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Learning Objectives
• Identify patients at high risk for the development of PAH.
• Utilize right heart catheterization to confirm the diagnosis of PAH.
• Evaluate right ventricular function using screening tools and
imaging tests.
• Weigh the risks versus benefits for a given mediation, in terms of
indication for use, route of administration, side effects, and longterm study data.
• Decide if and when combination therapy is a clinical necessity.
• Analyze multiple clinical endpoints to determine if treatment is
successful.
Lecture Outline
•
•
•
•
•
•
•
•
Pathology and genetics
Diagnostics
The right ventricle in PAH
High-risk patients
Evidence-based treatment
Ongoing research
Combination therapy
Prognostication and patient monitoring
Epidemiology and History of PAH
• Prevalence in the U.S.
– ≈ 50,000 to 100,000 (15,000 to 25,000 diagnosed and treated)
• Circa 1987
– Due to rapid progression of morbidity and mortality, once
patients were diagnosed with pulmonary hypertension they
were described as entering “the kingdom of the near-dead”
• 2015
– Patient survival has dramatically improved as treatment
options for PAH have increased
McGoon, et al. J Am Coll Cardiol. 2013;62(25):S51-9.
PAH is a
diagnosis of
exclusion
Clinical Classification of
Pulmonary Hypertension
Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41.
Types of PAH
Idiopathic
Heritable
• BMPR2
• ALK-1, ENG, SMAD9, CAV1, KCNK3
• Unknown
Drug- and toxin-induced
Associated with:
•
•
•
•
•
Connective tissue disease
HIV infection
Portal hypertension
Congenital heart disease
Schistosomiasis
Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41.
PAH Associated With
Connective Tissue Disease
Scleroderma
• Most prevalent and studied type of PAH associated with CTD
• Rate of occurrence of PAH = 7 to 12% of patients with
scleroderma; more common in limited scleroderma (CREST
syndrome)
• Prognosis is poorer than other types of PAH
• PAH is the leading cause of death; 1 year mortality rate = 30%
Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41.
Associated Conditions
PAH Associated With:
HIV infection
Portal hypertension
Rate of Occurrence
of PAH
0.5%
2 – 6%
Clinical Features
Improvement in survival since
HAART; 5-year survival > 70%
Prognosis negatively impacted by
cardiac dysfunction, severity of
liver disease / cirrhosis
Congenital heart disease
10%
Presence of PAH has negative
impact on clinical course
Schistosomiasis
5%
3-year survival ≈ 85%
Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41.
Patient Registries for PAH
Registry
Time Period
N
NIH
1981 – 1985
187
French
2002 – 2003
674
U.S. REVEAL
2006 – 2009
3515
U.S. PHC
1982 – 2006
578
PAH-QuERI
2005 – 2007
791
Scottish-SMR
1986 – 2001
374
Chinese
1999 – 2004
72
Spanish
1998 – 2008
866
U.K.
2001 – 2009
482
New Chinese Registry
2008 – 2011
956
Mayo
1995 – 2004
484
Compera
2007 – 2011
587
McGoon, et al. J Am Coll Cardiol. 2013;62(25):S51-9.
Observations From
Patient Registries for PAH
• Older age at diagnosis
– NIH registry: 36 (± 15 years)
– REVEAL: 50 - 65 (± 15 years)
• Population cohorts at greater risk
– Patient demographic – advanced age, male gender
– Etiology – heritable PAH, PAH associated with CTD or
portal hypertension
McGoon, et al. J Am Coll Cardiol. 2013;62(25):S51-9.
Older Patients With PAH
• Older age at diagnosis
– More advanced, severe disease
– Greater number of comorbidities
 Presence of comorbid conditions can mask symptoms of PAH and
delay diagnosis, and may contribute to morbidity and mortality
• Treatment strategies for older patients
– Exact influence of age on treatment success is unknown
– Older patients are underrepresented in clinical studies
Hoeper, et al. Eur Resp Rev. 2014;23(134):450-7.
Comorbid Conditions
in Patients With PAH
Patients (%)
N = 2959
Poms, et al. Chest. 2013;144(1):169-76.
