Professional Documents
Culture Documents
Chlorthalidone-Telmisartan The New Renaissance
Chlorthalidone-Telmisartan The New Renaissance
Chlorthalidone-Telmisartan The New Renaissance
Men
Women
60
40
20
0
10 12
Years
14
16 18
20
250
200
150
68-82
83-87
88-92
93-97
98-102
100
50
0
158167
148157
138147
128137
98127
Age-adjusted annual
incidence of CHD per 1000
60
50
50
40
40
Age 65-94
30
30
20
20
Age 35-64
10
10
Age 65-94
Age 35-64
<75
758595- 105+
84
94
104
Diastolic blood pressure (mmHg)
Based on 30 year follow-up of Framingham Heart Study subjects free of coronary heart
disease (CHD) at baseline
Framingham Heart Study, 30-year Follow-up. NHLBI, 1987.
Relative risk of
CHD mortality
3
2
1
0
Decile
SBP (mmHg)
DBP (mmHg)
(lowest 10%)
<112 112- 118<71
71-
76-
121-
125-
129-
132-
79-
81-
84-
86-
10
89-
92-
>98
(highest 10%)
137- 142- >151
Relative risk of
stroke death
Decile
SBP (mmHg)
DBP (mmHg)
(lowest 10%)
<112 112- 118<71
71-
76-
121-
125-
129-
132-
79-
81-
84-
86-
10
89-
92-
>98
(highest 10%)
137- 142- >151
100
80
82
2.4
60
40
20
0
43
33
18
Men
Women
Inadequate Management of BP in a VA
Hypertensive Population: Clinical Inertia
800 hypertensive men @ 5 VAs in New England over a 2 yr period in
early 1990s.
>6 HTN-related visits/yr; ave age: 65.5 years.
BP control:
With compelling
indications
Normal
Prehypertension
Stage 1 Hypertension
Stage 2 Hypertension
With compelling
indications
Normal
Prehypertension
Stage 1 Hypertension
Stage 2 Hypertension
With compelling
indications
Normal
Prehypertension
Stage 1 Hypertension
Stage 2 Hypertension
With compelling
indications
Normal
Prehypertension
Stage 1 Hypertension
Stage 2 Hypertension
With compelling
indications
Normal
Prehypertension
Stage 1 Hypertension
Stage 2 Hypertension
60
Diuretics
50
40
-Blocker
30
20
ACE Inhibitors
10
CCBs
ARBs
0
1978
1981
1984
1987
1990
Year
1993
1996
1999
2002
Stage 1 Hypertension
Chlorthalidone: Relationship
Thiazide diuretics
Thiazide diuretics became available in the late 1950s and were the first
effective oral antihypertensive agents with an acceptable side-effect profile.
These agents reduce blood pressure when administered as monotherapy,
enhance the efficacy of other antihypertensive agents, and reduce
hypertension-related morbidity and mortality.
Thiazide-type diuretics, especially HCTZ, have been used as a cornerstone of
antihypertensive treatment for years.
There is substantial evidence that low doses of Chlorthalidone (25 mg daily) are effective
reducing CVD morbidity and mortality.
Recent outcome trials showing CVD benefits with thiazide-type diuretics have
primarily used chlorthalidone or indapamide
(Lancet. 1985;1:1349-1354., BMJ. 1992;304:405-412.)
