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`The New England Journal of Medicine
`
`LONG-TERM TREATMENT OF PRIMARY PULMONARY HYPERTENSION
`WITH AEROSOLIZED ILOPROST, A PROSTACYCLIN ANALOGUE
`
`, R.N.,
`-S
` A
`, A
` E
`, S
` S
`, M.D., M
` M. H
`M
`CHUERMEYER
`DLER
`NGELIKA
`HLERDING
`TEFAN
`CHWARZE
`ICHAEL
`OEPER
`ARIUS
` S
`, M.D., J
` N
`, M.D., M
` H
`, M.D.,
` H
` F
`, M.D.
`E
`ELMUT
`AND
`AMM
`IEDERMEYER
`PIEKERKOETTER
`DDA
`OST
`ICHAEL
`ABEL
`
`A
`BSTRACT
`Background
`Continuous intravenous infusion of
`epoprostenol (prostacyclin) is an effective treatment
`for primary pulmonary hypertension. This approach
`requires the insertion of a permanent central venous
`catheter, with the associated risk of serious compli-
`cations. Recently, aerosolized iloprost, a stable pros-
`tacyclin analogue, has been introduced as an alter-
`native therapy for severe pulmonary hypertension.
`Methods
`We evaluated the effects of aerosolized
`iloprost on exercise capacity and hemodynamic var-
`iables over a one-year period in patients with primary
`pulmonary hypertension.
`Results
`Twenty-four patients with primary pulmo-
`nary hypertension received aerosolized iloprost at a
`daily dose of 100 or 150 µg for at least one year. The
`mean (±SD) distance covered in the six-minute walk
`test increased from 278±96 m at base line to 363±
`135 m after 12 months (P<0.001). During the same
`period, the mean pulmonary arterial pressure before
`the inhalation of iloprost declined from 59±10 mm Hg
`to 52±15 mm Hg (P=0.006), cardiac output increased
`from 3.8±1.4 liters per minute to 4.4±1.3 liters per
`minute (P=0.02), and pulmonary vascular resistance
`declined from 1205±467 dyn·sec·cm
` to 925±469
`¡5
`(P<0.001). The treatment was generally
`dyn·sec·cm
`¡5
`well tolerated, except for mild coughing, minor head-
`ache, and jaw pain in some patients.
`Conclusions
`Long-term treatment with aerosolized
`iloprost is safe and has sustained effects on exercise
`capacity and pulmonary hemodynamics in patients
`with primary pulmonary hypertension. (N Engl J Med
`2000;342:1866-70.)
`©2000, Massachusetts Medical Society.
`
`S
`
`EVERAL studies have shown that continuous
`intravenous epoprostenol (prostacyclin) im-
`proves exercise tolerance, hemodynamic vari-
`ables, and survival in patients with primary
`pulmonary hypertension.
` This treatment, however,
`1-7
`has two substantial drawbacks. One is the occurrence
`of tolerance, which in some patients necessitates con-
`tinuous dose escalation and therefore contributes to
`the high cost of treatment. The other, clinically more
`pertinent problem is the risk of serious infection, cath-
`eter thrombosis, and pump failure associated with
`the permanent central venous catheter and delivery
`system. Although the risk of these complications has
`been reported to be low,
` they are potentially life-
`4,7
`threatening.
`
`1866
`
`·
`
`June 22, 2000
`
`These shortcomings might be overcome by the ad-
` a stable prosta-
`ministration of aerosolized iloprost,
`8
`cyclin analogue, as suggested by Olschewski et al.
`9,10
`When administered by inhalation, iloprost is a potent
`pulmonary vasodilator with more pronounced short-
`term hemodynamic effects than inhaled nitric oxide
`in patients with primary pulmonary hypertension.
`11
`Preliminary studies have shown that intermittent in-
`halation of iloprost has beneficial short-term effects
`in patients with primary and secondary pulmonary
` However, only limited data are avail-
`hypertension.
