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The role of new PAH therapies
Options for the treatment of pulmonary arterial hypertension grew considerably in 2013 with the approval of three new medications. Health care professionals and patients now have access to macitentan, riociguat and oral treprostinil.
Before the approval of riociguat (Adempas, Bayer HealthCare), an agent with a novel mechanism of action, PAH was primarily treated with four medication classes: calcium channel blockers for patients who are vasoreactive positive to nitric oxide testing, phosphodiesterase 5 (PDE-5) inhibitors, endothelin receptor antagonists (ERAs) and prostanoids.
Melissa R. Meyer
Karen J. McConnell
Although various medication classes are available to treat WHO Group 1 PAH, which is caused by connective tissue diseases, medications/toxins, HIV and congenital heart disease, initial treatment is largely dependent upon a patient’s WHO functional class. According to the updated PAH treatment algorithm published in 2013, patients in WHO functional class II (mild limitations with physical activity) may be initially treated with an ERA, riociguat, sildenafil (Revatio, Pfizer) or tadalafil (Cialis, Lilly); this is a class I recommendation, level of evidence A or B. However, priorities have not been proposed among these medications given the lack of head-to-head, comparator trial data. For patients in WHO functional class III (marked limitations with physical activity), treatment options are expanded to also include subcutaneous or inhaled treprostinil, IV epoprostenol or inhaled iloprost; this is a class I recommendation, similar clinical evidence.
The choice of initial treatment also depends on a variety of other clinical factors, including the etiology of a patient’s PAH, physician experience, route of administration, adverse event profiles, patient preferences and comorbidities, and cost. Based on average wholesale prices, monthly treatment costs for these new medications vary by dose, ranging from approximately $8,000 to $10,000, and usually require prior authorization for new starts.
Use of macitentan
Macitentan (Opsumit, Actelion Pharmaceuticals) is a new dual ERA developed by modifying the structure of bosentan to allow sustained receptor binding and increased tissue penetration.
It is the only PAH oral therapy shown to reduce morbidity and mortality (HR=0.55; 95% CI, 0.32-0.76) and increase exercise capacity among patients with PAH as demonstrated in the long-term, 2-year, event-driven, placebo-controlled SERAPHIN study. The composite endpoint of time from initiation of treatment to first event related to PAH was primarily driven by worsening PAH (24.4% with placebo vs. 37.2% with macitentan 10 mg), rather than death from any cause (6.6% vs. 6.8%, respectively). Macitentan was not associated with liver toxicity in the SERAPHIN study, whereas bosentan has been associated with dose-related elevated transaminases, and monthly monitoring is required. Dosage adjustment and increased monitoring are recommended for patients who develop aminotransferase elevations on bosentan. For example, if aminotransferase levels are greater than three times the upper limit of normal but five times the upper limit of normal or lower, a reduction of bosentan to 62.5 mg twice daily or to interrupt treatment, and measure liver function tests every 2 weeks until aminotransferase levels normalize.
Given that ERAs are recommended as initial treatment options for patients with WHO functional class II and III, some important differences in dosing, safety and monitoring are provided in the Table.
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Use of oral treprostinil
Despite two prior denials for approval, the FDA approved oral treprostinil (Orenitram, United Therapeutics Corp.) to improve exercise capacity in patients with WHO Group 1 PAH (WHO functional class II or III). Unlike the inhaled, subcutaneous and IV formulations, which have established roles in the treatment of PAH, the role of oral treprostinil in therapy is unclear.
Primary efficacy was assessed in the FREEDOM-M study, which showed that the median 6-minute walk distance improved by 23 m for patients who received twice-daily oral treprostinil compared with placebo. The most common adverse effects were nausea, diarrhea and headache. Although oral treprostinil has a small treatment effect, the oral formulation adds to the repertoire of treatment options for PAH and may delay the need for more complex treatment with IV or subcutaneous prostaniods, although benefits of this strategy are unknown.
Use of riociguat
As the first soluble guanylate cyclase stimulator (sGC), riociguat restores nitric oxide by directly stimulating sGC and sensitizes sGC to low levels of nitric oxide. Although PDE-5 inhibitors slow cyclic guanosine monophosphate degradation, riociguat enhances production of this second messenger resulting in vasodilation.
Riociguat is the first medication to show clinical benefit in the treatment of patients with WHO Group 4 PAH (chronic thromboembolic pulmonary hypertension). The therapy is also FDA approved for patients in WHO Group 1 to improve exercise capacity and delay clinical worsening.
Riociguat moderately improved exercise capacity as measured by the mean placebo-corrected 6-minute walk distance by 36 m over 12 weeks in the PATENT-1 study and by 46 m in the 16-week CHEST-1 trial. Syncope was the most common serious adverse event in clinical trials, but other potential adverse effects include headache, dyspepsia, dizziness and diarrhea. In comparison, the mean placebo-corrected 6-minute walk distance was improved by 33 m for patients who received tadalafil 40 mg/day and by 45 m for patients who received sildenafil 20 mg three times daily in the PHIRST and SUPER trials, respectively. The combination of riociguat and PDE-5 inhibitors is contraindicated due to increased risk for hypotension. Additionally, riociguat is contraindicated with nitrates, amyl nitrite and nonspecific PDE inhibitors like dipyridamole or theophylline. Given the cost of riociguat compared with generic sildenafil and the thrice-daily dosing frequency compared with once-daily brand tadalafil (Adcirca, United Therapeutics Corp.), the role of riociguat in therapy for Group 1 PAH may be limited.
Future use
For patients with an inadequate clinical response to monotherapy, sequential combination therapy can be considered with ERAs, prostanoids, and either a PDE-5 inhibitor or riociguat.
Despite recent advances in treatment options for PAH, additional trials are needed to determine the therapeutic role of riociguat and oral treprostinil. Additionally, head-to-head comparator trials are needed to determine the best first-line treatment options and efficacy of specific combination therapies for patients with WHO Group 1 PAH. Perhaps the ongoing AMBITION trial, comparing combination therapy with ambrisentan and tadalafil vs. first-line monotherapy with ambrisentan or tadalafil, will help shed some light on clinical efficacy among ERAs, PDE-5 inhibitors and initial combination therapy.
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Melissa R. Meyer, PharmD, is a clinical pharmacy specialist in primary care at Kaiser Permanente of Colorado. Karen J. McConnell, PharmD, FCCP, BCPS (AQ Cardiology), is a clinical pharmacy specialist in cardiology at Kaiser Permanente of Colorado and clinical associate professor, department of clinical pharmacy, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado. Sarah A. Spinler, PharmD, FCCP, FAHA, FASHP, AACC, BCPS (AQ Cardiology), is professor of clinical pharmacy and the residency and industry fellowship programs coordinator at Philadelphia College of Pharmacy at University of the Sciences in Philadelphia. Spinler is the Cardiology Today Pharmacology Consult column editor. She can be reached at Philadelphia College of Pharmacy at University of the Sciences, 600 S. 43rd St., Philadelphia, PA 19104; email: s.spinle@usciences.edu.
Disclosure: The authors report no relevant financial disclosures.