1. 4/8/2017
肺高壓的診斷與治療
國立成功大學附設醫院
許志新　醫師
2012/05/26, Tainan

2. What is PH ? What is PAH ?

3. Pulmonary Hypertension
Pulmonary hypertension is defined as an increase in mean pulmonary artery pressure ≧ 25 mmHg at rest
Pulmonary hypertension is a hemodynamic and pathophysiological state that can be found in multiple clinical condition

4. Pulmonary Arterial Hypertension Diagnostic Classification
• 1.1Idiopathic PAH
• 1.2 Heritable
• 1.3 Drugs and toxin related
• 1.4 Associated with (APAH)
1.4.1 Connective tissue diseases
1.4.2 HIV
1.4.3 Portal hypertension
1.4.4 Congenital heart diseases
1.4.5 Schistosomiasis
1.4.6 Chronic haemolytic anaemia
• 1.5 Persist PH of the newborn
1’ Pulmonary veno-occlusive disease
3. PH with Lung Diseases/Hypoxemia
• 3.1 COPD
• 3.2 Interstitial lung diseases
3.3 mixed restrictive and obstructive pattern
• 3.4 Sleep-disordered breathing
3.5 Alveolar hypoventilation disorders
3.6 Chronic exposure to high altitude
• 3.7 Developmental abnormalities
4. Chronic thromboembolicPH
• TE obstruction of proximal PA
• TE obstruction of distal PA
• Non thrombotic P embolism
5. PH with unclear and /or
multifactorial mechanisms
2. PH with left heart disease
• 2.1 Systolic dysfunction
• 2.2 Diastolic dysfunction
2.3 Valvular disease
Dana Point 2008

5. Pulmonary Arterial Hypertension
Pulmonary hypertension
Elevated pressure in the pulmonary vascular bed, without specify the location of the pathology
Pulmonary arterial hypertension
Elevated pressure in the pulmonary vascular bed, specially ascribed to pathology in the pulmonary arterial tree.

6. Definition of PAH by WHO
Mean PAP > 25mmHg at rest
PAWP < 15 mmHg

7. What do we face ?
Rare
Miss diagnosis
Rapid progress
Poor prognosis

8. Really rare ? Or Under diagnosis?
4/8/2017
Really rare ? Or Under diagnosis?

9. 4/8/2017
Prevalence of PAH
This is the title slide for Session 4: Pulmonary arterial hypertension (PAH): what challenges do we face?

10. PAH is a rare disease: Prevalence of PAH
4/8/2017
PAH is a rare disease: Prevalence of PAH
France:
15 cases/million
England and Wales:
Severe PAH: 30–50 cases/million
Estimated prevalence of 120,000 pts with PAH in the USA, EU, Canada and Japan.
- US 50,000 to 100,000
- 15,000 to 25,000 diagnosed and treated
Estimated 260,000 pts hospitalized/year with all cause PH in USA (medicare database)
Key message: PAH is a rare orphan disease, although the prevalence varies, being substantially higher in at-risk groups.
References
1. Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results from a national registry. Am J Resp Crit Care Med 2006; 173: 1023–30.
2. Peacock AJ. Treatment of pulmonary hypertension. BMJ 2003; 326: 835–6.
3. Sitbon O, Lascoux-Combe C, Delfrissy JF, et al. Prevalence of HIV-related pulmonary arterial hypertension in the current antiretroviral therapy era. Am J Respir Crit Care Med 2008; 177: 108–113.
4. Lin EE, Rodgers GP, Gladwin MT. Hemolytic anemia-associated pulmonary hypertension in sickle cell disease. Curr Hematol Rep 2005; 4: 117–25.
5. McGoon M, Gutterman D, Steen V, et al. Screening, early detection, and diagnosis of pulmonary arterial hypertension: ACCP evidence-based clinical practice guidelines. Chest 2004; 126(1 Suppl): 14S–34S.
Humbert, et al. Am J Resp Crit Care Med 2006; 173: 1023–30
Peacock. BMJ 2003; 326: 835–6
Link J. Chest 2011; 139:
Gomberg-Maitland M. Chest 2011;139:

11. Prevalence of PAH in Associated Conditions
Systemic sclerosis
7-12 %
HIV infection %
Portal hypertension
2-6 %
Congenital heart disease
per million in those with congenital systemic-to-pulmonary shunts → % affected by Eisenmenger syndrome
Schistosomiasis
4.6 % in those with hepatosplenic disease
Chronic hemolytic anemia
Highly variable; currently being studied
The prevalence of PAH in associated conditions varies dramatically. Patients with systemic sclerosis have an estimated prevalence of 7-12%. Those with HIV infection have an estimated prevalence of less than 0.5%. The prevalence is 2-6% for patients with portal hypertension. PAH is prevalent in per million of patients with congenital systemic to pulmonary shunts. Furthermore, 25-50% go on to be affected by Eisenmenger syndrome. Just less than 5% of patients with hepatosplenic disease develop PAH. Patients with chronic hemolytic anemia are at an increased risk of developing PAH; however, the prevalence rates are highly variable and are being actively studied.
Simonneau, et al. J Am Coll Cardiol. 2009;54(1):S43-54.

