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`The New England Journal of Medicine
`
`INHALED ILOPROST FOR SEVERE PULMONARY HYPERTENSION
`
`, M.D.,
` H
`, M.D., T
` G
`, M.D., N
` S
`, M.D., G
` O
`H
`IGENBOTTAM
`IMOTHY
`ALIÈ
`AZZARENO
`IMONNEAU
`ERALD
`LSCHEWSKI
`ORST
` N
`, M.D., L
` J. R
`, M.D., S
` N
`, M.D., R
` S
`, M.D., M
` M. H
`, M.D.,
`R
`ARIUS
`PEICH
`UDOLF
`EWIS
`OBERT
`AEIJE
`UBIN
`YLVIA
`IKKHO
`OEPER
`J
` B
`, M.D., J
` W
`, M.D., O
` S
`, M.D., W
` P
`, M.D.,
`ÜRGEN
`EHR
`ÖRG
`INKLER
`LIVIER
`ITBON
`LADIMIR
`OPOV
` G
`, M.D., A
` M
`, M.D., D
` G. K
`, M.D., R
` E
`, M.D.,
`H. A
`RDESCHIR
`HOFRANI
`LESSANDRA
`ANES
`AVID
`IELY
`ALPH
`WERT
` M
`, M.D., P
` A. C
`, F.R.C.P., M
` D
`, M.D., M
` G
`-S
`, M.D.,
`A
`NDREAS
`EYER
`AUL
`ORRIS
`ARION
`ELCROIX
`IGUEL
`OMEZ
`ANCHEZ
`H
` S
`, D
`.S
`.,
` W
` S
`, M.D.,
`ARALD
`IEDENTOP
`IPL
`TAT
`AND
`ERNER
`EEGER
`
` A
` I
` R
` S
` G
`*
`FOR
`THE
`EROSOLIZED
`LOPROST
`ANDOMIZED
`TUDY
`ROUP
`
`A
`BSTRACT
`Background
`Uncontrolled studies suggested that
`aerosolized iloprost, a stable analogue of prostacyclin,
`causes selective pulmonary vasodilatation and im-
`proves hemodynamics and exercise capacity in pa-
`tients 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, af-
`ter 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 clin-
`ical 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 dis-
`tance 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 sub-
`group of patients with primary pulmonary hyperten-
`sion. 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 com-
`mon 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 thera-
`py for patients with severe pulmonary hypertension.
`(N Engl J Med 2002;347:322-9.)
`Copyright © 2002 Massachusetts Medical Society.
`
`A
`
` CONTINUOUS infusion of prostacyclin
`was the first therapy shown to reduce mor-
`tality in a controlled study of patients with
`severe pulmonary hypertension.
` However,
`1
`its use is associated with a number of serious draw-
`backs. The lack of pulmonary selectivity results in
`systemic side effects, tolerance leads to progressive
`increases in the dose, and there may be recurrent in-
`fections of the intravenous catheter.
` As an alternative,
`2
`inhaled nitric oxide possesses pulmonary selectivity,
`but it is less potent than prostacyclin in the pulmo-
`nary vasculature.
` Moreover, an interruption in the
`3,4
`inhalation of continuous nitric oxide may cause re-
`bound pulmonary hypertension.
` Designed to com-
`5,6
`bine the beneficial effects of prostacyclin with those
`of an inhalational application, aerosolized prostacy-
`clin was found to be a potent pulmonary vasodilator
`in patients with acute respiratory failure, exerting
`preferential vasodilatation in well-ventilated lung re-
` Similar results were obtained in spontane-
`gions.
`7-10
`ously breathing patients who had lung fibrosis and
`severe pulmonary hypertension.
`11
`Iloprost is a stable analogue of prostacyclin that is
`associated with a longer duration of vasodilatation.
