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
Major Outcomes in High Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic
The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)
Treatment and complications among the million Americans with hypertension are estimated to cost the nation $37 billion annually, with antihypertensive drug costs alone accounting for an estimated $15.5 billion/year. There is conclusive evidence that antihypertensive drug therapy can substantially reduce the risk of hypertension-related morbidity and mortality. However, the optimal choice for initial pharmacotherapy of hypertension is uncertain.
Earlier clinical trials documented the benefit of lowering blood pressure (BP) using primarily thiazide diuretics or beta-blockers. After these studies, several newer classes of antihypertensive agents, i.e. angiotensin-converting-enzyme inhibitors (ACEIs), calcium channel blockers (CCBs), alpha-adrenergic blockers, and more recently angiotensin receptor blockers (ARBs) became available. Over the past decade, major placebo-controlled trials have documented that ACEIs and CCBs reduce cardiovascular events in hypertensive individuals. However, their relative value compared with older, less expensive agents remains unclear. There has been considerable uncertainty regarding effects of some classes of antihypertensive drugs on risk of coronary heart disease (CHD). The relative benefit of various agents in high-risk subgroups such as older, diabetic, and Black hypertensive persons also needed to be established.
The ALLHAT Collaborative Research Group
Sponsored by the National Heart, Lung, and Blood Institute (NHLBI)
JAMA 2002;288:

2. Antihypertensive Trial Design
ALLHAT
Antihypertensive Trial Design
Randomized, double-blind, multi-center clinical trial
Determine whether occurrence of fatal CHD or nonfatal MI is lower for high-risk hypertensive patients treated with newer agents (CCB, ACEI, alpha-blocker) compared with a diuretic
42,418 high-risk hypertensive patients ≥ 55 years
The Antihypertensive and Lipid‑Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), a randomized, double‑blind, multi‑center, clinical trial sponsored by the National Heart Lung and Blood Institute (NHLBI), was designed to determine whether the occurrence of fatal CHD or nonfatal myocardial infarction (MI) is lower for high‑risk hypertensive patients treated with a CCB (represented by amlodipine), an ACEI (represented by lisinopril), or an alpha blocker (represented by doxazosin), each compared with diuretic treatment (represented by chlorthalidone). 42,418 high-risk hypertensive patients age 55 and older were randomized.

3. Background
ALLHAT
In addition to their BP lowering potential all antihypertensive agents have other important mechanisms of action and indications.
These actions may convey benefits or risks independent of BP lowering
By having a common BP goal for all treatment arms, ALLHAT aimed to evaluate the health effects of these non-BP actions

4. ALLHAT Secondary Outcomes All-cause mortality Stroke
Combined CHD – nonfatal MI, CHD death, coronary revascularization, hospitalized angina
Combined CVD – (CHD, stroke, coronary revascularizations, heart failure [treated non-hospitalized, hospitalized, fatal], angina (treated non-hospitalized, hospitalized), peripheral arterial disease (revascularization procedure)
Other secondary objectives were to examine effects on all-cause mortality fatal and nonfatal stroke, and other cardiovascular (CVD) events. Definitions were:
combined CHD (the primary outcome, coronary revascularization, hospitalized angina), and
combined CVD (combined CHD, stroke, other treated angina, HF [fatal, hospitalized, or treated non-hospitalized], and peripheral arterial disease).
Coronary revascularization included coronary artery bypass graft, percutaneous angioplasty, insertion of stents, and atherectomy.
Other secondary objectives were to examine effects on renal outcomes (including dialysis, renal transplant, renal death, or slope of the reciprocal of longitudinal serum creatinine measurements) and cancer.
Individual components of the combined outcomes were pre-specified and examined. Estimated glomerular filtration rate was examined post-hoc.

5. Secondary Outcomes (Continued)
ALLHAT
Secondary Outcomes (Continued)
HQOL (Health-related quality of life)
GI Bleeding
Costs

6. Step 1 Treatment Protocol
ALLHAT
Step 1 Treatment Protocol
Step 1 Agent
Initial Dose*
Dose 1*
Dose 2*
Dose 3*
Chlorthalidone
12.5 25
Amlodipine
2.5 5 10
Lisinopril 20 40
Doxazosin 1 2 4 8
* mg/day
Step 1 drugs were encapsulated and identical in appearance, so that the identity of each agent was double-masked at each dosage level. Dosages were 12.5, 12.5 (sham titration), and 25 mg/d for chlorthalidone; 2.5, 5, and 10 mg/d for amlodipine; and 10, 20, and 40 mg/d for lisinopril.

