Acknowledgements
• ABcomm, Inc. is accredited by the Accreditation
Council for Continuing Medical Education to provide
continuing medical education for physicians.
• Support for this educational activity is provided by an
independent educational grant from Gilead Sciences
Medical Affairs.
Targeted Approach to
Treatment of PAH
Learning Objectives
• Intensify the treatment plan when right ventricular
impairment is evident.
• Adopt a goal-directed treatment approach to adjust the
treatment plan when clinical decompensation occurs.
• Utilize a combination of agents with proven combined
efficacy and an acceptable safety profile.
• Monitor relevant prognostic variables in patients with
PAH.
• Incorporate progressive treatment strategies and
protocols when appropriate.
Lecture Outline
•
•
•
•
•
•
•
General measures and supportive therapy
Pathways and mechanisms of action
Evidence-based treatment algorithm
FDA-approved treatment options
Combination therapy
Prognostication and patient monitoring
Ongoing research
Treatment of PAH
• Complex strategy which includes:
– Evaluation of disease severity
– Adoption of general measures and supportive therapy
– Assessment of vasoreactivity
– Estimation of drug efficacy
– Combination of different drugs and interventions
(e.g. balloon atrial septostomy, lung transplantation)
Ghofrani, et al. Int J Cardiol. 2011;154(1):S20-33.
General Measures and
Supportive Therapy
General measures
Supportive therapy
Referral to specialized PAH patient care center
Cardiac catheterization / Acute vasoreactivity testing
Chronic CCB therapy
Adapted from: Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.
General Measures and
Supportive Therapy
General Measures
• Rehabilitation / Exercise
– Recommended after stabilized and on therapy
– Requires close supervision by an experienced PAH care center
– Optimal method, duration, and intensity of activity are unknown
• Psychosocial support
• Family planning
– Pregnancy is associated with a considerable mortality rate in patients
with PAH, and oral contraceptives are not contraindicated
• Vaccinations
– Influenza and pneumococcal immunization
Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.
General Measures and
Supportive Therapy
Supportive Therapy
• Anticoagulants
• Diuretics
• Oxygen
• Digoxin
Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.
General Measures and
Supportive Therapy
Cardiac Catheterization / Acute Vasoreactivity Testing
• Mandatory in patients with idiopathic PAH, may be
considered in patients with PAH associated conditions
• Identifies patients who will respond to chronic treatment
with high-dose CCBs
• Inhaled nitric oxide (10 – 20 parts per million) is the
preferred testing compound
– Alternates: epoprostenol IV or adenosine IV
Adapted from: Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.
General Measures and
Supportive Therapy
Chronic CCB Therapy
• Responders
– Patients with a positive response to acute vasoreactivity
testing
– Positive response = reduction of mean PAP ≥ 10 mm Hg to
reach a mean PAP ≤ 40 mm Hg with a normalized or
increased cardiac output
– < 10% of patients with idiopathic PAH
• Therapeutics
Amlodipine
20 – 30 mg/day
Nifedipine
180 – 240 mg/day
Diltiazem
720 – 960 mg/day
Agarwal, et al. Am Heart J. 2011;162:201-13. Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.
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
Iloprost
Inhalation
Treprostinil
Subcutaneous, IV, inhalation, oral
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
NOS
L-Citrulline
NO
sGC
PDE-5
cGMP
GMP
Vasodilation
Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.
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
Evidence-Based Treatment Algorithm
WHO FC II
IA/B
Bosentan
Ambrisentan
Macitentan
Sildenafil
Tadalafil
Riociguat
WHO FC III
Bosentan
Ambrisentan
Macitentan
Sildenafil
Tadalafil
Riociguat
Epoprostenol IV
Iloprost inhalation
Treprostinil sc, inhalation
Treprostinil IV
IIaC
WHO FC IV
Epoprostenol IV
Sequential
Sequential
Combination
Combination
Therapy
Therapy
+
PA
Bosentan
Ambrisentan
Macitentan
Sildenafil
Tadalafil
Riociguat
Iloprost inhalation
Treprostinil sc, inhalation, IV
ERA
+
+
PDE-5i
sGCS
Inadequate clinical
response on
maximal therapy
Interventional Procedure
BAS
IIbC
Initial combination therapy
Initial combination therapy
Lung Transplantation
Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.
