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Acknowledgements ABcomm, Inc. is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

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Presentation on theme: "Acknowledgements ABcomm, Inc. is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians."— Presentation transcript:

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2 Acknowledgements ABcomm, Inc. is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Support for this educational activity is provided by an independent educational grant from Gilead Sciences Medical Affairs.

3 Targeted Approach to Treatment of PAH

4 Learning Objectives Intensify the treatment plan when right ventricular impairment is evident. Adopt a goal-directed treatment approach to adjust the treatment plan when clinical decompensation occurs. Utilize a combination of agents with proven combined efficacy and an acceptable safety profile. Monitor relevant prognostic variables in patients with PAH. Incorporate progressive treatment strategies and protocols when appropriate. The learning objectives for this program are as follows: Intensify the treatment plan when right ventricular impairment is evident; Adopt a goal-directed treatment approach to adjust the treatment plan when clinical decompensation occurs; Utilize a combination of agents with proven combined efficacy and an acceptable safety profile; Monitor relevant prognostic variables in patients with PAH; Incorporate progressive treatment strategies and protocols when appropriate. 4

5 Lecture Outline General measures and supportive therapy
Pathways and mechanisms of action Evidence-based treatment algorithm FDA-approved treatment options Combination therapy Prognostication and patient monitoring Ongoing research This lecture details the general measures and supportive treatments that are used in the management of patients with PAH. It describes the pathways of disease, and how the mechanisms of action of the available treatments address this pathology. The evidence-based treatment algorithm for PAH is broken down into initial therapy and combination therapy action steps. The FDA-approved treatment options for PAH are outlined in detail, including supportive clinical studies. Combination therapy, including early use, or first-line use, of combination therapy is addressed. Prognostication in PAH is described, and clinical endpoints and outcome measures reviewed. The lecture concludes with a brief mention of the ongoing research in the field of PAH. 5

6 Treatment of PAH Complex strategy which includes:
Evaluation of disease severity Adoption of general measures and supportive therapy Assessment of vasoreactivity Estimation of drug efficacy Combination of different drugs and interventions (e.g. balloon atrial septostomy, lung transplantation) The treatment of PAH is complicated by numerous disease, patient, and medication variables. In order to address these factors, clinicians need to evaluate disease severity, adopt supportive and general ancillary measures, assess vasoreactive response, determine drug efficacy, and combine multiple procedures, interventions, and medications. Ghofrani, et al. Int J Cardiol. 2011;154(1):S20-33. 6

7 General Measures and Supportive Therapy
Referral to specialized PAH patient care center Cardiac catheterization / Acute vasoreactivity testing Chronic CCB therapy CCB = calcium channel blocker Proceedings from the 5th world symposium on pulmonary hypertension confirm the continued use of general measures and supportive therapy as initial and ongoing steps for patients with PAH. Included would be: general measures, supportive therapies, patient referral to a specialized center, acute vasoreactivity testing, and chronic calcium channel blocker therapy in appropriate patients. Adapted from: Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. 7

8 General Measures and Supportive Therapy
Rehabilitation / Exercise Recommended after stabilized and on therapy Requires close supervision by an experienced PAH care center Optimal method, duration, and intensity of activity are unknown Psychosocial support Family planning Pregnancy is associated with a considerable mortality rate in patients with PAH, and oral contraceptives are not contraindicated Vaccinations Influenza and pneumococcal immunization There are several general care measures employed for patients with PAH. First, rehabilitation and exercise therapy should be undertaken by stable, physically-capable patients, under the close supervision of a specialized PAH patient care center. Unfortunately, the method of exercise, the duration, and the intensity of the activity are unknown at this time. Given the chronic, debilitating nature of PAH, psychosocial support is recommended for the patient and family. Since pregnancy is associated with a substantial mortality rate, family planning is recommended, and oral contraceptive are not contraindicated. Given the compromised, baseline health and immune response of patients with PAH, influenza and pneumococcal vaccinations should be given. Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. 8

9 General Measures and Supportive Therapy
Anticoagulants Diuretics Oxygen Digoxin Clinical research supports the use of oral anticoagulants in certain subsets of patients with PAH: idiopathic PAH, heritable PAH, PAH associated with anorexigens, and PAH associated with other conditions. Clinicians often use measures to minimize hypoxemia and reduce volume overload in patients with PAH. Oxygen supplementation and administration of diuretics work to those ends. Digoxin may be appropriate in patients with low cardiac output. Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. 9

10 General Measures and Supportive Therapy
Cardiac Catheterization / Acute Vasoreactivity Testing Mandatory in patients with idiopathic PAH, may be considered in patients with PAH associated conditions Identifies patients who will respond to chronic treatment with high-dose CCBs Inhaled nitric oxide (10 – 20 parts per million) is the preferred testing compound Alternates: epoprostenol IV or adenosine IV CCB = calcium channel blocker Acute vasoreactivity testing is mandatory in patients with idiopathic PAH. In addition, it may be considered in patients with PAH associated conditions. The test identifies patients who will respond to long-term treatment with high-dose calcium channel blockers. Inhaled nitric oxide is the preferred testing compound, but epoprostenol IV or adenosine can also be used if the patient has a contraindication to the nitric oxide. The dose for epoprostenol IV is 2 to 12 ng/kg/min; the dose for adenosine IV is 50 to 350 μg/min. Adapted from: Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. 10