EWPHE (1985)
MRC (1992)
SHEP (1991)
TOMHS (1993)
ALLHAT (2002)
ACCOMPLISH (2008)
HCTZ 50-100 mg
Chlorothiazide 500-1000 mg
Chlorthalidone 25-100 mg
HCTZ 50-100 mg (BID) or
Chlorthalidone 50-100 mg
HCTZ 25-50 mg
HCTZ 25-50 mg
Chlorthalidone 12.5-25 mg
Chlorthalidone 15-30 mg
Chlorthalidone 12.5-25 mg
HCTZ 12.5-25 mg
BENDROFLUMETHIAZIDE
CHLOROTHIAZIDE
TRx (000s)
3,000
CHLORTHALIDONE
HYDROCHLOROTHIAZIDE
2,500
HYDROFLUMETHIAZIDE
INDAPAMIDE
2,000
METHYCLOTHIAZIDE
METOLAZONE
1,500
POLYTHIAZIDE
QUINETHAZONE
1,000
500
Fe
b0
M 1
ay
-0
Au 1
g0
No 1
v0
Fe 1
b0
M 2
ay
-0
Au 2
g0
No 2
v0
Fe 2
b0
M 3
ay
-0
Au 3
g0
No 3
v0
Fe 3
b0
M 4
ay
-0
Au 4
g0
No 4
v0
Fe 4
b0
M 5
ay
-0
Au 5
g0
No 5
v0
Fe 5
b0
M 6
ay
-0
Au 6
g0
No 6
v06
IMSIMS
Health
NDTI,
Data Source:
NPA - 72
months2001-06.
ending January 2007
TRICHLORMETHIAZIDE
ABPM Differences
Week 2
Office
Blood
Pressure*
4.5 2.1
15.7 2.2
p = 0.001
Week 4
7.6 2.8
17.4 2.9
p = 0.069
Week 6
9.3 3.2
19.6 3.4
p = 0.109
Week 8
10.8 3.5
17.1 3.7
p = 0.842
6
2
-2
-6
-10
-14
-18
Hydrochlorothiazide 50 mg daily
-22
Chlorthalidone 25 mg daily
-26
-30
Hours
6am
8am
10am
12pm
2pm
4pm
6pm
8pm
*All values are expressed as means the standard deviation. The p values
reported are Bonferroni adjusted p values (unadjusted p value 4 tests).
Ernst ME, et al. Hypertension. 2006;47:352-358,
10pm
12am
2am
4am
Hydrochlorothiazide Vs Chlorthalidone
BP lowering effect of Hydrochlorothiazide and Chlorthalidone
SBP reduction
Chlorthalidone
25mg/day
HCTZ 50mg/day
15.7 2.2 mm
4.5 2.1 mm Hg
(Hypertension. 2006;47:352-358.)
P value
P=.001
MRFIT
The Multiple Risk Factor Intervention Trial
Hypertension. 2011;57:689694.
MRFIT
Men ages 35-57 years, upper 10%-15% of CHD
risk, randomization to Special Intervention (SI)
or Usual Care (UC), stratified by clinical center
Choice of diuretic allowed to initiate treatment
in SI group; some clinics predominantly used
HCTZ (50 or 100 mg) while others used
predominantly chlorthalidone (50 or 100 mg)
No. Clinics
No. Participants
% Hypertensive at entry
No. SI
No. UC
Baseline BP
SBP (mm Hg)
DBP (mm Hg)
H Clinics
C Clinics
9
5,466
6
3,193
62.2 %
1725
1674
66.1%
1046
1066
141.5
95.5
142.0
95.8
H- Hydrochlorothiazide C- Chlorthalidone
MRFIT
Four years into the study the DSMB
requested all SI participants on HCTZ be
converted to chlorthalidone.
MRFIT
Probability of event-free cardiovascular events with thiazide-type diuretic
Hypertension. 2011;57:689694
MRFIT
Leading up to protocol change
H clinics: 44% more CHD, 16% more death
(vs UC patients)
C clinics: 58% less CHD, 41% less death
(vs UC patients; majority of diuretic use in
UC remained HCTZ)
After switch to C
H clinics: 28% less CHD, 26% less death vs
UC (P = 0.04, 0.06)
Multiple Risk Factor Intervention Trial Research Group. Circulation. 1990;82:1616-1628.
Bartsch G et al. Circulation. 1984;70(suppl II):II-1438.
ALLHAT
ALLHAT
Purpose
To determine whether, in hypertensive patients, the calcium channel
blocker amlodipine or the angiotensin converting enzyme inhibitor
lisinopril reduces coronary heart disease and other cardiovascular
disease compared with the thiazide diuretic chlorthalidone
The ALLHAT Officers and Coordinators for the ALLHAT
Collaborative Research Group.
Heart Attack Trial. JAMA 2002;288:298197.
