Triple Drug Combination

for Hypertension
Dr. Devendra Khandke MD
Head- Medical Services
Alembic Pharmaceutical
Limited
1

Hypertension is the most powerful risk factor for

cardiovascular morbidity and mortality
Global burden of disease

Global mortality
16 million

128 million

78 million

59 million

39 million

30 million

Ezzati et al. PloS Med 2005;2:e133

43 million

All cardiovascular
High BP
High cholesterol
Overweight and obesity

23 million

Proportion of Deaths Attributable to Leading Risk Factors

Worldwide (2000)
High blood pressure
Tobacco
High cholesterol
Underweight
Unsafe sex

Systolic blood pressure

greater than 115 mmHg

High BMI
Physical inactivity
Alcohol
Indoor smoke from solid fuels
Iron deficiency
0

Attributable Mortality
WHO 2000 Report. Lancet. 2002;360:1347-1360.

The Two Key Components of BP

Regulation

Grassi. J Hypertens. 2001;19:17131716; modified.

Each of the main classes of anti-hypertensive drugs affects

the renin-angiotensin system
Angiotensinogen
Volume

Renin

Na+
+

Beta-blockers

Renin

Kidney

Angiotensin I

Diuretic
Calcium
channel

ACE

ACE inhibitor

Angiotensin II

blocker

AT1 receptor

Angiotensin receptor
blocker
Vasoconstriction

Arteries vascular tone

Brown. Heart 2007;93:102633

Sodium retention
SNS activation
Inflammation
Growth-promoting effects
Aldosterone 5
Apoptosis

Hypertension: Predisposing factors

Age > 60 years

Sex (men and postmenopausal women)

Family history of cardiovascular disease

Smoking

High cholesterol diet

Co-existing disorders such as diabetes, obesity and

hyperlipidaemia

High intake of alcohol

Sedentary life style

Diseases Attributable to
Hypertension
Left Ventricular

Heart
Gangrene of the
Failure
Lower Extremities

Hypertrophy Myocardial
Infarction
Hypertensive
Encephalopathy

Aortic
Aneurym

HYPERTENSION

Blindness

Coronary
Heart Disease

Cerebral
Chronic
Preeclampsi Hemorrhage
Kidney Stroke
a/Eclampsia
Failure
Adapted from Dustan HP et al. Arch Intern Med. 1996; 156: 1926-1935

Risk of Hypertension

Blood Pressure and Risk of Stroke Mortality

9
Lancet
2002;360:1903-13.

Blood Pressure and Risk of Ischemic Heart

Disease (IHD) Mortality

Lancet 2002;360: 190310

13.

Each 20/10 mmHg BP increase doubles the risk of CV mortality

Fold Increase in Relative CV Risk*

115/75

135/85

155/95

175/105

SBP/DBP, mmHG
* Individuals aged 4069 years (N = 1 million).
Lewington S, et al. Lancet. 2002;360:19031913.

11

Lowering BP reduces cardiovascular risk

Meta-analysis of 61 prospective, observational studies
One million adults, 12.7 million person-years
7% reduction in
risk of ischaemic
heart disease and
other vascular
disease mortality

2 mmHg
decrease in
mean SBP

10% reduction in risk

of stroke mortality
Small SBP reductions
yield significant
benefit
Lewington et al. Lancet. 2002;360:19031913

12

Prevalence %

Epidemiologic impact on mortality of blood

pressure reduction in the population
After
Intervention

Before
Intervention

Reduction in BP

Reduction
in SBP

% Reduction in Mortality

(mmHg)

Stroke

CHD

Total

2
3

-6
-8

-4
-5

-3
-4

-14

-9

-7

Adapted from Whelton, P. K. et al. JAMA 2002;288:1882-1888

13

Goals of Therapy JNC 7

BP < 140/90 mmHg

In diabetics or in patients with chronic

renal disease:
<130/80 mmHg

ISH : SBP in persons>50 years:

<140 mmHg

14

Major Anti-Hypertensive Drugs

1.

Diuretics: Hydrochlorothiazide, Chlorthalidone

2.

Beta blockers : Atenolol, nebivolol, metoprolol

3.

ACE inhibitors : Enalapril, Lisinopril, Ramipril etc

4.

AT1 receptor antagonists:Losartan, valsartan, telmisartan etc

5.

