Formulary implications of management of pulmonary arterial hypertension: part I--an overview of existing and new pharmacological treatment options.

Pulmonary arterial hypertension (PAH) represents a significant challenge to physicians, particularly because of its etiology and nonspecific presentation. Unfortunately, the majority of patients are not diagnosed until the condition is at an advanced stage. In this two-part White Paper from The Pharmacy and Therapeutics Society, prostanoids, administered as continuous intravenous or subcutaneous infusions, are the most effective treatments but are inconvenient and costly, owing to complex parenteral administration. The endothelin-receptor antagonist bosentan and the phosphodiesterase-5 inhibitor sildenafil are currently the only oral therapies licensed for PAH; however, bosentan has an identified risk of liver toxicity. Newer PAH treatments may offer benefits over existing therapies in terms of less potential for liver damage and more favorable interaction profiles.

**********

Pulmonary hypertension is a generic term for a group of conditions characterized by elevated pulmonary arterial pressure. Of these conditions, pulmonary arterial hypertension (PAH), which is defined as a mean pulmonary arterial pressure of greater than 25 mm Hg at rest or greater than 30 mm Hg during exercise in conjunction with normal pulmonary capillary wedge pressure (PCWP), is the most complex and challenging to manage. (1,2)

PULMONARY ARTERIAL HYPERTENSION

Clinical Presentation and Classification. The clinical characteristics of PAH include persistently elevated pulmonary arterial pressure, in combination with normal PCWP and increased pulmonary vascular resistance. As the condition progresses, cardiac output drops and right ventricular hypertrophy and dilation occur that ultimately lead to right heart failure. (2) In the early stages of the condition, the patient experiences symptoms during exercise, but as the right ventricle begins to fail, symptoms will appear with less exertion.

A National Institutes of Health (NIH) national registry for primary pulmonary hypertension was established in the 1980s, before effective medical treatments were available. (3) A prospective follow-up of 32 centers between 1981 and 1988 showed that the median survival of patients with untreated primary pulmonary hypertension was 2.8 years from diagnosis. (3) The estimated yearly survival rates were 68% at one year, 48% at three years, and 34% at five years. (3) Poor survival rates were closely correlated with advanced World Health Organization (WHO) class, marked elevated pulmonary artery pressure and right atrial pressure, and cardiac index (Figure 1). (3)

[FIGURE 1 OMITTED]

The current classification of pulmonary hypertension was first established at a WHO meeting in Evian, France, in 1988 and was subsequently refined in Venice in 2003. This classification divides pulmonary hypertension into five broad categories (Table I). (4)

Despite the widely disseminated WHO classification of pulmonary hypertension, references to the older classification system of "primary" and "secondary" pulmonary hypertension are still observed in the literature. Under this classification, primary pulmonary hypertension refers to idiopathic or unexplained pulmonary hypertension, whereas secondary pulmonary hypertension refers to conditions where elevated pulmonary pressure has emerged as a complication of, for example, connective tissue disease (CTD), human immunodeficiency virus (HIV) infection, or exposure to drugs. (4)

In addition to the etiological classification, WHO established a classification system for the functional status of patients with pulmonary hypertension (Table II). This system was borrowed from the congestive heart failure classification system often referred to as the New York Heart Association class system, and forms the basis for assessment of the severity of PAH. (5)

Epidemiology. Epidemiological studies in this setting tend to consider pulmonary hypertension as a whole, with little data specifically on PAH. Older studies have estimated the incidence of idiopathic pulmonary hypertension to be one to two cases per million, with autopsy studies showing a prevalence of 1,300 per million. (6)

A summary of national mortality and hospitalization data from 1980 to 2002 showed that the total number of deaths attributed to pulmonary hypertension increased from 10,922 to 15,668 and that this increase was observed only in women. (7) The number of hospitalizations associated with pulmonary hypertension tripled overall, equivalent to a doubling of the rate in men and a quadrupling of that in women. Among Medicare enrollees aged 65 years and over, the age-standardized hospitalization rate increased from 197.8 in 1990 to 649.7 in 2002. (7)

A survey based on interviews with leading experts in the area conducted in 2003 estimated the total prevalence of PAH in the United States to be 55,500 patients. In the same study, the incidence was estimated to be 0.2% per year, which forecasts a total of 56,100 patients in this country by 2008. (8)

Diagnosis. Early PAH is often asymptomatic, and the majority of patients with PAH are diagnosed with stage III or IV disease (Table II). The mean time from onset of symptoms to diagnosis is three years. (3)

Evaluating patients with suspected PAH requires comprehensive evaluation aimed at identifying co-morbid diseases that may contribute to or cause PAH. For most patients, PAH is eventually considered based on echocardiographic findings of elevated estimated pulmonary artery pressures. Less commonly, an electrocardiogram (ECG) or chest x-ray may suggest the diagnosis. Confirmation of a PAH diagnosis requires invasive measurement of pulmonary arterial pressures with right-heart catheterization (RHC), ideally performed by a physician familiar with PAH. (2) Right-heart catheterization allows pressures and cardiac output to be accurately measured, and pulmonary vascular resistance to be calculated. Vasodilator testing is also performed during RHC.

Increasingly, patients with left ventricular diastolic dysfunction (LVDD) are being referred to pulmonary hypertension centers for evaluation of abnormal echocardiography suggesting pulmonary hypertension. By performing careful measurements of PCWP at rest and with exercise, LVDD is easily identified.