YEAR 1
YEAR 5
Intent-toTreat
Analysis
Discontinued
early at 3.3 yrs
Randomized
n=42,418
Chlorthalidone
n=15,255
Amlodipine
n=9,048
Lisinopril
n=9,054
n=13,854
n=8,215
n=8,158
2,235 (16.1%)
stopped drug
1,357 (16.5%)
stopped drug
1,842 (22.6%)
stopped drug
n=6,210
n=3,769
n=3,605
1,873 (30.2%)
stopped drug
1,052 (27.9%)
stopped drug
1,399 (38.8%)
stopped drug
n=15,255
n=9,048
n=9,054
www.hypertensiononline.org
ALLHAT Endpoints
Primary endpoint
Composite of fatal coronary heart disease (CHD) or nonfatal
myocardial infarction (MI)
Other predefined endpoints
all-cause mortality
stroke
combined CHD nonfatal MI, CHD death, coronary
revascularization, hospitalized angina
combined cardiovascular disease combined CHD, stroke,
lower extremity revascularization, treated angina, fatal/
hospitalized/treated congestive heart failure, hospitalized or
outpatient peripheral arterial disease
other renal
ALLHAT Research Group. JAMA. 2002;288:2981-2997.
www.hypertensiononline.org
Amlodipine
150
Lisinopril
145
Compared to chlorthalidone:
SBP significantly higher in
amlodipine (~1 mmHg) and
lisinopril (~2 mmHg) groups.
140
135
130
Diastolic BP (mmHg)
Systolic BP (mmHg)
Chlorthalidone
90
Amlodipine
Lisinopril
85
Compared to chlorthalidone:
DBP significantly lower in
amlodipine group (~1 mmHg).
80
75
70
6
0
1
Follow-up, yrs
ALLHAT BP Controlled
to <140/90 mmHg
Chlorthalidone
Amlodipine
% Patients with
BP <140/90 mmHg
70
60
*
50
Lisinopril
Year 4
Year 5
40
30
20
10
0
Baseline
Year 1
Year 2
Year 3
www.hypertensiononline.org
20
16
12
8
Chlorthalidone
Amlodipine
Lisinopril
0
0
TOTAL
1.04
(0.99-1.09)
1.10
(1.05-1.16)
Age <65
1.03
(0.94-1.12)
1.05
(0.97-1.15)
Age 65
1.05
(0.99-1.12)
1.13
(1.06-1.20)
Men
1.04
(0.98-1.11)
1.08
(1.02-1.15)
Women
1.04
(0.96-1.13)
1.12
(1.03-1.21)
Black
1.06
(0.96-1.16)
1.19
(1.09-1.30)
Nonblack
1.04
(0.97-1.10)
1.06
(1.00-1.13)
Diabetic
1.06
(0.98-1.15)
1.08
(1.00-1.17)
Nondiabetic
1.02
(0.96-1.09)
1.12
(1.05-1.19)
0.5
Favors
Favors
lisinopril chlorthalidone
0.5
www.hypertensiononline.org
ALLHAT Stroke
Relative Risk Favors
Relative Risk
Favors
(95% CI) amlodipine chlorthalidone (95% CI)
TOTAL
0.93
(0.82-1.06)
1.15
(1.02-1.30)
Age <65
0.93
(0.73-1.19)
1.21
(0.97-1.52)
Age 65
0.93
(0.81-1.08)
1.13
(0.98-1.30)
Men
1.00
(0.85-1.18)
1.10
(0.94-1.29)
Women
0.84
(0.69-1.03)
1.22
(1.01-1.46)
Black
0.93
(0.76-1.14)
1.40
(1.17-1.68)
Nonblack
0.93
(0.79-1.10)
1.00
(0.85-1.17)
Diabetic
0.90
(0.75-1.08)
1.07
(0.90-1.28)
Nondiabetic
0.96
(0.81-1.14)
1.23
(1.05-1.44)
0.5
Favors
Favors
lisinopril chlorthalidone
0.5
www.hypertensiononline.org
No. at Risk
