Effect of Rosuvastatin Versus Placebo on Cardiovascular Outcomes in Patients with End-Stage Renal Disease on Hemodialysis

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 Universitys 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 F262F272 2. Baigent C et al. Lancet 2000
356 147152 3. Baigent C et al. Lancet 2005
366 126712784. Ridker PM et al. N Engl J Med
2008 359 21952207
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 RR0.68 (95 CI 0.530.86) p0.002
No statin
0.7
0 0.5 1.0 1.5 2.0
Time from study start (years)
CIconfidence interval RRrelative risk
Seliger SL et al. Kidney Int 2002 61 297304
5
4D study in diabetic hemodialysis patients no
benefit of statin therapy
p0.37
No. at risk No. at risk No. at risk No. at risk No. at risk No. at risk No. at risk No. at risk
Placebo 636 532 383 252 136 51 19
Atorvastatin 619 515 378 252 136 58 29
4DDie Deutsche Diabetes Dialyse Studie
Wanner C et al. N Engl J Med 2005 353 238248
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
AURORA study design

Screening
Treatment
0 2
14 days 1
64
Month Visit
33
125
6-monthly 6
Final
Patients (n2750) Inclusion criteria ESRD, on
hemodialysis for 3 months 5080
years Exclusion criteria Statin within 6
months Kidney transplant likely within 1
year Creatine kinase gt3xULN ALT gt3xULN TSH
gt1.5xULN
Rosuvastatin 10 mg daily (n1350)
Randomization 11
Matching placebo (n1350)
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 9Fellström B et al. Kidney Blood
Press Res 2007 30 314322
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 314322
11
Results
12
Enrolled population (n3021)
Not randomized (n245), because Adverse event
(n19) Screening criteria not fulfilled
(n156) Chose not to participate (n70)
4-week placebo run-in
Patients randomly assigned to treatment (n2776)
Placebo (n1385)
Rosuvastatin 10 mg (n1391)
Lost to follow-up (n0) Did not receive study
treatment (n7) Discontinued treatment before end
of study (n1018) for Adverse event (n234)
Renal transplant (n174) Death (n336)
Other reasons (n274)
Lost to follow-up (n0) Did not receive study
treatment (n2) Discontinued treatment before end
of study (n1018) for Adverse event (n208)
Renal transplant (n197) Death (n330)
Other reasons (n283)
Excluded from ITT analysis (n1)
Excluded from ITT analysis (n2)
Included in ITT analysis (n1384)
Included in ITT analysis (n1389)
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(n1389) Placebo(n1384)
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 (2.013.6) 5.2 (2.114.4)
LDL-Clow-density lipoprotein cholesterol
HDL-Chigh-density lipoprotein cholesterol
TGtriglycerides Hs-CRPhigh-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
200
120
LDL-C 43 reduction
TG 16.2 reduction
100
160
80
120
LDL-C (mg/dL)
60
TG (mg/dL)
plt0.0001
80
40
plt0.0001
40
20
0
0
0
1
4
5
3
2
4
0
1
5
3
2
Year
Year
Hs-CRP 11.5 decrease
HDL-C 2.9 increase
60
Plt0.0001
50
40
p0.045
HDL-C (mg/dL)
30
Hs-CRP (mg/L)
20
10
0
0
1
4
5
3
2
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 endpointKaplan-Meier estimate of
time to first major CV event
Placebo
Rosuvastatin
Cumulative incidence of primary endpoint ()
HR0.96 (95 CI 0.841.11) P0.59
0
1
2
3
4
5
Years from randomization
No. at risk No. at risk No. at risk No. at risk
Rosuvastatin 1390 1152 962 826 551 148 148
Placebo 1384 1163 952 809 534 153 153
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Primary and secondary endpointsForest plot of
adjudicated endpoints
HR (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 endpointForest plot of predefined
subgroups
HR (95 CI)
Subgroup
p value
Gender
Male
Female
Age (years)
lt65
65
Smoking status
No
Yes
Diabetes
No
Yes
History of CVD
No
Yes
0.5
0.75
1
1.25
1.5
1.75
2
Favors rosuvastatin
Favors placebo
20
Primary endpointForest plot of predefined
subgroups (cont.)
HR (95 CI)

Subgroup
p value
Body mass index (kg/m2)
lt23
23.026.6
gt26.6
Systolic BP (mm Hg)

lt127
127146
gt146
Diastolic BP (mm Hg)

lt71
7180
gt80
LDL-C (mg/dL)

lt83
83111
gt111
Hs-CRP (mg/L)
lt2.9
2.98.5
gt8.5
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
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AURORA safety
subjects with AE Rosuvastatin (n1389) Placebo (n1378) 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 gt3 X ULN 0.7 0.6 0.64
Musculoskeletal disorder 22 25 0.21
Creatine kinase gt5 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
22
Limitations

• Patients excluded
• those already on statin treatment
• those considered by investigator to have an
  indication for statin treatment
• young patients (lt50 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 238248
25
NEJM publication available online
Fellström BC et al. N Engl J Med 2009 360
13951407
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 www.nejm.org

27
Back up slides
28
Baseline characteristics
Parameter Rosuvastatin(n1389) Placebo(n1384)
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 137/76 137/76
Current smoker, n () 202 (15) 227 (16)
Time on hemodialysis, years 3.5 (3.9) 3.5 (3.9)
Dialysis, hours/week 11.9 (1.8) 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 historyand medication
Parameter Rosuvastatin(n1389) Placebo(n1384)
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(n1389) Placebo(n1384)
Hemoglobin, g/dL 11.7 (1.6) 11.7 (1.6)
Albumin, g/L 39.7 (3.5) 39.7 (3.4)
Calcium, mmol/L 2.3 (0.2) 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 (lt50 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
2382482. Tonelli M et al. Circulation 2004
110 155715633. Holdass H et al. Am J
Transplant 2005 5 29262936
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
2382482. Tonelli M et al. Circulation 2004
110 155715633. Holdass H et al. Am J
Transplant 2005 5 29262936
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