39
Initial Therapy for PAH
Strength of
recommendation
and clinical
evidence
IA/B
WHO FC II
Bosentan
Ambrisentan
Macitentan
Sildenafil
Tadalafil
Riociguat
WHO FC III
Bosentan
Ambrisentan
Macitentan
Sildenafil
Tadalafil
Riociguat
Epoprostenol IV
Iloprost inhalation
Treprostinil sc, inhalation
Epoprostenol IV
Treprostinil IV
Bosentan
Ambrisentan
Macitentan
Sildenafil
Tadalafil
Riociguat
Iloprost inhalation
Treprostinil sc, inhalation, IV
Initial combination therapy
Initial combination therapy
IIaC
IIbC
WHO FC IV
Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.
Epoprostenol for PAH
• Prostacyclin analog
• Indication – functional class III and IV
• Administration
– Continuous IV infusion via central venous catheter
– Inhalation form is available in the hospital
• Dosage = 20 – 40 ng/kg/min
• Two branded versions of epoprostenol are available:
– One is only stable at room temperature for 8 hours; therefore,
it must be kept cool (ice packs or refrigeration)
– Other is a thermostable formulation
Epoprostenol for PAH
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
Treprostinil for PAH
• Prostacyclin analog
• Indication – functional class II, III, and IV
• Administration
–
–
–
–
Subcutaneous (SC)
IV
Inhalation
Oral (extended-release tablets; twice daily dosing)
• Dosage
– Initial dosage = 1.25 ng/kg/min
– Usual dosage = 30 – 100 ng/kg/min
Treprostinil SC for PAH
Change in 6-MWD (From Baseline to Week 12)
40
36.1
N = 470
35
P = 0.03
30
25
20
20
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
N = 14
*P < 0.05
Change in Functional Class
Number of Patients
Change from Baseline (meters)
Change in 6-MWD*
Weeks
Tapson, et al. Chest. 2006;129:683-8.
Baseline
12 Weeks
Treprostinil Inhalation for PAH:
TRIUMPH Clinical Trials
RCT1
Open-label extension2
• N = 212 patients who were
symptomatic on bosentan or
sildenafil
• Addition of treprostinil up to 54
μg, four times daily for 12
weeks
• Study results – significantly
greater improvement in 6-MWD
and quality of life with
combination therapy
• N = 206
• Treprostinil with bosentan
(69%) or sildenafil (31%) for 24
months
• Study results – treatment
benefit and improvements in 6MWD, symptoms, functional
class, and quality of life were
maintained for 24 months
1) McLaughlin, et al. J Am Coll Cardiol. 2010;55(18):1915-22. 2) Benza, et al. J Heart Lung Transplant. 2011;30(12):1327-33.
Treprostinil Oral for PAH:
FREEDOM-C Clinical Trial
• Study design
– Randomized, double-blind, placebo-controlled study
– 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)
– Randomized, doubleblind, placebo-controlled
study
– 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.
Iloprost for PAH
• Prostacyclin analog
• Indication – functional class III and IV
• Administration
– Ultrasonic nebulizer used in well-ventilated areas
– Theoretical advantage of pulmonary vs systemic drug delivery
• Dosage
– Usual dosage = 2.5-5 μg, 6 to 9 times daily
– Maximum dosage = 45 μg
Iloprost for PAH
Composite Primary Endpoint (at Week 12)
Responders (% Patients)
45
43
40
35
P = 0.0033
30
25
20
26
25
19
15
10
5
0
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
N = 203
Placebo
Iloprost
Bosentan for PAH
• Endothelin receptor antagonist
• Indication – functional class II, III, and IV
• Administration – oral
• Dosage = 62.5 mg twice daily for 4 weeks, then
titrate to 125 mg 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
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
Change in 6-MWD (From Baseline to Week 24)
Change from Baseline (meters)
25
20
15
11.2
10
Bosentan (N = 86)
P = 0.076
5
0
5
10
- 7.9
15
20
12 Weeks
Galie, et al. Lancet. 2008.371(9630):2093-100.
Valerio et al. Vasc Health Risk Manag. 2009;5:607-19.
Placebo (N = 91)
24 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
Galie, et al. Lancet. 2008.371(9630):2093-100.
Valerio et al. Vasc Health Risk Manag. 2009;5:607-19.