PHARMACOLOGICAL MANAGEMENT OF PULMONARY ARTERIAL HYPERTENSION

Studies of the molecular mechanism involved in PAH have identified three molecular pathways as targets for pharmacological treatment of the condition: the (1) prostacyclin, (2) endothelin (ET), and (3) nitric oxide (NO) pathways (Figure 2). (9) Food and Drug Administration (FDA)--approved therapies are available in all three groups, either for intravenous or subcutaneous infusion or inhalation (prostanoid therapies) or as oral agents (endothelin-receptor antagonists and phosphodiesterase type-5 [PDE-5] inhibitors). Analogues of greater potency and/or selectivity are in clinical development. In addition, the three pathways are interrelated, and recent clinical studies have provided evidence that combined therapy utilizing different pathways may further improve clinical efficacy. However, these combination therapy protocols have yet to be approved by the FDA. (10-13)

[FIGURE 2 OMITTED]

Prostacyclin Pathway. Impaired production of vasodilators, including prostacyclin, is thought to occur as a consequence of endothelial dysfunction in the early stages of PAH. (9) Prostacyclin exerts its vasodilatory effect through a cyclic adenosine monophosphate (cAMP)-dependent pathway (Figure 2). Additionally, prostacyclin blocks proliferation of vascular smooth cells and platelet aggregation.9 Pulmonary arterial hypertension is characterized by reduced expression of prostacyclin synthase, (14) which provides a rationale for prostanoid replacement therapy.

Prostanoid therapies currently licensed by the FDA include epoprostenol, for continuous intravenous infusion; treprostinil, for continuous subcutaneous and intravenous infusion; and iloprost, for inhalation. An oral form, beraprost, though available in Japan, is not available in the United States.

Endothelin Pathway. Recent clinical developments in PAH have focused on the endothelin pathway. Endothelin-1 (ET-1) was the first to be identified in a family of 21-amino acid peptides with potent vasoconstrictor and smooth-muscle mitogenic properties. (15) It is thought to play a critical part in the development and progression of PAH by modulating vasoconstriction and vascular smooth muscle cell proliferation, and ET-1 levels have been found to be increased in the lung and plasma of patients with PAH.16 In addition, elevated plasma levels of ET-1 have been shown to correlate with PAH severity. (17)

Two isoforms of the ET-1 receptor have been identified: (1) [ET.sub.A] and (2) [ET.sub.B]. The [ET.sub.A] receptors are expressed on pulmonary vascular smooth muscle cells, and activation promotes vasoconstriction and proliferation (Figure 2). (15) In normal lungs, [ET.sub.B] receptors are found predominantly on pulmonary vascular endothelial cells, and activation mediates vasodilation through increased production of prostacyclins and NO, and clearance of circulating ET-1. However, studies have suggested that [ET.sub.B] receptors are upregulated in PAH, and that [ET.sub.B] activation may mediate vasoconstriction through a population of [ET.sub.B] receptors located on vascular smooth muscle cells. (15)

A recent study in patients with PAH demonstrated that the elevated levels of ET-1 are predominantly caused by excess production rather than decreased clearance. Moreover, the clearance function of the [ET.sub.B] receptor is largely maintained, which may ultimately play a role in the choice of selective or nonselective agents. (18) A compound is generally considered selective if its affinity is greater than 100-fold for the [ET.sub.A]-receptor subtype. (19)

The only ET-1 receptor antagonist (ETRA) currently marketed in the United States, bosentan, is a nonselective [ET.sub.A]/[ET.sub.B]-receptor antagonist. Sitaxsentan, which may gain approval in 2006, and ambrisentan, currently in late phase 3 trials, are both more selective [ET.sub.A]-receptor antagonists. The orally administered ETRA class is thought to convey significant benefits in terms of dosing convenience and patient acceptance, relative to parenteral and inhaled prostanoids.

Nitric Oxide Pathway. In the lungs, NO is produced by NO synthases located in the vascular endothelium and airway epithelium, where it exerts a vasodilatory effect alongside prostacyclin and other endogenous vasodilators. (9) The pathway for this vasodilation is dependent on cyclic guanosine monophosphate (cGMP) (Figure 2). In PAH, NO synthase expression in the vascular endothelium is reduced. A recent innovative strategy for restoring NO-dependent vasodilation in PAH has been to block the breakdown of cGMP by inhibiting the action of PDE-5. (9) Based on this rationale, sildenafil has gained approval for the treatment of PAH. Tadalafil, a longer-acting PDE-5 inhibitor, is currently under study in phase 3 trials.

PROSTACYCLIN THERAPIES

Epoprostenol. Epoprostenol is the gold standard for the treatment of PAH, reflecting its long history of efficacy and important mortality benefit demonstrated in the original pivotal trials. (20,21) Owing to its very short half-life (approximately 6 min), epoprostenol requires administration through continuous intravenous infusion. The starting dose is usually quite low (1-2 ng/kg/min) and is then titrated up to a maintenance dose where the patient gains optimal clinical benefit with minimum side effects. (22)

Patients involved in early clinical trials with epoprostenol were included in the NIH registry. Although this was only a small population of 18 patients with idiopathic PAH, epoprostenol was associated with significantly improved survival rates: one-, two-, and three-year survival rates for patients in the epoprostenol population were 86.9%, 72.4%, and 63.3%, respectively, compared with 77.4%, 51.6%, and 40.6% for the NIH registry as a whole (hazard ratio 2.9 [95% confidence interval 1.0-8.0; P = .045]) (Figure 3). (20)

[FIGURE 3 OMITTED]

In 1996, Barst and colleagues (21) performed a randomized, controlled multicenter study in 81 patients with idiopathic PAH, WHO class III and IV, comparing epoprostenol plus conventional therapy, (including calcium-channel blockers and anticoagulants) with conventional therapy alone during a 12-week period. Patients receiving epoprostenol experienced a mean increase in exercise capacity of 31 m in the six-minute walk test, compared with a reduction of 29 m in patients receiving conventional therapy alone (P < .002 between groups).

