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Oral agents in the treatment of PAH
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Pulmonary arterial hypertension is characterized by elevated pulmonary pressures and increased pulmonary vascular resistance, eventually leading to right-sided HF and premature death. The goals of therapy are to relieve symptoms, including dyspnea on exertion, fatigue, syncope and lower extremity edema, as well as delay progression, increase exercise capacity and improve survival.
Although the exact pathogenesis remains unknown, PAH is recognized as a multifactorial process that includes vasoconstriction, obstructive remodeling of the pulmonary vessel wall, inflammation and thrombosis. Since the imbalance of vasoconstrictors, primarily endothelin 1 (ET-1), and the vasodilator mediator nitric oxide (NO) play a key role in the pathogenesis of PAH, recent drug development for PAH has focused on targeting the ET-1 and NO pathways.
Aileen Le
Jaekyu Shin
Drugs that target the ET-1 pathway
ET-1 is a potent vasoconstrictor and smooth-muscle mitogen. Its effects are mediated through two ET receptor isoforms, ETA and ETB. Activation of the ETA receptor results in proliferation of vascular smooth muscle cells and vasoconstriction, whereas activation of ETB results in the clearance of ET and the production of NO and prostacyclin.
Bosentan (Tracleer, Actelion Pharmaceuticals) is a nonselective ETA and ETB receptor antagonist. The safety and efficacy of bosentan (62.5 mg to 125 mg twice daily) were established in two randomized, placebo-controlled trials: BREATHE-1 and Effects of the Dual Endothelin-Receptor Antagonist Bosentan in Patients with Pulmonary Hypertension (Study 351). Bosentan demonstrated an improvement in exercise capacity (BREATHE-1: mean 6-minute walk distance [6MWD] difference for combined bosentan groups, 44 m; P<.001; Study 351: mean 6MWD difference, 76 m; P=.021), hemodynamics (Study 351: cardiac index difference, 1 L/min/m2; P<.001; pulmonary vascular resistance [PVR] difference, –415 dyn·sec·cm–5; P<.0002) and time to clinical worsening (BREATHE-1: P=.002). The most common adverse effects associated with bosentan were syncope, flushing and abnormal liver function. Abnormal liver function was found to be dose-dependent and reversible after dose reduction or discontinuation. Fluid retention and anemia were also reported in patients assigned bosentan.
Ambrisentan (Letairis, Gilead Sciences) is a selective ETA receptor antagonist with safety and efficacy demonstrated in the ARIES-1 and ARIES-2 studies. Ambrisentan (5 mg to 10 mg) once daily was compared with placebo for 12 weeks. Results showed a significant increase in exercise capacity across all doses (ARIES-1: +51 m [10 mg; P<.001] and +31 m [5 mg; P=.008]; ARIES-2: +59 m [5 mg; P<.001]). There was a dose-response trend for improved exercise capacity without any apparent dose-response increase in adverse events. Common adverse effects included peripheral edema, headache and nasal congestion. No patients in the ambrisentan groups experienced elevated aminotransferase enzymes more than three times the upper limit of normal.
Drugs that target the NO pathway
NO is a potent vasodilator. It activates soluble guanylate cyclase in vascular smooth muscle and results in production of cyclic guanosine monophosphate (cGMP), which decreases cellular concentrations of calcium, leading to vasodilation. Importantly, cGMP is degraded by phosphodiesterase (PDE). Because PDE-5 is the predominant and selective PDE in the pulmonary tissue, one strategy to prolong the effects of cGMP and maintain NO levels is to inhibit cGMP breakdown with PDE-5 inhibitors such as sildenafil and tadalafil.
