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

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.

Pulmonary Arterial Hypertension: Aggressive Treatment for a Progressive Disease Complete Slide Set

Learning Objectives Generalized Audience
Identify patients at high risk for the development of PAH. Utilize right heart catheterization to confirm the diagnosis of PAH. Evaluate right ventricular function using screening tools and imaging tests. Weigh the risks versus benefits for a given mediation, in terms of indication for use, route of administration, side effects, and long-term study data. Decide if and when combination therapy is a clinical necessity. Analyze multiple clinical endpoints to determine if treatment is successful. The learning objectives for this program are as follows: Identify patients at high risk for the development of PAH; Utilize right heart catheterization to confirm the diagnosis of PAH; Evaluate right ventricular function using screening tools and imaging tests; Weigh the risks versus benefits for a given mediation, in terms of indication for use, route of administration, side effects, and long-term study data; Decide if and when combination therapy is a clinical necessity; Analyze multiple clinical endpoints to determine if treatment is successful.

Learning Objectives Specialized Audience
Suspect PAH when symptoms are out of proportion to “underlying disease” or if patient is not responding to traditional therapies. Monitor high-risk patients for the hemodynamic and clinical features associated with PAH. Design a course of treatment that takes into consideration drug administration, efficacy, and overall safety. Intensify the treatment plan and consider combination therapy when right ventricular impairment or clinical decline is evident. Appraise newly-approved agents for inclusion in the treatment algorithm for PAH. Assess a patient’s prognosis based on proven determinants of risk. The learning objectives for this program are as follows: Suspect PAH when symptoms are out of proportion to “underlying disease” or if patient is not responding to traditional therapies; Monitor high-risk patients for the hemodynamic and clinical features associated with PAH; Design a course of treatment that takes into consideration drug administration, efficacy, and overall safety; Intensify the treatment plan and consider combination therapy when right ventricular impairment or clinical decline is evident; Appraise newly-approved agents for inclusion in the treatment algorithm for PAH; Assess a patient’s prognosis based on proven determinants of risk.

Lecture Outline Pathology and genetics Diagnostics
The right ventricle in PAH High-risk patients Evidence-based treatment Ongoing research Combination therapy Prognostication and patient monitoring This lecture will cover the following key topics: The pathology and genetics associated with PAH. Diagnostics, including a diagnostic algorithm for PAH. The right ventricle in patients with PAH. Screening patients at high risk for the development of PAH. Evidence-based treatment options for PAH. Ongoing clinical research in the field. Combination therapy, including upfront combination therapy. Prognostication and routine patient monitoring.

Epidemiology and History of PAH
Prevalence in the U.S. ≈ 50,000 to 100,000 (15,000 to 25,000 diagnosed and treated) Circa 1987 Due to rapid progression of morbidity and mortality, once patients were diagnosed with pulmonary hypertension they were described as entering “the kingdom of the near-dead” 2015 Patient survival has dramatically improved as treatment options for PAH have increased Robin ED. The kingdom of the near-dead: the shortened unnatural life history of primary pulmonary hypertension. Chest. 1987;92:330-4. The prevalence of PAH is estimated at nearly 50,000 to 100,000, with only 15,000 to 25,000 patients diagnosed and treated. The disease course and prognosis for patients with PAH has dramatically improved over the last several decades. Given that PAH is a rare disease, it is remarkable the progress that has been made in the availability of treatment options for patients with PAH. Nearly two decades ago, no treatment options were available for patients. This contrasts greatly with the dozen treatment options that are currently FDA approved for patients. McGoon, et al. J Am Coll Cardiol. 2013;62(25):S51-9.

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 Drug- and toxin-induced Associated with: Connective tissue disease HIV infection Portal hypertension Congenital heart disease Schistosomiasis 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.

Types of PAH: REVEAL Registry
N = 2967 1.9% 3.5% 5.3% 5.3% 46.2% 9.8% 25.3% IPAH = idiopathic PAH; H-PAH = heritable PAH; CTD = connective tissue disease; CHD = congenital heart disease Badesch and colleagues recorded the types of PAH present in the nearly 3,000 patients they evaluated (interim analysis, published in 2010) from the REVEAL registry. Idiopathic PAH was present in almost half the study population. CTD-associated PAH was present in a quarter of the population. 2.7% Badesch, et al. Chest. 2010;137(2):

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.

PAH Associated With Connective Tissue Disease
Scleroderma Most prevalent and studied type of PAH associated with CTD Rate of occurrence of PAH = 7 to 12% of patients with scleroderma; more common in limited scleroderma (CREST syndrome) Prognosis is poorer than other types of PAH PAH is the leading cause of death; 1 year mortality rate = 30% CTD = connective tissue disease The most studied type of connective tissue disease, in terms of PAH associated connective tissue disease, would be scleroderma. The rate of occurrence of PAH in patients with scleroderma ranges between 7 and 12 percent. Researchers have noted that the long-term prognosis in these patients is diminished compared to other types of PAH. In fact, the 1 year mortality rate is high, at an estimated 30%. Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41.

Associated Conditions
PAH Associated With: Rate of Occurrence of PAH Clinical Features HIV infection 0.5% Improvement in survival since HAART; 5-year survival > 70% Portal hypertension 2 – 6% Prognosis negatively impacted by cardiac dysfunction, severity of liver disease / cirrhosis Congenital heart disease 10% Presence of PAH has negative impact on clinical course Schistosomiasis 5% 3-year survival ≈ 85% HAART = highly-active antiretroviral therapies Simonneau and colleagues reported a stabilizing of the percent prevalence of PAH in patients with HIV over the last decade. Currently, the rate of occurrence of PAH is 0.5% of patients with HIV. In addition, patient prognosis has improved since the introduction of aggressive treatment of HIV in the form of HAART. In fact, the French registry noted a 5-year survival rate of over 70%. Portal hypertension is another associated condition for PAH. The rate of occurrence ranges between 2 and 6% of patients with portal hypertension. Long-term survival in patients with PAH associated with portal hypertension is related to the severity of liver disease (or cirrhosis) and to cardiac dysfunction. Due to improvements in disease management, there are greater numbers of children with congenital heart disease that survive into adulthood. This means a greater number of adults with congenital heart disease. The rate of occurrence of PAH in these adults is approximately 10%. The presence of PAH only serves to confound the complex management of this patient group. According to the Centers for Disease Control (CDC), schistosomiasis, also known as bilharzia, is a parasitic disease caused by blood flukes. The number of patients infected worldwide is over 200 million. Of these individuals, 10% develop hepatosplenic schistosomiasis. The presence of hepatosplenic schistosomiasis puts the patient at risk of developing PAH. The 3-year mortality rate of PAH associated schistosomiasis is approximately 15%. Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41.