16
20
24
28
32 Weeks
Ambrisentan for PAH
• Endothelin receptor antagonist
• Indication – functional class II, III, and IV
• Administration – oral
• Dosage = 5 mg and 10 mg daily
Ambrisentan for PAH
Change in 6-MWD (From Baseline to Week 12)
ARIES-1
Change from Baseline (meters)
50
ARIES-2
N = 202
44*
60
*P < 0.05
N = 192
49*
10 mg
5 mg
40
23*
25
22*
5 mg
2.5 mg
20
0
0
-8
Placebo
-10
Placebo
-20
-25
4
8
Galie, et al. Circulation. 2008;117:3010-9.
12 Weeks
4
8
12 Weeks
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
• Change in 6-MWD from
baseline to week 24
– Increased by 21 meters
(P < 0.05)
• Change in BNP levels from
baseline to week 24
– Decreased by 26%
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
0
-10
-20
28
23
7
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
• Endothelin receptor antagonist
– Sustained receptor binding and enhanced tissue
penetration
• Indication – functional class II, III, and IV
• Administration – oral
• Dosage = 10 mg daily
Macitentan for PAH:
SERAPHIN Clinical Trials
RCT1
Open-label extension2
• N = 742
• Macitentan 3 mg or 10 mg
once daily
• Study duration = event
driven
• Study endpoint = time to
clinical worsening
• N = 550
• Macitentan 10 mg once
daily
• Study duration = event
driven
• Study endpoint = safety
1) www.clinicaltrials.gov/ct2/show/NCT00660179 2) www.clinicaltrials.gov/ct2/show/NCT00667823
Macitentan for PAH:
SERAPHIN Clinical Trial
3 mg
10 mg
N = 250
N = 242
Duration of treatment (event driven)
99.5 weeks
103.9 weeks
Risk reduction in the occurrence of
morbidity and mortality events
versus placebo (N = 250)
30%
(P < 0.05)
45%
(P < 0.05)
 With background therapy
17%
38%
 Without background therapy
47%
55%
Overall risk reduction:
Pulido, et al. NEJM. 2013;369(9):809-18.
Sildenafil for PAH
• Phosphodiesterase-5 inhibitor – targets the nitric
oxide pathway
• Indication – functional class II, III, and IV
• Administration and dosage
– Oral = 20 mg three times daily
– IV = 10 mg three times daily
Sildenafil for PAH:
SUPER-1 Clinical Trial
Change in Functional Class
Change in 6-MWD
Galie, et al. N Engl J Med. 2005;353:2148-57.
Patients With an Improvement
In Functional Class (%)
Placebo-Adjusted Change
from Baseline (meters)
P < 0.05
P < 0.05
Sildenafil for PAH:
SUPER-2 Clinical Trial
Study Design
Study Results
• Long-term, open-label
extension
• N = 170 patients who
completed both studies
• Sildenafil 80 mg three times
daily
• Second agent added in
18% of patients by end of
study period (3 years)
• 6-MWD
– Maintained or improved
in 46% of patients
• Functional class
– Maintained or improved
in 60% of patients
• Estimated patient survival
rate at 3 years = 79%
Rubin, et al. Chest. 2011:140(5):1274-83.
Sildenafil for PAH:
PACES Clinical Trial
Study Design
Study Results
• Randomized, double-blind,
placebo-controlled study
• Sildenafil 80 mg three times
daily in combination with
epoprostenol (N = 214)
compared to epoprostenol
monotherapy (N = 53)
• Study duration = 16 weeks
• 6-MWD
Simonneau, et al. Ann Intern Med. 2008;149(8):521-30.
*P < 0.05
– Placebo-adjusted
improvement = 28 meters*
• Clinical worsening event
– 6% vs 18.5% of patients on
monotherapy*
• Time to clinical worsening
– Significant delay compared to
monotherapy*
Tadalafil for PAH
• Phosphodiesterase-5 inhibitor – targets the nitric
oxide pathway
• Indication – functional class II, III, IV
• Administration – oral
• Dosage = 40 mg daily
Tadalafil for PAH:
PHIRST-1 Clinical Trial
Study Design
Study Results
• Randomized, double-blind,
placebo-controlled study
• Tadalafil in combination
with bosentan (N = 216)
compared to tadalafil
monotherapy (N = 189)
• Study duration = 16 weeks
• 6-MWD
*P < 0.05
(40 mg dose)
– Significant improvement* but
less than monotherapy
• Quality of life
– Significant improvement
• Clinical worsening events
– Significantly less*
– 68% relative risk reduction
• Time to clinical worsening
– Significant delay*
Galie, et al. Circulation. 2009;119(22):2894-903.
