Journal of Cardiovascular Pharmacology and

Therapeutics
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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
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Article

Conversion From Sildenafil to Tadalafil:

Results From the Sildenafil to Tadalafil
in Pulmonary Arterial Hypertension
(SITAR) Study

Journal of Cardiovascular
Pharmacology and Therapeutics
1-8
The Author(s) 2014
Reprints and permission:
sagepub.com/journalsPermissions.nav
DOI: 10.1177/1074248414528066
cpt.sagepub.com

Robert P. Frantz, MD1, Louise Durst, RN2, Charles D. Burger, MD3,

Ronald J. Oudiz, MD4, Robert C. Bourge, MD5,
Veronica Franco, MD6, Aaron B. Waxman, MD, PhD7,
Susanne McDevitt, RN, MSN, ACNP8, and Susan Walker, MS8

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

Division of Cardiovascular Diseases, College of Medicine, Mayo Clinic,

Rochester, MN, USA
2
Mayo Clinic, Rochester, MN, USA
3
Division of Pulmonary Medicine, Mayo Clinic, Jacksonville, FL, USA
4
Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center,
Torrance, CA, USA
5
Cardiovascular Medicine, University of Alabama at Birmingham, Birmingham,
AL, USA
6
Cardiovascular Medicine, Ohio State University Medical Center, Columbus,
OH, USA
7
Cardiovascular Medicine, Brigham and Womens Hospital, Boston, MA, USA
8
United Therapeutics Corporation, Research Triangle Park, NC, USA
Manuscript submitted: July 26, 2013; accepted: February 20, 2014.
Corresponding Author:
Robert P. Frantz, 200 First Street SW, Mayo Clinic, Gonda 5, Rochester, MN
55905, USA.
Email: frantz.robert@mayo.edu

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Journal of Cardiovascular Pharmacology and Therapeutics

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

choose transition from sildenafil to tadalafil therapy. However,

there is little reported clinical experience in converting patients
from sildenafil to tadalafil. In this prospective multicenter
open-label study, safety and patient satisfaction with conversion from sildenafil to tadalafil were assessed.

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

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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.

Patient Disposition and Transition Dosing Considerations

All patients were switched from sildenafil to tadalafil per the
specified dosing regimen. Mean duration of sildenafil treatment was 124 + 100 weeks (range 10-385 weeks). At the time
of transition, 20% of the patients were on >20 mg 3 times daily
of sildenafil, with 1 patient receiving as high as 100 mg 3 times
daily of sildenafil. Clinicians cited that the majority of patients
were converted from sildenafil to tadalafil for convenience and
cost reasons (Table 2). Of the 35 patients transitioned from sildenafil to tadalafil, 5 (14%) transitioned back to sildenafil.
Four patients required the addition of a parenteral prostanoid
within the 6-month period after transitioning to tadalafil.

Tolerability of Conversion from Sildenafil to Tadalafil

Transition from sildenafil to tadalafil was generally well tolerated, with headache, myalgia, dizziness, diarrhea, flushing, and
nausea reported as common AEs (Figure 1). Most AEs were

Table 1. Patient Demographics and Characteristics.

Parameter

Patients (N 35)

Age, y, mean (range)

Male:female, n
PAH etiology, n (%)
Idiopathic or heritable
CTD
Other
Missing
Echo parameters, mean + SD
RVSP, mm Hg
TAPSE, cm
CO, L/min
WHO functional class, n
I:II:III
PAH/Background medications, n (%)
PDE-5I monotherapy
PDE-5I ERA
PDE-5I ERA inhaled prostanoid
PDE-5I ERA parenteral prostanoid
PDE-5I parenteral prostanoid
Sildenafil dose at transition, n (%)
20 mg tid
>20 mg tid
Duration of sildenafil, mean + SD, week
6MWD before transition, mean + SD, m
BNP, median (range), pg/mL
NT-proBNP, median (range), pg/mL

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

Abbreviations: BNP, B-type natriuretic peptide; CO, cardiac output; CTD,

connective tissue disease; echo, echocardiography; ERA, endothelin receptor
antagonist; 6MWD, 6-minute walk distance; NT-proBNP, N-terminal proBNP; PAH, pulmonary arterial hypertension; PDE-5I, phosphodiesterase type
5 inhibitor; RVSP, right ventricular systolic pressure; SD, standard deviation;
TAPSE, tricuspid annual plane systolic excursion; tid, 3 times daily; WHO,
World Health Organization.
a
n 31.
b
n 23.
c
n 24.
d
n 33.
e
n 30.
f
n 32.
g
n 17.
h
n 15.

