Transcript Module 3 chapter 3a - The Association of Physicians of India

MODULE 3 CHAPTER 3A
IMPORTANT TRIALS IN
HYPERTENSION
Landmark Clinical Trials
Hypertension Treatment and Cardiovascular Disease
Outcomes
1967 – VA Cooperative Study on DBP 115129
1970 – VA Cooperative Study on DBP 90114
1979 – HDFP
1980 – Australian Trial, Oslo Trial
1985 – MRC I, EWPHE
1991 – SHEP, STOP-Hypertension
1992 – MRC II in the elderly
1997 – Syst-Eur
2002 – LIFE
2002 – ALLHAT
www.hypertensiononline.
org
Relative Risk for Coronary Heart
Disease Odds ratios and
95% confidence intervals
Veterans Administration, 1967
Veterans Administration, 1970
Hypertension Stroke Study,
1974
USPHS Study, 1977
EWPHE Study, 1985
Coope and Warrender, 1986
SHEP Study, 1991
STOP-Hypertension Study,
1991
MRC Study, 1992
0.79
(0.69 to 0.90)
Syst-Eur Study, 1997
0
0.
1
1.5
2
Active treatment
Active treatment
Total
5
www.hypertensiononline.
He J, et al. Am Heart J. 1999; 138:211- better than placebo
worse than placebo
org
219.
Copyright 1999, Mosby, Inc.
Relative Risk for Stroke
Odds ratios and
95% confidence intervals
Veterans Administration, 1967
Veterans Administration, 1970
Hypertension Stroke Study,
1974
USPHS Study, 1977
EWPHE Study, 1985
Coope and Warrender, 1986
SHEP Study, 1991
STOP-Hypertension Study,
1991
MRC Study, 1992
0.63
(0.55 to 0.72)
Syst-Eur Study, 1997
Total
He J, et al. Am Heart J. 1999; 138:211219.
Copyright 1999, Mosby, Inc.
0
2
0.
1.5
1
Active
treatment
Active treatment
5
www.hypertensiononline.
worse than placebo
better than placebo
org
The Veterans Administration
Cooperative Study
on Antihypertensive Agents
www.hypertensiononline.
org
The VA Cooperative Study, 1967
Cohort
143 men
Mean age 51 years
Eligibility Diastolic BP 115-129 mmHg
Design
Double blind; placebo control
Therapy
HCTZ, reserpine, hydralazine
Duration
1.5 years
BP
change
-43/30 mmHg
HCTZ=hydrochlorothiazide
www.hypertensiononline.
VA Cooperative Study Group. JAMA. 1967;202:1028-1034.
org
The VA Cooperative Study, 1967:
Change in Systolic and Diastolic Blood
Pressure
50
Placebo
40
40
30
30
Percent of patients
Percent of patients
50
20
10
0
50
40
Active drugs
30
20
20
10
0
50
40
20
10
0
0
Decrease
(-)
28
(+)
Increase
Active drugs
30
10
-76 -60-44-28 -12 0 12
Placebo
-76 -60-44-28-12 0 12 28
Decrease
(-)
(+)
Increase
Change in Systolic BP
Change in Diastolic BP
www.hypertensiononline.
(mmHg)
VA Cooperative Study
Group. JAMA. 1967;202:1028-1034. (mmHg)
org
Copyright ©1967, American Medical Association.
The VA Cooperative Study, 1967:
Assessable Morbid/Fatal Events
Placeb
o
n=70
Active
Rx*
n=73
12
0
Stroke
4
1
Coronary event
2
0
CHF
2
0
Renal damage
2
0
Deaths
4
0
Accelerated
hypertension
*P<0.001 active drug therapy vs placebo
www.hypertensiononline.
VA Cooperative Study Group. JAMA. 1967;202:1028-1034.
org
The VA Cooperative Study, 1967:
Conclusions
 The actively treated group
experienced a reduction in multiple
hypertension-related endpoints
 21 morbid/fatal events on
placebo
 1 morbid/fatal event on active
therapy
www.hypertensiononline.
VA Cooperative Study Group. JAMA. 1967;202:1028-1034.
org
The VA Cooperative Study, 1970
Cohort
380 men
Mean age 50 years
Eligibility Diastolic BP 90-114 mmHg
Design
Double blind; placebo
control
Therapy
HCTZ, reserpine,
hydralazine
Duration
5.5 years (mean=3.8 yrs)
BP
change
Diastolic BP -19 mmHg
www.hypertensiononline.
VA Cooperative Study Group. JAMA. 1970;213:1143-1152.
org
The VA Cooperative Study, 1970:
Assessable Morbid/Fatal Events
Placebo
n=194
Active
Rx*
n=186
4
0
Stroke
20
5
Total coronary event
13
11
Fatal coronary event
11
6
Congestive heart
failure
11
0
Accelerated
hypertension
*P<0.001 active drug therapy vs placebo
www.hypertensiononline.
Renal
damage
3
0
VA Cooperative Study Group. JAMA. 1970;213:1143-1152.
org
The VA Cooperative Study, 1970:
Conclusions
 Active treatment reduced fatal and
nonfatal endpoints
 A subsequent analysis revealed that
benefits were statistically significant
only for those with baseline diastolic
blood pressure 105-114 mmHg
www.hypertensiononline.
VA Cooperative Study Group. Circulation. 1972; 45 (5):991-1004.
org
VA Cooperative Study Group. JAMA. 1970;213:1143-1152.
The Systolic Hypertension
in Europe (Syst-Eur) Trial, 1997
The Systolic Hypertension
in Europe Trial, 1997
Cohort
Age
4,695; 67% women
 60 yrs old
Systolic BP 160–219 mmHg and
Eligibility
diastolic BP <95 mmHg
Design
Double blind; placebo control
Therapy
Nitrendipine (enalapril, HCTZ as
Step 2)
Duration
Median 2 yrs (1-97 months)
BP
differenc -10/5 mmHg
Staessene
JA, et al. Lancet. 1997;350:757-764.
www.hypertensiononline.
org
Syst-Eur Mean Sitting
Systolic Blood Pressure
Placebo (n=2,297)
Systolic BP (mmHg)
180
Active treatment (n=2,398)
170
160
150
P<0.001
0
1
2
3
Years since randomization
Syst-Eur=Systolic Hypertension in Europe Trial
Staessen JA, et al. Lancet. 1997;350:757-764.
Reprinted with permission from Elsevier Science.
4
www.hypertensiononline.
org
Syst-Eur Mean Sitting
Diastolic Blood Pressure
Diastolic BP (mmHg)
85
P<0.001
80
Placebo (n=2,297)
Active treatment (n=2,398)
75
0
1
2
3
Years since randomization
Syst-Eur=Systolic Hypertension in Europe Trial
Staessen JA, et al. Lancet. 1997;350:757-764.
Reprinted with permission from Elsevier Science.
4
www.hypertensiononline.
org
Events per 100 patients
Syst-Eur Primary Endpoint
Fatal and Nonfatal Stroke
P=0.003
Placebo (n=2,297)
6
Active treatment (n=2,398)
5
4
3
2
1
0
0
1
2
3
Years since randomization
Syst-Eur=Systolic Hypertension in Europe Trial
Staessen JA, et al. Lancet. 1997;350:757-764.
Reprinted with permission from Elsevier Science.
4
www.hypertensiononline.
org
Percentage relative
risk reduction (95% CI)
Syst-Eur
Cardiovascular Disease
Endpoints
20
Active therapy vs. placebo
0
14%
-20
-40
-60
-80
29%
30%
P<0.00
1
42%
P=0.00
3
Stroke
31%
MI
CHF
All CVD
Death
MI=myocardial infarction; CHF=congestive heart failure; CVD=cardiovascular disease
Syst-Eur=Systolic Hypertension in Europe Trial
Staessen JA, et al. Lancet. 1997;350:757-764.
www.hypertensiononline.
org
Syst-Eur Conclusions
• Older men and women with isolated systolic
hypertension who received active treatment
with a dihydropyridine calcium channel blocker
experienced fewer strokes and cardiovascular
disease (CVD) events than those receiving
placebo.
• Treatment of 1,000 patients for 5 years with
this type of regimen could prevent 29 strokes
or 53 major CVD endpoints.
Syst-Eur=Systolic Hypertension in Europe Trial
Staessen JA, et al. Lancet. 1997;350:757-764.
www.hypertensiononline.
org
ALLHAT TRIAL
The Antihypertensive and
Lipid-Lowering Treatment
to Prevent Heart Attack Trial
ALLHAT study overview
Double-blind, randomized trial to determine whether the
occurrence of fatal CHD or nonfatal MI is lower for high-risk
hypertensive patients treated with newer agents
(amlodipine,
lisinopril, or doxazosin) compared with a diuretic
(chlorthalidone)
Cohort
• 42,418 patients (55 years old) from 623 sites in North
America
– Stage 1 or 2 hypertension
– 1 additional risk factor for CHD
• Comparisons between chlorthalidone and amlodipine and
chlorthalidone and lisinopril have been reported together,
excluding the doxazosin arm (n=9,062), which was
www.hypertensiononline.
terminated early
ALLHAT Research Group. JAMA. 2002;288:2981-2997.
org
ALLHAT Study Design
Doxazosin
n=9,062
Discontinued
early at 3.3
yrs
Chlorthalidone
n=15,255
YEAR 1
n=13,854
Randomized
n=42,418
Amlodipin
e
n=9,048
n=8,215
Lisinopril
n=9,054
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
YEAR 5
1,873 (30.2%)
stopped drug
1,052 (27.9%)
stopped drug
1,399 (38.8%)
stopped drug
Intent-toTreat
Analysis
n=15,255
n=9,048
n=9,054
339 (2.2%) lost to followup
80 (0.5%) refused follow-up
200 (2.2%) lost to follow-up
58 (0.6%) refused follow-up
218 (2.4%) lost to followup
58 (0.6%) refused follow-up
ALLHAT Research Group. JAMA. 2002;288:2981-2997. www.hypertensiononline.
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
www.hypertensiononline.
ALLHAT Research Group. JAMA. 2002;288:2981-2997.
org
ALLHAT Baseline Characteristics
Chlorthalidon
e n=15,255
Amlodipine
n=9,048
Lisinopril
n=9,054
systoli diastoli
diastoli systoli diastoli
systolic
c
c
c
c
c
Mean BP (mmHg)
146
84
146
84
146
84
Treated (90%)
145
83
145
83
145
84
156
89
157
90
156
89
Untreated
(10%)
Mean age (yrs)
67
67
67
Black (%)
35
36
36
Women (%)
47
47
46
Current smoking
(%)
22
22
22
History of CHD
(%)
26
24
25
Type 2 diabetes
(%)
36
37
36
ALLHAT Mean Systolic and Diastolic
Blood Pressure During Follow-up
Chlorthalidone
Amlodipine
150
Lisinopril
145
Compared to
chlorthalidone:
140
SBP significantly higher in
amlodipine (~1 mmHg) and
lisinopril (~2 mmHg)
groups.
