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					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 –                 Modest level
                        Oxford University’s
                        Clinical Trial Service Unit
          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

                                                                                    Statin
Survival
              0.8
                        Statin treatment was associated
                        with a 32% reduction in the
                        adjusted relative risk of death:
              0.7       RR=0.68 (95% CI 0.53–0.86)                            No statin
                        p=0.002

                    0            0.5           1.0               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
Cumulative                                                     Atorvastatin
incidence of 30
primary
endpoint     20
(%)
                 10

                  0
                       0     1    2         3         4        5         6

  No. at risk:                     Time (years)
  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                             Treatment



Month: –14 days                 0       3         6        12    6-monthly
Visit:    1                     2       3         4         5       6                         Final†


Patients (n~2750)
Inclusion criteria                    Rosuvastatin 10 mg daily (n~1350)
ESRD, on hemodialysis for
   ≥3 months
50–80 years
Exclusion criteria
                                    Randomization 1:1
Statin within 6 months
Kidney transplant likely
   within 1 year
Creatine kinase >3xULN
ALT >3xULN                                  Matching placebo (n~1350)
TSH >1.5xULN


†
    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
               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
             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)

                                                            Not randomized (n=245), because
                                          4-week              Adverse event (n=19)
                                          placebo             Screening criteria not fulfilled
                                           run-in             (n=156)
                                                              Chose not to participate (n=70)

                             Patients randomly assigned to
                                  treatment (n=2776)


                       Rosuvastatin 10 mg             Placebo
                           (n=1391)                  (n=1385)

Lost to follow-up (n=0)                               Lost to follow-up (n=0)
Did not receive study treatment (n=2)                 Did not receive study treatment (n=7)
Discontinued treatment before                         Discontinued treatment before
end of study (n=1018) for                             end of study (n=1018) for
  Adverse event (n=208)                                 Adverse event (n=234)
   Renal transplant (n=197)                             Renal transplant (n=174)
   Death (n=330)                                        Death (n=336)
   Other reasons (n=283)                                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
                                          Rosuvastatin                    Placebo
                                           (n=1389)                      (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)
           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†
                120        LDL-C: 43% reduction                          200        TG: 16.2% reduction
                100                                                      160
LDL-C (mg/dL)




                                                          TG (mg/dL)
                80                                                                                                   Rosuvastatin
                                                                         120
                60                                                                                                   Placebo
                                                                         80        p<0.0001
                40
                          p<0.0001
                20                                                       40

                 0                                                        0
                      0      1       2       3   4   5                         0      1       2          3   4   5
                                         Year                                                     Year
                 60        HDL-C: 2.9% increase                            7        Hs-CRP: 11.5% decrease
                                                                           6             P<0.0001
                 50
HDL-C (mg/dL)




                                                         Hs-CRP (mg/L)


                                                                           5                                         Rosuvastatin
                 40
                                                                           4                                         Placebo
                 30       p=0.045
                                                                           3
                 20
                                                                           2
                 10                                                        1
                 0                                     0
                      0      1  3    24     5             Baseline 3 months      1 year
                            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
          AURORA: primary endpoint
                     Kaplan-Meier estimate of time to
                           first major CV event

                    40                              Placebo
                    35

                    30
                                                            Rosuvastatin
Cumulative          25
incidence of
primary             20
endpoint            15
(%)
                    10
                                                 HR=0.96 (95% CI 0.84–1.11)
                     5                           P=0.59
                     0

                          0      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
        Primary and secondary endpoints
                Forest plot of adjudicated endpoints
                                                       HR
            Event                                   (95% CI)                           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
            Primary endpoint
  Forest plot of predefined subgroups
                                  HR
Subgroup                       (95% CI)                           p value


Gender                                                               0.71
    Male
    Female
Age (years)                                                          0.90
    <65
     ≥65
Smoking status                                                       0.84
    No
    Yes
Diabetes                                                             0.23
    No
    Yes
History of CVD                                                       0.87
    No
    Yes

                 0.5    0.75       1      1.25       1.5      1.75          2
                 Favors rosuvastatin             Favors placebo
                          Primary endpoint
      Forest plot of predefined subgroups (cont.)
                      †                                HR
           Subgroup                                 (95% CI)                             p value

           Body mass index (kg/m2)                                                          0.16
               <23
               23.0–26.6
               >26.6
           Systolic BP (mm Hg)                                                              0.18
               <127
               127–146
               >146
           Diastolic BP (mm Hg)                                                             0.97
               <71
               71–80
               >80
           LDL-C (mg/dL)                                                                    0.27
               <83
               83–111
               >111
           Hs-CRP (mg/L)                                                                    0.32
               <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
                     AURORA: safety

% subjects with AE            Rosuvastatin    Placebo   p value
                               (n=1389)      (n=1378)
Any serious AE                    82            84       0.80
  Event leading to death          46            48       0.49
  Event requiring permanent       32            32       0.78
  withdrawal
  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
                   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 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 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
Back up slides
                  Baseline characteristics

    Parameter†                                          Rosuvastatin    Placebo
                                                         (n=1389)      (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       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
               Baseline medical history
                   and medication
Parameter                           Rosuvastatin    Placebo
                                     (n=1389)      (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/     497 (36)      523 (38)
   angiotensin receptor blocker
   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)
           Baseline blood biochemistry

    Parameter†              Rosuvastatin    Placebo
                             (n=1389)      (n=1384)
    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)
                  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
 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: 238–248
                             2. Tonelli M et al. Circulation 2004; 110: 1557–1563
                        3. Holdass H et al. Am J Transplant 2005; 5: 2926–2936
               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: 238–248
                              2. Tonelli M et al. Circulation 2004; 110: 1557–1563
                         3. Holdass H et al. Am J Transplant 2005; 5: 2926–2936
            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

				
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