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Conversion From Sildenafil to Tadalafil: Results From the Sildenafil to Tadalafil in Pulmonary Arterial
Hypertension (SITAR) Study
Robert P. Frantz, Louise Durst, Charles D. Burger, Ronald J. Oudiz, Robert C. Bourge, Veronica Franco, Aaron B.
Waxman, Susanne McDevitt and Susan Walker
J CARDIOVASC PHARMACOL THER published online 17 April 2014
DOI: 10.1177/1074248414528066
The online version of this article can be found at:
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Article
Journal of Cardiovascular
Pharmacology and Therapeutics
1-8
The Author(s) 2014
Reprints and permission:
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DOI: 10.1177/1074248414528066
cpt.sagepub.com
Abstract
Purpose: Among phosphodiesterase type 5 inhibitors, tadalafil offers clinicians a once-daily alternative to 3 times daily sildenafil
for the treatment of pulmonary arterial hypertension (PAH). This study assessed the safety and patient satisfaction with conversion from sildenafil to tadalafil. Methods: In this multicenter, prospective, 6-month study, patients with PAH were instructed to
take their last dose of sildenafil in the evening and initiate tadalafil 40 mg/d the next morning. Patients completed the Treatment
Satisfaction Questionnaire for Medication at baseline and 30, 90, and 180 days after transition to assess PAH symptoms and
patient satisfaction. Safety was assessed on the basis of recorded adverse events (AEs). Results: Of the 35 patients who met
the study criteria, 56% were receiving 2 PAH therapies. At the time of transition, the sildenafil dose ranged from 40 to 300 mg/d,
with 20% of the patients on >20 mg of sildenafil 3 times daily. Transition to tadalafil was generally well tolerated, and the incidence
of common AEs, except for myalgia, appeared to decrease over time on tadalafil therapy. Five (14%) patients switched back to
sildenafil. A greater percentage of patients were satisfied than were dissatisfied after conversion to tadalafil (55% vs 19% at 90
days), while 26% felt about the same degree of satisfaction. Conversion to tadalafil resulted in significant improvement in patient
ratings of therapy convenience. Conclusions: Transition of patients from sildenafil to tadalafil was usually well tolerated, with
improved convenience and may enhance treatment satisfaction.
Keywords
sildenafil, tadalafil, switch, pulmonary arterial hypertension, patient satisfaction
Introduction
Pulmonary arterial hypertension (PAH) is a rare, progressive
disease characterized by increasing pulmonary arterial pressure
and pulmonary vascular resistance, ultimately leading to right
ventricular (RV) failure and death.1,2 Greater disease awareness and improved diagnostics, coupled with a marked
increase in the number of PAH-targeted therapies recently,
have advanced management of patients with PAH. Widely
used PAH therapies target 1 or more of the 3 main pathways
in disease pathogenesis: prostacyclin, endothelin receptor
antagonists (ERAs), and phosphodiesterase type 5 inhibitors
(PDE-5Is). The PDE-5I class of PAH treatment blocks
phosphodiesterase type 5-dependent inactivation of cyclic
guanosine monophosphate, increasing nitric oxide-mediated
pulmonary arterial vasodilation.3-5
Sildenafil was the first PDE-5I approved for treatment of
PAH on the basis of the results of the Sildenafil Use in
Pulmonary Arterial Hypertension (SUPER-1) study that randomized treatment-naive patients with PAH to sildenafil 20, 40,
or 80 mg 3 times daily or placebo.5 Although the US Food and
Drug Administration (FDA) approved sildenafil 20 mg 3 times
daily for the treatment of PAH6 on the basis of the finding that
there were no significant differences in 6-minute walk distance
(6MWD) between the 20-, 40-, or 80-mg dosing groups, a
greater hemodynamic effect was seen with the 80-mg 3 times
daily dose, raising the possibility that the maximum approved
dose was not the most hemodynamically effective dose for at
least some patient subsets.5 In the open-label extension,
patients receiving sildenafil 80 mg 3 times daily appeared to
experience sustained benefit to the extent that this can be
assessed in an open-label setting. However, there are no data
regarding durability of treatment when patients are maintained
on a 20-mg 3 times daily dose. Additionally, when sildenafil is
used in combination with an ERA, bosentan, there are
decreased plasma levels of sildenafil, providing more rationale
for the use of higher doses of sildenafil.7 Thus, the optimal dosing regimen for sildenafil is controversial and has resulted in
confusion among some clinicians who have been treating
patients with sildenafil doses substantially above the FDArecommended dose. Treating patients above the FDArecommended dose can create challenges such as added cost
and insurance coverage restrictions. Furthermore, dosing with
a 3 times daily medication may lead to increased pill burden
and lack of adherence in patients with PAH.