Barst, et al. J Heart Lung Transplant. 2011;30(6):632-43.
Tadalafil for PAH:
PHIRST-2 Clinical Trial
Study Design
• Long-term, open-label
extension
• N = 293 patients from
PHIRST-1
• Tadalafil 20 mg or 40 mg
once daily
• Background bosentan
permitted (54% of patients)
• Study duration = 52 weeks
Oudiz, et al. J Am Coll Cardiol. 2012;60:768-74.
Study Results
• 6-MWD
– Sustained improvement
through long-term
extension (68 weeks total)
• Clinical worsening events
– Significantly less in
patients on combination
therapy
Riociguat for PAH
• Soluble guanylate cyclase stimulator – targets the
nitric oxide pathway
• Indication – functional class II, III, and IV
• Administration – oral
• Dosage = 1 mg – 2.5 mg three times daily
Riociguat for PAH:
PATENT Clinical Trials
RCT1
• N = 445
• Riociguat 1 mg, 1.5 mg,
2 mg, or 2.5 mg three
times daily
• Study duration = 12
weeks
• Study endpoint = 6-MWD
Open-label extension2
• N = 396
• Riociguat 1 mg, 1.5 mg,
2 mg, or 2.5 mg three
times daily
• Study duration = event
driven
• Study endpoint = safety
1) www.clinicaltrials.gov/ct2/show/NCT00810693 2) www.clinicaltrials.gov/ct2/show/NCT00863681
Riociguat for PAH:
PATENT Clinical Trial
Change from Baseline (meters)
Change in 6-MWD
N = 443
*P < 0.05
P < 0.05
Ghofrani, et al. NEJM. 2013;369(4):330-40.
Significant Improvement*
PVR
NT-proBNP
Functional class
Borg Dyspnea Scale score
Quality of life measures
Time to clinical worsening
Combination Therapy for PAH
• To target multiple disease pathways
• Used when therapy needs to be augmented
because response to initial therapy is inadequate
• Sequential combination therapy
– Starting in one drug class and adding an agent from
another drug class when necessary
• REVEAL: 34% of patients on 2 or more treatments
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
Clinical
Study
Agents
N
Study
Duration
Study Endpoints
Statistical
Significance
BREATHE-21
Epoprostenol
Bosentan
33
16 weeks
Hemodynamics, 6-MWD,
functional class
No
STEP-12
Iloprost
Bosentan
67
12 weeks
Hemodynamics, 6-MWD,
functional class, TTCW
Yes
COMBI3
Iloprost
Bosentan
40
12 weeks
6-MWD, functional class,
TTCW
No
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.
Early Initiation of
Combination Therapy for PAH
• Combination therapy used in early PAH disease
• Debated by clinicians and researchers
• May improve patient outcomes
• May prevent or slow disease progression
• May reduce costs associated with managing clinical
worsening
• Well-controlled studies are needed to test this practice
Affuso, et al. World J Cardiol. 2010;2(3):68-70.
Combination Therapy for PAH
Clinical Study
Status
Study
Design
Study
Study
Duration Endpoints
Agents
N
RCT
Sildenafil +/Bosentan
334
Event
driven
TTCW
COMPASS-21
Ongoing
COMPASS-32
Completed
OL
Bosentan +/Sildenafil
100
28 weeks
6-MWD
NCT00323297
Completed
RCT
Bosentan +/Sildenafil
104
12 weeks
6-MWD
TTCW
858
Event
driven
TTCW
6-MWD
FREEDOM-Ev3
Ongoing
RCT*
• Treprostinil oral +
PDE-5i or ERA
• PDE-5i or ERA
AMBITION4
Ongoing
RCT*
Ambrisentan +/Tadalafil
614
Event
driven
TTCW
ATHENA-15
Completed
OL
Sildenafil or Tadalafil
+/- Ambrisentan
38
24 weeks
PVR
1) NCT00303459; 2) NCT00433329; 3) NCT01560624; 4) NCT01178073; 5) NCT00617305 *Early combination therapy
Interventional Procedures:
Balloon Atrial Septostomy
• In order to:
–
–
–
–
–
Decompress right heart chambers
Increase left ventricle preload
Increase cardiac output
Improve systemic oxygen transport
Decrease sympathetic hyperactivity
• Creation of an interatrial right-to-left shunt
• 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
– Bilateral lung transplant – most common
– Heart-lung transplant – increasingly less common, with
about 70 – 90 performed every year*
• Lung transplantation remains the standard of care
for patients with PAH who fail aggressive medical
therapy, until the age of 75 (depending on 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.
