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American Journal of Respiratory and Critical Care Medicine Vol 165. pp. 1209-1216, (2002)
© 2002 American Thoracic Society

Pulmonary Perspective

New Treatments for Pulmonary Arterial Hypertension

Marius M. Hoeper, Nazzareno Galiè, Gerald Simonneau and Lewis J. Rubin

Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany; Institute of Cardiology, University of Bologna, Bologna, Italy; Pneumology Unit, Hôpital Antoine Béclère, Clamart, France; and Division of Pulmonary and Critical Care Medicine, University of California, San Diego, California

Correspondence and requests for reprints should be addressed to Marius M. Hoeper, M.D., Department of Respiratory Medicine, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625 Hannover, Germany. E-mail: hoeper.marius{at}mh-hannover.de

We have witnessed tremendous advancements in our understanding of the pathogenesis of pulmonary arterial hypertension (PAH). Several of these new insights have led to the development and clinical application of novel treatments for this devastating disease. Before 1999, no placebo-controlled trials had been conducted in pulmonary hypertension; since 2000, however, five clinical trials have been concluded that demonstrate therapeutic efficacy for novel prostaglandins and endothelin antagonists. Comparative studies of these new treatments and with intravenous prostacyclin have not, as yet, been performed. Accordingly, the selection and timing of the most suitable therapy for an individual patient have become more complex and challenging than ever before. This perspective (1) describes the most recent developments in our understanding of the pathogenesis of PAH and how they relate to novel therapeutic approaches; (2) summarizes the results of clinical trials on emerging new therapies; and (3) provides our recommendations for a tailored therapeutic approach (see Figure 1) . Other treatments for PAH, including anticoagulation, atrial septostomy, and lung transplantation, have been reviewed elsewhere (1–3) and are not addressed in this perspective.



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  		Figure 1 . Treatment of pulmonary arterial hypertension. Initial therapy should be guided by the results of acute vasodilator challenge. (1) In patients who show a fall in pulmonary arterial pressure and pulmonary vascular resistance to near-normal values, calcium channel blockers remain a reasonable therapeutic option. Nonresponders and responders who are not in NYHA Class I or II while being treated with calcium channel blockers should be offered the endothelin receptor antagonist bosentan or one of the novel prostaglandins. In case of deterioration or in patients with advanced disease, intravenous epoprostenol or iloprost should be started and atrial septostomy or lung transplantation should be considered. (2) The combination of epoprostenol and bosentan is currently being evaluated in clinical studies. (3) Iloprost is not available in the United States and has not received official approval for treatment of pulmonary hypertension in Europe. (4) Some of these substances have not been approved in the United States and Europe. See text for further details.

 
PATHOGENESIS AND RATIONALE FOR TREATMENT APPROACHES

Pulmonary arterial hypertension is characterized by progressive obliteration of the pulmonary vascular bed, which almost inevitably results in progressive right heart failure and death (2, 4). Our understanding of the pathogenesis of primary pulmonary hypertension (PPH) and related conditions has increased substantially (5). Endothelial dysfunction in pulmonary vascular disease results in exaggerated vasoconstriction and impaired vasodilation, both recognized features of pulmonary hypertension. Synthesis of both endothelial nitric oxide and prostacyclin is diminished in patients with PPH, owing to diminished expression of nitric-oxide synthase and prostacyclin synthase (6–8). Endothelin, a potent vasoconstrictor and mitogen, is overexpressed in the lungs of patients with pulmonary hypertension (9), and elevated plasma endothelin concentrations have been correlated with severity of prognosis (10, 11). The underexpression of vasodilators such as nitric oxide and prostacyclin and overexpression of vasoconstrictors such as endothelin are likely not only to affect pulmonary vasomotor tone but also to promote vascular remodeling. Accordingly, these abnormalities provide a rational therapeutic target (12).

