Inhaled iloprost for patients with precapillary pulmonary hypertension and right-side heart failure.

BACKGROUND: Pulmonary hypertension (PH) can lead to right-side heart failure (RHF) and death. There are no therapeutic recommendations for patients experiencing acute RHF in the course of PH. This study aimed to examine the safety and efficacy of inhaled iloprost in patients with precapillary PH and RHF. METHODS AND
RESULTS: Between October 2007 and December 2008, 7 patients with precapillary PH and RHF were enrolled. Per protocol, iloprost was inhaled hourly for a minimum of 12 hours during a 24-hour period. The starting dose of 2.5 μg was increased hourly by 2.5 μg as long as the increases were tolerated. Safety and efficacy were determined by continuous invasive monitoring of systemic and pulmonary hemodynamic parameters. Systemic pressures remained stable during inhalation (66.1 ± 6.9 mm Hg at baseline and 69.1 ± 6.4 mm Hg immediately after inhalation therapy, P = 0.48). Cardiac index increased from 2.4 ± 0.7 L/min/m(2) to 2.9 ± 0.9 L/min/m(2) (P = .008). Pulmonary vascular resistance decreased from 634.6 ± 218.3 dyn·s·cm(-5) to 489.6 ± 173.8 dyn·s·cm(-5) (P = .044), and N-terminal B-type natriuretic peptide levels decreased from 13,591 ± 10,939 pg/mL to 9,944 ± 8,569 pg/mL (P = .051).
CONCLUSION: Blood pressure-guided hourly inhalation of iloprost may offer a safe and effective strategy for the treatment of PH patients with RHF.

Precapillary pulmonary hypertension (PH) is a rare but life-threatening condition. Progressive obliteration of the pulmonary arterial bed leads to increasing right ventricular afterload, and ultimately to death from right-side heart failure (RHF). Since 1990, 21 randomized placebo-controlled trials have been conducted to test the efficacy of pulmonary vasodilators in patients with pulmonary arterial hypertension (PAH). Improvements in hemodynamic parameters and exercise capacity led to the approval of 3 classes of drugs: prostanoids, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors. Because patients with overt RHF have been systematically excluded from randomized controlled trials, no specific treatment recommendations have been developed for individuals who experience acute RHF in the course of PH. The fact that RHF is associated with low systemic perfusion pressures limits the systemic use of potent vasodilators. Ideally, therapeutic interventions should be directed toward decreasing right ventricular afterload without significantly affecting the systemic circulation.

When inhaled, iloprost, a synthetic prostacyclin analog, is thought to target the pulmonary circulation selectively without causing clinically relevant systemic side effects. In the present study, critically ill patients hospitalized for overt RHF as a consequence of precapillary PH were treated with inhaled iloprost in addition to any pulmonary vasodilator therapy that they were receiving before the start of the study. Hourly inhalation of iloprost with up-titration of dose guided by blood pressure measurements improved pulmonary vascular resistance (PVR) and cardiac index (CI) and decreased serum N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels, without affecting systemic pressures.

Methods

Setting and Study Patients

The study was conducted in the Critical Care Unit of the Division of Cardiology, Medical University of Vienna (MUV), and was approved by the Ethics Committee of the MUV and the Vienna General Hospital (accession no. 228/2007). Each of the participants gave written informed consent. Between October 2007 and December 2008, consecutive patients with an established diagnosis of precapillary PH (Dana Point classes I or IV) and acute RHF were enrolled in the study. RHF was defined as an echocardiographically estimated mean right atrial pressure (mRAP) >15 mm Hg and a clinical presentation suggestive of heart failure, such as dyspnea at rest, tachycardia, and fluid retention. Patients already receiving vasodilator treatment could enter the study if they had been on a stable treatment in the month before enrollment. Patients already receiving inhaled iloprost therapy were excluded from the study. Preexisting background therapies, including diuretics, were not changed during the study period. Based on our previous experience in patients with severe PH requiring intensive care, the start of inotropes is generally associated with adverse outcomes and was not a preferred option in this study.

