Safety and Long-Term Efficacy of Transition from Sildenafilto Tadalafil due to Side Effects in Patients with PulmonaryArterial Hypertension

Mona Lichtblau • Dominik Harzheim •

Nicola Ehlken • Alberto Marra • Fabiola Pena Pinado •

Ekkehard Grunig • Benjamin Egenlauf

Received: 14 July 2014 / Accepted: 7 October 2014

� Springer Science+Business Media New York 2014

Abstract

Introduction Two phosphodiesterase-type 5 (PDE-5) inhib-

itors, sildenafil and tadalafil, are approved for treatment of

pulmonary arterial hypertension (PAH). It has not yet been

observed if transition from sildenafil to tadalafil is beneficial in

patients suffering from adverse reactions. Aim of this study was

to analyze safety and long-term effects in PAH patients whose

treatment was transitioned from sildenafil to tadalafil due to

intolerable side-effects.

Methods A retrospective analysis of PAH-patients who

were stable on sildenafil for [3 months and transitioned to

tadalafil due to adverse events was performed. Data collected

included demographics, PAH-etiology, WHO-functional

class, 6 min walking distance (6MWD), echocardiography,

lung function tests, and NTproBNP pre-transition and 3, 6,

and 12 months post-transition.

Results Included were 13 PAH patients (8 females mean

age 64 ± 10 years) who had been on sildenafil for a mean

of 12 ± 8.4 months. In six patients (46.1 %) a switch to

tadalafil was feasible and resulted in tolerable side effects

and a stable clinical course with improvement of symp-

toms, 6MWD, stable echocardiographic findings, and

NTproBNP-levels during a follow-up of 11 ± 3 months. In

5 out of 13 patients (38.5 %) adverse events occurred under

tadalafil as well and therapy with PDE-5 inhibitors was

discontinued. In two patients (15.4 %) sildenafil-treatment

could be successfully restarted after an intermittent switch

to tadalafil.

Conclusions The observations of this study indicate that a

transition of sildenafil to tadalafil in case of intolerable side

effects is a reasonable therapy option in about 50 % of the

patients. These results should be verified by a larger pro-

spective study.

Keywords Pulmonary artery hypertension � Sildenafil �Tadalafil � Phosphodiesterase

List of Abbreviations

6MWD 6 min walking distance

NO Nitric oxide

NTproBNP N-terminal prohormone of brain natriuretic

peptideMona Lichtblau and Dominik Harzheim made an equal contribution

to the study.

M. Lichtblau (&) � D. Harzheim � N. Ehlken � A. Marra �F. P. Pinado � E. Grunig � B. Egenlauf

Centre for Pulmonary Hypertension, Thoraxklinik of University

Hospital Heidelberg, Amalienstrasse 5, 69126 Heidelberg,

Germany

e-mail: mona.lichtblau@med.uni-heidelberg.de

D. Harzheim

e-mail: Dominik.Harzheim@med.uni-heidelberg.de

N. Ehlken

e-mail: Nicola.Ehlken@med.uni-heidelberg.de

A. Marra

e-mail: Alberto.Marra@med.uni-heidelberg.de

F. P. Pinado

e-mail: pinado_70@hotmail.com

E. Grunig

e-mail: Ekkehard.Gruenig@med.uni-heidelberg.de

B. Egenlauf

e-mail: Benjamin.Egenlauf@med.uni-heidelberg.de

A. Marra

Department of Translational Medical Sciences, ‘‘Federico II’’

University, Naples, Italy

123

Lung

DOI 10.1007/s00408-014-9657-7

PAH Pulmonary arterial hypertension

PASP Systolic pulmonary arterial pressures

PDE-5 Phosphodiesterase-type 5

PH Pulmonary hypertension

q.d. Quaque die

TAPSE Tricuspid annular plane systolic excursion

t.i.d. Ter in die

WHO World Health Organization

Background

Within the last years several new therapeutic options have

been developed for the treatment of pulmonary arterial

hypertension (PAH) [1–3]. Treatment with phosphodies-

terase-type 5 inhibitors (PDE-5) turned out to be safe and

highly effective in PAH [3–7] leading to a class IA rec-

ommendation in the European guidelines [2] and at the last

world congress in Nice 2013 [1].

By inhibiting the degradation of NO’s second messen-

ger, cyclic guanosine monophosphate, both PDE-5 inhibi-

tors increase the effects of locally produced nitric oxide

(NO) and lead to a pulmonary vasodilation and inhibition

of smooth muscle cell growth [3, 8].