Patients with WHO PAH functional class II or class III symptoms were evaluated in the SUPER-1 study, which compared sildenafil 20 mg, 40 mg and 80 mg three times daily vs. placebo. The 6MWD increased significantly from baseline in all sildenafil groups. Mean placebo-corrected increases in 6MWD were 45 m, 46 m and 50 m for the 20 mg, 40 mg and 80 mg sildenafil doses, respectively (P<.001 for all comparisons). Compared with placebo, all sildenafil doses significantly reduced the mean pulmonary artery pressure (placebo: 0.6 mm Hg; 20 mg: –2.1 mm Hg, P=.04; 40 mg: –2.6 mm Hg, P=.01; 80 mg: –4.7 mm Hg, P<.001) and a significantly higher proportion of patients experienced improvement of at least one WHO functional class (placebo: 7%; 20 mg: 28%, P=.003; 40 mg: 36%, P<.001; 80 mg: 42%, P<.001). Although the FDA-approved maximum dose of sildenafil is 20 mg three times daily for PAH, it is frequently titrated to 80 mg three times daily based on the results of SUPER-2, the open-label, uncontrolled, observational extension study of SUPER-1. After 3 years of follow-up, 87% of 183 patients were taking sildenafil 80 mg three times daily; 127 patients had an increased 6MWD, 81 improved and 86 maintained functional class. Common adverse effects associated with sildenafil in both studies included flushing, dyspepsia, blurry vision and diarrhea. Because sildenafil is also selective for PDE-6, which is expressed in the retina, vision disturbances have also been observed at higher doses.
Tadalafil (Adcirca, United Therapeutics Corp.; Cialis, Eli Lilly) 20 mg to 40 mg was compared with placebo in the 16-week PHIRST-1 study. Tadalafil demonstrated an increase in 6MWD (mean placebo-corrected walk distance, +33 m, P=.0004), improvement in the time to clinical worsening (P<.041) and a 38% lower incidence of clinical worsening (P=.038). Tadalafil has a higher selectivity for PDE-11, which is predominantly in skeletal muscles, and myalgia was observed during follow-up in PHIRST-1. Other adverse effects included headache and flushing.
Lastly, riociguat (Adempas, Bayer HealthCare) is a soluble guanylate cyclase (sGC) stimulator that received FDA approval in October for use in WHO Group 1 and Group 4 patients. Stimulation of sGC is a novel mechanism to increase cGMP and has demonstrated promising responses in PAH WHO Group 1 and chronic thromboembolic disease (WHO PAH Group 4) patients. PATENT-1, a 12-week, placebo-controlled study, evaluated WHO Group 1 patients and found a significant increase in 6MWD (least-squares mean difference, +36 m, P<.0001), PVR (least-squares mean difference, –226 dyn·sec·cm–5, P<.001), time to clinical worsening (P=.005), as well as a significant decrease in mean Borg dyspnea score (placebo: 0.1; riociguat: –0.4; P=.002). The CHEST-1 study evaluated WHO Group 4 patients for 16 weeks and also found significant improvements in 6MWD (least-squares mean difference, +46 m, P<.001), PVR (least-squares mean difference, –246 dyn·sec·cm–5, P<.001) and WHO functional class (P=.003). Both trials evaluated patients at individually adjusted doses of riociguat capped at 2.5 mg three times daily. Frequent adverse effects in the riociguat groups included headache, dizziness, dyspepsia, peripheral edema, nausea, diarrhea and vomiting.
Adempas carries a boxed warning alerting patients and health care professionals that it should not be taken by pregnant women because it can harm the developing fetus. Female patients can only receive Adempas through the mandated restricted distribution program, which requires prescribers to be certified by enrolling in the program. Pharmacies must also be certified and can dispense Adempas only to women who are eligible to receive it under the FDA-approved Risk Evaluation and Mitigation Strategy (REMS).
How to choose the right drug
The decision to begin a particular drug in a patient with PAH depends on the patient profile and the individual risk for developing adverse effects. Ambrisentan and bosentan are teratogenic and are contraindicated in women who are or may become pregnant. Bosentan also carries a black box warning for increased risk for liver injury and therefore is not recommended for patients with liver impairment. Due to these serious adverse effects, both drugs may only be obtained through restricted pharmacy distribution programs. Drug interactions must also be considered with bosentan. As a substrate and inducer of cytochrome P450 3A4 and CYP2C9, bosentan interacts with sildenafil and warfarin. Some factors to consider when selecting a PDE-5 inhibitor include the need for nitrates as concomitant administration is contraindicated, as well as dosing frequency (once-daily tadalafil vs. thrice-daily sildenafil). Cost and prescription insurance plans may also be factors because, currently, only sildenafil is available in a generic formulation.
Despite significant progress in treatment options, patients with PAH continue to experience symptoms and poor outcomes. However, with advances in novel therapies such as sGCs and oral prostacyclin analogs, continued improvements in oral drug therapy options for PAH may be on the horizon.
Disclosure: The authors report no relevant financial disclosures.