Study Design

This was a 24-hour single-center study with a single treatment arm. After admission to the critical care unit, patients received a permanent intra-arterial line (radial artery) and a Swan-Ganz catheter via jugular or subclavian access. After catheter insertion, patients were allowed to rest for 30 minutes before the first hemodynamic parameters were recorded. Pressure recordings included radial pressure, right atrial pressure (RAP), pulmonary arterial pressure (PAP), and pulmonary capillary wedge pressure (PCWP), and cardiac output (CO) was continuously assessed with the use of a Vigilance II monitor (Edwards Lifesciences, Irvine, California). PVR was calculated as the ratio of mean PAP (mPAP)−PCWP and CO. In addition, mixed venous oxygen saturation (MVS) and peripheral oxygen saturation (sO2) were determined along with the hemodynamic measurements. Electrocardiograms were continuously monitored throughout the study. Serum levels of NT-proBNP were determined at baseline and after 24 hours.

The diagnosis of precapillary PH was confirmed if the following criteria were met: mPAP ≥25 mm Hg, PVR >240 dyn·s·cm−5, and PCWP <15 mm Hg.

Per protocol, nebulized iloprost (Ventavis, 10 μg/mL; Bayer HealthCare Pharmaceuticals, Berlin, Germany) was administered hourly for a minimum of 12 hours, allowing patients to rest overnight. A portable electric ultrasonic (vibrating mesh) nebulizer (I-neb Adaptive Aerosol Delivery [AAD] System [power level 10]; Philips Respironics, Parsippany, New Jersey), which delivers aerosol only during inhalation, was used for repeated inhalations. Standard AAD disks (2.5 μg or 5 μg) were used. Therapy was started at a dose of 2.5 μg (as delivered at the nebulizer mouthpiece, ie, the standard starting dose for patients with PH) and increased in 2.5 μg steps, as long as the drug was hemodynamically and clinically tolerated. In cases of poor tolerability, the dose was not further increased or was reduced in 2.5 μg steps. The I-neb nebulization chamber can deliver a maximum of 5 μg Ventavis. To achieve gradual increases at each hourly administration, the chamber was refilled and inhalation times were extended up to 40 minutes to achieve a total dose of 20 μg iloprost. Preexisting background vasodilator therapy was continued. Hemodynamic parameters were recorded at baseline as well as before and after each inhalation. Changes in mean arterial pressure (mAP) and sO2 served as safety measures; change in PVR was the primary efficacy measure. Further efficacy measures were CI, mPAP, MVS, and NT-proBNP.

Statistical Analyses

To assess safety and efficacy parameters, baseline measures were compared with the corresponding values recorded after the last inhalation (baseline vs last). Owing to different dosages and durations of inhalation, comparisons were calculated using an analysis of covariance with repeated measures, controlling for cumulative dose and number of inhalations. Results are presented as mean ± SD percentage change in each parameter relative to baseline. The level of significance was set at 5% (P < .05). All statistical computations were performed using SPSS version 17.

Results

Clinical Characteristics

The clinical characteristics of individual patients are summarized in Table 1. Seven patients (3 female, 4 male) fulfilled the study inclusion criteria. Their mean ± SD age was 59.14 ± 8.24 years. According to the Dana Point classification, 3 patients suffered from idiopathic PAH, 3 had PAH associated with connective tissue disease, and 1 patient suffered from chronic thromboembolic PH. The mean time from PH diagnosis to study inclusion was 24.7 ± 44.3 months (range 1–124 months). PH-specific background therapies were high-dose subcutaneous treprostinil in 4 patients and oral endothelin-receptor blockers in 3 patients.