In Germany, sildenafil has been the only PDE-5 inhib-

itor available until November 2009, when tadalafil was

approved for PAH as well. While sildenafil has to be taken

three times a day, tadalafil offers a once daily regimen

which might be an advantage regarding therapeutic com-

pliance and convenience especially in patients with upti-

trated dosages of sildenafil from 60 to 100 mg t.i.d.

resulting in 12–15 pills/day. On the other hand sildenafil

treatment has a longer history, due to its earlier drug

approval [4]. It was also discussed, that sildenafil seemed

to be slightly more efficient than tadalafil with a better

improvement of the 6MWD [9]. In contrast, an improve-

ment of time to clinical worsening could only be shown for

tadalafil [4, 5]. Due to the lack of studies with a head-to-

head comparison of safety and efficacy between the two

drugs a final conclusion is not possible. Main adverse side-

effects such as headache, flushing, gastrointestinal reac-

tions as dyspepsia, and diarrhea are similar in both drugs

and often occur temporarily when treatment is started.

However, in some patients with good clinical response to

sildenafil, adverse effects remain intolerable leading to

necessity to discontinue treatment. Therefore, it may be

worth to try a switch from one PDE-5 inhibitor to the other

especially in those cases in which beneficial clinical

response has already been shown. Previously, three retro-

spective transition studies have been performed to observe

safety, tolerability, and efficacy of transition from sildenafil

to tadalafil in PAH-patients [10–12]. In these studies

transition has been performed in patients who were stable

mostly on higher dosages of sildenafil (80–100 mg t.i.d)

who were switched to improve patients’ convenience (less

pill burden), drug adherence, and costs [10–12]. It has not

been analyzed yet, if transition from sildenafil to tadalafil

due to adverse events, which is a different, more difficult

and potentially dangerous situation, is a rational thera-

peutic option and useful for the clinical practice. Therefore,

the aim of this study was to investigate whether transition

of sildenafil to tadalafil treatment due to adverse events is

tolerable and beneficial in a long-term follow-up.

Methods

A retrospective chart-review of all patients treated with

PDE-5 inhibitors in the center for pulmonary hypertension of

the Thoraxclinic at the University of Heidelberg in 2012 was

performed. Patients with invasively confirmed PAH, in whom

transition of sildenafil to tadalafil treatment was performed

due to adverse effects, were included in the study. Patients had

to be on a stable clinical course with no further change in

targeted PAH-medication for at least 3 months. Transition of

treatment had been discussed during the regular control visits.

All patients were instructed to take their evening dose of sil-

denafil (last dose) and to start with tadalafil the following

morning. Patients on 80–100 mg ter in die (t.i.d.) of sildenafil

were transitioned directly to 40 mg quaque die (q.d.) of

tadalafil. Patients on B60 mg t.i.d. of sildenafil were transi-

tioned initially to 20 mg q.d. of tadalafil and then the dose was

escalated within 3–7 days (usually) to the indicated dosage of

40 mg q.d. of tadalafil as performed before by Shapiro et al.

[12]. All patients performed 6-min walking distance

(6MWD), echocardiography, WHO-functional class, lung

function tests, and laboratory assessments with N-terminal

prohormone of brain natriuretic peptide (NTproBNP) pre-

transition and 3, 6, and 12 months post-transition. Adverse

effects were recorded at every visit. The patients were clas-

sified into a ‘‘success-group’’ defined as a successful transition

from sildenafil to tadalafil with continuation of treatment

without intolerable side effects and stable clinical course for at

least 6 months. The ‘‘failure group’’ included those patients

who had to discontinue PDE-5 inhibitor treatment during

follow-up due to persistent side effects or clinical worsening

with tadalafil. The ‘‘restart group’’ included those patients

who underwent transition from sildenafil to tadalafil due to

side effects, followed by a second transition back to sildenafil

because of the patient’s subjective preference of the first

treatment. Patients maintained on sildenafil for at least

6 months after the second transition.

The study was approved by the ethics committee

Heidelberg (reference number S188/2014).

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123

Statistics

This retrospective analysis is of exploratory character.

Demographic data and baseline statistics are given as

mean ± standard deviation. The clinical course of the

patients is given as absolute values, mean, and standard

deviation of the different subgroups.

