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published online 17 April 2014J CARDIOVASC PHARMACOL THERWaxman, Susanne McDevitt and Susan Walker

Robert P. Frantz, Louise Durst, Charles D. Burger, Ronald J. Oudiz, Robert C. Bourge, Veronica Franco, Aaron B.Hypertension (SITAR) Study

Conversion From Sildenafil to Tadalafil: Results From the Sildenafil to Tadalafil in Pulmonary Arterial  

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Article

Conversion From Sildenafil to Tadalafil:Results From the Sildenafil to Tadalafilin Pulmonary Arterial Hypertension(SITAR) Study

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

AbstractPurpose: Among phosphodiesterase type 5 inhibitors, tadalafil offers clinicians a once-daily alternative to 3 times daily sildenafilfor the treatment of pulmonary arterial hypertension (PAH). This study assessed the safety and patient satisfaction with conver-sion from sildenafil to tadalafil. Methods: In this multicenter, prospective, 6-month study, patients with PAH were instructed totake their last dose of sildenafil in the evening and initiate tadalafil 40 mg/d the next morning. Patients completed the TreatmentSatisfaction Questionnaire for Medication at baseline and 30, 90, and 180 days after transition to assess PAH symptoms andpatient satisfaction. Safety was assessed on the basis of recorded adverse events (AEs). Results: Of the 35 patients who metthe 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 incidenceof common AEs, except for myalgia, appeared to decrease over time on tadalafil therapy. Five (14%) patients switched back tosildenafil. A greater percentage of patients were satisfied than were dissatisfied after conversion to tadalafil (55% vs 19% at 90days), while 26% felt about the same degree of satisfaction. Conversion to tadalafil resulted in significant improvement in patientratings of therapy convenience. Conclusions: Transition of patients from sildenafil to tadalafil was usually well tolerated, withimproved convenience and may enhance treatment satisfaction.

Keywordssildenafil, 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 aware-

ness 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

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

Rochester, MN, USA2 Mayo Clinic, Rochester, MN, USA3 Division of Pulmonary Medicine, Mayo Clinic, Jacksonville, FL, USA4 Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center,

Torrance, CA, USA5 Cardiovascular Medicine, University of Alabama at Birmingham, Birmingham,

AL, USA6 Cardiovascular Medicine, Ohio State University Medical Center, Columbus,

OH, USA7 Cardiovascular Medicine, Brigham and Women’s Hospital, Boston, MA, USA8 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

Journal of CardiovascularPharmacology and Therapeutics1-8ª The Author(s) 2014Reprints and permission:sagepub.com/journalsPermissions.navDOI: 10.1177/1074248414528066cpt.sagepub.com

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Pulmonary Arterial Hypertension (SUPER-1) study that rando-

mized 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 dos-

ing regimen for sildenafil is controversial and has resulted in

confusion among some clinicians who have been treating

patients with sildenafil doses substantially above the FDA-

recommended dose. Treating patients above the FDA-

recommended 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 treat-

ment of patients with World Health Organization (WHO)

group 1 PAH at a dose of 40 mg daily.8 Tadalafil’s 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, multicen-

ter, 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 wor-

sening. Tadalafil 40 mg also improved time to clinical wor-

sening 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 sil-

denafil 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 conver-

sion 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 ill-

ness or hospitalization for PAH within 4 weeks before enroll-

ment; 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 con-

comitant use of nitrates or potent CYP3A inhibitors. No limita-

tions 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 con-

sent 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 tada-

lafil (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 tolerabil-

ity, patient preferences, and symptoms were measured by hav-

ing 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 satis-

fied,’’ ‘‘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 informa-

tion regarding why the patient was transitioning from sildenafil

to tadalafil. Clinical assessments were recorded as available

2 Journal of Cardiovascular Pharmacology and Therapeutics

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according to each center’s routine clinical practice. Demo-

graphic 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 col-

lected 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 clini-

cally 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 cen-

ters from April 2010 to February 2011 and met the study entry

criteria were switched from sildenafil to tadalafil. Demo-

graphic and baseline disease characteristics of the patients con-

verted 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 treat-

ment 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 sil-

denafil 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 toler-

ated, with headache, myalgia, dizziness, diarrhea, flushing, and

nausea reported as common AEs (Figure 1). Most AEs were

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 dif-

ferences in the AE profile, but headache early following con-

version may have been more common while diarrhea and

flushing seemed to be less prominent. The most common

Table 1. Patient Demographics and Characteristics.