135
130
0
1
2
3
4
5
Diastolic BP (mmHg)
Systolic BP (mmHg)
Chlorthalidone
90
Amlodipine
Lisinopril
85
80
Compared to chlorthalidone:
DBP significantly lower in
amlodipine group (~1
mmHg).
75
70
6
0 1
Follow-up, yrs
2
3
4
5
6
SBP=systolic blood pressure DBP=diastolic blood
www.hypertensiononline.
pressure
org
ALLHAT BP Controlled
to <140/90 mmHg
Chlorthalidone
% Patients with
BP <140/90 mmHg
70
60
*
†
50
Amlodipine
*
†
†
Lisinopril
†
†
Year 4
Year 5
40
30
20
10
0
Baseline
Year 1
Year 2
Year 3
*P<0.001 for amlodipine vs chlorthalidone
www.hypertensiononline.
†P<0.001 for lisinopril vs chlorthalidone
org
ALLHAT Research Group. JAMA. 2002;288:2981-2997.
ALLHAT Treatment
and Blood Pressure Control
1 Drug
3 Drugs
2 Drugs
2.0
100
2
Patients (%)
80
1.3
1.6
1.4
60
1.2
40
0.8
20
0.4
0
6 mos
1 yr
3 yr
5 yr
Average # of drugs
1.7
0
Blood pressure controlled <140/90 mmHg
49.8%
55.2%
62.3%
65.6%
Cushman WC, et al. J Clin Hypertens. 2002;4:393-405. www.hypertensiononline.
Cumulative Fatal CHD and
Nonfatal MI event rate (%)
ALLHAT Primary Outcome
by Treatment Group
20
Chlorthalidone
Amlodipine
16
Lisinopril
12
8
4
0
0
No. at Risk
Chlorthalidone 15255
Amlodipine 9048
Lisinopril 9054
1
14477
8576
8535
2
13820
8218
8123
3
4
5
Time to event,
13102 yrs
11362
6340
6
7
2956
209
7843
6824
3870
1878
215
7711
6662
3832
1770
195
ALLHAT Research Group. JAMA. 2002;288:2981-2997. www.hypertensiononline.
org
Copyright ©2002, American Medical Association.
ALLHAT CHD Death and Nonfatal
MI
Relative Risk Favors
Relative Risk Favors
Favors
Favors
(95% CI) amlodipinechlorthalidone (95% CI)
lisinoprilchlorthalidone
TOTAL
0.98
(0.90-1.07)
0.99
(0.91-1.08)
Age <65
0.99
(0.85-1.16)
0.95
(0.81-1.12)
Age 65
0.97
(0.88-1.08)
1.01
(0.91-1.12)
Men
0.98
(0.87-1.09)
0.94
(0.85-1.05)
Women
0.99
(0.85-1.15)
1.06
(0.92-1.23)
Black
1.01
(0.86-1.18)
1.10
(0.94-1.28)
Nonblack
0.97
(0.87-1.08)
0.94
(0.85-1.05)
Diabetic
0.99
(0.87-1.13)
1.00
(0.87-1.14)
Nondiabeti
c
0.97
(0.86-1.09)
0.99
(0.88-1.11)
0.5
1
2
0.5
1
2
ALLHAT Research Group. JAMA. 2002;288:2981-2997. www.hypertensiononline.
org
Copyright ©2002, American Medical Association.
ALLHAT All-Cause Mortality
Relative Risk Favors
Relative Risk Favors
Favors
Favors
(95% CI) amlodipinechlorthalidone (95% CI) lisinoprilchlorthalidone
TOTAL
0.96
(0.89-1.02)
1.00
(0.94-1.08)
Age <65
0.96
(0.83-1.10)
0.93
(0.81-1.08)
Age 65
0.96
(0.88-1.03)
1.03
(0.95-1.12)
Men
0.95
(0.87-1.04)
0.99
(0.91-1.08)
Women
0.96
(0.86-1.07)
1.02
(0.91-1.13)
Black
0.97
(0.87-1.09)
1.06
(0.95-1.18)
Nonblack
0.94
(0.87-1.03)
0.97
(0.89-1.06)
Diabetic
0.96
(0.87-1.07)
1.02
(0.91-1.13)
Nondiabeti
c
0.95
(0.87-1.04)
1.00
(0.91-1.09)
0.5
1
2
0.5
1
2
ALLHAT Research Group. JAMA. 2002;288:2981-2997. www.hypertensiononline.
org
Copyright ©2002, American Medical Association.
ALLHAT Combined CV Disease
Relative Risk Favors
Relative Risk Favors
Favors
Favors
(95% CI) amlodipinechlorthalidone (95% CI) lisinoprilchlorthalidone
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)
Nondiabeti
c
1.02
(0.96-1.09)
1.12
(1.05-1.19)
0.5
1
2
0.5
1
2
ALLHAT Research Group. JAMA. 2002;288:2981-2997. www.hypertensiononline.
org
Copyright ©2002, American Medical Association.
Cumulative event rate (%)
ALLHAT Stroke
by Treatment Group
10
Chlorthalidone
Amlodipine
8
Lisinopril
6
4
2
0
0
1
2
3
4
5
Time to event,
13309 yrs
11570
6385
6
7
No. at Risk
14515
13934
3217
567
Chlorthalidone 15255
9048
8617
8271
7949
6937
3845
1813
506
Amlodipine
9054
8543
8172
7784
6765
3891
1828
949
Lisinopril
www.hypertensiononline.
ALLHAT Research Group. JAMA. 2002;288:2981-2997.
org
Copyright ©2002, American Medical Association.
ALLHAT Stroke
Relative Risk Favors
Relative Risk Favors
Favors
Favors
(95% CI) amlodipinechlorthalidone (95% CI) lisinoprilchlorthalidone
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)
Nondiabeti
c
0.96
(0.81-1.14)
1.23
(1.05-1.44)
0.5
1
2
0.5
1
2
ALLHAT Research Group. JAMA. 2002;288:2981-2997. www.hypertensiononline.
org
Copyright ©2002, American Medical Association.
Cumulative event rate (%)
ALLHAT Heart Failure
by Treatment Group
15
Chlorthalidone
Amlodipine
12
P<0.001 for chlorthalidone
vs amlodipine and
chlorthalidone vs lisinopril
Lisinopril
9
6
3
0
0
No. at Risk
Chlorthalidone 15255
Amlodipine 9048
Lisinopril 9054
1
2
14528
8535
8496
13898
8185
8096
3
4
5
Time to event,
13224 yrs
11511
6369
6
7
3016
384
7801
6785
3775
1780
210
7689
6698
3789
1837
313
ALLHAT Research Group. JAMA. 2002;288:2981-2997. www.hypertensiononline.
org
Copyright ©2002, American Medical Association.
ALLHAT Heart Failure
Relative Risk Favors
Relative Risk Favors
Favors
Favors
(95% CI) amlodipinechlorthalidone (95% CI) lisinoprilchlorthalidone
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)
Nondiabeti
c
1.33
(1.16-1.52)
1.20
(1.04-1.38)
0.5
1
2
0.5
1
2
ALLHAT Research Group. JAMA. 2002;288:2981-2997. www.hypertensiononline.
org
Copyright ©2002, American Medical Association.
ALLHAT Conclusions
• Better control of systolic BP was achieved with
chlorthalidone than with amlodipine or lisinopril
• There were no differences in risk for CHD
death/nonfatal MI between chlorthalidone and
amlodipine or lisinopril
• In secondary endpoints, chlorthalidone was
associated with lower risk for
– stroke, combined CVD, and HF compared
with lisinopril
– HF compared with amlodipine
MI=myocardial infarction
CHD=coronary heart disease
HF=heart
failure ALLHAT Research Group. JAMA. 2002;288:2981-2997.
ALLHAT Implications
• Unless contraindicated, or unless specific
indications are present that would favor use of
another drug class, diuretics should be the
initial drug of choice in antihypertensive
regimens
• Only 30 percent of patients achieve both
systolic BP <140 mmHg and diastolic BP <90
mmHg on monotherapy
• Many high-risk hypertensive patients will
require 2 or more drugs for BP control
www.hypertensiononline.
org
ALLHAT Research Group. JAMA. 2002;288:2981-2997.
Second Australian National
Blood Pressure Study
ANBP
2
Conducted by the High Blood Pressure
Research Council of Australia in
conjunction with Australia’s General
Practitioners
Background
• Treatment of hypertension based on diuretics
and/or beta blockers provides a definite
outcome benefit
• Additional benefit beyond that resulting from
blood pressure reduction may result with
therapy based on agents inhibiting the reninangiotensin system
New Engl J Med, 2003;348:583-92.
ANBP2
Antihypertensive Drug Use in Australia
Diuretics
700000
600000
Beta Blockers
500000
400000
300000
Calcium Channel
Blockers
200000
ACE Inhibitors
100000
1998
1997
1996
1995
1994
0
1993
Patient numbers (Hypertension)
Hypertension Patient Numbers 1993-98
Angiotensin II
Antagonists
Background
• No outcome data with ACE inhibitor based regimens
• Potential benefits include
– Reduction in LVH
– Improved survival with cardiac failure
– Enhanced insulin sensitivity
– Lipid “neutrality”
Will outcome be the same better or worse than those
of published studies?
ANBP2
Main Aim
To determine in hypertensive patients aged
65-84 years whether there is any difference
in total cardiovascular events (fatal and nonfatal) over a 5 year treatment period
between treatment with either a diuretic-
based regimen or an ACE inhibitor-based
regimen
New Engl J Med, 2003;348:583-92.
ANBP2
Study Design
P
R
O
B
E
prospective
Features
randomised
open label
blinded
•
•
•
•
•
Intention to treat
General practice based
600 practices
6000 patients
Recruitment: 2.5 years
endpoints
New Engl J Med, 2003;348:583-92.
ANBP2
Study Organisation
Management
Committee
(HBPRCA)
Sub Committees
National Centre (BMRI)
Regional Centers
SA
VIC
QLD
NSW
WA
General Practice
Data monitoring
End - point
Audit
Substudies: ABPM,
LVH,
Genetic, Health Econ
Data Management
Centre
(Uni of Adelaide)
ANBP2
Study Subjects
Inclusion Criteria
•
•
•
•
•
Men and women 65 - 84 years
Previously treated or newly diagnosed hypertensives
Untreated sitting SBP > 160 and/or DBP > 90 mmHg
Able to give consent and to attend GP practice
No recent cardiovascular morbidity
Exclusion Criteria
•
•
•
•
•
•
•
Any cardiovascular end-point in the past 6 months
Dementia
Plasma creatinine > 0.2 mmol/L
Any life threatening illness (unlikely to survive 5 years)
Unwillingness of GP to enter subject into study
Unable to attend GP practice
Absolute contraindication to ACE or diuretic
ANBP2
New Engl J Med, 2003;348:583-92.