`12
`When administered during a short aerosolization ma-
`
`From the Department of Internal Medicine II, University Clinic, Gies-
`sen, Germany (H.O., H.A.G., W.S.); Service de Pneumologie, Hôpital An-
`toine Béclère, Clamart, France (G.S., O.S.); Istituto di Cardiologia, Univer-
`sità di Bologna, Bologna, Italy (N.G., A.M.); Royal Hallamshire Hospital,
`Sheffield, United Kingdom (T.H., D.G.K.); Department of Cardiology, Er-
`asme University Hospital, Brussels, Belgium (R.N.); University of Califor-
`nia at San Diego Medical Center, La Jolla (L.J.R.); Schering, Berlin, Ger-
`many (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.); De-
`partment of Pneumology, University Clinic, Leipzig, Germany (J.W.); De-
`partment of Pneumology and Infectious Diseases, Ernst Moritz Arndt
`University, Greisswald, Germany (R.E.); Bereich Pneumologie, Medizinische
`Kernklinik und Poliklinik, Universitätsklinikum Hamburg-Eppendorf, Ham-
`burg, 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 werner.seeger@innere.med.
`uni-giessen.de.
`*The other members of the Aerosolized Iloprost Randomized (AIR)
`study group are listed in the Appendix.
`
`322
`
`·
`
`N Engl J Med, Vol. 347, No. 5
`
`·
`
`August 1, 2002
`
`·
`
`www.nejm.org
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on September 29, 2020. For personal use only. No other uses without permission.
`
` Copyright © 2002 Massachusetts Medical Society. All rights reserved.
`
`Liquidia's Exhibit 1065
`Page 1
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`INHALED ILOPROST FOR SEVERE PULMONARY HYPERTENSION
`
`neuver to patients with pulmonary hypertension, its
`pulmonary vasodilative potency was similar to that of
`prostacyclin, but its effects lasted for 30 to 90 min-
`utes, as compared with 15 minutes.
` Several
`4,11,13-15
`open-label, uncontrolled studies of patients with se-
`vere pulmonary hypertension suggested that long-
`term use of aerosolized iloprost results in substantial
`clinical improvement.
` Our objective in this
`11,13,16-20
`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 includ-
`ed appetite-suppressant–associated and scleroderma-associated
`pulmonary hypertension as well as inoperable chronic thromboem-
`bolic 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-min-
`ute walk test,
` and a New York Heart Association (NYHA) func-
`21
`tional class of III or IV
` despite the use of standard conventional
`22
`therapy (anticoagulants, diuretics, digitalis, calcium-channel block-
`ers, and supplemental oxygen). Patients who were taking investi-
`gational 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 ran-
`domly 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 pa-
`tients’ 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 neb-
`ulizer (HaloLite, MedicAid). This device delivered short pulses of
`aerosolized particles (geometric median [±SD] aerodynamic diam-
`eter of particles, 4.3±0.05 µm)
` during the first part of each in-
`23
`spiration 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 inha-
`lation 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 com-
`pleted a six-minute walk test, the Mahler Dyspnea Index ques-
`
` and the 12-item Medical
` the EuroQol questionnaire,
`tionnaire,
`25
`24
`Outcomes Study Short-Form General Health Survey.
`26
`Patients were removed from the study if they met two or more
`of the following predefined criteria for a deterioration in their con-
`dition: refractory systolic arterial hypotension (blood pressure, less
`than 85 mm Hg); worsening right ventricular failure (e.g., as in-
`dicated 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 pres-
`sure 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
`
`T
`
`ABLE
`
` 1.