Statistical analyses were performed using IBM SPSS 20

(SPSS Statistics V20, IBM Corporation, Somers, New

York).

Results

Thirteen patients with PAH (mean age 64 ± 10 years, 8

female, mean pulmonary arterial pressure 35 ± 7 mmHg,

cardiac index 2.6 ± 0.6 L/min/m2), whose PDE-5 inhibitor

treatment had been changed, were included in the retro-

spective analysis (Table 1).

On average, transition of PDE-5 inhibitor therapy was

performed after 12 ± 8.4 months of initial treatment. At

baseline prior to transition, eight patients were on a PDE-5

inhibitor monotherapy, whereas five patients received

combination therapy. Dosage of sildenafil before transition

ranged between 10 and 60 mg t.i.d.

Reasons for transition of treatment were adverse reac-

tions such as gastrointestinal complaints, dryness of

mucosa, and increased dyspnea (Table 2). Those patients

who tolerated transition to tadalafil well had an adverse

reaction of Sildenafil for at least 3 months before change of

treatment. Patients who went back to Sildenafil or stopped

treatment had a shorter duration with adverse reactions of

Sildenafil 1 month (patients 7–9 and 11–13) or 2 months

(patient 10).

Clinical examination, 6MWD, lung function tests, blood tests

(NTproBNP), and echocardiography were performed during

regular follow-up visits 3, 6, 9, and 12 months post-transition.

Mean follow-up period was 11 ± 3 months (Fig. 1).

Success Group

Transition from sildenafil to tadalafil was well tolerated in

6 out of 13 patients (46 %). Subsequently these patients

had less severe or even no side-effects after the transition

and could continue with tadalafil for at least six further

Table 1 Demography and

hemodynamics of the patients

Values are given as

mean ± standard deviation

or as n and (%)

PAH pulmonary arterial

hypertension, PH pulmonary

hypertension, mPAP mean

pulmonary arterial pressure,

PCWP pulmonary capillary

wedge pressure, CO cardiac

output, CI ardiac Index, PVR

pulmonary vascular resistance,

RA right atrial, RV right

ventricular, TAPSE tricuspid

annular plane systolic

excursion, sPAP systolic

pulmonary arterial pressure,

6MWD 6 min walking distance

N = 13 All

Age, years 65 ± 10

Height (cm) 168 ± 8

Weight (kg) 76 ± 14

Diagnosis

PAH 11 (85 %)

PH due to other causes 2 (15 %)

WHO-functional class

II 2 (15 %)

III 10 (77 %)

IV 1 (8 %)

PH-therapy

Monotherapy 8 (62 %)

Double therapy 5 (38 %)

Right heart catheterization

mPAP (mmHg) 35 ± 7

PCWP (mmHg) 13 ± 7

CO (L/min) 4.6 ± 1.1

CI (L/min/m2) 2.6 ± 0.6

PVR (dynes) 389 ± 181

Echocardiography

RA area (cm2) 18.3 ± 6.5

RV area (cm2) 23.4 ± 8.3

TAPSE 21.3 ± 3.9

sPAP (mmHg) 41 ± 13

6MWD (m) 410 ± 128

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123

months. However, one patient died 8 months after change

of treatment due to a severe pulmonary infection. In this

patient clinical control visits showed a stable clinical

course of PAH after transition.

The successfully transitioned patients showed a mean

improvement of 35.5 ± 64 m in 6MWD after 6 months. In

none of the follow-up investigations after 3, 6, and 12 months,

a decrease of more than 10 % referring to baseline was

observed (Table 3). An increase of NTproBNP above 10 %

was noticed in two out of six patients after 3 months (Table 3).

However, the echocardiographic control assessment indicated

a stable course of the disease in the successfully transitioned

patients with stable systolic pulmonary arterial pressures

(PASP; change B 15 mmHg) after 6 months and right ven-

tricular pump function assessed by tricuspid annular plane

systolic excursion (TAPSE; Table 3). No dose modifications

were necessary in the successfully switched patients within

the 12-months period of follow-up. Prior to transition, one of

the successfully switched patients had received a combination

treatment with an endothelin receptor antagonist.

Failure Group

In five patients (38.5 %) intolerable adverse reactions

occurred under treatment with tadalafil as well. Therefore

PDE-5 inhibitor treatment had been stopped. In almost half

of these cases, adverse reactions were similar to those with

sildenafil, in the other half, different side effects led to

discontinuation of treatment (Table 2).