Study Protocol
• Blood Pressure Screening
•
•
•
•
3 visits conducted by Study Nurses
3 measurements (average of 2nd and 3rd)
Mercury sphygmomanometer
Entry BP - average of 2nd and 3rd visit readings
• Randomisation
• Central - Data Management Centre (Adelaide)
• Stratified for age (> or  75)
• Follow-Up
•
•
•
•
GP manages patient according to usual practice
Conform (where possible) to randomisation arm
Achieve subject goal BP
At least 2 visits per year
New Engl J Med, 2003;348:583-92.
ANBP2
Study Drug Treatments
• ACE Inhibitor Group
•
•
•
•
Step 1.
Step 2.
Step 3.
Step 4.
ACE Inhibitor (enalapril recommended)
Beta or alpha blocker or calcium antagonist
Drug from class not used in Step 2 or diuretic
Drug from class not used in step 2 or 3
• Diuretic Group
•
•
•
•
Step 1.
Step 2.
Step 3.
Step 4.
Thiazide type diuretic (low dose)
Beta or alpha blocker or calcium antagonist
Drug from class not used in Step 2
Drug from class not used in step 2 or 3
ANBP2
New Engl J Med, 2003;348:583-92.
Study End-points
• Obtained by study nurses from GP case notes,
hospital case records and death certificates
• End-point Committee (blinded to treatment allocation)
evaluated all data relating to potential study endpoints
• Primary Outcome: All cardiovascular events (initial and
subsequent) or death from any cause – ‘total burden of
cardiovascular disease’
• Any first event or death – ‘event-free survival’
• Cause-specific first events
ANBP2
New Engl J Med, 2003;348:583-92.
End-points
• myocardial infarction (fatal and non-fatal)
• sudden or rapid or ‘other’ cardiac death
• coronary events resulting in coronary therapeutic
procedures
• cardiac failure (fatal or non-fatal)
• stroke (fatal or non-fatal)
• transient cerebral ischaemic attacks
• acute non-coronary or non-cerebral vascular
occlusion
• other vascular deaths
• dissecting or ruptured aortic aneurysm
New Engl J Med, 2003;348:583-92.
ANBP2
Data Analysis
• Multivariate proportional hazards (Cox) models incorporating:
– Wei-Lin-Weissfeld method for multiple failure time
data
– Li-Lagakos application of WLW method to analyse
recurrent event data with a terminating event
– Robust variance estimation
– Validation by simulation
• Proportional hazards (Cox) models for cause-specific first
events
New Engl J Med, 2003;348:583-92.
ANBP2
GP Involvement in ANBP2
2681 - GPs
1594 - Practices
500
299
361
200
472
224
390
270
958
601
New Engl J Med, 2003;348:583-92.
ANBP2
ANBP2 Subject Recruitment
Screened 54288
Randomised 6083
Rate 11%
7448
763
10%
7530
849
11%
14669
1310
9%
7607
672
9%
17145
2489
15%
ANBP2
Study profile
54288
screened
25805 ineligible
16899 unwilling to participate
5501 did not meet inclusion criteria
~ 3 yrs
6083
randomised
ACE
3044
Diuretic
3039
ITT* analysis
0
2
ACE
3044
Observation Time
Median
yrs
No Vital Status
New Engl J Med, 2003;348:583-92.
* Intention
Diuretic
3037
to treat
4.1
Patient yrs
24702
ANBP2
Baseline data
Male: Female
ACE
(3044)
Diuretic
(3039)
50:50
48:52
Age (yr)
Blood Pressure (mmHg)
72.0
71.9
167 ± 13
91 ± 8
168 ± 1
91 ± 8
Previously Treated
62%
62%
Body Mass Index (kg/m2)
27 ± 4
27 ± 4
Current Smokers
Physically Active
7%
78%
7%
76%
New Engl J Med, 2003;348:583-92.
ANBP2
Baseline data
ACE
(3044)
Coronary Heart Disease
Diuretic
(3039)
8%
8%
Cerebrovascular Disease
5%
5%
Diabetes Mellitus
8%
7%
Hypercholesterolaemia
- lipid lowering drugs
New Engl J Med, 2003;348:583-92.
38%
13%
36%
13%
ANBP2
Drug treatments
(3039)
At Randomisation
ACE
Diuretic
(3044) (3039)
At Study End
ACE
Diuretic
(3044)
Allocated Therapy
83%
83%
58%
62%
Monotherapy
82%
82%
65%
67%
 3 agents
No drugs
New Engl J Med, 2003;348:583-92.
16%
15%
6%
5%
4%
3%
ANBP2
Antihypertensive Medication Use at Study End
ACE
Diuretic
ACE
Beta Blocker
Ca Blocker
Diuretic
62
58
11
23
18
14
25
Single Drug
2 Drugs
25
3 + Drugs
65
Data represent %
New Engl J Med, 2003;348:583-92.
24
67
25
6
5
ANBP2
In-study blood pressure
170
6083
Systolic
-26 mmHg
6035
150
5585
5487
4323
1183
140
130
ACE
Diuretic
||
Blood Pressure (mm Hg)
160
95
6083
90
85
Diastolic
6035
-12 mmHg
5583
5487
4320
2
3
4
80
1183
75
0
1
New Engl J Med, 2003;348:583-92.
Years Since Randomization
ANBP2
5
Primary Result
Event
ACE
n
Rate
Diuretic
n
Rate
HR
(95%CI) p
All cardiovascular
692
events or any death
55.8
732
59.5
0.89 (0.79,1.00)
First cardiovascular
event or death
490
41.9
529
45.7
0.89 (0.79,1.01)
Death
195
15.7
210
17.1
0.90 (0.75,1.09)
Rate per 1000 patient years
Adjusted for age, gender
New Engl J Med, 2003;348:583-92.
ANBP2
Primary Result
Rate per 1000 patient years
Adjusted for age, gender
ANBP2
Cause-specific first
events
Hazard Ratio (95% CI) p
ACE better
0.2
Cardiovascular
0.88 (0.77,1.01) 0.07
Non-Fatal Cardiovascular
0.86 (0.74,0.99) 0.03
Cerebrovascular
0.90 (0.73,1.12) 0.35
Stroke
1.02 (0.78,1.33) 0.91
Coronary
0.86 (0.70,1.06) 0.16
Myocardial Infarction
0.68 (0.47,0.98) 0.04
Other Cardiovascular
0.90 (0.71,1.14) 0.36
Heart Failure
0.85 (0.62,1.18) 0.33
Diuretic better
1.0
5.0
All subjects - first any events
New Engl J Med, 2003;348:583-92.
ANBP2
Cause-specific fatal events
Hazard Ratio (95% CI) p
ACE better
0.2
Cardiovascular
0.99 (0.72,1.35) 0.94
Non-Cardiovascular
0.84 (0.66,1.08) 0.18
Cancer
0.98 (0.73,1.32) 0.89
Trauma
2.87 (0.31,26.9) 0.36
Other Non-Cardiovascular
0.57 (0.37,0.90) 0.01
Stroke
1.91 (1.04,3.50) 0.04
Coronary
0.74 (0.49,1.11) 0.14
Myocardial Infarction
0.79 (0.31,1.99) 0.61
Other Cardiovascular
0.95 (0.46,1.96) 0.89
Heart Failure
0.24 (0.03,1.94) 0.18
New Engl J Med, 2003;348:583-92.
All subjects - fatal events
Diuretic better
1.0
5.0
ANBP2
Cause-specific non-fatal events
Hazard Ratio (95% CI) p
ACE better
0.2
Stroke
0.93 (0.70,1.26) 0.65
Coronary
0.92 (0.73,1.16) 0.49
Myocardial Infarction
0.68 (0.47,0.99) 0.05
Other Cardiovascular
0.84 (0.66,1.07) 0.17
Heart Failure
0.85 (0.62,1.17) 0.32
Diuretic better
1.0
5.0
All subjects - first non-fatal events
New Engl J Med, 2003;348:583-92.
ANBP2
Summary
• 11% reduction in total cardiovascular events (or
death from any cause) with ACE inhibitor treatment
• 11% reduction in first events with ACE inhibitor
treatment
• 17% reduction in total events in males and no effect
in females
New Engl J Med, 2003;348:583-92.
ANBP2
Summary
• No difference between treatments
– total or cardiovascular mortality
– all cerebrovascular events
– all coronary events
• With ACE inhibitor treatment
– reduction in first non-fatal cardiovascular events
(HR 0.86)
– reduction in non-fatal myocardial infarctions
(HR 0.68)
– increase in fatal strokes (HR 1.91)
– cause-specific effects only in males
ANBP2
New Engl J Med, 2003;348:583-92.
Conclusion
Initiation of antihypertensive treatment in older
patients with an ACE inhibitor particularly in
males has a modest but definite outcome
advantage over a diuretic despite a similar
reduction in blood pressure
ANBP2
New Engl J Med, 2003;348:583-92.
