Blood pressure variability over 24-hour:

Implications and Treatment with

Single Pill Combination
Budi Baktijasa, MD

Agenda
Introduction & Background

Single Pill Combination Concept & Why ARB + CCB

Telmisartan + Amlodipine Clinical Studies

Summary

Agenda
Introduction & Background

Single Pill Combination Concept & Why ARB + CCB

Telmisartan + Amlodipine Clinical Studies

Summary

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
Normal

SBP
(mmHg)

DBP
(mmHg)

<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

2014 Hypertension Guideline Management Algorithm (JNC

8)

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

The Relationship Between BP

and Risk of CVD events
Benefits of Lowering BP

35-40%
Stroke
Incidence

*Individuals aged 40-70 years, from BP

115/75 mm Hg to 185/115 mmHg.

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

50 %
HF
20-25 %
MI

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

24-51%

29-58%

Noncompliant

Nonpersistent

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

with inadequately BP control
- 40-66% with concurrent
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 favored, 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

2013 ESH-ESC Guidelines for Arterial Hypertension:

Choice of antihypertensive drugs

ARB+CCB is one of the preffered

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

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 patients 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 than those offered by a single agent. (e.g :
RAAS + CCB reduces oedema) 1
6. Convenient once-daily administration of a single tablet, with potential compliance benefits2
7. Effectively lowers BP in patients with an inadequate response to monotherapy2

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

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

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

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

Mancia et al. Jounal of Hypertension 2013. 31:1281-1357
Suarez C. Drugs 2011. 71(17):2295-2305
Drugs The Perspect 2011;Vol.27. No. 5

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
Peripheral Oedema

RAS SNS
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

Effects of CCB & RAS

on Capillary Pressure and Oedema Formation
a CCB monotherapy
Arteriolar vasodilation

Increased
capillary
pressure

Venous resistance
unchanged

Oedema formation

b RAS inhibitor + CCB

Arteriolar vasodilation

Venous vasodilation

Capillary
pressure
lower than
in A
Oedema formation
reduced

Sierra. Journal of Human Hypertension 2009. 23:503-511

CCB monotherapy
Selective vasodilation of the
arteriolar side of the circulation
Increased pressure within the
capillary bed, leading to fluid
transudation and oedema
formation
ARB + CCB (Telmisartan+Amlodipine)
Cause both arteriolar and venous
vasodilation
Reduces the pressure within the
capillary bed, thereby ameliorating
the oedema

Telmisartan has Unique Pharmacology among ARBs

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
8

10
5

Nifedipine Nimodipine Nicardipine Nisoldipine Felodipine Amlodipine

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

Agenda
Introduction & Background

Single Pill Combination Concept & Why ARB + CCB

Telmisartan + Amlodipine Clinical Studies

Summary

Telmisartan + Amlodipine: Provides consistent BP

Reductions across hypertension severities1,2

Telmisartan + Amlodipine: Consistently High BP reductions

in added-risk Hypertensive Patients1

Telmisartan + Amlodipine: Provides Significant Greater BP

Reductions Compared to Amlodipine monotherapy after 1
week

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

Mean SBP (mmHg)

185.4

(n =379)

Baseline

80%*
Week 2

147.5
47.5 mmHg

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

Week 8

Twynsta: The BP reductions needed

to get hypertensive patients to goal1

Incidence of peripheral oedema in hypertensive patients

treated for 8 weeks

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 distribution6

Amlodipine has the longest half life in class7

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

1.
2.
3.
4.
5.
6.
7.
8.

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

James P et al. JAMA. 2013;289: E1-E14
Mancia et al. Jounal of Hypertension 2013. 31:1281-1357
Weber M et al. The Journal of Clinical Hypertension. 2013. 1-13
Suarez C. Drugs 2011. 71(17):2295-2305
Adapted from Verdecchia., et al. Expert Rev. Clin. Pharmacol. 4(2). 151-161 (2011)
Abernethy et al. The new England Journal of Medicine 2009. 341:1447-57
Little john et al. J. Clin. Hyp 2009: 11:207-213