Protecting patients with hypertension

How to maximize patient benefit ?

Pr Roland Asmar

How to maximize patient benefit

Goals of
Antihypertensive Treatment
ESH/ESC 2007

< 140/90
mmHg

Hypertensive
patients
Diabetes
Patient at high
risk

< 130/80
mmHg

How to maximize patient benefit

Worldwide Blood Pressure Control in

Treated Hypertensive Patients
Canada
41.0

USA
53.1
Mexico
21.8

Turkey
19.8

Germany
33.6

England
29.2
Greece
49.5

Japan
55.7

China
28.8
Taiwan
18.0

Spain
38.8
Egypt
33.5
South
Africa
47.6

Italy
37.5

How to maximize patient benefit

Kearney et al. J Hypertens 2004; 22: 11

HOT: Need for Combination Therapy

How to maximize patient benefit

Hansson et al., Lancet 1998, 351: 1755-62

Percentage of Patients with Combination

Treatment in Clinical Trials
VA
HDFP
ANBPS
MRC-1
IPPPH
MAPHY
HAPPHY
EWPHE
COOPE
STOP-1
SHEP
MRC II
Syst-Eur
HOT
Syts-China
IDNT
RENAAL
LIFE
INSIGHT
CONVINCE

100

47

33
34

46

35

45
41

70

49

66
51
68
66
68

20

84

65

30

93

70

40

How to maximize patient benefit

60

80

100 %

ESH/ESC Guidelines - 2007

Pharmacological Rationale
for Combination Therapy

How to maximize patient benefit

Rationale for Combination Therapy

Increase Efficacy
Synergistic & additive effects on BP
Effects on several patho-physiological mechanisms
of HT
Inhibition of the contra-regulation mechanisms
Decrease Side effects
Inhibition of the contra-regulation
Low dose
Decrease dose-dependent
side effects

How to maximize patient benefit

Advantages of Combination Therapy

Efficacy

How to maximize patient benefit

Rationale of Combination Therapy

Pathogenetic Mechanisms in Hypertension
Patient A
Patient C

Patient B

Sympathetic nervous system

Renin-angiotensin system
Total body sodium
Waeber B. 2004

How to maximize patient benefit

11

Titration vs. Combination

Diastolic BP

How to maximize patient benefit

Frishman WH et al,Arch Intern Med 1994;154:146112

Efficacy: Up-titration vs Combination

V80
V80 HCT12.5 Ol20 Ol40

Change in SBP (mm Hg)

T40 T80

T40
T40 HCT12.5 V80 V160

How to maximize patient benefit

13

O20
Ol20 HCT12.5

Value of combination treatment: analysis of

354 randomised placebo controlled trials
Effects of two different drugs on BP separately and in combination (results from 119 trials)
Treatment
Observed
First drug alone
Second drug alone
Both drugs together
Expected
Sum of first and second drugs alone
Difference between observed and
expected (95% CI)

SBP

DBP

7.0 (0.4)
8.1 (0.3)
14.6 (0.5)

4.1 (0.3)
4.6 (0.3)
8.6 (0.4)

15.1
-0.5 (-1.4 to 0.4)

8.7
-0.1 (-1.0 to 0.8)

How to maximize patient benefit

Law MR BMJ 2003

14

Advantages of Combination
Therapy

Side
Effects
How to maximize patient benefit

15

Effect of ARB and HCTZ on Serum

Potassium

Adjusted
mean
from baseline
at 8 weeks
(mEq/L)

300
100
37.5
0

6.25

12.5

ARB dose
(mg/d)

25

HCTZ dose (mg/d)

How to maximize patient benefit

16J Hypertens. 1999;12:797

Kochar M, et al. Am

Drug related symptoms: comparison

between monotherapy & combination
50 trials testing drugs of two different categories separately and in combination,

SYMPTOMS
Single drugs

5.2% (3. To 6.6)

Two drugs

7.5% (5.8 to 9.3)