Work combining histologic with molecular studies has suggested that abnormal proliferation of both endothelial and smooth muscle cells plays a crucial role in the pathogenesis of pulmonary hypertension (13–18). Tuder and coworkers have shown that plexiform lesions consist of proliferating endothelial cells (13, 17) and that these lesions exhibit features of disordered angiogenesis reminiscent of that seen in malignancy (19, 20). Vascular endothelial cell growth factor (VEGF), an endothelial cell mitogen, is abundantly expressed in the vicinity of plexiform lesions (21). Although this observation raises the possibility that VEGF plays a detrimental role in the pathogenesis of pulmonary hypertension, experimental studies suggest the opposite. In monocrotaline-treated rats, overexpression of VEGF by cell-based gene transfer inhibited the development of pulmonary hypertension (22). In contrast, blockade of VEGF receptors produced mild pulmonary hypertension and pulmonary vascular remodeling in normoxic rats and severe, irreversible pulmonary hypertension associated with precapillary arterial occlusions by proliferating endothelial cells in chronically hypoxic rats (23). These findings may indicate an adaptive or even protective role for VEGF in the pathogenesis of pulmonary hypertension. Furthermore, this effect may help explain the therapeutic effects of prostaglandins, because prostacyclin and its stable analog iloprost stimulate the production of VEGF synthesis in vitro (24).

The importance of viewing pulmonary arterial hypertension as a proliferative disorder was underscored by the discovery of mutations of the bone morphogenetic protein receptor type II (BMPR-II), a member of the transforming growth factor receptor family, in patients with familial PPH (25–27). Germ line BMPR-II mutations have also been found in up to 30% of sporadic cases of PPH (28). There is growing evidence that dysfunction of this receptor is directly associated with abnormal proliferation of pulmonary vascular cells (29–31), although the mechanism by which BMPR-II mutations contribute to the pathogenesis of PAH remains incompletely understood. Because not all individuals who carry BMPR-II mutations develop pulmonary hypertension, it is likely that additional factors are necessary. These factors may include mutations of other members of the transforming growth factor receptor family (32), mutations of genes linked to apoptosis (32), decreased expression of potassium channels (33, 34), and overexpression of serotonin transporters on pulmonary artery smooth muscle cells (35, 36).

The conceptual shift in the pathogenesis of pulmonary hypertension from a vasoconstrictive to a vasoproliferative process has been paralleled by a shift in the approach to treatment. Until the mid-1990s, vasodilators, especially calcium channel blockers, were widely used to treat pulmonary hypertension (37), but it is now evident that only a small proportion of patients benefit from these drugs (38). It is becoming increasingly clear that effective treatment of PAH must target vascular remodeling, including the abnormal proliferation of pulmonary vascular cells. The introduction of agents that likely possess antiproliferative activity, including prostaglandins and, more recently, endothelin receptor antagonists, has substantially broadened the therapeutic options for PAH.

PROSTAGLANDINS

Continuous Intravenous Epoprostenol (Prostacyclin) and Iloprost
Intravenous epoprostenol (prostacyclin) was first used to treat pulmonary hypertension in the early 1980s and was the first drug approved for this indication by the Food and Drug Administration and several European agencies (39). In addition to possessing both vasodilatory and platelet antiaggregatory effects, epoprostenol may also affect pulmonary vascular remodeling through several other mechanisms: stimulation of prostacyclin receptors has antiproliferative effects in cultured vascular smooth muscle cells (40, 41); and the stable prostacyclin analog iloprost suppresses the production of connective tissue growth factor, a profibrotic cytokine, in fibroblasts and in the skin of patients with systemic sclerosis (42). Experimental studies also suggest that prostacyclin may possess anti-inflammatory actions that may also be of therapeutic value (43, 44). The potential importance of stimulation of VEGF synthesis by prostaglandins has been mentioned previously.

Intravenous epoprostenol has been shown to improve exercise capacity, hemodynamics, and survival in a short-term, randomized controlled trial in PPH (45). However, only limited data are available about long-term survival with continuous intravenous epoprostenol. McLaughlin and coworkers reported 27 patients with PPH treated with epoprostenol for an average of 16 months: hemodynamic improvement, accompanied by increased exercise capacity, was observed in almost all these patients and none died during the observation period (46). Shapiro and coworkers studied 69 patients with PPH treated with intravenous epoprostenol, of whom 13 (19%) died (47). The 1-, 2-, and 3-year survival rates were better in the epoprostenol-treated group compared with the historic control group.

