Transcript METEOR

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)
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 –
Oxford University’s
Clinical Trial Service Unit
Modest level
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–F272
2. Baigent C et al. Lancet 2000; 356: 147–152
3. Baigent C et al. Lancet 2005; 366: 1267–1278
4. Ridker PM et al. N Engl J Med 2008; 359: 2195–2207
Observational study of ESRD
patients: statins reduce mortality
1.0
0.9
Survival
Statin
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
0
0.5
1.0
No statin
1.5
2.0
Time from study start (years)
CI=confidence interval; RR=relative risk
Seliger SL et al. Kidney Int 2002; 61: 297–304
4D study in diabetic hemodialysis
patients: no benefit of statin therapy
60
Placebo
50
p=0.37
40
Atorvastatin
Cumulative
incidence of 30
primary
endpoint
20
(%)
10
0
0
1
2
3
4
5
6
Time (years)
No. at risk:
Placebo
636
532
383
252
136
51
19
Atorvastatin
619
515
378
252
136
58
29
4D=Die Deutsche Diabetes Dialyse Studie
Wanner C et al. N Engl J Med 2005; 353: 238–248
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
AURORA: study design
Screening
Month: –14 days
Visit:
1
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
†Study
Treatment
0
2
3
3
6
4
12
5
6-monthly
6
Final†
Rosuvastatin 10 mg daily (n~1350)
Randomization 1:1
Matching placebo (n~1350)
medication was administered until 620 patients had experienced a major CV event
Fellström B et al. Curr Control Trials Cardiovasc Med 2005; 6: 9
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 Creactive protein
Fellström B et al. Curr Control Trials Cardiovasc Med 2005; 6: 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
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
Results
Enrolled population
(n=3021)
4-week
placebo
run-in
Not randomized (n=245), because
Adverse event (n=19)
Screening criteria not fulfilled
(n=156)
Chose not to participate (n=70)
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)
Excluded from ITT analysis (n=2)
Excluded from ITT analysis (n=1)
Included in ITT analysis (n=1389)
Included in ITT analysis (n=1384)
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
Baseline lipid variables
and Hs-CRP
Lipid levels†, mg/dL
Total cholesterol
LDL-C
HDL-C
TG
Hs-CRP‡, mg/L
Rosuvastatin
(n=1389)
Placebo
(n=1384)
176 (42)
100 (35)
45 (15)
157 (95)
4.8 (2.0–13.6)
174 (43)
99 (34)
45 (16)
154 (97)
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)
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
Changes in lipids and Hs-CRP†
TG (mg/dL)
100
80
60
40
p<0.0001
20
0
0
1
2
50
40
p=0.045
30
20
10
0
3
Year
4
TG: 16.2% reduction
160
Rosuvastatin
Placebo
120
p<0.0001
80
40
0
5
HDL-C: 2.9% increase
60
HDL-C (mg/dL)
200
LDL-C: 43% reduction
7
Hs-CRP (mg/L)
LDL-C (mg/dL)
120
6
5
4
0
1
2
Year
3
4
5
Hs-CRP: 11.5% decrease
P<0.0001
Rosuvastatin
Placebo
3
2
1
0
Baseline 3 months
1 year
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
0
1
2
AURORA: primary endpoint
Kaplan-Meier estimate of time to
first major CV event
40
Placebo
35
30
Cumulative
incidence of
primary
endpoint
(%)
Rosuvastatin
25
20
15
10
HR=0.96 (95% CI 0.84–1.11)
P=0.59
5
0
0
No. at risk:
Rosuvastatin
Placebo
1390
1384
1
3
4
2
Years from randomization
1152
1163
962
952
826
809
551
534
5
148
153
Primary and secondary endpoints
Forest plot of adjudicated endpoints
HR
(95% CI)
Event
Primary
endpoints
Secondary
endpoints
p value
Major CV event
0.59
CV death
0.97
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
Atherosclerotic cardiac event
0.64
Vascular access procedure
0.19
Revascularization
0.88
0.5
0.75
Favors rosuvastatin
1
1.25
1.5
1.75
Favors placebo
2
Primary endpoint
Forest plot of predefined subgroups
HR
(95% CI)
Subgroup
p value
Gender
Male
Female
Age (years)
<65
≥65
Smoking status
No
Yes
Diabetes
No
Yes
History of CVD
No
Yes
0.71
0.90
0.84
0.23
0.87
0.5
0.75
Favors rosuvastatin
1
1.25
1.5
1.75
Favors placebo
2
Primary endpoint
Forest plot of predefined subgroups (cont.)
Subgroup
HR
(95% CI)
†
p value
Body mass index (kg/m2)
<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
0.16
0.18
0.97
0.27
0.32
0.75
Favors rosuvastatin
†The
1
1.25
1.5
1.75
Favors placebo
three subgroups represent patients whose baseline values fall into tertiles 1, 2 or 3
2
AURORA: safety
% subjects with AE
Rosuvastatin
(n=1389)
Placebo
(n=1378)
p value
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
Any serious AE
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
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
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 nonrenal 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 online
Fellström BC et al. N Engl J Med 2009; 360: 1395–1407
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