Expected adding
2 drugs
How to maximize patient benefit

10.4%
BMJ 2003;326:1427

17

Advantages of Combination
Therapy

Convenience

How to maximize patient benefit

18

Fixed-dose Combination Therapy

Increases Compliance to Treatment

Persistence (%)

Persistence rates of one pill of lisinopril/HCTZ in fixed-combination vs

two separate pills of lisinopril and HCTZ
100
95
90
85
80
75
70
65
60
55
50

Lisinopril/HCTZ (1 pill)
Lisinopril and HCTZ (2 pills)

68.7
18.8%
57.8
0

10

11 12

Dezii CM. Manag Care 2000; 9 : s2

Months

Advantages of Combination
Therapy

Equal
efficacy?
How to maximize patient benefit

20


Hypertension
in control
special
Blood pressure
with ARBs patient
and in Fixed Dosepopulations
Combination
ARBs-FDC
Protocol

Endpoints
Primary

endpoint

Changes from baseline in SBP during

last 6 hours of dosing interval using
ABPM

Secondary
n=294

n=160

n=297

endpoints

Changes from:
Baseline in DBP during the last
6 hours of dosing interval
Baseline in pulse pressure during the
last 6 hours of dosing interval
Baseline in the 24-hour mean SBP
and DBP

Neutel JM, et al. Hypertens Res 2005;28:555

ABPM Comparison of
Telmisartan HCTZ & Losartan HCTZ
Parallel Group Comparison after 6 weeks Therapy
Time after dosing (h)
2

Change from baseline (mmHg)

-8

-12

10

14

18

Time after dosing (h)

2

22

10

14

18

22

-6

Systolic BP
Telmisartan 80mg + HCTZ 12.5mg
Telmisartan 40mg + HCTZ 12.5mg
Losartan 50mg + HCTZ 12.5mg

Diastolic BP
-8

-10
-16
-12
-20
-14
-24

-16
How to maximize patient benefit

Neutel et al. Hypertens Res. 2005;28:555 22


Study of telMisartan On Obese/overweight Type2 diabetics with Hypertension

Protocol

Endpoints
Primary

endpoint

Changes from baseline in SBP during

last 6 hours of dosing interval using
ABPM

Secondary

endpoints

Changes in other ABPM-derived

parameters
Changes in trough cuff SBP and
DBP
Metabolic blood markers
(e.g.cholesterol)
Urine markers (e.g. proteinuria)

Sharma AM, et al. Cardiovascular Diabetology. 2007;6:28

Telmisartan + HCTZ vsValsartan + HCTZ

SBP change from baseline (mmHg)

Powerful 24 hr SBP reductions

***

***p < 0.001 T + H vs V + H 24-hour and last 6-hour mean SBP

How to maximize patient benefit

Sharma et al. Hypertension 2005;46:89824

Telmisartan 80mg/HCTZ 12.5 mg vs

Olmesartan 20mg/HCTZ12.5 mg
Systolic
BP

Diastolic
BP

How to maximize patient benefit

25

Fogari & al Current Therapeutic Research; 2008; 69


A comparison of Telmisartan plus HCTZ with amlodipine plus HCTZ in Older
patients with predominantly Systolic hypertension

Protocol

Endpoints
Primary

endpoint

Changes from baseline in SBP during

last 6 hours of dosing interval using
ABPM

n=497

n=503

Secondary

endpoints

Changes from:
Baseline in DBP during the last
6 hours of dosing interval
Baseline in pulse pressure during the
last 6 hours of dosing interval
Baseline in the 24-hour mean SBP
and DBP

Neldam S, et al. AJGC 2006;15:151-60.