Tadalafil is a once-daily PDE-5I approved for the treatment of patients with World Health Organization (WHO)
group 1 PAH at a dose of 40 mg daily.8 Tadalafils longer
half-life of 17.5 hours in healthy individuals and 35 hours in
patients with PAH,9 compared with that of sildenafil at 4 to
5 hours,10 allows for once-daily dosing. In a large, multicenter, placebo-controlled pivotal study (PHIRST-1), patients
were randomized to placebo or 2.5 mg, 10 mg, 20 mg, or
40 mg of tadalafil daily for 16 weeks.11 Approximately half
of the patients were on bosentan at the time of study entry and
half were treatment naive. A dose-dependent improvement in
6MWD was observed, with the highest dose studied (40 mg
daily) having the greatest effect on 6MWD and clinical worsening. Tadalafil 40 mg also improved time to clinical worsening and health-related quality of life. In a hemodynamic
substudy, there was a statistically significant improvement
in hemodynamics in the tadalafil 40-mg group versus placebo.
Treatment with tadalafil may offer several benefits over sildenafil therapy.12 Tadalafil therapy with once-daily dosing and
a low pill burden (2 pills per day) may offer convenience and
improved adherence to treatment. Sildenafil therapy with doses
of 80 mg 3 times daily may result in a substantial pill burden
(12-15 pills per day), which can also increase nonadherence.
Sildenafil doses >20 mg 3 times daily may not be fully covered
by insurance and, therefore, patient out-of-pocket and overall
health care system costs may be reduced with tadalafil therapy.
Additionally, there are long-term data for treatment durability
at the FDA-approved dose for tadalafil.13 It is anticipated that
because of these benefits, many patients and clinicians may
Methods
Study Design
This was a multicenter, prospective, open-label, 6-month study
of patients with PAH who were transitioned from sildenafil to
tadalafil treatment at home (in the outpatient setting). Adult
males and females with WHO group 1 PAH, who were treated
with sildenafil at a dose of 20 mg 3 times daily or greater for at
least 30 days, and for whom a clinical decision to transition to
tadalafil had been made, were included in this study. Patients
were excluded from the study if they had any other disease
associated with PAH that was non-WHO group 1; advanced
liver or kidney disease; acute decompensation of underlying illness or hospitalization for PAH within 4 weeks before enrollment; a history of hypersensitivity reaction or adverse effect
related to tadalafil use; participated in an investigational drug
or device clinical study within 4 weeks of enrollment; or concomitant use of nitrates or potent CYP3A inhibitors. No limitations were set as to the number and types of non-PDE-5I
background therapies that patients could be on, including ERAs
and inhaled and parenteral prostanoid therapies. Informed consent was obtained from all participants. The study was
approved by the institutional review boards and was registered
with ClinicalTrials.gov (NCT01043627).
Method of Transition
After baseline data collection, patients were instructed to take
the last dose of sildenafil in the evening and then initiate tadalafil (usually 40 mg) the next morning. The tadalafil dose was
reduced (eg, 20 mg) if there were any adverse events (AEs)
attributable to tadalafil therapy.
Clinical Assessments
Patients were evaluated at baseline and at 30 days, 3 months,
and 6 months after transition to tadalafil. Treatment tolerability, patient preferences, and symptoms were measured by having patients complete the Treatment Satisfaction Questionnaire
for Medication (TSQM)14 at baseline and at 30 days, 3 months,
and 6 months after conversion to tadalafil. Patients reported
satisfaction with treatment in this survey as much less satisfied, less satisfied, about same, more satisfied, or
much more satisfied. Patients were also asked to rate their
PAH symptoms as much worse, somewhat worse, about
same, somewhat better, or much better.
Aside from the serial questionnaires, no protocol-mandated
tests were performed. The treating clinician provided information regarding why the patient was transitioning from sildenafil
to tadalafil. Clinical assessments were recorded as available
Frantz et al
according to each centers routine clinical practice. Demographic parameters, disease characteristics, use of concomitant
medications, and any echocardiographic and 6-minute walk
data that had been clinically obtained within 3 months of study
enrollment and without change in PAH medication were collected at baseline. As available, serial parameters from 3 and
6 months following conversion were also abstracted from the
charts and entered into the case report forms. Safety was
assessed on the basis of recorded AEs, vital signs, and clinically available laboratory measures.
Statistical Analysis
Data for all variables collected in this study were summarized
using descriptive statistics. Continuous variables (6MWD and
echocardiography parameters) were summarized using mean
and standard deviation. Categorical variables (WHO functional
class, response to TSQM, and AEs) were summarized using the
number and percentage of patients in each category.
