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 AstraZeneca Significant level
Consulting fees Novartis, Roche, Wyeth Modest level
Lecture fees Astellas, Novartis, Wyeth Modest level
Grant support Novartis, Roche, Wyeth Significant level
National Co-ordinator SHARP study – Modest level Oxford University’s Clinical Trial Service Unit

3. Rationale for AURORA End-stage renal disease (ESRD) and hemodialysis :
cholesterol levels low or normal1
pattern of cardiovascular disease (CVD) differs from the general population2
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. Observational study of ESRD patients: statins reduce mortality
1.0
0.9
Statin
Survival
0.8
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
0.7
No statin
Time from study start (years)
CI=confidence interval; RR=relative risk
Seliger SL et al. Kidney Int 2002; 61: 297–304

5. 4D study in diabetic hemodialysis patients: no benefit of statin therapy
Cumulative incidence of primary endpoint (%)
Time (years)
Atorvastatin
Placebo 60 50 40 30 20 10 6 1 2 3 4 5
p=0.37
No. at risk:
Placebo
636
532
383
252
136 51 19
Atorvastatin
619
515
378 58 29
4D=Die Deutsche Diabetes Dialyse Studie
Wanner C et al. N Engl J Med 2005; 353: 238–248

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

7. Rosuvastatin 10 mg daily (n~1350)
AURORA: study design
Screening
Treatment
Month: Visit:
–14 days 1 2
3 3
6 4
12 5
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
Rosuvastatin 10 mg daily (n~1350)
Randomization 1:1
Matching placebo (n~1350)
†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

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. Not randomized (n=245), because Adverse event (n=19)
Enrolled population
(n=3021)
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
Patients randomly assigned to treatment (n=2776)
Rosuvastatin 10 mg
(n=1391)
Placebo
(n=1385)
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)
Other reasons for early withdrawal include patients not willing to continue treatment, those that developed study specific discontinuation criteria and patients for whom no specific reason for discontinuation was given
Patients who were incorrectly randomized were excluded from the ITT population
Excluded from ITT analysis (n=2)
Excluded from ITT analysis (n=1)
Included in ITT analysis (n=1389)
Included in ITT analysis (n=1384)

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. Baseline lipid variables and Hs-CRP
Rosuvastatin (n=1389)
Placebo (n=1384)
Lipid levels†, mg/dL
Total cholesterol
176 (42)
174 (43)
LDL-C
100 (35)
99 (34)
HDL-C
45 (15)
45 (16) TG
157 (95)
154 (97)
Hs-CRP‡, mg/L
4.8 (2.0–13.6)
5.2 (2.1–14.4)
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
Rosuvastatin
Placebo
Total
Major CV event
396
408
804
Death
332
342
674
Adverse event
207
233
440
Renal transplant
197
173
370

16. Changes in lipids and Hs-CRP†
120
LDL-C: 43% reduction
200
TG: 16.2% reduction
100
160 80
Rosuvastatin
Placebo
120
LDL-C (mg/dL) 60
TG (mg/dL)
p<0.0001 80 40
p<0.0001 40 20 1 2 3 4 5 1 2 3 4 5
Year
Year 60
HDL-C: 2.9% increase 7 6 5 4 3 2 1
3 months
Baseline
1 year
Hs-CRP: 11.5% decrease
P<0.0001 50
Rosuvastatin
Placebo 40
HDL-C (mg/dL)
p=0.045 30
Hs-CRP (mg/L) 20 10 1 2 3 4 5
Year
†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. AURORA: primary endpoint Kaplan-Meier estimate of time to first major CV event5 10 15 20 25 30 35 40
Placebo
Rosuvastatin
Cumulative incidence of primary endpoint (%)
HR=0.96 (95% CI 0.84–1.11)
P=0.59 1 2 3 4 5
Years from randomization
No. at risk:
Rosuvastatin
1390
1152
962
826
551
148
Placebo
1384
1163
952
809
534
153

18. Primary and secondary endpoints Forest plot of adjudicated endpointsHR
(95% CI)
Event
p value
Major CV event
0.59
CV death
0.97
Primary endpoints
Non-fatal MI
0.23
Non-fatal stroke
0.42
Death (any cause)
0.51
Major CV event/cause specific death
0.30
Non-CV death
0.34
Secondary endpoints
Atherosclerotic cardiac event
0.64
Vascular access procedure
0.19
Revascularization
0.88
0.5
0.75 1
1.25
1.5
1.75 2
Favors rosuvastatin
Favors placebo