7. Step Up Treatment Protocol
ALLHAT
Step 2 Agents:
Dose 1*
Dose 2*
Dose 3*
Reserpine
0.05 qd
or 0.1 qod
0.1 qd
0.2 qd
Clonidine (oral)
0.1 bid
0.2 bid
0.3 bid
Atenolol
25 qd
50 qd
100 qd
Step 3 Agent:
Hydralazine
25 bid
50 bid
100 bid
*All doses in mg
Doses of study-supplied open-label drugs were: step 2 -- atenolol, mg/d; reserpine, mg/d; or clonidine, mg twice/day, and step 3 -- hydralazine, mg twice/day.
Other drugs, including low doses of open-label step 1 drug classes, were permitted if clinically indicated.
After initial titration visits, participants were seen every 3 months during the first year and every 4 months thereafter.

8. Baseline Characteristics
ALLHAT
Baseline Characteristics
Chlorthalidone 15,255
Amlodipine 9,048
Lisinopril 9,054
Mean SBP/DBP
146 / 84
Treated (90%)
Untreated (10%)
145 / 83
156 / 89
157 / 90
145 / 84
Mean age, y 67
Black, % 35 36
Women, % 47 46
Current smoking % 22
History of CHD, % 26 24 25
Type 2 diabetes, % 37
There were nearly identical distributions of baseline factors in the three treatment groups. The mean baseline blood pressure was 146/84 mm Hg. The mean age was 67 years; 35% were Black, 47% were women, 22% were current cigarette smokers, 25% had a history of CHD, and 36% were diabetic.

9. On Step 1 or Equivalent Treatment by Antihypertensive Treatment Group
ALLHAT
On Step 1 or Equivalent Treatment by Antihypertensive Treatment Group
Among participants in the chlorthalidone group who were contacted in the clinic or by telephone within 12 months of annual scheduled visits, 87% were taking chlorthalidone or another diuretic at 1 year, decreasing to 80% at 5 years.
Among participants in the amlodipine group, 88% were taking amlodipine or another CCB at 1 year, decreasing to 80% at 5 years.
Among participants in the lisinopril group, 82% were taking lisinopril or another ACEI at 1 year, decreasing to 73% at 5 years.
The most common reasons for not taking step 1 medication at 5 years in the chlorthalidone, amlodipine, and lisinopril groups, respectively, were unspecified refusals [41%, 40%, and 38%], and symptomatic adverse effects [15%, 16%, and 18%]. Elevated BP [4%, 4%, and 9%] or other adverse effects such as abnormal laboratory values [4%, 2%, and 2%] were other reasons given for discontinuation of step 1 medications.

10. BP Results by Treatment Group
ALLHAT
BP Results by Treatment Group BL 6M 1Y 3Y 5Y C
84.0
80.1
79.2
77.1
75.4 A
83.9
79.7
78.5
76.1
74.5 L
84.1
80.8
77.2 BL 6M 1Y 3Y 5Y C
146.2
138.2
136.6
134.6
134.1 A
140.0
138.3
135.4
134.9 L
146.4
141.4
139.7
136.4
136.1
Mean seated BP at randomization was about 146/84 mm Hg in all three groups, with 90% of participants reporting current antihypertensive drug treatment. Among participants returning for follow-up visits, the mean BP at 1 year was 137/79 mm Hg, 138/79 mm Hg, and 140/80 in the chlorthalidone, amlodipine, and lisinopril groups, respectively; at 5 years, the corresponding BP’s were 134/75, 135/75, and 136/75 mm Hg.
Compared to chlorthalidone. SBP was significantly higher in the amlodipine group (~1 mm Hg) and the lisinopril group (~2 mm Hg).
Compared to chlorthalidone, DBP was significantly lower in the amlodipine group (~1 mm Hg).
At the initial visit, the proportion of participants at or below the BP goal (<140/90 mm Hg) was 26-28%; at 5 years, it was 68%, 66%, and 61% for the chlorthalidone, amlodipine, and lisinopril groups, respectively.
Compared to chlorthalidone:
SBP significantly higher in the amlodipine group (~1 mm Hg) and the lisinopril group (~2 mm Hg).
Compared to chlorthalidone:
DBP significantly lower in the amlodipine group (~1 mm Hg).