In addition, epoprostenol was associated with significant improvements of hemodynamic variables compared with conventional therapy alone, including mean pulmonary-artery pressure (P < .002 between treatments) and pulmonary vascular resistance (P < .001 between treatments). Eight deaths occurred during the study; these were all in the conventional therapy-alone group.

Treprostinil. Treprostinil is a prostacyclin analogue of greater chemical stability than epoprostenol. Its longer half-life of three to four hours allows administration by way of continuous subcutaneous infusion. Subcutaneous delivery may offer a benefit over intravenous infusion, because it is associated with a lower risk of such complications as bacteremic line infections and disruptions owing to catheter displacement. (22)

A large randomized placebo-controlled study involving 469 patients with PAH of different etiologies (idiopathic PAH, CTD, and congenital heart disease) showed that treprostinil increased the mean six-minute walk distance by 16 m (P = .006 vs. placebo). (23) The increase was greater in patients with more severe illness and in patients who were able to tolerate a higher dose of treprostinil (> 13.8 ng/kg/ min), but it appeared to be independent of etiology. Patients in the treprostinil group also showed significant improvements in hemodynamic variables, including mean pulmonary artery pressure (P = .0003 vs. placebo), cardiac index, and pulmonary vascular resistance (P = .0001 vs. placebo on both). Seven patients in each group died during the study. A total of 85% of patients reported infusion site pain as an adverse event, and 8% discontinued treatment as a consequence. Overall, site pain remains an important barrier to broader acceptance by patients and PAH specialists.

Recent studies have shown that intravenous treprostinil produces sustained benefits in hemodynamics and walk distance, comparable with those found with epoprostenol. (24,25) Site pain does not appear to be a problem when treprostinil is administered intravenously.

Iloprost. Developed for inhaled therapy in PAH, iloprost has a half-life of approximately 25 minutes and is administered through ultrasonic nebulization six to nine times daily. (22) A 12-week randomized placebo-controlled study by Olschewski and colleagues (26) in patients with PAH of different etiologies showed significant benefits of iloprost on exercise capacity (36-m increase in 6-min walk distance) and post-administration hemodynamic variables. A 12-month compassionate-use program involving 24 patients with idiopathic PAH receiving inhaled iloprost 100 [micro]g or 150 [micro]g daily showed sustained clinical benefits in terms of exercise capacity and hemodynamics, and demonstrated that iloprost was well tolerated by the patients. (27) In clinical practice, the frequent administration regimen remains a major obstacle with iloprost.

Summary. The available prostanoid therapies are effective for the treatment of PAH, but administration by continuous infusion or multiple inhalations is inconvenient for the patient and may be painful, in addition to the potential risk of side effects at the site of infusion or catheter-related infections. The cost of prostanoid therapy is also considerable, ranging from approximately $50,000 yearly for iloprost, $72,000 for epoprostenol infusion, and as much as $93,000 per year for treprostinil. (28) The patent expiration of epoprostenol in May 2006 is likely to affect the economic aspects of prostanoid therapy; however, the clinical considerations related to management of patients with PAH will remain the same.

ENDOTHELIN-RECEPTOR ANTAGONISTS

Bosentan. The nonselective [ET.sub.A]/[ET.sub.B] antagonist bosentan was the first ETRA to receive FDA approval for the treatment of PAH in patients with WHO Class III and IV functional status. Administered orally twice daily, bosentan represents a great improvement in patient convenience compared with epoprostenol, treprostinil, and iloprost.

Channick and colleagues (29) performed the first randomized, placebo-controlled, multicenter study of bosentan in 2001. In this study, 32 patients with idiopathic PAH received bosentan (62.5 mg bid for 4 wk, then 125 mg bid) or placebo for a treatment period of 12 weeks. The six-minute walking distance improved by 70 m in the bosentan group, whereas it worsened by 6 m in the placebo group (P = .021 between treatments). Significant improvements were also seen in hemodynamic variables including cardiac index (P < .0001 between treatments) and pulmonary vascular resistance (P = .0002 between treatments), Borg dyspnea index, and WHO functional class. Three withdrawals resulting from clinical worsening occurred, all in the placebo group (P = .033).

A pivotal placebo-controlled study, BREATHE-1, comprised 213 patients with idiopathic PAH or PAH relating to CTD who received bosentan (62.5 mg bid for 4 wk, then 125 mg or 250 mg bid) or placebo for a treatment period of 16 weeks. This study demonstrated improvements in six-minute walking distance of 35 m in the group receiving 125 mg and 54 m in the 250 mg bid bosentan group, compared with a deterioration of 8 m in the placebo group (Figure 4). (30) Whereas BREATHE-1 did not evaluate hemodynamic variables, significant improvements were also seen in dyspnea, WHO functional class, time to clinical worsening, and a number of ECG and Doppler parameters relating to right ventricular systolic function and left ventricular diastolic filling.

