Hemodynamic Changes in PAH

Therapy: Rx- SQ Treprostinil, Macitentan Sildenafil to Riociguat 49 YO with PH on empiric Sildenafil 20 mg tid based on echo PASP of 70 followed at OSH NYHA FC IV 6MWT-- 38 m BMI- 44 Echo: LVEF 55-60%, PASP 120, dilated RV PFTs: Restricted DLCO: 22% OSA- treated VQ- low prob CT chest- mild ILD RHC DATA: 2014 PAP: 90/53, mPAP: 65 PAWP: 14 TDCO: 4.27 Calculated CI: 1.78 Calculated PVR: 955 or 11.9 WU MRAP: 16 Distal PA sat: 40.9 % Post iNO PAP 91/47 (63), mPAWP 15 Therapy: Rx- SQ Treprostinil, Macitentan Sildenafil to Riociguat Died within 3 months of diagnosis

The Expansion of Treatment Options for PAH 18 years ago No treatments for PAH 12 years ago 1 treatment for PAH Today 13 treatment options for PAH 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. Pulmonary Hypertension Association, January 2014. 4

Targeted therapy for PAH Prostacyclin pathway (PAs) Endothelin pathway (ERAs) Nitric oxide pathway (PDE5-I, sGC) 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 analogues 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;351:1425-1436. 5

The Expansion of Treatment Options for PAH Nitric Oxide pathway Endothelin Receptor Antagonists Bosentan (Tracleer) Ambrisentan (Letairis) Macitentan (Opsumit) Phosphodiesterase inhibitors Sildenafil (Revatio) Tadalafil (Adcirca) sGC stimulator Riociguat (Adempas) Prostacyclin Analogs Epoprostenol IV (Flolan, Veletri) Treprostinil IV (Remodulin) Treprostinil SQ (Remodulin) Treprostinil oral (Orenitram) Treprostinil inhaled (Tyvaso) Iloprost inhaled (Ventavis) Selexipag oral (Uptravi)

World Health Organization (WHO) functional classification of pulmonary hypertension Patients with PH but without resulting limitations of physical activity. Ordinary physical activity does not cause undue fatigue, dyspnea, chest pain or pre-syncope or syncope II Patients with PH resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity results in undue fatigue or dyspnea, chest pain, pre-syncope or syncope III Patients with PH resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary physical activity results in undue fatigue, dyspnea, chest pain, pre-syncope or syncope IV Patients with PH resulting in inability to carry on any physical activity without symptoms. These patients manifest signs of right heart failure, pre-syncope, syncope. Dyspnea and/or fatigue may be present even at rest Data from: Rich, S. Primary pulmonary hypertension; executive summary. Evian, France. WHO 1998

