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

3. 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 ALLHAT Manual of Operations 5.4.2

4. 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 ALLHAT Manual of Operations 5.4.2

5. 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 ALLHAT

6. Baseline Characteristics AgeChlorthalidoneAmlodipineLisinopril N15,2559,0489,054 Age – mean (sd)66.9 (7.7) Women (%)47.047.346.2 SBP – mean (sd)146 (16) DBP – mean (sd)84 (10) Current smokers (%)21.9 ASCVD (%)51.851.051.7 Diabetes (%)36.236.735.5 ALLHAT

7. 0.00 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 Cumulative Stroke Rate 01234567 Years to Stroke Stroke Rate by Treatment Group Chlorthalidone Amlodipine Lisinopril HR (95% CI)p value A/C0.93 (0.82-1.06)0.28 L/C1.15 (1.02-1.30)0.02 L/A1.23 (1.08-1.41)0.003 ALLHAT

8. Multiple Strokes by Treatment Group ChlorthalidoneAmlodipineLisinopril 1 stroke606 (90%)333 (88%)405 (89%) 2 strokes58 (9%)35 (9%)45 (10%) 3+ strokes11 (2%)9 (2%)7 (2%) Total ppts with stroke 675377457 Compared with Cp = 0.63p = 0.77 Compared with Ap = 0.65 ALLHAT

9. Description of Fatal Strokes by Treatment Group HR (95% CI)p value A/C0.95 (0.74 – 1.23)0.71 L/C1.26 (0.99 – 1.59)0.06 L/A1.32 (1.01 – 1.73)0.05 There are no significant differences in treatment group effect across subgroups. ALLHAT ChlorAmlodLisin In-hospital137 (85%)72 (78%)88 (73%) Out-of-hospital22 (14%)16 (17%)27 (22%) DK3 (2%)4 (4%)6 (5%) Total16292121 Compared with Cp=0.36p=0.04 Compared with Ap=0.36

10. Years from 1st Nonfatal Stroke to Death 0.00 0.10 0.20 0.30 0.40 0.50 Cumulative Death Rate 0123456 Years Chlorthalidone Amlodipine Lisinopril ALLHAT HR (95% CI)p value A/C1.00 (0.74 – 1.35)0.99 L/C0.93 (0.69 – 1.24)0.60 L/A0.93 (0.67 – 1.29)0.67

11. Stroke – Subgroup Comparisons – RR (95% CI) ALLHAT Favors Amlodipine Favors Chlorthalidone 0.5012 Non-Black0.93 (0.79, 1.10) Black0.93 (0.76, 1.14) Total0.93 (0.82, 1.06) Favors Lisinopril Favors Chlorthalidone 0.5012 Non-Black1.00 (0.85, 1.17) Black1.40 (1.17, 1.68) Total1.15 (1.02, 1.30) P =.002 for interaction Favors Lisinopril Favors Amlodipine 0.5012 Non-black1.07 (0.89-1.28) Black1.51 (1.22-1.86) Total1.23 (1.08-1.41) P =.01 for interaction

12. Favors Lisinopril Favors Amlodipine 0.5012 Non-black1.07 (0.89-1.28) Black1.51 (1.22-1.86) Women1.45 (1.17-1.79) Men1.10 (0.92-1.31) Total1.23 (1.08-1.41) Lisinopril/Amlodipine ALLHAT Stroke – Subgroup Comparisons – RR (95% CI) P =.01 for interaction P =.04 for interaction

13. 0.00 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.09 Cumulative Stroke Rate 01234567 Years to Stroke Stroke Rate by Treatment Group – Black Participants Chlorthalidone Amlodipine Lisinopril HR (95% CI)p value A/C0.93 (0.76-1.14)0.49 L/C1.40 (1.17-1.68)<0.001 L/A1.51 (1.22-1.86)<0.001 ALLHAT

14. 0.00 0.01 0.02 0.03 0.04 0.05 0.06 0.07 Cumulative Stroke Rate 01234567 Years to Stroke Stroke Rate by Treatment Group - Non-Black Participants Chlorthalidone Amlodipine Lisinopril HR (95% CI)p value A/C0.93 (0.79-1.10)0.40 L/C1.00 (0.85-1.17)0.97 L/A1.07 (0.89-1.28)0.47 ALLHAT

