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
What is PH ? What is PAH ?
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
1. Pulmonary arterial hypertension
• 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
Dana Point 2008
Pulmonary Arterial Hypertension Diagnostic Classification
2. PH with left heart disease • 2.1 Systolic dysfunction • 2.2 Diastolic dysfunction 2.3 Valvular disease
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.
Definition of PAH by WHO
Mean PAP > 25mmHg at rest
PAWP < 15 mmHg
What do we face ?
Rare Miss diagnosis Rapid progress Poor prognosis
Really rare ? Or Under diagnosis?
Prevalence of PAH
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 theUSA, 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)
Humbert, et al. Am J Resp Crit Care Med 2006; 173: 1023–30 Peacock. BMJ 2003; 326: 835–6 Link J. Chest 2011; 139:497-504.Gomberg-Maitland M. Chest 2011;139:482-483
Prevalence of PAH in Associated Conditions
Associated Condition Prevalence of PAHSystemic sclerosis 7-12 %
HIV infection 0.46-0.5 %
Portal hypertension 2-6 %
Congenital heart disease 1.6-12.5 per million in those with congenital systemic-to-pulmonary shunts → 25-50 % affected by Eisenmenger syndrome
Schistosomiasis 4.6 % in those with hepatosplenic disease
Chronic hemolytic anemia Highly variable; currently being studied
Simonneau, et al. J Am Coll Cardiol. 2009;54(1):S43-54.Simonneau, et al. J Am Coll Cardiol. 2009;54(1):S43-54.
NORMAL REVERSIBLE DISEASE IRREVERSIBLE DISEASE
Pathogenesis of Pulmonary ArterialPathogenesis of Pulmonary ArterialHypertensionHypertension
PAH: Pathophysiology
Pulmonary vessel
remodeling
Pulmonary vascular
resistance increase
RV remodeling
RV dysfunction
Do we have a luxury time ?
IPreclinical /
no symptoms
IISymptomatic /
stable
IIIProgression /
declining
Pulm. pressure
Cardiac outputLev
el
Time
Years Months
Therapeutic window
PAH: a rapidly evolving disease
RV function
Severity of Pulmonary Hypertension
Degree of disease
– Mild
– Moderate
– Severe
Mean PAP (mmHg)
– 25 - 40
– 41 - 55
– >55
NYHA/WHO classification of functional status
Class Description
IPatients 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
IIPatients 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
IIIPatients 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
1. Barst RJ et al. J Am Coll Cardiol 2004 16; 43 (12 Suppl S): 40S–47S
Brenot F. Chest 1994; 105: 33S–36S
0 12 24 36 48 60 72 84 960
25
50
75
100
WHO class I – II (n = 30)
WHO class III – IV (n = 75)
Months
Su
rviv
al (
%)
Early diagnosis of PAH and early intervention improves survival prospects
PAH progresses rapidly if left untreated... even in mildly symptomatic disease
Prognosis of Pulmonary Hypertension
Survival years
Early diagnosis is important, but is it easy ?
24%
63%
12%
1%0%
10%
20%
30%
40%
50%
60%
70%
80%
Class I Class II Class III Class IV
n = 674
Humbert M, et al. Am J Resp Crit Care Med 2006; 173: 1023–30
PAH is still often diagnosed late:French National Registry 2002–2003
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 )
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
Progressive Dyspnea Pedal edema Non-productive
Cough Fatigue Syncope Chest Pain
85%
30% 19% 13% 12% 7%
SuspectPAH: Clinical Presentation
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
How to I know the patient really got PAH?
