Understanding the role of

Sildenafil in PAH Management

 Pathogenesis of PAH
RISK FACTORS AND VASCULAR INJURY DISEASE PROGRESSION
ASSOCIATED CONDITIONS
Endothelial dysfunction
CTD
CHD ↓NO synthase
SUSCEPTIBILITY
Portal hypertension
BMPR2 mutation
↓PGI2 production
HIV
Other genetic factors ↑Thromboxane production
Drugs and toxins
Pregnancy ↑ET-1 production
Smooth muscle
Vascular smooth muscle dysfunction hypertrophy

Adventitial and intimal

Adventitia proliferation
Smooth muscle
Media hypertrophy In situ
thrombosis
Intima

Early intimal
Plexiform
proliferation
lesion

Vasoconstriction Advanced vascular lesion

Reversible Irreversible
Normal
disease disease
BMPR2 = bone morphogenetic protein receptor type 2 ; CHD = congenital heart disease; CTD = connective tissue disease;
ET-1 = endothelin-1; HIV = human immunodeficiency disease; NO = nitric oxide; PAH = pulmonary arterial hypertension; PGI2 = prostacyclin
Adapted from Gaine S. JAMA 2000;284:3160–8.
 Risk Stratification

Galie N, et al. Eur Respir J 2019;53:1801889

Galie N, et al. Eur Respir j 2015;46:879-882
 Risk Stratification and Medical Therapy of PAH

Galie N, et al. Eur Respir J 2019;53:1801889

 PAH Treatment Molecular Pathway

Humbert M et al. NEJM 2004

 The Molecular
Targets of Approved
Treatments for
Pulmonary Arterial
Hypertension

Humbert M, Ghofrani H-A. Thorax 2016;71:73–83

 Pulmonary vascular tone:
regulated by endothelium-derived factors
• ET-11,2
• Proliferative activity
• Potent vasoconstrictor
• NO3,4
• Potent vasodilator
• Anti-proliferative activity
• PGI24
• Potent vasodilator
• Anti-proliferative activity
ET-1 = endothelin-1; NO = nitric oxide; PGI2 = prostacyclin
.
1. Spieker LE, et al. J Am Coll Cardiol 2001;37:1493–505.
2. Luscher TF and Barton M. Circulation 2000;102:2434–40.
3. Albrecht EW, et al. J Pathol 2003;199:8–17.
4. Hankins SR and Horn EM. Curr Cardiol Rep 2000;2:244–51
 Therapy for Pulmonary Arterial Hypertension in Adults
Update of the CHEST Guideline and Expert Panel Report

Klinger et al. CHEST 2019; 155(3):565-586

 Recommendations for
efficacy of drug
monotherapy for
pulmonary arterial
hypertension according
to World Health
Organization functional
class

Galie N, et al. Eur Respir J 2015; 46: 903–975

 Recommendations for efficacy of
initial drug
combination therapy for
pulmonary arterial hypertension
(group 1) according to World
Health Organization functional
class.

Galie N, et al. Eur Respir J 2015; 46: 903–975

 Recommendations for efficacy of sequential drug combination therapy for
pulmonary arterial hypertension according to WHO functional class.

Galie N, et al. Eur Respir J 2015; 46: 903–975

 Sildenafil for Pulmonary
Arterial Hypertension

 Sildenafil has proven beneficial effects in the

improvement of symptoms, time to clinical
worsening, and makes available a higher quality
of life.
 Combining sildenafil with other agents for PAH
has been associated with improved outcomes

Bhogal S et al, American Journal of Therapeutics 26, e520–e526 (2019)

 SUPER-1
Sildenafil Use in Pulmonary
Arterial HypERtension

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

 SUPER-1: study design
Placebo, n=70

Sildenafil 20 mg (TID), n=69

Screening and Titration to sildenafil 80 mg
randomisation (TID), n=259
Sildenafil 40 mg (TID), n=68

Sildenafil 80 mg
(40 mg:7 days) (TID), n=71

0 2 4 6 8 10 12 52

Screening baseline Weeks Titration into extension phase

SUPER-1 SUPER-2
TID = three times a day

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

 SUPER-1: improvements in 6MWD

70 * *p<0.001 vs placebo
60 *
* Placebo
Change from baseline (m) 50 Sildenafil 20 mg TID
40 Sildenafil 40 mg TID
30 Sildenafil 80 mg TID

50 m
45 m
46 m
20
10
0
-10
-20
-30
Week 4 Week 8 Week 12

Sildenafil 20 mg TID is the licensed dose

6MWD = 6-minute walk distance; TID = three times a day

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

 SUPER-1: improvements in all subpopulations
Number of patients
S P
23 23
6MWD <325 m 23
26
23
23
44 43
325 m 41
43
43
43

