Review Article
Pulmonary Arterial Hypertension: A Review in Pharmacotherapy Bhaumik B. Patel, PharmD, Ying Feng, PharmD, and Angela Cheng-Lai, PharmD
Abstract: Pulmonary arterial hypertension (PAH) is a progressive disease that remains incurable. The past 2 decades have witnessed many advances in PAH-directed therapies. More recently, 3 new oral agents have become available in the United States within the past 2 years. Treprostinil is now available in extended-release oral tablets. Macitentan is the third endothelin receptor antagonist approved for use, demonstrating benefits on morbidity and mortality among patients with PAH in an event-driven study. Riociguat is the first soluble guanylate cyclase stimulator that has been approved for use in the United States. This article reviews the clinical efficacy and safety of these 3 agents and the roles they play in the management of PAH. Additionally, we review the limitations of using surrogate markers such as change in 6-minute walk distance to assess disease progression. Key Words: riociguat, macitentan, oral treprostinil, six-minute walk distance (Cardiology in Review 2015;23: 33–51)
T
his article reviews the 3 newest agents approved for the treatment of pulmonary arterial hypertension (PAH): oral treprostinil, macitentan, and riociguat. The use of 6-minute walk distance (6MWD) as a surrogate marker and other end points that may serve as better predictors of efficacy in the assessment of PAH therapies will also be discussed.
EPIDEMIOLOGY AND PATHOPHYSIOLOGY OF PULMONARY ARTERIAL HYPERTENSION In 1891, a German physician named Ernst von Romberg first described pulmonary vascular lesions seen on autopsy as “pulmonary vascular sclerosis.”1 Over the course of the 20th century, through many experiments and discoveries, scientists have categorized “pulmonary vascular sclerosis” as part of a very debilitating group of diseases known as PAH. PAH, an umbrella term, is a group of rare and progressive diseases characterized by pulmonary artery remodeling. Through various mechanisms and modalities, PAH is associated with and leads to increased pulmonary vascular resistance, right ventricular dysfunction, and eventually death.2 Due to the infrequent diagnosis of PAH, the epidemiology of this group of diseases is difficult to quantify. However, results of various registries have estimated the prevalence of PAH to be about 5–52 cases per 1 million adults.3 PAH is the first of 5 general categories of pulmonary hypertension (PH). The most current PH classification and diagnostic criteria was presented at the 5th World Symposium on Pulmonary Hypertension (WSPH) in 2013 in Nice, France.4 Briefly, group 1 PH consists
From the Department of Pharmacy, Montefiore Medical Center, Bronx, NY. Disclosure: The authors declare no conflict of interest to report. Correspondence: Bhaumik B. Patel, PharmD, Department of Pharmacy, Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467. E-mail: [email protected]. Copyright © 2014 Lippincott Williams & Wilkins ISSN: 1061-5377/15/2301-0033 DOI: 10.1097/CRD.0000000000000042
of heritable PAH, idiopathic PAH, and PAH associated with conditions such as the human immunodeficiency virus (HIV) infection, congenital heart disease, connective tissue disease, portal hypertension, exposures to drugs/toxins, and persistent PH of the new born. Groups 2–4 describe PH caused by left heart disease, lung disease/ hypoxia, and chronic thromboembolic disease, respectively. Group 5 PH is associated with unclear multifactorial mechanisms (eg, patients with chronic renal failure who are on dialysis). Patients are staged according to symptom severity and functional ability, using New York Heart Association or World Health Organization functional class (WHO-FC) I (easily tolerates normal physical activity) through IV (persistent symptoms even at rest).5 Historically, the prognosis for patients with PAH has been poor. In the mid-1980s, 1-, 3-, and 5-year survival rates of patients enrolled in a National Institutes of Health Registry were 68%, 48%, and 34%, respectively, with a median survival of 2.8 years.6 Fortunately, mortality from PAH has improved considerably with the advent of PAHdirected therapies. More recent data from the REVEAL registry reported a diagnosis-to-3-year survival rate of 74% for idiopathic PAH.7 For advanced disease that is uncontrolled in spite of maximal pharmacotherapy, a last line option is lung transplantation. The estimated 5-year survival rate after lung transplantation is ~50%.2 Early PAH management begins with general measures and supportive therapy (eg, pregnancy avoidance, exercise training, anticoagulation, and supplemental oxygen). Patients who may be candidates for chronic calcium channel blocker therapy should undergo vasoreactivity testing.8 For the minority (40 ng/kg/ min - Oral: Starting dose −0.25 mg BID then titrate dose q 3–4 days by 0.25 mg q 12 hours to treatment effect. Max dose is determined by tolerability 6 minutes 7–9 minutes ~4 hours ~9 hours
Epoprostenol11,12
Macitentan20
Riociguat23
Sildenafil21 PDE-5 inhibitor
Tadalafil22
Oral-tablets
5 hours
16 hours (active metabolite 48 hours)
62.5–125 mg BID 10 mg daily
Oral-tablets
12 hours
0.5–2.5 mg TID
Oral-tablets
Oral-tablets
~4 hours
(Continued)
35 hours (for PAH dosing)
IV: 2.5 or 10 mg 40 mg once daily TID Oral: 5 or 20 mg TID (taken 4–6 hours apart)
IV, oral-tablets
PAH WHO group PAH WHO group PAH WHO group PAH WHO group PAH WHO group 1; FC II, III, IV 1; FC not 1; FC II and III 1; FC not 1; FC II, III specified specified
Antagonist of ET-1 Antagonist of ET-1 Stimulates soluble PDE-5 inhibitor receptor types A receptor types A guanylate and B and B cyclase leading to downstream activation of the nitric oxide pathway
Bosentan18
Table 1. Characteristics of Pulmonary Arterial Hypertension-Specific Pharmacotherapies
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REMS program
Boxed warnings
Dose adjustment
Properties
Iloprost13
Treprostinil14–16
Ambrisentan17
- No dose - No dose - No dose - No dose adjustment adjustment adjustment adjustment necessary for provided in necessary for necessary for manufacturer’s renal impairment renal impairment renal or hepatic labeling for Hepatic Hepatic impairment impairment renal or hepatic impairment: - Inhalation: Titrate impairment - Child–Pugh class slowly B or C: Consider - IV & SubQ increasing infusion: Mild to dosing interval moderate hepatic (eg, every 3–4 impairment: hours) based on Initial: 0.625 ng/ response kg/min (ideal body weight). Use with caution and titrate slowly. Severe hepatic impairment: There are no dosage adjustments provided in manufacturer’s labeling (has not been studied). Use with caution and titrate slowly -Oral: Mild hepatic impairment: Initial: 0.125 mg q 12 hours; increase in increments of 0.125 mg every 12 hours every 3–4 days Moderate hepatic impairment: Avoid use Severe hepatic impairment: Use is contraindicated N/A N/A N/A Embryo-fetal toxicity No No No Yes
Epoprostenol11,12
Table 1. (Continued) Macitentan20
Riociguat23
Sildenafil21
Tadalafil22
Hepatotoxicity, Teratogenicity Yes
Embryo-fetal toxicity Yes
Embryo-fetal toxicity Yes
No
N/A
No
N/A
(Continued)
- No dose No dose adjustment - Renal impairment:- No dose Renal Impairment: adjustment necessary for Severe (CrCl adjustment CrCl 31–80 mL/ necessary for renal or hepatic 2.5 mg 3 times/ day; consider dose decrease with smoking cessation
Bosentan18
Patel et al Cardiology in Review • Volume 23, Number 1, January/February 2015
© 2014 Lippincott Williams & Wilkins
Epoprostenol11,12
Iloprost13
Treprostinil14–16
Contraindications - Hypersensitivity N/A Oral: Severe to epoprostenol hepatic or to structurallyimpairment related (Child–Pugh compounds class C) - Chronic use in patients with heart failure due to severe left ventricular systolic dysfunction - Patients who develop pulmonary edema during dose initiation Adverse drug - Tachycardia - Flushing - Flushing reactions - Flushing - Hypotension - Headache - Hypotension - Headache - Skin rash - Dizziness - Nausea - Diarrhea - Headache - Jaw pain - Nausea - Anxiety - Cough - Pain at injection - Nausea - Flu-like syndrome site (subQ) - Vomiting - Trismus - Infusion site - Diarrhea reaction (IV) - Infection - Limb pain (Oral) - Skin, jaw, - Jaw pain musculoskeletal - Cough pain (inhalation) - Skin ulcer - Throat irritation - Chills/fever/flu(inhalation) like syndrome
Properties
Table 1. (Continued)
© 2014 Lippincott Williams & Wilkins - Anemia - Nasopharyngitis - Bronchitis - Headache - Influenza - Urinary tract infection
- RTI - Headache - Edema - Chest pain - Syncope - Sinusitis - Flushing - Hypotension - Anemia
- Peripheral edema - Nasal congestion - Sinusitis - Flushing
Macitentan20
- Pregnancy - Pregnancy - Concurrent use of cyclosporine or glyburide
Bosentan18
- Pregnancy - IPF
Ambrisentan17
Sildenafil21
Tadalafil22
- Peripheral edema - Headache - Dyspepsia - Anemia - Nausea - Vomiting - Diarrhea
(Continued)
- Flushing - Flushing - Headache - Headache - Dyspepsia - Dyspepsia - Visual disturbance - Myalgia - Epistaxis - Back/extremity pain - RTI - Nasopharyngitis
- Pregnancy - Hypersensitivity - Concurrent use - Coadministration to sildenafil or with nitrates of with nitrates any component any dosage form or nitric oxide of the donors (eg, amyl formulation nitrite) in any - Concurrent use form with nitrates of - Concomitant any dosage form administration with specific PDE and nonspecific PDE inhibitors
Riociguat23
Cardiology in Review • Volume 23, Number 1, January/February 2015 Pulmonary Arterial Hypertension
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Epoprostenol11,12
Iloprost13
Treprostinil14–16
Ambrisentan17
Bosentan18
Macitentan20
40 | www.cardiologyinreview.com Sildenafil21
Tadalafil22
$7875
Oral: $125 (generic equivalent) IV: $190 for a 10 mg/12.5 mL vial
$1785
- The concurrent - The concurrent - The concurrent use of riociguat use of sildenafil use of tadalafil with nitrates with nitrates or with nitrates or or PDEI is other PDEI is other PDEI is contraindicated contraindicated contraindicated - Strong CYP3A - Monitor blood - Monitor blood inhibitors: pressure when pressure when Consider starting co-administering co-administerat 0.5 mg with ing with TID to avoid antihypertensive antihypertensive hypotension agents agents - PGP/BCRP - Concomitant use - Concomitant inhibitors: of ritonavir and use of ritonavir Consider starting other strong and other at 0.5 mg CYP 3A4 strong CYP 3A TID to avoid inhibitors with inhibitors with hypotension sildenafil is not tadalafil is not - Strong CYP3A recommended recommended inducers may - Concomitant reduce riociguat use with strong exposure CYP 3A - Antacids decrease inducers is not riociguat recommended absorption. Antacids should not be taken within 1 hour of taking riociguat
Riociguat23
Mild hepatic impairment: Child–Pugh class A; mild–moderate hepatic impairment: Child–Pugh class A and B; moderate–severe hepatic impairment: Child–Pugh class B and C; moderate hepatic impairment: Child–Pugh class B; severe hepatic impairment: Child–Pugh class C. *Cost estimates for oral treprostinil and intravenous sildenafil were obtained from UptoDate; all other cost estimations were obtained from the Massachusetts Medicaid claims website. †Estimated cost does not include any additional administration, supply, or labor costs. BCRP indicates breast cancer resistance protein; ESRD, endstage renal disease; ET, endothelin; FC, functional class; IPF, idiopathic pulmonary fibrosis; PDEI, phosphodiesterase type 5 inhibitors; PGP, P-glycoprotein; REMS, risk evaluation and mitigation strategies; RTI, respiratory tract infection; SubQ, subcutaneous injection.
