CHEST Edizione Italiana | 2012 | ANNO XIV
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Ambrisentan Therapy in Patients
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3-Year Outcome
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CHEST Edizione Italiana | 2012 | ANNO XIV
Supplement
CHEST 2011 Scientific Highlights
Abstracts of Original Investigations and
Case Reports
Ambrisentan Therapy in Patients
with Pulmonary Arterial Hypertension:
3-Year Outcome
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CHEST
Supplement
CHEST 2011 Scientific Highlights
Abstracts of Original Investigations and
Case Reports
Ambrisentan Therapy in Patients
with Pulmonary Arterial Hypertension:
3-Year Outcome
RJ Oudiz, M Allard, C Blair, and H Gillies on Behalf of the ARIES Study Group
Gilead Sciences, Inc.
333 Lakeside Drive
Foster City, CA 94404
Tel: (650) 574-3000
Fax: (650) 578-9264
Poster Number
2622
American College of Chest Physicians
International Conference
October 22-26, 2011
Honolulu, Hawaii, USA
CHEST
Supplement
CHEST 2011 Scientific Highlights
Abstracts of Original Investigations and
Case Reports
Ambrisentan Therapy in Patients
with Pulmonary Arterial Hypertension:
3-Year Outcome
RJ Oudiz1, M Allard2, C Blair2, and H Gillies2 on Behalf of the ARIES Study Group
Ambrisentan for Pulmonary Arterial Hypertension
(PAH)
Objective
This analysis was designed to evaluate the longerterm (3-years) safety and efficacy of ambrisentan in
patients with PAH treated in the ARIES studies
Ambrisentan is a once-daily, oral, propanoic-acid
based ETA-selective endothelin receptor antagonist
approved at doses of 5 mg and 10 mg for the treatment of PAH.
Methods
Background
ARIES-1 and ARIES-2 were the pivotal 12-week
placebo-controlled trials that led to the approval of
ambrisentan for PAH.1
– In these studies, ambrisentan improved exercise
capacity and delayed clinical worsening in patients
with PAH.
Following the 12-week trials, patients continued
treatment with ambrisentan in a long-term extension
study (ARIES-E).2
– In ARIES-E, 2-year ambrisentan treatment was
associated with sustained improvements in exercise capacity and a low risk of clinical worsening
and death.
– Ambrisentan was generally well-tolerated, with a
low risk of aminotransferase abnormalities over
the 2-year study period.
1 LA Biomedical Research Institute at Harbor-UCLA, Torrance,
CA, USA;
2 Gilead Sciences Inc., Foster City, CA, USA.
The poster was presented Wednesday, October 26, 2011 in the Pulmonary Vascular Disease session during CHEST 2011 in Honolulu.
ARIES-E Study Design
Common long-term extension study for patients participating in ARIES-1 or ARIES-2.
Patients who received placebo in previous studies
were randomized to ambrisentan.
– ARIES-1: 5 or 10 mg once daily.
– ARIES-2: 2.5 or 5 mg once daily.
Patients who received ambrisentan in previous studies remained on their current dose for the first 24
weeks.
First 24 weeks was a blinded, fixed-dose period.
After the blinded fixed-dose period, investigators
were allowed to adjust the dose as clinically needed.
– Available doses: 2.5mg, 5mg, 10mg.
Concomitant prostanoid and/or PDE5 inhibitors
were permitted.
CHEST / Edizione Italiana / Supplement 2012
3
ARIES-E Data Analysis
6MWD, WHO functional class, and Borg Dyspnea
Index (BDI) data are presented for 1 year (48
weeks), 2 years (96 to 108 weeks), and 3 years (144
to 156 weeks).
– Placebo patients were randomized to ambrisentan
12 weeks later.
Missing data were imputed using last observation
carried forward (LOCF).
Kaplan-Meier analyses for survival, clinical worsening, safety, and LFTs are presented through 3 years
(156 weeks) of treatment for all patients who
received ambrisentan.
– Survival status was collected retrospectively after
study closure for subjects with an unknown outcome at the end of the study.
Descriptive statistics are presented without formal
hypothesis testing.
Results
383 Randomized
1-Year Cumulative Data
• 315 (82%) Ongoing Study
• 0 (0% ) Completed Studyc
– 314 Ongoing Study Drug
• 287 (91%) Monotherapy
• 27 (9%) Combination Therapy
2-Years Cumulative Data
3-Years Cumulative Data
• 120 (31%) Discontinued Study
– 55 Deaths
– 21 Adverse Events a
– 44 Otherb
a. Includes discontinuation due to Early Escape (n=4);
b. Voluntary withdrawal, non-compliance, lost to follow-up, inadequate
clinical response, and sponsor/investigator discretion;
c. Patients could either transition to commercial drug or enroll into an
alternate long-term extension ambrisentan study
Figure 1. Patient Disposition.
