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Learning Objectives
• Utilize knowledge regarding the specific disease pathways for
PAH in order to identify the sites and targets for common
therapies, including prostacyclin analogs, endothelin receptor
antagonists, and phosphodiesterase-5 inhibitors.
• Evaluate patients for comorbid conditions to determine the
relative risk for PAH.
• Use evidence-based guidelines to select the most appropriate
treatment.
• Apply determinants of risk to assess a patient’s prognosis
and recognize when therapy needs to be augmented.
• Compare the side effect profiles and drug interaction potential
of available PAH treatments to gauge the risk-benefit ratio of
each option and to determine areas for patient monitoring.
Overview of PAH
• US prevalence = estimates up to 50,000 to
100,000
– 15,000 to 25,000 diagnosed and treated
• Disease of small pulmonary arteries
characterized by vascular narrowing and
increased vascular resistance
– Vasoconstriction
– Cell proliferation and pulmonary vascular remodeling
– Thrombosis in situ
• Common cause of death:
Right ventricular (RV) failure
Humbert, et al. J Am Coll Cardiol. 2004;43:13S-24S.
Mechanisms of Pathology for PAH
Endothelin pathway
Prostacyclin pathway
Nitric oxide pathway
Endothelial
cells
Preproendothelin
L-arginine
Proendothelin
Arachidonic acid
Prostaglandin I2
NOS
Endothelinreceptor A
Nitric oxide
Endothelin-1
Endothelinreceptor B
Exogenous
nitric oxide
cGMP
Endothelinreceptor
antagonists
Prostaglandin I2
Phosphodiesterase type
5
Vasodilatation and
antiproliferation
Vasoconstriction and
proliferation
Phosphodiesterase
type 5 inhibitor
Humbert, et al. N Engl J Med. 2004;351:1425-1436.
cAMP
Prostacyclin
derivates
Vasodilatation and
antiproliferation
Pathophysiology of PAH
Genetic
Predisposition
Other Risk
Factors
(CTD, CHD, toxins, etc.)
Altered Pathways
And Mediators
}
Vasoconstriction
Cell Proliferation
Thrombosis
Vascular
Remodeling
Genetic Mutations in PAH
• Mutations in the gene that codes
for BMPR2
– BMPR2 mutations are
identified in ~ 70% of patients
with heritable PAH
– BMPR2 mutations are also
found in ~ 20% of patients
with I-PAH
» Clinical course – poor response
to acute vasodilator testing and
treatment with calcium channel
blockers
Machado, et al. J Am Coll Cardiol. 2009;54:S32-42.
• Mutations in the gene that codes
for:
– Activin receptor-like kinase type
1 (ALK1)
– Endoglin (ENG)
» Cause hereditary hemorrhagic
telangiectasia (HHT) and may
lead to the development of PAH
Vasoconstriction in PAH
Vasoconstriction
Vasodilation
Impaired Vasodilation
↓ Prostacyclin
↓ Nitric oxide
↓ Nitric oxide synthase
Enhanced Vasoconstriction
↑ Endothelin
↑ Serotonin (5-HT)
↑ Thromboxane
↓ Potassium channel
expression/activity
Cell Proliferation in PAH
High PVR
• Proliferative / angiogenic / apoptosis resistant
– ↑ Endothelin, serotonin (5-HT), VEGF, BMPR2 and ALK1
mutations
– ↓ Potassium channel expression/activity
Vascular Remodeling in PAH
•
•
•
•
Poorly understood
PAH cells are pro-proliferative
Many factors implicated in pro-proliferative phenotype
Proliferative and obstructive remodeling of the pulmonary
vessel wall
• Some new therapies aimed at controlling cell growth
• Several potential mediators
– Alterations in gene expression in growth-controlling pathways
– Growth factors
– Inflammatory mediators
Galie, et al. Eur Heart J. 2009;30:2493-2537.
Revised Classification of
Pulmonary Hypertension
Group 1: Pulmonary Arterial Hypertension (PAH)
Criteria
• mPAP ≥ 25 mm Hg
• PCWP  15 mm Hg
• No significant:
– Obstructive/Restrictive lung
disease
– Left heart disease
– Thromboembolic disease
Types
• Idiopathic PAH
• Heritable PAH
– BMPR2, ALK1, Endoglin
• Drug- and toxin-induced
• Associated with:
–
–
–
–
–
–
Connective tissue disease
HIV
Portal pulmonary
Congenital heart diseases
Schistosomiasis
Chronic hemolytic anemia
• Persistent pulmonary
hypertension of the newborn
Simonneau, et al. J Am Coll Cardiol. 2009;54:S43-54.