Table 2. Reasons for Conversion to Tadalafil.a

Reason
Convenience
Cost
Sildenafil dose >20 mg tid
Other

Patients n (%)
14 (40)
15 (43)
5 (14)
15 (43)

Abbreviation: tid, 3 times daily.

a
Patients could have been converted for multiple reasons.

mild to moderate. Before conversion to tadalafil, common AEs

with sildenafil therapy included diarrhea, flushing, dizziness,
myalgia, and headache. We did not observe any substantial differences in the AE profile, but headache early following conversion may have been more common while diarrhea and
flushing seemed to be less prominent. The most common

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Journal of Cardiovascular Pharmacology and Therapeutics

30

SIL baseline (n = 35)

TAD 30 days (n = 35)
TAD 90 days (n = 35)
TAD 180 days (n = 35)

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.

severe AEs associated with the conversion to tadalafil included

headache, nasal congestion, pain in extremity, myalgia, and
dizziness, which were more common in the initial 30 days after
conversion.
Details of failed transitions
Patient 1. A 59-year-old female with IPAH on therapy with
amlodipine and sildenafil 20 mg 3 times daily, with blood pressure (BP) 96/50 prior to transition. Prior history notable for
severe chronic fatigue. She noted myalgias and worsening fatigue after transition. Tadalafil dose reduction to 20 mg
improved but did not resolve the aggravation of these symptoms so she was converted back to sildenafil.
Patient 2. A 52-year-old female with IPAH on therapy with
bosentan and sildenafil 20 mg 3 times daily. Light sensitivity
after the transition that resolved after several days and worsening gastroesophageal reflux that improved with omeprazole
were noted. She also described myalgias, nasal stuffiness, and
constipation. The possibility of reducing the dose of tadalafil
was discussed, but she elected to transition back to sildenafil
2 weeks after starting the tadalafil.
Patient 3. A 74-year-old female with IPAH, on therapy with
80 ng/kg/min intravenous (iv) treprostinil and sildenafil 20 mg
3 times daily. She had an estimated glomerular filtration rate of
31 mL/min. Following transition, she experienced symptomatic lightheadedness and worsening dyspnea. She remained
functional class III before and after the transition so converted
back to sildenafil. Potentially, 20 mg of tadalafil would have
been a more optimal starting dose in such a setting. Down titrating the tadalafil rather than switching back to sildenafil could
have been considered.
Patient 4. For this patient, a reason for the transition back to
sildenafil was not provided.

Patient 5. A 42-year-old female with IPAH on therapy with

bosentan and sildenafil 20 mg 3 times daily. Following transition, she noted significant lower extremity aching unresponsive
to ibuprofen and mild pedal edema. Two months after transition, she was converted back to sildenafil. There was not an
attempt to reduce her tadalafil dose.
Symptoms of PAH and satisfaction with therapy. Among patients
who answered the questionnaire at each time point, there
appeared to be a greater percentage of patients who reported the
same or improved general PAH symptoms over time (Figure
2). Within 30 days after conversion to tadalafil, 88% of patients
reported the same or improved general PAH symptoms
(n 32). After 90 (n 31) and 180 days (n 26) of having
transitioned to tadalafil, 87% and 85% of patients reported the
same or improved PAH symptoms, respectively. In addition,
48% and 38% of patients reported improvement in PAH symptoms after 90 and 180 days of having transitioned to tadalafil,
respectively.
There was a greater percentage of patients who were satisfied
(more satisfied and much more satisfied) than were dissatisfied
(less satisfied and much less satisfied) after conversion to tadalafil
(30 days, 47% vs 16%; 90 days, 55% vs 19%; 180 days, 50% vs
8%; Figure 3). Two patients reported much less satisfied in the
90-day survey only following conversion to tadalafil.
Although global satisfaction score following transition to
tadalafil did not significantly improve versus baseline (mean
improvement of 0.3 after 180 days; P .7309), TSQM scores
showed a significant improvement in convenience (mean
improvement of 15.9 after 180 days; P .0312).

Summary of Clinically Available Serial Testing

Given the small number of patients who had serial 6MWD available, we can only say that for most of them there was no

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Frantz et al

70

TAD 30 days (n = 32)

Percent of Patients

TAD 90 days (n = 31)

59

60

TAD 180 days (n = 26)

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

TAD 30 days (n = 32)

TAD 90 days (n = 31)
TAD 180 days (n = 26)

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

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Journal of Cardiovascular Pharmacology and Therapeutics

