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Effect of Rosuvastatin Versus Placebo on Cardiovascular Outcomes in Patients with End-Stage Renal Disease on Hemodialysis – Results of the AURORA Study.

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Presentation on theme: "Effect of Rosuvastatin Versus Placebo on Cardiovascular Outcomes in Patients with End-Stage Renal Disease on Hemodialysis – Results of the AURORA Study."— Presentation transcript:

1 Effect of Rosuvastatin Versus Placebo on Cardiovascular Outcomes in Patients with End-Stage Renal Disease on Hemodialysis – Results of the AURORA Study Bengt Fellström (Uppsala, Sweden) Alan G Jardine (Glasgow, UK) Hallvard Holdaas (Oslo, Norway) Roland E Schmieder (Erlangen, Germany) Mattis Gottlow (Mölndal, Sweden) Eva Johnsson (Mölndal, Sweden) Faiez Zannad (Toul, France)

2 Presenter disclosure information Bengt Fellström The following relationships exist related to this presentation Consulting fees AstraZenecaSignificant level Consulting fees Novartis, Roche, WyethModest level Lecture feesAstellas, Novartis, WyethModest level Grant supportNovartis, Roche, WyethSignificant level National Co-ordinatorSHARP study –Modest level Oxford Universitys Clinical Trial Service Unit

3 Rationale for AURORA End-stage renal disease (ESRD) and hemodialysis : –cholesterol levels low or normal 1 –pattern of cardiovascular disease (CVD) differs from the general population 2 Statin therapy reduces CV events and mortality irrespective of baseline lipid levels in non-renal patients and in patients with modest renal failure 3,4 The benefits of statin therapy on CV outcomes in ESRD need to be established in prospective trials 1. Vaziri ND. Am J Physiol Renal Physiol 2006; 290: F262–F Baigent C et al. Lancet 2000; 356: 147– Baigent C et al. Lancet 2005; 366: 1267– Ridker PM et al. N Engl J Med 2008; 359: 2195–2207

4 Survival Statin No statin Time from study start (years) Statin treatment was associated with a 32% reduction in the adjusted relative risk of death: RR=0.68 (95% CI 0.53–0.86) p=0.002 Observational study of ESRD patients: statins reduce mortality CI=confidence interval; RR=relative risk Seliger SL et al. Kidney Int 2002; 61: 297–304

5 p=0.37 4D study in diabetic hemodialysis patients: no benefit of statin therapy 4D=Die Deutsche Diabetes Dialyse Studie No. at risk: Placebo Atorvastatin Wanner C et al. N Engl J Med 2005; 353: 238–248 Cumulative incidence of primary endpoint (%) Time (years) Atorvastatin Placebo

6 To compare the effects of rosuvastatin 10 mg daily versus placebo on CV morbidity and mortality in chronic hemodialysis patients AURORA: objective Fellström B et al. Curr Control Trials Cardiovasc Med 2005; 6: 9

7 AURORA: study design Matching placebo (n~1350) Screening 6-monthly 6 Final Patients (n~2750) Inclusion criteria ESRD, on hemodialysis for 3 months 50–80 years Exclusion criteria Statin within 6 months Kidney transplant likely within 1 year Creatine kinase >3xULN ALT >3xULN TSH >1.5xULN –14 days Month: Visit: Rosuvastatin 10 mg daily (n~1350) Treatment Study medication was administered until 620 patients had experienced a major CV event Fellström B et al. Curr Control Trials Cardiovasc Med 2005; 6: 9 Randomization 1:1

8 Study endpoints Primary –time to major CV event (CV death, non-fatal myocardial infarction [MI] or non-fatal stroke) adjudicated by blinded clinical endpoint committee Secondary –all-cause mortality –CV event-free survival –CV and non-CV death –procedures for stenosis or thrombosis of the vascular access for hemodialysis –coronary or peripheral revascularizations –adverse events Tertiary : Change from baseline in lipids, and C- reactive protein Fellström B et al. Curr Control Trials Cardiovasc Med 2005; 6: 9

9 Statistical analysis 2750 patients required –to detect 25% reduction in event rate/year –with 90% power –assumed ~4-year follow-up, annual placebo event rate 11%, withdrawal 9.3% Cox proportional-hazards model (unadjusted) –for primary endpoint –using intent-to-treat (ITT) population Interim analysis when 305 patients had experienced a major CV event –Data Safety Monitoring Board recommended that the study continued as planned Fellström B et al. Curr Control Trials Cardiovasc Med 2005; 6: 9 Fellström B et al. Kidney Blood Press Res 2007; 30: 314–322

10 Patients and centers Altogether 2776 patients were recruited –from 284 dialysis centers –in 25 countries –from all continents, except Africa Fellström B et al. Kidney Blood Press Res 2007; 30: 314–322