Differential Diagnosis of PAH
•
•
•
•
•
•
•
•
•
•
•
Clinical presentation
Electrocardiogram (ECG)
Chest radiograph
Pulmonary function tests and arterial blood gases
ECHO (right heart hemodynamics)
Ventilation / perfusion lung scan
High-resolution CT, contrast CT, pulmonary angiography
Cardiac MRI
Blood tests and immunology
Abdominal ultrasound scan
Right heart catheterization and vasoreactivity
Galie, et al. Eur Heart J. 2009;30:2493-2537.
Invasive Diagnostic
Testing for PAH
Right heart catheterization
–
–
–
–
–
Mandatory for all patients being tested for PAH
Pulmonary arterial pressure (PAP)
Cardiac output (CO)
Right atrial pressure (RAP)
Pulmonary arterial wedge pressure (PAWP)
Badesch, et al. J Am Coll Cardiol. 2009;54:S55-66.
Prevalence of PAH in Associated Conditions
4th World Symposium on PH (2008)
Associated Condition
Prevalence of PAH
Systemic 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-topulmonary 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.
Patient Evaluation
Confirm presence of PH
Determine type of PH present (PAH?)
Gauge functional capacity
Estimate prognosis (survival)
Determine treatment and monitoring plan
NYHA/WHO Functional
Classification for PAH
Class I
No limitation of physical activity. Ordinary physical activity does not cause undue
dyspnea, fatigue, chest pain, or near syncope.
Class II
Slight limitation of physical activity; no discomfort at rest. Ordinary activity causes
undue dyspnea, fatigue, chest pain, or near syncope.
Class III
Marked limitation of physical activity; no discomfort at rest. Less than ordinary
physical activity causes undue dyspnea, fatigue, chest pain, or near syncope.
Class IV
Inability to perform any physical activity without symptoms; signs of right ventricular
failure or syncope; dyspnea and/or fatigue may be present at rest; discomfort is
increased by any physical activity.
Taichman, et al. Clin Chest Med. 2007;28:1-22.
Predicting Survival in PAH
• Hemodynamics
• Response to acute vasodilator therapy
(calcium channel blockers, CCB)
• Exercise capacity
• NYHA/WHO functional class
• Biomarkers (i.e., BNP levels)
Badesch, et al. J Am Coll Cardiol. 2009;54:S55-66.
Response to CCB Therapy and
Survival in Patients with PAH
1.0
Long-term CCB responders
(~50% of acute responders
or ≤ 6% of IPAH patients)
Cumulative
Survival
0.8
0.6
P = 0.0007
Long-term CCB non-responders
0.4
0.2
0.0
0
Patients
at risk (N)
2
4
6
8
38
33
30
22
13
19
12
7
4
0
Sitbon, et al. Circulation. 2005;111:3105-11.
10
8
12
3
14
3
16
2
18 Years
1
Long-term CCB
responders
Long-term CCB
non-responders
Impact of Delay in Treatment
on Patient Survival
96%
Event-Free Survival (% Patients)
100
84%
86%
80
Ambrisentan
↑Transition placebo
76%
Placebo Ambrisentan
group to ambrisentan
60
40
20
0
0
N = 251
N = 122
12
242
110
24
226
100
36
209
94
48
52 Weeks
195 Ambrisentan
95 Placebo → Ambrisentan
ABSTRACT: McLaughlin, et al. Am J Respir Crit Care Med. 2008;177:A697.
Goals for Patients with PAH
• Ultimate goals
– Feel better
– Do more
– Live longer
• Gap in understanding →
? Promote vasorelaxation
? Suppress cellular proliferation
? Induce apoptosis within pulmonary artery wall
Archer, et al. N Engl J Med. 2009;361:1864-71.
