(Chest. 2005;128:714-719.)
© 2005
American College of Chest Physicians
Effects of Lipo-Prostaglandin E1 on Pulmonary Hemodynamics and Clinical Outcomes in Patients With Pulmonary Arterial Hypertension*
Jieyan Shen, MD;
Ben He, PhD and
Binyao Wang, MD
* From the Department of Cardiology, Shanghai Second Medical University-Affiliated Renji Hospital, Shanghai, Republic of China.
Correspondence to: Jieyan Shen, MD, Department of Cardiology, Renji Hospital, 1630 Dong Fang Rd, Shanghai 200127, ROC; e-mail: Shenjieyan_66{at}hotmail.com
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Abstract
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Objective: To determine whether lipid microspheres containing prostaglandin E1 (lipo-PGE1) improve pulmonary hemodynamics and clinical outcomes in patients with pulmonary arterial hypertension (PAH).
Methods: Forty-nine patients with PAH (8 patients with primary pulmonary hypertension, 21 patients with collagen vascular disease, 20 patients with congenital systemic-to-pulmonary shunts) were randomly classified into a conventional therapy group (n = 22) or a group receiving lipo-PGE1 plus conventional drugs (lipo-PGE1 group; n = 27). Echocardiographic pulmonary parameters, New York Heart Association (NYHA) functional class, and Bruce treadmill test results for exercise capacity were recorded before and after treatment.
Results: After 2 weeks of treatment with lipo-PGE1 (10 µg bid for 14 days), there were significant improvements in the values (± SD) for systolic pulmonary arterial pressure (SPAP) [76.9 ± 27.9 mm Hg vs 66.5 ± 22.8 mm Hg, p < 0.001]; total pulmonary resistance (27.2 ± 13.3 dyne·s·cm–5 vs 20.2 ± 10.7 dyne·s·cm–5, p < 0.001); left ventricular ejection fraction (58.7 ± 9.6% vs 64.4 ± 6.8%, p < 0.001); and cardiac output (3.1 ± 0.8 L/min vs 3.7 ± 1.1 L/min, p < 0.01). The NYHA functional class decreased from 3.0 ± 0.6 to 2.5 ± 0.6 (p < 0.001), and the exercise capacity increased from 2.8 ± 1.0 to 4.3 ± 1.3 metabolic equivalents (MET) [p < 0.001]. Compared with the conventional therapy group, the lipo-PGE1 group achieved significant reduction of SPAP (10.4 ± 10.3 mm Hg vs 2.2 ± 5.6 mm Hg, p = 0.002) and a significant elevation of exercise capacity (1.5 ± 0.9 MET vs 0.6 ± 1.1 MET, p = 0.018).
Conclusion: Lipo-PGE1 can decrease pulmonary artery pressure and increase exercise capacity in patients with PAH.
Key Words: echocardiography • exercise capacity • lipo-prostaglandin E1 • pulmonary arterial hypertension • pulmonary hemodynamics
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Introduction
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Pulmonary hypertension is a debilitating disease with short life expectancy that often affects young people. Continuous IV administration of prostacyclin I2 (PGI2) has been used for pulmonary vasodilation and was shown to improve exercise capacity and survival in patients with pulmonary hypertension.123 However, this drug and other prostacyclin analogues are not available in Shanghai, China. Prostaglandin E1 (PGE1) has similar vasodilatory and antithrombotic action, but is not as potent as PGI2. Lipid microspheres, as carriers, are known to accumulate in sites of inflammation or vascular lesions and thus enhance the effects of the drugs and alleviate the side effects45. Whether or not lipid microspheres containing PGE1 (lipo-PGE1) have potential effects on pulmonary hemodynamics in patients with pulmonary hypertension is not known. In this report, a prospective, randomized, control study was done to investigate the effects of lipo-PGE1 on pulmonary hemodynamics and clinical outcomes in patients with pulmonary arterial hypertension (PAH).
