Endothelin Receptor Antagonists in Treatment of Pulmonary Arterial Hypertension

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The recent World Health Organization (WHO) classification designates PAH as Group I and includes idiopathic PAH (IPAH), formally known as primary pulmonary hypertension (PPH), familial PAH, and PAH associated with various systemic disorders such as collagen vascular diseases, congenital systemic-to-pulmonary shunts, portal hypertension, anorexigen use, and human immunodeficiency virus (HIV) infection.

Whether idiopathic or related to a systemic disorder, the histologic appearance of lung tissue in each of these conditions share common features which include intimal fibrosis, increased medial thickness, pulmonary arteriolar occlusion and formation of plexiform lesions. Left untreated, PAH is associated with poor outcome. Significant advances in understanding the molecular mechanisms in PAH have delivered insight into the key role played by endothelial dysfunction in initiating and propagating the pulmonary vascular remodeling process: specifically, impaired production of vasoactive mediators, such as prostacyclin and nitric oxide, along with chronic overproduction of vasoconstrictors such as endothelin-1 (ET-1).

The Biology of ET-1 and Endothelin Receptors i n PAH

Since its initial discovery by Yanagisawa and co-workers in 1988, ET-1 has been extensively studied and is recognized as a key mediator of pulmonary vascular biology and pathophysiology in PAH. It is a 21-amino peptide predominantly produced by endothelial cells. The effects of ET-1 include vasoconstriction, and it is recognized as the most potent vasoconstrictive agent discovered to date. It also acts as a strong mitogen by stimulating production of several growth factors, and it induces myocardial fibrosis and hypertrophy, as well as vascular fibrosis with extracellular matrix proliferation. Furthermore,ET-1 is also produced in leukocytes where it increases the production of cytokines in the inflammatory response. In PAH, not only is the plasma levels of ET-1 increased, its level is inversely proportional to the magnitude of the pulmonary blood flow and cardiac output, suggesting that these hemodyanmic changes are influenced directly by this vascular effector. ET-1 exerts its vascular effects through activation of the ETA and ETB receptors. ETA receptors are located on smooth muscle cells whereas ETB receptors are found predominantly on vascular endothelial cells and to a lesser extent on smooth muscle cells. Activation of the ETA and ETB receptors on smooth muscle cells induces vasocon-striction and cellular proliferation and hypertrophy. In contrast, stimulation of ETB receptors on endothelial cells results in production of vasodilators nitric oxide and prostacyclin. In addition, ETB receptors are involved in the clearance of ET-1 from the circulatory system, particulary in the lungs and kidneys. In non-diseased state, a regulated balance is maintained between the production and clearance of ET-1 to keep the circulating level low, a process which is mediated by ETB.

Selective versus Dual Endothelin Receptor Antagonists in PAH

Dual ETA and ETB receptor blockers and selective ETA receptor antagonist have been developed for treatment of PAH. The proposed rationale for utilizing selective ETA receptor blockade stems from the observation that there may be advantages for selectively blocking the vasoconstrictive and proliferative effects of ETA receptor only while maintaining the vasodilator and ET-1 clearance function of the ETB receptors. Conversely, blocking both ETA and ETB receptors have been stated as necessary to completely negate all the deleterious effects of ET-1 on pulmonary vasculature since ETB receptors have been reported to be up regulated in certain disease states (scleroderma lung disease, congenital heart disease, and thromboembolic disease).

Indeed, evidence exists to support effectiveness of both strategies in animal and human studies. In rat model of PAH, both selective ETA receptor antagonist and dual ETA/ETB receptor blockers have been shown to modify pulmonary vascular remodeling that occurs in response to chronic hypoxic exposure. Furthermore, both groups of animals demonstrated reversal of pulmonary vascular remodeling with their respective therapies. Similarly, studies have been performed on healthy volunteers and on those with vascular diseased states that demonstrate superiority of one type of receptor antagonist over the other. With ETA selective antagonist sitaxsentan, the degree of vasodilation was shown to be greater with selective antagonist than dual receptor antagonist. Conversely, the dual ETA/ETB receptor antagonist bosentan was demonstrated to cause more percent change in forearm blood flow in hypertensive patients than the selective ETA blockade. Further complicating the question is that the spatial distribution of the up regulated ETB receptors in certain disease states, whether the receptors are increased in endothelial cells or smooth muscle cells, has not been well elucidated. A recent study has also reported finding that ETB receptor-mediated extraction of ET-1 is highly preserved, and that high circulating ET-1 levels in PAH patients must be predominantly due to excess synthesis rather than reduced clearance. Indeed, whether selective or dual endothelin receptor antagonism will provide the most benefit in patients with PAH remain to be seen.

