1 U.S. Department of Health and Human Services Major Outcomes in High Risk Hypertensive Patients Randomized to Angiotensin-Converting Enzyme Inhibitor or Calcium Channel Blocker vs Diuretic National Institutes of Health The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial () The Collaborative Research Group National Heart, Lung, and Blood Institute Sponsored by the National Heart, Lung, and Blood Institute (NHLBI) JAMA. 2002;288:2981-2997
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 Secondary Objectives: Subgroups Pre-specified Age 65+ Women African-Americans Diabetic patients Post-hoc Baseline CHD
4 Secondary Outcomes All-cause mortality Stroke Combined CHD nonfatal MI, CHD death, coronary revascularization, hospitalized angina Combined CVD combined CHD, stroke, lower extremity revascularization, treated angina, fatal / hospitalized / treated CHF, hospitalized or outpatient PAD Other renal (reciprocal serum creatinine, ESRD, estimated GFR) and cancer
5 Sites in 623 clinical sites United States, Canada, Puerto Rico, US Virgin Islands VA, private & group general medicine practices, community health centers, HMOs, specialty practices Variety of research experience
6 High-risk hypertensive patients Randomized Design Consent / Randomize (42,418) of Amlodipine Chlorthalidone Doxazosin Lisinopril Eligible for lipidlowering Not eligible for lipid-lowering Consent / Randomize (10,355) Pravastatin Usual care Follow for CHD and other outcomes until death or end of study (up to 8 yr).
7 Inclusion Criteria for Antihypertensive Trial Age/sex: men and women aged > 55 years BP eligibility: Untreated systolic and/or diastolic hypertension ( 140/90 mm Hg but 180/110 mm Hg at two visits) Treated hypertension 160/100 mm Hg on 1-2 antihypertensive drugs at Visit 1 180/110 mm Hg at Visit 2, when medication may have been partially withdrawn No washout period was required in.
8 Inclusion Criteria: Risk Factors At least one of the following: Myocardial infarction or stroke: at least 6 months old, or age-indeterminate History of revascularization procedure Major ST segment depression or T-wave inversion Other documented ASCVD
9 Inclusion Criteria: Risk Factors At least one of the following (cont.) Type 2 diabetes mellitus HDL cholesterol < 35 mg/dl on any 2 or more determinations in past 5 years Left ventricular hypertrophy (past 2 years) ECG, or echo (septum + posterior wall thickness 25 mm) Current cigarette smoking
10 Major Exclusion Criteria MI, stroke, or angina within 6 months Symptomatic CHF or ejection fraction < 35% Known renal insufficiency - creatinine 2 mg/dl Requiring diuretics, CCB, ACEI, or alpha blockers for reasons other than hypertension
11 Sample Size Assumptions & Statistical Methods 83% power to detect 16% reduction in risk for primary outcome 2-sided α=.0178 (z=2.37) Accounts for multiple comparisons Analysis according to intent to treat Cumulative event rates Kaplan-Meier Differences between event curves - Log-rank tests & Cox proportional hazards (PH) model PH assumption tested by log-log plots, tests with treatment by time interaction If violated, 2 x 2 table used
12 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
13 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
14 Safety Outcomes Angioedema Hospitalization for gastrointestinal bleeding Records from the VA hospitalization database Records from the Center for Medicare & Medicaid Services (CMS) database (participants age 65 or older)