11 General Measures and Supportive Therapy
Chronic CCB Therapy Responders Patients with a positive response to acute vasoreactivity testing Positive response = reduction of mean PAP ≥ 10 mm Hg to reach a mean PAP ≤ 40 mm Hg with a normalized or increased cardiac output < 10% of patients with idiopathic PAH Therapeutics CCB = calcium channel blocker; PAP = pulmonary artery pressure A patient with PAH is considered a “responder” or “vasoreactive” if acute vasoreactivity testing generates a positive response. A positive response is defined as a reduction of mean PAP ≥ 10 mm Hg to reach a mean PAP ≤ 40 mm Hg with a normalized or increased cardiac output. The calcium channel blockers and doses used in vasoreactive patients are as follows: amlodipine mg/day, nifedipine mg/day, and diltiazem mg/day. The doses of these agents are higher than the doses used to treat systemic hypertension. Amlodipine 20 – 30 mg/day Nifedipine 180 – 240 mg/day Diltiazem 720 – 960 mg/day Agarwal, et al. Am Heart J. 2011;162: Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. 11

12 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 Adapted from: Humbert, et al. N Engl J Med. 2004;351: 12

13 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 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, iloprost, and treprostinil. Epoprostenol Continuous IV infusion, inhalation Iloprost Inhalation Treprostinil Subcutaneous, IV, inhalation, oral Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. 13

14 Endothelin Pathway Endothelin Endothelin receptor antagonists
Plasma levels are elevated in patients with PAH Increases vasoconstriction Mitogenic properties Endothelin receptor antagonists 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. Bosentan Oral Ambrisentan Macitentan Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. 14

15 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. 15

16 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. 16

17 Evidence-Based Treatment Algorithm
WHO FC II WHO FC III WHO FC IV Bosentan Ambrisentan Macitentan Sildenafil Tadalafil Riociguat Epoprostenol IV Iloprost inhalation Treprostinil sc, inhalation Treprostinil IV Treprostinil sc, inhalation, IV Initial combination therapy Sequential Combination Therapy Interventional Procedure IA/B IIbC IIaC ERA PA PDE-5i sGCS BAS Lung Transplantation Inadequate clinical response Inadequate clinical response on maximal therapy + Sequential Combination Therapy 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 WHO = World Health Organization; 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 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. Interventional Procedure Lung Transplantation Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. 39 17 17 17

18 Initial Therapy for PAH
Strength of recommendation and clinical evidence WHO FC II WHO FC III WHO FC IV Bosentan Ambrisentan Macitentan Sildenafil Tadalafil Riociguat Epoprostenol IV Iloprost inhalation Treprostinil sc, inhalation Treprostinil IV Treprostinil sc, inhalation, IV Initial combination therapy IA/B 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 WHO = World Health Organization; 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 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 IIbC Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. 18

19 Epoprostenol for PAH Prostacyclin analog
Indication – functional class III and IV Administration Continuous IV infusion via central venous catheter Inhalation form is available in the hospital Dosage = 20 – 40 ng/kg/min Two branded versions of epoprostenol are available: One is only stable at room temperature for 8 hours; therefore, it must be kept cool (ice packs or refrigeration) Other is a thermostable formulation Epoprostenol is a prostacyclin analog 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. The other is room temperature stable. 19

20 Epoprostenol for PAH Patient Survival
100 80 60 40 20 Weeks Epoprostenol (N = 41) 2 4 6 8 12 10 Conventional therapy (N = 40) Patient Survival (%) P = 0.003 NOTE: This is the only PAH clinical study to demonstrate a patient survival benefit. The graph illustrates findings from a study by Barst and colleagues. Following 12 weeks of treatment, patients receiving epoprostenol had significantly greater survival rates compared to patients receiving conventional therapy for PAH. Barst, et al. N Engl J Med. 1996;334: 20

21 Treprostinil for PAH Prostacyclin analog
Indication – functional class II, III, and IV Administration Subcutaneous (SC) IV Inhalation Oral (extended-release tablets; twice daily dosing) Dosage Initial dosage = 1.25 ng/kg/min Usual dosage = 30 – 100 ng/kg/min Treprostinil is a prostacyclin analog 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. 21

22 Treprostinil SC for PAH Change in 6-MWD (From Baseline to Week 12)
5 10 15 20 25 30 35 40 < 5.0 ng/kg/min ng/kg/min 8.2 – 13.8 ng/kg/min > ng/kg/min 3.3 1.4 36.1 Change from Baseline (meters) P = 0.03 N = 470 Simonneau and colleagues evaluated treprostinil subcutaneous in patients with PAH. Change in 6-MWD from baseline to week 12 was greatest for the highest dose of treprostinil. Simonneau, et al. Am J Respir Crit Care Med. 2002;165:800-4. 22

23 Treprostinil IV for PAH
Change in 6-MWD* Change in Functional Class Change from Baseline (meters) Number of Patients Tapson and colleagues measured the change in 6-MWD and the change in functional class for patients with PAH treated with treprostinil IV for 12 weeks. The results for change in 6-MWD can be found in the bar chart on the left. The results for change in functional class can be found in the bar chart on the right. Weeks Baseline 12 Weeks Tapson, et al. Chest. 2006;129:683-8. 23

24 Treprostinil Inhalation for PAH: TRIUMPH Clinical Trials
RCT1 N = 212 patients who were symptomatic on bosentan or sildenafil Addition of treprostinil up to 54 μg, four times daily for 12 weeks Study results – significantly greater improvement in 6-MWD and quality of life with combination therapy Open-label extension2 N = 206 Treprostinil with bosentan (69%) or sildenafil (31%) for 24 months Study results – treatment benefit and improvements in 6-MWD, symptoms, functional class, and quality of life were maintained for 24 months RCT = randomized, double-blind, placebo-controlled trial McLaughlin and colleagues reported results from the TRIUMPH-1 clinical study. Patients enrolled in this 12-week study were symptomatic at baseline despite bosentan or sildenafil monotherapy. Upon enrollment, patients were randomized to receive either treprostinil inhalation or placebo as add-on therapy. After 12 weeks, patients in the combination therapy group reported significantly greater improvement in exercise capacity and quality of life scores. Following 12 weeks of treatment, 206 patients entered a 24-month, open-label extension. Treatment benefit (defined as a lack of clinical worsening) was maintained for 24 months. Improvements in exercise capacity, symptom relief, WHO functional class, and quality of life were sustained over the additional 24 months of treatment with combination therapy. Patient survival rates were 97% at 12 months; 94% at 18 months; and 91% at 24 months. 1) McLaughlin, et al. J Am Coll Cardiol. 2010;55(18): ) Benza, et al. J Heart Lung Transplant. 2011;30(12): 24