12. Pathogenesis of Pulmonary Arterial
NORMAL
REVERSIBLE DISEASE
IRREVERSIBLE DISEASE
Pathogenesis of Pulmonary Arterial
Hypertension
4/8/2017

13. PAH: Pathophysiology RV remodeling Pulmonary vessel remodeling
RV dysfunction
Pulmonary vessel remodeling
Pulmonary vascular resistance increase

14. Do we have a luxury time ?

15. PAH: a rapidly evolving disease
4/8/2017
PAH: a rapidly evolving disease I
Preclinical /
no symptoms II
Symptomatic /
stable
III
Progression /
declining
RV function
Pulm. pressure
Level
Cardiac output
Therapeutic window
Key message: PAH is a rapidly evolving disease especially in the later stages (WHO Functional Class III).
Years
Months
Time

16. Severity of Pulmonary Hypertension
Degree of disease
Mild
Moderate
Severe
Mean PAP (mmHg)
>55

17. NYHA/WHO classification of functional status
Description I
Patients with pulmonary hypertension in whom there is no limitation of usual physical activity: ordinary physical activity does not cause increased dyspnoea, fatigue, chest pain or pre-syncope II
Patients with pulmonary hypertension who have mild limitation of physical activity. There is no discomfort at rest but normal physical activity causes increased dyspnoea, fatigue, chest pain or pre-syncope
III
Patients with pulmonary hypertension who have a marked limitation of physical activity. There is no discomfort at rest but less than ordinary activity causes increased dyspnoea, fatigue, chest pain or pre-syncope IV
Patients with pulmonary hypertension who are unable to perform any physical activity and who may have signs of right ventricular failure at rest. Dyspnoea and/or fatigue may be present at rest and symptoms are increased by almost any physical activity
Barst RJ et al. J Am Coll Cardiol ; 43 (12 Suppl S): 40S–47S

18. 4/8/2017
PAH progresses rapidly if left untreated ... even in mildly symptomatic disease
Early diagnosis of PAH and early intervention improves survival prospects
100 75
WHO class I – II (n = 30)
Survival (%) 50 25
Key message: Early diagnosis of PAH is important along with early intervention to improve survival prospects.
Reference
Brenot F. Primary pulmonary hypertension. Case series from France. Chest 1994; 105:
33S–36S.
WHO class III – IV (n = 75) 12 24 36 48 60 72 84 96
Months
Brenot F. Chest 1994; 105: 33S–36S 18

19. Prognosis of Pulmonary Hypertension
Survival years

20. Early diagnosis is important, but is it easy ?

21. PAH is still often diagnosed late: French National Registry 2002–2003
4/8/2017
PAH is still often diagnosed late: French National Registry 2002–2003
n = 674
80%
70%
63%
60%
50%
40%
30%
24%
20%
12%
Key message: Since diagnosis of PAH is difficult, it is still often diagnosed late (predominantly at the stage of Functional Classes II and III).
Reference
Humbert M, Sitbon O, Chaouat A, et al. Pulmonary arterial hypertension in France: results
from a national registry. Am J Resp Crit Care Med 2006; 173: 1023–30.
10% 1% 0%
Class I
Class II
Class III
Class IV
Humbert M, et al. Am J Resp Crit Care Med 2006; 173: 1023–30 21 21

22. Symptoms Symptoms may include: Dyspnea ● Fatigue Syncope ● Edema
Dizziness ● Chest Pain
Non-specific nature of complaint can lead to:
Misdiagnosis
Delayed diagnosis ( It takes an average of 3 years from first symptoms to diagnosis )

23. Why is missed?
Young patient with non specific symptom with “normal” CXR and EKG
Lack of practical therapy in the earlier era lead to therapeutic nihilism
Co-mobid condition have similar symptoms

24. Suspect PAH: Clinical Presentation
Progressive Dyspnea
Pedal edema
Non-productive Cough
Fatigue
Syncope
Chest Pain
85%
30%
19%
13%
12% 7%

25. Reason to suspect PAH Unexplained dyspnea Typical symptom with signs
“At risk“ condition
CREST, liver disease, HIV, sickle cell
Family history of PAH
History of stimulant/anorexigen drug use

26. How to I know the patient really got PAH?

27. Diagnosis of PAH: a four-stage process
1. Suspicion of pulmonary hypertension
2. Detection of pulmonary hypertension
3. Pulmonary hypertension class identification
4. Pulmonary arterial hypertension evaluation
Symptoms and physical examination
Screening procedures
Incidental findings
Electrocardiogram
Chest radiograph
Transthoracic Doppler echocardiography
Pulmonary function tests and arterial blood gases
Ventilation/perfusion lung scan
High-resolution CT
Spiral CT
Pulmonary angiography
Type (blood tests and immunology, HIV test, abdominal ultrasound)
Exercise capacity (6MWD, peak oxygen consumption)
Haemodynamics (right- heart catheterisation)
Diagnosis 4 stage
On of exclusion until final confirmation via r heart cath
Will inform whether idepathic or 2ary to other diease e.g. CTD, HIV
2nd stage – treatment evolution opportunity inc early dx & early referral
3rd stage – spirometry excludes other lung disease i.e. PAH secondary to COPD
4th stage via PWP / PVR confirms right sided, artrerial bed
Galiè N et al Eur Heart J 2004; 25: 2243–2278

28. Case 2006/03/11
21 y/o female
Dyspnea and fatigue for about several months
Visited LMD for help but in vain
Condition get worse and worse----

29. NCKUH ER Physical examination
BP: 150/80 mmHg, HR: 120 bpm, RR: 24/min, SaO2: 90%
Lip: mild cyanotic change
Jugular vein enlargement
Breathing sound: clear
Heart : tachycardia, fix split S2 , increased P2, systolic murmur GrIV/VI over LLSB, RV heave (+)
Extremities: warm, mild edema.
ABG: PaO2: 52mmHg

30. Electrocardiography
Sinus tachycardia
RAD
RVH

31. CXR
Cardiomegaly
C/T ratio: 0.59
Dilated pulmonary trunk

32. Echocardiography Dilated RA,RV. RV hypertrophy
Adequate LV performance.
Moderate to severe TR with Pul.HTN <systolic PAP= 140mmHg>

33. Pulmonary hypertension with right heart failure was suspected, R/O pulmonary embolism, R/O congenital heart disease, R/O primary pulmonary hypertension
Admitted to CCU for further care

