1. Health and Human Services National Heart, Lung, and Blood Institute
U.S. Department of
Health and Human Services
National Institutes
of Health
National Heart, Lung, and Blood Institute
ALLHAT
Outcomes in High Risk Hypertensives Randomized to CCB vs. ACE Inhibitor in ALLHAT
Frans Leenen MD, PhD, Chuke Nwachuku MA, MPH, Dr PH, William Cushman MD, Henry Black MD, Lara Simpson MS, Barry Davis MD, PhD.
For the ALLHAT Collaborative Research Group
Sponsored by the National Heart, Lung and Blood Institute (NHLBI)

2. Primary Objective POST-HOC ANALYSIS ALLHAT
Determine whether treatment with the newer agents (CCB, ACEI, alpha-blocker) results in less fatal CHD and nonfatal MI compared with a diuretic
POST-HOC ANALYSIS
- Comparison of cardiovascular and other outcomes
among 18,102 patients randomized to ACEI or
dihydropyridine CCB
- For sub-groups, emphasis on outcomes in Blacks
vs non-Blacks considering the previously reported
interaction for several major outcomes with lisinopril.

3. Hypertension Trial ALLHAT 42,418 high-risk hypertensive patients
90% previously treated
10% untreated
STEP 1 AGENTS
Chlorthalidone mg
Amlodipine mg
Lisinopril
10-40 mg
Doxazosin
1-8 mg
This post-hoc comparison is of lisinopril (n=9054, 3210 Blacks) versus amlodipine (n=9048, 3213 Blacks).
N=15,255
N=9,048
N=9,054
N=9,061
STEP 2 AND 3 AGENTS (5 years)
Atenolol
28.0%
Clonidine
10.6%
Reserpine
4.3%
Hydralazine
10.9%

4. Baseline Characteristics
ALLHAT
Amlodipine
(n=9048)
Lisinopril
(n=9054)
P value
Lisinopril vs. Amlodipine
Age in yrs, mean (SD)
66.9 (7.7)
0.83
On antihypertensive meds (%)
8171 (90)
8164 (90)
Type 2 diabetes (%)
3323 (37)
3212 (35)
0.08
History of CHD (%)
2202 (24)
2270 (25)
0.25
Cigarette smoker (%)
1980 (22)
1981 (22)
0.90
Female (%)
4280 (47)
4187 (46)
0.15
Blacks (%)
3213 (36)
3210 (35)
0.94
On aspirin (%)
3268 (36)
3258 (36)
0.85
There were no significant differences between the two groups for major baseline characteristics.

5. Baseline and Follow-up Blood Pressures
ALLHAT
Baseline and Follow-up Blood Pressures
148
148
148
146
146
146
144
144
144
142
142
142
mm Hg BP
mm Hg BP
140
140
140
138
138
138
Amlodipine
136
136
136
134
134
134
Lisinopril 74 76 78 80 82 84 86 86 86 74 76 78 80 82 84 86 84 84 82 82
Mean seated BP at randomization was 146/84 mmHg in both groups. BP deceased progressively but remained higher by mmHg in the lisinopril compared to the amlodipine arm.
mm Hg BP
mm Hg BP
mm Hg BP 80 80 78 78 76 76 74 74 BL BL BL 3m 3m 3m 6m 6m 6m Y1 Y1 Y1 Y2 Y2 Y2 Y3 Y3 Y3 Y4 Y4 Y4
Number at
Risk:
Amlodipine
9048
7609
6883
6381
5637
Lisinopril
9054
7521
6700
6076
5325

6. Baseline and Follow-up BPs by Race
ALLHAT
Baseline and Follow-up BPs by Race
148
146
Δ=3.4
144
142
mmHg SBP
Δ=1.6
140
138
Amlodipine - Blacks
Amlodipine - Non-Blacks
Lisinopril - Blacks
Lisinopril - Non-Blacks
136
134
132 86 84
Δ=1.8 82
Among the pre-specified subgroups, in non-Blacks the two treatments showed only minor (<1 mmHg) differences. In contrast, in Blacks, BP remained higher in the lisinopril arm by 3.4/1.8 mmHg at year 2 and by 1.6/1.1 mmHg at year 4.
mmHg DBP 80
Δ=1.1 78 76
Δ=0.5
Δ=0.8 74 BL 3m 6m Y1 Y2 Y3 Y4
Mean # of Meds:
Amlodipine
Blacks
1.4
1.5
1.6
1.7
Non-Blacks -
1.4
1.5
1.7
1.8
Lisinopril
Blacks
1.6
1.8
1.9
2.0
Non-Blacks -
1.4
1.6
1.7
1.8