- Concomitant - Concomitant - Coadminstration Cyclosporine: - Discontinue - Avoid administration of administration of with CYP2C8 - Dose adjustment bosentan 36 coadministration antihypertensives antihypertensives inducers may necessary, limit hours before with strong and other and other decrease plasma ambrisentan dose initiation of CYP3A4 vasodilators with vasodilators with exposure of to 5 mg/d ritonavir; wait inducers epoprostenol illoprost may parenteral and at least 10 - Avoid may increase risk increase risk for oral treprostinil days before coadministration for hypotension hypotension - Coadminstration reinitiating with strong - Concomitant - Concomitant with CYP2C8 bosentan CYP3A4 administration administration inhibitors may - Decreased serum inhibitors of anticoagulants of anticoagulants increase plasma concentration of with with illoprost exposure of contraceptives epoprostenol may increase risk parenteral and - Reduced may increase risk of bleeding oral treprostinil concentrations of bleeding - Concomitant of medications - Concomitant administration of that are CYP3A4 administration antihypertensives substrates of digoxin with and other epoprostenol may vasodilators with increase serum parenteral and concentration of oral treprostinil digoxin may increase risk for hypotension - Concomitant administration of anticoagulants with parenteral and oral treprostinil may increase risk of bleeding $14,554.00 Oral: 3.5mg twice $6773 $7183 $7182 Estimated cost per Flolan®: $5688 Veletri®: $6098 daily $10,000 month*†, 13–15 IV: $18,571; Inhalation: $13,032
Drug interactions
Properties
Table 1. (Continued) Patel et al Cardiology in Review • Volume 23, Number 1, January/February 2015
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Cardiology in Review • Volume 23, Number 1, January/February 2015
play a role in the excretion of macitentan.36 In a phase I pharmacokinetic study of 6 healthy patients who were administered radiolabeled macitentan, approximately 50% of the drug was eliminated in the urine and about 24% of the drug was recovered from feces.36 Contents recovered from the urine were neither the unchanged drug nor the active metabolite. A recent phase I pharmacokinetic study assessed the impact of renal and hepatic impairment on the pharmacokinetics of macitentan.37 In this clinical trial, 2 substudies were conducted, 1 for patients with hepatic impairment (n = 8) and 1 for patients with renal impairment (n = 8). The investigators found that in patients with hepatic impairment, the mean plasma concentration and Cmax of macitentan was lower when compared to healthy subjects. In patients with mild, moderate, and severe hepatic impairment, the mean Cmax of macitentan was 152, 104, and 161 ng/mL, respectively; whereas the mean Cmax of macitentan was 197 ng/mL in healthy subjects. Similarly, the mean Cmax of the active metabolite, ACT-132577, was found to be lower in patients with mild, moderate and severe hepatic impairment (117, 124, and 120 ng/mL, respectively) compared to that of healthy subjects (158 ng/mL). In patients with renal impairment, the mean Cmax was 11% higher, half-life was 8% longer and AUC (Area Under the Curve) had an increase of 24% when compared to healthy subjects. Because of the relatively small changes in pharmacokinetic parameters, the authors concluded that the effects of hepatic or renal impairment on the pharmacokinetics and safety of macitentan and ACT-132577 are not clinically relevant and therefore no dose adjustments are required in these patients.
Pharmacodynamics The pharmacodynamic properties, in particular, differentiate macitentan from its ERA counterparts (ie, ambrisentan and bosentan).38 In an in vivo study, Gatfield et al38 found that macitentan has slower receptor dissociation from ETA and ETB compared to the ambrisentan and bosentan. Macitentan’s overwhelming inhibition of ETA and ETB appears to increase plasma concentration of ET-1 by displacing ET-1 from its receptor sites. A 2013 double-blinded, randomized, controlled trial which assessed the pharmacokinetics and pharmacodynamics of various doses of macitentan found a trend of increasing plasma ET-1 concentrations with increasing doses of macitentan (ie, 1, 3, 10, and 30 mg). On day 10 (at steady state) the investigators found a statistically significant dose-dependent increase in plasma concentration of ET-1 for the 10 and 30 mg doses when compared to the 1 and 3 mg doses.39 The maximum increase in ET-1 was seen with the10 mg dose, which increased ET-1 concentrations by twofold. A further increase in plasma ET-1 concentration was not seen with the 30 mg dose; thus, the study of this higher dosage strength was not pursued. A cardiac hemodynamic substudy of patients from the study with an Endothelin Receptor Antagonist in PAH to Improve Clinical Outcome (SERAPHIN) trial assessed the treatment effect of macitentan on hemodynamic variables from baseline to month 6.40 The study found that patients treated with macitentan 10 mg (n = 57) had a median reduction of 37% [95% confidence interval (CI), 22–49] in pulmonary vascular resistance and an increase of 0.6 L/min/m2 (95% CI, 0.3–0.9) in cardiac index compared to placebo (n = 67).
Clinical Studies In October 2013, macitentan received approval from the FDA for the treatment of PAH WHO group I based on the results of the SERAPHIN trial.41 SERAPHIN was a multicenter, double blinded, randomized, placebo-controlled, event driven, phase 3 trial.42 Patients were included in the study if they met the following criteria: 12 years of age or older, a history of Idiopathic PAH, heritable PAH or PAH related to connective-tissue disease, repaired congenital systemic to pulmonary shunts, HIV, or drug use or toxin exposure, confirmation with right heart catheterization, a 6MWD of 50 m or more, © 2014 Lippincott Williams & Wilkins
Pulmonary Arterial Hypertension
and WHO-FC II, III, IV. Patients were allowed to have background therapy with an PDE-5 inhibitor, oral or inhaled prostanoids, calcium channel blockers, and/or arginine if they were stable on the therapy for at least 3 months. Patients were randomized based on a 1:1:1 stratification within 28 days of screening to placebo once daily, macitentan 3 mg once-daily or macitentan 10 mg once-daily. Patients were monitored for 6MWD and WHO-FC at 3 months, 6 months, and every 6 months thereafter. The primary end point was time from the initiation of treatment to the first event related to PAH or death from any cause.42 A first event related to PAH was defined as worsening of PAH, initiation of treatment with intravenous or subcutaneous prostanoids, lung transplantation, or atrial septostomy. Worsening of PAH was defined as having the following 3 criteria: (1) at least 15% decrease in 6MWD from baseline (reconfirmed within 2 weeks), (2) worsening of PAH symptoms, and (3) the need of additional treatment for PAH. The criteria for worsening of PAH symptoms were defined as: change to higher WHO-FC from baseline and/or the appearance or worsening of signs of right heart failure that did not respond to oral diuretic therapy. The secondary outcomes of the study were change in 6MWD at month 6 from baseline, percentage of patients with an improvement in WHO-FC at month 6, death due to PAH or hospitalization due to PAH, and death from any cause. Safety end points included adverse events and laboratory abnormalities. A total of 742 patients were enrolled. There were 116 primary end point events in the placebo arm, 95 primary end point events in the macitentan 3 mg arm [hazard ratio (HR): 0.70 (0.52–0.96), P < 0.01 compared to placebo] and 76 primary end point events in the macitentan 10 mg arm [HR: 0.55 (0.32–0.76), P < 0.001 compared to placebo] (total primary end point events = 287). The most frequent cause of the primary end point was worsening of PAH. With regards to secondary end points, the composite end point of death due to PAH or hospitalization for PAH as a first-time event occurred in 84 patients in the placebo, 65 patients in the macitentan 3 mg arm [HR: 0.67 (0.46–0.97), P < 0.01 compared to placebo] and 50 patients in the macitentan 10 mg arm [HR: 0.50 (0.34–0.75), P < 0.001 compared to placebo]. The 6MWD, from baseline to 6 months, decreased by a mean of 9.4 m in the placebo arm, increased by a mean of 7.4 m in the macitentan 3 mg arm (treatment effect with a 3 mg dose vs placebo, 16.8 m; 97.5% CI, −2.7 to 36.4 m; P = 0.01), and increased by a mean of 12.5 m in the macitentan 10 mg arm (treatment effect with a 10 mg dose vs placebo, 22.0 m; 97.5% CI, 3.2 –40.8 m; P = 0.008). The WHO-FC from baseline to 6 months improved in 13% of patients in the placebo arm, improved in 20% of patients in the macitentan 3 mg arm (P = 0.04) and improved in 22% of patients in the macitentan 10 mg arm (P = 0.006). Treatment discontinuation, due to adverse events, was observed in 31 patients (12.4%) in the placebo group, 34 patients (13.6%) in the macitentan 3 mg group and 26 patients (10.7%) in the macitentan 10 mg group. The incidence of peripheral edema, and mean increases in Aspartate Aminotransferase (AST)/Alanine Transaminase (ALT) (3 times above the upper normal limit) was similar among the 3 groups. The authors conclude that macitentan significantly reduced morbidity and mortality in patients with PAH. The SERAPHIN trial took a novel approach in assessing the efficacy of macitentan in patients with PAH. Traditionally, the 6MWD has been considered the gold standard marker in assessing functional status of patients with PAH.43 The SERAPHIN trial, the first of its kind, assessed efficacy with an event-driven approach over a long period of time (ie, median follow up time of 2.2 years). This approach may have a better correlation between treatment effectiveness and long-term clinical outcomes compared to the 6MWD.44
Adverse Effects Macitentan may cause fetal harm and is therefore contraindicated in females who are pregnant. Therefore, for females, www.cardiologyinreview.com | 41