Chlorthalidone
Amlodipine
Lisinopril
15
Chlorthalidone
Amlodipine
12
Lisinopril
9
6
3
0
15255
9048
9054
14528
8535
8496
13898
8185
8096
3
4
5
Time to event, yrs
13224
7801
7689
11511
6785
6698
6369
3775
3789
3016
1780
1837
384
210
313
www.hypertensiononline.org
TOTAL
1.38
(1.25-1.52)
1.20
(1.09-1.34)
Age <65
1.51
(1.25-1.82)
1.23
(1.01-1.50)
Age 65
1.33
(1.18-1.49)
1.20
(1.06-1.35)
Men
1.41
(1.24-1.61)
1.19
(1.03-1.36)
Women
1.33
(1.14-1.55)
1.23
(1.05-1.43)
Black
1.47
(1.24-1.74)
1.32
(1.11-1.58)
Nonblack
1.33
(1.18-1.51)
1.15
(1.01-1.30)
Diabetic
1.42
(1.23-1.64)
1.22
(1.05-1.42)
Nondiabetic
1.33
(1.16-1.52)
1.20
(1.04-1.38)
0.5
Favors
Favors
lisinopril chlorthalidone
0.5
www.hypertensiononline.org
ALLHAT
ALLHAT Conclusions
HF=heart failure
www.hypertensiononline.org
ALLHAT
ALLHAT Implications
www.hypertensiononline.org
Age
Eligibility
Design
Therapy
Duration
4.5 years
BP change
Systolic BP 12 mmHg
BP=blood pressure
SHEP Research Group. JAMA. 1991;265:3255-3264.
SHEP
Change in Blood Pressure
Diastolic BP
Change in BP (mmHg)
Systolic BP
80
180
170
Placebo (n=2,371)
75
Placebo (n=2,371)
160
70
150
Active Rx (n=2,365)
Active Rx (n=2,365)
65
140
2 3
Years
2 3
Years
BP=blood pressure
SHEP
Average Blood Pressure During Follow-up
200
185
170
155
140
125
110
95
80
65
50
0
12
24
36
Months of follow-up
SHEP=Systolic Hypertension in the Elderly Program
SHEP Research Group. JAMA. 1991;265:3255-3264.
Copyright 1991, American Medical Association.
48
60
SHEP
Cumulative Stroke Rate
10
9
8
7
6
5
4
3
2
1
0
P=0.0003
Placebo
(n=2,371)
Active Rx
(n=2,365)
12
24
36
48
Months of follow-up
SHEP=Systolic Hypertension in the Elderly Program
SHEP Research Group. JAMA. 1991;265:3255-3264.
Copyright 1991, American Medical Association.
60
72
SHEP
Cardiovascular Disease Endpoints
Active Therapy vs. Placebo
1.60
1.40
1.20
1.00
0.80
0.60
0.87
0.63
0.68
0.75
0.46
0.40
0.20
Stroke
CHD
CHF
CVD
Death
SHEP
Conclusions
SHEP was the first clinical trial to demonstrate that
reduction of blood pressure in patients with isolated
systolic hypertension reduced cardiovascular (CV)
mortality
The relative risk of stroke was reduced by 36% with
chlorthalidone compared to placebo (P=0.0003)
The 5-year absolute benefits were a reduction in 30
strokes and 55 major CV disease events per 1,000
persons
SHEP=Systolic Hypertension in the Elderly Program
SHEP Research Group. JAMA. 1991;265:3255-3264.
Eligibility
Design
Therapy
Duration
4 yrs
BP
difference
-6 mmHg
Diastolic blood
pressure (mmHg)
104
Placebo
100
Active
96
92
88
84
80
At Screening
During Trial
Active (n=1,721)
No.
Rate
No.
