Download DOI: 10.1161/CIRCULATIONAHA.108.839274 published online May

Tadalafil Therapy for Pulmonary Arterial Hypertension
Nazzareno Galiè, Bruce H. Brundage, Hossein A. Ghofrani, Ronald J. Oudiz, Gerald
Simonneau, Zeenat Safdar, Shelley Shapiro, R. James White, Melanie Chan, Anthony
Beardsworth, Lyn Frumkin, Robyn J. Barst and on behalf of the Pulmonary Arterial
Hypertension and Response to Tadalafil (PHIRST) Study Group
Circulation published online May 26, 2009;
DOI: 10.1161/CIRCULATIONAHA.108.839274
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Hypertension
Tadalafil Therapy for Pulmonary Arterial Hypertension
Nazzareno Galiè, MD; Bruce H. Brundage, MD; Hossein A. Ghofrani, MD; Ronald J. Oudiz, MD;
Gerald Simonneau, MD; Zeenat Safdar, MD; Shelley Shapiro, MD; R. James White, MD;
Melanie Chan, PhD; Anthony Beardsworth, MD; Lyn Frumkin, MD, PhD; Robyn J. Barst, MD;
on behalf of the Pulmonary Arterial Hypertension and Response to Tadalafil (PHIRST) Study Group*
Background—Treatment options for pulmonary arterial hypertension target the prostacyclin, endothelin, or nitric oxide
pathways. Tadalafil, a phosphodiesterase type-5 inhibitor, increases cGMP, the final mediator in the nitric oxide pathway.
Methods and Results—In this 16-week, double-blind, placebo-controlled study, 405 patients with pulmonary arterial
hypertension (idiopathic or associated), either treatment-naive or on background therapy with the endothelin receptor
antagonist bosentan, were randomized to placebo or tadalafil 2.5, 10, 20, or 40 mg orally once daily. The primary end
point was the change from baseline to week 16 in the distance walked in 6 minutes. Changes in World Health
Organization functional class, clinical worsening, and health-related quality of life were also assessed. Patients
completing the 16-week study could enter a long-term extension study. Tadalafil increased the distance walked in 6
minutes in a dose-dependent manner; only the 40-mg dose met the prespecified level of statistical significance (P 0.01).
Overall, the mean placebo-corrected treatment effect was 33 m (95% confidence interval, 15 to 50 m). In the
bosentan-naive group, the treatment effect was 44 m (95% confidence interval, 20 to 69 m) compared with 23 m (95%
confidence interval, 2 to 48 m) in patients on background bosentan therapy. Tadalafil 40 mg improved the time to
clinical worsening (P 0.041), incidence of clinical worsening (68% relative risk reduction; P 0.038), and healthrelated quality of life. The changes in World Health Organization functional class were not statistically significant. The
most common treatment-related adverse events reported with tadalafil were headache, myalgia, and flushing.
Conclusions—In patients with pulmonary arterial hypertension, tadalafil 40 mg was well tolerated and improved exercise
capacity and quality of life measures and reduced clinical worsening. (Circulation. 2009;119:000-000.)
Key Words: hypertension, pulmonary
P
ulmonary arterial hypertension (PAH) is a progressive
disease defined by chronic elevation in the pulmonary
arterial pressure, often leading to right heart failure and
death.1,2 The pathogenesis of PAH is poorly understood, but
an imbalance between vascular cell proliferation and apoptosis, an influx of cellular inflammation, excess vasoconstriction, and in situ thrombosis all contribute to the narrowing or
obliteration of the pulmonary arteriolar lumens and increased
pulmonary vascular resistance.3–5
Clinical Perspective on p
There is no cure for PAH; however, the currently approved
treatment options (ie, prostanoids, endothelin receptor antag-
phosphodiesterase inhibitors
tadalafil
onists, and the phosphodiesterase type-5 inhibitor sildenafil)6
improve symptoms, exercise capacity, and clinical outcome
but are limited by either parenteral or inhaled delivery
systems, the need for laboratory monitoring, or frequent
dosing schedules. Thus, a convenient and safe oral once-daily
therapy could be a significant advance in the treatment
algorithm for PAH.7
PAH is associated with impaired release of nitric oxide8 at
least in part because of reduced expression of nitric oxide
synthase in the vascular endothelium of pulmonary arteries.9
Downstream activation of soluble guanylate cyclase is thus
reduced, with less cellular synthesis of cGMP. Phosphodiesterase type-5 inactivates cGMP in the pulmonary vasculature,
Received November 30, 2008; accepted April 10, 2009.
From the Institute of Cardiology, Università di Bologna, Bologna, Italy (N.G.); Heart Institute of the Cascades, Bend, Ore (B.H.B.); University
Hospital, Justus-Liebig University, Giessen, Germany (H.A.G.); Los Angeles Biomedical Research Institute at Harbor–University of California at Los
Angeles, Torrance, Calif (R.J.O.); Antoine Béclère University Hospital, Clamart, France (G.S.); Division of Pulmonary and Critical Care Medicine,
Baylor College of Medicine, Houston, Tex (Z.S.); Greater Los Angeles Veterans Affairs Healthcare System, David Geffen University of California at
Los Angeles School of Medicine (S.S.); Division of Pulmonary and Critical Care Medicine, University of Rochester, Rochester, NY (R.J.W.); Eli Lilly
and Company, Erl Wood, United Kingdom (A.B.); Eli Lilly and Company, Toronto, Ontario, Canada (M.C.); ICOS Corporation, Bothell, Wash (L.F.);
and Schneider Children’s Hospital North Shore–Long Island Jewish Health System, New Hyde Park, NY (R.J.B.).
