.,
Ralph Ewert, M.D., Andreas Meyer, M.D., Paul A. Corris, F.R.C.P., Marion
Delcroix, M.D., Miguel Gomez-Sanchez, M.D., Harald Siedentop, Dipl.Stat.,
Werner Seeger, M.D., for the Aerosolized Iloprost Randomized Study Group


ABSTRACT
Background Uncontrolled studies suggested that aerosolized iloprost, a
stable analogue of prostacyclin, causes selective pulmonary vasodilatation
and improves hemodynamics and exercise capacity in patients with pulmonary
hypertension.
Methods We compared repeated daily inhalations of 2.5 or 5.0 µg of iloprost
(six or nine times per day; median inhaled dose, 30 µg per day) with
inhalation of placebo. A total of 203 patients with selected forms of severe
pulmonary arterial hypertension and chronic thromboembolic pulmonary
hypertension (New York Heart Association [NYHA] functional class III or IV)
were included. The primary end point was met if, after week 12, the NYHA
class and distance walked in six minutes were improved by at least one class
and at least 10 percent, respectively, in the absence of clinical
deterioration according to predefined criteria and death.
Results The combined clinical end point was met by 16.8 percent of the
patients receiving iloprost, as compared with 4.9 percent of the patients
receiving placebo (P=0.007). There were increases in the distance walked in
six minutes of 36.4 m in the iloprost group as a whole (P=0.004) and of 58.8
m in the subgroup of patients with primary pulmonary hypertension. Overall,
4.0 percent of patients in the iloprost group (including one who died) and
13.7 percent of those in the placebo group (including four who died) did not
complete the study (P=0.024); the most common reason for withdrawal was
clinical deterioration. As compared with base-line values, hemodynamic
values were significantly improved at 12 weeks when measured after iloprost
inhalation (P<0.001), were largely unchanged when measured before iloprost
inhalation, and were significantly worse in the placebo group. Further
significant beneficial effects of iloprost treatment included an improvement
in the NYHA class (P=0.03), dyspnea (P=0.015), and quality of life
(P=0.026). Syncope occurred with similar frequency in the two groups but was
more frequently rated as serious in the iloprost group, although this
adverse effect was not associated with clinical deterioration.
Conclusions Inhaled iloprost is an effective therapy for patients with
severe pulmonary hypertension.
  _____