`11,12
`able on the long-term efficacy of treatment with aer-
`osolized iloprost in patients with primary pulmonary
`hypertension.
`9
`We studied the effects of administering aerosolized
`iloprost over a one-year period to patients with pri-
`mary pulmonary hypertension.
`
`METHODS
`
`Patients
`We studied the clinical course of consecutive patients who were
`referred to our center for the treatment of pulmonary hyperten-
`sion between March 1997 and June 1998 and who had primary
`pulmonary hypertension according to the diagnostic criteria of
`the National Institutes of Health Registry on Primary Pulmonary
`Hypertension.
` Patients with secondary pulmonary hypertension
`13
`were excluded, as were patients with severe right heart failure who
`were receiving catecholamines at the time of their initial presen-
`tation and those lost to follow-up.
`
`Treatment and Follow-up
`In Germany, neither intravenous epoprostenol nor aerosolized
`iloprost has been licensed for the treatment of pulmonary hyper-
`tension. At our center, aerosolized iloprost is being offered, on a
`compassionate-use basis, as first-line therapy for the majority of
`patients with advanced primary pulmonary hypertension. This ap-
`proach was approved by our institution’s ethics committee; all pa-
`tients in this study were informed about the investigational char-
`acter of the treatment and gave written informed consent.
`To be eligible for treatment with aerosolized iloprost, patients
`had to have pulmonary hypertension with severe limitation of ex-
`ercise capacity (New York Heart Association functional class III
`or IV) that was refractory to conventional medical treatment, in-
`cluding the use of calcium-channel blockers. Exercise capacity was
`determined by the six-minute walk test after the patient had per-
`formed one or two walks to become familiar with the route.
`14
`Hemodynamic variables were assessed by catheterization of the
`right side of the heart. Cardiac output was measured by the ther-
`modilution technique.
` After the base-line hemodynamic variables
`15
`had been recorded, the short-term hemodynamic response to aer-
`
`From the Department of Respiratory Medicine, Hannover Medical
`School, Hannover, Germany. Address reprint requests to Dr. Hoeper at the
`Department of Respiratory Medicine, Hannover Medical School, 30623
`Hannover, Germany, or at kmhoeper@aol.com.
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on January 6, 2021. For personal use only. No other uses without permission.
`
` Copyright © 2000 Massachusetts Medical Society. All rights reserved.
`
`Liquidia's Exhibit 1047
`Page 1
`
`

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`LONG-TERM TREATMENT OF PRIMARY PULMONARY HYPERTENSION WITH AEROSOLIZED ILOPROST
`
`osolized iloprost was measured. For that purpose, 50 µg of iloprost
`(Ilomedin, Schering, Berlin, Germany) was diluted in 5 ml of iso-
`tonic saline, aerosolized in a jet nebulizer (Ilo-Neb, Nebu-Tec, El-
`senfeld, Germany) and administered over a period of 10 to 15 min-
`utes, which resulted in a cumulative dose of nebulized iloprost
`between 14 and 17 µg. Immediately after inhalation and every 15
`minutes thereafter for up to 1 hour, the hemodynamic variables
`were measured in order to determine the maximal short-term effect
`of inhaled iloprost and the timing of the hemodynamic response.
`All patients started treatment with a daily dose of 100 µg of
`aerosolized iloprost, divided into six or eight inhalations given ev-
`ery two to three hours, without interruption of bed rest at night.
`Since pharmacokinetic studies of aerosolized iloprost were not avail-
`able when treatment was started, the daily dose was adapted from
`the initial report by Olschewski et al.
` The dosage per inhalation
`9
`and the inhalation interval were determined on the basis of infor-
`mation gained from pulmonary-artery catheter testing at base line.
`If the pulmonary vascular resistance fell by more than 20 percent
`after the inhalation of iloprost but returned to base line within less
`than 60 minutes, the patient was asked to inhale eight times per
`day. All other patients inhaled six times per day. The dose was in-
`creased to 150 µg in six patients after three months.