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Materials and Methods
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Patients
Forty-nine consecutive patients with PAH, as defined by the World Health Organization symposium in 1998,6 were referred to our wards between June 2000 and July 2003. Eight of these patients had primary pulmonary hypertension (PPH), 21 patients had collagen vascular disease (CVD) [including 14 patients with systemic lupus erythematosus, 4 with mixed connective tissue disease, and 3 with systemic sclerosis], 20 patients had congenital systemic-to-pulmonary shunts (CSPS) [19 patients with congenital atrium septal defect, and 1 with Lutembacher syndrome]. We have two clinics and two wards. Both belong to one department, and the physicians were blinded to the study. Patients were randomly sent to either clinic. Patients referred to the west wards were treated with lipo-PGE1 in addition to conventional therapy (lipo-PGE1 group, n = 27; 20 women and 7 men); patients referred to the east wards were treated with conventional therapy alone (n = 22; 15 women and 7 men). Clinical evaluations, including New York Heart Association (NYHA) functional class evaluation, ECG, chest radiography, and Doppler echocardiography were performed in all patients before treatment. Patients who were able to stand underwent treadmill testing for maximal exercise capacity according to the Bruce protocol.
Echocardiography
Combined Doppler echocardiography was performed by technicians blinded to the study with ultrasound imaging system. Standard parasternal long-axis, short-axis, and apical four- and two-chamber views were obtained. The following major pulmonary parameters were measured: (1) systolic pulmonary arterial pressure (SPAP), calculated from the sum of the peak tricuspid insufficiency Doppler pressure gradient and an estimate of right atrial pressure7; this method was also verified by right-heart catheter measurement in our study 3–4 years ago8; (2) end-systolic and end-diastolic left ventricular cross-sectional areas and diameters were measured in parasternal short-axis and apical four-chamber views; left ventricular ejection fraction (LVEF) and cardiac output (CO) were calculated by a modified Simpson formula programmed into the system; and (3) total pulmonary resistance (TPR) was calculated by dividing SPAP by CO.9
Treatment
Both groups of patients were treated with conventional therapy, such as digitalis, diuretics, nitrates, and angiotensin-converting enzyme inhibitors. Calcium antagonists were only used for systemic hypertension. Prednisone was mainly used in patients with CVD. For patients with inactive disease, the daily dosage was approximately 30 to 60 mg; for patients with active disease, the dosage was approximately 1 to 2 mg/kg/d. PPH patients with pulmonary thrombotic complications also received oral anticoagulants. Besides these conventional treatments, patients in the lipo-PGE1 group also received lipo-PGE1, 10 µg plus 10 mL normal saline solution through peripheral IV injection bid for 2 weeks (infusion rate, 20 ng/kg/min; interval, 6 to 8 h). Both group of patients were followed up with clinical evaluations, ECG, chest radiography, and Doppler echocardiography; some patients underwent treadmill testing for exercise capacity after 2 weeks of treatment.
Statistical Analysis
All data were expressed as mean ± SD. The hemodynamic effects of the therapy were analyzed with the paired Student t test. To determine whether lipo-PGE1 therapy was more effective than conventional therapy, the improvement values (the difference between before and after treatment) were compared. The two-sided analysis of covariance, the independent-samples t test, and 
2 tests were performed to test for significant difference between two groups and exclude possible within-group variance (SPSS 10.09 on the WIN-PRO platform; SPSS; Chicago, IL). A p value < 0.05 was considered statistically significant.
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Results
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The demographic, clinical, and hemodynamic data at baseline were not significantly different between the lipo-PGE1 group and the conventional therapy group (Tables 1
, 2
). There was no difference in conventional therapy between the two groups (Table 3
).
