The Powerful 24 Hours of Blood Pressure

Reduction with Single Pill Combination

Budi Arief Waskito

 Agenda

Introduction & Background

Single Pill Combination Concept & Why ARB+CCB

Telmisartan+Amlodipine Clinical Studies

Summary
 Hypertension is an important
public health challenge worldwide
Population (in millions)
with hypertension globally
In 2000,
> quarter of global
population with
hypertension

Kearney PM, et al. Lancet. 2005;365:217-223.

Untreated Hypertension Is Associated With Macrovascular
and Microvascular Complications

Cushman WC. J Clin Hypertens. 2003;5(suppl 2):14-22.

The challenge of BP
control
 Uncontrolled hypertension carries the same
CV risk as untreated hypertension

Third National Health and Nutrition Examination Survey (NHANES III)

48%
Not treated (n = 2,458) Both are at equally
increased risk compared
with controlled BP
(p>0.05)
35%
BP uncontrolled
(n = 1,756)

17%
BP controlled (n = 872)

Gu Q, et al. Am J Hypertens 2010;23(1):38-45

The importance of treatment
adherence
Highly adherent patients are more likely
to achieve BP control
BP Controlled (%)
50 Highly adherent patients were 45% more likely to achieve BP control
45
40
35
30
25
20
15
10
5
0
LowLow
(<50%) Medium
Medium (50-79%) HighHigh
(>=80%) Adherence (MPR)
(n = 46) (n = 165) (n = 629)

MPR = Medication possession ratio

* <140/90 mmHg or <130/85 mmHg for patients with diabetes (Defined by JNC 6)
Bramley TJ,et al.J Manag Care Pharm 2006;12:239–45
High adherent patients are at lower CV risk

Cox Proportional-Hazards Models (%)

100%
90%
80% High adherence to AHT is associated
with a 38% decreased risk of CVEs
70%
compared with lower adherence
60%
50%
40%
30%
20%
10%
0%
Adherence (PDC)
LowLow
(<40%) Medium
Medium (40-79%) HighHigh
(>=80%)
(n = 9,666) (n = 7,624) (n = 1,516)

PDC = Proportion of days covered

Mazzaglia et al. Circulation 2009;120:1598-1605

 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

Guideline recommendation
 2014 Hypertension Guideline Management Algorithm
(JNC 8)

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

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
– if patients at high cardiovascular risk, identified by
increased BP and other risk factors

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
 2013 ESC-ESH Guidelines for Arterial Hypertension :
Choice of antihypertensive drugs

ARB+CCB is one of the preffered

antihypertensive combination
Green continuous lines: preferred combinations; green dashed line: useful combination (with some
limitations); black dashed lines: possible but less well tested combinations; red continuous line: not recommended combination. Although verapamil and diltiazem
are sometimes used with a beta-blocker to improve ventricular rate control in permanent atrial fibrillation, only dihydropyridine calcium antagonists should normally
be combined with beta-blockers.

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
 Considerations of (Single-Pill) Combination
Therapy
• BP goal may be achieved more rapidly than with monotherapy1-4
• Greater reductions in BP1,2 and higher BP response and control rates3,4
vs monotherapy
• Reduced AEs due to lower doses of individual agents (lower doses
Benefits effective due to complementary mode of action 3,4
• Fixed-dose, single-pill combinations reduce pill burden,1,2 improved
compliance and treatment adherence,3,4 and may cost less than
individual components prescribed

• Most hypertensive patients will require two or more agents to achieve

Patients target BP1,2

• Drugs should have a complimentary mechanism of action 2

Combinations • Evidence that BP reduction with combination therapy is greater than
that of each individual component alone2

Limitations • Loss of flexibility with single-pill combinations2

1. Chobanian et al. Hypertension. 2003;42:1206–1252; 2. Mancia et al. Eur Heart J. 2007:28:1462–1536;

3. Tedesco et al. J Clin Hypertens. 2006;8:634–641; 4. Wald et al. Am J Med. 2009;122:290–300.
 Agenda

Introduction & Background

Single Pill Combination Concept & Why ARB+CCB

Telmisartan+Amlodipine Clinical Studies

Summary
 CCB + ARB:
The Synergies of Counter-Regulation (1)