CAMELOT
INVEST STUDY
International Verapamil-Trandolapril
Study (INVEST)
Overview
• Prospective, Randomized, Open, Blinded End-Point
Evaluation (PROBE) trial comparing verapamil- vs.
atenolol-based treatment strategies
• Designed to determine if one treatment strategy was
equivalent to the other in reducing all-cause mortality,
nonfatal myocardial infarction, or stroke
• Men and women (n=22,576) ≥ 50 years of age with
hypertension and coronary artery disease
• The patient population was selected to reflect the
composition of a primary care practice including
women, diabetics, ethnic minorities, and the elderly
Pepine CJ, et al. JAMA. 2003;290:2805-2816
International Verapamil-Trandolapril
Study (INVEST)
Treatment strategies
• Calcium antagonist strategy (CAS) using
verapamil-SR
• Non-calcium antagonist strategy (NCAS) using
atenolol
• Addition of trandolapril to the regimen of patients
with concomitant diabetes, renal failure, or heart
failure was recommended
• Additional antihypertensive therapy was allowed
to achieve and maintain goal blood pressure
Pepine CJ, et al. JAMA. 2003;290:2805-2816
INVEST: Primary and Secondary
Endpoints
Primary composite endpoint
First occurrence of
• Death (all-cause), or
• Nonfatal myocardial infarction, or
• Nonfatal stroke
Secondary endpoints
•
•
•
•
•
•
•
Each of the above as individual endpoints
Cardiovascular death
Time to most serious event (death, then MI, then stroke)
Angina
Cardiovascular hospitalizations
Blood pressure control
Cancer, Alzheimer’s disease, Parkinson’s disease, and
gastrointestinal bleeding
• New diagnosis of diabetes mellitus
Pepine CJ, et al. JAMA. 2003;290:2805-2816
INVEST: Design
Calcium Antagonist Strategy
Verapamil-SR 240 mg/d, plus
trandolapril 2 mg/d for patients with
diabetes, renal impairment, or heart
failure*
Verapamil-SR 240 mg/d, plus
trandolapril 2 mg/d
Non-Calcium Antagonist Strategy
Step 1
Step 2
Add Drug
Atenolol 50 mg/d, plus trandolapril
2 mg/d for patients with diabetes,
renal impairment, or heart failure
Atenolol 50 mg/d, plus
hydrochlorothiazide 25 mg/d
Verapamil-SR 180 mg twice daily,
plus trandolapril 2 mg twice daily
Step 3
Increase
Dose
Atenolol 50 mg twice daily, plus
hydrochlorothiazide 25 mg twice
daily
Verapamil-SR 180 mg twice daily,
plus trandolapril 2 mg twice daily,
plus hydrochlorothiazide 25 mg/d
Step 4
Add Drug
Atenolol 50 mg twice daily, plus
hydrochlorothiazide 25 mg twice
daily, plus trandolapril 2 mg/d
Maximum
Treatment
Maximum tolerated dose and/or
add nonstudy antihypertensive
medication
Maximum tolerated dose and/or
add nonstudy antihypertensive
medication
The drugs, order of addition, and recommended doses for each step of each strategy are summarized. Nonstudy
antihypertensive drugs could be added to control blood pressure except for β-blockers in those assigned to the
calcium antagonist strategy and calcium antagonists for those assigned to the non-calcium antagonist strategy.
Titration ranges: atenolol, 25-200 mg/d; hydrochlorothiazide, 12.5-100 mg/d; trandolapril, 1-8 mg/d; and
verapamil sustained release (Verapamil-SR), 120-480 mg/d.
*For patients with creatinine levels of ≥2.0 mg/dL (≥1.77 mol/L), the recommended starting dose was 0.5 mg/d
of trandolapril.
Pepine CJ, et al. JAMA. 2003;290:2805-2816
INVEST: Baseline Demographics
Calcium
Antagonist Strategy
(n=11,267)
Non-Calcium
Antagonist Strategy
(n=11,309)
Mean age (yrs)
66.0
66.1
Women (%)
51.9
52.3
White
48.5
48.3
Hispanic
35.7
35.6
Black
13.4
13.5
Asian
0.6
0.8
Other
1.9
1.9
29.1
29.2
Race/ethnicity (%)
Mean BMI (kg/m2)
BMI = Body Mass Index
Pepine CJ, et al. JAMA. 2003;290:2805-2816
INVEST: Baseline Conditions
(expressed as percentages)
Calcium Antagonist
Strategy
(n=11,267)
Non-Calcium Antagonist
Strategy
(n=11,309)
Myocardial infarction
32.1
31.8
Abnormal angiogram
38.9
39.5
Concordant stress abnormalities
21.3
21.1
Angina pectoris
66.2
67.0
CABG or PCI
27.3
27.3
5.3
5.0
Left ventricular hypertrophy
21.5
22.3
Unstable angina > 1 mo ago
11.4
11.5
Arrhythmia
7.1
7.1
Heart failure (class I-III)
5.5
5.6
History of smoking
46.6
46.0
Diabetes*
28.1
28.6
Stroke
Hypercholesterolemia*
55.9
*History of or currently taking antidiabetic or lipid-lowering medications
55.6
CABG= Coronary Artery Bypass Graft(s); PCI= Percutaneous Coronary Interventions
Pepine CJ, et al. JAMA. 2003;290:2805-2816
INVEST: Baseline Medications
(expressed as percentages)
Calcium Antagonist
Strategy
(n=11,267)
Non-Calcium Antagonist
Strategy
(n=11,309)
Aspirin or other
antiplatelet drugs
57.0
56.4
Other NSAIDS
17.6
17.9
Antidiabetic medications
22.1
22.9
Lipid-lowering agent
36.8
36.6
Nitrates
35.4
36.6
Potassium supplements
6.9
6.9
Hormone replacement*
17.7
18.5
*Data for women only (n=5,850 for CAS; 5,920 for NCAS)
NSAIDS = Nonsteroidal anti-inflammatory drugs
Pepine CJ, et al. JAMA. 2003;290:2805-2816
INVEST: Baseline Blood Pressures
Antihypertensive Medication Use
Mean systolic blood pressure (mmHg)
Mean diastolic blood pressure (mmHg)
Calcium
Antagonist
Strategy
Non-Calcium
Antagonist
Strategy
(n=9,758)
(n=9,791)
149.5
149.5
86.3
86.3
Blood pressure controlled (%)
Systolic
24.4
24.1
Diastolic
53.7
54.2
Both
22.1
21.6
(n=1,509)
(n=1,518)
159.2
160.1
92.9
92.6
No Antihypertensive Medication Use
Mean systolic blood pressure (mmHg)
Mean diastolic blood pressure (mmHg)
Pepine CJ, et al. JAMA. 2003;290:2805-2816
INVEST: Protocol-Specified Drug
Use at 12 and 24 Months
Patients (%)
Verapamil-SR
100
90
80
70
60
50
40
30
20
10
0
Atenolol
Trandolapril
12 Months
Hydrochlorothiazide
24 Months
*P<0.001
*
Calcium
Antagonist
Strategy
*P<0.001
*
Non-Calcium
Antagonist
Strategy
Pepine CJ, et al. JAMA. 2003;290:2805-2816
*
Calcium
Antagonist
Strategy
*
Non-Calcium
Antagonist
Strategy
INVEST: Number of ProtocolSpecified Drugs at 24 Months
100%
3 Drugs
Patients (%)
80%
60%
2 Drugs
40%
1 Drugs
20%
0 Drugs
0%
Calcium Antagonist
Strategy
Pepine CJ, et al. JAMA. 2003;290:2805-2816
Non-Calcium Antagonist
Strategy
INVEST: Mean Systolic and Diastolic
Blood Pressure During Study
Level (mmHg)
Level (mmHg)
Calcium Antagonist Strategy (CAS)
Non-Calcium Antagonist Strategy (NCAS)
Systolic Blood Pressure
170
150
130
110
Diastolic Blood Pressure
100
90
80
70
60
No. of Pts.
0
CAS 11267
NCAS 11309
6
12
18
8558
8573
8639
8694
7758
7710
24
30
Time, mo
7842
7850
Pepine CJ, et al. JAMA. 2003;290:2805-2816
5721
5834
36
42
48
3659
3679
1458
1473
796
817
INVEST: Patients with Controlled BP
by Treatment Group at 24 Months
Calcium
Antagonist
Strategy
Non-Calcium
Antagonist
Strategy
P Value
SBP <140 mmHg and
DBP <90 mmHg
72%
71%
0.18
JNC-VI SBP goals
achieved *
65%
64%
0.23
JNC-VI DBP goals
achieved †
89%
88%
0.46
BP Control Criteria
*SBP <140 mmHg for hypertensives and <130 mmHg for diabetes mellitus or renal impairment
†DBP <90 mmHg for hypertensives and <85 mmHg for diabetes mellitus or renal impairment
Pepine CJ, et al. JAMA. 2003;290:2805-2816
INVEST: Primary Composite
Endpoint by Treatment Group
Cumulative %
25
Calcium Antagonist Strategy (CAS)
Non-Calcium Antagonist Strategy (NCAS)
20
RR = 0.98 (0.90 – 1.06)
15
Log-Rank P=.57
10
5
0
No.
at Risk
0
6
12
18
24
30
36
Time, mo
11267 10921 10716 10512 10008
CAS
NCAS 11309 10991 10785 10536 10048
6612
6604
Pepine CJ, et al. JAMA. 2003;290:2805-2816
3738
3706
42
48
54
60
1568
1563
974
960
393
390
35
33
INVEST: Primary and Secondary
Outcomes by Treatment Group
Calcium Antagonist
Strategy
(n=11,267)
Non-Calcium Antagonist
Strategy
(n=11,309)
No. (%)
Rate per
1,000 patient
years
No. (%)
Rate per
1,000 patient
years
1,119 (9.93)
36
1,150 (10.17)
37
Death
873 (7.75)
28
893 (7.90)
29
Nonfatal MI
151 (1.34)
5
153 (1.35)
5
Nonfatal stroke
131 (1.16)
4
148 (1.31)
5
Cardiovascular
death
431 (3.83)
14
431 (3.81)
14
Cardiovascular
hospitalization
726 (6.44)
24
709 (6.27)
23
First event*
* Primary Outcome = first occurrence of death, nonfatal MI, or nonfatal stroke
Pepine CJ, et al. JAMA. 2003;290:2805-2816
INVEST: Relative Risk of Primary
and Secondary Outcomes
RR
(95% CI)
Favors
CAS
First event*
0.98 (0.90 – 1.06)
Death
0.98 (0.90 – 1.07)
Nonfatal MI
0.99 (0.79 – 1.24)
Nonfatal stroke
0.89 (0.70 – 1.12)
Cardiovascular death
1.00 (0.88 – 1.14)
Cardiovascular hospitalization
1.03 (0.93 – 1.14)
CAS = Calcium Antagonist Strategy
NCAS = Non-Calcium Antagonist Strategy
Favors
NCAS
0.6 0.8 1.0 1.2 1.4
RR (95% CI)
* Primary Outcome = first occurrence of death, nonfatal MI, or nonfatal stroke
Pepine CJ, et al. JAMA. 2003;290:2805-2816
INVEST: Primary Composite Endpoint
in Subgroups by Treatment Strategy
Clinical Characteristics
Favors CAS
Favors NCAS
Age ≤70
Age >70
Female
Male
White
Black
Hispanic
Other ethnicities
Diabetes
No diabetes
Hypercholesterolemia
No hypercholesterolemia
0.4
CAS = Calcium Antagonist Strategy
NCAS = Non-Calcium Antagonist Strategy
0.6
Pepine CJ, et al. JAMA. 2003;290:2805-2816
0.8
1.0
1.2
RR (95% CI)
1.4
1.6
1.8
INVEST: Primary Composite Endpoint
in Subgroups by Treatment Strategy
Cardiovascular Conditions
Favors CAS
Favors NCAS
Prior myocardial infarction
No prior myocardial infarction
Congestive heart failure
No congestive heart failure
Revascularization
No revascularization
Left ventricular hypertrophy
No left ventricular hypertrophy
CAS = Calcium Antagonist Strategy
0.4
0.6
NCAS = Non-Calcium Antagonist Strategy
Pepine CJ, et al. JAMA. 2003;290:2805-2816
0.8
1.0
1.2
RR (95% CI)
1.4
1.6
1.8
INVEST: New Onset of
Diabetes During Study
10
RR = 0.85 (0.77 – 0.95)
8.23
Patients (%)
8
7.03
6
4
2
0
Calcium Antagonist
Strategy
Pepine CJ, et al. JAMA. 2003;290:2805-2816
Non-Calcium Antagonist
Strategy
INVEST: Summary
•
The verapamil-based regimen (calcium antagonist
strategy) and the atenolol-based regimen (noncalcium antagonist strategy) on the primary
composite endpoint of all-cause mortality, nonfatal
MI, or nonfatal stroke were similar
•
The verapamil- and atenolol-based regimens
showed similar efficacy in blood pressure control,
cardiovascular death, and cardiovascular
hospitalizations
•
The verapamil-based regimen was associated with
a small but significantly lower incidence of new
onset diabetes
Pepine CJ, et al. JAMA. 2003;290:2805-2816
INVEST: Conclusions for the Clinician
• The verapamil-based regimen (calcium antagonist
strategy) was as effective as the atenolol-based
regimen (non-calcium antagonist strategy) in
reducing morbidity and mortality in patients with
both hypertension and coronary artery disease
• Multi-drug treatment regimens can achieve goal
blood pressures in a majority of patients with
hypertension and coronary artery disease
• Benefits with each treatment regimen were
observed in all study subgroups (women, ethnic
minorities, elderly, and diabetics)
Pepine CJ, et al. JAMA. 2003;290:2805-2816
LIFE STUDY
Losartan Intervention For
Endpoint Reduction in
Hypertension Study
LIFE Study Overview
Double-blind, randomized trial to compare the effects of
losartan and atenolol on cardiovascular morbidity and
mortality in high-risk patients with hypertension and left
ventricular hypertrophy (LVH)
Population
• 9,193 patients (55 to 80 years old) from 945 sites in 7
countries
– previously treated or untreated essential hypertension
(systolic BP 160–200 mmHg or diastolic BP 95–115
mmHg)
– ECG LVH
• 1,195 patients (13%) had diabetes at baseline
Dahlof B, et al. Lancet. 2002;359:995-1003.