Calcium antagonists : Amlodipine, Nifedipine, Diltiazem

6.

Alpha blockers : Prazosin, terazosin, doxazosin

7.

Aldosterone antagonist: Spironolactone, Eplerenone

8.

Renin inhibitor: Aliskiren

15

Diuretics

Act on kidneys-Increase excretion of sodium & water

Inhibits Na+ and Cl- reabsorption in the distal tubules resulting in
decreased H2O reabsorption
Dilates arterioles causing decreased resistance
Reduce Blood Volume [ Preload ]
Reduce BP

First-line treatment in mild ( Stage 1 ) hypertension

Often used in combination with other antihypertensive agents e.g. ACEIs, AT1 blockers, beta blockers
Indications
Hypertension
Heart failure
Isolated Systolic Hypertension
Elderly Hypertensives
E.g Hydrochlorothiazide, Indapamide, Fluresemide

16

Calcium Antagonists

CCBs block the L type calcium channels present within blood vessels- prevent entry of calcium ions into vascular
smooth muscle fibers
relaxing large and small arteries and reducing peripheral resistance ( PVR )
Reduce force of contraction of myocardium

Drugs of choice in elderly hypertensives and those with co-existing asthma

Neutral effect on glucose and lipid levels

Drawbacks

Adverse effects: Flushing, headache, Pedal edema

3 groups:
1.Dihydropyridine
1.Dihydropyridine derivatives: Nifedipine, felodipine, amlodipine etc
2.Benzothiazepines: Diltiazem
3.Phenylalkylamines:
3.Phenylalkylamines: Verapamil

Indications

Hypertension

Angina

Myocardial Infarction

17

Angiotensin II Receptor Blockers

(ARBs)- Sartans

Mechanism of action: Blocks binding of Angiotensin II to its receptor sites

Therapeutic effects

Decreased BP: Decreased vasoconstriction, decreased vascular resistance,

decreased afterload
Major use is afterload reduction in CHF and MI
Frequently a second line treatment for patients who do not tolerate ACE-I

ARBs are as effective as ACE inhibitors & other antihypertensives

4 to 6 weeks of therapy are required to achieve the full therapeutic effects

of ARBs

Better tolerated than ACE inhibitors- do not produce dry cough

e.g. Losartan, candesartan, valsartan, telmisartan etc

18

The Challenge of BP Control

19

BP control is particularly poor in

hypertensive patients at high risk
Hypertension controlled (%)
Total n=4,646

CAD, coronary artery disease; CHF, congestive heart failure; CKD, chronic kidney
disease; DM, diabetes mellitus; HTN, hypertension; PAD, peripheral arterial
disease.
* Based on BP target <130/80 mmHg

Wong et al. Arch Intern Med 2007;167:2431-2436

20

Uncontrolled hypertension carries the same CV

risk as untreated hypertension
Third National Health and Nutrition Examination Survey (NHANES III)

Not treated

48%
(n = 2,458)

BP
uncontrolled

35%
(n = 1,756)

BP controlled

17%
(n = 872)

Gu Q, et al. Am J Hypertens 2009; doi:10.1038/ajh.2009.191

Both are at equally

increased risk compared
with controlled BP
(p>0.05)

21

Patients with BP control (%)

The Minority of Patients Achieve

BP Control on Monotherapy

BP < 140/90 mmHg

22 Dickerson et al. Lancet. 1999:353:20082013.

BP < 135/85 mmHg

22

The Majority of Hypertensive Patients Need

Combination Therapy to Achieve BP Goals
Trial (SBP achieved)
ASCOT-BPLA (137 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)
1
2
3
4
Average number of antihypertensive medications
Bakris et al. Am J Med. 2004;116(5A):30S38S;

23 Dahlf et al. Lancet. 2005;366:895906.

23

ESH/ESC

JNC VII

Also Guidelines Acknowledge That Most Patients

Need Combination Therapy to Achieve BP Goals

NICE
JSH

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

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 Japanese Society of

Hypertension Committee for
Guidelines for the
Management of Hypertension
2009

24

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

Chobanian et al. JAMA. 2003;289:25602572; Mancia et al. Eur Heart J. 2007;28:14621536; http://www.nice.org.uk/
download.aspx?o=CG034fullguideline (accessed January 2010); Ogihara et al. Hypertens Res. 2009;32:3107.