Parameter Patients (N ¼ 35)

Age, y, mean (range) 56 (20-84)Male:female, n 9:26PAH etiology, n (%)

Idiopathic or heritable 22 (63)CTD 4 (11)Other 8 (23)Missing 1 (3)

Echo parameters, mean + SDRVSP, mm Hg 77 + 20a

TAPSE, cm 1.9 + 5.7b

CO, L/min 4.5 + 3.0c

WHO functional class, nI:II:III 1:14:18d

PAH/Background medications, n (%)PDE-5I monotherapy 16 (46)PDE-5I þ ERA 10 (29)PDE-5I þ ERA þ inhaled prostanoid 1 (3)PDE-5I þ ERA þ parenteral prostanoid 5 (14)PDE-5I þ parenteral prostanoid 3 (9)

Sildenafil dose at transition, n (%)�20 mg tid 28 (80)>20 mg tid 7 (20)

Duration of sildenafil, mean + SD, week 124 + 104e

6MWD before transition, mean + SD, m 394 + 101f

BNP, median (range), pg/mL 170 (12-6129)g

NT-proBNP, median (range), pg/mL 349 (21-7765)h

Abbreviations: BNP, B-type natriuretic peptide; CO, cardiac output; CTD,connective tissue disease; echo, echocardiography; ERA, endothelin receptorantagonist; 6MWD, 6-minute walk distance; NT-proBNP, N-terminal pro-BNP; PAH, pulmonary arterial hypertension; PDE-5I, phosphodiesterase type5 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 ¼ 31.b n ¼ 23.c n ¼ 24.d n ¼ 33.e n ¼ 30.f n ¼ 32.g n ¼ 17.h n ¼ 15.

Table 2. Reasons for Conversion to Tadalafil.a

Reason Patients n (%)

Convenience 14 (40)Cost 15 (43)Sildenafil dose >20 mg tid 5 (14)Other 15 (43)

Abbreviation: tid, 3 times daily.a Patients could have been converted for multiple reasons.

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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 transitionsPatient 1. A 59-year-old female with IPAH on therapy with

amlodipine and sildenafil 20 mg 3 times daily, with blood pres-

sure (BP) 96/50 prior to transition. Prior history notable for

severe chronic fatigue. She noted myalgias and worsening fati-

gue after transition. Tadalafil dose reduction to 20 mg

improved but did not resolve the aggravation of these symp-

toms 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 worsen-

ing 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 sympto-

matic 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 titrat-

ing 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 transi-

tion, she noted significant lower extremity aching unresponsive

to ibuprofen and mild pedal edema. Two months after transi-

tion, 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 ¼ 32). After 90 (n ¼ 31) and 180 days (n ¼ 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 symp-

toms 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 ¼ .7309), TSQM scores

showed a significant improvement in convenience (mean

improvement of 15.9 after 180 days; P ¼ .0312).

Summary of Clinically Available Serial Testing

Given the small number of patients who had serial 6MWD avail-

able, we can only say that for most of them there was no

26

30 SIL baseline (n = 35) TAD 30 days (n = 35)TAD 90 days (n = 35)

20

17

20

TAD 180 days (n = 35)

14

9 9

14 14

1717

11 1111

14

6

11

9

11

6 6 6

9

6

10

Perc

ent o

f Pat

ient

s

3 3

0

Headache Dizziness Flushing NauseaMyalgia DiarrheaDizziness Flushing NauseaDiarrhea

Figure 1. Common adverse events associated with PDE-5I therapy before conversion to tadalafil and by time on tadalafil. PDE-5I indicatesphosphodiesterase type 5 inhibitor; SIL, sildenafil; TAD, tadalafil.

4 Journal of Cardiovascular Pharmacology and Therapeutics

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conspicuous pattern of change in walk distance after transition-

ing 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 (n¼ 7), 90 days (n¼ 13), and

180 days (n¼ 14) of having transitioned from sildenafil to tada-

lafil 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 ¼ 11) and 180 days (n ¼ 11), respec-

tively, compared with baseline, after transitioning to tadalafil.