`
` B
`
`ASE
`
`-L
`
`INE
`
` C
`
`HARACTERISTICS
`
`
`
`OF
`
`
`
`THE
`
` P
`
`ATIENTS
`
`.*
`
`C
`HARACTERISTIC
`
`Age — yr
`Weight — kg
`Sex — %
`Male
`Female
`Underlying disease — no. (%)
`Primary pulmonary hypertension
`Nonprimary pulmonary hypertension
`Appetite suppressants
`Collagen vascular disease
`Chronic thromboembolic pulmonary
`hypertension
`Oral vasodilator therapy — no. (%)
`NYHA functional class — no. (%)
`III
`IV
`Mahler Dyspnea Index†
`6-Minute walk distance — m
`Hemodynamic variables‡
`Pulmonary-artery pressure — mm Hg
`Cardiac output — liters/min
`Pulmonary vascular resistance —
`dyn·sec·cm
`¡5
`Systemic vascular resistance —
`dyn·sec·cm
`¡5
`Central venous pressure — mm Hg
`Pulmonary-artery wedge pressure
`— mm Hg
`Arterial oxygen saturation — %
`Mixed venous oxygen saturation — %
`Heart rate — beats/min
`
`I
`LOPROST
`G
`ROUP
`(N=101)
`
`P
`LACEBO
`G
`ROUP
`(N=102)
`
`51.2±13.2
`71.3±14.6
`
`52.8±12.0
`72.6±13.9
`
`31.7
`68.3
`
`51 (50.5)
`50 (49.5)
`4 (4.0)
`13 (12.9)
`33 (32.7)
`
`33.3
`66.7
`
`51 (50.0)
`51 (50.0)
`5 (4.9)
`22 (21.6)
`24 (23.5)
`
`52 (51.5)
`
`58 (56.9)
`
`60 (59.4)
`41 (40.6)
`4.14±1.8
`332±93
`
`59 (57.8)
`43 (42.2)
`4.27±1.8
`315±96
`
`52.8±11.5
`3.8±1.1
`1029±390
`
`53.8±14.1
`3.8±0.9
`1041±493
`
`1872±673
`
`1827±503
`
`9.2±5.3
`7.5±3.3
`
`8.2±5.0
`7.6±3.9
`
`92.6±4.4
`60.4±7.5
`83.9±12.2
`
`92.2±5.0
`60.5±8.2
`81.8±15.4
`
`*Plus–minus values are means ±SD. NYHA denotes New York Heart
`Association. There were no significant differences between the iloprost and
`the placebo groups. Data on all variables were available for all patients except
`in the following categories: pulmonary-artery pressure, 1 patient in each
`group; cardiac output, 1 patient in the iloprost group and 6 in the placebo
`group; pulmonary vascular resistance, 10 and 6, respectively; systemic vas-
`cular resistance, 11 and 14; central venous pressure, 5 and 7; pulmonary-
`artery wedge pressure, 8 and 3; arterial oxygen saturation, 35 and 31; mixed
`venous oxygen saturation, 16 and 18; and heart rate, 2 and 3.
`†On this 12-point scale, higher scores indicate less dyspnea.
`‡Patients who were receiving long-term oxygen therapy received nasal
`oxygen during the measurement of base-line hemodynamic variables.
`
`N Engl J Med, Vol. 347, No. 5
`
`·
`
`August 1, 2002
`
`·
`
`www.nejm.org
`
`·
`
`323
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on September 29, 2020. For personal use only. No other uses without permission.
`
` Copyright © 2002 Massachusetts Medical Society. All rights reserved.
`
`Liquidia's Exhibit 1065
`Page 2
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`

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`The New England Journal of Medicine
`
`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 In-
`dex 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 pa-
`tients. 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,
` stratified according to
`27
`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 accord-
`ing to the type of pulmonary hypertension (primary or nonpri-
`mary) 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. 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.
`
`Primary Efficacy End Point
`For the primary end point, we found a significant
`effect of treatment in favor of iloprost (P=0.007)
`(Fig. 1). The estimated odds of an effect in the ilo-
`prost 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 signif-
`icant heterogeneity among the four subgroups cate-
`gorized according to type of pulmonary hyperten-
`sion and NYHA class at base line (P=0.79 by the
`Breslow–Day test). The secondary analysis of the pri-
`mary end point was a logistic-regression model that
`included treatment assignment, demographic data,
`and base-line characteristics. Only treatment assign-
`ment (P=0.01) contributed significantly to the prob-
`ability of a response.
`
`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 min-
`utes at week 12 was slightly, but not significantly,
`higher in the iloprost group than in the placebo
`group (P=0.06) (Table 2). 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).
`The absolute change in the distance walked in six
`minutes was significantly larger (by 36.4 m) in the
`
`Iloprost
`
`P=0.004
`
`Placebo
`
`Base Line
`
`4 Wk
`
`8 Wk
`
`12 Wk
`
`40
`
`20
`
`0
`
`¡20
`
`¡40
`
`Mean Change in Distance Walked (m)
`
`Figure 1.