Compared to baseline, after 2 weeks of treatment with lipo-PGE1 and conventional drugs, the lipo-PGE1 group showed significant improvements in SPAP (from 76.9 ± 27.9 mm Hg to 66.5 ± 22.8 mm Hg, p < 0.001), TPR (from 27.2 ± 13.3 to 20.2 ± 10.7 dyne·s·cm–5, p < 0.001), LVEF (from 58.7 ± 9.6% to 64.4 ± 6.8%, p < 0.001), and CO (from 3.1 ± 0.8 L/min to 3.7 ± 1.1 L/min, p < 0.01). Also, the NYHA functional class decreased from 3.0 ± 0.6 to 2.5 ± 0.6 (p < 0.001), and exercise capacity increased from 2.8 ± 1.0 to 4.3 ± 1.3 metabolic equivalents (MET) [p < 0.001; Fig 1
].
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Figure 1.. The effect of lipo-PGE1 on SPAP (top left, A), TPR (top center, B), LVEF (top right, C), CO (bottom left, D), exercise capacity (bottom center, E), and NYHA functional class (bottom right, F).
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Compared to baseline, the conventional therapy group also showed a significant increase in LVEF (58.0 ± 7.9% vs 61.5 ± 7.0%, p < 0.05), CO (3.2 ± 0.9 L/min vs 3.6 ± 0.9 L/min, p < 0.05), a significant decrease in TPR (24.9 ± 12.7 dyne·s·cm–5 vs 21.3 ± 9.9 dyne·s·cm–5, p < 0.005), and NYHA functional class (3.0 ± 0.4 vs 2.6 ± 0.5, p < 0.005). But SPAP (73.8 ± 29.2 mm Hg vs 71.6 ± 28.4 mm Hg, p > 0.05) and exercise capacity (2.9 ± 1.2 MET vs 3.5 ± 0.9 MET, p > 0.05) did not change (Fig 2
).
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Figure 2.. The effect of conventional therapy on SPAP (top left, A), TPR (top center, B), LVEF (top right, C), CO (bottom left, D), exercise capacity (bottom center, E), and NYHA functional class (bottom right, F).
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To compare the treatment effects between the two groups, the improvement values of the parameters were calculated. Compared to the conventional therapy group, the lipo-PGE1 group achieved a significant reduction in SPAP (10.4 ± 10.3 mm Hg vs 2.2 ± 5.6 mm Hg, p = 0.002), a nonsignificant reduction in TPR (6.9 ± 6.3 dyne·s·cm–5 vs 3.6 ± 5.5 dyne·s·cm–5, p = 0.057), and a significant elevation in exercise capacity (1.5 ± 0.9 MET vs 0.6 ± 1.1 MET, p = 0.018) [Fig 3
]. With the baseline value of the parameters acting as covariates in addition to the treatment, the results of covariance analysis showed no differences in between-subject effects or within-group variance.
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Figure 3.. The comparisons of improvement values of SPAP (left, A) and exercise capacity (right, B) between the lipo-PGE1 group and the conventional therapy group (p = 0.002 and p = 0.018, respectively).
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Within 2 weeks of the administration of lipo-PGE1, significant side effects were seen in six patients (22%) in the treatment group: local irritation in two patients, nausea in two patients, itchy sensation in one patient, and a warm sensation of the chest during infusion in one patient. No patient complained of symptoms related to systemic hypotension.
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Discussion
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PAH is characterized by elevation of pulmonary artery pressure and pulmonary resistance, in the absence of left-sided heart disease, lung disease, or pulmonary thromboembolic disease. PAH can be idiopathic or familial, and can arise in association with CVD, CSPS, portal hypertension, HIV infection, and exposure to anorexigens.610 In this report, we included patients with PPH (now idiopathic PAH is a better term since the 2003 World Health Organization classification of pulmonary hypertension) and PAH associated with CVD and CSPS.