Results
Baseline Characteristics
A total of 35 patients who were prospectively enrolled at 6 centers from April 2010 to February 2011 and met the study entry
criteria were switched from sildenafil to tadalafil. Demographic and baseline disease characteristics of the patients converted from sildenafil to tadalafil are shown in Table 1. The
majority of patients were female with idiopathic PAH
(IPAH)/heritable PAH and were in WHO functional classes
II and III. About 21% of patients in the study were receiving
calcium channel blocker therapy. Most (54%) patients were
receiving 2 or more PAH therapies, and 17% of patients were
on 3 PAH therapies. About 26% of the patients were receiving
inhaled or parenteral prostacyclin therapy. The mean 6MWD
was 394 + 102 m at baseline.
Patients (N 35)
56 (20-84)
9:26
22 (63)
4 (11)
8 (23)
1 (3)
77 + 20a
1.9 + 5.7b
4.5 + 3.0c
1:14:18d
16 (46)
10 (29)
1 (3)
5 (14)
3 (9)
28 (80)
7 (20)
124 + 104e
394 + 101f
170 (12-6129)g
349 (21-7765)h
Patients n (%)
14 (40)
15 (43)
5 (14)
15 (43)
30
Percent of Patients
26
20
20
17
14
14
14
11
10
17
17
14
11
11
11
9
6 6
9
6
6
3
3
0
Headache
Myalgia
Dizziness
Diarrhea
Flushing
Nausea
Figure 1. Common adverse events associated with PDE-5I therapy before conversion to tadalafil and by time on tadalafil. PDE-5I indicates
phosphodiesterase type 5 inhibitor; SIL, sildenafil; TAD, tadalafil.
Frantz et al
70
Percent of Patients
59
60
50
46
39
40
30
22
20
12 10
10
0
26
23
23
15
15
6
Much worse
Somewhat worse
About same
Somewhat better
Much better
Figure 2. Patient assessment of pulmonary arterial hypertension symptoms after conversion from sildenafil to tadalafil, by time on tadalafil. TAD
indicates tadalafil.
50
42
38
Percent of Patients
40
38
29
30
31
26
26
20
19
16
13
10
6
0
Much less
satisfied
Less satisfied
About same
More satisfied
Much more
satisfied
Figure 3. Patient assessment of satisfaction with pulmonary arterial hypertension treatment after conversion from sildenafil to tadalafil, by time
on tadalafil. TAD indicates tadalafil.
conspicuous pattern of change in walk distance after transitioning to tadalafil therapy (Figure 4). The change in mean 6MWD
(+standard error) from baseline was 11.0 (9.0) m, 10.8 (33.7) m,
and 17.3 (25.6) m after 30 days (n 7), 90 days (n 13), and
180 days (n 14) of having transitioned from sildenafil to tadalafil therapy, respectively. No particular trends in the mean RV
systolic pressure (RVSP) were observed (4.4 mm Hg and 4.3
mm Hg after 90 days (n 11) and 180 days (n 11), respectively, compared with baseline, after transitioning to tadalafil.
There was no significant change in tricuspid annual plane systolic excursion (0.34 and 0.36 cm after 90 days (n 8) and 180
days (n 8), respectively, after having transitioned to tadalafil,
and the very small number of patients with serial data precludes
meaningful conclusions.
Detailed review of the 2 patients with major drop in 6MWD
Patient 1. Transient drop in walk that was felt not to be representative of clinical compensation. A 67-year-old female
with diet drug-related PAH in the context of obesity, type 2 diabetes mellitus, obstructive sleep apnea controlled with CPAP,
and need for supplemental oxygen of 3 L/min during activity.
She was receiving 100 mg 3 times daily of sildenafil as monotherapy for her PAH and was switched to tadalafil 40 mg daily
when her insurance carrier refused to continue payment for
B
n=7
700
n = 14
700
600
600
500
500
500
400
400
400
300
200
100
6MWD, m
600
6MWD, m
6MWD, m
700
300
Baseline
Day 30
300
200
200
100
100
n = 13
Baseline
Month 3
Baseline
Month 6
Figure 4. Change in 6MWD from baseline for patients with serial data available. A, Baseline to day 30. B, Baseline to month 3. C, Baseline to
month 6. Mean 6MWD is plotted as dotted lines. 6MWD indicates 6-minute walk distance.
sildenafil. She had previously been intolerant of inhaled iloprost and oral treprostinil and had not had clinical benefit from
bosentan. One month prior to the switch, she was WHO functional class III, with 6-minute walk of 372 m on 3L oxygen
with drop in systemic saturation from 95% to 82%. Her
N-terminal pro-B-type natriuretic peptide (NT-proBNP) level
was 264 pg/mL. The RVSP by implanted Chronicle hemodynamic monitor was 95 mm Hg, with RVEDP of 7 mm Hg.