The optimal dosing of epoprostenol remains undefined. McLaughlin and coworkers increased the epoprostenol dose when there was clinical evidence of deterioration, which resulted in a mean dose of 40 ± 15 ng/kg per minute after 17 ± 5 months. In a subsequent study, these authors reported that some of their patients developed inappropriately high levels of cardiac output, sometimes above 10 L/minute, with this regimen. It was possible to reduce the epoprostenol dose without clinical deterioration in these patients (48).

In the absence of evidence regarding the optimal dosing regimen for intravenous epoprostenol, initiation of epoprostenol treatment at a dose of 2–4 ng/kg per minute is recommended, followed by dosing increments of 1–2 ng/kg per minute until either clinical improvement is manifest or further dose escalation is precluded by side effects.

Randomized controlled trials using epoprostenol for other forms of PAH have been performed only in scleroderma. In these patients, epoprostenol significantly increased exercise capacity and improved hemodynamics. However, epoprostenol did not improve survival compared with conventional therapy during the 3-month duration of this study (49). In an earlier open study, Klings and coworkers reported improved symptoms and exercise tolerance in all 16 patients with systemic sclerosis and pulmonary hypertension immediately after initiation of intravenous epoprostenol therapy. Follow-up hemodynamic testing revealed persistent favorable responses in all four patients studied after 1 year (50). In contrast, Humbert and coworkers reported that long-term treatment (14–154 weeks) with intravenous epoprostenol was effective in only 7 of 15 patients with PAH associated with collagen vascular disease (51).

The effects of epoprostenol in PAH associated with other collagen vascular diseases (52), human immunodeficiency virus infection (53), congenital heart disease (54, 55), or portal–pulmonary hypertension (55, 56) have been reported primarily in case series that lack data on long-term efficacy or survival.

Commonly observed side effects of epoprostenol include flushing, headache, jaw pain, leg pain, diarrhea, and nausea. These side effects are generally mild and dose related. More serious complications are related to the complex delivery system. A permanent central venous access is required, usually a Hickman catheter or a venous port, and carries the risk of potentially serious complications such as infection or catheter-related thrombosis. The incidence of catheter-related sepsis has been reported to be between 0.1 and 0.4 per patient-year (45, 46). Pump failure or dislocation of the central venous catheter may lead to interruption in drug supply. Because epoprostenol is unstable in aqueous solution and decays with a half-life of 1–2 minutes, infusion interruption may result in a sudden and life-threatening loss of its hemodynamic effects. For this reason, a more stable prostacyclin analog such as iloprost offers theoretic advantages. Iloprost is a stable prostacyclin derivative with a half-life of 20–30 minutes (57). Administered intravenously, its acute hemodynamic effects are similar to those of intravenous prostacyclin. Data comparing long-term efficacy of intravenous iloprost are limited. Higenbottam and coworkers have shown in a cross-over study of eight patients with pulmonary hypertension that both compounds were equally effective in improving exercise capacity and pulmonary hemodynamics during a mean observation period of 7 weeks for both treatments (58). Although iloprost is available in several European countries, it has not received approval by the Food and Drug Administration or any other national regulatory agency except for New Zealand.

The dosing regimen for intravenous iloprost is substantially lower than for intravenous epoprostenol. The usual starting dose of iloprost is between 0.5 and 1.0 ng/kg per minute in most patients, and maintenance doses of 2–4 (or 8) ng/kg per minute are usually sufficient to achieve substantial clinical improvement.

Until recently, most experts chose intravenous prostaglandins as the first-line treatment for patients with pulmonary arterial hypertension falling into New York Heart Association (NYHA) functional Classes III and IV. With the introduction of novel prostaglandins and endothelin receptor antagonists, it is likely that patients with less advanced disease (NYHA Classes II and III) will be treated initially with one of these newer agents. Although such a decision seems reasonable given the inconveniences, costs, and risks associated with intravenous prostacyclins, it is important to keep in mind that there has been no controlled study comparing these new treatment modalities with each other or with epoprostenol.

