Vasodilators in PAH Kailash Kumar Goyal.

Vasodilators in PAH Kailash Kumar Goyal

Definition of Pulmonary Hypertension
General definition Mean PAP ≥ 25 mm Hg at rest, measured by right heart catheterization Hemodynamic characterization of PAH Mean PAP ≥ 25 mm Hg, PAWP ≤ 15 mm Hg, elevated PVR (> 3 Wood Units) PAP = pulmonary artery pressure; PAWP = pulmonary artery wedge pressure; PVR = pulmonary vascular resistance Several recommendations were published following the 5th world symposium on pulmonary hypertension. First, the general definition for pulmonary hypertension was agreed to be a mean PAP ≥ 25 mm Hg at rest as measured by right heart catheterization. Also, the hemodynamic characterization of PAH was determined to be a mean PAP ≥ 25 mm Hg, PAWP ≤ 15 mm Hg, and an elevated PVR (> 3 Wood Units). Hoeper, et al. J Am Coll Cardiol. 2013;62(25):S42-50.

Clinical Classification of Pulmonary Hypertension
PAH is a diagnosis of exclusion The clinical classification for patients with pulmonary hypertension was updated at the 5th world symposium on pulmonary hypertension. Group 1 includes patients with pulmonary arterial hypertension (PAH). Of note are the designations of a group 1’ – patients with pulmonary veno-occlusive disease and / or pulmonary capillary hemangiomatosis, and a group 1” – patients with persistent pulmonary hypertension of the newborn (PPHN). The other groups are as follows: group 2 – pulmonary hypertension due to left heart disease; group 3 – pulmonary hypertension due to lung diseases and / or hypoxia; group 4 – chronic thromboembolic pulmonary hypertension; and group 5 – pulmonary hypertension with unclear multifactorial mechanisms. Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41.

Types of PAH Idiopathic Heritable Drug- and toxin-induced
BMPR2 ALK-1, ENG, SMAD9, CAV1, KCNK3 Unknown Heritable Drug- and toxin-induced Connective tissue disease HIV infection Portal hypertension Congenital heart disease Schistosomiasis Associated with: BMPR2 = bone morphogenetic protein receptor type 2; ALK-1 = activin A receptor type II-like kinase-1; ENG = endoglin; CAV1 = caveolin-1 The types of PAH are listed on the slide. Idiopathic PAH is designated as Heritable PAH is designated as 1.2 and includes patients with the following genetic mutations: BMPR2, ALK-1, ENG, SMAD9, CAV1, KCNK3, and unknown. Drug and toxin induced PAH is designated as Associated conditions are found under the last category of PAH (1.4) and include: connective tissue disease, HIV infection, portal hypertension, congenital heart disease, and Schistosomiasis. Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41.

Drug- and Toxin-Induced PAH
Definite Aminorex • Toxic rapeseed oil Fenfluramine • Benfluorex Dexfenfluramine • SSRIs Likely Amphetamines L-Tryptophan Methamphetamines Dasatinib Possible Cocaine • Chemotherapeutic agents Phenylpropanolamine • Interferon α and β St. John’s wort • Amphetamine-like drugs Unlikely Oral contraceptives Estrogen Cigarette smoking The list of substances that can potentially induce PAH was updated at the 5th world symposium on pulmonary hypertension. The categories are: definite, likely, possible, and unlikely. These designations are based on clinical research and case reports, and they describe the likelihood of a substance leading to PAH in a given individual. Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41.

Diagnostic Algorithm for PAH: Consensus From 5th WSPH
PAH is a diagnosis of exclusion WSPH = world symposium on pulmonary hypertension; V/Q = ventilation / perfusion lung scan; CTEPH = chronic thromboembolic pulmonary hypertension; RHC = right heart catheterization; PAP = pulmonary artery pressure; PAWP = pulmonary artery wedge pressure; PVR = pulmonary vascular resistance; WU = wood units A step-wise approach can be taken when evaluating patients for possible diagnosis of PAH. A diagnosis of PAH requires the exclusion of other causes of pulmonary hypertension. As such, heart and lung disease need to be ruled out. Also, chronic thromboembolic pulmonary hypertension (CTEPH) is ruled out by performing a V/Q scan and obtaining negative results. Right heart catheterization is mandatory for diagnostic confirmation. Hoeper, et al. J Am Coll Cardiol. 2013;62(25):S42-50.

Pathophysiology in PAH
Gaine, JAMA, 2000.

Pulmonary vasodilator testing
Establishes the relative contribution of reversible vasoconstriction verses fixed stenosis in patients with PAH. Patient with significant reversible vasoconstrictive component may benefit from long term use of calcium channel blockers. Not useful in patients who are not candidates to receive CCBs or who are already benefiting for them.

Criteria for a positive test
Multiple criteria for a positive pulmonary vasodilator test have been suggested. The latest criterion improve the specificity thereby avoiding adverse effects of CCB treatment in patients not likely to respond to CCBs. According to Sitbon et al, the sensitivity, specificity, positive and negative predictive values using the new criteria are 69, 87, 78 and 81 percent respectively.

Frequency of a positive test
The percentage of a positive test depends on the criteria used. Observed in 10-15% patients using the current criteria. Not all the patients with a positive test are responders. Sitbon et al., 2005

DRUGS USED FOR VASODILATOR TESTING

Pulmonary Vasodilator Test
ESC/ERS 2015 guidelines

Limitations Positive only in a minority of patients, predominantly those with IPAH and anorexigen induced PAH. All positive patients may not be long term CCBs responders. Potential adverse effects depending on the agent used. Time consuming. Cost.