The current pharmacologic treatment of PAH is directed at preventing or reversing vasoconstriction, vasoproliferation, and thrombosis101112. Continuous IV infusion of PGI2 is an effective treatment to lower both pulmonary pressure and resistance, and it has been shown to improve exercise tolerance and enhance the quality of life.123 Other prostacyclin analogues administered by continuous subcutaneous infusion,13 orally,14 or by intermittent inhalation15 all show promise. PGE1, like prostacyclin, is a vasodilator with antiplatelet and antiproliferative effects. The use of PGE1 in pulmonary hypertension with CVD,16 open-heart surgery in children,17 and PPH has previously been reported. However, since PGE1 is not as potent as PGI2 and increase of dosage leads to serious side effects, PGE1 is not widely accepted in clinical practice.
Lipid microspheres, acting as drug carriers, can target the drug to diseased sites, such as inflammatory and vascular lesions, especially the subendothelial space, protecting the drugs from being rapidly metabolized, increasing the clinical efficacy and relieving the adverse effects of the drug. Lipo-PGE1, a lipid microsphere formula of PGE1, shows a stronger pharmacologic effect than PGE1. In various clinical trials, 10 µg/d of lipo-PGE1 was administered, and its clinical efficacy had been confirmed in the treatment of peripheral vascular disorders resulting from collagen disease, arteriosclerosis obliterans, and ductus arteriosus-dependent congenital heart disease45. However, its effects on pulmonary hypertension have not been reported. According to Naeije et al,18 PGE1 at an infusion rate of 20 ng/kg/min decreases pulmonary pressure and systemic pressure by 20% and 7%, respectively; while at an infusion rate of 40 ng/kg/min, it could lower pulmonary pressure and systemic pressure by 24% and 14%, respectively. In order to enhance the clinical effects and alleviate the side effects of systemic hypotension, we used 10 µg bid of lipo-PGE1, with an infusion rate of 20 ng/kg/min. After 2 weeks of treatment, we found there was a significant decrease in pulmonary artery pressure and a significant increase in exercise capacity by treadmill testing in patients with PAH. No serious side effects were detected.
Although PAH presents similar pathologic findings of plexogenic arteriopathy,611 the etiologies and pathogenesis of pulmonary hypertension vary. The vascular changes in congenital heart disease are secondary rather than primary. Pulmonary hypertension in patients with systemic lupus erythematosus or mixed connective tissue diseases might be associated with inflammation, while pulmonary hypertension in systemic sclerosis patients might be associated with bland vasculopathy. The inclusion of heterogeneous patients might have affected the results of our study, and this is one of the drawbacks of the study, as we found the effects of lipo-PGE1 somewhat differed in different kinds of PAH. Individual subjects even deteriorated after receiving lipo-PGE1. However, the numbers in the subgroups were too small for us to draw any substantial conclusions.
Our study had other limitations. We did not use placebo or PGE1 infusions to compare the effects of lipo-PGE1, and we did not have long-term observations; therefore, our current data are too preliminary to allow recommendations for new therapeutic strategies. Furthermore, no definitive conclusion about the influence of etiology of the disease on treatment response can be made at this stage. A longer study with a more uniform group of patients and a further study with a placebo control is needed to address these issues.
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Conclusion
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IV infusion of lipo-PGE1 can effectively lower pulmonary pressure and improve the exercise tolerance in patients with PAH.
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Footnotes
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Abbreviations: CO = cardiac output; CSPS = congenital systemic-to-pulmonary shunts; CVD = collagen vascular disease; lipo-PGE1 = lipid microspheres containing prostaglandin E1; LVEF = left ventricular ejection fraction; MET = metabolic equivalents; NYHA = New York Heart Association; PAH = pulmonary arterial hypertension; PGE1 = prostaglandin E1; PGI2 = prostacyclin I2; PPH = primary pulmonary hypertension; SPAP = systolic pulmonary arterial pressure; TPR = total pulmonary resistance
Received for publication January 30, 2004.
Accepted for publication January 20, 2005.
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Abstract
Introduction