Subcutaneous Treprostinil
The serious nature of central venous catheter-related infections in patients treated with continuous intravenous epoprostenol led to the development of treprostinil (formerly known as UT-15), a stable prostacyclin analog, for subcutaneous infusion. The drug is administered as a continuous subcutaneous infusion by a minipump system that has been used extensively for insulin treatment of diabetes mellitus. Treprostinil has a half-life of 45 minutes when administered intravenously and of 3–4 hours when administered subcutaneously (59). Its acute hemodynamic effects are similar to those seen with intravenous prostacyclin. A multicenter, randomized, placebo-controlled trial comparing treprostinil with placebo in 470 patients with PAH has concluded (60). The most frequent diagnosis was PPH, followed by PAH associated with congenital heart disease and collagen vascular disease. Fourteen patients died during the 3-month study period: seven in each group. The 6-minute walk distance improved with treprostinil (+ 17 m) along with small, but statistically significant improvements in pulmonary arterial pressure and cardiac output. A clear dose–effect relationship was found. Those patients who tolerated doses above 13.8 ng/kg per minute had the greatest improvement in exercise tolerance (mean increase of 36 m). Local pain at the infusion site was the most common side effect, occurring in 85% of the patients and necessitating discontinuation in 8%. An open label extension study has shown that the effects are persistent for periods up to 18 months (61).

Oral Beraprost
Beraprost sodium is an orally active prostacyclin analog that has been reported in uncontrolled studies to improve hemodynamics in PAH (62). Beraprost is rapidly absorbed: peak plasma concentrations are reached within 30 minutes and the half-life is 30–40 minutes. A trial of beraprost performed with 24 patients with PPH found increased survival compared with a historic control group of 34 patients receiving conventional treatment (63). On the basis of these results, beraprost has been approved in Japan and Korea for treatment of PPH. A European placebo-controlled multicenter trial (ALPHABET) of 130 patients with PAH in NYHA Class II (50%) and III (50%) has been completed (64). The study enrolled patients with primary pulmonary hypertension, pulmonary hypertension associated with collagen vascular disease, congenital systemic-to-pulmonary shunts, portal hypertension, and human immunodeficiency virus infection.

At a median dose of 80 µg administered four times a day, beraprost improved the 6-minute walk distance compared with placebo (+ 25 m); patients with PPH manifested the greatest response (+ 46 m). The Borg dyspnea index was also improved. Hemodynamic variables were not significantly improved. Minor side effects attributable to systemic vasodilatation were common only during the initial titration period.

On the basis of currently available experience, beraprost should be considered only for patients with less severe pulmonary hypertension, primarily those in NYHA Class II and, possibly, early stable NYHA Class III.

Inhaled Iloprost
Preliminary observations of the favorable effects of inhaled iloprost in patients with PAH were first reported in 1996 (65), and since then many aspects of this treatment have been refined. Among these, the most critical is that the delivery system used to nebulize iloprost be capable of delivering aerosol particles of the appropriate size (optimal mass median diameter, 3.0–5.0 µm) to ensure alveolar deposition (66).

Aerosolized iloprost is a potent pulmonary vasodilator that is more effective in decreasing pulmonary artery pressure and increasing cardiac output than inhaled nitric oxide (67). Furthermore, inhalation of iloprost improves exercise capacity and oxygen uptake (68). A European multicenter, randomized, placebo-controlled trial of 203 NYHA Class III and IV patients with primary pulmonary hypertension, pulmonary hypertension associated with collagen vascular disease, and inoperable chronic thromboembolic pulmonary hypertension (Aerosolized Iloprost Randomized [AIR] Study) has been concluded. The combined end point of a 10% improvement in 6-minute walk distance and NYHA functional class improvement was achieved in 17% of patients receiving iloprost compared with 4% of placebo-treated patients. The difference in 6-minute walking distance between the placebo group and the treatment group was 36 m (57 m for patients with primary pulmonary hypertension). The long-term efficacy of aerosolized iloprost, however, is still a matter of debate. Whereas some studies have confirmed a persistent effect (69, 70), others have been less encouraging (71). These findings could be explained by a variable individual response to iloprost aerosol that might be predictable by the hemodynamic response during acute drug challenge (70). The relatively short duration of action is a major disadvantage of this form of treatment because 6 to 12 inhalations/day may be needed to maintain the desired clinical effect. Studies are currently being performed to determine whether the addition of phosphodiesterase inhibitors may improve the therapeutic efficacy (72, 73).

