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New Insight of Pulmonary

Hypertension in Indonesia
Dr. dr. Lucia Kris Dinarti, Sp.JP(k)
Working Group On Pulmonary Hypertension Indonesia Heart Association
CASE ILLUSTRATION 1

 Femaie, 30y.o,
 Complaint of SOB
 Cardiomegaly with wide fixed split S2
 TTE: ASD II 11-15 mm, L to R shunt, HighProb PH, TR Moderate, TVG
95mmHg,
 TOE: ASD II 11-15 mm, L to R shunt, HighProb PH, TR Moderate
 RHC: mAO 110mmHg, mPAP 59mmHg, PCWP 10mmHg, Pari 22.8, FR
1.22 (Pulmonary Hypertension Low Flow High Resistance)
 DIAGNOSIS : ASD II PAH Low Flow High Resistance
 Tx : Sildenafil 20 mg 3x1
CASE ILLUSTRATION 2

 Female, 29y.o., G3P2A0 5th weeks of gestational age


 Complaint of SOB
 Pansytolic murmur 3/6 SIC III LPSS, peripheral saturation 98% room air
 TTE: ASD sinus venosus 6-8 mm, bidirectional shunt, HighProb PH, TR
moderate, TVG 118mmHg
 TEE: ASD sinus venosus 6-8 mm, bidirectional shunt, HighProb PH, TR
moderate
 MSCT: PAPVD, RLPV conjoined with IVC to RA
 RHC: mAo 93mmHg, mPAP 74 mmHg, PCWP 14mmHg, PARI 19.5, FR
1.77, (Pulmonary Hypertension
 DIAGNOSIS : G3P2A0 5 WEEKS in ASD SINUS VENOSUS DEFECT
with PAH high flow high resistance
Pulmonary Hypertension
Classification

Simonneau G, et al. Eur Respir J 2019;53:1801913


Klinger et al. CHEST 2019; 155(3):565-586
Distribution of PAH Patients in
Sardjito General Hospital Yogyakarta
COHARD PH REGISTRY 2012-2020
Etiology
1
1
62 2 1

1242

CHD Primary PH SLE POPH Scleroderma HIV


The COngenital HeARt Disease in adult and Pulmonary Hypertension (COHARD-
PH) registry: a descriptive study from single center hospital registry of adult
congenital heart disease and pulmonary hypertension in Indonesia

Lucia Kris Dinarti*, Anggoro Budi Hartopo*, Arditya Damar Kusuma, Muhammad Gahan Satwiko, Muhammad Reyhan
Hadwiono, Aditya Doni Pradana and Dyah Wulan Anggrahini

Dinarti LK et al. BMC Cardiovascular Disorders (2020) 20:163


The COngenital HeARt Disease in adult and Pulmonary Hypertension (COHARD-
PH) registry: a descriptive study from single center hospital registry of adult
congenital heart disease and pulmonary hypertension in Indonesia

Dinarti LK et al. BMC Cardiovascular Disorders (2020) 20:163


The COngenital HeARt Disease in adult and Pulmonary Hypertension
(COHARD-PH) registry: a descriptive study from single center
hospital registry of adult congenital heart disease and pulmonary
hypertension in Indonesia

Dinarti LK et al. BMC Cardiovascular Disorders (2020) 20:163


Hartopo AB et al . Pulmonary Circulation 2019; 9(4) 1-9
Severe Pulmonary
Hypertension and Reduced
Right Ventricle Systolic
Function Associated with
Maternal Mortality in
Pregnant Uncorrected
Congenital Heart Diseases

Hartopo AB et al
Pulmonary Circulation 2019; 9(4) 1-9
Severe Pulmonary
Hypertension and Reduced
Right Ventricle Systolic
Function Associated with
Maternal Mortality in
Pregnant Uncorrected
Congenital Heart Diseases

Hartopo AB et al Pulmonary Circulation 2019; 9(4) 1-9


The Molecular
Targets of
Approved
Treatments for
Pulmonary Arterial
Hypertension

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


R
V LV

RA LA

Humbert M et al. NEJM 2004


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


Risk Stratification and Medical Therapy of
Pulmonary Arterial Hypertension

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
Pulmonary Arterial Hypertension

Galie N, et al.
Eur Respir J 2019 ; 53:1801889
COMBINATION THERAPY STRATEGIES TESTED IN
RANDOMIZED CONTROLLED CLINICAL TRIALS

Humbert M, Ghofrani H-A.


