Emerging medical therapies for pulmonary arterial hypertension

Emerging Medical Therapies for Pulmonary Arterial Hypertension Nazzareno Galie`, Alessandra Manes, and Angelo Branzi

Until a few years ago, “conventional” treatment for pulmonary arterial hypertension (PAH) included oral anticoagulants, calcium channel blockers, diuretics, digoxin, and oxygen. In the 1990s, 3 randomized studies demonstrated that the continuous intravenous infusion of epoprostenol improved functional capacity, cardiopulmonary hemodynamics, and survival in patients with severe PAH. Recently, the thromboxane inhibitor terbogrel, the prostacyclin analogues treprostinil, beraprost, and iloprost, and the endothelin receptor antagonist bosentan have been tested in clinical trials in more than 1,100 patients. Except for terbogrel, all compounds have improved by different degrees the mean exercise capacity as assessed by 6 minutes walking distance. Conversely, these trials differ for the severity and etiology of included PAH patients as well as for the effects on combined clinical events, on quality of life, and on hemodynamics. No trials have shown effects on mortality, and each new compound presents different side effects that seem unpredictable in the individual patient. At present, additional new compounds such as sitaxentan, ambisentan, L-arginine, and sildenafil are studied in clinical trials. The new therapeutic options are currently in different phases of approval by regulatory agencies, and when they will become available we will have the opportunity to select the most appropriate treatment for the single patient, according to an individualized benefit-to-risk ratio. Copyright 2002, Elsevier Science (USA). All rights reserved.

P

ulmonary arterial hypertension (PAH) is defined according to the 1998 World Health Organization Classification1 as a group of diseases characterized by virtually identical obstructive pathologic changes of the pulmonary microcirculation2 and by a favorable response to the long-term administration of prostacyclin.3,4 PAH includes primary pulmonary hypertension

(PPH)5 and pulmonary hypertension associated with various conditions such as collagen vascular diseases,6 congenital systemic-to-pulmonary shunts,7 portal hypertension,8 and human immunodeficiency virus (HIV) infection.9 All these conditions share comparable clinical pictures, and the outcome is usually related to a progressive increase of pulmonary vascular resistance leading to right ventricular failure and death.5,10 Until recently, the only treatment for PAH was symptomatic and based on empiric experience and uncontrolled trials.11 “Conventional” treatment included oral anticoagulants, calcium channel blockers (in the minority of patients who respond to acute or vasoreactivity test, ie, 20% of cases, depending on the definition of response), diuretics, digoxin, and oxygen. In the 1990s, 3 randomized studies12-14 provided a rational basis for treating PAH by demonstrating that the continuous intravenous infusion of epoprostenol (synthetic salt of prostacyclin), a vasodilator and antiproliferative agent, improved functional capacity, cardiopulmonary hemodynamics, and survival in patients in New York Heart Association (NYHA) functional classes III and IV with PPH or PAH associated with scleroderma (Table 1). Since then, intravenous epoprostenol has become the reference treatment for advanced PAH, either as a bridge to transplantation or as an alternative treat-

From the Institute of Cardiology, University of Bologna, Italy. Address reprint requests to Dr. Nazzareno Galie`, Istituto di Cardiologia, Universita` di Bologna, via Massarenti, 9, 40138-Bologna, Italy. Copyright 2002, Elsevier Science (USA). All rights reserved. 0033-0620/02/4503-0001$35.00/22/1/130160 doi:10.1053/pcad.2002.130160

Progress in Cardiovascular Diseases, Vol. 45, No. 3, (November/December) 2002: pp 213-224

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TABLE 1. Controlled Clinical Trials with Epoprostenol in Patients with Pulmonary Arterial Hypertension Trial Patients, n Drug NYHA functional class Etiology 6-min walk distance (mean), m Treatment effect 6-min walk distance mean change (m) Overall population Primary pulmonary Hypertension Hemodynamic parameters Clinical events

Epoprostenol PPH

Epoprostenol PPH

Epoprostenol Scleroderma

23 Epoprostenol III-IV PPH 226

81 Epoprostenol III-IV PPH 293

111 Epoprostenol III-IV CTD 255

45 45

47 47

94

Improved Reduced

Improved Reduced

Improved No-change

—

Abbreviations: CTD, connective tissue disease (scleroderma); PPH, primary pulmonary hypertension.