Patient 3-Year Survival Rates:
REVEAL Registry
P < 0.05
N = 263
Barst, et al. Chest. 2013;144(1):160-8.
N = 645
N = 74
Pathology of Pulmonary Hypertension
Plexiform lesion
Thrombus
Overview
• Obstructive lung
panvasculopathy
• Prognosis is primarily
determined by the
functional status of the
RV
• Most common cause
of death is RV failure
Dilated vessels
Tuder, et al. J Am Coll Cardiol. 2013;62(25):S4-12. Image: www.pathhsw5m54.ucsf.edu/Image61.html
Pathology of Pulmonary Hypertension
Metabolic
dysfunction
Dysregulation
of growth
factors
Proliferative,
apoptosisresistant
state
Persistent
inflammation
Tuder, et al. J Am Coll Cardiol. 2013;62(25):S4-12.
Disordered
mitochondrial
structure
Interplay of several pathobiological
and environmental factors on a
“background of genetic predisposition”
Pathology of Pulmonary Hypertension
Excessive
pulmonary
vascular
remodeling
Sustained
vasoconstriction
In situ
thrombosis
Increased
PVR
Tuder, et al. J Am Coll Cardiol. 2013;62(25):S4-12.
Mechanisms of Pathology for PAH
Endothelin Pathway
Prostacyclin Pathway
Nitric Oxide Pathway
Endothelial
cells
Preproendothelin
L-arginine
Proendothelin
Arachidonic acid
Prostaglandin I2
NOS
Nitric oxide
Endothelinreceptor A
Endothelin-1
Endothelinreceptor B
sGC
stimulator
Prostaglandin I2
GTP
Exogenous
nitric oxide
cGMP
Endothelinreceptor
antagonists
Phosphodiesterase
type 5
Vasodilatation and
antiproliferation
Vasoconstriction and
proliferation
Phosphodiesterase
type 5 inhibitor
Adapted from: Humbert, et al. N Engl J Med. 2004;351:1425-1436.
cAMP
Prostacyclin
derivates
Vasodilatation and
antiproliferation
Genetic Mutations in PAH
• BMPR2
–
–
–
–
Major predisposing gene
Over 300 mutations have been identified
Found in >70% of patients with H-PAH
Found in ≈ 20% of patients with IPAH
• ALK-1
– Major gene when PAH is associated with
hereditary hemorrhagic telanglectasia (HHT)
• Less common mutations:
– Endoglin, SMAD9, Caveolin-1, KCNK3
Soubrier, et al. J Am Coll Cardiol. 2013;62(25):S13-21.
BMPR2
Group 1’ Pulmonary Hypertension
• Overlapping pathological features
– Disordered endothelial growth or
proliferation
– Histologic changes in pulmonary
parenchyma
– Development of pulmonary arterial
intimal thickening and medial
hypertrophy
• May have similar clinical
presentation
• Genetic predisposition
– Mutations in BMPR2, EIF2AK4?
Langleben. Chest. 2014;145(2):197-8. Simonneau, et al. J Am Coll Cardiol. 2009;54:S43-54.
Definition of Pulmonary Hypertension
• General definition
– Mean PAP ≥ 25 mm Hg at rest, measured
by right heart catheterization
• Hemodynamic characterization of PAH
– Mean PAP ≥ 25 mm Hg, PAWP ≤ 15 mm
Hg, elevated PVR (> 3 Wood Units)
Hoeper, et al. J Am Coll Cardiol. 2013;62(25):S42-50.
Diagnostic Algorithm for PAH:
Consensus From 5th WSPH
PAH is a
diagnosis of
exclusion
Hoeper, et al. J Am Coll Cardiol. 2013;62(25):S42-50.
Clinical Presentation of PAH
Symptoms
•
•
•
•
•
•
•
Dyspnea
Fatigue
Syncope
Weakness
Angina
Abdominal distension
Edema
McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573-1619.