How to maximize patient benefit

Neldam S, et al. AJGC 2006;15:151-60. 27

Telmisartan
in combination
HCTZ 25 mg

How to maximize patient benefit

28

Comparison of Telmisartan HCTZ

& Valsartan HCTZ
Change in clinic trough BP from baseline after 8 weeks therapy

Change from baseline (mmHg)

Systolic BP

Diastolic BP

-5

-10

-15

-20

-25

-1.8 (-3.0, - 0.6) p<0.02

-2.8 (-4.6, -1.0) p<0.004

How to maximize patient benefit

Telmisartan-HCTZ 80/25mg (n=467)

Valsartan-HCTZ 160/25mg (n=479)
Placebo (n=120)
29
White et al. J Hypertens
Suppl. 2003;21:S9-15.

Comparison of Telmisartan HCTZ

& Valsartan HCTZ

Change in clinic trough BP from baseline after 8 weeks therapy

How to maximize patient benefit

30al BP Monitoring 2008, 13:21

White W &

AIIA + CCB

How to maximize patient benefit

31

Composed end-point comparing a fixed

combination of a CCB +ACEI vs a thiazide+ACEI
ACCOMPLISH Trial

Incidence of eventos

HR: 0,80; IC 95%: 0,72 0,90

Time for events

How to maximize patient benefit

Jamerson K et al. NEJM; 2008; 359:2417

32

ASCOT - Summary of all end points Unadjusted Hazard

ratio (95% CI)
0.90 (0.79-1.02)

Primary
Non-fatal MI (incl silent) + fatal CHD
Secondary
Non-fatal MI (exc. Silent) +fatal CHD
Total coronary end point
Total CV event and procedures
All-cause mortality
Cardiovascular mortality
Fatal and non-fatal stroke
Fatal and non-fatal heart failure
Tertiary
Silent MI
Unstable angina
Chronic stable angina
Peripheral arterial disease
Life-threatening arrhythmias
New-onset diabetes mellitus
New-onset renal impairment

0.87 (0.76-1.00)
0.87 (0.79-0.96)
0.84 (0.78-0.90)
0.89 (0.81-0.99)
0.76 (0.65-0.90)
0.77 (0.66-0.89)
0.84 (0.66-1.05)
1.27 (0.80-2.00)
0.68 (0.51-0.92)
0.98 (0.81-1.19)
0.65 (0.52-0.81)
1.07 (0.62-1.85)
0.70 (0.63-.078)
0.85 (0.75-0.97)

Post hoc
Primary end point + coronary revasc procs
CV death + MI + strok

0.86 (0.77-0.96)
0.84 (0.76-0.92)

e
0.50

0.70

1.00

Amlodipine perindopril better

1.45

2.00

Atenolol thiazide better

The area of the blue square is proportional to the amount of statistical information
How to maximize patient benefit

33

Chemical structures
Telmisartan and other angiotensin II antagonists

Losartan Valsartan
Irbesartan
Candesartan
Olmesartan
(active form)
(active form)
(active form)
H3C

CI

CO2H

CO2H

OCH2CH3

CH3
OH

COOH

COOH

N
N
N NH

N
N
N NH

N
N
N NH

N
N
N NH

N
N
N NH

Telmisartan
CH3

CH3

OH

CH3

How to maximize patient benefit

34

Dissociation Half-Lives of ARBs

from Human AT1 Receptors
Telmisartan

95% CI
202-226 min

Olmesartan

151-184 min

Candesartan

121-149 min

Valsartan

60-83 min

Losartan

60-77 min

EXP3174

73-91 min
0

50

100

150

200

250

Dissociation half-life (min)

How to maximize patient benefit
Kakuta et al. Int J Clin Pharmacol Res. 2005;25:41-6.

