1 U.S. Department of Health and Human Services National Institutes of Health Major Outcomes in High Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic The Antihypertensive and Lipid-Lowering Lowering Treatment to Prevent Heart Attack Trial () The Collaborative Research Group Sponsored by the National Heart, Lung, and Blood Institute (NHLBI) National Heart, Lung, and Blood Institute www.allhat.org JAMA 2002;288:2981-2997 2997
2 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
3 Background 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, aimed to evaluate the health effects of these non-bp actions
4 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 nonhospitalized, hospitalized, fatal], angina (treated non-hospitalized, hospitalized), peripheral arterial disease (revascularization procedure)
5 Secondary Outcomes (Continued) HQOL (Health-related quality of life) GI Bleeding Costs
6 Step 1 Treatment 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
7 Step Up Treatment Protocol Step 2 Agents: Dose 1* Dose 2* Dose 3* Reserpine 0.05 qd 0.1 qd 0.2 qd or 0.1 qod 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
8 Baseline Characteristics Chlorthalidone 15,255 Amlodipine 9,048 Lisinopril 9,054 Mean SBP/DBP 146 / 84 146 / 84 146 / 84 Treated (90%) 145 / 83 145 / 83 145 / 84 Untreated (10%) 156 / 89 157 / 90 156 / 89 Mean age, y 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
9 On Step 1 or Equivalent Treatment by Antihypertensive Treatment Group 100.0 80.0 60.0 % 40.0 20.0 0.0 1 Year 2 Years 3 Years 4 Years 5 Years Chlor 87.1 84.7 82.7 80.8 80.5 Aml 87.6 85.2 83.2 80.5 80.4 Lis 82.4 78.4 77.1 74.8 72.6
10 BP Results by Treatment Group Chlorthalidone Amlodipine Lisinopril 150 145 C A L BL 146.2 146.2 146.4 6M 138.2 140.0 141.4 1Y 136.6 138.3 139.7 3Y 134.6 135.4 136.4 5Y 134.1 134.9 136.1 90 85 C A L BL 84.0 83.9 84.1 6M 80.1 79.7 80.8 1Y 79.2 78.5 79.7 3Y 77.1 76.1 77.2 5Y 75.4 74.5 75.4 mm Hg BP 140 mm Hg BP 80 135 75 130 70 0 1 2 3 4 5 6 Years 0 1 2 3 4 5 6 Years 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 1.6 = mean number of drugs DBP<90 SBP<140 BP<140/90 Percent 100 80 60 40 20 92% 86% 88% 90% 91% 68% 58 60 64 67 67 66 62 65 55 58 2.0 31 27 1.6 1.7 1.8 1.4 0 0 1 2 3 4 5 @ 5 years: Years of Follow-up 62% were on >2 2 drugs 30% were on 1 drug and controlled Cushman, et al. J Clin Hypertens 2002;4:393 4:393-404404
12 Biochemical Results Serum cholesterol- mg/dl Baseline 4 Years Serum cholesterol - > 240 mg/dl Baseline 3838 (26.5) 4 Years 1223 (14.4) Serum potassium mmol/l Baseline 4 Years Serum potassium <3.5mEq/L Baseline 4 Years * p<.05 compared to chlorthalidone Ann Intern Med. 1999;130:461-470 Chlorthalidone 216.1 (43.8) 197.2 (42.1) 4.3 (0.7) 4.1 (0.7) 493 (3.4) 707 (8.5) Amlodipine 216.5 (44.1) 195.6 (41.0)* 2284 (26.6) 673 (13.4) 4.3 (0.7) 4.4 (0.7)* 292 (3.4) 93 (1.9) Lisinopril 215.6 (42.4) 195.0 (40.6)* 2178 (25.4) 603 (12.8) 4.4 (0.7)* 4.5 (0.7)* 223 (2.6) 37 (0.8)
13 USE OF POTASSIUM SUPPLEMENTATION Chlorthalidone Amlodipine Lisinopril 12 11 % on potassium suppl. 10 8 6 4 2 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 5.9 4 0 Year 1 Year 2 Year 3 Year 4 Year 5 Year 6
