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RON OUDIZ, MDRON OUDIZ, MDAssociate Professor of Medicine
David Geffen School of Medicine at UCLA LA Biomedical Research Institute at
Harbor-UCLA Medical CenterTorrance, California
Long-term Management of Patients with PAH
2
Learning Objectives (CME, CE, CPE)
● At the completion of this educational activity, participants should be able to:
& Discuss the data regarding long-term medical therapy for PAH
& Describe the limitations to the long-term data of medical therapy for PAH
& Report on the data regarding combination medical therapy for PAH
& Discuss interventional and surgical approaches to PAH
Trends in Long-term Survival with PAH
4
Updated Definition of PAH
Adapted from Badesch DB, et al. J Am Coll Cardiol. 2009;54(suppl 1):S55–S66Adapted from McLaughlin VV, et al. Circulation. 2009;119(16):2250-2294.
Increased mean pulmonary arterial pressure (mPAP)*
>25 mm Hg at rest
Normal pulmonary capillary wedge pressure (PCWP)
<15 mm Hg
Increased pulmonary vascular resistance (PVR)†
>3 Wood units
Right Heart Catheterization Confirmed
* Normal resting mPAP = 8 – 20 mm Hg. † In ACCP/AHA expert consensus; in 4th World Symposium on PH, increased PVR given without a value. Significance of mPAP from 21 – 24 mm Hg unclear.
5
Survival of PAH Patients in Current Era: Comparison with NIH Historical Controls
Thennapan T, et al. Chest. 2007;132(4 suppl):487S.
N = 276, IPAH and FPAH patients diagnosed from 1982-2006; matched for disease variables at baseline with historical controls
6765
32
10091
76
43
0
10
20
30
40
50
60
70
80
90
100
Baseline 1 year 3 year 5 year
Per
cen
tag
e (%
) S
urv
ival Observed
Predicted (NIH)
^
6
PAH Survival in Current Era: Insights from REVEAL Registry
● REVEAL is an ongoing registry of patients with PAH
● Participating centers include 54 major PAH referral sites in the US
● >3000 patients screened; initial data set includes 2967 patients meeting entry criteria
Badesch DB et al. Chest. 2009; DOI 10.1378/chest.09-1140. E-pub ahead of print.
7
REVEAL: Heritable (Familial) PAH and IPAH Comparisons
Sarkar PK. Presented at Chest 2009. Oct. 31 – Nov. 5, 2009. San Diego CA. #8906
^
Two-year Survival HPAH/IPAH
HPAH IPAHAge at diagnosis, years 37 + 16 47 + 18mPAP at diagnosis, mm HG 57 + 14 53 + 14PVRI at diagnosis, units.m2 29 + 13 23 + 12Use of parenteral prostacyclins, % 51 35
IPAH 1439 1403 1345 1325 1288 1244 1225 1182 1130 1117 1052 961 953
FPAH 91 90 89 87 82 78 77 73 71 70 65 62 62
100
90
IPAH, n=1439FPAH, n=91
0
Per
cen
tag
e (%
) S
urv
ival
80
240 2 4 6 8 10 12 14 16 18 20 22Time from Enrollment (month)
Number at Risk
Key HPAH/IPAH Comparisons in REVEAL
100
90
IPAH, n=1439FPAH, n=91
0
Per
cen
tag
e (%
) S
urv
ival
80
240 2 4 6 8 10 12 14 16 18 20 22Time from Enrollment (month)
Number at Risk
P=0.14
8
REVEAL Registry: Two-year Survival of SSc-PAH and SLE-PAH
Chung L. Presented at the ACR/ACHP Scientific Meeting. Oct. 17-21, 2009. Philadelphia, PA. 1730.