[FIGURE 4 OMITTED]

Long-term follow-up has shown that treatment with bosentan for more than one year resulted in improvements in hemodynamic parameters and WHO functional class. (31) Bosentan treatment was well tolerated overall, and no patient underwent transplantation or died.

The use of bosentan in PAH is limited by the risk of hepatic toxicity. In the BREATHE-1 study, a dose-dependent increase in hepatic transaminase concentrations was observed in the bosentan groups. (30) During the long-term follow-up studies, increases in liver alanine aminotransferase and aspartate aminotransferase levels of three times the normal level were seen in approximately 14% of patients; a small percentage of patients experienced increases of up to eight times the normal level. (31) Bosentan is contraindicated in patients with advanced liver disease. Liver function should be monitored on at least a monthly basis during treatment. (32)

Both CYP2C9 and CYP3A4 are involved in bosentan metabolism, and the drug has been shown to have a complex interaction profile that includes interactions with oral contraceptives, statins, glyburide, and warfarin. (32) Bosentan is also known to have teratogenic potential and is therefore contraindicated in pregnancy. (32) It should be noted that interaction between bosentan and sildenafil causes increased levels of bosentan with reduced levels of sildenafil, thereby maximizing the potential toxicity of bosentan and minimizing sildenafil efficacy.

Sitaxsentan. Sitaxsentan, a highly selective ETA-receptor antagonist (6,500:1 for [ET.sub.A]:[ET.sub.B]) is currently awaiting FDA approval. Although the clinical relevance of selective [ET.sub.A] blockade remains unproven, the rationale is that it will block the vasoconstricting effect of ET-1 on [ET.sub.A] receptors, leaving [ET.sub.B] receptors on vascular endothelial cells free to mediate vasodilation and clearance of circulating ET-1.

The Sitaxsentan To Relieve ImpaireD Exercise (STRIDE)-1 study, a large, randomized, placebo-controlled study, involved 178 patients with PAH of different etiologies. (33) Patients were randomized to receive sitaxsentan 100 mg or 300 mg) or placebo, once daily for 12 weeks. The six-minute walking distance increased by 22 m in the sitaxsentan 100-mg group and by 20 m in the 300-mg group, compared with a 13-m decrease in the placebo group (P < .01 vs. placebo for both sitaxsentan doses) (Figure 5). The two sitaxsentan groups showed significantly greater improvements in hemodynamic variables, including pulmonary vascular resistance (P < .001 for both doses) and cardiac index (P = .013 for 100 mg and P < .001 for 300 mg), and WHO functional class status (P < .02 for both) compared with placebo. The incidence of liver enzyme abnormalities was 3% (2/59) for the placebo group, 0% for the sitaxsentan 100-mg group, and 10% (6/63) for the sitaxsentan 300-mg group, and was reversible in all cases. No premature discontinuations were seen in the 100-mg group, compared with 8% of patients taking placebo and 11% of patients in the 300-mg group. In an extension phase for up to 58 weeks, the incidence of liver enzyme abnormalities increased to 5% (4/77) for the sitaxsentan 100-mg group and 21% (19/91) for the sitaxsentan 300-mg group. (33) As a result of the unacceptably high rates of abnormal liver functions tests at the higher dose, the 100-mg dose was chosen for further study.

[FIGURE 5 OMITTED]

The STRIDE-2 study, comprising 247 patients, confirmed 100 mg once daily as the optimal dose for sitaxsentan, and provided comparative data through inclusion of an open-label bosentan arm. (34) After 18 weeks of treatment, patients treated with sitaxsentan 100 mg increased their six-minute walking distance by 31 m compared with the placebo group (P = .03). The bosentan group increased their six-minute walking distance by 29.5 m (P = .05 vs. placebo). The WHO functional class status improved significantly in the sitaxsentan 100-mg group over placebo (P = .04). The safety analysis showed that the incidence of elevated hepatic transaminase levels was 6% for placebo, 3% for sitaxsentan 100 mg, and 11% for bosentan. Similar to STRIDE-1, premature discontinuations in the 100-mg group were fewer than in placebo- and bosentan-treated patients.

Patients who completed the STRIDE-2 trial were eligible for inclusion in the STRIDE-2X extension phase, which compared long-term treatment with open-label sitaxsentan 100 mg once daily and bosentan. The mean exposure time on monotherapy in the sitaxsentan group was significantly longer, owing to a higher discontinuation rate in the bosentan group (44 wk vs. 37 wk, respectively). (35) One-year survival rates, as determined by Kaplan-Meier analysis, were 96% in the sitaxsentan group and 89% in the bosentan group. Over the first year of therapy, 33% of patients treated with bosentan experienced a clinical worsening event (primarily hospitalization) compared with 22% of patients receiving sitaxsentan (P = .03). The one-year risk of developing elevated liver transaminases was 3% for patients treated with sitaxsentan, compared with 14% for those receiving bosentan, and the risk of withdrawal because of elevated liver enzyme levels during the first year was 2% in the sitaxsentan group compared with 9% in the bosentan group. (36)

A recent randomized double-blind multicenter study, STRIDE-6, investigated the efficacy and safety of sitaxsentan 50 mg and 100 mg once daily in patients with PAH who had ceased bosentan therapy because of lack of efficacy. (37) Patients received treatment for 12 weeks. The six-minute walking distance improved in 10% of patients taking sitaxsentan 50 mg and in 33% of patients in the 100-mg group. Similar improvements were seen for the Borg dyspnea index, whereas WHO functional class status improved in 5% and 7% of patients, respectively (Table III). None of the patients developed liver function abnormalities.