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macitentan is only available through a restricted risk evaluation and mitigation strategy (REMS) program called the OPSUMIT REMS program because of the risk of embryo-fetal toxicity.20 Safety data for macitentan was primarily obtained from the SERAPHIN study.42 The incidence of treatment discontinuations because of adverse events was similar between macitentan and placebo (approximately 11%). The most common adverse events observed for macitentan and placebo respectively were: anemia (13% vs 3%), nasopharyngitis/pharyngitis (20% vs 13%), bronchitis (12% vs 6%), headache (14% vs 9%), influenza (6% vs 2%), and urinary tract infections (9% vs 6%).42 ERAs are known to cause aminotransferase elevation.9 The incidence of discontinuation due to hepatic adverse events was 3.3% in the macitentan group and 1.6% in the placebo group. In the SERAPHIN study, the incidence of elevated aminotransferases to greater than 3 times the upper limits of normal was 3.4% in the macitentan group vs 4.5% in the placebo group and the incidence of elevated aminotransferases to greater than 8 times the upper limits of normal was 2.1% in the macitentan group vs 0.4% in the placebo group.42 Of note, a decrease in hemoglobin to less than 10.0 g/dL was reported in 8.7% of the macitentan group and in 3.4% of the placebo group in the SERAPHIN study.42
Drug–Drug Interactions Macitentan is predominantly metabolized by the CYP3A4 enzyme. This characteristic predisposes macitentan to various drug–drug interactions. Based on the results of in vivo studies, macitentan should not be used concomitantly with potent CYP3A4 inducers or inhibitors such as rifampin or ketoconazole due to clinically significant alterations in the AUC and the serum concentration of macitentan.20 A 2012 phase 1 study by Bruderer et al45 sought to assess the impact of multidose cyclosporine and rifampin (2 part 1 sequence crossover study) on the pharmacokinetics of macitentan. Twenty male patients were enrolled (10 patients randomized to macitentan followed by macitentan + cyclosporine and 10 patients randomized to macitentan followed by macitentan + rifampin). The study found that when macitentan was co-administered with cyclosporine, there was no clinically relevant alteration in the pharmacokinetics of macitentan (Ctr of macitentan alone 159 ng/mL vs 220 ng/mL for macitentan + cyclosporine). However, when macitentan was co-administered with rifampin, the serum concentration of macitentan was lower when compared to the administration of macitentan alone (Ctr 11 vs 157 ng/mL, respectively). Interestingly, no significant difference was seen in the serum concentration of the active metabolite, ACT132577, when macitentan was co-administered with rifampin compared to macitentan administration alone. The authors concluded that cyclosporine does not impact the pharmacokinetics of macitentan to a clinically relevant extent. However, macitentan may have reduced efficacy when rifampin is co-administered.45 Atsmon et al conducted a phase 1, open-label study to assess the impact of the potent CYP3A4 inhibitor ketoconazole on the pharmacokinetics of macitentan.46 Twelve males were randomized to either 1 single dose of macitentan alone (group A) or ketoconazole for 4 days followed by 1 dose of macitentan on day 5 and ketoconazole thereafter daily until day 19 (group B). The study found that the mean half life of macitentan in group A was 14.1 and 28.5 hours in group B. The Cmax was 227 ng/mL in group A and 290 ng/mL in group B. As expected, the Cmax of active metabolite ACT-132577 was lower in group B compared to that of group A (87.6 vs 178 ng/mL, respectively). The authors state that although the Cmax of the active metabolite is lower when macitentan is given with ketoconazole compared to macitentan being given alone, ACT-132577 is 5 times less potent 42 | www.cardiologyinreview.com
compared to the unchanged parent molecule and thus the lower Cmax does not impact the efficacy to a clinically relevant extent. They concluded that the co-administration of ketoconazole with macitentan does not warrant dose adjustment.46
Indication, Dosage, Administration, and Cost Macitentan is a nonselective ERA indicated for the treatment of PAH to delay disease progression.20 It is available as oral filmcoated tablets, and the daily recommended dose is 10 mg.20 Doses higher than 10 mg were not found to further increase ET-1 concentrations, and should not be used.39 Macitentan can be administered with or without food, though the tablet should not be crushed, split, or chewed before swallowing.20 If a dose of macitentan is missed, it should be taken as soon as the patient remembers that day, and the next dose should be taken at the regular time; 2 doses should not be taken at the same time to make up for a missed dose.20 The cost for a 1-month supply of macitentan 10 mg daily is greater than $7000 (Table 1).47
RIOCIGUAT sGC is a key intracellular enzyme in the NO signaling pathway that catalyzes the synthesis of cyclic guanosine monophosphate (cGMP), a second messenger that promotes vasodilation. sGC has attracted interest as a therapeutic target due to the association between impaired NO and cGMP signaling and cardiovascular disease in general, including PH.24 In addition to vasodilation, sGC activation also initiates a series of beneficial downstream effects including inhibition of smooth muscle proliferation, leukocyte recruitment, and platelet aggregation. Organic nitrates and NO donors have long been used in the treatment of cardiovascular disease. However, the use of direct NO supplementation is limited by the tolerance that patients often develop with long-term therapy, and the association between cardiovascular disease and NO resistance.24 In a similar vein, PDE-5 inhibitors augment existing NO by preventing its degradation, but have a limited role in environmental conditions when there is little to no endogenous NO.8 sGC modulation offers an alternative method of stimulating the NO-sGC-cGMP pathway. Oral riociguat is the first sGC stimulator on the market, and has a dual mechanism of action.23 It stabilizes NO-sGC binding, thereby sensitizing sGC to endogenous NO. Additionally, it directly stimulates sGC in the absence of NO.23,24 In vitro, riociguat increases sGC activity up to 73-fold via direct stimulation, and up to 122-fold in the presence of NO.24 Currently, riociguat is recommended for inoperable or persistent chronic thromboembolic PH and for both initial monotherapy and sequential combination therapy for PAH.8,9
Pharmacokinetics Riociguat has an absolute oral bioavailability of 94%, with peak plasma concentrations occurring 1.5 hours after ingestion, regardless of co-administration with food.23 Riociguat exhibits dose proportional pharmacokinetics in healthy males given single doses of 0.5–2.5 mg; there is a direct relationship between riociguat plasma concentrations and hemodynamic parameters such as pulmonary vascular resistance, cardiac output, and systolic blood pressure.23,48 The volume of distribution is approximately 30 L. Riociguat is mainly metabolized hepatically by CYP2C8, CYP2J2, CYP3A, and CYP1A1, the last of which catalyzes the formation of the major active metabolite, M1. M1 exhibits 10–33% of the activity of riociguat, and is inactivated by N-glucuronidation; the ratio of riociguat to M1 in PAH patients is roughly 2:1.23 Riociguat’s terminal elimination halflife is 12 hours in PAH patients and 7 hours in healthy subjects; it is eliminated both renally and fecally. The AUC and Cmax of riociguat and M1 are not significantly affected by Child-Pugh A/B hepatic impairment, mild to severe renal impairment, age >65 (as compared © 2014 Lippincott Williams & Wilkins
Cardiology in Review • Volume 23, Number 1, January/February 2015
to age >45), or gender. The safety and efficacy of riociguat has not been demonstrated in patients on dialysis, with creatinine clearance of less than 15 mL/min, or with severe hepatic impairment (Child Pugh C). Riociguat is highly protein bound, and is not expected to be dialyzable in the event of an overdose.23
Clinical Studies The major double-blinded, placebo-controlled, multicenter clinical trials evaluating the safety and efficacy of riociguat for PH indications are PATENT-1 (PAH sGC-Stimulator Trial 1) and CHEST-1 (Riociguat for the Treatment of Chronic Thromboembolic PH), both of which also include long-term extension trials (CHEST-2 and PATENT-2).49,50 Both studies enrolled adults ≥18 years of age, and studied the primary end point of change in 6MWD from baseline over 12 weeks (PATENT-1) and 16 weeks (CHEST-1). Secondary end points included change in pulmonary vascular resistance, levels of N-terminal prohormone brain-type natriuretic peptide (NT-proBNP), WHO-FC, and time to clinical worsening. Taken together, PATENT-1 and CHEST-1 show that riociguat, as monotherapy and adjunctive therapy, produces clinically significant changes in 6MWD. In both studies, a sensitivity analysis indicated that the results were reliable in spite of the missing follow-up efficacy measurements in patients lost to follow-up.49,50 PATENT-1 took place in 124 centers in 30 countries, and enrolled 443 symptomatic PAH patients who were not on pharmacotherapy (50%), or on a stable dose of an ERA (44%) or a nonintravenous prostacyclin analogue (6%) at baseline.49 The majority of the enrolled patients had symptomatic idiopathic PAH (61%). Oral anticoagulants, diuretics, and supplemental oxygen at stable doses were permitted, but patients were excluded if they were receiving a PDE-5 inhibitor. In the treatment arm, riociguat doses were individually titrated, as tolerated by blood pressure, to a maximum of 2.5 mg 3 times daily. Additionally, 63 patients were randomized to an exploratory arm with a 1.5 mg 3 times daily dose cap. At baseline, the study participants predominately fell into WHO-FC II (42%) and WHO-FC III (54%), and had a mean 6MWD of 363 ± 69 m.49 Riociguat displayed a significant benefit in 6MWD at the end of 12 weeks, with a least squares mean (LSM) difference of 36 m between the placebo and treatment groups (95% CI, 20–52 m, P < 0.001) in a modified intention-to-treat analysis (2 patients were randomized in error, and never received study drug).49 This treatment effect was similar for patients regardless of baseline pharmacotherapy status, but patients with more advanced disease showed greater benefit (LSM difference 59 m; 95% CI, 37–81) than patients with less advanced disease (LSM difference of 14 m; 95% CI, −9 to 36). The majority (75%) of the patients in the treatment group were receiving the maximal riociguat dose at week 12, and the proportion of patients who required dose decreases over the study time frame was similar between the 2 groups (12% riociguat, 9% placebo). Riociguat significantly improved many secondary end points, including pulmonary vascular resistance (LSM difference = −226 dyn∙s∙cm−5, P < 0.001), mean pulmonary-artery pressure (LSM difference = −7 mm Hg, P < 0.001), cardiac output (LSM difference = 0.9 L/min, P < 0.001), NT-proBNP levels (LSM difference = −432 pg/mL, P < 0.001), and WHO-FC (21%/4% in the riociguat group moved to a lower class/ higher class, vs 14%/14% in the placebo group, P = 0.003). Furthermore, patients in the treatment group experienced fewer overall episodes of clinical worsening (1% riociguat vs 6% placebo, respectively, P = 0.05), which included hospitalization, initiation of new treatment, decrease in 6MWD, worsening of WHO-FC, and death.49 CHEST-1 enrolled 261 adult chronic thromboembolic PH patients not receiving pharmacotherapy for PH (an ERA, prostacyclin analogue, PDE-5 inhibitor, or NO donor) whose disease was judged to be technically inoperable, or who experienced persistent disease after pulmonary endarterectomy.50 Patients were randomized © 2014 Lippincott Williams & Wilkins
