Curriculum Vitae

Nama : Dr. Masrul Syafri SpPD, SpJP (K), FIHA

Tempat & Tanggal Lahir : Padang, 14 Oktober 1962
Jabatan : Ketua Bagian Kardiologi & Kedokteran Vaskuler FK UNAND Padang
Pendidikan
1. Dokter Umum : FK UNAND 1982 1989
2. Dokter Spesialis Penyakit Dalam : FK UNAND 1994-1999
3. Dokter Spesialis Penyakit Jantung dan Pembuluh Darah : FKUI 2003-2006
Pekerjaan
1. Kepala Puskesmas Matur 1990 - 1993
2. RSUD Muara Labuh 2000 2002
3. RS PJNHK 2003-2006
4. RS Dr. M. Djamil Padang 2006 - sekarang
The Use of Single Pill Combination Therapy
as a New Paradigm for the Modern Clinical
Management of Hypertension

Masrul Syafri, MD
RS. M Djamil
Padang
The Use of Single Pill Combination Therapy
as a New Paradigm for the
Modern Clinical Management of
Hypertension
 Agenda

Introduction & Background

Single Pill Combination Concept & Why ARB+CCB

Telmisartan+Amlodipine Clinical Studies

Summary
 Percentage of Adult Population with Hypertension in
Indonesia

Adult Population with

Only 24%
Aware of
Hypertension

Hypertensive
Status

Krishnan A. Regional Health Forum. Vol 17, Number 1;2013;7-11

 WHO Age-standardized Estimates of the Prevalence of
Hypertension in Sout East Asia Region

Estimates of age-standardized prevalence (%) of raised blood pressure in adults aged 25+
years in countries of the SEA Region, 2008
Country Men Women Both
44.3 39.8 42.0
Myanmar
(37.7-50.5) (33.1-46.5) (37.2-46.8)
42.7 39.2 41.0
Indonesia
(35.3-49.9) (32.5-46.0) (35.9-45.8)
36 34.2 35.2
India
(29.7-41.8) (28.6-39.9) (30.9-35.2)
37.0 31.6 34.2
Thailand
(31.3-42.5) (26.0-37.1) (30.0-38.1)
37.6 35.4 36.6
Asia Tenggara
(32.6-42.4) (30.9-39.8) (33.1-39.8)
40.8 36.0 38.4
Global
(37.7-43.7) (33.3-38.6) (36.3-40.5)

Krishnan A. Regional Health Forum. Vol 17, Number 1;2013;7-11

 Classification of Blood Pressure (JNC 7)

BP category SBP DBP

(mmHg) (mmHg)
Normal <120 and <80

Pre-hypertension 120139 or 8089

Stage 1 140159 or 9099

Stage 2 160 or 100

Chobanian A et al. JAMA 2003. 289:2560-72

2014 Hypertension Guideline Management Algorithm
(JNC 8)

James P et al. JAMA. 2013;289: E1-E14

James P et al. JAMA. 2013;289: E1-E14
The Relationship Between BP and Risk of CVD events

Benefits of Lowering BP

50 %
35-40%
HF
Stroke
Incidence
20-25 %
MI

*Individuals aged 40-70 years, from BP

115/75 mm Hg to 185/115 mmHg.

Chobanian A et al. JAMA 2003. 289:2560-72

Rate of Controlled Patients

28% ------------------------------
---
Unaware of their
hypertension

39% ------------------------------
---
Not Receiving therapy

65% ------------------------------
---
Do not have their BP
controlled to levels below
140/90 mmHg

Chobanian A.. NEJM 2009. 361:878-87

 Poor Compliance with Antihypertensive Treatment

- 1/3 1/2 patients in US & Canada

24-51% 29-58% with inadequately BP control
Non- Non- - 40-66% with concurrent
compliant persistent hypertension & diabetes
- In Euro : > 2/3 of treated patients
with inadequately BP control

Consequences of poor adherence &

compliance
- Encompasses a higher risk of CVD,
hospitalization and increased
health care utilization cost
- Nonpersistence
15% AMI, 28% Stroke

Barkas F, et al. Hellenic Journal of Atherosclerosis 1 (1):18-

25
Guidelines worldwide Acknowledge That Most Patients Need
Combination Therapy to Achieve BP Goals

JNC 8 ; 20141
Initiate therapy with 2 drugs simultaneously
If SBP is > 20 mmHg above goal and/or DBP is > 10 mmHg
above goal

ESH/ESC 20132
Combination of two antihypertensive drugs at fixed doses in a
single tablet may be recommended and favoured, because
reducing the number of daily pills improves adherence, which
is low in patients with hypertension.

