1. 6/5/2006 - 1 1 CARDIOVASCULAR DISEASE OUTCOMES IN HYPERTENSIVE PATIENTS STRATIFIED BY BASELINE GLOMERULAR FILTRATION RATE (4 GROUPS by GFR) ALLHAT

2. 6/5/2006 - 2 2 Introduction Over 13 million Americans are estimated to have chronic kidney disease (CKD) Patients with CKD are at very high risk for cardiovascular disease (CVD) There are limited data about the comparative effects of antihypertensive therapy on CVD outcomes in CKD patients Since risk of CVD is much higher than risk for ESRD in CKD patients, choices of therapy need to be guided by effects on CVD outcomes 17.7% (n=7116) of ALLHAT participants had an estimated GFR <60 ml/min/1.73m 2 at baseline ALLHAT

3. 6/5/2006 - 3 3 Other Studies Many trials that studied patients with CKD do not have adequate assessment / reporting or power to evaluate CV events –HOPE demonstrated increased CV risk in patients with renal insufficiency and that ramipril reduced risk in this subgroup compared to placebo –IDNT and RENAAL showed similar CV event rates with ARB vs CCB (IDNT) and placebo (RENAAL), except hospitalization for first heart failure in RENAAL was lower with the ARB –AASK (beta blocker, ACE, CCB) showed no difference in CV event rates ALLHAT

4. 4 Normal GFR (  90) Mild  GFR (60-89) Moderate  GFR (30- 59) Severe  GFR (<30) N8,12618,1095,480182 Mean age, y63.367.3**70.7**70.3** Black non-Hisp, %43.127.7**24.9**42.9 Women, %46.644.5**52.1**58.8** Mean SBP145.9146.3146.6**150.0** Mean DBP84.982.5**84.1**83.7 Type 2 diabetes, %45.232.8**33.1**41.8 History of CHD***, %21.226.3**30.6**28.0** Baseline Characteristics Stratified By Estimated GFR* *Estimated (eGFR) (ml/min/1.73 m 2 ) calculated by simplified MDRD equation (Levey et al., J Am Soc Nephrol 11, A 0828. 2000.) ** p<.05 compared with normal GFR ***p<0.022, amlodipine (28%) vs. chlorthalidone (31%) in participants with GFR 30-59. ALLHAT

5. 6/5/2006 - 5 5 Estimated (eGFR) (ml/min/1.73 m 2 ) calculated by simplified MDRD equation * P <0.001 vs. GFR90+ ALLHAT * Relative Risk of Combined CVD by Baseline GFR Group (Adjusted for age, race, gender, BMI, SBP, DBP, HDL- cholesterol, LDL-cholesterol, fasting triglycerides, history of diabetes, and cigarette smoking) * *

6. 6/5/2006 - 6 6 Blood Pressure at 4 Years by Treatment Group and Baseline GFR GFRChlorAmlodLisin SBP - mean (sd,N)  90 133.4 (15.2, 2276)134.6 (14.4, 1462)*135.6 (17.3, 1301)* 60-89133.6 (15.5, 5310)134.5 (14.6, 3127)*135.2 (16.9, 3024)* 30-59135.6 (17.2, 1488)135.9 (17.0, 855)136.4 (18.3, 797) <30130.9 (14.8, 23)133.5 (18.2, 14)137.4 (15.9, 16) DBP - mean (sd,N)  90 76.8 (9.5, 2276)76.4 (9.0, 1462)77.6 (10.1, 1301)* 60-8976.5 (9.6, 5308)75.8 (9.6, 3127)*76.3 (10.2, 3024) 30-5975.6 (9.9, 1488)74.2 (9.7, 855)*75.7 (11.3, 797) <3073.0 (12.1, 23)69.9 (11.0, 14)75.4 (9.7, 16) * p<0.05 compared with chlorthalidone ALLHAT

