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
Humbert, et al. N Engl J Med. 2004;351:1425-1436.
Nitric oxide
cGMP
Vasodilatation and antiproliferation
Endothelial cells
Nitric oxide pathway
Preproendothelin ProendothelinL-arginine
NOS
Arachidonic acid Prostaglandin I2
Prostaglandin I2
cAMPVasodilatation and
antiproliferationVasoconstriction and
proliferation
Endothelin-receptor A
Endothelin-receptor B
Endothelin pathway Prostacyclin pathway
Endothelin-1
Endothelin-receptor
antagonists
Exogenous nitric oxide
Prostacyclinderivates
Phosphodiesterase type 5 inhibitor
Phosphodiesterase type 5
Pathophysiology of PAH
Genetic Predisposition
Other Risk Factors
(CTD, CHD, toxins, etc.)
Altered Pathways And Mediators
Vasoconstriction
Cell Proliferation
Thrombosis
VascularRemodeling}
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
• 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
Machado, et al. J Am Coll Cardiol. 2009;54:S32-42.
Vasoconstriction in PAH
Impaired Vasodilation↓ Prostacyclin↓ Nitric oxide↓ Nitric oxide synthase
Vasodilation
Vasoconstriction
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.Galie, et al. Eur Heart J. 2009;30:2493-2537.
Revised Classification ofPulmonary 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 DiagnosticTesting 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 Conditions4th World Symposium on PH (2008)
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.
Patient Evaluation
Confirm presence of PHConfirm presence of PH
Determine type of PH present (PAH?)Determine type of PH present (PAH?)
Gauge functional capacityGauge functional capacity
Estimate prognosis (survival)Estimate prognosis (survival)
Determine treatment and monitoring planDetermine treatment and monitoring plan
NYHA/WHO FunctionalClassification 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.
Years
Long-term CCB responders(~50% of acute respondersor ≤ 6% of IPAH patients)
Long-term CCB non-responders
38 33 30 22 13 8 3 3 2 1
19 12 7 4 0
Patientsat risk (N)
Cum
ulat
ive
Sur
viva
l
Long-term CCBresponders
Long-term CCBnon-responders
0.0
0.2
0.4
0.6
0.8
1.0
0 2 4 6 8 10 12 14 16 18
Sitbon, et al. Circulation. 2005;111:3105-11.
P = 0.0007
Response to CCB Therapy andSurvival in Patients with PAH
Impact of Delay in Treatmenton Patient Survival
0
20
40
60
80
100
0 12 24 36 48 52
Ambrisentan
Placebo -Ambrisentan
ABSTRACT: McLaughlin, et al. Am J Respir Crit Care Med. 2008;177:A697.ABSTRACT: McLaughlin, et al. Am J Respir Crit Care Med. 2008;177:A697.
N = 251 242 226 209 195 AmbrisentanN = 122 110 100 94 95 Placebo → AmbrisentanN = 251 242 226 209 195 AmbrisentanN = 122 110 100 94 95 Placebo → Ambrisentan
Eve
nt-F
ree
Sur
viva
l (%
Pat
ient
s)E
vent
-Fre
e S
urvi
val (
% P
atie
nts) 86%86%
96%96%
84%84%
76%76%↑Transition placebogroup to ambrisentan
↑Transition placebogroup to ambrisentan
WeeksWeeks
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.Archer, et al. N Engl J Med. 2009;361:1864-71.
Amlodipine, diltiazem, nifedipine (B)
YES
ACUTE RESPONDER
WHO Class I-IVAmlodipine, diltiazem,
nifedipine (B)
Sustained response (WHO I-II)
Atrial septostomy (E/B) and/orlung transplant (E/A)
INADEQUATE CLINICAL RESPONSE
NO
PAH Evidence-Based Treatment Algorithm
Acute vasoreactivity test (A for IPAH)(E/C for APAH)
Expert referral (E/A)
Supportive therapy and general measures Avoid excessive physical exertion (E/A)Birth control (E/A)Psychosocial support (E/C)Infection prevention (E/A)
Oral anticoagulants (E/B) – IPAH/HPAHDiuretics (E/A)Oxygen (E/A)Digoxin (E/C)Supervised rehabilitation (E/B)
Strength of Recommendation WHO Class II WHO Class III WHO Class IV
AAmbrisentan, Bosentan, Sildenafil
Ambrisentan, Bosentan,Epoprostenol IV, Iloprost inh, Sildenafil
Epoprostenol IV
B Sitaxsentan, Tadalafil Sitaxsentan, Tadalafil, Treprostinil SC
Iloprost inh
C Beraprost Treprostinil SC
E/BIloprost IV, Treprostinil IV Iloprost IV, Treprostinil IV
Initial combination therapy (see below)
E/CAmbrisentan, Bosentan, Sildenafil, Sitaxsentan, Tadalafil
Not approved Treprostinil inh Treprostinil inh
Sequential combination therapy
PDE-5 I ERA + (B)
+ (B)+ (B)Prostanoids
NON-RESPONDER
4th World Symposium on PH. Dana Point, CA. 2008.Barst, et al. J Am Coll Cardiol. 2009;54:S78-84.
