1. 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 2998 - 3007

2. 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

3. 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

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

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

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

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

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

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

10. 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

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. 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.

13. Pravastatin (5170) Usual Care (5185) Mean BL* LDL, mg/dL Mean BL TC, mg/dL 146 224 146 224 Mean age, years Black, % Women, % 66 3937 49 History of CHD, % Type 2 diabetes, % Current smoking, % 1315 3634 23 Baseline Characteristics *BL = baseline

14. 0.0 20.0 40.0 60.0 80.0 100.0 % 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 82429964295 84830634353

15. 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

16. Total Cholesterol Total Cholesterol in mg/dL Year of Blood Draw 0246 170 180 190 200 210 220 230 Pravastatin Usual Care 4% * 8% 11% 15% 17% 20% * Percent decrease from baseline. No. of Participants 854278137635139Usual Care 912299841025134Pravastatin

17. LDL-C LDL-C in mg/dL 0246 100 110 120 130 140 150 Usual Care Pravastatin 7% * 11% 16% 23% 28% 30% Year of Blood Draw * Percent decrease from baseline. No. of Participants Pravastatin5129850572157 Usual Care5131508330 75 ALLHAT

18. 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)

19. Cumulative Mortality Rate, % RR = 0.99 95% CI = (0.89, 1.11) p = 0.88 Pravastatin/Usual Care Time to Death, years 0 1 2 34 5 6 0 3 6 9 12 15 Usual Care Pravastatin All-Cause Mortality No. at Risk Pravastatin5170508849564809381921731132 Usual Care5185510449944845383221791138

20. All-Cause Mortality Pravastatin/Usual Care Relative Risk and 95% Confidence Intervals Favors Pravastatin Favors Usual Care 0.5012 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 55-64 y 0.99 (0.89, 1.11)Total

21. 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 0.5012 1.18 (0.90, 1.56) 0.96 (0.84, 1.11) CHD at baseline 0.95 (0.74, 1.23)

22. CHD (Nonfatal MI + CHD Death) Cumulative CHD Event Rate, % RR = 0.91 95% CI = (0.79, 1.04) p = 0.16 Pravastatin/Usual Care Time to CHD Event, years 0 1 2 3 4 5 6 0 3 6 9 12 15 Usual Care Pravastatin 988196035234558478249715185 Usual Care 992196635464543476149625170 Pravastatin No. at Risk

23. 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). 0.5012 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 55-64 y

24. CHD (Nonfatal MI + CHD Death) Pravastatin/Usual Care Relative Risk and 95% Confidence Intervals Favors Pravastatin Favors Usual Care 0.5012 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)

25. ALLHAT Cancer Incidence Site Pravastatin N = 5170 Usual Care N = 5185 Total Prostate Lung Colon Breast Other/Unknown 378* 86 63 46 34 162 369 79 78 38 37 140 *The numbers don’t add to the total because some participants have more than one type of cancer.

26. 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 0.50 12 ALLHAT

27. Meta-Analysis of Large Long-Term Statin Trials and Impact of ALLHAT - LLT TrialN%∆TC † Odds Ratio (95% CI) MortalityCHD 8 Statin Trials* 54,38120.2% 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 64,73618.5% 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

28. Relation of total cholesterol (TC) differential in active treatment (TRT) versus control group (CTL) to log odds ratio for mortality. -0.8 -0.6 -0.4 -0.2 -0 0.2 0.4 0.6 051015202530 ALLHAT-LLT HPS Post-CABG AFCAPS CARE LIPID WOSCOPS LIPS 4S %ΔTC (CTL-TRT) ln OR (TRT/CTL) Meta-Regression Analysis All-Cause Mortality

29. 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. -0.8 -0.6 -0.4 -0.2 0 0.2 0.4 051015202530 ALLHAT-LLT HPS Post-CABG AFCAPS CARE LIPID WOSCOPS LIPS 4S %ΔTC (CTL-TRT) ln OR (TRT/CTL)

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

31. 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

32. 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.