Evidence-Based Treatment Algorithm WHO FC II WHO FC III WHO FC IV Ambrisentan + Tadalafil Bosentan Ambrisentan Macitentan Sildenafil Tadalafil Riociguat Bosentan (Tracleer) Ambrisentan (Letairis) Macitentan (Opsumit) Sildenafil (Revatio) Tadalafil (Adcirca) Riociguat (Adempas) Epoprostenol IV (Flolan/Veletri) Iloprost inhalation (Ventavis) Treprostinil sc/IV, inhalation (Remodulin/Tyvaso) Treprostinil oral (Orenitram) Epoprostenol IV Treprostinil IV Iloprost inhalation Treprostinil sc, inhalation, IV Initial combination oral therapy Inadequate clinical response Add onTherapy IA/B ERA PA PDE-5i sGCS + Inadequate clinical response on maximal therapy Strength of recommendation and clinical evidence: IA/B = Evidence and/or general agreement that a given treatment or procedure is beneficial, useful, effective; data from randomized clinical trial(s), meta-analyses, or large nonrandomizedBosentan (Tracleer) Ambrisentan (Letairis) Macitentan (Opsumit) Sildenafil (Revatio) Tadalafil (Adcirca) Riociguat (Adempas) Epoprostenol IV (Flolan/Veletri) Iloprost inhalation (Ventavis) Treprostinil sc/IV, inhalation (Remodulin/Tyvaso) Treprostinil oral (Orenitram) Epoprostenol IV studies; treatment is recommended IIaC = Weight of evidence/opinion is in favor of usefulness/efficacy; consensus of opinion of the experts and/or small studies, retrospective studies, registries; treatment should be considered IIbC = Usefulness/efficacy is less well established by evidence/opinion; consensus of opinion of the experts and/or small studies, retrospective studies, registries; treatment may be considered WHO = World Health Organization; FC = functional class; IV = intravenous; sc = subcutaneous; ERA = endothelin receptor antagonist; PA = prostacyclin analog; PDE-5i = phosphodiesterase-5 inhibitor; sGCS = soluble guanylate cyclase stimulator; BAS = balloon atrial septostomy General measures and supportive therapy are the first steps in the standard of care for patients with PAH. Next, patients are referred to a care center that specializes in the treatment of PAH. Acute vasoreactivity testing is performed. Patients who are not vasoreactive, or who fail to maintain vasoreactivity over time, begin initial therapy for PAH. The slide gives the treatment algorithm for initial therapy. Agents are recommended based on the functional classification of the given patient. Only FDA-approved agents are listed in this slide. Interventional Procedure IIA/C BAS Lung Transplantation Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. II B/C 8

Determinants of Prognosis in PAH Galie et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2016 Jan 1;37(1):67-119

Patient 3-Year Survival Rates: REVEAL Registry 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. 10

Diagnostic Delay REVEAL Interim analysis1 (N = 2967) Mean duration between symptom onset and diagnostic right heart catheterization = 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 they are not responding to treatment 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. Badesch, et al. Chest. 2010;137(2):376-87. 2) Brown, et al. Chest. 2011;140(1):19-26 11

WHO Group 4 PH- Chronic Thromboembolic Pulmonary Hypertension (CTEPH) Incidence is estimated at 1-5% in survivors of acute PE The diagnosis of CTEPH requires that both of the following criteria be confirmed : Pulmonary hypertension, defined as a mean pulmonary arterial pressure (PAP) ≥25 mmHg at rest in the absence of an elevated pulmonary capillary wedge pressure (ie, PAWP is ≤15 mmHg) Thromboembolic occlusion of the proximal or distal pulmonary vasculature must exist and be the presumed cause of the pulmonary hypertension Potentially curable form of PH Treatment of choice is pulmonary thromboendarterectomy, Riociguat is approved in in-operable patients or for residual PH after surgery

73 YO with H/O PE and progressive DOE and pedal edema: CTA 2012, 2013 x 2 RHC- 1/2014 NYHA FC III-IV PAP: RPA: 96/27, LPA 89/33 mPAP: RPA 50, LPA 51 mPAWP: 12 TDCO:3.4 CI: 2.05 PVR: 917 VQ- 1/2014

2/2014 Pulmonary thromboendarterectomy (PTE) at UCSD Pre-op PAP 94/33, mPAP 55, PCWP 5, mRAP 10, TDCO 3.2, CCI 2.1, PVR 1250 Post op PAP 62/13, mPAP 27, CO 4.1, CCI 2.7 RHC- 8/2014 NYHA FC II PAP (m): 60/23 (36) mPAWP: 10 TDCO: 3.97 PVR: 6.54 WU or 523 2018: Stable at WHO FC II, Echo PASP 55 Riociguat started

WHO Group 2, 3 and 5 PH What we know: Coexisting PH with patients with cardio-pulmonary diseases is associated with Increased mortality Increased functional intolerance ? Increased exacerbations or hospitalizations General therapies can be used: diuretics, digoxin, anticoagulation, oxygen, diet and activity, contraception No evidence yet from adequate RCTs supporting use of targeted PAH agents in treatment of Groups 2 and 3 PH: current task force guidelines do not support use of PAH therapy in these subgroups (III C) Treat underlying disease, refer to PH specialist for evaluation on a case by case basis and consider enrollment in clinical trials Galie et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2016 Jan 1;37(1):67-119