Signs
• Loud P2 (listen at apex)
• RV lift (left parasternal –
fingertips)
• RV S3, RV S4
• Systolic murmur (TR;
inspiratory augmentation)
• Early systolic click
• Midsystolic ejection murmur
• Diastolic murmur (PR)
• Increased jugular “a” wave
Echocardiography for PAH
• Screening tool, NOT a
diagnostic tool
• Non-invasive estimation of
PAP
• Examine ECHO results for:
– RV size and function
– Left ventricular systolic
and diastolic dysfunction
– Left-sided chamber
enlargement
– Valvular heart disease
• Examine ECHO with contrast
results for intracardiac shunt
Badesch, et al. J Am Coll Cardiol. 2009;54:S55-66.
Right Heart Catheterization for PAH
Required test for
diagnostic confirmation
• Measures:
–
–
–
–
PAP
PAWP
CO
RAP
• Allows calculation of
pulmonary and systemic
vascular resistance
Badesch, et al. J Am Coll Cardiol. 2009;54:S55-66.
Anatomy and Physiology
of the RV and LV
Complex interplay
between contractility,
afterload, compliance,
and heart rate
Subject to significant
size and shape change
Rich. Cardiol Clin. 2012;30:257-69. Vachiery, et al. Eur Resp Rev. 2012;21(123):40-7.
RV Failure Syndrome
Pulmonary hypertension ↑ PAP (pressure overload)
Adaptive RV hypertrophy
Progressive contractile impairment
RV dilatation
Contractile dysfunction progresses
RV failure:
High RV filling pressures, diastolic dysfunction, ↓ CO
Vonk-Noordegraaf, et al. J Am Coll Cardiol. 2013;62(25):S22-33.
Continuum of RV Impairment and
Action Towards Reversal
• When compensatory mechanisms in the RV are
exceeded, RV dysfunction develops
• RV failure manifests clinically as exercise limitation
and fluid retention
• FDA-approved therapies for PAH reverse RV
remodeling
– Reduction of afterload
– Vasodilation
Vonk-Noordegraaf, et al. J Am Coll Cardiol. 2013;62(25):S22-33.
Evaluation of RV Function
Echocardiography
•
•
•
•
•
Pericardial effusion
TAPSE
Right atrial area
LV eccentricity
2D, 3DE volumes /
ejection fraction
• RV strain
• Tei index
Right Heart
Catheterization
• Right atrial
pressure
• Cardiac index
• Cardiac output
(CO)
Cardiac MRI
• RV mass
• RV volume
• RV ejection
fraction
Vachiery, et al. Eur Resp Rev. 2012;21(123):40-7. Vonk-Noordegraaf, et al. J Am Coll Cardiol. 2013;62(25):S22-33.
Impact of RV Function on Therapy
• RV function can highlight the subtle changes in
early disease and prompt rapid initiation of therapy
• RV function determines the patient’s functional
capacity and survival
• Deterioration in RV function mirrors disease
progression
• Treatment escalation can be guided by RV function
correlates
Badano, et al. Eur J Echocardiography. 2010;11(1):27-37.
Diagnostic Issues
• Misdiagnosis1
– Most patients see three or more physicians over a threeyear period before an accurate diagnosis is made
• Diagnostic delay1
– Time to reach diagnosis has not improved in 20 years
• Advanced disease at diagnosis2
– Approximately 75% of patients have advanced disease at
diagnosis (functional class III and IV)
1) Deano, et al. JAMA Intern Med. 2013;173(10):887-93. 2) Thenappan, et al. Eur Respir J. 2007;30(6):1103-10.
Patient Screening
• “Systematic testing of asymptomatic individuals to search for
preclinical disease and mildly symptomatic patients to
prevent progression and / or development of the disease”
• Appropriate for PAH since symptoms are nonspecific and
condition is uncommon and progressive; however,
presentation is confounded by diversity of PAH
• Determine which screening populations to preselect
Proper
screening
Earlier
diagnosis
Schwaiger, et al. Eur Resp Rev. 2013;22(130):515-25.
Rapid
intervention
Improved
outcomes
Patients at High Risk for PAH
Heritable PAH
• Patients with a family history of PAH
Drug- and toxin-induced PAH
• Patients with a history of high-risk drug / toxin use
Associated conditions
• Patients with an associated condition:
• Connective tissue disease
• HIV infection
• Portal hypertension
• Congenital heart disease
• Schistosomiasis
Simonneau, et al. J Am Coll Cardiol. 2013;62(25):S34-41.