Thorax 2016;71:73–83
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)
Profile of Endothelin-1, Nitric Oxide, and Prostacyclin
Levels in Pulmonary Arterial Hypertension Related to
Uncorrected Atrial Septal Defect: Results from a Single
Center Study in Indonesia

Dinarti LK et al, Cardiology Research and Practice, Volume 2020, Article ID 7526608
Economic evaluation of sildenafil for the treatment of
pulmonary arterial hypertension in Indonesia

Lilyasari et al, BMC health services research 2019 19(1), 573


SUPER-1
Sildenafil Use in Pulmonary Arterial HypERtension
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
Galiè N, et
al. New
Placebo-corrected change in 6MWD (m)
Engl J Med Sildenafil 20 mg TID is the licensed dose
2005;353:2 CTD = connective tissue disease; IPAH = idiopathic pulmonary arterial hypertension; mPAP = mean pulmonary arterial pressure; 6MWD = 6-minute walk
148–57. 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)
Galiè N, et
al. New Sildenafil 20 mg TID is the licensed dose
Engl J Med CTD = connective tissue disease; IPAH = idiopathic pulmonary arterial hypertension; mPAP = mean pulmonary arterial pressure; 6MWD = 6-minute walk
2005;353:2 distance; P = placebo; PAH = pulmonary arterial hypertension; PVRI = pulmonary vascular resistance index; S = sildenafil; TID = three times a day
148–57.
SUPER-1
Dose-dependent reductions in Dose-dependent reductions in
mPAP PVR
4 200
Placebo
Change from baseline at

Change from baseline at


Placebo
2 100

Week 12 (dyn•s/cm5)
Sildenafil 20 Sildenafil 40 Sildenafil 80 Sildenafil 20 mg Sildenafil 40 mgSildenafil 80 mg
0 mg TID mg TID mg TID TID TID TID
0
Week 12
(mmHg)

-2 +0.6 +49
-100

-4 -200
-2.1 -2.6 -122 -143
-6 p=0.04 p=0.01 -300 p=0.01 p=0.01
vs vs placebo vs placebo vs placebo
placebo -4.7
-8 p<0.001 -400 -261
vs placebo p<0.001
vs placebo
Sildenafil 20 mg TID is the licensed dose
mPAP = mean pulmonary arterial pressure; TID = three times a day
PVR = pulmonary vascular resistance; 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-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

This medical slide resource is for internal training purposes and for reactive use
in external medical communications conducted by Medical and Scientific
Relations only
SUPER-2: Long-Term Treatment with Sildenafil Citrate inPulmonary
Arterial Hypertension

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 in All, %
≥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
Dinarti LK
Acta Cadiologica Indonesiana
(vol 3 no2) 2017 [supplement]
Yogyakarta
Screening
Program
 Background: Early diagnosis of congenital heart disease reduces
significant morbidity and mortality in adulthood. Screening of CHD
in school students has been well established in high-income
countries; however data from low-to-middle income countries
including Indonesia have been limited. Aim: This study aimed to
evaluate the ability of CHD screening method by cardiac
auscultation and 12-lead electrocardiogram to obtain the
frequency of CHD among Indonesian school students.
 Methods: We conducted a screening program in first-year
elementary school students in the Province of Special Region of
Yogyakarta, Indonesia. The schools were determined by
purposive sampling. The CHD screening was integrated into the
annual heath screening program. The trained general
practitioners and nurses in community health centers were
participated in the screening. The physical examinations, which
focused on cardiac auscultation, and 12-lead electrocardiogram
examination, were performed. Here, we reported the results of
primary screening by cardiac auscultation and electrocardiogram
examination.
 Results: A total of 130 elementary schools and 60 health centers
performed the screening with 6,367 school students being
screened in two years periods (2018 and 2019). As many as 330
(5.2%) school students were suspected with heart abnormalities.
Of those, 45 students (13.64%) had heart murmurs only, 279
students (84.55%) had abnormal electrocardiogram readings
only, and 6 students (1.82%) had both abnormalities.
 Conclusions: About 5% of first-year elementary school students
Cardiology in the young, 2020 undergoing primary screening by cardiac auscultation and 12-
lead electrocardiogram were suspected with CHD and more than
Under submission two-third had abnormal electrocardiogram findings.
CHD Patients Referred to Yogyakarta

CohardPH Registry – Center for Health Policy and Management, Universitas Gadjah Mada
Yogyakarta CHD Patients Distribution

CohardPH Registry – Center for Health Policy and Management, Universitas Gadjah Mada
Conclusion
 PH is one of the serious conditions that need proper
management for patients
 Sildenafil is recommended by 2015 ESC/ESR Guidelines
and 6th WSPH 2018 as one of the therapy for patients
with PAH with class of recommendation IA
 Sildenafil has a proven efficacy in 6MWD and WHO
functional class, in short term and long term
 The importance of early detection of CHD by school
screening to prevent PH in the future
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