Ambrisentan. Ambrisentan is an [ET.sub.A]-selective ETRA (77:1 [ET.sub.A]:[ET.sub.B]), currently undergoing phase 3 clinical trials. A double-blind dose-ranging study was conducted in 64 patients with idiopathic PAH or PAH related to CTD, HIV, or use of appetite-suppressing drugs. (38) Patients were randomized to receive ambrisentan 1 mg, 2.5 mg, 5 mg, or 10 mg for 12 weeks, followed by a 12-week open-label phase. The six-minute walking distance improved in all ambrisentan groups; the mean increase was 36 m (P < .0001 vs. baseline) and was not dose-dependent. Similar, non-dose dependent improvements were seen in hemodynamic variables, including mean pulmonary artery pressure, cardiac index, pulmonary vascular resistance, WHO functional class status, and dyspnea. The incidence of liver function abnormalities was low in all treatment groups levels with four patients (6%) developing elevated liver transaminases levels; two of these patients (3%) discontinued therapy. No cases developed in the highest dose of 10 mg. (38)

The pivotal ARIES-1 and ARIES-2 studies investigated the clinical efficacy and safety of ambrisentan in PAH. In ARIES-1, 202 patients received 5 mg and 10 mg once daily; in ARIES-2, 192 patients received 2.5 mg and 5 mg once daily. (39) The integrated efficacy analysis showed that all doses of ambrisentan increased the primary variable six-minute walking distance significantly from baseline. The improvement in the 2.5-mg dose group was 32.3 m (P = .0219 vs. baseline); in the 5-mg dose group, 44.6 m (P < .0001 vs. baseline); and in the 10-mg dose group, 51.4 m (P = .0001 vs. baseline). In addition, all groups significantly improved in time to clinical worsening, WHO functional class, dyspnea, and Short Form-36 scores (P < .05 for all).

Summary. The available ETRA options constitute an effective oral treatment alternative to prostanoids for PAH. Bosentan is priced at $39,105 per year (28) and is currently the only ETRA approved by the FDA. However, approval for the selective [ET.sub.A]-receptor antagonists sitaxsentan is imminent, and is also expected for ambrisentan. Bosentan therapy is associated with a significant risk of developing liver function abnormalities; this does not appear to be the case for sitaxsentan and ambrisentan.

PHOSPHODIESTERASE--5 INHIBITORS

Sildenafil. Sildenafil has been shown to be a potent and pulmonary-selective vasodilator (40) and is the first PDE-5 inhibitor to be granted a license for the treatment of PAH. The labeled dose is 20 mg tid; however, reports of improvements in clinical efficacy at doses up to 80 mg tid have been noted, and higher doses than labeled are prescribed within the setting of specialist PAH referral centers. (41) However, clinical studies have yet to demonstrate a statistically significant benefit of the 80-mg tid regimen compared with the 20-mg tid regimen.

The Sildenafil Use in Pulmonary arterial hypERtension (SUPER)-1 randomized, placebo-controlled study comprised 278 patients with idiopathic PAH or PAH related to CTD or CHD, who received treatment with sildenafil 20-, 40-, or 80-mg tid or placebo for 12 weeks. (42) The six-minute walking distance improved by 45, 46, and 50 m, respectively (P < .001 vs. placebo for all) (Figure 6). Improvements were also noted in hemodynamic variables, including mean pulmonary pressure, cardiac index and pulmonary vascular resistance, and in WHO functional class status. After the 12-week randomized treatment period, 222 patients completed a long-term extension phase and received treatment with sildenafil 80 mg for up to one year; at the end of the extension phase, the mean six-minute walking distance was 51 m. Sildenafil was well tolerated throughout the study at all doses, with the majority of adverse events reported being mild or moderate in severity, and with no evidence of a dose-response relationship in the randomized 12-week phase. (42)

[FIGURE 6 OMITTED]

The study called Sildenafil versus Endothelin Receptor Antagonist for Pulmonary Hypertension (SERAPH) compared sildenafil with bosentan, and showed nonsignificant differences in favor of sildenafil in right ventricular mass and six-minute walking distance. (43)

Tadalafil. Tadalafil is a PDE-5 inhibitor with an approximately five fold longer plasma half-life than sildenafil, thus potentially allowing once-daily dosing. (44) Tadalafil is currently in phase 3 clinical trials for the treatment of PAH; however, to date no clinical trials, observational reports, or case studies have been published on the use of tadalafil in the treatment of PAH in humans.

Summary. The PDE-5 inhibitors appear to be effective and well tolerated for the treatment of PAH and at the lowest dose, cost about $11,000 per year for sildenafil. (45) However, the optimal sildenafil dose for maintenance therapy is not yet established and may be considerably higher than the labeled dose.

COMBINATION THERAPY

Some evidence exists that combining treatments may improve outcomes in patients with PAH of all severities. The rationale for combining therapies can be understood when examining the biochemical interactions between the prostacyclin, endothelin, and NO pathways, which all mediate their pharmacodynamic effect by way of vasodilation, inhibiting vascular smooth muscle proliferation, and inhibiting fibrosis. It has been suggested that combining therapies with complementary mechanisms of action may achieve synergistic clinical responses which exceed those of the individual treatments, while minimizing side effects.