Pulmonary Arterial Hypertension
to receive riociguat, starting at 1 mg 3 times daily and titrated to a maximum of 2.5 mg 3 times daily, or placebo. At baseline, the patients were predominantly in WHO-FC II (31%) and WHO-FC III (64%), with an average age of 59 ± 14 years and an average 6MWD of 347 ± 80 m. Most (72%) of those enrolled had inoperable disease. Though 77% of patients remaining at week 16 were receiving the maximal dose, end doses ranged from 0.5 mg to 2.5 mg 3 times daily.50 At 16 weeks, riociguat had produced a greater increase in 6MWD than had placebo (LSM difference 46 m; 95% CI, 25–67; P < 0.001), with consistent effects across patient subgroups (inoperable vs postoperative disease, WHO-FC, baseline 6MWD, age, and sex). Riociguat also showed benefits on secondary end points of pulmonary vascular resistance (LSM difference −246 dyn∙s∙cm−5; 95% CI, −303 to −190; P < 0.001), improvement in pulmonary-artery pressure (LSM difference = −5 mm Hg, P < 0.001), cardiac output (LSM difference = 0.9 L/min, P < 0.001), reductions in NT-proBNP levels (LSM difference = −444 pg/mL, P < 0.001), and change in WHO-FC (in the riociguat group 33% moved to a lower FC, whereas 5% moved to a higher FC, and in the placebo group 15% moved to a lower FC, whereas 7% moved to a higher FC). There was no significant difference in incidence of clinical-worsening events.50
Adverse Effects When adverse drug reactions from PATENT-1 and CHEST-1 were pooled, the most common side effects observed for riociguat and placebo, respectively, were: headache (27% vs 18%), dyspepsia (21% vs 8%), dizziness (20% vs 13%), nausea (14% vs 11%), diarrhea (12% vs 8%), and hypotension (10% vs 4%). Other observed effects included vomiting, constipation, GERD, and anemia.23 Rare adverse reactions that resulted in study discontinuation included increased hepatic enzyme levels (n = 1), acute renal failure (n = 1), syncope (n = 3), esophageal pain/swelling (n = 1), as well as supraventricular tachycardia, hypotension, edema, and neck pain. Interestingly, the pooled discontinuation rate was lower for riociguat (2.9%) than for placebo (5.1%).23
Drug Interactions/Contraindications/Warnings The concomitant use of riociguat with nitrates, NO donors, or PDE-5 inhibitors is contraindicated.23 In the phase II drug interaction study PATENT PLUS, combination therapy of riociguat and sildenafil did not show benefit in 6MWD, WHO-FC, or pulmonary hemodynamics. Furthermore, the combination displayed a high drop-out rate due to hypotension in the long-term extension.9,51 Exposure to polycyclic aromatic hydrocarbons, such as those found in cigarette smoke, induces the production of riociguat’s major active metabolite.23 Cigarette smokers may warrant doses higher than 2.5 mg thrice daily, as plasma concentrations of riociguat are reduced 50–60% in this population when compared to nonsmokers. Conversely, downtitration of dosage may be required if patients successfully cease smoking. Antacid medications should not be given within an hour of riociguat administration due to their ability to decrease riociguat’s absorption. Strong CYP/P-glycoprotein/BCRP inhibitors will increase drug exposure, and would warrant particularly close monitoring for symptoms of hypotension; a lower starting dose (0.5 mg 3 times daily) may be considered.23 Riociguat is contraindicated in pregnancy (category X).23 For women of reproductive potential (premenarchal through menopause), riociguat is only available through a REMS program which requires monthly pregnancy testing and use of acceptable methods of contraception until 1 month after medication discontinuation. In animal studies, an increase in spontaneous abortions was seen in rabbits given 4 times the human exposure, and postimplantation loss was significantly increased in rats at 2 times the human exposure. www.cardiologyinreview.com | 43
Change in 6MWD from Baseline
In a 2009 meta-analysis of 3 studies63 (N = 213), the mean change in 6MWD from the pooled results was 81 m (95% CI, 45–117)
AIR study64 Mean placebo-corrected change in 6MWD was 36.4 m in the iloprost group (P = 0.004) at week 12
Medication
Epoprostenol
Iloprost
44 | www.cardiologyinreview.com N/A
AIR study64 N/A Clinical deterioration at 12 weeks: (P = 0.41) • Placebo (n = 102): 8.8% • Iloprost (n = 101): 4.9%
N/A
Clinical Worsening
Hospitalization WHO FC II: • Parenteral prostanoids should not be used as initial therapy in treatment naive patients, but may be used as second line therapy for nontreatment naive patients who have not met their goal (WSPH makes no recommendation for epoprostenol in WHO FC II++)
Guideline Consensus+
(Continued)
WHO FC III: • For treatment naive patients who have evidence of rapid progression of disease or other markers of poor prognosis, consider initial initiation of parenteral prostanoid: • Improve FC (Grade CB) • Improve 6MWD (Grade CB) • Improve cardiopulmonary hemodynamics • For patients on 1 or 2 classes of oral agents, consider addition of inhaled or parenteral prostanoid if there is evidence of disease progression or poor clinical prognosis to: • Improve FC (Grade CB) • Improve 6MWD (Grade CB) • Improve cardiopulmonary hemodynamics WHO FC III or IV patients: Patients symptomatic on stable doses of intravenous epoprostenol, consider up titration of intravenous epoprostenol to improve 6MWD (Grade CB) WHO FC II: AIR study64 Death at 12 weeks: (P = 0.37) • Inhaled prostanoids should not be used as initial therapy • Placebo (n = 102): 4 (0.90%) in treatment naive patients, but may be used as second line • Iloprost (n = 101): 1 (3.57%) therapy for nontreatment naive patients who have not met their goal WHO FC III: • For patients remaining symptomatic on stable and appropriate doses of an ERA or PDE-5I, consider, addition of inhaled Iloprost to improve WHO FC (Grade CB) • Use to delay time to clinical worsening (Grade CB) WHO FC IV • Treatment naive PAH patients who are unable to tolerate or do not desire parenteral prostanoid therapy, use iloprost to: • Improve 6MWD (Grade CB) • Improve WHO FC (Grade CB) WHO FC III or IV patients: Symptomatic patients on stable doses of ERA or PDE-5I, inhaled iloprost can be added to improve 6MWD (Grade CB)
63
Death 2009 meta-analysis • Number of studies assessed: 3 • N = 215 • OR: 0.37 in favor of epoprostenol (95% CI, 0.09–1.57) 5 deaths in epoprostenol group; 16 deaths occurred in the placebo group
Table 2. Clinical Attributes of Pulmonary Arterial Hypertension-Specific Pharmacotherapies
Patel et al Cardiology in Review • Volume 23, Number 1, January/February 2015
© 2014 Lippincott Williams & Wilkins
Treprostinil
Clinical Worsening
Change in 6MWD from Baseline
TRIUMPH study65 (N = 235): TRIUMPH open-label extension Inhaled treprostinil between study (N = 206),66 number of cumulative clinical worsening treatment (ie, patients in events (including death): both standard therapy and 12 months: 34 intervention group were on 24 months: 54 background therapy with a PDE-5I or ERA) median difference at week 12: 20 m (95% CI: 8.0–32.8, P = 0.0004) TRIUMPH open-label extension study, median change in 6MWD66: • 6 months: 28 m (P < 0.0001, n = 170) • 12 months: 31 m (P < 0.0001, n = 152) • 18 months: 32 m (P < 0.0001, n = 134) • 24 months: 18 m (P < 0.0001, n =118) Parenteral treprostinil: In a double-blinded study of 470 patients,67 the difference in median distance walked between the subcutaneous treprostinil and placebo groups, at week 12, was 16 m (95% CI, 4.4 m–27.6 m, Hodges–Lehmann estimate of the median difference, P = 0.006) Placebo corrected median difference in 6MWD from baseline for oral treprostinil studies: • FREEDOM-M (N = 228†): 23 m (P = 0.0125)28,68 • FREEDOM-C (N = 354): 11 m (P = 0.07)29 • FREEDOM-C2 (N = 310): 10 m (P = 0.089)30
Medication
Table 2. (Continued) Hospitalization TRIUMPH study65: • Inhaled treprostinil (n = 115): 4 (3%) • Placebo (n = 120): 5 (4%)
Death TRIUMPH study65: • Inhaled treprostinil (n = 115): 0 • Placebo (n = 120): 1 (
Pulmonary Arterial Hypertension: A Review in Pharmacotherapy Bhaumik B. Patel, PharmD, Ying Feng, PharmD, and Angela Cheng-Lai, PharmD
Abstract: Pulmonary arterial hypertension (PAH) is a progressive disease that remains incurable. The past 2 decades have witnessed many advances in PAH-directed therapies. More recently, 3 new oral agents have become available in the United States within the past 2 years. Treprostinil is now available in extended-release oral tablets. Macitentan is the third endothelin receptor antagonist approved for use, demonstrating benefits on morbidity and mortality among patients with PAH in an event-driven study. Riociguat is the first soluble guanylate cyclase stimulator that has been approved for use in the United States. This article reviews the clinical efficacy and safety of these 3 agents and the roles they play in the management of PAH. Additionally, we review the limitations of using surrogate markers such as change in 6-minute walk distance to assess disease progression. Key Words: riociguat, macitentan, oral treprostinil, six-minute walk distance (Cardiology in Review 2015;23: 33–51)
T
his article reviews the 3 newest agents approved for the treatment of pulmonary arterial hypertension (PAH): oral treprostinil, macitentan, and riociguat. The use of 6-minute walk distance (6MWD) as a surrogate marker and other end points that may serve as better predictors of efficacy in the assessment of PAH therapies will also be discussed.