Diagnosis of PAH: a four-stage process
Galiè N et al Eur Heart J 2004; 25: 2243–2278
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 Dopplerechocardiography
•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)
Case2006/03/11
21 y/o female Dyspnea and fatigue for about several
months Visited LMD for help but in vain Condition get worse and worse----
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
Electrocardiography
Sinus tachycardia
RAD
RVH
CXR
Cardiomegaly C/T ratio: 0.59 Dilated pulmonary trunk
Echocardiography
Dilated RA,RV. RV hypertrophy Adequate LV performance. Moderate to severe TR with
Pul.HTN <systolic PAP= 140mmHg>
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
Chest CT
Dilated pulmonary trunk and pulmonary artery
No evidence of pulmonary embolism
No evidence of lung disease
TEE: No congenital heart disease Autoimmune screen: Normal HIV: Negative Pregnancy test : Negative
Diagnosis
Primary pulmonary hypertension was impressed. (WHO FC IV)
How long do I have ? How can I do ?
Could you help me ?
How can your patient do ?
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)
Could we help patient ?
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
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}
Diuretics
Treat edema May need combine therapy
Anticoagulation
Studies only show benefit in iPAH patients Other PAH groups not as clear Aim for INR 2-2.5 Benefit thought to be Reduction of in-situ thrombosis Reduction DVT risk in low CO status
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
Humbert M, et al. NEJM 2004; 351:1425-36.
FDA-Approved Agents for theTreatment of PAH
Prostacyclin analogs (PA)– Epoprostenol– Iloprost– Treprostinil
Endothelin-receptor antagonists (ERA)– Bosentan– Ambrisentan
Phosphodiesterase-5 inhibitors (PDE-I)– Sildenafil– Tadalafil
Endothelin Receptor Antagonist(ERA)
Endothelin is increased in IPAH and PAH associated with other Diseases
Stewart et al., Ann Inter Med,1991 Vancheeswaran et al., J. Rheum, 1994 Yoshibayashi et al., Circulation, 1991
Congenital Heart Disease
Non-PH PH0
1
2
3
4
5 P<0.001
Del
ta E
T-L
I (P
V-R
V)
(pg/
ml)
IPAH
IrE
T-1
(pg
/ml)
Non-PPH PPH0
2
4
6
8
10
Scleroderma
Con
cent
ratio
n of
ET
-1(p
g/m
l)
4
6
8
10
LcSSc PAH
LcSSc Non-PAH
P<0.05P<0.001
Endothelin is a Key Pathogenic Mediator*
Clozel. Ann Med. 2003
*Based on observations reported from in-vitro, in-vivo, or animal models. The clinical significance in humans is unknown.
Proliferation Vascular Smooth Muscle
Fibroblasts
Fibrosis Fibroblast Proliferation
Extracellular Matrix Proteins Collagenase Production
Inflammation Vascular Permeability
Neutrophil / Mast Cell Activation Promotes Cellular Adhesion
Cytokine Production
Hypertrophy Cardiac/Vascular
Vasoconstriction Direct Or Via Facilitation Of
Other Vasoconstrictor Systems (Renin
Angiotensin System, Sympathetic)ET
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
62.5 mg bid 125 or 250 mg bid Bosentan
-40
-20
0
20
40
60
80
Bosentan (N = 144)
Placebo (N = 69)
Baseline Week 4 Week 8 Week 16
P = 0.0002
Cha
nge
from
Bas
elin
e (m
eter
s)
Rubin, et al. N Engl J Med. 2002;346:896-903.
Bosentan for PAH:BREATHE Clinical Trial
Change in 6-MWD (from Baseline to Week 16)
Long-term outcomes on bosentan
Event rate/year (exponential): 5.5%
0 6 12 18 24 30 36 Time (Months )
169 167 163 153 113 23 16 Patients at risk
0
10
20
30
40
50
60
70
80
90
100
Cu
mu
lati
ve S
urv
ival
(%
)
Predicted (NIH)
Bosentan
69%57%
48%
96% 89% 86%
McLaughlin VV et al. Eur Respir J. 2005;25:244-249.
85% and 70% were on bosentan monotherapy at 12 and 24 mos, respectively
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 < 0.0001)• 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
Galie, et al. Lancet. 2008.371(9630):2093-100.Valerio et al. Vasc Health Risk Manag. 2009;5:607-19.
