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Prostacyclin Therapy for Pulmonary Arterial Hypertension: New Directions Mardi Gomberg-Maitland, M.D., M.Sc.1 and Ioana R. Preston, M.D.2

ABSTRACT

Pulmonary arterial hypertension (PAH) is characterized by vasoconstriction and smooth muscle cell proliferation of the pulmonary arterioles, as well as in situ thrombosis of the small pulmonary arteries. Prostacyclin is involved in PAH vascular remodeling. It is unclear if decreased prostacyclin in the lungs is a cause or a consequence of PAH, but the relative lack of prostacyclin and its positive effects on the pulmonary vascular bed support the theory that long-term prostacyclin replacement is effective. Current therapies based on evidence-based medicine include epoprostenol, treprostinil, iloprost, and beraprost, each with limitations based on the drugs’ inherent properties and administration route. Treatment of PAH by inhibiting multiple pathways concurrently may produce additive benefit.

Because prostacyclin therapy is not curative and does not normalize pulmonary hemodynamics in the majority of cases, combining a prostacyclin with other PAH agents may be a promising approach.

KEYWORDS: Pulmonary arterial hypertension, prostacyclin, combination therapies

Objectives: Upon completion of this article, the reader will: (1) understand the molecular basis for prostacyclin use in pulmonary arterial hypertension; (2) have learned the current data in support of prostacyclin therapy; (3) understand the differences among prostacyclin analogs; and (4) have learned about novel approaches to therapy.

Accreditation: The University of Michigan is accredited by the Accreditation Council for Continuing Medical Education to sponsor continuing medical education for physicians.

Credits: The University of Michigan designates this educational activity for a maximum of 1 category 1 credit toward the AMA Physician’s Recognition Award.

P

ulmonary arterial hypertension (PAH) comprises a spectrum of diseases characterized by elevated mean pulmonary artery pressure above 25 mm Hg at rest, or 30 mm Hg with exercise. PAH is characterized by vasoconstriction and smooth muscle cell proliferation of the pulmonary arterioles, a process known as vascular remodeling, as well as in situ thrombosis of the small pulmonary arteries.

PULMONARY VASCULATURE Normally, the smooth muscle layer of the pulmonary vessels is maintained in a state of relaxation. This is achieved through the release of pulmonary vasodilators that counterbalance the effects of pulmonary vasoconstrictors. The presence of vascular remodeling seen in PAH suggests that there is a dysfunction that shifts the balance toward factors that

Pulmonary Arterial Hypertension; Editor in Chief, Joseph P. Lynch, III, M.D.; Guest Editor, Victor F. Tapson, M.D. Seminars in Respiratory and Critical Care Medicine, volume 26, number 4, 2005. Address for correspondence and reprint requests: Mardi Gomberg-Maitland, M.D., M.Sc., Division of Cardiology, University of Chicago Hospitals, 5841 S. Maryland Ave., MC2016, Chicago, IL 60637. E-mail: mgomberg@medicine. bsd.uchicago.edu. 1Division of Cardiology, University of Chicago Hospitals, Chicago, Illinois; 2Pulmonary Critical Care and Sleep Division, Tufts– New England Medical Center, Boston, Massachusetts. Copyright # 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. 1069-3424,p;2005,26,04,394,401,ftx,en;srm00391x.

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produce vasoconstriction and smooth muscle cell proliferation.