Patient Registries for PAH
Registry Time Period N NIH 1981 – 1985 187 French 2002 – 2003 674 U.S. REVEAL 2006 – 2009 3515 U.S. PHC 1982 – 2006 578 PAH-QuERI 2005 – 2007 791 Scottish-SMR 1986 – 2001 374 Chinese 1999 – 2004 72 Spanish 1998 – 2008 866 U.K. 2001 – 2009 482 New Chinese Registry 2008 – 2011 956 Mayo 1995 – 2004 484 Compera 2007 – 2011 587 NIH = National Institutes of Health; PHC = pulmonary hypertension connection; PAH-QuERI = PAH quality enhancement research initiative; SMR = Scottish morbidity record PAH patient registries are listed in the table. The three major registries are: NIH, French, and U.S. Reveal. The NIH registry took place in the early 1980s and followed 187 patients. The French registry took place in the early 2000s and followed 674 patients. The largest of the registries would be the U.S. REVEAL, which followed over 3500 patients from 2006 to 2009. McGoon, et al. J Am Coll Cardiol. 2013;62(25):S51-9.

Observations From Patient Registries for PAH
Older age at diagnosis NIH registry: 36 (± 15 years) REVEAL: (± 15 years) Population cohorts at greater risk Patient demographic – advanced age, male gender Etiology – heritable PAH, PAH associated with CTD or portal hypertension CTD = connective tissue disease Patient registries give researchers and clinicians insight into the nuances of a disease, and help describe the patients affected by the disease. An observation from the patient registries for PAH is an older age at diagnosis. The registries have also specified patient cohorts with reduced rates of survival. Patients at greater risk include those at an advanced age, men, and those with either heritable PAH, connective tissue disease-associated PAH, or portopulmonary hypertension. McGoon, et al. J Am Coll Cardiol. 2013;62(25):S51-9.

Older Patients with PAH
Older age at diagnosis More advanced, severe disease Greater number of comorbidities Presence of comorbid conditions can mask symptoms of PAH and delay diagnosis, and may contribute to morbidity and mortality Treatment strategies for older patients Exact influence of age on treatment success is unknown Older patients are underrepresented in clinical studies An article by Hoeper and Gibbs reviewed the change in demographics for patients with PAH, as reported by recent PAH patient registries. Of major note would be an increased patient age at diagnosis. With an older age at diagnosis, patients present with more advanced disease. Compared to younger patients, older patients are more likely to present at functional class III or IV. In addition, older patients have a greater number of comorbidities. The presence of comorbid conditions can not only mask the symptoms of PAH and therefore delay the diagnosis, but these conditions can also contribute to poorer patient outcomes. Regarding treatment of PAH, the impact of age on the success of therapy is unknown. What is know is that this older patient population is underrepresented in clinical trials for PAH. Hoeper, et al. Eur Resp Rev. 2014;23(134):450-7.

Comorbid Conditions in Patients with PAH
NIDDM = non-insulin dependent diabetes mellitus; COPD = chronic obstructive pulmonary disease The presence of comorbid conditions can confound the timely diagnosis of PAH. Results from the REVEAL patient registry have recently been published. Poms and colleagues reported demographic information regarding the enrolled patients. A range of comorbid conditions have affected patients with PAH. The chart displays the percent occurrence of a number of these comorbidities in the nearly three thousand patients followed as part of the REVEAL registry. Coexisting systemic hypertension and obesity were the most common comorbid conditions. Poms, et al. Chest. 2013;144(1):

Patient Registries for PAH: Outcome Predictors
Low Risk High Risk Patient demographics Male gender, advanced age Etiology – heritable, associated with CTD or portal hypertension Functional capacity Lower FC Longer 6-MWD Higher FC Shorter 6-MWD Laboratory / Biomarkers Lower BNP, NT-proBNP Higher BNP, NT-proBNP Higher creatinine Imaging ECHO – pericardial effusion Lung function studies Higher predicted DLCO Lower predicted DLCO Hemodynamics Higher CO or CI Higher mRAP or PVR Lower CO or CI CTD = connective tissue disease; FC = functional class; BNP = B-type natriuretic peptide ; NT-proBNP = N-terminal pro-B-type natriuretic peptide; DLCO = diffusing capacity of the lung for carbon monoxide; mRAP = mean right atrial pressure; PVR = pulmonary vascular resistance; CO = cardiac output; CI = cardiac index The patient registries for PAH have yielded useful information regarding predictors of clinical outcomes in patients. The table lists the areas where patients are at an increased risk of poor outcomes, and the areas where patients are at a decreased risk of poor outcomes. Under patient demographics an increased risk would be: male gender, advanced age (over 65 years old), type of PAH – heritable, or associated with CTD or portal hypertension. Under functional capacity an increased risk would be: higher functional class and a shorter 6-MWD. Patients with higher BNP / NT-proBNP levels are at an increased risk of poor outcomes. If an echocardiography shows pericardial effusion, the patient is considered high risk. Under lung function studies, a lower predicted DLCO is considered higher risk. Finally, the hemodynamic parameters associated with an increased risk are: higher mRAP, higher PVR, lower CO, and lower CI. McGoon, et al. J Am Coll Cardiol. 2013;62(25):S51-9.

Patient 3-Year Survival Rates: REVEAL Registry
FC = functional class Barst and colleagues published results from the REVEAL registry regarding patient survival (total cohort, N = 982). The researchers found an increase in 3-year survival in those patients who improved their functional classification, specifically from functional class III to functional I or II within one year of enrollment. In contrast, those patients who had an unchanged functional classification (remained at functional class III) had a reduced percent survival rate. Those patients who had a worsening of functional classification (change in functional class III to IV) had the poorest rates of survival. The differences in survival rates were statistically significant (P < 0.05). N = 263 N = 645 N = 74 Barst, et al. Chest. 2013;144(1):160-8.