Bosentan for PAH:EARLY Clinical Trial
Change in PVR (from Baseline to Week 24)
Galie, et al. Lancet. 2008.371(9630):2093-100.Valerio et al. Vasc Health Risk Manag. 2009;5:607-19.
% o
f B
asel
ine
PV
R a
t W
eek
24(g
eom
etric
me
ans)
P < 0.0001
Decrease in PVR:Surrogate marker for
delaying disease progression
Treatment effect =- 22.6%
Treatment effect =- 22.6%
Bosentan for PAH:EARLY Clinical Trial
10
5
0
5
10
15
20
12 24 weeks
Placebo (N= 91)
Bosentan (N= 86)P = 0.076
25
20
15
Change in 6-MWD (from Baseline to Week 24)
Treatment effect =+ 19.1 meters
Treatment effect =+ 19.1 meters
Cha
nge
in 6
-MW
D (
met
ers)
Galie, et al. Lancet. 2008.371(9630):2093-100.Valerio et al. Vasc Health Risk Manag. 2009;5:607-19.
11.2
- 7.9
weeks
Bosentan for PAH:EARLY Clinical Trial
100
80
60
40
20
00 4 8 12 16 20 2824 32
92 90 89 86 84 83 1877 993 92 87 85 84 83 2780 15
Eve
nt-
Fre
e P
atie
nts
(%
)
Patients at risk (N)
Placebo
Bosentan
P < 0.02
Time to Clinical Worsening (from Baseline to Week 32)
weeksweeks
Galie, et al. Lancet. 2008.371(9630):2093-100.Valerio et al. Vasc Health Risk Manag. 2009;5:607-19.
NTUH data
Bosentan have benefit effects on functional status, exercise capacity, right heart function and pulmonary function.
Respiratory Medicine 2007
Ambrisentan for PAH
Endothelin receptor antagonist (ETA selective)
Indication – WHO group I - functional class II, III
Dosage – 5 mg and 10 mg oral daily
Ambrisentan for PAH
Galie, et al. Circulation. 2008;117:3010-9.
-25
0
25
50
4 8 12 weeks
10 mg:+43.6 m
5 mg:+22.8 m
Placebo:-7.8 m
N = 202
4 8 12 weeks
5 mg:+49.4 m
2.5 mg+22.2 m
Placebo:-10.1 m
-20
0
20
40
60N = 192
Cha
nge
from
Bas
elin
e (m
eter
s)
ARIES 1 ARIES 2
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
Change in 6-MWD (from Baseline to Week 12)
Endothelin Receptor AntagonistsComparison of Agents
Source: FDA-approved product labeling for individual agents. Source: FDA-approved product labeling for individual agents.
Bosentan Ambrisentan
Use in pregnancy
Pregnancy category X (non-hormonal birth control method required)
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
Endothelin Receptor AntagonistsComparison of Drug-Drug Interactions
Source: FDA-approved product labeling for individual agents. 1) Barst, et al. J Am Coll Cardiol. 2009;54:S78-84. 2) Galie, et al. Eur Heart J. 2009;30:2493-2537. 3) Spence, et al. ATS. San Diego, CA.
May 15-20, 2009. 4) Harrison, et al. ATS. San Diego, CA. May 15-20, 2009.
Source: FDA-approved product labeling for individual agents. 1) Barst, et al. J Am Coll Cardiol. 2009;54:S78-84. 2) Galie, et al. Eur Heart J. 2009;30:2493-2537. 3) Spence, et al. ATS. San Diego, CA.
May 15-20, 2009. 4) Harrison, et al. ATS. San Diego, CA. May 15-20, 2009.
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
Ritonavir
Rifampin
Cyclosporine A
Hormonal contraceptives3
Omeprazole4
Ketoconazole2,4
Phosphodiesterase-5 inhibitors (PDE5-I)
Sildenafil (Viagra, Revatio)
HypertensionHypertension
19819855 AnginaAngina
19891989
EEDD
19921992 19981998
PAHPAH
L-Arginine Nitricoxide
cGMP Lowers PA
pressure
eNOS
GMP
PDE-5PDE-5I
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
Wharton J et al. Am J Respir Crit Care Med. 2005;172:105-113.