34. Chest CT Dilated pulmonary trunk and pulmonary artery
No evidence of pulmonary embolism
No evidence of lung disease

35. TEE: No congenital heart disease
Autoimmune screen: Normal
HIV: Negative
Pregnancy test : Negative

36. Diagnosis
Primary pulmonary hypertension was impressed. (WHO FC IV)

37. How long do I have ? How can I do ? Could you help me ?

38. How can your patient do ?

39. PAH Therapy: Life style considerations
Sodium restriction
Abstinence from smoking
Avoid high altitude
<4,000 feet above sea level
Avoid physical exertion in setting of pre- or frank syncope
Avoid pregnancy
Immunization for illnesses (Influenza and pneumococcal vaccination)

41. Could we help patient ?

42. Goals of Therapy
Alleviate symptoms, improve exercise capacity and quality of life
Improve cardiopulmonary hemodynamics and prevent right heart failure
Delay time to clinical worsening
Reduce morbidity and mortality

43. PAH: Traditional Therapy
Pharmacologic
Calcium channel blocker
Supplemental O2
Anticoagulation (INR≈ 2-3)
Diuretics (excessive preload)
Digoxin
IV inotropes (low dose dobutamine,
dopamine 1-2 mcg/kg/min) }
Rx for RV
failure

44. Diuretics
Treat edema
May need combine therapy

45. Anticoagulation Studies only show benefit in iPAH patients
Other PAH groups not as clear
Aim for INR
Benefit thought to be
Reduction of in-situ thrombosis
Reduction DVT risk in low CO status

46. Oxygen Formal assessment of nocturnal and exertion oxygen levels
Minimal added insult of hypoxic vasocontriction
Aim to keep oxygen saturation > 90%
Often impossible in large right to left shunt patients

47. 4/8/2017
Humbert M, et al. NEJM 2004; 351:

48. FDA-Approved Agents for the Treatment of PAH
Prostacyclin analogs (PA)
Epoprostenol
Iloprost
Treprostinil
Endothelin-receptor antagonists (ERA)
Bosentan
Ambrisentan
Phosphodiesterase-5 inhibitors (PDE-I)
Sildenafil
Tadalafil

49. Endothelin Receptor Antagonist (ERA)

50. Endothelin is increased in IPAH and PAH associated with other Diseases
Congenital Heart Disease
IPAH
Scleroderma
P<0.001
P<0.05 5
P<0.001 10 10 4 8 8 3 6
Delta ET-LI (PV-RV) (pg/ml)
IrET-1 (pg/ml)
Concentration of ET-1(pg/ml) 2 4 6 2 1
This slide is not designed to compare between trials. What these 3 studies show is that ET is key in each of these patient PAH populations.
Stewart et al. demonstrated that in 27 patients with PAH, immunoreactive endothelin-1, measured by a specific radioimmunoassay, was significantly higher (3.5 +/- 2.5 pg/mL), than in normal subjects (1.45 +/ pg/mL), (p<0.001).
Vancheeswara et al. demonstrated that serum levels of ET are significantly increased in patients with SSC compared with healthy controls (p<0.05). Furthermore, localized cutaneous (lC) SSc patients with PAH had significantly higher levels of ET than comparable patients with no PAH (p=0.025)
Yoshibayasi et al. demonstrated significantly increased plasma ET concentrations in patients with CHD’s and PAH (n=18) compared to those without PAH (n=27); (p<0.001). The bar graph above depicts increments of plasma ET-like immunoreactivity concentrations sampled from right ventricle (RV) to pulmonary vein (PV). 4
Non-PPH
PPH
LcSSc Non-PAH
LcSSc PAH
Non-PH PH
Stewart et al., Ann Inter Med, Vancheeswaran et al., J. Rheum, Yoshibayashi et al., Circulation, 1991

51. Endothelin is a Key Pathogenic Mediator*
Proliferation
Vascular Smooth Muscle
Fibroblasts
Vasoconstriction
Direct Or Via Facilitation Of Other
Vasoconstrictor Systems (Renin
Angiotensin System, Sympathetic) ET
Hypertrophy
Cardiac/Vascular
Inflammation
 Vascular Permeability
Neutrophil / Mast Cell Activation
Promotes Cellular Adhesion
 Cytokine Production
Fibrosis
Fibroblast Proliferation
 Extracellular Matrix Proteins
 Collagenase Production
ET is a mediator of diverse effects including vasoconstriction, vascular hypertrophy, fibrosis, and inflammation. These effects are deleterious and are thought to play a key role in PAH pathogenesis. ET is therefore thought to be a key pathogenic mediator in PAH.
Details not included on slide:
ET stimulates production of the following cytokines - IL-1b, IL-6, IL-8, TNFa, TGFb;
promotion of cellular adhesion relates to increased neutrophil adhesion to endothelium and induction of expression of adhesion molecules.
*Based on observations reported from in-vitro, in-vivo, or animal models. The clinical significance in humans is unknown.
Clozel. Ann Med

52. Bosentan for PAH
Endothelin receptor antagonist (ETA/ETB non selective)
Indication – WHO group I - functional class II, III, IV
Dosage – 62.5 mg oral twice daily for 4 weeks then 125 mg oral twice daily
Bosentan is an endothelin receptor antagonist indicated for the treatment of PAH, functional class II, III, and IV. The initial dosage of bosentan is 62.5 mg oral twice daily for 4 weeks. Patients are then titrated to 125 mg oral twice daily.