ISHLT Guidelines for
Lung Transplantation
 Persistent functional class III or IV despite maximal
medical therapy
 Low (< 350 meters) or declining 6-MWD
 Failing even while on a parenteral prostacyclin analog
 Cardiac index < 2 L/min/m2
 Right atrial pressure > 15 mm Hg
ISHLT = International Society for Heart Lung Transplantation
Long, et al. Pulm Circ. 2011;1(3):327-33.
Goal-Directed Therapy
Diagnosis of PAH
Vasoreactivity test: negative
Baseline exam and 3 - 6 monthly re-evaluation to assess treatment goals:
Clinically stable, functional class II, 6-MWD > 400 meters, RAP / CI normal
Treatment goals NOT met
Treatment goals met
Start ERA or PDE-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
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 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.
REVEAL Risk Calculator
Parameter
Low risk
Score
High risk
Score
Type of PAH
Heritable
CTD
Portal hypertension
+2
+1
+2
Demographics/
Comorbidities
Male > 60 years old
Renal insufficiency
+2
+1
III
IV
+1
+2
SBP < 110 mm Hg
HR > 92 bpm
+1
+1
Functional class
I
-2
Vital signs
6-MWD
≥ 440 meters
-1
< 165 meters
+1
BNP
< 50 pg/mL
-2
> 180 pg/mL
+1
Pericardial effusion
+1
% pred DLCO ≤ 32%
+1
mPAP > 20 mm Hg
PVR > 32 WU
+1
+2
ECHO
PFT
RHC
% pred DLCO ≥ 80%
-1
Benza, et al. Circulation. 2010;122:164-72. Benza, et al. Chest. 2012;141:354-62.
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
Time to Clinical Worsening
• Composite endpoint of adverse clinical events:
- Death
- Lung transplantation
- Hospitalization for worsening PAH
- Initiation of IV therapy due to worsening PAH
- Worsening of function
- Worsening of PAH symptoms
Gomberg-Maitland, et al. J Am Coll Cardiol. 2013;62(25):S82-91.
Longitudinal Patient Monitoring
ACCF / AHA Recommendations
Stable
patient
Unstable
patient
Patient
Evaluation
6-MWD
Every 3-6
months
Every
visit
Every 1-3
months
Every
visit
Functional
Class
Every visit
Every visit
BNP
ECHO
RHC
Center
dependent
Every 12
months
If clinical
deterioration
Every 6-12
months
Every 6-12
months or if
clinical
deterioration
Center
dependent
McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573-1619. McLaughlin. Am J Cardiol. 2013;111:S10-5.
Treatment Goals
6-MWD
CPET
> 380 – 440
meters
Peak VO2 > 15
mL/min/kg
EqCO2 < 45 L/min
Functional
Class
I or II
McLaughlin, et al. J Am Coll Cardiol. 2013;62(25):S73-81.
BNP
ECHO
Hemodynamics
Normal
levels
Normal or near
normal RV size
and function
RAP < 8 mm Hg
CI > 2.5 - 3 L/min/m2
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
Investigational Agents for PAH
Selexipag
• Prostacyclin IP receptor
agonist
• Targets the prostacyclin
pathway
• GRIPHON clinical trials1,2
• Research is ongoing
Imatinib
• Tyrosine kinase inhibitor
• PDGF receptor inhibitor
(vascular remodeling)
• Antiproliferative
• IMPRES clinical trials3,4,5
• Regulatory consideration
has been terminated
1) NCT01106014; 2) NCT01112306; 3) NCT00902174; 4) NCT01117987; 5) Hoeper, et al. Circulation. 2013;127(10):
1128-38.
Summary
• Management of patients with PAH involves a complex
strategy which includes supportive therapy and diseasetargeted medications.
• The evidence-based treatment algorithm for PAH
streamlines decision making and drug selection.
• Combination therapy is the standard of care when initial
therapy becomes inadequate.
• Prognostication and patient monitoring involves the use
of clinically-relevant parameters and endpoints.