ASH/ISH Hypertension Guidelines 20133

If the untreated blood pressure is at least 20/10 mmHg above the
target blood pressure, consider starting treatment immediately
with 2 drugs

1. James P et al. JAMA. 2013;289: E1-E14

2. Mancia et al. Jounal of Hypertension 2013. 31:1281-1357
3. Weber M et al. The Journal of Clinical Hypertension. 2013. 1-13
 Mancia et al. Jounal of Hypertension 2013. 31:1281-1357

ARB+CCB is one of the preffered

antihypertensive combination
 Agenda

Introduction & Background

Single Pill Combination Concept & Why ARB+CCB

Telmisartan+Amlodipine Clinical Studies

Summary
 Pros and cons of
Monotherapy and combination therapy

Monotherapy
1.Monotherapy can effectively reduce BP in only a limited number of hypertensive
patients1

Combination Therapy
1.The most patiens require the combination of at least two drugs to achieve BP
control1
2.The advantage of initiating with combination therapy is potentially beneficial in
high-risk patients1
3.A greater probability of achieving the target BP in patients with higher BP values
and a lower probability of discouraging patient adherence with many treatment
changes1
4.Lower drop-out rate than patients given any monotherapy1
5.Fewer side effects and provide larger benefits thant those offered by a single agent.
(e.g : RAAS + CCB reduces oedema) 1
6.Convinient once-daily administration of a single tablet, with potential compliance
benefits2
7.Effectively lowers BP in patients with an inadequate response to monotherapy2
1. Mancia et al. Jounal of Hypertension 2013. 31:1281-1357
2. Drugs The Perspect 2011;Vol.27. No. 5
 Loose Combination or
Single-pill Combination ?

Single-pill combination (SPC)

1.Reducing the number of pills to be taken daily improves adherence/patient
compliance (Simplify treatment regimens) 1,2,3
2.Provide superior BP-lowering Efficacy2
3.Increases the rate of BP control1
4.Enhanced patient adherence2
5.Reducing healthcare costs3
6.Improved tolerability profile2

1. Mancia et al. Jounal of Hypertension 2013. 31:1281-1357

2. Suarez C. Drugs 2011. 71(17):2295-2305
3. Drugs The Perspect 2011;Vol.27. No. 5
Benefits of Single Pill Combination Concept

Single Pill Combination

Good levels of compliance

More rapid and sustained BP control

Reduce cardiovascular morbidity & mortality

1. Mancia et al. Jounal of Hypertension 2013. 31:1281-1357
2. Suarez C. Drugs 2011. 71(17):2295-2305
3. Volpe M, et al. European Journal of Cardiovascular Medicine 2012, 2:1:90-97
 Fixed-dose Combinations Provide a Strong
Armamentarium in Chronic Disease Management

Non-compliance
to medication
regimens is
reduced by
24-26%
with fixed-dose
combinations
regimens

Effect of fixed-dose combination vs free-drug combination on the risk

of medication non-compliance in cohort with hypertension

Bangalore S et al. The American Journal of Medicine (2007) 120, 713-719

 Why ARB + CCB ???

Natriuresis

Vasodilation
Arterial +
Arterial
Venous
CCB ARB RAS inhibition

RAS SNS RAS SNS

Peripheral Oedema Attenuates peripheral oedema
The advantages of ARB+CCB :
1.Synergistic mechanism of action
2.Vascular protective effects due to the improvement in endothelial dysfunction
3.A neutral metabolic profile
4.Nephroprotective effect due to its capacity to dilate the renal arterioles
5.Reduced incidence of oedema secondary to the use of CCBs
6.Greater capacity to reduce morbidity/mortality rates in high-risk hypertensive patients than the
RASI-diuretic combination

Suarez C. Drugs 2011. 71(17):2295-2305

 CCB + ARB :
The Synergies of Counter-Regulation

CCB ARB
Vasodilation of the arterioles RAS blockade
Activating the SNS CHF and renal
benefits
BP

ARB CCB
Attenuates peripheral oedema Synergistic RAS activation
BP reduction No renal or CHF
Complementary benefits
clinical benefits

