Article

The Role of Oral Vasoactive Agents in the Treatment of Pulmonary Arterial Hypertension

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Pulmonary arterial hypertension (PAH) is a disorder of the pulmonary circulation in which elevated pressure in the pulmonary vascular circuit, when severe, can lead to right heart failure and eventually cause death. The last three decades have seen significant advances in our understanding of this group of disorders and, with this understanding, the development of novel therapies to assist in their treatment. A successful and comprehensive approach to the diagnosis and treatment of this complex and rapidly progressive disease requires a collaboration between the patient, the resources at the pulmonary hypertension center, and the resources at the community level.1 The treatment options for patients with PAH have expanded greatly in the recent past, with novel therapies now available and others on the way.2

This article will outline the oral agents available or undergoing trials (see Table 1) for PAH therapy and will summarize the evidence regarding the role of oral agents in treating these patients.

Calcium-channel Blockers

In view of the proven efficacy of newer therapies, it is now recommended that calcium-channel blockers (CCBs) should only be used in patients with demonstrated vasoreactivity and never be used to empirically treat PAH. Patients demonstrating vasoreactivity, initiated on CCBs alone, should be followed very closely for signs of progressive disease, since approximately 50% of these patients will experience deterioration over time, necessitating the addition of newer forms of therapy.3

Endothelin Antagonists

Endothelin-1 (ET-1) is a potent vasoconstrictor and a mediator of the pulmonary vascular remodeling seen in PAH.4 Two receptors for ET-1 have been identified, ETA and ETB, with the former mediating vasoconstriction and remodeling and the latter involved in the clearance of ET-1 and perhaps also in vasodilatation and nitric oxide (NO) release. Many ET receptor antagonists, including sitaxsentan and ambrisentan, are being studied in PH; however, only bosentan is currently available for use in the US.

Bosentan blocks both the ETA and ETB receptors and was the first available ET antagonist. Bosentan is dispensed as a tablet that is taken twice daily.2 The first randomized, placebo-controlled trial of bosentan showed a significant improvements in 6-minute walk distance (6MWD) (p<0.05), cardiac output (p<0.001), pulmonary vascular resistance (p<0.001), and functional class,5 over 12 weeks, in 32 New York Heart Association (NYHA) Class III patients with PAH.A second, larger, randomized, double-blind, placebo-controlled study was performed over 16 weeks in 213 NYHA Class III or IV patients with either idiopathic PAH (IPAH) or PAH associated with connective tissue disease (CTD).6 Patients in the Bosentan Randomized Trial of Endothelin Receptor Antagonist Therapy of Pulmonary Hypertension (BREATHE-1) study were randomized to receive placebo, bosentan 125mg twice daily, or bosentan 250mg twice daily. Treatment with bosentan was shown to improve 6MWD (36-meter improvement in the bosentan group verses an eight-meter fall in the control group; p=0.002), time to clinical worsening (p=0.0015 with log-rank test), and functional class at week 16.

Bosentan is associated with abnormal hepatic function and it should not be prescribed to patients with moderate to severe hepatic impairment.The US Food and Drug Administraton (FDA) requires that liver function tests (LFTs) be checked monthly in patients taking bosentan. Pregnancy must be excluded prior to beginning therapy with bosentan, and females of childbearing age on bosentan should be counseled regarding contraception. Bosentan has been associated with testicular atrophy, worsening of peripheral edema, and mild anemia, and has many drug interactions.7

McLaughlin et al. reported on the long-term survival of 139 functional class III and IV patients treated with bosentan as first-line therapy over 36 months.8 At the end of one year, 96% of patients initially treated with bosentan monotherapy were still alive and at the end of two years 89% were alive, compared with the 69% and 57% expected survival based on the National Institutes of Health (NIH) Registry prediction equation (see Figure 1).9 Factors associated with a worse outcome included NYHA Class IV symptoms and 6MWD less than 358 meters at baseline.

Selective ETA Antagonists

Selective ETA antagonists are under study, with the rationale that selective blockade of the ETA receptor will allow the continued favorable activity of the ETB receptor.7The two agents that have received the greatest attention are sitaxsentan and ambrisentan.