11. Blood Pressure Control
ALLHAT
1.6
= mean number of drugs
2.0
1.8
1.7
1.6
1.4
@ 5 years:
62% were on >2 drugs
30% were on 1 drug and controlled
Cushman, et al. J Clin Hypertens 2002;4:

12. ALLHAT Biochemical Results Chlorthalidone Amlodipine Lisinopril
Serum cholesterol- mg/dL
Baseline
216.1 (43.8)
216.5 (44.1)
215.6 (42.4)
4 Years
197.2 (42.1)
195.6 (41.0)*
195.0 (40.6)*
Serum cholesterol - > 240 mg/dL
Baseline (26.5)
2284 (26.6)
2178 (25.4)
4 Years (14.4)
673 (13.4)
603 (12.8)
Serum potassium – mmol/L
4.3 (0.7)
4.4 (0.7)*
4.1 (0.7)
4.5 (0.7)*
Serum potassium – <3.5mEq/L
493 (3.4)
292 (3.4)
223 (2.6)
707 (8.5)
93 (1.9)
37 (0.8)
Mean total serum cholesterol levels at baseline were about 216 mg/dL ( mmol/L) in all three groups. At 4 years, the respective mean levels were (chlorthalidone), (amlodipine), and (lisinopril) mg/dL (5.10, 5.07, and 5.05 mmol/L). Both comparisons with the chlorthalidone group were statistically significant at p<.05. By 4 years, about 35-36% of participants in all three groups reported taking lipid-lowering drugs, largely HMG CoA reductase inhibitors, some as a result of participation in the ALLHAT lipid trial.
Mean serum potassium levels at baseline were mmol/L; at 4 years, the respective mean levels were 4.1, 4.4, and 4.5 mmol/L for those in the chlorthalidone, amlodipine, and lisinopril groups, respectively. Both comparisons with the chlorthalidone group were statistically significant at p<.05. About 8% of the chlorthalidone group were on potassium supplementation at 5 years, compared with 4% in the amlodipine group and 2% in the lisinopril group.
Mean estimated GFR at baseline was about 78 mL/min/1.73 m2 in all groups. At 4 years, it was 70.0, 75.1, and 70.7 mL/min/1.73 m2 in the chlorthalidone, amlodipine, lisinopril groups, respectively. Both comparisons with the chlorthalidone group were statistically significant at p<.05.
The slopes of the reciprocal of serum creatinine over time, which are not shown here, were virtually identical in the chlorthalidone and lisinopril groups, whereas the decline in the amlodipine slope was less than that of the chlorthalidone slope.
* p<.05 compared to chlorthalidone
† Ann Intern Med. 1999;130:

13. ALLHAT USE OF POTASSIUM SUPPLEMENTATION
% on potassium suppl.

14. Biochemical Results – Fasting Glucose – mg/dL
ALLHAT
Biochemical Results – Fasting Glucose – mg/dL
Chlorthalidone
Amlodipine
Lisinopril
Total
Baseline
123.5 (58.3)
123.1 (57.0)
122.9 (56.1)
4 Years
126.3 (55.6)
123.7 (52.0)
121.5 (51.3)*
Among baseline nondiabetics with baseline <126 mg/dL
93.1 (11.7)
93.0 (11.4)
93.3 (11.8)
104.4 (28.5)
103.1 (27.7)
100.5 (19.5)*
Diabetes Incidence (follow-up fasting glucose  126 mg/dL)
11.6%
9.8%*
8.1%*
The respective mean fasting serum glucose levels at baseline were 123.5, 123.1, and mg/dL (6.9, 6.8 and 6.8 mmol/L); at 4 years, the respective mean levels were 126.3, 123.7, and mg/dL (7.0, 6.9, and 6.7 mmol/L). The comparison of the lisinopril and chlorthalidone groups was statistically significant at p<.05.
Among individuals classified as nondiabetic at baseline, with baseline fasting serum glucose less than 126 mg/dl (7.0 mmol/L), incidence of diabetes (fasting serum glucose 126 mg/dl) at four years was 11.6%, 9.8%, and 8.1%, respectively. Both comparisons with the chlorthalidone group were statistically significant at p<.05.
*p<.05 compared to chlorthalidone

15. Renal Outcomes ALLHAT C A L A/C L/C ESRD (Rate/100 # events) 1.8 (0.1)
193
2.1 (0.2)
129
2.0(0.2)
126
RR=1.12
p=.98
RR=1.11
p=0.38
GFR (4 Year)
Mean
(sd)
70.0 (19.7)
75.1
(20.7)
70.7
(20)
p<.001
p=0.03
C = Chlorthalidone; A = Amlodipine; L = Lisinopril

16. ALLHAT
Cumulative Event Rates for the Primary Outcome (Fatal CHD or Nonfatal MI) by ALLHAT Treatment Group
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
A/C
0.98 ( )
0.65
L/C
0.99 ( )
0.81
Chlorthalidone
Amlodipine
Lisinopril
No significant difference was observed between amlodipine (the red line) and chlorthalidone (the blue line) for the primary outcome. The relative risk for amlodipine compared to chlorthalidone was 0.98, with a 95% confidence interval of
Also, no significant difference was observed between lisinopril (the green line) and chlorthalidone for the primary outcome. The relative risk was 0.99, with a 95% confidence interval of
Number at Risk:
Chlorthalidone
15,255
14,477
13,820
13,102
11,362
6,340
2,956
209
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

17. ALLHAT Cumulative Event Rates for Stroke by ALLHAT Treatment Group
Cumulative Stroke Rate
Years to Stroke 1 2 3 4 5 6 7
.02
.04
.06
.08 .1
RR (95% CI)
p value
A/C
0.93 ( )
0.28
L/C
1.15 ( )
0.02
Chlorthalidone
Amlodipine
Lisinopril
There was no difference for stroke between the amlodipine and chlorthalidone groups. The lisinopril group had a 15% higher risk for stroke.
Number at risk:
Chlor
15,255
14,515
13,934
13,309
11,570
6,385
3,217
567
Amlo
9,048
8,617
8,271
7,949
6,937
3,845
1,813
506
Lisin
9,054
8,543
8,172
7,784
6,765
3,891
1,828
949

18. ALLHAT Stroke – Subgroup Comparisons – RR (95% CI)
Amlodipine Better Chlorthalidone Better
0.50 1 2
Non-Diabetic
0.96 (0.81, 1.14)
Diabetic
0.90 (0.75, 1.08)
Non-Black
0.93 (0.79, 1.10)
Black
0.93 (0.76, 1.14)
Women
0.84 (0.69, 1.03)
Men
1.00 (0.85, 1.18)
Age >= 65
0.93 (0.81, 1.08)
Age < 65
0.93 (0.73, 1.19)
Total
0.93 (0.82, 1.06)
Lisinopril Better Chlorthalidone Better
1.23 (1.05, 1.44)
1.07 (0.90, 1.28)
1.00 (0.85, 1.17)
1.40 (1.17, 1.68)
1.22 (1.01, 1.46)
1.10 (0.94, 1.29)
1.13 (0.98, 1.30)
1.21 (0.97, 1.52)
1.15 (1.02, 1.30)
P = .01 for interaction
There was no difference across the pre-defined subgroups for the amlodipine vs chlorthalidone comparison.
For stroke, there was a significant differential effect by race, with p = .01 for interaction. The relative risks (lisinopril versus chlorthalidone) for stroke were 1.40 (p < .001) in Blacks and 1.00 (p=.96) in non-Blacks.
The mean follow-up systolic BP for all participants was 2 mm Hg higher in the lisinopril group than the chlorthalidone group, 4 mm Hg higher in Blacks. Adjustment for follow-up BP as time-dependent covariates in a proportional hazards model slightly reduced the relative risks for stroke (RR 1.15 to 1.11), overall and in the Black subgroup (stroke RR 1.40 to 1.36), but the results remained statistically significant. For various reasons, such adjusted analyses need to be interpreted cautiously.