Guidelines for Screening
High-Risk Patients
• Heritable PAH
– Yearly echocardiography in asymptomatic carriers of
BMPR2 mutation and RHC if the echocardiograph is
abnormal
• Associated conditions
– Scleroderma – yearly echocardiography in symptomatic
patients, optional in asymptomatic patients
– HIV infection – echocardiography recommended if
unexplained dyspnea
Schwaiger, et al. Eur Resp Rev. 2013;22(130):515-25.
Treatment of PAH
Strategy:
–
–
–
–
–
Evaluation of disease severity
Adoption of general measures and supportive therapy
Assessment of vasoreactivity
Estimation of drug efficacy
Combination of different drugs and interventions
Goals of therapy:
– Improve symptoms, hemodynamics, exercise capacity,
functional class, quality of life
– Prevent clinical decline
– Reduce hospitalizations
– Extend survival
Ghofrani, et al. Int J Cardiol. 2011;154(1):S20-33.
General Measures and
Supportive Therapy
General
Measures
• Rehabilitation /
exercise
• Psychosocial support
• Family planning
• Vaccinations
Supportive
Therapy
•
•
•
•
Anticoagulants
Diuretics
Oxygen
Digoxin
Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.
Referral to a
PAH Clinic
• Multidisciplinary care
• Continuous monitoring
• Patient and family
education
• Psychosocial support
• Access to clinical trials
• Disease advocacy
• Society participation
General Measures and
Supportive Therapy
Cardiac catheterization / acute vasoreactivity testing
– Mandatory if IPAH (optional if associated condition)
– Identifies patients who are responders
– Inhaled nitric oxide (10 – 20 parts per million) or inhaled
epoprostenol (50 ng/kg/min) are the preferred testing agents
Chronic CCB therapy
– Appropriate for patients with a positive response = reduction of
mean PAP ≥ 10 mm Hg to reach a mean PAP ≤ 40 mm Hg
with a normalized or increased CO
– Therapeutics – amlodipine, nifedipine, or diltiazem
Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. Agarwal, et al. Am Heart J. 2011;162:201-13
Mechanisms of Pathology for PAH
Endothelin Pathway
Prostacyclin Pathway
Nitric Oxide Pathway
Endothelial
cells
Preproendothelin
L-arginine
Proendothelin
Arachidonic acid
Prostaglandin I2
NOS
Nitric oxide
Endothelinreceptor A
Endothelin-1
Endothelinreceptor B
sGC
stimulator
Prostaglandin I2
GTP
Exogenous
nitric oxide
cGMP
Endothelinreceptor
antagonists
Phosphodiesterase
type 5
Vasodilatation and
antiproliferation
Vasoconstriction and
proliferation
Phosphodiesterase
type 5 inhibitor
Adapted from: Humbert, et al. N Engl J Med. 2004;351:1425-1436.
cAMP
Prostacyclin
derivates
Vasodilatation and
antiproliferation
Prostacyclin Pathway
• Prostacyclin
–
–
–
–
Produced primarily by endothelial cells
Induces potent vasodilation of vascular beds
Inhibits platelet aggregation
Cytoprotective and antiproliferative properties
• Prostacyclin analogs
Epoprostenol
Continuous IV infusion, inhalation
Treprostinil
Subcutaneous, IV, inhalation, oral
Iloprost
Inhalation
Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.
Endothelin Pathway
• Endothelin
– Plasma levels are elevated in patients with PAH
– Increases vasoconstriction
– Mitogenic properties
• Endothelin receptor antagonists
Bosentan
Oral
Ambrisentan
Oral
Macitentan
Oral
Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.
Nitric Oxide Pathway
• Nitric oxide
L-Arginine
– Impairment of nitric
oxide (NO) synthesis
and signaling in patients
with PAH
– Mediated through the
NO-sGC-cGMP pathway
L-Citrulline
NO
sGC
PDE-5
GMP
Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.