7. 1 / 10 / 2005 - 7 Evaluating Treatment Effects by Subgroup Significant Test for Treatment x Subgroup Interaction? YesNo Significant treatment difference within 1 or more subgroups? YesInteractionNo interaction NoInteractionNo interaction Interaction – Use subgroup estimates of treatment effects No interaction – Use estimate of treatment effect in total population

8. 6/5/2006 - 8 8 6-year rates per 100 (se) & total events / N Relative Risk (A/C) (95% CI) p value ChlorthalidoneAmlodipine GFR  90 8.7 (0.6) 252 / 3648 7.6 (0.7) 141 / 2274 0.90 (0.73 - 1.10) 0.29 GFR 60-8910.9 (0.4) 740 / 8360 10.9 (0.6) 427 / 4850 0.98 (0.87 – 1.10) 0.72 GFR 30-5915.1 (0.9) 303 / 2530 16.2 (1.2) 192 / 1471 1.10 (0.92 – 1.32) 0.29 GFR <3020.6 (5.1) 15 / 83 4.9 (3.4) 2 / 45 0.25 (0.06 – 1.08) 0.06 Total11.5 (0.3) 1362 / 15,255 11.3 (0.4) 798 / 9048 0.98 (0.91 – 1.08) 0.81 Differences among treatment group effects by baseline GFR group are not statistically significant. ALLHAT CHD (Nonfatal MI & Fatal CHD) by Baseline GFR & Treatment – Amlodipine vs Chlorthalidone

9. 6/5/2006 - 9 9 6-year rates per 100 (se) & total events / N Relative Risk (A/C) (95% CI) p value ChlorthalidoneLisinopril GFR  90 8.7 (0.6) 252 / 3648 9.0 (0.8) 157 / 2204 1.04 (0.86 – 1.28) 0.67 GFR 60-8910.9 (0.4) 740 / 8360 10.6 (0.6) 421 / 4899 0.97 (0.86 – 1.09) 0.59 GFR 30-5915.1 (0.9) 303 / 2530 14.8 (1.1) 173 / 1479 0.99 (0.82 – 1.20) 0.95 GFR <3020.6 (5.1) 15 / 83 23.4 (6.3) 11 / 54 1.22 (0.56 – 2.67) 0.61 Total11.5 (0.3) 1362 / 15,255 11.4 (0.4) 796 / 9054 0.99 (0.91 – 1.08) 0.81 Differences among treatment group effects by baseline GFR group are not statistically significant. ALLHAT CHD (Nonfatal MI & Fatal CHD) by Baseline GFR & Treatment – Lisinopril vs Chlorthalidone

10. 6/5/2006 - 10 10 6-year rates per 100 (se) & total events / N Relative Risk (A/C) (95% CI) p value ChlorthalidoneAmlodipine GFR  90 10.0 (0.9) 133 / 1667 9.2 (1.2) 72 / 1026 0.88 (0.66 – 1.18) 0.40 GFR 60-8913.9 (0.8) 304 / 2755 14.4 (1.1) 184 / 1626 1.00 (0.84 – 1.21) 0.96 GFR 30-5919.2 (1.7) 126 / 848 21.9 (2.4) 83 / 486 1.13 (0.85 – 1.49) 0.40 GFR <3024.2 (9.2) 6 / 33 --- 0 / 20 --- Total13.5 (0.6) 592 / 5528 13.8 (0.8) 358 / 3323 0.99 (0.87 – 1.13) 0.93 Differences among treatment group effects by baseline GFR group are not statistically significant. ALLHAT CHD (Nonfatal MI & Fatal CHD) by Baseline GFR & Treatment in Diabetic Participants – Amlodipine vs Chlorthalidone

