CLINICAL REVIEW
Riociguat
CLINICAL REVIEW
ar Layar
Riociguat for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension
P
ulmonary arterial hypertension (PAH) is a progressive disease characterized by a remodeling of the pulmonary artery and its associated vasculature. This remodeling leads to an increase in pressure in the pulmonary arterial vasculature, which leads to right-sided heart failure and subsequent death.1 PAH is a subclassification of pulmonary hypertension and is distinct from systemic arterial hypertension.2 Chronic thromboembolic pulmonary hypertension (CTEPH) is also a subclassification of pulmonary hypertension.2 Therapies traditionally used to treat systemic arterial hypertension are often of little benefit in PAH.3,4 Due to the progressive nature of PAH, its associated high mortality, and limited treatment options, unique therapies that target the remodeling that occurs in the pulmonary vasculature are often used for the treatment of PAH and CTEPH. Riociguat, the first member of a new class of drugs called soluble guanylate cyclase (sGC) stimulators, was approved by the Food and Drug Administration in October 2013.5 Like the phosphodiesterase type-5
Bryan M. Bishop Purpose. The pharmacology, pharmacokinetics, clinical efficacy, safety, and role in therapy for riociguat are reviewed. Summary. Riociguat is the first member of a new class of medications, soluble guanylate cyclase stimulators. Riociguat is indicated for patients with resistant or recurrent chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary endarterectomy who have World Health Organization (WHO) functional class IV pulmonary arterial hypertension (PAH) and in patients with inoperable CTEPH, regardless of WHO functional class, to improve exercise capacity and WHO functional class. Riociguat is indicated in patients with WHO functional class II PAH to improve exercise capacity, improve functional class, and delay clinical worsening. The mechanism of action of riociguat is within the nitric oxide pathway in the pulmonary vasculature. Clinical trials have demonstrated improvements in exercise capacity as measured by the six-
(PDE5) inhibitors, riociguat acts on the nitric oxide pathway. Nitric oxide exerts a vasodilatory effect by increasing the production of cyclic guanosine monophosphate (cGMP) via activation of sGC. Riociguat activates sGC
Bryan M. Bishop, B.S., Pharm.D., BCPS, is Clinical Pharmacist, Department of Pharmacy, St. Rita’s Medical Center, Lima, OH, and Assistant Professor, Rudolph H. Raabe College of Pharmacy, Ohio Northern University, Ada, OH. Address correspondence to Dr. Bishop ([email protected]). The author has declared no potential conflicts of interest.
minute walk distance test and in pulmonary arterial hemodynamics as measured by invasive pulmonary monitoring. Riociguat must be administered three times daily and requires dosage adjustments. Riociguat is a pregnancy category X drug and interacts with numerous medications. The two most serious adverse effects related to riociguat are hypotension and bleeding. Riociguat’s role in the therapy of both PAH and CTEPH will be determined as more clinical experience and data are collected. Riociguat will likely cost approximately $90,000 annually. Conclusion. Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of CTEPH and PAH. It can be considered first-line therapy for the treatment of CTEPH and should be considered as an alternative to phosphodiesterase type-5 inhibitors in patients with PAH. Am J Health-Syst Pharm. 2014; 71:183944
directly irrespective of nitric oxide while increasing the sensitivity of sGC to low levels of endogenous nitric oxide.6,7 This article describes the pharmacology, pharmacokinetics, clinical efficacy, and safety of riociguat.
Copyright © 2014, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/14/1101-1839. DOI 10.2146/ajhp130777
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Background Current therapies and pathways. The pathological pathways currently targeted for the treatment of PAH and CTEPH include the prostaglandin pathway, the nitric oxide pathway, and the endothelin pathway.8,9 Of note, calcium channel blockers can be used to treat systemic arterial hypertension in a very small number of patients diagnosed with PAH. However, doses of calcium channel blockers used in the treatment of PAH are much higher than typically used for other patients and are poorly tolerated by the few patients who are eligible for treatment.8 Prostanoids. The first class of drugs to target a specific pathway in PAH was the prostanoids, which mimic endogenous prostaglandins and lead to an increase in cyclic adenosine monophosphate (cAMP).10 This increase in cAMP in the pulmonary arterial vasculature results in vasodilation, antiproliferative effects, and the inhibition of local platelet aggregation. The first agent in this class was epoprostenol and is given by continuous infusion. Treprostinil is available as a parenteral product for continuous subcutaneous or i.v. infusion, an inhaled formulation, and an oral formulation.11 Iloprost, the third commercially available prostanoid in the United States, is only available as an inhaled formulation.8 Endothelin antagonists. The endothelin pathway is an appealing target for medication therapy, as excess levels of endothelin-1 in the pulmonary arterial vasculature lead to pulmonary arterial vasoconstriction, smooth muscle cell proliferation, and pulmonary vasculature remodeling.12 Endothelin-1 exerts its effect by acting on two endothelin receptors, endothelin A (ETA) and endothelin B (ETB). ETA receptors are located primarily on smooth muscle cells and heart tissue, whereas ETB receptors are located primarily on endothelial cells. The blocking of ETA receptors located on smooth 1840
muscle cells will interrupt the pathological processes of PAH, leading to clinical improvement.13 Stimulation of ETB on endothelial cells enhances endothelin-1 clearance, stimulates nitric oxide release, and directly induces pulmonary arterial vasodilation.13 Bosentan was the first commercially available endothelin antagonist and is frequently associated with liver enzyme elevations, anemia, and numerous drug–drug interactions. Ambrisentan, another endothelin antagonist, is associated with less liver and blood toxicity as well as fewer drug–drug interactions. Macitentan is the most recently approved endothelin antagonist and is associated with low toxicity while possessing greater tissue penetration and receptor binding duration than either bosentan or ambrisentan.12-15 Phosphodiesterase inhibitors. In the endothelium, nitric oxide is produced by nitric oxide synthase. Nitric oxide then binds to sGC and, via the production of cGMP, induces vasodilation and inhibits cell proliferation.16 In PAH, nitric oxide production is impaired; thus, therapies targeting this pathway have been explored, and some have been shown to be efficacious. Exogenous inhaled nitric oxide is used as part of a “vasodilator test” when the initial diagnosis of PAH is made and staging of the disease is done.8 Utilizing nitric oxide in the treatment of PAH has also been evaluated; while the therapy did produce levels of pulmonary vasodilation, this was counterbalanced by peripheral vasoconstriction and reflex tachycardia, both of which can worsen symptoms in patients with PAH.17 The enzyme PDE5 catalyzes the conversion of cGMP to guanosine monophosphate. By inhibiting PDE5, levels of cGMP are preserved. Sildenafil was the first PDE5 inhibitor to be evaluated and approved for use in patients with PAH. Tadalafil is also approved for use in PAH.
