Upload
michelle-stiller
View
217
Download
2
Tags:
Embed Size (px)
Citation preview
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 andSupportive 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 andSupportive Therapy
Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.
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
General Measures andSupportive Therapy
Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.
Supportive Therapy
• Anticoagulants
• Diuretics
• Oxygen
• Digoxin
General Measures andSupportive Therapy
Adapted from: Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.
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
General Measures andSupportive Therapy
Agarwal, et al. Am Heart J. 2011;162:201-13. Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.
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
• TherapeuticsAmlodipine 20 – 30 mg/day
Nifedipine 180 – 240 mg/day
Diltiazem 720 – 960 mg/day
Mechanisms of Pathology for PAH
Adapted from: 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
GTPsGC stimulator
Prostacyclin Pathway
• Prostacyclin– Produced primarily by endothelial cells– Induces potent vasodilation of vascular beds– Inhibits platelet aggregation– Cytoprotective and antiproliferative properties
• Prostacyclin analogs
Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.
Epoprostenol Continuous IV infusion, inhalation
Iloprost Inhalation
Treprostinil Subcutaneous, IV, inhalation, oral
Endothelin Pathway
• Endothelin– Plasma levels are elevated in patients with PAH– Increases vasoconstriction– Mitogenic properties
• Endothelin receptor antagonists
Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.
Bosentan Oral
Ambrisentan Oral
Macitentan Oral
Nitric Oxide Pathway
• Nitric oxide – Impairment of nitric
oxide (NO) synthesis and signaling in patients with PAH
– Mediated through the NO-sGC-cGMP pathway
NOS NO
sGC cGMP
Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.
L-Arginine L-Citrulline
GMPVasodilation
PDE-5
Nitric Oxide Pathway
• Phosphodiesterase-5 inhibitors– Inhibit the cGMP degrading enzyme, PDE-5– Enhance the pathway, slowing cGMP
degradation– Vasodilation and antiproliferative effects
• Soluble guanylate cyclase stimulators– Increase cGMP production– Antiproliferative and antiremodeling properties
Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.
Sildenafil Oral, IV
Tadalafil Oral
Riociguat Oral
Evidence-Based Treatment Algorithm
Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.
WHO FC II WHO FC III WHO FC IV
BosentanAmbrisentanMacitentanSildenafilTadalafilRiociguat
BosentanAmbrisentanMacitentanSildenafilTadalafilRiociguatEpoprostenol IVIloprost inhalationTreprostinil sc, inhalation
Epoprostenol IV
Treprostinil IV BosentanAmbrisentanMacitentanSildenafilTadalafilRiociguatIloprost inhalationTreprostinil sc, inhalation, IV
Initial combination therapy Initial combination therapy
Sequential Combination Therapy
Interventional Procedure
IA/B
IIbC
IIaC
ERA
PA PDE-5isGCS
BAS
Lung Transplantation
Inadequate clinical response
Inadequate clinical response onmaximal therapy
+ +
+
Lung Transplantation
Interventional Procedure
Sequential Combination Therapy
39
Initial Therapy for PAHWHO FC II WHO FC III WHO FC IV
BosentanAmbrisentanMacitentanSildenafilTadalafilRiociguat
BosentanAmbrisentanMacitentanSildenafilTadalafilRiociguatEpoprostenol IVIloprost inhalationTreprostinil sc, inhalation
Epoprostenol IV
Treprostinil IV BosentanAmbrisentanMacitentanSildenafilTadalafilRiociguatIloprost inhalationTreprostinil sc, inhalation, IV
Initial combination therapy Initial combination therapy
Galie, et al. J Am Coll Cardiol. 2013;62(25):S60-72.
IA/B
IIbC
IIaC
Strength of recommendation
and clinical evidence
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
100
80
60
40
20
0Weeks
Epoprostenol (N = 41)
0 2 4 6 8 1210
Conventional therapy (N = 40)
Pat
ien
t S
urv
ival
(%
)
P = 0.003
Barst, et al. N Engl J Med. 1996;334:296-301.
Epoprostenol for PAHPatient Survival
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)
Simonneau, et al. Am J Respir Crit Care Med. 2002;165:800-4.