A continuous infusion of prostacyclin was the first therapy shown to reduce
mortality in a controlled study of patients with severe pulmonary
hypertension. 1 <http://content.nejm.org/cgi/content/full/347/5/#R1>
However, its use is associated with a number of serious drawbacks. The lack
of pulmonary selectivity results in systemic side effects, tolerance leads
to progressive increases in the dose, and there may be recurrent infections
of the intravenous catheter. 2
<http://content.nejm.org/cgi/content/full/347/5/#R2>  As an alternative,
inhaled nitric oxide possesses pulmonary selectivity, but it is less potent
than prostacyclin in the pulmonary vasculature. 3
<http://content.nejm.org/cgi/content/full/347/5/#R3> , 4
<http://content.nejm.org/cgi/content/full/347/5/#R4>  Moreover, an
interruption in the inhalation of continuous nitric oxide may cause rebound
pulmonary hypertension. 5
<http://content.nejm.org/cgi/content/full/347/5/#R5> , 6
<http://content.nejm.org/cgi/content/full/347/5/#R6>  Designed to combine
the beneficial effects of prostacyclin with those of an inhalational
application, aerosolized prostacyclin was found to be a potent pulmonary
vasodilator in patients with acute respiratory failure, exerting
preferential vasodilatation in well-ventilated lung regions. 7
<http://content.nejm.org/cgi/content/full/347/5/#R7> , 8
<http://content.nejm.org/cgi/content/full/347/5/#R8> , 9
<http://content.nejm.org/cgi/content/full/347/5/#R9> , 10
<http://content.nejm.org/cgi/content/full/347/5/#R10>  Similar results were
obtained in spontaneously breathing patients who had lung fibrosis and
severe pulmonary hypertension. 11
<http://content.nejm.org/cgi/content/full/347/5/#R11>
Iloprost is a stable analogue of prostacyclin that is associated with a
longer duration of vasodilatation. 12
<http://content.nejm.org/cgi/content/full/347/5/#R12>  When administered
during a short aerosolization maneuver to patients with pulmonary
hypertension, its pulmonary vasodilative potency was similar to that of
prostacyclin, but its effects lasted for 30 to 90 minutes, as compared with
15 minutes. 4 <http://content.nejm.org/cgi/content/full/347/5/#R4> , 11
<http://content.nejm.org/cgi/content/full/347/5/#R11> , 13
<http://content.nejm.org/cgi/content/full/347/5/#R13> , 14
<http://content.nejm.org/cgi/content/full/347/5/#R14> , 15
<http://content.nejm.org/cgi/content/full/347/5/#R15>  Several open-label,
uncontrolled studies of patients with severe pulmonary hypertension
suggested that long-term use of aerosolized iloprost results in substantial
clinical improvement. 11
<http://content.nejm.org/cgi/content/full/347/5/#R11> , 13
<http://content.nejm.org/cgi/content/full/347/5/#R13> , 16
<http://content.nejm.org/cgi/content/full/347/5/#R16> , 17
<http://content.nejm.org/cgi/content/full/347/5/#R17> , 18
<http://content.nejm.org/cgi/content/full/347/5/#R18> , 19
<http://content.nejm.org/cgi/content/full/347/5/#R19> , 20
<http://content.nejm.org/cgi/content/full/347/5/#R20>  Our objective in this
trial was to evaluate the effects of inhaled iloprost using a rigorous end
point of clinical efficacy.
Methods
Selection of Patients
Patients with primary pulmonary hypertension and selected forms of
nonprimary pulmonary hypertension were candidates for the study. The forms
of nonprimary pulmonary hypertension included
appetite-suppressant–associated and scleroderma-associated pulmonary
hypertension as well as inoperable chronic thromboembolic pulmonary
hypertension. The inclusion criteria were a mean pulmonary-artery pressure
greater than 30 mm Hg, the ability to cover between 50 and 500 m without
encouragement on a six-minute walk test, 21
<http://content.nejm.org/cgi/content/full/347/5/#R21>  and a New York Heart
Association (NYHA) functional class of III or IV 22
<http://content.nejm.org/cgi/content/full/347/5/#R22>  despite the use of
standard conventional therapy (anticoagulants, diuretics, digitalis,
calcium-channel blockers, and supplemental oxygen). Patients who were taking
investigational drugs, prostanoids, or beta-blockers were excluded. The
doses of calcium-channel blockers had to be constant for more than six weeks
before study entry. Exclusion criteria were a pulmonary-artery wedge
pressure at rest of more than 15 mm Hg, a cardiac index at rest of less than
1.5 or more than 4 liters per minute per square meter of body-surface area,
bleeding disorders, a bilirubin level of more than 3 mg per deciliter (51
µmol per liter), creatinine clearance below 30 ml per minute, a forced vital
capacity below 50 percent, a forced expiratory volume in one second that was
less than the mean normal value minus twice the standard deviation, and
clinical instability.
Study Design
A total of 203 patients participated after giving written informed consent