The Clinical Efficacy and Safety of Endothelin Receptor Antagonists in PAH

Bosentan (Tracleer™), a dual ETA/ETB endothelin receptor antagonist, was the first oral therapy to be approved for treatment of PAH. The first multicenter study by Channick et al reported the result of a 12-week randomized, placebo-controlled, double-blind trial in 32 patients with IPAH (n=27) and PAH associated with scleroderma (n=5). The participants were all WHO functional class III and there was 2:1 randomization to the bosentan group in relation to placebo.Patients in the bosentan group received the drug at a dose of 62.5mg twice a daily for four weeks followed by 125mg twice daily. A 70 meter improvement was seen in the six-minute walk distance (6MWD) at 12 weeks whereas it worsened by six meters for the patients receiving placebo (p<0.05). Treatment with bosentan also improved hemodyanmics (increased cardiac index and decreased pulmonary vascular resistance and mean pulmonary arterial pressure) and functional class.

In a subsequent study Bosentan Randomized Trial of Endothelin Antagonist Therapy (BREATHE-1), 213 patients with IPAH (n=150) or PAH related to scleroderma (n=47) or systemic lupus erythematosus (n=16) were enrolled. Majority of the patients were in WHO functional class III (94% in placebo and 90% in treatment group) and a few were in functional class IV. The mean 6MWD was about 330 meters and the mean pulmonary artery pressure was about 55mmHg. Patients were randomly assigned to receive placebo or bosentan titrated to a target dose of either 125mg twice per day or 250mg twice per day for 16 weeks. At the end of the treatment period, the 6MWD improved by 36 meters in the bosentan group whereas a deterioration of eight meters was seen in the placebo group. The differences were statistically significant for both 125mg and 250mg groups; there was no significant difference between the two bosentan groups. Patients treated with bosentan also had improvement in the time to clinical worsening, defined as death, lung transplantation, hospitalization for pulmonary hypertension, lack of improvement or worsening leading to discontinuation, or need for epoprostenol therapy or atrial septostomy.

The primary safety issue in prescribing bosentan relates to its effect on liver function tests. Bosentan is primarily metabolized by hepatic metabolism through the P450 enzyme systems CYP2C9 and CYP3A4. In the BREATHE-1 study, there was a dose-dependent increase in hepatic transaminases noted with a significant elevation in 14% of the patients randomized to 250mg bosentan and 4% among patients receiving 125mg. The liver abnormalities were often asymptomatic and all resolved with dose reduction or cessation. Animal studies have demonstrated that bosentan-induced liver injury is likely mediated by drug-induced inhibition of the hepatocanalicular bilesalt export pump. All patients receiving bosentan are required to have liver function tests before drug initiation and then monthly. Patients with baseline hepatic dysfunction should not treated with bosentan.

Bosentan is teratogenic so is contraindicated in pregnancy, and pregnancy must be excluded before therapy initiation.Women of childbearing age must be counseled that hormonal forms of contraception cannot be relied on as sole form of contraception while on bosentan. Several drugs have been shown to have significant interaction with bosentan through the P460 system and glyburide and cyclosporine A are contraindicated with bosentan therapy. No clinically significant effect has been reported on warfarin level using the approved doses.

Bosentan received approval in November 2001 for treatment of PAH for WHO functional class III or IV symptoms to improve exercise capacity and decrease the rate of clinical worsening. Since then, data on long-term efficacy of bosentan have emerged. Sitbon et al. reported the result of an open-label extension of the initial double-blind, placebo-controlled study of 32 patients.Twenty-nine patients received bosentan for an additional year (62.6mg twice a day for four weeks and then 125mg twice a day). Patients continuing bosentan treatment maintained the improvement in walk distance observed at the end of initial study and patients starting bosentan improved their walk distance by 45 ± 13 meters. Hemodynamic measurements performed on 11 patients after mean of 15 months of therapy demonstrated significant improvement in cardiac index and pulmonary vascular resistance. Overall bosentan treatment was well tolerated in this cohort.There were no deaths during the course of the study and one patient was initiated on epoprostenol therapy due to worsening PAH.