Hoeper and colleagues (10) reported on a three-year study in which 135 patients with PAH received treatment according to a protocol of first-line bosentan, with subsequent addition of sildenafil, inhaled iloprost, and intravenous iloprost as the condition progressed. Compared with a historical control group, survival rates at one, two, and three years were significantly higher in patients receiving combined treatment (93%, 83%, and 80% vs. 90%, 75%, and 63%, respectively) (Figure 7). Patients receiving combination therapy also had higher transplantation-free survival, and treatment free from intravenous prostaglandins. (10)

[FIGURE 7 OMITTED]

One study found no significant benefit of adding bosentan to epoprostenol treatment compared with epoprostenol alone on exercise capacity, hemodynamics, or functional class. (11) In contrast, Ghofrani and colleagues (12) found the combination of sildenafil and iloprost was significantly more effective in reducing pulmonary vascular resistance and improving cardiac index than each agent as monotherapy (P < .001 for both).

In a phase 2, double-blind, placebo-controlled trial, patients with PAH treated with bosentan received either inhaled iloprost or placebo in combination with bosentan for 12 weeks. (13) A total of 65 patients were enrolled. The combination-therapy group showed greater improvements in the six-minute walking test (P = .051 vs. placebo) and WHO functional class (P = .002). In addition, patients receiving combination therapy experienced a reduction in mean pulmonary artery pressure (P < .0001) and a delay in clinical deterioration (P = .022). However, studies are needed to investigate the long-term effectiveness of these combinations.

In clinical practice, the complexity and severity of PAH regardless of etiology means that patients may benefit from combination therapy at some point during long-term treatment. Pending updated evidence-based guidelines, further studies are needed to establish the relative efficacy and tolerability of a range of combination protocols. The oral agents, ETRAs, and PDE-5 inhibitors in particular, should be subjected to combination therapy studies; this may reduce or delay the need for prostanoid infusion and have a favorable effect on patients' quality of life. The cost of combination therapy and the implications for coinsurance and/or copays should also be considered.

CONCLUSION

Pulmonary arterial hypertension management has rapidly evolved from few effective treatments and a very poor prognosis to an area of intense research and a range of new therapeutic options based on the complex, multitarget disease mechanism. Pending updated clinical practice guidelines, cardiologists and pulmonologists rely on published evidence and expert recommendations when prescribing new agents. Large-scale clinical trials are needed to establish the relative efficacy of new treatments for PAH, and to investigate whether combination therapy may offer further clinical benefits.

REFERENCES

(1.) Gaine S, Rubin L: Primary pulmonary hypertension. Lancet 1998;352:719-725.

(2.) Levine DJ: Diagnosis and management of pulmonary arterial hypertension: Implications for respiratory care. Respir Care 2006;51:368-381.

(3.) D'Alonzo GE, Barst RJ, Ayres SM, et al: Survival in patients with primary pulmonary hypertension: Results from a national prospective registry. Ann Intern Med 1991;115:343-349.

(4.) Simonneau G, Galie N, Rubin L, et al: Clinical classification of pulmonary hypertension. J Am Coll Cardiol 2004;43(12 suppl S):5-12.

(5.) Barst R, McGoon M, Torbicki A, et al: Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43(12 suppl S):40-47.

(6.) McDonnell P, Toye P, Hutchins G: Primary pulmonary hypertension and cirrhosis: Are they related? Am Rev Respir Dis 1983;127:437-441.

(7.) Hyduk A, Croft JB, Ayala C, et al: Pulmonary hypertension surveillance--United States, 1980-2002. MMWR Surveill Summ 2005;54(5):1-28

(8.) Brown R, Mehta N, Vora P: Pulmonary Arterial Hypertension. Waltham, MA, Pharmacor Decision Resources, Inc., February 2005.

(9.) Humbert M, Morrell N, Archer S, et al: Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol 2004;43(12 suppl S):13-24.

(10.) Hoeper MM, Markevych I, Spiekerkoetter E, et al: Goal-oriented treatment and combination therapy for pulmonary arterial hypertension. Eur Respir J 2005;26:858-863.

(11.) Humbert M, Barst RJ, Robbins IM, et al: Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J 2004;24:353-359.

(12.) Ghofrani HA, Wiedemann R, Rose F, et al: Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med 2002;136:515-522.

(13.) CoTherix, Inc.: New Ventavis data presented at CHEST meeting. PR Newswire, Oct. 31, 2005.

(14.) Tuder RM, Cool CD, Geraci MW, et al: Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med 1999;159:1925-1932.

(15.) Channick RN, Sitbon O, Barst RJ, et al: Endothelin receptor antagonists in pulmonary arterial hypertension. J Am Coll Cardiol 2004;43(12 suppl S):62-67.

(16.) Giaid A, Yanagisawa M, Langleben D, et al: Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 1993;328:1732-1739.

(17.) Rubens C, Ewert R, Halank M, et al: Big endothelin-1 and endothelin-1 plasma levels are correlated with the severity of primary pulmonary hypertension. Chest 2001;120:1562-1569.

(18.) Langleben D, Dupuis J, Langleben I, et al: Etiology-specific endothelin-1 clearance in human precapillary pulmonary hypertension. Chest 2006;129:689-695.