7. Cumulative Event Rates for the Primary Outcome (Fatal CHD or Nonfatal MI) by Treatment Group
ALLHAT
Years to CHD Event 1 2 3 4 5 6 7
Cumulative CHD Event Rate
.04
.08
.12
.16 .2
RR (95% CI)
p value
L/A
1.01 ( )
0.85
Blacks
1.09 ( )
0.33
Non-Blacks
0.97 ( )
0.66
Amlodipine
Lisinopril
No significant difference was observed between amlodipine (the red line) and lisinopril (the green line) for the primary outcome. The relative risk was 1.01, with a 95% confidence interval of
The number at risk in each interval is the number of persons alive at the start of the interval; those experiencing the outcome or those withdrawn during an interval are removed before the start of the next interval.
Those randomized late in the trial ( ) contribute less follow-up time (4-5 years) than those randomized earlier (1994 – 8 years). Thus, at years 4 through 6 the number at risk begin to decline significantly as those randomized later conclude their contribution to the trial.
Number at Risk:
Amlodipine
9,048
8,576
8,218
7,843
6,824
3,870
1,878
215
Lisinopril
9,054
8,535
8,123
7,711
6,662
3,832
1,770
195

8. Secondary Endpoints: No Differences Between Treatment Groups For
ALLHAT
Lisinopril vs. Amlodipine
RR (95% CI)
P value
Combined CHD
1.04 ( )
0.24
All-Cause Mortality
1.05 ( )
0.21
ESRD
0.99 ( )
0.93
Blacks (L vs. A)
Non-Blacks (L vs. A)
RR (95% CI)
P value
Combined CHD
1.12 ( )
0.11
1.02 ( )
0.73
All-Cause Mortality
1.01 ( )
0.19
1.03 ( )
0.59
ESRD
1.12 ( )
0.51
0.86 ( )
0.43

9. Cumulative Event Rates for Stroke by Treatment Group
ALLHAT
Cumulative Event Rates for Stroke by Treatment Group
Cumulative Stroke Rate
.02
.04
.06
.08 .1
RR (95% CI)
p value
L/A
1.23 ( )
0.003
Amlodipine
Lisinopril
The lisinopril group had a 23% higher risk for stroke than the amlodipine group.
The number at risk in each interval is the number of persons alive at the start of the interval; those experiencing the outcome or those withdrawn during an interval are removed before the start of the next interval.
Those randomized late in the trial ( ) contribute less follow-up time (4-5 years) than those randomized earlier (1994 – 8 years). Thus, at years 4 through 6 the number at risk begin to decline significantly as those randomized later conclude their contribution to the trial.
Years to Stroke 1 2 3 4 5 6 7
Number at risk:
Amlodipine
9,048
8,617
8,271
7,949
6,937
3,845
1,813
506
Lisinopril
9,054
8,543
8,172
7,784
6,765
3,891
1,828
949

10. Cumulative Event Rates for Stroke by Race and Treatment Group
ALLHAT
Cumulative Event Rates for Stroke by Race and Treatment Group
0.00
0.05
0.10 1 2 3 4 5 6 7
Years to Stroke
Amlodipine
Lisinopril
Blacks
0.00
0.05
0.10 1 2 3 4 5 6 7
Years to Stroke
Amlodipine
Lisinopril
Non-Blacks
Cumulative Stroke Rate
RR (95%CI)
P value
L/A
1.51 ( )
<0.001
RR (95%CI)
P value
L/A
1.07 ( )
0.47

11. Stroke Interaction by Gender and Race
ALLHAT
Stroke Interaction by Gender and Race
Lisinopril versus Amlodipine
Blacks
Non-Blacks
Males
Females
6 Yr Event Rate per 100 Pts
9.2 vs 6.7
7.0 vs 4.9
5.2 vs 5.9
5.3 vs 3.7 Δ
+ 37 %
+ 45 %
- 11 %
+ 46 %
Six-year Kaplan-Meier event rates by race and gender
+ favors amlodipine
- favors lisinopril
p=0.02 for interaction of gender within non-blacks

12. Cumulative Event Rates for Combined CVD by Treatment Group
ALLHAT
Cumulative Combined CVD Event Rate .1 .2 .3 .4 .5
Number at risk:
RR (95% CI)
p value
L/A
1.06 ( )
0.047
Blacks
1.13 ( )
0.02
Non-Blacks
1.03 ( )
0.47
Amlodipine
Lisinopril
The lisinopril group had a 6% higher risk of combined CVD (p =0.047) than the amlodipine group.
The number at risk in each interval is the number of persons alive at the start of the interval; those experiencing the outcome or those withdrawn during an interval are removed before the start of the next interval.
Those randomized late in the trial ( ) contribute less follow-up time (4-5 years) than those randomized earlier (1994 – 8 years). Thus, at years 4 through 6 the number at risk begin to decline significantly as those randomized later conclude their contribution to the trial.
Years to Combined CVD Event 1 2 3 4 5 6 7
Amlodipine
9,048
8,118
7,451
6,837
5,724
3,049
1,411
153
Lisinopril
9,054
7,962
7,259
6,631
5,560
3,011
1,375
139