EPIDEMIOLOGY AND PATHOPHYSIOLOGY OF PULMONARY ARTERIAL HYPERTENSION In 1891, a German physician named Ernst von Romberg first described pulmonary vascular lesions seen on autopsy as “pulmonary vascular sclerosis.”1 Over the course of the 20th century, through many experiments and discoveries, scientists have categorized “pulmonary vascular sclerosis” as part of a very debilitating group of diseases known as PAH. PAH, an umbrella term, is a group of rare and progressive diseases characterized by pulmonary artery remodeling. Through various mechanisms and modalities, PAH is associated with and leads to increased pulmonary vascular resistance, right ventricular dysfunction, and eventually death.2 Due to the infrequent diagnosis of PAH, the epidemiology of this group of diseases is difficult to quantify. However, results of various registries have estimated the prevalence of PAH to be about 5–52 cases per 1 million adults.3 PAH is the first of 5 general categories of pulmonary hypertension (PH). The most current PH classification and diagnostic criteria was presented at the 5th World Symposium on Pulmonary Hypertension (WSPH) in 2013 in Nice, France.4 Briefly, group 1 PH consists
From the Department of Pharmacy, Montefiore Medical Center, Bronx, NY. Disclosure: The authors declare no conflict of interest to report. Correspondence: Bhaumik B. Patel, PharmD, Department of Pharmacy, Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467. E-mail: [email protected]. Copyright © 2014 Lippincott Williams & Wilkins ISSN: 1061-5377/15/2301-0033 DOI: 10.1097/CRD.0000000000000042
of heritable PAH, idiopathic PAH, and PAH associated with conditions such as the human immunodeficiency virus (HIV) infection, congenital heart disease, connective tissue disease, portal hypertension, exposures to drugs/toxins, and persistent PH of the new born. Groups 2–4 describe PH caused by left heart disease, lung disease/ hypoxia, and chronic thromboembolic disease, respectively. Group 5 PH is associated with unclear multifactorial mechanisms (eg, patients with chronic renal failure who are on dialysis). Patients are staged according to symptom severity and functional ability, using New York Heart Association or World Health Organization functional class (WHO-FC) I (easily tolerates normal physical activity) through IV (persistent symptoms even at rest).5 Historically, the prognosis for patients with PAH has been poor. In the mid-1980s, 1-, 3-, and 5-year survival rates of patients enrolled in a National Institutes of Health Registry were 68%, 48%, and 34%, respectively, with a median survival of 2.8 years.6 Fortunately, mortality from PAH has improved considerably with the advent of PAHdirected therapies. More recent data from the REVEAL registry reported a diagnosis-to-3-year survival rate of 74% for idiopathic PAH.7 For advanced disease that is uncontrolled in spite of maximal pharmacotherapy, a last line option is lung transplantation. The estimated 5-year survival rate after lung transplantation is ~50%.2 Early PAH management begins with general measures and supportive therapy (eg, pregnancy avoidance, exercise training, anticoagulation, and supplemental oxygen). Patients who may be candidates for chronic calcium channel blocker therapy should undergo vasoreactivity testing.8 For the minority (40 ng/kg/ min - Oral: Starting dose −0.25 mg BID then titrate dose q 3–4 days by 0.25 mg q 12 hours to treatment effect. Max dose is determined by tolerability 6 minutes 7–9 minutes ~4 hours ~9 hours
Epoprostenol11,12
Macitentan20
Riociguat23
Sildenafil21 PDE-5 inhibitor
Tadalafil22
Oral-tablets
5 hours
16 hours (active metabolite 48 hours)
62.5–125 mg BID 10 mg daily
Oral-tablets
12 hours
0.5–2.5 mg TID
Oral-tablets
Oral-tablets
~4 hours
(Continued)
35 hours (for PAH dosing)
IV: 2.5 or 10 mg 40 mg once daily TID Oral: 5 or 20 mg TID (taken 4–6 hours apart)
IV, oral-tablets
PAH WHO group PAH WHO group PAH WHO group PAH WHO group PAH WHO group 1; FC II, III, IV 1; FC not 1; FC II and III 1; FC not 1; FC II, III specified specified
Antagonist of ET-1 Antagonist of ET-1 Stimulates soluble PDE-5 inhibitor receptor types A receptor types A guanylate and B and B cyclase leading to downstream activation of the nitric oxide pathway
Bosentan18
Table 1. Characteristics of Pulmonary Arterial Hypertension-Specific Pharmacotherapies
Cardiology in Review • Volume 23, Number 1, January/February 2015 Pulmonary Arterial Hypertension
www.cardiologyinreview.com | 37
38 | www.cardiologyinreview.com
REMS program
Boxed warnings
Dose adjustment
Properties
Iloprost13
Treprostinil14–16
Ambrisentan17
- No dose - No dose - No dose - No dose adjustment adjustment adjustment adjustment necessary for provided in necessary for necessary for manufacturer’s renal impairment renal impairment renal or hepatic labeling for Hepatic Hepatic impairment impairment renal or hepatic impairment: - Inhalation: Titrate impairment - Child–Pugh class slowly B or C: Consider - IV & SubQ increasing infusion: Mild to dosing interval moderate hepatic (eg, every 3–4 impairment: hours) based on Initial: 0.625 ng/ response kg/min (ideal body weight). Use with caution and titrate slowly. Severe hepatic impairment: There are no dosage adjustments provided in manufacturer’s labeling (has not been studied). Use with caution and titrate slowly -Oral: Mild hepatic impairment: Initial: 0.125 mg q 12 hours; increase in increments of 0.125 mg every 12 hours every 3–4 days Moderate hepatic impairment: Avoid use Severe hepatic impairment: Use is contraindicated N/A N/A N/A Embryo-fetal toxicity No No No Yes
Epoprostenol11,12
Table 1. (Continued) Macitentan20
Riociguat23
Sildenafil21
Tadalafil22
Hepatotoxicity, Teratogenicity Yes
Embryo-fetal toxicity Yes
Embryo-fetal toxicity Yes
No
N/A
No
N/A
(Continued)
- No dose No dose adjustment - Renal impairment:- No dose Renal Impairment: adjustment necessary for Severe (CrCl adjustment CrCl 31–80 mL/ necessary for renal or hepatic 2.5 mg 3 times/ day; consider dose decrease with smoking cessation
Bosentan18
Patel et al Cardiology in Review • Volume 23, Number 1, January/February 2015
© 2014 Lippincott Williams & Wilkins
Epoprostenol11,12
Iloprost13
Treprostinil14–16
Contraindications - Hypersensitivity N/A Oral: Severe to epoprostenol hepatic or to structurallyimpairment related (Child–Pugh compounds class C) - Chronic use in patients with heart failure due to severe left ventricular systolic dysfunction - Patients who develop pulmonary edema during dose initiation Adverse drug - Tachycardia - Flushing - Flushing reactions - Flushing - Hypotension - Headache - Hypotension - Headache - Skin rash - Dizziness - Nausea - Diarrhea - Headache - Jaw pain - Nausea - Anxiety - Cough - Pain at injection - Nausea - Flu-like syndrome site (subQ) - Vomiting - Trismus - Infusion site - Diarrhea reaction (IV) - Infection - Limb pain (Oral) - Skin, jaw, - Jaw pain musculoskeletal - Cough pain (inhalation) - Skin ulcer - Throat irritation - Chills/fever/flu(inhalation) like syndrome
Properties
Table 1. (Continued)
© 2014 Lippincott Williams & Wilkins - Anemia - Nasopharyngitis - Bronchitis - Headache - Influenza - Urinary tract infection
- RTI - Headache - Edema - Chest pain - Syncope - Sinusitis - Flushing - Hypotension - Anemia
- Peripheral edema - Nasal congestion - Sinusitis - Flushing
Macitentan20
- Pregnancy - Pregnancy - Concurrent use of cyclosporine or glyburide
Bosentan18
- Pregnancy - IPF
Ambrisentan17
Sildenafil21
Tadalafil22
- Peripheral edema - Headache - Dyspepsia - Anemia - Nausea - Vomiting - Diarrhea
(Continued)
- Flushing - Flushing - Headache - Headache - Dyspepsia - Dyspepsia - Visual disturbance - Myalgia - Epistaxis - Back/extremity pain - RTI - Nasopharyngitis
- Pregnancy - Hypersensitivity - Concurrent use - Coadministration to sildenafil or with nitrates of with nitrates any component any dosage form or nitric oxide of the donors (eg, amyl formulation nitrite) in any - Concurrent use form with nitrates of - Concomitant any dosage form administration with specific PDE and nonspecific PDE inhibitors
Riociguat23
Cardiology in Review • Volume 23, Number 1, January/February 2015 Pulmonary Arterial Hypertension
www.cardiologyinreview.com | 39
Epoprostenol11,12
Iloprost13
Treprostinil14–16
Ambrisentan17
Bosentan18
Macitentan20
40 | www.cardiologyinreview.com Sildenafil21
Tadalafil22
$7875
Oral: $125 (generic equivalent) IV: $190 for a 10 mg/12.5 mL vial
$1785
- The concurrent - The concurrent - The concurrent use of riociguat use of sildenafil use of tadalafil with nitrates with nitrates or with nitrates or or PDEI is other PDEI is other PDEI is contraindicated contraindicated contraindicated - Strong CYP3A - Monitor blood - Monitor blood inhibitors: pressure when pressure when Consider starting co-administering co-administerat 0.5 mg with ing with TID to avoid antihypertensive antihypertensive hypotension agents agents - PGP/BCRP - Concomitant use - Concomitant inhibitors: of ritonavir and use of ritonavir Consider starting other strong and other at 0.5 mg CYP 3A4 strong CYP 3A TID to avoid inhibitors with inhibitors with hypotension sildenafil is not tadalafil is not - Strong CYP3A recommended recommended inducers may - Concomitant reduce riociguat use with strong exposure CYP 3A - Antacids decrease inducers is not riociguat recommended absorption. Antacids should not be taken within 1 hour of taking riociguat
Riociguat23
Mild hepatic impairment: Child–Pugh class A; mild–moderate hepatic impairment: Child–Pugh class A and B; moderate–severe hepatic impairment: Child–Pugh class B and C; moderate hepatic impairment: Child–Pugh class B; severe hepatic impairment: Child–Pugh class C. *Cost estimates for oral treprostinil and intravenous sildenafil were obtained from UptoDate; all other cost estimations were obtained from the Massachusetts Medicaid claims website. †Estimated cost does not include any additional administration, supply, or labor costs. BCRP indicates breast cancer resistance protein; ESRD, endstage renal disease; ET, endothelin; FC, functional class; IPF, idiopathic pulmonary fibrosis; PDEI, phosphodiesterase type 5 inhibitors; PGP, P-glycoprotein; REMS, risk evaluation and mitigation strategies; RTI, respiratory tract infection; SubQ, subcutaneous injection.