Pathology of Pulmonary Hypertension
Plexiform lesion Thrombus Overview Obstructive lung panvasculopathy Prognosis is primarily determined by the functional status of the RV Most common cause of death is RV failure RV = right ventricle To begin, pulmonary hypertension (PH) can be considered an obstructive lung panvasculopathy. The right ventricle plays an important role in the pathology of the disease. In fact, patient prognosis is primarily determined by the functional status of the right ventricle. Indeed, the most common cause of death is RV failure. Dilated vessels Tuder, et al. J Am Coll Cardiol. 2013;62(25):S Image:

The factors believed to be responsible for the development of pulmonary hypertension are numerous and varied. Tuder and colleagues opined that an interplay of several pathobiological and environmental factors on a “background of genetic predisposition” were likely causative. Included would be metabolic dysfunction, disordered mitochondrial structure, early and persistent inflammation, and dysregulation of growth factors. These events, in a genetically-susceptible individual, would lead to a proliferative, apoptosis-resistant state. Over time, the aforementioned pathology would lead to disease. Interplay of several pathobiological and environmental factors on a “background of genetic predisposition” Tuder, et al. J Am Coll Cardiol. 2013;62(25):S4-12.

PVR = pulmonary vascular resistance Increased pulmonary vascular resistance is the hallmark of pulmonary hypertension. This increase is due to: sustained vasoconstriction, excessive pulmonary vascular remodeling, and in situ thrombosis. Tuder, et al. J Am Coll Cardiol. 2013;62(25):S4-12.

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:

Genetic Mutations in PAH
BMPR2 BMPR2 Major predisposing gene Over 300 mutations have been identified Found in >70% of patients with H-PAH Found in ≈ 20% of patients with IPAH ALK-1 Major gene when PAH is associated with hereditary hemorrhagic telanglectasia (HHT) Less common mutations: Endoglin, SMAD9, Caveolin-1, KCNK3 ; H-PAH = heritable PAH; IPAH = idiopathic PAH; ALK-1 = activin A receptor type II-like kinase-1 Image of BMPR2: kimgen677s10.weebly.com/protein-3d-structure.html Hereditary predisposition to PAH is an important area of research in this field. Over 300 BMPR2 mutations have been identified. This mutation has been found in over 70% of patients with heritable PAH. ALK1 is recognized as the major gene when PAH is associated with hereditary hemorrhagic telanglectasia. Less common mutations include: endoglin, SMAD9, and Caveolin-1. Recently, researchers uncovered a missense variant in the potassium channel, KCNK3, while exome sequencing a group of family members with heritable PAH. Soubrier, et al. J Am Coll Cardiol. 2013;62(25):S13-21.

Group 1’ Pulmonary Hypertension
Overlapping pathological features Disordered endothelial growth or proliferation Histologic changes in pulmonary parenchyma Development of pulmonary arterial intimal thickening and medial hypertrophy May have similar clinical presentation Genetic predisposition Mutations in BMPR2, EIF2AK4? PVOD = pulmonary veno-occlusive disease; PCH = pulmonary capillary hemangiomatosis; BMPR2 = bone morphogenetic protein receptor type 2; EIF2AK4 = eukaryotic translation initiation factor 2 alpha kinase 4 Under the clinical classification of pulmonary hypertension, group 1’ are patients with pulmonary veno-occlusive disease and / or pulmonary capillary hemangiomatosis. PVOD and PCH are similar in terms of changes in the pulmonary parenchyma – ie, pulmonary hemosiderosis, interstitial edema, and lymphatic dilation. They are also similar with regard to development of pulmonary arterial intimal fibrosis and medial hypertrophy, both of which are also found in patients with PAH. The clinical presentation for all three conditions is nearly identical, so much so that misdiagnosis can occur. Some of the risk factors / associated conditions for PAH – specifically scleroderma spectrum of disease, HIV infection, and anorexigen use – can also be risk factors for the development of PVOD and PCH. Much like PAH, there has been a reported familial occurrence with PVOD and PCH. BMPR2 mutations have been documented in patients with PVOD. In addition, mutations in the gene for EIF2AK4 have been identified in a family and in individual patients with PCH, and in families with PVOD. Simonneau and colleagues opined that because of similarities in histologic changes, clinical presentation, risk factors, and genetics, “PVOD, PCH, and PAH may represent different components of a single spectrum of disease.” Langleben. Chest. 2014;145(2): Simonneau, et al. J Am Coll Cardiol. 2009;54:S43-54.

Genetic Screening and Counseling
Screening recommendations Subject to debate since it is impossible to determine which carriers of a mutation will develop PAH Patients with a family history of H-PAH Patients with IPAH, to determine if they are genetic carriers Counseling Schedule for routine evaluation Considerations for family planning H-PAH = heritable PAH; IPAH = idiopathic PAH Given the strong genetic link that has been confirmed for PAH, screening for PAH-associated genetic mutations has been recommended by many researchers. However, identification of a mutation in a high-risk individual does not guarantee future development of the disease. The expense and availability of genetic screening must be taken into consideration. Patients who are likely candidates for genetic profiling include those with a family history of heritable PAH and those with idiopathic PAH, in order to determine if they are genetic carriers. If they are indeed carriers, referral for reproductive education / family planning is recommended. If the patient (with a family history) has a mutation, then a plan for routine monitoring for PAH should be set in motion. Soubrier, et al. J Am Coll Cardiol. 2013;62(25):S13-21.

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.

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.

Clinical Presentation of PAH
Symptoms Dyspnea Fatigue Syncope Weakness Angina Abdominal distension Edema Signs Loud P2 (listen at apex) RV lift (left parasternal – fingertips) RV S3, RV S4 Systolic murmur (TR; inspiratory augmentation) Early systolic click Midsystolic ejection murmur Diastolic murmur (PR) Increased jugular “a” wave RV = right ventricle In general, the clinical symptoms associated with PAH are rather non-specific, and may go unreported by patients or unrecognized by clinicians. Patients can present with one or more of the following symptoms: breathlessness, fatigue, weakness, angina, syncope, abdominal distension, and edema. Patients who present with unexplained dyspnea on exertion, presyncope, syncope, or signs of right ventricular dysfunction are candidates for additional diagnostic screening. Physical signs that are associated with PAH include: loud P2 (listen at apex); RV lift (left parasternal – fingertips); RV S3, RV S4; systolic murmur (TR; inspiratory augmentation); early systolic click; midsystolic ejection murmur; diastolic murmur (PR); and increased jugular “a” wave. McLaughlin, et al. J Am Coll Cardiol. 2009;53:

Echocardiography for PAH
Screening tool, NOT a diagnostic tool Non-invasive estimation of PAP Examine ECHO results for: RV size and function Left ventricular systolic and diastolic dysfunction Left-sided chamber enlargement Valvular heart disease Examine ECHO with contrast results for intracardiac shunt PAP = pulmonary artery pressure; RV = right ventricle “Right ventricular hypertrophy and dilatation at initial investigation with transthoracic echocardiography. “ Image for educational purposes: Springerimages.com Doppler ECHO gives a non-invasive estimation of PAP, but it can not definitively diagnose PAH. Instead, ECHO results can be examined for left ventricular (LV) systolic and diastolic dysfunction, left-sided chamber enlargement, and valvular heart disease. ECHO with contrast can show if intracardiac shunting is present. Badesch, et al. J Am Coll Cardiol. 2009;54:S55-66.