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Clinical trials Early phase trials. An initial hemodynamic study of riociguat was conducted in adults diagnosed with PAH, CTEPH, or pulmonary hypertension associated with interstitial lung disease and a pulmonary vascular resistance (PVR) exceeding 300 dyn·s·cm–5.7 The goal of the study was to assess the pharmacodynamics and pharmacokinetics of a single dose of riociguat in 19 patients with moderate-to-severe PAH, CTEPH, or pulmonary hypertension. The safety, tolerability, and efficacy of riociguat were also evaluated. The administration of a single dose of riociguat 1 or 2.5 mg resulted in clinically relevant and significant reductions in hemodynamic variables, including mean pulmonary arterial pressure (mPAP), PVR, systemic vascular resistance (SVR), and systolic blood pressure (SBP). The pharmacokinetic results from this study revealed that riociguat has dose-dependent plasma concentrations after the administration of a single dose, with notable interpatient variability. Peak riociguat concentrations occurred 0.25–1.5 hours after administration, and the drug had a half-life of 8–12 hours. This study was a proof-ofconcept study that established only the potential of riociguat as an option for the treatment of PAH and CTEPH. Based on the results of this study, a Phase II study was conducted to evaluate the safety, tolerability, and dosing of riociguat.18 A Phase II, 12-week, open-label, dosage-escalation study was conducted at 15 centers in Germany.18 Patients with PAH or CTEPH were eligible for enrollment. Patients were allowed to be taking only endothelin receptor antagonists for long-term therapy for PAH or CTEPH before enrollment. The primary endpoints of the study were the feasibility, safety, and tolerability of individual dosage adjustments of riociguat based on peripheral SBP. Patients received immediate-release tablets of
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riociguat starting at 1 mg three times daily; every 2 weeks the dosage was increased by 0.5 mg up to a maximum dose of 2.5 mg. A total of 75 patients (42 with CTEPH and 33 with PAH) were enrolled in the trial, 72 of whom completed the 12-week study. At the end of the study, 52 patients were receiving the maximum 2.5mg dose three times daily, 4 patients were taking 1 mg three times daily, and 1 patient was receiving 0.5 mg three times daily. Exercise capacity, as measured by the six-minute walk distance (6MWD) test, increased in the total patient population (median increase of 55 m, p < 0.0001) as well as in both the CTEPH (median increase of 55 m, p < 0.0001) and PAH (median increase of 57 m, p < 0.0001) subpopulations. Patients with World Health Organization (WHO) functional class II PAH (i.e., ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope) at baseline had an improvement in 6MWD of 71.5 m (p = 0.0001) compared with patients with WHO functional class III PAH who had an improvement in 6MWD of 50 m (p < 0.0001). The improvement in 6MWD was similar in patients taking riociguat with an endothelin receptor antagonist and in those taking riociguat alone. In exploratory analyses, WHO functional class improved in 22 patients and deteriorated in only 1 patient. Emergent adverse effects seen in the study included dyspepsia, headache, hypotension, peripheral edema, tachycardia, fatigue, upper abdominal pain, dizziness, vertigo, vomiting, diarrhea, constipation, epistaxis, gastrointestinal infection, nasopharyngitis, respiratory tract infection, and syncope. A total of 50 patients had invasive hemodynamic monitoring performed at baseline and at the conclusion of the trial. In these patients, riociguat resulted in significant decreases in mPAP (–4.5 mm Hg, p < 0.0001), PVR (–215 dyn·s·cm–5, p < 0.0001), and SVR (–441 dyn·s·cm–5, p < 0.0001). The
authors of the study concluded that riociguat demonstrated a favorable safety profile with clinically meaningful improvements in exercise capacity and pulmonary hemodynamics. Based on the results of this Phase II study, two Phase III studies were conducted in patients with PAH or CTEPH.19,20 Phase III trials. The CHEST-1 study was a Phase III, randomized, multicenter, double-blind, placebocontrolled trial conducted over 16 weeks.19 In this trial, 261 patients with CTEPH that was determined to be either inoperable or persistent/ recurrent after pulmonary endarterectomy were randomized in a 1:2 fashion to receive either placebo or dose- adjusted riociguat (range, 0.5–2.5 mg three times daily). Patients were excluded if they received PDE5 inhibitors, prostanoids, endothelin receptor antagonists, or nitric oxide donor agents within the three months before study enrollment. The primary endpoint was the change in 6MWD at 16 weeks from baseline. Secondary endpoints included changes in PVR, WHO functional class, and time until clinical worsening. Adverse effects were monitored throughout the trial. The majority of the patients enrolled in the trial had WHO functional class II or III PAH at baseline, and 72% were classified as having inoperable CTEPH. A total of 18 patients withdrew from the study before the end of 16 weeks. At the end of the study, 77% of patients were taking the 2.5mg dose three times daily, and 12%, 6%, 4%, and 1% were taking the 2-, 1.5-,1-, and 0.5-mg doses three times daily, respectively. With respect to the primary endpoint at 16 weeks, the mean 6MWD increased by 39 m in the riociguat group and decreased by 6 m in the placebo group (leastsquares mean difference, 46 m; 95% confidence interval [CI], 25 to 67 m; p < 0.001) in the intention-to-treat population. This result was maintained when analyzed in the per-
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protocol population. With respect to the secondary endpoints, riociguat resulted in significant reductions in PVR (–246 dyn·s·cm–5; 95% CI, –303 to –190 dyn·s·cm–5; p < 0.001) and improvement in WHO functional class (p = 0.003). There was no difference between the riociguat group and the placebo group with respect to time until clinical worsening (2% and 6%, respectively; p = 0.17). There were significant improvements in mPAP (–5 mm Hg; 95% CI, –7 to –3 mm Hg; p < 0.001), mean arterial pressure (–9 mm Hg; 95% CI, –12 to –6 mm Hg; p < 0.001), and mean cardiac output (0.9 L/min; 95% CI, 0.6 to 1.1 L/min; p < 0.001) in the riociguat group compared with the placebo group. A total of 5 patients in the riociguat group and 2 patients in the placebo group withdrew from the study secondary to adverse effects. One case of acute renal failure during the trial was attributed to riociguat. Currently, an open-label extension study (CHEST-2) is being carried out with the patients enrolled in this study.21 Published concomitantly with the CHEST-1 study, the PATENT-1 study was a 12-week, double-blind, placebo-controlled trial conducted in patients with PAH.20 In this study, 443 patients with symptomatic PAH were randomized in a 2:4:1 fashion to placebo, dose-adjusted riociguat with a maximum dosage of 2.5 mg three times daily, or dose-adjusted riociguat with a maximum dosage of 1.5 mg three times daily. Data from the 1.5-mg maximum-dose group were included only for exploratory purposes to study lower doses of riociguat; results from this group were not included in the primary efficacy analyses. The primary endpoint of the study was the change in 6MWD at 12 weeks from baseline. Secondary endpoints included changes in PVR, WHO functional class, and time until clinical worsening. Adverse effects were monitored throughout the trial. Patients had to have been on either