Table 1

Baseline Characteristics of Individual Study Patients

Patient	1	2	3	4	5	6	7
Gender (male)	0	1	0	0	1	1	1
PH group (Dana point classification)	I	I	I	I	IV	I	I
Age (y)	72	59	52	65	55	48	63
Disease duration (mo)	6	1	5	22	124	3	12
Comorbidities	CREST syndrome, hepatitis C	None	CREST syndrome	Systemic lupus erythematosus	None	None	Diabetes mellitus type 2
Baseline PH therapy	SC treprostinil	Bosentan	SC treprostinil	SC treprostinil	SC treprostinil	Sitaxentan	Sitaxentan
Diuretics (TDD, mg)	F (40), S (50)	None	F (40), S (150)	S (100)	F (160), S (50)	None	None
Urine output (mL/24 h)	500	630	1710	920	3230	1200	105∗
Inhalation (h)	17	15	14	12	8	6	4
Lactate (mmol/L)	1.0	1.2	1.2	1.1	1.3	2.4	2.0
NT-proBNP (pg/mL)	9,690	10,636	9,340	8,964	1,265	20,239	35,000
CO (L/min)	4.1	7.3	2.9	4.8	3.6	4.55	5.2
CI (L·min·m−2)	2.24	2.50	1.76	2.47	1.87	2.47	2.49
mPAP (mm Hg)	46	46	52	40	55	58	47
PVR (dyn·s·cm−5)	702	339	966	417	689	791	538
RAP (mm Hg)	15	18	20	19	15	18	19
PCWP (mm Hg)	10	13	12	12	14	13	12

PH, pulmonary hypertension; CREST, calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia; SC, subcutaneous; TDD, total daily dose; F, furosemide; S, spironolactone; NT-proBNP, N-terminal B-type natriuretic peptide; CO, cardiac output; CI, cardiac index; mPAP, mean pulmonary arterial pressure; PVR, pulmonary vascular resistance; RAP, right atrial pressure; PCWP, pulmonary capillary wedge pressure.

Urine output after 4 h.

Tolerability and Safety

Four patients completed the protocol without adverse events. Three patients discontinued prematurely for the following reasons: death from RHF (n = 1), need for mechanical ventilation (n = 1), and inability to inhale owing to physical weakness (n = 1). The total inhaled iloprost dose ranged from 17.5 μg to 230.0 μg (Fig. 1). The highest tolerated dose was 20 μg per inhalation. There were no significant effects on mAP (baseline 66.1 ± 6.9 mm Hg, last 69.1 ± 6.4 mm Hg; P = .48; Fig. 2) or sO2 (baseline 87.6 ± 15.9%, last 86.6 ± 16.6%; P = .50; Fig. 2).

Fig. 1

Individual up-titrations and cumulative doses of inhaled iloprost. Each horizontal block represents a patient, numbers within lanes show doses of iloprost in μg at given time points.

Fig. 2

Percentage change from baseline in safety endpoints. After the final iloprost inhalation, there were no relevant changes from baseline in arterial oxygen saturation (sO2) or mean arterial pressure (mAP).

Efficacy

Hourly inhalation of nebulized iloprost was effective, with a significant decrease in mean PVR (baseline 634.6 ± 218.3 dyn·s·cm−5; last: 489.6 ± 173.8 dyn·s·cm−5, P = 0.044, Figs 3 and 4). Concomitantly, CI increased from 2.4 ± 0.7 L/min/m2 at baseline to 2.9 ± 0.9 L/min/m2 (P = 0.008) after the last inhalation, but there was no statistically significant change in mPAP (baseline: 49.1 ± 6.2 mm Hg; last: 47.1 ± 6.9 mm Hg, P = 0.45, Fig. 3).

Fig. 3

Percentage change from baseline in efficacy endpoints. After the final iloprost inhalation, there were significant improvements in pulmonary vascular resistance (PVR) and cardiac index (CI). The drop in N-terminal B-type natriuretic peptide (NT-proBNP) reached borderline significance. Statistically significant differences are marked with an asterisk. mPAP, mean pulmonary arterial pressure; MVS, mixed venous oxygen saturation.

MVS and serum NT-proBNP levels were used as surrogate markers for right ventricular function. In the absence of changes in sO2, MVS improved from 52.8 ± 15.9% to 55.7 ± 19.1%, but this change did not reach statistical significance (P = 0.139, Fig. 3). Serum NT-proBNP levels dropped from 13 591 ± 10 939 pg/mL at baseline to 9944 ± 8569 pg/mL after 24 hours (P = 0.051, Fig. 3).