Screening Tools and Tests
Results ECG RV hypertrophy and strain; right atrial dilatation CXR Enlarged pulmonary arteries, right heart structures PFT and ABG Airflow obstruction V/Q scan Pulmonary disease; CTEPH Blood tests and immunology Liver disease, CTD, HIV ECG = electrocardiogram; RV = right ventricle; CXR = chest x-ray; PFT = pulmonary function tests; ABG = arterial blood gases; V/Q scan = ventilation / perfusion lung scan; CTEPH = chronic thromboembolic pulmonary hypertension; CTD = connective tissue disease There are tests and procedures that can assist in the diagnosis of PAH. Included in these screening tools and test are: electrocardiogram, chest radiography, pulmonary function tests and arterial blood gases, ventilation / perfusion lung scan, and blood tests. Galie, et al. Eur Heart J. 2009;30: Preston. Am J Cardiol. 2013;111(8):S2-9.

Right Heart Catheterization for PAH
Required test for diagnostic confirmation Measures: PAP PAWP CO RAP Allows calculation of pulmonary and systemic vascular resistance PAP = pulmonary artery pressure; PAWP = pulmonary artery wedge pressure; CO = cardiac output; RAP = right atrial pressure Right heart catheterization is mandatory for all patients being tested for PAH. This diagnostic test measures PAP, CO, RAP, and PAWP. It allows calculation of pulmonary and systemic vascular resistance. Badesch, et al. J Am Coll Cardiol. 2009;54:S55-66.

Anatomy and Physiology of the RV and LV
Complex interplay between contractility, afterload, compliance, and heart rate RV = right ventricle; LV = left ventricle The anatomy and physiology of the right ventricle is quite different to that of the left ventricle. First, the thickness of the ventricles varies. The right ventricle is thin walled, while the left ventricle has a greater thickness. The right ventricle is crescent in shape and the left ventricle is cone or spherical shaped. Ventricular contraction is also different. For the right ventricle, peristaltic contraction begins at the inflow region and progresses toward the outflow tract (apex to base). In contrast, the left ventricle contracts in a squeezing, twisting motion from the apex to the outflow tract (base). The right ventricle can adapt to volume overload conditions, which is an important compensation in patients with PAH. The left ventricle can adapt to pressure overload conditions. The normal functioning of the right ventricle is said to represent a complex interplay between contractility, afterload, compliance, and heart rate. Anatomically and physiologically, the right ventricle is quite dissimilar to the left ventricle. It is thin walled and distensible, which makes it capable of significant size and shape adaptation. Subject to significant size and shape change Rich. Cardiol Clin. 2012;30: Vachiery, et al. Eur Resp Rev. 2012;21(123):40-7.

RV Failure Syndrome Pulmonary hypertension ↑ PAP (pressure overload)
Adaptive RV hypertrophy Progressive contractile impairment RV dilatation Contractile dysfunction progresses RV failure: High RV filling pressures, diastolic dysfunction, ↓ CO RV = right ventricle; PAP = pulmonary artery pressure; CO = cardiac output A cascade of pathologic events involving the right ventricle occurs in patients with PAH. Even though the RV is highly adaptive, progressive impairment in patients with PAH is inevitable. In patients with pulmonary hypertension, pressure overload and elevated PAP are present. This starts the cascade of events. The first adaptation by the RV is myocardial hypertrophy. The hypertrophy eventually impairs contractility. In order to compensate, the RV dilates. Contractile dysfunction continues, and RV failure occurs. The RV failure is characterized by high RV filling pressures, diastolic dysfunction, and a reduced cardiac output. Vonk-Noordegraaf, et al. J Am Coll Cardiol. 2013;62(25):S22-33.

Continuum of RV Impairment and Action Towards Reversal
When compensatory mechanisms in the RV are exceeded, RV dysfunction develops RV failure manifests clinically as exercise limitation and fluid retention FDA-approved therapies for PAH reverse RV remodeling Reduction of afterload Vasodilation RV = right ventricle For patients with PAH, the compensatory mechanisms of the RV are eventually overwhelmed and RV dysfunction takes place. Right heart failure is a complex clinical syndrome that manifests in patients as significant exercise limitation and fluid retention. Treatments for PAH improve exercise capacity and pulmonary vascular resistance, as well as reverse remodeling of the RV. Vonk-Noordegraaf, et al. J Am Coll Cardiol. 2013;62(25):S22-33.

RV Failure Syndrome Clinical evidence Treatment
Peripheral edema, angina, syncopal episodes, RV S3, elevated JVP, hepatojugular reflux, ascites, hepatomegaly, cool extremities Treatment Decrease afterload with drugs targeting pulmonary circulation Manage fluids to optimize volume overload and ventricular diastolic interactions Use inotropic interventions to reverse cardiogenic shock RV = right ventricle; JVP = jugular venous pressure An article by Naeije and Manes compared and contrasted the properties and pathology of the right ventricle in health individuals and in patients with PAH. They listed the definition for RV failure, as endorsed by the 5th World Symposium on Pulmonary Hypertension: “a dyspnoea fatigue syndrome with eventual systemic venous congestion, caused by the inability of the right ventricle to maintain flow output in response to metabolic demand without heterometric adaptation, and consequent increase in right heart filling pressures.” The clinical evidence that points to right ventricular failure in patients with PAH is the onset of peripheral edema, angina, and / or syncopal episodes. Other signs would be RV S3, elevated jugular venous pressure, hepatojugular reflux, ascites, hepatomegaly, cool extremities. Naeije and Manes also specified the action steps to take when treating RV failure in patients with PAH. The steps are as follows: decrease afterload with drugs targeting pulmonary circulation; manage fluids to optimize ventricular diastolic interactions; and use inotropic interventions to reverse cardiogenic shock. Vonk-Noordegraaf, et al. J Am Coll Cardiol. 2013;62(25):S22-33.