On the basis of the demonstration of efficacy and a low incidence of side effects, inhaled iloprost might be considered for patients with NYHA Class III disease if they are willing to accept the inconveniences of repeated daily inhalations.

ENDOTHELIN RECEPTOR ANTAGONISTS

The 21-amino acid peptide endothelin-1, the predominant isoform of the endothelin peptide family, has been implicated in the pathogenesis of pulmonary arterial hypertension (6, 9, 74). Endothelin-1 mediates vasoconstriction and smooth muscle cell proliferation through endothelin-A (ETA) receptors but it can also induce vasodilation through endothelial ETB receptors (75). Bosentan is an orally available dual endothelin receptor antagonist that exerts acute vasodilatation of the pulmonary and systemic vascular beds when administered intravenously (76). A double-blind, randomized, placebo-controlled trial evaluating the efficacy of oral bosentan in patients with PPH and PAH associated with scleroderma has been concluded (77). In this study, 32 patients with NYHA Class III or IV disease were randomized to treatment with bosentan (n = 21) or placebo (n = 11). After 12 weeks, there was a significant increase in the 6-minute walk distance in the bosentan group (+ 72 m) accompanied by significant improvements in pulmonary artery pressure and cardiac output. Adverse effects were reported as minimal, but two patients developed liver enzymes elevations that improved despite continuation of bosentan. The results of the BREATHE-1 (Bosentan [Tracleer]: Randomized Trial of Endothelin Receptor Antagonist Therapy for Pulmonary Hypertension) trial, a 4-month study of the effects of bosentan in 213 NYHA Class III patients with pulmonary arterial hypertension, have been published: 6-minute walk distance improved in treated patients (+ 44 m) as compared with patients treated with placebo. Time to clinical worsening, NYHA functional class, and Borg dyspnea index also improved. Increases in hepatic enzymes were observed in 14% of patients, were transient in most cases, and necessitated discontinuation of the treatment in only three patients (78). In November 2001, the Food and Drug Administration approved bosentan for treatment of symptomatic PAH but noted that liver function must be monitored monthly.

Preliminary results from a small, randomized, double-blind study of the oral selective ETA receptor blocker sitaxsentan have also suggested a beneficial effect of this drug in patients with PAH (79).

Long-term experience with bosentan is still limited. However, taking two pills a day is clearly the most convenient treatment currently available for advanced PAH. Because the efficacy of bosentan has been demonstrated in two independent randomized trials, it is likely that this drug will soon be used by many clinicians as the first-line treatment for patients with moderately severe (NYHA Class III) PAH. However, it is unknown whether hepatic dysfunction will become a major limitation for long-term use of endothelin receptor blockers. Because of safety concerns, bosentan should not be administered to patients with portal–pulmonary hypertension.

PHOSPHODIESTERASE INHIBITORS

Mammalian phosphodiesterases (PDEs) consist of at least 11 isoenzymes. Isoenzymes 3 and 4 are involved in hydrolysis of cAMP (and to a lesser extent, cGMP). The second messenger cAMP is primarily responsible for the vasodilatory action of prostacyclin, whereas cGMP mediates the vasodilatory action of nitric oxide. The PDE-3/4 inhibitor tolafentrine has been shown to prolong and augment the hemodynamic effects of inhaled prostacyclins (80), but the long-term effects of PDE-3/4 inhibitors in patients with PAH have not been reported.

