1. Hemodynamic Changes in PAH

2. 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 WU
MRAP: 16
Distal PA sat: %
Post iNO
PAP 91/47 (63), mPAWP 15
Therapy:
Rx- SQ Treprostinil, Macitentan
Sildenafil to Riociguat
Died within 3 months of diagnosis

4. 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

5. 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: 5

6. 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)

7. 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

8. 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

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

10. 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

11. 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): ) Brown, et al. Chest. 2011;140(1):19-26 11

12. 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

13. 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: PVR: 917
VQ- 1/2014

14. 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

15. 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 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J Jan 1;37(1):67-119

16. 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 (FEV 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

17. 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

18. 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

19. RHC
BASELINE HEMODYNAMIC DATA: 1. PAP - 60/12, mean PAWP Cardiac output Cardiac index SVO2 66%. 6. PVR 345 dynes-sec-cm-5. Inhaled nitric oxide at 40 PPM INO at 40 PPM: 1. PAP 50/12, mean Cardiac output Cardiac index SVO2 75%.
POST EXERCISE HEMODYNAMIC DATA:
1. PAP- 83/32 mmHg, mean 49 mmHg. 2. Cardiac output on CCO monitor 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

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

21. 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 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

22. 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 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

23. 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 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

24. 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%

25. 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

26. 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

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

29. Think PH !!
Thanks!