350
Combined PAH Therapy
300
ABS Monotherapy
250
200
150
91%*
100
83%
79%
2
3
50
0
Ambrisentan (N = 383)
79
51 ± 15
72 ± 18
77
3
43
46
8
347 ± 85
3.9 ± 2.4
49 ± 14
8±5
2.5 ± 0.8
11 ± 7
Mean ± standard deviation; Baseline assessed prior to first dose of
ambrisentan except historical hemodynamic measurements; Data
presented by randomized dose; ARIES-1 and ARIES-2 placebo
subjects RHC measurements were performed at least 12 weeks
before ambrisentan initiation.
1
Years
*% Patients on ambrisentan monotherapy / % Patients on
Combined PAH therapy
Of those patients who remained on ambrisentan in
the study, the majority remained on ambrisentan
monotherapy through year 3
Figure 2. Ambrisentan Monotherapy Status.
100
Percent (%)
Female, %
Age, yr
Weight, kg
Caucasian, %
WHO Class I, %
WHO Class II, %
WHO Class III, %
WHO Class IV, %
6MWD, meters
Borg Dyspnea Index, Score
mPAP, mmHg
mRAP, mmHg
Cardiac Index, L/min/m2
PVR, wood units
• 100 (26%) Discontinued Study
– 42 Deaths
– 20 Adverse Events a
– 38 Otherb
• 190 (50%) Ongoing Study
• 73 (19%) Completed Studyc
– 186 Ongoing study Drug
• 147 (79%) Monotherapy
• 39 (21%) Combination Therapy
Table 1—Baseline Demographics and Disease
Characteristics
Characteristics
• 68 (18%) Discontinued Study
– 20 Deaths
– 19 Adverse Events a
– 29 Otherb
• 260 (68%) Ongoing Study
• 23 (6%) Completed Studyc
– 259 Ongoing Study Drug
• 214 (83%) Monotherapy
• 45 (17%) Combination Therapy
Patient Number
Efficacy and safety assessments were measured from
the time of the first dose of ambrisentan.
– Data is presented by randomized dose through 3
years of treatment from ARIES-1, ARIES-2 and
ARIES-E.
2.5 mg
Dose Group
5 mg
Dose Group
10 mg
Dose Group
75
50
25
0
0.0
1.0
2.0
3.0
0.0
1.0
2.0
3.0
0.0
1.0
2.0
3.0
Years
2.5 mg
5 mg
10 mg
All patients by randomized dose
Figure 3. Ambrisentan Dose Adjustments Over Time.
4
CHEST / Edizione Italiana / Supplement 2012
Table 2—Number of Patients on Ambrisentan by Dose Group Through 3 Years
Dose
1 Year
2 Years
3 Years
Patient Number
at Randomization
Patient
Number
Same Dose*
n, (%)
Patient
Number
Same Dose
n, (%)*
Patient
Number
Same Dose
n, (%)*
96
190
97
81
152
81
70 (86)
129 (85)
78 (96)
69
124
66
48 (70)
88 (71)
64 (97)
60
92
34
33 (55)
58 (63)
34 (100)
2.5 mg
5 mg
10 mg
*Same dose = Patients remaining at same randomized dose at 1, 2 and 3 years
Ambrisentan Dose Adjustments
70
60
50
40
30
20
10
0
-10
-20
10 mg
5 mg
2.5 mg
2.5 mg, n=
5 mg, n=
10 mg, n=
0
1
96
190
97
93
186
96
Years
2
Change in 6MWD (m)
Change in 6MWD (m)
At 3 years, for those patients still on ambrisentan in
the study:
– Almost half of the patients randomized to 2.5 mg
were titrated to 5 mg and 10 mg
– A third of the patients randomized to 5 mg were
titrated to 10 mg
70
60
50
40
30
20
10
0
-10
-20
3
93
186
96
2.5 mg, n=
5 mg, n=
10 mg, n=
93
186
96
10 mg
5 mg
2.5 mg
0
1
96
190
97
77
147
81
Years
2
3
67
132
68
58
101
46
Mean ± 95% confidence interval; Observed Case
Mean ± 95% confidence interval
Last observation carried forward for missing data
Figure 4. 6-minute Walk Distance—Change from Baseline by
Randomized Dose (LOCF).