On the morning following an overnight rest during which iloprost was paused, CI decreased from 2.9 ± 0.6 L·min·m−2 to 2.3 ± 0.7 L·min·m−2 (P = .027), while PVR and mPAP were statistically unchanged (night vs morning: PVR 504.2 ± 161.6 dyn·s·cm−5 vs 626.5 ± 185.2 dyn·s·cm−5 [P = .12]; mPAP 47.7 ± 5.8 mm Hg vs. 47.7 ± 4.8 mm Hg [P = 1.0]).

Discussion

RHF is a life-threatening and commonly fatal complication of PH that is hard to treat. Despite a beneficial effect of vasodilators on right ventricular afterload, concomitant systemic vasodilation may aggravate the condition. Administration of vasodilator therapy via inhalation targets the lungs directly. Inhaled nitric oxide is used in the treatment of persistent PH of the newborn and as an acute vasoreactivity testing agent. However, it is an expensive therapy, and abrupt cessation of treatment can lead to rebound PH. Administration of the prostacyclin epoprostenol by inhalation has been shown to reduce pulmonary arterial pressures selectively in a number of studies. However, epoprostenol is diluted in a glycine buffer that tends to adhere to ventilator valves, impairing their function and necessitating regular replacement of ventilator filters. Inhaled iloprost is not diluted in glycine buffer and therefore does not have the same limitation as epoprostenol. Furthermore, iloprost doses of 14–20 μg (administered during a period of 10–15 minutes) have shown greater potency than 40 ppm inhaled nitric oxide in vasoreactivity tests, and inhaled iloprost therapy has been reported to be less costly than treatment with inhaled nitric oxide.

In the present study, we investigated the efficacy and safety of inhaled iloprost in 7 patients who had precapillary PH and RHF. Its short half-life, together with its target organ–directed route of administration and potential advantages over other inhaled therapies as described above, provides a strong rationale for the use of aerosolized iloprost in this setting. Hourly inhalation of escalating doses of iloprost did not affect systemic blood pressure while it significantly lowered PVR and increased CI. A clinically irrelevant but statistically significant reduction in blood pressure has been documented in earlier studies investigating the effectiveness of inhaled iloprost. For example, patients in the pivotal Aerosolized Iloprost Randomized trial experienced a statistically significant decrease in systemic blood pressure after 12 weeks of treatment with iloprost (median dose 30 μg/d). Similarly, Hoeper et al reported a reduction in mean blood pressure (−3.5 ± 7.0 mm Hg, range −21 to +14 mm Hg) in patients with PH treated with 14–17 μg of aerosolized iloprost.

In contrast to earlier iloprost trials, the present study focused on patients who were hemodynamically unstable with a baseline mean systemic blood pressure of 66.1 ± 6.9 mm Hg (range 52–80 mm Hg). To avoid even small decreases of systemic blood pressure, which may be detrimental in patients with decompensated RHF, we chose a study design that allowed us to titrate iloprost doses according to actual blood pressure levels. Despite a very cautious mode of up-titration, study patients experienced improvement in pulmonary hemodynamic parameters. Given a mean final dose that was lower than that previously used for acute hemodynamic testing, the effect on PVR and CO was less pronounced (mean change in PVR and CO −447 ± 340 dyn·s·cm−5 and +0.7 ± 0.6 L/min, respectively, in an earlier study versus −145 ± 150 dyn·s·cm−5 and +0.9 ± 0.7 L/min in the present study) but still reached statistical significance compared with baseline values (CO: P = .009; PVR: P = .044). These changes were accompanied by a decrease in serum NT-proBNP levels (13,591 ± 10,939 pg/mL vs 9,944 pg/mL ± 8,569 pg/mL; P = 0.051). NT-proBNP has a plasma half-life of ∼25–70 minutes, and its clearance is mostly dependent on renal function. Impaired renal function in all study patients may be responsible for prolonged plasma half-lives of NT-proBNP and only moderate changes after iloprost therapy.