Patients of the failure group stopped treatment with

tadalafil after 2–6 weeks, except patient 7 who stopped

after 4 days due to severe limb aches.

Most frequently dryness of the nasal and oral mucosa and

peripheral edema were reported. Three of those patients had a

combination treatment with an endothelin receptor antagonist

prior to transition. After 6 months an average decrease of

30 m regarding 6MWD was noted, whereas one patient

showed a decrease of[10 % (Table 3). Furthermore, an

increase of NTproBNP of [10 % was observed in all cases

with adverse reactions under treatment with tadalafil

(Table 3). The echocardiographic control assessment showed

Table 2 Reason for switch and adverse reactions

Pat

ID

Sildenafil

dosage

(mg)/die

Reason for

switch

Adverse reaction Follow-up

medication

outcome after

switch

Reason for discontinuation Initiation of further PH

treatment

1 120 Compliance 4 After 6 months ERA, stopped

after 6 months due to AE

2 60 AR Diarrhea 4 –

3 30 AR Restlessness and

sleeping disorder

4 –

4 60 AR Dip phenomenon 4 –

5 120 AR Chest pain during

the night

4 –

6 40 AR Epistaxis 4 –

7 30 AR Dyspnea 7 Limb aches After 3 months Riociguat,

stopped after 6 months due to

peripheral edema

8 180 AR Dryness and

itching of eyes

7 Dryness and redness of eyes –

9 120 AR Dryness of

respiratory tract

and oral mucosa

7 Dryness of respiratory tract and

coughing

After 7 months Imatinib (study)

10 60 AR Itching of eyes and

telangiectasia

7 Peripheral edema After 12 months Treprostinil

11 60 Lack of

effect

Dryness of

respiratory tract,

caugh

7 Lack of effect –

12 60 AR Diarrhea Flushing, facial edema, dryness

of oral and nasal mucosa,

peripheral edema

–

13 60 AR Dizziness Facial edema –

Sild sildenafil, Tad tadalafil, AR adverse reaction, 4 continued, 7 stopped, first medication restarted

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123

an increase of PASP ([15 mmHg) and a decrease of TAPSE

([5 mm) in 50 % of cases after 6 months.

Restart Group

After a therapeutic attempt with tadalafil two patients were

reintroduced to sildenafil by their own request. The patients

had the feeling that tadalafil was less effective and wished

another try with sildenafil despite the adverse events which

had initially occurred. Both patients restarted Sildenafil

after 4 weeks of treatment with Tadalafil. One patient had a

combination treatment with an endothelin receptor antag-

onist before transition. Both patients could then continue

with sildenafil treatment for more than 3 months and had

stable findings within controls visits regarding the 6MWD

after 6 and 12 months. However, an elevation of more than

10 % in NTproBNP was observed in both patients during

the follow-up time. An increase of PASP of more than

10 % was noted in one patient, whereas the measurement

of tricuspid annular plane systolic excursion showed stable

values in the one and an increase of more than 10 % in the

other patient.