`After familiarization with the equipment, the patients were dis-
`charged and were seen every 4 to 12 weeks on an outpatient basis.
`Readmissions were scheduled after 3 to 12 months for the deter-
`mination of exercise capacity and repeated right-heart catheteriza-
`tion. The six-minute walk tests during follow-up were performed
`more than one hour after the last inhalation. All six-minute walk
`tests were performed over the same route. The catheter tests start-
`ed early in the morning before the first inhalation of iloprost — that
`is, between 10 and 12 hours after the last inhalation of iloprost
`— and the same protocol was used as for the base-line evaluation.
`
`Statistical Analysis
`All hemodynamic variables and the results of the six-minute walk
`test are presented as means ±SD. The short-term hemodynamic
`effects of iloprost challenge were analyzed with Student’s paired
`t-test. The results of the six-minute walk tests and the hemody-
`namic variables at base line and after 3 and 12 months of treat-
`
`ment with inhaled iloprost were compared by analysis of variance
`for repeated measurements. If this global test revealed significant
`differences, the paired t-test was applied to differences between spe-
`cific groups. Patients who were unable to walk were assigned a score
`of 0 m on the six-minute walk test. Statistical comparisons of the
`hemodynamic variables were performed only for the data obtained
`before the inhalation of iloprost (preinhalation values). Linear re-
`gression analysis was used to compare the short-term changes in
`pulmonary vascular resistance in response to inhaled iloprost at
` All tests
`base line with the changes after 12 months of treatment.
`16
`were two-sided. A P value of less than 0.05 was considered to in-
`dicate statistical significance.
`
`RESULTS
`Between March 1997 and June 1998, treatment
`with aerosolized iloprost was initiated in 31 patients
`with primary pulmonary hypertension. None of the
`patients died within the observation period. Seven
`patients were excluded from the analysis because fol-
`low-up examinations were performed at other cen-
`ters or by other physicians. The remaining 24 patients
`received treatment with aerosolized iloprost for at
`least one year and completed exercise-testing and
`catheter studies. Fifteen of these patients were wom-
`en and nine were men. The mean age was 38±12
`years (range, 22 to 65). As shown in Table 1, all 24
`patients had severe pulmonary hypertension and were
`in New York Heart Association functional class III
`(20 patients) or IV (4 patients).
`The initial daily dose of aerosolized iloprost was
`100 µg in all patients. This dose was subsequently in-
`creased to 150 µg in six patients whose exercise capac-
`ity did not improve after three months of treatment.
`In the remaining patients, the dose was kept con-
`
`T
`
`ABLE
`
` 1.
`
`H
`
`EMODYNAMIC
`
` V
`
`ARIABLES
`
`
`
`AND
`
`
` 24 P
`
` C
` E
`WITH
`ATIENTS
`IN
`APACITY
`XERCISE
`T
`
` I
` I
`.*
`REATED
`WITH
`NHALED
`LOPROST
`
` P
`
`RIMARY
`
` P
`
`ULMONARY
`
` H
`
`YPERTENSION
`
`
`
`M
`EASUREMENT
`
` L
`B
`INE
`ASE
`PREINHALATION POSTINHALATION
`
`3 M
`O
`PREINHALATION POSTINHALATION
`
`12 M
`O
`PREINHALATION POSTINHALATION
`
`Heart rate (beats/min)
`Mean systemic arterial pressure
`(mm Hg)
`Mean pulmonary arterial pressure
`(mm Hg)
`Mean right atrial pressure (mm Hg)
`Cardiac output (liters/min)
`Pulmonary vascular resistance
`)
`(dyn·sec·cm
`¡5
`Systemic vascular resistance
`(dyn·sec·cm
`)
`¡5
`Stroke volume (ml/beat)
`Mixed venous oxygen saturation (%)
`6-Minute walk distance (m)
`
`84±13
`98±14
`
`59±10
`
`8±7
`3.8±1.4
`1205±467
`
`84±13
`100±14
`
`50±13
`
`7±6
`4.5±1.4
`866±415
`
`82±15
`93±10†
`
`52±11†
`
`79±13
`92±12
`
`44±12
`
`5±4†
`4.0±1.2
`1001±437†
`
`4±4
`4.5±1.2
`728±330
`
`82±10
`90±13†
`
`52±15†
`
`5±4†
`4.4±1.3†
`925±469†
`
`80±10
`89±13
`
`43±16
`
`4±4
`4.8±1.4
`704±440
`
`2088±712
`
`1791±508
`
`1884±506†
`
`1646±397
`
`1660±494†‡
`
`1534±467
`
`46±16
`62±8
`278±96
`
`55±16
`68±8
`ND
`
`50±16†
`65±7†
`353±69†
`
`57±15
`70±7
`ND
`
`55±16†‡
`67±8†
`363±135†
`
`61±19
`70±7
`ND
`
`*Values are means ±SD. Preinhalation and postinhalation denote before and immediately after inhalation of iloprost; ND denotes not done.