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no medications before enrollment or stable doses for 90 days of endothelin receptor antagonists or nonintravenous prostanoids. Patients treated with intravenous prostanoids or PDE5 inhibitors were excluded. Of the patients enrolled, 44% were taking endothelin receptor antagonists before enrollment, 6% were taking prostanoids, and 50% were not taking any medications. In the 2.5-mg maximum-dose group, 75% of patients were receiving the maximum dose at 12 weeks; 15%, 6%, 3%, and 2% were taking 2, 1.5, 1, and 0.5 mg three times daily, respectively. In the 1.5-mg maximum-dose group, 96% of patients were taking the maximum dose at 12 weeks. With respect to the primary endpoint, the 6MWD increased by a mean of 30 m in the 2.5mg maximum-dose group and decreased by 6 m in the placebo group (least-squares mean difference, 36 m; 95% CI, 20 to 52 m; p < 0.001) in the intention-to-treat population. This result was maintained, regardless of whether the patient was on therapy for PAH at baseline. Patients who had WHO functional class III or IV PAH (least-squares mean difference, 59 m; 95% CI, 37 to 81 m) at baseline had a notably better response than did those who had WHO functional class I or II PAH (least-squares mean difference, 14 m; 95% CI, –9 to 36 m). Of enrolled patients in the trial, 201 were WHO functional class I or II at baseline and 241 were WHO functional class III or IV; data were missing for 1 patient. Patients in the riociguat 2.5-mg maximum dose group had significant improvement in PVR (–226 dyn·s·cm–5; 95% CI, –281 to –170 dyn·s·cm–5; p < 0.001) and WHO functional class (p = 0.003) compared to the placebo group as well as a lower frequency of clinical worsening when compared to the placebo group. A total of 8 patients (3%) in the 2.5-mg riociguat group and 9 patients (7%) in the placebo group discontinued the study secondary to adverse effects. In the 1842
2.5-mg maximum-dose group, single cases of elevated hepatic enzyme levels, acute renal failure, syncope, esophageal pain and swelling, supraventricular tachycardia, hypotension, generalized edema, and neck pain were attributed to the study medication. Currently, an open-label extension study (PATENT-2) is being conducted with the patients enrolled in this study.22 Role in therapy Riociguat’s role in the therapy of both PAH and CTEPH will be determined as more clinical experience and data are collected. However, based on the studies discussed herein, riociguat should likely be considered an alternative to the use of a PDE5 inhibitor in patients with PAH. There are no clinical data establishing riociguat as superior to or preferred over any other agents used to treat PAH. Riociguat will likely cost approximately $90,000 annually,23 compared with approximately $19,000 annually for sildenafil and $15,000 annually for tadalafil.8 Riociguat has been studied as either monotherapy or in combination with either endothelin receptor antagonists or prostanoids. Detailed information and long-term clinical data are not yet available to give a clear picture of the role of riociguat in combination therapy, which is frequently used in the treatment of PAH.2 Riociguat is indicated for the treatment of WHO functional class II and III PAH only. WHO functional class IV PAH is typically treated with prostanoid therapy with or without other agents.2 Although riociguat is the first medication approved specifically for the treatment of CTEPH, agents used to treat PAH have been studied in patients with CTEPH and are already commonly used to treat CTEPH (e.g., epoprostenol, treprostinil, iloprost). 24 Many patients with CTEPH may benefit extensively from or be cured by a surgical pro-
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cedure called pulmonary endarterectomy, during which blood clots in the pulmonary vasculature are removed. It has been recommended that riociguat be used in patients with CTEPH that is considered inoperable by an expert in pulmonary endarterectomy.25 One factor affecting the potential use of riociguat in both PAH and CTEPH is the three-times-daily dosing schedule. If three days of therapy are missed, the dosage must be readjusted. As riociguat would be considered an alternative therapy to PDE5 inhibitors, it should be noted that sildenafil is administered three times daily and tadalafil is administered once daily and neither requires a dosage-adjustment schedule. In addition, when initiating riociguat, the dosage schedule requiring a physician visit every two weeks may prove burdensome, as every patient’s blood pressure must be closely monitored during the initiation and during the adjustment phase. Dosage and administration Riociguat was approved for the treatment of CTEPH and PAH. 26 Riociguat is indicated for patients with resistant/recurrent CTEPH after pulmonary endarterectomy who have WHO functional class IV PAH and in patients with inoperable CTEPH, regardless of WHO functional class, to improve exercise capacity and WHO functional class. Riociguat is indicated in patients with WHO functional class II or III PAH to improve exercise capacity, improve functional class, and delay clinical worsening. The recommended starting dosage of riociguat is 1 mg three times daily.26 It may be started at 0.5 mg three times daily in patients unable to tolerate the 1-mg dose. The dosage may be increased by 0.5-mg increments no greater than once every two weeks if the patient’s SBP is greater than 95 mm Hg and the patient has no signs or symptoms of hypoten-
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sion. The maximum dosage is 2.5 mg three times daily. If at any time a patient experiences dosage-related hypotension, the dosage should be decreased by 0.5 mg. If a dose is missed, the patient should take the next scheduled dose; however, if riociguat therapy is interrupted for three or more days, therapy should be restarted from the initial dosage.26 Safety Drug interactions. Patients who smoke may require dosages higher than the maximum 2.5-mg dose three times daily.26 Further, patients who quit smoking during treatment with riociguat may require a dosage decrease after quitting. Patients taking strong cytochrome P-450 inhibitors and P-glycoprotein/breast cancer resistance protein (BCRP) inhibitors such as azole antifungals (i.e., ketoconazole or itraconazole) or protease inhibitors (e.g., ritonavir) should be initiated on riociguat at 0.5 mg three times daily, and the dosage should be cautiously increased. The package insert provides no information about dosing riociguat when used concomitantly with a strong cytochrome P-450 inducer and P-glycoprotein/ BCRP inducer. Administration of riociguat and antacids should be separated by one hour secondary to decreased riociguat absorption.26 Riociguat has pharmacodynamic interactions with PDE5 inhibitors such as sildenafil, tadalafil, vardenafil, and avanafil secondary to similar end results, even though they have different mechanisms of action. Of note, sildenafil and tadalafil are indicated for the treatment of PAH. Concomitant administration of riociguat with PDE5 inhibitors is contraindicated due to the potential for high levels of nitric oxide and resultant symptomatic hypotension. Riociguat is also contraindicated with nitrates and nitric oxide donor agents (e.g., amyl nitrite) for similar concerns regarding symptomatic hypotension.20 With respect to nitrates, riociguat should