Evaluation of RV Function
Echocardiography Pericardial effusion TAPSE Right atrial area LV eccentricity 2D, 3DE volumes / ejection fraction RV strain Tei index Right Heart Catheterization Right atrial pressure Cardiac index Cardiac output (CO) Cardiac MRI RV mass RV volume RV ejection fraction TAPSE = tricuspid annular plane systolic excursion; LV = left ventricle; RV = right ventricle There are multiple tools and assessments used to monitor patients with PAH. These tools can be used to evaluate RV function and monitor disease progression. Echocardiography not only aids in the screening of patients for PAH, but it also is used for patient monitoring. In fact, it is the most common method used in clinical practice to evaluate the RV. It can be used to assess and measure the size and functioning of the RV. Right heart catheterization is invasive, yet it can be used to determine right atrial pressure, cardiac index, and cardiac output. Clinicians and researchers have found cardiac MRI to be the most accurate method for evaluating RV mass, volume, and ejection fraction in patients with PAH. Other potential uses for cardiac MRI include: to quantify regurgitant volumes, delayed enhancement, myocardial strain, coronary perfusion, and pulmonary pulsatility. Clinicians should consider imaging techniques, such as Echocardiography and cardiac MRI, as complementary instead of alternative. Echocardiography is widely available; however, the RV mass and volumes are correctly measured using cardiac MRI. Vachiery, et al. Eur Resp Rev. 2012;21(123): Vonk-Noordegraaf, et al. J Am Coll Cardiol. 2013;62(25):S22-33.

Impact of RV Function on Therapy
RV function can highlight the subtle changes in early disease and prompt rapid initiation of therapy RV function determines the patient’s functional capacity and survival Deterioration in RV function mirrors disease progression Treatment escalation can be guided by RV function correlates Regular assessment of RV function can guide decision making regarding drug therapy in patients with PAH. The RV is sensitive to the early, subtle changes of disease and can prompt initiation of treatment. The RV function is used to determine a patient’s functional capacity. Deterioration in RV function means disease progression; therefore, RV function correlates can be used to determine if intervention and treatment escalation is necessary. Badano, et al. Eur J Echocardiography. 2010;11(1):27-37.

Diagnostic Issues Misdiagnosis1 Diagnostic delay1
Most patients see three or more physicians over a three-year period before an accurate diagnosis is made Diagnostic delay1 Time to reach diagnosis has not improved in 20 years Advanced disease at diagnosis2 Approximately 75% of patients have advanced disease at diagnosis (functional class III and IV) The gravity of issues regarding proper diagnosis of PAH can not be understated. Most patients see three or more physicians over a three-year period before an accurate diagnosis is made. The delay in diagnosis is significant, and time to reach diagnosis has not improved in 20 years. Lastly, due to misdiagnosis and diagnostic delay, nearly 75% of patients have advanced disease at diagnosis (functional class III and IV). 1) Deano, et al. JAMA Intern Med. 2013;173(10): ) Thenappan, et al. Eur Respir J. 2007;30(6):

Diagnostic Delay REVEAL Interim analysis1 (N = 2967)
Mean duration between symptom onset and RHC = 2.8 years Cohort study2 (N = 2493) 21% of patients had symptoms for > 2 years before diagnosis Delay was more common in younger patients (< 36 years old) and those with a history of respiratory disorders Clinicians should be suspicious if symptoms are out of proportion to “underlying disease” or unresponsive to treatment RHC = right heart catheterization An interim analysis of the REVEAL patient registry was completed, with study data reported by Badesch and colleagues. A total of 2967 patients were evaluated. The investigators found the following patient demographics: mean age of 53 years old; 79.5% of the population was female; mean duration between symptom onset and diagnostic right heart catheterization of 2.8 years. A cohort study of the REVEAL registry data was completed by Brown and colleagues. They found approximately one in five patients (N = 2493) had symptoms for more than 2 years before being diagnosed. The diagnostic delay was more common in younger patients and those with a history of respiratory disorders (e.g. obstructive lung disease or sleep apnea). Based on the results of the study, the investigators encourage clinicians to be suspicious when a patient’s symptoms are out of proportion to the suspected, underlying disease, or when the patient is not responding to the traditional treatments for the suspected disease. Such patients would be candidates for evaluation and screening for pulmonary hypertension. 1) Badesch, et al. Chest. 2010;137(2): ) Brown, et al. Chest. 2011;140(1):19-26

Patient Screening “Systematic testing of asymptomatic individuals to search for preclinical disease and mildly symptomatic patients to prevent progression and / or development of the disease” Appropriate for PAH since symptoms are nonspecific and condition is uncommon and progressive; however, presentation is confounded by diversity of PAH Determine which screening populations to preselect An article by Schwaiger and colleagues reviewed the screening protocols for patients at high risk of developing PAH. They defined patient screening as the “systematic testing of asymptomatic individuals to search for preclinical disease and mildly symptomatic patients to prevent progression and/or development of the disease.” PAH was determined to be an appropriate disease for which to screen since the symptoms are nonspecific and the condition is both rare and progressive. Adding to the complexity of patient screening is that patient presentation is confounded by the diversity of diseases associated with PAH. The first step for patient screening would be to determine which patient populations are at high risk for PAH. In theory, proper screening would lead to an earlier diagnosis for an at-risk patient, which would allow immediate therapeutic intervention, which would hopefully improve the patient’s overall clinical outcome. Schwaiger, et al. Eur Resp Rev. 2013;22(130):

Patients at High Risk for PAH
Heritable PAH Patients with a family history of PAH Drug- and toxin-induced PAH Patients with a history of high-risk drug / toxin use Associated conditions Patients with an associated condition: Connective tissue disease HIV infection Portal hypertension Congenital heart disease Schistosomiasis Patients at high risk of developing PAH should be routinely screened for the disease, especially when multiple risk factors are present or symptomatology exists. Patients with a family history of PAH are candidates for screening. Another subpopulation at risk would be patients who have taken one or more of the recognized drug / toxins that can lead to PAH. Finally, those with an associated condition (listed on the slide) are at a greater risk for developing PAH; therefore, evaluation for PAH should be included as part of routine patient monitoring. Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41.