`†P<0.05 for the comparison of preinhalation variables at 3 months or 12 months with preinhalation variables at base line.
`‡P<0.05 for the comparison of preinhalation variables at 12 months with preinhalation variables at 3 months.
`
`Volume 342 Number 25
`
`·
`
`1867
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on January 6, 2021. For personal use only. No other uses without permission.
`
` Copyright © 2000 Massachusetts Medical Society. All rights reserved.
`
`Liquidia's Exhibit 1047
`Page 2
`
`

`

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`The New England Journal of Medicine
`
`Base Line
`
`3 Mo
`
`12 Mo
`
`2500
`
`2000
`
`1500
`
`1000
`
`500
`
`0
`
`Pulmonary Vascular ResistanceL
`
`(dyn · sec · cm¡5)
`
`Figure 1.
` Pulmonary Vascular Resistance at Base Line and after
`3 Months and 12 Months of Treatment with Aerosolized Ilo-
`prost.
`The pulmonary vascular resistance declined in all but two pa-
`tients after 3 months of treatment with iloprost aerosol, fol-
`lowed by a further decline in all but six patients after 12
`months. When compared with base-line values, pulmonary
`vascular resistance was lower after 12 months of treatment
`with aerosolized iloprost in 19 of 24 patients.
`
`long-term treatment, we compared the short-term
`changes in pulmonary vascular resistance after inha-
`lation of iloprost at base line with the effects of treat-
`ment with aerosolized iloprost on preinhalation pul-
`monary vascular resistance after 12 months (Fig. 2).
`In general, patients with a more pronounced short-
`term response to inhaled iloprost were more likely
`to have a sustained long-term reduction in pulmonary
`vascular resistance (r=0.66, P<0.001). However, of
`the 12 patients in whom the pulmonary vascular re-
`sistance dropped by less than 20 percent during short-
`term drug challenge, 7 had sustained reductions in
`pulmonary vascular resistance after 12 months of
`treatment, whereas 1 patient had stable hemodynam-
`ic variables and the remaining 4 patients had increased
`levels of pulmonary vascular resistance, indicating wor-
`sening pulmonary hypertension (Fig. 2). Two of the
`latter patients were eventually switched to contin-
`uous intravenous iloprost but did not have clinical
`improvement; they are currently awaiting lung trans-
`plantation.
`Treatment with aerosolized iloprost was tolerated
`well by all patients. Coughing during inhalation was
`common during the first days of treatment but in-
`variably disappeared spontaneously within the first
`four weeks. Lung function remained stable in all pa-
`tients throughout the observation period, as did blood
`counts, serum electrolyte concentrations, creatinine
`concentrations, and the results of liver-function tests
`(data not shown). Five patients reported flushing,
`
`stant throughout the observation period. All patients
`received anticoagulants. Diuretics were used as clin-
`ically indicated. Patients receiving concomitant treat-
`ment with digitalis or calcium-channel blockers con-
`tinued the treatment during the observation period.