Sitaxsentan is approximately 6,000-fold more selective for the ETA than the ETB receptors than is bosentan. In 2004, Barst et al. published the results of the Sitaxsentan to Relieve Impaired Exercise (STRIDE-1) study, a prospective, randomized, double-blind, placebo-controlled trial involving 178 NYHA Class II, III, and IV patients with PAH who were randomized to placebo or one of two doses of sitaxsentan, 100mg or 300mg daily.10 The groups receiving the 100mg dose improved 6MWD by 35m (p<0.01) and the group receiving the 300mg dose improved their 6MWD by 33m (p<0.01). Both groups showed statistically significant improvements in hemodynamics and functional class compared with placebo. The incidence of liver function abnormalities was only 3% with the 100mg dose.

Another study, STRIDE-2, enrolled 247 patients with class II, III, or IV symptoms and a 6MWD distance of ≤450 meters.11 Patients in this study were randomized to placebo or 50mg or 100mg doses of sitaxsentan and were also compared with an open-label group of patients receiving bosentan 125mg twice daily. The 50mg dose was found to be sub-therapeutic but, compared with placebo, over 18 weeks, the 6MWD distance improved by 31.4m (p=0.03) in the group receiving 100mg sitaxsentan (p=0.04), and by 29.5m (p=0.05) in the group receiving bosentan (see Figure 2). A statistically significant improvement in functional class was also seen in the group receiving 100mg sitaxsentan (p=0.04). The incidence of liver function abnormalities was 3% in the sitaxsentan 100mg group and 11% in the bosentan group. Sitaxsentan has many drug interactions (including warfarin) and carries concern regarding liver toxicity, testicular atrophy, male infertility, peripheral edema, and teratogenesis. The most frequently reported side effect is an elevated INR (when the drug is used concomitantly with coumadin). This can be managed by adjusting the warfarin dose to achieve the desired INR. Patients enrolled in the STRIDE 2 study were rolled over into the open-label extension arm, STRIDE 2X. Preliminary results indicate improvement in 6MWD, cardiac output, pulmonary vascular resistance, and functional class with only a minority of patients requiring escalation of therapy with epoprostenol.12 Sitaxsentan is not currently available for use in the US and is undergoing FDA review for approval.

Ambrisentan has also been studied in phase III studies in patients with PAH. Galie et al. demonstrated in a randomized, placebo-controlled trial that three months of therapy with ambrisentan improved exercise capacity,WHO functional class, and hemodynamics. In addition, an increased 6MWD was observed similar to distances found in bosentan and sitaxsentan trials. Approximately 3.1% of patients demonstrated elevation of liver enzymes in the trial.13 Olshewski et al. recently reported the preliminary results of a phase III randomized, placebo-controlled study of two doses of ambrisentan (2.5mg twice daily and 5mg twice daily) in patients with PAH.14 The study showed a 54m improvement in 6MWD with the 5mg dose and a 34m improvement in 6MWD with the 2.5mg dose at 12 weeks. This study is yet to undergo peer review for publication consideration.

Phosphodiesterase Inhibitors

Cyclic guanosine 3-5' monophosphate (cGMP) plays a critical role in the regulation of vascular smooth muscle tone by acting as a catalyst in a series of intracellular reactions that mediate vasodilatation. Phosphodiesterases rapidly degrade cGMP, thereby limiting nitric oxide (NO)-mediated pulmonary vasodilation. Phosphodiesterase type 5 (PDE5), while normally strongly expressed in the lung, has been shown to be present at higher levels than normal in chronic PH.7 PDE5 inhibitors such as sildenafil or tadalafil can block the effects of PDE5, thereby increasing cGMP levels and potentiating NO-mediated vasodilatation.