and after the study had been approved by the local ethics committees at 37
European specialist centers. Patients were randomly assigned to receive
iloprost (Ilomedin, Schering) or placebo after stratification according to
NYHA functional class (III or IV) and type of pulmonary hypertension
(primary or nonprimary) by an independent committee whose members were
unaware of patients' identities. A total of 101 patients were randomly
assigned to the iloprost group, and 102 were assigned to the placebo group.
For inhalation, iloprost or placebo was diluted with saline to a
concentration of 10 µg per milliliter, and 2 ml was added to a nebulizer
(HaloLite, MedicAid). This device delivered short pulses of aerosolized
particles (geometric median [±SD] aerodynamic diameter of particles,
4.3±0.05 µm) 23 <http://content.nejm.org/cgi/content/full/347/5/#R23>
during the first part of each inspiration until a predefined total inhaled
dose of 2.5 µg had been dispensed. The inhalation was then stopped or
repeated once, to achieve a total dose of 5.0 µg, depending on how well the
patient tolerated the treatment. After each inhalation, the residual volume
in the nebulizer was discarded. This maneuver was repeated six or nine times
daily, with an overnight break. The frequency of inhalation and the dose
were individually determined within the first eight days of therapy
according to a predefined dosing algorithm.
Right-heart catheterization was performed in all patients at base line and
after 12 weeks. The acute effects of inhaled iloprost were evaluated after
12 weeks in all patients, but not at base line, to avert unblinding. At base
line and after 4, 8, and 12 weeks, patients completed a six-minute walk
test, the Mahler Dyspnea Index questionnaire, 24
<http://content.nejm.org/cgi/content/full/347/5/#R24>  the EuroQol
questionnaire, 25 <http://content.nejm.org/cgi/content/full/347/5/#R25>  and
the 12-item Medical Outcomes Study Short-Form General Health Survey. 26
<http://content.nejm.org/cgi/content/full/347/5/#R26>
Patients were removed from the study if they met two or more of the
following predefined criteria for a deterioration in their condition:
refractory systolic arterial hypotension (blood pressure, less than 85 mm
Hg); worsening right ventricular failure (e.g., as indicated by the
development of refractory edema or ascites); rapidly progressing
cardiogenic, hepatic, or renal failure; a decrease of at least 30 percent in
the distance walked in six minutes; and a decline in measures of hemodynamic
function, such as central venous pressure and mixed venous oxygen
saturation.
Outcome Measures
The primary end point of the study consisted of an increase of at least 10
percent in the distance walked in six minutes and an improvement in the NYHA
functional class in the absence of a deterioration in the clinical condition
or death during the 12 weeks of the study. Secondary efficacy variables were
changes in the values for the six-minute walk test, the NYHA class, Mahler
Dyspnea Index scores, hemodynamic variables, and the quality of life;
clinical deterioration; death; and the need for transplantation.
Statistical Analysis
The primary evaluation of efficacy included all randomized patients. Data
are presented as means ±SD, unless otherwise stated. We included data on
patients who prematurely discontinued the study using a
last-observation-carried-forward analysis for the six-minute walk test.
Patients who died were assigned a value of 0 m. All statistical tests for
efficacy variables were two-tailed, with an alpha level of 0.05.
To analyze the primary efficacy end point and the improvement criteria, we
used the Mantel–Haenszel test, 27
<http://content.nejm.org/cgi/content/full/347/5/#R27>  stratified according
to the type of pulmonary hypertension (primary or nonprimary) and NYHA class
(III or IV). Patients with missing data on the primary end point at week 12
were considered not to have had a response.
Changes in the results of the six-minute walk were evaluated with use of
nonparametric analysis of covariance stratified according to the type of
pulmonary hypertension (primary or nonprimary) and the NYHA class (III or
IV), with use of the base-line value as the covariate (analysis of
covariance), and the Wilcoxon signed-rank test.
Changes from base line in hemodynamic values were analyzed with
t-statistics. The investigators had full access to the data and performed
the analyses independently of the sponsor.
Results
Base-line demographic and hemodynamic data are given in Table 1
<http://content.nejm.org/cgi/content/full/347/5/#T1> . The mean frequency of
inhalation was 7.5 times per day. Ninety-one percent of patients received
5.0 µg per inhalation, and 9 percent received 2.5 µg, corresponding to a
median inhaled dose of 30 µg per day.