Lung tissue is normally active in the synthesis, metabolism, and release of several prostaglandins, some of which play a role in regulation of the pulmonary vascular resistance. Among these, prostacyclin (PGI2) has vasodilatory effects on the pulmonary vasculature, whereas thromboxane is a potent pulmonary vasoconstrictor and stimulus for platelet aggregation. Pulmonary endothelial cells have an abundance of prostacyclin synthase (PGI2 synthase), the enzyme that produces prostacyclin. Prostacyclin acts as a local hormone. It is released by endothelial cells and produces relaxation of the underlying vascular smooth muscle and prevents platelet aggregation. (Fig. 1) Prostacyclin is involved in PAH vascular remodeling. In two experimental forms of PAH, overexpression of PGI2 synthase in lungs of either rats exposed to monocrotaline or mice exposed to hypoxia protects from the development of PAH.1,2 In addition, loss of expression of PGI2 synthase has been reported in remodeled pulmonary vessels from patients with PAH.3 It is unclear if decreased prostacyclin in the lungs is a cause or a consequence of PAH, but abnormal prostacyclin levels may play a part in the development and maintenance of PAH. In support of an active role of prostacyclin on vascular remodeling is its antiproliferative effect on smooth muscle cells in vitro.4 The pathogenesis of PAH is an imbalance between prostacyclin and thromboxane. Excess vasoconstrictors may play a role in medial hypertrophy in PAH. Patients with severe PAH have decreased urinary excretion of the prostacyclin metabolite, 6-keto PG2a, evidence of decreased prostacyclin production, whereas 11-dehydro-thromboxane B2 (a stable metabolite of thromboxane A2) is increased.5 Another important pathological feature of PAH is the widespread development of in situ thrombosis of the small pulmonary arteries with intraluminal thrombin deposition. Interaction of growth factors and platelets with dysfunctional endothelial cells creates a procoagu-

Figure 1 Effects of prostacyclin as a pulmonary antihypertensive agent.

lant environment within the pulmonary vascular bed.

The release of vasoconstrictors, such as serotonin and thromboxane is associated with platelet activation and thrombosis. This is seen by a prolonged fibrinogen half-life and diminished fibrinolytic activity.6 Besides its potent vasodilator activity, prostacyclin has been shown to have antithrombotic and antiplatelet effects both in vitro7,8 and in vivo.9 Effects of prostacyclin on pulmonary vasculature are presented in Fig. 1.

In addition to vasodilatory, antiplatelet and antiremodeling effects, prostacyclin probably has a direct inotropic effect on the heart. Acute and long-term vasodilator studies with intravenous epoprostenol, subcutaneous treprostinil, and the inhaled form of prostacyclin, iloprost, demonstrated not only a decrease in mean pulmonary artery pressures but an enhancement in cardiac output.10–12 The acute effect is possibly due to an increase in cyclic adenosine monophosphate (cAMP) on cardiomyocytes, resulting in a direct positive inotropic effect. The long-term improvement in cardiac output is not well understood but may be due to the antiremodeling effect of prostacyclin on the pulmonary vasculature, with improvement in blood flow through the pulmonary vessels and enhanced preload of the left ventricle.11 Epoprostenol, treprostinil, and iloprost are the prostacyclin analogues approved by the Food and Drug Administration (FDA) for the treatment of PAH, whereas oral beraprost is still investigational. Analogues may have different properties because of binding properties of the prostacyclin receptors. Treprostinil is more potent than iloprost or beraprost on inhibition of human pulmonary artery smooth muscle cells proliferation in vitro.13 There have been no clinical trials comparing one prostacyclin analogue to another, and therefore differences in efficacy remain to be proven.

In conclusion, based on the pathophysiology, the relative lack of prostacyclin seen in PAH and its positive effects on the pulmonary vascular bed support the theory that long-term prostacyclin replacement is effective therapy.

Table 1 summarizes the characteristics of different prostacyclin analogues available for clinical use.

INTRAVENOUS PROSTACYCLIN (EPOPROSTENOL) The first and most proven therapy approved for PAH is intravenous prostacyclin (epoprostenol). Epoprostenol cannot be administered orally because it is not stable at pH < 10.5 and has a half-life of no more than 6 minutes, obligating continuous intravenous therapy.14 Testing with continuous therapy in laboratory animals with elevated pulmonary pressures from pulmonary vasoconstrictors led to the initial justification for human trials.15,16 Early individual experience and small-scale

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Table 1

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Prostacyclin Analogues Available for the Treatment of Pulmonary Arterial Hypertension