Rate
35
5.1
25
3.6
Cardiovascular
18
2.6
1.1
Non-cardiovascular
17
2.5
17
2.4
Non-fatal TEP
133
19.4
113
16.2
All TEP
168
24.5
138
19.7
Active
n=1,721
Fatal
11
22
28
Nonfatal other
76
65
16
10
Other fatal
18
17
Other nonfatal
10
Cerebrovascular events
Fatal
Nonfatal
Hemorrhage or thrombosis
Transient cerebral ischemic attacks
140
120
Active (n=1,721)
All TEP
P<0.01
Placebo (n=1,706)
100
80
60
All Fatal TEP
40
P<0.05
20
0
400
600
1200
Days in trial
1600
2000
Placebo
-26
-15
-9
-4
- 11-14
- 3-4
Goal BP achievement(%)
65-72
32-40
P-value
158 d
P=.009
105 d
P=.07
215.2 d
130.7 d
215.3 d
195.6 d
Chlorthalidone
Head-to-head studies favor chlorthalidone as a more
effective blood pressure lowering agent compared with
HCTZ
CTD produce superior 24-hour blood pressure control
compared with HCTZ
When comparing the 2 drugs, CTD had significantly fewer
CVEs compared with HCTZ.
SHEP trial: Chlorthalidone treatment was associated with
36% reduction in total stroke incidence
27% lower incidence of nonfatal MI and coronary death
32% reduction in all cardiovascular event
Hypertension. 2011; 57: 689-694
Chlorthalidone
Each month of chlorthalidone therapy associated with an
additional day free from risk of cardiovascular death
CTD displayed significantly lower SBP, total cholesterol,
low-density lipoprotein cholesterol, potassium, and higher
uric acid compared with HCTZ.
Given the documented irregular intake of antihypertensive
drugs, the prolonged efficacy of chlorthalidone makes this
agent a "forgiving drug" with a definite advantage over
hydrochlorothiazide.
Non-DHP CCBs and clonidine should not be combined with bblockers (DHPs combine well).
b-blockers
AT1-receptor
blockers
a-blockers
Calcium
antagonists
ACE inhibitors
ESH/ESC Guidelines Committee. J Hypertens. 2003;21:1011-1053.
Angiotensin II
Non-ACE pathways
escape
(e.g. chymase, tPA,
cathepsin)
Angiotensinogen
Vasoconstriction
Cell growth
Sodium/water retention
Sympathetic activation
Angiotensin I
AT1 receptor
ACE
Bradykinin
ACE
Angiotensin II
Inactive fragment
Aldosterone
Sodium/water
retention
AT2 receptor
Vasodilation
Antiproliferation
Tissue regeneration
Natriuresis
RAAS
Renal
Sodium
Retention
Sympathetic
Nerve
Activity
Preload
Contractility
Heart Rate
Vasoconstriction
Oxidative Stress
Inflammation
LDL peroxidation
LOX-1 expression
Angiotensin II
Production of
inflammatory mediators
Nitric oxide
Proliferation of VSMCs
Vasoconstriction
PAI-1 activation
Platelet aggregation
Endothelial dysfunction
Matrix deposition
MMP activation
Tissue remodelling
Myocardial infarction
and stroke
Atherosclerosis
and
left ventricular
hypertrophy
Risk factors
Remodelling
CV High-Risk
Ventricular dilation/
cognitive dysfunction
Hypertension
Angiotensin II
Adapted from
Dzau VJ, et al. Circulation 2006;114:28502870; Figure adapted from Dzau V, Braunwald E.
Am Heart J 1991;121:12441263; Yusuf S, et al. Lancet 2004;364:937952
HF
Death
Death
Angiotensin converting
enzyme inhibitors (ACE)
Captopril,
Enalapril,
Lisinopril
Ramipril
Perindopril
Angiotensin II receptor
Blockers (ARBs)
Losartan
Irbesartan
Olmesartan
Candesartan
Valsartan
Telmisartan
Azilsartan
Bradykinin/NO
Angiotensin I
ACEACE
Inhibitor
Inactive fragments
ACE-independent
ANG II formation
by Chymase, etc.