Echocardiography showed moderate RV enlargement, moderate tricuspid regurgitation, and tricuspid annular plane systolic
excursion of 19 mm, with estimated cardiac index of 3.0 L/min/
m2. Four months following conversion to tadalafil, she felt
clinically unchanged and remained functional class III. Her
walk distance of only 114 m was performed the day after she
had a very busy day entertaining guests and had arisen at 3
AM in order to attend the clinic. She felt exhausted and stopped
walking after only 1 minute 46 seconds and felt the walk was
not representative of her overall clinical status. N-terminal pro
B-type natriuretic peptide was 485 pg/mL, and interrogation of
her implantable hemodynamic monitor showed no change in
her hemodynamics compared to prior to switching to tadalafil.
Echocardiography-estimated cardiac index was preserved at
2.7 L/min/m2. Her therapy was not changed. Ten months following conversion, she remained functional class III on tadalafil without additional therapy, with 6-minute walk of 337 m and
NT-proBNP of 592 pg/mL. At most recent follow-up, 3 years
following the switch, she remains functional class III on
tadalafil monotherapy, with stable echo parameters, a 6minute walk of 313 m, and NT-proBNP of 557 pg/mL.
Patient 2. Stable walk at 3 months, but reduction in walk at
6 months. This patient was on triple therapy with sildenafil
30 mg 3 times daily, bosentan 125 mg twice daily, and iv epoprostenol 115 ng/kg/min with 6-minute walk of 390 m prior to
conversion to tadalafil. At 3-month follow-up after conversion,
her 6MWD was preserved at 395 m with preserved B-type
natriuretic peptide (BNP) level of 144 pg/mL. However, at the
6-month follow-up, she had developed pulmonary infiltrates,
was more hypoxic, and her walk had deteriorated to 126 m,
with BNP 587 pg/mL. She was diagnosed with anti-PR3 vasculitis that responded to rituximab. Two months later, her walk
had improved to 239 m with BNP 485 pg/mL. She was subsequently converted to treprostinil in an effort to deal with worsening thrombocytopenia. She stayed on tadalafil throughout
her course, and 2 years later required lung transplantation.
It was not felt that the deterioration in walk distance at 6 months
was related to the prior conversion to tadalafil.
Discussion
In this prospective study, most patients were successfully converted from sildenafil to tadalafil in the outpatient setting while
maintaining PAH therapeutic class efficacy and improving
treatment satisfaction. Factors of convenience and cost were
Frantz et al
for United Therapeutics, without personal financial gain, aside from coverage of travel expenses, in keeping with the Mayo Clinics conflict of
interest policy for clinical investigators. He has received research funding for unrelated research projects and educational grants from United
Therapeutics, without personal financial gain. LD serves on a steering
committee for Medtronic, without personal financial gain, aside from
coverage of travel expenses, in keeping with the Mayo Clinics conflict
of interest policy for study staff. CB has received research funding from
Actelion Pharmaceuticals, Gilead Sciences, and United Therapeutics,
without personal financial gain. RO has received consulting and/or steering committee honoraria from Actelion Pharmaceuticals, Bayer, Gilead
Sciences, Lung Rx, Medtronic, Novartis Pharmaceuticals, Pfizer, and
United Therapeutics. RO has received grant support for clinical trials
from Actelion Pharmaceuticals, Bayer, Gilead Sciences, Lung Rx, Pfizer, and United Therapeutics. He has also received speaker fees from
Gilead Sciences and United Therapeutics. RB has received research support from Pfizer, United Therapeutics, Gilead Sciences, Actelion Pharmaceuticals, Novartis Pharmaceuticals, Medtronic, GeNO, and Bayer.
He serves as a consultant for United Therapeutics, Gilead Sciences, Actelion Pharmaceuticals, Novartis Pharmaceuticals, and Medtronic. He also
has received compensation for participation in speakers bureaus for
Gilead Sciences and United Therapeutics. VF has served on advisory
boards for Gilead Sciences and Bayer and has received compensation for
participation in Gilead Sciences speakers bureau. AW is a consultant for
United Therapeutics, Gilead Sciences, Pfizer, and Medtronic. He has also
received research support from United Therapeutics, Gilead Sciences,
Pfizer, and Medtronic, without personal financial gain. SM and SW are
employees of United Therapeutics.
Funding
The author(s) received no financial support for the research,
authorship, and/or publication of this article.
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