Protecting patients with hypertension
How to maximize patient benefit ?
Pr Roland Asmar
How to maximize patient benefit
1
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
2
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
3
HOT: Need for Combination Therapy
How to maximize patient benefit
Hansson et al., Lancet 1998, 351: 1755-62
4
Percentage of Patients with Combination
Treatment in Clinical Trials
100
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
47
33
34
70
49
46
35
93
66
45
51
41
68
66
68
84
65
30
70
0
20
40
60
How to maximize patient benefit
80
100 %
5
ESH/ESC Guidelines - 2007
Pharmacological Rationale
for Combination Therapy
How to maximize patient benefit
7
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
8
Advantages of Combination Therapy
Efficacy
How to maximize patient benefit
9
Rationale of Combination Therapy
Pathogenetic Mechanisms in Hypertension
Patient A
Patient B
Patient C
Sympathetic nervous system
Renin-angiotensin system
Total body sodium
Waeber B. 2004
How to maximize patient benefit
11
Titration vs. Combination
Diastolic BP
HTZ 6.26 - HTZ 25
B10 - B40
HTZ 6.25 + B10
0
0
-1
-0,5
-2
-1
mmHg
mmHg
-3
-4
B10 + HTZ6.25
-3,2
-5
-6
-1,5
-1,5
-2
-2,5
-7
-3
-8
-9
-8,5
-3,5
How to maximize patient benefit
-3,1
Frishman WH et al,Arch Intern Med 1994;154:1461
12
Efficacy: Up-titration vs Combination
Change in SBP (mm Hg)
0
T40 T80
T40
T40 HCT12.5 V80 V160
V80
V80 HCT12.5 Ol20 Ol40
O20
Ol20 HCT12.5
-5
-6,9
-6,9
-8,2
-8,2
-10
-12,2
-12,6
-15
-16,8
-20
-15,2
-16,4
-15,2
-18,8
-20,4
-25
How to maximize patient benefit
13
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
0,2
0,1
Adjusted
0
mean D
from baseline -0,1
at 8 weeks
-0,2
(mEq/L)
300
100
-0,3
37.5
-0,4
0
0
6.25
12.5
ARB dose
(mg/d)
25
HCTZ dose (mg/d)
How to maximize patient benefit Kochar M, et al. Am J Hypertens. 1999;12:797
16
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
10.4%
How to maximize patient benefit
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
1
2
3
4
5
6
7
8
9
10
11 12
Dezii CM. Manag Care 2000; 9 : s2
Months
Advantages of Combination
Therapy
Equal
efficacy?
How to maximize patient benefit
20
®
Blood pressure control with ARBs and in Fixed Dose Combination
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
6
10
14
18
Time after dosing (h)
2
22
Systolic BP
Change from baseline (mmHg)
10
14
18
22
-6
-8
-12
6
Diastolic BP
Telmisartan 80mg + HCTZ 12.5mg
Telmisartan 40mg + HCTZ 12.5mg
Losartan 50mg + HCTZ 12.5mg
-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
Powerful 24 hr SBP reductions
0
4
Time post dose (hours)
8
12
16
20
24
SBP change from baseline (mmHg)
0
-2
-4
-6
Valsartan 160 mg + HCTZ
Telmisartan 80 mg + HCTZ
***
-8
-10
-12
-14
-16
-18
-20
***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;46:898
24
Telmisartan 80mg/HCTZ 12.5 mg vs
Olmesartan 20mg/HCTZ12.5 mg
Systolic
BP
Diastolic
BP
How to maximize patient benefit
Fogari & al Current Therapeutic Research; 2008; 69
25
®
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)
0
Systolic BP
Diastolic BP
-5
-10
-15
-20
-1.8 (-3.0, - 0.6) p<0.02
-25
Telmisartan-HCTZ 80/25mg (n=467)
Valsartan-HCTZ 160/25mg (n=479)
Placebo (n=120)
-2.8 (-4.6, -1.0) p<0.004
How to maximize patient benefit
White et al. J Hypertens Suppl. 2003;21:S9-15.29
Comparison of Telmisartan HCTZ
& Valsartan HCTZ
Change in clinic trough BP from baseline after 8 weeks therapy
How to maximize patient benefit
White W & al BP Monitoring 2008, 13:21
30
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 ValsartanIrbesartan
Candesartan
Olmesartan
(active form)
(active form)
(active form
H3C
N
O
N
N
CH3
C
CI
CO2H
N
CO2H
N
N
N
O
N
OCH2CH3
OH
N
COOH
COOH
N
N
N NH
N
N
N NH
N
N
N NH
N
N
N NH
N
N
N NH
Telmisartan
CH3
N
CH3
N
N
O
N
OH
CH3
How to maximize patient benefit
34
Dissociation Half-Lives of ARB’s
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)
35
How to maximize patient benefit
Kakuta et al. Int J Clin Pharmacol Res. 2005;25:41-6.