24

JNC VII: Treatment Algorithm of Hypertension

Heart failure, post-MI,
coronary disease risk, diabetes,
CKD and recurrent stroke
prevention

Lifestyle modifications
Not at goal BP*

Hypertension without
compelling indications

Stage 1

Stage 2

Thiazide-type diuretics
for most. May consider
ACE-I, ARB, B, CCB or
combination

Two-drug combination
for most
(usually including
thiazide-type diuretic)

*< 140/90 mmHg or

< 130/80 mmHg for
those
with diabetes or CKD

Hypertension with
compelling indications

Drug(s) for the

compelling indications
Other antihypertensive
drugs (diuretics, ACE-I,
ARB, B, CCB) as
needed

If not at goal, optimize dosages or add additional drugs until goal BP is achieved.
Consider consultation with hypertension specialist
25 Chobanian et al. JAMA. 2003;289:25602572.

25

ESH/ESC: Treatment Algorithm of Hypertension

Consider: BP level before treatment /absence or presence
of target organ damage and risk factors
- Mild BP elevation
- Low/moderate CV risk
- Conventional BP target

- Marked BP elevation
- High/very high CV risk
- Lower BP target

Low-dose single agent

Low-dose two-drug combination

Not at BP goal
Full dose of
single agent

Switch to
different agent
at low dose

Full dose of
two-drug
combination

Add a
third drug
at low dose

Not at BP goal
Two/three-drug
combination
at full dose

Full-dose
single agent

26 Mancia et al. Eur Heart J. 2007;28:14621536.

Full doses of
two/three-drug combination

26

NICE: Treatment Algorithm of Hypertension

Step 1

< 55 y

55 y or Black
patients at any age

ACE-I (or ARB*)

CCB or thiazidetype diuretic

Step 2

ACE-I (or ARB*) + CCB or

ACE-I (or ARB*) + thiazide-type diuretic

Step 3

ACE-I (or ARB*) + CCB + thiazide-type diuretic

Step 4

Add further diuretic therapy, or -blocker or B.

Consider seeking specialist advice

* If ACE-I not tolerated

27

http://www.nice.org.uk/download.aspx?o=CG034fullguideline (accessed January 2010).

27

Reappraisal of ESH/ESC Guidelines Suggests Four Preferred

Antihypertensive Drug Classes
2009

2007

Diuretics

Diuretics
B

ARB

ARB

ONTARGET
ACCOMPLISH
HYVET

CCB

CCB

-blockers
ACE-I

ACE-I

Most rational combinations

Combinations used as necessary
28

Mancia et al. Eur Heart J. 2007;28:14621536;

Mancia et al. J Hypertens. 2009;27:21212158.

28

Advantages of Multi-Drug Therapy In

HT

Increased efficacy of each drug versus either as

monotherapy
Complimentary mechanisms of action
More prompt achievement of goal BP
Reduced adverse effects of both clinical and
metabolic
Alterations of pharmacodynamics possibly
allowing for longer duration of action
Broader spectrum of response
If given as fixed dose combination potiential for
improved adherence to therapy
29

Advantages of fixed dose combinations as

antihypertensive therapy
Simplification

of regime
Improved adherence
Reduced pill burden

30

31

Treatment adherence is highest with ARBs

Diuretics

1.83

Total n = 445,356

-blockers

1.64

-blockers

1.23

Calcium channel blockers

1.08

ACE inhibitors

1.00

ARBs

0.92
0.5

1.0

2.0

Cause-specific hazard ratio (95% CI) for discontinuation*

* Relative to ACE inhibitors after 1 year of treatment
ARB, angiotensin II receptor blocker; CI, confidence interval
Corrrao et al. J Hypertens 2008;26:819-24.

