U.S. Department of Health and Human Services National Institutes of Health National Heart, Lung, and Blood Institute ALLHAT Major Outcomes in Moderately.

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

Primary Objective ALLHAT - LLT ALLHAT 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

Randomized Design High-risk hypertensive patients Consent / Randomize (N = 42,418) Amlodipine Chlorthalidone Doxazosin Lisinopril 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). ALLHAT

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

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

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

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

Eligibility Criteria ALLHAT Moderate hypercholesterolemia LDL mg/dL without CHD LDL mg/dL with known CHD

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

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

Vital Status at 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 ALLHAT Observed/expected person-years: 99% Pravastatin and usual care groups similar with respect to vital status at closeout.

Pravastatin (5170) Usual Care (5185) Mean BL* LDL, mg/dL Mean BL TC, mg/dL Mean age, years Black, % Women, % History of CHD, % Type 2 diabetes, % Current smoking, % Baseline Characteristics *BL = baseline

% Pravastatin, N* Usual Care, N 2 Years4 Years6 Years 88% 84% 83% * N gives the total number of participants at the visit. 8% 17% 26% Percent on Statin ALLHAT

Pravastatin Mean (N) Usual Care Mean (N) Mean BL* LDL, mg/dL146 (5129)146 (5131) Mean LDL at 4 yrs, mg/dL104 ( 572)129 ( 330) % decrease LDL BL to 4 yrs28 ( 567)11 ( 326) Mean BL TC, mg/dL224 (5134)224 (5139) Mean TC at 4 yrs, mg/dL184 (2998)206 (2781) % decrease TC BL to 4 yrs17 (2977)8 (2756) Mean BL HDL, mg/dL48 (5134)47 (5137) Mean HDL at 4 yrs, mg/dL49 ( 593)46 ( 348) % increase HDL BL to 4yrs3 ( 589)2 ( 344) Lipid Results ALLHAT *BL = baseline

Total Cholesterol Total Cholesterol in mg/dL Year of Blood Draw Pravastatin Usual Care 4% * 8% 11% 15% 17% 20% * Percent decrease from baseline. No. of Participants Usual Care Pravastatin

LDL-C LDL-C in mg/dL Usual Care Pravastatin 7% * 11% 16% 23% 28% 30% Year of Blood Draw * Percent decrease from baseline. No. of Participants Pravastatin Usual Care ALLHAT

Cause-Specific Mortality Number of Deaths (6-Year Rate per 100 Participants) Cause of Death Pravastatin N = 5170 Usual Care N = 5185 All-cause631 (14.9)641 (15.3) CVD295 (6.9)300 (7.1) Non-CVD302 (7.7)302 (7.8) Cause unknown34 (1.0)39 (1.1)

Cumulative Mortality Rate, % RR = % CI = (0.89, 1.11) p = 0.88 Pravastatin/Usual Care Time to Death, years Usual Care Pravastatin All-Cause Mortality No. at Risk Pravastatin Usual Care

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

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

CHD (Nonfatal MI + CHD Death) Cumulative CHD Event Rate, % RR = % CI = (0.79, 1.04) p = 0.16 Pravastatin/Usual Care Time to CHD Event, years Usual Care Pravastatin Usual Care Pravastatin No. at Risk

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

CHD (Nonfatal MI + CHD Death) Pravastatin/Usual Care Relative Risk and 95% Confidence Intervals Favors Pravastatin Favors Usual Care CHD at baseline1.03 (0.77, 1.38) No CHD & LDL-C ≥ 130 mg/dL 0.92 (0.77, 1.09) No CHD & LDL-C < 130 mg/dL 0.73 (0.49, 1.07)

ALLHAT Cancer Incidence Site Pravastatin N = 5170 Usual Care N = 5185 Total Prostate Lung Colon Breast Other/Unknown 378* *The numbers don’t add to the total because some participants have more than one type of cancer.

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

Meta-Analysis of Large Long-Term Statin Trials and Impact of ALLHAT - LLT TrialN%∆TC † Odds Ratio (95% CI) MortalityCHD 8 Statin Trials* 54, % 0.83 (0.78, 0.88) 0.70 (0.67, 0.74) ALLHAT- LLT 10,3559.6% 0.99 (0.89, 1.11) 0.91 (0.79, 1.04) Total 64, % 0.86 (0.82, 0.90) 0.73 (0.69, 0.77) *4S, WOSCOPS, CARE, LIPID, AFCAPS/TexCAPS, Post-CABG, HPS, LIPS †Percent change in total cholesterol

Relation of total cholesterol (TC) differential in active treatment (TRT) versus control group (CTL) to log odds ratio for mortality ALLHAT-LLT HPS Post-CABG AFCAPS CARE LIPID WOSCOPS LIPS 4S %ΔTC (CTL-TRT) ln OR (TRT/CTL) Meta-Regression Analysis All-Cause Mortality

Meta-Regression Analysis CHD (Nonfatal MI + CHD Death) Relation of total cholesterol (TC) differential in active treatment (TRT) versus control group (CTL) to log odds ratio for CHD events ALLHAT-LLT HPS Post-CABG AFCAPS CARE LIPID WOSCOPS LIPS 4S %ΔTC (CTL-TRT) ln OR (TRT/CTL)

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

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

Conclusions ALLHAT - LLT ALLHAT 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.