Name

Route

Half-Life

Advantages

Disadvantages

FDA Approved

Epoprostenol

IV

6 minutes

Easy to titrate

Requires permanent

Yes

Longest experience

Flolan

intravenous catheter Risk of line infection Risk of syncope or cardiovascular collapse with infusion interruption Need for ice packs Mixing every 24 hours

Treprostinil

SC

4.6 hours

Smaller pump (Minimed)

Pain at the site of infusion

Yes

Risks associated with the

Yes

No mixing required

Remodulin

Change site every 3–4 days IV

4.4 hours

No need for intravenous catheter Cassette changed every 48 hours No need for ice packs

presence of a permanent

Theoretically, less risk of

intravenous catheter

cardiovascular collapse in case of accidental interruption Iloprost

Inhaled

Ventavis

6.5–9.4 minutes postinhalation

IV

23 minute

No need for intravenous catheter

6–9 inhalations a day

Local delivery limits side effects

More risk of syncope

(headache, jaw pain) Same as epoprostenol, but less

Same as epoprostenol

No

Gastrointestinal intolerance

No

Yes

experience Beraprost

oral

35–40 minutes

Oral delivery

Unclear efficacy

registries 17–20 demonstrated improvement in symptoms and hemodynamics.

Investigators began testing vasodilatory reserve with therapy during heart catheterization. It was unclear if lack of acute change in hemodynamics (drop in pulmonary artery pressure, improvement in cardiac output) determined overall response to therapy. Baseline measurements and measurements after acute administration demonstrated benefits in lowering pulmonary artery pressure and pulmonary vascular resistance. However, subjects lacking an acute hemodynamic response to vasodilatory testing still appeared to benefit from longterm treatment.21

Vasodilatory Testing Several vasodilators are currently used to assess pulmonary vasoreactivity in subjects with PAH. Adenosine, an intermediary product of adenosine triphosphate, acts on the endothelial cell and vascular smooth muscle A2 receptors causing vasodilation. This increases cAMP, inducing smooth muscle relaxation. Adenosine’s short half-life, less than 5 seconds, allows for safe and easy administration. It is infused at a dose of 50 mg/kg/min and titrated upward every 2 minutes until discomfort (flushing, chest discomfort, dyspnea) or a dose of 250 mg/kg/min. Adenosine response predicts chronic

effects of intravenous prostacyclin and oral calcium channel blockers.22 Epoprostenol may also be used to assess acute pulmonary vasoreactivity because it has a short half-life; however, side effects of headache, flushing, nausea, and emesis persist longer and testing requires more time.23 It is administered at 2 ng/kg/min and uptitrated every 15 to 30 minutes. Nitric oxide (NO) inhalation results in selective pulmonary vascular effects without effects on the systemic circulation.24 It is given at 20 to 40 ppm (parts per million) concurrently with 100% oxygen by face mask. Inhalation requires a skilled technician and is an expensive agent for acute testing. Ricciardi et al compared nifedipine and NO testing and demonstrated a similar response.25 However, it is recommended to choose one agent for testing because multiple testing can lead to interpretative error.

Clinical Trials The design of the first prospective, randomized, openlabel placebo trial of epoprostenol in addition to conventional therapy (warfarin, digoxin, oxygen, and oral vasodilators) was the pivotal trial in PAH treatment.26 Eighty-one subjects with primary pulmonary hypertension (PPH), classified as New York Heart Association (NYHA) functional class III or IV, were enrolled for

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12 weeks. Subjects on active therapy had improvement in exercise capacity as the mean 6 minute walk test improved by 32 m compared with a decrease of 15 m in the conventional therapy group (p < .003). Hemodynamic improvement was evidenced by a decrease in pulmonary artery pressure of 8% in the epoprostenol group versus an increase of 3% in the conventional group (difference in mean change 6.7 mm Hg, 95% CI ¼ 10.7 to 2.6 mm Hg; p < .002). The mean pulmonary vascular resistance decreased by 21% in the epoprostenol group versus an increase of 9% in the conventional group (difference in means 4.9 mm Hg/L/min, CI ¼ 7.6 to 2.3 mm Hg/L/min, p < .001). Eight patients died during the 12-week trial, all in the conventional therapy group (p ¼ .003).

