The Efficacy and Safety of Vardenafil in The Treatment of
Transcript of The Efficacy and Safety of Vardenafil in The Treatment of
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