53. 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 =
Placebo (N = 69)
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.
Baseline
Week 4
Week 8
Week 16
62.5 mg bid
125 or 250 mg bid Bosentan
Rubin, et al. N Engl J Med. 2002;346:

54. Long-term outcomes on bosentan
96%
89%
86%
100 90
Bosentan 80 70 60
69%
Cumulative Survival (%) 50
57%
Predicted (NIH) 40
48% 30
85% and 70% were on bosentan monotherapy
at 12 and 24 mos, respectively 20
LO: She has the slide as hidden, so I did NOT edit or make any changes. 10 6 12 18 24 30 36
Time (Months）
169
167
163
153
113 23 16
Patients at risk
Event rate/year (exponential): 5.5%
McLaughlin VV et al. Eur Respir J. 2005;25: 54

55. Bosentan for PAH: EARLY Clinical Trial
Study design
Randomized, double-blind, placebo-controlled, six-month study
Patients
N = 177
Mildly-symptomatic PAH (WHO group II)
Study results
Primary study endpoints
Decreased PVR (P < )
No significant change in 6-MWD (P = 0.076)
Secondary study endpoints
Delayed time to clinical worsening (P = 0.018; 70% reduction in risk)
Safety
Consistent with previous studies
PVR is expressed as the geometric means of the % of baseline at month 6. The geometric mean is used as the clinical interest focuses in a fold change from baseline. In other words, patients who change from 300 to 100 or from 450 to 150 have a 3-fold reduction, which is considered the same in the statistical analysis, regardless of having an absolute change of 200 and 300. This allows to account for baseline heterogeneity.
After 6 months of treatment, mean PVR had decreased from baseline in the bosentan group to 83% and increased in the placebo group to 107%.
Values at Month 6 expressed as a percent of baseline values showed a significant 22.6% reduction in PVR in the bosentan group compared with placebo.
Imputation rules:
Missing values for either PVR at Month 6 were replaced by carrying forward the last available post-baseline value in the treatment period unless one of the following applied:
If the patient died during the treatment period or experienced a treatment-emergent adverse event that led to permanent discontinuation and resulted in death, the worst value (the worst between the absolute change and maximum value for PVR) was used to replace the missing value.
If the patient was alive but otherwise experienced clinical worsening during the treatment period, the worst between the absolute change and maximum value for PVR was used to replace the missing value.
Actual imputation:
For three patients in each treatment group, missing values were substituted with worst values.
Galie, et al. Lancet (9630):
Valerio et al. Vasc Health Risk Manag. 2009;5: 55 55

56. Bosentan for PAH: EARLY Clinical Trial
Change in PVR (from Baseline to Week 24)
Decrease in PVR:
Surrogate marker for delaying disease progression
P <
% of Baseline PVR at Week 24 (geometric means)
Treatment effect =
- 22.6%
Galie, et al. Lancet (9630):
Valerio et al. Vasc Health Risk Manag. 2009;5:

57. Bosentan for PAH: EARLY Clinical Trial
Change in 6-MWD (from Baseline to Week 24) 25 20 15
11.2
Placebo (N= 91) 10
P = 0.076
Bosentan (N= 86) 5
Change in 6-MWD (meters) 5 12
weeks 24
weeks
In this slide, change in 6-MWD from baseline to week 24 is plotted. Patients treated with bosentan had a significant improvement in exercise capacity compared to patients taking placebo. The 6-MWD increased by 11.2 meters (on average) in the bosentan group and decreased by 7.9 meters (on average) in the placebo group. The average treatment effect was an improvement of 19.1 meters.
10
- 7.9
15
Treatment effect =
meters
20
Galie, et al. Lancet (9630):
Valerio et al. Vasc Health Risk Manag. 2009;5: 57

58. Bosentan for PAH: EARLY Clinical Trial
Slide Template
4/8/2017 5:05 AM
Time to Clinical Worsening (from Baseline to Week 32)
100
P < 0.02 80
Placebo 60
Bosentan
Event-Free Patients (%) 40 20
A significant delay in the time to clinical worsening was observed with bosentan compared with placebo, which could be discerned before 16 weeks of treatment.
The hazard ratio was 0.227, indicating that, overall, treatment with bosentan was likely to reduce the rate of clinical worsening by 77% of that experienced by placebo-treated patients.
The date of clinical worsening was defined as the earliest among the date of death, the date of hospitalization due to PAH complications, and the date of symptomatic progression of PAH.
The proportions of patients without clinical worsening were estimated at Weeks 4, 8, 12, 16, 20, 24, and 28 and at the last observed value (longest period of observation before a censoring or an event denoting clinical worsening) using the Kaplan-Meier method and displayed with 95% confidence intervals. Patients without clinical worsening were censored at the end of double-blind treatment plus 1 day. For some patients (recruited in early stage of study and following original protocol, which did not fix the treatment period to 6-months) double-blind treatment period lasted up to 32 weeks. 4 8 12 16 20 24 28 32
weeks
Patients at risk (N) 92 90 89 86 84 83 18 77 9 93 92 87 85 84 83 27 80 15
Galie, et al. Lancet (9630):
Valerio et al. Vasc Health Risk Manag. 2009;5: 58 58

59. NTUH data Respiratory Medicine 2007
Bosentan have benefit effects on functional status, exercise capacity, right heart function and pulmonary function.
Respiratory Medicine 2007

60. Ambrisentan for PAH Endothelin receptor antagonist (ETA selective)
Indication – WHO group I - functional class II, III
Dosage – 5 mg and 10 mg oral daily 60