NOS
cGMP
Vasodilation
Nitric Oxide Pathway
• Phosphodiesterase-5 inhibitors
– Inhibit the cGMP degrading enzyme, PDE-5
– Enhance the pathway, slowing cGMP
Sildenafil
degradation
Tadalafil
– Vasodilation and antiproliferative effects
Oral, IV
Oral
• Soluble guanylate cyclase stimulators
Riociguat
– Increase cGMP production
– Antiproliferative and antiremodeling properties
Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.
Oral
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.
Evidence-Based Treatment Algorithm:
Consensus From 5th WSPH
FC II
Bosentan
Ambrisentan
Macitentan
IA/B Sildenafil
Tadalafil
Riociguat
FC III
Bosentan
Ambrisentan
Macitentan
Sildenafil
Tadalafil
Riociguat
Epoprostenol IV
Treprostinil sc, inhalation
Iloprost inhalation
Epoprostenol IV
Treprostinil IV
Bosentan
Ambrisentan
Macitentan
Sildenafil
Tadalafil
Riociguat
Treprostinil sc, inhalation, IV
Iloprost inhalation
IIaC
IIbC
FC IV
Initial combination therapy
Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.
Sequential
Combination Therapy
+
PA
Initial combination therapy
ERA
+
+
PDE-5i
sGCS
Inadequate clinical
response on
maximal therapy
Interventional Procedure
BAS
Lung Transplantation
Initial Therapy for PAH:
Consensus From 5th WSPH
Strength of
recommendation
and clinical
evidence
IA/B
FC II
Bosentan
Ambrisentan
Macitentan
Sildenafil
Tadalafil
Riociguat
FC III
Bosentan
Ambrisentan
Macitentan
Sildenafil
Tadalafil
Riociguat
Epoprostenol IV
Treprostinil sc, inhalation
Iloprost inhalation
Epoprostenol IV
Treprostinil IV
Bosentan
Ambrisentan
Macitentan
Sildenafil
Tadalafil
Riociguat
Treprostinil sc, inhalation, IV
Iloprost inhalation
Initial combination therapy
Initial combination therapy
IIaC
IIbC
FC IV
Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.
Prostacyclin Analogs
Epoprostenol
Indication / FC
Administration
Dosage
Other
Treprostinil
Iloprost
III, IV
II, III, IV
III, IV
Continuous IV
Inhalation
SC
IV
Inhalation
Oral
Inhalation
20-40 ng/kg/min
Initial = 1.25 ng/kg/min
Usual = 2.5-5 µg,
Usual = 30-100 ng/kg/min 6-9 times per day
2 branded versions
available
Only PAH clinical
study to demonstrate
survival benefit
Administer in wellventilated areas
Max dosage = 45 µg
Treprostinil for PAH
Clinical
Study
Route of
Administration
N
Study
Duration
Study Results
Simonneau1
SC
470
12 weeks
SS improvement in 6-MWD
Tapson2
IV
14
12 weeks
SS improvements in 6-MWD,
FC
McLaughlin3
Inhalation
+ Bosentan or
sildenafil
RCT = 212
12 weeks
OL = 206
24 months
Benza4
SS improvements in 6-MWD,
QOL with combination
therapy, which were
sustained for OL extension
1) Simonneau, et al. Am J Respir Crit Care Med. 2002;165:800-4. 2) Tapson, et al. Chest. 2006;129:683-8.
3) McLaughlin, et al. J Am Coll Cardiol. 2010;55(18):1915-22. 4) Benza, et al. J Heart Lung Transplant. 2011;30(12):1327-33.
Treprostinil Oral for PAH:
FREEDOM-C Clinical Trial
• Study design
– RCT
– N = 350 patients with background ERA or PDE-5 inhibitor
– Study duration = 16 weeks
• Study results
– High discontinuation rate: 22% of treprostinil-treated patients
and 14% of placebo-treated patients
– Improvement in 6-MWD did not reach statistical significance
– Reduced efficacy may be due to the low dose of treprostinil or
presence of background therapy
Tapson, et al. Chest. 2012;142(6):1383-90.
Treprostinil Oral for PAH:
FREEDOM-M Clinical Trial
• Study design
*
Change from Baseline (meters)
– RCT
– N = 228 treatment-naïve
patients, no background
therapy permitted
– Study duration = 12
weeks
Change in 6-MWD
*P < 0.05
*
Weeks
Jing, et al. Circulation. 2013;127:624-33.