`As shown in Table 1, results of the six-minute walk
`test confirmed the presence of severe functional im-
`pairment at base line. The distance covered in this
`test increased significantly, by 75±67 m, after three
`months of treatment with aerosolized iloprost (P<
`0.001). This effect was sustained after 12 months, but
`there was no further significant increase in the walking
`distance as compared with the results at 3 months.
`Challenge with inhaled iloprost caused a short-term
`decline of 9±9.2 mm Hg in mean pulmonary ar-
`terial pressure (mean change, ¡15 percent [the neg-
`ative value indicates a decrease]; P<0.001), accom-
`panied by an increase in cardiac output of 0.7±0.5
`liter per minute (mean change, +18 percent; P<
`0.001) and a reduction in pulmonary vascular resist-
`ance of 339±260 dyn·sec·cm
` (mean change, ¡28
`¡5
`percent; P<0.001) (Table 1). The heart rate and sys-
`temic arterial pressure remained practically unaffected.
`Almost identical short-term hemodynamic effects were
`obtained with repeated iloprost challenge after 3 and
`12 months (Table 1).
`As compared with base line, after three months of
`treatment with aerosolized iloprost there was signif-
`icant improvement in the values before the inhala-
`tion of iloprost for mean pulmonary arterial pressure,
`mean right atrial pressure, pulmonary vascular resist-
`ance, stroke volume, and mixed venous oxygen satu-
`ration (Table 1). These effects were sustained at 12
`months. At this time, there was also a significant in-
`crease in cardiac output as compared with base line,
`suggesting effective improvement in right ventricular
`performance with long-term administration of aero-
`solized iloprost. As compared with base line, preinha-
`lation mean pulmonary arterial pressure was reduced
`by 7±8.7 mm Hg after 12 months of treatment (mean
`change, ¡12 percent; P=0.006), pulmonary vascular
`resistance by 280±323 dyn·sec·cm
` (mean change,
`¡5
`¡23 percent; P<0.001), and mean right atrial pres-
`sure by 3±4 mm Hg (P=0.01). In addition, prein-
`halation cardiac output increased by 0.6±1.3 liter per
`minute (mean change, +16 percent; P=0.02), heart
`rate remained nearly constant, stroke volume rose by
`9±16 ml (mean change, +20 percent; P=0.009), and
`mixed venous oxygen saturation increased by 5±8
`percentage points (mean change, +8 percent; P=
`0.01) (Table 1). Thirteen of the 24 patients (54 per-
`cent) had a long-term reduction of at least 20 percent
`in preinhalation pulmonary vascular resistance (Fig.
`1). At all times, there was further improvement in
`these variables immediately after the inhalation of il-
`oprost (Table 1).
`To assess the value of short-term drug challenge
`with inhaled iloprost for predicting the response to
`
`1868
`
`·
`
`June 22, 2000
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on January 6, 2021. For personal use only. No other uses without permission.
`
` Copyright © 2000 Massachusetts Medical Society. All rights reserved.
`
`Liquidia's Exhibit 1047
`Page 3
`
`

`

`LONG-TERM TREATMENT OF PRIMARY PULMONARY HYPERTENSION WITH AEROSOLIZED ILOPROST
`
`
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`
`course of the disease are incompletely understood.
`Several studies have shown that the long-term effects
`of epoprostenol in pulmonary hypertension go be-
`yond vasodilation. Other factors involved may include
`antithrombotic and antiproliferative effects as well as
`modulating effects on growth factors and vascular
`remodeling.
` Some of these effects, such as in-
`4,7,8,17-19
`hibition of platelet aggregation, could outlast the
`presence of prostaglandins. In the case of inhaled il-
`oprost, however, it is not yet clear whether plasma
`concentrations reach sufficient levels to exert an ef-
`fect on platelet function.
`In addition, it is unknown whether prostaglandins
`need to be administered continuously to exert their
`therapeutic effect in patients with pulmonary hyper-
`tension. The answer to this question, however, is es-
`sential for deciding whether to use aerosolized ilo-
`prost as an alternative treatment in these patients.