14 Biochemical Results Fasting Glucose mg/dl Chlorthalidone Amlodipine Total Baseline 123.5 (58.3) 123.1 (57.0) 4 Years 126.3 (55.6) 123.7 (52.0) Among baseline nondiabetics with baseline <126 mg/dl Baseline 93.1 (11.7) 93.0 (11.4) 4 Years 104.4 (28.5) 103.1 (27.7) Diabetes Incidence (follow-up fasting glucose 126 mg/dl) 4 Years 11.6% 9.8%* Lisinopril 122.9 (56.1) 121.5 (51.3)* 93.3 (11.8) 100.5 (19.5)* 8.1%* *p<.05 compared to chlorthalidone
15 Renal Outcomes 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
16.2 Cumulative Event Rates for the Primary Outcome (Fatal CHD or Nonfatal MI) by Treatment Group RR (95% CI) p value.16 A/C 0.98 (0.90-1.07) 0.65 Cumulative CHD Event Rate.12.08.04 L/C 0.99 (0.91-1.08) Chlorthalidone Amlodipine Lisinopril 0.81 0 0 1 2 3 4 5 6 7 Years to CHD Event 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 Cumulative Event Rates for Stroke by Treatment Group.1 RR (95% CI) p value.08 A/C L/C 0.93 (0.81-1.06) 1.15 (1.02-1.30) 0.28 0.02 Cumulative Stroke Rate.06.04.02 Chlorthalidone Amlodipine Lisinopril 0 0 1 2 3 4 5 6 7 Years to 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 Stroke Subgroup Comparisons RR (95% CI) Total 0.93 (0.82, 1.06) Age < 65 0.93 (0.73, 1.19) Age >= 65 0.93 (0.81, 1.08) Men 1.00 (0.85, 1.18) Women 0.84 (0.69, 1.03) Black 0.93 (0.76, 1.14) Non-Black 0.93 (0.79, 1.10) Diabetic 0.90 (0.75, 1.08) Non-Diabetic 0.96 (0.81, 1.14) 0.50 1 2 Amlodipine Better Chlorthalidone Better Total 1.15 (1.02, 1.30) Age < 65 1.21 (0.97, 1.52) Age >= 65 1.13 (0.98, 1.30) Men 1.10 (0.94, 1.29) Women 1.22 (1.01, 1.46) Black 1.40 (1.17, 1.68) Non-Black 1.00 (0.85, 1.17) Diabetic 1.07 (0.90, 1.28) Non-Diabetic 1.23 (1.05, 1.44) 0.50 1 2 Lisinopril Better Chlorthalidone Better P =.01 for interaction
19.3.25 Cumulative Event Rates for All-Cause Mortality by Treatment Group A/C L/C RR (95% CI) 0.96 (0.89-1.02) 1.00 (0.94-1.08) p value 0.20 0.90 Cumulative Mortality Rate.2.15.1.05 Chlorthalidone Amlodipine Lisinopril 0 0 1 2 3 4 5 6 7 Years to Death 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 Treatment Group.5 RR (95% CI) p value A/C 1.04 (0.99-1.09) 0.12 Cumulative Combined CVD Event Rate.4.3.2.1 L/C 1.10 (1.05-1.16) Chlorthalidone Amlodipine Lisinopril <0.001 0 0 1 2 3 4 5 6 7 Years to Combined CVD Event 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 Combined CVD Subgroup Comparisons RR (95% CI) Total 1.04 (0.99, 1.09) Age < 65 1.03 (0.94, 1.12) Age >= 65 1.05 (0.99, 1.12) Men 1.04 (0.98, 1.11) Women 1.04 (0.96, 1.13) Black 1.06 (0.96, 1.16) Non-Black 1.04 (0.97, 1.10) Diabetic 1.06 (0.98, 1.15) Non-Diabetic 1.02 (0.96, 1.09) 0.50 1 2 Amlodipine Better Chlorthalidone Better Total 1.10 (1.05, 1.16) Age < 65 1.05 (0.97, 1.15) Age >= 65 1.13 (1.06, 1.20) Men 1.08 (1.02, 1.15) Women 1.12 (1.03, 1.21) Black 1.19 (1.09, 1.30) Non-Black 1.06 (1.00, 1.13) Diabetic 1.08 (1.00, 1.17) Non-Diabetic 1.12 (1.05, 1.19) 0.50 1 2 Lisinopril Better Chlorthalidone Better P =.04 for interaction
22 Cumulative CHF Rate.15.12.09.06.03 Cumulative Event Rates for Heart Failure by Treatment Group A/C L/C RR (95% CI) 1.38 (1.25-1.52) 1.19 (1.07-1.31) Chlorthalidone Amlodipine Lisinopril p value <.001 <.001 0 0 1 2 3 4 5 6 7 Years to HF 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 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.