ment. Two recent reports have confirmed the efficacy of this form of therapy in long-term studies on large patient populations.15,16 However, the treatment requires permanent intravenous catheters and portable infusion pumps; it is associated with potentially life-threatening complications and a range of troublesome side effects. For all these reasons, effective alternatives to intravenous epoprostenol are required, and recently, we have faced an extraordinary

effort of the scientific community that has led for the first time to the completion of 6 blinded controlled clinical trials (Table 2) enrolling more than 1,100 patients. The new compounds that have been tested in these studies are the thromboxane inhibitor terbogrel,17 the prostacyclin analogues treprostinil (subcutaneous),18 beraprost (oral),19 and iloprost (inhaled),20 and the endothelin receptor antagonist bosentan.21,22

TABLE 2. Controlled Clinical Trials with New Compounds in Patients with Pulmonary Arterial Hypertension BosentanPilot

BREATHE-1

ALPHABET

AIR

33 Bosentan Oral III PPH, CTD

213 Bosentan Oral III-IV PPH, CTD

358

335

130 Beraprost Oral II-III PPH, CHD, CTD, HIV, PPH 372

203 Iloprost Inhaled III-IV PPH, CTD, CTEPH 324

16* 19*

76 76

44 52

25 45

35 57

Improved Reduced

Improved Reduced

Improved** Reduced

No change No change

Improved*** Reduced

Trial

Terbogrel

Treprostinil

Patients, n Drug Route of administration NYHA functional class Etiology

71 Terbogrel Oral II-III PPH

6-min walk distance (mean), m Treatment effect 6-min walk distance mean change (m) Overall population Primary Pulmonary Hypertension Hemodynamic parameters Clinical events

393

469 Treprostinil Subcutaneous II-IV PPH, CHD, CTD 327

0 0 No change Increased

Abbreviations: CHD, congenital heart disease (congenital systemic to pulmonary shunts); CTD, connective tissue disease (the majority of CTD were due to scleroderma); CTEPH, chronic thromboembolic pulmonary hypertension; PPH, primary pulmonary hypertension; HIV, human immunodeficiency virus; P-PH, porto-pulmonary hypertension. *Median change; **improvement in Doppler derived cardiac index and other echocardiographic parameters; ***only pulmonary vascular resistance improved in pre-inhalation period and a more consistent improvement of other parameters is observed in post-inhalation period.

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215

Fig 1. Endothelial dysfunction and its pharmacologic correction in pulmonary arterial hypertension. Arach A, archidonic acid; cAMP, cyclic adenosine monophosphate; cGMP, cyclic guanosine monophosphate; EC, endothelial cell; ET, endothelin; NO, nitric oxide; PDE, phosphodyesterase; PGI2, prostacyclin; S, synthase; SMC, smooth muscle cell; TxA2, thromboxane A2. 2 and 1 denote pathobiological changes typical of pulmonary arterial hypertension. Boxes and arrows denote substances, sites, and modality of therapeutic interventions.

Endothelial Dysfunction in PAH and Rationale for the New Treatments Pulmonary endothelial cells are clearly involved in the pathobiological mechanisms in patients with PAH. Physiologic vascular tone and function are regulated by multiple interactions including those between endothelial cells and smooth muscle cells of the vessel wall (Fig 1). The endothelial cells modulate vascular smooth muscle cell activity by producing vasodilators/antimitotics, such as prostacyclin and nitric oxide and vasoconstrictors/mitogens, such as thromboxane A2 and endothelin-1.

Thromboxane A2 and Prostacyclin Pathway Thromboxane A2 and prostacyclin are both produced in the arachidonic acid cascade of vascular endothelial cells. Thromboxane A2, besides

vasoconstriction and proliferative activities (Fig 1A), is also a potent stimulus for platelet aggregation. An increase of 24-hour excretion of a thromboxane A2 metabolite (and reduced excretion of a prostacyclin metabolite) has been demonstrated in PAH patients.23 These findings represent the rationale for the use of drugs such as terbogrel that can inhibit thromboxane production and increase prostacyclin levels (Fig 1A). Prostacyclin is an endogenous substance produced by vascular endothelium that has vasodilating antiplatelet aggregation and antiproliferative effects.24 The rationale for the administration of prostacyclin in PAH patients is based on the demonstration of several changes of its metabolic pathways in patients and in experimental models of pulmonary hypertension.25 In fact, a reduction of epoprostenol (PGI2) urinary metabolites has been shown in patients with PPH.23 Moreover,