Table 3 Clinical course of echocardiographic parameters

Pat ID Switch Pre-transition 3 months post-transition

RA area RV area SPAP TAPSE RA area RV area SPAP TAPSE

1 Sild-Tad 4 18 20 45 22 17 25 50 23

2 Sild-Tad 4 20 23 35 19 20 20 35 19

3 Sild-Tad 4 34 39 55 34 34 50

4 Sild-Tad 4 14 14 30 21 11 15 30 29

5 Sild-Tad 4 12 16 35 18 15 19 45 19

6 Sild-Tad 4 18 21 65 22 15 17 50 24

Mean ± SD 19 ± 8 22 ± 9 44 ± 14 20 ± 2 19 ± 8 22 ± 7 43 ± 9 23 ± 4

7 Sild-Tad 7 15 20 50 15 18 26 65 17

8 Sild-Tad 7 18 32 58 21 32 34 60 15

9 Sild-Tad 7 21 35 50 30 24 34 50 22

10 Sild-Tad 7 10 18 25 23 10 14 18 26

11 Sild-Tad 7 17 25 17 26 22 25 14

Mean ± SD 16 ± 5 24 ± 8 42 ± 16 21 ± 6 22 ± 8 26 ± 9 44 ± 21 19 ± 5

12 Sild-Tad 14 16 30 22 14 13 25 24

13 Sild-Tad 25 33 35 25 15 28 40 25

Pat ID Switch 6 months post-transition 12 months post-transition

RA area RV area SPAP TAPSE RA area RV area SPAP TAPSE

1 Sild-Tad 4 18 28 55 23 20 28 55 19

2 Sild-Tad 4 20 20 20 20 25 21 45 20

3 Sild-Tad 4 50 36 55 17 47 28 55 25

4 Sild-Tad 4 7 13 30 28 12 17 45 22

5 Sild-Tad 4 18 20 45 17 – – – –

6 Sild-Tad 4 – – – – – – – –

Mean ± SD 23 ± 16 23 ± 9 41 ± 16 21 ± 5 26 ± 15 24 ± 6 50 ± 6 22 ± 3

7 Sild-Tad 7 23 28 50 21 35 33 65 17

8 Sild-Tad 7 26 28 55 17 – – – –

9 Sild-Tad 7 24 38 85 – 19 40 70 23

10 Sild-Tad 7 21 50 26 16 23 45 21

11 Sild-Tad 7 – – 27 28 45 18

Mean ± SD 24 ± 2 29 ± 7 60 ± 17 21 ± 5 24 ± 9 31 ± 7 56 ± 13 20 ± 3

12 Sild-Tad 14 10 25 24 14 15 32,5 27

13 Sild-Tad 18 28 44 21 16 28 40 24

Pat patient, Sild sildenafil, Tad tadalafil, AR adverse reaction, SD standard deviation, 4 continued, 7 stopped, first medication restarted,

RA right atrium, RV right ventricle, sPAP systolic pulmonary arterial pressure, TAPSE tricuspid plane systolic annular excursion

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Discussion

This is the first study investigating feasibility of switching

PAH patients from sildenafil to tadalafil-treatment due to

intolerable side effects of sildenafil. The study showed that

in 46 % of the cases with initial intolerability of sildenafil a

transition to tadalafil was feasible and resulted in less severe

or even missing side effects and a stable clinical course

during a mean follow-up of 11 ± 3 months. Only in 38.5 %

of patients PDE-5 inhibitors had to be permanently discon-

tinued. In 15.4 % sildenafil-treatment could be successfully

restarted after an intermediate transition to tadalafil. The

study indicates that transition of sildenafil to tadalafil due to

adverse events is a reasonable therapy option in terms of

clinical feasibility and stability of clinical course. These

results should be verified by a larger, prospective study.

Previous Data to Transition in the Literature

Previous studies were performed to observe safety, tolera-

bility, and efficacy of transition from sildenafil to tadalafil in

stable patients without adverse reaction to sildenafil [10–12].

The studies showed that transition was safe in most cases but

resulted in clinical worsening and adverse events in some

patients [11]. Our study had a similar result with about 50 %

of patients staying stable on tadalafil of more than 6 months

post-transition. The analyses of 6MWD, echocardiographic

parameters, and NTproBNP values indicated a distinctively

better development in the successfully transitioned patients

in comparison to those who had to stop PDE-5 inhibitor

treatment. Even compared to patients who restarted silde-

nafil medication, fewer elevations of NTproBNP over 10 %

were recorded and adverse events could be avoided. How-

ever, in our study there was a higher proportion of failed

transition than previously reported (about 50 vs. 5 %). That

was most likely due to the setting in which we analyzed

patients with intolerable side effects to sildenafil only. The

first transition trial in humans was performed by Tay et al.

[10]. Twelve voluntarily elected patients were successfully

transitioned from sildenafil to tadalafil without occurrence of

adverse events. Significant improvement in 6MWD, WHO-

functional class, Borg-index, and SF-36 physical function

Fig. 1 Changes in systolic pulmonary artery pressure, TAPSE,

6-MWD, and NTproBNP. The clinical course is given for each

patient as dotted line for the success group, dashed line (short dashes)

for the failure group and dashed line (long dashes) for the restart

patients. Mean values are given as solid line for success and failure

group. Change of clinical course was measured pre-transition, 3-, 6-

and 12-months after transition by echocardiography. a Systolic

pulmonary artery pressure and b tricuspid annular plane systolic

excursion, by c 6-min walking distance and by laboratory

d NTproBNP levels

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score were detected [10]. In another retrospective study 30

out 35 patients were successfully transitioned from sildenafil

to tadalafil. In this study five patients were switched back

due to clinical worsening or adverse events related to tad-

alafil. Patients who did not tolerate the transition tended to

have a more severe disease and higher proportion of com-

bination therapy [11]. This has been observed in our study as

well. A higher chance for a successful transition may

therefore be expected among stable patients on sildenafil

monotherapy.