25 Treprostinil Oral for PAH: FREEDOM-C Clinical Trial
Study design Randomized, double-blind, placebo-controlled study N = 350 patients with background ERA or PDE-5 inhibitor Study duration = 16 weeks Study results High discontinuation rate: 22% of treprostinil-treated patients and 14% of placebo-treated patients Improvement in 6-MWD did not reach statistical significance Reduced efficacy may be due to the low dose of treprostinil or presence of background therapy ERA = endothelin receptor antagonist; PDE-5 = phosphodiesterase-5 Tapson and colleagues reported the results of the FREEDOM-C clinical trial. This randomized, double-blind, placebo-controlled study enrolled 350 patients, who were also receiving background therapy with either an endothelin receptor antagonist or a phosphodiesterase-5 inhibitor. After 16 weeks of treatment, the study endpoint of 6-MWD was evaluated. The change in 6-MWD did not reach statistical significance in the treated patients. The researchers opined that the reduction in efficacy of treprostinil seen in this study may be due in part to the lower dose used, or to the background therapy which limited the effect of treprostinil on 6-MWD. Tapson, et al. Chest. 2012;142(6): 25

26 Treprostinil Oral for PAH: FREEDOM-M Clinical Trial
Study Design Randomized, double-blind, placebo-controlled study N = 228 treatment-naïve patients, no background therapy permitted Study duration = 12 weeks Change in 6-MWD * * Change from Baseline (meters) 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: 26

27 Iloprost for PAH Prostacyclin analog
Indication – functional class III and IV Administration Ultrasonic nebulizer used in well-ventilated areas Theoretical advantage of pulmonary vs systemic drug delivery Dosage Usual dosage = μg, 6 to 9 times daily Maximum dosage = 45 μg Iloprost is a prostacyclin analog 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. 27

28 Iloprost for PAH Composite Primary Endpoint (at Week 12)
Responders (% Patients) A study by Olschewski and colleagues measured the response to iloprost in 203 patients with PAH. After 12 weeks, improvement in the composite primary endpoint was significantly greater in iloprost-treated patients compared to placebo-treated patients. The composite primary endpoint combined change in exercise capacity, functional class, and clinical deterioration. Olschewski, et al. N Engl J Med. 2002;347:322-9.

29 Bosentan for PAH Endothelin receptor antagonist
Indication – functional class II, III, and IV Administration – oral Dosage = 62.5 mg twice daily for 4 weeks, then titrate to 125 mg twice daily 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. 29

30 Change from Baseline (meters)
Bosentan for PAH: BREATHE Clinical Trial 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: 30

31 Change from Baseline (meters)
Bosentan for PAH: EARLY Clinical Trial Change in 6-MWD (From Baseline to Week 24) 25 20 15 11.2 Placebo (N = 91) 10 P = 0.076 Bosentan (N = 86) 5 Change from Baseline (meters) 5 Results from the EARLY clinical trial are graphically represented in these next slides. The EARLY clinical trial included a sub-group of patients receiving combination therapy with sildenafil (N= 29). In this slide, change in 6-MWD from baseline to week 24 is plotted. Patients treated with bosentan had a significant improvement in exercise capacity 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. 10 - 7.9 15 20 12 Weeks 24 Weeks Galie, et al. Lancet (9630): Valerio et al. Vasc Health Risk Manag. 2009;5: 31 31

32 Event-Free Patients (%)
Bosentan for PAH: EARLY Clinical Trial Time to Clinical Worsening (From Baseline to Week 32) 100 80 60 40 20 4 8 12 16 28 24 32 Event-Free Patients (%) Placebo Bosentan P < 0.02 Weeks The EARLY trial also examined time to clinical worsening (as a secondary endpoint) in patients with PAH. A significant delay in the time to clinical worsening was seen in bosentan-treated patients compared to placebo-treated patients. The EARLY clinical trial included a sub-group of patients receiving combination therapy with sildenafil (N= 29). Galie, et al. Lancet (9630): Valerio et al. Vasc Health Risk Manag. 2009;5: 32 32

33 Ambrisentan for PAH Endothelin receptor antagonist
Indication – functional class II, III, and IV Administration – oral Dosage = 5 mg and 10 mg 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. 33

34 Ambrisentan for PAH Change in 6-MWD (From Baseline to Week 12)
-25 25 50 4 8 12 Weeks 10 mg 5 mg Placebo N = 202 2.5 mg -20 20 40 60 N = 192 Change from Baseline (meters) ARIES-1 ARIES-2 *P < 0.05 44* 23* -8 49* 22* -10 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. Galie, et al. Circulation. 2008;117: 34 34

35 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 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: 35 35

36 Ambrisentan for PAH: ARIES-3 Clinical Trial
Patient Population (N = 224) Study Results Change in 6-MWD from baseline to week 24 Increased by 21 meters (P < 0.05) Change in BNP levels from baseline to week 24 Decreased by 26% CTD = connective tissue disease; CTEPH = chronic thromboembolic pulmonary hypertension Badesch and colleagues recently published results from the ARIES-3 clinical trial. Patients enrolled in the other ARIES studies (1 and 2) were eligible to participate in this long-term, open-label extension (24 weeks). The study population included a diverse group of patients with different types of pulmonary hypertension (PH). Patients received either ambrisentan monotherapy (47%) or combination therapy (53%) with background sildenafil and/or chronic prostanoid therapy. In the ARIES-3 clinical trial, a third of the patients had idiopathic or heritable PAH. After the 24-week study period, 6-MWD improved by 21 meters and BNP levels decreased by 26%. Badesch, et al. Cardiovasc Ther. 2012;30(2):93-9. 36