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Table 1. Base-Line Characteristics of the Patients.

Primary Efficacy End Point
For the primary end point, we found a significant effect of treatment in
favor of iloprost (P=0.007) ( Figure 1
<http://content.nejm.org/cgi/content/full/347/5/#F1> ). The estimated odds
of an effect in the iloprost group, as compared with the placebo group, were
3.97 (95 percent confidence interval, 1.47 to 10.75, by the Mantel–Haenszel
test), with no significant heterogeneity among the four subgroups
categorized according to type of pulmonary hypertension and NYHA class at
base line (P=0.79 by the Breslow–Day test). The secondary analysis of the
primary end point was a logistic-regression model that included treatment
assignment, demographic data, and base-line characteristics. Only treatment
assignment (P=0.01) contributed significantly to the probability of a
response.


  <http://content.nejm.org/cgi/content/full/347/5/322/F1>
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Figure 1. Effect of Inhaled Iloprost and Placebo on the Mean (±SE) Change
from Base Line in the Distance Walked in Six Minutes, According to an
Intention-to-Treat Analysis.
The P value was obtained with Wilcoxon's test for two independent samples.

Secondary End Points
            Six-Minute Walk Test
The percentage of patients who had an increase of at least 10 percent in the
distance walked in six minutes at week 12 was slightly, but not
significantly, higher in the iloprost group than in the placebo group
(P=0.06) ( Table 2 <http://content.nejm.org/cgi/content/full/347/5/#T2> ).
The type of pulmonary hypertension had no significant effect on the outcome
in either group (P=0.90). A higher percentage of patients in the placebo
group than in the iloprost group had a decrease in the distance walked of at
least 10 percent or did not complete the study ( Table 2
<http://content.nejm.org/cgi/content/full/347/5/#T2> ).


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Table 2. Effects of 12 Weeks of Therapy with Inhaled Iloprost or Placebo on
the New York Heart Association (NYHA) Class and the Six-Minute Walk Test.

The absolute change in the distance walked in six minutes was significantly
larger (by 36.4 m) in the iloprost group than in the placebo group (P=0.004)
( Figure 1 <http://content.nejm.org/cgi/content/full/347/5/#F1> ): 58.8 m
among those with primary pulmonary hypertension and 12 m among those with
nonprimary pulmonary hypertension. A parametric analysis of covariance,
which included the absolute value on the six-minute walk test at week 12 as
a dependent variable and the treatment assignment (P=0.02), type of
pulmonary hypertension (P=0.06), and distance walked at base line (P<0.001)
did not show a statistically significant interaction between treatment and
type of pulmonary hypertension (P=0.09).
NYHA Class
More patients in the iloprost group than in the placebo group had an
improvement in the severity of heart failure, as assessed by the NYHA class
(P=0.03) ( Table 2 <http://content.nejm.org/cgi/content/full/347/5/#T2> ).
The type of pulmonary hypertension had no effect on the outcome in either
group (P=0.39). The percentage of patients with a deterioration in NYHA
class did not differ significantly between the groups, but the analysis did
not include patients who left the study early owing to death or other
reasons. A larger proportion of patients in the placebo group than in the
iloprost group did not complete the study ( Table 2
<http://content.nejm.org/cgi/content/full/347/5/#T2>  and Figure 2
<http://content.nejm.org/cgi/content/full/347/5/#F2> ). Reasons included
death, discontinuation of study medication, and withdrawal of consent,
mostly owing to clinical deterioration, insufficient clinical benefit, or
both.


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Figure 2. Kaplan–Meier Estimates of the Likelihood of Completing the 12-Week
Study.
Reasons for not completing the study included death, discontinuation of
study medication, and withdrawal of consent (see Table 2).