15 Decision to Drop an Arm January 24, 2000 NHLBI Director accepts the recommendation of an independent review group to terminate doxazosin arm Futility of finding a significant difference for primary outcome Statistically significant 25 percent higher rate of major secondary endpoint, combined CVD outcomes
16 Cumulative Event Rate 0.30 0.25 0.20 0.15 0.10 0.05 0.00 0 1 2 3 4 C: 15,268 D: 9,067 Cardiovascular Disease Rel Risk 1.25 doxazosin 12,990 7,382 95% CI 1.17-1.33 z = 6.77, p < 0.0001 chlorthalidone 9,443 5,285 Years of Follow-up 4,827 2,654 2,010 1,083 JAMA. 2000;283:1967-1975
17 Cumulative Event Rate 0.10 0.08 0.06 0.04 0.02 0.00 C: 15,268 D: 9,067 Heart Failure Rel Risk 2.04 doxazosin 95% CI 1.79-2.32 z = 10.95, p < 0.0001 Years of Follow-up chlorthalidone 9,541 5,531 2,427 13,644 5,457 3,089 1,351 0 1 7,845 2 3 4 JAMA. 2000;283:1967-1975
18 Comparison of Doxazosin with Chlorthalidone - Conclusions Doxazosin is not recommended as firstline therapy in hypertension. does not allow an assessment of the effect of doxazosin compared with placebo on the incidence of CVD. The use of doxazosin as a step-up drug for treating hypertension was not tested in this trial. These findings are likely to apply to all alpha-blockers. JAMA. 2000;283:1967-1975
19 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
20 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
21 15.0 Full Crossovers by Antihypertensive Treatment Group Chlorthalidone: not on assigned medicine or open-label diuretic, but on open-label calcium channel blocker or ACE-inhibitor Amlodipine: not on assigned medicine or open-label calcium channel blocker, but on open-label diuretic Lisinopril: not on assigned medicine or open-label ACE-inhibitor, but on open-label diuretic % 10.0 5.0 0.0 1 Year 2 Years 3 Years 4 Years 5 Years Chlor 5.1 6.7 7.7 8.2 9.0 Amlodipine 2.8 4.5 5.0 6.0 6.9 Lisinopril 3.5 5.1 6.0 7.0 8.5
22 On Step 2 or Step 3 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 26.7 32.2 35.6 38.0 40.7 Aml 25.9 32.0 35.2 36.9 39.5 Lis 32.6 36.3 38.8 40.7 43.0
23 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).
24 Biochemical Results Serum cholesterol- mg/dl, mean (SD) Baseline 4 Years Serum potassium mmol/l, mean (SD) Baseline 4 Years Estimated GFR ml/min/1.73m 2,mean (SD) 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) 77.6 (19.7) 70.0 (19.7) Amlodipine 216.5 (44.1) 195.6 (41.0)* 4.3 (0.7) 4.4 (0.7)* 78.0 (19.7) 75.1 (20.7)* Lisinopril 215.6 (42.4) 195.0 (40.6)* 4.4 (0.7)* 4.5 (0.7)* 77.7 (19.9) 70.7 (20.1)*
25 Biochemical Results Fasting Glucose mg/dl Chlorthalidone Amlodipine Lisinopril Total mean (SD) 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 mean (SD) Baseline 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
26 Follow-Up Chlorthalidone Amlodipine Lisinopril Randomized 15,255 9,048 9,054 Known alive 12,530 (82.1%) 7,479 (82.7%) 7,412 (81.9%) Confirmed deaths 2,203 (14.4%) 1,256 (13.9%) 1,314 (14.5%) Deaths pending confirmation 103 (0.7%) 55 (0.6%) 52 (0.6%) Lost 339 (2.2%) 200 (2.2%) 218 (2.4%) Refused 80 (0.5%) 58 (0.6%) 58 (0.6%) Person-years 99% 99% 99% (% obs/exp)