11. 6/5/2006 - 11 11 6-year rates per 100 (se) & total events / N Relative Risk (A/C) (95% CI) p value ChlorthalidoneLisinopril GFR  90 10.0 (0.9) 133 / 1667 9.7 (1.1) 79 / 981 1.02 (0.77 – 1.35) 0.87 GFR 60-8913.9 (0.8) 304 / 2755 13.2 (1.1) 167 / 1563 0.98 (0.81 – 1.18) 0.81 GFR 30-5919.2 (1.7) 126 / 848 17.7 (2.0) 70 / 478 1.00 (0.75 – 1.35) 0.98 GFR <3024.2 (9.2) 6 / 33 29.4 (10.3) 6 / 23 1.43 (0.46 – 4.44) 0.54 Total13.5 (0.6) 592 / 5528 12.8 (0.7) 339 / 3212 1.00 (0.87 – 1.14) 0.97 Differences among treatment group effects by baseline GFR group are not statistically significant. ALLHAT CHD (Nonfatal MI & Fatal CHD) by Baseline GFR & Treatment in Diabetic Participants – Lisinopril vs Chlorthalidone

12. 6/5/2006 - 12 12 6-year rates per 100 (se) & total events / N Relative Risk (A/C) (95% CI) p value ChlorthalidoneAmlodipine GFR  90 25.6 (0.9) 803 / 3648 25.3 (1.1) 487 / 2274 0.97 (0.86 – 1.08) 0.56 GFR 60-8929.6 (0.6) 2125 / 8360 31.2 (0.8) 1312 / 4850 1.06 (0.99 – 1.14) 0.08 GFR 30-5938.1 (1.2) 839 / 2530 41.1 (1.6) 522 / 1471 1.10 (0.98 – 1.23) 0.09 GFR <3055.3 (6.4) 41 / 83 37.9 (7.8) 15 / 45 0.64 (0.35 – 1.16) 0.14 Total30.9 (0.5) 3941 / 15,255 32.0 (0.6) 2432 / 9048 1.04 (0.99 – 1.09) 0.12 Combined CVD = CHD death, nonfatal MI, stroke, coronary revascularization procedures, hospitalized or treated angina, treated or hospitalized HF, and peripheral arterial disease (hospitalized, or outpatient revascularization) Differences among treatment group effects by baseline GFR group are not statistically significant. ALLHAT Combined CVD by Baseline GFR & Treatment – Amlodipine vs Chlorthalidone

13. 6/5/2006 - 13 13 6-year rates per 100 (se) & total events / N Relative Risk (A/C) (95% CI) p value ChlorthalidoneLisinopril GFR  90 25.6 (0.9) 803 / 3648 29.1 (1.2) 526 / 2204 1.11 (0.99 – 1.24) 0.06 GFR 60-8929.6 (0.6) 2125 / 8360 31.3 (0.8) 1330 / 4899 1.09 (1.02 – 1.17) 0.02 GFR 30-5938.1 (1.2) 839 / 2530 41.1 (1.6) 525 / 1479 1.13 (1.02 – 1.26) 0.03 GFR <3055.3 (6.4) 41 / 83 46.2 (7.5) 22 / 54 0.85 (0.50 – 1.43) 0.53 Total30.9 (0.5) 3941 / 15,255 33.3 (0.6) 2514 / 9054 1.10 (1.05 – 1.16) <0.001 Combined CVD = CHD death, nonfatal MI, stroke, coronary revascularization procedures, hospitalized or treated angina, treated or hospitalized HF, and peripheral arterial disease (hospitalized, or outpatient revascularization) Differences among treatment group effects by baseline GFR group are not statistically significant. ALLHAT Combined CVD by Baseline GFR & Treatment – Lisinopril vs Chlorthalidone