be thought of no differently than any PDE5 inhibitor, and this interaction should be treated as potentially fatal. Riociguat does not interact with warfarin, which is important, as most patients with CTEPH are taking concomitant warfarin therapy.27 Pregnancy. Riociguat is a pregnancy category X drug and thus contraindicated in patients who are pregnant.26 Before females of reproductive potential can be started on riociguat, they should have a negative pregnancy test, be advised of the use of appropriate contraception while on riociguat, and receive monthly pregnancy tests. For all female patients, regardless of age, riociguat is available only through a restrictedaccess program, the Adempas risk evaluation and mitigation strategy program; male patients do not need to be enrolled in the program. Adverse effects. The two most serious adverse effects related to riociguat are hypotension and bleeding.26 The decrease in blood pressure seen with riociguat is expected, and an asymptomatic decrease in blood pressure is not a reason to stop riociguat therapy. Patients should be counseled on this and closely monitored for symptomatic hypotension related to either drug effect or nondrug effect (i.e., hypovolemia, ischemia, or treatment with additional antihypertensive medications). In clinical studies of riociguat, serious episodes of bleeding occurred in 2.4% of patients treated with riociguat compared with 0% of patients taking placebo. 19,20 Five episodes (1%) of serious hemoptysis occurred in patients taking riociguat compared with zero episodes in patients taking placebo. Of the episodes of hemoptysis, one was fatal.20 Other hemorrhagic events included vaginal bleeding, catheter site bleeding, subdural hematoma, hematemesis, and intraabdominal bleeding.19,20,26 The adverse effects of the CHEST-1 and PATENT-1 trials were pooled. The adverse effects occur-
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ring more frequently (≥3%) in the riociguat group compared with the placebo group included headache, dyspepsia and gastritis, dizziness, nausea, diarrhea, hypotension, vomiting, anemia, gastroesophageal reflux disease, and constipation.26 Conclusion Riociguat is a sGC stimulator approved for the treatment of CTEPH and PAH. It can be considered firstline therapy for the treatment of CTEPH and should be considered as an alternative to PDE5 inhibitors in patients with PAH. References 1. Rubin LJ. Primary pulmonary hypertension. N Engl J Med. 1997; 336:111-7 2. McLaughlin VV, Archer SL, Badesch DB et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension. Circulation. 2009; 119:2250-94. 3. Provencher S, Herve P, Jais X et al. Deleterious effects of beta-blockers on exercise capacity and hemodynamics in patients with portopulmonary hypertension. Gastroenterology. 2006; 130:120-6. 4. Handoko ML, de Man FS, Allaart CP et al. Perspectives on novel therapeutic strategies for right heart failure in pulmonary arterial hypertension: lessons from the left heart. Eur Respir Rev. 2010; 19:72-82. 5. Food and Drug Administration. FDA approves Adempas to treat pulmonary hypertension. www.fda.gov/newsevents/ newsroom/pressannouncements/ ucm370866.htm (accessed 2014 Mar 5). 6. Schermuly R, Stasch JP, Pullamsetti SS et al. Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension. Eur Respir J. 2008; 32:88191. 7. Grimminger F, Weimann G, Frey R et al. First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J. 2009; 33:785-92. 8. Bishop BM, Mauro VF, Khouri SJ. Practical considerations for the pharmacotherapy of pulmonary arterial hypertension. Pharmacotherapy. 2012; 32:838-55. 9. Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med. 2004; 351:1655-65. 10. Dorris SL, Peeblas RS Jr. PGI2 as a regulator of inflammatory diseases. Mediators Inflamm. 2012; 2012:926968. 11. Tapson VF, Jing CZ, Xu KF et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients receiving background endothelin receptor antagonist and phosphodiesterase type
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12.
13.
14.
15.
16.
5 inhibitor therapy (the FREEDOM-C2 study): a randomized controlled trial. Chest. 2013; 144:952-8. Gatfield J, Mueller Grandjean C, Sasse T et al. Slow receptor dissociation kinetics differentiate macitentan from other endothelin receptor antagonists in pulmonary arterial smooth muscle cells. PloS One. 2012; 7:e47662. Rubin LJ, Badesch DB, Barst RJ et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002; 346:896-903. Iglarz M, Binkert C, Morrison K et al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther. 2008; 327:736-45. Rubin L, Pulido T, Channick R et al. Effect of macitentan on morbidity and mortality in pulmonary arterial hypertension (PAH): results from the SERAPHIN trial. Chest. 2012; 142:1026A. McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation. 2006; 114:1417-31.
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17. Atz AM, Adatia I, Wessel DL. Rebound pulmonary hypertension after inhalation of nitric oxide. Ann Thorac Surg. 1996; 62:1759-64. 18. Ghofrani HA, Hoeper MM, Halank M et al. Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study. Eur Respir J. 2010; 36:792-9. 19. Ghofrani HA, D’Armini AM, Grimminger F et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013; 369:319-29. 20. Ghofrani HA, Galie N, Grimminger F et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013; 369:330-40. 21. ClinicalTrials.gov. BAY63-2521—longterm extension study in patients with chronic thromboembolic pulmonary hypertension (CHEST-2). www.clinicaltrials. gov/ct2/show/NCT00910429 (accessed 2013 Dec 14). 22. ClinicalTrials.gov. BAY63-2521: longterm extension study in patients with pulmonar y ar ter ial hy per tension
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23.
24.
25. 26. 27.
(PATENT-2). www.clinicaltrials.gov/ ct2/show/NCT00863681 (accessed 2013 Dec 14). Express Scripts Holding Company. Adempas approved for pulmonary hypertension. www.afspa.org/wp-content/ uploads/2013/10/This-is-an-ExpressScripts-Clinical-Flash-11-October-2013. pdf (accessed 2014 Mar 8). Wilkens H, Lang I, Behr J et al. Chronic thromboembolic pulmonary hypertension (CTEPH): updated recommendations of the Cologne Consensus Conference 2011. Int J Cardiol. 2011; 154(suppl 1):S54-60. Auger WR, Jamieson SW. Riociguat for pulmonary arterial hypertension. N Engl J Med. 2013; 369:2266. Adempas (riociguat) package insert. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2013 Oct. Frey R, Mück W, Kirschbaum N et al. Riociguat (BAY 63-2521) and warfarin: a pharmacodynamic and pharmacokinetic interaction study. J Clin Pharmacol. 2011; 51:1051-60.
