Dr Ajay K Gupta International Centre for Circulatory Health, ICTU, Imperial College London, UK

1. Cardiovascular and All-Cause Mortality Outcomes Among Hypertensive Patients With Moderate Renal Dysfunction in the ASCOT-LLA, and its Extended Follow-up Dr Ajay K Gupta International Centre for Circulatory Health, ICTU, Imperial College London, UK Presented on Behalf of the ASCOT Investigators

2. Background: CKD and Cardiovascular morbidity and mortality An eGFR less than 60 mL/min/1・73 m2 is an independent predictor of all-cause mortality and cardiovascular mortality in the general population. The Lancet, Vol 375, Pages 2073 - 2081, 12 June 2010

3. Trial evidence: statin use among those with CKD In clinical trials on chronic kidney disease (CKD) patients on haemodialysis, the use of statins was not associated with any cardiovascular (CV) benefits (AURORA trial & 4D study). Among non-dialysis CKD patients, the use of statins also failed to show any extra CV benefits (PREVEND-IT & ALERT). Among hypertensive patients with renal dysfunction in the lipid-lowering arm of the ALLHAT trial, the use of pravastatin had no added CV benefits, beyond that of usual care.

4. Statin among those with CKD In contrast, in post-hoc secondary analyses of the JUPITER trial , CARDS & TNT, allocation to the statin therapy was found to have protective effects on some, but not all, CV outcomes among patients with renal dysfunction. In the SHARP trial, among CKD patients, the use of ezetimibe/simvastatin combination was associated with: 17% and 19% (significant) reduction in major vascular events and stroke, respectively. No significant impact on total coronary events or all-cause mortality.

5. Comparison of the impact of statin on non-fatal MI in the Renal and non-Renal trials Events (% pa) Allocated Allocated Risk ratio (RR) per p Trial LDL-C reduction control mmol/L LDL-C reduction LDL-C reduction Control better better 33 (1.91) 35 (2.02) 4D c 2 ALERT 54 (1.03) 65 (1.24) = 0.3 3 (p = 0.96) 91 (1.97) 107 (2.33) AURORA 134 (0.71) 159 (0.85) SHARP 312 (1.02) 366 (1.21) 0.83 (0.70 - 0.98) 0.03 Subtotal: 4 renal trials 23 other trials 3307 (0.97) 4386 (1.29) 0.73 (0.70 - 0.76) <0.0001 3619 (0.97) 4752 (1.29) 0.74 (0.70 - 0.77) All trials <0.0001 2 c 2.2 (p = 0.14) = Difference between renal and non-renal trials: 1 99% or 95% CI 0.5 0.75 1 1.5 2 *modified from the SHARP presentation

6. Comparison of impact of statin on Vascular death in the Renal vs Non-Renal trials Events (% pa) Allocated Allocated Risk ratio (RR) per p Trial LDL-C reduction control mmol/L LDL-C reduction LDL-C reduction Control better better 4D 151 (8.52) 167 (9.36) 2 c 66 (1.23) 73 (1.36) ALERT = 0.9 3 (p = 0.82) 324 (6.87) 324 (6.86) AURORA 361 (1.82) 388 (1.97) SHARP Subtotal: 4 renal trials 902 (2.85) 952 (3.01) 0.94 (0.85 - 1.04) 0.27 3679 (1.05) 4230 (1.21) 0.85 (0.81 - 0.89) 23 other trials <0.0001 4581 (1.20) 5182 (1.36) 0.86 (0.83 - 0.90) All trials <0.0001 c 2 = 3.8 (p = 0.05) Difference between renal and non-renal trials: 1 99% or 95% CI 0.5 0.75 1 1.5 2 *modified from the SHARP presentation

7. ASCOT-LLA-Extension • Early closure of ASCOT-LLA • Median follow-up 3.3 years • Atorvastatin versus placebo: • 36% reduction in the primary endpoint • 27% reduction in stroke • ASCOT-LLA-extended • Offering atorvastatin 10 mg daily to all patients in LLA • Continued for a further 2.2 years until the closure of ASCOT-BPLA • Statin usage at the end of LLA-extended Values are n (%) *Also the end of LLA-extension

8. Methods • Based on mean estimated glomerular filtration rate (eGFR) (MDRD-method), patients at baseline were allocated to have a moderate renal damage (CKD) (eGFR 30-60 mL/min/1.73 m2) or not. • Outcomes: • Non-fatal myocardial infarction (MI) plus fatal CHD plus revascularisation . • Secondary outcomes: total coronary events, fatal and non-fatal stroke, CV mortality & all-cause mortality.