^
Per
cen
tag
e (%
) S
urv
ival
SSc-APAH (n=399)SLE-APAH (n=110) log rank P value =0.0009
0 2 4 6 8 10 12 14 16 18 20 22 240
50
60
70
80
90
100
Time from Enrollment (months)
9
REVEAL: Outcomes of PAH Due to Anorexigen Use
Barst RJ. Presented at Chest 2009. Oct. 31 – Nov. 5, 2009. San Diego CA. #8379
Females aged 19 and over at diagnosis
^
Fen/Dex Exposure 75 73 71 71 68 68 65 64 63 63 61 55 55
IPAH/FPAH 609 604 595 588 580 569 561 553 542 535 513 466 463
Number at Risk Time from Enrollment (month)
Fen/Dex Exposure, n=75IPAH/FPAH, n=609P
erce
nta
ge
(%)
Su
rviv
al 100
90
0
80
240 2 4 6 8 10 12 14 16 18 20 22
10
Gender Differences in PAH 5-year Mortality: REVEAL Registry
Shapiro S, et al. Am J Respir Crit Care Med. 179;2009:A2648.
Time from Diagnosis (Years)
Per
cen
tag
e (
%)
Mo
rtal
ity
Mortality EstimateMale (n=649)Female (n=2318)
0 1 2 3 4 50
5
10
15
20
25
30
35
40
45
50
^
Measuring Outcomes in PAH Therapy
12
Goals of Management of PAH
● Improve survival
● Prevent clinical worsening
● Improve hemodynamics (right-heart function)
● Maintain or improve functional class
● Improve exercise capacity
● Improve daily functioning and quality of life
13
The Problem is…
● Clinical trial endpoints do not necessarily study endpoints that are relevant to the goals of clinical management
● Definition of “clinical worsening” and related terms can be very variable across clinical trials
● Functional class assessment is subjective
● 6MWD test has inherent problems in reproducibility and correlation with disease severity
● Accurate hemodynamic measurements are invasive; improvements do not necessarily correlate with clinical status
McLaughlin VV, et al. J Am Coll Cardiol. 2009; 54 (Suppl S):S97–S107.
14
Prognostic Factors for Risk ofPAH Disease Progression
Adapted from McLaughlin VV, et al. Circulation. 2009;119:2250-2294.
Lower Risk Higher Risk
Evidence of RV failure No YesProgression of symptoms
Gradual Rapid
WHO class II, III IV6-minute walk distance >400 m <300 m
CPET peak VO2>10.4 mL/kg/min <10.4 mL/kg/min
Echo findings Minimal RV dysfunction
Pericardial effusion; significant RV
dysfunction, RA enlargement
Hemodynamics RAP <10 mm Hg, CI >2.5 L/min/m2
RAP >20 mm Hg,CI <2.0 L/min/m2
Brain natriuretic peptide Minimal elevation Significantly elevated
15
Change in 6MWD Did Not Predict Survival in Long-term Epoprostenol Therapy
Sitbon O, et al. J Am Coll Cardiol. 2002;40:780–788.
78
78
63
60
48
35
31
25
19
16
13
8
5
2
2
1
1Subjects at risk, n
∆ 6’ WT ≥ 112 m
∆ 6’ WT < 112 m
∆ 6’ WT < 112 m
∆ 6’ WT ≥ 112 m
Su
rviv
al
0
0.4
0.6
0.8
1.0
0.2
(Months)0 1089684726048362412
16
Long-term Management of PAH: Recommended Tests
Adapted from Galie N, et al. Eur Heart J. 2009;30:2493-2537.
Baseline Ea 4 – 6 months
3 – 4 months after therapy initiation or
change
@ clinical worsening
Clinical AssessmentWHO functional class
ECG
6MWD
CPET
BNP/NT-proBNP
Echo
Right heart catheterization
or
PAH Therapy
18
Mechanisms of Action ofTherapies for PH
Humbert M, et al. N Engl J Med. 2004;351:1425-1436.
Nitric oxide
cGMP
Vasodilation and antiproliferation
Endothelial cells
Nitric oxide pathway
Preproendothelin ProendothelinL-arginine
NOS
Arachidonic acid Prostaglandin I2
Prostaglandin I2
cAMPVasodilation and antiproliferation
Vasoconstriction 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
19
REVEAL Database: Therapy Choices at Enrollment
PDE5 Inhibitor ERA
305
417 452290
190
224
At-enrollment therapy of first 2438 patients in REVEAL. Excludes patients enrolled in blinded controlled trials.
Prostacyclin (IV, IM and Inhaled)
295No PAH Therapy = 266
Badesch DB, et al. Chest. 2009; DOI 10.1378/chest.09-1140. Epub ahead of print.