CCB
 Arteriodilation
 Peripheral oedema
 Effective in low-renin patients
 Reduces cardiac ischaemia
BP

CCB
Synergistic  RAS activation
BP reduction  No renal or CHF
Complementary benefits
clinical benefits

Mistry et al. Expert Opin Pharmacother. 2006;7:575–581;

Sica. Drugs. 2002;62:443–462; Quan et al. Am J Cardiovasc Drugs. 2006;6:103113.
 CCB + ARB:
The Synergies of Counter-Regulation (2)

CCB
 Arteriodilation ARB
 Peripheral oedema  RAS blockade
 Effective in low-renin patients  CHF and renal
 Reduces cardiac ischaemia benefits
BP

ARB CCB
 Venodilation Synergistic  RAS activation
 Attenuates peripheral oedema BP reduction  minimal renal or
 Effective in high-renin patients CHF benefits
Complementary
 No effect on cardiac ischaemia
clinical benefits
Venous Fluid Leakage Induced by CCBs
…
Fluid leakage

Arterial No
dilation venous
(CCBs) dilation

Fluid leakage
Capillary bed
… Gets Reduced by Co-administration of ARBs

Arterial
Venous
dilation
dilation
(CCB and
(ARB)
ARB)

Capillary bed
Telmisartan Plus Amlodipine Phase III/IV Clinical Trials
Programme

22
Telmisartan + Amlodipine : Provides consistent BP
Reductions across hypertension severities
Telmisartan Plus Amlodipine Provides Consistently High BP
Reductions in Hypertensive at-Risk Patients

Obese Metabolic Elderly Severe HTN

Diabetic BMI ≥ 30kg/m syndrome* ≥ 65 y Black ≥ 180/95 mmHg
(n = 62) (n = 175) (n = 36) (n = 100) (n = 30) (n = 379)
0
Mean SBP reductions from

-10
baseline (mmHg)

-20

-30

-40
-43.2 -44.2 -46,1
-50 -46,8 -46,6 -47,5

T80/A10
-60

Mean baseline BP = 185.4/103.2 mmHg

* Diabetes, obesity (BMI  30kg/m2), and HTN
 Telmisartan + Amlodipine : Provides Greater BP
Reductions Compared to Amlodipine monotherapy after 1
week

Neutel JM, 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/A5 T80/A10
(n = 405) (n =379)
185.4 Baseline
Mean SBP (mmHg)

80%*
–37.9 mmHg
147.7 Week 2
–47.5 mmHg
137.9 Week 8

* 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 JM, et al. The Journal of Clinical Hypertension 2012; 14:206-215
 Telmisartan Plus Amlodipine Provides Consistent 24-h
ABPM Dose Response

24-h mean SBP reduction 24-h mean DBP reduction

(mmHg) (mmHg)
***††† ***†††
***††† ***†††
25 ***††† 16 **†††
***††† ***†††
20 14
12
15 10
8
10 6
5 10 4 10
5 2 5
0 0 0 0
80 40 0 80 40 0
Telmisartan (mg) Telmisartan (mg)

** p < 0.001; *** p < 0.0001 vs Telmisartan alone; †††

p < 0.0001 vs Amlodipine alone; n = 562
 Telmisartan Plus Amlodipine is Associated With Less
Peripheral Oedema Compared With Amlodipine 10 mg

* p<0.0001 vs amlodipine 10 mg
Littlejohn et al. J Clin Hypertens. 2009;11:207–213.
 Agenda

Introduction & Background

Single Pill Combination Concept & Why ARB+CCB

Telmisartan+Amlodipine Clinical Studies

Summary
 Summary

• Hypertension is a major CV risk factor

• There is still a huge unmet medical need in the treatment of hypertension,
with many patients being uncontrolled
• Most patients need combination therapy to reach their BP goals
• ARB plus CCB combination exhibit complementary and synergistic MoA with
high BP reductions and a good safety and tolerability profile
• Telmisartan + Amlodipine provides powerful and consistent BP reductions,
as well as high BP goal and response rates, including in hypertensive at-risk
(complex) patients, combined with an tolerable safety profile
Thank You