1. 1 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 The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) The ALLHAT Collaborative Research Group Sponsored by the National Heart, Lung, and Blood Institute (NHLBI) ALLHAT JAMA. 2002;288:2981-2997

2. 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 ALLHAT

3. 3 Secondary Objectives: Subgroups Pre-specified – Age 65+ – Women – African-Americans – Diabetic patients Post-hoc – Baseline CHD ALLHAT

4. 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 ALLHAT

5. 5 Sites in ALLHAT 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 ALLHAT

6. 6 Randomized Design of ALLHAT High-risk hypertensive patients Consent / Randomize (42,418) Amlodipine Chlorthalidone Doxazosin Lisinopril Eligible for lipid- lowering 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). ALLHAT

7. 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mm Hg on 1-2 antihypertensive drugs at Visit 1 ≤ 180/110 mm Hg at Visit 2, when medication may have been partially withdrawn – No washout period was required in ALLHAT. ALLHAT

8. 8 ALLHAT 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 ALLHAT

9. 9 ALLHAT 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 ALLHAT

10. 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 ALLHAT

11. 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 ALLHAT

12. 12 Step 1 Treatment Protocol Step 1 AgentInitial Dose*Dose 1*Dose 2*Dose 3* Chlorthalidone12.5 25 Amlodipine2.5 510 Lisinopril10 2040 Doxazosin1248 * mg/day ALLHAT

13. 13 Step 2 Agents:Dose 1*Dose 2*Dose 3* Reserpine0.05 qd or 0.1 qod 0.1 qd0.2 qd Clonidine (oral)0.1 bid0.2 bid0.3 bid Atenolol25 qd50 qd100 qd Step 3 Agent: Hydralazine25 bid50 bid100 bid *All doses in mg ALLHAT Step Up Treatment Protocol

14. 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) ALLHAT

15. 15 Decision to Drop an ALLHAT 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 ALLHAT

16. 16 Cumulative Event Rate Years of Follow-up doxazosin chlorthalidone Cardiovascular Disease C: 15,268 D: 9,067 12,990 7,382 9,443 5,285 4,827 2,654 2,010 1,083 Rel Risk 1.25 z = 6.77, p < 0.0001 95% CI 1.17-1.33 ALLHAT JAMA. 2000;283:1967-1975

17. 17 Cumulative Event Rate Years of Follow-up doxazosin chlorthalidone Heart Failure C: 15,268 D: 9,067 13,644 7,845 5,531 3,089 2,427 1,351 9,541 5,457 Rel Risk 2.04 z = 10.95, p < 0.0001 95% CI 1.79-2.32 ALLHAT JAMA. 2000;283:1967-1975

18. 18 Comparison of Doxazosin with Chlorthalidone - Conclusions Doxazosin is not recommended as first- line therapy in hypertension. ALLHAT 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. ALLHAT JAMA. 2000;283:1967-1975

19. 19 Baseline Characteristics Chlorthalidone 15,255 Amlodipine 9,048 Lisinopril 9,054 Mean SBP/DBP146 / 84 Treated (90%) Untreated (10%) 145 / 83 156 / 89 145 / 83 157 / 90 145 / 84 156 / 89 Mean age, y67 Black, %3536 Women, %47 46 Current smoking %22 History of CHD, %262425 Type 2 diabetes, %363736 ALLHAT

20. 20 On Step 1 or Equivalent Treatment by Antihypertensive Treatment Group ALLHAT

21. 21 Full Crossovers by Antihypertensive Treatment Group ALLHAT 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

22. 22 On Step 2 or Step 3 Treatment by Antihypertensive Treatment Group ALLHAT

23. 23 BP Results by Treatment Group 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). ALLHAT BL6M1Y3Y5Y C146.2138.2136.6134.6134.1 A146.2140.0138.3135.4134.9 L146.4141.4139.7136.4136.1 BL6M1Y3Y5Y C84.080.179.277.175.4 A83.979.778.576.174.5 L84.180.879.777.275.4

24. 24 Biochemical Results ChlorthalidoneAmlodipineLisinopril Serum cholesterol- mg/dL, mean (SD) Baseline216.1 (43.8)216.5 (44.1)215.6 (42.4) 4 Years197.2 (42.1)195.6 (41.0)*195.0 (40.6)* Serum potassium – mmol/L, mean (SD) Baseline4.3 (0.7) 4.4 (0.7)* 4 Years4.1 (0.7)4.4 (0.7)*4.5 (0.7)* Estimated GFR† – mL/min/1.73m 2,mean (SD) Baseline77.6 (19.7)78.0 (19.7)77.7 (19.9) 4 Years70.0 (19.7)75.1 (20.7)*70.7 (20.1)* * p<.05 compared to chlorthalidone † Ann Intern Med. 1999;130:461-470 ALLHAT