*Study Group participants are listed in the Appendix.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.108.839274/DC1.
Clinical trial registration information—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00125918.
Correspondence to Nazzareno Galiè, MD, Institute of Cardiology, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy. E-mail
[email protected]
© 2009 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.108.839274
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June 9, 2009
Figure 1. Numbers of patients enrolled in the 16-week study and in the long-term extension study who underwent screening and randomization. The data cutoff for patients in the long-term extension study was October 4, 2007.
and it appears to be upregulated in pulmonary hypertension.10,11 Inhibition of phosphodiesterase type-5 increases
cGMP levels, which may mediate the antiproliferative12 and
vasodilating13 effects of endogenous nitric oxide. Controlled
trials of sildenafil in the treatment of PAH patients have
shown improvement in exercise capacity and hemodynamic
parameters.14 –16 However, sildenafil did not delay the time to
clinical worsening, and these studies provided no information
about the efficacy or safety of sildenafil when combined with
the endothelin receptor antagonist bosentan.
Tadalafil, an orally administered, once-daily dosing, selective
inhibitor of phosphodiesterase type-5, is currently approved for
the treatment of erectile dysfunction.17 Data on tadalafil for the
treatment of PAH are limited to a single-dose hemodynamic
evaluation18 or anecdotal clinical use.19 The objectives of our
double-blind, placebo-controlled clinical trial were to investigate
the efficacy and tolerability of 4 doses of oral tadalafil 2.5, 10,
20, and 40 mg given once daily for 16 weeks in PAH patients
with or without background bosentan therapy.
Selection of Patients
Methods
Patients were at least 12 years of age and had symptomatic PAH that
was idiopathic/heritable or related to anorexigen use, connective
tissue disease, HIV infection, or congenital systemic-to-pulmonary
shunts (ie, an atrial septal defect with resting arterial oxygen
saturation 88% on room air or at least 1-year postsurgical repair of
a ventricular septal defect and/or patent ductus arteriosus).
The diagnosis of PAH included resting mean pulmonary artery
pressure 25 mm Hg, pulmonary wedge pressure 15 mm Hg, and
pulmonary vascular resistance 3 Wood units. Patients with a
6-minute walk distance of 150 m or 450 m were excluded.
Treatment with intravenous epoprostenol, intravenous or inhaled
iloprost, or subcutaneous treprostinil was prohibited. Patients taking
a maximal stable dose of 125 mg bosentan twice daily for a minimum
of 12 weeks at the time of screening continued on bosentan in addition
to the study medication. Local institutional review boards or independent ethics committees approved the protocol, and written informed
consent (and assent when appropriate) was obtained from all patients.
Study Design
This was a 16-week, randomized, double-blind, double-dummy,
placebo-controlled, multicenter study conducted in 84 centers in
Canada, the United States, Europe, and Japan between August 2005
and August 2007. Patients were randomized to groups receiving 1 of
5 treatments (tadalafil 2.5 mg, 10 mg, 20 mg, 40 mg, or placebo once
daily). The randomization was stratified for baseline walking distance ( 325 m or 325 m), Type of PAH (idiopathic/heritable and
anorexigen use versus other types), and bosentan use. Hemodynamic
parameters, by right heart catheterization, were measured at baseline
and at week 16 in patients recruited at 26 sites in North America,
Europe, and Japan (hemodynamic substudy). All patients who
completed the 16-week, double-blind study (or who discontinued
because of clinical worsening and who were not receiving tadalafil
40 mg) were eligible for a long-term extension study and received
either tadalafil 20 mg (those who received this dose during the
16-week study) or 40 mg (all other doses groups) in a blinded
fashion.
Outcome Measures
The primary efficacy measure was the placebo-corrected change
from baseline to week 16 in 6-minute walk distance.20 Secondary
efficacy evaluations included World Health Organization (WHO)
functional class,21 time from randomization to clinical worsening
(defined as death; lung or heart-lung transplantation; atrial septostomy; hospitalization due to worsening PAH; initiation of new PAHapproved therapy; worsening WHO functional class), Borg dyspnea
score,20 quality of life by the Medical Outcomes Study 36-item short
form version 222 and the EuroQol-5D questionnaire,23 and hemodynamic measurements in a subset of patients. Six-minute walk distance,
WHO functional class, and Borg dyspnea score were measured at
baseline and at weeks 4, 8, 12, and 16. Safety evaluations included the
recording of adverse events, laboratory tests, and vital signs.
Statistical Analysis
The database and all statistical outputs were retained by the sponsor.
All authors had access to the database. The statistician involved in
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Galiè et al
Table 1.