216 PGI2-synthase expression is reduced in pulmonary arteries of patients with pulmonary arterial hypertension.26 Endothelial cells cultured from pulmonary arteries of calves with hypoxia-induced pulmonary hypertension produce a reduced amount of PGI2.25 Prostacyclin has a short half-life in the circulation (3 to 5 minutes), and it is rapidly converted to stable breakdown products or metabolites, and this explains why prostacyclin needs to be administered by a continuous intravenous route by means of infusion pumps. Therapy with continuous intravenous epoprostenol (synthetic salt of prostacyclin) has been shown to improve symptoms and prognosis in NYHA functional class III and IV patients with different types of PAH.15,16,27-32 However, PGI2 is instable at room temperature, requires permanent intravenous catheters and portable pumps, and is associated with several side effects and potentially serious complications. For these reasons, alternatives to intravenous prostacyclin have been sought, and this has led to analogues, which can be administered subcutaneously (treprostinil), orally (beraprost sodium), or by inhalation (iloprost).11

Nitric Oxide Pathway Nitric oxide is a simple molecule that acts as an important regulator of vascular tone and is produced by endothelial cells. It is generated by the conversion of L-arginine to L-citrulline under the influence of nitric oxide synthase (Fig 1B). Once produced, nitric oxide diffuses from endothelial cells to smooth muscle cells, which it induces to relax by activating guanylate cyclase, which in turn promotes the production of cyclic guanosine monophosphate (cGMP). Nitric oxide also inhibits the growth of smooth muscle cells. Endothelial nitric oxide synthase (NOS) expression is reduced in the pulmonary circulation of patients with PPH,33 but lung nitric oxide production, which may or may not reflect pulmonary vascular nitric oxide production, is enhanced34 or preserved.35 In addition, PPH patients have higher urinary cGMP concentrations than control subjects36 testifying to a possible increase in nitric oxide synthesis. The acute administration of nitric oxide to PAH patients37 reduced pulmonary arterial pressure (PAP), whereas chronic administration has been reported to give favorable results, albeit in a small

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series.38 Nitric oxide production rates can also be increased by administering supplements of the NOS substrate, L-arginine.39 Increases of cyclic guanosine monophosphate (cGMP), the final mediator of the nitric oxide pathway (Fig 1), can be achieved also by the administration of sildenafil, an orally active, potent, and selective inhibitor of cGMP specific phosphodiesterase type 5 (PDE-5), which is the predominant PDE isoenzyme in human corpora cavernosa and in the pulmonary vasculature.

Endothelin-1 Pathway Increased plasma levels of endothelin-1, a vasoconstrictor and mitogen polypeptide produced by the endothelial cells (Fig 1C), have been reported in both experimental animal models and human PAH.40,41 It is not clear whether the overexpression of endothelin-1 is a marker or a mediator of PAH; in patients with PPH, endothelin-1 plasma levels are inversely related to cardiac output and directly related to right atrial pressure and pulmonary vascular resistance.41 In addition, elevated plasma levels of endothelin-1 in the same group identify a subset of patients with the worst prognosis.42 Moreover, an elevated grade of endothelin-1 like immunoreactivity has been identified in almost all sections of the pulmonary vascular bed including plexiform lesions, suggesting that the local production of endothelin-1 may contribute to the pathogenesis of PPH.43 All of these changes represent a strong rationale for attempting to antagonize the effects of endothelin-1. The direct blockade of endothelin-1 receptors represents the most efficacious mechanism to antagonize the system, and it has been achieved by peptide and nonpeptide drugs.44 Two pharmacologically and molecularly distinct endothelin receptors subtypes have been identified: ETA and ETB. Both receptors are abundant in vascular smooth muscle cells, and their stimulation produces vasoconstriction and proliferation. ETB receptors are predominant in vascular endothelial cells where their stimulation favors endothelin-1 clearance and induces the production of nitric oxide and prostacyclin. This last physiologic negative feedback mechanism is aimed to protect against excessive activation of the endothelin system. Endothelin-1 receptor antagonists pre-

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vent and reverse pathologic and hemodynamic changes in both experimental models of hypoxiaand monocrotaline-induced pulmonary hypertension.45 The favorable effects observed in experimental models have led to clinical trials in patients with PAH. Currently the results of 2 randomized clinical trials with the orally active dual endothelin-1 (ETA and ETB) receptor antagonist bosentan in PAH are available.