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CLINICAL REVIEW
ar Layar
Riociguat for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension
P
ulmonary arterial hypertension (PAH) is a progressive disease characterized by a remodeling of the pulmonary artery and its associated vasculature. This remodeling leads to an increase in pressure in the pulmonary arterial vasculature, which leads to right-sided heart failure and subsequent death.1 PAH is a subclassification of pulmonary hypertension and is distinct from systemic arterial hypertension.2 Chronic thromboembolic pulmonary hypertension (CTEPH) is also a subclassification of pulmonary hypertension.2 Therapies traditionally used to treat systemic arterial hypertension are often of little benefit in PAH.3,4 Due to the progressive nature of PAH, its associated high mortality, and limited treatment options, unique therapies that target the remodeling that occurs in the pulmonary vasculature are often used for the treatment of PAH and CTEPH. Riociguat, the first member of a new class of drugs called soluble guanylate cyclase (sGC) stimulators, was approved by the Food and Drug Administration in October 2013.5 Like the phosphodiesterase type-5
Bryan M. Bishop Purpose. The pharmacology, pharmacokinetics, clinical efficacy, safety, and role in therapy for riociguat are reviewed. Summary. Riociguat is the first member of a new class of medications, soluble guanylate cyclase stimulators. Riociguat is indicated for patients with resistant or recurrent chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary endarterectomy who have World Health Organization (WHO) functional class IV pulmonary arterial hypertension (PAH) and in patients with inoperable CTEPH, regardless of WHO functional class, to improve exercise capacity and WHO functional class. Riociguat is indicated in patients with WHO functional class II PAH to improve exercise capacity, improve functional class, and delay clinical worsening. The mechanism of action of riociguat is within the nitric oxide pathway in the pulmonary vasculature. Clinical trials have demonstrated improvements in exercise capacity as measured by the six-
(PDE5) inhibitors, riociguat acts on the nitric oxide pathway. Nitric oxide exerts a vasodilatory effect by increasing the production of cyclic guanosine monophosphate (cGMP) via activation of sGC. Riociguat activates sGC
Bryan M. Bishop, B.S., Pharm.D., BCPS, is Clinical Pharmacist, Department of Pharmacy, St. Rita’s Medical Center, Lima, OH, and Assistant Professor, Rudolph H. Raabe College of Pharmacy, Ohio Northern University, Ada, OH. Address correspondence to Dr. Bishop ([email protected]). The author has declared no potential conflicts of interest.
minute walk distance test and in pulmonary arterial hemodynamics as measured by invasive pulmonary monitoring. Riociguat must be administered three times daily and requires dosage adjustments. Riociguat is a pregnancy category X drug and interacts with numerous medications. The two most serious adverse effects related to riociguat are hypotension and bleeding. Riociguat’s role in the therapy of both PAH and CTEPH will be determined as more clinical experience and data are collected. Riociguat will likely cost approximately $90,000 annually. Conclusion. Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of CTEPH and PAH. It can be considered first-line therapy for the treatment of CTEPH and should be considered as an alternative to phosphodiesterase type-5 inhibitors in patients with PAH. Am J Health-Syst Pharm. 2014; 71:183944
directly irrespective of nitric oxide while increasing the sensitivity of sGC to low levels of endogenous nitric oxide.6,7 This article describes the pharmacology, pharmacokinetics, clinical efficacy, and safety of riociguat.
Copyright © 2014, American Society of Health-System Pharmacists, Inc. All rights reserved. 1079-2082/14/1101-1839. DOI 10.2146/ajhp130777
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Background Current therapies and pathways. The pathological pathways currently targeted for the treatment of PAH and CTEPH include the prostaglandin pathway, the nitric oxide pathway, and the endothelin pathway.8,9 Of note, calcium channel blockers can be used to treat systemic arterial hypertension in a very small number of patients diagnosed with PAH. However, doses of calcium channel blockers used in the treatment of PAH are much higher than typically used for other patients and are poorly tolerated by the few patients who are eligible for treatment.8 Prostanoids. The first class of drugs to target a specific pathway in PAH was the prostanoids, which mimic endogenous prostaglandins and lead to an increase in cyclic adenosine monophosphate (cAMP).10 This increase in cAMP in the pulmonary arterial vasculature results in vasodilation, antiproliferative effects, and the inhibition of local platelet aggregation. The first agent in this class was epoprostenol and is given by continuous infusion. Treprostinil is available as a parenteral product for continuous subcutaneous or i.v. infusion, an inhaled formulation, and an oral formulation.11 Iloprost, the third commercially available prostanoid in the United States, is only available as an inhaled formulation.8 Endothelin antagonists. The endothelin pathway is an appealing target for medication therapy, as excess levels of endothelin-1 in the pulmonary arterial vasculature lead to pulmonary arterial vasoconstriction, smooth muscle cell proliferation, and pulmonary vasculature remodeling.12 Endothelin-1 exerts its effect by acting on two endothelin receptors, endothelin A (ETA) and endothelin B (ETB). ETA receptors are located primarily on smooth muscle cells and heart tissue, whereas ETB receptors are located primarily on endothelial cells. The blocking of ETA receptors located on smooth 1840
muscle cells will interrupt the pathological processes of PAH, leading to clinical improvement.13 Stimulation of ETB on endothelial cells enhances endothelin-1 clearance, stimulates nitric oxide release, and directly induces pulmonary arterial vasodilation.13 Bosentan was the first commercially available endothelin antagonist and is frequently associated with liver enzyme elevations, anemia, and numerous drug–drug interactions. Ambrisentan, another endothelin antagonist, is associated with less liver and blood toxicity as well as fewer drug–drug interactions. Macitentan is the most recently approved endothelin antagonist and is associated with low toxicity while possessing greater tissue penetration and receptor binding duration than either bosentan or ambrisentan.12-15 Phosphodiesterase inhibitors. In the endothelium, nitric oxide is produced by nitric oxide synthase. Nitric oxide then binds to sGC and, via the production of cGMP, induces vasodilation and inhibits cell proliferation.16 In PAH, nitric oxide production is impaired; thus, therapies targeting this pathway have been explored, and some have been shown to be efficacious. Exogenous inhaled nitric oxide is used as part of a “vasodilator test” when the initial diagnosis of PAH is made and staging of the disease is done.8 Utilizing nitric oxide in the treatment of PAH has also been evaluated; while the therapy did produce levels of pulmonary vasodilation, this was counterbalanced by peripheral vasoconstriction and reflex tachycardia, both of which can worsen symptoms in patients with PAH.17 The enzyme PDE5 catalyzes the conversion of cGMP to guanosine monophosphate. By inhibiting PDE5, levels of cGMP are preserved. Sildenafil was the first PDE5 inhibitor to be evaluated and approved for use in patients with PAH. Tadalafil is also approved for use in PAH.
