Hypertension remains a major global health issue, with over 7 million deaths annually associated with it. Less than 50% of hypertensive patients receive therapy, and approximately 70% of treated patients do not reach blood pressure goals. Most guidelines recommend initiating treatment with two drugs when blood pressure is more than 20/10 mmHg above goal or for those at high cardiovascular risk. Clinical trials have shown that the amlodipine/valsartan combination effectively lowers blood pressure and helps more patients achieve goals compared to monotherapy. Real-world Indonesian studies found that amlodipine/valsartan combination therapy was effective at controlling blood pressure in the majority of uncontrolled hypertensive patients switched from monotherapy.

1. Dr Erwin SpPD
PIT IDI VIII BOGOR 2015
Achieving Blood Pressure Goal: From Clinical
Trial into Real-World Data

2. Hypertension remains a leading cause of mortality
Annually over 7 million deaths world-wide associated with hypertension
 Hypertension causes a large direct and
indirect economic burden
 accounted for $73.4 billion in US in 20091
 responsible for ~7.6 million deaths
worldwide in 20012
 The global incidence of hypertension is
increasing3
 Less than 50% of hypertensive patients
in US receive therapy. In Canada and
Europe approximately 66-75% were
untreated4
 Approximately 70% of patients do not
reach BP goals.
Population with hypertension (%)
30
Overall
26
28
Males Females
2000
2025
24
1. Cohen JD. Manag Care 2009;18:51–8;
2. Lawes et al. Lancet 2008;371:1513–8;
3. Kearney et al. Lancet 2005;365:217–23;
4. Wolf-Maier et al. Hypertension 2004;43:10–17.
Kearney et al. Lancet 2005;365:217–23
Flack et al. Managed Care Interface 2002, Nov 28-36
Major cardiovascular events/year*
10 000
20 000
30 000
40 000
50 000
Medicated Unmedicated Total
0
DBP/SBP uncontrolled
DBP uncontrolled
SBP uncontrolled
The global incidence of hypertension will
exceed 29% by 2025
Uncontrolled BP results in >40,000 major CV
events per year in the USA

4. >50% have 2 or more comorbidities
Men
Kannel WB. Am J Hypertens. 2000:13:3S-10S.
Comorbidities:
• Obesity
• Glucose intolerance
• Hyperinsulinemia
• Reduced HDL-C
• Elevated LDL-C
• Elevated TG
• LVH
≥ Four
8%
Three
22%
Two
25%
One
26%
None
19%
Women
≥ Four
12%
Three
20%
Two
24%
One
27%
None
17%
More Than 80% of Hypertensive Patients Have Additional
Comorbidities

5. Approximately 70% of Patients* Who Receive Treatment Do Not
Reach BP Goal in Europe
Wolf-Maier et al. Hypertension 2004;43:10–17
*Treated for hypertension
BP goal is <140/90 mmHg
60 79 70 81 72
0
20
40
60
80
100
BP goal achieved BP goal not achievedPatients (%)
England Sweden Germany Spain Italy

6. Blood pressure (BP) control rates in hypertensive patients in
developing economies
Thailand*,#,2
47.8
51.8%
China*,1
27.4%
1Wang et al. Chin J Epidemiol 2012;33:903–6;
2Aekplakorn et al. J Hypertens 2012; 30:1734–42
3Chiang et al. J Formos Med Assoc 2010;109:740–3;
4Sison et al. PJC 2007;35:1–9
5Erem et al. J Public Health 2009;31:47–58
6Hernández-Hernández et al. J Hypertens. 2010;28:24-34
Turkey*,5
24.3%
*Treated population
#Control rate: 47.8% in males, 51.8% in females
†Control rate: 21% in males, 29% in females
Taiwan
†,3
2129%
Philippines*,4
20.0%
BP controlled
BP uncontrolled
24.0%
Latam*,6

7. Physician-Related Barriers to Effective
Antihypertensive Treatment
Wang TJ, Vasan RS. Circulation. 2005;112:1651-1662;
Chobanian AV, et al. JAMA. 2003;289:2560-2572;
Okonofua EC, et al. Hypertension. 2006;47:345-351.
 Therapeutic inertia
 Overestimation of adherence to
guideline
 Disagreement with guidelines
 ISH
 Concern about the relationship
between DBP and MI (i.e. J
curve)
 Reluctance to treat a seemingly
“asymptomatic condition”
 Unfamiliarity with current treatment
guideline
 BP thresholds
 ISH
 Threshold for diabetic patients
 Use of monotherapy to treat
patients with difficult-to-control
blood pressure
 Belief that in-office BP tends to be
higher than at-home BP