Tadalafil in Pulmonary Arterial Hypertension
3
Baseline Characteristics of the Patients
Tadalafil
Placebo (n 82)
2.5 mg (n 82)
10 mg (n 80)
20 mg (n 82)
40 mg (n 79)
55 15
54 16
54 15
53 16
53 15
Female
65 (79)
64 (78)
67 (84)
62 (76)
59 (75)
Male
17 (21)
18 (22)
13 (16)
20 (24)
20 (25)
White
72 (88)
65 (79)
64 (80)
61 (74)
64 (81)
Asian
3 (4)
9 (11)
5 (6)
9 (11)
8 (10)
African descent
7 (9)
7 (9)
8 (10)
8 (10)
4 (5)
Other
0 (0)
1 (1)
3 (4)
4 (5)
3 (4)
Weight, kg
77 22
76 20
74 21
76 21
74 19
Characteristic
Age, y
Gender, n (%)
Race, n (%)
Duration of PAH, n (%)
0 to
2y
49 (60)
41 (50)
47 (59)
46 (56)
41 (52)
2 to
4y
13 (16)
16 (20)
22 (28)
12 (15)
14 (18)
20 (24)
25 (30)
11 (14)
24 (29)
24 (30)
54 (66)
45 (55)
52 (65)
50 (61)
46 (58)
2 (2)
5 (6)
1 (1)
4 (5)
4 (5)
16 (20)
16 (20)
23 (29)
21 (26)
19 (24)
4y
Pathogenesis, n (%)
Idiopathic/familial
Anorexigen use
Connective tissue disease
Associated with an atrial septal defect
9 (11)
7 (9)
4 (5)
4 (5)
8 (10)
Surgical repair of VSD or PDA
duration
1 (1)
9 (11)
0 (0)
3 (4)
2 (3)
1-year
Concomitant use of bosentan, n (%)
Six-minute walk distance, m
Borg dyspnea score
45 (55)
43 (52)
41 (51)
45 (55)
42 (53)
343 84
347 71
338 75
338 74
352 78
4 2
4 2
4 2
4 2
4 2
WHO functional class, n (%)
Class I
1 (1)
1 (1)
0 (0)
0 (0)
2 (3)
Class II
23 (28)
29 (35)
24 (30)
28 (34)
26 (33)
Class III
56 (68)
49 (60)
54 (68)
54 (66)
51 (65)
Class IV
2 (2)
3 (4)
2 (3)
0 (0)
0 (0)
16
24
18
17
18
Hemodynamic parameters at baseline in the
patients enrolled in the hemodynamic substudy
n
Mean pulmonary artery pressure, mm Hg
Cardiac index, L min
1
m
2
Pulmonary vascular resistance, dyne s cm
5
49 12
54 15
51 16
58 13
54 8
2.4 0.5
2.5 0.7
2.6 0.8
2.6 0.4
2.6 0.7
827 399
852 416
843 475
972 392
901 488
Plus-minus values are mean SD. PAH indicates pulmonary arterial hypertension; VSD, ventricular septal defect; PDA, patent ductus arteriosus.
the analysis (M.C.) is an employee of the sponsor. The authors
assume full responsibility for the completeness and accuracy of the
content of the manuscript.
Analysis of efficacy end points included all randomized patients
who received study medication (intent-to-treat analysis). Step-down
testing began with the tadalafil 40 mg dose and then proceeded
downward on the basis of achieving a 2-sided significance level of
0.01 for the preceding test for primary end point. If the primary end
point for the dose was statistically significant, the secondary end
points were then evaluated in this order: WHO functional class, time
to first occurrence of clinical worsening, and change in Borg dyspnea
score, with no inferential testing beyond a nonsignificant result. The
significance level for secondary end points was a 2-sided significance level of 0.05.
The primary end point was tested with a permutation test on rank,
stratified by randomization factors. For patients who died or clini-
cally worsened, the lowest rank was used. No change was assumed
when rank was assigned in patients who discontinued the study
because of treatment-related adverse events. For all other patients, the change from baseline to last nonmissing observation
was used to assign the rank. Treatment difference was estimated
by the ANCOVA model with type II sum of squares including terms
for randomization factors.
Patients in each treatment group who improved, had no change, or
worsened from baseline to week 16, as assessed by WHO functional
class, were analyzed by Cochran-Mantel-Haenszel test, which controlled for stratification factors. Patients with missing data at week
16 were considered to worsen from baseline.
Time from randomization to the first occurrence of clinical
worsening was analyzed with a permutation test on the log-rank
score stratified by randomization factors. Subjects who completed
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June 9, 2009
the study or discontinued early without clinical worsening were
considered censored at the time of study completion. Frequency of
subjects who experienced clinical worsening was tested by Fisher
exact test. Borg dyspnea score was analyzed by the same technique
used for the 6-minute walk distance.
Change from baseline to week 16 in both quality of life surveys
was compared with placebo with an ANCOVA model that controlled
for randomization factors. Hemodynamic parameters at week 16
were compared with baseline with a paired t test.