There was no significant change in tricuspid annual plane systo-

lic excursion (�0.34 and�0.36 cm after 90 days (n¼ 8) and 180

days (n ¼ 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 6MWDPatient 1. Transient drop in walk that was felt not to be rep-

resentative of clinical compensation. A 67-year-old female

with diet drug-related PAH in the context of obesity, type 2 dia-

betes 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 mono-

therapy for her PAH and was switched to tadalafil 40 mg daily

when her insurance carrier refused to continue payment for

5960

70 TAD 30 days (n = 32)TAD 90 days (n = 31)

4650

TAD 180 days (n = 26)

39

2630

40

12

22

10

23

15

23

15

10

20Perc

ent o

f Pat

ient

s

0

63

00

10

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. TADindicates tadalafil.

42

50 TAD 30 days (n = 32)TAD 90 days (n = 31)TAD 180 days (n = 26)

2931

40

26

38 38

26

1920

30

16

9

6

13

810

Perc

ent o

f Pat

ient

s

0 00

Much less Less satisfied About same More satisfied Much moresatisfied satisfied

Figure 3. Patient assessment of satisfaction with pulmonary arterial hypertension treatment after conversion from sildenafil to tadalafil, by timeon tadalafil. TAD indicates tadalafil.

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sildenafil. She had previously been intolerant of inhaled ilo-

prost and oral treprostinil and had not had clinical benefit from

bosentan. One month prior to the switch, she was WHO func-

tional 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 hemody-

namic monitor was 95 mm Hg, with RVEDP of 7 mm Hg.

Echocardiography showed moderate RV enlargement, moder-

ate 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 fol-

lowing conversion, she remained functional class III on tadala-

fil 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 6-

minute 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 epo-

prostenol 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 vascu-

litis that responded to rituximab. Two months later, her walk

had improved to 239 m with BNP 485 pg/mL. She was subse-

quently converted to treprostinil in an effort to deal with wor-

sening thrombocytopenia. She stayed on tadalafil throughout

her course, and 2½ 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 con-

verted from sildenafil to tadalafil in the outpatient setting while

maintaining PAH therapeutic class efficacy and improving

treatment satisfaction. Factors of convenience and cost were

CA Bn = 13n = 7 n = 14

600

700

600

700

600

700

500 500 500

D, m

D, m

D, m

400 400 400

6MW

6MW

6MW

200

300

200

300

200

300

100

200

100 100

0Baseline Day 30

0Baseline Month 3

0Baseline 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 tomonth 6. Mean 6MWD is plotted as dotted lines. 6MWD indicates 6-minute walk distance.

6 Journal of Cardiovascular Pharmacology and Therapeutics

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commonly cited as reasons for transition to tadalafil. Improved

treatment satisfaction with tadalafil appeared to relate primar-

ily to the improved sense of convenience reported by patients.

The patients in this study were stable on sildenafil before tran-

sition 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 tol-

erated. 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 open-

label 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 toler-

ability, with subsequent dose increase if tolerated. It

should be noted that, unlike sildenafil, there are no ran-

domized clinical trial data regarding the addition of

tadalafil to parenteral prostanoids so information

regarding this combination is quite limited.

Possible Explanation for Improved TreatmentSatisfaction With Tadalafil Compared to Sildenafil

The greater proportion of patients reporting improved treat-

ment 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 compli-

ance have been well described in the HIV population along with

improvements in outcomes related to simplifying of therapy regi-

men,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%, com-

pared 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 proto-

col 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 adher-

ence. 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 conve-

nience and pill burden, potential for fewer drug–drug interac-

tions 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 rel-

atively 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 conclu-

sion, converting directly from sildenafil to tadalafil was gener-

ally 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: Sup-

port 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

Frantz et al 7

at Erciyes Universitesi on May 2, 2014cpt.sagepub.comDownloaded from

for United Therapeutics, without personal financial gain, aside from cov-

erage of travel expenses, in keeping with the Mayo Clinic’s conflict of

interest policy for clinical investigators. He has received research fund-

ing 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 Clinic’s 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 steer-

ing 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, Pfi-

zer, and United Therapeutics. He has also received speaker fees from

Gilead Sciences and United Therapeutics. RB has received research sup-

port from Pfizer, United Therapeutics, Gilead Sciences, Actelion Phar-

maceuticals, Novartis Pharmaceuticals, Medtronic, GeNO, and Bayer.

He serves as a consultant for United Therapeutics, Gilead Sciences, Acte-

lion 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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