15. Baseline Characteristics AgeBlackNon-Black N11,79221,565 Age – mean (sd)66.3 (7.8)67.2 (7.7) Women (%)54.542.7 SBP – mean (sd)146.2 (15.8)146.3 (15.6) DBP – mean (sd)84.8 (10.2)83.6 (10.0) Current smokers (%)25.120.1 ASCVD (%)44.855.2 Diabetes (%)40.234.0 ALLHAT

16. 0.00 0.01 0.02 0.03 0.04 0.05 0.06 0.07 Cumulative Stroke Rate 01234567 Years to Stroke Chlorthalidone Amlodipine Lisinopril HR (95% CI)p value A/C1.00 (0.85-1.18)0.99 L/C1.10 (0.94-1.29)0.23 L/A1.10 (0.92-1.31)0.29 Stroke Rate by Treatment Group - Men ALLHAT

17. 0.00 0.01 0.02 0.03 0.04 0.05 0.06 0.07 Cumulative Stroke Rate 01234567 Years to Stroke Chlorthalidone Amlodipine Lisinopril HR (95% CI)p value A/C0.84 (0.69-1.03)0.09 L/C1.22 (1.01-1.46)0.03 L/A1.45 (1.17-1.79)0.001 Stroke Rate by Treatment Group - Women ALLHAT

18. 130 135 140 145 150 0123456 Years mm Hg SBP BP Results by Treatment Group by Race Black-ChlorBlack–AmlodBlack–Lisin Nonblack–ChlorNonblack–AmlodNonblack–Lisin ALLHAT

19. 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. 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. 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. ALLHAT

20. 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. ALLHAT

21. Predictors of Stroke – Categorical Variables ComparisonUniv. HR & PMultiv. HR & P Black / Nonblack1.25<0.0011.39<0.001 Male / Female1.22<0.0011.32<0.001 Diabetic / Nondiabetic1.47<0.0011.67<0.001 CHD at entry / No CHD at entry1.28<0.0011.28<0.001 Treated at entry / Untreated at entry 1.140.151.180.12 Smokers / Never or past smokers1.060.391.51<0.001 EGFR <60 / EGFR ≥601.60<0.0011.38<0.001 Atrial fibrillation / No atrial fibrillation3.75<0.0013.13<0.001 Amlodipine / Chlorthalidone0.930.280.950.45 Lisinopril / Chlorthalidone1.150.021.190.009 ALLHAT

22. Predictors of Stroke – Continuous Variables ComparisonUniv. HR & PMultiv. HR & P Age per 5 years1.29<0.0011.28<0.001 SBP per 10 mm Hg 1.13<0.0011.12<0.001 DBP per 10 mm Hg 0.960.101.000.91 BMI per unit0.98<0.0010.990.27 ALLHAT

23. 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 ALLHAT

24. 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. ALLHAT

25. Extra Slides

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

27. 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 ALLHAT

28. 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 ALLHAT Manual of Operations 5.4.2

29. Discovery Of A Possible 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 ALLHAT Manual of Operations 5.4.2

30. Fatality of First Strokes by Treatment Group ChlorthalidoneAmlodipineLisinopril Fatal136 (20%)75 (20%)96 (21%) Nonfatal539 (80%)302 (80%)361 (79%) Total ppts with stroke 675377457 Compared with C p = 0.92p = 0.73 Compared with A p = 0.69 ALLHAT

31. Length of Hospital Stay* by Treatment Group ChlorthalidoneAmlodipineLisinopril N218111135 Median556 1-3 days68 (31%)32 (29%)31 (23%) 4-6 days75 (34%)31 (28%)47 (35%) 7-10 days32 (15%)21 (19%)30 (22%) 11-15 days19 (9%)12 (11%)11 (8%) 16-20 days8 (4%)6 (5%)5 (4%) >20 days16 (7%)9 (8%)11 (8%) Compared with Cp = 0.63p = 0.77 Compared with Ap = 0.71 * Based on strokes matching HCFA & VA databases ALLHAT