^
PAH Monotherapy
21
PAH Long-term Monotherapy Trials - Caveats
● Most long-term trials were open-label extensions of placebo-controlled trials without a comparator arm
● All trials allowed add-on therapy in the setting of clinical worsening
- Some trials do not define add-on therapy as a clinical endpoint
● The relative contribution of the “primary” study medication is therefore difficult to assess
22
Intravenous Epoprostenol forSevere PAH: 3-Year Survival
N=162 consecutive patients with IPAH in NYHA Class III or IV. 3-year survival with IV epoprostenol compared with expected survival from NIH historical controls. *P<0.001 at all time points.
McLaughlin VV, et al. Circulation. 2002;106:1477-1482.
0 6 12 18 24 30 36Months
20
40
60
80
100
Per
cen
tag
e (%
) S
urv
ival
*
*
*
ObservedExpected
23
Long-Term OutcomesWith Subcutaneous Treprostinil
Barst RJ, et al. Eur Respir J. 2006;28:1195-1203.
0
10
20
30
Pat
ien
ts (
%)
Discontinue forDeterioration
Death
N=860.Patients followed for up to 4 years.
SwitchTherapy
AddTherapy
Discontinue forAdverse Events
14%16%
11%
15%
23%
24
Long-term Inhaled Iloprost In IPAH:Event-free Survival
Opitz CF, et al. Eur Heart J. 2005;26:1895-1902.
Event-free = freedom from death, transplantation, switch to intravenous therapy, or addition of oral therapy to inhaled iloprost monotherapy.
Cu
mu
lati
ve E
ven
t-F
ree
Su
rviv
al (
%)
Time (Years)
0
40
60
80
100
20
0 54321
No. at risk 76 39 20 13 4 2No. of events 0 335 52 58 59 60
25
Survival WithInitial Bosentan Therapy in IPAH
McLaughlin VV, et al. Eur Respir J. 2005;25:244-249.
N=169. Data from 2 placebo-controlled trials and their extensions.Includes 39 patients who received additional therapy instead of or in addition to bosentan.
Bosentan
Predicted
100
Eve
nt-
Fre
e P
atie
nts
(%
) 90
80
70
60
50
40
30
20
0
10
0 6 12 18 24 30 36Months
26
Long-term Outcome with Initial Bosentan Therapy
Provencher S, et al. Eur Heart J. 2006;27:589-595.
Event-free = survival without lung transplantation, initiation of prostanoid therapy, or hospitalization for right-heart failure.
Survival
Event-free
103
103
76
49
48
26
20
11
12
6
0
0
Subjects at risk, n
of mortality
of event
Per
cen
tag
e S
urv
ival
an
dE
ven
t-F
ree
Sta
tus
0
40
60
80
100
20
(Months)
0 6048362412
27
ARIES-E: Survival WithLong-Term Ambrisentan Therapy
Oudiz RJ, et al. J Am Coll Cardiol. 2009;54:1975-1981.
0
20
40
60
80
100
0.0 0.5 1.0 1.5 2.0Years
Su
rviv
al (
%) 2 Year = 88%1 Year = 94%
Combined doses 2.5 mg5 mg10 mg
At Risk: n=383 n=334 n=315 n=298 n=255
^
28
ARIES-E: Long-term Ambrisentan Survival by Etiology
2009 ATS Abstract. Pulido T. Am J Respir Crit Care Med. 179;2009:A3356.
0
Eve
nt
Fre
e (%
)
100
60
0
20
80
40
0.5 1.0 1.5
1 Year94% (90% to 97%)
2.0
91% (82% to 95%)
2 Year89% (83% to 93%)87% (77% to 92%)
YearsAt Risk n=178 n=161 n=151 n=145 n=122At Risk n=94 n=81 n=71 n=69 n=57
IPAHPAH-CTD
^
29
SUPER-2: Sildenafil Open-label Extension Clinical Outcomes at 3 Years
Improved6MWD
Worsened6MWD
Discontinued/Lost
Died
45.8%
17.7% 17.3% 19.1%
0%
20%
40%
60%
80%
100%
Per
cen
tag
e (%
)
N=259.