Nitric Oxide/ PDE-5 Inhibitors Increase cGMP
SUPER-1 study
REV-EM-0807001
REV-EM-0807001
Phosphodiesterase-5 InhibitorsComparison of Drug-Drug Interactions
Sildenafil TadalafilNitrates
Alpha blockers
Amlodipine
Ritonavir
Bosentan1
HMG CoA reductase inhibitors1
Phenytoin1
Erythromycin1
Ketoconazole1
Cimetidine1
Rifampin1
Phenobarbital1
Carbamazepine1
Nitrates
Alpha blockers
Antihypertensive agents
Ketoconazole
Rifampin
Ritonavir
Bosentan1
Source: FDA-approved product labeling for individual agents. 1) Galie, et al. Eur Heart J. 2009;30:2493-2537.Source: FDA-approved product labeling for individual agents. 1) Galie, et al. Eur Heart J. 2009;30:2493-2537.
PROSTENOIDS
SMC IP
PGI2PGI2
Smooth Muscle Cell relaxation
Inhibits SMC proliferation
? Apoptosis
Anti-thrombotic
GSGS
Adenylate cyclaseAdenylate cyclasecATPcATP
cAMPcAMP
Prostacyclins
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)
Prostenoid Analogue
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
Iloprost for PAHComposite Primary Endpoint at Week 12
Olschewski, et al. N Engl J Med. 2002;347:322-9.
Res
pond
ers
(% P
atie
nts)
P = 0.0033
N = 203
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
CADD pump Central line
Epoprostenol for PAH
Prostacyclin analog Indication – WHO group I
- functional class III, IV Administration –
continuous IV infusion via central venous catheter
Dosage – 20-40 ng/kg/min
Storage – must keep medication cold with ice packs (stable for 8 hours at room temp)
100
80
60
40
20
0Weeks
Epoprostenol (N = 41)
0 2 4 6 8 1210
Conventional therapy (N = 40)
Pat
ient
Sur
viva
l (%
)
P = 0.003P = 0.003
Barst, et al. N Engl J Med. 1996;334:296-301.
Epoprostenol vs. Conventional Therapy for IPAHPatient Survival
Subcutaneous Treprostinil(Remodulin )
•SQ administration•Longer half-life than epoprostenol•Pre-mixed•Stable at room temperature
Treprostinil SC for PAH
Change in 6-MWD (from Baseline to Week 12)
0
5
10
15
20
25
30
35
40
< 5.0ng/kg/min
5.0 - 8.1ng/kg/min
8.2 – 13.8ng/kg/min
> 13.8 ng/kg/min
3.31.4
20
36.1
Cha
nge
from
Bas
elin
e (m
eter
s)
P = 0.03
Simonneau, et al. Am J Respir Crit Care Med. 2002;165:800-4.
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
Infusion site reaction
Which treatment is better ?
Comparison of Agents
AgentRoute 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 Oral Hepatotoxicity (LFT elevation ≥ 3x ULN ~ 2.8%), peripheral edema
Sildenafil Oral Headache, flushing, dyspepsia, epistaxis
Tadalafil Oral Headache, dyspepsia, back pain, myalgia, flushing
Adapted from McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573-1619. *Benza, et al. ATS. San Diego, CA. May 15-20, 2009.
Adapted from McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573-1619. *Benza, et al. ATS. San Diego, CA. May 15-20, 2009.
ESC guidelines for PAH , Eur Heart J 2009;30: 2498-2537
How do I evaluate the efficacy ?
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
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
2007/03/21
Dilated RA,RV. RV hypertrophy Adequate LV performance. Moderate TR with
Pul.HTN<systolic PAP= 81mmHg>
Dilated PA with PR.
2009
Function Class: IV -> I BNP: 52.9 pg/ml Radionuclide ventriculography :Right ventricular
Ejection Fraction: 72 % (normal range 45~70%)
CXR
C/T ratio: 53 %
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
Critical PAH Patient
Cardiac arrest occurs frequently in critically ill patients with severe PAH.