PAH Evidence-Based Treatment Algorithm
Oral anticoagulants (E/B) – IPAH/HPAH
Diuretics (E/A)
Oxygen (E/A)
Digoxin (E/C)
Supervised rehabilitation (E/B)
Supportive therapy and general measures
Expert referral (E/A)
Avoid excessive physical exertion (E/A)
Birth control (E/A)
Psychosocial support (E/C)
Infection prevention (E/A)
Acute vasoreactivity test (A for IPAH)
(E/C for APAH)
ACUTE RESPONDER
NON-RESPONDER
WHO Class I-IV
Amlodipine, diltiazem,
nifedipine (B)
Strength of
Recommendation
Sustained response
(WHO I-II)
B
A
WHO Class II
Ambrisentan, Bosentan,
Sildenafil
Sitaxsentan, Tadalafil
C
WHO Class III
Ambrisentan, Bosentan,
Epoprostenol IV, Iloprost inh,
Sildenafil
Sitaxsentan, Tadalafil,
Treprostinil SC
Beraprost
Iloprost IV, Treprostinil IV
E/B
YES
NO
E/C
Not approved
Treprostinil inh
Amlodipine, diltiazem,
nifedipine (B)
Iloprost inh
Treprostinil SC
Iloprost IV, Treprostinil IV
Initial combination therapy
(see below)
Ambrisentan, Bosentan,
Sildenafil, Sitaxsentan,
Tadalafil
Treprostinil inh
INADEQUATE CLINICAL RESPONSE
Sequential combination therapy
4th World Symposium on PH. Dana
Point, CA. 2008.
Barst, et al. J Am Coll Cardiol.
2009;54:S78-84.
WHO Class IV
Epoprostenol IV
+ (B)
PDE-5 I
Prostanoids
+ (B)
+ (B)
ERA
INADEQUATE CLINICAL RESPONSE
Atrial septostomy (E/B) and/or
lung transplant (E/A)
Acute Vasoreactivity Test for PAH
• Calcium Channel Blockers (CCB)
– Acute vasoreactive response =
Reduction of mean PAP ≥ 10 mm Hg to reach a mean PAP ≤ 40 mm Hg
with a normalized or increased CO with acute pulmonary vasodilator
challenge with either inhaled NO or IV epoprostenol
– Positive response in < 10% of patients with IPAH
– Responders are on higher than ordinary doses of CCB:
amlodipine 10 mg twice daily; diltiazem 360 mg twice daily
– Moderate recommendation based on scientific evidence
Barst, et al. J Am Coll Cardiol. 2009;54:S78-84.
FDA-Approved Agents for the
Treatment of PAH
• Prostacyclin analogs (PA)
– Epoprostenol
– Iloprost
– Treprostinil
• Endothelin-receptor antagonists (ERA)
– Ambrisentan
– Bosentan
• Phosphodiesterase-5 inhibitors (PDE-I)
– Sildenafil
– Tadalafil
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
» Pain and erythema at injection site, headache, nausea,
diarrhea, rash
» Headache, jaw pain, flushing, nausea, diarrhea, skin rash,
musculoskeletal pain
» IV
» Inhalation*
» Cough, headache, flushing, throat irritation, nausea
Ambrisentan
Oral
Hepatotoxicity (LFT elevation ≥ 3x ULN ~ 2.8%), peripheral
edema
Bosentan
Oral
Hepatotoxicity (LFT elevation ≥ 3x ULN ~ 11%), peripheral
edema, anemia
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.
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)
CADD pump
Central line
Epoprostenol for IPAH
Patient Survival
Epoprostenol (N=41)
100
Patient Survival (%)
P = 0.003
80
Conventional therapy (N = 40)
60
40
20
0
0
2
Barst, et al. N Engl J Med. 1996;334:296-301.
4
6
8
10
12
Weeks
Iloprost for PAH
• Prostacyclin analog
• Indication – WHO group I - functional
class III, IV
• Administration
– Ultrasonic nebulizer
– Dosage = 2.5 to 5 mg, 6 to 9 times daily;
maximum daily dosage evaluated in clinical
studies = 45 mg
– Administration in well-ventilated areas
• Theoretical advantage of selectivity
– Pulmonary vs systemic administration
Iloprost for PAH
Composite Primary Endpoint at Week 12
Responders (% Patients)
45
40
35
43
P = 0.0033
30
25
20
26
19
15
10
5
0
Iloprost
Placebo
25
N = 203
13
8
4
10% Improvement
in 6-MWD
Improvement in
Functional Class
Olschewski, et al. N Engl J Med. 2002;347:322-9.