Hemodynamics and Gas Exchange
In the placebo group, cardiac output, systemic arterial oxygen saturation,
and mixed venous oxygen saturation decreased significantly after 12 weeks
and pulmonary vascular resistance and right atrial pressure increased
significantly ( Table 3
<http://content.nejm.org/cgi/content/full/347/5/#T3> ). In the iloprost
group, values assessed at 12 weeks, before the first morning dose of inhaled
iloprost, were largely unchanged from base line, whereas values assessed
after inhalation were significantly decreased (in the case of
pulmonary-artery pressure, pulmonary vascular resistance, systemic arterial
pressure, and systemic arterial oxygen saturation) or increased (in the case
of carbon monoxide and pulmonary-artery wedge pressure). At the completion
of the 12-week study, acute hemodynamic responsiveness to inhaled iloprost
was equivalent in the placebo group and the iloprost group, though the
latter group had been exposed to daily iloprost inhalation for three months
(data not shown).


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Table 3. Mean (±SD) Change from Base Line in Hemodynamic Values during 12
Weeks of Therapy with Inhaled Iloprost or Placebo.

Mahler Dyspnea Index
The mean Mahler Dyspnea Index transition score was significantly better at
week 12 in the iloprost group than in the placebo group (change, +1.42±2.59
vs. +0.30±2.45; P=0.015). The type of pulmonary hypertension had no effect
on this outcome.
Quality of Life
Mean scores on the EuroQol visual-analogue scale improved significantly
(from 46.9±15.9 to 52.8±19.1) in the iloprost group but were virtually
unchanged in the placebo group (dropping from 48.6±16.9 to 47.4±21.1,
P=0.026 by analysis of covariance). The EuroQol health-state score improved
from 0.49±0.28 to 0.58±0.27 in the iloprost group and was unchanged in the
placebo group (0.56±0.29 to 0.56±0.31, P=0.11 by analysis of covariance).
None of the other measures of the quality of life were significantly
different between the groups.
Clinical Deterioration and Death
One patient died in the iloprost group during the 12-week study, as compared
with four patients in the placebo group (P=0.37) ( Table 2
<http://content.nejm.org/cgi/content/full/347/5/#T2> ). Criteria for
clinical deterioration were met in 4.9 percent of patients in the iloprost
group and 8.8 percent of those in the placebo group (P=0.41). This indicated
that fewer patients either died or deteriorated in the iloprost group than
in the placebo group (4.9 percent vs. 11.8 percent, P=0.09). The type of
pulmonary hypertension had no effect on the outcome. During the study
period, none of the patients received a lung transplant.
Safety
The total number of patients who had serious adverse events did not differ
significantly between the groups ( Table 4
<http://content.nejm.org/cgi/content/full/347/5/#T4> ). Right ventricular
failure and edema were more than twice as frequent in the placebo group as
in the iloprost group. The total number of syncopal events in each of the
two groups was similar (eight in the iloprost group and five in the placebo
group), but these events were more often considered serious in the iloprost
group. Syncope was not associated with clinical deterioration or premature
withdrawal from the study. Syncopal events occurred more than two hours
after the last inhalation (often after an overnight break), were
exercise-induced in two patients, were induced by bradycardia in two
patients (associated with gastroenteritis in one patient and with verapamil
therapy in the other), and resulted in head trauma in one patient. Flushing
and jaw pain were more common in the iloprost group, but these adverse
effects were mostly transient and mild and were not considered to be serious
in any patient.


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Table 4. Incidence of Serious and Other Adverse Events.