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

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Frantz et al

commonly cited as reasons for transition to tadalafil. Improved

treatment satisfaction with tadalafil appeared to relate primarily to the improved sense of convenience reported by patients.
The patients in this study were stable on sildenafil before transition to tadalafil with many of the patients on combination
therapies, including 37% on 2 PAH therapies and 17% on 3
PAH therapies. Furthermore, patients taking >20 mg 3 times
daily of sildenafil were successfully transitioned to tadalafil
40 mg once daily.
Transition to tadalafil from sildenafil was generally well tolerated. Most patients who transitioned to tadalafil remained on
tadalafil throughout the 6 months of our study, but some
patients switched back to sildenafil due to more problematic
side effects or, in 1 patient, increased dyspnea. The incidence
of common AEs appeared to decrease over time on tadalafil
therapy, with the exception of myalgia. Although there was a
higher incidence of headache (28%) within the first 30 days
of transition in this study, the incidence decreased over time
(14% by 6 months). Headache and myalgia were also 2 of the
most commonly reported AEs in the 16-week PHIRST-1
trial.11 Similar to this study, the incidence of headache
decreased rapidly after 1 week of tadalafil therapy in the
PHIRST-1 trial and remained infrequent through the openlabel PHIRST-2 trial (68 weeks).15 These results suggest that
the incidence of AEs such as headache may be initially higher
when patients are transitioned to tadalafil but these tend to
diminish in frequency upon continued treatment.

Practical Lessons Regarding the Transition Process

1. For patients with mild to moderate renal insufficiency, a
starting dose of 20 mg daily is recommended, with
potential to increase to 40 mg daily if tolerated. For
patients with severe renal insufficiency, tadalafil should
be avoided.
2. A dose of tadalafil of 40 mg daily appears to have a
more maximally phosphodiesterase-5 inhibiting effect
than 20 mg 3 times daily of sildenafil. Accordingly for
patients who have been on 20 mg of sildenafil 3 times
daily with particularly low blood pressure, for example,
less than 100 mg Hg prior to transition, a starting dose
of 20 mg daily should be considered.
3. For patients already on parenteral prostanoids who have
been on 20 mg of sildenafil 3 times daily, starting with
tadalafil 20 mg daily may be advisable to assess tolerability, with subsequent dose increase if tolerated. It
should be noted that, unlike sildenafil, there are no randomized clinical trial data regarding the addition of
tadalafil to parenteral prostanoids so information
regarding this combination is quite limited.

Possible Explanation for Improved Treatment

Satisfaction With Tadalafil Compared to Sildenafil
The greater proportion of patients reporting improved treatment satisfaction with tadalafil therapy in this study may in part

be because of the reduced pill burden and frequency of dosing.

Although not specifically examined in this study, reducing the pill
burden from an often high number of pills per day on a 3 times
daily schedule for sildenafil to 2 pills taken once daily for tadalafil
may improve patient adherence. Pill fatigue and lack of compliance have been well described in the HIV population along with
improvements in outcomes related to simplifying of therapy regimen,16,17 A similar finding may occur in PAH as well, and thus,
decreasing pill burden may have a positive impact. In a recent
analysis of pharmacy claims (specialty pharmacy services and
retail) from Medco Health Solutions, Inc, conducted between
2008 and 2010, the overall adherence to tadalafil was 61%, compared with 44% for sildenafil (P < .0001).18
Limitations of this study include the open-label nature of the
study and the small sample size. Awareness of the transition
may create bias, generating a perceived improvement from the
transition. Echocardiography and 6MWD tests were not protocol mandated and thus were only available for some of the
patients during follow-up. Because of the small sample size and
lack of protocol-mandated testing, the study was not powered
to rigorously assess clinical outcomes; therefore, in this regard
it is exploratory in nature. Finally, although treatment with
tadalafil is expected to result in improved compliance with
therapy, this study did not specifically assess medication adherence. Despite these limitations, this multicenter prospective
study provides important information on how to transition
patients from sildenafil to tadalafil.
Sildenafil and tadalafil appear to have similar efficacy and
safety profiles in patients with PAH (functional classes II or
III).5,11 In this context, other potential attributes may rise in
relative importance. Indeed, tadalafil may have characteristics
that make it a useful alternative to sildenafil, including convenience and pill burden, potential for fewer drugdrug interactions in combination with ERAs, and clear dosing in which
the FDA-approved dose is the most effective dose with data for
treatment durability.7,19,20 Because of these benefits and its relatively low cost, tadalafil may be a useful alternative in patients
with PAH. Consistent with the results from this study, a recent
small study reported that transitioning patients from sildenafil
to tadalafil was safe and generally well tolerated.21 In conclusion, converting directly from sildenafil to tadalafil was generally well tolerated without any obvious safety issues. There was
a greater percentage of patients who were satisfied than were
dissatisfied after conversion to tadalafil.
Declaration of Conflicting Interests
The author(s) declared the following potential conflicts of interest with
respect to the research, authorship, and/or publication of this article: Support for this study was provided by United Therapeutics Corporation.
Editorial assistance was provided under the direction of the authors by
MedThink Communications with support from United Therapeutics
Corporation. United Therapeutics Corporation provided support for data
collection, data management, and statistical analysis. SM and SW are
employees of United Therapeutics Corporation and as authors were
involved in data interpretation and had the right to approve or disapprove
publication of the finished manuscript. RF has served on advisory boards

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Journal of Cardiovascular Pharmacology and Therapeutics

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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