61. Ambrisentan for PAH Change in 6-MWD (from Baseline to Week 12) ARIES 150 60
N = 202
N = 192
10 mg:
+43.6 m
5 mg:
+49.4 m 40 25
5 mg:
+22.8 m
2.5 mg
+22.2 m 20
Change from Baseline (meters)
Ambrisentan in PAH: ARIES-1 and ARIES-2
ARIES-1 and ARIES-2 were concurrent, double-blind, placebo-controlled studies of ambrisentan, a selective ETA receptor antagonist.
The primary endpoint for each study was the change in 6-minute walk distance from baseline to week 12.
The 6-minute walk distance increased in all ambrisentan groups; mean placebo-corrected treatment effects were 31 meters (p = 0.008) and 51 meters (p < 0.001) in ARIES-1 for 5mg and 10mg ambrisentan, and 32 meters (p = 0.022) and 59 meters (p < 0.001) in ARIES-2 for 2.5mg and 5mg ambrisentan.
Improvements in time to clinical worsening (ARIES-2), World Health Organization functional class (ARIES-1), Short Form-36 score (ARIES-2), Borg dyspnea score (both studies), and B-type natriuretic peptide (both studies) were observed.
These are the studies than led to FDA approval of ambrisentan.
Placebo:
-7.8 m
Placebo:
-10.1 m
-20
-25 4 8
12 weeks 4 8
12 weeks
Placebo-adjusted change at week 12:
Ambrisentan 5 mg = 31 m; 10 mg = 51 m
Placebo-adjusted change at week 12:
Ambrisentan 2.5 mg = 32 m; 5 mg = 59 m
Galie, et al. Circulation. 2008;117: 61 61

62. Endothelin Receptor Antagonists Comparison of Agents
Bosentan
Ambrisentan
Use in pregnancy
Pregnancy category X (non-hormonal birth control method required)
LFT elevation
Monthly LFT monitoring required; ≥ 3x ULN in ~ 11% patients (pooled data from 16-week studies)
≥ 3x ULN in 0.8% patients in 12-week studies, 2.8% patients in 1-year studies
Peripheral edema
1.7% patients (placebo-adjusted; fluid retention/edema)
6% patients (placebo-adjusted)
Additional adverse events
Respiratory tract infections, headache, fainting, flushing, low blood pressure, sinusitis, joint pain, irregular heartbeat
Nasal congestion, sinusitis, flushing, palpitations, nasopharyngitis, abdominal pain, constipation
This table compares the endothelin receptor antagonists, bosentan and ambrisentan. Both agents are pregnancy category X. Monthly LFT monitoring is required for both agents. However, the incidence of LFT elevation differs between the two medications. A greater than three times the upper level of normal increase in LFT has been reported in nearly 11% of bosentan-treated patients and 0.8% or 2.8% of ambrisentan-treated patients. The incidence of peripheral edema is approximately 1.7% for bosentan and 6% for ambrisentan. Adverse events reported during bosentan therapy include respiratory tract infections, headache, fainting, flushing, low blood pressure, sinusitis, joint pain, and irregular heartbeat. Adverse events reported during ambrisentan therapy include nasal congestion, sinusitis, flushing, palpitations, nasopharyngitis, abdominal pain, and constipation.
Source: FDA-approved product labeling for individual agents.

63. Endothelin Receptor Antagonists Comparison of Drug-Drug Interactions
Bosentan
Ambrisentan
Ritonavir
Rifampin
Cyclosporine A
Hormonal contraceptives
Sildenafil
Tadalafil1
Glyburide
Simvastatin (+ other CYP3A-metabolized statins)
CYP2C9 inhibitors (fluconazole, amiodarone)
CYP3A inhibitors (ketoconazole, itraconazole, amprenavir, erythromycin, fluconazole, diltiazem)
Tacrolimus
Phenytoin2
Warfarin2
Hormonal contraceptives3
Omeprazole4
Ketoconazole2,4
This table compares the drug-drug interactions for bosentan and ambrisentan. Common to both medications are drug interactions with: ritonavir, rifampin, cyclosporine A, hormonal contraceptives, and ketoconazole.
Source: FDA-approved product labeling for individual agents. 1) Barst, et al. J Am Coll Cardiol. 2009;54:S ) Galie, et al. Eur Heart J. 2009;30: ) Spence, et al. ATS. San Diego, CA. May 15-20, ) Harrison, et al. ATS. San Diego, CA. May 15-20, 2009.

64. Phosphodiesterase-5 inhibitors (PDE5-I)

65. Sildenafil (Viagra, Revatio)
1985
1989
1992
1998
Hypertension
Angina ED
PAH

66. Nitric Oxide/ PDE-5 Inhibitors Increase cGMP
PDE-5 located in pulmonary circulation
PDE-5 responsible for cGMP hydrolysis in the lung
cGMP appears to regulate pulmonary vascular tone and growth
PDE-5 inhibitor raises cGMP levels
Nitric oxide
L-Arginine
cGMP
Lowers PA
pressure
eNOS
PDE-5I
PDE-5
What is the rationale for sildenafil or other PDE5 inhibitors?
PDE5 is located PDE-5 located in pulmonary circulation
PDE-5 is responsible for cGMP hydrolysis in the lung
cGMP appears to regulate pulmonary vascular tone and growth
PDE-5 inhibitor raises cGMP levels
GMP
Wharton J et al. Am J Respir Crit Care Med. 2005;172:

67. SUPER-1 study

68. REV-EM

69. REV-EM

70. Phosphodiesterase-5 Inhibitors Comparison of Drug-Drug Interactions
Sildenafil
Tadalafil
Nitrates
Alpha blockers
Amlodipine
Ritonavir
Bosentan1
HMG CoA reductase inhibitors1
Phenytoin1
Erythromycin1
Ketoconazole1
Cimetidine1
Rifampin1
Phenobarbital1
Carbamazepine1
Antihypertensive agents
Ketoconazole
Rifampin
This table compares the drug-drug interactions associated with sildenafil and tadalafil. Common to both medications are interactions with nitrates, alpha blockers, ketoconazole, ritonavir, rifampin, and bosentan.
Source: FDA-approved product labeling for individual agents. 1) Galie, et al. Eur Heart J. 2009;30:

71. PROSTENOIDS

72. Smooth Muscle Cell relaxation Inhibits SMC proliferation
Prostacyclins
PGI2
SMC IP GS
cATP
Adenylate cyclase
cAMP
At the smooth muscle cell, PGI2 binds to the IP receptor. With the help of adenylate cyclase, cATP is converted to cAMP leading to smooth muscle cell relaxation, inhibition of smooth muscle cell proliferation, less clotting, and may alter apopotosis.
Smooth Muscle Cell relaxation
Inhibits SMC proliferation
? Apoptosis
Anti-thrombotic