19. Primary endpoint Forest plot of predefined subgroupsHR
(95% CI)
Subgroup
p value
Gender
0.90
0.84
0.23
0.87
0.71
Male
Female
Age (years)
<65
≥65
Smoking status No
Yes
Diabetes No
Yes
AURORA: subgroup analysis of the primary endpoint
The primary endpoint was assessed in prespecified subgroups, including patients with
Diabetes
Pre-existing CV disease
High blood pressure, LDL-C levels and Hs-CRP levels
The lack of effect of rosuvatatin on the primary endpoint was consistent across all subgroups
There was also no relationship between baseline lipid level and the primary cardiovascular endpoint (per mg/dL; HR 1.00, 95% CI 0.82–1.29; p=0.83)
History of CVD No
Yes
0.5
0.75 1
1.25
1.5
1.75 2
Favors rosuvastatin
Favors placebo

20. Primary endpoint Forest plot of predefined subgroups (cont.)HR
(95% CI)
Subgroup †
p value
Body mass index (kg/m2)
0.18
0.97
0.27
0.32
0.16
<23
23.0–26.6
>26.6
Systolic BP (mm Hg)
<127
127–146
>146
Diastolic BP (mm Hg)
<71
71–80
>80
LDL-C (mg/dL)
<83
83–111
>111
Hs-CRP (mg/L)
<2.9
2.9–8.5
>8.5
0.5
0.75 1
1.25
1.5
1.75 2
Favors rosuvastatin
Favors placebo
†The three subgroups represent patients whose baseline values fall into tertiles 1, 2 or 3

21. AURORA: safety % subjects with AE Rosuvastatin (n=1389) Placebo
p value
Any serious AE 82 84
0.80
Event leading to death 46 48
0.49
Event requiring permanent withdrawal 32
0.78
Drug-related serious AE
1.2
0.8
0.35
Hepatic disorder
4.8
3.9
0.28
ALT >3 X ULN
0.7
0.6
0.64
Musculoskeletal disorder 22 25
0.21
Creatine kinase >5 X ULN
0.2
0.99
New diagnosis of cancer
7.7
8.6
0.41
New onset diabetes
1.0
0.40
Rhabdomyolysis
0.1
0.66
CK >10xULN occurred in one patient in the rosuvastatin group and no patient in the placebo group

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 4D1 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, years
64 (8.6)
64 (8.7)
Caucasian, n (%)
1174 (85)
1180 (85)
Body mass index, kg/m2
25.4 (4.7)
25.4 (5.1)
Mean systolic/diastolic BP, mm Hg
137/76
Current smoker, n (%)
202 (15)
227 (16)
Time on hemodialysis, years
3.5 (3.9)
Dialysis, hours/week
11.9 (1.8)
Cause of ESRD, n (%)
Nephrosclerosis
273 (20)
281 (20)
Glomerulonephritis/vasculitis
250 (18)
262 (19)
Diabetes
286 (21)
249 (18)
Tubulointerstitial disease
206 (15)
193 (14)
Hereditary
171 (12)
185 (13)
Other
203 (15)
214 (15)
†All values are means (SD) unless stated otherwise

29. Baseline medical history and medication
Parameter
Rosuvastatin (n=1389)
Placebo (n=1384)
Medical history, n (%)
Diabetes
388 (28)
343 (25)
CVD
549 (40)
556 (40) MI
146 (11)
136 (10)
Coronary revascularization
82 (6)
91 (7)
Peripheral vascular disease
212 (15)
210 (15)
Drug therapy, n (%)
Angiotensin-converting enzyme/ angiotensin receptor blocker
497 (36)
523 (38)
Calcium channel blocker
480 (35)
501 (36)
Beta blocker
534 (38)
498 (36)
Diuretic
428 (31)
422 (30)
Thrombocyte inhibitor
593 (43)
571 (41)
Vitamin D
643 (46)
659 (48)
Calcium substitution
1032 (74)
1027 (74)
Sevelamer
398 (29)
366 (26)
Erythropoietin
1204 (87)
1225 (89)

30. Baseline blood biochemistry
Parameter†
Rosuvastatin (n=1389)
Placebo (n=1384)
Hemoglobin, g/dL
11.7 (1.6)
Albumin, g/L
39.7 (3.5)
39.7 (3.4)
Calcium, mmol/L
2.3 (0.2)
Phosphate, mmol/L
1.8 (0.6)
1.8 (0.5)
†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 4D1 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 4D1 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