Sildenafil, a potent inhibitor of PDE5, increases intracellular levels of cGMP and thus causes vasodilatation.2,7 The Sildenafil Use in Pulmonary Hypertension (SUPER-1) trial enrolled 279 patients with PAH. This was a randomized, double-blind, placebo-controlled 12-week trial comparing three doses (20mg, 40mg, or 80mg three times daily) of sildenafil to placebo in 278 patients with NYHA Class II, III, or IV PAH.15 All three doses of sildenafil improved 6MWD over placebo, with a 36m improvement in the 20mg group (p<0.001), a 46m improvement in the 40mg group (p<0.001), and a 50m improvement in the 80mg group (p<0.001) (see Figure 3). Sildenafil also produced a significant improvement in NYHA functional class and hemodynamics compared with placebo.15 Based on data from this trial, the FDA approved sildenafil for use in patients with PAH at a dose of 20mg three times a day with no NYHA functional class restriction.

Patients who completed the SUPER-1 study had the option to enroll in the extension, open-label, SUPER-2 study, where all patients were transitioned to a dose of 80mg three times a day. Preliminary results from the SUPER-2 study16,17 were presented at the American Thoracic Society meeting in May 2005. Data presented suggested sustained benefit in 6MWD and NYHA functional class at 12 months, and only 6% of patients required an escalation of therapy. The observed mortality in the group treated with sildenafil was 96% at one year, much lower than the expected survival of 71% as estimated based on the NIH Registry prediction equation.9 Overall, sildenafil appears to be well tolerated, with side effects that include headache and hypotension.There have also been recent reports of visual loss that appear to be dose-related and a class effect. No specific lab measurements are needed, but sildenafil should not be used in patients taking nitrates because of potentiation of hypotension.

The safety and efficacy of tadalafil in patients with PAH is the subject of an ongoing phase III randomized, placebo-controlled study.

On the Horizon

L-arginine is the sole substrate for NO synthase, the enzyme responsible for generating NO. Studies examining the short-term intravenous administration of L-arginine on hemodynamics have been mixed.18 Animal models suggest that HMG-CoA reductase inhibitors may slow or inhibit vascular remodeling and improve hemodynamics in rat models of PAH.19 A case series has recently been published in which therapy with an HMG-CoA reductase inhibitor improved 6MWD and hemodynamics in patients with PAH.20 Further studies need to be performed to confirm these preliminary findings. An oral preparation of the prostanoid analogue treprostinil is also currently under investigation.

Combination Therapy

Given the different mechanisms of action for the main classes of medications used to treat PAH, it would seem that these medicines would complement each other and achieve a greater effect when given together rather than alone. Two recent reports21,22 suggest that the addition of sildenafil can produce a sustained improvement in 6MWD and NYHA functional class in patients who have deteriorated while on bosentan therapy alone. Hoeper et al., in a two-year study of 123 PAH patients treated according to a goal-oriented therapeutic strategy, demonstrated a 93, 83, and 79.9% survival at one, two, and three years, respectively, which was better than the survival of a historical control group.23

Preliminary evidence from recently completed trials demonstrated that, in NYHA III or IV patients with IPAH or PAH associated with CTD, repaired coronoary heart disease (CHD), HIV, or anorexigen use, the addition of inhaled iloprost to patients on stable doses of bosentan produced a 26m improvement in 6MWD (p=0.051).24 In another study, the addition of sildenafil produced a significant improvement in 6MWD in PAH patients on epoprostenol.25 While more definitive conclusions should await the publication of complete results from these trials in peer-reviewed journals, they do provide hope that combination therapy will prove feasible and efficacious in improving functional outcomes and survival in patients with PAH.

As many of these medicines have only recently been approved, there are more questions than answers regarding the validity of the concept of combination therapy. These questions include the proper combinations of medicines, the appropriate timing to institute combination therapy, the 'acceptable' level of benefit, and the proper patients in whom combination therapy is appropriate.These questions can be answered only via well-designed, prospective trials showing added efficacy, safety, and, one hopes, survival benefit.

As we conclude the discussion on oral therapies in PAH, even though there is cause for hope, there is also reason for caution. Physicians caring for these patients should bear in mind that patients with severe disease may not be candidates for oral therapy. It important to remember that PAH is a progressive and deadly disease with no known cure and the most effective, long-term medications remain intravenous prostanoids.26,27 Patients on oral therapies should be followed closely to look for symptoms and signs of deterioration, which should prompt transition to intravenous therapy and consideration of surgical options.7,28

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