11 Results

12 Patients randomly assigned to treatment (n=2776) Included in ITT analysis (n=1384) Included in ITT analysis (n=1389) Placebo (n=1385) Rosuvastatin 10 mg (n=1391) Excluded from ITT analysis (n=1) Excluded from ITT analysis (n=2) Lost to follow-up (n=0) Did not receive study treatment (n=2) Discontinued treatment before end of study (n=1018) for Adverse event (n=208) Renal transplant (n=197) Death (n=330) Other reasons (n=283) Lost to follow-up (n=0) Did not receive study treatment (n=7) Discontinued treatment before end of study (n=1018) for Adverse event (n=234) Renal transplant (n=174) Death (n=336) Other reasons (n=274) Not randomized (n=245), because Adverse event (n=19) Screening criteria not fulfilled (n=156) Chose not to participate (n=70) 4-week placebo run-in Enrolled population (n=3021)

13 Baseline characteristics Rosuvastatin and placebo groups were well balanced at baseline for –gender, age, race, body mass index –blood pressure (BP), smoking status, blood biochemistry values –time on hemodialysis, duration of weekly dialysis sessions, causes of ESRD –Previous medical history –Drug therapies Mean (SD) time on hemodialysis was 3.5 ± 3.9 years in rosuvastatin group versus 3.5 ± 3.8 years in the placebo group

14 Rosuvastatin (n=1389) Placebo (n=1384) Lipid levels, mg/dL Total cholesterol176 (42)174 (43) LDL-C100 (35)99 (34) HDL-C45 (15)45 (16) TG157 (95)154 (97) Hs-CRP, mg/L4.8 (2.0–13.6)5.2 (2.1–14.4) Baseline lipid variables and Hs-CRP LDL-C=low-density lipoprotein cholesterol; HDL-C=high-density lipoprotein cholesterol; TG=triglycerides; Hs-CRP=high-sensitivity C-reactive protein Values are mean (SD); values are median (interquartile range)

15 Duration of follow-up and discontinuations No patients were lost to follow-up Mean length of follow-up was 3.2 years (maximum 5.6 years) Mean duration of study medication was 2.4 years Reasons for discontinuation RosuvastatinPlaceboTotal Major CV event Death Adverse event Renal transplant

16 Hs-CRP: 11.5% decrease Changes in lipids and Hs-CRP Changes in lipids and Hs-CRP Hs-CRP (mg/L) monthsBaseline1 year Rosuvastatin Placebo Year LDL-C (mg/dL) p< LDL-C: 43% reduction Rosuvastatin Placebo Year TG (mg/dL) p< TG: 16.2% reduction Year HDL-C (mg/dL) 32 p=0.045 HDL-C: 2.9% increase P< Values are means (95% CI) for LDL-C, TG and HDL-C and medians (95% CI) for Hs-CRP; % change from baseline at 3 months is quoted and p values are for change at 3 months versus placebo

17 Placebo AURORA: primary endpoint Kaplan-Meier estimate of time to first major CV event No. at risk: Rosuvastatin Placebo Cumulative incidence of primary endpoint (%) Years from randomization Rosuvastatin HR=0.96 (95% CI 0.84–1.11) P=

18 Primary and secondary endpoints Forest plot of adjudicated endpoints HR (95% CI) Event p value Major CV event CV death Non-fatal MI Non-fatal stroke Death (any cause) Major CV event/cause specific death Non-CV death Atherosclerotic cardiac event Vascular access procedure Revascularization Primary endpoints Secondary endpoints Favors rosuvastatin Favors placebo

19 Smoking status Primary endpoint Forest plot of predefined subgroups <65 65 Age (years) No Yes No Yes Diabetes No Yes History of CVD Male Female Gender Favors rosuvastatin Favors placebo HR (95% CI) p value Subgroup

20 127–146 Primary endpoint Forest plot of predefined subgroups (cont.) The three subgroups represent patients whose baseline values fall into tertiles 1, 2 or 3 LDL-C (mg/dL) Hs-CRP (mg/L) >80 >111 Systolic BP (mm Hg) Diastolic BP (mm Hg) Body mass index (kg/m 2 ) <71 71–80 < –8.5 >8.5 <83 83–111 <127 >146 < –26.6 > Favors rosuvastatin Favors placebo HR (95% CI) p value Subgroup

21 AURORA: safety % subjects with AERosuvastatin (n=1389) Placebo (n=1378) p value Any serious AE Event leading to death Event requiring permanent withdrawal Drug-related serious AE Hepatic disorder ALT >3 X ULN Musculoskeletal disorder Creatine kinase >5 X ULN New diagnosis of cancer New onset diabetes Rhabdomyolysis