43 39
IPAH 42 39
46 39
Aetiology 20 21
PAH–CTD 18
19
21
21
4 6
PAH–surgical repair 4 6
4 6

22 31
Class I/II 21 31
Functional class 27 31
45 35
Class III/IV 43 35
42 35

30 29
39 29
<Median 31 29
mPAP (mmHg)
Median 36
24
37
37
38 37

23 22
<Median 28 22
PVRI (dyne•s/cm5/m2) 35
26
22
32
Median 24 32
Sildenafil 20 mg TID 26 32
Sildenafil 40 mg TID
Sildenafil 80 mg TID -20 0 20 40 60 80 100 120 140 160
Placebo-corrected change in 6MWD (m)
Sildenafil 20 mg TID is the licensed dose
CTD = connective tissue disease; IPAH = idiopathic pulmonary arterial hypertension; mPAP = mean pulmonary arterial pressure; 6MWD = 6-minute walk
Galiè N, et al. New Engl J Med 2005;353:2148–57. distance; P = placebo; PAH = pulmonary arterial hypertension; PVRI = pulmonary vascular resistance index; S = sildenafil; TID = three times a day
 SUPER-1: improvements – 20 mg sildenafil
Number of patients
S P
6MWD <325 m 23 23

325 m 44 43

IPAH 43 39

Aetiology
PAH–CTD 20 21

PAH–surgical repair 4 6

Class I/II 22 31
Functional class
Class III/IV 45 35

<Median 30 29
mPAP (mmHg)
Median 36 37

<Median 23 22

PVRI (dyn•s/cm5/m2)
Median 26 32
Sildenafil 20 mg TID

-20 0 20 40 60 80 100 120 140 160

Placebo-corrected change in 6MWD (m)
Sildenafil 20 mg TID is the licensed dose
CTD = connective tissue disease; IPAH = idiopathic pulmonary arterial hypertension; mPAP = mean pulmonary arterial pressure; 6MWD = 6-minute walk
distance; P = placebo; PAH = pulmonary arterial hypertension; PVRI = pulmonary vascular resistance index; S = sildenafil; TID = three times a day
Galiè N, et al. New Engl J Med 2005;353:2148–57.
 SUPER-1: dose-dependent reductions in mPAP
4

Change from baseline at Week 12

Placebo
2
Sildenafil 20 mg Sildenafil 40 mg Sildenafil 80 mg
TID TID TID
(mmHg) 0

+0.6
-2

-4
-2.1 -2.6
-6 p=0.04 p=0.01
vs placebo vs placebo
-4.7
-8 p<0.001
vs placebo

Sildenafil 20 mg TID is the licensed dose

mPAP = mean pulmonary arterial pressure; TID = three times a day

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

 SUPER-1: dose-dependent reductions in PVR

200

Change from baseline at Week 12

Placebo

100
Sildenafil 20 mg Sildenafil 40 mg Sildenafil 80 mg
TID TID TID
(dyn•s/cm5) 0

-100 +49

-200
-122 -143
-300 p=0.01 p=0.01
vs placebo vs placebo

-400 -261
p<0.001
vs placebo

PVR = pulmonary vascular resistance; TID = three times a day

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

 SUPER-1: improvements in WHO FC status
Improvement of WHO FC
(at least 1 functional class)

45%
40% **
*
35% *
30% *
25% *
42%
20% 36%
15% 28%

10%
5% 7%

0%
Placebo 20mg 40mg 80mb

Improvement of WHO FC

*placebo-corrected difference, 21 percent; 95 percent confidence interval, 9 to 33 percent; P=0.003

**placebo-corrected difference, 29 percent; 95 percent confidence interval, 16 to 42 percent; P<0.001
***placebo-corrected difference, 35 percent; 95 percent confidence interval, 22 to 48 percent; P<0.001
Galiè N, et al. New Engl J Med 2005;353:2148–57.
 SUPER-1: incidence of clinical worsening
Sildenafil 20 mg Sildenafil 40 mg Sildenafil 80 mg
Placebo TID TID TID
(n=70) (n=69) (n=67) (n=71)
Proportion worsened (%) 10 4 3 7

Incidence of clinical worsening, events (%)

Death 1 (1) 1 (1) 0 (0) 2† (3)

Hospitalisation due to PH 7 (10) 2 (3) 2 (3) 2 (3)

Initiation of prostacyclin 1 (1) 0 (0) 0 (0) 0 (0)

Initiation of bosentan 0 (0) 0 (0) 1 (1) 2 (3)

†One patient in the sildenafil 80 mg group died during the 1st week while receiving sildenafil 40 mg

