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U.S. Department of Health and Human Services

ALLHAT. Major Outcomes in Moderately Hypercholesterolemic, Hypertensive Patients Randomized to Pravastatin vs Usual Care*. U.S. Department of Health and Human Services. National Institutes of Health. The ALLHAT Collaborative Research Group.

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U.S. Department of Health and Human Services

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  1. ALLHAT Major Outcomes in Moderately Hypercholesterolemic, Hypertensive Patients Randomized to Pravastatin vs Usual Care* U.S. Department of Health and Human Services National Institutes of Health The ALLHAT Collaborative Research Group Sponsored by the National Heart, Lung, and BIood Institute (NHLBI) National Heart, Lung, and Blood Institute *JAMA, December 18, 2002 – Vol. 288, No. 23, pp 2998 - 3007

  2. ALLHAT Primary ObjectiveALLHAT - LLT To determine whether pravastatin* compared with usual care reduces all-cause mortality in moderately hypercholesterolemic, hypertensive, older participants with at least one additional CHD risk factor. *40 mg/d

  3. ALLHAT Randomized Design Amlodipine Chlorthalidone Doxazosin Lisinopril Consent / Randomize(N = 42,418) High-risk hypertensive patients Eligible for lipid-lowering Not eligible for lipid-lowering Consent / Randomize (N = 10,355) Pravastatin Usual care Follow until death or end of study (max 7.8 yr, average 4.8 yr).

  4. ALLHAT Secondary Outcomes • CHD • Cause-specific mortality • Total and site-specific cancers

  5. ALLHAT Major Subgroups (a priori) • Age 65+ • Women • African-Americans • Type 2 Diabetes

  6. ALLHAT Major Subgroups(post hoc) • CHD at Baseline • No CHD and LDL-C ≥ 130 mg/dL • No CHD and LDL-C < 130 mg/dL

  7. Eligibility Criteria ALLHAT Eligible for and enrolled in antihypertensive trial Triglyceride level <350 mg/dL

  8. ALLHAT Eligibility Criteria • Moderate • hypercholesterolemia • • LDL 120-189 mg/dL • without CHD • • LDL 100-129 mg/dL • with known CHD

  9. ALLHAT Exclusion Criteria • Continuing use of prescribed lipid-lowering agents • Contraindications to statins • Secondary cause of elevated serum cholesterol • ALT > 2 times ULN

  10. ALLHAT Clinical Sites in LLT • 513 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

  11. Sample Size Assumptions & Statistical Methods • 84% power to detect 20% reduction in risk for primary outcome • 2-sided α = 0.05 • 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

  12. ALLHAT Vital Statusat Closeout 8776 (84.8%) known alive 1272 (12.3%) confirmed deaths 55 ( 0.5%) confirmation of death pending 206 ( 2.0%) lost 46 ( 0.4%) refused Observed/expected person-years: 99% Pravastatin and usual care groups similar with respect to vital status at closeout.

  13. Baseline Characteristics *BL = baseline

  14. ALLHAT Percent on Statin 100.0 88% 83% 84% 80.0 60.0 % 40.0 26% 17% 8% 20.0 0.0 2 Years 4 Years 6 Years 4353 3063 848 Pravastatin, N* 4295 2996 824 Usual Care, N * N gives the total number of participants at the visit.

  15. ALLHAT Lipid Results *BL = baseline

  16. Total Cholesterol 230 4% * 220 Usual Care 8% 210 Total Cholesterol in mg/dL 11% 200 15% 17% 190 20% 180 Pravastatin * Percent decrease from baseline. 170 0 2 4 6 No. of Participants Year of Blood Draw Pravastatin 5134 4102 2998 912 Usual Care 5139 3763 2781 854

  17. ALLHAT LDL-C 150 7%* 140 11% 130 LDL-C in mg/dL 16% Usual Care 120 23% 28% 110 30% * Percent decrease from baseline. Pravastatin 100 0 2 4 6 Year of Blood Draw

  18. Cause-Specific MortalityNumber of Deaths (6-Year Rate per 100 Participants)

  19. All-Cause Mortality 15 12 Pravastatin 9 Usual Care Cumulative Mortality Rate, % 6 RR = 0.99 95% CI = (0.89, 1.11) p = 0.88 Pravastatin/Usual Care 3 0 2 6 3 4 1 5 0 Time to Death, years

  20. All-Cause Mortality ALLHAT Total 0.99 (0.89, 1.11) Age 55-64 y 0.93 (0.74, 1.16) Age ≥ 65 y 1.01 (0.89, 1.15) Men 0.99 (0.86, 1.14) Women 0.98 (0.83, 1.17) Black 1.01 (0.85, 1.19) Non-Black 0.98 (0.85, 1.13) Type 2 Diabetes 1.03 (0.86, 1.22) No Diabetes 0.96 (0.84, 1.11) Pravastatin/Usual Care Relative Risk and 95% Confidence Intervals 0.50 1 2 Favors Pravastatin Favors Usual Care