14. 6/5/2006 - 14 14 6-year rates per 100 (se) & total events / N Relative Risk (A/C) (95% CI) p value ChlorthalidoneAmlodipine GFR  90 27.9 (1.3) 402 / 1667 30.4 (1.8) 256 / 1026 1.04 (0.89 – 1.22) 0.61 GFR 60-8934.3 (1.1) 814 / 2755 35.2 (1.4) 499 / 1626 1.03 (0.92 – 1.15) 0.62 GFR 30-5942.4 (2.0) 309 / 848 51.2 (2.7) 219 / 486 1.25 (1.05 – 1.49) 0.01 GFR <3063.8 (10.3) 17 / 33 29.1 (11.1) 5 / 20 0.42 (0.15 – 1.13) 0.09 Total33.9 (0.8) 1609 / 5528 36.2 (1.0) 1030 / 3323 1.06 (0.98 – 1.15) 0.12 Combined CVD = CHD death, nonfatal MI, stroke, coronary revasc procedures, hosp or treated angina, treated or hosp HF, and peripheral arterial disease (hosp or outpatient revasc) Differences among treatment group effects by baseline GFR group are not statistically significant. ALLHAT Combined CVD by Baseline GFR & Treatment in Diabetic Participants – Amlodipine vs Chlorthalidone

15. 6/5/2006 - 15 15 6-year rates per 100 (se) & total events / N Relative Risk (A/C) (95% CI) p value ChlorthalidoneLisinopril GFR  90 27.9 (1.3) 402 / 1667 31.4 (1.8) 257 / 981 1.12 (0.95 – 1.31) 0.17 GFR 60-8934.3 (1.1) 814 / 2755 35.0 (1.4) 482 / 1563 1.07 (0.96 – 1.20) 0.24 GFR 30-5942.4 (2.0) 209 / 848 43.7 (2.6) 182 / 478 1.09 (0.90 – 1.30) 0.38 GFR <3063.8 (10.3) 17 / 33 54.1 (11.4) 11 / 23 0.82 (0.39 – 1.76) 0.62 Total33.9 (0.8) 1609 / 5528 35.5 (1.0) 985 / 3212 1.08 (1.00 – 1.17) 0.049 Combined CVD = CHD death, nonfatal MI, stroke, coronary revasc procedures, hosp or treated angina, treated or hosp HF, and peripheral arterial disease (hosp or outpatient revasc) Differences among treatment group effects by baseline GFR group are not statistically significant. ALLHAT Combined CVD by Baseline GFR & Treatment in Diabetic Participants – Lisinopril vs Chlorthalidone

16. 6/5/2006 - 16 16 6-year rates per 100 (se) & total events / N Relative Risk (A/C) (95% CI) p value ChlorthalidoneAmlodipine GFR  90 4.0 (0.4) 118 / 3648 3.5 (0.5) 70 / 2274 0.95 (0.70 – 1.27) 0.71 GFR 60-895.2 (0.3) 366 / 8360 4.7 (0.4) 185 / 4850 0.85 (0.71 – 1.02) 0.08 GFR 30-597.5 (0.6) 149 / 2530 8.7 (1.0) 96 / 1471 1.13 (0.87 – 1.46) 0.35 GFR <308 / 83 10.7 (3.6) 4 / 45 19.6 (6.8) 0.93 (0.28 – 3.09) 0.91 Total5.6 (0.2) 675 / 15,255 5.4 (0.3) 377 / 9048 0.93 (0.82 – 1.06) 0.28 Differences among treatment group effects by baseline GFR group are not statistically significant. ALLHAT Stroke by Baseline GFR & Treatment – Amlodipine vs Chlorthalidone

17. 6/5/2006 - 17 17 6-year rates per 100 (se) & total events / N Relative Risk (A/C) (95% CI) p value ChlorthalidoneLisinopril GFR  90 4.0 (0.4) 118 / 3648 5.7 (0.6) 101 / 2204 1.43 (1.10 – 1.87) 0.01 GFR 60-895.2 (0.3) 366 / 8360 5.9 (0.4) 239 / 4899 1.12 (0.95 – 1.31) 0.19 GFR 30-597.5 (0.6) 149 / 2530 7.5 (0.8) 96 / 1479 1.08 (0.83 – 1.40) 0.56 GFR <3010.7 (3.6) 8 / 83 19.6 (6.8) 7 / 54 1.38 (0.50 – 3.79) 0.54 Total5.6 (0.2) 675 / 15,255 6.3 (0.3) 457 / 9054 1.15 (1.02 – 1.30) 0.02 Differences among treatment group effects by baseline GFR group are not statistically significant. ALLHAT Stroke by Baseline GFR & Treatment – Lisinopril vs Chlorthalidone