Angiotensin II
ARB
AT1 RECEPTOR
Vasoconstriction
Sodium retention
SNS activation
Inflammation
Growth-promoting effects
Aldosterone
Apoptosis
AT2 RECEPTOR
Vasodilation
Natriuresis
Tissue regeneration
Inhibition of inappropriate cell growth
Differentiation
Anti-inflammation
Apoptosis
Percent (%)
P value*
<0.001
<0.001
<0.001
0.060
High affinity towards AT1 receptor (telmisartan > olmesartan > candesartan >
valsaratan > losartan)
Very slow dissociation rate
Liters
500
450
400
350
300
250
200
150
100
50
Candesartan Valsartan
Olmesartan
Losartan
Losartan
Metabolite
Irbesartan
Telmisartan
16
14
12
10
8
6
4
2
Losartan
Olmesartan
Eprosartan
Irbesartan
5 micromolar
Valsartan
Candesartan
Telmisartan
Hypertension
Indicated for treatment of hypertension
May be used alone or in combination with other antihypertensive agents
90
Ambulatory DBP
(mm HG)
85
80
75
70
Baseline
65
Final Visit
60
8:00 AM
n=1628
12:00 PM
4:00 PM
8:00 PM
12:00 AM
4:00 AM
Time of day
8:00 AM
SBP
DBP
-5
-7.08.9
-10
-11.513.2
-15
Early-morning BP control:
Telmisartan Vs existing therapy
Additional DBP reductions (mm HG) when telmisartan is added to
patients uncontrolled on current therapy at the end of the dosing period
Beta Blockers
CCBs
-4.8
n=56
-0.2
n=56
-5.8
n=35
ACE Inhibitors
-2.3
n=36
-6.8
n=49
HCTZ
-5.2
n=50
-10.6
n=14
1.9
n=15
Change in BP in Last 6
Hours of the Dosing Period
(mm HG)
SBP
-5
-10
-15
n=448
-20
-18.3
No overall differences in effectiveness and safety of telmisartan was observed in elderly patients
compared with younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Neldam S, Edwards C, on behalf of the ATHOS Study Group. Am J Geriatr Cardiol. 2006;15(3):151-160.
100
90
80
90
90%
91%
80
82%
79%
70
70
60
60
50
SBP
<140
ABPM (n=1628)
100
DBP
<90
SBP/DBP
<140/90
71%
70%
50
SBP
<130
DBP
<85
SBP/DBP
<130/85
Telmisartan
Olmesartan
24 hrs
13 hrs
66 -100 %
60 -80%
24 hr control of BP*
Complete 24 hr control of
BP covers early morning
Hour
Incomplete 24 hr control
of BP
1% urine
99% stools
35-50% urine
50% stools
No dosage adjustment
20 mg maximum in severe
disease
Absent
Elimination
Half- life (hr)
Lipophilicity
Elimination
Renal Insufficiency
PPAR Agonistic activity
Telmisartan Vs Losartan
Aim: Anti-hypertensive efficacy & tolerability of Telmisartan and
Losartan compared with placebo in a
6-week study
Patients: 223 patients with mild-to moderate Hypertension
Treatment: Telmisartan 40 mg, telmisartan 80 mg, losartan 50 mg, or
placebo
Telmisartan Vs Losartan
Telmisartan more effective anti-hypertensive during
18-24 hour peroid after dosing( P<0.05)
Reduction in Blood
Pressure
Telmisartan 40mg
-5
Telmisartan 80mg
-6/3.7 mm Hg
-10
-10.7/6.8mm Hg
-12.2/7.1 mm Hg
Losartan 50mg
-15
% of
Patient
showing
Reduction
of SBP >
or =
80
70
68%
Telmisartan
Atenolol
60
Result
Final SBP/DBP reductions of 20.9/14.4 mm Hg for Telmisartan versus
16.7/13.3 mm Hg for Atenolol
Difference in SBP was significant (P = 0.005)
Safety Profile:
Incidence of mild to moderate adverse effect was lower in Telmisartan as
compared to Atenolol. ( 52.7% vs 61.2% )
Incidence of Fatigue and male impotence more common in Atenololtreated patients (3.4% vs 4.0%)
