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