Discussion
The results of this clinical trial demonstrate that long-term inhaled
administration of aerosolized iloprost, a stable analogue of prostacyclin,
improves a clinically important combined end point consisting of exercise
capacity, NYHA class, and clinical deterioration in patients with selected
forms of pulmonary arterial hypertension and chronic thromboembolic
pulmonary hypertension. Moreover, iloprost improved several secondary end
points.
Since intravenous epoprostenol was shown to improve survival among the most
severely ill patients with primary pulmonary hypertension, it has been
unethical to perform randomized clinical trials among patients with
pulmonary hypertension in which survival is used as an end point. We chose a
combined rather than a single end point (e.g., the distance walked in six
minutes) in order to make a more rigorous determination of whether inhaled
iloprost was efficacious. Nearly 40 percent of all patients who were treated
with iloprost increased their six-minute walking distance by at least 10
percent. However, only half as many patients also had improvement in the
NYHA class; conversely, not all patients with an improvement in NYHA class
had an increase of at least 10 percent in the distance walked in six
minutes. Thus, although only 17 percent of patients in the iloprost group
reached the combined end point, a substantial number of the remaining
patients met less strict criteria for clinical improvement that would
warrant continued therapy. Furthermore, significantly fewer patients in the
iloprost group than in the placebo group prematurely discontinued the study
as a result of lack of efficacy or other reasons, suggesting that even when
iloprost therapy does not produce substantial improvement, it may stabilize
the clinical condition.
The mean inhaled dose of iloprost corresponded to 0.37 ng per kilogram of
body weight per minute, which is considerably lower than an effective
intravenous or subcutaneous dose. 2
<http://content.nejm.org/cgi/content/full/347/5/#R2> , 28
<http://content.nejm.org/cgi/content/full/347/5/#R28>  Thus, targeted
delivery of prostanoids to the pulmonary vasculature by means of inhalation
may substantially reduce the drug requirements.
Like other investigators, we found that the benefit was greatest among
patients with primary pulmonary hypertension and was similar to that of
epoprostenol 1 <http://content.nejm.org/cgi/content/full/347/5/#R1>  and
bosentan. 29 <http://content.nejm.org/cgi/content/full/347/5/#R29>  Although
patients with nonprimary pulmonary hypertension had improvement in the
scores for the Mahler Dyspnea Index and quality-of-life measures that were
similar to those achieved in patients with primary pulmonary hypertension,
fewer such patients reached the combined end point, and they also had a
smaller absolute change in the distance walked in six minutes. Similar
results have been obtained with the use of other drugs for pulmonary
hypertension, including epoprostenol, 30
<http://content.nejm.org/cgi/content/full/347/5/#R30>  beraprost, 31
<http://content.nejm.org/cgi/content/full/347/5/#R31>  and treprostinil. 28
<http://content.nejm.org/cgi/content/full/347/5/#R28>
Hemodynamic assessments of preinhalation values showed that values
stabilized in the iloprost group, whereas they deteriorated in the placebo
group. The degree of deterioration may be underestimated, since patients who
discontinued treatment prematurely did not undergo follow-up hemodynamic
examination. Postinhalation assessments of hemodynamic variables
demonstrated a significant improvement in the iloprost group, as was
anticipated on the basis of previous reports. 4
<http://content.nejm.org/cgi/content/full/347/5/#R4> , 11
<http://content.nejm.org/cgi/content/full/347/5/#R11> , 13
<http://content.nejm.org/cgi/content/full/347/5/#R13> , 16
<http://content.nejm.org/cgi/content/full/347/5/#R16>  Since the acute
hemodynamic response did not differ between the groups, it appears unlikely
that tolerance developed over the 12-week course of iloprost treatment.
During long-term treatment, the patients' hemodynamic status is somewhere
between preinhalation and postinhalation values. In comparison, continuous
intravenous therapy may result in a more sustained hemodynamic improvement
32 <http://content.nejm.org/cgi/content/full/347/5/#R32> ; however,
continuous intravenous therapy also poses considerable risks, including
relapse after the interruption of therapy and complications, and is
difficult to administer.
With respect to adverse events, flushing was more common in the iloprost
group, but the frequency of most of the other inhalation-associated side
effects was similar. There were more syncopal episodes in the iloprost group
than in the placebo group (eight vs. five), and these episodes were more
frequently defined as serious adverse events, but they were not associated
with clinical deterioration. Since syncope occurred a relatively long time
(two to nine hours) after the last inhalation, the loss of an effect of
iloprost may have caused these events. However, the same side effect was
observed with bosentan therapy, suggesting that these drugs may have a more
pronounced effect on blood pressure during exercise. Alternatively, patients
who had clinical improvement with therapy may have become more physically
active, challenging the limits of their cardiac reserve. We would advise
patients to increase their physical activity gradually after the initiation
of therapy for pulmonary hypertension.
The inhalation device that we used provided accurate doses of iloprost.
However, it is not battery-driven, and inhalation commonly required 10
minutes. Different techniques of administering aerosolized iloprost result
in similar acute hemodynamic effects as long as identical doses are
delivered to the respiratory tract in a particle size suitable for alveolar
deposition. 14 <http://content.nejm.org/cgi/content/full/347/5/#R14> , 33
<http://content.nejm.org/cgi/content/full/347/5/#R33>  With other
techniques, the duration of inhalation may be shortened considerably. 14
<http://content.nejm.org/cgi/content/full/347/5/#R14>
In conclusion, this large, placebo-controlled trial demonstrates the
efficacy and safety of inhaled iloprost for the treatment of severe primary
pulmonary hypertension and selected forms of pulmonary arterial and chronic
thromboembolic pulmonary hypertension. The advantages of intermittent
inhaled therapy over intravenous therapy, coupled with the improvement in a
number of clinically meaningful variables, suggest that inhaled iloprost
therapy is effective. It may be a suitable alternative to continuous
intravenous prostacyclin, especially in patients who do not derive a clear
survival benefit with intravenous therapy.
Supported by Schering, Berlin, Germany. All the authors have financial
relationships with Schering, the sponsor of the study. The relationships
differ among the authors and include employment, consultancy, membership in
the scientific advisory board, and support for work as investigators.
* The other members of the Aerosolized Iloprost Randomized (AIR) study group
are listed in the Appendix.
<http://content.nejm.org/cgi/content/full/347/5/#RFN1>

