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ALLHAT. U.S. Department of Health and Human Services. National Institutes of Health. National Heart, Lung, and Blood Institute. Major Outcomes in High Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic. - PowerPoint PPT Presentation
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1
U.S. Department of Health and Human
Services
National Institutes of Health
National Heart, Lung, and Blood Institute
Major Outcomes in High Risk Major Outcomes in High Risk Hypertensive Patients Randomized to Hypertensive Patients Randomized to
Angiotensin-Converting Enzyme Inhibitor Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diureticor Calcium Channel Blocker vs Diuretic
The Antihypertensive and Lipid-Lowering The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)Treatment to Prevent Heart Attack Trial (ALLHAT)
The ALLHAT Collaborative Research GroupThe ALLHAT Collaborative Research Group
Sponsored by the National Heart, Lung, and Blood Sponsored by the National Heart, Lung, and Blood Institute (NHLBI)Institute (NHLBI)
ALLHAT
www.allhat.org JAMA 2002;288:2981-2997 JAMA 2002;288:2981-2997
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AntihypertensiveTrial 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
ALLHAT
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BackgroundBackground
• In addition to their BP lowering potential all In addition to their BP lowering potential all antihypertensive agents have other antihypertensive agents have other important mechanisms of action and important mechanisms of action and indications.indications.
• These actions may convey benefits or risks These actions may convey benefits or risks independent of BP loweringindependent of BP lowering
• By having a common BP goal for all By having a common BP goal for all treatment arms, ALLHAT aimed to evaluate treatment arms, ALLHAT aimed to evaluate the health effects of these non-BP actionsthe health effects of these non-BP actions
ALLHAT
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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)
ALLHAT
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Secondary Outcomes(Continued)
ALLHAT
•HQOL (Health-related quality of life)
•GI Bleeding
•Costs
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Step 1Treatment Protocol
Step 1 Agent Initial Dose* Dose 1* Dose 2* Dose 3*
Chlorthalidone 12.5 12.5 12.5 25
Amlodipine 2.5 2.5 5 10
Lisinopril 10 10 20 40
Doxazosin 1 2 4 8
* mg/day
ALLHAT
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Step 2 Agents: Dose 1* Dose 2* Dose 3*
Reserpine 0.05 qdor 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
ALLHATStep Up
Treatment Protocol
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Baseline Characteristics
Chlorthalidone 15,255
Amlodipine 9,048
Lisinopril 9,054
Mean SBP/DBP 146 / 84 146 / 84 146 / 84 Treated (90%) Untreated (10%)
145 / 83156 / 89
145 / 83157 / 90
145 / 84156 / 89
Mean age, y 67 67 67Black, % 35 36 36Women, % 47 47 46Current smoking % 22 22 22History of CHD, % 26 24 25Type 2 diabetes, % 36 37 36
ALLHAT
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On Step 1 or Equivalent Treatment by Antihypertensive Treatment Group
0.0
20.0
40.0
60.0
80.0
100.0
%
Chlor 87.1 84.7 82.7 80.8 80.5Aml 87.6 85.2 83.2 80.5 80.4Lis 82.4 78.4 77.1 74.8 72.6
1 Year 2 Years 3 Years 4 Years 5 Years
ALLHAT
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BP Results by Treatment GroupALLHAT
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).
BL 6M 1Y 3Y 5Y
C 146.2 138.2 136.6 134.6 134.1
A 146.2 140.0 138.3 135.4 134.9
L 146.4 141.4 139.7 136.4 136.1
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 79.7 77.2 75.4
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Blood Pressure ControlBlood Pressure Control
31
58 60 64 67 67
92%91%90%88%86%
68% 66656258
27
55
0
20
40
60
80
100
0 1 2 3 4 5
Years of Follow-up
Perc
ent
DBP<90 SBP<140 BP<140/90
ALLHATALLHAT
1.41.6 1.7 1.8
2.0
1.6 = mean number of drugs= mean number of drugs
Cushman, et al. J Clin Hypertens 2002;Cushman, et al. J Clin Hypertens 2002;4:393-4044:393-404
@ 5 years:@ 5 years:62% were on 62% were on >>2 drugs2 drugs30% were on 1 drug and controlled30% were on 1 drug and controlled
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Biochemical Results
Chlorthalidone Amlodipine LisinoprilSerum 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 3838 (26.5) 2284 (26.6) 2178 (25.4)
4 Years 1223 (14.4) 673 (13.4) 603 (12.8)
Serum potassium – mmol/LBaseline 4.3 (0.7) 4.3 (0.7) 4.4 (0.7)*
4 Years 4.1 (0.7) 4.4 (0.7)* 4.5 (0.7)*
Serum potassium – <3.5mEq/LBaseline 493 (3.4) 292 (3.4) 223 (2.6)
4 Years 707 (8.5) 93 (1.9) 37 (0.8)
* p<.05 compared to chlorthalidone† Ann Intern Med. 1999;130:461-470
ALLHAT
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ALLHATUSE OF POTASSIUM SUPPLEMENTATION
2.2 0.6
0.8
3.6
1.1
1.1
4.6
2.1
1.6
5.4
2.6
1.7
7.9
3.5
2.3
11
5.9
4
0
2
4
6
8
10
12
Year 1 Year 2 Year 3 Year 4 Year 5 Year 6
Chlorthalidone Amlodipine Lisinopril
% o
n po
tass
ium
sup
pl.