Endothelin Receptor Antagonists
Bosentan
Ambrisentan
Macitentan
Indication / FC
II, III, IV
II, III, IV
II, III, IV
Administration
Oral
Oral
Oral
5 mg and 10 mg
daily
10 mg daily
Dosage
62.5 mg twice daily
for 4 weeks then
125 mg twice daily
Other
Sustained receptor
binding and enhanced
tissue penetration
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
62.5 mg twice daily
4
Rubin, et al. N Engl J Med. 2002;346:896-903.
125 or 250 mg twice daily
8
16 Weeks
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
0
4
8
12
16
20
24
28
32
Weeks
Galie, et al. Lancet. 2008.371(9630):2093-100. Valerio et al. Vasc Health Risk Manag. 2009;5:607-19.
Ambrisentan for PAH:
ARIES Clinical Trials
Time to Clinical Worsening (From Baseline to Week 12)
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
12 Weeks
Ambrisentan → 71% relative risk reduction
Galie, et al. Circulation. 2008;117:3010-9.
Ambrisentan for PAH:
ARIES-3 Clinical Trial
Patient population (N = 224)
Study results
• 6-MWD
– Increased by 21 meters
(P < 0.05)
• BNP levels
– Decreased by 26%
(NSS)
Badesch, et al. Cardiovasc Ther. 2012;30(2):93-9.
Ambrisentan for PAH:
ARIES-E Clinical Trial
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
23
7
0
-10
-20
0.0
0.25
0.5
1.0
1.5
2.0
Years
Oudiz, et al. J Am Coll Cardiol. 2009;54(21):1971-81.
Macitentan for PAH:
SERAPHIN Clinical Trial
*P < 0.05
Macitentan 10 mg
(N = 242)
Average duration of treatment (event driven)1
103.9 weeks
Risk reduction in the occurrence of morbidity
and mortality events versus placebo1
45%*
All-cause hospitalizations2
Risk reduced by 32%* and rate
reduced by 33%*
PAH-related hospitalizations2
Risk reduced by 52%* and rate
reduced by 50%*
1) Pulido, et al. NEJM. 2013;369(9):809-18. 2) Channick, et al. JACC Heart Fail. 2015;3(1):1-8.
Nitric Oxide Pathway Agents
Sildenafil
Tadalafil
Riociguat
Type
PDE-5 inhibitor
PDE-5 inhibitor
Soluble guanylate
cyclase stimulator
Indication / FC
II, III, IV
II, III, IV
II, III, IV
Administration
Oral
IV
Oral
Oral
40 mg daily
Dosage
20 mg oral three
times daily
10 mg IV three times
daily
1 mg – 2.5 mg three
times daily
Sildenafil for PAH
Clinical
Study
SUPER-11
SUPER-22
PACES3
Study
Design
RCT
OL
RCT
Agents
N
Study
Duration
Study Results
Sildenafil 20 - 80 mg 278
three times daily
12 weeks
SS improvements in 6MWD, FC
• Sildenafil 80 mg
three times daily
• 2nd agent added in
18% of patients
170
3 years
46% maintained or
improved 6-MWD
60% maintained or
improved FC
Patient survival = 79%
• Epoprostenol
• Epoprostenol +
sildenafil 80 mg
three times daily
• 53
• 214
16 weeks
Patients on combination
therapy had SS
improvement in 6-MWD,
fewer clinical worsening
events, and delayed TTCW
1) Galie, et al. N Engl J Med. 2005;353:2148-57. 2) Rubin, et al. Chest. 2011:140(5):1274-83.
3) Simonneau, et al. Ann Intern Med. 2008;149(8):521-30.
Tadalafil for PAH
Clinical
Study
PHIRST-11
PHIRST-22
Study
Design
Agents
N
189
RCT
• Tadalafil 20 or
40 mg daily
• Tadalafil +
bosentan
135
OL
• Tadalafil 20 or
40 mg daily
• Tadalafil +
bosentan
Study
Duration
16 weeks
SS improvements in 6-MWD,
QOL, clinical worsening
events, TTCW, especially in
treatment-naïve patients
52 weeks
Improvements in 6-MWD,
clinical worsening events
were sustained
216
158
Study Results
1) Galie, et al. Circulation. 2009;119(22):2894-903. Barst, et al. J Heart Lung Transplant. 2011;30(6):632-43.