8. Number of antihypertensive agents needed to reach
blood pressure (BP) goal
MDRD study group, NEJM 1994; 330:877; Kjeldsen et al Hypertension 1998: 31: 1014-1020; Breener et al NEJM 345: 861-69; Bakris et al. Am J Med 2004;116(5A):30S–8;
Lewis et al, NEJM; 2001; 345: 851-860; UKPDS group Lancet, 1998: 352: 854-865; AASK research group Arch Intern Med 168: 832-839; Dahlöf et al. Lancet 2005;366:895–906
van Eijsden et al, Int J Epidemiol 2011, 40: 1176-1186. ALLHAT research group 2002; 288: 2981-2997: Jamerson et al. N Engl J Med 2008;359:241728
Average no. of antihypertensive medications
1 2 3 4
Trial (SBP achieved)
ASCOT-BPLA (136.9 mmHg)
ALLHAT (138 mmHg)
IDNT (138 mmHg)
RENAAL (141 mmHg)
UKPDS (144 mmHg)
ABCD (132 mmHg)
MDRD (132 mmHg)
HOT (138 mmHg)
AASK (128 mmHg)
ACCOMPLISH (132 mmHg)
Initial 2-drug combination therapy
SBP: systolic blood pressure

9. When and Which Anti-hypertension
Combination?

10. Guidelines Worldwide Acknowledge That Most Patients
Need Combination Therapy to Achieve BP Goals
 Most patients with hypertension will require two or more
antihypertensive medications to achieve their BP goals
 When BP is > 20/10 mmHg above goal, consideration should
be given to initiating therapy with two drugs
 Combination treatment should be considered as first choice when there
is high CV risk
 i.e., in individuals in whom BP is markedly above the
hypertension threshold (> 20/10 mmHg), or associated with
multiple risk factors sub-clinical organ damage, diabetes,
renal or CV disease
Chobanian et al. JAMA. 2003;289:2560–2572; Mancia et al. Eur Heart J. 2007;28:1462–1536; http://www.nice.org.uk/
download.aspx?o=CG034fullguideline (accessed January 2010); Ogihara et al. Hypertens Res. 2009;32:3–107.
 Many patients will require more than one drug to achieve adequate
BP control
– Pathophysiological reasoning suggests that adding an ACE-I/ARB
to a CCB or a diuretic (or vice versa in the younger group) are
logical combinations
 The use of two or three drugs in combination is often necessary
to achieve the target BP control
– A low dose of a diuretic should be included in this combination
JNCVIIESH/ESCNICE
The Japanese Society of
Hypertension Committee for
Guidelines for the
Management of Hypertension
2009
JSH

11. Cardiovascular Risk Stratification
ESHESC Guidelines 2013
Mancia et al. Eur Heart J 2013;34(28):2159-219

12. Initiation of Antihypertensive Treatment
ESH-ESC Guideline 2013
Mancia et al. Eur Heart J 2013;34(28):2159-219

13. HYPERTENSION MANAGEMENT ALGORITHM
ESH-ESC 2013
Mancia et al. Eur Heart J 2013;34(28):2159-219

14. 2013 ESH–ESC Recommendation:
Combining blood pressure lowering drugs
Solid lines represent preferred drug combinations in patients with hypertension
ACEI(s): angiotensin-converting enzyme inhibitor(s); ARB(s): angiotensin receptor
blocker(s); CCB(s): calcium channel blocker(s); ESH: European Society of
Hypertension; ESC: European Society of Cardiology
 ARB/diuretic and ARB/CCB are
rational combinations available in a
single pill
Preferred combinations
Useful combination
(with some limitations)
Not recommended
Possible, but less
well-tested combinations
Mancia et al. Eur Heart J 2013;34:2159–219