- Concomitant - Concomitant - Coadminstration Cyclosporine: - Discontinue - Avoid administration of administration of with CYP2C8 - Dose adjustment bosentan 36 coadministration antihypertensives antihypertensives inducers may necessary, limit hours before with strong and other and other decrease plasma ambrisentan dose initiation of CYP3A4 vasodilators with vasodilators with exposure of to 5 mg/d ritonavir; wait inducers epoprostenol illoprost may parenteral and at least 10 - Avoid may increase risk increase risk for oral treprostinil days before coadministration for hypotension hypotension - Coadminstration reinitiating with strong - Concomitant - Concomitant with CYP2C8 bosentan CYP3A4 administration administration inhibitors may - Decreased serum inhibitors of anticoagulants of anticoagulants increase plasma concentration of with with illoprost exposure of contraceptives epoprostenol may increase risk parenteral and - Reduced may increase risk of bleeding oral treprostinil concentrations of bleeding - Concomitant of medications - Concomitant administration of that are CYP3A4 administration antihypertensives substrates of digoxin with and other epoprostenol may vasodilators with increase serum parenteral and concentration of oral treprostinil digoxin may increase risk for hypotension - Concomitant administration of anticoagulants with parenteral and oral treprostinil may increase risk of bleeding $14,554.00 Oral: 3.5mg twice $6773 $7183 $7182 Estimated cost per Flolan®: $5688 Veletri®: $6098 daily $10,000 month*†, 13–15 IV: $18,571; Inhalation: $13,032
Drug interactions
Properties
Table 1. (Continued) Patel et al Cardiology in Review • Volume 23, Number 1, January/February 2015
© 2014 Lippincott Williams & Wilkins
Cardiology in Review • Volume 23, Number 1, January/February 2015
play a role in the excretion of macitentan.36 In a phase I pharmacokinetic study of 6 healthy patients who were administered radiolabeled macitentan, approximately 50% of the drug was eliminated in the urine and about 24% of the drug was recovered from feces.36 Contents recovered from the urine were neither the unchanged drug nor the active metabolite. A recent phase I pharmacokinetic study assessed the impact of renal and hepatic impairment on the pharmacokinetics of macitentan.37 In this clinical trial, 2 substudies were conducted, 1 for patients with hepatic impairment (n = 8) and 1 for patients with renal impairment (n = 8). The investigators found that in patients with hepatic impairment, the mean plasma concentration and Cmax of macitentan was lower when compared to healthy subjects. In patients with mild, moderate, and severe hepatic impairment, the mean Cmax of macitentan was 152, 104, and 161 ng/mL, respectively; whereas the mean Cmax of macitentan was 197 ng/mL in healthy subjects. Similarly, the mean Cmax of the active metabolite, ACT-132577, was found to be lower in patients with mild, moderate and severe hepatic impairment (117, 124, and 120 ng/mL, respectively) compared to that of healthy subjects (158 ng/mL). In patients with renal impairment, the mean Cmax was 11% higher, half-life was 8% longer and AUC (Area Under the Curve) had an increase of 24% when compared to healthy subjects. Because of the relatively small changes in pharmacokinetic parameters, the authors concluded that the effects of hepatic or renal impairment on the pharmacokinetics and safety of macitentan and ACT-132577 are not clinically relevant and therefore no dose adjustments are required in these patients.
Pharmacodynamics The pharmacodynamic properties, in particular, differentiate macitentan from its ERA counterparts (ie, ambrisentan and bosentan).38 In an in vivo study, Gatfield et al38 found that macitentan has slower receptor dissociation from ETA and ETB compared to the ambrisentan and bosentan. Macitentan’s overwhelming inhibition of ETA and ETB appears to increase plasma concentration of ET-1 by displacing ET-1 from its receptor sites. A 2013 double-blinded, randomized, controlled trial which assessed the pharmacokinetics and pharmacodynamics of various doses of macitentan found a trend of increasing plasma ET-1 concentrations with increasing doses of macitentan (ie, 1, 3, 10, and 30 mg). On day 10 (at steady state) the investigators found a statistically significant dose-dependent increase in plasma concentration of ET-1 for the 10 and 30 mg doses when compared to the 1 and 3 mg doses.39 The maximum increase in ET-1 was seen with the10 mg dose, which increased ET-1 concentrations by twofold. A further increase in plasma ET-1 concentration was not seen with the 30 mg dose; thus, the study of this higher dosage strength was not pursued. A cardiac hemodynamic substudy of patients from the study with an Endothelin Receptor Antagonist in PAH to Improve Clinical Outcome (SERAPHIN) trial assessed the treatment effect of macitentan on hemodynamic variables from baseline to month 6.40 The study found that patients treated with macitentan 10 mg (n = 57) had a median reduction of 37% [95% confidence interval (CI), 22–49] in pulmonary vascular resistance and an increase of 0.6 L/min/m2 (95% CI, 0.3–0.9) in cardiac index compared to placebo (n = 67).
Clinical Studies In October 2013, macitentan received approval from the FDA for the treatment of PAH WHO group I based on the results of the SERAPHIN trial.41 SERAPHIN was a multicenter, double blinded, randomized, placebo-controlled, event driven, phase 3 trial.42 Patients were included in the study if they met the following criteria: 12 years of age or older, a history of Idiopathic PAH, heritable PAH or PAH related to connective-tissue disease, repaired congenital systemic to pulmonary shunts, HIV, or drug use or toxin exposure, confirmation with right heart catheterization, a 6MWD of 50 m or more, © 2014 Lippincott Williams & Wilkins
Pulmonary Arterial Hypertension
and WHO-FC II, III, IV. Patients were allowed to have background therapy with an PDE-5 inhibitor, oral or inhaled prostanoids, calcium channel blockers, and/or arginine if they were stable on the therapy for at least 3 months. Patients were randomized based on a 1:1:1 stratification within 28 days of screening to placebo once daily, macitentan 3 mg once-daily or macitentan 10 mg once-daily. Patients were monitored for 6MWD and WHO-FC at 3 months, 6 months, and every 6 months thereafter. The primary end point was time from the initiation of treatment to the first event related to PAH or death from any cause.42 A first event related to PAH was defined as worsening of PAH, initiation of treatment with intravenous or subcutaneous prostanoids, lung transplantation, or atrial septostomy. Worsening of PAH was defined as having the following 3 criteria: (1) at least 15% decrease in 6MWD from baseline (reconfirmed within 2 weeks), (2) worsening of PAH symptoms, and (3) the need of additional treatment for PAH. The criteria for worsening of PAH symptoms were defined as: change to higher WHO-FC from baseline and/or the appearance or worsening of signs of right heart failure that did not respond to oral diuretic therapy. The secondary outcomes of the study were change in 6MWD at month 6 from baseline, percentage of patients with an improvement in WHO-FC at month 6, death due to PAH or hospitalization due to PAH, and death from any cause. Safety end points included adverse events and laboratory abnormalities. A total of 742 patients were enrolled. There were 116 primary end point events in the placebo arm, 95 primary end point events in the macitentan 3 mg arm [hazard ratio (HR): 0.70 (0.52–0.96), P < 0.01 compared to placebo] and 76 primary end point events in the macitentan 10 mg arm [HR: 0.55 (0.32–0.76), P < 0.001 compared to placebo] (total primary end point events = 287). The most frequent cause of the primary end point was worsening of PAH. With regards to secondary end points, the composite end point of death due to PAH or hospitalization for PAH as a first-time event occurred in 84 patients in the placebo, 65 patients in the macitentan 3 mg arm [HR: 0.67 (0.46–0.97), P < 0.01 compared to placebo] and 50 patients in the macitentan 10 mg arm [HR: 0.50 (0.34–0.75), P < 0.001 compared to placebo]. The 6MWD, from baseline to 6 months, decreased by a mean of 9.4 m in the placebo arm, increased by a mean of 7.4 m in the macitentan 3 mg arm (treatment effect with a 3 mg dose vs placebo, 16.8 m; 97.5% CI, −2.7 to 36.4 m; P = 0.01), and increased by a mean of 12.5 m in the macitentan 10 mg arm (treatment effect with a 10 mg dose vs placebo, 22.0 m; 97.5% CI, 3.2 –40.8 m; P = 0.008). The WHO-FC from baseline to 6 months improved in 13% of patients in the placebo arm, improved in 20% of patients in the macitentan 3 mg arm (P = 0.04) and improved in 22% of patients in the macitentan 10 mg arm (P = 0.006). Treatment discontinuation, due to adverse events, was observed in 31 patients (12.4%) in the placebo group, 34 patients (13.6%) in the macitentan 3 mg group and 26 patients (10.7%) in the macitentan 10 mg group. The incidence of peripheral edema, and mean increases in Aspartate Aminotransferase (AST)/Alanine Transaminase (ALT) (3 times above the upper normal limit) was similar among the 3 groups. The authors conclude that macitentan significantly reduced morbidity and mortality in patients with PAH. The SERAPHIN trial took a novel approach in assessing the efficacy of macitentan in patients with PAH. Traditionally, the 6MWD has been considered the gold standard marker in assessing functional status of patients with PAH.43 The SERAPHIN trial, the first of its kind, assessed efficacy with an event-driven approach over a long period of time (ie, median follow up time of 2.2 years). This approach may have a better correlation between treatment effectiveness and long-term clinical outcomes compared to the 6MWD.44
Adverse Effects Macitentan may cause fetal harm and is therefore contraindicated in females who are pregnant. Therefore, for females, www.cardiologyinreview.com | 41