13. Other Components of Combined CVD
ALLHAT
Other Components of Combined CVD
Amlodipine
Lisinopril
Lisinopril vs Amlodipine
No. of Total
Events
6-yr rate
per 100
Persons (SE)
6-yr rate per 100 RR
(95% CI) P
Value
Heart failure
706
10.2 (0.4)
612
8.7 (0.4)
0.87
( )*
0.007
Hospitalized/fatal
heart failure
578
8.4 (0.4)
471
6.9 (0.4)
0.81
( )*
<0.001
Angina (hospitalized or treated)
950
12.6 (0.4)
1019
13.6 (0.4)
1.09
( )
0.055
Angina (hospitalized)
630
693
9.6 (0.4)
1.12
( )
0.045
Coronary revascularizations
725
10.0 (0.4)
718
1.00
( )
0.943
Peripheral arterial disease (hospitalized
or fatal)
265
3.7 (0.2)
311
4.7 (0.4)
1.19
( )
0.036
* 2X2 table RR rather than Cox PH

14. Cumulative Event Rates for Heart Failure by Treatment Group
ALLHAT
Cumulative Event Rates for Heart Failure by Treatment Group
Cumulative HF Rate
.03
.06
.09
.12
.15
RR (95% CI)
p value
L/A
0.87 ( )
0.007
Blacks
0.89 ( )
0.18
Non-Blacks
0.85 ( )
0.02
Amlodipine
Lisinopril
The amlodipine group had a 13% higher risk of HF (p=.007) (RR calculated from a 2x2 table rather than Cox PH).
The number at risk in each interval is the number of persons alive at the start of the interval; those experiencing the outcome or those withdrawn during an interval are removed before the start of the next interval.
Those randomized late in the trial ( ) contribute less follow-up time (4-5 years) than those randomized earlier (1994 – 8 years). Thus, at years 4 through 6 the number at risk begin to decline significantly as those randomized later conclude their contribution to the trial.
Years to HF 1 2 3 4 5 6 7
Number at risk:
Amlodipine
9,048
8,535
8,185
7,801
6,785
3,775
1,780
210
Lisinopril
9,054
8,496
8,096
7,689
6,698
3,789
1,837
313

15. Lisinopril vs. Amlodipine
ALLHAT
Safety Parameters
Lisinopril vs. Amlodipine
RR (95% CI)
P value
Cancer
1.01 ( )
0.91
GI Bleed
1.20 ( )
0.004
Blacks (L vs. A)
Non-Blacks (L vs. A)
RR (95% CI)
P value
Cancer
1.06 ( )
0.54
0.98 ( )
0.75
GI Bleed
1.28 ( )
0.02
1.16 ( )
0.07
Lisinopril (n)
Amlodipine (n)
P value
Angioedema 38 3
<0.001
Blacks (n)
Non-Blacks (n)
Lisinopril
Amlodipine P
Angioedema 23 2
<0.001 15 1

16. Summary Lisinopril vs. Amlodipine
ALLHAT
Summary Lisinopril vs. Amlodipine
Non-Blacks
Blacks
SBP Control
<+0.5 mmHg
+ 2-3 mmHg
# antihypertensive drugs
similar
+ 0.3
CHD, Combined CHD, Mortality, ESRD, cancer
similar
Stroke
similar
but men -11%, women +46%
+ 45%
Combined CVD HF
similar
- 15%
+ 13%
- 11%
GI Bleed
+ 16%
+ 28%
Angioedema
>
>>
+favors amlodipine
- favors lisinopril

17. ALLHAT Conclusions Non-Black Older Hypertensives
At apparently equivalent BP control, most outcomes are similar on lisinopril vs. amlodipine-initiated treatment except for
less HF on lisinopril
more strokes (in women), GI bleed, and angioedema on lisinopril
Black Older Hypertensives
Several outcomes are similar on lisinopril vs. amlodipine-initiated treatment, but
Less HF on lisinopril
Less BP control and more cardiovascular events, including stroke, on lisinopril
more GI bleeds and angioedema on lisinopril
Clinical Implications
ALLHAT was not designed to identify the best step-one drug alternative if a thiazide-type diuretic cannot be used. However, considering the totality of the outcome measures, amlodipine would appear to have an advantage over lisinopril, particularly in Blacks and Women, but this depends on how clinicians weigh outcomes that favor the respective arms.