Calcium Channel Blockers

Choice of CCBs is based on patients heart rate at baseline.
Relative bradycardia- nifedipine or amlodipine Relative tachycardia- diltiazem. Nifedipine mg Amlodipine- upto 20mg Diltiazem mg ESC/ERS 2015 guidelines

Calcium Channel Blockers
ESC/ERS 2015 guidelines

Mechanisms of Pathology for PAH
Endothelin Pathway Prostacyclin Pathway Nitric Oxide Pathway Endothelial cells L-arginine Preproendothelin Proendothelin Arachidonic acid Prostaglandin I2 NOS Nitric oxide Endothelin-1 Prostaglandin I2 sGC stimulator Endothelin-receptor A GTP Endothelin-receptor B The graphic shows three pathways that are believed to play a key role in the pathology of PAH: the endothelin pathway, nitric oxide pathway, and the prostacyclin pathway. The illustration also shows the sites and targets for common treatment options. Endothelin receptor antagonists act on the endothelin receptors in that pathway. The target for the phosphodiesterase-5 inhibitors, as well as the newly-approved agent riociguat, is the nitric oxide pathway. Meanwhile, the prostacyclin analogs target the prostacyclin pathway. Exogenous nitric oxide Prostacyclin derivates Endothelin-receptor antagonists cGMP cAMP Phosphodiesterase type 5 Vasodilatation and antiproliferation Vasodilatation and antiproliferation Vasoconstriction and proliferation Phosphodiesterase type 5 inhibitor Humbert, et al. N Engl J Med. 2004;351:

Targets for Therapy in PAH
McLaughlin VV, McGoon MD. Circulation 2006;114:

Pathways and Agents SC = subcutaneous; PDE-5 = phosphodiesterase-5 The prostacyclin pathway has been implicated in the pathogenesis of PAH. Prostacyclin is produced primarily by endothelial cells. It induces potent vasodilation of vascular beds, and inhibits platelet aggregation. In addition, prostacyclin has cytoprotective and antiproliferative properties. In patients with PAH, the prostacyclin pathway is said to be dysregulated. The prostacyclin analogs FDA approved for use in patients with PAH are: epoprostenol, treprostinil, and iloprost. The endothelin pathway has been implicated in the pathogenesis of PAH. Endothelin levels are increased in patients with PAH. It is not yet known if the increase is the cause or the result of the pathology of the disease. Endothelin causes vasoconstriction, and also has mitogenic properties. In patients with PAH, the endothelin system is activated. Endothelin receptor antagonists are used in patients to mitigate this pathology. The endothelin receptor antagonists that are FDA approved for use in patients with PAH are: bosentan, ambrisentan, and macitentan. The nitric oxide pathway has been implicated in the pathogenesis of PAH. Patients with PAH have impaired nitric oxide synthesis and signaling. The impairment is mediated through the NO-sCG-CGMP pathway. The phosphodiesterase-5 inhibitors inhibit the cGMP degrading enzyme, PDE-5. This enzyme inhibition enhances the NO-sGC-cGMP pathway, and slows down the degradation of cGMP. These agents cause vasodilation and have antiproliferative action. Currently, sildenafil and tadalafil are approved for use in patients with PAH. The soluble guanylate cyclase stimulators increase cGMP production, and have antiproliferative and antiremodeling properties. At this time, only riociguat is approved for use in patients with PAH. Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.

Prostacyclin Pathway Prostacyclin Prostacyclin analogs
Produced primarily by endothelial cells Induces potent vasodilation of vascular beds Inhibits platelet aggregation Cytoprotective and antiproliferative properties Prostacyclin analogs Epoprostenol Continuous IV infusion Treprostinil Subcutaneous, IV, inhalation, oral Iloprost Inhalation The prostacyclin pathway has been implicated in the pathogenesis of PAH. Prostacyclin is produced primarily by endothelial cells. It induces potent vasodilation of vascular beds, and inhibits platelet aggregation. In addition, prostacyclin has cytoprotective and antiproliferative properties. In patients with PAH, the prostacyclin pathway is said to be dysregulated. The prostacyclin analogs FDA approved for use in patients with PAH are: epoprostenol, treprostinil, and iloprost. Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.

Endothelin Pathway Endothelin Endothelin receptor antagonists
Plasma levels are elevated in patients with PAH Increases vasoconstriction Mitogenic properties Endothelin receptor antagonists Bosentan Oral Ambrisentan Macitentan The endothelin pathway has been implicated in the pathogenesis of PAH. Endothelin levels are increased in patients with PAH. It is not yet known if the increase is the cause or the result of the pathology of the disease. Endothelin causes vasoconstriction, and also has mitogenic properties. In patients with PAH, the endothelin system is activated. Endothelin receptor antagonists are used in patients to mitigate this pathology. The endothelin receptor antagonists that are FDA approved for use in patients with PAH are: bosentan, ambrisentan, and macitentan. Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.

Nitric Oxide Pathway Nitric oxide
Impairment of nitric oxide (NO) synthesis and signaling in patients with PAH Mediated through the NO-sGC-cGMP pathway NOS NO sGC cGMP L-Arginine L-Citrulline sGC = soluble guanylate cyclase; cGMP = cyclic guanosine monophosphate, NOS = nitric oxide synthase; PDE-5 = phosphodiesterase-5 The nitric oxide pathway has been implicated in the pathogenesis of PAH. Patients with PAH have impaired nitric oxide synthesis and signaling. The impairment is mediated through the NO-sCG-CGMP pathway. PDE-5 GMP Vasodilation Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.