With the FDA approval of epoprostenol, it is unethical to conduct a long-term, randomized placebo trial of epoprostenol. However, cohort analyses in Europe and in the United States have provided convincing evidence of its long-term benefits. In France, after 1 year of therapy 162 subjects had improvement in clinical function with modest hemodynamic improvement.27 In the United States, 178 subjects had improved survival compared with the National Institutes of Health (NIH) registry used as a historical control.28 The survival rate at 1 year was 85 versus 58%, 2 years 70 versus 43%, 3 years 63 versus 33%, and at 5 years 55 versus 28%, p < .001). Prognostic factors included a clinical history of right heart failure, functional class, and hemodynamic parameters such as right atrial pressure and cardiac index. The impact of epoprostenol therapy on survival in idiopathic pulmonary arterial hypertension (IPAH) patients is presented in Table 2.

Evidence now supports epoprostenol use in PAH from associated etiologies. A multicenter randomized study demonstrated improved exercise capacity in scleroderma PAH subjects.29 Subjects with scleroderma treated with epoprostenol appear to have a worse prognosis than subjects with PPH in uncontrolled analyses.30,31 Similar improvements in exercise functional

capacity and functional class have been seen in subjects with congenital left to right cardiac shunts,32 portal hypertension,33,34 and infection with the human immunodeficiency virus (HIV).35,36 Over the past decade, increasing use of epoprostenol has delayed and obviated the use of lung transplantation in subjects with severe disease. A U.S. survey indicated that treatment with epoprostenol allowed two thirds of subjects to deactivate from the transplant list.36a However, it is unclear how long the disease will remain stable and therefore frequent follow-up with examination, exercise, and hemodynamics is recommended.37–39

Limitations of Therapy Epoprostenol is usually well tolerated in most subjects.

Side effects are minimal and include flushing, headache, nausea, loose stool, jaw discomfort with ‘‘first bite,’’ and foot pain with prolonged standing or walking. 26–28 Long-term administration requires a permanent central venous catheter and a portable infusion pump.26 Medication needs to be prepared daily. The complex delivery system requires education of sterile technique, operation of the pump, and care of the catheter. A strong support system, a ‘‘partner,’’ is often strongly recommended to obviate problems if the subject is too ill or unable to prepare medication on a given day. Medication needs to be kept cold, requiring ice packs to be worn, with medication in 24 hour cassettes. Serious complications include infection and thrombosis of the catheter and temporary interruption of the infusion because of iatrogenic ‘‘switching’’ or pump malfunction31 The incidence of catheter-related sepsis ranges from 0.l to 0.6 case per patient-year.27,31

TREPROSTINIL (SUBCUTANEOUS/ INTRAVENOUS) Treprostinil is a tricyclic benzidene prostacyclin analogue that shares pharmacological actions similar to

Table 2 Studies Using a Combination of a Prostacyclin Analogue with Another Agent for the Treatment of Pulmonary Arterial Hypertension Trial

No. of Patients

Time

Results

Epoprostenol þ bosentan

Humbert et al, 2004 (RCT 2:1).51

33

16 weeks

No difference in clinical

Iloprost or beraprost þ bosentan

Hoeper et al, 2003 (open label)52

20

3 months

Improvement in exercise capacity and maximal

Iloprost þ sildenafil

Ghofrani et al, 2003 (open label)54

73

9–12 months

Improved exercise capacity

Epoprostenol þ sildenafil

Stiebellehner et al, 2003 (open label)55

5 months

Improved exercise capacity

outcome or hemodynamics

oxygen consumption and hemodynamics 3

and hemodynamics RCT, randomized controlled trial.