McLaughlin et al presented survival data in 169 patients treated with bosentan as first-line therapy.The Kaplan-Meier survival estimate at two years was 89%. The predicted two-year survival of these patients based on the NIH equation was 57%. In this study, 70% of the patients remained on bosentan monotherapy while 23% of patients received additional therapies or were transitioned to prostanoid-based therapies. The rate of liver function test abnormality reported was 14.9% though there no serious irreversible hepatic dysfunction occurred. This long-term observation emphasizes the importance of following patients every month for this potentially serious adverse event and that for stable functional class III patients with PAH, it is reasonable to consider bosentan as a first-line therapy.

Selective ETA Receptor Antagonist

Sitaxsentan is a selective ETA antagonist currently under review by the US Food and Drug Administration (FDA) for treatment of PAH. Sitaxsentan sodium is approximately 6,500-fold more selective as an antagonist for ETA compared with ETB receptors. In the Sitaxsentan To Relieve Impaired Exercise Trial (STRIDE-1), 178 New York Heart Association (NYHA) functional class II (33%), III (66%), and IV (1%) patients with either IPAH (53%), PAH related to connective tissue disease (24%) or congenital systemic-to- pulmonary shunts (24%) were randomized equally to receive placebo, sitxsentan 100mg or 300mg orally once a day.

The primary efficacy end point of maximum oxygen consumption was not improved by sitaxsentan compared with placebo; however, the 6MWD improved for both 100mg (35 meters; p<0.01) and 300mg groups (33 meters; p<0.01). Improvements in the NYHA functional class and hemodyanmic parameters were also resulted from treatment with sitaxsentan.

Liver function abnormalities were also noted with sitaxsentan therapy in dose dependent manner. In the 12-week trial, the incidence of hepatic enzyme elevations (aminotransferase values >3 times upper limit of normal) was 3% (2/59) for the placebo group, 0% for the 100mg group, and 10% (6/63) for the 300mg group. All abnormalities were reversed in this study group; however, in an earlier pilot study, sitaxentan was associated with fatal hepatitis when used at higher doses. The investigators note that when the placebo-controlled trial results were combined with an extension trial that randomized all patients to receive sitaxsentan 100mg or 300mg, the incidence of liver function abnormalities increased to 5% (4/77) for the 100mg group and 21% (19/91) for the 300mg group for duration of therapy (median 26 weeks). The other significant laboratory abnormality reported was increase in international normalized ratio (INR).This is because sitaxsentan is an inhibitor of CYP2C9 P450 enzyme, the principal hepatic enzyme involved in the metabolism of warfarin and it occurred with both doses of sitaxsentan. The investigators report the need to reduce the dose of warfarin when patients are receiving concurrent therapy with sitaxsentan.

Recently, STRIDE-2 was published which addressed some unresolved questions from STRIDE-1 trial (20). First, since the safety profile was not acceptable with the 300mg dose, the optimal dose on the basis of risk and benefit considerations were studied.This was a double-blind, placebo-controlled, 18-week study of 245 PAH patients (IPAH 59%; connective tissue disease 30%; congenital heart disease 11%) randomized to receive placebo (n=62); sitaxsentan 50mg (n=62) or 100mg (n=61) or open label bosentan (n=60). The placebo-subtracted treatment effects were 24.2 meters (p=0.07) for the sitaxsentan 50mg group, 31.4 meters (p=0.03) for the 100mg group, and 29.5 meters (p=0.05) for the bosentan group.

The incidence of abnormal transaminases (>3x the upper limit of normal) was 6% for placebo, 5% for sitaxsentan 50mg, 3% for sitaxsentan 100mg and 11% for bosentan. The warfarin was reduced by 80% for patients not randomized to bosentan at baseline, with adjustments as needed to maintain a therapeutic INR. Using the decreased dosing schedule, the proportion of patients with INR>3.5 was comparable for the sitaxsentan and placbo groups (33% to 42%) and lower for the bosentan group (20%; p=0.17). From efficacy standpoint, a direct comparison between bosentan and sitaxsentan cannot be made since bosentan therapy was given in open label for observational purpose only; however, it is interesting to note that the 6MWD was similar between the 100mg sitaxsentan and bosentan treated patients. From safety issues, the incidence of liver function abnormalities were less for the 100mg sitaxsentan then bosentan patients; however, the episodes of increased INR was greater for the sitaxsentan treated group despite lowered warfarin doses although the bleeding events were reported to be rare.