Nitric Oxide Pathway Phosphodiesterase-5 inhibitors
Inhibit the cGMP degrading enzyme, PDE-5 Enhance the pathway, slowing cGMP degradation Vasodilation and antiproliferative effects Soluble guanylate cyclase stimulators Increase cGMP production Antiproliferative and antiremodeling properties Sildenafil Oral, IV Tadalafil Oral cGMP = cyclic guanosine monophosphate; PDE-5 = phosphodiesterase-5 Listed on the slide are categories of medications that act via the nitric oxide pathway and are FDA-approved for patients with PAH. First, the phosphodiesterase-5 inhibitors inhibit the cGMP degrading enzyme, PDE-5. This enzyme inhibition enhances the NO-sGC-cGMP pathway, and slows down the degradation of cGMP. These agents cause vasodilation and have antiproliferative action. Currently, sildenafil and tadalafil are approved for use in patients with PAH. The next category of medications that act on the nitric oxide pathway would be the soluble guanylate cyclase stimulators. These agents increase cGMP production, and have antiproliferative and antiremodeling properties. At this time, only riociguat is approved for use in patients with PAH. Riociguat Oral Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.

Trial design: What is Optimum ?
End Points Mortality Vital importance in a fatal disease like PAH Effect of drug on survival Since the incidence of disease is low – limit applicability Morbidity end points Various – hospitalization, decrease in exercise capacity 6 MWD Easy & inexpensive Most commonly used primary end point Carries prognostic significance Clinically relevant improvement in 6 MWD not established Composite - Time to Clinical Worsening Has been used as secondary end point in majority of studies Has variously included death, hospitalization, clinical worsening, decrease in 6 MWD Should be included as the primary end point & uniformly defined JACC;2009,Vol. 54, No. 1, Suppl S; S97–107

Head to head comparisons
Follow up Most trials – wk duration Longer follow up is required – to bring out significance of hard end points like mortality Head to head comparisons Between drugs of same and different group is lacking

Prostacyclin Analogs Epoprostenol Treprostinil Iloprost
Indication / FC III, IV II, III, IV Administration Continuous IV I SC IV Inhalation Dosage 20-40 ng/kg/min Initial = 1.25 ng/kg/min Usual = ng/kg/min Usual = µg, 6-9 times per day Other Only PAH clinical study to demonstrate survival benefit Max dosage = 45 µg FC = functional class; SC = subcutaneous Epoprostenol is indicated for patients with PAH, functional class III and IV. It is administered via continuous IV infusion. An inhalation dosage form is available in the hospital. The typical dosage is ng/kg/min. There are two branded versions of epoprostenol available. Each brand differs with regard to drug storage. One must be kept cold with ice packs or refrigeration (it is only room temperature stable for 8 hours). The other is room temperature stable. A study by Barst and colleagues (N Engl J Med. 1996;334: ) revealed noteworthy findings. Following 12 weeks of treatment, patients receiving epoprostenol (N = 41) had significantly greater survival rates compared to patients receiving conventional therapy for PAH (N = 40). Treprostinil is a indicated for patients with PAH, functional class II, III, and IV. The initial dosage is 1.25 ng/kg/min, and the average dosage ranges between 30 and 100 ng/kg/min. The routes of administration for treprostinil are: subcutaneous, IV, inhalation, and oral (extended-release tablets; twice daily dosing). Iloprost is indicated for patients with PAH, functional class III and IV. It is administered via ultrasonic nebulizer. The typical dosage is 2.5 to 5 μg, 6 to 9 times daily. The maximum daily dosage evaluated in clinical studies was 45 μg. It needs to be administered in well-ventilated areas. The route of administration of iloprost takes advantage of the theoretical superiority of pulmonary administration.

Epoprostenol Short half life of 3-5 minutes.
Stable at room temperature for only 8 hours. Requires cooling and continuous administration by means of an infusion pump and a permanent tunnelled catheter. Tested in three unblinded randomized controlled trials.

Epoprostenol

Epoprostenol Improves functional status & survival in children with PHN (Barst et al, 1996) 92% at 5 yr in CCB nonresponders Controls decreased 6 min walk by 66 m Mean PAP decreased 8% vs increase of 3% in controls. Also shown to decrease PVR (Rich, 1997) NYHA = new york heart association

Treprostinil

Treprostinil Simonneau G. et al. Am J Resp Crit Care Med 2002;165:

Treprostinil 6 minute walk distance compared
Simonneau G. et al. Am J Resp Crit Care Med 2002;165:

TRIUMPH 1 STUDY

TRIUMPH 1 McLaughlin V et al, JACC 2010

TRIUMPH 1

FREEDOM STUDIES

Treprostinil Oral for PAH: FREEDOM-M Clinical Trial
Study design RCT N = 228 treatment-naïve patients, no background therapy permitted Study duration = 12 weeks Change in 6-MWD * * Change from Baseline (meters) RCT = randomized, double-blind, placebo-controlled trial Jing and colleagues reported the results from the FREEDOM-M clinical trial. This clinical trial was a randomized, double-blind, placebo-controlled study in 228 patients with PAH, none of whom were receiving background therapy. The study evaluated change in 6-MWD from baseline to peak plasma concentration weeks – weeks 4, 8, and 12. A statistically significant improvement in 6-MWD was noted at 8 and 12 weeks in the modified intent-to-treat population of patients (N = 228). Weeks Jing, et al. Circulation. 2013;127:

Iloprost

Inhalational Iloprost
Olschewski et al, NEJM 2002, 347:322-9

Iloprost Inhalation Solution: Dosage and Administration
Indicated for inhalation via the Prodose® AAD® system only 2.5 mcg initial dose increase to 5 mcg if 2.5 mcg dose is tolerated maintain at maximum tolerable dose (2.5 mcg or 5 mcg) 6-9 inhalations daily during waking hours; 8-10 minutes each Prostacyclin may soon be available in an inhaled formulation to eliminate the inconvenience and associated side effects of IV or SQ dosing. Inhaled iloprost is currently seeking approval at the FDA for the treatment of PAH in patients with NYHA class III or IV symptoms and is presently available in Europe. The dosing for inhaled iloprost (Trade name Ventavis) is via the breath-actuated nebulizer (ProDose®) in six to nine daily doses during the waking hours. The benefits seen with epoprostenol but limited by its dose route and regimen would be possibly extended to patients in this more convenient formulation. THIS MAY NEED TWEAKING!!!