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Clinical trials Early phase trials. An initial hemodynamic study of riociguat was conducted in adults diagnosed with PAH, CTEPH, or pulmonary hypertension associated with interstitial lung disease and a pulmonary vascular resistance (PVR) exceeding 300 dyn·s·cm–5.7 The goal of the study was to assess the pharmacodynamics and pharmacokinetics of a single dose of riociguat in 19 patients with moderate-to-severe PAH, CTEPH, or pulmonary hypertension. The safety, tolerability, and efficacy of riociguat were also evaluated. The administration of a single dose of riociguat 1 or 2.5 mg resulted in clinically relevant and significant reductions in hemodynamic variables, including mean pulmonary arterial pressure (mPAP), PVR, systemic vascular resistance (SVR), and systolic blood pressure (SBP). The pharmacokinetic results from this study revealed that riociguat has dose-dependent plasma concentrations after the administration of a single dose, with notable interpatient variability. Peak riociguat concentrations occurred 0.25–1.5 hours after administration, and the drug had a half-life of 8–12 hours. This study was a proof-ofconcept study that established only the potential of riociguat as an option for the treatment of PAH and CTEPH. Based on the results of this study, a Phase II study was conducted to evaluate the safety, tolerability, and dosing of riociguat.18 A Phase II, 12-week, open-label, dosage-escalation study was conducted at 15 centers in Germany.18 Patients with PAH or CTEPH were eligible for enrollment. Patients were allowed to be taking only endothelin receptor antagonists for long-term therapy for PAH or CTEPH before enrollment. The primary endpoints of the study were the feasibility, safety, and tolerability of individual dosage adjustments of riociguat based on peripheral SBP. Patients received immediate-release tablets of
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riociguat starting at 1 mg three times daily; every 2 weeks the dosage was increased by 0.5 mg up to a maximum dose of 2.5 mg. A total of 75 patients (42 with CTEPH and 33 with PAH) were enrolled in the trial, 72 of whom completed the 12-week study. At the end of the study, 52 patients were receiving the maximum 2.5mg dose three times daily, 4 patients were taking 1 mg three times daily, and 1 patient was receiving 0.5 mg three times daily. Exercise capacity, as measured by the six-minute walk distance (6MWD) test, increased in the total patient population (median increase of 55 m, p < 0.0001) as well as in both the CTEPH (median increase of 55 m, p < 0.0001) and PAH (median increase of 57 m, p < 0.0001) subpopulations. Patients with World Health Organization (WHO) functional class II PAH (i.e., ordinary physical activity causes undue dyspnea or fatigue, chest pain, or near syncope) at baseline had an improvement in 6MWD of 71.5 m (p = 0.0001) compared with patients with WHO functional class III PAH who had an improvement in 6MWD of 50 m (p < 0.0001). The improvement in 6MWD was similar in patients taking riociguat with an endothelin receptor antagonist and in those taking riociguat alone. In exploratory analyses, WHO functional class improved in 22 patients and deteriorated in only 1 patient. Emergent adverse effects seen in the study included dyspepsia, headache, hypotension, peripheral edema, tachycardia, fatigue, upper abdominal pain, dizziness, vertigo, vomiting, diarrhea, constipation, epistaxis, gastrointestinal infection, nasopharyngitis, respiratory tract infection, and syncope. A total of 50 patients had invasive hemodynamic monitoring performed at baseline and at the conclusion of the trial. In these patients, riociguat resulted in significant decreases in mPAP (–4.5 mm Hg, p < 0.0001), PVR (–215 dyn·s·cm–5, p < 0.0001), and SVR (–441 dyn·s·cm–5, p < 0.0001). The
authors of the study concluded that riociguat demonstrated a favorable safety profile with clinically meaningful improvements in exercise capacity and pulmonary hemodynamics. Based on the results of this Phase II study, two Phase III studies were conducted in patients with PAH or CTEPH.19,20 Phase III trials. The CHEST-1 study was a Phase III, randomized, multicenter, double-blind, placebocontrolled trial conducted over 16 weeks.19 In this trial, 261 patients with CTEPH that was determined to be either inoperable or persistent/ recurrent after pulmonary endarterectomy were randomized in a 1:2 fashion to receive either placebo or dose- adjusted riociguat (range, 0.5–2.5 mg three times daily). Patients were excluded if they received PDE5 inhibitors, prostanoids, endothelin receptor antagonists, or nitric oxide donor agents within the three months before study enrollment. The primary endpoint was the change in 6MWD at 16 weeks from baseline. Secondary endpoints included changes in PVR, WHO functional class, and time until clinical worsening. Adverse effects were monitored throughout the trial. The majority of the patients enrolled in the trial had WHO functional class II or III PAH at baseline, and 72% were classified as having inoperable CTEPH. A total of 18 patients withdrew from the study before the end of 16 weeks. At the end of the study, 77% of patients were taking the 2.5mg dose three times daily, and 12%, 6%, 4%, and 1% were taking the 2-, 1.5-,1-, and 0.5-mg doses three times daily, respectively. With respect to the primary endpoint at 16 weeks, the mean 6MWD increased by 39 m in the riociguat group and decreased by 6 m in the placebo group (leastsquares mean difference, 46 m; 95% confidence interval [CI], 25 to 67 m; p < 0.001) in the intention-to-treat population. This result was maintained when analyzed in the per-
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protocol population. With respect to the secondary endpoints, riociguat resulted in significant reductions in PVR (–246 dyn·s·cm–5; 95% CI, –303 to –190 dyn·s·cm–5; p < 0.001) and improvement in WHO functional class (p = 0.003). There was no difference between the riociguat group and the placebo group with respect to time until clinical worsening (2% and 6%, respectively; p = 0.17). There were significant improvements in mPAP (–5 mm Hg; 95% CI, –7 to –3 mm Hg; p < 0.001), mean arterial pressure (–9 mm Hg; 95% CI, –12 to –6 mm Hg; p < 0.001), and mean cardiac output (0.9 L/min; 95% CI, 0.6 to 1.1 L/min; p < 0.001) in the riociguat group compared with the placebo group. A total of 5 patients in the riociguat group and 2 patients in the placebo group withdrew from the study secondary to adverse effects. One case of acute renal failure during the trial was attributed to riociguat. Currently, an open-label extension study (CHEST-2) is being carried out with the patients enrolled in this study.21 Published concomitantly with the CHEST-1 study, the PATENT-1 study was a 12-week, double-blind, placebo-controlled trial conducted in patients with PAH.20 In this study, 443 patients with symptomatic PAH were randomized in a 2:4:1 fashion to placebo, dose-adjusted riociguat with a maximum dosage of 2.5 mg three times daily, or dose-adjusted riociguat with a maximum dosage of 1.5 mg three times daily. Data from the 1.5-mg maximum-dose group were included only for exploratory purposes to study lower doses of riociguat; results from this group were not included in the primary efficacy analyses. The primary endpoint of the study was the change in 6MWD at 12 weeks from baseline. Secondary endpoints included changes in PVR, WHO functional class, and time until clinical worsening. Adverse effects were monitored throughout the trial. Patients had to have been on either