37 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) Years -20 -10 10 20 30 40 50 60 0.0 0.25 0.5 1.0 1.5 2.0 70 7 23 28 Change from Baseline (meters) 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. Oudiz, et al. J Am Coll Cardiol. 2009;54(21): 37

38 Macitentan for PAH Endothelin receptor antagonist
Sustained receptor binding and enhanced tissue penetration Indication – functional class II, III, and IV Administration – oral Dosage = 10 mg 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. 38

39 Macitentan for PAH: SERAPHIN Clinical Trials
RCT1 N = 742 Macitentan 3 mg or 10 mg once daily Study duration = event driven Study endpoint = time to clinical worsening Open-label extension2 N = 550 Macitentan 10 mg once daily Study duration = event driven Study endpoint = safety RCT = randomized, double-blind, placebo-controlled study The SERAPHIN open-label extension is still ongoing. Accessed January, 2014. The SERAPHIN clinical trials are evaluating macitentan for the treatment of PAH. The placebo-controlled study determined time to clinical worsening in 742 patients with PAH. The open-label extension is monitoring the long-term safety (adverse events) of the 10 mg dose in 550 patients who completed the placebo-controlled study. Both study durations are event driven, meaning that the study will continue until a predefined clinical event occur 1) 2) 39

40 Macitentan for PAH: SERAPHIN Clinical Trial
3 mg 10 mg N = 250 N = 242 Duration of treatment (event driven) 99.5 weeks 103.9 weeks Risk reduction in the occurrence of morbidity and mortality events versus placebo (N = 250) 30% (P < 0.05) 45% Overall risk reduction: With background therapy Without background therapy 17% 47% 38% 55% Results from the SERAPHIN clinical trial were presented by Rubin and colleagues at the CHEST meeting in 2012, and published by Pulido and colleagues in The investigators reported total number of patients enrolled in each treatment arm, duration of treatment, and percent of risk reduction associated with the use of two dosages of macitentan. The total number of randomized patients was comparable among the treatment arms. The length of treatment varied because the study duration was event driven and not a pre-specified period of time. Macitentan significantly reduced the risk of occurrence of morbidity and mortality events versus placebo. (Morbidity or mortality event was defined as death, atrial septostomy, lung transplantation, initiation of parenteral prostacyclin analog, or worsening of PAH.) The risk reduction was evident in patients who were on background therapy for PAH, as well as patients who were not on background therapy. Background therapy was mainly phosphodiesterase-5 inhibitors. Macitentan was well tolerated in this study. The incidence of medication-related adverse events, including peripheral edema and elevation of liver enzymes, was similar to that seen in patients receiving placebo. Pulido, et al. NEJM. 2013;369(9): 40

41 Sildenafil for PAH Phosphodiesterase-5 inhibitor – targets the nitric oxide pathway Indication – functional class II, III, and IV Administration and dosage Oral = 20 mg three times daily IV = 10 mg three times daily 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. 41

42 Sildenafil for PAH: SUPER-1 Clinical Trial
Change in 6-MWD Change in Functional Class P < 0.05 P < 0.05 Placebo-Adjusted Change from Baseline (meters) Patients With an Improvement In Functional Class (%) 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. Galie, et al. N Engl J Med. 2005;353: 42

43 Sildenafil for PAH: SUPER-2 Clinical Trial
Study Design Long-term, open-label extension N = 170 patients who completed both studies Sildenafil 80 mg three times daily Second agent added in 18% of patients by end of study period (3 years) Study Results 6-MWD Maintained or improved in 46% of patients Functional class Maintained or improved in 60% of patients Estimated patient survival rate at 3 years = 79% 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 survival rate was 79%. Rubin, et al. Chest. 2011:140(5): 43

44 Sildenafil for PAH: PACES Clinical Trial
Study Design Randomized, double-blind, placebo-controlled study Sildenafil 80 mg three times daily in combination with epoprostenol (N = 214) compared to epoprostenol monotherapy (N = 53) Study duration = 16 weeks Study Results 6-MWD Placebo-adjusted improvement = 28 meters* Clinical worsening event 6% vs 18.5% of patients on monotherapy* Time to clinical worsening Significant delay compared to monotherapy* *P < 0.05 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 was significantly superior to the “placebo” (epoprostenol monotherapy) 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. Time to clinical worsening was measured by the investigators. 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. Simonneau, et al. Ann Intern Med. 2008;149(8): 44

45 Tadalafil for PAH Phosphodiesterase-5 inhibitor – targets the nitric oxide pathway Indication – functional class II, III, IV Administration – oral Dosage = 40 mg 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. 45

46 Tadalafil for PAH: PHIRST-1 Clinical Trial
Study Design Randomized, double-blind, placebo-controlled study Tadalafil in combination with bosentan (N = 216) compared to tadalafil monotherapy (N = 189) Study duration = 16 weeks Study Results 6-MWD Significant improvement* but less than monotherapy Quality of life Significant improvement Clinical worsening events Significantly less* 68% relative risk reduction Time to clinical worsening Significant delay* *P < 0.05 (40 mg dose) 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 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. The most common adverse events reported were headache, myalgia, and flushing. All adverse events were considered mild to moderate in severity. Galie, et al. Circulation. 2009;119(22): Barst, et al. J Heart Lung Transplant. 2011;30(6): 46