73. Prostenoid Analogue
Inhalational Iloprost (Ventavis®) Approved for WHO Class III, IV patients with PAH
Properties:
Selective pulmonary vasodilator
Vasodilatory potency similar to PGI2
Exerts preferential vasodilation in well- ventilated lung regions
Longer duration of vasodilation than PGI2 (30-90 vs 15 min)

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

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

76. FLOLAN ® (epoprostenol): Synthetic prostenoid
Sodium epoprostenol (Flolan)--short-lived relatively locally acting vasodilator, t1/2 3-5 minutes.
Most potent effect -- cardiac output in patients with PAH
Resting heart rate, mean right atrial pressure, and a marked improvement in survival.
Abrupt cessation can be fatal
Contraindicated in veno-occlusive disease

77. Epoprostenol for PAH Prostacyclin analog
Indication – WHO group I - functional class III, IV
Administration – continuous IV infusion via central venous catheter
Dosage – ng/kg/min
Storage – must keep medication cold with ice packs (stable for 8 hours at room temp)
CADD pump
Central line
Epoprostenol has a short half-life (3–5 minutes) and a rapid onset of action, reaching plasma steady-state concentrations within 15 minutes. It is stable at room temperature for only 8 hours after dissolved in buffer. Direct vasodilatation and inhibition of platelet aggregation are two major actions of epoprostenol. 77

78. Epoprostenol vs. Conventional Therapy for IPAH Patient Survival
Epoprostenol (N = 41)
100 80 60 40 20
P = 0.003
Conventional therapy (N = 40)
Patient Survival (%)
LO: This slide to replace her slide 8. Content is the same.
NOTE: Only PAH clinical study to demonstrate a patient survival benefit
Epoprostenol vs. Conventional Therapy in IPAH: Survival
Epoprostenol therapy added to conventional therapy resulted in improvements in symptoms, hemodynamics and survival.
Eight patients died in the 12 week study period, and all were on conventional therapy only (p = 0.003).
Performance of the six-minute walk at baseline was an independent predictor of survival (p < 0.05). However, survival remained significantly improved in the epoprostenol group after adjustment for that variable (p < 0.002).
Survival also remained significantly improved in the epoprostenol group (p < 0.001) after adjustment for the changes in stroke volume and in systemic vascular resistance in response to the short-term infusion of epoprostenol (the only significant differences between the groups). 2 4 6 8 12 10
Weeks
Barst, et al. N Engl J Med. 1996;334: 78

79. Subcutaneous Treprostinil (Remodulin )
SQ administration
Longer half-life than epoprostenol
Pre-mixed
Stable at room temperature

80. Treprostinil SC for PAH Change in 6-MWD (from Baseline to Week 12)5 10 15 20 25 30 35 40
36.1
P = 0.03 20
Change from Baseline (meters)
3.3
1.4
Subcutaneous Treprostinil in PAH: 6MWD Change vs Dose (week 12)
This 12 week, double-blind, placebo-controlled multicenter trial in 470 patients with PAH by Simonneau evaluated the improvement in exercise capacity associated with SQ infusions of treprostinil.
6MW scores improved with treprostinil therapy, and was unchanged with placebo. The between treatment group difference in median six-minute walking distance was 16 meters (p = 0.006).
The most common adverse events were: infusion site pain, infusion site reactions, infusion site bleeding/bruising, headache, diarrhea, nausea, rash, and jaw pain.
The most benefit is at the highest doses, so if subcutaneous treprostinil is to be used, the dose should be aggressively titrated.
< 5.0
ng/kg/min
ng/kg/min
8.2 – 13.8 ng/kg/min
> ng/kg/min
Simonneau, et al. Am J Respir Crit Care Med. 2002;165:800-4. 80

81. Administration of Treprostinil
Subcutaneous Administration
Continuous infusion using ambulatory pump designed for SC infusions
Self-inserted SC catheter
Store at room temperature
Change medication every 48 hours (half-life > 4 hours)
Limitations
Requires capable patient
Possible pain (~ 85% of patients), erythema, and induration at infusion site
Mixed results with treatments for pain (ice or heat, capsaicin, lidocaine patches, collagenase, NSAIDs, gabapentin, pregabalin, transdermal gels, low-dose narcotics)
Mini-Med
CADDms3
LO: Reworked her slide 16, basically same content.
Infusion site reaction 81

82. Which treatment is better ?

83. Route of Administration
Comparison of Agents
Agent
Route of Administration
Adverse Events
Epoprostenol
Continuous IV infusion
Headache, jaw pain, flushing, nausea, diarrhea, skin rash, musculoskeletal pain
Iloprost
Inhalation
Headache, cough, flushing, jaw pain
Treprostinil
» Subcutaneous
» IV
» Inhalation*
» Pain and erythema at injection site, headache, nausea, diarrhea, rash
» Headache, jaw pain, flushing, nausea, diarrhea, skin rash, musculoskeletal pain
» Cough, headache, flushing, throat irritation, nausea
Bosentan
Oral
Hepatotoxicity (LFT elevation ≥ 3x ULN ~ 11%), peripheral edema, anemia
Ambrisentan
Hepatotoxicity (LFT elevation ≥ 3x ULN ~ 2.8%), peripheral edema
Sildenafil
Headache, flushing, dyspepsia, epistaxis
Tadalafil
Headache, dyspepsia, back pain, myalgia, flushing
The table compares the individual agents in terms of route of administration used and adverse events reported. Epoprostenol is administered via continuous IV infusion. Iloprost is administered via inhalation (ultrasonic nebulizer). Treprostinil can be delivered subcutaneously, intravenously, or through inhalation. Adverse events common to these three agents include headache, jaw pain, and flushing. Injection site reactions are also possible for epoprostenol and treprostinil IV. Bosentan and ambrisentan are both administered orally. Bosentan has a greater incidence of LFT elevation compared to ambrisentan. Peripheral edema has been reported with both medications. Sildenafil and tadalafil are both administered orally. Headache, flushing, and dyspepsia have been reported with both agents.
Adapted from McLaughlin, et al. J Am Coll Cardiol. 2009;53: *Benza, et al. ATS. San Diego, CA. May 15-20, 2009.