(19.) Davenport AP, Battistini B: Classification of endothelin receptors and antagonists in clinical development. Clin Sci 2002;103(suppl 48):1-3.

(20.) Barst RJ, Rubin LJ, McGoon MD, et al: Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann Intern Med 1994;121:409-415.

(21.) Barst RJ, Rubin LJ, Long WA, et al: A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996;334:296-301.

(22.) Badesch D, McLaughlin V, Delcroix M, et al: Prostanoid therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2004;43(12 suppl S):56-61.

(23.) Simonneau G, Barst RJ, Galie N, et al: Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: A double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 2002;165:800-804.

(24.) Gomberg-Maitland M, Tapson VF, Benza RL, et al: Transition from intravenous epoprostenol to intravenous treprostinil in pulmonary hypertension. Am J Respir Crit Care Med 2005; 172:1586-1589.

(25.) Tapson VF, Gomberg-Maitland M, McLaughlin VV, et al: Safety and efficacy of IV treprostinil for pulmonary arterial hypertension: a prospective, multicenter, open-label, 12-week trial. Chest 2006;129:683-688.

(26.) Olschewski H, Simonneau G, Galie N, et al: Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002;347:322-329.

(27.) Hoeper MM, Schwarze M, Ehlerding S, et al: Long-term treatment of primary pulmonary hypertension with aerosolized iloprost, a prostacyclin analogue. N Engl J Med 2000; 342:1866-1870.

(28.) Morrow L, Malesker MA, Tilleman JA: Management of pulmonary arterial hypertension. US Pharm 2005;30:HS18-HS38.

(29.) Channick RN, Simonneau G, Sitbon O, et al: Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: A randomised placebo-controlled study. Lancet 2001;358:1119-1123.

(30.) Rubin LJ, Badesch DB, Barst RJ, et al: Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346:896-903.

(31.) Sitbon O, Badesch DB, Channick RN, et al: Effects of the dual endothelin receptor antagonist bosentan in patients with pulmonary arterial hypertension: A 1-year follow-up study. Chest 2003;124:247-254.

(32.) Tracleer prescribing information. South San Francisco, Actelion Pharmaceuticals U.S., Inc., 2005.

(33.) Barst RJ, Langleben D, Frost A, et al: Sitaxsentan therapy for pulmonary arterial hypertension. Am J Respir Crit Care Med 2004;169:441-447.

(34.) Barst RJ, Langleben D, Badesch D, et al: Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan. J Am Coll Cardiol 2006;47:2049-2056.

(35.) Benza R, Frost A, Girgis R, et al: Chronic treatment of pulmonary arterial hypertension (PAH) with sitaxsentan and bosentan. Presented at the American Thoracic Society conference. San Diego, May 19-24, 2006.

(36.) Girgis RE, Keogh AM, Benza RL, et al: Incidence of abnormal liver function tests in patients with pulmonary arterial hypertension (PAH) treated for one year with sitaxsentan or bosentan. Presented at the annual International Society for Heart and Lung Transplantation meeting. Madrid, Spain, April 5-8, 2006.

(37.) Benza RL, Mehta S, Koegh A, et al: Sitaxsentan treatment for patients with pulmonary arterial hypertension failing bosentan treatment due to lack of efficacy. Presented at the annual European League Against Rheumatism conference. Vienna, Austria, June 8-11, 2005.

(38.) Galie N, Badesch D, Oudiz R, et al: Ambrisentan therapy for pulmonary arterial hypertension. J Am Coll Cardiol 2005; 46:529-535.

(39.) Myogen reports results for the integrated analysis of ARIES-1 and ARIES-2 pivotal trials of ambrisentan in pulmonary arterial hypertension; significant improvements observed for all primary and secondary endpoints. Business Wire, May 3, 2006.

(40.) Ghofrani H, Pepke-Zaba J, Barbera J, et al: Nitric oxide pathway and phosphodiesterase inhibitors in pulmonary arterial hypertension. J Am Coll Cardiol 2004;43(12 suppl S):68-72.

(41.) Hayakawa I, Shirasaki F, Hirano T, et al: Successful treatment with sildenafil in systemic sclerosis patients with isolated pulmonary arterial hypertension: Two case reports. Rheumatol Int 2006;26:270-273.

(42.) Galie N, Ghofrani HA, Torbicki A, et al: Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005;353:2148-2157.

(43.) Wilkins MR, Paul GA, Strange JW, et al: Sildenafil versus endothelin receptor antagonist for pulmonary hypertension (SERAPH) study. Am J Resp Crit Care Med 2005;171:1292-1297.

(44.) Palmieri EA, Affuso F, Fazio S, et al: Tadalafil in primary pulmonary arterial hypertension. Ann Intern Med 2004;141: 743-744.

(45.) Morrow T: Sharp strategy needed with new treatment options for PAH. Manag Care 2006;15:66-67.

DISCLOSURE

Dr. Feldman has disclosed he received grant/research support from Encysive Pharmaceuticals; has served as a consultant to United Therapeutics, Encysive, CoTherix, and Actelion; and served on the speakers' bureau of Encysive, Actelion, United Therapeutics, Myogen, and Pfizer. Dr. Berenbeim disclosed he has served as a consultant for multiple pharmaceutical companies.

Address for correspondence: Jeremy Feldman, MD, 500 W. Thomas Road, Suite 950, Phoenix, Arizona 85013. E-mail: jpfeldman1@ yahoo.com.