The PDE-5/6 inhibitor sildenafil, originally developed for the treatment of erectile dysfunction, is an effective pulmonary vasodilator (81–83). Inhibition of PDE-5 increases not only the intracellular concentration of cGMP but of cAMP as well, because cGMP can inhibit PDE-3 (84). Oral sildenafil augments and prolongs the vasodilatory action of aerosolized iloprost (73). Several case reports have suggested a long-term beneficial effect of sildenafil in primary pulmonary hypertension (85, 86). The experience with sildenafil remains preliminary, and more rigorous trials are needed to determine the efficacy and safety of this drug for treatment of pulmonary arterial hypertension. Concerns about long-term use of sildenafil have been expressed because of the potential risk of irreversible retinal damage, which has been linked to PDE-6 inhibition (87, 88).

NITRIC OXIDE AND L-ARGININE

Inhaled nitric oxide is an effective acute pulmonary vasodilator in PAH. Inhaled nitric oxide improves exercise capacity in patients with pulmonary hypertension (89). However, this treatment requires a continuous inhalation device and may not be practical. Because nitric oxide is synthesized from the amino acid L-arginine by nitric-oxide synthase (90), supplementation of L-arginine may have beneficial effects in pulmonary hypertension. In a study of patients with pulmonary hypertension, intravenous administration of L-arginine decreased pulmonary vascular resistance by increasing the endogenous production of nitric oxide (91), although this finding could not be reproduced in another study (92).

In a placebo-controlled study of a 1-week supplementation with oral L-arginine administered to patients with pulmonary arterial hypertension, Nagaya and coworkers have shown a beneficial effect on hemodynamics and exercise capacity (93) with no major side effects. The role of L-arginine supplementation in the treatment of pulmonary arterial hypertension is currently being addressed in a controlled clinical trial.

CONCLUSIONS FOR THE PRACTICE

Intravenous prostacyclin or iloprost, subcutaneous treprostinil, inhaled iloprost, oral beraprost, the dual endothelin receptor antagonist bosentan, and perhaps L-arginine and the phosphodiesterase inhibitor sildenafil all have beneficial effects in patients with PAH. Clinical experience is most extensive with intravenous prostacyclin, which, together with intravenous iloprost, is probably the most potent medical therapy for pulmonary hypertension available today. However, data about the long-term effects are insufficient for all these treatment modalities. Because there is strong evidence that prostaglandins improve survival of patients with pulmonary arterial hypertension, extended placebo-controlled trials would be unethical. However, there is a substantial need for long-term observational studies comparing the different treatments that address survival, side effects, quality of life, and costs.

Until these data are available, the choice of treatment will depend on regional experience and administrative regulations, as well as the clinical context and the preferences of the patient. Furthermore, costs of these drugs vary largely between countries, which may also lead to regional differences in the choice of the preferred treatment. Epoprostenol is available for treatment of pulmonary hypertension in North America and several European countries. Approval of treprostinil, beraprost, and bosentan has occurred or is expected in North America and in Europe by the end of 2001 or in 2002, respectively. Iloprost is not available in the United States but is available throughout Europe; approval of aerosolized iloprost, however, is not expected before the end of 2002.

In patients with primary pulmonary hypertension with less severe impairment, that is, NYHA Classes I and II, continuous intravenous treatment with epoprostenol or iloprost is not warranted. In patients with a favorable acute response to vasodilators such as inhaled nitric oxide (94, 95) or adenosine (96), calcium channel blockers remain the treatment of choice. It is important to note, however, that there is no universally accepted definition of the magnitude of acute response that predicts successful long-term treatment with calcium channel blockers. Most experts now agree that the original definition of an "acute response" as a decrease in pulmonary arterial pressure and pulmonary vascular resistance of more than 20% from baseline, as suggested by Rich and coworkers (37), is imprecise; most patients who exhibit a substantial long-term improvement with calcium channel blockers have reductions of pulmonary arterial pressure to near-normal levels during acute vasodilator challenge.

In NYHA Class II patients unresponsive to vasodilators, oral or inhaled prostaglandins or oral bosentan may be considered. Oral beraprost improved exercise capacity in patients with Class II disease, whereas most experience with bosentan comes from patients with NYHA Class III and IV disease. It is still unclear whether prostaglandins or endothelin antagonists can halt or reverse progression of the disease. Therefore, in stable patients with mild impairment (NYHA Class I or II), conventional therapy including oral anticoagulants and watchful waiting may be justified. On the other hand, the favorable effects observed with beraprost may justify the use of this oral drug. Endothelin receptor antagonists need to be further investigated in patients with milder forms of pulmonary arterial hypertension.