47 Tadalafil for PAH: PHIRST-2 Clinical Trial
Study Design Long-term, open-label extension N = 293 patients from PHIRST-1 Tadalafil 20 mg or 40 mg once daily Background bosentan permitted (54% of patients) Study duration = 52 weeks Study Results 6-MWD Sustained improvement through long-term extension (68 weeks total) Clinical worsening events Significantly less in patients on combination therapy 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. It is important to note that patients could continue their background bosentan therapy during the study period. In total, 54% were receiving background bosentan. Oudiz, et al. J Am Coll Cardiol. 2012;60: 47

48 Riociguat for PAH Soluble guanylate cyclase stimulator – targets the nitric oxide pathway Indication – functional class II, III, and IV Administration – oral Dosage = 1 mg – 2.5 mg three times 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. 48

49 Riociguat for PAH: PATENT Clinical Trials
RCT1 N = 445 Riociguat 1 mg, 1.5 mg, 2 mg, or 2.5 mg three times daily Study duration = 12 weeks Study endpoint = 6-MWD Open-label extension2 N = 396 Riociguat 1 mg, 1.5 mg, 2 mg, or 2.5 mg three times daily Study duration = event driven Study endpoint = safety RCT = randomized, double-blind, placebo-controlled study The PATENT placebo-controlled study has been completed. The PATENT open-label extension is still ongoing. Accessed January 2014. The PATENT phase III clinical trials are evaluating riociguat for the treatment of PAH. The placebo-controlled study assessed 6-MWD in 445 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. 1) 2) 49

50 Riociguat for PAH: PATENT Clinical Trial
Change in 6-MWD N = 443 *P < 0.05 P < 0.05 Significant Improvement* PVR NT-proBNP Functional class Borg Dyspnea Scale score Quality of life measures Time to clinical worsening Change from Baseline (meters) PVR = pulmonary vascular resistance; NT-proBNP = N-terminal-pro-fragment BNP 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): 50

51 Combination Therapy for PAH
To target multiple disease pathways Used when therapy needs to be augmented because response to initial therapy is inadequate Sequential combination therapy Starting in one drug class and adding an agent from another drug class when necessary REVEAL: 34% of patients on 2 or more treatments 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 registry recorded a high percentage of patients (34%) receiving combination therapy (N = 2967). Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. Badesch, et al. Chest. 2010;137(2): 51

52 Combination Therapy for PAH
Clinical Study Agents N Study Duration Study Endpoints Statistical Significance BREATHE-21 Epoprostenol Bosentan 33 16 weeks Hemodynamics, 6-MWD, functional class No STEP-12 Iloprost 67 12 weeks Hemodynamics, 6-MWD, functional class, TTCW Yes COMBI3 40 6-MWD, functional class, TTCW TTCW = time to clinical worsening Combination therapy has been evaluated in several randomized, double-blind, placebo-controlled studies. This table summarizes the results from three of these studies. Humbert and colleagues studied epoprostenol and bosentan in 33 patients for a 16-week period. Improvements in hemodynamics, exercise capacity, and functional class were not statistically significant. McLaughlin and colleagues studied iloprost and bosentan in 67 patients for a 12-week period. Improvements in hemodynamics, exercise capacity, functional class, and time to clinical worsening were statistically superior in the combination therapy group. Hoeper and colleagues studied iloprost and bosentan in 40 patients for a 12-week period. Improvements in exercise capacity, functional class, and time to clinical worsening were not statistically significant. 1) Humbert, et al. Eur Respir J. 2004;24: ) McLaughlin, et al. Am J Respir Crit Care Med. 2006;174: 3) Hoeper, et al. Eur Respir J. 2006;28:691-4. 52

53 Early Initiation of Combination Therapy for PAH
Combination therapy used in early PAH disease Debated by clinicians and researchers May improve patient outcomes May prevent or slow disease progression May reduce costs associated with managing clinical worsening Well-controlled studies are needed to test this practice 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. Well-controlled studies evaluating early initiation of combination therapy need to take place before this practice can be routinely recommended. Affuso, et al. World J Cardiol. 2010;2(3):68-70. 53

54 Combination Therapy for PAH
Clinical Study Status Study Design Agents N Study Duration Study Endpoints COMPASS-21 Ongoing RCT Sildenafil +/- Bosentan 334 Event driven TTCW COMPASS-32 Completed OL Bosentan +/- Sildenafil 100 28 weeks 6-MWD NCT 104 12 weeks FREEDOM-Ev3 RCT* • Treprostinil oral + PDE-5i or ERA • PDE-5i or ERA 858 AMBITION4 Ambrisentan +/- Tadalafil 614 ATHENA-15 Sildenafil or Tadalafil +/- Ambrisentan 38 24 weeks PVR RCT = randomized, double-blind, placebo-controlled study; TTCW = time to clinical worsening; OL = open-label extension study; PDE-5i = phosphodiesterase-5 inhibitor; ERA = endothelin receptor antagonist; PVR = pulmonary vascular resistance. Accessed February COMPASS-2 is an ongoing, RCT of the efficacy of sildenafil with and without bosentan in patients with PAH (N = 334). The study duration is event driven, and the primary endpoint is time to clinical worsening. COMPASS-3 was an OL of bosentan for 28 weeks, with the addition of sildenafil at week 16 if 6-MWD was less than 380 meters. The study enrolled 100 patients for 28 weeks. Publication of results is pending. Another study that evaluated the combination of bosentan and sildenafil (NCT ) enrolled 104 patients for 12 weeks. The investigators of this study measured change in 6-MWD and time to clinical worsening. Publication of results is pending. The FREEDOM-Ev clinical trial is evaluating early combination therapy versus monotherapy in patients with PAH (N = 858). Monotherapy would be the patient’s initial background therapy of a PDE-5 inhibitor or an ERA. Combination therapy would be the patient’s initial therapy combined with treprostinil oral. Primary study endpoints are time to clinical worsening and 6-MWD. Patients who successfully complete this RCT will be eligible for participation in the OL. The AMBITION clinical trial is an ongoing, RCT comparing the efficacy of first-line monotherapy to first-line combination therapy. Patients with PAH (N = 614) were randomized to receive either ambrisentan alone or in combination with tadalafil. The study is event driven, with time to clinical worsening as the primary endpoint. The ATHENA-1 clinical trial was an OL that examined the efficacy of combination therapy (PDE-5i and ambrisentan) after inadequate hemodynamic response (PVR) on the PDE-5i alone. A total of 38 patients were followed for 24 weeks. Publication of results is pending. 1) NCT ; 2) NCT ; 3) NCT ; 4) NCT ; 5) NCT *Early combination therapy 54