Suarez C. Drugs 2011. 71(17):2295-2305

 Telmisartan : No Posology Adjustment is Required for
Patients with Renal Impairment, including those on
Haemodialysis

Drug Elimination
(feces/urine)

Telmisartan >98% fecal

Losartan 60/35

Valsartan 83/13

Irbesartan 80/20

Candesartan 67/33

Eprosartan 90/10

Olmesartan 35-49% urinary recovery rate*

*For Intravenous olmesartan

1. Local Product Information of Micardis, 2014

2. Adapted from Verdecchia., et al. Expert Rev. Clin. Pharmacol. 4(2). 151-161 (2011)
 Amlodipine The longest Half-life in Class

Plasma elimination half-life (h) 35

50
30

25

20
16
15 12
10 8
5 2 2
0
Nifedipine Nimodipine Nicardipine Nisoldipine Felodipine Amlodipine

Abernethy et al. The new England Journal of Medicine 1999. 341(9):1447-57

 Effects of CCB & RAS
on Capillary Pressure and Oedema Formation

a CCB monotherapy

Arteriolar vasodilation
CCB monotherapy
Venous resistance -Selective vasodilation of the
unchanged
Increased arteriolar side of the circulation
capillary -Increased pressure within the
pressure capillary bed, leading to fluid
transudation and oedema formation
Oedema formation
ARB + CCB
b RAS inhibitor + (Telmisartan+Amlodipine)
CCB -Cause both arteriolar and venous
Arteriolar vasodilation Venous vasodilation
vasodilation
Capillary
-Reduces the pressure within the
pressure
capillary bed, thereby ameliorating
lower than
the oedema
in A
Oedema formation
reduced Sierra. Journal of Human Hypertension 2009. 23:503-511
 Agenda

Introduction & Background

Single Pill Combination Concept & Why ARB+CCB

Telmisartan+Amlodipine Clinical Studies

Summary
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Neutel et al. The Journal of Clinical Hypertension 2012; 14:206-215
 Telmisartan + Amlodipine
Provides 80% of its Maximum Effect After Just 2 Weeks of Treatment

Mean SBP reduction (mmHg)

T80/A10
(n =379)
185.4 Baseline
Mean SBP (mmHg)

80%*

Week 2
147.5
47.5 mmHg
Week 8
137.9

* Percentage of effect achieved after 2 weeks of treatment compared with

end of study (Week 8)
A5 and T80/A5 for the first 2 weeks, then forced-titration to A10 and T80/A10, respectively;
baseline BP = 185.4/103.2 mmHg

Neutel J et al. The Journal of Clinical Hypertension. April 2012

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 Agenda

Introduction & Background

Single Pill Combination Concept & Why ARB+CCB

Telmisartan+Amlodipine Clinical Studies

Summary
 Summary
Hypertension is the single most important risk factor for mortality in South-East Asia (SEA) region1

Guidelines on hypertension have consistently recommended early diagnosis and treatment of

hypertension in order to reduce cardiovascular morbidity and mortality2,3,4

Single Pill Combination simplify treatment regimen, enhanced patient adherence and provide
superior BP-lowering efficacy and improved tolerability profile5

Why Telmisartan + Amlodipine, because :

Telmisartan has the longest plasma half-life, and long duration of action, higher binding affinity and
longer blockade AT1 receptor, high lipophilicity and large volume distribution 6

Amlodipine has the longest half life in class 7

Twynsta reduces incidence of peripheral oedema in hypertensive patients up to 90%8

Telmisartan + Amlodipine are well tolerated and provide the combined benefits of powerful BP
reduction and CV protection for difficult-to-manage patients with additional risk factors6

, reduced CV risk
1. Krishnan A. Regional Health Forum. Vol 17, Number 1;2013;7-11
2. James P et al. JAMA. 2013;289: E1-E14
3. Mancia et al. Jounal of Hypertension 2013. 31:1281-1357
4. Weber M et al. The Journal of Clinical Hypertension. 2013. 1-13
5. Suarez C. Drugs 2011. 71(17):2295-2305
6. Adapted from Verdecchia., et al. Expert Rev. Clin. Pharmacol. 4(2). 151-161 (2011)
7. Abernethy et al. The new England Journal of Medicine 2009. 341:1447-57
8. Little john et al. J. Clin. Hyp 2009: 11:207-213
Thank You