In patients with more severe pulmonary hypertension (NYHA Class III), it is necessary to choose between the newer nonparenteral prostaglandins or endothelin antagonists as the first-line treatment, but these patients must be monitored carefully. In the event of further deterioration, switching to intravenous prostacyclin or iloprost should be considered. Those patients with the most severe pulmonary arterial hypertension and advanced right heart failure (NYHA Class IV) should not be considered candidates for oral beraprost or subcutaneous treprostinil because a clinical response, which is dependent on achieving a therapeutic dose, is usually not seen for several weeks. In these patients, the treatment of choice is intravenous prostacyclin or iloprost. Because there have been reports of successfully managing patients with life-threatening right heart failure with aerosolized iloprost, which may have an almost immediate hemodynamic and clinical effect (69), centers experienced with this form of treatment may consider this option for patients with acute hemodynamic instability. Compared with intravenous prostaglandins, inhaled iloprost may be better tolerated by some patients with profound systemic hypotension (97). However, if inhaled iloprost fails to improve the clinical and hemodynamic situation rapidly in this fragile group of patients, no time should be lost in initiating intravenous prostacyclin or iloprost. In patients with pulmonary arterial hypertension associated with scleroderma or the CREST (calcinosis cutis, Raynaud's phenomenon, esophageal dysmotility, scleroderma, telangiectasias) syndrome, the efficacy of intravenous prostacyclin is well documented. Available data from the trials of oral beraprost, subcutaneous treprostinil, and inhaled iloprost suggest that these drugs may be less effective in this group of patients than in primary pulmonary hypertension. Thus, the novel prostaglandins must be studied more extensively in patients with the scleroderma spectrum of disease. The same is true for the other forms of pulmonary arterial hypertension, especially those associated with congenital heart disease and porto–pulmonary hypertension and for which open label studies with intravenous prostacyclin have shown beneficial effects, but for which the novel prostaglandins and endothelin antagonists have not been sufficiently investigated.

FUTURE PERSPECTIVES

It is likely that we will soon witness a major step forward in the treatment of pulmonary arterial hypertension. Comparative studies will be addressing safety profiles and efficacy of the different prostaglandins. The development of newer prostacyclin analogs with greater stability and longer half-lives may improve the therapeutic potential of prostaglandins, especially those administered via the oral or inhaled route (98). With the introduction of endothelin receptor antagonists and phosphodiesterase inhibitors, alternatives to prostaglandins are emerging. However, it is likely that prostacyclin derivatives will keep a central role in the treatment of patients with pulmonary hypertension. Phosphodiesterase inhibitors may be of value in patients with less advanced disease or may be used to augment the efficacy of prostaglandins (72, 73, 82, 85, 99). Endothelin receptor antagonists may be used as first-line therapy of pulmonary arterial hypertension but may also be even more effective in conjunction with prostaglandins. Studies are now addressing the combined efficacy and safety of the dual endothelin receptor antagonist bosentan and intravenous prostacyclin. On the basis of pathophysiologic considerations, both prostaglandins and endothelin receptor antagonists may have beneficial effects, less as pulmonary vasodilators than by affecting pulmonary vascular remodeling.

The advances in our understanding of the pathogenesis of pulmonary arterial hypertension will eventually lead to the development of novel approaches focusing directly on the abnormal proliferation of vascular endothelial and smooth muscle cells (100, 101). Cowan and coworkers have demonstrated that regression of established pulmonary vascular remodeling may become a realistic therapeutic goal (102–104). Although it is unclear how the new information about mutations affecting BMPR-II will affect future treatment of pulmonary hypertension, it is likely that gene therapy will eventually play an important role in halting and potentially reversing pulmonary vascular remodeling (105, 106).

Received in original form October 12, 2001; accepted in final form February 22, 2002

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