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Biochemical Results – Fasting Glucose – mg/dLChlorthalidone Amlodipine Lisinopril
TotalBaseline 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/dLBaseline 93.1 (11.7) 93.0 (11.4) 93.3 (11.8)
4 Years 104.4 (28.5) 103.1 (27.7) 100.5 (19.5)*
Diabetes Incidence (follow-up fasting glucose 126 mg/dL)4 Years 11.6% 9.8%* 8.1%*
*p<.05 compared to chlorthalidone
ALLHAT
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Renal Outcomes
C A L A/C L/CESRD(Rate/100 # events)
1.8 (0.1)193
2.1 (0.2)129
2.0(0.2)126
RR=1.12 p=.98
RR=1.11p=0.38
GFR (4 Year)Mean (sd)
70.0 (19.7)
75.1 (20.7)
70.7 (20) p<.001 p=0.03
ALLHAT
C = Chlorthalidone; A = Amlodipine; L = Lisinopril
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Years to CHD Event0 1 2 3 4 5 6 7
Cumulative CHD Event Rate
0
.04
.08
.12
.16
.2
Number at Risk: Chlorthalidone 15,255 14,477 13,820 13,102 11,362 6,340 2,956 209Amlodipine 9,048 8,576 8,218 7,843 6,824 3,870 1,878 215Lisinopril 9,054 8,535 8,123 7,711 6,662 3,832 1,770 195
Cumulative Event Rates for the Primary Outcome (Fatal CHD or Nonfatal MI) by ALLHAT Treatment Group
RR (95% CI) p value
A/C 0.98 (0.90-1.07) 0.65L/C 0.99 (0.91-1.08) 0.81
ChlorthalidoneAmlodipineLisinopril
ALLHAT
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Cumulative Event Rates for Stroke by ALLHAT Treatment Group ALLHAT
Cumulative Stroke Rate
Years to Stroke0 1 2 3 4 5 6 7
0
.02
.04
.06
.08
.1
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
RR (95% CI) p valueA/C 0.93 (0.81-1.06) 0.28L/C 1.15 (1.02-1.30) 0.02
ChlorthalidoneAmlodipineLisinopril
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Stroke – Subgroup Comparisons – RR (95% CI)ALLHAT
Amlodipine Better Chlorthalidone Better0.50 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 Better0.50 1 2
Non-Diabetic 1.23 (1.05, 1.44)
Diabetic 1.07 (0.90, 1.28)
Non-Black 1.00 (0.85, 1.17)
Black 1.40 (1.17, 1.68)
Women 1.22 (1.01, 1.46)
Men 1.10 (0.94, 1.29)
Age >= 65 1.13 (0.98, 1.30)
Age < 65 1.21 (0.97, 1.52)
Total 1.15 (1.02, 1.30)
P = .01 for interaction
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Cumulative Event Rates for All-Cause Mortality by ALLHAT Treatment Group ALLHAT
Cumulative Mortality Rate
Years to Death0 1 2 3 4 5 6 7
0
.05
.1
.15
.2
.25
.3RR (95% CI) p value
A/C 0.96 (0.89-1.02) 0.20L/C 1.00 (0.94-1.08) 0.90
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
RR (95% CI) p valueA/C 0.96 (0.89-1.02) 0.20L/C 1.00 (0.94-1.08) 0.90
ChlorthalidoneAmlodipineLisinopril
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Cumulative Event Rates for Combined CVD by ALLHAT Treatment Group ALLHAT
Cumulative Combined CVD Event Rate
Years to Combined CVD Event0 1 2 3 4 5 6 7
0
.1
.2
.3
.4
.5
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
RR (95% CI) p valueA/C 1.04 (0.99-1.09) 0.12L/C 1.10 (1.05-1.16) <0.001
ChlorthalidoneAmlodipineLisinopril
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Combined CVD – Subgroup Comparisons – RR (95% CI)ALLHAT
Amlodipine Better Chlorthalidone Better0.50 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 Better0.50 1 2
Non-Diabetic 1.12 (1.05, 1.19)
Diabetic 1.08 (1.00, 1.17)
Non-Black 1.06 (1.00, 1.13)
Black 1.19 (1.09, 1.30)
Women 1.12 (1.03, 1.21)
Men 1.08 (1.02, 1.15)
Age >= 65 1.13 (1.06, 1.20)
Age < 65 1.05 (0.97, 1.15)
Total 1.10 (1.05, 1.16)
P = .04 for interaction
22
Cumulative Event Rates for Heart Failure by ALLHAT Treatment Group ALLHAT
Cumulative CHF Rate
Years to HF0 1 2 3 4 5 6 7
0
.03
.06
.09
.12
.15RR (95% CI) p value
A/C 1.38 (1.25-1.52) <.001L/C 1.19 (1.07-1.31) <.001
ChlorthalidoneAmlodipineLisinopril
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
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Overall ConclusionsALLHAT
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.