Zhi-Cheng JING, MD,FCCP

Dept. of Cardio-pulmonary Circulation

Shanghai Pulmonary Hospital

Tongji University, Shanghai, China

ESC-2010

The Efficacy and Safety of

Vardenafil in The Treatment of

Pulmonary Arterial Hypertension

(EVALUATION study)

Disclosures

Received consultant and lecture honoraria from Pfizer, Actelion, United Therapeutics, Bayer-Schering, GlaxoSmithKline, Boehringer-Ingelheim within past 3 years

Received research grants from Pfizer, Actelion, United Therapeutics, Bayer-Schering, GlaxoSmithKline within past 3 years

No personal financial support from a non-commercial source relevant to medicine, within past 3 years

Zhi-Cheng JING M.D, FCCP

Background

Increased expression of phosphodiesterase 5 (PDE-5) and then caused NO insufficient

The abundance of PDE-5 in pulmonary vasculature offers the possibility of relatively selective pulmonary vasodilatation with PDE-5 inhibitors (PDE-5i)

Sildenafil and tadalafil were both proved as new agents in the treatment of PAH with good efficacy and tolerability

Lin CS, et al. Biochem Biophys Res Commun. 2000; 268: 596–602.

Nagendran J, et al. Circulation. 2007; 16: 238–48.

Galiè N, et al. N Engl J Med. 2005; 353: 2148–57.

Galiè N, et al. Circulation. 2009; 119: 2894–903.

Background

Another new PDE-5i, vardenafil, with more potent in inhibited PDE-5

Acute hemodynamics demonstrated vardenafil lack the selectivity in pulmonary vasodilation

Previous open-label study demonstrated a favorable effects with oral low dose vardenafil in PAH with an acceptable cost

Jing ZC, et al. Heart. 2009; 95: 1531-26

Corbin JD, et al. Biochem Biophys Res Commun. 2005; 334: 930–38.

Ghofrani HA, et al. J Am Coll Cardiol. 2004;44:1488–96.

Objectives

To investigate the efficacy and safety profile of

Vardenafil therapy for Pulmonary arterial

hypertension in a more powered study

Methods

A randomized, placebo-controlled clinical trial

was launched at 2008 in 9 Chinese centers

Registration in Clinicaltrial.gov

Methods

Included criteria IPAH or CTD-PAH or repaired CHD-PAH (at least 3 years)

MPAP > 30 mm Hg and PCWP <15 mm Hg and PVR > 4

Wood U

Age > 12 and < 65 years

WHO FC II or III

6MWD > 150 and < 550 meters

No PAH-specific treatment and a stable supportive

therapies for at least 3 months

Methods

Excluded criteria

Other etiologies of PH or PAH

WHO FC IV

Serious disease involved liver, kidney, and brain or have

to use potent CYP3A4 inhibitor or nitrate to treat the

underlying diseases

Treated with PAH-specific drugs within 3 months

Methods

Randomization was computer generated using

the DMS System

Block size of 6

Randomizations ratio = 2/1 (vardenafil /placebo)

Methods

Placebo PlaceboVardenafil

5 mg b.i.d

Patients

Enrollment

Vardenafil

5 mg q.d

Vardenafil

5 mg b.i.d

Vardenafil

5 mg b.i.d

Week 0 4 12 24

Placebo-control Extension study

Methods

Primary endpoint

6MWD at week 12

Secondary endpoints

Hemodynamics

WHO FC

Borg dysponea index (BDI)

Methods

Safety assessment

Clinical worsen

- Death

- Lung transplantation

- Initial prostanoids or combination therapy with ERAs

Side effects

Laboratory tests

Methods

6MWT

RHC

DSA

CO

Methods

Statistics Patients death or no follow-up data recorded were

assigned the worst rank for the 6MWD and BDI

and WHO FC

Withdrawn patients were excluded from

hemodynamic evaluation

Methods

The protocol was conducted according to the provisions of the Helsinki Declaration and local guidelines for GCP

Approved by ethics committees in all centers

Written informed consent was obtained from all patients

Results-Trial profile

Results- baseline characteristics

Placebo (n=20) Vardenafil (n=44)

Demographic variables

Sex

Men / Women (n, %)

Age (mean [SD], years)

3 / 17 (15 / 85)

29 [8]

8 / 36 (18 / 82)

32 [12]

BSA (mean [SD], m2) 1.6 [0.2] 1.6 [0.2]

Etiologies of PAH

Idiopathic (n, %) 14 (70) 25 (57)

Connective tissue disease (n, %) 4 (20) 15 (34)

Repaired R-to-L shunting (n, %) 2 (10) 4 (9)

WHO functional class

II (n, %) 9 (45) 21 (48)

III (n, %) 11 (55) 23 (52)

6-min walking distance (mean [SD], m) 388 [83] 395 [80]

Borg dyspnoea index (mean [SD]) 2.8 [0.9] 2.6 [1.3]

Conventional therapies 13 [65] 28 [64]

Results-baseline hemodynamics

Placebo (n=20) Vardenafil (n=44)

HR (mean [SD], bpm) 82 [13] 81 [10]

BP (mean [SD], mm Hg) 86 [11] 85 [11]

Mean RAP (mean [SD], mm Hg) 8.9 [4.2] 9.0 [5.1]

Mean PAP (mean [SD], mm Hg) 64 [16] 60 [16]

Mean PCWP (mean [SD], mm Hg) 9.3 [2.5] 8.9 [2.6]

CI (mean [SD], L·min-1·m-2) 2.5 [0.6] 2.2 [0.7]