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epoprostenol, including antiproliferative activity on human pulmonary arterial smooth muscle cells.13 Treprostinil differs from epoprostenol in that it is chemically stable at room temperature and neutral pH and has a longer half-life (3–4 hours).40 The improved stability of this compound and its solubility at physiological pH enables subcutaneous delivery, thereby avoiding the potential complications of the epoprostenol intravenous delivery system. The bioavailability of treprostinil is excellent, as demonstrated on healthy volunteers.40 Subcutaneous treprostinil was approved in 2002 for the treatment of NYHA class II–IV PAH patients. A 12-week multicenter, randomized, double-blind trial that enrolled patients with idiopathic PAH, PAH related to congenital heart defects, or connective tissue disease, compared treprostinil to placebo in a total of 470 patients.41 Treprostinil improved symptoms of pulmonary hypertension and quality of life. Class IV patients and patients receiving higher doses of treprostinil had a more significant improvement. At 12 weeks, there was also an improvement in hemodynamic parameters, including right atrial pressure, mean pulmonary artery pressure, pulmonary vascular resistance, and cardiac output. In subset analyses from the subcutaneous trials, patients who had PAH related to connective tissue disease had improvement in exercise capacity, symptoms of PAH, and hemodynamics.10 Subcutaneous infusion of treprostinil does not require daily mixing and preparation of the infusion.

The infusion site is changed every 3 to 4 days, the drug comes in a premixed syringe, and there is no need for ice packs or intravenous catheter care. The most common side effect is pain at the site of infusion, which usually responds to a combination of local anesthetic solutions, nonsteroidal anti-inflammatories, gabapentins, or low dose narcotics. The pain appears not to be dose related, and it is unclear why the pain occurs and which patients will develop severe pain.

Most recently, the FDA approved the use of intravenous treprostinil based on bioequivalence to subcutaneous therapy.42 The advantage over epoprostenol is that the cassette is changed every other day and it does not require ice packs. The longer half-life of intravenous treprostinil, 4.4 hours, may also decrease the risk of cardiovascular collapse in case of inadvertent interruption of the infusion. Investigational trials with intravenous therapy are in progress.

ILOPROST (INHALED) A targeted approach, with direct inhalation of prostacyclin, allows for more selective pulmonary effects. Iloprost is a chemically stable prostacyclin analogue that can be delivered by inhaler/nebulizer.43 To ensure alveolar deposition, the delivery system produces small aerosol-

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ized particles (median diameter of 0.5–3.0 mm).44 However, because of its short duration of action, it must be inhaled 6 to 12 times a day.43,45 Iloprost is an effective agent in PAH subjects with significant limitation in functional capacity. Two hundred and seven subjects with PPH, PAH associated with connective tissue diseases, or inoperable chronic thromboembolic pulmonary hypertension with NYHA Class III or IV functional class enrolled in a 12-week multicenter, placebo-controlled trial.45 The efficacy end point was a 10% increase in subjects’ scores on a 6-minute walk test and improvement in NYHA functional class. Seventeen percent of patients on iloprost reached this end point compared with 4% in the placebo group (p ¼ .007). The mean increase in 6-minute walk test was 36.5 m (p ¼ .004) and 58.8 m among subjects with PPH. Subjects’ well-being improved as evidenced by quality of life scores and the Mahler dyspnea index.

Hemodynamic measures at 12 weeks also improved in the treatment group compared with baseline values (p < .001) and subjects on placebo had significant declines in values. Side effects consisted of symptoms related to systemic vasodilation. More syncopal episodes occurred in the iloprost group although they were not associated with clinical deterioration. Iloprost is safe and effective and is approved in Europe awaiting U.S. trial data.

Intravenous iloprost is also approved in Europe for PAH patients. Intravenous iloprost has similar acute hemodynamic changes to inhaled iloprost,46,47 but the inhaled therapy is more pulmonary selective.46,47 Because intravenous therapy has similar limitations to epoprostenol in that it requires a permanent catheter and routine sterile mixing procedures, inhaled therapy is more attractive. It is unclear if the two therapies will have similar long-term efficacy.