The highest tolerated dose of iloprost in the present study was 20 μg per inhalation (at the nebulizer mouthpiece), which is substantially higher than the standard recommended dose for the treatment of PH (2.5 μg or 5 μg at the mouthpiece). This high dose necessitated inhalation times of up to 40 minutes, which would not be feasible in long-term treatment in patients' homes. Some earlier studies of iloprost in patients with severe PH used a different nebulizer with more rapid drug delivery; the Multisonic compact ultrasonic nebulizer (Schill Co, Probstzella, Germany) has a reported output rate at the mouthpiece of 140 μL/min. However, despite the longer inhalation times, the I-neb has a number of advantages over the Multisonic device, and the latter is not currently approved for the administration of iloprost in Europe. Iloprost is supplied in aliquots of 1 mL or 2 mL, which are compatible with the I-neb system, whereas the optimum volume for nebulization using the Multisonic device is 3–4 mL. The accuracy of drug delivery to the lungs is also an important consideration; the I-neb device adapts to the individual patient's breathing pattern and pulses aerosol only during inspiration to reduce waste and deliver a more precise dose. The speed of drug delivery using the I-neb device may be improved by using a more concentrated solution of iloprost; we used the standard concentration available in Europe (10 μg/mL), but in the USA a 20 μg/mL solution is available for patients who repeatedly experience significantly prolonged inhalation times. Altering the I-neb power level may also influence inhalation times. We used the standard European power level (power disk 10) in our study, whereas a preclinical study suggested that changing to power level 15 can additionally shorten inhalation times.

At study entry, all patients were receiving specific vasodilator treatment. Four patients were on high-dose parenteral prostanoids, and 3 were on oral endothelin receptor antagonists. Notably, the reported improvement in hemodynamic parameters was in addition to that achieved by any underlying vasodilator treatment, which was continued per protocol. This is in line with results from a randomized controlled trial in patients with PAH, in which inhaled iloprost was added to existing dual endothelin receptor antagonist therapy. After 12 weeks of treatment (5 μg iloprost per inhalation and a mean number of 5.6 inhalations per day), the reduction in mean PVR measured immediately after inhalation compared with baseline was 164 ± 223 dyn·s·cm−5. Comparison of basement level with invasive hemodynamic assessment before inhalation, however, failed to demonstrate any improvement in the main hemodynamic outcome measures.

The treatment effects of inhaled iloprost are most prominent after inhalation and wane after 1–2 hours. The need for repeated inhalations for maintenance of pulmonary vasodilation may be inconvenient, particularly in outpatients. However, the disadvantage of a short half-life may become advantageous in hemodynamically unstable patients, in whom maintenance of systemic blood pressure is mandatory.

Our study has several limitations. First, the number of patients studied was small. However, we were able to prove the concept that vasodilator application in overtly decompensated patients is not only effective, but also feasible and well tolerated. From a clinical point of view, our findings need to be complemented by data from larger-scale trials exploring clinically relevant endpoints, such as morbidity and mortality. Second, despite a lack of evidence regarding vasodilator treatment in this group of patients, we thought that withholding a potentially life-saving therapy in the context of a placebo-controlled design would not be ethical. Finally, we included patients with precapillary PH of different etiologies, thereby possibly mixing groups with different responsiveness to iloprost.

In conclusion, hourly inhalation of iloprost with up-titration of dose guided by blood pressure measurements was shown to be effective and well tolerated in patients with RHF who were already receiving other vasodilator therapies.

Acknowledgments

The authors thank Dr Catriona Turnbull of Oxford PharmaGenesis, who provided editorial assistance funded by Bayer HealthCare Pharmaceuticals, Berlin, Germany.

Disclosures

D.B. has received research grants and speaker honoraria from Bayer HealthCare Pharmaceuticals (Berlin, Germany) and is a member of Bayer advisory boards. All other authors report no conflicts.