Mean PVR (mean [SD], Wood U) 15 [8] 16 [9]

Mean SVR (mean [SD], Wood U) 21 [8] 23 [7]

SvO2 (%) 60 [7] 62 [11]

SaO2 (%) 94 [3] 94 [6]

Results- improvement of 6MWD

0 12 weeks 24 weeks-20

0

20

40

60

80

100Vardenafil

Placebo

Placebo-control open-label

Ch

an

ges o

f 6M

WD

(m

)

Results- improvement of BDI

-1.0

-0.5

0.0

0.5

1.0

1.5

2.0

Placebo

VardenafilP = 0.009

Ch

an

ge o

f B

DI

Results- improvement of WHO FC

Placebo-b

aseline

Placebo-1

2 w

Vardenafil

-baselin

e

Vardenafil

-12 w

0

25

50

75

100Class I

Class II

Class III

Class IV

NS P = 0.032P

erse

nta

ge

of

pat

ien

ts

Results - hemodynamics

Change from baseline

Placebo (n=18) Vardenafil (n=40)

Difference between treatments

Difference (95% CI) P value

HR (bpm) -0.3 [3.3] -4.3 [1.4] -4.0 [-10.0 to -2.0] 0.272

BP (mm Hg) -3.8 [1.9] -1.1 [1.6] 2.6 [8.3 to 2.8] 0.359

Mean RAP (mm Hg) 0.8 [0.9] -1.2 [0.6] -2.0 [-4.3 to 0.3] 0.085

Mean PCWP (mm Hg) -0.1 [0.5] 0 [0.4] -0.1 [1.5 to -1.7] 0.923

Mean PAP (mm Hg) 0.6 [1.5] -4.8 [1.6] -5.3 [-10.6 to -0.1] 0.047

CI (L·min-1·m-2) -0.16 [0.08] 0.23 [0.07] 0.39 [0.13 to 0.65] 0.005

PVR (Wood U) 1.4 [1.0] -3.3 [0.9] -4.7 [-7.8 to -1.7] 0.003

SVR (Wood U) -0.4 [1.2] -2.8 [1.1] -3.1 [-7.0 to 0.7] 0.107

SvO2 (%) 0.3 [1.3] 2.1 [0.9] 1.8 [-1.5 to 5.2] 0.277

Results- side effectsPlacebo (n = 20) Vardenafil (n = 44)

Clinical worsening, n (%) 4 (20.0) 1 (2.3)#

Death 2 (10) 0 (0)

Hospitalization for worsening PAH 2 (10) 1 (2.3)

Initiation of new PAH therapy 2 (10) 1 (2.3)

Worsening WHO functional class 2 (10) 1 (2.3)

Adverse events, n (%) 6 (30) 25 (57)

Headache 2 (10) 8 (18.)

Flushing 2 (10) 20 (45)

Diarrhea 1 (5) 0 (0)

Myalgia 0 (0) 1 (2.3)

Muscle pain 1 (5) 1 (2.3)

Nasal congestion 0 (0) 2 (5)

Vision disturbance 1 (5) 0 (0)

Dizzleness 1 (5) 3 (6.8)

Chest pain 1 (5) 0 (0)

Insomnia 0 (0) 1 (2.3)

Respiratory infection 1 (5) 1 (2.3)

Results-clinical worsen

0 28 56 840

20

40

60

80

100vardenafil

placebo

P = 0.013

days

weeks 0 4 8 12

patients

at risk

placebo

vardenafil

20

44

18

44

16

43

16

43

even

t fr

ee s

urv

ival

(%

)

Discussions

The current trial was the first study to assess the therapeutic value of Vardenafil in PAH patients

We further confirmed the efficacy of oral low dose vardenafil in PAH

The study is the 2nd but the largest RDBPC study organised and conducted in developing coutries, and it was sponsored by Shanghai Government funding

Discussions

Long term therapy of vardenafil could significantly reduce the mPAP and PVR, without decreasing the systemic blood pressure, despite no selective pulmonary vasodilated effect was observed in previous acute hemodynamic study compared with sildenafil and tadalafil

A important evidence to support oral vardenafil could serve as a treatment option in PAH like the other two marketed PDE-5i

Ghofrani HA, et al. J Am Coll Cardiol. 2004;44:1488–96.

Discussions

Long-term treatment was needed in almost all PAH patients, Cost/effects ratio should be considered not just in developing countries

The survival of PAH is not ideal in the Modern therapy era, we should develop more new agents into the clinical practices: more choices for treatment and combination therapy

Vardenafil or other PDE-5i may serve as first line options to treat PAH patients for whom the medical cost must be considered

limitations

Relatively small samples

Only one dosage, not dose citrated design

No WHO FC IV patients were enrolled

Conclusions

Low dosage Oral vardenafil was a effective and safe agent to treat patients with PAH

Further studies need to assess the appreciate dosage with prefer efficacy and acceptable side-effects profile

The treatment value in other etiologies of PAH and combination with other PAH specific drugs need to be investigated in future studies

AcknowledgementsProf. Zai-Xin YU；Prof. Bing-Xiang WU; Prof. Jie-Yan SHEN

Prof. Kai-Feng XU; Prof.Xian-Yang ZHU；Prof. Lei PAN;

Associated Prof. Yong WANG；Prof. Zhuo-Li ZHANG;

Associated Prof. Xue-Qin LIU；Prof. Yu-Shun ZHANG; Xin JIANG M.D.

Prof. Rubin L; Prof. Galie N; Prof Simonneau G; Prof. Humbert M