84. ESC guidelines for PAH , Eur Heart J 2009;30: 2498-2537

85. How do I evaluate the efficacy ?

86. Parameters using in evaluation for treatment efficacy
6 minute-walking distance (MWD)
Cardiopulmonary exercising testing
Peak oxygen uptake (V’O2)
Hemodynamics
Cardiac index
Right atrial pressure
Biomarkers
B-type natriuretic peptide (BNP)
N-terminal pro-BNP

87. 2006/04/10 Bosentan 62.5mg bid Symptom improved post 2 dose
Keep treatment and F/U liver function one month later (GOT/GPT: 48/55)
Bosentan 125 mg bid 1 month later

88. 2007/03/21 Dilated RA,RV. RV hypertrophy Adequate LV performance.
Moderate TR with Pul.HTN<systolic PAP= 81mmHg>
Dilated PA with PR.

89. 2009 Function Class: IV -> I BNP: 52.9 pg/ml
Radionuclide ventriculography :Right ventricular Ejection Fraction: 72 % (normal range 45~70%)

90. CXR
C/T ratio: 53 %

92. But………. The patient suffered from progressive dyspnea since 2010/06
Syncope (+)
Screening cardiac echo
Estimated PAP > 200 mmHg
Admitted to ICU on 2010/07/02

93. Critical PAH Patient
Cardiac arrest occurs frequently in critically ill patients with severe PAH.
Survival 90 days post-cardiac arrest was only 6 percent.

94. PH and RV Failure: The Downward Spiral
RVEDP
HYPOTENSION
Adaptation of Price lC et al. Crit Care. 2010;14:R169

95. Management Principles
Optimal volume status: avoid filling if RV volume overload, diuretics if necessary
Augment CO
Reduce PVR :
a) use pulmonary vasodilators
b)treat reversible factors that may increase PVR
Maintain adequate systemic pressure: Keep PVR well below SVR; use pressors if necessary

96. Course of hospitalization
ICU
Milrinone infusion
Diuretics for symptom
Bosentan 125mg bid po
Iloprost 5 mg q4h inhalation
Sildenafil 25mg tid po
Symptom improved gradually
Shift iloprost to prn use
Discharge on 2010/07/13
Bosentan 125mg bid + Sildenafil 25 mg tid + iloprost 5mg inhalation prn

97. Adaptation of Price lC et al. Crit Care. 2010;14:R169
Mechanical Devices
Devices
indication
Comments
RV-assist devices
Used in primary RV dysfunction and have been used with coexisting PH
Pulsatile devices may cause pulmonary microcirculatory damage in PH . A pumpless "lung assist" device has been used in patients bridging to transplant.
Extracorporeal membrane oxygenation
Used in severe PH as a bridge to lung transplant and after endarterectomy or massive PE.
Intraaortic balloon counterpulsation
Used for RV failure after CPB and transplantation
Improves CO by augmenting left coronary flow rather than by direct RV effects
Adaptation of Price lC et al. Crit Care. 2010;14:R169 97

98. Case 55 y/o male Progressive dyspnea, leg edema and hypotension
Pulmonary hypertension was noted
Transfer to CCU under the impression of PAH with right heart failure complicated with shock and multiple organ failure

99. Case 2se 11/21 Levophd Primacor 11/25 illoprast 11/27 ECMO CVVHD 11/30
Revatio
12/07
Remove ECMO
12/12
Stop CVVHD
1/25
Discharge
BP:89/65
sPA:90
BNP:721
Urine:1600
BP:56/46
sPA:90
Urine:115
BP:97/55
BP:127/73
Crea:1.21
ALT:33
Urine:345
BP:122/65
sPA:55
BNP:183
Crea:0.96
Urine:2935
BP:110/70
BNP:152
Crea:0.5
Urine:2060

100. Goal-Directed Therapy
Diagnosis of PAH
vasoreactivity test negative
Baseline exam and 3-6 monthly re-evaluation to assess treatment goals
(Clinically stable, functional class II, 6-MWD > 400 meters, RAP/CI normal)
Treatment goals NOT met
Treatment goals met
Start ERA or PDE-I
Continue treatment
Add ERA or PDE-I
Continue treatment
LO: Editing and other changes to slide. This is similar to a slide we had in the source deck. I merged the two slides. She adapted information from the Hoeper article, so I noted that in the citation.
Parenteral PA and/or enrollment in clinical trials
Continue treatment
Urgent lung transplantation
Adapted from: Hoeper, et al. Eur Respir J. 2005;26:

101. Improved Patient Survival With Goal-Directed Therapy
1.0
Treatment group
( )
0.8
Historical control group
( )
0.6
Cumulative Patient Survival
Expected survival
0.4
P = Treatment Vs. historical
P < Treatment Vs. expected
0.2 6 12 18 24 30 36
Months
Patients at risk (N) 89 67 83 64 69 47 61 38 46 31 43 23 37 20
Treatment group
Historical control group
Hoeper, et al. Eur Respir J. 2005;26:

102. Combination therapy: frequently utilised strategy in PAH treatment
2017/4/8
Combination therapy: frequently utilised strategy in PAH treatment
Background therapy only (8%)
Triple combination (9%)
Monotherapy (47%):
13% bosentan\ambrisenten
13% sildenafil
8% epoprostenol
2% sitaxentan
4% calcium channel blocker
Dual combination (36%):
Key message: Because of the challenges in PAH, combination therapy is frequently and increasingly being used to treat the disease.
8% bosentan and sildenafil
3% bosentan and epoprostenol
3% bosentan and iloprost
8% epoprostenol and sildenafil
2% sildenafil and iloprost
Reference
McGoon MD, Barst RJ, Doyle RL, et al. Reveal registry: treatment history and treatment at baseline. Chest 2007; 132: 631S (Abstract).
Patients with PAH
n=1226
McGoon, et al. Chest 2007; 132: 631S

103. NCKUH

104. Bosentan + Sildenafil Patients Dosing Results P Mathai et al. 45
B 125 mg bid + S mg tid
6 MWD + 46 m
NYHA improved in 5 of 13
0.05 NS
Hoper et al. 9
B 125 mg bid +S 25-50mg tid
6MWD +115 m
VO2 max +3.4 ml/min/kg
<0.007
0.006
European
4996
Bosentan vs bosentan+sildenafil
Safety reports were similar
Early trial 29
S + B
vs S + Placebo
Lower PVR 20.4%
6MWD +17M
<0.05
0.855

105. Bosentan + Prostacyclin
Combination
Patients
Result p
Hoper et al
Bosentan+iloprost/beraprost 20
6 MWD +45 M
<0.05
Channick et al.
Bosentan+treprostinil ih 11
6MWD +67M
PAP-10%
PVR-26%
0.01
0.041
0.052
Benza RL et al.
SC remodulin + Bosentan 19
6 MWD
Brog dyspnea
PAP
0.001
0.02
<0.001
BREATH-2
Bosentan + Epo 33
PVR: 36 % vs 23 % NS
STEP
Bosentan+ iloprost 67
6MWD
Delayed TCW
0.051
0.022

106. Prostacyclin+ PDE inhibitors
Combination
Patients
Result p
Ghofrani et al
Iloprost+sildenafil 14
6 MWD +90 M
0.002
Goberg-Matiland M et al.
Treprostinil sc + sildenafil
TET time +42%
0.049
Ruiz MJ et al.
Prostanoids+ sildenafil 20
6 MWD+79m (1 year)
MWD +105m (2years)
NYHA improved
<0.005
Simonneau G et al.
Epo+sildenafil
267
6MWD+26M TCW delay
0.0088
0.012

107. CASE 3
38 y/o male
IPAH was diagnosed at 2008/8
Bosentan used since 2008/8/19
Add Iloprost since 2010/4/16

108. 6 minute walk test 2008/08/19 Bosentan 2010/4/16 Iloprost 375m 378m

109. 2011
RA： 18
RV： 52/24
PA： 54/46/39
PCWP： 9
Cardiac output: 2.46 L/min
PVR： 15 woods
2008
RA:22
RV:55/32
PA:60/56/53
PCW: 15
Cardiac output: 6.7 L/min
PVR: 6.1 woods

110. Application Remodulin (2011/10/8)
Discuss with patient about lung transplant evaluation

111. Remodulin daily record
Dose
Blood pressure
Site pain
Jaw pain
Diarrea
Headache
BNP
NT-pro BNP
Day 1
2ng/kg/min
108/66 -
320
1890
Day 2
4ng/kg/min
108/64 2
Day 3
6ng/kg/min
97/58
3-4
256
1124
Day 4
8ng/kg/min
104/59 5
Day 5
10ng/kg/min
107/67
Day 6
12ng/kg/min
99/57
5-7
Day 7
14ng/kg/min
93/57 6
197
1214
Day 8
16ng/kg/min
94/63
Day 9
89/54
Day 10
97/56
Day 11
94/58
6-8
Day 12
95/59
191
Day 13
94/59
2-3
mild
Day 14
96/80

112. 3 month later NYHA Fc III =>II
6 minute walk distance: 347 m ( increase 28.5 %)

113. Surgical Therapy
Transplantation - lung / heart-lung
Reserved for patients who continue to deteriorate with poor QOL despite aggressive pharmacologic therapy
1 year survival %
5 year survival %

114. Team work is necessary !!

115. NCKUH Team Members
PAH- specific Cardiologist (PAH clinic, 24 hr on call)
Special nurse (24 hr on call)
Radiologist
Pharmacist
Dietician
Critical care team (24 hr on call)
ECMO team (24 hr on call)
Lung transplant team
Lab

116. Core member training
Whole member
training
Multiple center
education program

117. How about the next five year ?

118. Investigational Treatments for PAH
Targeted Mechanism
Investigational Agents
Prostacyclin Pathway
Iloprost
Treprostinil
Beraprost
Selexipeg
Endothelin Pathway
Macisentan
Nitric Oxide Pathway
Riociguat
Cicletanine
Growth Factors Signaling
Imatinib
Sorafenib
Aviptadil (Vasoactive intestinal peptide)
Cell Therapy
Progenitor cells combined with gene therapy

119. Future Directions in PAH: Potential New Therapeutic Targets
Tyrosine kinase/growth factor receptor inhibitors (imatinib, sorafenib, nilotinib)
Vasoactive intestinal peptide (VIP) (aviptadil)
Serotonin transporter agonists
Tissue-targeting ERA (macitentan)
Non-prostanoid IP receptor antagonist (selexipag)
Adrenomedullin
Rho-kinase inhibitors
Nitric oxide enhancement (cicletanine)
Soluble guanylate cyclase stimulator (riociguat)
ECE/NEP inhibitor (daglutril)
Monoclonal antibody to CD20 (rituximab)
Endothelial progenitor cells
Gene therapy (vectors expressing prostacyclin synthase, endothelial NOS, or vascular endothelial growth factor )

120. A cure for PAH ---is only a matter of time