  21. All-Cause Mortality ALLHAT Pravastatin/Usual Care Relative Risk and 95% Confidence Intervals CHD at baseline 0.95 (0.74, 1.23) 0.96 (0.84, 1.11) No CHD & LDL-C ≥ 130 mg/dL No CHD & LDL-C < 130 mg/dL 1.18 (0.90, 1.56) 0.50 1 2 Favors Pravastatin Favors Usual Care

  22. CHD (Nonfatal MI + CHD Death) 15 12 Pravastatin Usual Care 9 Cumulative CHD Event Rate, % 6 RR = 0.91 95% CI = (0.79, 1.04) p = 0.16 Pravastatin/Usual Care 3 0 5 2 6 1 4 3 0 Time to CHD Event, years No. at Risk Pravastatin 5170 4962 4761 4543 3546 1966 992 Usual Care 5185 4971 4782 4558 3523 1960 988

  23. CHD (Nonfatal MI + CHD Death) Pravastatin/Usual Care Relative Risk and 95% Confidence Intervals Total 0.91 (0.79, 1.04) Age 55-64 y 0.83 (0.65, 1.06) Age ≥ 65 y 0.94 (0.80, 1.12) Men 0.84 (0.71, 1.00) Women 1.02 (0.81, 1.28) Black* 0.73 (0.58, 0.92) Non-Black* 1.02 (0.86, 1.21) Type 2 Diabetes 0.89 (0.71, 1.10) No Diabetes 0.92 (0.76, 1.10) 0.50 1 2 Favors Pravastatin Favors Usual Care *There is a Black/Non-Black by Treatment interaction (p = 0.025).

  24. CHD (Nonfatal MI + CHD Death) Pravastatin/Usual Care Relative Risk and 95% Confidence Intervals 0.50 1 2 Favors Pravastatin Favors Usual Care

  25. ALLHAT Cancer Incidence *The numbers don’t add to the total because some participants have more than one type of cancer.

  26. ALLHAT All-Cause Mortality Pravastatin/Usual Care Relative Risk and 95% Confidence Intervals Total 0.99 (0.89, 1.11) Doxazosin 0.91 (0.71, 1.16) Chlorthalidone 1.03 (0.86, 1.23) Amlodipine 1.06 (0.84, 1.35) Lisinopril 0.95 (0.75, 1.21) 0.50 1 2 Favors Pravastatin Favors Usual Care

  27. Meta-Analysis of Large Long-Term Statin Trialsand Impact of ALLHAT - LLT *4S, WOSCOPS, CARE, LIPID, AFCAPS/TexCAPS, Post-CABG, HPS, LIPS †Percent change in total cholesterol

  28. Meta-Regression AnalysisAll-Cause Mortality 0.6 Post - CABG AFCAPS 0.4 0.2 ALLHAT - LLT CARE LIPS -0 OR (TRT/CTL) HPS -0.2 ln -0.4 4S LIPID WOSCOPS -0.6 -0.8 0 5 10 15 20 25 30 % Δ TC (CTL - TRT) Relation of total cholesterol (TC) differential in active treatment (TRT) versus control group (CTL) to log odds ratio for mortality.

  29. Meta-Regression AnalysisCHD (Nonfatal MI + CHD Death) 0.4 Post - CABG 0.2 ALLHAT - LLT LIPS 0 CARE LIPID -0.2 OR (TRT/CTL) HPS -0.4 4S ln -0.6 WOSCOPS -0.8 AFCAPS -1 0 5 10 15 20 25 30 % Δ TC (CTL - TRT) Relation of total cholesterol (TC) differential in active treatment (TRT) versus control group (CTL) to log odds ratio for CHD events.

  30. ALLHAT ConclusionsALLHAT - LLT ALLHAT pravastatin and usual care groups both attained substantial cholesterol reductions, resulting in a relatively modest cholesterol difference between them.

  31. ALLHAT ConclusionsALLHAT - LLT Accordingly, ALLHAT found only a small decrease in CVD event rates (non-significant) for pravastatin compared with usual care and no difference in mortality.

  32. ALLHAT ConclusionsALLHAT - LLT The study results do not alter current cholesterol treatment guidelines, which are based on a series of clinical trials with larger cholesterol reductions than those observed in ALLHAT. Thus, cholesterol lowering by lifestyle changes and drug treatment is recommended to reduce CVD morbidity and mortality.

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