Permutation test was performed with StatXact with 10 000 Monte
Carlo samples.24 Other tests were performed with SAS version 8
(SAS Statistical Software, version 8, 1999; SAS Institute Inc, Cary,
NC). A sample size of 400 patients (80 patients per treatment group)
provided 90% power at an level (2-sided) of 0.001 to detect a
45-meter placebo-adjusted treatment effect in 6-minute walk
distance.
Results
A total of 405 patients were randomized into 1 of 5 treatment
arms and received study medication (Figure 1) between
August 2005 and August 2007.
Baseline Patient Characteristics
Baseline patient characteristics were balanced across treatment arms (Table 1). The majority of patients had symptoms
in WHO functional class II or III and had idiopathic/heritable
PAH; 53% of patients were receiving background bosentan
therapy. Baseline characteristics were generally well balanced across background treatment groups; however, patients
on background bosentan tended to be younger, had a longer
duration of PAH, and had a slightly higher baseline 6-minute
walk distance than those patients not on background bosentan
(data not shown).
Exercise Capacity
Tadalafil 10, 20, and 40 mg (but not 2.5 mg), compared with
placebo, significantly improved the distance walked in 6
minutes in a dose-dependent manner at week 16 (Figure 2).
Tadalafil 40 mg was the only dose that achieved the prespecified value of statistical significance (P 0.01). The mean
placebo-corrected treatment effects among the 392 patients
with postbaseline assessment were 14 m among those receiving tadalafil 2.5 mg (n 79; 95% confidence interval [CI], 6
to 33); 20 m for those receiving 10 mg (n 78; 95% CI, 1 to
39); 27 m for those receiving 20 mg (n 82; 95% CI, 11 to
44); and 33 m for those receiving 40 mg (n 79; 95% CI, 15
to 50). In 11 patients, a 6-minute walk distance measured
before 16 weeks was used in the analysis (1, 5, 3, 2, and 0
patients in the placebo and tadalafil 2.5, 10, 20, and 40 mg
groups, respectively).
Treatment Effect Between Patient Subgroups
The treatment effects for the primary end point in predefined
subgroups were evaluated (Figure 3). Tadalafil 40 mg consistently demonstrated improvements in 6-minute walk distance compared with placebo. The placebo-adjusted change
in 6-minute walk distance in treatment-naive patients was 44 m
(n 186; 95% CI, 20 to 69; P 0.01) compared with 23 m
(n 206; 95% CI, 2 to 48; P 0.09) for patients on background
bosentan. The placebo-adjusted change in 6-minute walk distance in WHO functional class I and II patients was 24 m (95%
Figure 2. Mean changes from baseline, with 95% CIs, in the
6-minute walking distance at week 16 in the tadalafil and placebo groups. With the use of a permutation test on rank stratified according to baseline walking distance, cause of PAH, and
bosentan use, P 0.402, P 0.047, P 0.028, and P 0.001 for
the comparison of tadalafil in doses of 2.5, 10, 20, and 40 mg,
respectively, with placebo. In this intention-to-treat analysis, 392
patients for whom outcome data were available were included
in descriptive statistics. The dosing schedule for all study medications was once daily.
CI, 0 to 48; P 0.04) compared with 36 m (95% CI, 11 to 60;
P 0.02) in WHO class III and IV patients.
WHO Functional Class
No statistically significant differences in the proportion of
patients with improved WHO functional class and no change
in WHO functional class or worsening in WHO functional
class were observed with tadalafil compared with placebo. A
post hoc exploratory analysis based on background bosentan
use was done. In treatment-naive patients, 37.8% improved
and 10.8% worsened in the tadalafil 40 mg group; 16.2% of
patients improved and 21.6% worsened in the placebo group
(P 0.03). In the patients on background bosentan therapy,
9.5% improved and 9.5% worsened in the tadalafil 40 mg
group; 24.4% of patients improved and 11.1% worsened in
the placebo group (P 0.05).
Clinical Worsening
Time to clinical worsening was significantly improved in the
tadalafil 40 mg group compared with placebo (P 0.041)
(Figure 4). Additionally, the incidence of clinical worsening
was reduced in the tadalafil 40 mg group (P 0.038; relative
risk reduction 68% less than placebo). Individual components
of clinical worsening are shown in Table 2; hospitalization
and worsening of WHO functional class rates were lower in
the tadalafil 40 mg group compared with the placebo group.
Borg Dyspnea Score
Changes in the Borg dyspnea scale did not differ between
patients treated with tadalafil and those receiving placebo.
Quality of Life
Statistically significant improvements, compared with placebo,
from baseline to week 16 were observed in 6 of the 8 domains
of the Medical Outcomes Study 36-item short form version 2
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Galiè et al
Tadalafil in Pulmonary Arterial Hypertension
5
Figure 3. Placebo-corrected effect of treatment on the 6-minute walking distance from baseline to week 16 in patients subgroups. The
treatment effects, with 95% CIs, are presented for each tadalafil dose. ITT indicates intention-to-treat; S-P, systemic-to-pulmonary. In
this analysis, 392 patients for whom outcome data were available were included. The dosing schedule for all study medications was
once daily.
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June 9, 2009
Figure 4. Kaplan–Meier estimates of the proportion of patients with clinical worsening. With the
use of a permutation test on log-rank stratified
according to baseline walking distance, cause of
PAH, and bosentan use, *P 0.041 for the comparison of tadalafil in dose of 40 mg versus placebo.