Shapiro et al. published another retrospective analysis

about transition from sildenafil to tadalafil. In this study 96

out of 98 patients (97 %) were successfully transitioned

and stable on tadalafil. One patient discontinued due to

worsening of erectile dysfunction, the other due to wors-

ening of headache [12].

Frequency of Side Effects of PDE-5 Inhibitors Leading

to Therapy Discontinuation

Many thousand PH-patients world-wide receive PDE-5

inhibitors. Most common adverse effects of sildenafil

20 mg t.i.d. were headache (46 vs. 39 % with placebo),

dyspepsia (13 vs. 7 %), flushing (10 vs. 4 %), and epistaxis

(9 vs. 1 %) [7]. For tadalafil 40 mg o.d. adverse events

were headache (42 vs. 15 %), diarrhea (11 vs. 10 %),

nausea (11 vs. 6 %), dyspepsia (10 vs. 2 %), flushing (13

vs. 2 %), myalgia (14 vs. 4 %), nasal congestion (9 vs.

1 %) [5].

However, the frequency of severe adverse events leading

to drug discontinuation was relatively small. In the SUPER-

1 trail only four patients (1.4 %) of patients withdrew sil-

denafil due to side effects including decreased renal func-

tion, lower-leg edema, cardiac arrhythmia, and headache [4].

In the open-label extension study (SUPER-2) nine patients

(3.5 %) withdrew due to side effects as chest tightness, neck

stiffness, myalgia, headache, visual field constriction,

dyspnea, abdominal pain, diarrhea, nausea, vomiting, diz-

ziness, worsening hypotension, and drug hypersensitivity

[7]. In the approval study of tadalafil (PHIRST-1-trail)

8.4 % (34) patients discontinued due to adverse reactions

[5]. Eight percent (30 patients) withdrew in the open-label

trial (PHIRST-2) due to side effects [6].

Slightly Different Adverse Events in Tadalafil

and Sildenafil

Adverse event profiles are likely to be influenced by the

receptor selectivity of the two agents. Although belonging to

the same class of drugs, tadalafil is structurally different

from sildenafil and has different pharmacokinetic and

pharmacodynamic properties [13]. While tadalafil has a half-

life of approximately 17 h and therefore offers a once daily

dosing regimen, sildenafil, with a half-life of approximately

4 h, has to be taken three times daily. Furthermore the two

available PDE-5 inhibitors have different selectivity for the

various PDE receptor subgroups. While sildenafil already

has a very high selectivity for the PDE-5 receptor, tadalafil,

with the exception of the PDE-11A receptor, shows even

higher PDE-5 receptor selectivity [14]. The higher selec-

tivity of tadalafil might be a reason for the successful tran-

sition of 50 % of patients with only mild or missing side

effects after lack of tolerability of sildenafil. The clinical

importance of this receptor selectivity regarding adverse

events profiles has yet to be determined.

Limitations

There are a number of limitations to this study, including

the small sample size and retrospective design which only

allowed an exploratory analysis and description of findings.

However, alternative prospective designs to assess these

questions are difficult to perform. Randomization and

double-blinding will not be easily possible for this study

goal; selection bias can hardly be excluded in such a study.

In general, side effects have a highly subjective component

in the decision making process for both sides as in the

patients and in medical professionals.

Conclusions

In summary, this study demonstrates that transition of sil-

denafil to tadalafil due to intolerable adverse events is a

beneficiary treatment option in about half of the cases.

Thus, intraclass substitution of PDE-5 inhibitors should be

considered in case of intolerable side effects. Further, lar-

ger scaled, prospective studies are necessary to confirm

these findings.

Acknowledgments This study was funded by Eli Lilly and

Company.

Conflict of interest ML: receives consultancy fees from Actelion.

DH: nothing to disclose. NE: receives speaker fees from Bayer

HealthCare, Pfizer, Actelion, Lilly. AM: nothing to disclose. FP:

nothing to disclose. EG: receives consultancy/speaker fees from Ba-

yer HealthCare, Pfizer, Actelion, Lilly, Encysive, Alexion, United

Therapeutics, GlaxoSmithKline, Miltenyi, Sinoxa Pharma and Nov-

artis. BE: nothing to disclose.

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