32

The RAS - the

cornerstone in modern
antihypertensive therapy

33

Telmisartan
A Unique ARB
Novel AT1 receptor
antagonist
34

Telmisartan has a different structure which explains its

unique pharmacology

Ries et al. J Med Chem 1993;36:40404051

35

Telmisartan is the Most Studied Amongst ARBs in Mortality and

Morbidity Endpoint Trials
51,878

Number of patients

44,264

19,335
12,565
1,405
Eprosartan
MOSES1

4,449
Olmesartan
ROADMAP2

6,405
Irbesartan

Losartan

Valsartan

Telmisartan

IRMA II3

SCOPE6

RENAAL8

Val-HeFT12

TRANSCEND16

IDNT4

CHARM7

ELITE II9

NAVIGATOR13

PRoFESS16

I-Preserve

36

Candesartan

OPTIMAAL10

VALIANT

LIFE11

VALUE15

1. Schrader et al. Stroke. 2005;36:12181226; 2. http://www.roadmapstudy.org/resident.aspx; 3. Parving et al. N Engl J Med. 2001;345:870878; 4. Lewis et al. N Engl J Med. 2001;345:851860; 5.
Carson et al. J Card Fail. 2005;11:576585; 6. Papademetriou et al. J Am Coll Cardiol. 2004;44:11751180; 7. www.atacand.com; 8. Brenner et al. N Engl J Med. 2001;345:861869; 9. Pitt et al.
Lancet. 2000;355:15821587; 10. Dickstein et al. Lancet. 2002;360:752760; 11. Dahlof et al. Lancet. 2002;359:9551003; 12. Cohn et al. N Engl J Med. 2001;345:16671675; 13.
www.novartis.com; 14. Pfeffer et al. N Engl J Med. 2003;349:18931906; 15. Julius et al. Lancet. 2004;363:20222031; 15. www.ontarget-micardis.com.

14

ONTARGET16

36

Telmisartan
Mechanism Of action

Telmisartan prevents the effects of angiotensin II by

selectively blocking the binding of angiotensin II to the AT1
receptors in many tissues, such as
vascular smooth muscle
adrenal gland

Lowers PVR and preload- lowering of BP

Its action is therefore independent of the pathways for

angiotensin II synthesis

Telmisartan produces more complete inhibition of RAAS as

compared to ACE inhibitors
37

Telmisartan has long half life : 24 hours

9
24
10-15

Losartan

11-15

Irbesartan

5-9

Eprosartan

10

Telmisartan
Olmesartan

2.5-9

Valsartan

Candesartan
15

20

25

High affinity towards AT1 receptor (telmisartan > olmesartan > candesartan >
valsaratan > losartan)
Very slow dissociation rate
Long terminal half-life supports a once-daily dosing regimen and suggests that
drug concentrations do not decline below therapeutic levels even if a dose is
delayed
These unique properties of Telmisartan ensure improved 24- hr control of blood
pressure as compared to other ARBs
Goodman & Gilman p 812-813 11th edition
38

Telmisartan

Additional Beneficial Metabolic effects:

Telmisartan is a partial agonist of PPAR (perioxisome
proliferators activated receptor ), that plays a role in the
regulation of carbohydrate and lipid metabolism

Improves insulin sensitivity

Decreases adipocyte cell size

Decrease hepatic fat storage

39

Telmisartans unique pharmacology among ARBs

range

Volume of distribution (L)

Eprosartan
500

LoValCande- Olme- Irbe- Telmisartan sartan sartan sartan sartan sartan

Most lipophilic within ARB class

(high tissue penetration)

range

Cande- Olme- ValLoIrbeEpro- Telmisartan sartan sartan sartan sartan sartan sartan

Highest receptor affinity

within ARB class

Active metabolite EXP 3174

Valsartan
PPAR fold activation

Plasma half life (h)

Longest plasma half life

within ARB class

Receptor dissociation
half life (min)

Longest half life, Highest receptor affinity, Highest tissue penetration and selective PPAR
activation

Losartan

Candesartan

Olmesartan

Telmisartan

Highest selective PPAR

activation within ARB class

Telmi- Irbe- Cande- ValOlme- Epro- EXP 3174

sartan sartan sartan sartan sartan sartan (Losartan)

Burnier M. & Brunner H.R., Lancet 2000;355:637645; Brunner H.R., J Hum Hypertens 2002;16(Suppl
2):S13S16; Kakuta H., et al. Int J Clin Pharmacol Res 2005;25:4146; Wienen W., et al. Br J
Pharmacol 1993;110:245-252; Song J.C. & White C.M., Formulary 2001;36:487499; Asmar,R., Int J
Clin Pract. 2006;60:315-320; Israili,Z.H., J Hum.Hypertens. 2000;14 Suppl 1: S73-S86; Benson S.C. et
al. Hypertension 2004;43:9931002

40

Telmisartan

INDICATIONS
Telmisartan is indicated for the treatment of hypertension
US FDA has approved it for the reduction of the risk of
myocardial infarction (heart attack), stroke, or death from
cardiovascular (CV) causes in patients 55 years of age or
older at high risk of developing major CV events who are
unable to take ACE inhibitors
European Commission has approved telmisartan for the
reduction of cardiovascular morbidity in patients with:
I. manifest atherothrombotic cardiovascular disease (history
of coronary heart disease, stroke, or peripheral arterial
disease) or,
II. type 2 diabetes mellitus with documented target organ
damage.