55 Interventional Procedures: Balloon Atrial Septostomy
In order to: Decompress right heart chambers Increase left ventricle preload Increase cardiac output Improve systemic oxygen transport Decrease sympathetic hyperactivity Creation of an interatrial right-to-left shunt Considered a palliative or bridging procedure Patients refractory to medical therapy Patients awaiting lung transplantation Invasive, interventional procedures are used in patients with PAH when medical therapy has been maximized, yet clinical deterioration is ongoing. Balloon atrial septostomy is one of these procedures. It involves creation of an interatrial right-to-left shunt. This allows the following actions to take place: decompression of the right heart chambers, an increase in left ventricle preload, an increase in cardiac output, improvement in systemic oxygen transport, and a decrease in sympathetic hyperactivity. Balloon atrial septostomy is considered a palliative or bridging procedure. It is reserved for patients who are refractory to medical therapy, or for those who are awaiting lung transplantation. It would also be considered if medical therapy is unavailable. Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. 55

56 Interventional Procedures: Lung Transplantation
Surgical procedures Single lung transplant Bilateral lung transplant – most common Heart-lung transplant – increasingly less common, with about 70 – 90 performed every year* Lung transplantation remains the standard of care for patients with PAH who fail aggressive medical therapy, until the age of 75 (depending on the transplant center) Long and colleagues reviewed the surgical treatment choices for patients with PAH. Transplantation options include: single or bilateral lung transplantation and heart-lung transplantation. They noted that the number of heart-lung transplantations in patients with PAH has declined over the last two decades. In its place, the number of bilateral lung transplants has increased and this type of transplantation is now the most commonly used in patients with PAH. Still, lung transplantation is an extremely invasive procedure with signifcant associated risks; therefore, it is considered for patients with the most severe disease and poorest prognosis. *Long, et al. Pulm Circ. 2011;1(3): Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. 56

57 ISHLT Guidelines for Lung Transplantation
Persistent functional class III or IV despite maximal medical therapy Low (< 350 meters) or declining 6-MWD Failing even while on a parenteral prostacyclin analog Cardiac index < 2 L/min/m2 Right atrial pressure > 15 mm Hg The International Society for Heart Lung Transplantation has published guidelines for lung transplantation in patients with PAH. Patients meeting any of the following criteria should be referred to a specialized transplantation center for complete evaluation: persistent functional class III or IV despite maximal medical therapy; low or declining 6-MWD; failing even while taking a parenteral prostacyclin analog; cardiac index < 2 L/min/m2; and / or right atrial pressure > 15 mm Hg. ISHLT = International Society for Heart Lung Transplantation Long, et al. Pulm Circ. 2011;1(3): 57

58 Goal-Directed Therapy
Diagnosis of PAH Vasoreactivity test: negative Baseline exam and monthly re-evaluation to assess treatment goals: Clinically stable, functional class II, 6-MWD > 400 meters, RAP / CI normal Treatment goals NOT met Treatment goals met Start ERA or PDE-5i Continue treatment Add ERA or PDE-5i Continue treatment RAP = right atrial pressure; CI = cardiac index; ERA = endothelin receptor antagonist; PDE-5i = phosphodiesterase-5 inhibitor; PA = prostacyclin analog Over time, patient response to initial therapy for PAH diminishes. As a result, a more aggressive approach to treatment is warranted. A treatment strategy that uses prognostic indicators as treatment targets helps with the timing of treatment escalation. This algorithm developed by Hoeper and colleagues provides a goal-directed approach to treatment in patients with PAH and a negative vasoreactivity test. Patients are evaluated every three to six months. The goal is for patients to be: clinically stable, in WHO functional class II, able to complete a 6-MWD of more than 400 meters, and RAP / CI normal. If treatment goals are met, the existing treatment regimen is continued. If treatment goals are not met, additional agents are added in a step-wise manner. Parenteral PA and / or enrollment in clinical trials Continue treatment Urgent lung transplantation Adapted from: Hoeper, et al. Eur Respir J. 2005;26: 58

59 Prognostication: Determinants of Patient Risk ACC / AHA Expert Consensus
Low risk Determinants of risk High risk No Clinical evidence of RV failure Yes Gradual Disease progression Rapid II, III WHO functional class IV Longer (> 400 meters) 6-MWD Shorter (< 300 meters) Peak VO2 > 10.4 mL/kg/min Cardiopulmonary exercise testing Peak VO2 < 10.4 mL/kg/min Minimally elevated and stable BNP / NT-proBNP Significantly elevated PaCO2 > 34 mm Hg Blood gasses PaCO2 < 32 mm Hg Minimal RV dysfunction ECHO cardiography Pericardial effusion, RV dysfunction, RA enlargement RAP < 10 mm Hg; CI > 2.5 L/min/m2 Pulmonary hemodynamics RAP > 20 mm Hg; CI < 2 L/min/m2 The American College of Cardiology (ACC) and the American Heart Association (AHA) came to a consensus on which factors can be used to determine a patient’s risk with regard to PAH. The center column lists the factors, or determinants of patient risk. The left column lists the values or answers if the patient is at low risk. The right column lists the values or answers if the patient is at high risk. McLaughlin, et al. Circulation. 2006;114: McLaughlin, et al. J Am Coll Cardiol. 2009;53: 59