15. Tolerability and Risk Factor Modification: CCB-induced
Peripheral Edema Minimized by the RAS Inhibitor
Single mode of
action of the CCB
Dual mode of action
of the CCB/RAS
Inhibitor
Illustration modified from www.lotrel.com
RAS inhibitor dilates
arteries and veins
Reduces
CCB-induced
peripheral
edema
Capillary
overload
forces fluid
into
surrounding
tissue
CCB dilates
arteries
Veins remain
constricted
Messerli et al. Am J Hypertens 2001;14:978–9

16. ARB
• ↓ RAS  ↓ SNS
• Arterio- and venodilation
• Effective in high-renin patients
• Congestive heart failure and renal benefits
• Attenuates peripheral edema
• No effect on cardiac ischemia
CCB
• ↑ SNS  ↑ RAS
• Arteriodilation
• Effective in low-renin patients
• No renal or congestive heart failure benefits
• Peripheral edema
• Reduces cardiac ischemia
negative
sodium balance
reinforces the
effects of the
ARB
Vasodilation
Arterial +
Venous
CCBs and ARBs Interact Synergistically on Vascular and Renal Function,
Sympathetic Nervous System and Renin-Angiotensin System Activity
Natriuresis
Arterial
SNS = sympathetic nervous system; RAS = renin-angiotensin system

17. SPC
(amlodipine/benazepril)
(n=2,839)
Free combination
(CCB + ACEI)
(n=3,367)
Medication possession ratio†
p<0.0001
88%
69%
0% 20% 40% 60% 80% 100%
Improved compliance with single-pill combination (SPC) therapy
versus free-combination therapy
Gerbino & Shoheiber. Am J Health System Pharm
2007;64:1279–83
†Defined as the total number of days of therapy for medication dispensed/365
days of study follow-up
ACEI: angiotensin-converting enzyme inhibitor; CCB: calcium channel blocker

18. What did the clinical trials showed on
Amlodipine/Valsartan Combination?

19. Overall β-blocker CCB ARB ACEI Diuretic
Antihypertensive class prior to randomization in the trial
ChangeinsystolicBP(mmHg)from
baselinetoWeek8
Randomized, double-blind, multinational parallel-group, 16-week study
ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker;
BP: blood pressure; CCB: calcium channel blocker
Incremental BP drops after direct switch to amlodipine/valsartan in
patients previously uncontrolled on monotherapy
Amlodipine/valsartan 10/160 mg
Amlodipine/valsartan 5/160 mg
n= 440 449 76 55 53 70 175 175 92 105 41 39
0
–5
–10
–15
–20
–25
Allemann et al. J Clin Hypertens 2008;10:185–94
Baseline BP = 150/91 mmHg

20. Amlodipine/Valsartan: Up to 9 Out of 10 Patients Reach BP
Goal <140/90 mmHg
No hydrochlorothiazide add-on was permitted until after Week 8
Randomized, double-blind, multinational, parallel-group, 16-week study Allemann et al. J Clin Hypertens 2008;10:185–94
“Diabetic patients with BP <130/80 mmHg at Week 8 were
47.0% and 49.2% for 5/160 mg and 10/160 mg doses,
respectively”
5 of 10 hypertensive diabetic patients achieved BP goal
(<130/80 mmHg)

21. How about the real-world experiences on
amlodipine/valsartan combination in
hypertensive Indonesian patients?

22. Two real-world studies on Amlodipine/Valsartan Combination in Indonesian
Patients
MAX-FORCE and EXCITE Studies: almost total of 1000 patients were recruited
Arini et al. MAX FORCE Poster Publication at The 7th Scientific Meeting of InaSH 2013. Jakarta
Kalim H, et al. EXCITE Poster Publication at The 8th Scientific Meeting of InaSH 2014. Jakarta
Study design Study design
Inclusion criteria: male and female adult patients (age > 18
years) who consented to have their data collected, suffering from
essential hypertension not adequately controlled by monotherapy,
for whom an antihypertensive therapy with amlodipine/valsartan
combination (5/80, 5/160 or 10/160) daily was given at the
discretion of the attending physicians.
Objectives: The clinical EXCITE study evaluated the
effectiveness, safety, tolerability and treatment adherence of
Aml/Val Single Pill Combinations (SPCs) in patients with arterial
hypertension studied in a real-world setting.
Total patients recruited were 500 patients, 464 (92.8%) patients
completed the study, and 35 (7%) patients discontinued the study
due to lost to follow-up. Study period: Mar 2011 to Sept 2012
Inclusion criteria: male and female adult patients (age > 18
years) who consented to have their data collected, suffering from
essential hypertension not adequately controlled by monotherapy,
for whom an antihypertensive therapy with amlodipine/valsartan
combination (5/80, 5/160 or 10/160) daily was given at the
discretion of the attending physicians.
Objectives: This observational study was conducted to assess
safety, tolerability, and effectiveness of single pill combination
(SPC) amlodipine/valsartan in Indonesian hypertensive patients in
daily clinical practice.
Total patients recruited were 488 patients, 480 patients were
analyzed for safety and 468 patients were eligible for ITT
effectiveness analyses. Study period: Feb 2010 to May 2011

