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The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

ALLHAT. U.S. Department of Health and Human Services. National Institutes of Health. National Heart, Lung, and Blood Institute. STROKE RESULTS. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).

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The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)

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  1. ALLHAT U.S. Department of Health and Human Services National Institutes of Health National Heart, Lung, and Blood Institute STROKE RESULTS The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) Suzanne Oparil, Barry Davis, Chuke Nwachuku, Sara Pressel, Michael Alderman, David Calhoun, William Cushman, Jeffrey Cutler, Allan Ellsworth, Herbert Fendley, Stanley Franklin, Gabriel Habib, Frans Leenen, Jeffrey Probstfield, Sithiporn Sastrasinh for the ALLHAT Collaborative Research Group Suzanne Oparil, M.D.American Heart Association November 14, 2005

  2. ALLHAT 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

  3. ALLHAT Criteria For Stroke • Unequivocal objective findings of localizing neurologic deficit (+/- recent onset severe headache and loss of consciousness) • Duration >24 hrs, and • Absence of other disease process causing neurologic deficit, e.g., neoplasm, subdural hematoma, cerebral angiography, metabolic disorder OR • Abnormality on CT or MRI consistent with current neurologic symptoms or signs, OR • Positive lumbar puncture ALLHAT Manual of Operations 5.4.2

  4. ALLHAT Criteria For Fatal Stroke Death certificate listing stroke as consistent with, underlying or immediate cause of death, PLUS one or more: • Preterminal hospitalization with stroke as defined above • Previous stroke and no known potentially lethal non-cerebrovascular disease process and /or • Stroke diagnosed as cause of death at post-mortem examination ALLHAT Manual of Operations 5.4.2

  5. ALLHAT Concordance Between Clinical Sites And Endpoints Committee For Stroke Diagnosis • End points committee reviewed a 10% subset of hospitalized strokes for accuracy of the discharge diagnosis • Strokes reviewed:  153 • Confirmed by subcommittee:  129 (84%) • The diagnosis as originally submitted by the investigator was the diagnosis of record

  6. ALLHAT Baseline Characteristics

  7. ALLHAT Chlorthalidone Amlodipine Lisinopril Stroke Rate by Treatment Group 0.08 0.07 0.06 0.05 Cumulative Stroke Rate 0.04 0.03 0.02 0.01 0.00 0 1 2 3 4 5 6 7 Years to Stroke

  8. ALLHAT Multiple Strokesby Treatment Group

  9. ALLHAT Description of Fatal Strokesby Treatment Group

  10. ALLHAT Years from 1st Nonfatal Stroke to Death 0.50 Chlorthalidone Amlodipine 0.40 Lisinopril 0.30 Cumulative Death Rate 0.20 0.10 0.00 0 1 2 3 4 5 6 Years

  11. ALLHAT Total 1.23 (1.08-1.41) Black 1.51 (1.22-1.86) Non-black 1.07 (0.89-1.28) 0.50 1 2 Favors Lisinopril Favors Amlodipine Stroke – Subgroup Comparisons – RR (95% CI) Total 0.93 (0.82, 1.06) Total 1.15 (1.02, 1.30) Black 0.93 (0.76, 1.14) Black 1.40 (1.17, 1.68) Non-Black 0.93 (0.79, 1.10) Non-Black 1.00 (0.85, 1.17) 0.50 1 2 0.50 1 2 Favors Amlodipine Favors Chlorthalidone Favors Lisinopril Favors Chlorthalidone P = .002 for interaction P = .01 for interaction

  12. ALLHAT Total 1.23 (1.08-1.41) Men 1.10 (0.92-1.31) Women 1.45 (1.17-1.79) Black 1.51 (1.22-1.86) Non-black 1.07 (0.89-1.28) 0.50 1 2 Favors Lisinopril Favors Amlodipine Stroke – Subgroup Comparisons – RR (95% CI) Lisinopril/Amlodipine P = .04 for interaction P = .01 for interaction

  13. ALLHAT Chlorthalidone Amlodipine Lisinopril Stroke Rate by Treatment Group – Black Participants 0.09 0.08 0.07 0.06 0.05 Cumulative Stroke Rate 0.04 0.03 0.02 0.01 0.00 0 1 2 3 4 5 6 7 Years to Stroke

  14. ALLHAT Chlorthalidone Amlodipine Lisinopril Stroke Rate by Treatment Group - Non-Black Participants 0.07 0.06 0.05 0.04 Cumulative Stroke Rate 0.03 0.02 0.01 0.00 0 1 2 3 4 5 6 7 Years to Stroke

  15. ALLHAT Baseline Characteristics

  16. ALLHAT Chlorthalidone Amlodipine Lisinopril Stroke Rate by Treatment Group - Men 0.07 0.06 0.05 0.04 Cumulative Stroke Rate 0.03 0.02 0.01 0.00 0 1 2 3 4 5 6 7 Years to Stroke