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Cardiology in Review • Volume 23, Number 1, January/February 2015
macitentan is only available through a restricted risk evaluation and mitigation strategy (REMS) program called the OPSUMIT REMS program because of the risk of embryo-fetal toxicity.20 Safety data for macitentan was primarily obtained from the SERAPHIN study.42 The incidence of treatment discontinuations because of adverse events was similar between macitentan and placebo (approximately 11%). The most common adverse events observed for macitentan and placebo respectively were: anemia (13% vs 3%), nasopharyngitis/pharyngitis (20% vs 13%), bronchitis (12% vs 6%), headache (14% vs 9%), influenza (6% vs 2%), and urinary tract infections (9% vs 6%).42 ERAs are known to cause aminotransferase elevation.9 The incidence of discontinuation due to hepatic adverse events was 3.3% in the macitentan group and 1.6% in the placebo group. In the SERAPHIN study, the incidence of elevated aminotransferases to greater than 3 times the upper limits of normal was 3.4% in the macitentan group vs 4.5% in the placebo group and the incidence of elevated aminotransferases to greater than 8 times the upper limits of normal was 2.1% in the macitentan group vs 0.4% in the placebo group.42 Of note, a decrease in hemoglobin to less than 10.0 g/dL was reported in 8.7% of the macitentan group and in 3.4% of the placebo group in the SERAPHIN study.42
Drug–Drug Interactions Macitentan is predominantly metabolized by the CYP3A4 enzyme. This characteristic predisposes macitentan to various drug–drug interactions. Based on the results of in vivo studies, macitentan should not be used concomitantly with potent CYP3A4 inducers or inhibitors such as rifampin or ketoconazole due to clinically significant alterations in the AUC and the serum concentration of macitentan.20 A 2012 phase 1 study by Bruderer et al45 sought to assess the impact of multidose cyclosporine and rifampin (2 part 1 sequence crossover study) on the pharmacokinetics of macitentan. Twenty male patients were enrolled (10 patients randomized to macitentan followed by macitentan + cyclosporine and 10 patients randomized to macitentan followed by macitentan + rifampin). The study found that when macitentan was co-administered with cyclosporine, there was no clinically relevant alteration in the pharmacokinetics of macitentan (Ctr of macitentan alone 159 ng/mL vs 220 ng/mL for macitentan + cyclosporine). However, when macitentan was co-administered with rifampin, the serum concentration of macitentan was lower when compared to the administration of macitentan alone (Ctr 11 vs 157 ng/mL, respectively). Interestingly, no significant difference was seen in the serum concentration of the active metabolite, ACT132577, when macitentan was co-administered with rifampin compared to macitentan administration alone. The authors concluded that cyclosporine does not impact the pharmacokinetics of macitentan to a clinically relevant extent. However, macitentan may have reduced efficacy when rifampin is co-administered.45 Atsmon et al conducted a phase 1, open-label study to assess the impact of the potent CYP3A4 inhibitor ketoconazole on the pharmacokinetics of macitentan.46 Twelve males were randomized to either 1 single dose of macitentan alone (group A) or ketoconazole for 4 days followed by 1 dose of macitentan on day 5 and ketoconazole thereafter daily until day 19 (group B). The study found that the mean half life of macitentan in group A was 14.1 and 28.5 hours in group B. The Cmax was 227 ng/mL in group A and 290 ng/mL in group B. As expected, the Cmax of active metabolite ACT-132577 was lower in group B compared to that of group A (87.6 vs 178 ng/mL, respectively). The authors state that although the Cmax of the active metabolite is lower when macitentan is given with ketoconazole compared to macitentan being given alone, ACT-132577 is 5 times less potent 42 | www.cardiologyinreview.com
compared to the unchanged parent molecule and thus the lower Cmax does not impact the efficacy to a clinically relevant extent. They concluded that the co-administration of ketoconazole with macitentan does not warrant dose adjustment.46
Indication, Dosage, Administration, and Cost Macitentan is a nonselective ERA indicated for the treatment of PAH to delay disease progression.20 It is available as oral filmcoated tablets, and the daily recommended dose is 10 mg.20 Doses higher than 10 mg were not found to further increase ET-1 concentrations, and should not be used.39 Macitentan can be administered with or without food, though the tablet should not be crushed, split, or chewed before swallowing.20 If a dose of macitentan is missed, it should be taken as soon as the patient remembers that day, and the next dose should be taken at the regular time; 2 doses should not be taken at the same time to make up for a missed dose.20 The cost for a 1-month supply of macitentan 10 mg daily is greater than $7000 (Table 1).47
RIOCIGUAT sGC is a key intracellular enzyme in the NO signaling pathway that catalyzes the synthesis of cyclic guanosine monophosphate (cGMP), a second messenger that promotes vasodilation. sGC has attracted interest as a therapeutic target due to the association between impaired NO and cGMP signaling and cardiovascular disease in general, including PH.24 In addition to vasodilation, sGC activation also initiates a series of beneficial downstream effects including inhibition of smooth muscle proliferation, leukocyte recruitment, and platelet aggregation. Organic nitrates and NO donors have long been used in the treatment of cardiovascular disease. However, the use of direct NO supplementation is limited by the tolerance that patients often develop with long-term therapy, and the association between cardiovascular disease and NO resistance.24 In a similar vein, PDE-5 inhibitors augment existing NO by preventing its degradation, but have a limited role in environmental conditions when there is little to no endogenous NO.8 sGC modulation offers an alternative method of stimulating the NO-sGC-cGMP pathway. Oral riociguat is the first sGC stimulator on the market, and has a dual mechanism of action.23 It stabilizes NO-sGC binding, thereby sensitizing sGC to endogenous NO. Additionally, it directly stimulates sGC in the absence of NO.23,24 In vitro, riociguat increases sGC activity up to 73-fold via direct stimulation, and up to 122-fold in the presence of NO.24 Currently, riociguat is recommended for inoperable or persistent chronic thromboembolic PH and for both initial monotherapy and sequential combination therapy for PAH.8,9
Pharmacokinetics Riociguat has an absolute oral bioavailability of 94%, with peak plasma concentrations occurring 1.5 hours after ingestion, regardless of co-administration with food.23 Riociguat exhibits dose proportional pharmacokinetics in healthy males given single doses of 0.5–2.5 mg; there is a direct relationship between riociguat plasma concentrations and hemodynamic parameters such as pulmonary vascular resistance, cardiac output, and systolic blood pressure.23,48 The volume of distribution is approximately 30 L. Riociguat is mainly metabolized hepatically by CYP2C8, CYP2J2, CYP3A, and CYP1A1, the last of which catalyzes the formation of the major active metabolite, M1. M1 exhibits 10–33% of the activity of riociguat, and is inactivated by N-glucuronidation; the ratio of riociguat to M1 in PAH patients is roughly 2:1.23 Riociguat’s terminal elimination halflife is 12 hours in PAH patients and 7 hours in healthy subjects; it is eliminated both renally and fecally. The AUC and Cmax of riociguat and M1 are not significantly affected by Child-Pugh A/B hepatic impairment, mild to severe renal impairment, age >65 (as compared © 2014 Lippincott Williams & Wilkins
Cardiology in Review • Volume 23, Number 1, January/February 2015
to age >45), or gender. The safety and efficacy of riociguat has not been demonstrated in patients on dialysis, with creatinine clearance of less than 15 mL/min, or with severe hepatic impairment (Child Pugh C). Riociguat is highly protein bound, and is not expected to be dialyzable in the event of an overdose.23
Clinical Studies The major double-blinded, placebo-controlled, multicenter clinical trials evaluating the safety and efficacy of riociguat for PH indications are PATENT-1 (PAH sGC-Stimulator Trial 1) and CHEST-1 (Riociguat for the Treatment of Chronic Thromboembolic PH), both of which also include long-term extension trials (CHEST-2 and PATENT-2).49,50 Both studies enrolled adults ≥18 years of age, and studied the primary end point of change in 6MWD from baseline over 12 weeks (PATENT-1) and 16 weeks (CHEST-1). Secondary end points included change in pulmonary vascular resistance, levels of N-terminal prohormone brain-type natriuretic peptide (NT-proBNP), WHO-FC, and time to clinical worsening. Taken together, PATENT-1 and CHEST-1 show that riociguat, as monotherapy and adjunctive therapy, produces clinically significant changes in 6MWD. In both studies, a sensitivity analysis indicated that the results were reliable in spite of the missing follow-up efficacy measurements in patients lost to follow-up.49,50 PATENT-1 took place in 124 centers in 30 countries, and enrolled 443 symptomatic PAH patients who were not on pharmacotherapy (50%), or on a stable dose of an ERA (44%) or a nonintravenous prostacyclin analogue (6%) at baseline.49 The majority of the enrolled patients had symptomatic idiopathic PAH (61%). Oral anticoagulants, diuretics, and supplemental oxygen at stable doses were permitted, but patients were excluded if they were receiving a PDE-5 inhibitor. In the treatment arm, riociguat doses were individually titrated, as tolerated by blood pressure, to a maximum of 2.5 mg 3 times daily. Additionally, 63 patients were randomized to an exploratory arm with a 1.5 mg 3 times daily dose cap. At baseline, the study