Telmisartan is the first treatment in its class to be approved for this indication.
41

Telmisartan has an excellent safety and tolerability

profile
Incidence of AEs per patient-year

< 65 year
(n = 921)

65 year
(n = 246)

Placebo

< 65 year
(n = 3817)

65 year
(n = 1196)

Telmisartan

Schumacher H and Mancia G. Blood Press 2008;17(Suppl 1):32-40

< 65 year
(n = 1444)

65 year
(n = 399)

Telmisartan/HCTZ

42

ONTARGET Trial
Blood Pressure Control:
Mean blood pressure was lower in both the
telmisartan group (a 0.9/0.6 mm Hg greater
reduction) and the combination-therapy group (a
2.4/1.4 mm Hg greater reduction) than in the ramipril
group.
N Engl J Med 2008;358:1547-59
43

ONTARGET

As compared with the ramipril group,the telmisartan group had lower

rates of cough (1.1% vs. 4.2%, P<0.001) and angioedema
(0.1% vs. 0.3%, P = 0.01)

44

N Engl J Med 2008;358:1547-59

ONTARGET
Conclusion:

Telmisartan was equivalent to ramipril in patients

with vascular disease or highrisk diabetes and
was associated with less angioedema.

N Engl J Med 2008;358:1547-59

45

The Telmisartan Randomised Assessment

Study in ACE intolerant subjects with
cardiovascular Disease (TRANSCEND)
Results

Mean blood pressure in Telmisartan group lower

than placebo through out the study period

Primary Outcome:Fewer patients in the telmisartan

group experienced the primary composite outcome
of cardiovascular death,myocardial infarction, stroke,
or hospitalisation for heart failure than did patients in
the placebo group( 15.7% vs 17% )
46
Lancet 2008; 372: 1174-1183

The Telmisartan Randomised Assessment

Study in ACE intolerant subjects with
cardiovascular Disease (TRANSCEND)

Hospitalized cardiovascular reason: Fewer patients

were hospitalised for cardiovascular reasons in the
telmisartan group than in the placebo group ( 30.3%
vs 33%, p =0.025)

Fewer permanent discontinuations in Telmisartan

group than in placebo group (216%vs 238%
p=0055)

Lancet 2008; 372: 1174-1183

47

The Telmisartan Randomised

Assessment Study in ACE intolerant
subjects with cardiovascular Disease
(TRANSCEND)
Conclusion
Telmisartan well tolerated in patients unable to
tolerate ACE inhibitors
Modestly reduced risk of composite outcome of
cardiovascular death, myocardial infarction, or
stroke

1 Lancet 2008; 372: 1174-1183

48

Telmisartan is the Only ARB Indicated for CV Protection in CV High-risk

Patients
Based on the Data From The ONTARGET Trial Program

LoEprosarta
sartan
n

Hypertension
- Treatment of renal disease
- Prevention of stroke in LVH

Irbesartan

Olmesartan

Valsartan

Candesartan

Telmisartan

CV high risk
Atherothrombotic CV
disease such as:

- Coronary heart disease

- Peripheral vascular
disease

- Stroke

Type

2 diabetes with
target organ damage

Heart failure or LV
dysfunction

49 Product information provided by EMA (http://www.emea.europa.eu) and eMC (http://emc.medicines.org.uk).

49

Clinical Evidence With ARBs AFTER ONTARGET

CV high risk
ONTARGET trial programme

Heart failure
Hypertension

MI and
stroke

LIFE
VALUE

Microalbuminuria

Atherosclerosis
and LVH
Endothelial
dysfunction

Risk factors:
hypertension, diabetes,
obesity, smoking, age

50

VALIANT
CHARM
Val-HeFT
ELITE II

Remodelling

Macroproteinuria

Ventricular dilation/
cognitive dysfunction

Nephrotic
proteinuria

ESRD

Dzau et al. Circulation. 2006;114:28502870; Dzau, Braunwald. Am Heart J. 1991;121:12441263;

Yusuf et al. Lancet. 2004;364:937952; The ONTARGET Investigators. N Engl J Med. 2008;358:15471559.
.