In this intention-to-treat analysis, all 405 patients
who were randomized and treated were included.
The dosing schedule for all study medications was
once daily.
health survey (all P 0.01) and for all sections of the EuroQol-5D
questionnaire (all P 0.02) in the tadalafil 40 mg group.
Hemodynamic Parameters
Hemodynamic data were available for 93 patients. Improvements were observed with tadalafil 20 and 40 mg compared
with baseline in mean pulmonary arterial pressure
( 8.5 mm Hg; 95% CI, 13 to 4; n 17, P 0.001; and
4.3 mm Hg; 95% CI, 8 to 1; n 18, P 0.01, respectively) and pulmonary vascular resistance ( 254 dyne · s ·
cm 5; 95% CI, 388 to 120; n 17, P 0.001; and 209
dyne · s · cm 5; 95% CI, 406 to 13; n 18, P 0.039,
respectively). A statistically significant improvement in cardiac index was seen in the tadalafil 40 mg group (0.6 L/min
per square meter; 95% CI, 0.1 to 1.6; n 18, P 0.028). No
changes were observed on mean systemic blood pressure.
Although we recognize the limitations of background treatment subgroup analyses for the secondary outcome measures
due to the small sample sizes, the data showed uniformly
better results in the naive patients compared with the patients
on background bosentan therapy.
Safety
All doses of tadalafil were generally well tolerated, with the
most common adverse events being headache, myalgia, and
flushing. Most adverse events were reported as mild or
moderate (Table 2). Discontinuation rates were 16% and
similar across all treatment groups (Figure 1). No clinically
significant changes were seen in any laboratory variables
evaluated. Fifty-four patients reported 74 serious adverse events,
equally distributed across all treatment groups. However, investigators only considered 12 events as possibly related to study
medication; these included nausea, vomiting, retinal artery occlusion, dyspnea, priapism, esophageal varices hemorrhage,
hypotension, gastritis, menorrhagia, histiocytosis hematophagic
syndrome, headache, and drug hypersensitivity. Three deaths
occurred during the 16-week study: 1 patient in the placebo
group died because of PAH progression, 1 patient in the
10-mg tadalafil group died suddenly, and the third death was
due to histiocytosis hematophagic syndrome in a patient on
tadalafil 20 mg. Adverse events were not significantly different between the naive patients compared with the patients on
background bosentan therapy.
Long-Term Extension Study
Of the 341 patients who completed the randomized 16week study, 334 entered the long-term prospective extension study; 7 declined enrollment (Figure 1). In addition,
23 patients who prematurely discontinued the placebocontrolled study because of clinical worsening also entered
the extension study. Of the 357 patients enrolled in the
extension study, 62 patients discontinued (Figure 1). As of
October 2007, 213 of 357 patients (60%) enrolled in the
extension study had received tadalafil for at least 10 months.
After 16 weeks of treatment, the mean change from baseline
in the 6-minute walking distance for these patients was 37 m
(95% CI, 30 to 44); after 44 weeks, the mean change was
38 m (95% CI, 29 to 47).
Discussion
The results of this study show that tadalafil improves exercise
capacity, as assessed by the 6-minute walk distance, in
patients with PAH. Importantly, 53% of patients were on
background therapy with bosentan. The placebo-corrected
increase in walking distance in the group of patients treated
with 40 mg of tadalafil was 33 m (also including patients on
background bosentan therapy), and these data are consistent
with those observed in other pivotal studies, ranging from 16
to 59 m, on approved PAH medications utilized as monotherapy.15,25–30 In this study, the increase in walking distance
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Galiè et al
Tadalafil in Pulmonary Arterial Hypertension
7
Table 2. Incidence of Clinical Worsening and of Most Frequent Adverse Events in the Placebo and
Tadalafil Groups
Tadalafil
Clinical worsening, n (%)*
Placebo (n 82)
2.5 mg (n 82)
10 mg (n 80)
20 mg (n 82)
40 mg (n 79)
13 (16)
10 (12)
7 (9)
9 (11)
4 (5)‡
1
1§
Death
1
Hospitalization for worsening PAH
2
2
2
1
11
10
6
6
3
Headache
12 (15)
15 (18)
30 (38)
26 (32)
33 (42)
Diarrhea
8 (10)
9 (11)
9 (11)
6 (7)
9 (11)
Nausea
5 (6)
6 (7)
7 (9)
8 (10)
9 (11)
Back pain
5 (6)
5 (6)
5 (6)
10 (12)
8 (10)
Dyspepsia
2 (2)
4 (5)
2 (3)
11 (13)
8 (10)
Flushing
2 (2)
3 (4)
5 (6)
5 (6)
10 (13)
Myalgia
3 (4)
2 (2)
3 (4)
7 (9)
11 (14)
Dyspnea
3 (4)
8 (10)
4 (5)
4 (5)
5 (6)
Pain in extremity
2 (2)
3 (4)
4 (5)
4 (5)
9 (11)
Initiation of new PAH therapy
Worsening WHO functional class
3
1
1
Adverse event, n (%)*†
Muscle spasms
2 (2)
4 (5)
8 (10)
5 (6)
2 (3)
Upper respiratory tract infection
3 (4)
5 (6)
5 (6)
4 (5)
5 (6)
Epistaxis
3 (4)
6 (7)
4 (5)
5 (6)
3 (4)
Palpitations
2 (2)
5 (6)
7 (9)
3 (4)
1 (1)
Arthralgia
1 (1)
4 (5)
7 (9)
2 (2)
2 (3)
Chest pain
1 (1)
4 (5)
1 (1)
5 (6)
5 (6)
Vomiting
1 (1)
2 (2)
2 (3)
6 (7)
5 (6)
Fatigue
3 (4)
4 (5)
1 (1)
4 (5)
5 (6)
Nasal congestion
1 (1)
3 (4)
3 (4)
0 (0)
7 (9)
Edema
1 (1)
3 (4)
1 (1)
4 (5)
4 (5)
Bronchitis
0 (0)
3 (4)
3 (4)
1 (1)
4 (5)
Hot flush
2 (2)
4 (5)
2 (3)
2 (2)
3 (4)
Insomnia
2 (2)
2 (2)
1 (1)
4 (5)
3 (4)
Urinary tract infection
0 (0)
3 (4)
2 (3)
2 (2)
3 (4)
Vision blurred
1 (1)
2 (2)
2 (3)
4 (5)
2 (3)
*The analysis included all patients who received at least 1 dose of study medication. Some patients reported 1 event.