2) Oudiz, et al. J Am Coll Cardiol. 2012;60:768-74.
Riociguat for PAH
Clinical
Study
PATENT
Study
Design
RCT
Agents
Riociguat 1 mg,
1.5 mg, 2 mg, or
2.5 mg three
times daily
Ghofrani, et al. NEJM. 2013;369(4):330-40.
N
443
Study
Duration
12 weeks
Study Results
SS improvements in 6-MWD,
PVR, NT-proBNP, FC, Borg
Dyspnea Scale score, QOL
measures, TTCW
Ongoing Clinical Research in PAH
• PAH is a chronic, debilitating disease with
significant associated morbidity and mortality
• A cure for PAH has yet to be discovered
• Standard treatment eventually becomes inadequate
• Enrollment in clinical trials posits patients for
cutting-edge therapies and progressive treatment
protocols
Selexipag for PAH
• Investigational agent
• Mechanism of action
– Prostacyclin IP receptor
agonist
– Targets the prostacyclin
pathway
• Administration – oral
Image: www.chemspider.com/Chemical-Structure.8089417.html
Combination Therapy for PAH
Background
• Rationale – to target multiple disease pathways
• REVEAL: 34% of patients on 2 or more treatments
Sequential Therapy
• Starting in one drug class and adding an agent from another class
• Used when therapy needs to be augmented because response to
initial therapy is inadequate
Upfront Therapy
• Used in early PAH disease
• May improve patient outcomes, slow disease progression, and
reduce costs associated with managing clinical worsening
Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72. Badesch, et al. Chest. 2010;137(2):376-87.
Combination Therapy for PAH:
Published Studies
Clinical
Study
Agents
N
Study
Duration
BREATHE-21
Epoprostenol
Bosentan
33
16 weeks
Hemodynamics, 6-MWD,
FC
No
STEP-12
Iloprost
Bosentan
67
12 weeks
Hemodynamics, 6-MWD,
FC, TTCW
Yes
COMBI3
Iloprost
Bosentan
40
12 weeks
Zhuang4
Ambrisentan
Tadalafil
124
16 weeks
Study Endpoints
6-MWD, FC, TTCW
6-MWD, clinical
worsening events
Statistical
Significance
No
Yes
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) Zhuang, et al. Hypertens Res. 2014;37(6):507-12.
Combination Therapy for PAH:
COMPASS Clinical Trials
COMPASS-21
•
•
•
•
RCT
N = 334
Sildenafil +/- bosentan
Study duration = event
driven
• Study endpoint = TTCW
• Study results = NSS
COMPASS-32
•
•
•
•
•
•
Open-label extension
N = 100
Bosentan +/- sildenafil
Study duration = 28 weeks
Study endpoint = 6-MWD
Study results = 31% reached
6-MWD goal, 34% improved FC
1) McLaughlin, et al. Chest. 2014;146(4):ABSTRACT (NCT00303459)
2) Benza, et al. Chest. 2010;138(4):ABSTRACT (NCT00433329)
Upfront Combination Therapy
Patient Survival (%)
P = 0.07
Months
Kemp, et al. J Heart Lung Transplant. 2012;31(2):150-8.
Upfront Combination Therapy:
AMBITION Clinical Trial
Study design
Study results
*P < 0.05
• RCT
• Combination therapy
reduced the risk of clinical
• N = 500 treatment-naïve
patients
failure events by 50%*
• Study groups
• SS* improvements in:
– Ambrisentan
– 6-MWD
– NT-proBNP
– Tadalafil
– % Patients with a
– Ambrisentan + tadalafil
satisfactory clinical
• Study duration = event driven
response
• Primary endpoint = TTCW
Galie, et al. Eur Respir J. 2014;44(58):ABSTRACT.