Endothelin Receptor Antagonists
Bosentan Ambrisentan Macitentan Indication / FC II, III, IV Administration Oral Dosage 62.5 mg twice daily for 4 weeks then 125 mg twice daily 5 mg and 10 mg daily 10 mg daily Other Sustained receptor binding and enhanced tissue penetration FC = functional class Bosentan is an endothelin receptor antagonist indicated for the treatment of PAH, functional class II, III, and IV. The initial dosage of bosentan is 62.5 mg oral twice daily for 4 weeks. Patients are then titrated to 125 mg oral twice daily. Ambrisentan is an endothelin receptor antagonist indicated for the treatment of PAH, functional class II and III. The dosage of ambrisentan is 5 mg and 10 mg oral once daily. Macitentan is an endothelin receptor antagonist that has recently been approved for use in patients with PAH. It is indicated for patients in functional class II, III, and IV. The dosage of macitentan is 10 mg oral daily.

STUDY-351

Study Bosentan Channick R, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: Lancet 2001;358: Hemodynamic measurements were taken at baseline and 12 weeks in Study 351.

Study Bosentan Channick R, et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: Lancet 2001;358:

BREATHE-1

BREATHE-1 Change in 6-MWD (From Baseline to Week 16)
-40 -20 20 40 60 80 Bosentan (N = 144) Change from Baseline (meters) P = The BREATHE clinical trial was conducted by Rubin and colleagues. The trial was a double-blind, placebo-controlled, 16-week study in patients with PAH. Patients who received bosentan were titrated from 62.5 mg twice daily to 125 mg or 250 mg twice daily at week 4. A significant improvement in exercise capacity (6-MWD) was noted in patients treated with bosentan (N = 144) compared to patients treated with placebo (N = 69). The investigators also reported that bosentan was well tolerated in patients. Placebo (N = 69) 62.5 mg twice daily 125 or 250 mg twice daily 4 8 16 Weeks Rubin, et al. N Engl J Med. 2002;346:

BREATHE 1 – Time to Clinical Worsening
Over the course of the study, the risk of clinical worsening was significantly less in the bosentan-treated patients than in those on placebo (p = 0.0015, using the log-rank test). Kaplan-Meier estimates of event-free patients were 89% and 63% in Tracleer (bosentan) and placebo groups, respectively. The difference between treatments was apparent as early as Week 16, and in an exploratory analysis, this difference was also statistically significant (p = 0.0038, using the log-rank test, with Kaplan-Meier estimates of event-free patients of 95% and 75% in bosentan and placebo groups, respectively).

Event-Free Patients (%)
Bosentan for PAH: EARLY Clinical Trial Time to Clinical Worsening (From Baseline to Week 32) 100 P < 0.02 80 Placebo 60 Bosentan Event-Free Patients (%) 40 The efficacy of bosentan (N = 86) in patients with PAH was compared to placebo (N = 91) in the EARLY clinical trial. The trial included a sub-group of patients receiving combination therapy with sildenafil (N= 29). Patients treated with bosentan had a significant improvement in exercise capacity (primary study endpoint) compared to patients taking placebo. The 6-MWD increased by 11.2 meters (on average) in the bosentan group and decreased by 7.9 meters (on average) in the placebo group. The average treatment effect was an improvement of 19.1 meters. The EARLY trial also examined time to clinical worsening (as a secondary endpoint) in patients with PAH. A statistically significant delay in the time to clinical worsening was seen in bosentan-treated patients compared to placebo-treated patients (graphically represented on this slide). 20 4 8 12 16 20 24 28 32 Weeks Galie, et al. Lancet (9630): Valerio et al. Vasc Health Risk Manag. 2009;5:

Ambrisentan for PAH: ARIES Clinical Trials Time to Clinical Worsening (From Baseline to Week 12)
100 --- Placebo mg (P = 0.03) --- 5 mg (P = 0.005) mg (P = 0.03) 90 Event-Free Patients (%) 80 The ARIES-1 and ARIES-2 clinical trials were concurrent, double-blind, placebo-controlled studies of ambrisentan for patients with PAH. The primary endpoint for the studies was the change in 6-MWD from baseline to week 12. All ambrisentan groups showed significant improvement in 6-MWD. For ARIES-1, the placebo-adjusted improvement in 6-MWD was 31 meters for ambrisentan 5 mg and 51 meters for ambrisentan 10 mg. For ARIES-2, the placebo-adjusted improvement in 6-MWD was 32 meters for ambrisentan 2.5 mg and 59 meters for ambrisentan 5 mg. Another study endpoint for the ARIES clinical trials was time to clinical worsening. The definition of clinical worsening included death, lung transplantation, hospitalization, atrial septostomy, and/or study withdrawal. Ambrisentan was better than placebo at delaying time to clinical worsening. The relative risk reduction attributed to ambrisentan was 71%. 70 4 8 12 Weeks Ambrisentan → 71% relative risk reduction Galie, et al. Circulation. 2008;117:

Ambrisentan for PAH: ARIES-E Clinical Trial Change in 6-MWD (From Baseline to 24 Months)
2.5 mg (N = 93) 5 mg (N = 186) 10 mg (N = 96) 70 60 50 40 Change from Baseline (meters) 30 28 20 23 10 7 Oudiz and colleagues examined the long-term efficacy of ambrisentan in patients with PAH. Long-term ambrisentan treatment was associated with sustained improvements in 6-MWD for the 5 mg and 10 mg groups. -10 -20 0.0 0.25 0.5 1.0 1.5 2.0 Years Oudiz, et al. J Am Coll Cardiol. 2009;54(21):

Macitentan- SERAPHIN STUDY

SERAPHIN Study Symptomatic pulmonary arterial hypertension patients, randomized to receive placebo once daily, macitentan at once-daily dose of 3 mg or macitentan at once-daily dose of 10 mg. Concomitant use of PAH specific therapy (other than ERA) was allowed. Primary end point was the first occurrence of a composite end point of death, atrial septostomy, lung transplantation, initiation of treatment with intravenous or subcutaneous prostanoids, or worsening of pulmonary arterial hypertension. Secondary End Points – Significant improvement in WHO functional class, 6 MWD, cardiac index & decrease in PVR N Engl J Med 2013;369:809-18

Result: Composite Primary End Point

Result: Composite Secondary End Point

Conclusion - Macitentan significantly reduced morbidity and mortality among patients with pulmonary arterial hypertension in this event-driven study. Received US Food and Drug Administration approval in Oct 2013 for the treatment of pulmonary arterial hypertension (PAH, WHO Group I) to delay disease progression.

Nitric Oxide Pathway Agents
Sildenafil Tadalafil Riociguat Type PDE-5 inhibitor Soluble guanylate cyclase stimulator Indication / FC II, III, IV Administration Oral IV Dosage 20 mg oral three times daily 10 mg IV three times daily 40 mg daily 1 mg – 2.5 mg three times daily FC = functional class; PDE-5 = phosphodiesterase-5 Sildenafil is a phosphodiesterase-5 inhibitor which is used to increase exercise capacity and decrease clinical worsening in patients with PAH, functional class II, III, and IV. The dosage of sildenafil is 20 mg oral three times daily. An IV formulation for sildenafil is also available. The dosage for the IV formulation is 10 mg three times daily. Tadalafil is a phosphodiesterase-5 inhibitor which is used to increase exercise capacity and decrease clinical worsening in patients with PAH, functional class II, III, and IV. The dosage of tadalafil is 40 mg oral once daily. Riociguat is a guanylate cyclase stimulator that targets the nitric oxide pathway. It has recently been approved for use in patients with PAH. The dosage range for riociguat is between 1 mg and 2.5 mg oral three times daily.

Sildenafil for PAH Clinical Study Study Design Agents N Study Duration
Study Results SUPER-11 RCT Sildenafil mg three times daily 278 12 weeks SS improvements in 6-MWD, FC SUPER-22 OL • Sildenafil 80 mg three times daily • 2nd agent added in 18% of patients 170 3 years 46% maintained or improved 6-MWD 60% maintained or improved FC Patient survival = 79% PACES3 • Epoprostenol • Epoprostenol + sildenafil 80 mg three times daily • 53 • 214 16 weeks Patients on combination therapy had SS improvement in 6-MWD, fewer clinical worsening events, and delayed TTCW RCT = randomized, double-blind, placebo-controlled study; SS = statistically significant; FC = functional class; OL = open-label extension; TTCW = time to clinical worsening The SUPER clinical trial was a randomized, double-blind, placebo-controlled study. It measured change in 6-MWD from baseline to week 12 in patients treated with one of three doses of sildenafil. All sildenafil doses significantly improved 6-MWD. The greatest placebo-adjusted change from baseline occurred with the highest dose of sildenafil, 80 mg. The trial also examined change in functional class in patients over the 12-week study period. Compared to placebo, all sildenafil doses significantly improved functional class in patients. The percent of patients with an improvement of at least one functional class were as follows: 7% of placebo group, 28% of sildenafil 20 mg group, 36% of sildenafil 40 mg group, and 42% of sildenafil 80 mg group. Rubin and colleagues reported results from the SUPER-2 clinical trial. This open-label extension study enrolled patients who completed the randomized, double-blind, placebo-controlled study, SUPER-1. A total of 170 patients did in fact complete both studies. The dose of sildenafil used in this patient population was 80 mg three times daily. A second agent to treat PAH was necessary in 18% of study participants before the study was complete. Results at 3 years were as follow: 46% of patients maintained or improved 6-MWD; 60% of patients maintained or improved functional class; and the 3–year estimated patient survival rate was 79%. The PACES clinical trial examined sildenafil in combination with epoprostenol. This double-blind, placebo-controlled study added sildenafil 80 mg three times daily to 80% of a patient population already receiving epoprostenol. The PACES clinical trial measured change in 6-MWD from baseline to week 16. The improvement in 6-MWD for the epoprostenol and sildenafil combination group (N = 214) was significantly superior to the “placebo” (epoprostenol monotherapy; N = 53) group. The treatment-adjusted increase in 6-MWD for the combination group was 28 meters. At 16 weeks, the percent of patients with clinical worsening was significantly less in the combination group. Seven deaths occurred in the placebo group compared to zero deaths in the combination group. Clinical worsening events included death, lung transplantation, hospitalization due to PAH, change in the epoprostenol dose due to clinical deterioration, or initiation of bosentan therapy. The epoprostenol and sildenafil combination group displayed a significantly delayed time to clinical worsening compared to the placebo group. 1) Galie, et al. N Engl J Med. 2005;353: ) Rubin, et al. Chest. 2011:140(5): 3) Simonneau, et al. Ann Intern Med. 2008;149(8):