23. Overall Population
Indonesian Real-Life Experiences on Amlodipine/Valsartan SPC
Powerful BP reduction showed from two real-world studies
169.1 99.4 164.0 96.4Baseline
MAX-FORCE
Study: Open-
label,
observational,
prospective,
multicenter,
12 weeks
study, with 468
patients eligible
for Intent to
treat analysis
SPC: Single Pill
Combination
Arini et al. MAX FORCE Poster Publication at The 7th Scientific Meeting of InaSH 2013. Jakarta
Kalim H, et al. EXCITE Poster Publication at The 8th Scientific Meeting of InaSH 2014. Jakarta
EXCITE Study:
Multinational Asia-
Middle East-African
Countries (AMAC)
study, open-label,
observational,
prospective,
multicenter,
26 weeks study. Data
shown on this graph is
only reflected 500
patients from Indonesia
who were eligible for full
set analysis
n=468 n=500

24. Indonesian Real-World Experiences on Amlodipine/Valsartan SPC in
Diverse Type of Patients
Consistently showed powerful BP reduction efficacy
Arini et al. MAX FORCE Poster Publication at The 7th Scientific Meeting of InaSH 2013. Jakarta
Kalim H, et al. EXCITE Poster Publication at The 8th Scientific Meeting of InaSH 2014. Jakarta

25. Amlodipine/Valsartan SPC Showed Favorable Safety and
Tolerability Profile for Hypertensive Indonesian Patients
Arini et al. MAX FORCE Poster Publication at The 7th Scientific Meeting of InaSH 2013. Jakarta
Kalim H, et al. EXCITE Poster Publication at The 8th Scientific Meeting of InaSH 2014. Jakarta
• From 480 patients eligible for safety analysis,
10 patients (2.1%) reported AE. Three
patients (0.6%) with mild AE were suspected
to be related to study drug : 2 patients (0.4%)
with edema, and 1 patient (0.2%) with
headache.
• Total of 2 patients (0.4%) with edema already
had edema at baseline.
• No serious AE (SAEs) reported in this
study.
Conclusion: This study showed that in patients
with essential hypertension not adequately
controlled by monotherapy, switching to
amlodipine/valsartan combination resulted in
further decrease in BP and achieved target BP
with good safety, tolerability and effectiveness,
suggesting the use of this combination can be
recommended in daily clinical practice in
Indonesia.
• From 500 patients in the full analysis set, 57
patients (11.4%) reported at least one AE.
The most frequent AEs were dyslipidemia (13
patients, 3%), cough (9 patients, 2%),
headache (7 patients, 1%), and edema (6
patients, 1%).
• 5 (1%) patients reported serious adverse
events (SAE), four patients died due to stroke
or heart attacks, one patient reported a non-
fatal SAE. The events were not suspected to
be related to the study drug.
Conclusion: The Indonesian EXCITE study
analysis showed that in a real-world setting,
amlodipine/valsartan SPC is an effective and
well-tolerated SPC therapy for the
hypertensive population in Indonesia

26. Summary
 Hypertension is a major CV risk factor. There are still unmet need in
the treatment of hypertension, with many patients are uncontrolled.
Most of the patients need more than one agent to achieve BP target.
 CCB/ARB combination are recommended by guideline as preferred
combination for its efficacy, safety and tolerability profile.
 Amlodipine/Valsartan combination provides powerful BP reductions,
favorable safety profile, as well as high BP goal and response rates,
for hypertensive patients including those with comorbidities.
 Real-world experiences on SPC of amlodipine/valsartan in Indonesia
show consistent BP reduction powerful effectiveness with good
safety and tolerability in overall hypertensive patients and patients
with comorbidities.