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
N = 470
Treprostinil IV for PAH
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*P < 0.05
Treprostinil Inhalation for PAH:TRIUMPH Clinical Trials
RCT1
• 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
Open-label extension2
• N = 206
• Treprostinil with bosentan (69%)
or sildenafil (31%) for 24 months
• Study results – treatment benefit
and improvements in 6-MWD,
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– Randomized, double-
blind, placebo-controlled study
– N = 228 treatment-naïve patients, no background therapy permitted
– Study duration = 12 weeks
Jing, et al. Circulation. 2013;127:624-33.Weeks
Change in 6-MWD
Cha
nge
from
Bas
elin
e (m
eter
s)
*P < 0.05
*
*
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 PAHComposite Primary Endpoint (at Week 12)
26
43
8
25
13
4 4
19
0
5
10
15
20
25
30
35
40
45
10% Improvementin 6-MWD
Improvement inFunctional Class
Death or ClinicalWorsening
Composite PrimaryEndpoint
Placebo
Iloprost
Olschewski, et al. N Engl J Med. 2002;347:322-9.
Res
pond
ers
(% P
atie
nts)
P = 0.0033N = 203
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
62.5 mg twice daily 125 or 250 mg twice daily
-40
-20
0
20
40
60
80
Bosentan (N = 144)
Placebo (N = 69)
4 8 16 Weeks
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 PAH:EARLY Clinical Trial
Change in 6-MWD (From Baseline to Week 24)
10
5
0
5
10
15
20
12 Weeks 24 Weeks
Placebo (N = 91)
Bosentan (N = 86)P = 0.076
25
20
15Cha
nge
from
Bas
elin
e (m
eter
s)
Galie, et al. Lancet. 2008.371(9630):2093-100.Valerio et al. Vasc Health Risk Manag. 2009;5:607-19.
11.2
- 7.9
Bosentan for PAH:EARLY Clinical Trial
Time to Clinical Worsening (From Baseline to Week 32)
100
80
60
40
20
00 4 8 12 16 20 2824 32
Eve
nt-F
ree
Pat
ient
s (%
)
Placebo
Bosentan
P < 0.02
Weeks
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
• Indication – functional class II, III, and IV
• Administration – oral
• Dosage = 5 mg and 10 mg 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
5 mg
Placebo
N = 202
4 8 12 Weeks
5 mg
2.5 mg
Placebo
-20
0
20
40
60 N = 192
Cha
nge
from
Bas
elin
e (m
eter
s)
ARIES-1 ARIES-2 *P < 0.05
44*
23*
-8
49*
22*
-10
Ambrisentan for PAH:ARIES Clinical Trials
Time to Clinical Worsening (From Baseline to Week 12)
--- 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-3 Clinical Trial
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.
Patient Population (N = 224)
Ambrisentan for PAH:ARIES-E Clinical Trial
Change in 6-MWD (From Baseline to 24 Months)C
hang
e fr
om B
asel
ine
(met
ers) 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
23
28
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
• N = 742• Macitentan 3 mg or 10 mg
once daily• Study duration = event
driven• Study endpoint = time to
clinical worsening
Open-label extension2
• 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)
Overall risk reduction:
With background therapy
Without background therapy
17%
47%
38%
55%
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
Galie, et al. N Engl J Med. 2005;353:2148-57.
Pla
ceb
o-A
djus
ted
Cha
nge
from
Bas
elin
e (m
ete
rs)
Change in 6-MWD
P < 0.05
Change in Functional Class
Pat
ient
s W
ith a
n Im
prov
emen
tIn
Fun
ctio
nal C
lass
(%
)
P < 0.05
Sildenafil for PAH:SUPER-2 Clinical Trial
Study Design• 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)
Study Results• 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• 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
Study Results• 6-MWD
– 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*
Simonneau, et al. Ann Intern Med. 2008;149(8):521-30.
*P < 0.05
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• Randomized, double-blind,
placebo-controlled study• Tadalafil in combination
with bosentan (N = 216) compared to tadalafil monotherapy (N = 189)
• Study duration = 16 weeks
Study Results• 6-MWD
– 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.
*P < 0.05(40 mg dose)
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
Study Results• 6-MWD
– Sustained improvement through long-term extension (68 weeks total)
• Clinical worsening events– Significantly less in
patients on combination therapy
Oudiz, et al. J Am Coll Cardiol. 2012;60:768-74.