` Effect of Inhaled Iloprost and Placebo on the Mean (±SE) Change from Base Line in the Dis-
`tance Walked in Six Minutes, According to an Intention-to-Treat Analysis.
`The P value was obtained with Wilcoxon’s test for two independent samples.
`
`324
`
`·
`
`N Engl J Med, Vol. 347, No. 5
`
`·
`
`August 1, 2002
`
`·
`
`www.nejm.org
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on September 29, 2020. For personal use only. No other uses without permission.
`
` Copyright © 2002 Massachusetts Medical Society. All rights reserved.
`
`Liquidia's Exhibit 1065
`Page 3
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`INHALED ILOPROST FOR SEVERE PULMONARY HYPERTENSION
`
`iloprost group than in the placebo group (P=0.004)
`(Fig. 1): 58.8 m among those with primary pulmo-
`nary hypertension and 12 m among those with non-
`primary pulmonary hypertension. A parametric analy-
`sis 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 statis-
`tically significant interaction between treatment and
`type of pulmonary hypertension (P=0.09).
`
`NYHA Class
`More patients in the iloprost group than in the pla-
`cebo group had an improvement in the severity of
`heart failure, as assessed by the NYHA class (P=0.03)
`(Table 2). 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 and Fig. 2). Reasons included death, discon-
`tinuation of study medication, and withdrawal of con-
`
`sent, mostly owing to clinical deterioration, insufficient
`clinical benefit, or both.
`
`Hemodynamics and Gas Exchange
`In the placebo group, cardiac output, systemic ar-
`terial oxygen saturation, and mixed venous oxygen
`saturation decreased significantly after 12 weeks and
`pulmonary vascular resistance and right atrial pressure
`increased significantly (Table 3). 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, system-
`ic arterial pressure, and systemic arterial oxygen satu-
`ration) or increased (in the case of carbon monoxide
`and pulmonary-artery wedge pressure). At the com-
`pletion of the 12-week study, acute hemodynamic re-
`sponsiveness to inhaled iloprost was equivalent in the
`placebo group and the iloprost group, though the lat-
`ter group had been exposed to daily iloprost inhala-
`tion for three months (data not shown).
`
`Mahler Dyspnea Index
`The mean Mahler Dyspnea Index transition score
`was significantly better at week 12 in the iloprost
`
` 12 WEEKS OF THERAPY WITH INHALED ILOPROST OR PLACEBO
`
` E
` 2.
`T
`OF
`FFECTS
`ABLE
`ON THE NEW YORK HEART ASSOCIATION (NYHA) CLASS AND THE SIX-MINUTE WALK TEST.
`
`VARIABLE
`
`ILOPROST GROUP
`PATIENTS WITH
`PRIMARY
`PULMONARY
`HYPERTENSION
`
`PATIENTS WITH
`NONPRIMARY
`PULMONARY
`HYPERTENSION
`
`ALL PATIENTS
`
`PLACEBO GROUP
`PATIENTS WITH
`PRIMARY
`PULMONARY
`HYPERTENSION
`
`PATIENTS WITH
`NONPRIMARY
`PULMONARY
`HYPERTENSION
`
`ALL PATIENTS
`
`percentage of patients
`
`Change in NYHA class
`Improved by 2 classes
`Improved by 1 class
`Unchanged
`Worsened
`Data missing
`Noncompletion of study
`Death
`Other
`Change in 6-minute walk distance
`»10% increase
`<10% increase to <10% decrease
`»10% decrease
`Data missing
`Combined end point
`
`1.0*
`23.8*
`64.4
`5.9
`1.0
`4.0
`1.0
`3.0†
`
`37.6§
`42.6
`13.9
`5.9
`16.8¶
`
`1.9
`22.6
`66.0
`3.8
`1.9
`3.8
`1.9
`1.9
`
`49.1
`37.7
`5.7
`7.5
`20.8
`
`0.0
`25.0
`62.5
`8.3
`0.0
`4.2
`0.0
`4.2
`
`25.0
`47.9
`22.9
`4.2
`12.5
`
`0.0
`12.7
`65.7
`7.8
`0.0
`13.7
`3.9
`9.8‡
`
`25.5
`32.4
`25.5
`16.7
`4.9
`
`0.0
`7.3
`69.1
`10.9
`0.0
`12.7
`3.6
`9.1
`
`30.9
`20.0
`32.7
`16.4
`5.5
`
`0.0
`19.1
`61.7
`4.3
`0.0
`14.9
`4.3
`10.6
`
`19.1
`46.8
`17.0
`17.0
`4.3
`
`*P=0.03 for the comparison of rates of improvement (by one or two classes) with the placebo group.