9. Statistical Methods • For each of these outcomes, a separate Cox model was developed to assess the effect of statin therapy, after adjusting for a priori confounders: age, sex, race, socio-economic status (age at leaving education), systolic BP and allocated BP treatment, among those with and without CKD at baseline. • Heterogeneity in the treatment effect between those with or without CKD was assessed using an appropriate interaction test • These analyses were repeated using time to first event during the extended follow-up in the ASCOT-LLA-extended.

10. Trial Profile: patients with CKD in the ASCOT-lipid lowering arm 10,305 randomised 65 excluded because of protocol violations 5 excluded as serum creatinine at baseline > 200 μ mol/L 10,235 evaluable 5,103 in placebo arm 5,132 in statin arm 1,002(19.5%) with CKD 4,083(80.0%) without CKD 1,020(20.0 %) with CKD 4,130 (80.5%) without CKD

11. Lipids Levels During ASCOT-LLA and LLA-extended Atorvastatin Placebo *Lipid closeout visit (end of ASCOT-LLA)

12. Mean LDL-cholesterol among those with CKD, stratified by treatment CKD & Atorvastatin CKD & Placebo dif=0.9 P<0.0001 dif=mean difference in change in LDL-C from baseline to year 3 between atorvastatin (-1.2) and placebo (-0.3) LDL-C: low-density lipoprotein cholesterol; CKD: chronic kidney disease; Ator: atorvastatin

13. Event rates of cardiovascular outcomes and death, among those with and without presence of CKD

14. Cardiovascular events and deaths associated with statin therapy among those with and without CKD (ASCOT-LLA) Placebo Total events Atorvastatin Interaction Test NF MI+F CHD+ Revas Non-CKD 264 161 103 p=0.26 CKD 69 37 32 NF MI+NF Stroke +CV Death Non-CKD 405 240 165 p=0.10 CKD 121 62 59 CV Death Non-CKD 112 59 53 p=0.70 CKD 39 22 17 Total Stroke Non-CKD 153 90 63 p=0.35 CKD 52 27 25 All Cause Mortality Non-CKD 281 152 129 p=0.89 CKD 105 56 49 Total Coronary Events Non-CKD 328 190 138 p=0.97 CKD 90 52 38 0.5 0.6 0.7 0.8 0.9 1 1.2 1.5 Favors atorvastatin Favors placebo Hazard ratio and 95% CI (log scale) Adjusted for age, sex, baseline SBP, ethnicity, socio-economic status, randomised BP treatment

15. Cardiovascular events and deaths associated with statin therapy, after 2 years of further follow-up (LLA-extended) Placebo Interaction Test Total events Atorvastatin NF MI+F CHD+ Revas Non-CKD 437 170 267 p=0.09 CKD 114 54 60 NF MI+NF Stroke+CV Death Non-CKD 615 250 365 p=0.06 CKD 205 98 107 CV Death Non-CKD 210 93 117 p=0.59 CKD 84 40 44 Total Stroke Non-CKD 263 110 153 p=0.18 CKD 108 53 55 All Cause Mortality Non-CKD 590 269 321 p=0.58 CKD 222 107 115 Total Coronary Events Non-CKD 569 240 329 p=0.49 CKD 156 70 86 0.5 0.6 0.7 0.8 0.9 1 1.2 1.5 Favors atorvastatin Favors placebo Hazard ratio and 95% CI (log scale) Adjusted for age, sex, baseline SBP, ethnicity, socio-economic status , randomised BP treatment

16. Conclusions • Hypertensive patients with CKD are at a higher risk of cardiovascular events and death. • In the ASCOT LLA • Among those without CKD, allocation to atorvastatin therapy was associated with a significant reduction in coronary and stroke outcomes, but not for death. • There was no difference (statistically) in the effect of statin therapy among those with and without renal damage. • In ASCOT-LLA extended: • Statin therapy was associated with significant reduction in CV outcomes and death among those without CKD, and similar trends were noted among those with CKD. • The benefits of statin therapy remained unchanged, 2 years after the ASCOT-LLA closure. This was despite similar lipid levels at the end of LLA-extended. • .