Tadalafil for PAH Clinical Study Study Design Agents N Study Duration
Study Results PHIRST-11 RCT • Tadalafil 20 or 40 mg daily • Tadalafil + bosentan 189 216 16 weeks SS improvements in 6-MWD, QOL, clinical worsening events, TTCW, especially in treatment-naïve patients PHIRST-22 OL 135 158 52 weeks Improvements in 6-MWD, clinical worsening events were sustained RCT = randomized, double-blind, placebo-controlled study; QOL = quality of life; TTCW = time to clinical worsening; SS = statistically significant; FC = functional class; OL = open-label extension The PHIRST clinical trial was a double-blind, placebo-controlled, multicenter study. Tadalafil monotherapy (20 mg and 40 mg daily) was compared to combination therapy with background bosentan (125 mg twice daily). At 16 weeks, researchers witnessed greater improvement in 6-MWD in treatment-naïve patients compared to patients with background bosentan therapy. The investigators opined that the ability to detect improvements in endpoints may be reduced in the presence of effective background therapy. In other words, a “ceiling phenomenon” might be at play. Patients also demonstrated significant improvements in quality of life and time to and incidence of clinical worsening (40 mg dose of tadalafil). For clinical worsening events, the relative risk reduction was 68%. The most common adverse events reported were headache, myalgia, and flushing. All adverse events were considered mild to moderate in severity. Results for the long-term extension of the PHIRST clinical trial were published by Oudiz and colleagues. Patients who completed the double-blind, placebo-controlled PHIRST clinical trial were able to enroll in the long-term extension. Tadalafil (20 mg and 40 mg) was administered to patients for an additional 52 weeks. The initial improvement in 6-MWD was maintained over the long-term extension period (68 weeks total). It is important to note that patients could continue their background bosentan therapy during the study period. In total, 54% were receiving background bosentan. Clinical worsening events were significantly less in patients on combination therapy. 1) Galie, et al. Circulation. 2009;119(22): Barst, et al. J Heart Lung Transplant. 2011;30(6): 2) Oudiz, et al. J Am Coll Cardiol. 2012;60:

Riociguat Stimulates sGC directly, increasing the enzyme’s activity independently of NO, while also increasing sensitivity to low levels of NO Primarily metabolized in liver T ½ = 12 hrs n engl j med; july 25, 2013; 369;4 ;

Riociguat Contraindications Precaution
Pregnancy Use with nitrates, PDEIs Precaution PVOD Bleeding Hypotension Received US FDA approval for PAH and CTEPH in Oct 2013 Prodcut information sheet

Riociguat for PAH Clinical Study Study Design Agents N Study Duration
Study Results PATENT RCT Riociguat 1 mg, 1.5 mg, 2 mg, or 2.5 mg three times daily 443 12 weeks SS improvements in 6-MWD, PVR, NT-proBNP, FC, Borg Dyspnea Scale score, QOL measures, TTCW RCT = randomized, double-blind, placebo-controlled study; SS = statistically significant; PVR = pulmonary vascular resistance; NT-proBNP = N-terminal-pro-fragment BNP; FC = functional class; QOL = quality of life; TTCW = time to clinical worsening Accessed January The PATENT placebo-controlled study has been completed (NCT ). The PATENT open-label extension is still ongoing (NCT ). The PATENT phase III clinical trials are evaluating riociguat (1 mg, 1.5 mg, 2 mg, or 2.5 mg three times daily) for the treatment of PAH. The randomized, double-blind, placebo-controlled study assessed 6-MWD in 443 patients with PAH. The open-label extension is monitoring the long-term safety (adverse events) of riociguat in 396 patients who have completed the placebo-controlled study. The placebo-controlled study was 12 weeks long. In contrast, the open-label extension is event driven. Results from the PATENT clinical trial were presented by Ghofrani and colleagues at the CHEST meeting in 2012, and published in The investigators evaluated multiple clinical endpoints of efficacy for the treatment of PAH. After 12 weeks of treatment, riociguat demonstrated statistically significant improvement in the measured endpoints. Change in 6-MWD from baseline values was improved overall and in both subsets of patients, those pretreated with background PAH therapy (prostacyclin analog or endothelin receptor antagonist) and those without prior therapy. Fifty percent of study patients were on stable background therapy with either an endothelin receptor antagonist (44%) or a prostacyclin analog (6%). Statistically significant improvements were also noted in the following: PVR, NT-proBNP, WHO functional class, Borg Dyspnea Scale, quality of life (living with pulmonary hypertension) questionnaire, and clinical worsening. Ghofrani, et al. NEJM. 2013;369(4):

PATENT 1 STUDY

PATENT -1 Study PAH (Group 1) pts randomized to
Placebo (126) Riociguat 2.5 mg max dose (254) Riociguat 1.5 mg max dose (63) Primary end point – 6 MWD Secondary end points Changes in PVR, NT pro BNP, WHO functional class, Time to clinical worsening, Borg Dyspnoea Score, QOL scores Follow up – 12 wks Concomitant use of ERAs & prostanoids (non I/V) allowed The 1.5 mg–maximum group was included for exploratory purposes, to provide information about lower riociguat doses, and data from that group were not included in the efficacy analyses. N Engl J Med 2013;369:

Results & Conclusion Primary end point (placebo vs 2.5 mg group)
6 MWD had increased from baseline by a mean of 30 m in the 2.5 mg–maximum group and had decreased by a mean of 6 m in the placebo group (P<0.001) Secondary end points Significant improvement in NT pro BNP, WHO functional class, Borg Dyspnoea Score, clinical worsening events Significant improvement in PVR, mPAP, CI No significant difference seen in Euro QoL 5D Conclusion : Riociguat significantly improved exercise capacity and secondary efficacy end points in patients with pulmonary arterial hypertension.