19. ALLHAT
Cumulative Event Rates for All-Cause Mortality by ALLHAT Treatment Group
Cumulative Mortality Rate
Years to Death 1 2 3 4 5 6 7
.05 .1
.15 .2
.25 .3
RR (95% CI)
p value
A/C
0.96 ( )
0.20
L/C
1.00 ( )
0.90
RR (95% CI)
p value
A/C
0.96 ( )
0.20
L/C
1.00 ( )
0.90
Chlorthalidone
Amlodipine
Lisinopril
For all-cause mortality, neither the amlodipine vs chlorthalidone or the lisinopril vs chlorthalidone comparison were statistically significant.
Number at risk:
Chlor
15,255
14,933
14,564
14,077
12,480
7.185
3,523
428
Amlo
9,048
8,847
8,654
8,391
7,442
4,312
2,101
217
Lisin
9,054
8,853
8,612
8,318
7,382
4,304
2,121
144

20. Cumulative Event Rates for Combined CVD by ALLHAT Treatment Group
Cumulative Combined CVD Event Rate
Years to Combined CVD Event 1 2 3 4 5 6 7 .1 .2 .3 .4 .5
RR (95% CI)
p value
A/C
1.04 ( )
0.12
L/C
1.10 ( )
<0.001
Chlorthalidone
Amlodipine
Lisinopril
The amlodipine vs chlorthalidone comparison for combined CVD was not statistically significant.
The lisinopril group had a 10% higher risk of combined CVD (p < .001), with a 6-year absolute risk difference of 2.4%. Included in this were a 19% higher risk of HF (p < .001), a 10% higher risk of hospitalized/fatal HF (p = .11), an 11% higher risk of hospitalized/non-hospitalized treated angina (p= .01), and a 10% higher risk of coronary revascularization (p= .05).
Number at risk:
Chlor
15,255
13,752
12,594
11,517
9,643
5,167
2,362
288
Amlo
9,048
8,118
7,451
6,837
5,724
3,049
1,411
153
Lisin
9,054
7,962
7,259
6,631
5,560
3,011
1,375
139

21. ALLHAT Combined CVD – Subgroup Comparisons – RR (95% CI)
Amlodipine Better Chlorthalidone Better
0.50 1 2
Non-Diabetic
1.02 (0.96, 1.09)
Diabetic
1.06 (0.98, 1.15)
Non-Black
1.04 (0.97, 1.10)
Black
1.06 (0.96, 1.16)
Women
1.04 (0.96, 1.13)
Men
1.04 (0.98, 1.11)
Age >= 65
1.05 (0.99, 1.12)
Age < 65
1.03 (0.94, 1.12)
Total
1.04 (0.99, 1.09)
Lisinopril Better Chlorthalidone Better
1.12 (1.05, 1.19)
1.08 (1.00, 1.17)
1.06 (1.00, 1.13)
1.19 (1.09, 1.30)
1.12 (1.03, 1.21)
1.08 (1.02, 1.15)
1.13 (1.06, 1.20)
1.05 (0.97, 1.15)
1.10 (1.05, 1.16)
P = .04 for interaction
There was no difference across the pre-defined subgroups for the amlodipine vs chlorthalidone comparison.
There was a significant differential effect for combined CVD by race, with p=.04 for interaction. The relative risks (lisinopril versus chlorthalidone) were 1.19 (p<.001) and 1.06 (p=.05) in Blacks and non-Blacks, respectively.

22. ALLHAT
Cumulative Event Rates for Heart Failure by ALLHAT Treatment Group
RR (95% CI)
p value
A/C
1.38 ( )
<.001
L/C
1.19 ( )
Cumulative CHF Rate
Years to HF 1 2 3 4 5 6 7
.03
.06
.09
.12
.15
Chlorthalidone
Amlodipine
Lisinopril
The amlodipine group had a 38% higher risk of HF (p<.001) with a 6-year absolute risk difference of 2.5%.
The lisinopril group had a 19% higher risk of HF (p < .001).
Number at risk:
Chlor
15,255
14,528
13,898
13,224
11,511
6,369
3,016
384
Amlo
9,048
8,535
8,185
7,801
6,785
3,775
1,780
210
Lisin
9,054
8,496
8,096
7,689
6,698
3,789
1,837
313

23. Overall Conclusions ALLHAT
Because of the superiority of thiazide-type diuretics in preventing one or more major forms of CVD and their lower cost, they should be the drugs of choice for first-step antihypertensive drug therapy.
Because of the superiority of thiazide-type diuretics in preventing one or more major forms of CVD and their lower cost, they should be the drugs of choice for first-step antihypertensive drug therapy.