Rubin LJ. CHEST 2008; October 25-30, 2008, Philadelphia, PA. Session AS2244.
^
30
Long-term Tadalafil: 6MWD by Initial Treatment Assignment
2009 ATS Abstract. Oudiz RJ, et al. Am J Respir Crit Care Med. 179;2009:A1042.
Open-label extension of 16 week blinded study. Most patients titrated to 40 mg qd in open-label phase.
420
400
380
360
340
3200 4 8 10 13 16
Months
Extension Study16-Week Study
Abbreviation: 6MWD = 6-minute walk distance
Mea
n 6
MW
D (
m)
Placebo:40mg
20mg:20mg
2.5-20mg:40mg
40mg:40mg
^
PAH Combination Therapy
32
Combination Therapy Trials Caveats
● No trial to date has studied the question of monotherapy versus de novo combination therapy
● All currently reported trials featured “add-on” protocols
● Relative contribution of individual agents to treatment success difficult to assess
● Combination therapy trials often have only a short-term component, with no long-term follow-up
33
Combination Therapy: Sildenafil Added to Failing Inhaled Iloprost Monotherapy
Ghofrani HA, et al. J Am Coll Cardiol. 2003;42:158-164.
N = 14. Patients with inadequate response to inhaled iloprost.
6 M
inu
te W
alk
Dis
tan
ce (
m)
400
380
360
340
320
300
280
260
240
220
200
180
Inhaled iloprost+ oral sildenafil
p=0.002
p=0.002p=0.014+
+ +
Treatment interval18+/-4 months
Baseline Ilo3 mo. Pre-Sil
Sil-Ilo3 mo.
Sil-Ilo6 mo.
Sil-Ilo9-12 mo.
34
PACES: Sildenafil Add-On to Stable Epoprostenol Therapy
● 16-week study (N=267)
- Patients on stable epoprostenol for >3 months
- 80% of patients provided with sildenafil 80 mg tid
● Deaths at 16 weeks
- Placebo (n=7)
- Sildenafil (n=0)
0
2
4
6
8
10
12
14
16
18
20
Any Clinical Worsening Event at 16 Weeks
Pat
ien
ts (
%)
Placebo Sildenafil
Simonneau G, et al. Ann Intern Med. 2008;149:521-530.
35
BREATHE-2: Bosentan Add-On to Stable Epoprostenol Therapy
● Placebo-controlled prospective 16-week study (N=33)
● Patients initiated on epoprostenol, then assigned 2:1 to bosentan or placebo
● No statistical improvements in hemodynamics or WHO functional class
0
20
40
60
80
100
Mean Improvement in 6MWD
6MW
D (
m)
Bosentan
Humbert M, et al. Eur Respir J. 2004;24:353-359.
Placebo
6874
36
STEP: Add-On Inhaled Iloprost to Stable Bosentan Monotherapy
0
20
40
60
80
100
Pat
ien
ts (
%)
Improved 1 Class
34.4%
ClinicalDeterioration
6.0%
62.5%
N=67. Inhaled iloprost added to stable bosentan monotherapy for a mean of 17.6 to 18.8 months.94% of patients were NYHA class III at baseline.
IloprostPlacebo
McLaughlin VV, et al. Am J Respir Crit Care Med. 2006;174:1257-1263.
0%
15.2%
No Change
Change From Baseline in NYHA Class
91.0%
Worsened 1 Class
3% 0%
37
Goal-Directed Combination Therapy: Suggested Treatment Algorithm
Baseline and 2- to 6-Month Evaluation for Treatment Goals6-Minute Walk Distance >380 meters; Peak VO2 >10.4 mL/min/kg
Peak systolic BP >120 mm Hg during exercise
Oral Monotherapy
Dual-Class Oral Combination Therapy
Addition of Inhaled Prostanoid
Transition to Intravenous Prostanoid
Refer for Lung Transplantation
Hoeper MM, et al. Eur Respir J. 2005;26:858-863.
38
Tra
nsp
lan
tati
on
an
d In
trav
eno
us
Pro
stag
lan
din
-Fre
e T
reat
men
t
Goal-Directed Therapy: Transplantation- and IV Prostanoid-Free Survival
Hoeper MM, et al. Eur Respir J. 2005;26:858-863.