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no medications before enrollment or stable doses for 90 days of endothelin receptor antagonists or nonintravenous prostanoids. Patients treated with intravenous prostanoids or PDE5 inhibitors were excluded. Of the patients enrolled, 44% were taking endothelin receptor antagonists before enrollment, 6% were taking prostanoids, and 50% were not taking any medications. In the 2.5-mg maximum-dose group, 75% of patients were receiving the maximum dose at 12 weeks; 15%, 6%, 3%, and 2% were taking 2, 1.5, 1, and 0.5 mg three times daily, respectively. In the 1.5-mg maximum-dose group, 96% of patients were taking the maximum dose at 12 weeks. With respect to the primary endpoint, the 6MWD increased by a mean of 30 m in the 2.5mg maximum-dose group and decreased by 6 m in the placebo group (least-squares mean difference, 36 m; 95% CI, 20 to 52 m; p < 0.001) in the intention-to-treat population. This result was maintained, regardless of whether the patient was on therapy for PAH at baseline. Patients who had WHO functional class III or IV PAH (least-squares mean difference, 59 m; 95% CI, 37 to 81 m) at baseline had a notably better response than did those who had WHO functional class I or II PAH (least-squares mean difference, 14 m; 95% CI, –9 to 36 m). Of enrolled patients in the trial, 201 were WHO functional class I or II at baseline and 241 were WHO functional class III or IV; data were missing for 1 patient. Patients in the riociguat 2.5-mg maximum dose group had significant improvement in PVR (–226 dyn·s·cm–5; 95% CI, –281 to –170 dyn·s·cm–5; p < 0.001) and WHO functional class (p = 0.003) compared to the placebo group as well as a lower frequency of clinical worsening when compared to the placebo group. A total of 8 patients (3%) in the 2.5-mg riociguat group and 9 patients (7%) in the placebo group discontinued the study secondary to adverse effects. In the 1842
2.5-mg maximum-dose group, single cases of elevated hepatic enzyme levels, acute renal failure, syncope, esophageal pain and swelling, supraventricular tachycardia, hypotension, generalized edema, and neck pain were attributed to the study medication. Currently, an open-label extension study (PATENT-2) is being conducted with the patients enrolled in this study.22 Role in therapy Riociguat’s role in the therapy of both PAH and CTEPH will be determined as more clinical experience and data are collected. However, based on the studies discussed herein, riociguat should likely be considered an alternative to the use of a PDE5 inhibitor in patients with PAH. There are no clinical data establishing riociguat as superior to or preferred over any other agents used to treat PAH. Riociguat will likely cost approximately $90,000 annually,23 compared with approximately $19,000 annually for sildenafil and $15,000 annually for tadalafil.8 Riociguat has been studied as either monotherapy or in combination with either endothelin receptor antagonists or prostanoids. Detailed information and long-term clinical data are not yet available to give a clear picture of the role of riociguat in combination therapy, which is frequently used in the treatment of PAH.2 Riociguat is indicated for the treatment of WHO functional class II and III PAH only. WHO functional class IV PAH is typically treated with prostanoid therapy with or without other agents.2 Although riociguat is the first medication approved specifically for the treatment of CTEPH, agents used to treat PAH have been studied in patients with CTEPH and are already commonly used to treat CTEPH (e.g., epoprostenol, treprostinil, iloprost). 24 Many patients with CTEPH may benefit extensively from or be cured by a surgical pro-
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cedure called pulmonary endarterectomy, during which blood clots in the pulmonary vasculature are removed. It has been recommended that riociguat be used in patients with CTEPH that is considered inoperable by an expert in pulmonary endarterectomy.25 One factor affecting the potential use of riociguat in both PAH and CTEPH is the three-times-daily dosing schedule. If three days of therapy are missed, the dosage must be readjusted. As riociguat would be considered an alternative therapy to PDE5 inhibitors, it should be noted that sildenafil is administered three times daily and tadalafil is administered once daily and neither requires a dosage-adjustment schedule. In addition, when initiating riociguat, the dosage schedule requiring a physician visit every two weeks may prove burdensome, as every patient’s blood pressure must be closely monitored during the initiation and during the adjustment phase. Dosage and administration Riociguat was approved for the treatment of CTEPH and PAH. 26 Riociguat is indicated for patients with resistant/recurrent CTEPH after pulmonary endarterectomy who have WHO functional class IV PAH and in patients with inoperable CTEPH, regardless of WHO functional class, to improve exercise capacity and WHO functional class. Riociguat is indicated in patients with WHO functional class II or III PAH to improve exercise capacity, improve functional class, and delay clinical worsening. The recommended starting dosage of riociguat is 1 mg three times daily.26 It may be started at 0.5 mg three times daily in patients unable to tolerate the 1-mg dose. The dosage may be increased by 0.5-mg increments no greater than once every two weeks if the patient’s SBP is greater than 95 mm Hg and the patient has no signs or symptoms of hypoten-
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sion. The maximum dosage is 2.5 mg three times daily. If at any time a patient experiences dosage-related hypotension, the dosage should be decreased by 0.5 mg. If a dose is missed, the patient should take the next scheduled dose; however, if riociguat therapy is interrupted for three or more days, therapy should be restarted from the initial dosage.26 Safety Drug interactions. Patients who smoke may require dosages higher than the maximum 2.5-mg dose three times daily.26 Further, patients who quit smoking during treatment with riociguat may require a dosage decrease after quitting. Patients taking strong cytochrome P-450 inhibitors and P-glycoprotein/breast cancer resistance protein (BCRP) inhibitors such as azole antifungals (i.e., ketoconazole or itraconazole) or protease inhibitors (e.g., ritonavir) should be initiated on riociguat at 0.5 mg three times daily, and the dosage should be cautiously increased. The package insert provides no information about dosing riociguat when used concomitantly with a strong cytochrome P-450 inducer and P-glycoprotein/ BCRP inducer. Administration of riociguat and antacids should be separated by one hour secondary to decreased riociguat absorption.26 Riociguat has pharmacodynamic interactions with PDE5 inhibitors such as sildenafil, tadalafil, vardenafil, and avanafil secondary to similar end results, even though they have different mechanisms of action. Of note, sildenafil and tadalafil are indicated for the treatment of PAH. Concomitant administration of riociguat with PDE5 inhibitors is contraindicated due to the potential for high levels of nitric oxide and resultant symptomatic hypotension. Riociguat is also contraindicated with nitrates and nitric oxide donor agents (e.g., amyl nitrite) for similar concerns regarding symptomatic hypotension.20 With respect to nitrates, riociguat should