`Even if the plasma half-life of iloprost is 20 to 30
`minutes,
` the short-term hemodynamic effects of a
`8
`single inhaled dose almost invariably disappear with-
`in an hour after inhalation.
` Therefore, our observa-
`11
`tion of improved preinhalation hemodynamic variables
`(measured after an overnight break in inhalation ther-
`apy) after one year of treatment with aerosolized il-
`oprost suggests that mechanisms other than vasodila-
`tion contribute to its therapeutic effects. Our findings
`that the short-term vasodilator response to inhaled
`iloprost is preserved after 12 months of treatment
`and that the postinhalation reduction in pulmonary
`vascular resistance after 12 months exceeded the short-
`term hemodynamic effects at base line further sup-
`port this conclusion.
`The advantage of inhaled prostanoids over intra-
`venous epoprostenol is that they do not require in-
`sertion of a permanent central venous catheter. The
`main question is whether inhaled iloprost is as effec-
`tive as intravenous epoprostenol in improving exer-
`cise capacity and reducing mortality among patients
`with primary pulmonary hypertension. Despite the
`fact that intravenous epoprostenol has been used for
`more than 10 years to treat pulmonary hypertension,
`surprisingly little information is available on its long-
`term effects in this disease. McLaughlin et al. recently
`described their experience with long-term intrave-
`nous epoprostenol therapy in 27 patients with pri-
`mary pulmonary hypertension.
` Drug challenge with
`7
`intravenous adenosine had short-term hemodynamic
`effects similar to those of inhaled iloprost in our pa-
`tients. McLaughlin et al. reported a reduction of 53
`percent in pulmonary vascular resistance after 12 to
`24 months of treatment with intravenous epopros-
`tenol, which clearly exceeded the 23 percent reduc-
`tion in preinhalation pulmonary vascular resistance
`in our patients after 1 year of treatment with iloprost
`aerosol. However, in our patients the postinhalation
`pulmonary vascular resistance after one year of treat-
`ment was reduced by 42 percent from the base-line
`
`Volume 342 Number 25
`
`·
`
`1869
`
`r=0.66L
`P<0.001
`
`¡80
`
`¡60
`
`¡40
`
`¡20
`
`0
`
`+20
`
`Change after 12 Months (%)
`
`+20
`¡80
`¡60
`¡40
`¡20
`0
`Short-Term Change at Base Line (%)
`
`Figure 2.
` Regression Analysis of Short-Term Changes in Pulmo-
`nary Vascular Resistance in Response to Inhaled Iloprost at
`Base Line and Changes in Preinhalation Pulmonary Vascular Re-
`sistance after 12 Months of Treatment with Aerosolized Iloprost.
`In general, patients with the greatest short-term response to in-
`haled iloprost had the greatest reduction in pulmonary vascular
`resistance after 12 months of treatment. However, 7 of 12 pa-
`tients who had only slight short-term vasodilator responses had
`considerable reductions in preinhalation pulmonary vascular
`resistance after long-term treatment with aerosolized iloprost.
`
`headache, and jaw pain at the end of the inhalation,
`but all of these side effects were rated as mild, and
`specific treatment or discontinuation of iloprost was
`not required. Gastrointestinal problems were not re-
`ported. Hemodynamic studies revealed a significant
`decline in systemic arterial pressure and systemic vas-
`cular resistance (Table 1), but symptomatic hypoten-
`sion did not occur in any of the patients. In addition,
`there were no symptoms, such as dizziness or syncope,
`suggesting that no rebound phenomena occurred be-
`tween inhalations or overnight. However, almost all
`patients described some fluctuations in their exercise
`capacity, which was usually highest immediately after
`inhalation and then slowly deteriorated over the fol-
`lowing two to three hours until the next inhalation.