  17. ALLHAT Chlorthalidone Amlodipine Lisinopril Stroke Rate by Treatment Group - Women 0.07 0.06 0.05 0.04 Cumulative Stroke Rate 0.03 0.02 0.01 0.00 0 1 2 3 4 5 6 7 Years to Stroke

  18. ALLHAT 90 85 mm Hg DBP 80 75 70 0 1 2 3 4 5 6 Years BP Results by Treatment Group by Race 150 145 mm Hg SBP 140 135 130 0 1 2 3 4 5 6 Years

  19. ALLHAT BP Differences: Lisinopril vs Chlorthalidone • Mean follow-up SBP for all participants was 2 mm Hg higher in the lisinopril group than the chlorthalidone group, 4-5 mm Hg higher in Blacks and 1-2 mm Hg higher in non-Blacks. • Adjustment for follow-up BP as time-dependent covariates in a Cox proportional hazards regression model slightly reduced the RR for stroke overall (1.15 to 1.12) and in the black subgroup (1.40 to 1.35), but the results remained statistically significant.

  20. ALLHAT BP differences: Lisinopril versus Chlorthalidone (continued) • Prospective observational studies* predict 2 mm Hg → 6% lower stroke mortality vs 15% observed effect • Based on the same data, 4 mm Hg difference in Blacks would predict 12% lower stroke mortality vs 40% observed *Prospective studies collaboration. Lancet 2002;360:1903.

  21. ALLHAT Predictors of Stroke –Categorical Variables

  22. ALLHAT Predictors of Stroke –Continuous Variables

  23. ALLHAT CONCLUSION • CCBs and ACE inhibitors are not superior to thiazide-type diuretics for preventing fatal or nonfatal stroke • Among Blacks, diuretic-based treatment is superior to ACE inhibitor-based treatment in stroke prevention • Among Blacks and women, CCB-based treatment is superior to ACE inhibitor-based treatment in stroke prevention

  24. ALLHAT Antihypertensive Trial:Implications • Diuretics should be the drug of choice for initial 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. • In Black hypertensives whose major risk is for a CVD event, thiazide-type diuretics (or CCBs in those who cannot take a diuretic) are recommended over ACEIs • Most hypertensive patients require more than one drug. Diuretics should generally be part of the antihypertensive regimen. Lifestyle advice should also be provided.

  25. Extra Slides

  26. ALLHAT Randomized Design of ALLHAT BP Trial 42,418 High-risk hypertensive patients Consent / Randomize Amlodipine Chlorthalidone Doxazosin Lisinopril Follow until death or end of study (4-8 years, mean 4.9 years)

  27. ALLHAT 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

  28. ALLHAT Definition of Stroke Rapid onset of persistent neurologic deficit attributable to an obstruction or rupture of the arterial system, including stroke occurring during surgery, that is not known to be secondary to brain trauma, tumor, infection or other non-ischemic cause. • >24 hrs unless death or typical lesion on CT or MRI scan • Carotid endarterectomy or angioplasty ALLHAT Manual of Operations 5.4.2

  29. ALLHAT Discovery Of APossible Stroke Event • Study investigators submit an end points questionnaire to the CTC • For end points involving death or hospitalization, death certificate, hospital discharge summary or face sheet with the diagnosis is required • End points committee reviews a 10% subset of hospitalized strokes for accuracy of the discharge diagnosis ALLHAT Manual of Operations 5.4.2

  30. ALLHAT Fatality of First Strokesby Treatment Group

  31. ALLHAT Length of Hospital Stay*by Treatment Group

  32. ALLHAT Total 0.93 (0.82, 1.06) Total 1.15 (1.02, 1.30) Age < 65 0.93 (0.73, 1.19) Age < 65 1.21 (0.97, 1.52) Age >= 65 0.93 (0.81, 1.08) Age >= 65 1.13 (0.98, 1.30) Men 1.00 (0.85, 1.18) Men 1.10 (0.94, 1.29) Women 0.84 (0.69, 1.03) Women 1.22 (1.01, 1.46) Black 0.93 (0.76, 1.14) Black 1.40 (1.17, 1.68) Non-Black 0.93 (0.79, 1.10) Non-Black 1.00 (0.85, 1.17) Diabetic 0.90 (0.75, 1.08) Diabetic 1.07 (0.90, 1.28) Non-Diabetic 0.96 (0.81, 1.14) Non-Diabetic 1.23 (1.05, 1.44) 0.50 1 2 0.50 1 2 Amlodipine Better Chlorthalidone Better Lisinopril Better Chlorthalidone Better P = .01 for interaction Stroke – Subgroup Comparisons – RR (95% CI)