Guidelines for Screening High-Risk Patients
Heritable PAH Yearly echocardiography in asymptomatic carriers of BMPR2 mutation and RHC if the echocardiograph is abnormal Associated conditions Scleroderma – yearly echocardiography in symptomatic patients, optional in asymptomatic patients HIV infection – echocardiography recommended if unexplained dyspnea BMPR2 = bone morphogenetic protein receptor type 2; RHC = right heart catheterization An article by Schwaiger and colleagues reviewed the screening protocols for patients at high risk of developing PAH. The authors took into consideration the recommendations of the European Society of Cardiology and the European Respiratory Society. Based on their findings, patients with a family history of PAH should undergo echocardiography on a yearly basis if they are asymptomatic carriers of the BMPR2 mutation. Should the echocardiography yield abnormal results, these patients should undergo right heart catheterization and further diagnostic work-up. Unfortunately, there is a lack of a consensus for the ideal screening of patients with recognized PAH associated conditions. The protocol that appears appropriate for patients with scleroderma would be a yearly echocardiography in symptomatic patients and optional echocardiography in asymptomatic patients. For patients with HIV, an echocardiography is recommended if there is unexplained dyspnea. Schwaiger, et al. Eur Resp Rev. 2013;22(130):

Treatment of PAH Strategy: Goals of therapy:
Evaluation of disease severity Adoption of general measures and supportive therapy Assessment of vasoreactivity Estimation of drug efficacy Combination of different drugs and interventions Goals of therapy: Improve symptoms, hemodynamics, exercise capacity, functional class, quality of life Prevent clinical decline Reduce hospitalizations Extend survival 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 (including balloon atrial septostomy and lung transplantation), and medications. The goals of therapy are to: improve respiratory symptoms, pulmonary hemodynamics, exercise capacity (including 6-MWD), functional class, and quality of life; prevent clinical decline / worsening; reduce hospitalizations; and extend patient survival. Ghofrani, et al. Int J Cardiol. 2011;154(1):S20-33.

General Measures and Supportive Therapy
Rehabilitation / exercise Psychosocial support Family planning Vaccinations Supportive Therapy Anticoagulants Diuretics Oxygen Digoxin Referral to a PAH Clinic Multidisciplinary care Continuous monitoring Patient and family education Access to clinical trials Disease advocacy Society participation 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. 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 contraceptives can be used (they are not contraindicated). Given the compromised, baseline health and immune response of patients with PAH, influenza and pneumococcal vaccinations should be given. 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. Once a patient is diagnosed with PAH, referral to a specialized patient care center is critical. At a PAH clinic, the patient is able to receive the following services: multidisciplinary care, continuous clinical monitoring, patient and family education, psychosocial support, access to clinical trials, disease advocacy, and participation in pulmonary hypertension association (PHA) events and functions. Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.

General Measures and Supportive Therapy
Cardiac catheterization / acute vasoreactivity testing Mandatory if IPAH (optional if associated condition) Identifies patients who are responders Inhaled nitric oxide (10 – 20 parts per million) or inhaled epoprostenol (50 ng/kg/min) are the preferred testing agents Chronic CCB therapy Appropriate for patients with a positive response = reduction of mean PAP ≥ 10 mm Hg to reach a mean PAP ≤ 40 mm Hg with a normalized or increased CO Therapeutics – amlodipine, nifedipine, or diltiazem IPAH = idiopathic PAH; CCB = calcium channel blocker; PAP = pulmonary artery pressure; CO = cardiac output 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 or inhaled epoprostenol are the preferred testing agents, but epoprostenol IV or adenosine IV can also be used as alternates. The dose for epoprostenol IV is 2 to 12 ng/kg/min; the dose for adenosine IV is 50 to 350 μg/min. 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. Less than 10% of patients with IPAH achieve a positive response to acute vasoreactivity testing. 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. Galie, et al. J Am Coll Cardiol. 2013;62(25):S Agarwal, et al. Am Heart J. 2011;162:201-13

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:

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 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. Epoprostenol Continuous IV infusion, inhalation Treprostinil Subcutaneous, IV, inhalation, oral Iloprost Inhalation 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 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.

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.

WHO Functional Classification for PAH
No limitation of physical activity. Ordinary physical activity does not cause undue dyspnea, fatigue, chest pain, or near syncope. Class II Slight limitation of physical activity; no discomfort at rest. Ordinary activity causes undue dyspnea, fatigue, chest pain, or near syncope. Class III Marked limitation of physical activity; no discomfort at rest. Less than ordinary physical activity causes undue dyspnea, fatigue, chest pain, or near syncope. Class IV Inability to perform any physical activity without symptoms; signs of right ventricular failure or syncope; dyspnea and / or fatigue may be present at rest; discomfort is increased by any physical activity. The functional classification for PAH as developed and approved by the NYHA and WHO is listed in the table. A patient’s physical activity and abilities, comfort, and symptoms are used to determine the functional class. The class number increases as the patient’s health deteriorates. The classification is used to guide treatment selection, and it is featured prominently in the evidence-based treatment algorithm for PAH. Taichman, et al. Clin Chest Med. 2007;28:1-22.

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 Interventional Procedure 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 BAS IIbC Lung Transplantation Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.

Initial Therapy for PAH: Consensus From 5th WSPH
Strength of recommendation and clinical evidence 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 IA/B 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 IIbC Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.

Prostacyclin Analogs Epoprostenol Treprostinil Iloprost
Indication / FC III, IV II, III, IV Administration Continuous IV Inhalation SC IV Oral Dosage 20-40 ng/kg/min Initial = 1.25 ng/kg/min Usual = ng/kg/min Usual = µg, 6-9 times per day Other 2 branded versions available Only PAH clinical study to demonstrate survival benefit Administer in well-ventilated areas 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.

Route of Administration
Treprostinil for PAH Clinical Study Route of Administration N Study Duration Study Results Simonneau1 SC 470 12 weeks SS improvement in 6-MWD Tapson2 IV 14 SS improvements in 6-MWD, FC McLaughlin3 Benza4 Inhalation + Bosentan or sildenafil RCT = 212 OL = 206 24 months SS improvements in 6-MWD, QOL with combination therapy, which were sustained for OL extension SC = subcutaneous; SS = statistically significant; FC = functional class; RCT = randomized, double-blind, placebo-controlled trial; OL = open-label extension; QOL = quality of life 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 (> 13.8 ng/kg/min). Tapson and colleagues evaluated patients treated with treprostinil IV for 12 weeks. Compared to baseline, improvements in 6-MWD and functional class were statistically significant. 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 (up to 54 μg, four times daily) 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, 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) Simonneau, et al. Am J Respir Crit Care Med. 2002;165: ) Tapson, et al. Chest. 2006;129:683-8. 3) McLaughlin, et al. J Am Coll Cardiol. 2010;55(18): ) Benza, et al. J Heart Lung Transplant. 2011;30(12):

Treprostinil Oral for PAH: FREEDOM-C Clinical Trial
Study design RCT 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 RCT = randomized, double-blind, placebo-controlled trial; 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):

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:

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.