32. Stroke – Subgroup Comparisons – RR (95% CI) ALLHAT Amlodipine Better Chlorthalidone Better 0.5012 Non-Diabetic0.96 (0.81, 1.14) Diabetic0.90 (0.75, 1.08) Non-Black0.93 (0.79, 1.10) Black0.93 (0.76, 1.14) Women0.84 (0.69, 1.03) Men1.00 (0.85, 1.18) Age >= 650.93 (0.81, 1.08) Age < 650.93 (0.73, 1.19) Total0.93 (0.82, 1.06) Lisinopril Better Chlorthalidone Better 0.5012 Non-Diabetic1.23 (1.05, 1.44) Diabetic1.07 (0.90, 1.28) Non-Black1.00 (0.85, 1.17) Black1.40 (1.17, 1.68) Women1.22 (1.01, 1.46) Men1.10 (0.94, 1.29) Age >= 651.13 (0.98, 1.30) Age < 651.21 (0.97, 1.52) Total1.15 (1.02, 1.30) P =.01 for interaction

33. Stroke – Subgroup Comparisons – RR (95% CI) ALLHAT Favors Amlodipine Favors Chlorthalidone 0.5012 Non-Black0.93 (0.79, 1.10) Black0.93 (0.76, 1.14) Total0.93 (0.82, 1.06) Favors Lisinopril Favors Chlorthalidone 0.5012 Non-Black1.00 (0.85, 1.17) Black1.40 (1.17, 1.68) Total1.15 (1.02, 1.30) P =.002 for interaction Favors Lisinopril Favors Amlodipine 0.5012 Non-black1.07 (0.89-1.28) Black1.51 (1.22-1.86) Women1.45 (1.17-1.79) Men1.10 (0.92-1.31) Total1.23 (1.08-1.41) P =.01 for interaction P =.04 for interaction All comparisons combined

34. 0.00 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.09 0.10 0.11 0.12 Cumulative Event Rate 01234567 Years to Stroke Stroke Rate by Treatment Group – Black Men Chlorthalidone Amlodipine Lisinopril HR (95% CI)p value A/C0.95 (0.71 – 1.26)0.71 L/C1.45 (1.12 – 1.86)0.004 L/A1.53 (1.14 – 2.04)0.004 ALLHAT

35. 0.00 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.09 0.10 0.11 0.12 Cumulative Event Rate 01234567 Years to Stroke Stroke Rate by Treatment Group – Black Women Chlorthalidone Amlodipine Lisinopril HR (95% CI)p value A/C0.91 (0.68 – 1.22)0.54 L/C1.35 (1.04 – 1.76)0.03 L/A1.48 (1.09 – 2.01)0.01 ALLHAT

36. 0.00 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.09 0.10 0.11 0.12 Cumulative Event Rate 01234567 Years to Stroke Stroke Rate by Treatment Group – Non-Black Men Chlorthalidone Amlodipine Lisinopril HR (95% CI)p value A/C1.03 (0.84 - 1.25)0.79 L/C0.93 (0.76 - 1.14)0.48 L/A0.90 (0.72 - 1.13)0.38 ALLHAT

37. 0.00 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.09 0.10 0.11 0.12 Cumulative Event Rate 01234567 Years to Stroke Stroke Rate by Treatment Group – Non-Black Women Chlorthalidone Amlodipine Lisinopril HR (95% CI)p value A/C0.78 (0.60 - 1.03)0.08 L/C1.11 (0.86 - 1.42)0.43 L/A1.41 (1.04 - 1.90)0.03 ALLHAT

38. Systolic Blood Pressure Differences Between Treatments by Race ALLHAT BlackNon-BlackTotal A-CL-CL-AA-CL-CL-AA-CL-CL-A Baseline-0.2-0.1+0.1+0.1+0.3+0.20+0.2+0.2 6M+2.9+6.1+3.2+1.2+1.7+0.5+1.8+3.2+1.4 1Y+2.0+5.4+3.4+1.4+2.0+0.6+1.6+3.1+1.5 2Y+1.6+5.0+3.5+1.0+1.3+0.2+1.2+2.5+1.3 3Y+1.7+4.1+2.4+0.3+0.7+0.4+0.8+1.8+1.1 4Y+1.9+3.2+1.3+0.4+0.7+0.4+0.9+1.5+0.7 5Y+1.1+3.9+2.9+0.6+0.9+0.3+0.8+1.9+1.1 A= Amlodipine C=Chlorthalidone L=Lisinopril Values are mmHg