www.hypertensiononline.
org
LIFE Study Design
Assessed for eligibility
n=10,780
Randomized
n=9,222
Ineligible (n=1,558)
• failed protocol
criteria
(n=1,343)
• unwilling to
participate
Excluded(n=215)
for irregularities (n=29)
Losartan
n=4,605
Atenolol
n=4,588
4,605 available for
intention-to-treat analyses
4,588 available for
intention-to-treat analyses
44 withdrew consent
57 vital status only
4 lost to follow-up
34 withdrew consent
50 vital status only
8 lost to follow-up
Dahlof B, et al. Lancet. 2002;359:995-1003.
www.hypertensiononline.
org
LIFE Study Endpoints*
Primary Endpoint
• Composite of cardiovascular mortality, fatal and
non-fatal myocardial infarction, and fatal and
non-fatal stroke
Other predefined endpoints
– total mortality
– angina pectoris†
– heart failure†
– coronary or peripheral revascularization
procedures
– resuscitated cardiac arrest
– new-onset diabetes mellitus
*Each endpoint includes only first event; patients could appear in more than one
category.
†Requiring hospital admission
Dahlof B, et al. Lancet. 2002;359:995-1003.
www.hypertensiononline.
org
LIFE Study Distribution of 9,193
Participants Among 7 Countries
Iceland
1%
Finland
16%
Denmark
15%
Norway
15%
United
States
19%
United Kingdom
9%
Dahlof B, et al. Lancet. 2002;359:995-1003.
Sweden
24%
www.hypertensiononline.
org
LIFE Study Dosing
Titration to target
blood pressure
<140/90 mmHg
Losartan 100 mg
+ HCTZ 12.5-25 mg + others*
Losartan 100 mg
mg
Losartan 50 mg
+ HCTZ 12.5
+ HCTZ 12.5 mg
Losartan 50 mg
Placeb
Atenolol 50 mg
o
Atenolol 50 mg + HCTZ 12.5 mg
Atenolol 100 mg + HCTZ 12.5
mg
Atenolol 100 mg
+ HCTZ 12.5-25 mg + others*
14
7
DAY
1
1
2
4
6
1 1.5
MONTH
2
2.5
3
3.5
4
5
YEAR
*Other antihypertensives excluding ACEIs, AII antagonists,
beta-blockers
www.hypertensiononline.
Dahlof B, et al. Lancet. 2002;359:995-1003.
org
LIFE Study
Baseline Characteristics* (1)
Losartan
group
n=4,605
Atenolol
group
(n=4,588)
66.9
66.9
Female (%)
54
54
BMI (kg/m2)
28
28
174.3/97.9
174.5/97.7
73.9
73.7
2834.4
2824.1
Sokolow-Lyon (mm)
30
30.1
Framingham risk score
(%)
22
22
Smokers
(%)
Dahlof
B, et al.
Lancet. 2002;359:995-1003.
16
Age (yrs)
Blood pressure (mmHg)
Heart rate (bpm)
Cornell product (mm x
msec)
*P=NS for all comparisons
www.hypertensiononline.
17
org
LIFE Study
Baseline Characteristics* (2)
Losartan
(n=4,60
5)
Atenolol
(n=4,58
8)
Diabetes mellitus
13 %
13 %
Isolated systolic
hypertension (>160/<90
mmHg)
14 %
15 %
Coronary heart disease
17 %
15 %
Cerebrovascular disease
8%
8%
Peripheral vascular
disease
6%
5%
Medical History
*P=NSAtrial
for allfibrillation
comparisons
Dahlof B, et al. Lancet. 2002;359:995-1003.
3 www.hypertensiononline.
%
4%
org
LIFE Study Distribution of
Therapy*
Losartan (mean dosage 82 mg)
23%
4%
26%
50%
100 mg with or
without additional
drugs*
Alone
18%
18%
9%
2%
Atenolol (mean dosage 79
mg)
4%
27%
22%
43%
50 mg only
50 mg + additional
drugs*
Off study drugs
With HCTZ only
With other drugs
only
With HCTZ and
other drugs
16%
20%
10%
2%
*At endpoint or end of follow-up
Dahlof B, et al. Lancet. 2002;359:995-1003.
www.hypertensiononline.
org
LIFE Study Blood Pressure
and Heart Rate Results
Losartan
(n=4,60
5)
Atenolol
(n=4,58
8)
144.1
145.4
-30.2
-29.1
81.3
80.9
-16.6
-16.8
102.2
102.4
SBP last visit
(mmHg)
Change in SBP*
DBP last visit
(mmHg)
Change in DBP
MAP last visit
(mmHg)
BP <140/<90 (%)
*P=0.017SBP <140
†P<0.0001
(%)
mmHg
Dahlof B, et al. Lancet. 2002;359:995-1003.
DBP < 90 mmHg
48
49
45
46
www.hypertensiononline.
org
LIFE Study Blood Pressure
During Follow-up
180
160
Systolic
mmHg
140
120
Mean Arterial
100
80
60
Losartan
Atenolol
40
20
Diastolic
0
6
12
18
24
30
Study Month
Dahlof B, et al. Lancet. 2002;359:995-1003.
Reprinted with permission from Elsevier Science.
36
42
48
54
www.hypertensiononline.
org
LIFE Study Primary Composite
Endpoint
16
Proportion of patients
with first event (%)
Intention-to-treat
14
12
10
Adjusted risk reduction 13·0%, P=0·021
Unadjusted risk reduction 14·6%, P=0·009
Atenolol
8
6
Losartan
4
2
Study Month 0
6
12 18 24 30 36 42 48 54 60 66
Losartan (n)4605 4524 4460 4392 4312 4247 4189 4112 4047 3897 1889 901
Atenolol (n) 4588 4494 4414 4349 4289 4205 4135 4066 3992 3821 1854 876
Dahlof B, et al. Lancet. 2002;359:995-1003.
Reprinted with permission from Elsevier Science.
www.hypertensiononline.
org
LIFE Study Cardiovascular Mortality
8
Proportion of patients
with first event (%)
7
6
Intention-to-treat
Adjusted risk reduction 11·4%, P=0·21
Unadjusted risk reduction 13·3%, P=0·14
5
Atenolol
4
Losartan
3
2
1
0
6
12
18
24
36 42
Study
Dahlof B, et al. Lancet. 2002;359:995-1003.
Month
Reprinted with permission from Elsevier Science.
30
48
54
60
66
www.hypertensiononline.
org
LIFE Study Fatal and Non-Fatal
Myocardial Infarction
Proportion of patients
with first event (%)
7
6
5
Intention-to-treat
Adjusted Risk Reduction -7·3%, P=0·49
Unadjusted Risk Reduction -5·0%, P=0·63
Losartan
4
3
Atenolol
2
1
0
6
12
18
24
30 36 42
Study Month
Dahlof B, et al. Lancet. 2002;359:995-1003.
Reprinted with permission from Elsevier Science.
48
54
60
66
www.hypertensiononline.
org
Proportion of patients
with first event (%)
8
LIFE Study Fatal and Non-Fatal
Stroke
Intention-to-treat
7 Adjusted risk reduction 24·9%, P=0·001
Unadjusted risk reduction 25·8%, P=0·0006
6
Atenolol
5
Losartan
4
3
2
1
0
6
12
18
24
30 36 42
Study Month
Dahlof B, et al. Lancet. 2002;359:995-1003.
Reprinted with permission from Elsevier Science.
48
54
60
66
www.hypertensiononline.
org
LIFE Study New-Onset Diabetes
10
Intention-to-treat
Proportion of patients
with first event (%)
9
Adjusted risk reduction 25%, P=0·001
8 Unadjusted risk reduction 25%, P=0·001
7
Atenolol
6
5
Losartan
4
3
2
1
0
6
12
18
24
30
36
42
48
54 60 66
Study Month
Dahlof B, et al. Lancet. 2002;359:995-1003.
www.hypertensiononline.
Presented by B Dahlof at the American College of Cardiology
org
Scientific Sessions Late-Breaking Clinical Trials III, 2002.
Proportion of patients who
dropped-out because of AE (%)
LIFE Study Discontinuation
Rates
Due to Adverse Events (AE)
20
P<0.0001
16
12
P<0.0001
Atenolol
Losartan
8
4
P=0.006
0
All
Drug-related
Dahlof B, et al. Lancet. 2002;359:995-1003.