27 Cumulative CHD Event Rate.2.16.12.08.04 Cumulative Event Rates for the Primary Outcome (Fatal CHD or Nonfatal MI) by Treatment Group A/C L/C RR (95% CI) 0.98 (0.90-1.07) 0.99 (0.91-1.08) Chlorthalidone Amlodipine Lisinopril p value 0.65 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
28 Nonfatal MI + CHD Death Subgroup Comparisons RR (95% CI) Total 0.98 (0.90, 1.07) Age <65 0.99 (0.85, 1.16) Age>=65 0.97 (0.88, 1.08) Men 0.98 (0.87, 1.09) Women 0.99 (0.85, 1.15) Black 1.01 (0.86, 1.18) Non-Black 0.97 (0.87, 1.08) Diabetic 0.99 (0.87, 1.13) Non-Diabetic 0.97 (0.86, 1.09) 0.50 1 2 Amlodipine Better Chlorthalidone Better Total 0.99 (0.91, 1.08) Age < 65 0.95 (0.81, 1.12) Age >= 65 1.01 (0.91, 1.12) Men 0.94 (0.85, 1.05) Women 1.06 (0.92, 1.23) Black 1.10 (0.94, 1.28) Non-Black 0.94 (0.85, 1.05) Diabetic 1.00 (0.87, 1.14) Non-Diabetic 0.99 (0.88, 1.11) 0.50 1 2 Lisinopril Better Chlorthalidone Better
29 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
30 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
31.3.25 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
32 All-Cause Mortality Subgroup Comparisons RR (95% CI) Total 0.96 (0.89, 1.02) Age < 65 0.96 (0.83, 1.10) Age >= 65 0.96 (0.88, 1.03) Men 0.95 (0.87, 1.04) Women 0.96 (0.86, 1.07) Black 0.97 (0.87, 1.09) Non-Black 0.94 (0.87, 1.03) Diabetic 0.96 (0.87, 1.07) Non-Diabetic 0.95 (0.87, 1.04) 0.50 1 2 Amlodipine Better Chlorthalidone Better Total 1.00 (0.94, 1.08) Age < 65 0.93 (0.81, 1.08) Age >= 65 1.03 (0.95, 1.12) Men 0.99 (0.91, 1.08) Women 1.02 (0.91, 1.13) Black 1.06 (0.95, 1.18) Non-Black 0.97 (0.89, 1.06) Diabetic 1.02 (0.91, 1.13) Non-Diabetic 1.00 (0.91, 1.09) 0.50 1 2 Lisinopril Better Chlorthalidone Better
33 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
34 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
35 Cumulative Event Rates for Heart Failure by Treatment Group.15 A/C RR (95% CI) 1.38 (1.25-1.52) p value <.001 L/C 1.19 (1.07-1.31) <.001 Cumulative CHF Rate.12.09.06 Chlorthalidone Amlodipine Lisinopril.03 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
36 Heart Failure Subgroup Comparisons RR (95% CI) Total 1.38 (1.25, 1.52) Age < 65 1.51 (1.25, 1.82) Age >= 65 1.33 (1.18, 1.49) Men 1.41 (1.24, 1.61) Women 1.33 (1.14, 1.55) Black 1.47 (1.24, 1.74) Non-Black 1.33 (1.18, 1.51) Diabetic 1.42 (1.23, 1.64) Non-Diabetic 1.33 (1.16, 1.52) 0.50 1 2 Amlodipine Better Chlorthalidone Better Total 1.20 (1.09, 1.34) Age < 65 1.23 (1.01, 1.50) Age >= 65 1.20 (1.06, 1.35) Men 1.19 (1.03, 1.36) Women 1.23 (1.05, 1.43) Black 1.32 (1.11, 1.58) Non-Black 1.15 (1.01, 1.30) Diabetic 1.22 (1.05, 1.42) Non-Diabetic 1.20 (1.04, 1.38) 0.50 1 2 Lisinopril Better Chlorthalidone Better
37 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.
38 Other Conclusions Neither amlodipine (representing CCB) nor lisinopril (representing ACEI) was superior to chlorthalidone (representing thiazide-type diuretics) in preventing major coronary events or increasing overall survival. Although chlorthalidone did not differ from amlodipine in overall CVD event prevention, it was superior to amlodipine (by about onefourth) in preventing heart failure, overall and for hospitalized or fatal cases.
39 Other Conclusions Chlorthalidone was superior to lisinopril in preventing aggregate CV events, principally stroke, HF, angina, and coronary revascularization Chlorthalidone was superior to doxazosin (representing alpha-blockers) in preventing CV events, including both HF and other CVD.