After 1 year of ambrisentan treatment, improvements in 6MWD compared to baseline were
observed for all dose groups.
100
Percent (%)
Maintained or
Worsened Improved
After 2 and 3 years of ambrisentan treatment,
improvements compared to baseline in 6MWD were
maintained for the randomized 5 mg and 10 mg
dose groups.
80
60
10 mg, n = 96
5 mg, n = 187
2.5 mg, n = 94
40
20
0
-20
-40
0
1
Years
2
3
Last observation carried forward for missing data
Approximately 80% of patients either improved or
maintained their WHO functional class through 3
years of ambrisentan treatment.
Figure 6. WHO Functional Class—Change from Baseline by
Randomized Dose (LOCF).
Maintenance of treatment-effect over 3 years for the
randomized 2.5 mg dose group was not sustained
despite uptitration to 5 mg and 10 mg.
Similar to 6MWD, there appears to be maintenance
of the treatment effect with BDI over 3 years in the 5
mg and 10 mg dose groups
– Change from baseline BDI score at 2 years (LOCF).
5 mg dose group: -0.33 (95% CI: -0.68 to 0.03).
10 mg dose group: -0.65 (95% CI: -1.12 to -0.18)
– Change from baseline BDI score at 3 years (LOCF).
5 mg dose group: -0.14 (95% CI: -0.51 to 0.22).
10 mg dose group: -0.48 (95% CI: -0.93 to -0.03).
Figure 5. 6-minute Walk Distance—Change from Baseline by
Randomized Dose (Observed Case).
CHEST / Edizione Italiana / Supplement 2012
5
80
60
40
ABS 1 Year
ABS 3 Years
ABS 2 Years
83% (78% to 86%) 71% (66% to 76%) 64% (58% to 69%)
20
0
At Risk
2.5 mg, n=
5 mg, n=
10 mg, n =
ABS, n=
0
1
96
190
97
383
71
142
74
287
Years
2
3
59
110
54
2 23
49
81
26
1 56
80
60
*Kaplan-Meier estimates (95% CI); randomized dataset; Clinical worsening was defined as:
Time from initiation of ambrisentan to first occurrence of death, lung transplantation,
hospitalization for PAH, atrial septostomy, addition of prostanoid therapy, or study
withdrawal due to addition of other PAH therapy.
The majority of patients were free of clinical worsening events through 3 years of ambrisentan treatment.
ABS 1 Year
ABS 2 Years
ABS 3 Years
93% (91% to 96%) 85% (82% to 89%) 79% (75% to 83%)
40
20
0
At Risk
2.5 mg, n=
5 mg, n=
10 mg, n =
ABS, n=
0
1
96
190
97
38 3
Years
89
172
89
350
2
3
76
156
83
31 5
67
142
72
2 81
*Kaplan-Meier estimates (95% CI); randomized dataset
At 3 years, the Kaplan-Meier survival rate was 79%
for PAH patients randomized to ambrisentan.
Figure 9. Post-Study Outcome—Long-Term Survival.
Figure 7. Time to Clinical Worsening.
1 Year
383 Randomized
ABS
2.5 mg
5 mg
10 mg
100
Survival (%)*
Clinical Worsening
Event-Free (%)*
ABS
2.5 mg
5 mg
10 mg
100
– 350 (91%) Alive
– 25 (7%) Deceased
– 8 (2%) Unknown
2 Years
3 Years
– 315 (82%) Alive
– 55 (15%) Deceased
– 13 (3%) Unknown
– 282 (74%) Alive
– 77 (20%) Deceased
– 24 (5%) Unknown
At 3 years, 74% of the PAH patients taking first line ambrisentan therapy were still alive.
Figure 8. Post-study Outcome Status—Patient Disposition.
7
▲ Elevations of bilirubin >2xULN
▲
+ Normal
■
Maximum Bilirubin(xULN)
6
5
Temples Corollary
(n = 27, 7.13%)
(n = 343, 91.22%)
(n = 6, 1.60%)
7
6
▲
5
▲
▲
4
▲
▲
▲
3
▲▲
▲
▲
▲▲
4
▲
2
3
▲
▲ ▲ ▲
▲▲ ▲
▲ ▲▲
n = 27 n = 0
+++ +
+n+++=+ 343
n=
+++ +
+++
++
++
+
++++++ ++
+++
+++
++++++++++ ■
++
1 +
+++
+++++
+++++++
++
+++++
+
+
+++++
+
+
+
+
+
+
+
+
+
+
■
+++++++++++++++++ ■
+
++++++++
+
++++++++++ ++
■
2
6
1
■
■
0
0
0 1 2 3 4 5 6 7
8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45
Maximum ALT (xULN)
Figure 10. Hepatic Safety Monitoring—Evaluation of Drug-Induced Serious Hepatotoxicity (eDISH) Plot – Peak Bilirubin vs. ALT
Levels per Subject Through 3 Years.