To obtain reprints, please contact Kevin Chamberlain at [phone], ext. 202 or visit our website at www.medicomint.com. Copyright 2006 by Medicom International. All rights reserved.

Dr. Feldman is Director, Pulmonary Hypertension Program, St. Joseph's Hospital, Phoenix, and Dr. Berenbeim is Senior Vice President and Chief Medical Officer, MedImpact PBM Services, San Diego.

This White Paper of The Pharmacy and Therapeutics Society was supported by an unrestricted grant from Encysive Pharmaceuticals, Houston.

TABLE I: WORLD HEALTH ORGANIZATION CLASSIFICATION
OF PULMONARY HYPERTENSION

1. Pulmonary Arterial Hypertension (PAH)
 1.1 Idiopathic (IPAH)
 1.2 Familial (FPAH)
 1.3 Associated with (APAH)
 1.3.1 Collagen vascular disease
  1.3.2 Congenital systemic-to-pulmonary shunts *
  1.3.3 Portal hypertension
  1.3.4 HIV infection
  1.3.5 Drugs and toxins
  1.3.6 Other (thyroid disorders, glycogen storage disease, Gaucher
        disease, hereditary hemorrhagic telangiectasia,
        hemoglobinopathies, myeloproliferative disorders, splenectomy)
 1.4 Associated with significant venous or capillary involvement
  1.4.1 Pulmonary venoocclusive disease (PVOD)
  1.4.2 Pulmonary capillary hemangiomatosis (PCH)
 1.5 Persistent pulmonary hypertension of the newborn
2. Pulmonary Hypertension With Left Heart Disease
 2.1 Left-sided atrial or ventricular heart disease
 2.2 Left-sided valvular heart disease
3. Pulmonary Hypertension Associated With Lung Diseases and/or
   Hypoxemia
 3.1 Chronic obstructive pulmonary disease
 3.2 Interstitial lung disease
 3.3 Sleep-disordered breathing
 3.4 Alveolar hypoventilation disorders
 3.5 Chronic exposure to high altitude
 3.6 Developmental abnormalities
4. Pulmonary Hypertension Related to Chronic Thrombotic and/or Embolic
   Disease
 4.1 Thromboembolic obstruction of proximal pulmonary arteries
 4.2 Thromboembolic obstruction of distal pulmonary arteries
 4.3 Nonthrombotic pulmonary embolism (tumor, parasites, foreign
   material)
5. Miscellaneous
   Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of
   pulmonary vessels (adenopathy, tumor, fibrosing mediastinitis)

* Guidelines for Classification of Congenital Systemic-to-Pulmonary
  Shunts

1. Type
   Simple
    Atrial septal defect (ASD)
    Ventricular septal defect (VSD)
    Patent ductus arteriosus
    Total or partial unobstructed anomalous pulmonary venous return
   Combined
    Describe combination and define prevalent defect, if any
   Complex
    Truncus arteriosus
    Single ventricle with unobstructed pulmonary blood flow
    Atrioventricular septal defects
2. Dimensions
   Small (ASD [less than or equal to] 2.0 cm and VSD [less than or
   equal to] 1.0 cm)
   Large (ASD > 2.0 cm and VSD > 1.0 cm)
3. Associated Extracardiac Abnormalities
4. Correction status
   Noncorrected
   Partially corrected (age)
   Corrected: spontaneously or surgically (age)

Adapted from Simonneau G, Galie N, Rubin L, et al: Clinical
classification of pulmonary hypertension. J Am Coll Cardiol 2004;43(12
suppl S):5-12.

TABLE II: WORLD HEALTH ORGANIZATION
CLASSIFICATION OF PAH
FUNCTIONAL STATUS

   I. No limitation of usual physical activity; ordinary physical
activity does not cause increased dyspnea, fatigue,
chest pain, or presyncope

   II. Mild limitation of physical activity. There is no
discomfort at rest, but normal physical activity causes
increased dyspnea, fatigue, chest pain, or presyncope

   III. Marked limitation of physical activity. There is no discomfort
at rest, but less than ordinary activity causes increased
dyspnea, fatigue, chest pain, or presyncope

   IV. Unable to perform any physical activity at rest and
may have signs of right ventricular failure. Dyspnea and/or
fatigue may be present at rest and symptoms are increased
by almost any physical activity

PAH = Pulmonary arterial hypertension.

Adapted from Barst R, McGoon M, Torbicki A, et al: Diagnosis
and differential assessment of pulmonary arterial hypertension.
J Am Coll Cardiol 2004;43(12 suppl S):40-47.

TABLE III: RESULTS OF THE STRIDE-6 TRIAL

             50 mg  50 mg  50 mg  100 mg  100 mg  100 mg
Status       6MW    Borg   WHO     6MW    Borg     WHO

% Improved    10%    10%     5%     33%     27%      7%
% Unchanged   75%    75%    75%     47%     60%     80%
% Worsened    15%    15%    20%     20%     13%     13%

6MW = Six-minute walking test; Borg = Borg dyspnea index; WHO = World
Health Organization functional class status.

Adapted from Benza RL, Mehta S, Koegh A, et al: Sitaxsentan treatment
for patients with pulmonary arterial hypertension failing bosentan
treatment due to lack of efficacy. Presented at the annual European
League Against Rheumatism conference. Vienna, Austria, June 8-11, 2005.