`
`DISCUSSION
`Our data show that long-term treatment with aer-
`osolized iloprost has beneficial effects on exercise ca-
`pacity and hemodynamic variables in patients with
`primary pulmonary hypertension. The therapeutic ef-
`ficacy of intravenous epoprostenol in primary pulmo-
`nary hypertension has been well described, but the
`mechanisms by which prostacyclin influences the
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on January 6, 2021. For personal use only. No other uses without permission.
`
` Copyright © 2000 Massachusetts Medical Society. All rights reserved.
`
`Liquidia's Exhibit 1047
`Page 4
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`The New England Journal of Medicine
`
`preinhalation value, a reduction close to that obtained
`with intravenous epoprostenol in the study by Mc-
`Laughlin et al.
`The dose of aerosolized iloprost was kept constant
`at 100 µg per day in the majority of our patients; it
`was increased to 150 µg per day in six patients whose
`response was judged unsatisfactory. We do not know,
`however, whether the regimen we used had optimal
`efficacy or whether higher doses, different inhalation
`intervals, or a regimen including regular dose increas-
`es would have been better. In the study by Mc-
`Laughlin et al., the dose of intravenous epoprostenol
`was increased by an average of 2.4 ng per kilogram
`of body weight per minute each month, which re-
`sulted in a mean dose of approximately 40 ng per
`kilogram of body weight per minute after 12 to 24
`months of treatment.
` In Germany the annual cost of
`7
`treating a patient with intravenous epoprostenol at
`this dose would exceed $300,000. With the inhalation
`device used in our hospital, the annual cost of treat-
`ment with aerosolized iloprost is about $50,000 for a
`daily dose of 100 µg and $75,000 for a daily dose of
`150 µg. With newly developed ultrasonic nebulizers,
`these costs can be reduced by almost 50 percent.
`20
`Inhaled iloprost was generally well tolerated, and
`no patient discontinued treatment because of side
`effects. The occurrence of jaw pain and flushing in
`some patients, as well as a significant, albeit asymp-
`tomatic, decline in systemic arterial pressure, suggests
`that aerosolized iloprost is not a purely selective pul-
`monary vasodilator, but, rather, that there is some
`systemic spillover of the drug. There are further un-
`resolved issues regarding the safety of inhaled iloprost.
`Among these, the possibility of rebound pulmonary
`hypertension between inhalations and after the over-
`night break in inhalation therapy is of great concern.
`However, in our patients there were no clinical or he-
`modynamic signs of rebound pulmonary hyperten-
`sion. Rebound phenomena have been recognized as
`a potentially life-threatening complication in patients
`receiving intravenous epoprostenol with short-term
`interruptions of drug delivery.
` Still, almost all our
`21
`patients described some fluctuations in their exercise
`capacity between inhalations. These fluctuations were
`well tolerated by our patients but could be detrimen-
`tal in patients with advanced right heart failure. We
`also found that 5 of the 24 patients (21 percent) had
`no clinical response to treatment with aerosolized il-
`oprost; it is unclear whether these patients would
`benefit from a further increase in the dose of inhaled
`iloprost or whether they should be switched to intra-
`venous epoprostenol.
`Overall, our data support the conclusion that aer-
`osolized iloprost is an effective treatment for primary
`pulmonary hypertension. Currently, phase 3 studies
`are under way in Europe that are expected to result
`
`1870
`
`·
`
`June 22, 2000
`
`in the licensing of inhaled iloprost for the treatment
`of pulmonary hypertension. With this approach, the
`options for therapy in advanced pulmonary hyper-
`tension increase, but so do the uncertainties about
`the optimal first-line treatment of patients with this
`condition. The time has come for studies comparing
`the long-term effects of intravenous epoprostenol and
`aerosolized iloprost in patients with primary pulmo-
`nary hypertension.
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`The New England Journal of Medicine
`
`Downloaded from nejm.org on January 6, 2021. For personal use only. No other uses without permission.
`
` Copyright © 2000 Massachusetts Medical Society. All rights reserved.
`
`Liquidia's Exhibit 1047
`Page 5
`
`