25. 25 Biochemical Results – Fasting Glucose – mg/dL ChlorthalidoneAmlodipineLisinopril Total –mean (SD) Baseline123.5 (58.3)123.1 (57.0)122.9 (56.1) 4 Years126.3 (55.6)123.7 (52.0)121.5 (51.3)* Among baseline nondiabetics with baseline <126 mg/dL – mean (SD) Baseline93.1 (11.7)93.0 (11.4)93.3 (11.8) 4 Years104.4 (28.5)103.1 (27.7)100.5 (19.5)* Diabetes Incidence (follow-up fasting glucose  126 mg/dL) 4 Years11.6%9.8%*8.1%* *p<.05 compared to chlorthalidone ALLHAT

26. 26 Follow-Up ChlorthalidoneAmlodipineLisinopril Randomized15,2559,0489,054 Known alive12,530 (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%) Lost339 (2.2%)200 (2.2%)218 (2.4%) Refused80 (0.5%)58 (0.6%) Person-years (% obs/exp) 99% ALLHAT

27. 27 Years to CHD Event 01234567 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 2,956 209 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 Cumulative Event Rates for the Primary Outcome (Fatal CHD or Nonfatal MI) by ALLHAT Treatment Group RR (95% CI)p value A/C0.98 (0.90-1.07)0.65 L/C0.99 (0.91-1.08)0.81 ALLHAT Chlorthalidone Amlodipine Lisinopril

28. 28 Nonfatal MI + CHD Death – Subgroup Comparisons – RR (95% CI) ALLHAT Amlodipine Better Chlorthalidone Better 0.5012 Non-Diabetic0.97 (0.86, 1.09) Diabetic0.99 (0.87, 1.13) Non-Black0.97 (0.87, 1.08) Black1.01 (0.86, 1.18) Women0.99 (0.85, 1.15) Men0.98 (0.87, 1.09) Age>=650.97 (0.88, 1.08) Age <650.99 (0.85, 1.16) Total0.98 (0.90, 1.07) Lisinopril Better Chlorthalidone Better 0.5012 Non-Diabetic0.99 (0.88, 1.11) Diabetic1.00 (0.87, 1.14) Non-Black0.94 (0.85, 1.05) Black1.10 (0.94, 1.28) Women1.06 (0.92, 1.23) Men0.94 (0.85, 1.05) Age >= 651.01 (0.91, 1.12) Age < 650.95 (0.81, 1.12) Total0.99 (0.91, 1.08)

29. 29 Cumulative Stroke Rate Years to Stroke 01234567 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 Cumulative Event Rates for Stroke by ALLHAT Treatment Group RR (95% CI)p value A/C0.93 (0.81-1.06)0.28 L/C1.15 (1.02-1.30)0.02 ALLHAT Chlorthalidone Amlodipine Lisinopril

30. 30 Stroke – Subgroup Comparisons – RR (95% CI) ALLHAT Amlodipine Better Chlorthalidone Better 0.5012 Non-Diabetic0.96 (0.81, 1.14) Diabetic0.90 (0.75, 1.08) Non-Black0.93 (0.79, 1.10) Black0.93 (0.76, 1.14) Women0.84 (0.69, 1.03) Men1.00 (0.85, 1.18) Age >= 650.93 (0.81, 1.08) Age < 650.93 (0.73, 1.19) Total0.93 (0.82, 1.06) Lisinopril Better Chlorthalidone Better 0.5012 Non-Diabetic1.23 (1.05, 1.44) Diabetic1.07 (0.90, 1.28) Non-Black1.00 (0.85, 1.17) Black1.40 (1.17, 1.68) Women1.22 (1.01, 1.46) Men1.10 (0.94, 1.29) Age >= 651.13 (0.98, 1.30) Age < 651.21 (0.97, 1.52) Total1.15 (1.02, 1.30) P =.01 for interaction

31. 31 Cumulative Mortality Rate Years to Death 01234567 0.05.1.15.2.25.3 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 Cumulative Event Rates for All-Cause Mortality by ALLHAT Treatment Group RR (95% CI)p value A/C0.96 (0.89-1.02)0.20 L/C1.00 (0.94-1.08)0.90 ALLHAT Chlorthalidone Amlodipine Lisinopril