†Adverse events listed are those reported by 3% of patients and those that were reported more frequently in the tadalafil-treated
group than in the placebo group.
‡P 0.038 by Fisher exact test on the frequency of clinical worsening.
§The subject who died in the tadalafil 20 mg group was reported after study discontinuation. In the log-rank test, this subject was
censored at the time of study discontinuation.
with tadalafil 40 mg in the treatment-naive patients (44 m)
was higher than that observed in the patients on background
bosentan (23 m), although the latter was not statistically
significant (Figure 3). In addition, the effects on all secondary
end points tended to be better in treatment-naive patients
compared with bosentan-treated subjects. These comparative
data, observed for the first time within a single study, support
the hypothesis that increases in exercise capacity may be
blunted in patients already treated with PAH-targeted medications31,32 compared with treatment-naive subjects.15,25–30
The reasons for this observation are not clear but may be
related to a ceiling phenomenon33 that limits additional
improvements in exercise capacity in patients on background
therapy with targeted PAH medications. In addition, tadalafil
plasma levels are reduced if the dose of 40 mg is coadministered with bosentan34 because of a pharmacokinetic interaction mediated by the cytochrome P450 3A4, and this might
decrease tadalafil pharmacodynamic effects. A similar pharmacokinetic phenomenon is also observed with the coadministration of sildenafil and bosentan.35 Higher doses of phosphodiesterase type-5 inhibitors might theoretically be needed
in patients with bosentan background therapy, and specific
trials may be required to clarify this issue.
The extension study suggests that the favorable effect of
tadalafil on exercise capacity is durable for at least 10 months
of treatment. The proportion of patients who showed im-
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8
Circulation
June 9, 2009
provement in WHO functional class did not differ between
the placebo and the tadalafil 40 mg groups. The reasons for
this are unclear and may be due, in part, to the large
proportion of patients on background bosentan for whom it
may be more difficult to improve WHO functional class
compared with those without background therapy. The results
from the post hoc exploratory analysis on WHO functional
class improvement in the bosentan-naive patients treated with
tadalafil 40 mg support this hypothesis.
The tadalafil 40 mg group versus placebo significantly
decreased the incidence of clinical worsening (Figure 4), in
which fewer WHO functional class deteriorations and hospitalizations were observed (Table 2). Delay of clinical deterioration has been reported with PAH treatments either as
monotherapy27,29,30,36,37 or in combination trials31,32 but was
not observed in the pivotal sildenafil study.15 The reasons for
these differing observations among phosphodiesterase type-5
inhibitors are not clear and may include a difference in the
definitions used for clinical worsening, differences in trial
duration (12 versus 16 weeks), differences in the patient
populations studied, differences in the time in history or
countries in which the studies were performed, and/or differences in effects of the 2 drugs on this specific parameter.
Prevention of clinical deterioration is regarded as clinically
important supportive evidence for efficacy with PAH medications and has been suggested as a possible primary end
point in future PAH clinical trials provided that a uniform and
less subjective definition is used.37–39
The lack of a statistically or clinically significant improvement in Borg dyspnea score despite an improvement in
exercise capacity in this study has also been observed in other
studies with PAH medications.15,25,27–29,31,32,37 In fact, it is
rare to observe treatment effects 0.5 to 1.0 points (out of
10). It is possible that this phenomenon is related to the
tendency of the patients to maximize their effort in walking at
each study visit, resulting in a similar level of dyspnea
regardless of distance walked.
The improvement in quality of life indices demonstrated in
this study has been reported in previous PAH trials.25,26,29,32,37,40 It is particularly encouraging that the improvements observed in this trial were seen in a population
that included a large proportion of patients already on
background bosentan treatment, thus providing a rationale for
additional targeted therapy.