Controlled Clinical Trials With New Compounds Terbogrel Terbogrel is an orally active thromboxane receptor antagonist and thromboxane synthetase inhibitor in normal humans. In addition, by inhibiting thromboxane synthesis, it appears to shift the common precursor endoperoxide substrates for the formation of both thromboxane and prostacyclin toward prostacyclin synthesis. The effects of terbogrel were studied in a multicenter, randomized, placebo-controlled, 12week study in NYHA class II and III PPH patients17 (Table 2). The study was halted after only 71 patients had been randomized (planned enrollment was 135 patients) owing to the unforeseen side effect of leg pain, which occurred almost exclusively in terbogrel-treated patients. Leg pain resolved after drug discontinuation without any apparent residual damage, and its pathogenesis is unknown. In addition, several investigators reported that terbogrel administration caused an increase in the International Normalized Ratio (INR) despite reduced dose levels of warfarin. Only 52 patients completed the 12-week study, and only 22 patients (31%) were fully compliant with the study medication. By an intention-totreat analysis, there was no improvement in 6-minute walk distance (the leg pain confounded this primary endpoint) or in hemodynamics in terbogrel-treated patients. However, terbogrel was effective from a pharmacological standpoint, reducing thromboxane metabolites by up to 98% (P ⬍ .0001), with a modest but statistically insignificant (39%) increase in prostacyclin metabolites. A possible explanation of these data is that the plasma levels of prostacyclin that are effective

in PAH are likely much more elevated that those physiologically detected in normal individuals.

Treprostinil Treprostinil is a tricyclic benzidene analogue of epoprostenol, with sufficient chemical stability to be administered at ambient temperature in a physiologic solution. These characteristics allow the administration of the compound by intravenous as well as the subcutaneous route. Micro-infusion pumps and small subcutaneous catheters similar to those used for the administration of insulin in diabetic patients are used for the latter modality of administration. The subcutaneous route avoids all the problems related to a permanent central venous line such as infections, and the management of the system is much simpler for the patients. In a preliminary acute study on 12 subjects with severe congestive heart failure, intravenous treprostinil induced hemodynamic changes very similar to those of epoprostenol.46 The acute effect of subcutaneous treprostinil was compared with intravenous treprostinil in 25 patients with PPH, and a comparable reduction of pulmonary vascular resistance of about 20% was observed with both modalities of administration.47 The apparent half-life of the compound was 27 minutes when administered intravenously and 58 to 83 minutes when administered subcutaneously. A pilot randomized study on the chronic administration of treprostinil compared with placebo was completed in 26 patients with PPH, and after 8 weeks, a reduction of pulmonary vascular resistance and an increase of functional capacity as assessed by the 6-minute walk test were shown in the treated group.48 The efficacy of treprostinil in PAH patients has been tested in 2 randomized studies of which results have been combined and analyzed together (Table 2): 470 patients with NYHA class II, III, and IV PPH and PAH associated with congenital heart disease and connective tissue diseases have been enrolled in two 12-week controlled clinical trials.18 The treatment effect (between treatment group difference) in median 6-minute walking distance was 16 m (P ⫽ .006). Disease etiology did not show significant interaction with the change in exercise capacity. Conversely, the highest exercise

218 improvement was observed in patients who were more compromised at baseline and in subjects who could tolerate upper quartile dose (increase of 36.1 ⫾ 10 m from baseline in patients with dose ⬎ 13.8 ng/kg/min). Improvements were observed also in clinical scores, Borg dyspnea index, and physical dimension score of “Minnesota Living with Heart Failure Questionnaire” of quality of life. Cardiopulmonary hemodynamic parameters including right atrial pressure, mean pulmonary artery pressure, and cardiac index also improved. Event-free (death and hospitalization) survival occurred in 94% of treprostinil versus 88% of placebo patients (P ⫽ .05, unpublished data). Infusion site pain was the most common side effect of treprostinil leading to discontinuation of the treatment in 8% of cases and limiting progressive dose increases in an additional proportion of patients. Overall, mortality was 3% and no difference was present among treatment groups. Treprostinil has been recently approved by the Food and Drug Administration in the United States for NYHA classes II, III, and IV PAH. In Europe, an approval by the French Health Authority is pending.