39. 0.00 0.01 0.02 0.03 0.04 0.05 Cumulative Stroke Rate 01234567 Years to Stroke Chlorthalidone Amlodipine Lisinopril HR (95% CI)p value A/C0.93 (0.73-1.18)0.55 L/C1.22 (0.97-1.52)0.09 L/A1.31 (1.01-1.70)0.04 Stroke Rate by Treatment Group – Age <65 ALLHAT

40. 0.00 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.09 Cumulative Stroke Rate 01234567 Years to Stroke Chlorthalidone Amlodipine Lisinopril HR (95% CI)p value A/C0.93 (0.81-1.08)0.37 L/C1.13 (0.98-1.30)0.09 L/A1.21 (1.02-1.42)0.02 Stroke Rate by Treatment Group – Age 65+ ALLHAT

41. 0.00 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 0.09 Cumulative Stroke Rate 01234567 Years to Stroke Chlorthalidone Amlodipine Lisinopril HR (95% CI)p value A/C0.90 (0.75-1.08)0.26 L/C1.07 (0.90-1.28)0.45 L/A1.19 (0.97-1.47)0.09 Stroke Rate by Treatment Group - Diabetic Participants ALLHAT

42. 0.00 0.01 0.02 0.03 0.04 0.05 0.06 0.07 Cumulative Stroke Rate 01234567 Years to Stroke Chlorthalidone Amlodipine Lisinopril HR (95% CI)p value A/C0.96 (0.81-1.14)0.63 L/C1.23 (1.05-1.44)0.01 L/A1.28 (1.07-1.53)0.008 Stroke Rate by Treatment Group - Nondiabetic Participants ALLHAT

43. 0.00 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 Cumulative Stroke Rate 01234567 Years to Stroke Chlorthalidone Amlodipine Lisinopril HR (95% CI)p value A/C0.90 (0.71-1.13)0.36 L/C1.17 (0.94-1.45)0.15 L/A1.31 (1.01 - 1.69)0.04 Stroke Rate by Treatment Group – CHD at Baseline ALLHAT

44. 0.00 0.01 0.02 0.03 0.04 0.05 0.06 0.07 Cumulative Stroke Rate 01234567 Years to Stroke Chlorthalidone Amlodipine Lisinopril HR (95% CI)p value A/C0.96 (0.82-1.11)0.57 L/C1.15 (1.00-1.33)0.06 L/A1.20 (1.02 - 1.41)0.03 Stroke Rate by Treatment Group – No CHD at Baseline ALLHAT

45. 0.00 0.01 0.02 0.03 0.04 0.05 0.06 0.07 Cumulative Stroke Rate 01234567 Years to Stroke Chlorthalidone Amlodipine Lisinopril HR (95% CI)p value A/C0.92 (0.81-1.05)0.22 L/C1.13 (1.00-1.28)0.046 L/A1.23 (1.07 - 1.42)0.004 Stroke Rate by Treatment Group – Treated at Baseline ALLHAT

46. 0.00 0.01 0.02 0.03 0.04 0.05 0.06 0.07 0.08 Cumulative Stroke Rate 01234567 Years to Stroke Chlorthalidone Amlodipine Lisinopril HR (95% CI)p value A/C1.07 (0.70-1.66)0.75 L/C1.33 (0.88-2.00)0.17 L/A1.23 (0.78 - 1.95)0.37 Stroke Rate by Treatment Group – Untreated at Baseline ALLHAT

47. Predictors of Stroke by Race Black HR & p*Non-Black HR & p* Amlod0.980.890.930.42 Lisin1.54<0.0011.000.97 Age per 5 years1.23<0.0011.32<0.001 Male1.340.0021.32<0.001 Diabetic1.79<0.0011.61<0.001 CHD at entry1.040.821.270.07 Treated1.310.021.260.003 Smoking1.78<0.0011.320.004 SBP - 10 mm Hg1.110.0021.12<0.001 DBP - 10 mm Hg1.030.590.980.57 BMI per unit1.000.640.990.33 EGFR <601.53<0.0011.290.002 Atrial fib3.020.0023.11<0.001 * Multivariate ALLHAT

48. Cumulative Mortality Rate Years to Death 01234567 0.05.1.15.2.25.3 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 Cumulative Event Rates for All-Cause Mortality by ALLHAT Treatment Group RR (95% CI)p value A/C0.96 (0.89-1.02)0.20 L/C1.00 (0.94-1.08)0.90 ALLHAT Chlorthalidone Amlodipine Lisinopril