4
Death or Clinical Composite Primary
Worsening
Endpoint
Treprostinil for PAH
• Prostacyclin analog
• Indication – WHO group I functional class II, III, IV
• Dosage – 1.25 – 40 ng/kg/min
• Administration
– Subcutaneous
– IV
– Inhalation
Infusion site reaction
Treprostinil SC for PAH
Change in 6-MWD (from Baseline to Week 12)
40
36.1
35
P = 0.03
30
25
20
20
N = 470
15
10
5
3.3
1.4
0
< 5.0
ng/kg/min
5.0 - 8.1
ng/kg/min
Simonneau, et al. Am J Respir Crit Care Med. 2002;165:800-4.
8.2 – 13.8
ng/kg/min
> 13.8
ng/kg/min
Treprostinil IV for PAH
Change from Baseline to Week 12
Change in 6-MWD
14
400
350
375
315
250
200
150
100
10
6
4
4
2
0
0
6
Tapson, et al. Chest. 2006;129:683-8.
12 Weeks
9
8
50
0
13
12
400
Number of Patients
Change from Baseline (meters)
450
300
Change in Functional Class
N = 14
0
0
l
ll
lll
Baseline
1
1
lV
l
0
ll
lll
12 Weeks
lV
Treprostinil Inhalation for PAH:
TRIUMPH-1 Clinical Trial
 Treprostinil inhalation
 FDA approval – July, 2009
 Administered four times daily
 Study design – phase lll, randomized,
double-blind, placebo-controlled, 12week study
 Combination with bosentan or sildenafil
 Open-label extension for 24 months
 N= 206
 Adverse events – cough, headache,
nausea, diarrhea, flushing, throat
irritation
Change in 6-MWD from Baseline (meters)
60
50
50
40
30
31
34
20
10
0
12
18
24
Months
ABSTRACT: Benza, et al. ATS. San Diego, CA. May 15-20, 2009.
Endothelin Receptor Antagonists
Comparison of Agents
Bosentan
Ambrisentan
Use in pregnancy
Pregnancy category X (nonhormonal birth control method
required)
Pregnancy category X (nonhormonal birth control method
required)
LFT elevation
Monthly LFT monitoring required; ≥
3x ULN in ~ 11% patients (pooled
data from 16-week studies)
Monthly LFT monitoring required; ≥
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
Source: FDA-approved product labeling for individual agents.
Endothelin Receptor Antagonists
Comparison of Drug-Drug Interactions
Bosentan
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
Ambrisentan
Ritonavir
Rifampin
Cyclosporine A
Hormonal contraceptives3
Omeprazole4
Ketoconazole2,4
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 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 for PAH:
BREATHE Clinical Trial
Change in 6-MWD (from Baseline to Week 16)
Change from Baseline (meters)
80
60
Bosentan (N= 144)
40
20
P = 0.0002
0
-20
Placebo (N= 69)
-40
Baseline
Week 4
62.5 mg bid
Rubin, et al. N Engl J Med. 2002;346:896-903.
Week 8
125 or 250 mg bid Bosentan
Week 16
Bosentan for PAH
Comparison of 6-MWD in 6-Month, Open-Label Study
Change from Baseline (meters)
500
439
450
400
394
426
442
435
416
434
430
406
394
350
360
N= 29
Former placebo
patients
Former bosentan
patients
Combined group
(all bosentan)
300
Baseline
Baseline opencontrolled study
label study
Sitbon, et al. Chest. 2003;124:247-54.
1 month
6 months
Six-month, open-label study of bosentan (125 mg bid) after
a double-blind, placebo-controlled, four-month study
Delay in treatment in former placebo patients → less robust
improvement in 6-MWD during open-label extension
Bosentan for PAH:
EARLY Clinical Trial
Change in PVR (from Baseline to Week 24)
% of Baseline PVR at Week 24
(geometric means)
120
107.5
100
P < 0.0001
Decrease in PVR:
Surrogate marker for
delaying disease
progression
83.2
80
60
Placebo (N= 88)
Bosentan (N= 80)
40
20
0
Galie, et al. Lancet. 2008.371(9630):2093-100.