Beraprost Beraprost sodium is the first chemically stable and orally active prostacyclin analogue.49 It is absorbed rapidly in the fasting condition; peak concentration is reached after 30 minutes; and elimination half-life is 35 to 40 minutes after single oral administration. When administered at the beginning of a meal, peak concentration is smaller, and half-life is prolonged. Bioavailability is 50% to 70%. In experimental studies, beraprost sodium has been shown to exert a protective effect on the development of monocrotaline-induced pulmonary hypertension.50 Uncontrolled and retrospective experiences in patients with PPH have preliminarily shown that long-term oral treatment with beraprost sodium improves hemodynamics51 and may prolong survival.52 The first randomized, placebo-controlled study on beraprost in PAH has been performed in 13 centers in 6 European countries (ALPHABET ⫽ ArteriaL Pulmonary Hypertension And Beraprost European Trial)19 (Table 2). In this 12-week trial,

GALIE`, MANES, AND BRANZI

130 NYHA class II and III PAH patients with different etiologies were enrolled including PPH, and PAH associated with connective tissue diseases, HIV infection, portal hypertension, and congenital systemic-to-pulmonary shunts. Beraprost was administered orally 4 times a day at the highest tolerated dose, and the treatment effect in mean 6-minute walking distance was 25 m. Borg dyspnea index was also improved. In this trial, no interaction was detected between baseline functional class and exercise improvement while a different result was shown according to etiology. In fact, the treatment effect in patients with PPH was 45 m, whereas no significant changes were observed in the exercise capacity of subjects with the associated conditions. It is not clear whether this finding was linked to the tolerated doses of beraprost sodium that were substantially lower in patients with PAH associated with specific disease entities forms as compared with PPH for unknown reasons. Conversely, post-hoc analysis showed that exercise capacity, was increased mainly in patients who could tolerate a dose higher than 80 g 4 times daily (unpublished data). Interestingly, exercise capacity of placebotreated patients with PPH decreased after 12 weeks, while in PAH associated conditions remained unchanged. The beraprost-treated patients demonstrated trends that were not statistically significant toward the improvement of cardiopulmonary hemodynamics. Side effects linked to systemic vasodilatation were frequent in the initial titration period and were reduced in the maintenance phase. Overall mortality was 1.5%, and no difference was detected among treatment groups. No differences were detected regarding rates of hospitalization. A second randomized study has been interrupted prematurely in the United States for administrative reasons after the enrollment of more than 100 patients. In this trial, predominantly NYHA class II subjects were included and preliminary reports show no statistical difference between treated and placebo groups on exercise capacity as assessed by peak oxygen consumption Beraprost is approved in Japan for PAH patients, and an approval process is pending by the French Health Authority and the European Agency (EMEA).

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PULMONARY ARTERIAL HYPERTENSION

Iloprost Iloprost is a chemically stable prostacyclin analogue available for intravenous, oral, and inhaled administration. Continuous intravenous administration of iloprost appears to be as effective as epoprostenol in patients with PAH,53,54 even if the experience with iloprost is more limited. Intermittent intravenous administration of iloprost has been attempted in cases with PAH associated to connective tissue diseases, but only the results of single cases have been reported.55 The preliminary results on the effects of the acute administration of iloprost by inhalation in patients with PAH have been reported by Olschewski et al56: After a single inhalation of iloprost, a reduction of 10% to 20% of mean pulmonary artery pressure was observed, which lasted for 60 to 120 minutes. The acute administration of inhaled iloprost seems to be superior to the inhalation of 40 ppm of nitric oxide in reducing pulmonary vascular resistance in PPH patients.37 The short duration of action of inhaled iloprost requires frequent inhalations (from 6 to 12 times daily) to obtain a persistent effect in long-term treatments. Several uncontrolled studies have shown that inhaled iloprost exerts long-term hemodynamic, clinical, and exercise improvements in PAH patients.57,58 In addition, in a particular group of patients with pulmonary hypertension and lung fibrosis, the acute administration of inhaled iloprost caused marked pulmonary vasodilatation with maintenance of gas exchange and systemic arterial pressure59 showing a possible usefulness in this subset. The first randomized, placebo-controlled study on inhaled iloprost in PAH (AIR study: Aerosolized Iloprost Randomized study) has been performed in 37 centers in 8 European countries (Table 2): 204 NYHA class III and IV PAH patients20 were enrolled in a 12-week trial. Subjects with PPH, PAH associated with connective tissue disease, and inoperable chronic thromboembolic pulmonary hypertension were included. Daily repetitive iloprost inhalations (6 to 9 times 2.5 to 5 ␮g/day) were compared with placebo inhalation; the primary endpoint was a combination of an improvement in NYHA functional class and a ⬎10% improvement in a 6-minute walk at week 12 in the absence of any deterioration. The com-