`†Treatment was discontinued in all three patients.
`‡Treatment was discontinued in seven patients, and three patients withdrew their consent.
`§P=0.06 for the comparison with the placebo group.
`¶P=0.007 for the comparison with the placebo group.
`
`N Engl J Med, Vol. 347, No. 5
`
`·
`
`August 1, 2002
`
`·
`
`www.nejm.org
`
`·
`
`325
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`

`The New England Journal of Medicine
`
`Iloprost
`
`Placebo
`
`P=0.024
`
`1.0
`
`0.9
`
`0.8
`
`0.7
`
`0.6
`
`0
`
`10
`
`20
`
`30
`
`50
`40
`Days
`
`60
`
`70
`
`80
`
`90
`
`Proportion of Patients Remaining
`
`in the Study
`
`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).
`
`TABLE 3. MEAN (±SD) CHANGE FROM BASE LINE IN HEMODYNAMIC VALUES
`DURING 12 WEEKS OF THERAPY WITH INHALED ILOPROST OR PLACEBO.*
`
`VARIABLE
`
`PLACEBO GROUP
`
`ILOPROST GROUP
`BEFORE
`AFTER
`INHALATION
`INHALATION
`
`mean ±SD
`
`Pulmonary-artery pressure (mm Hg)
`Cardiac output (liters/min)
`Pulmonary vascular resistance (dyn·sec·cm¡5)
`Systemic arterial pressure (mm Hg)
`Right arterial pressure (mm Hg)
`Pulmonary-artery wedge pressure (mm Hg)
`Arterial oxygen saturation (%)
`Mixed venous oxygen saturation (%)
`Heart rate (beats/min)
`
`¡0.1±7.3
`¡0.2±6.9
`¡0.19±0.81‡ +0.05±0.86
`+96±322‡
`¡9±275§
`¡0.2±12.4
`¡1.7±12.8
`+1.4±4.8‡
`+0.5±4.6
`+0.7±3.6
`+1.1±4.7‡
`¡1.6±4.4‡
`¡0.4±3.7
`¡3.2±6.7†
`¡1.1±7.6
`¡1.2±9.5
`¡1.8±12.4
`
`¡4.6±9.3†
`+0.55±1.1†
`¡239±279†
`¡4.3±13.6¶
`¡0.8±4.6
`+1.8±5.3¶
`¡1.4±3.7‡
`+1.8±8.3
`¡2.25±12.6
`
`*For the iloprost group, both preinhalation and postinhalation values after 12 weeks are compared
`with the base-line values at study entry.
`†P<0.001 for the difference from base-line values.
`‡P<0.05 for the difference from base-line values.
`§P<0.01 for the comparison with the placebo group.
`¶P<0.01 for the difference from base-line values.
`
`group than in the placebo group (change, +1.42±
`2.59 vs. +0.30±2.45; P=0.015). The type of pulmo-
`nary 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 un-
`changed 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.
`
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`The New England Journal of Medicine
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`

`

`INHALED ILOPROST FOR SEVERE PULMONARY HYPERTENSION
`
`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). Criteria for clin-
`ical 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 hyperten-
`sion 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 ad-
`verse events did not differ significantly between the
`groups (Table 4). Right ventricular failure and ede-
`ma 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 sim-
`ilar (eight in the iloprost group and five in the pla-
`cebo group), but these events were more often con-
`sidered serious in the iloprost group. Syncope was
`not associated with clinical deterioration or prema-
`ture withdrawal from the study. Syncopal events oc-
`curred 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.