18. 6/5/2006 - 18 18 6-year rates per 100 (se) & total events / N Relative Risk (A/C) (95% CI) p value ChlorthalidoneAmlodipine GFR  90 4.4 (0.6) 55 / 1667 3.9 (0.8) 33 / 1026 0.98 (0.63 – 1.50) 0.92 GFR 60-897.7 (0.6) 176 / 2755 6.4 (0.7) 83 / 1626 0.77 (0.59 – 1.00) 0.05 GFR 30-598.6 (1.1) 60 / 848 11.1 (1.8) 41 / 486 1.20 (0.81 – 1.79) 0.36 GFR <3010.8 (6.0) 3 / 33 5.6 (5.4) 1 / 20 0.53 (0.06 – 5.11) 0.58 Total7.1 (0.4) 314 / 5528 6.6 (0.5) 172 / 3323 0.90 (0.75 – 1.08) 0.26 Differences among treatment group effects by baseline GFR group are not statistically significant. ALLHAT Stroke by Baseline GFR & Treatment in Diabetic Participants – Amlodipine vs Chlorthalidone

19. 6/5/2006 - 19 19 6-year rates per 100 (se) & total events / N Relative Risk (A/C) (95% CI) p value ChlorthalidoneLisinopril GFR  90 4.4 (0.6) 55 / 1667 7.0 (1.1) 53 / 981 1.66 (1.14 – 2.43) 0.01 GFR 60-897.7 (0.6) 176 / 2755 7.8 (0.8) 99 / 1563 1.00 (0.78 – 1.28) 1.00 GFR 30-598.6 (1.1) 60 / 848 7.4 (1.5) 29 / 478 0.87 (0.56 – 1.36) 0.55 GFR <3010.8 (6.0) 3 / 33 27.5 (11.8) 4 / 23 1.74 (0.39 – 7.78) 0.47 Total7.1 (0.4) 314 / 5528 7.6 (0.6) 193 / 3212 1.07 (0.90 – 1.28) 0.45 Differences among treatment group effects by baseline GFR group are not statistically significant. ALLHAT Stroke by Baseline GFR & Treatment in Diabetic Participants – Lisinopril vs Chlorthalidone

20. 6/5/2006 - 20 20 6-year rates per 100 (se) & total events / N Relative Risk (A/C) (95% CI) p value ChlorthalidoneAmlodipine GFR  90 5.1 (0.5) 147 / 3648 6.4 (0.6) 121 / 2274 1.34 (1.05 – 1.71) 0.02 GFR 60-896.7 (0.4) 435 / 8360 9.8 (0.5) 380 / 4850 1.55 (1.34 – 1.79) <0.001 GFR 30-5912.9 (0.9) 247 / 2530 14.9 (1.2) 168 / 1471 1.19 (0.97 – 1.47) 0.10 GFR <3021.9 (6.6) 12 / 83 16.2 (6.1) 6 / 45 0.91 (0.32 – 2.61) 0.86 Total7.7 (0.3) 870 / 15,255 10.2 (0.4) 706 / 9048 1.40 (1.26 – 1.55) <0.001 Differences among treatment group effects by baseline GFR group are not statistically significant. ALLHAT Heart Failure by Baseline GFR & Treatment – Amlodipine vs Chlorthalidone