bined clinical endpoint was met by 16.8% of iloprost versus 4.9% of placebo patients (P ⫽ .007) without inhomogeneity over subgroups. The treatment effect on the 6-minute walking distance was 36.4 m in favor of iloprost for all patients (P ⬍ .01) and 57 m for PPH. Premature termination of the study, mostly due to deterioration, occurred in 4.0% of iloprost (including 1 death) versus 13.7% of placebo patients (including 4 deaths) (P ⫽ .024). Overall, mortality was 2.5%. Hemodynamics deteriorated in placebo patients, while pulmonary vascular resistance improved iloprost-treated subjects in pre-inhalation conditions. The acute inhalation induced a significant improvement of pulmonary artery pressure and cardiac output that lasted for about 60 minutes. Further significant treatment effects included improvements in NYHA class (P ⫽ .032), in Mahler Dyspnea Transition Index (P ⫽ .015), and in EuroQol Visual Analogue Scale (P ⫽ .016). Adverse events reported more frequently for iloprost were flushing of the skin, jaw pain (transient and mild), and syncope that was more frequently rated serious but not associated with clinical deterioration. Iloprost-inhaled treatment is available by private insurances reimbursement in Germany, Austria, and Switzerland and an approval process in pending by the European agency (EMEA).

Bosentan The orally active dual ET-1 (ETA and ETB) receptor antagonist bosentan has been tested in 2 double-blind, placebo-controlled studies in patients with PPH or PAH associated with connective tissue diseases (Table 2). In the first pilot study, 33 NYHA class III patients were randomized 2:1 to receive either 125 mg twice daily of bosentan or placebo.21 After 12 weeks, a treatment effect of 76 m in favor of bosentan was observed in 6-minute walking distance and the difference was maintained after 20 weeks. An improvement of right atrial pressure, cardiac index, mean pulmonary artery pressure, and pulmonary vascular resistance was also assessed. Clinical endpoints such as Borg dyspnea index, NYHA functional class, and clinical worsening also improved in actively treated patients. Increases in plasma levels of aminotransferases were seen in 2 patients as-

220 signed to bosentan, but the levels returned to normal without discontinuation or change of dose. In the larger BREATHE-1 (Bosentan Randomized trial of Endothelin Antagonist Therapy for PAH) study, 213 NYHA class III and IV patients were randomized 1:1:1 to receive placebo or 62.5 mg of bosentan twice daily for 4 weeks followed by either bosentan 125 mg or 250 mg twice daily for a minimum of 12 weeks.22 At week 16, patients treated with bosentan improved their 6-minute walking distance; the mean difference between the placebo and bosentan groups was 44 m (95% CI, 21 to 67 m, P ⬍ .001). Although both bosentan dosages induced a significant treatment effect, the placebo-corrected improvement was more pronounced for the 250-mg twice daily than for the 125-mg twice daily dosage (⫹54 m and ⫹35 m, respectively). However, no dose response for efficacy could be ascertained. Although a similar treatment effect was achieved in patients with PPH and in those with PAH associated with scleroderma, bosentan improved the walking distance from baseline in the PPH patients (⫹46 m in the bosentan group versus ⫺5 m in the placebo group) whereas it prevented walk distance deterioration of the scleroderma patients (⫹3 m in the bosentan group versus ⫺40 m in the placebo group). Bosentan also improved the Borg dyspnea index and WHO functional class and above all increased the time to clinical worsening. Abnormal hepatic function was found to be dose dependent. Increases in hepatic aminotransferases 8 times the upper limit of normal occurred in 2 patients (2.6%) in the 125 mg twice daily group and 5 (7.1%) in the 250 mg twice daily group. Overall, mortality was 2.8% and no difference among groups was detected. An echocardiographic substudy was performed in 85 patients enrolled in 13 centers. Several echocardiographic and Doppler parameters related to PAH were improved in bosentan-treated patients including Doppler-derived cardiac index (⫹ 0.4 L/min/m2, P ⫽ .007), Tei index, right and left ventricular dimensions, and pericardial effusion score.60 In the open label extension of the bosentan studies, more than 150 adult patients have received the drug for at least 12 months maintaining the favorable results, and 1-year mortality was about 10%. An open-label, uncontrolled single- and multiple-dose study has been performed in children 4 to 17 years of

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age with PAH (BREATHE-3) to assess pharmacokinetics, tolerability, and safety of bosentan. A significant improvement of hemodynamics was observed after 12 weeks of treatment in the 18 enrolled children either with bosentan alone or in combination with epoprostenol.61 Bosentan has been approved for the treatment of NYHA class III and IV PAH patients in the United States, Canada, and Switzerland and preliminary approval has been granted also by the European Agency (EMEA).