In a subgroup of patients, tadalafil significantly improved
hemodynamic parameters. The improvements in pulmonary
artery pressure and cardiac index in the group treated with
tadalafil 40 mg were similar to those observed with other
PAH medications either as monotherapy25,30,36,37,41,42 or in
combination.31,32 The small number of patients enrolled in
this subgroup does not allow a comparison among tadalafil
doses. For example, the larger decrease in mean pulmonary
arterial pressure observed with the 20-mg dose compared
with the 40-mg dose may be due to chance alone because the
CIs are largely superimposed. Because hemodynamic variables have been related to survival in patients with idiopathic/
familial PAH, these hemodynamic data add further support to
the clinical utility of tadalafil.
For all doses of tadalafil, most adverse events were mild to
moderate in severity (Table 2); there were no clinically
significant changes in laboratory variables measured. Thus,
tadalafil, taken once daily, contrasts with the currently approved PAH medications, including those using complex
delivery systems,25,30 oral agents with effects on liver function,27–29 and agents requiring frequent dosing regimens.15,26
Although longer-term assessments are needed to confirm the
favorable safety profile of tadalafil, the benefit-to-risk ratio of
its combination with the endothelin receptor-A selective
antagonists (ambrisentan and sitaxsentan) and with prostanoids requires evaluation.
On the basis of our results, overall, tadalafil 40 mg appears
to be the optimal dose for PAH patients. Tadalafil 40 mg,
unlike lower doses of tadalafil, significantly improved exercise capacity, clinical worsening, quality of life, and hemodynamics and had a safety profile similar to that of the lower
doses. Of note, the findings of this study are related to the
“sequential” addition of tadalafil to patients already treated
with bosentan and do not address the possible benefit of the
concurrent initiation of the 2 drugs in treatment-naive
subjects.
In conclusion, this study demonstrates the safety and
efficacy of tadalafil for the treatment of patients with symptomatic PAH. The favorable efficacy-to-safety profile of
tadalafil 40 mg once daily offers a clinically meaningful
addition to the currently approved treatment options.
Appendix
The members of the Pulmonary Arterial Hypertension and Response
to Tadalafil (PHIRST) Study Group were as follows (in order of the
number of patients randomized at each center): A. Manes, Bologna,
Italy; L. Negro, Bologna, Italy; A. Palazzini, Bologna, Italy; Z.
Safdar, Houston, Tex; S. Shapiro, Los Angeles, Calif; R.J. White,
Rochester, NY; R.J. Barst, New York, NY; E. Berman Rosenzweig,
New York, NY; R. Girgis, Baltimore, Md; F. Grimminger, Giessen,
Germany; W. Seeger, Giessen, Germany; J. Feldman, Phoenix, Ariz;
G. Simonneau, Clamart, France; J. Klinger, Providence, RI; V.
Cottin, Bron Cedex, France; J. Granton, Toronto, Ontario, Canada;
N. Nakanishi, Osaka, Japan; G. Stahler, Loewenstein, Germany; S.
Mehta, London, Ontario, Canada; G. Coghlan, London, United
Kingdom; D. Ostrow, Vancouver, British Columbia, Canada; D.
Badesch, Denver, Colo; J. Behr, Muenchen, Germany; L. Bruch,
Berlin, Germany; H. Farber, Boston, Mass; C. Lawrence, Atlanta,
Ga; C. Markin, Portland, Ore; O. Minai, Cleveland, Ohio; G.
Saydain, Detroit, Mich; M. Widmer, Bend, Ore; B. Degano, Toulouse, France; S. Fazio, Napoli, Italy; M. Gomberg-Maitland, Chicago, Ill; D. Langleben, Montreal, Quebec, Canada; J. Meyer,
Heidelberg, Germany; J. Michaelson, Decatur, Ga; E. Michelakis,
Edmondton, Alberta, Canada; R. Naeije, Brussels, Belgium; A.
Peacock, Glasgow, United Kingdom; B. Rayburn, Birmingham, Ala;
M. Chakinala, St Louis, Mo; T. De Marco, San Francisco, Calif; F.
Fedele, Roma, Italy; R. Frantz, Rochester, Minn; M.A. GomezSanchez, Madrid, Spain; D. Helmersen, Calgary, Alberta, Canada; P.
Hernandez, Halifax, Nova Scotia, Canada; A. Hurewitz, Mineola,
NY; A. Waxman, Boston, Mass; D. Baratz, Phoenix, Ariz; C.
Campana, Pavia, Italy; E. Hachulla, Lille Cedex, France; N. Hill,
Boston, Mass; S. Knoper, Tucson, Ariz; K. Kusano, Okayama,
Japan; M. Mathier, Pittsburgh, Pa; S. Murali, Pittsburgh, Pa; S.
Ogawa, Tokyo, Japan; J. Pepke-Zaba, Cambridgeshire, United Kingdom; J. Barbera, Barcelona, Spain; R.J. Oudiz, Torrance, Calif; Z.