Valerio et al. Vasc Health Risk Manag. 2009;5:607-19.
Treatment effect =
- 22.6%
Bosentan for PAH:
EARLY Clinical Trial
Change in 6-MWD (from Baseline to Week 24)
Change in 6-MWD (meters)
25
20
15
11.2
Placebo (N= 91)
10
Bosentan (N= 86)
P = 0.076
5
0
5
12 weeks
10
15
20
Galie, et al. Lancet. 2008.371(9630):2093-100.
Valerio et al. Vasc Health Risk Manag. 2009;5:607-19.
24 weeks
- 7.9
Treatment effect =
+ 19.1 meters
Bosentan for PAH:
EARLY Clinical Trial
Time to Clinical Worsening (from Baseline to Week 32)
Event-Free Patients (%)
100
P < 0.02
80
Placebo
Bosentan
60
40
20
0
Patients at
risk (N)
0
4
8
12
16
20
24
28
32 weeks
92
93
90
92
89
87
86
85
84
84
83
83
77
80
18
27
9
15
Galie, et al. Lancet. 2008.371(9630):2093-100.
Valerio et al. Vasc Health Risk Manag. 2009;5:607-19.
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
Change in 6-MWD (from Baseline to Week 12)
ARIES 1
Change from Baseline (meters)
50
ARIES 2
60
N= 202
N=192
10 mg:
+43.6 m
5 mg:
+49.4 m
40
25
5 mg:
+22.8 m
0
2.5 mg
+22.2 m
20
0
Placebo:
-7.8 m
Placebo:
-10.1 m
-20
-25
4
8
12 weeks
Placebo-adjusted change at week 12:
Ambrisentan 5 mg = 31 m; 10 mg = 51 m
Galie, et al. Circulation. 2008;117:3010-9.
4
8
12 weeks
Placebo-adjusted change at week 12:
Ambrisentan 2.5 mg = 32 m; 5 mg = 59 m
Ambrisentan for PAH:
ARIES 1 and 2 Clinical Trials
Time to Clinical Worsening
Event-Free Patients (%)
100
--- Placebo
--- 2.5 mg (P = 0.03)
--- 5 mg (P = 0.005)
--- 10 mg (P = 0.03)
90
80
70
0
4
8
Ambrisentan → 71% relative risk reduction
Galie, et al. Circulation. 2008;117:3010-9.
12
Weeks
Ambrisentan for PAH:
ARIES-E
Change from Baseline (meters)
Change in 6-MWD (from Baseline to 24 Months)
2.5 mg (N = 93)
5 mg (N = 186)
10 mg (N = 96)
70
60
50
40
30
20
10
28 m
23 m
7m
0
-10
-20
0.0
0.25
0.5
1.0
Years
Oudiz, et al. J Am Coll Cardiol. 2009;54(21):1971-81.
1.5
2.0
Mean ± 95% CI; LOCF for missing data
Ambrisentan for PAH:
ARIES-E
Change in WHO Functional Class
90%
86%
79%
80
60
Patients (%)
Worsened
Maintained or
Improved
100
2.5 mg (N= 94)
5 mg (N = 187)
10 mg (N = 96)
40
20
0
10%
14%
21%
20
40
0.0
0.25
0.5
1.0
Years
Oudiz, et al. J Am Coll Cardiol. 2009;54(21):1971-81.
1.5
2.0
LOCF for missing data
Phosphodiesterase-5 Inhibitors
Comparison of Drug-Drug Interactions
Sildenafil
Nitrates
Alpha blockers
Amlodipine
Ritonavir
Bosentan1
HMG CoA reductase inhibitors1
Phenytoin1
Erythromycin1
Ketoconazole1
Cimetidine1
Rifampin1
Phenobarbital1
Carbamazepine1
Tadalafil
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.
Sildenafil for PAH
• PDE-5 inhibitor
• Indication – to increase exercise capacity,
decrease clinical worsening in patients with
WHO group I – functional class II, III, IV
• Dosage – 20 mg oral three times daily
• IV formulation
– Approved December, 2009
– Dosage – 10 mg three times daily
Sildenafil for PAH:
SUPER Clinical Trial
Change in WHO Functional Class (from Baseline to Week 12)
Placebo (N= 70)
Sildenafil (N= 203)
100%
Patients (%)
80%
60%
40%
20%
0%
Baseline
Class I
Galie, et al. N Engl J Med. 2005;353:2148-57.