43 year old man with history of asthma and previous sarcoidosis was seen for limiting exertional breathlessness attributed to poor control of pulmonary problems but not helped by bronchodilators and steroids Mild symptoms for 5 years, more noticeable for 6 months with severe exertion like cutting grass and lifting loads, attributed to physical inactivity Symptoms worse over a month prior to presentation – unable to play with his kids in the yard, unable to rush from his car to office, stopping after climbing 1 flight of stairs at home PFTs: Normal spirometry (FEV1 4.26 L or 106% of predicted) CXR: Unremarkable Echo stress test: Poor acoustic windows, no TR jet visualized, mild RV enlargement, LVEF mildly reduced with no regional wall motion abnormalities

RHC: PAP 25/7, mean 15, PAWP 6, TDCO 6.2, PA sat 75% and no step up LHC: 100% ostial LAD lesion with distal filling from RCA, 90% Circumflex lesion, 70% and 100% RCA lesions Underwent 3 V CABG and subsequent PCI to un-grafted obstructions and is doing well. Runs 3-4 miles 5 times a week

2009: 48 YO with sarcoidosis at FC IV- referred for LTX, unable to rehab PFTs- FEV1 28%, TLC 58%, DLCO 30% Echo- LVEF 65%, Poor acoustic windows, RVSP not assessed 6MWD- 104 m on 5 L/min

RHC BASELINE HEMODYNAMIC DATA: 1. PAP - 60/12, mean 28 2. PAWP - 9. 3. Cardiac output 4.4 4. Cardiac index 2.7 5. SVO2 66%. 6. PVR 345 dynes-sec-cm-5. Inhaled nitric oxide at 40 PPM INO at 40 PPM: 1. PAP 50/12, mean 24 2. Cardiac output 5.1 3. Cardiac index 3.1 4. SVO2 75%. POST EXERCISE HEMODYNAMIC DATA: 1. PAP- 83/32 mmHg, mean 49 mmHg. 2. Cardiac output on CCO monitor 2.8-3 L/min/m2. 3. SVO2 27% which was confirmed on venous blood gas analysis that showed a mixed venous saturation of 26%. THERAPY: Sildenafil 40 mg tid Pulm rehab Lung Tx

Bilateral lung transplant- 2/2010 8+ years post transplant On room air PAH medicines stopped Bronchodilators stopped

Exercise training Mereles et al from Germany, 2006, Multicenter , N=30 Randomized to 15 week study period into training group or sedentary group Patients: PAH (n=23), CTEPH (n=7), WHO FC II-IV, stable medical regimen for 3 months Primary end points: 6 MWD, health related QOL measured by Short Form Health Survey Secondary end points: Borg dyspnea scale, FC change, stress echo parameters (PASP, RV and RA areas, CPET parameters Both groups received nutritional program, physical therapy, massages, counseling, respiratory training and muscle relaxation Data measured at baseline, week 3, week 15 Intervention group: supervised exercise for 3 weeks 7 day a week regimen of 10-25 mins on bicycle ergometer limited by peak HR of >120, SpO2 <85% and perceived physical exertion 60 mins of walking (level/uphill) 5 days/week 30 mins of dumb bell training 5 days/week 30 mins of respiratory training 5 days/week Yoga After 3 weeks of hospital training they were discharged with individualized training manual Bicycle ergometer15-30 mins 5 times/week at target heart rate Dumb bell training 30/ resp muscle training every other day Phone monitoring Sedentary group offered the same program after 15 weeks