Bshouty, Winnipeg, Manitoba, Canada; D. Camanga, Torrance,
Calif; M. Colvin-Adams, Minneapolis, Minn; M. Delcroix, Leuven,
Belgium; R. Ewert, Greifswald, Germany; J. Gossage, Augusta, Ga;
F. Grimminger, Lich, Germany; H. Matsubara, Okayama, Japan; O.
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Galiè et al
Miera, Berlin, Germany; M. Mizoguchi, Fukuoka, Japan; M. Pfeifer,
Regensburg, Germany; M. Reynaud-Gaubert, Marseille, France; H.
Watanabe, Shizuoka, Japan; D. Zwicke, Milwaukee, Wis; P. Corris,
Newcastle on Tyne, United Kingdom; G. Elliott, Salt Lake City,
Utah; H. Endo, Kanagawa, Japan; P. Fairman, Richmond, Va; S.
Gaine, Dublin, Ireland; D. Kiely, Sheffield, United Kingdom; Y.
Kihara, Hyogo, Japan; H. Kuraishi, Kanagawa, Japan; P. MoralesMartin, Valencia, Spain; J. Suzuki, Tokyo, Japan; Y. Takeda, Aichi,
Japan; T. Zieldalski, Everett, Wash.
Acknowledgments
Tadalafil in Pulmonary Arterial Hypertension
9.
10.
11.
Michael Anne Shane, MS, assisted in the coordination and editing of
this manuscript.
12.
Source of Funding
13.
Disclosures
14.
The study was funded by Eli Lilly and Company.
Nazzareno Galiè, MD, has served as a member of the PHIRST
steering committee for Eli Lilly and has participated in advisory
board activities for Actelion, Pfizer, United Therapeutics, Eli Lilly,
Bayer-Schering, Encysive, and GlaxoSmithKline. He has been a paid
lecturer for Actelion, Pfizer, Bayer-Schering, and Encysive. Bruce
H. Brundage, MD, has served as a consultant or advisory board
member for the following companies: Actelion, GTx, Pfizer, Gilead,
Medtronics, Eli Lilly, United Therapeutics. Hossein A. Ghofrani,
MD, has received honoraria and acts as a consultant for Actelion,
Bayer Schering, Encysive, Ergonex, GlaxoSmithKline, Novartis, and
Pfizer. Ronald J. Oudiz, MD, has served as member of the PHIRST
steering committee/advisory board for Eli Lilly . Gerald Simonneau,
MD, has served as member of the PHIRST steering committee for
Eli Lilly/ICOS and has participated in advisory board activities and
has served as consultant for Actelion, Pfizer, United Therapeutics,
Eli Lilly, Bayer-Schering, and GlaxoSmithKline. He is a paid
lecturer for Actelion, Pfizer, and Bayer-Schering. Zeenat Safdar,
MD, has consulting agreements with Actelion, Encysive, Gilead, and
United Therapeutics. Shelley Shapiro, MD, has speaker and consulting agreements with Actelion, Eli Lilly, Gilead, and United Therapeutics. R. James White, MD, acts as a consultant for Actelion,
Gilead, and United Therapeutics and has received research funds
from a US NIH grant to the University of Rochester General Clinical
Research Center. Melanie Chan, PhD, is an employee and stockholder of Eli Lilly . Anthony Beardsworth, MD, is an employee and
stockholder of Eli Lilly. Lyn Frumkin, MD, PhD, is a former
employee at ICOS Corporation, the codeveloper (with Eli Lilly) of
tadalafil. Robyn J. Barst, MD, serves as a consultant to Actelion, Eli
Lilly, Gilead, Pfizer, Novartis, and GlaxoSmithKline.
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CLINICAL PERSPECTIVE
There is no cure for pulmonary arterial hypertension, a devastating, progressive disease with increasingly debilitating
symptoms. Currently approved treatment options include prostanoids, endothelin receptor antagonists, and a phosphodiesterase type-5 inhibitor. These therapies improve symptoms, exercise capacity, hemodynamics, and clinical outcome but
are limited by either parenteral or inhaled delivery systems, the need for laboratory monitoring, or frequent dosing
schedules. In addition, the majority of pivotal trials have shown the efficacy-to-safety balance of the approved medications
when administered as monotherapy, and less information is available on the effects of these drugs when combined with
background therapy with other approved compounds. The results of the Pulmonary Arterial Hypertension and Response
to Tadalafil (PHIRST) study provide evidence for the efficacy of the orally active phosphodiesterase type-5 inhibitor
tadalafil at a dose of 40 mg once daily. The effects on exercise capacity and hemodynamics are comparable to those of the
other drugs approved for pulmonary arterial hypertension. Furthermore, tadalafil 40 mg is able to improve time to clinical
worsening, most adverse events were mild to moderate in severity, and there were no clinically significant changes in
laboratory variables measured. Therefore, the favorable efficacy-to-safety profile of tadalafil 40 mg once daily offers a
clinically meaningful addition to the currently approved treatment options. Approximately 50% of the patients enrolled in
the PHIRST study were on background therapy with the endothelin receptor antagonist bosentan; in this subgroup as well,
the favorable effects of tadalafil 40 mg were confirmed, although by a lesser extent. These data may support the use of
combination therapy in pulmonary arterial hypertension.
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