Week 12
Class II
Baseline
Class III
Week 12
Class IV
Sildenafil for PAH:
Long-Term Extension of SUPER Clinical Trial
Change in 6-MWD (from Baseline)
Change from Baseline (meters)
55
50
51
48
45
40
12 weeks
(N= 273)
Galie, et al. N Engl J Med. 2005;353:2148-57.
12 months
(N= 222)
Sildenafil for PAH:
SUPER 2 Clinical Trial
• Study design
– Open-label, long-term extension of SUPER clinical trial
• Patients
– N= 259 enrolled; 180 completed 3 years of follow-up
• Dosage = 20-80 mg three times daily
• Study results at 3 years
–
–
–
–
–
Functional class – improved in 30%; unchanged in 31%
Kaplan-Meier estimated survival = 79%
Patient disposition – 53 patients died (29%); 44 discontinued therapy (24%)
Combination therapy – 20%
Adverse effects – mild/moderate in severity
ABSTRACT: Rubin, et al. CHEST. Philadelphia, PA. Oct. 25-30, 2008.
Tadalafil for PAH
• FDA approval – May, 2009
• PDE-5 inhibitor
• Indication – to increase exercise capacity, decrease
clinical worsening in patients with WHO group I –
functional class II, III, IV
• Dosage – 40 mg oral daily
Tadalafil for PAH:
PHIRST Clinical Trial
Subgroup analysis:
 Study design – phase lll, doubleblind, placebo-controlled,
multicenter, 16-week study
 Comparison of tadalafil
monotherapy (N= 189) to
combination therapy with bosentan
125 mg twice daily (N= 216)
 Dosage of tadalafil = 20 mg and 40
mg
 Study results
No greater improvement in 6-MWD
with combination therapy compared
to monotherapy
Change in 6-MWD from Baseline (meters)
45
40
35
30
25
20
15
10
5
0
44
32
23
23
Week 16
Monotherapy 20 mg
Monotherapy 40 mg
ABSTRACT: Barst, et al. ATS. San Diego, CA. May 15-20, 2009.
Pepke-Zaba, et al. Curr Med Res Opin. 2009;25(10):2479-85.
Combination therapy 20 mg
Combination therapy 40 mg
Tadalafil for PAH:
PHIRST Clinical Trial
Study Results
• Efficacy
– Greater improvement in 6-MWD in treatment-naïve patients
compared to patients with background bosentan
– Significant improvements in quality of life and time to and incidence
of clinical worsening (68% relative risk reduction)
• Safety
– Most common adverse events were headache, myalgia, and flushing
which were mild to moderate in severity
Galie, et al. Circulation. 2009;Epub May 26.
Pepke-Zaba, et al. Curr Med Res Opin. 2009;25(10):2479-85.
Tadalafil for PAH:
PHIRST Clinical Trial
Mean Change from Baseline to Week 16
Short Form 36 (SF-36) Domains
14
12
10
13
10
8
-4
9
8
6
4
2
0
-2
Quality of life measure:
Higher scores reflect
better functioning and
health status
7
7
Placebo
Tadalafil 40 mg
3
P< 0.01 vs Placebo
1.5
-1
-2
-1
-3.5
Physical
Functioning
RolePhysical
Bodily Pain
General
Health
Pepke-Zaba, et al. Curr Med Res Opin. 2009;25(10):2479-85.
Vitality
Social
Functioning
Tadalafil for PAH:
Long-Term Extension of PHIRST
 Study design – phase lll, double-blind,
placebo-controlled study (16 weeks) →
long-term extension study (44 weeks)
 Dosage = 20 mg and 40 mg
 N = 241
 Study results
Efficacy
6-MWD: sustained improvement over 44
weeks
Safety
62 patients withdrew from study including:
17 due to PAH progression; 12 due to
adverse events; 11 due to death
Change in 6-MWD from Baseline (meters)
40
38
37
35
30
16
ABSTRACT: Oudiz, et al. ATS. San Diego, CA. May 15-20, 2009.
ABSTRACT: Oudiz, et al. ERS. Vienna, Austria. September 14, 2009.