22 Limitations Patients excluded –those already on statin treatment –those considered by investigator to have an indication for statin treatment –young patients (<50 years) High discontinuation rate reflects difficulty in performing longterm studies in a dialysis population

23 Conclusions I The AURORA trial is the largest ever study of CV events in ESRD on hemodialysis Initiation of rosuvastatin did not cause a reduction in the combined endpoint of CV death, MI or stroke, even though –LDL-C was significantly reduced –a minor reduction in Hs-CRP occurred Rosuvastatin treatment was well tolerated

24 Conclusions II Lack of CV benefit with statins in both AURORA and 4D 1 suggests that CVD in hemodialysis patients is different compared with that in a non- renal population There is a need for further research and analysis of data and to explore new approaches and treatment strategies for reduction of the high risk of CVD in hemodialysis patients 1. Wanner C et al. N Engl J Med 2005; 353: 238–248

25 NEJM publication available online Fellström BC et al. N Engl J Med 2009; 360: 1395–1407

26 Acknowledgements For making this trial possible, we thank –all participating patients, nurses and investigators * –the AURORA Data Safety Monitoring Board –the AURORA Clinical Endpoint Committee –AstraZeneca, for sponsoring the study * Appendix in the NEJM publication

27 Back up slides

28 Baseline characteristics Parameter Rosuvastatin (n=1389) Placebo (n=1384) Female gender, n (%)538 (39)512 (37) Age, years64 (8.6)64 (8.7) Caucasian, n (%)1174 (85)1180 (85) Body mass index, kg/m (4.7)25.4 (5.1) Mean systolic/diastolic BP, mm Hg137/76 Current smoker, n (%)202 (15)227 (16) Time on hemodialysis, years3.5 (3.9) Dialysis, hours/week11.9 (1.8) Cause of ESRD, n (%) Nephrosclerosis273 (20)281 (20) Glomerulonephritis/vasculitis250 (18)262 (19) Diabetes286 (21)249 (18) Tubulointerstitial disease206 (15)193 (14) Hereditary171 (12)185 (13) Other203 (15)214 (15) All values are means (SD) unless stated otherwise

29 Baseline medical history and medication ParameterRosuvastatin (n=1389) Placebo (n=1384) Medical history, n (%) Diabetes388 (28)343 (25) CVD549 (40)556 (40) MI146 (11)136 (10) Coronary revascularization82 (6)91 (7) Peripheral vascular disease212 (15)210 (15) Drug therapy, n (%) Angiotensin-converting enzyme/ angiotensin receptor blocker 497 (36)523 (38) Calcium channel blocker480 (35)501 (36) Beta blocker534 (38)498 (36) Diuretic428 (31)422 (30) Thrombocyte inhibitor593 (43)571 (41) Vitamin D643 (46)659 (48) Calcium substitution1032 (74)1027 (74) Sevelamer398 (29)366 (26) Erythropoietin1204 (87)1225 (89)

30 Parameter Rosuvastatin (n=1389) Placebo (n=1384) Hemoglobin, g/dL11.7 (1.6) Albumin, g/L39.7 (3.5)39.7 (3.4) Calcium, mmol/L2.3 (0.2) Phosphate, mmol/L1.8 (0.6)1.8 (0.5) Baseline blood biochemistry Values are means (SD)

31 Limitations Some patients were excluded –those already on statin treatment –those considered by investigator to have an indication for open statin treatment –young patients (<50 years) High discontinuation rate –this reflects difficulty in performing studies in the dialysis population

32 Interpretation & Future activities AURORA and 4D 1 suggest a lack of CV benefit of initiating statins in patients on chronic hemodialysis treatment Other studies, 2,3 mostly post-hoc assessments of CKD patients from larger studies or renal transplantation patients, suggest statins reduce CV events Does statin therapy become ineffective with progression of renal disease? Confounding factors that need to be taken into account ( inflammation ? ) in order to identify renal patients that may benefit from statins ? 1. Wanner C et al. N Engl J Med 2005; 353: 238– Tonelli M et al. Circulation 2004; 110: 1557– Holdass H et al. Am J Transplant 2005; 5: 2926–2936

33 Interpretation AURORA and 4D 1 suggest a lack of CV benefit of initiating statins in patients on chronic hemodialysis treatment Post-hoc assessments 2,3 of CKD patients from larger studies or renal transplantation patients, suggest statins reduce CV events Does statin therapy become ineffective with progression of renal disease? 1. Wanner C et al. N Engl J Med 2005; 353: 238– Tonelli M et al. Circulation 2004; 110: 1557– Holdass H et al. Am J Transplant 2005; 5: 2926–2936

34 Interpretions 2 ESRD patients CV disease driven by other mechanisms LDL is not a risk factor Inflammation and calcification plays a major role, not treatable with a statin Degree of CRP reduction seems to be of great importance


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