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Major Cardiovascular Events in Hypertensive Patients Randomized to Doxazosin vs Chlorthalidone

ALLHAT. Major Cardiovascular Events in Hypertensive Patients Randomized to Doxazosin vs Chlorthalidone. Final Results From The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). The ALLHAT Collaborative Research Group

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Major Cardiovascular Events in Hypertensive Patients Randomized to Doxazosin vs Chlorthalidone

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  1. ALLHAT Major Cardiovascular Events in Hypertensive Patients Randomized to Doxazosin vs Chlorthalidone Final Results From 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) Hypertension. 2003;42:239-246

  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 Secondary Objectives: Subgroups

  4. 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 non-hospitalized CHF, hospitalized or outpatient PAD • Other clinical outcomes – renal (reciprocal serum creatinine, ESRD, estimated GFR) and cancer

  5. ALLHAT 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

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mm Hg on 1-2 antihypertensive drugs at Visit 1 • ≤ 180/110 mm Hg at Visit 2, when medication may have been partially withdrawn • No washout period was required in ALLHAT.

  7. ALLHAT 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

  8. ALLHAT 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

  9. ALLHAT 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

  10. ALLHAT Sample Size Assumptions & Statistical Methods • 83% power to detect 16% reduction in risk for primary outcome • 99% power to detect 20% reduction with the observed event rate • 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

  11. ALLHAT Randomized Design of ALLHAT Amlodipine Chlorthalidone Doxazosin Lisinopril High-risk hypertensive patients Consent / Randomize Eligible for lipid-lowering Not eligible for lipid-lowering Consent / Randomize Pravastatin Usual care Follow until death or end of study (4-8 yr, ave 6 yr).

  12. ALLHAT Step 1Treatment Protocol

  13. ALLHAT Step UpTreatment Protocol

  14. ALLHAT 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. ALLHAT Decision to Dropan 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

  16. ALLHAT Baseline Characteristics

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

  18. ALLHAT Full Crossovers by Antihypertensive Treatment Group Chlorthalidone: not on assigned medicine or open-label diuretic, but on open-label alpha-blocker Doxazosin: not on assigned medicine or open-label alpha-blocker, but on open-label diuretic

  19. ALLHAT SBP Results by Treatment Group

  20. ALLHAT DBP Results by Treatment Group

  21. Vital Status by Antihypertensive Treatment Group ALLHAT

  22. ALLHAT Combined CVD Rates by ALLHAT Treatment Group .4 .3 Chlorthalidone Doxazosin Combined CVD Event Rate .2 .1 0 0 1 2 3 4 5 Years to Combined CVD Event

  23. ALLHAT RR and 95% CI for Combined CVD Total Total 1.20 (1.13, 1.27) 1.20 (1.13, 1.27) Age < 65 Age < 65 1.15 (1.04, 1.27) 1.15 (1.04, 1.27) Age >= 65 Age >= 65 1.23 (1.14, 1.32) 1.23 (1.14, 1.32) Men Men 1.21 (1.13, 1.30) 1.21 (1.13, 1.30) Women Women 1.17 (1.07, 1.29) 1.17 (1.07, 1.29) Black Black 1.28 (1.16, 1.42) 1.28 (1.16, 1.42) Non Non - - Black Black 1.16 (1.09, 1.25) 1.16 (1.09, 1.25) Diabetic Diabetic 1.22 (1.11, 1.33) 1.22 (1.11, 1.33) Nondiabetic Nondiabetic 1.19 (1.10, 1.28) 1.19 (1.10, 1.28) Untreated Untreated 1.39 (1.14, 1.70) 1.39 (1.14, 1.70) Treated Treated 1.18 (1.11, 1.26) 1.18 (1.11, 1.26) CHD CHD 1.14 (1.04, 1.25) 1.14 (1.04, 1.25) No CHD No CHD 1.24 (1.15, 1.34) 0.33 0.50 1 2 3 Favors Doxazosin Favors Chlorthalidone

  24. ALLHAT Heart Failure Rates by ALLHAT Treatment Group .15 Chlorthalidone Doxazosin .1 Cumulative HF Rate .05 0 0 1 2 3 4 5 Years to HF

  25. ALLHAT RR and 95% CI for Heart Failure Total Total 1.80 (1.61, 2.02) 1.80 (1.61, 2.02) Age < 65 Age < 65 1.76 (1.40, 2.22) 1.76 (1.40, 2.22) Age >= 65 Age >= 65 1.89 (1.65, 2.17) 1.89 (1.65, 2.17) Men Men 1.89 (1.62, 2.20) 1.89 (1.62, 2.20) Women Women 1.78 (1.49, 2.14) 1.78 (1.49, 2.14) Black Black 1.84 (1.51, 2.24) 1.84 (1.51, 2.24) Non Non - - Black Black 1.85 (1.60, 2.14) 1.85 (1.60, 2.14) Diabetic Diabetic 1.85 (1.56, 2.19) 1.85 (1.56, 2.19) Nondiabetic Nondiabetic 1.88 (1.60, 2.20) 1.88 (1.60, 2.20) Untreated Untreated 1.54 (0.98, 2.42) 1.54 (0.98, 2.42) Treated Treated 1.87 (1.66, 2.11) 1.87 (1.66, 2.11) CHD CHD 1.75 (1.46, 2.11) 1.75 (1.46, 2.11) No CHD No CHD 1.91 (1.64, 2.22) 1.91 (1.64, 2.22) 0.33 0.33 0.50 0.50 1 1 2 2 3 3 Favors Doxazosin Favors Chlorthalidone