% patients with
Twenty four-hour
mean ABPM DBP <
85 mmHg
80
71%
55%
60
40
Telmisartan
20
Amlodipine
Twenty four-hour mean ABPM DBP < 85 mmHg were observed in 71% of Telmisartan
patients and in 55% of patients administered Amlodipine
Hypertension
Losartan
Epro-sartan
Irbe-sartan
Olme-sartan
Valsartan
Cande-sartan
CV High-Risk
Telmisartan
Telmi-sartan
Stroke
ONTARGET trial
CV High-Risk
patients
CV death, MI,
stroke and HF hosp in those with CVD or DM in the absence of ventricular
dysfunction or heart failure
Teo K, et al. Am Heart J 2004;148:5261; The ONTARGET Investigators. N Engl J Med 2008;358:15471559
n=25,620
n=8,542
Telmisartan 80 mg
n=8,576
Ramipril 10 mg
n=8,502
Telmisartan 80 mg + Ramipril 10 mg
5.5 years
(i.e. with a history of: coronary artery disease, peripheral arterial occlusive disease (PAD),
cerebrovascular event, or diabetes mellitus with end-organ damage)
Teo K, et al. Am Heart J 2004;148:5261; The ONTARGET Investigators. N Engl J Med 2008;358:15471559
0.20
0.15
0.10
0.05
0
No. at risk
Telmisartan
Ramipril
Telmisartan
Ramipril
8,452
8,576
8,177
8,214
7,778
7,832
7,420
7,472
7,051
7,093
Reduction in composite CV risk (Primary endpoint: cardiovascular mortality, non-fatal myocardial infarction,
hospitalisation for congestive heart failure, non-fatal stroke)
The ONTARGET Investigators. N Engl J Med 2008;358:15471559
Years of followup
1,687
1,703
5
ONTARGET
Myocardial infarction
and stroke
LIFE
VALUE
Atherosclerosis
and
left ventricular
hypertrophy
Risk factors
Hypertension
CV High-Risk
Remodelling
ValHeFT
VALIANT
CHARM
Ventricular dilation/
cognitive dysfunction
HF
Death
Adapted from
Dzau VJ, et al. Circulation 2006;114:28502870; Figure adapted from Dzau V, Braunwald E.
Am Heart J 1991;121:12441263; Yusuf S, et al. Lancet 2004;364:937952
TRANSCEND:
Telmisartan Randomized
AssesmeNt Study in aCE iNtolerant Subjects with Cardiovascular Disease
ONTARGET / TRANSCEND Investigators
Koon K. Teo, MB, PhD, FRCPC
TRANSCEND :
Question:
1. Is telmisartan superior to placebo in patients at high risk of CV events who are intolerant
of ACE-I?
Outcome:
1. Primary: CV death, MI, stroke, CHF hosp
2. Key secondary: CV death, MI, stroke (HOPE trial outcome)
Design:
Single blind run-in (n=6,666)
Randomized, double blind, placebo controlled study conducted in 630 centers in 40
countries (n=5,926)
56 months follow-up with 99.7% outcome ascertainment
The TRANSCEND Investigators. Lancet 2008; 372:1174-83.
Plac
HR (CI)
Primary
CV death, MI,
Stroke
465 (15.7%)
504 (17.0%)
0.92 (0.81-1.05)
0.2158
384 (13.0%)
440 (14.8%)
0.87 (0.76-1.00)
0.0475
227 (7.7%)
223 (7.5%)
1.03 (0.85-1.24)
116 (3.9%)
147 (5.0%)
0.79 (0.62-1.01)
112 (3.8%)
136 (4.6%)
0.83 (0.64-1.06)
134 (4.5%)
129 (4.3%)
1.05 (0.82-1.34)
CV death
MI
Stroke
CHF hosp
Cumulative incidence
(%)
Years of
follow-up
n at risk
Telmisartan
+ Standard of Care
Standard of Care
2,954
2,839
2,745
2,634
2,344
1,127
2,972
2,866
2,745
2,626
2,306
1,103
Reduction of composite CV risk (Secondary endpoint: CV death, MI, stroke [=HOPE primary endpoint])
Primary endpoint (Composite endpoint of CV death, MI, Stroke and hospitalization for Heart failure)
Hazard ratio 0.92 (not significant)