6
CHEST / Edizione Italiana / Supplement 2012
Table 3—Adverse Events that Led to Study Drug
or Study Discontinuation, or Death at 3 Years
Patient, n (% incidence) N = 383
Adverse Events
Cumulative Events at 3 Years
Pulmonary Hypertension Right Ventricular failure Acute Respiratory Failure Cardio-respiratory Arrest Pneumonia 21 (5.5%)
17 (4.4%)
4 (1%)
4 (1%)
4 (1%)
Includes adverse events occurring in at least 4 patients. All data
presented by randomized ambrisentan dose.
– Majority of the patients in ARIES-E remained on
ambrisentan monotherapy.
– Maintained or improved WHO functional class for
the majority of patients.
– A low risk of clinical worsening and death
– Majority of patients free of clinical worsening
events through 3 years of ambrisentan treatment
– At 3 years, the Kaplan-Meier survival rate was
79% for PAH patients taking fi rst line ambrisentan therapy.
Adverse Events Through 3 Years
The 3-year safety profile was similar to the 2-year
safety profi le (JACC 2009).
– A 3-year ambrisentan safety profi le consistent
with previous ambrisentan 2-year data
– Low risk of aminotransferase abnormalities with
an annualized incidence rate of 1.6% - a rate
similar to that of placebo rates.
The most frequent AEs were:
– Peripheral edema, Headache, Upper respiratory
tract infection, Cough, Right Ventricular Failure,
Dizziness, Arthralgia.
These data support the long-term use of ambrisentan
in the treatment of PAH.
Most AEs of peripheral edema were mild or moderate with only 6 (1.6%) AEs considered severe and 1
(0.3%) AE leading to discontinuation of study.
Most frequent AEs leading to discontinuation were
consistent with worsening PH.
Estimated risk of developing serum aminotransferase abnormalities (ALT/AST >3X ULN) was:
– 1.8% (95% CI: 0.8% to 3.9%) at 1 year
– 3.9% (95% CI: 2.2% to 6.8%) at 2 years
– 4.8% (95% CI: 2.8% to 8%) over 3 years for an
annualized risk of approximately 1.6%
Conclusions
ARIES 3-Year Data
Long-term ambrisentan treatment was associated
with:
– Sustained improvements for the 5 mg and 10 mg
randomized dose groups.
– Exercise ability and dyspnea.
References
1. G alie N, Olschewski H, Oudiz RJ et al. Results of the
ambrisentan in pulmonary arterial hypertension, randomized,
double-blind, placebo-controlled, multicenter, efficacy
(ARIES) study 1 and 2. Circulation 2008;117:3010-3019.
2. O udiz RJ, Galie N, Olschewski H et al. Long-Term
Ambrisentan Therapy for the Treatment of Pulmonary Arterial Hypertension. J Am Coll Cardiol 2009;54:1971-1981.
Disclosures and Acknowledgements
This study was sponsored by Gilead Sciences Inc.,
Foster City, California.
Dr. Oudiz has received Grant support (GS), consultant (C), speakers bureau (SB) from: NIH/NCRR:
GS; Actelion: GS, C; Bayer: GS,C; Gilead: GS, C,
SB; LungRx: GS, C, SB; Novartis: C; Pfizer: GS, C,
SB; United Therapeutics: GS, C, SB.
We acknowledge the Investigators and the Study
coordinators of the ARIES study group.
doi:10.1378/chest.1114459
(Chest. 2011; 140:742A)
© 2012 American College of Chest Physicians
http://chestjournal.chestpubs.org/cgi/content/meeting_abstract/140/4_MeetingAbstracts/742A?sid=a215af737109-4933-9c8a-3ec7143a02f1
http://www.midiaonline.it/pdf/MeetingAbstractsChest2011.pdf
CHEST / Edizione Italiana / Supplement 2012
7
Da consegnare unitamente all’RCP Volibris (ambrisentan)
Depositato presso AIFA – Ufficio informazione medico scientifica ai sensi degli artt. 119-120 del D.L.vo n. 219/06, in data 13/03/2012