CHF/
secondary stroke

Cardio/
cerebrovascular
death

50

Telmisartan vs. Olmesartan

Parameters

Telmisartan

Olmesartan

24 hr control of BP*

Complete 24 hr control of BP Incomplete 24 hr control

Covers early morning hour
of BP

Trough Peak Ratio

66 -100 %

60 -80%

PPAR Agonistic Present therefore Improves Absent

activity
insulin sensitivity and lipid
profile
Lipophilicity

More Lipophilic
tissue penetration
better inhibition
RAAS

so
and
of

Renal Insufficiency

No dosage adjustment

better
hence
tissue

Less lipophilic so less

inhibition
of
tissue
RAAS.

20 mg maximum in
severe disease
51

Telmisartan plus HCTZ12.5 is superior to Valsartan plus HCTZ12.5 in

24 hour ABPM reduction

SBP change from baseline (mmHg)

***

***

***

***

***
12.5 mg (n=412)
12.5 mg (n=428)

***p < 0.001 vs Valsartan + HCTZ

Sharma AM, et al. Cardiovasc Diabetol 2007;6(1):28

52

AMLODIPINE

53

Amlodipine (DHP-CCB): Mode of Action

Inhibits

the transmembrane influx of

calcium ions into vascular smooth muscle
and cardiac muscle

Inhibition is selective, with a greater effect on

vascular smooth muscle cells

Is

a peripheral arterial vasodilator

Acts

directly on vascular smooth muscle

leading to a reduction in peripheral vascular
resistance and a subsequent reduction in
BP

54 Murdoch, Heel. Drugs. 1991;41:478505.

54

Effects of CCB on BP Regulation

CCBs

inhibit SNS-induced vasoconstriction by

blocking influx of calcium ions (needed for
contraction) through voltage-gated calcium
channels
Vasodilation2,3

Other

effects: natriuresis; inhibition of

aldosterone release; interference with
angiotensin II-mediated vasoconstriction3

55

1. Mancia et al. J Hypertens Suppl. 2006;24(1):S51S56; 2. Robertson and Robertson. In: Hardman JG, Limbard JG, eds-in-chief. Goodman
& Gilmans The Pharmacological Basis of Therapeutics. 9th ed. 1996. p759779; 3. Prisant. In: Oparil S, Weber MA,
eds. Hypertension: Companion to Brenner & Rectors The Kidney. 2nd ed. 2005. p683704.

55

Plasma elimination half-life (h)

Amlodipine has the Longest Plasma Elimination Half-life in

its Class (CCB)

Lercanidipine

Nifedipine

56 Based on available online product information.

Nimodipine

Nisoldipine

Nicardipine

Felodipine

Lacidipine

Amlodipine

56

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

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

BP

Synergistic
BP reduction
Complementary
clinical benefits

57

Mistry et al. Expert Opin Pharmacother. 2006;7:575581;

Sica. Drugs. 2002;62:443462; Quan et al. Am J Cardiovasc Drugs. 2006;6:103113.

CCB
RAS activation
No renal or CHF
benefits

57

CCB + ARB:
The Synergies of Counter-Regulation (2)
CCB
Arteriodilation
Peripheral oedema
Effective in low-renin patients
Reduces cardiac ischaemia

ARB
Venodilation
Attenuates peripheral oedema
Effective in high-renin patients
No effect on cardiac ischaemia

58

BP

Synergistic
BP reduction
Complementary
clinical benefits

Mistry et al. Expert Opin Pharmacother. 2006;7:575581; Sica. Drugs. 2002;62:443462;

Quan et al. Am J Cardiovasc Drugs. 2006;6:103113.