CHEST-1 Double blind randomized 16 wk trial of Riociguat (2.5 mg) vs Placebo recruiting 261 pts of CTEPH Considered inoperable ( 70%) Persistent PAH after TEA (30%) Primary end point – 6 MWD Secondary end points Changes in PVR, NT pro BNP, WHO functional class, Time to clinical worsening, Borg Dyspnea Score, QOL scores N Engl J Med 2013;369:319-29

Results and Conclusion
Primary end point 6 MWD had increased from baseline by a mean of 39 m in the riociguat group and had decreased by a mean of 6 m in the placebo group (P<0.001) Secondary end points Significant improvement in NT pro BNP, WHO functional class, Borg Dyspnoea Score Significant improvement in PVR, mPAP, CI No significant difference seen in clinical worsening events Nominally significant difference in Euro QoL 5D Conclusion : Riociguat significantly improved exercise capacity and pulmonary vascular resistance in patients with chronic thromboembolic pulmonary hypertension

Riociguat for PAH: RESPITE Clinical Trial
Study design Open-label N = 60 patients with poor response to a PDE-5i Study duration = 24 weeks Study endpoints 6-MWD, cardiac index, NT-proBNP, functional class, quality of life, TTCW Study is ongoing PDE-5i = phosphodiesterase-5 inhibitor; NT-proBNP = N-terminal-pro-fragment BNP; TTCW = time to clinical worsening The RESPITE clinical trial is an ongoing, open-label study which will evaluate the efficacy of riociguat in patients with PAH who did not demonstrate a sufficient response to either sildenafil or tadalafil. The PDE-5i needed to be administered for at least 3 months to determine if the clinical response was indeed insufficient. A total of 60 patients will receive riociguat for 24 weeks (after a wash-out period). The investigators will measure any change in 6-MWD, cardiac index, NT-proBNP, functional class, quality of life, and time to clinical worsening.

RESPITE

Selexipag for PAH Latest drug to be approved. Mechanism of action
Prostacyclin IP receptor agonist Targets the prostacyclin pathway Administration – oral Selexipag is an investigational agent being studied for use in patients with PAH. It is a prostacyclin IP receptor agonist that targets the prostacyclin pathway. Image:

Selexipag Selective agonist of prostacyclin IP receptor
A phase II study, involving 43 PAH patients showed significant reductions in PVR (−30.3% versus placebo) compared with placebo ERJ October 1, 2012 vol. 40 no. 4

GRIPHON

Combination Therapy for PAH
Rationale – to target multiple disease pathways REVEAL: 34% of patients on 2 or more treatments Background Starting in one drug class and adding an agent from another class Used when therapy needs to be augmented because response to initial therapy is inadequate Sequential Therapy Used in early PAH disease May improve patient outcomes, slow disease progression, and reduce costs associated with managing clinical worsening Upfront Therapy Combination therapy is used in PAH to target multiple disease pathways. Endothelin receptor antagonists target the endothelin pathway. PDE-5 inhibitors and soluble guanylate cyclase stimulators target the nitric oxide pathway. The combination of a PDE-5 inhibitor and a soluble guanylate cyclase stimulator would be contraindicated. Prostacyclin analogs target the prostacyclin pathway. In theory, combination therapy could have an additive or synergistic effect. There could also be reduced adverse effects because individual medications are at lower doses. Clinicians make the decision to use combination therapy when response to monotherapy is inadequate. If response to dual combination therapy is inadequate, triple combination therapy should be considered. The interim report from the REVEAL patient registry recorded a high percentage of patients (34%) receiving combination therapy (N = 2967). The concept of using combination therapy first line, or near first line, in patients with PAH has been debated by both clinicians and researchers. The theory is that early initiation of combination therapy may improve overall patient outcomes by slowing the progression of disease. A cost benefit may also be realized if clinical worsening events fail to occur. Galie, et al. J Am Coll Cardiol. 2013;62(25):S Badesch, et al. Chest. 2010;137(2):

Upfront Combination Therapy: AMBITION Clinical Trial
Study design RCT N = 500 treatment-naïve patients Study groups Ambrisentan Tadalafil Ambrisentan + tadalafil Study duration = event driven Primary endpoint = TTCW *P < 0.05 Study results Combination therapy reduced the risk of clinical failure events by 50%* SS* improvements in: 6-MWD NT-proBNP % Patients with a satisfactory clinical response RCT = randomized, double-blind, placebo-controlled study; TTCW = time to clinical worsening; SS = statistically significant; NT-proBNP = N-terminal-pro-fragment BNP The AMBITION clinical trial was a randomized clinical trial that compared the efficacy of upfront monotherapy to upfront combination therapy. Treatment-naïve patients with PAH (N = 500; functional class II or III) were randomized to receive either ambrisentan alone, tadalafil alone, or both in combination. The study was event driven, with time to clinical worsening as the primary endpoint. Clinical worsening was defined as: death, hospitalization for worsening PAH, disease progression, or unsatisfactory clinical response. An abstract of study results was recently presented and published. According to the researchers, combination therapy (N = 253) significantly reduced (P < 0.05) the risk of clinical failure events by 50%, when compared to monotherapy with either ambrisentan (N = 126; 10 mg daily) or tadalafil (N = 121; 40 mg daily). The main treatment effect was driven by hospitalizations for worsening PAH. If fact, time to first hospitalization was delayed by 63 percent in the combination therapy group (P < 0.05). Additional statistical significant improvements (measured at 24 weeks and compared to baseline) included: change in 6-MWD, change in NT-proBNP, and percent of patients with a satisfactory clinical response. Galie, et al. Eur Respir J. 2014;44(58):ABSTRACT.