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:

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 20 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). 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-3 Clinical Trial
Patient population (N = 224) Study results 6-MWD Increased by 21 meters (P < 0.05) BNP levels Decreased by 26% (NSS) CTD = connective tissue disease; CTEPH = chronic thromboembolic pulmonary hypertension; NSS = non-statistically significant 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.

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 for PAH: SERAPHIN Clinical Trial
Macitentan 10 mg (N = 242) Average duration of treatment (event driven)1 103.9 weeks Risk reduction in the occurrence of morbidity and mortality events versus placebo1 45%* All-cause hospitalizations2 Risk reduced by 32%* and rate reduced by 33%* PAH-related hospitalizations2 Risk reduced by 52%* and rate reduced by 50%* Accessed January The SERAPHIN randomized, double-blind, placebo-controlled study has been completed (NCT ) The SERAPHIN open-label extension is still ongoing (NCT ). 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 occurs. 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 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 (N = 250). (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 (overall risk reduction = 38%), as well as patients who were not on background therapy (55%). 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. Channick and colleagues reported additional study results from the SERAPHIN clinical trial. The effect of macitentan on hospitalizations was evaluated. Macitentan 10 mg reduced the risk and rate of all-cause hospitalizations (32% and 33% respectively). This reduction was driven by reductions in the risk and rate of PAH-related hospitalizations (52% and 50% respectively). These aforementioned reductions were statistically significant, and the reductions resulted in decreases in the number of annual hospital days for patients. 1) Pulido, et al. NEJM. 2013;369(9): ) Channick, et al. JACC Heart Fail. 2015;3(1):1-8.

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 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):

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.

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 and progressive treatment protocols 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.

Selexipag for PAH Investigational agent 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 for PAH: GRIPHON Clinical Trials
RCT1 N = 1156 Selexipag 200 to 800 µg oral twice daily Study duration = event driven Study endpoint = TTCW Preliminary results – reduced the risk of an adverse clinical event by 39% Open-label extension2 N = 670 Selexipag 200 to 800 µg oral twice daily Study duration = event driven Study endpoint = safety RCT = randomized, double-blind, placebo-controlled study; TTCW = time to clinical worsening The GRIPHON placebo-controlled study is still active with formal results pending publication; however, preliminary results have been reported. The GRIPHON open-label extension is still ongoing. Accessed January 2015. 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. 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. A press release from the manufacturer states preliminary study results (which are pending publication in a peer-reviewed journal) demonstrate that selexipag reduced the risk of a morbidity / mortality event by 39% compared to placebo. 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. 1) 2)

Combination Therapy for PAH
Background Rationale – to target multiple disease pathways REVEAL: 34% of patients on 2 or more treatments Sequential Therapy 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 Upfront Therapy Used in early PAH disease May improve patient outcomes, slow disease progression, and reduce costs associated with managing clinical worsening 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):

Combination Therapy for PAH: Published Studies
Clinical Study Agents N Study Duration Study Endpoints Statistical Significance BREATHE-21 Epoprostenol Bosentan 33 16 weeks Hemodynamics, 6-MWD, FC No STEP-12 Iloprost 67 12 weeks Hemodynamics, 6-MWD, FC, TTCW Yes COMBI3 40 6-MWD, FC, TTCW Zhuang4 Ambrisentan Tadalafil 124 6-MWD, clinical worsening events FC = functional class; TTCW = time to clinical worsening Combination therapy has been evaluated in several randomized, double-blind, placebo-controlled studies. This table summarizes the results from four of these studies. Humbert and colleagues evaluated 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 evaluated 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. Zhuang and colleagues reported results from a randomized, double-blind study in 124 patients with PAH. Patients were required to have at least 4 months of ambrisentan therapy and stable 6-MWD and functional class (for at least one month) prior to study enrollment. Patients were randomized to receive add-on tadalafil (N = 60) or placebo (N = 64) for 16 weeks. Compared to patients taking ambrisentan alone, patients taking combination therapy had significantly improved exercise capacity, as measured via 6-MWD (P < 0.05). In addition, clinical worsening events were reported in only 5 patients taking combination therapy versus 14 patients taking ambrisentan alone (P < 0.05). Functional class was improved in a greater number of patients on combination therapy (43.3%); however, this difference was not statistically better than the number of patients on ambrisentan alone (31.3%). 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: ) Zhuang, et al. Hypertens Res. 2014;37(6):

Combination Therapy for PAH: Ongoing and Recent Studies
Clinical Study Agents N Study Duration Study Endpoints Study Results NCT Bosentan +/- Sildenafil 105 12 weeks 6-MWD, TTCW Publication pending FREEDOM-Ev1 • Treprostinil oral + PDE-5i or ERA • PDE-5i or ERA 858 Event driven Study ongoing ATHENA-12 Sildenafil or Tadalafil +/- Ambrisentan 33 24 weeks 6-MWD, PVR, mPAP, CI SS improvements TTCW = time to clinical worsening; PDE-5i = phosphodiesterase-5 inhibitor; ERA = endothelin receptor antagonist; PVR = pulmonary vascular resistance; mPAP = mean pulmonary arterial pressure; CI = cardiac index; SS = statistically significant. Accessed January The first study listed in the chart was a randomized, double-blind, placebo-controlled study that evaluated the combination of bosentan and sildenafil (NCT ) in 105 patients for 12 weeks. The investigators of this study measured change in 6-MWD and time to clinical worsening. A publication of study 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 randomized, double-blind trial will be eligible for participation in the open-label, long-term extension study. The study is still ongoing. The ATHENA-1 clinical trial was an open-label study that examined the efficacy of combination therapy (PDE-5 inhibitor and ambrisentan) after inadequate hemodynamic response (PVR) on the PDE-5 inhibitor alone. A total of 33 patients were followed for 24 weeks. An abstract of the study results was presented and published. The investigators observed that adding ambrisentan to patients with a sub-optimal response to PDE-5 inhibitor therapy alone improved pulmonary hemodynamics (PVR, mPAP, cardiac index) and exercise capacity (as measured by 6-MWD). 1) NCT ) Oudiz, et al. Chest. 2011;140(4):ABSTRACT (NCT )