35

Selective Nuclear Hormone

Receptor Modulation
Peroxisome Proliferator-Activated Receptor Gamma (PPAR ) interaction

Pioglitazone
Full Agonists

Rosiglitazone

Telmisartan
Selective Modulation
Selective Peroxisome Proliferator-Activated
Receptor Gamma Modulators (SPPARMS)

PPAR

Insulin Sensitivity
NO Weight Gain
NO Oedema
How to maximize patient benefit

Insulin Sensitivity
Weight Gain
Oedema
36

Difference between Thiazolodinediones & ARBs

in the Interaction with PPARReceptor

Fold Activation

150

Full Agonists

100
Partial
Agonist

50

0
rosiglitazone

pioglitazone

telmisartan

How to maximize patient benefit

irbesartan

eprosartan

37
Benson et al. Hypertension. 2004;43:993

Activation of PPAR by ARBs

25

Fold Activation

20

Telmisartan was the only ARB that activated PPAR

at concentrations (1-5 mol/l) attained in plasma with
conventional oral dosing

15
10
5
0

Telmisartan

Candesartan
Irbesartan

Olmesartan
Valsartan

How to maximize patient benefit

EXP 3174
Eprosartan

Benson et al. Hypertension. 2004;43:993.

38

Effects of Telmisartan & Losartan in

Patients with metabolic syndrome
FPG

FPI

HOMA IR

HbA1c

Change from baseline (%)

-10
P<0.05

P<0.05

P<0.06

-20

P<0.05

Telmisartan (n=20)
Losartan (n=20)

-30
How to maximize patient benefit

Vitale et al. Cardiovasc Diabetol. 2005;15:6.

39

Effects of Telmisartan and Amlodipine

on Metabolic Parameters
in Type 2 Diabetic Hypertensives
HbA1c

TG

HOMA IR

120

-2

100

-6
-8
-10
-12

FPI

Telmisartan
Amlodipine

60
40
20
0
-20
-40

-14
-16

Adiponectin

80

-4

% change from baseline

% change from baseline

FPG

**

n.s.

-60

n.s.

* p<0.05 & ** p<0.01 vs amlodipine

How to maximize patient benefit

Negro et al. JRAA 2006:243-6.

40

Effects of telmisartan on fat distribution in

individuals with metabolic syndrome
Change in the Visceral Fat Area (VFA)

Change in waist circumference

300

100

+10%
p=0.046

+3%
Waist circumference (cm)

VFA cm

250

-12%
p=0.008

200

150

100

50

-5%

98

96

94

92

90

Amlodipine

Telmisartan
Baseline

How to maximize patient benefit

Amlodipine

Telmisartan

24 wks treatment
Shimabukuro, J Hypertens 2007;25:841
41

Comparative
Cardio-Metabolic Studies with Telmisartan
Trial

Patients

Duration
(weeks)

Comparator
Agent(s)

BP
differential

Improved
Insulin
Sensitivity

Improved
Lipid
Profile

Anti-oxidant/
Inflammatory
Action

Derosa 2004a

HT, T2DM

119

52

Eprosartan/Placebo

No (P yes)

No

Yes

Derosa 2004b

HT, T2DM

116

52

Nifedipine GITS

No

No

Yes

Vitale 2005

HT, MS

40

12

Losartan

Yes?

Yes

Miura 2005

HT, T2DM

18

12

Candesartan/Valsartan

No

Yes

Yes

Yes

Koulouris 2005

NT, T2DM

40

12

Ramipril

No

No

No

Yes

Honjo 2005

HT, T2DM

38

12

Candesartan

Yes

HT

37

Nisoldipine

No?

Yes

Negro 2006a

HT, T2DM

40

16

Amlodipine

No

Yes

Yes

Negro 2006b

HT, obese,IR

46

26

Irbesaratn

No

Yes

Yes

Bahadir 2007

HT, MS

42

10

Losartan

No?

Yes?