40 Other Conclusions Given the large sample size, almost all biochemical differences between treatment groups at 4 years were statistically significant. Total cholesterol 1-2 mg/dl higher in chlorthalidone compared to amlodipine and lisinopril. Serum potassium 0.3-0.4 mmol/l lower in chlorthalidone compared to amlodipine and lisinopril. Potassium <3.5 mmol/l 6-8% higher among those randomized to chlorthalidone Fasting glucose 3 mg/dl higher in chlorthalidone than amlodipine group, 5 mg/dl higher in chlorthalidone than lisinopril group.
41 Other Conclusions Among nondiabetic participants, incidence of fasting glucose 126 mg/dl at 4 years was 1.8% higher in chlorthalidone vs amlodipine, and 3.5% higher in chlorthalidone vs lisinopril. Estimated GFR decreased by 7-8 units at 4 years in chlorthalidone and lisinopril arms, but decreased only by about 3 units in the amlodipine arm. Overall, metabolic differences did not translate into more adverse cardiovascular events, or into higher all-cause mortality, with chlorthalidone.
42 Further Conclusions: Amlodipine versus Chlorthalidone Drug tolerance and blood pressure control were similar (and high): The percent of participants who remained on the assigned drug or another of the same class was essentially identical (80% of those attending the 5- year visit) Mean SBP averaged about 1 mm Hg higher, and mean DBP about 1 mm Hg lower, in the amlodipine group BP control averaged about 2% better in the chlorthalidone group, reaching 68% after 5 years
43 Further Conclusions: Amlodipine versus Chlorthalidone There were no differences for other secondary outcomes: Cardiovascular stroke, angina, coronary revascularization, peripheral arterial disease End stage renal disease Cancer incidence and mortality Hospitalization for gastrointestinal bleeding (in a subset of the cohort) All-cause mortality
44 Further Conclusions: Amlodipine versus Chlorthalidone Results for all cited outcomes were consistent for major (pre-specified) subgroups: Men and women Black and nonblack participants Older and younger participants (<65 and 65+) Diabetic and non-diabetic participants
45 Further Conclusions: Lisinopril versus Chlorthalidone Drug tolerance and blood pressure control were better with chlorthalidone, especially for black patients: The percent of participants remaining on lisinopril or another ACEI averaged about 5-6% less than participants assigned to the diuretic About 6-8% more of the participants in the lisinopril group than those in the chlorthalidone group required additional antihypertensive drugs
46 Further Conclusions: Lisinopril versus Chlorthalidone Mean SBP averaged about 2 mm Hg higher in the lisinopril than the chlorthalidone group (4 mm Hg for blacks); mean DBPs were equivalent BP control averaged about 4-7% better in the chlorthalidone group Of patients in the lisinopril group who remained on an ACEI, 19% were also on a diuretic at 5 years
47 Further Conclusions: Lisinopril versus Chlorthalidone There were no differences for other secondary outcomes peripheral arterial disease end stage renal disease cancer incidence and mortality all-cause mortality
48 Further Conclusions: Lisinopril versus Chlorthalidone Results were consistent for all outcomes by age, gender, race, and diabetic status, except for stroke and CVD, where there was significant heterogeneity by race (p=.01 and p=.04, respectively) Among black participants assigned to lisinopril, the stroke rate was increased 40% compared to the chlorthalidone group. (No difference among nonblack participants.) The combined CVD rate was increased 19% in blacks and by 6% in whites. Angiodema, a rare adverse effect, was more frequent with lisinopril, especially in blacks
49 Antihypertensive Trial: Implications Diuretics should be the drug of choice for first step therapy of hypertension For the patient who cannot take a diuretic (which should be an unusual circumstance), CCB s and ACEI s may be considered. Most hypertensive patients require more than one drug. Diuretics should generally be part of the antihypertensive regimen. Lifestyle advice should also be provided.
50 Angioedema Total Blacks Nonblacks Chlorthalidone 8 / 15,255 2 / 5,369 6 / 9,886 0.1% <0.1% 0.1% Lisinopril 38 / 9,054 23 / 3,210 15 / 5,844 0.4% 0.7% 0.3% p<.001 p<.001 p=.002 There were 3 cases (<0.1%) of angioedema in the amlodipine group (comparison to chlorthalidone not significant).