Combination Therapy for PAH: COMPASS Clinical Trials
RCT N = 334 Sildenafil +/- bosentan Study duration = event driven Study endpoint = TTCW Study results = NSS COMPASS-32 Open-label extension N = 100 Bosentan +/- sildenafil Study duration = 28 weeks Study endpoint = 6-MWD Study results = 31% reached 6-MWD goal, 34% improved FC RCT = randomized, double-blind, placebo-controlled study; TTCW = time to clinical worsening; NSS = non-statistically significant; FC = functional class Accessed January An abstract of study results from COMPASS-2 was recently presented and published. This randomized, double-blind, placebo-controlled trial evaluated the efficacy of sildenafil with and without bosentan in patients with PAH (N = 334). The study duration was event driven, and the primary endpoint was time to clinical worsening. According to the abstract from the CHEST meeting, the addition of bosentan did not significantly prolong the time to first morbidity / mortality event. However, improvements in 6-MWD and NT-proBNP were observed. An abstract of study results from COMPASS-3 was presented and published. This was an open-label trial 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. The primary endpoint parameter was 6-MWD. At 16 weeks, 16 patients had reached the 380 meter threshold on monotherapy. At 28 weeks, 15 patients had reached the 380 meter threshold on combination therapy. By the end of the study (28 weeks), 31% of patients had reached the 380 meter threshold and 34% of patients had at least one functional class improvement from baseline. 1) McLaughlin, et al. Chest. 2014;146(4):ABSTRACT (NCT ) 2) Benza, et al. Chest. 2010;138(4):ABSTRACT (NCT )

Upfront Combination Therapy
Patient Survival (%) Kemp and colleagues performed a retrospective analysis of upfront combination therapy with epoprostenol and bosentan in patients with advanced PAH. Patients taking the combination of epoprostenol IV and bosentan oral included 16 patients in functional class III and 7 patients in functional class IV. As a point of comparison, the investigators used matched historical controls taking epoprostenol monotherapy. The graph shows a trend (not statistically significant) toward improved survival rates in patients on upfront combination therapy compared to epoprostenol monotherapy (matched historical controls). Improvement in PVR was significantly greater in patients treated with upfront combination therapy (epoprostenol and bosentan) compared to epoprostenol monotherapy. Months Kemp, et al. J Heart Lung Transplant. 2012;31(2):150-8.

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 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 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):

Interventional Procedures: Balloon Atrial Septostomy
Creation of an interatrial right-to-left shunt In order to: Decompress right heart chambers Increase LV preload Increase CO Improve systemic oxygen transport Decrease sympathetic hyperactivity Considered a palliative or bridging procedure Patients refractory to medical therapy Patients awaiting lung transplantation LV = left ventricle; CO = cardiac output 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.

Interventional Procedures: Lung Transplantation
Surgical procedures Single lung transplant – rare Bilateral (sequential) lung transplant – most common Heart-lung transplant – increasingly less common; only 70 – 90 performed per year* Lung transplantation remains the standard of care for select patients who fail aggressive medical therapy, with specific eligibility criteria determined by 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.

ISHLT Guidelines for Lung Transplantation
Persistent FC III or IV despite maximal medical therapy Low (< 350 meters) or declining 6-MWD Failing even while on a parenteral prostacyclin analog CI < 2 L/min/m2 RAP > 15 mm Hg FC = functional class; CI = cardiac index; RAP = right atrial pressure 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):

Goal-Directed Therapy
Diagnosis of PAH Vasoreactivity test: negative Baseline exam and monthly re-evaluation to assess treatment goals: Clinically stable, FC 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 FC = functional class; 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:

Determinants of Patient Risk
Prognostication: Determinants of Patient Risk Low Risk Determinants of Risk High Risk No Clinical evidence of RV failure Yes Gradual Disease progression Rapid II, III Functional class IV Longer (> 400 meters) 6-MWD Shorter (< 300 meters) Peak VO2 > 10.4 mL/kg/min CPET 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 RV = right ventricle; CPET = cardiopulmonary exercise testing 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:

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 FC 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; FC = functional class; 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:

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. 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. 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. 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. 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.

PAH-SYMPACT Questionnaire
PAH symptoms and impact questionnaire Disease-specific patient reported outcome (PRO) instrument Ongoing studies to validate its widespread use Studies using macitentan to psychometrically validate the questionnaire: NCT , NCT , NCT , NCT The PAH-SYMPACT questionnaire is an instrument which was developed to evaluate the effect of therapies on PAH symptoms. It requires patient self-reporting of symptoms and their impact on well-being. The questionnaire is currently being evaluated for widespread use in a variety of PAH patient populations in several countries. Accessed January NCT – ORCHESTRA study in France, Italy, Spain; 16-week, open-label study; N= 160 NCT – ORCHESTRA-EXT study in France, Italy, Spain; 6-month, open-label study; N= 160 NCT – SYMPHONY study; 16-week, open-label study; N= 275 NCT – SYMPHONY-EXT ; long-term extension, open-label study; N= 4 (reported as completed) McCollister, et al. ATS. 2013;5:ABSTRACT.

Longitudinal Patient Monitoring: ACCF / AHA Recommendations
Patient Evaluation 6-MWD FC 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 deterioration FC = functional class; BNP = brain natriuretic peptide; ECHO = echocardiography; RHC = right heart catheterization; RV = right ventricle 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.

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.

Summary Expedient diagnosis sets in motion timely and focused patient care. The continuum of RV impairment in PAH must be met with aggressive action towards reversal. The evidence-based treatment algorithm provides a foundation for disease management. Upfront combination therapy may become the standard of care for patients. In order to capture and address any subtle change in a patient’s clinical condition, comprehensive patient monitoring is essential. To summarize this lecture, the slide lists key take-home points. Expedient diagnosis sets in motion timely and focused patient care. The continuum of RV impairment in PAH must be met with aggressive action towards reversal. The evidence-based treatment algorithm provides a foundation for disease management. Upfront combination therapy may become the standard of care for patients. In order to capture and address any subtle change in a patient’s clinical condition, comprehensive patient monitoring is essential.

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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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