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
Significant Improvement*
PVR
NT-proBNP
Functional class
Borg Dyspnea Scale score
Quality of life measures
Time to clinical worsening
Ghofrani, et al. NEJM. 2013;369(4):330-40.
Change in 6-MWD
P < 0.05
Cha
nge
from
Bas
elin
e (m
eter
s)
N = 443*P < 0.05
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
• 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
Combination Therapy for PAH
Clinical Study Agents N
Study Duration Study Endpoints
Statistical Significance
BREATHE-21 EpoprostenolBosentan 33 16 weeks Hemodynamics, 6-MWD,
functional class No
STEP-12 IloprostBosentan 67 12 weeks Hemodynamics, 6-MWD,
functional class, TTCW Yes
COMBI3 IloprostBosentan 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 ofCombination 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 StatusStudy
Design Agents NStudy
DurationStudy
Endpoints
COMPASS-21 Ongoing RCT Sildenafil +/-Bosentan 334 Event
driven TTCW
COMPASS-32 Completed OL Bosentan +/-Sildenafil 100 28 weeks 6-MWD
NCT00323297 Completed RCTBosentan +/-
Sildenafil 104 12 weeks 6-MWDTTCW
FREEDOM-Ev3 Ongoing RCT*• Treprostinil oral +
PDE-5i or ERA• PDE-5i or ERA
858 Event driven
TTCW6-MWD
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 transplantationGalie, 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 forLung 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 TransplantationLong, et al. Pulm Circ. 2011;1(3):327-33.
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
Add ERA or PDE-5i
Parenteral PA and / or enrollmentin clinical trials
Urgent lung transplantation
Continue treatment
Continue treatment
Continue treatment
Goal-Directed Therapy
Adapted from: Hoeper, et al. Eur Respir J. 2005;26:858-63.
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 hemodynamicsRAP > 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.
Prognostication: Determinants of Patient RiskACC / AHA Expert Consensus
REVEAL Risk CalculatorParameter Low risk Score High risk Score
Type of PAHHeritableCTDPortal hypertension
+2+1+2
Demographics/Comorbidities
Male > 60 years oldRenal insufficiency
+2+1
Functional class I -2 IIIIV
+1+2
Vital signs SBP < 110 mm HgHR > 92 bpm
+1+1
6-MWD ≥ 440 meters -1 < 165 meters +1
BNP < 50 pg/mL -2 > 180 pg/mL +1
ECHO Pericardial effusion +1
PFT % pred DLCO ≥ 80% -1 % pred DLCO ≤ 32% +1
RHC mPAP > 20 mm HgPVR > 32 WU
+1+2
Benza, et al. Circulation. 2010;122:164-72. Benza, et al. Chest. 2012;141:354-62.
Clinical Endpoints
Exercise Capacity6-MWDCPET
Treadmill
Functional Class
BiomarkersBNP / NT-proBNPHemodynamics(PVR, PAP, CO)
ImagingCardiac MRI
2D3DE
Gomberg-Maitland, et al. J Am Coll Cardiol. 2013;62(25):S82-91.
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 MonitoringACCF / AHA Recommendations
Patient Evaluation 6-MWD
Functional Class BNP ECHO RHC
Stable patient
Every 3-6 months
Every visit Every visit Center
dependentEvery 12 months
If clinical deterioration
Unstable patient
Every 1-3 months
Every visit Every visit Center
dependentEvery 6-12
months
Every 6-12 months or if
clinical deterioration
McLaughlin, et al. J Am Coll Cardiol. 2009;53:1573-1619. McLaughlin. Am J Cardiol. 2013;111:S10-5.
Treatment Goals
6-MWD CPETFunctional
Class BNP ECHO Hemodynamics
> 380 – 440 meters
Peak VO2 > 15 mL/min/kg
EqCO2 < 45 L/minI or II Normal
levels
Normal or near normal RV size
and function
RAP < 8 mm HgCI > 2.5 - 3 L/min/m2
McLaughlin, et al. J Am Coll Cardiol. 2013;62(25):S73-81.
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 disease-targeted 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.