CI = confidence interval; PH = pulmonary hypertension; TID = three times a day

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

 SUPER-1: adverse events >3% and sildenafil > placebo
Patients reporting event (%)
Adverse event Sildenafil (n=207) Placebo (n=70)
Headache 46 39
Flushing 12 4
Dyspepsia 12 7
Back pain 12 11
Diarrhoea 11 6
Limb pain 10 6
Myalgia 9 4
Cough 7 6
Epistaxis 7 1
Pyrexia 6 3
Influenza 5 3
Gastritis 3 0
Insomnia 6 1
Visual disturbance 4 0

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

 SUPER-1: conclusions
• Sildenafil significantly improved (vs placebo)
• 6MWD
• mPAP, PVR, CI
• WHO FC
• Other favourable clinical trends included:
• Fewer hospitalisations for PAH
• Reduced breathlessness during exercise
• Sildenafil is generally well tolerated
• Sildenafil is efficacious in treating patients with PAH

CI = cardiac index ; FC = functional class; mPAP = mean pulmonary arterial pressure; 6MWD = 6-minute walk distance;
PAH = pulmonary arterial hypertension; PVR = pulmonary vascular resistance; WHO = World Health Organization

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

 SUPER-2
Long-Term Treatment with Sildenafil Citrate in
Pulmonary Arterial Hypertension

Rubin LJ, et al. Long-term treatment with sildenafil citrate in pulmonary arterial hypertension: SUPER-2. Chest. Epub May 2011
 SUPER-2: study design (1)
Titration into extension study

Placebo
Regimen A

Titration
Titration to sildenafil
Sildenafil 20 mg (TID) to sildenafil
40 mg (TID)
Screening and 80 mg (TID)
randomisation
Sildenafil 40 mg (TID)
Regimen B

Dummy titration to sildenafil

Sildenafil 80 mg (TID)
80 mg (TID)

12 weeks 3 years

Double-blind Open-label
Screening baseline extension
phase

SUPER-1 SUPER-2

TID = three times a day

Rubin LJ, et al. Long-term treatment with sildenafil citrate in pulmonary arterial hypertension: SUPER-2. Chest. Epub May 2011
 SUPER-2: Kaplan-Meier survival estimate
Survival analysis population (%)*
Sildenafil Sildenafil Sildenafil
Survival All Placebo 20 mg TID 40 mg TID 80 mg TID
period n=277 n=70 n=69 n=67 n=71

Percent
1 year 94 86 96 100 93
survived

Percent
2 years 88 81 91 95 86
survived

Percent
3 years 79 68 84 84 78
survived

*Analysis includes 18 patients from the double-blind study who did not enter the extension trial
Sildenafil 20 mg TID is the licensed dose
TID = three times a day

Rubin LJ, et al. Long-term treatment with sildenafil citrate in pulmonary arterial hypertension: SUPER-2. Chest. Epub May 2011
 SUPER-2: safety
Treatment-related adverse events All, %
in ≥5% of subjects n=259*
Headache 16.2

Dyspepsia 10.4

Diarrhoea** 8.1

Blurred vision 7.3

Nausea 5.8

Abdominal pain** 5.4

Abdominal pain upper 5.0

*Includes only patients who entered the extension trial

**Not otherwise specified

Rubin LJ, et al. Long-term treatment with sildenafil citrate in pulmonary arterial hypertension: SUPER-2. Chest. Epub May 2011
 SUPER-2: treatment-related serious adverse events
• Perceived treatment related SAEs included:
• Grand mal seizure
• Hypotension
• Drug hypersensitivity
• Urticaria and angioedema
• Gastro-oesophageal reflux disease
• Posterior subcapsular cataract
• Nine patients permanently discontinued due to
perceived sildenafil-related AEs
SAEs = serious adverse events

Rubin LJ, et al. Long-term treatment with sildenafil citrate in pulmonary arterial hypertension: SUPER-2. Chest. Epub May 2011
 SUPER-2: conclusions
• After 3 years
• 46% of patients maintained or improved 6MWD
• 60% of patients maintained or improved their functional status
• Kaplan-Meier estimated survival was 79%
• Most treatment-related adverse events were mild to moderate in
severity, and included headache, dyspepsia, diarrhoea, blurred vision,
nausea, and abdominal pain

6MWD = 6-minute walk distance

Rubin LJ, et al. Long-term treatment with sildenafil citrate in pulmonary arterial hypertension: SUPER-2. Chest. Epub May 2011
https://www.medscape.org/viewarticle/919529
Conclusion
• There are 3 pathways in PAH management: endothelin, NO and
prostacyclin pathway
• Sildenafil has proven beneficial effects in the improvement of
symptoms, time to clinical worsening, and makes available a higher
quality of life in patients with PAH
• Sildenafil 20 mg tid is proven to be effective and tolerable in PAH
patients with WHO FC II and III.
• Collaborative care is needed in PAH management