  26. ALLHAT Stroke Rates by ALLHAT Treatment Group .08 .06 Chlorthalidone Doxazosin .04 Cumulative Stroke Rate .02 0 0 1 2 3 4 5 Years to Stroke

  27. ALLHAT Total Age<65 Age>=65 Men Women Black Non-Black Diabetic Non-Diabetic Untreated Treated CHD No CHD STROKE 1.26 (1.00 - 1.46) 1.22 (0.93 - 1.61) 1.28 (1.08 - 1.51) 0.32 (0.10 - 1.59) 1.18 (0.94 - 1.49) 1.38 (1.10 - 1.73) 1.18 (0.98 - 1.42) 1.21 (0.98 - 1.51) 1.32 (1.09 - 1.60) 1.60 (0.99 - 2.59) 1.23 (1.06 - 1.43) 1.23 (0.96 - 1.58) 1.27 (1.07 - 1.52) 0.50 1 2 Favors Doxazosin Favors Chlorthalidone

  28. ALLHAT CHD Rates by ALLHAT Treatment Group .12 .09 Chlorthalidone Doxazosin .06 Cumulative CHD Event Rate .03 0 0 1 2 3 4 5 Years to CHD Event

  29. ALLHAT CHD 1.03 (0.92 - 1.15) 1.05 (0.86 - 1.27) 1.02 (0.89 - 1.17) 0.97 (0.85 - 1.11) 1.15 (0.94 - 1.39) 1.12 (0.90 - 1.36) 1.00 (0.88 - 1.15) 1.07 (0.91 - 1.27) 1.00 (0.87 - 1.16) 0.93 (0.63 - 1.36) 1.04 (0.92 - 1.17) 1.05 (0.88 - 1.25) 1.01 (0.87 - 1.17) 0.5 1.0 2.0 Favors Doxazosin Favors Chlorthalidone

  30. ALLHAT All-Cause Mortality by ALLHAT Treatment Group .16 .12 Chlorthalidone Doxazosin .08 Cumulative Mortality Rate .04 0 0 1 2 3 4 5 Years to Death

  31. ALLHAT TOTAL MORTALITY 1.03 (0.84 - 1.13) 0.90 (0.75 - 1.09) 1.07 (0.97 - 1.19) 0.99 (0.88 - 1.11) 1.10 (0.95 - 1.27) 1.06 (0.92 - 1.22) 1.01 (0.90 - 1.14) 0.99 (0.86 - 1.14) 1.07 (0.95 - 1.20) 1.16 (0.86 - 1.55) 1.02 (0.93 - 1.12) 1.02 (0.88 - 1.20) 1.03 (0.93 - 1.15) 0.50 1 2 Favors Doxazosin Favors Chlorthalidone

  32. ALLHAT ESRD 1.04 (0.84 – 1.76) 0.85 (0.49 - 1.48) 1.15 (0.79 - 1.68) 0.97 (0.65 - 1.44) 1.14 (0.71 - 1.85) 0.99 (0.63 - 1.55) 1.08 (0.70 - 1.67) 1.26 (0.84 - 1.88) 0.83 (0.51 - 1.35) 0.97 (0.29 - 3.33) 1.05 (0.76 - 1.44) 0.73 (0.41 - 1.32) 1.21 (0.84 - 1.76) 0.25 0.50 1 2 3 4 Favors Doxazosin Favors Chlorthalidone

  33. ALLHAT Biochemical Changes

  34. ALLHAT Diabetes Incidence

  35. ALLHAT Final Results Confirm That for Doxazosin / Chlorthalidone: • 20% ↑ risk of combined CVD • 80% ↑ risk of heart failure • 26% ↑ risk of stroke • No difference for CHD or for total mortality Increased risk for some CV events for doxazosin in spite of lower total cholesterol and lower fasting glucose.

  36. ALLHAT Conclusions Chlorthalidone is superior to doxazosin for: • Hypertension control • Drug compliance • Reduction of cardiovascular complications In addition, chlorthalidone is much less expensive

  37. ALLHAT Lessons Learned - 1 • For some drugs, BP lowering is an inadequate marker (surrogate) of health benefits in hypertension • Antihypertensive drugs can have important non-BP actions that may alter the benefit of BP lowering

  38. ALLHAT Lessons Learned - 2 • Comparative outcome trials, like ALLHAT, are essential for documenting optimal drug benefit / risk balance and for guiding the practice of medicine • All major health outcomes of a treatment should be evaluated

  39. ALLHAT Recommendations • Chlorthalidone (diuretic) is the recommended drug of choice for initial antihypertensive treatment in high risk hypertensive patients. • Doxazosin is not recommended as first-line therapy in hypertension.

  40. ALLHAT Additional Comments • 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.

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