ARB
RAS blockade
CHF and renal
benefits

CCB
RAS activation
No renal or CHF
benefits

58

Telmisartan Plus Amlodipine

as Initial Therapy

59

59

Telmisartan Plus Amlodipine Provides Consistent BP Reductions Across

HTN Severities
Moderate HTN
Baseline SBP = 160 < 1701

(n = 13)

180 < 1902

(n = 305)

190 < 2002

(n = 71)

Mean SBP reductions from

baseline (mmHg)

(n = 31)

170 < 1801

Severe HTN

T80/A10 (n = 1361; n = 3792)

60

1. Littlejohn et al. J Clin Hypertens. 2009;11:207213; 2. Neutel et al. J Clin Hypertens. 2010: In press; ASH 2010
poster presentation (LB-PO-10) & data on file

60

Telmisartan Plus Amlodipine Provides BP Reductions of 50 mmHg in

Almost 50% of Patients With Severe HTN*
T80/A10

Patients (%)

A10

(n = 65)

(n = 183)

(n = 37)

(n = 117)

(n = 20)

(n = 61)

55 mmHg
60 mmHg
50 mmHg
Mean SBP reductions from baseline*
* Mean baseline BP = 185.4/103.2 mmHg
61 Neutel et al. J Clin Hypertens. 2010: In press; ASH 2010 poster presentation (LB-PO-10).

61

Telmisartan Plus Amlodipine Provides Consistently High BP Reductions in

Hypertensive at-Risk Patients

Diabetic

Obese
BMI 30kg/m1
(n = 175)

Metabolic
syndrome1*
(n = 36)

Elderly
65 y1

Black

(n = 100)

(n = 30)

Severe HTN
180/95 mmHg2
(n = 379)

Mean SBP reductions from

baseline (mmHg)

(n = 62)

T80/A10
Mean baseline BP = 185.4/103.2 mmHg
* Diabetes, obesity (BMI 30kg/m2), and HTN
62

1. TEAMSTA Severe HTN study (data on file; Boehringer Ingelheim Pharmaceuticals, Inc);
2. Neutel et al. J Clin Hypertens. 2010: In press; ASH 2010 poster presentation (LB-PO-10).

62

Telmisartan/Amlodipine Provides 80% of its Maximum Effect After Just

2 Weeks of Treatment
Mean SBP reduction (mmHg)

Mean SBP (mmHg)

185.4

T80/A5

T80/A10

(n = 405)

(n =379)

Baseline

80%*
147.7
137.9

37.9 mmHg

Week 2

47.5 mmHg

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
63 Neutel et al. J Clin Hypertens. 2010: In press; ASH 2010 poster presentation (LB-PO-10).

63

Telmisartan Plus Amlodipine

24-h ABPM

64

64

Telmisartan Plus Amlodipine Provides Superior 24-h ABPM Goal Rate

Achievement (< 130/80 mmHg*) in > 82% of Patients

Patients achieving 24-h

ABPM goal* (%)

p < 0.0001

A10

T80/A10

(n = 58)

(n = 52)

* AHA criteria for 24-h BP goal

65 Littlejohn et al. J Hypertens. 2008;26(suppl 1):S494; White et al. Blood Press Monit. 2010: In press.

65

Telmisartan Plus Amlodipine

Safety and Tolerability

66

66

Patients with
AEs > 1% incidence (%)

Telmisartan Plus Amlodipine Has a Safety and Tolerability

Profile Similar to Placebo

Placebo (n = 46)

Fatigue Oedema Sinusitis

67 Littlejohn et al. J Clin Hypertens. 2009;11:207213.

A mono (n = 319)

NasoUpper Influenza
pharyn- respiratory
gitis
tract
infection

T/A (n = 789)

Back
pain

Dizziness

Headache Peripheral
oedema

67

Venous Fluid Leakage Induced by CCBs

Fluid leakage

Arterial
dilation
(CCBs)

No
venous
dilation

Fluid leakage
Capillary bed

68

Opie et al. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:4273; White et al. Clin Pharmacol Ther.
1986;39:4348; Gustaffson. J Cardiovasc Pharmacol. 1987;10:S121S131.

68

 Gets Reduced by Co-administration of

ARBs

Arterial
dilation
(CCB and
ARB)

Venous
dilation
(ARB)

Capillary bed

69

Opie et al. In: Opie LH, editor. Drugs for the Heart. 3rd ed. 1991:4273; White et al. Clin Pharmacol Ther. 1986;39:4348;
Gustaffson. J Cardiovasc Pharmacol. 1987;10:S121S131; Messerli et al. Am J Cardiol. 2000;86:11821187.