44
Weeks
PAH Determinants of Patient Risk
ACC/AHA Expert Consensus
Low Risk
Determinants of Risk
High Risk
No
Clinical evidence of RV failure
Yes
Gradual
Disease progression
Rapid
II, III
WHO functional class
IV
Longer (> 400 meters)
6-MWD
Shorter (< 300 meters)
Peak VO2 > 10.4 mL/kg/min
Cardiopulmonary exercise testing
Peak VO2 < 10.4 mL/kg/min
Minimally elevated and stable
BNP/NT-proBNP
Significantly elevated
PaCO2 > 34 mm Hg
Blood gasses
PaCO2 < 32 mm Hg
Minimal RV dysfunction
ECHO findings
Pericardial effusion, RV dysfunction,
RA enlargement
RAP < 10 mm Hg;
CI > 2.5 L/min/m2
Hemodynamics
RAP > 20 mm Hg;
CI < 2 L/min/m2
McLaughlin, et al. Circulation. 2006;114:1417-31.
McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573-1619.
Combination Therapy for PAH
• To target multiple disease pathways
– Endothelin pathway (endothelin receptor antagonists)
– Nitric oxide pathway (PDE-5 inhibitors)
– Prostacyclin pathway (prostacyclin analogs)
• Used clinically with little evidence to date
• Used when therapy needs to be augmented because patient
response to monotherapy is inadequate
• Must consider the drug interaction potential of agents to be
combined (risk-benefit analysis)
– Drug interaction between bosentan and sildenafil
– Drug interaction between bosentan and tadalafil
Barst, et al. J Am Coll Cardiol. 2009;54:S78-84.
Combination Therapy for PAH
Clinical Study
Humbert, et al1
McLaughlin, et al2
Hoeper, et al3
Simonneau, et al4
Galie, et al5
Agents
Study Design
Epoprostenol Randomized, doubleblind, placebo-controlled;
Bosentan
16 weeks
Iloprost
Randomized, doubleblind, placebo-controlled,
Bosentan
multicenter; 12 weeks
Iloprost
Randomized, placebocontrolled, multicenter;
Bosentan
12 weeks
Epoprostenol Randomized, doubleblind, placebo-controlled,
Sildenafil
multicenter; 16 weeks
Bosentan
Randomized, doubleblind, placebo-controlled;
Tadalafil
16 weeks
N
Study Endpoints
Statistical
Significance
33
Hemodynamics, exercise NSS findings
capacity, functional class
67
Hemodynamics, exercise SS improvement in
capacity, functional class, parameters
TTCW
Exercise capacity,
NSS findings
functional class, TTCW
40
256
405
Hemodynamics, exercise SS improvement in
capacity, TTCW
exercise capacity,
TTCW
Hemodynamics, exercise SS improvement in all
capacity, functional class, parameters, except
TTCW, quality of life
functional class
TTCW = time to clinical worsening; NSS = non-statistically significant; SS = statistically significant
1) Humbert, et al. Eur Respir J. 2004;24:353-9. 2) McLaughlin, et al. Am J Respir Crit Care Med. 2006;174:1257-63. 3) Hoeper, et al. Eur
Respir J. 2006;28:691-4. 4) Simonneau, et al. Ann Intern Med. 2008;149:521-30. 5) Galie, et al. Circulation. 2009;119(22):2894-903.
Monitoring Schedule for
Patients with PAH
Parameter
Baseline
(pretreatment)
Every 3-6
months
3-4 Months after start or
change in therapy
If clinical
worsening
Clinical assessment
WHO functional class
ECG
X
X
X
X
6-MWD
X
X
X
X
Cardiopulmonary exercise
testing
X
X
X
BNP/NT-proBNP
X
X
X
ECHO
X
X
X
Right heart catheterization
X
X
X
Galie, et al. Eur Heart J. 2009;30:2493-2537.
X
Summary
• Comprehensive management of PAH involves optimizing
multiple supportive therapies
• Early, evidence-based treatment of PAH is associated with
improved patient outcomes
• Agents for the treatment of PAH vary with regard to:
– Indication, administration, adverse effect profile, drug-drug
interactions, clinical study data
• Therefore, a comparison of the risk-benefit ratio of available
agents is needed to guide PAH treatment selection