INADEQUATE CLINICAL RESPONSE
Acute Vasoreactivity Test for PAH
• Calcium Channel Blockers (CCB)
– Acute vasoreactive response =
– 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.
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
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
FDA-Approved Agents for theTreatment of PAH
• Prostacyclin analogs (PA)– Epoprostenol– Iloprost– Treprostinil
• Endothelin-receptor antagonists (ERA)– Ambrisentan– Bosentan
• Phosphodiesterase-5 inhibitors (PDE-I)– Sildenafil– Tadalafil
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
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. Adapted from McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573-1619. *Benza, et al. ATS. San Diego, CA. May 15-20, 2009.
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)
Epoprostenol for IPAHPatient Survival
Pat
ient
Sur
viva
l (%
)
P = 0.003P = 0.003
Barst, et al. N Engl J Med. 1996;334:296-301.
• Prostacyclin analog
• Indication – WHO group I - functional class III, IV
• Administration– Ultrasonic nebulizer
– Dosage = 2.5 to 5 g, 6 to 9 times daily; maximum daily dosage evaluated in clinical studies = 45 g
– Administration in well-ventilated areas
• Theoretical advantage of selectivity – Pulmonary vs systemic administration
Iloprost for PAH
Iloprost for PAHComposite Primary Endpoint at Week 12
43
2625
84
13
19
40
5
10
15
20
25
30
35
40
45
10% Improvementin 6-MWD
Improvement inFunctional Class
Death or ClinicalWorsening
Composite PrimaryEndpoint
Iloprost
Placebo
Olschewski, et al. N Engl J Med. 2002;347:322-9.
Res
pond
ers
(% P
atie
nts)
P = 0.0033
N = 203
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)
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.
N = 470
Treprostinil IV for PAHChange from Baseline to Week 12
400375
315
0
50
100
150
200
250
300
350
400
450
0 6 12
0 0
4
011
9
13
0
2
4
6
8
10
12
14
l ll lll lV l ll lll lV
Change in 6-MWD
Cha
nge
from
Bas
elin
e (m
eter
s)
Tapson, et al. Chest. 2006;129:683-8.
Weeks
Num
ber
of
Pat
ien
ts
Change in Functional Class
12 WeeksBaseline
N = 14
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, 12-week study
Combination with bosentan or sildenafil Open-label extension for 24 months N= 206 Adverse events – cough, headache,
nausea, diarrhea, flushing, throat irritation
50
3431
0
10
20
30
40
50
60
12 18 24MonthsMonths
Change in 6-MWD from Baseline (meters)Change in 6-MWD from Baseline (meters)
ABSTRACT: Benza, et al. ATS. San Diego, CA. May 15-20, 2009. ABSTRACT: Benza, et al. ATS. San Diego, CA. May 15-20, 2009.
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)
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
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 AmbrisentanRitonavir
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
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)
Bosentan for PAHComparison of 6-MWD in 6-Month, Open-Label Study
406
360
434
416
394
394
439 442
426435 430
300
350
400
450
500
Baselinecontrolled study
Baseline open-label study
1 month 6 months
Former placebopatients
Former bosentanpatientsCombined group(all bosentan)
Sitbon, et al. Chest. 2003;124:247-54.
Six-month, open-label study of bosentan (125 mg bid) aftera double-blind, placebo-controlled, four-month study
Delay in treatment in former placebo patients → less robust improvement in 6-MWD during open-label extension
N= 29
Cha
nge
from
Bas
elin
e (m
eter
s)
Bosentan for PAH:EARLY Clinical Trial
107.5
83.2
0
20
40
60
80
100
120
Placebo (N= 88)
Bosentan (N= 80)
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-F
ree
Pat
ient
s (%
)
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.
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 PAHChange in 6-MWD (from Baseline to Week 12)
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
Ambrisentan for PAH:ARIES 1 and 2 Clinical Trials
Time to Clinical Worsening
--- Placebo--- 2.5 mg (P = 0.03)--- 5 mg (P = 0.005)--- 10 mg (P = 0.03)
70
80
90
100
0 4 8 12 Weeks
Eve
nt-F
ree
Pat
ient
s (%
)
Ambrisentan → 71% relative risk reduction
Galie, et al. Circulation. 2008;117:3010-9.
Ambrisentan for PAH:ARIES-E
Change in 6-MWD (from Baseline to 24 Months)
Mean ± 95% CI; LOCF for missing data
Cha
nge
from
Bas
elin
e (m
eter
s)
2.5 mg (N = 93)5 mg (N = 186)10 mg (N = 96)
Years
-20
-100
1020
3040
50
60
0.0 0.25 0.5 1.0 1.5 2.0
70
7 m
23 m28 m
Oudiz, et al. J Am Coll Cardiol. 2009;54(21):1971-81.