Survival 90 days post-cardiac arrest was only 6 percent.
PH and RV Failure: The Downward Spiral
Adaptation of Price lC et al. Crit Care. 2010;14:R169
HYPOTENSION
RVEDP
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
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
Mechanical Devices
Devices indication CommentsRV-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
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
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
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
Add ERA or PDE-I
Parenteral PA and/or enrollment in clinical trials
Urgent lung transplantation
Continue treatment
Continue treatment
Continue treatment
Goal-Directed Therapy
Adapted from: Hoeper, et al. Eur Respir J. 2005;26:858-63.
Improved Patient Survival With Goal-Directed Therapy
Hoeper, et al. Eur Respir J. 2005;26:858-63.
Cum
ulat
ive
Pat
ient
Sur
viva
l
1.0
0.8
0.6
0.4
0.2
0 6 12 18 24 30 36 Months
Patients at risk (N)
Treatment group
Historical control group
Treatment group(2002 -2004)
Historical control group(1999 -2001)
Expected survival
89
67
83
64
69
47
61
38
46
31
43
23
37
20
P = 0.011 Treatment Vs. historicalP < 0.001 Treatment Vs. expected
Combination therapy: frequently utilised strategy in PAH treatment
Monotherapy (47%):• 13% bosentan\ambrisenten• 13% sildenafil• 8% epoprostenol• 2% sitaxentan• 4% calcium channel blocker
Dual combination (36%):
Background therapy only (8%)
Triple combination (9%)
McGoon, et al. Chest 2007; 132: 631S
Patients with PAH
n=1226
NCKUH
Bosentan + Sildenafil
Patients Dosing Results P
Mathai et al. 45 B 125 mg bid + S 20-100mg tid
6 MWD + 46 m NYHA improved in 5 of 13
0.05NS
Hoper et al. 9 B 125 mg bid +S 25-50mg tid
6MWD +115 mVO2 max +3.4 ml/min/kg
<0.0070.006
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
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 +67MPAP-10%PVR-26%
0.010.0410.052
Benza RL et al.
SC remodulin + Bosentan
19 6 MWDBrog dyspneaPAP
0.0010.02<0.001
BREATH-2 Bosentan + Epo
33 PVR: 36 % vs 23 %
NS
STEP Bosentan+ iloprost
67 6MWDDelayed TCW
0.0510.022
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
0.00880.012
CASE 3
38 y/o maleIPAH was diagnosed at 2008/8Bosentan used since
2008/8/19Add Iloprost since 2010/4/16
6 minute walk test 6 minute walk test
2008/08/19 Bosentan375m 378m
350m
2010/4/16 Iloprost
320m
270m
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
Application Remodulin (2011/10/8) Discuss with patient about lung
transplant evaluation
Remodulin daily recordRemodulin daily record
DoseBlood pressure
Site pain
Jaw pain
DiarreaHeadache
BNP NT-pro BNP
Day 1 2ng/kg/min 108/66 0 - - - 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 5 - - -
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 6 - - -
Day 9 16ng/kg/min 89/54 6 - - -
Day 10 16ng/kg/min 97/56 6 - - -
Day 11 16ng/kg/min 94/58 6-8 - - -
Day 12 16ng/kg/min 95/59 6 - - - 191
Day 13 16ng/kg/min 94/59 2-3 mild - -
Day 14 16ng/kg/min 96/80 5 mild - -
3 month later
NYHA Fc III =>II 6 minute walk distance: 347 m ( increase
28.5 %)
Surgical Therapy
Transplantation - lung / heart-lung
• Reserved for patients who continue to
deteriorate with poor QOL despite
aggressive pharmacologic therapy
• 1 year survival - 65-70%
• 5 year survival - 40-50%
Team work is necessary !!
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
Core member training
Whole member training
Multiple centereducation program
How about the next five
year ?
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
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 )
A cure for PAH ---is only a matter of time