Source Information
From the Department of Internal Medicine II, University Clinic, Giessen,
Germany (H.O., H.A.G., W.S.); Service de Pneumologie, Hôpital Antoine
Béclère, Clamart, France (G.S., O.S.); Istituto di Cardiologia, Università
di Bologna, Bologna, Italy (N.G., A.M.); Royal Hallamshire Hospital,
Sheffield, United Kingdom (T.H., D.G.K.); Department of Cardiology, Erasme
University Hospital, Brussels, Belgium (R.N.); University of California at
San Diego Medical Center, La Jolla (L.J.R.); Schering, Berlin, Germany
(S.N., H.S.); Department of Internal Medicine, University Hospital, Zurich,
Switzerland (R.S., W.P.); Department of Pneumology, Hannover Medical School,
Hannover, Germany (M.M.H.); the Division of Pulmonary Diseases, University
of Munich–Großhadern, Munich, Germany (J.B.); Department of Pneumology,
University Clinic, Leipzig, Germany (J.W.); Department of Pneumology and
Infectious Diseases, Ernst Moritz Arndt University, Greisswald, Germany
(R.E.); Bereich Pneumologie, Medizinische Kernklinik und Poliklinik,
Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany (A.M.); Freeman
Hospital, High Heaton, Newcastle-upon-Tyne, United Kingdom (P.A.C.);
Department of Pneumology, Gasthuisberg University Clinic, Leuven, Belgium
(M.D.); and Pulmonary Hypertension Unit, Hospital 12 de Octubre, Madrid
(M.G.-S.).
Address reprint requests to Dr. Seeger at the Department of Internal
Medicine II, University Clinic, Klinikstr. 36, D-35392 Giessen, Germany, or
at [log in to unmask]
<mailto:[log in to unmask]> .
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Edward E. Rylander, M.D.
Diplomat American Board of Family Practice.
Diplomat American Board of Palliative Medicine.