Ambrisentan for PAH:ARIES-E
Change in WHO Functional Class
40
20
0
20
40
60
80
100
0.0 0.25 0.5 1.0 1.5 2.0
Years
Pat
ient
s (%
)
Ma
inta
ine
d o
r Im
pro
ved
Wo
rsen
ed
2.5 mg (N= 94)5 mg (N = 187)10 mg (N = 96)
LOCF for missing data
79%86%90%
10%14%21%
Oudiz, et al. J Am Coll Cardiol. 2009;54(21):1971-81.
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.
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)
Pat
ient
s (%
)
0%
20%
40%
60%
80%
100%
Baseline Week 12 Baseline Week 12
Class I Class II Class III Class IV
Galie, et al. N Engl J Med. 2005;353:2148-57.
Sildenafil for PAH:Long-Term Extension of SUPER Clinical Trial
Change in 6-MWD (from Baseline)
48
51
40
45
50
55
12 weeks 12 months
Cha
nge
from
Bas
elin
e (m
eter
s)
(N= 222)(N= 273)
Galie, et al. N Engl J Med. 2005;353:2148-57.
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, double-
blind, 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 resultsNo greater improvement in 6-MWD with combination therapy compared to monotherapy
32
44
23 23
05
101520
253035
4045
Week 16
Monotherapy 20 mg
Monotherapy 40 mg
Combination therapy 20 mg
Combination therapy 40 mgABSTRACT: Barst, et al. ATS. San Diego, CA. May 15-20, 2009.Pepke-Zaba, et al. Curr Med Res Opin. 2009;25(10):2479-85.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.
Change in 6-MWD from Baseline (meters)Change in 6-MWD from Baseline (meters)
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.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
-1
7
3
13
1.5
10
-2
8
-1
7
-3.5
9
-4
-2
0
2
4
6
8
10
12
14
PhysicalFunctioning
Role-Physical
Bodily Pain GeneralHealth
Vitality SocialFunctioning
Placebo
Tadalafil 40 mg
Pepke-Zaba, et al. Curr Med Res Opin. 2009;25(10):2479-85.Pepke-Zaba, et al. Curr Med Res Opin. 2009;25(10):2479-85.
P< 0.01 vs Placebo
Mea
n C
han
ge f
rom
Ba
selin
e to
Wee
k 16
Short Form 36 (SF-36) Domains
Quality of life measure:Higher scores reflect better functioning and health status
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
Efficacy6-MWD: sustained improvement over 44 weeksSafety62 patients withdrew from study including: 17 due to PAH progression; 12 due to adverse events; 11 due to death
37
38
30
35
40
16 44
ABSTRACT: Oudiz, et al. ATS. San Diego, CA. May 15-20, 2009.ABSTRACT: Oudiz, et al. ERS. Vienna, Austria. September 14, 2009.ABSTRACT: Oudiz, et al. ATS. San Diego, CA. May 15-20, 2009.ABSTRACT: Oudiz, et al. ERS. Vienna, Austria. September 14, 2009.
Change in 6-MWD from Baseline (meters)Change in 6-MWD from Baseline (meters)
WeeksWeeks
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 findingsPericardial effusion, RV dysfunction,
RA enlargement
RAP < 10 mm Hg;
CI > 2.5 L/min/m2Hemodynamics
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.
PAH Determinants of Patient RiskACC/AHA Expert Consensus
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
TTCW = time to clinical worsening; NSS = non-statistically significant; SS = statistically significant1) 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.
Clinical Study Agents Study Design N Study Endpoints Statistical Significance
Humbert, et al1 Epoprostenol
Bosentan
Randomized, double-blind, placebo-controlled; 16 weeks
33 Hemodynamics, exercise capacity, functional class
NSS findings
McLaughlin, et al2 Iloprost
Bosentan
Randomized, double-blind, placebo-controlled, multicenter; 12 weeks
67 Hemodynamics, exercise capacity, functional class, TTCW
SS improvement in parameters
Hoeper, et al3 Iloprost
Bosentan
Randomized, placebo-controlled, multicenter; 12 weeks
40 Exercise capacity, functional class, TTCW
NSS findings
Simonneau, et al4 Epoprostenol
Sildenafil
Randomized, double-blind, placebo-controlled, multicenter; 16 weeks
256 Hemodynamics, exercise capacity, TTCW
SS improvement in exercise capacity, TTCW
Galie, et al5 Bosentan
Tadalafil
Randomized, double-blind, placebo-controlled; 16 weeks
405 Hemodynamics, exercise capacity, functional class, TTCW, quality of life
SS improvement in all parameters, except functional class
Monitoring Schedule forPatients 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 XCardiopulmonary exercise testing
X X X
BNP/NT-proBNP X X X XECHO X X X
Right heart catheterization X X X
Galie, et al. Eur Heart J. 2009;30:2493-2537.Galie, et al. Eur Heart J. 2009;30:2493-2537.
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