69

Telmisartan significantly reduces peripheral oedema associated with

Amlodipine

Incidence of peripheral oedema (%)

* p <0.05; p <0.0001
Littlejohn TW et al. J Clin Hypertension. 2009;11(4):207-213

70

Telmisartan Plus Amlodipine is Associated With Less Peripheral Oedema Compared

With Amlodipine 10 mg
p < 0.0001

Patients with peripheral

oedema (%)

p < 0.0001

A10
(n = 124)

71 Littlejohn et al. J Clin Hypertens. 2009;11:207213.

90%

71%

T4080+A5

T4080+A5A10

(n = 264)

(n = 543)

71

Telmisartan + Amlodipine Data Conclusion

Fast

and superior BP reductions of > 31 mmHg (SBP) already after 1

week of treatment1
Up to 80% of maximum effect already after 2 weeks of treatment 1
Consistent and strong BP reductions of up to 49.5 mmHg (SBP) across
hypertension severities and a wide range of hypertensive at-risk
(complex) patients1
SBP reduction of 50 mmHg in almost 50% of patients with baseline
SBP 180 mmHg1
High BP response rates of up to 99.7% of patients1
Superior and dose dependent 24-h ABPM reductions
Superior 24-h ABPM goal rate achievement (< 130/80 mmHg) of >
82%2,3
Superior efficacy and safety in patients not at goal with amlodipine 4
A safety and tolerability profile similar to placebo, with up to 90% lower
oedema rates compared with A10 monotherapy5

72

1. Neutel et al. J Clin Hypertens. 2010: In press; 2. White et al. Blood Press Monit. 2010: In press; 3. Littlejohn et al. J Hypertens.
2008;26(suppl 1):S494; 4. Neldam, Lang. J Clin Hypertens. 2009;11(Suppl s1):114 (P279); 5. Littlejohn et al.
J Clin Hypertens 2009:11:207213.

72

TRIPLE DRUG COMBINATION

FOR HT
TELLZY-AH

73

Considerations of (Single-Pill) Combination Therapy

Benefits

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
effective due to complementary mode of action3,4
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

Patients

Most hypertensive patients will require two or more agents to achieve

target BP1,2

Combinations

Drugs should have a complimentary mechanism of action2

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

Limitations

Loss of flexibility with single-pill combinations 2

1. Chobanian et al. Hypertension. 2003;42:12061252; 2. Mancia et al. Eur Heart J. 2007:28:14621536;

74 3. Tedesco et al. J Clin Hypertens. 2006;8:634641; 4. Wald et al. Am J Med. 2009;122:290300.

74

Telmisartan/Amlodipine/Hydrochlorothiazide
Parameter

Telmisartan

Amlodipine

HCTZ

Tellzy-AH

MOA

AT1 Receptor
Blocker

Block the L
type calcium
channels

Diuretic

Complementary
effect

Pre load ( Blood

Volume)

Decrease

--------------

Decrease

Additive effect

After Load
(PVR)

Decrease

Decrease

Decrease

Additive effect

RAAS

Suppression

Activation

Activation

Neutral effect

Dosing

OD

OD

OD

OD

75

Telmisartan/Amlodipine/Hydrochlorothiazide
Parameter

Telmisartan

Amlodipine

HCTZ

Tellzy-AH

Renin Levels

Decrease

Increase

Increase

No Change

Potassium
Levels

Increase

No change

Decrease

No Change

Edema

Decreased

Increased

No Change

Less effect

Reflex
Tachycardia

No change

May be
present

No change

Less effect

No Risk of Electrolytic imbalance

Improved tolerability
Matching Pharmacokinetics
Additive Antihypertensive action
Very well tolerated improved patient compliance
Improved quality of life
Reduced pill burden

76

Conclusions

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 + CCB + Diuretic combination exhibit complementary and synergistic MoA with high BP
reductions and a good safety and tolerability profile

ARB + CCB + Diuretic combinations are favorable in hypertensive patients at-risk

Tellzy-AH (Telmisartan + Amlodipine + Hydrochlorothiazide) 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 excellent safety and tolerability profile

All 3 components have a huge clinical evidence-based database for CV protection, and
Telmisartan is the only ARB with a CV protection indication

77

77

Thank You
78