60 REVEAL Risk Calculator
Parameter Low risk Score High risk Type of PAH Heritable CTD Portal hypertension +2 +1 Demographics/ Comorbidities Male > 60 years old Renal insufficiency Functional class I -2 III IV Vital signs SBP < 110 mm Hg HR > 92 bpm 6-MWD ≥ 440 meters -1 < 165 meters BNP < 50 pg/mL > 180 pg/mL ECHO Pericardial effusion PFT % pred DLCO ≥ 80% % pred DLCO ≤ 32% RHC mPAP > 20 mm Hg PVR > 32 WU CTD= connective tissue disease; SBP = systolic blood pressure; HR = heart rate; BNP = brain natriuretic peptide; ECHO = echocardiography; PFT = pulmonary function test; pred = predicted; DLCO = carbon monoxide diffusing capacity; RHC = right heart catheterization; mPAP = median pulmonary artery pressure; PVR = pulmonary vascular resistance Benza and colleagues used data from the REVEAL registry to assess predictors of 1-year survival in patients with PAH (N = 2716). They found several variables that were independently associated with increased mortality. The parameters listed in the table are the ones that were used by the researchers to formulate a prognostic equation. Although the equation is complex, it may ultimately help clinicians during patient assessment, monitoring, and development of a treatment plan. A score is assigned to certain parameters that are prognostic in patients with PAH. A higher score is associated with a greater risk of mortality. This table is adapted from the REVEAL risk calculator, which is also organized into 9 categories or rows. As the total risk score increases, the predicted one-year survival rate decreases. Benza, et al. Circulation. 2010;122: Benza, et al. Chest. 2012;141: 60

61 Clinical Endpoints Exercise Capacity 6-MWD CPET Treadmill
Functional Class Biomarkers BNP / NT-proBNP Hemodynamics (PVR, PAP, CO) Imaging Cardiac MRI 2D 3DE Clinical Variables Quality of life TTCW CPET = cardiopulmonary exercise testing; BNP = brain natriuretic peptide; NT-proBNP = N-terminal-pro-fragment BNP; PVR = pulmonary vascular resistance; PAP = pulmonary artery pressure; CO = cardiac output; TTCW = time to clinical worsening Exercise capacity is considered an indirect measure, one that is dependent on “patient motivation or clinical judgment.” The most common primary endpoint used in clinical trials of PAH is 6-MWD. It measures a patient’s functional limitation. It is most appropriate for patients in WHO functional class III and IV, and it appears less discerning when patients are early in the course of the disease. It is very simple to administer and has almost no cost associated with it. The results of 6-MWD are prognostically significant in patients with PAH. Cardiopulmonary exercise testing (CPET) and the treadmill are additional methods used to measure exercise capacity. WHO functional classification is a clinical variable that is often used to monitor patients with PAH. Determining a patient’s functional class is simple and includes evaluating exercise tolerance, clinical symptoms, the presence of syncope, and other quality of life parameters. It can provide clinical evidence of right ventricular failure. Class designation is a strong predictor of patient survival. Patients in WHO functional class I or II have a median survival of 6 years; patients in class III have a median survival of two and a half years; and patients in class IV have a median survival of 6 months. A biomarker is considered an indirect outcome measure, a surrogate endpoint used to substitute for a “clinically meaningful” endpoint. The biomarkers used to monitor patients with PAH are: BNP / NT-proBNP or pulmonary hemodynamic measures, such as PVR, PAP, and CO, especially those that reflect right ventricular function. Brain natriuretic peptide is found primarily in the cardiac ventricles. It has natriuretic, vasodilatory, and antiproliferative properties. Measurement of the inactive N-terminal-pro-fragment BNP (NT-pro BNP) is often preferred over measurement of BNP since it is more stable in assays. This biomarker is highly sensitive to changes in the left and right ventricles. Overall, levels correlate with the severity of pulmonary hemodynamic and functional impairment. The higher the level, the greater the functional incapacity. Measurement of BNP / NT-proBNP is relatively easy and inexpensive. Imaging and hemodynamic assessment can be achieved via cardiac MRI. This test takes measurements throughout the cardiac cycle, at rest and during exercise. Of major importance, it examines right ventricular mass, morphology, and function. It is a non-invasive test; however, it is expensive to run and technically challenging to perform. Clinical variables include measures of quality of life and time to clinical worsening. A patient’s quality of life can be evaluated using quality of life questionnaires and the modified Borg Dyspnea Scale, which quantifies shortness of breath. Time to clinical worsening is a composite endpoint that measures the time until the patient reaches a pre-determined, pre-defined, adverse outcome. Gomberg-Maitland, et al. J Am Coll Cardiol. 2013;62(25):S82-91. 61

62 Time to Clinical Worsening
Composite endpoint of adverse clinical events: Death Lung transplantation Hospitalization for worsening PAH Initiation of IV therapy due to worsening PAH Worsening of function Worsening of PAH symptoms Time to clinical worsening is a composite endpoint. Following the 5th world symposium on pulmonary hypertension, Gomberg-Maitland and colleagues published criteria for this endpoint. The definition was made to include: death; lung transplantation; hospitalization for worsening PAH (including atrial septostomy); initiation of IV therapy due to worsening PAH; worsening of function (ie, worsening functional class and exercise capacity); and worsening of PAH symptoms (ie, worsening of at least 2 of the 4 symptoms: dyspnea, chest pain, dizziness / syncope, fatigue / activity level). Gomberg-Maitland, et al. J Am Coll Cardiol. 2013;62(25):S82-91. 62