Reprinted with permission from Elsevier Science.
Serious,
drug-related
www.hypertensiononline.
org
Change from baseline (%)
LIFE Study Change in Cornell
Voltage Duration Product and
Sokolow-Lyon
0
Cornell Product
Sokolow-Lyon
-2
-4
-6
-8
-10
-12
-14
-16
P<0.0001
Losartan
Atenolol
P<0.0001
-18
Dahlof B, et al. Lancet. 2002;359:995-1003.
Reprinted with permission from Elsevier Science.
www.hypertensiononline.
org
LIFE Study Diabetes Subgroup
Primary Composite Endpoint
Proportion of patients
with first event (%)
24
Adjusted risk reduction 24·5%, P=0·031
20Unadjusted risk reduction 26.7%, P=0·017
16
Atenolol
Losartan
12
8
4
Study Month 0
Losartan (n)586
Atenolol (n) 609
6
569
588
12
558
562
18
548
552
24
532
540
30
520
527
36
513
507
Lindholm LH, et al. Lancet. 2002;359:1004-1010.
Reprinted with permission from Elsevier Science.
42
501
486
48
484
472
54
459
434
60
237
204
66
127
99
www.hypertensiononline.
org
LIFE Study Diabetes Subgroup
Primary Composite Endpoint and
Components
Endpoint
s
Composite
No. of
P
events value
242
0.031
99
0.028
116
NS
Myocardial
infarction
91
NS
Total Mortality
167
0.002
CV Death
Stroke
Adjusted
hazard ratio (95% CI)
0.5
1
1.5
Favors
Favors
losarta
Lindholm LH, et al. Lancet. 2002;359:1004-1010.
atenolol
www.hypertensiononline.
Presented by B Dahlof at the American College of Cardiology
n
org
Scientific Sessions Late-Breaking Clinical Trials III, 2002.
LIFE Study Diabetes Subgroup
Total Mortality
Proportion of patients
with first event(%)
24
Adjusted risk reduction 38·7%,
P=0·002
Unadjusted risk reduction 40·1%,
P=0·001
20
16
Atenolol
12
8
Losartan
4
0
6
12
18
24
30
36
42
Study Month
Lindholm LH, et al. Lancet. 2002;359:1004-1010.
Reprinted with permission from Elsevier Science.
48
54
60
66
www.hypertensiononline.
org
LIFE Study Summary
• Losartan-based compared with atenololbased
antihypertensive therapy was associated
with:
– A reduction in the combined primary endpoint of
cardiovascular death, stroke or MI (-13%)
– fewer strokes (-25%)
– similar blood pressure reduction
• Losartan reduced the rate of new-onset
diabetes (-25%)
• In the diabetic subgroup, losartan reduced
the rate of:
– combined endpoint of cardiovascular death,
stroke and MI (-25%)
– all-cause mortality (-39%)
Dahlof B, et al. Lancet. 2002;359:995-1003.
Lindholm LH, et al. Lancet. 2002;359:1004-1010.
www.hypertensiononline.
org
LIFE Study Conclusions
• Losartan reduced the combined risk of
cardiovascular morbidity and mortality
compared to atenolol with benefits not
explained by blood pressure reduction
• Losartan reduced the rate of new-onset
diabetes
• Losartan was significantly better
tolerated than atenolol
• Among diabetics, losartan reduced
cardiovascular morbidity and mortality
Dahlof B, et al. Lancet. 2002;359:995-1003.
Lindholm LH, et al. Lancet. 2002;359:1004-1010.
www.hypertensiononline.
org
LIFE Study Isolated Systolic
Hypertension Subgroup
Overview
Double-blind, randomized trial to compare the effects of
losartan and atenolol on cardiovascular morbidity and
mortality in patients with isolated systolic hypertension who
were a subgroup of high-risk hypertensive patients in the
LIFE study (n=9,193)
Cohort
1,326 patients (55 to 80 years old) from 945 sites in 7
countries who were enrolled in the LIFE study
– Isolated systolic hypertension
• systolic blood pressure 160–200 mmHg
• diastolic blood pressure <90 mmHg
• previously treated or untreated
– ECG criteria for LVH
LIFE=Losartan Intervention for Endpoints
Dahlof B, et al. Am J Hypertens. 1997;10:705-713.
Kjeldsen SE, et al. JAMA. 2002;228:1491-1498.
www.hypertensiononline.
org
LIFE Study ISH Subgroup Design
Assessed for
eligibility
n=10,778
Randomized
n=9,222
Ineligible (n=1,556)
•Did not meet protocol criteria
(n=1,341)
•Unwilling to participate
(n=215)
Excluded for irregularities (n=29)
Losartan
n=660
Isolated systolic
hypertension
n=1,326
Atenolo
l
n=666
650 available for
intention-to-treat analyses
Vital status only (n=12)
Withdrawn consent (n=10)
Lost to follow-up (n=0)
659 available for
intention-to-treat
analyses
Vital status only (n=8)
Withdrawn consent
(n=5)
Isolated systolic hypertension (ISH) defined as systolic blood
pressure
160
Lost to
follow-up
(n=2)
www.hypertensiononline.
mmHg, with diastolic blood pressure <90 mmHg.
Kjeldsen SE, et al. JAMA. 2002;228:1491-1498.
org
LIFE Study ISH Subgroup
Baseline Characteristics
Losartan
n=660
Atenolol
n=666
Age (yrs)
70.2
70.4
Female (n)
388
408
174.2/83.
0
174.5/82.3
Heart rate (bpm)
71.5
71.5
Body mass index (kg/m2)
27.2
27.7
Current smokers (n)
95
102
Framingham risk score (%)
23
24
Cornell VD Product (mm 
msec)
2772
2820
Kjeldsen
SE, et al. JAMA.
2002;228:1491-1498.
Sokolow-Lyon
Voltage
(mm)
30.8
31.4
Blood pressure (mmHg)
www.hypertensiononline.
org
LIFE Study ISH Subgroup
Medical History
Losartan
n=660
Atenolol
n=666
n
%
n
%
Previously untreated
hypertension
233
35.3
211
31.7
Coronary heart disease
158
23.9
140
21.0
Cerebrovascular disease
70
10.6
86
12.9
Peripheral vascular
disease
57
8.6
55
8.3
Atrial fibrillation
28
4.2
39
5.9
103
15.6
131
19.7
Diabetes
Kjeldsen SE, et al. JAMA. 2002;228:1491-1498.
www.hypertensiononline.
org
LIFE Study ISH Subgroup
Drug Use at Endpoint or
Termination
Losartan
(%)
Atenolo
l (%)
30.4
30.9
9.8
8.7
20.6
22.2
44.1
36.8
2.3
1.4
16.1
13.5
3.6
2.6
22.1
19.4
Off study therapy
25.5
32.3
*including hydrochlorothiazide (HCTZ)
Kjeldsen SE, et al. JAMA. 2002;228:1491-1498.
www.hypertensiononline.
org
50 mg (total)
Alone
50 mg plus other therapy*
100 mg (total)
Alone
With HCTZ only
With other therapy only
With HCTZ & other
LIFE Study ISH Subgroup
Composite of CV Death, Stroke, and
MI
Endpoint rate (%)
18 Unadjusted relative risk=29%; P=0.02
16
Adjusted relative risk reduction=25%; P=0.06
14
12
10
8
6
Atenolol
Losartan
4
2
0
0
6
12 18 24 30 36 42 48 54 60 66
Study monthCV=cardiovascular
Kjeldsen SE, et al. JAMA. 2002;228:1491-1498.
Copyright 2002, American Medical Association.
MI=myocardial
www.hypertensiononline.
infarction
org
LIFE Study ISH Subgroup
Cardiovascular Mortality
Endpoint rate (%)
10 Unadjusted relative risk reduction=49%;
8
P=0.004
Adjusted relative risk reduction=46%; P=0.01
6
4
Atenolol
Losartan
2
0
0
6
12 18 24 30 36 42 48 54 60 66
Study month
Kjeldsen SE, et al. JAMA. 2002;228:1491-1498.
Copyright 2002, American Medical Association.
www.hypertensiononline.
org
LIFE Study ISH Subgroup
Fatal and Non-fatal Stroke
Endpoint rate (%)
10 Unadjusted relative risk reduction=44%;
8
P=0.008
Adjusted relative risk reduction=40%;
P=0.02
6
4
Atenolol
Losartan
2
0
0
6
12 18 24 30 36 42 48 54 60 66
Study month
Kjeldsen SE, et al. JAMA. 2002;228:1491-1498.
Copyright 2002, American Medical Association.
www.hypertensiononline.
org
LIFE Study ISH Subgroup
Fatal and Non-fatal Myocardial
Infarction
Endpoint rate (%)
10
8
Unadjusted relative risk reduction=14%;
P=0.54
Adjusted relative risk reduction=11%;
P=0.64
6
4
Atenolol
Losartan
2
0
0
6
12 18 24 30 36 42 48 54 60 66
Study month
Kjeldsen SE, et al. JAMA. 2002;228:1491-1498.
Copyright 2002, American Medical Association.
www.hypertensiononline.
org
LIFE Study ISH Subgroup
Total Mortality
18
Endpoint rate (%)
16
14
12
Unadjusted relative risk reduction=30%;
P=0.03
Adjusted relative risk reduction=28%;
P=0.046
10
8
6
4
Atenolol
Losartan
2
0
0
6
12 18 24 30 36 42 48 54 60 66
Study month
Kjeldsen SE, et al. JAMA. 2002;228:1491-1498.
Copyright 2002, American Medical Association.
www.hypertensiononline.
org
LIFE Study ISH Subgroup
New-Onset Diabetes
Endpoint rate (%)
12
10
8
Unadjusted relative risk reduction=37%;
P=0.04
Adjusted relative risk reduction=38%;
P=0.04
6
4
Atenolol
Losartan
2
0
0
6
12 18 24 30 36 42 48 54 60 66
Study month
Kjeldsen SE, et al. JAMA. 2002;228:1491-1498.
www.hypertensiononline.
org
LIFE Study ISH Subgroup
Blood Pressure During Follow-up
180
Atenolol
Mean BP reduction=28/9 mmHg
160
Systolic
140
mmHg
Losartan
120
100
Mean Arterial
80
Diastolic
60
40
0
6
12
18
24
30
36
42
48
54
Study month
www.hypertensiononline.
Kjeldsen SE, et al. JAMA. 2002;228:1491-1498.