No

Derosa 2007

HT, T2DM

188

52

Irbesartan

No

Yes

Yes

Yes

Sharma 2007

HT, obese

840

10

Valsartan HCTZ

Yes

No

No

Benndorf 2006

How to maximize patient benefit

42

Conclusions
Use of more than one agent is necessary to achieve
target BP in the majority of patients.
Combination therapy is related with a higher BP
reduction and CV protection
Fixed combinations of two drugs can simplify
treatment schedule and improve compliance and
tolerability.
A combination of two drugs should be preferred as
first step treatment when initial BP is in the grade 2
or 3 range or total cardiovascular risk is high or very
high
Are all the combination therapies equipotent

Backup

How to maximize patient benefit

44

Combination Therapy
Study / Drugs

BP

Mo- Mort

STOP 2

Old/Recent

BACRI

ARB + HCTZ /
ACEI + Verap

NA

INVEST

BB + HCTZ /
Verap + ACEI

EXFORGE

ARB + CCB /
ACEI + HCTZ

ou

NA

ASCOT

BB + HCTZ /
ACEI + CCB

ou

LIFE

BB + HCTZ /
ARB + HCTZ

ACCOMPLISH

ACEI + HCTZ /
ACEI + CCB

ONTARGET

ACEI + ARB /
ACEI

Side effects ++

How to maximize patient benefit

45

The HOT Study:

CV Risk Reduction in Diabetics

major CV events/1000 patient.y

25
p < 0.005 for trend (n = 1501)

20
15
10
5

0
Target
Achieved

< 90 mmHg
85 mmHg

< 85 mmHg
83 mmHg

How to maximize patient benefit

< 80 mmHg
81 mmHg

Hansson L, et46al. Lancet 1998;351:175562.

Management of BP for adultsJNC VII

Initial drug therapy

SBP*
mmHg

DBP
mmHg

Lifestyle
modification

<120

and <80

Encourage

Prehypertension

120139

or 8089

Yes

No antihypertensive
indicated.

Stage 1
Hypertension

140159

or 9099

Yes

Stage 2
Hypertension

>160

or >100

Yes

Thiazide-type diuretics for

for
the
most.
May consider ACEI, Drug(s)
compelling
ARB,
BB,
CCB,
or
indications.
combination.
Other antihypertensive
Two-drug combination for drugs (diuretics, ACEI,
most (usually thiazide-type ARB, BB, CCB) as
diuretic and ACEI or ARB or needed.
BB or CCB).

BP classification
Normal

Without compelling indication

With compelling
indications

drug Drug(s) for compelling

indications.

Initial combined therapy should be used cautiously in those at risk for orthostatic hypotension.
Treat patients with chronic kidney disease or diabetes to BP goal of <130/80 mmHg.

How to maximize patient benefit

47

Adverse Events: HCTZ 25 mg vs

ARB + HCTZ 25 mg
HCTZ

ARB + HCTZ

Potassium
Insulin
Glucose
Lipids
Uric Acid
Adverse
events
Impotence

How to maximize patient benefit

48

Effect of Telmisartan
HCTZ 25 mg

Change in clinic trough BP from baseline after 8 weeks therapy

How to maximize patient benefit

Neldam &49
al J Clin Hypertens 2008; 10:612

INVEST: Primary Composite

Endpoint by Treatment Group
Calcium Antagonist Strategy (CAS) (Verap + ACEI)

Cumulative %

Non-Calcium Antagonist Strategy (NCAS) (BB + HCTZ)

No.
at Risk
CAS
NCAS

RR = 0.98 (0.90 1.06)

Log-Rank P=.57

11267 10921
11309 10991

12

18

24

10716
10785

10512
10536

10008
10048

30
36
Time, mo
6612
6604

3738
3706

42

48

54

60

1568
1563

974
960

393
390

35
33

Pepine CJ, et al. JAMA. 2003;290:2805

ONTARGET Combination

Yr 2

Yr 3

Yr 4

8576
8502

7832
7740

7473
7377

7095
7023

8214
8134

0 .1 5

0 .2 0

T&R

# at Risk Yr 1

0 .0 5

0 .1 0

Ramipril
Tel. & Ram.

0 .0

C u m u la tiv e H a z a rd R a te s

0 .2 5

ACEI + ARB vs ACE

Years of Follow-up

How to maximize patient benefit

The ONTARGET Investigators N EJM 2008;358:1547

51