Upfront Triple Combination Therapy
Study design
• Retrospective review
• N = 18 treatment-naïve
patients in FC III or IV
• Epoprostenol + bosentan +
sildenafil
• First assessment of
endpoints at 4 months
Sitbon, et al. Eur Respir J. 2014;43(6):1691-7.
Study results
*P < 0.05
• SS* improvements in
– 6-MWD
– Hemodynamics
• Functional class
– Improvement to FC I or II
for 17 patients
• Overall patient survival
– 100% at 1, 2, and 3 years
Interventional Procedures:
Balloon Atrial Septostomy
• Creation of an interatrial right-to-left shunt
• In order to:
›
›
›
›
›
Decompress right heart chambers
Increase LV preload
Increase CO
Improve systemic oxygen transport
Decrease sympathetic hyperactivity
• Considered a palliative or bridging procedure
– Patients refractory to medical therapy
– Patients awaiting lung transplantation
Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.
Interventional Procedures:
Lung Transplantation
• Surgical procedures
– Single lung transplant – rare
– Bilateral (sequential) lung transplant – most common
– Heart-lung transplant – increasingly less common; only
70 – 90 performed per year*
• Lung transplantation remains the standard of care
for select patients who fail aggressive medical
therapy, with specific eligibility criteria determined
by the transplant center
*Long, et al. Pulm Circ. 2011;1(3):327-33. Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.
Goal-Directed Therapy
Diagnosis of PAH
Vasoreactivity test: negative
Baseline exam and 3 - 6 monthly re-evaluation to assess treatment goals:
Clinically stable, FC II, 6-MWD > 400 meters, RAP / CI normal
Treatment goals NOT met
Treatment goals met
Start ERA or PDE-5i
Continue treatment
Add ERA or PDE-5i
Continue treatment
Parenteral PA and / or enrollment
in clinical trials
Continue treatment
Urgent lung transplantation
Adapted from: Hoeper, et al. Eur Respir J. 2005;26:858-63.
Prognostication:
Determinants of Patient Risk
Low Risk
Determinants of Risk
High Risk
No
Clinical evidence of RV failure
Yes
Gradual
Disease progression
Rapid
II, III
Functional class
IV
Longer (> 400 meters)
6-MWD
Shorter (< 300 meters)
Peak VO2 > 10.4 mL/kg/min
CPET
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 cardiography
Pericardial effusion, RV
dysfunction, RA enlargement
RAP < 10 mm Hg;
CI > 2.5 L/min/m2
Pulmonary 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.
Clinical Endpoints
Exercise Capacity
6-MWD
CPET
Treadmill
Functional Class
Imaging
Cardiac MRI
2D
3DE
Gomberg-Maitland, et al. J Am Coll Cardiol. 2013;62(25):S82-91.
Biomarkers
BNP / NT-proBNP
Hemodynamics
(PVR, PAP, CO)
Clinical Variables
Quality of life
TTCW
Longitudinal Patient Monitoring:
ACCF / AHA Recommendations
Patient
Evaluation
Stable
patient
6-MWD
FC
BNP
ECHO
RHC
Every 3-6
months
Every
visit
Every
visit
Center
dependent
Every 12
months
If clinical
deterioration
Unstable Every 1-3
patient months
Every
visit
Every
visit
Center
dependent
Every 6-12
months
Every 6-12
months or if
deterioration
McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573-1619. McLaughlin. Am J Cardiol. 2013;111:S10-5.
Treatment Goals:
Consensus From 5th WSPH
6-MWD
CPET
FC
BNP
ECHO
Hemodynamics
Peak VO2 >
> 380 –
15 mL/min/kg
I or II
440 meters EqCO2 < 45
L/min
Normal
levels
Normal or near
normal RV size
and function
RAP < 8 mm Hg
CI > 2.5 - 3 L/min/m2
McLaughlin, et al. J Am Coll Cardiol. 2013;62(25):S73-81.
Summary
• Expedient diagnosis sets in motion timely and focused
patient care.
• The continuum of RV impairment in PAH must be met
with aggressive action towards reversal.
• The evidence-based treatment algorithm provides a
foundation for disease management.
• Upfront combination therapy may become the standard
of care for patients.
• In order to capture and address any subtle change in a
patient’s clinical condition, comprehensive patient
monitoring is essential.