*P=0.002 versus historical controls.Dual therapy (43.2%), triple therapy (16.1%), and IV prostanoid (4.2%).
1.0
0.8
0.6
0.4
0.2
00 6 12 18 24 30 36
Subjectsat Risk (n)
Patient Population
Historical Control Group
123 113 87 70 57 53 38
84 70 54 42 34 27 18
Months
Historical Controls
Goal-DirectedTreatment*
Interventional and Surgical Modalities in PAH
40
Surgical Interventions for PAH: When to Refer for Transplantation
● Although drug therapy may delay transplantation, a class IV patient who fulfills criteria should be referred for consideration for transplantation
● Patients who improve to WHO class II with therapy may be removed from the waiting list
● Patients remaining in or progressing to WHO class III after combination therapy should be assessed for transplantation
● Patients with PVOD/PCH should be referred immediately at time of diagnosis
Keogh AM, et al. J Am Coll Cardiol. 2009;54 (Suppl S):S67-S77.
41
Type of Transplantation in PAH
● Heart-lung or bilateral lung transplants are preferred
- Single-lung transplantation has been abandoned as ineffective in IPAH
● Choice of surgery dependent on several variables
- Etiology of PAH
- Donor organ availability
- Center experience
Keogh AM, et al. J Am Coll Cardiol. 2009;54 (Suppl S):S67-S77.
42
IPAH Long-term Transplant Survival at University of Pittsburgh Transplant Center
Toyoda Y, et al. Ann Throac Surg. 2008;86:1116-1122.
8675
66
0
20
40
60
80
100
Per
cen
tag
e (%
) S
urv
ival
1 year 5 year 10 year
N = 30. Transplanted between 1994 to 2006 with a diagnosis of IPAH.
43
Transplant Survival – IPAH, PAH-SSc and IPF
Schachna L, et al. Arthritis Rheum. 2006;54:3954-3961.
Su
rviv
al
No. at risk: SSc 29 20 17 16 15IPF 70 56 41 33 26
IPAH 38 30 28 24 22
Months after Transplantation
1.0
0.9
0.8
0.7
0.6
0.5
0 6 12 18 24
SScIPF
IPAH
Johns Hopkins and University of Pittsburgh transplant centers.
44
Atrial Septostomy
● Indications
- Failure of maximal medical therapy with persisting RV failure and/or recurrent syncope
- Bridge to transplantation
- When no other therapeutic options exist
● Right-to-left shunting increases systemic output, decompresses failing RV and LV
● Increases O2 transport
● Stepwise balloon dilatation is procedure of choice
Keogh AM, et al. J Am Coll Cardiol. 2009;54 (Suppl S):S67-S77.
45
Recommendations to Reduce Procedure-related Morality in Atrial Septostomy
● Only perform in a PAH center
● Contraindications
- Severe RV failure or cardiorespiratory support
- mRAP >20 mm Hg
- PVRI >55 U/m2
- Resting O2 saturation <90% on room air
- LVEDP >18 mm Hg
Adapted from Keogh AM, et al. J Am Coll Cardiol. 2009;54 (Suppl S):S67-S77.
46
Recommendations to Reduce Procedure-related Morality in Atrial Septostomy
● Pre-procedure
- Optimize cardiac function with adequate RH filling pressure and inotropic support
● During procedure
- Supplemental O2
- Appropriate sedation
- Monitoring LAP SaO2%, and mPAP
- Tailor defect to <10% decrease in O2 saturation
● Postprocedure
- Optimize O2 delivery with transfusion or packed red blood cells or darbepoetin before and after
Adapted from Keogh AM, et al. J Am Coll Cardiol. 2009;54 (Suppl S):S67-S77.
47
Summary: Long-term Management of Patients with PAH
● Patients with PAH appear to be surviving longer on medical therapy
● Long-term data on choice of initial medical therapy, de novo combination therapy, or therapy sequencing are still incomplete
● Considerations for initial therapy selection should include decisions on long-term efficacy, safety, and second-line choices
● In patients with severe disease or failing under medical therapy, early referral for possible surgical interventions is important
Recommended