  33. ALLHAT Total 1.23 (1.08-1.41) Men 1.10 (0.92-1.31) P = .04 for interaction Women 1.45 (1.17-1.79) Black 1.51 (1.22-1.86) P = .01 for interaction Non-black 1.07 (0.89-1.28) 0.50 1 2 Favors Lisinopril Favors Amlodipine Stroke – Subgroup Comparisons – RR (95% CI) Total 0.93 (0.82, 1.06) Black 0.93 (0.76, 1.14) Non-Black 0.93 (0.79, 1.10) 0.50 1 2 Favors Amlodipine Favors Chlorthalidone Total 1.15 (1.02, 1.30) Black 1.40 (1.17, 1.68) Non-Black 1.00 (0.85, 1.17) 0.50 1 2 All comparisons combined Favors Lisinopril Favors Chlorthalidone P = .002 for interaction

  34. ALLHAT 0.12 0.11 0.10 0.09 0.08 0.07 Chlorthalidone Amlodipine Lisinopril 0.06 0.05 Cumulative Event Rate 0.04 0.03 0.02 0.01 0.00 0 1 2 3 4 5 6 7 Years to Stroke Stroke Rate by Treatment Group – Black Men

  35. ALLHAT 0.12 0.11 0.10 0.09 0.08 0.07 Chlorthalidone Amlodipine Lisinopril 0.06 0.05 Cumulative Event Rate 0.04 0.03 0.02 0.01 0.00 0 1 2 3 4 5 6 7 Years to Stroke Stroke Rate by Treatment Group – Black Women

  36. ALLHAT 0.12 0.11 0.10 0.09 0.08 0.07 Chlorthalidone Amlodipine Lisinopril 0.06 Cumulative Event Rate 0.05 0.04 0.03 0.02 0.01 0.00 0 1 2 3 4 5 6 7 Years to Stroke Stroke Rate by Treatment Group – Non-Black Men

  37. ALLHAT 0.12 0.11 0.10 0.09 0.08 0.07 Chlorthalidone Amlodipine Lisinopril 0.06 0.05 Cumulative Event Rate 0.04 0.03 0.02 0.01 0.00 0 1 2 3 4 5 6 7 Years to Stroke Stroke Rate by Treatment Group – Non-Black Women

  38. ALLHAT Systolic Blood Pressure Differences Between Treatments by Race

  39. ALLHAT Chlorthalidone Amlodipine Lisinopril Stroke Rate by Treatment Group – Age <65 0.05 0.04 0.03 Cumulative Stroke Rate 0.02 0.01 0.00 0 1 2 3 4 5 6 7 Years to Stroke

  40. ALLHAT Chlorthalidone Amlodipine Lisinopril Stroke Rate by Treatment Group – Age 65+ 0.09 0.08 0.07 0.06 0.05 Cumulative Stroke Rate 0.04 0.03 0.02 0.01 0.00 0 1 2 3 4 5 6 7 Years to Stroke

  41. ALLHAT Chlorthalidone Amlodipine Lisinopril Stroke Rate by Treatment Group - Diabetic Participants 0.09 0.08 0.07 0.06 0.05 Cumulative Stroke Rate 0.04 0.03 0.02 0.01 0.00 0 1 2 3 4 5 6 7 Years to Stroke

  42. ALLHAT Chlorthalidone Amlodipine Lisinopril Stroke Rate by Treatment Group - Nondiabetic Participants 0.07 0.06 0.05 0.04 Cumulative Stroke Rate 0.03 0.02 0.01 0.00 0 1 2 3 4 5 6 7 Years to Stroke

  43. ALLHAT Chlorthalidone Amlodipine Lisinopril Stroke Rate by Treatment Group – CHD at Baseline 0.08 0.07 0.06 0.05 Cumulative Stroke Rate 0.04 0.03 0.02 0.01 0.00 0 1 2 3 4 5 6 7 Years to Stroke

  44. ALLHAT Chlorthalidone Amlodipine Lisinopril Stroke Rate by Treatment Group – No CHD at Baseline 0.07 0.06 0.05 0.04 Cumulative Stroke Rate 0.03 0.02 0.01 0.00 0 1 2 3 4 5 6 7 Years to Stroke

  45. ALLHAT Chlorthalidone Amlodipine Lisinopril Stroke Rate by Treatment Group – Treated at Baseline 0.07 0.06 0.05 0.04 Cumulative Stroke Rate 0.03 0.02 0.01 0.00 0 1 2 3 4 5 6 7 Years to Stroke

  46. ALLHAT Chlorthalidone Amlodipine Lisinopril Stroke Rate by Treatment Group – Untreated at Baseline 0.08 0.07 0.06 0.05 Cumulative Stroke Rate 0.04 0.03 0.02 0.01 0.00 0 1 2 3 4 5 6 7 Years to Stroke

  47. ALLHAT Predictors of Stroke by Race

  48. ALLHAT .3 .25 .2 .15 Cumulative Mortality Rate .1 .05 0 0 1 2 3 4 5 6 7 Years to Death Cumulative Event Rates for All-Cause Mortality by ALLHAT Treatment Group Chlorthalidone Amlodipine Lisinopril 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

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