17. Acknowledgements All ASCOT patients and investigators Professor Peter Sever, Professor Neil R Poulter, Bjorn Dahlof, C L Chang and staff at ICCH, Imperial College London, UK

18. Thank you for your attention

19. Kaplan-Meier curve for total coronary events by CKD status HR: adjusted for age, sex, baseline SBP, ethnicity, socio-economic status (education completion age) and randomised BP treatment

20. Kaplan-Meier curve for fatal and non-fatal stroke by CKD status HR: adjusted for age, sex, baseline SBP, ethnicity, socio-economic status (education completion age) and randomised BP treatment

21. Kaplan-Meier curve for all-cause mortality by CKD status HR: adjusted for age, sex, baseline SBP, ethnicity, socio-economic status (education completion age) and randomised BP treatment

22. Kaplan-Meier curve for non-fatal MI and fatal CHD and revascularisation by chronic kidney disease status HR: adjusted for age, sex, baseline SBP, ethnicity, socio-economic status (education completion age) and randomised BP treatment

23. Kaplan-Meier curve for non-fatal MI, non-fatal stroke and CV deaths by chronic kidney disease status HR: adjusted for age, sex, baseline SBP, ethnicity, socio-economic status (education completion age) and randomised BP treatment

24. Kaplan-Meier curve for cardiovascular deaths by chronic kidney disease status HR: adjusted for age, sex, baseline SBP, ethnicity, socio-economic status (education completion age) and randomised BP treatment

25. Relationship Between Estimated GFR (eGFR) and Clinical Outcomes Death from Any CauseTotal Events = 51,424 Cardiovascular Events Total Events = 139,011 Any Hospitalization Total Events = 554,651 Age-Standardized Event Rate(per 100 Person-Yr) 60 45–59 30–44 15–29 <15 60 45–59 30–44 15–29 <15 60 45–59 30–44 15–29 <15 eGFR (mL/min/1.73 m2) Go AS, et al. N Engl J Med. 2004;351:1296-305.

26. ASCOT-LLA and LLA-extended: overview • ASCOT-LLA : 10,305 hypertensive patients, with no pre-existing coronary heart disease (CHD), were randomised, using a 22 factorial design, to receive placebo or atorvastatin (10 mg/d). • Median follow-up: 3.3 years • ASCOT-LLA (extended): Patients were further followed up for an average of 2 years after closure of the LLA (as a part of the blood pressure lowering arm of the ASCOT trial [ASCOT-BPLA]). • Median follow-up: 5.5 years

27. Changes in LDL cholesterol until the end of LLA extended mmol/L mg/Dl Atorvastatin Placebo

28. Effect of Statins Compared With Placebo or No Treatment on CV Events in Pre-Dialysis, Dialysis, and Transplant Patients Study or subcategory Statinn/N Placebon/N Relative risk(random) (95% CI) Weight(%) Relative risk(random) (95% CI) Year Pre-dialysis patientsFried 2001HPS 2003 PPP 2004PEVEND IT 2004 Lemos 2005 Subtotal (95% CI)Total events: 1391 (statin), 1806 (placebo)Test for heterogeneity: X2=5.78, df=4, P=0.22, I2=30.7% Test for overall effect: z=4.58, P<0.001 Dialysis patients 4D trial 2005 Subtotal (95% CI) Total events: 205 (statin), 246 (placebo) Test for heterogeneity: not applicable Test for overall effect: z=2.05, P=0.04 Transplant patients Holdaas 2003 Subtotal (95% CI) Total events: 46 (statin), 66 (placebo) Test for heterogeneity: not applicable Test for overall effect: z=1.92, P=0.05 Mixed population (pre-dialysis and dialysis patients) Stegmayr 2005 Sub total (95% CI) Total events: 6 (statin), 10 (placebo) Test for heterogeneity: not applicable Test for overall effect: z=0.96, P=0.34 Total (95% CI) Total events: 1648 (statin), 2128 (placebo) Test for heterogeneity: X2=7.68, df=7, P=0.36, I2=8.9% Test for overall effect: z=6.72, P<0.001 0/17 182/646 1174/8376 15/433 20/150 9622 205/619 619 46/1050 1050 6/70 70 11 361 1/19 268/683 1474/8448 19/431 44/160 9741 246/636 636 66/1052 1052 10/73 73 11 502 0.37 (0.02 to 8.53) 0.72 (0.62 to 0.84) 0.80 (0.75 to 0.86) 0.79 (0.40 to 1.53) 0.48 (0.30 to 0.78) 0.75 (0.66 to 0.85) 0.86 (0.74 to 0.99) 0.86 (0.74 to 0.99) 0.70 (0.48 to 1.01) 0.70 (0.48 to 1.01) 0.63 (0.24 to 1.63) 0.63 (0.24 to 1.63) 0.78 (0.73 to 0.84) 2001 2003 2004 2004 2005 2005 2003 2005 0.05 18.12 54.92 1.15 2.18 76.43 19.33 19.33 3.69 3.69 0.56 0.56 100.00 Only studies with at least 1 event are included in the plot 0.01 0.1 1 10 100 Favors statin Favors placebo Giovanni FM. BMJ 2008;336;645-651.