Copyright 2002, American Medical Association.
org
Change from baseline (%)
LIFE Study ISH Subgroup
ECG-LVH Regression
0
-2
Cornell VD Product Sokolow-Lyon
-63*
-4
-6
-8
211*
P<0.001
-2.3*
-10
-12
-14
Losartan
Atenolol
-3.9*
P<0.001
*absolute change from baseline
Kjeldsen SE, et al. JAMA. 2002;228:1491-1498.
www.hypertensiononline.
org
LIFE Study ISH Subgroup
Discontinuation Due to Adverse
Events
Patients discontinued
due to adverse event (%)
25
P=0.002
Losartan
Atenolol
20
15
P<0.001
10
P=0.18
5
0
P=0.84
All
Drug-relatedSerious
Kjeldsen SE, et al. JAMA. 2002;228:1491-1498.
Serious,
drug-related
www.hypertensiononline.
org
LIFE Study ISH Subgroup
Summary
• Losartan was not significantly different from atenolol
against the combined primary endpoint of
cardiovascular (CV) death, stroke and myocardial
infarction (P=0.06) in patients with isolated systolic
hypertension (ISH) after adjustment for blood
pressure and Framingham risk score
• Losartan vs. atenolol decreased CV mortality (P=0.01)
and stroke (P=0.02) but not MI (P=0.64) in patients
with ISH
• Losartan induced stronger regression of left
ventricular hypertrophy (LVH) than atenolol
– Cornell VD Product P<0.001
– Sokolow-Lyon P<0.001
• Losartan compared to atenolol reduced the rate of new
onset diabetes (P=0.04)
Kjeldsen SE, et al. JAMA. 2002;228:1491-1498.
www.hypertensiononline.
org
LIFE Study ISH Subgroup
Conclusions
• The greater effect of treatment with losartan vs. atenolol
on combined CV mortality, stroke and MI in patients with
isolated systolic hypertension (ISH) (RRR = 25%)
compared to the larger LIFE study cohort (RRR = 13%)
suggested a particular cardiovascular protective effect of
losartan in ISH
• Losartan achieved the same level of blood pressure
reduction as atenolol
• Losartan was significantly better tolerated than atenolol
• These results suggest that losartan-based compared to
atenolol-based therapy may be preferred in patients with
isolated systolic hypertension and left ventricular
hypertrophy
• It is currently not known whether losartan is superior to
diuretics, calcium channel blockers, or other first-line
of reduction
isolated systolic hypertension.
RRRtreatments
= relative risk
www.hypertensiononline.
Kjeldsen SE, et al. JAMA. 2002;228:1491-1498.
org
ACCOMPLISH STUDY
Avoiding Cardiovascular Events
through
COMbination Therapy in Patients
LIving with Systolic Hypertension
Kenneth Jamerson1, George L. Bakris2, Bjorn Dahlof3, Bertram Pitt1,
Eric J. Velazquez4, and Michael A. Weber5
for the ACCOMPLISH Investigators
University of Michigan Health System, Ann Arbor, MI1; University of Chicago-Pritzker School of Medicine,
Chicago, IL2; Sahlgrenska University Hospital, Gothenburg, Sweden3; Duke University School of Medicine,
Durham, NC4; SUNY Downstate Medical College, Brooklyn, NY5
ACCOMPLISH: A Novel
Hypertension Trial
• Traditional approach to hypertension
management:
– Initiate monotherapy then sequentially add
medications to achieve target BP
• ACCOMPLISH:
– Initiate single tablet combination therapy
in high-risk hypertension
– Specific combinations may confer target
organ protection in addition to their BPlowering effects
ACCOMPLISH Hypothesis
ACCOMPLISH will test a new strategy for
the treatment of hypertension – the first
outcomes trial to compare initial therapy
with two different combinations
The combination of benazepril and
amlodipine will reduce cardiovascular
morbidity and mortality in patients with
high-risk hypertension by 15% when
compared to the combination of
benazepril and HCTZ
Primary Endpoint
Primary Endpoint
Cardiovascular Mortality and
Morbidity, defined as:
– Cardiovascular death
– Non-fatal myocardial infarction
– Non-fatal stroke
– Hospitalization for unstable angina
– Coronary revascularization
procedure (PCI or CABG)
– Resuscitated sudden death
Jamerson KA et al. Am J Hypertens. 2003;16(part2)193A.
Targeted Population for Recruitment
into the ACCOMPLISH Study
• Men or women age ≥ 55 years
• SBP ≥ 160 mmHg or currently on
antihypertensive therapy
• Evidence of cardiovascular or renal
disease or target organ damage
ACCOMPLISH Patients Were Receiving
Significant Medical Management at
Baseline
• 78% of patients on ACEI or ARB
• 67% of patients on lipid-lowering
agents
• 63% of patients on anti-platelet
therapy
• Mean LDL 101.6 mg/dl
Baseline Traits of the ACCOMPLISH
Cohort
• 50% of patients were obese
• 60% of patients had Diabetes Mellitus
• 97% of patients were treated
previously for hypertension
• 74% of patients were treated with ≥ 2
antihypertensive agents
• Only 37.5% of patients were
controlled to <140/90 mmHg
ACCOMPLISH: Design
Free add-on
antihypertensive
agents*
Amlodipine 10 +
benazepril 40 mg
Screening
Randomization
Amlodipine 5 mg +
benazepril 40 mg
Amlodipine 5 mg +
benazepril 20 mg
Benazepril 20 mg +
HCTZ 12.5 mg
Benazepril 40 mg +
HCTZ 12.5 mg
Benazepril 40 mg +
HCTZ 25 mg
Titrated to achieve BP<140/90 mmHg;
<130/80 mmHg in patients with diabetes or
renal insufficiency
14 Days
Day 1
Month 1
Free add-on
antihypertensive
agents*
Month 2
*Beta blockers; alpha blockers; clonidine; (loop diuretics).
Jamerson KA et al. Am J Hypertens. 2003;16(part2)193A
Month 3
Year 5
Baseline Demographics
ACEI / HCTZ
CCB / ACEI
N=5741 (%)
N=5721 (%)
Gender
Male
Female
3509 (61.1)
2226 (38.8)
3436 (60.1)
2283 (39.9)
Race
Caucasian
Black
Asian
Other
4789 (83.4)
699 (12.2)
27 (0.5)
220 (3.8)
4814 (84.1)
675 (11.8)
22 (0.4)
208 (3.6)
Age
Mean (years)
< 70
≥ 70
68.3
3407 (59.3)
2328 (40.6)
68.4
3367 (58.9)
2351 (41.1)
Region
Nordic countries*
United States
1676 (29.2)
4059 (70.7)
1677 (29.3)
4042 (70.7)
*Denmark, Finland, Norway or Sweden
Systolic Blood Pressure Over
Time
ACEI / HCTZ
N=5733
CCB / ACEI
mm Hg
N=5713
130mmHg
Difference of 0.7 mmHg p<0.05*
129.3 mmHg
Month
Patients
5731
5709
5387
5377
5206
5154
4999
4980
*Mean values are taken at 30 months F/U
visitDBP: 71.1
DBP: 72.8
4804
4831
4285
4286
2520
2594
1045
1075
ACCOMPLISH: Exceptional Control
Rates
with Initial Combination Therapy
90
Control rate (%)
80
78.5
81.7
70
60
50
40
30
37.2
37.9
ACEI / HCTZ
CCB / ACEI
20
10
N=5733
P<0.001 at 30 months
follow-up
Control defined as <140/90 mmHg
N=5713
Baseline
Control
Rates
Low Pill Burden in ACCOMPLISH
ACEI / HCTZ
CCB / ACEI
Study Medication Only
Study Medication Only
Study + 1 Add-on
Study + 1 Add-on
Study + ≥ 2 Add-on
Study + ≥ 2 Add-on
Drug Interruption
Drug Interruption
N=5733
N=5713
Includes patients receiving beta blockers, alpha blockers, clonidine, loop diuretics.
The number of patients with free add-on antihypertensive agents only include
those patients who has reached dose level 3.
At 30 month follow-up
DSMB Oct 17 2007
• Pre-specified efficacy boundary was
crossed with 60% of the expected trial
information
• Executive Committee accepted the
recommendation
• Last patient last visit was Jan 24, 2008
• Total of 1176 unique patients with events
• 95.3% of primary events are adjudicated
Kaplan Meier for Primary Endpoint
Cumulative event rate
ACEI / HCTZ
CCB / ACEI
20% Risk Reduction
650
526
p = 0 .0002
Time to 1st CV morbidity/mortality (days)
HR (95% CI): 0.80 (0.72, 0.90)
INTERIM RESULTS Mar 08
Primary Endpoint and Components
Incidence of adjudicated primary endpoints, based upon cut-off analysis date 3/24/2008
(Intent-to-treat population)
Risk Ratio
(95%)
Composite CV mortality/morbidity
0.80 (0.72–0.90)
Cardiovascular mortality
0.81 (0.62-1.06)
Non-fatal MI
0.81 (0.63-1.05)
Non-fatal stroke
0.87 (0.67-1.13)
Hospitalization for unstable angina
0.74 (0.49-1.11)
Coronary revascularization procedure
0.85 (0.74-0.99)
Resuscitated sudden death
1.75 (0.73-4.17)
0.5
INTERIM RESULTS Mar 08
Favors
CCB / ACEI
1.0
2.0
Favors
ACEI / HCTZ
Primary and Other Endpoints
Incidence of adjudicated primary endpoints, based upon cut-off analysis date 3/24/2008
(Intent-to-treat population)
Risk Ratio
(95%)
0.80 (0.72–
Composite CV mortality/morbidity
0.90)
Primary w/o revascularization
0.79 (0.68–
Hard CV endpoint
0.92)
(CV death, non-fatal MI, non-fatal stroke)
0.80 (0.68–
All cause mortality
0.5
Favors
CCB / ACEI
INTERIM RESULTS Mar 08
1.0
2.0
Favors
ACEI / HCTZ
0.94)
0.90 (0.75–
1.08)
Summary
• Single tablet combination therapy was
initiated in 11,462 high risk
hypertensive patients
• After mean follow-up of 39 months,
– The combination of ACEI / CCB was superior
to ACEI / diuretic
– CV morbidity / mortality was reduced by
20% (p=0.0002)
– Hard CV Endpoint (CV death, stroke and MI)
was reduced by 20% (p=0.007)
Summary (cont’d)
• Prior to study entry, 97% of patients were
on antihypertensive medication, 74%
receiving > 2 therapies
• After mean follow up of 30 months,
– Overall BP control rates increased from
37% to 80%
– Mean SBP decreased from 145 to <130
mmHg
– 50% of participants required only one
tablet
Conclusions
ACCOMPLISH achieved exceptional BP
control with combination therapy
providing a new option for cardiovascular
risk reduction to millions of patients with
hypertension.