Upfront Triple Combination Therapy
Study design Retrospective review N = 18 treatment-naïve patients in FC III or IV Epoprostenol + bosentan + sildenafil First assessment of endpoints at 4 months Study results SS* improvements in 6-MWD Hemodynamics Functional class Improvement to FC I or II for 17 patients Overall patient survival 100% at 1, 2, and 3 years *P < 0.05 FC = functional class; SS = statistically significant Sitbon and colleagues reported results from a pilot study that retrospectively reviewed the treatment of 18 patients with severe PAH (functional class III or IV). An additional patient would have been included in the review, however the patient underwent an urgent heart-lung transplant at month 3, so follow-up ceased at that time. The 18 treatment-naïve patients received triple combination therapy: epoprostenol IV, bosentan oral, and sildenafil oral. Each of these agents covers one of the three key pathways implicated in the pathogenesis of PAH (prostacyclin, endothelin, and nitric oxide pathways). Endpoints (6-MWD, hemodynamics, functional class) were assessed at the 4-month mark and beyond. Patient survival was determined at 1, 2, and 3 years. Overall, the patients experienced statistically significant improvements in 6-MWD and hemodynamics (increase in cardiac index, decrease in pulmonary vascular resistance). Right heart catheterization was used to evaluate patients. Functional class improved to I or II in 17 of the 18 patients. All of these improvements were sustained for the long-term follow up. Patient survival was 100% at 1, 2, and 3 years. This contrasts with expected survival rates – calculated using the French registry equation – which were 75% at 1 year, 60% at 2 years, and 49% at 3 years. Of particular note, 2 patients discontinued bosentan after 11.5 and 32 months (respectively) because of liver enzyme elevation, yet they continued on the dual combination therapy (epoprostenol and sildenafil) for the remainder of the evaluation period. Otherwise, most adverse events were common to epoprostenol IV therapy, including jaw pain, mild / moderate headache, diarrhea, and flushing. Sitbon, et al. Eur Respir J. 2014;43(6):

Treatment Goals: Consensus From 5th WSPH
6-MWD CPET FC BNP ECHO Hemodynamics > 380 – 440 meters Peak VO2 > 15 mL/min/kg EqCO2 < 45 L/min I or II Normal levels Normal or near normal RV size and function RAP < 8 mm Hg CI > L/min/m2 WSPH = world symposium on pulmonary hypertension; CPET = cardiopulmonary exercise testing; FC = functional class; BNP = brain natriuretic peptide; ECHO = echocardiography; VO2 = oxygen consumption; EqCO2 = ventilatory equivalent for carbon dioxide; RV = right ventricle; RAP = right atrial pressure; CI = cardiac index Following the 5th world symposium on pulmonary hypertension, McLaughlin and colleagues published treatment goals for patients with pulmonary hypertension. The table summarizes these goals and lists the target values under their respective test or procedure. For 6-MWD, a target of greater than 380 to 440 meters is ideal. For CPET, the goal for peak oxygen consumption is greater than 15 mL/min/kg. The goal for functional class is I or II. Levels of BNP should be normal. For some patients, the “lowest possible” BNP may be the appropriate goal. Right ventricular size and function should be normal or near normal, as assessed via echocardiography or cardiac MRI. Finally, hemodynamic parameters should show normalization of right ventricular function, ie RAP < 8 mm Hg and CI > L/min/m2. McLaughlin, et al. J Am Coll Cardiol. 2013;62(25):S73-81.

Evidence-Based Treatment Algorithm: Consensus From 5th WSPH
FC II FC III FC IV Bosentan Ambrisentan Macitentan Sildenafil Tadalafil Riociguat Epoprostenol IV Treprostinil sc, inhalation Iloprost inhalation Treprostinil IV Treprostinil sc, inhalation, IV Initial combination therapy Inadequate clinical response Sequential Combination Therapy IA/B ERA PA PDE-5i sGCS + Inadequate clinical response on maximal therapy WSPH = world symposium on pulmonary hypertension; FC = functional class; IV = intravenous; sc = subcutaneous; ERA = endothelin receptor antagonist; PA = prostacyclin analog; PDE-5i = phosphodiesterase-5 inhibitor; sGCS = soluble guanylate cyclase stimulator; BAS = balloon atrial septostomy Strength of recommendation and clinical evidence: IA/B = Evidence and/or general agreement that a given treatment or procedure is beneficial, useful, effective; data from randomized clinical trial(s), meta-analyses, or large nonrandomized studies; treatment is recommended IIaC = Weight of evidence/opinion is in favor of usefulness/efficacy; consensus of opinion of the experts and/or small studies, retrospective studies, registries; treatment should be considered IIbC = Usefulness/efficacy is less well established by evidence/opinion; consensus of opinion of the experts and/or small studies, retrospective studies, registries; treatment may be considered General measures and supportive therapy are the first steps in the standard of care for patients with PAH. Next, patients are referred to a care center that specializes in the treatment of PAH. Acute vasoreactivity testing is performed. Patients who are not vasoreactive, or who fail to maintain vasoreactivity over time, begin initial therapy for PAH. The slide gives the treatment algorithm for initial therapy. Agents are recommended based on the functional classification of the given patient. Only FDA-approved agents are listed in this slide. IIaC Interventional Procedure BAS IIbC Lung Transplantation Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.

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Vasodilators in PAH Kailash Kumar Goyal.

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Vasodilators in PAH Kailash Kumar Goyal.

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