Improved WHO functional class Baseline Exercise group Control group PAH with PVR 969+/- 44 902+/- 358 6 MWD 439 +/- 82 411+/-86 At 15 weeks Mean Difference on 6 MWD 111 m (95% confidence interval 65-139 m; P <0.001) Mean 6MWT distance increased in the exercise group and decreased in the sedentary group (+96m versus -15 m) Following crossover, sedentary group improved their 6MWT distance by +74m Improved WHO functional class

Quebec study 5 IPAH patients treated with a single oral agent 12 week outpt cardiopulmonary rehab program Baseline 6MWT, CPET, endurance cycle testing Volitional and non-volitional quadriceps strength at maximal voluntary contraction (MVC) 3 times/week program Exercise prescription was individualized 10-15 mins of cycling personalized to CPET results Resistance exercises consisting of 2 sets of 10-12 repetitions for 6-8 muscle groups 15 mins of treadmill walking at 85% of mean 6MWT speed Intensity of the program was increased as tolerated Measurements before and after the program 6MWT Cycle endurance test Limb muscle cross-sectional area Quadriceps function by MVC and magnetic stimulation Muscle biopsy Results: Mean increase in 6MWT distance: 13% Endurance time 53% Type 1 muscle fiber increased Capillary /fiber ratio increased

45 year old Caucasian man was referred in 10/2010 for evaluation of pulmonary hypertension and dilated right heart identified on echocardiogram History 2006: Triathlon athlete, stopped competing after his daughter was born 2008: Enrolled in soccer team at Capital one, noticed exertional breathlessness Attributed this to being out of shape and stopped training Played Bicycle Polo with friends on the weekends 2010 (Jan-April): Decided to try outdoor running Could not complete his previous training routes Attributed this to seasonal allergies and decided to join an indoor gym 2010 (May-June): Established a routine where he was able to complete 30 mins at 6 miles/hr Achieved a target heart rate of 140/min but felt he had to push himself considerably Exercise stress test in June: 12 minutes on Bruce protocol, read normal 2010 (July): Started getting breathless running up 2 flights of stairs at work and home. 2010 (September): Began noticing lightheadedness while rising from squatting positions during strength training with weights 2010 (October): Echo– Markedly dilated right atrium and ventricle, PASP 80-90, LVEF 55%

Right heart catheterization 10/2010: PAP 81/18, mean 39, TDCO 4.43, PVR 613, PA sat 67.6% 6MWD 11/2010: 415 m Therapy: Adcirca, digoxin, coumadin, lasix, aldactone Advised stationary bicycle ergometer for 30 mins Felt better and resumed Bike Polo with friends on the weekend- did need to take breaks, no syncope Echo 2/2012: persistently dilated right heart, small right to left shunt, PASP >100 RHC 3/2012: PAP 87/26, mean 46, mPAOP 5, TDCO 5.5, PVR 596, PA sat 69.8% Therapy: Adcirca, Letairis, Tyvaso, digoxin, coumadin, lasix, aldactone >> looking towards IV prostanoids and transplantation Bicycle polo restricted, stationary exercise ergometer, treadmill with no incline allowed. ??? Ideal exercise prescription

81 year old female with mild COPD and OSA, was referred for severe pulmonary hypertension and dilated right heart chambers on echocardiogram on 10/2011. RHC confirmed PAH: PAP 80/26, mean 44, mRAP 14, TDCO 2.4, PVR 900, PA sat 54% History: Progressive exertional breathlessness for the past year Intractable pedal edema for 6 months Fatigue, malaise Nausea, vomiting, diarrhea RUQ abdominal pain Eating in bed, using bedpan, needing considerable assistance from members of her family to get into the chair or walk to the bathroom, depressed Managed with IV dobutamine, diuretics and eventually discharged on IV epoprostenol 3 mcg/kg/min, eventually has been titrated up to 13 mcg/kg/min Coming down to the dinner table, ambulating around the house, interacting with grand-children ??? Ideal exercise prescription

Exercise prescription in patients with PAH: Needs to be individualized 85% of mean 6MWT speed (treadmill)

Think PH !! Thanks!