Selective Nuclear Hormone
Receptor Modulation
Peroxisome Proliferator-Activated Receptor Gamma (PPAR g) interaction
Pioglitazone
Full Agonists
Rosiglitazone
Telmisartan
Selective Modulation
Selective Peroxisome Proliferator-Activated
Receptor Gamma Modulators (SPPARMS)
PPAR g
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 PPARg Receptor
Fold Activation
150
Full Agonists
100
Partial
Agonist
50
0
rosiglitazone
pioglitazone
telmisartan
How to maximize patient benefit
irbesartan
eprosartan
Benson et al. Hypertension. 2004;43:993
37
Activation of PPARg by ARB’s
25
Telmisartan was the only ARB that activated PPARg
at concentrations (1-5 mmol/l) attained in plasma with
conventional oral dosing
Fold Activation
20
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 (%)
0
-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
0
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 cm²
250
-12%
p=0.008
200
150
100
50
-5%
98
96
94
92
90
Amlodipine
Telmisartan
Baseline
Amlodipine
Telmisartan
24 wks treatment
How to maximize patient benefit
Shimabukuro, J Hypertens 2007;25:841
41
Comparative
Cardio-Metabolic Studies with Telmisartan
Trial
Patients
N
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
6
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
46
Hansson L, et al. Lancet 1998;351:1755–62.
Management of BP for adultsJNC VII
Initial drug therapy
SBP*
mmHg
DBP
mmHg
Lifestyle
modification
<120
and <80
Encourage
Prehypertension
120–139
or 80–89
Yes
No antihypertensive
indicated.
Stage 1
Hypertension
140–159
or 90–99
Yes
Thiazide-type diuretics for
most. May consider ACEI,
ARB,
BB,
CCB,
or
combination.
Stage 2
Hypertension
>160
or >100
Yes
BP classification
Normal
†Initial
‡Treat
Without compelling indication
With compelling
indications
drug Drug(s) for compelling
indications. ‡
Drug(s)
for
the
compelling
indications.‡
Other
Two-drug combination for antihypertensive
most† (usually thiazide-type drugs (diuretics, ACEI,
diuretic and ACEI or ARB or ARB, BB, CCB) as
needed.
BB or CCB).
combined therapy should be used cautiously in those at risk for orthostatic hypotension.
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
49
Neldam & al J Clin Hypertens 2008; 10:612
INVEST: Primary Composite
Endpoint by Treatment Group
25
Calcium Antagonist Strategy (CAS) (Verap + ACEI)
Non-Calcium Antagonist Strategy (NCAS) (BB + HCTZ)
Cumulative %
20
RR = 0.98 (0.90 – 1.06)
15
Log-Rank P=.57
10
5
0
0
6
12
18
24
10716
10785
10512
10536
10008
10048
No.
at Risk
CAS
NCAS
11267 10921
11309 10991
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
ACEI + ARB vs ACE
T&R
Yr 2
Yr 3
Yr 4
8576
8502
7832
7740
7473
7377
7095
7023
8214
8134
0.15
0.05
0.10
Ramipril
Tel. & Ram.
0.0
Cumulative Hazard Rates
0.20
0.25
R
# at Risk Yr 1
0
1
2
3
4
Years of Follow-up
How to maximize patient benefitThe ONTARGET Investigators N EJM 2008;358:1547
51