be thought of no differently than any PDE5 inhibitor, and this interaction should be treated as potentially fatal. Riociguat does not interact with warfarin, which is important, as most patients with CTEPH are taking concomitant warfarin therapy.27 Pregnancy. Riociguat is a pregnancy category X drug and thus contraindicated in patients who are pregnant.26 Before females of reproductive potential can be started on riociguat, they should have a negative pregnancy test, be advised of the use of appropriate contraception while on riociguat, and receive monthly pregnancy tests. For all female patients, regardless of age, riociguat is available only through a restrictedaccess program, the Adempas risk evaluation and mitigation strategy program; male patients do not need to be enrolled in the program. Adverse effects. The two most serious adverse effects related to riociguat are hypotension and bleeding.26 The decrease in blood pressure seen with riociguat is expected, and an asymptomatic decrease in blood pressure is not a reason to stop riociguat therapy. Patients should be counseled on this and closely monitored for symptomatic hypotension related to either drug effect or nondrug effect (i.e., hypovolemia, ischemia, or treatment with additional antihypertensive medications). In clinical studies of riociguat, serious episodes of bleeding occurred in 2.4% of patients treated with riociguat compared with 0% of patients taking placebo. 19,20 Five episodes (1%) of serious hemoptysis occurred in patients taking riociguat compared with zero episodes in patients taking placebo. Of the episodes of hemoptysis, one was fatal.20 Other hemorrhagic events included vaginal bleeding, catheter site bleeding, subdural hematoma, hematemesis, and intraabdominal bleeding.19,20,26 The adverse effects of the CHEST-1 and PATENT-1 trials were pooled. The adverse effects occur-
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ring more frequently (≥3%) in the riociguat group compared with the placebo group included headache, dyspepsia and gastritis, dizziness, nausea, diarrhea, hypotension, vomiting, anemia, gastroesophageal reflux disease, and constipation.26 Conclusion Riociguat is a sGC stimulator approved for the treatment of CTEPH and PAH. It can be considered firstline therapy for the treatment of CTEPH and should be considered as an alternative to PDE5 inhibitors in patients with PAH. References 1. Rubin LJ. Primary pulmonary hypertension. N Engl J Med. 1997; 336:111-7 2. McLaughlin VV, Archer SL, Badesch DB et al. ACCF/AHA 2009 expert consensus document on pulmonary hypertension. Circulation. 2009; 119:2250-94. 3. Provencher S, Herve P, Jais X et al. Deleterious effects of beta-blockers on exercise capacity and hemodynamics in patients with portopulmonary hypertension. Gastroenterology. 2006; 130:120-6. 4. Handoko ML, de Man FS, Allaart CP et al. Perspectives on novel therapeutic strategies for right heart failure in pulmonary arterial hypertension: lessons from the left heart. Eur Respir Rev. 2010; 19:72-82. 5. Food and Drug Administration. FDA approves Adempas to treat pulmonary hypertension. www.fda.gov/newsevents/ newsroom/pressannouncements/ ucm370866.htm (accessed 2014 Mar 5). 6. Schermuly R, Stasch JP, Pullamsetti SS et al. Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension. Eur Respir J. 2008; 32:88191. 7. Grimminger F, Weimann G, Frey R et al. First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J. 2009; 33:785-92. 8. Bishop BM, Mauro VF, Khouri SJ. Practical considerations for the pharmacotherapy of pulmonary arterial hypertension. Pharmacotherapy. 2012; 32:838-55. 9. Farber HW, Loscalzo J. Pulmonary arterial hypertension. N Engl J Med. 2004; 351:1655-65. 10. Dorris SL, Peeblas RS Jr. PGI2 as a regulator of inflammatory diseases. Mediators Inflamm. 2012; 2012:926968. 11. Tapson VF, Jing CZ, Xu KF et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients receiving background endothelin receptor antagonist and phosphodiesterase type
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5 inhibitor therapy (the FREEDOM-C2 study): a randomized controlled trial. Chest. 2013; 144:952-8. Gatfield J, Mueller Grandjean C, Sasse T et al. Slow receptor dissociation kinetics differentiate macitentan from other endothelin receptor antagonists in pulmonary arterial smooth muscle cells. PloS One. 2012; 7:e47662. Rubin LJ, Badesch DB, Barst RJ et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med. 2002; 346:896-903. Iglarz M, Binkert C, Morrison K et al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist. J Pharmacol Exp Ther. 2008; 327:736-45. Rubin L, Pulido T, Channick R et al. Effect of macitentan on morbidity and mortality in pulmonary arterial hypertension (PAH): results from the SERAPHIN trial. Chest. 2012; 142:1026A. McLaughlin VV, McGoon MD. Pulmonary arterial hypertension. Circulation. 2006; 114:1417-31.
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17. Atz AM, Adatia I, Wessel DL. Rebound pulmonary hypertension after inhalation of nitric oxide. Ann Thorac Surg. 1996; 62:1759-64. 18. Ghofrani HA, Hoeper MM, Halank M et al. Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study. Eur Respir J. 2010; 36:792-9. 19. Ghofrani HA, D’Armini AM, Grimminger F et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013; 369:319-29. 20. Ghofrani HA, Galie N, Grimminger F et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013; 369:330-40. 21. ClinicalTrials.gov. BAY63-2521—longterm extension study in patients with chronic thromboembolic pulmonary hypertension (CHEST-2). www.clinicaltrials. gov/ct2/show/NCT00910429 (accessed 2013 Dec 14). 22. ClinicalTrials.gov. BAY63-2521: longterm extension study in patients with pulmonar y ar ter ial hy per tension
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25. 26. 27.
(PATENT-2). www.clinicaltrials.gov/ ct2/show/NCT00863681 (accessed 2013 Dec 14). Express Scripts Holding Company. Adempas approved for pulmonary hypertension. www.afspa.org/wp-content/ uploads/2013/10/This-is-an-ExpressScripts-Clinical-Flash-11-October-2013. pdf (accessed 2014 Mar 8). Wilkens H, Lang I, Behr J et al. Chronic thromboembolic pulmonary hypertension (CTEPH): updated recommendations of the Cologne Consensus Conference 2011. Int J Cardiol. 2011; 154(suppl 1):S54-60. Auger WR, Jamieson SW. Riociguat for pulmonary arterial hypertension. N Engl J Med. 2013; 369:2266. Adempas (riociguat) package insert. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc.; 2013 Oct. Frey R, Mück W, Kirschbaum N et al. Riociguat (BAY 63-2521) and warfarin: a pharmacodynamic and pharmacokinetic interaction study. J Clin Pharmacol. 2011; 51:1051-60.