63 Longitudinal Patient Monitoring ACCF / AHA Recommendations
Patient Evaluation 6-MWD Functional Class BNP ECHO RHC Stable patient Every 3-6 months Every visit Center dependent Every 12 months If clinical deterioration Unstable patient Every 1-3 months Every 6-12 months Every 6-12 months or if clinical deterioration BNP = brain natriuretic peptide; ECHO = echocardiography; RHC = right heart catheterization McLaughlin and colleagues published ACCF / AHA recommended guidelines for longitudinal monitoring for patients with PAH. In 2013, Dr. McLaughlin published an additional article regarding optimizing treatment outcomes and following outcome predictors in patients with PAH. The timing of assessment or test performed varies if the patient is deemed stable or unstable. A stable patient has: no increase in symptoms, no decompensation. An unstable patient has: an increase in symptoms or decompensation. The table lists the tests: patient evaluation, functional class assessment, 6-MWD, BNP, ECHO cardiography, and right heart catheterization. McLaughlin, et al. J Am Coll Cardiol. 2009;53: McLaughlin. Am J Cardiol. 2013;111:S10-5. 63

64 Normal or near normal RV size and function
Treatment Goals 6-MWD CPET FunctionalClass 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 CPET = cardiopulmonary exercise testing; 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. 64

65 Ongoing Clinical Research in PAH
PAH is a chronic, debilitating disease with significant associated morbidity and mortality A cure for PAH has yet to be discovered Standard treatment eventually becomes inadequate Enrollment in clinical trials posits patients for cutting-edge therapies The clinical course for patients with PAH is marred by significant morbidity and premature mortality. Unfortunately, a cure for PAH has yet to be discovered. Eventually, standard treatment options fail to mitigate symptoms and prevent disease progression. Enrollment in clinical trials posits patients for cutting-edge therapies which may otherwise be unavailable. Also, participation in clinical trials allows clinicians access to progressive treatment protocols and investigational medications. 65

66 Investigational Agents for PAH
Selexipag Prostacyclin IP receptor agonist Targets the prostacyclin pathway GRIPHON clinical trials1,2 Research is ongoing Imatinib Tyrosine kinase inhibitor PDGF receptor inhibitor (vascular remodeling) Antiproliferative IMPRES clinical trials3,4,5 Regulatory consideration has been terminated PDGF = platelet-derived growth factor Accessed February Selexipag is a prostacyclin IP receptor agonist that targets the prostacyclin pathway. It is being investigated for use in patients with PAH. The dosage in clinical studies has ranged from 200 to 800 µg oral twice daily. Both GRIPHON phase III studies are ongoing. The GRIPHON clinical trials are evaluating selexipag for the treatment of PAH. The placebo-controlled study is monitoring time to clinical worsening in 1156 patients with PAH. The open-label extension is monitoring long-term safety (adverse events) in 670 patients who have completed the placebo-controlled study. Both study durations are event driven, meaning that the study will continue until a predefined event occurs. Imatinib is a tyrosine kinase inhibitor and a platelet-derived growth factor receptor inhibitor. It has anti-proliferative properties. Imatinib has been investigated for use in patients with PAH. The dosage is 200 mg to 400 mg oral daily. PDGF is a vascular smooth muscle cell mitogen activating signal transduction pathways associated with smooth muscle hyperplasia in pulmonary hypertension. The IMPRES placebo-controlled study has been completed. The IMPRES open-label extension is still ongoing. The IMPRES phase III clinical trials are evaluating imatinib for the treatment of PAH. The placebo-controlled study assessed 6-MWD in 202 patients with PAH. The open-label extension is monitoring the long-term safety (adverse events) of imatinib in 144 patients who have completed the placebo-controlled study. The placebo-controlled study was 24 weeks long. In contrast, the open-label extension is event driven. Hoeper and colleagues published results from the IMPRES clinical trial. Patients were continued on their background PAH therapy for the duration of the study period. After 24-weeks of treatment, patients treated with imatinib demonstrated statistically significant improvements in 6-MWD and PVR when compared to placebo (P < 0.05). Of concern, however, was the seriousness of adverse events seen in imatinib-treated patients. Overall, 44% of imatinib-treated patients, compared to 30% of placebo-treated patients reported serious adverse events. In particular, 2 patients in the controlled study and 6 patients in the long-term extension had a subdural hematoma. Study discontinuations were also more common in imatinib-treated patients (33% vs 18%). 1) NCT ; 2) NCT ; 3) NCT ; 4) NCT ; 5) Hoeper, et al. Circulation. 2013;127(10): 66

67 Summary Management of patients with PAH involves a complex strategy which includes supportive therapy and disease- targeted medications. The evidence-based treatment algorithm for PAH streamlines decision making and drug selection. Combination therapy is the standard of care when initial therapy becomes inadequate. Prognostication and patient monitoring involves the use of clinically-relevant parameters and endpoints. To summarize this lecture, the slide lists several key, take-home points. The management of patients with PAH involves multiple healthcare disciplines, as well as supportive therapies and disease-targeted treatments. The 5th world symposium on pulmonary hypertension updated the evidence-based treatment algorithm for PAH. This multi-tiered algorithm acts as a guide in drug selection and aids in the timing of treatment escalation. The therapeutic expectation in patients with advanced disease is combination therapy. Clinically-relevant endpoints, targets or goals, and parameters are used to monitor patients with PAH, and they are also used when determining a patient’s prognosis. 67


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