BERAPROST (ORAL) Difficulties with prostacyclin administration led to the development of an oral biologically stable prostacyclin analogue, beraprost sodium. Beraprost is absorbed rapidly after the administration of an oral dose under fasting conditions; it reaches a peak concentration after 30 minutes and has an elimination half-life of 35 to 40 minutes.48 In Europe, 130 NYHA Class II and IIII subjects enrolled in a 12 week randomized, double-blind, placebo-controlled trial of beraprost.48 Subjects had PAH caused by idiopathic PAH, connective tissue diseases, congenital left to right shunts, portal hypertension, and HIV. At a median dose of 80 mg/4 times daily, subjects had a mean increase of 25 m on 6-minute walk testing (p ¼ .04). Subjects with PPH had a mean increase of 46 m (p ¼ .04) whereas PAH from other causes had no significant improvement. In the United States, a similar trial was designed but with a 12-month study

PROSTACYCLIN THERAPY FOR PAH/GOMBERG-MAITLAND, PRESTON

duration. This study demonstrated improved 6-minute walk distance at 3 and 6 months compared with the placebo group that was not sustained at 9 and 12 months.49 Beraprost is not approved in the United States but is an approved therapy in Japan.

COMBINATION THERAPY Treatment of PAH by inhibiting multiple pathways concurrently may produce additive benefit. Because prostacyclin therapy is neither curative nor does it normalize pulmonary hemodynamics in the majority of cases, investigators have examined combining a prostacyclin with agents that act on the endothelin pathway and agents that increase cyclic guanosine phosphate (cGMP). Bosentan, an orally active nonselective endothelin receptor antagonist is currently the only FDA approved medication for PAH.50 Thirty-three subjects with PAH were started on epoprostenol with uptitration for 16 weeks and randomized in a 2:1 ratio to bosentan (62.5 mg twice daily for 4 weeks and then 125 mg twice daily) or placebo.51 There was a trend, but no significant benefit in clinical or hemodynamic measurements. Hoeper et al52 studied 20 patients with IPAH that were on either inhaled iloprost or oral beraprost.

Three-month therapy with bosentan added to the prostacyclin resulted in improvement in exercise capacity and maximal oxygen consumption. Therefore, it is unclear whether treatment with a stable dose of prostacyclin can be improved with the addition of bosentan.

A newer strategy is to increase cGMP in the smooth muscle cell, and, by reducing intracellular calcium, to produce vasodilatation. This is accomplished by inhibition of the phosphodiesterase 5 enzyme (PDE-5), which degrades cGMP in the vascular smooth muscle cell. The pulmonary vasculature has a higher concentration of the PDE-5 enzyme than most vascular beds.

Sildenafil, a PDE-5 enzyme inhibitor, in combination with prostacyclin, may be better than either agent alone. Sildenafil in combination with beraprost limited progression of PAH and improved survival in the monocrotaline rat model.53 Oral sildenafil in combination with iloprost in 73 PAH patients over 9 to 12 months follow-up improved exercise capacity and hemodynamics.54 Patients in this study demonstrated a decline in 6-minute walk test on iloprost prior to enrollment.

Open, uncontrolled experience adding sildenafil to epoprostenol also improved hemodynamics.55 A large placebo-controlled multicenter trial is currently in progress.

Addition of oral sildenafil may be used as a bridge to intravenous therapy but it is unknown if this delay will affect the vasculature’s ability to respond to intravenous medications in the future. Table 2 summarizes the results from combination therapies.

CONCLUSION Prostacyclin therapies are effective treatments of PAH. New analogues are more convenient and have an improved safety profile, although their administration requires either continuous infusion (treprostinil), or frequent inhalations (iloprost). Long-term data of efficacy are not available yet, but should parallel epoprostenol. Although data on combination therapies consist of small open-label trials, initial data are promising.

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