Effect of Rosuvastatin Versus Effect of Rosuvastatin Versus Placebo on Cardiovascular Placebo on Cardiovascular Outcomes in Patients with Outcomes in Patients with End-Stage Renal Disease End-Stage Renal Disease
on Hemodialysis – on Hemodialysis – Results of the AURORA Study 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)
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
Rationale for AURORARationale 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–F272 2. Baigent C et al. Lancet 2000; 356: 147–152
3. Baigent C et al. Lancet 2005; 366: 1267–12784. Ridker PM et al. N Engl J Med 2008; 359: 2195–2207
SurvivalStatin
No statin
0 0.5 1.0 1.5 2.0
Time from study start (years)
0.7
0.8
0.9
1.0
Statin treatment was associatedwith 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 Observational study of ESRD patients: statins reduce mortalitypatients: statins reduce mortality
CI=confidence interval; RR=relative risk Seliger SL et al. Kidney Int 2002; 61: 297–304
p=0.37
4D study in diabetic hemodialysis 4D study in diabetic hemodialysis patients: no benefit of statin therapypatients: no benefit of statin therapy
4D=Die Deutsche Diabetes Dialyse Studie
No. at risk:
Placebo 636 532 383 252 136 51 19
Atorvastatin 619 515 378 252 136 58 29
Wanner C et al. N Engl J Med 2005; 353: 238–248
Cumulative incidence of primary endpoint (%)
Time (years)
Atorvastatin
Placebo60
50
40
30
20
10
060 1 2 3 4 5
• To compare the effects of rosuvastatin 10 mg daily versus placebo on CV morbidity and mortality in chronic hemodialysis patients
AURORA: objectiveAURORA: objective
Fellström B et al. Curr Control Trials Cardiovasc Med 2005; 6: 9
AURORA: study designAURORA: study design
Matching placebo (n~1350)
Screening
6-monthly 6 Final†
Patients (n~2750)Inclusion criteriaESRD, on hemodialysis for ≥3 months 50–80 yearsExclusion criteriaStatin within 6 monthsKidney transplant likely within 1 yearCreatine kinase >3xULNALT >3xULNTSH >1.5xULN
–14 days 1
0 2
64
Month: Visit:
Rosuvastatin 10 mg daily (n~1350)
33
125
Treatment
†Study medication was administered until 620 patients had experienced a major CV eventFellström B et al. Curr Control Trials Cardiovasc Med 2005; 6: 9
Randomization 1:1
Study endpointsStudy 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
Statistical analysisStatistical 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: 9Fellström B et al. Kidney Blood Press Res 2007; 30: 314–322
Patients and centersPatients 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
ResultsResults
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 beforeend 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 beforeend 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-weekplaceborun-in
Enrolled population(n=3021)
Baseline characteristics 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
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)
Baseline lipid variables Baseline lipid variables and Hs-CRP 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)
Duration of follow-up Duration of follow-up and discontinuationsand 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
Hs-CRP: 11.5% decrease
Changes in lipids and Hs-CRPChanges in lipids and Hs-CRP††
Hs-C
RP
(m
g/L
)7
6
5
4
3
2
1
03 monthsBaseline 1 year
RosuvastatinPlacebo
Year
LD
L-C
(m
g/d
L)
0 1 4 532
120
100
80
60
40
20
0
p<0.0001
LDL-C: 43% reduction
RosuvastatinPlacebo
200
160
120
80
40
0
Year
TG
(m
g/d
L)
0 1 4 532
p<0.0001
TG: 16.2% reduction
60
50
40
30
20
10
00 1 4 5
Year
HD
L-C
(m
g/d
L)
32
p=0.045
HDL-C: 2.9% increaseP<0.0001
†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
Placebo
AURORA: primary endpointAURORA: primary endpointKaplan-Meier estimate of time to Kaplan-Meier estimate of time to
first major CV eventfirst major CV event
No. at risk:
Rosuvastatin 1390 1152 962 826 551 148
Placebo 1384 1163 952 809 534 153
Cumulative incidence of primary endpoint (%)
Years from randomization
Rosuvastatin
HR=0.96 (95% CI 0.84–1.11)P=0.59
0
5
10
15
20
25
30
35
40
0 1 2 3 4 5
Primary and secondary endpointsPrimary and secondary endpointsForest plot of adjudicated endpointsForest 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
0.59
0.97
0.23
0.42
0.51
0.30
0.34
0.64
0.19
0.88
Primary endpoints
Secondary endpoints
0.5 0.75 1 1.25 1.5 1.75 2
Favors rosuvastatin Favors placebo
Smoking status
Primary endpointPrimary endpointForest plot of predefined subgroupsForest plot of predefined subgroups
0.90
0.84
0.23
0.87
0.71
<65 ≥65
Age (years)
NoYes
NoYes
Diabetes
NoYes
History of CVD
MaleFemale
Gender
0.5 0.75 1 1.25 1.5 1.75 2
Favors rosuvastatin Favors placebo
HR(95% CI) p valueSubgroup
127–146
Primary endpointPrimary endpointForest plot of predefined subgroups (cont.)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)
0.18
0.97
0.27
0.32
0.16
>80
>111
Systolic BP (mm Hg)
Diastolic BP (mm Hg)
Body mass index (kg/m2)
<7171–80
<2.9 2.9–8.5>8.5
<8383–111
<127
>146
<2323.0–26.6>26.6
0.5 0.75 1 1.25 1.5 1.75 2
Favors rosuvastatin Favors placebo
HR(95% CI) p valueSubgroup †
AURORA: safetyAURORA: safety
% subjects with AE Rosuvastatin (n=1389)
Placebo (n=1378)
p value
Any serious AE 82 84 0.80
Event leading to death 46 48 0.49
Event requiring permanent withdrawal
32 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 0.2 0.99
New diagnosis of cancer 7.7 8.6 0.41
New onset diabetes 0.7 1.0 0.40
Rhabdomyolysis 0.2 0.1 0.66
LimitationsLimitations
• 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
Conclusions IConclusions 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
Conclusions IIConclusions 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
NEJM publication available onlineNEJM publication available online
Fellström BC et al. N Engl J Med 2009; 360: 1395–1407
AcknowledgementsAcknowledgements
• 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 www.nejm.org