participants predominately fell into WHO-FC II (42%) and WHO-FC III (54%), and had a mean 6MWD of 363 ± 69 m.49 Riociguat displayed a significant benefit in 6MWD at the end of 12 weeks, with a least squares mean (LSM) difference of 36 m between the placebo and treatment groups (95% CI, 20–52 m, P < 0.001) in a modified intention-to-treat analysis (2 patients were randomized in error, and never received study drug).49 This treatment effect was similar for patients regardless of baseline pharmacotherapy status, but patients with more advanced disease showed greater benefit (LSM difference 59 m; 95% CI, 37–81) than patients with less advanced disease (LSM difference of 14 m; 95% CI, −9 to 36). The majority (75%) of the patients in the treatment group were receiving the maximal riociguat dose at week 12, and the proportion of patients who required dose decreases over the study time frame was similar between the 2 groups (12% riociguat, 9% placebo). Riociguat significantly improved many secondary end points, including pulmonary vascular resistance (LSM difference = −226 dyn∙s∙cm−5, P < 0.001), mean pulmonary-artery pressure (LSM difference = −7 mm Hg, P < 0.001), cardiac output (LSM difference = 0.9 L/min, P < 0.001), NT-proBNP levels (LSM difference = −432 pg/mL, P < 0.001), and WHO-FC (21%/4% in the riociguat group moved to a lower class/ higher class, vs 14%/14% in the placebo group, P = 0.003). Furthermore, patients in the treatment group experienced fewer overall episodes of clinical worsening (1% riociguat vs 6% placebo, respectively, P = 0.05), which included hospitalization, initiation of new treatment, decrease in 6MWD, worsening of WHO-FC, and death.49 CHEST-1 enrolled 261 adult chronic thromboembolic PH patients not receiving pharmacotherapy for PH (an ERA, prostacyclin analogue, PDE-5 inhibitor, or NO donor) whose disease was judged to be technically inoperable, or who experienced persistent disease after pulmonary endarterectomy.50 Patients were randomized © 2014 Lippincott Williams & Wilkins
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to receive riociguat, starting at 1 mg 3 times daily and titrated to a maximum of 2.5 mg 3 times daily, or placebo. At baseline, the patients were predominantly in WHO-FC II (31%) and WHO-FC III (64%), with an average age of 59 ± 14 years and an average 6MWD of 347 ± 80 m. Most (72%) of those enrolled had inoperable disease. Though 77% of patients remaining at week 16 were receiving the maximal dose, end doses ranged from 0.5 mg to 2.5 mg 3 times daily.50 At 16 weeks, riociguat had produced a greater increase in 6MWD than had placebo (LSM difference 46 m; 95% CI, 25–67; P < 0.001), with consistent effects across patient subgroups (inoperable vs postoperative disease, WHO-FC, baseline 6MWD, age, and sex). Riociguat also showed benefits on secondary end points of pulmonary vascular resistance (LSM difference −246 dyn∙s∙cm−5; 95% CI, −303 to −190; P < 0.001), improvement in pulmonary-artery pressure (LSM difference = −5 mm Hg, P < 0.001), cardiac output (LSM difference = 0.9 L/min, P < 0.001), reductions in NT-proBNP levels (LSM difference = −444 pg/mL, P < 0.001), and change in WHO-FC (in the riociguat group 33% moved to a lower FC, whereas 5% moved to a higher FC, and in the placebo group 15% moved to a lower FC, whereas 7% moved to a higher FC). There was no significant difference in incidence of clinical-worsening events.50
Adverse Effects When adverse drug reactions from PATENT-1 and CHEST-1 were pooled, the most common side effects observed for riociguat and placebo, respectively, were: headache (27% vs 18%), dyspepsia (21% vs 8%), dizziness (20% vs 13%), nausea (14% vs 11%), diarrhea (12% vs 8%), and hypotension (10% vs 4%). Other observed effects included vomiting, constipation, GERD, and anemia.23 Rare adverse reactions that resulted in study discontinuation included increased hepatic enzyme levels (n = 1), acute renal failure (n = 1), syncope (n = 3), esophageal pain/swelling (n = 1), as well as supraventricular tachycardia, hypotension, edema, and neck pain. Interestingly, the pooled discontinuation rate was lower for riociguat (2.9%) than for placebo (5.1%).23
Drug Interactions/Contraindications/Warnings The concomitant use of riociguat with nitrates, NO donors, or PDE-5 inhibitors is contraindicated.23 In the phase II drug interaction study PATENT PLUS, combination therapy of riociguat and sildenafil did not show benefit in 6MWD, WHO-FC, or pulmonary hemodynamics. Furthermore, the combination displayed a high drop-out rate due to hypotension in the long-term extension.9,51 Exposure to polycyclic aromatic hydrocarbons, such as those found in cigarette smoke, induces the production of riociguat’s major active metabolite.23 Cigarette smokers may warrant doses higher than 2.5 mg thrice daily, as plasma concentrations of riociguat are reduced 50–60% in this population when compared to nonsmokers. Conversely, downtitration of dosage may be required if patients successfully cease smoking. Antacid medications should not be given within an hour of riociguat administration due to their ability to decrease riociguat’s absorption. Strong CYP/P-glycoprotein/BCRP inhibitors will increase drug exposure, and would warrant particularly close monitoring for symptoms of hypotension; a lower starting dose (0.5 mg 3 times daily) may be considered.23 Riociguat is contraindicated in pregnancy (category X).23 For women of reproductive potential (premenarchal through menopause), riociguat is only available through a REMS program which requires monthly pregnancy testing and use of acceptable methods of contraception until 1 month after medication discontinuation. In animal studies, an increase in spontaneous abortions was seen in rabbits given 4 times the human exposure, and postimplantation loss was significantly increased in rats at 2 times the human exposure. www.cardiologyinreview.com | 43
Change in 6MWD from Baseline
In a 2009 meta-analysis of 3 studies63 (N = 213), the mean change in 6MWD from the pooled results was 81 m (95% CI, 45–117)
AIR study64 Mean placebo-corrected change in 6MWD was 36.4 m in the iloprost group (P = 0.004) at week 12
Medication
Epoprostenol
Iloprost
44 | www.cardiologyinreview.com N/A
AIR study64 N/A Clinical deterioration at 12 weeks: (P = 0.41) • Placebo (n = 102): 8.8% • Iloprost (n = 101): 4.9%
N/A
Clinical Worsening
Hospitalization WHO FC II: • Parenteral prostanoids should not be used as initial therapy in treatment naive patients, but may be used as second line therapy for nontreatment naive patients who have not met their goal (WSPH makes no recommendation for epoprostenol in WHO FC II++)
Guideline Consensus+
(Continued)
WHO FC III: • For treatment naive patients who have evidence of rapid progression of disease or other markers of poor prognosis, consider initial initiation of parenteral prostanoid: • Improve FC (Grade CB) • Improve 6MWD (Grade CB) • Improve cardiopulmonary hemodynamics • For patients on 1 or 2 classes of oral agents, consider addition of inhaled or parenteral prostanoid if there is evidence of disease progression or poor clinical prognosis to: • Improve FC (Grade CB) • Improve 6MWD (Grade CB) • Improve cardiopulmonary hemodynamics WHO FC III or IV patients: Patients symptomatic on stable doses of intravenous epoprostenol, consider up titration of intravenous epoprostenol to improve 6MWD (Grade CB) WHO FC II: AIR study64 Death at 12 weeks: (P = 0.37) • Inhaled prostanoids should not be used as initial therapy • Placebo (n = 102): 4 (0.90%) in treatment naive patients, but may be used as second line • Iloprost (n = 101): 1 (3.57%) therapy for nontreatment naive patients who have not met their goal WHO FC III: • For patients remaining symptomatic on stable and appropriate doses of an ERA or PDE-5I, consider, addition of inhaled Iloprost to improve WHO FC (Grade CB) • Use to delay time to clinical worsening (Grade CB) WHO FC IV • Treatment naive PAH patients who are unable to tolerate or do not desire parenteral prostanoid therapy, use iloprost to: • Improve 6MWD (Grade CB) • Improve WHO FC (Grade CB) WHO FC III or IV patients: Symptomatic patients on stable doses of ERA or PDE-5I, inhaled iloprost can be added to improve 6MWD (Grade CB)
63
Death 2009 meta-analysis • Number of studies assessed: 3 • N = 215 • OR: 0.37 in favor of epoprostenol (95% CI, 0.09–1.57) 5 deaths in epoprostenol group; 16 deaths occurred in the placebo group
Table 2. Clinical Attributes of Pulmonary Arterial Hypertension-Specific Pharmacotherapies
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Treprostinil
Clinical Worsening
Change in 6MWD from Baseline
TRIUMPH study65 (N = 235): TRIUMPH open-label extension Inhaled treprostinil between study (N = 206),66 number of cumulative clinical worsening treatment (ie, patients in events (including death): both standard therapy and 12 months: 34 intervention group were on 24 months: 54 background therapy with a PDE-5I or ERA) median difference at week 12: 20 m (95% CI: 8.0–32.8, P = 0.0004) TRIUMPH open-label extension study, median change in 6MWD66: • 6 months: 28 m (P < 0.0001, n = 170) • 12 months: 31 m (P < 0.0001, n = 152) • 18 months: 32 m (P < 0.0001, n = 134) • 24 months: 18 m (P < 0.0001, n =118) Parenteral treprostinil: In a double-blinded study of 470 patients,67 the difference in median distance walked between the subcutaneous treprostinil and placebo groups, at week 12, was 16 m (95% CI, 4.4 m–27.6 m, Hodges–Lehmann estimate of the median difference, P = 0.006) Placebo corrected median difference in 6MWD from baseline for oral treprostinil studies: • FREEDOM-M (N = 228†): 23 m (P = 0.0125)28,68 • FREEDOM-C (N = 354): 11 m (P = 0.07)29 • FREEDOM-C2 (N = 310): 10 m (P = 0.089)30
Medication
Table 2. (Continued) Hospitalization TRIUMPH study65: • Inhaled treprostinil (n = 115): 4 (3%) • Placebo (n = 120): 5 (4%)
Death TRIUMPH study65: • Inhaled treprostinil (n = 115): 0 • Placebo (n = 120): 1 (