The results of ACCOMPLISH provide
compelling evidence for initial
combination therapy with ACEI / CCB and
challenge current diuretic-based
guidelines.
Treatment of uncomplicated
hypertension:
Implications on the
management of hypertension
•
•
•
•
Need for ASCOT – BPLA
ASCOT – BPLA
Results of ASCOT – BPLA
Implications
A large majority of hypertensive
patients require combination
treatment …
85%
75%
ALLHAT
HOT
Required 2 or more drugs for blood pressure control
Lancet 2005; 366: 895–906.
Lancet 1998;351:1755-1762.
And yet ...up to ASCOT...no study
assessed treatment regimens...for
example...
In ALLHAT.. 33357 patients..
Lisinopril
Amlodipine
Diuretic
Atenolol
Clonidine
Reserpine
Atenolol
Clonidine
Reserpine
Atenolol
Clonidine
Reserpine
...Second step drugs were common to randomized groups
in effect...only the initial treatment was randomly compared
JAMA 2002;288:2981-97
NEJM 2003;348:583-92
By contrast...
In ASCOT..19257 patients..
Randomized to…
And in the 9/10
uncontrolled patients
Amlodipine
Atenolol
Amlodipine +
Perindopril
Atenolol +
Diuretic
Addition of Doxazosin
GITS in both the groups
…the comparison was therefore between treatment
regimens…
Amlodipine + perindopril versus Atenolol + diuretic
Lancet 2005; 366: 895–906
At present therefore..only two drug regimens have been properly assessed
End points
• To assess nonfatal MI and fatal CHD
with a standard anti-hypertensive
regimen (beta blocker + diuretic
combination) with a more contemporary
regimen (Amlodipine + Perindopril
combination)
–
–
–
–
–
–
All-cause mortality
Total CV mortality
Total stroke
Total heart failure
All CV events and procedures
Total coronary events including silent MI
– Development of diabetes mellitus
ASCOT-BPLA Lancet 2005; 366: 895–906.
Inclusion criteria
• Hypertension at baseline BP > 160/100 mmHg
untreated or > 140/90 mmHg treated with one
or more drugs
• Patients aged 40-79 years
• Patients with 3 or more risk factors for a future
cardiovascular event






Male sex
Age > 55 years
LVH
NIDDM
Smoking
ECG abnormalities
ASCOT-BPLA Lancet 2005; 366: 895–906.
 History of cerebrovascular event
 History of early CHD in first-degree
relative
 Plasma TC/ HDL ratio > 6
 Peripheral vascular disease
 Microalbuminuria / proteinuria
Risk factors at baseline
100
Hypertension
84
Age ≥ 55 years
81
Male
62
Microalbumin/proteinuria
33
Smoker
Type 2 diabetes
27
Family history of early coronary disease
26
23
ECG abnormalities
22
LVH
14
11
Plasma LDL > 6
Previous CVA
Peripheral vascular disease 6
0
ASCOT-BPLA Lancet 2005; 366: 895–906.
10
20
30
40
50
60
70
80
90
100
Baseline characteristics
Amlodipine + Perindopril
b-blocker+ diuretic
combination
combination
Demographics and clinical characteristics
Woman
White
Current smoker
Age (years)
SBP (mm Hg)
DBP (mm Hg)
Heart rate (bpm)
BMI (kg/m2)
Risk factors
n = 9639
2258 (23.4%)
9187 (95.3%)
3168 (32.9%)
63.0 (8.5)
164.1 (18.1)
94.8 (10.4)
71.9 (12.7)
28.7 (4.6)
3.7 (0.9)
n = 9618
2257 (23.5%)
9170 (95.3%)
3110 (32.3%)
63.0 (8.5)
163.9 (18.0)
94.5 (10.4)
71.8 (12.6)
28.7 (4.5)
3.7 (0.9)
Drug therapy
Previous antihypertensive treatments
0
1
≥2
Lipid-lowering therapy
Aspirin
1841 (19.1%)
4280 (44.4%)
3518 (36.5%)
1009 (10.5%)
1810 (18.8%)
1825 (19.0%)
4283 (44.5%)
3510 (36.5%)
980 (10.2%)
1801 (18.7%)
ASCOT-BPLA Lancet 2005; 366: 895–906.
Data Safety Monitoring Board
• In October 2004 the DSMB recommended
that the BP arm of ASCOT should be
stopped on account of concerns that
those patients receiving b-blocker +
diuretic combination would continue to be
disadvantaged compared with the
Amlodipine + Perindopril combination.
• The Steering Committee endorsed the
recommendation of the DSMB, and trial
closure began in December 2004 after a
median follow-up period of 5.4 years.
ASCOT-BPLA Lancet 2005; 366: 895–906.
Possible to achieve
guideline BP levels
b-blocker + diuretic
combination
Amlodipine + Perindopril
combination
P<0.0001
ASCOT-BPLA Lancet 2005; 366: 895–906.
All-cause mortality
b-blocker + diuretic combination
Amlodipine + Perindopril
combination
11
%
P<0.0247
ASCOT-BPLA Lancet 2005; 366: 895–906.
Nonfatal MI and CHD death
b-blocker + diuretic
combination
Amlodipine + Perindopril
combination
10
%
P=0.1052
ASCOT-BPLA Lancet 2005; 366: 895–906.
Superior reduction in
Cardiovascular mortality…
b-blocker + diuretic
combination
Amlodipine + Perindopril
combination
24
%
… with Amlodipine + Perindopril
combination
ASCOT-BPLA Lancet 2005; 366: 895–906.
P=0.001
Superior reduction in Stroke…
b-blocker + diuretic
combination
Amlodipine + Perindopril
combination
23
%
… with Amlodipine + Perindopril
combination
ASCOT-BPLA Lancet 2005; 366: 895–906.
P=0.0003
Amlodipine + Perindopril
combination…
b-blocker + diuretic
combination
Amlodipine + Perindopril
combination
30
%
P<0.0001
…prevents new onset of diabetes
ASCOT-BPLA Lancet 2005; 366: 895–906.
Superior reduction with
Amlodipine + Perindopril
combination
on
all
end-points
Amlodipine + Perindopril
b-blocker + diuretic
combination
better
ASCOT-BPLA Lancet 2005; 366: 895–906.
combination
better
Despite good BP control combination
with the newer treatment
(Amlodipine + Perindopril)
yielded better outcomes than
combination with
traditional treatment (b-blockers +
diuretic)

Nonfatal MI +CHD death
-10%
0.12

Cardiovascular mortality
-24%
< 0.001

Total mortality
-11%
< 0.001

Total coronary events
-13%
0.005

Fatal and nonfatal strokes
-23%
< 0.001

Total CV events and procedures -16%

New onset of diabetes
ASCOT-BPLA Lancet 2005; 366: 895–906.
< 0.001
-30%
< 0.001
Conclusion
• For the first time ever, a new combination of
antihypertensives, (Amlodipine + Perindopril)
demonstrated a reduction in mortality and
cardiovascular events in comparison with
(b-blockers + diuretics) therapy in
hypertensive patients.
• No other combination of CCB + ACEI or ARBs
has demonstrated such an effect so far
• This should lead to modification of
antihypertensive treatment in large populations
of hypertensive patients.
ASCOT-BPLA Lancet 2005; 366: 895–906.
HYVET TRIAL
Blood Pressure Lowering Therapy Evidence:
Primary Prevention
Hypertension in the Very Elderly (HYVET) Trial
Rate/1000 patient years (%)
3,845 patients >80 years with SBP >160 mm Hg randomized to treatment to
indapamide (1.5 mg) and perindopril (2-4 mg if needed) vs. placebo for 2 years
70
P=0.02
60
P<0.001
50
40
30
P=0.06
20
Indapamide +/perindopril
P<0.001
P=0.05
Placebo
10
0
Fatal or
Nonfatal
CVA*
Death
All cause Any heart
from CVA mortality
failure
Any CV
event
(Primary end point)
Blood pressure control in patients >80 years of age provides benefit
CV=Cardiovascular, CVA=Stroke
Source: Beckett NS et al. NEJM 2008;358:1887-98
VALUE TRIAL
Blood Pressure Lowering Therapy Evidence:
Secondary Prevention
Valsartan Antihypertensive Long-Term Use Evaluation (VALUE)
Trial
15,245 patients with untreated HTN and high CV risk randomized to a BP
lowering strategy with valsartan (160 mg) or amlodipine (10 mg) for 4.2 years
Primary cardiac composite endpoint
Cardiac mortality
Cardiac morbidity
All myocardial infarction
All congestive heart failure
All stroke
All-cause death
New-onset diabetes
0.5
1
2
Favors valsartan
Favors amlodipine
Both blood pressure lowering regimens provide similar efficacy
CV=Cardiovascular
Source: Julius S et al. Lancet 2004;363:2022-2031
HOT TRIAL
Blood Pressure Lowering Therapy Evidence:
Effect of Intensive Blood Pressure Control
Hypertension Optimal Treatment (HOT) Study
18,790 patients with a baseline diastolic BP of 100-115 mm Hg randomized
to a target diastolic BP of <90 mm Hg, <85 mm Hg, or <80 mm Hg
Patients with
Diabetes
Major CV events per
1000 patient-years
30
25
Patients without
Diabetes
25
20
20
15
15
10
10
5
5
0
0
<90
<85
<80
Diastolic BP goal
<90
<85
<80
Diastolic BP goal
More intensive blood pressure control provides greater benefit in diabetics
Source: Hansson L et al. Lancet. 1998;351:1755-1762.
ACCORD BPLA TRIAL
Blood Pressure Lowering Therapy Evidence:
Effect of Intensive Blood Pressure Control
Action to Control Cardiovascular Risk in Diabetes (ACCORD)
Blood Pressure Trial
4,733 diabetic patients randomized to intensive BP control (target SBP <120
mm Hg) or standard BP control (target SBP <140 mm Hg) for 4.7 years
HR=0.88
95% CI (0.73-1.06)
HR=0.59
95% CI (0.39-0.89)
15
10
5
0
Patients with Events (%)
20
Total stroke
Patients with Events (%)
Nonfatal MI, nonfatal
stroke, or CV death
20
15
10
5
0
0
1
2
3
4
5
6
7
Years Post-Randomization
8
0
1
2
3
4
5
6
7
8
Years Post-Randomization
Intensive BP control in DM does not reduce a composite of adverse CV
events, but does reduce the rate of stroke
BP=Blood pressure, DM=Diabetes mellitus,
HR=Hazard ratio, SBP=Systolic blood pressure
ACCORD study group. NEJM 2010;362:1575-85.
END OF MODULE 3
CHAPTER 3A