`
`DISCUSSION
`The results of this clinical trial demonstrate that
`long-term inhaled administration of aerosolized ilo-
`prost, a stable analogue of prostacyclin, improves a
`clinically important combined end point consisting
`of exercise capacity, NYHA class, and clinical deteri-
`oration 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 im-
`prove 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 sur-
`vival 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 rig-
`orous determination of whether inhaled iloprost was
`efficacious. Nearly 40 percent of all patients who were
`treated with iloprost increased their six-minute walk-
`
`ing 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 num-
`ber 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 prema-
`turely discontinued the study as a result of lack of
`efficacy or other reasons, suggesting that even when
`iloprost therapy does not produce substantial improve-
`ment, 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 intrave-
`nous or subcutaneous dose.2,28 Thus, targeted delivery
`of prostanoids to the pulmonary vasculature by means
`of inhalation may substantially reduce the drug re-
`quirements.
`
`TABLE 4. INCIDENCE OF SERIOUS AND OTHER ADVERSE EVENTS.*
`
`VARIABLE
`
`ILOPROST GROUP
`(N=101)
`
`PLACEBO GROUP
`(N=102)
`
`P
`VALUE
`
`no. of patients (%)
`
`Serious adverse event
`Any event
`Right ventricular failure
`and edema
`Syncope
`Other†
`Adverse event‡
`Any event
`Increased cough
`Headache
`Flushing
`Influenza-like syndrome
`Peripheral edema
`Nausea
`Jaw pain
`Hypotension
`Diarrhea
`Vertigo
`Syncope
`Other adverse events§
`
`28 (27.7)
`4 (4.0)
`
`5 (5.0)
`33 (32.7)
`
`91 (90.1)
`39 (38.6)
`30 (29.7)
`27 (26.7)
`14 (13.9)
`13 (12.9)
`13 (12.9)
`12 (11.9)
`11 (10.9)
`9 (8.9)
`7 (6.9)
`8 (7.9)
`296
`
`25 (24.5)
`10 (9.8)
`
`0
`35 (34.3)
`
`90 (89.2)
`26 (25.5)
`20 (19.6)
`9 (8.8)
`10 (9.8)
`16 (15.7)
`8 (7.8)
`3 (2.9)
`6 (5.9)
`11 (10.8)
`11 (10.8)
`5 (4.9)
`277
`
`0.63
`0.16
`
`0.03
`0.88
`
`0.82
`0.05
`0.11
`0.001
`0.39
`0.69
`0.26
`0.02
`0.22
`0.81
`0.46
`0.41
`
`*The most common adverse events are listed.
`†These events included an aggravation reaction (an event causing con-
`cern about possible deterioration) in four patients in the iloprost group and
`five patients in the placebo group, hypoxemia in two patients in the placebo
`group, pneumonia in two patients in the iloprost group, tachycardia in two
`patients in the iloprost group and one in the placebo group, laboratory-
`test abnormalities in two patients in the iloprost group, chest pain in two
`patients in each group, and dyspnea in two patients in each group.
`‡Data were available for 101 patients in the placebo group.
`§The number is the total number of other adverse events.
`
`N Engl J Med, Vol. 347, No. 5 · August 1, 2002 · www.nejm.org · 327
`
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`
`Downloaded from nejm.org on September 29, 2020. For personal use only. No other uses without permission.
`
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`
`

`

`The New England Journal of Medicine
`
`Like other investigators, we found that the benefit
`was greatest among patients with primary pulmonary
`hypertension and was similar to that of epoprostenol1
`and bosentan.29 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, few-
`er such patients reached the combined end point,
`and they also had a smaller absolute change in the dis-
`tance walked in six minutes. Similar results have been
`obtained with the use of other drugs for pulmonary
`hypertension, including epoprostenol,30 beraprost,31
`and treprostinil.28
`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 ilo-
`prost group, as was anticipated on the basis of pre-
`vious reports.4,11,13,16 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 treat-
`ment, the patients’ hemodynamic status is somewhere
`between preinhalation and postinhalation values. In
`comparison, continuous intravenous therapy may re-
`sult in a more sustained hemodynamic improvement32;
`however, continuous intravenous therapy also poses
`considerable risks, including relapse after the inter-
`ruption 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