Selective ET-1 Receptor Antagonists, L-Arginine and Sildenafil A clinical trial on the ETA selective endothelinreceptor antagonist sitaxsentan62 has been performed on 180 PAH patients in the USA, and preliminary results will be available in Autumn 2002. Another study on the ETA selective endothelinreceptor antagonist ambisentan (BSF208075)63 will start soon in the United States and Europe, including also patients with PAH associated with HIV infection. As nitric oxide is synthesized from the amino acid L-arginine by NOS,39 supplementation of Larginine may have beneficial effects in pulmonary hypertension. In a study in patients with pulmonary hypertension, intravenous administration of L-arginine has been shown to decrease pulmonary vascular resistance by increasing the endogenous production of nitric oxide.64 In addition, in a placebo-controlled study, it has been shown that 1-week supplementation of oral L-arginine to patients with pulmonary arterial hypertension resulted in a beneficial effect on hemodynamics and exercise capacity.65 A clinical trial on the effects of the oral supplementation of L-arginine in 120 PAH patients (PHAST) is currently ongoing in 15 centers worldwide. Sildenafil is an orally active, potent, and selective inhibitor of cyclic guanosine monophosphate (cGMP) specific phosphodiesterase type 5 (PDE5), which is the predominant PDE isoenzyme in human corpora cavernosa. PDE-5 is selectively abundant in the pulmonary vasculature compared with systemic vessels, and in experimental models of pulmonary hypertension, sildenafil is able to reduce pulmonary artery pressure.66 Many uncontrolled experiences have recently been re-

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ported on the favorable effects of sildenafil in PAH.67,68 At the time of writing, a clinical trial on the effects of sildenafil in PAH patients is starting and will enroll 220 patients worldwide.

Treatments, Transition, and Combination The availability of various therapies has made possible the concepts of “transition” from a treatment to a different one and of “combination” of diverse drugs. Preliminary reports have shown the possibility to transition patients from epoprostenol to treprostinil.69 Obviously, those attempts should be performed only in experienced centers. Other investigators have reported still unpublished data on the transition of adult patients from intravenous epoprostenol to bosentan. A study on the combination of epoprostenol and bosentan (BREATHE-2) has been performed in 33 PAH patients. Preliminary results show that the combination of bosentan with initiation of epoprostenol may provide additional benefits compared with initiation of epoprostenol alone in patients with severe PAH. Favorable effects have been reported recently with the combination of inhaled iloprost and oral sildenafil.70 Many other transitions and combinations will be possible with the increase of available treatments, and it would be advisable to collect such experiences in registries to verify effects and to develop specific protocols.

Conclusions The trials with new compounds have produced a tremendous increase of both knowledge and therapeutic options in patients with PAH. In fact, the analysis of placebo-treated groups in the various trials has allowed a better understanding of the natural history of PAH: A slow deterioration was detectable as early as after 12 weeks in a proportion of patients. Except for the terbogrel study, all compounds have improved by different degrees the mean exercise capacity as assessed by 6 minutes walking distance. Conversely, in the evaluation of the clinical relevance of exercise capacity improvements, additional elements need to be considered such as baseline functional class and concomitant favorable effects on combined clini-

cal events (including hospitalizations, mortality, rescue therapies), on quality of life, and on hemodynamics. The lack of effect on mortality can be explained by the study protocols that were not designed for assessing this specific end point. Each new compound presents side effects that are unpredictable in the individual patients and require an appropriate attention on treatment initiation and maintenance. The availability of these new therapeutic options are of extreme importance to adapt the most appropriate treatment to a given patient according to an individualized benefit-to-risk ratio. Nevertheless, additional longterm experience needs to be collected to fully understand the real impact of new treatments in day to day patient management. In this complex process of decision making, the role of expert pulmonary hypertension centers is determinant to optimize the therapeutic strategy in each case. We have not yet found the cure for PAH as available medical treatments still fail in a substantial proportion of patients and additional compounds need to be actively investigated.

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