32. 32 All-Cause Mortality – Subgroup Comparisons – RR (95% CI) ALLHAT Amlodipine Better Chlorthalidone Better 0.5012 Non-Diabetic0.95 (0.87, 1.04) Diabetic0.96 (0.87, 1.07) Non-Black0.94 (0.87, 1.03) Black0.97 (0.87, 1.09) Women0.96 (0.86, 1.07) Men0.95 (0.87, 1.04) Age >= 650.96 (0.88, 1.03) Age < 650.96 (0.83, 1.10) Total0.96 (0.89, 1.02) Lisinopril Better Chlorthalidone Better 0.5012 Non-Diabetic1.00 (0.91, 1.09) Diabetic1.02 (0.91, 1.13) Non-Black0.97 (0.89, 1.06) Black1.06 (0.95, 1.18) Women1.02 (0.91, 1.13) Men0.99 (0.91, 1.08) Age >= 651.03 (0.95, 1.12) Age < 650.93 (0.81, 1.08) Total1.00 (0.94, 1.08)

33. 33 Cumulative Combined CVD Event Rate Years to Combined CVD Event 01234567 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 Cumulative Event Rates for Combined CVD by ALLHAT Treatment Group RR (95% CI)p value A/C1.04 (0.99-1.09)0.12 L/C1.10 (1.05-1.16)<0.001 ALLHAT Chlorthalidone Amlodipine Lisinopril

34. 34 Combined CVD – Subgroup Comparisons – RR (95% CI) ALLHAT Amlodipine Better Chlorthalidone Better 0.5012 Non-Diabetic1.02 (0.96, 1.09) Diabetic1.06 (0.98, 1.15) Non-Black1.04 (0.97, 1.10) Black1.06 (0.96, 1.16) Women1.04 (0.96, 1.13) Men1.04 (0.98, 1.11) Age >= 651.05 (0.99, 1.12) Age < 651.03 (0.94, 1.12) Total1.04 (0.99, 1.09) Lisinopril Better Chlorthalidone Better 0.5012 Non-Diabetic1.12 (1.05, 1.19) Diabetic1.08 (1.00, 1.17) Non-Black1.06 (1.00, 1.13) Black1.19 (1.09, 1.30) Women1.12 (1.03, 1.21) Men1.08 (1.02, 1.15) Age >= 651.13 (1.06, 1.20) Age < 651.05 (0.97, 1.15) Total1.10 (1.05, 1.16) P =.04 for interaction

35. 35 Cumulative CHF Rate Years to HF 01234567 0.03.06.09.12.15 Cumulative Event Rates for Heart Failure by ALLHAT Treatment Group RR (95% CI)p value A/C1.38 (1.25-1.52)<.001 L/C1.19 (1.07-1.31)<.001 ALLHAT Chlorthalidone Amlodipine Lisinopril 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. 36 Heart Failure – Subgroup Comparisons – RR (95% CI) ALLHAT Amlodipine Better Chlorthalidone Better 0.5012 Non-Diabetic1.33 (1.16, 1.52) Diabetic1.42 (1.23, 1.64) Non-Black1.33 (1.18, 1.51) Black1.47 (1.24, 1.74) Women1.33 (1.14, 1.55) Men1.41 (1.24, 1.61) Age >= 651.33 (1.18, 1.49) Age < 651.51 (1.25, 1.82) Total1.38 (1.25, 1.52) Lisinopril Better Chlorthalidone Better 0.5012 Non-Diabetic1.20 (1.04, 1.38) Diabetic1.22 (1.05, 1.42) Non-Black1.15 (1.01, 1.30) Black1.32 (1.11, 1.58) Women1.23 (1.05, 1.43) Men1.19 (1.03, 1.36) Age >= 651.20 (1.06, 1.35) Age < 651.23 (1.01, 1.50) Total1.20 (1.09, 1.34)

37. 37 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.

38. 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 one- fourth) in preventing heart failure, overall and for hospitalized or fatal cases. ALLHAT

39. 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. ALLHAT

40. 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. ALLHAT

41. 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. ALLHAT

42. 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 ALLHAT

43. 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 ALLHAT

44. 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 ALLHAT

45. 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 ALLHAT

46. 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 ALLHAT

47. 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 ALLHAT

48. 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 non- black 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 ALLHAT

49. 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. ALLHAT

50. 50 Angioedema TotalBlacks Non- blacks Chlorthalidone8 / 15,255 0.1% 2 / 5,369 <0.1% 6 / 9,886 0.1% Lisinopril38 / 9,054 0.4% 23 / 3,210 0.7% 15 / 5,844 0.3% p<.001 p=.002 There were 3 cases (<0.1%) of angioedema in the amlodipine group (comparison to chlorthalidone not significant). ALLHAT