21. 6/5/2006 - 21 21 6-year rates per 100 (se) & total events / N Relative Risk (A/C) (95% CI) p value ChlorthalidoneLisinopril GFR  90 5.1 (0.5) 147 / 3648 6.1 (0.6) 110 / 2204 1.25 (0.97 – 1.61) 0.08 GFR 60-896.7 (0.4) 435 / 8360 6.9 (0.4) 278 / 4899 1.10 (0.94 – 1.28) 0.25 GFR 30-5912.9 (0.9) 247 / 2530 15.4 (1.2) 180 / 1479 1.28 (1.04 – 1.57) 0.02 GFR <3021.9 (6.6) 12 / 83 24.8 (6.6) 11 / 54 1.51 (0.61 – 3.73) 0.37 Total7.7 (0.3) 870 / 15,255 8.7 (0.4) 612 / 9054 1.20 (1.08 – 1.33) 0.001 Differences among treatment group effects by baseline GFR group are not statistically significant. ALLHAT Heart Failure by Baseline GFR & Treatment – Lisinopril vs Chlorthalidone

22. 6/5/2006 - 22 22 6-year rates per 100 (se) & total events / N Relative Risk (A/C) (95% CI) p value ChlorthalidoneAmlodipine GFR  90 6.5 (0.8) 87 / 1667 8.0 (1.1) 65 / 1026 1.23 (0.88 – 1.71) 0.22 GFR 60-899.9 (0.7) 203 / 2755 13.4 (1.0) 177 / 1626 1.54 (1.24 – 1.90) <0.001 GFR 30-5915.5 (1.6) 100 / 848 22.4 (2.5) 85 / 486 1.59 (1.16 – 2.17) 0.004 GFR <3013.5 (6.3) 4 / 33 12.5 (8.3) 2 / 20 0.81 (0.13 – 4.89) 0.81 Total9.7 (0.5) 410 / 5528 13.1 (0.7) 347 / 3323 1.46 (1.25 – 1.69) <0.001 Differences among treatment group effects by baseline GFR group are not statistically significant. ALLHAT Heart Failure by Baseline GFR & Treatment in Diabetic Participants – Amlodipine vs Chlorthalidone

23. 6/5/2006 - 23 23 6-year rates per 100 (se) & total events / N Relative Risk (A/C) (95% CI) p value ChlorthalidoneLisinopril GFR  90 6.5 (0.8) 87 / 1667 8.1 (1.0) 68 / 981 1.35 (0.97 – 1.88) 0.07 GFR 60-899.9 (0.7) 203 / 2755 9.1 (0.9) 119 / 1563 1.04 (0.82 – 1.31) 0.77 GFR 30-5915.5 (1.6) 100 / 848 20.0 (2.2) 75 / 478 1.39 (1.01 – 1.92) 0.04 GFR <3013.5 (6.3) 4 / 33 29.1 (10.2) 6 / 23 2.56 (0.63 – 10.37) 0.19 Total9.7 (0.5) 410 / 5528 10.9 (0.7) 284 / 3212 1.21 (1.03 – 1.42) 0.02 Differences among treatment group effects by baseline GFR group are not statistically significant. ALLHAT Heart Failure by Baseline GFR & Treatment in Diabetic Participants – Lisinopril vs Chlorthalidone

24. 6/5/2006 - 24 24 Discussion ALLHAT confirms increased risk for CVD in patients with reduced GFR. The overall study results of no difference in the primary outcome for the lisinopril vs. chlorthalidone and amlodipine vs. chlorthalidone comparisons was consistent across diabetes, GFR, and diabetes-GFR subgroups. ALLHAT

25. 6/5/2006 - 25 25 Conclusion Amlodipine and lisinopril are not superior to chlorthalidone in preventing fatal CHD/non fatal MI Chlorthalidone and amlodipine are similar but chlorthalidone is superior to lisinopril in reducing combined CVD events independent of level of renal function. ALLHAT In high risk hypertensive patients with impaired renal function: