IN THE LITERATURE
AURORA: Is There a Role for Statin Therapy in Dialysis Patients?
Commentary on Fellstrom BC, Jardine AG, Schmieder RE, et al; AURORA Study Group.
Rosuvastatin and cardiovascular events in patients undergoing hemodialysis. N Engl J Med.
2009;360(14):1395-1407.
M ortality in patients treated with mainte-
nance hemodialysis is exceedingly high,
especially in patients aged 65 years, in whom
survival is similar to that for people with meta-
static cancer.1 Traditional cardiovascular (CV)
disease (CVD) risk factors are common in hemo-
dialysis patients; 80% have known CVD at the
time of dialysis therapy initiation, and CVD is a
leading cause of death in people with kidney
failure.1 In the general population, 3-hydroxy-3-
methylglutaryl coenzyme A (HMG CoA) reduc-
tase inhibitors (statins) are highly effective for
preventing CV morbidity and mortality, espe-
cially in patients at higher baseline risk. Random-
ized trials have consistently shown that statin
treatment reduces the risk of CV death in parallel
with low-density lipoprotein cholesterol (LDL-C)
level regardless of baseline lipid levels. Post hoc
subgroup analyses of large statin trials in the
general population suggest that the benefit of
statin treatment in people with stage 3 chronic
kidney disease is similar to or greater than that in
people with normal kidney function.2 In addition
to the traditional Framingham risk factors, recent
evidence suggests that increased levels of C-
reactive protein (CRP) also identify patients at
higher CVD risk, including those who will de-
rive particular benefit from statin treatment.3-6
Because hemodialysis patients have high base-
line CVD risk and higher than average CRP
levels, it seems logical that the clinical benefits
of statins would be similar or greater in this
population than in people who do not require
dialysis treatment. This question was evaluated
in AURORA (A Study to Evaluate the Use of
Rosuvastatin in Subjects on Regular Haemodialy-
sis: An Assessment of Survival and Cardiovascu-
lar Events), published in 2009 in the New En-
gland Journal of Medicine.7
WHAT DOES THIS IMPORTANT
STUDY SHOW?
AURORA was a randomized double-blind trial
that enrolled 2,776 patients aged 50-80 years
who had been treated with maintenance hemodi-
American Journal of Kidney Diseases, Vol 55, No 2 (February), 2010: pp 237-240
alysis for at least 3 months (median duration, 3.5
years).7 Participants were randomly assigned to
treatment with rosuvastatin, 10 mg/d, versus pla-
cebo. The primary end point was time to a major
CV event (CV death, nonfatal myocardial infarc-
tion [MI], or nonfatal stroke), and an appropriate
selection of secondary end points also was con-
sidered, including changes in serum lipid and
CRP levels. The authors predicted a 19.5% de-
crease in major CV events with active treatment;
for 0.05, it was estimated that 805 major CV
events would yield 87% power to show a signifi-
cant difference between treatment groups.
Compared with placebo after 3 months of
study drug administration, rosuvastatin treat-
ment led to a net decrease in LDL-C levels of
41%, a net decrease in total cholesterol levels of
27%, and a net increase in high-density lipopro-
tein cholesterol levels of 2%. Rosuvastatin recipi-
ents experienced a 14% decrease in CRP levels
at 3 months compared with a 4% increase in
placebo recipients. After a mean follow-up of 3.2
years, the primary end point occurred in 408
placebo recipients and 396 rosuvastatin recipi-
ents (hazard ratio, 0.96; 95% confidence interval
[CI], 0.84-1.11; P 0.59) using an intent-to-
treat analysis; results were similar when a per-
protocol analysis was performed. Rosuvastatin
did not significantly reduce the risk of any indi-
vidual component of the composite primary end
point or any secondary end point. Moreover,
rosuvastatin treatment did not significantly re-
duce the incidence of the primary end point in
any prespecified subgroup. No patients were lost
to follow-up; however, 50% of patients in each
Originally published online as doi:10.1053/j.ajkd.2009.
09.018 on November 18, 2009.
No paper or electronic reprints will be available.
Address correspondence to Marcello Tonelli, MD, 7-129
Clinical Science Bldg, 8440 112 St, Edmonton, Alberta T6B
2B7, Canada.
2010 by the National Kidney Foundation, Inc.
0272-6386/10/5502-0011$36.00/0
doi:10.1053/j.ajkd.2009.09.018
237
238
treatment arm discontinued treatment before study
completion (because of an adverse event, kidney
transplant, or other reasons). The risk of adverse
events was similar between treatment groups
(including muscle symptoms and increase in
creatine kinase and alanine aminotransferase
levels).
HOW DOES THIS STUDY COMPARE WITH
PRIOR STUDIES?
Observational studies of dialysis patients sug-
gested that statin therapy is associated with de-
creased mortality. In a cohort of 3,716 patients
starting hemodialysis or peritoneal dialysis
therapy, statin therapy was associated with de-
creases in total mortality of 32% and CV-specific
mortality of 37%.8 Similar findings were ob-
served in an observational study of 7,365 preva-
lent hemodialysis patients enrolled in DOPPS
(Dialysis Outcome and Practice Patterns Study).9
However, observational studies are prone to bias
caused by confounding by indication and other
unmeasured characteristics.
4D (Die Deutsche Diabetes Dialyse Studie)
was the first adequately powered randomized
controlled trial to assess whether statins prevent
CV events in dialysis patients.10 This double-
blinded study enrolled 1,255 patients in Ger-
many with type 2 diabetes receiving mainte-
nance hemodialysis and compared atorvastatin,
20 mg/d, with placebo for the composite out-
come of death from cardiac causes, nonfatal MI,
and stroke. Despite a significant decrease in
LDL-C levels, atorvastatin did not significantly
reduce this primary composite outcome (relative
risk, 0.92; 95% CI, 0.77-1.10; P 0.37). The
secondary end point of all cardiac events was
significantly decreased by 18% (relative risk,
0.82; 95% CI, 0.68-0.99; P 0.03), but statin
treatment did not decrease the risk of the other 2
secondary outcomes (P 0.49 for all cerebrovas-
cular events and P 0.33 for all-cause death).
Treatment of hemodialysis patients with rosu-
vastatin in AURORA and with atorvastatin in 4D
decreased LDL-C levels by 43% (mean de-
crease, 1.1 mmol/L) and 42% (median decrease,
1.3 mmol/L), respectively. Post hoc analysis of
4D showed that atorvastatin prevented an in-
crease in CRP levels over time that was observed
in placebo recipients, but did not reduce the risk
Shurraw and Tonelli
of the primary end point in any quartile of
baseline CRP level.11 Rosuvastatin treatment in
AURORA decreased CRP levels by 11.5% (vs an
increase in CRP levels over time in placebo
recipients); however, similar to 4D, there was no
significant interaction between baseline CRP level
and the clinical benefit of statin treatment. Statin
use did not prevent the composite primary out-
come of combined CV death, MI, and stroke in
either study despite these apparently beneficial
effects on LDL-C and CRP levels and high CV
event rates during the course of the study. These
findings substantially differ from those of statin
trials in people without kidney failure: a meta-
analysis of 14 such trials found that each
1-mmol/L decrease in LDL-C level led to a 21%
decrease in risk of major CV event.12 Similarly,
data from patients without kidney failure suggest
that the CRP level decrease with statin therapy
may further decrease mortality independently of
LDL-C level decrease.3,6
WHAT SHOULD CLINICIANS AND
RESEARCHERS DO?
Why did 4D and AURORA show no benefit in
treating hemodialysis patients with statins? This
question deserves consideration before deciding
how the findings of these trials should affect
clinical practice.13
First, there were significant drop-outs and/or
drop-ins between treatment arms in both studies.
In 4D, after 2 years, 17% of statin-assigned
patients discontinued their drug therapy and 15%
of placebo-assigned patients ended up using a
nonstudy statin. In AURORA, 50% of patients
dropped out of each treatment group, and the
proportion of patients who received a nonstudy
statin was not reported. By the end of both
studies, LDL-C level differences between groups
were only 0.78 mmol/L (4D) and 0.5 mmol/L
(AURORA), and this analysis overestimates the
true difference between groups because patients
who had dropped out were not included.
Second, AURORA excluded patients who cli-
nicians believe would benefit the most from
statins (ie, patients who had received a statin
within the previous 6 months). Although 4D did
not exclude patients receiving statins at baseline
(nonstudy statin therapy was discontinued upon
enrollment), less than one-third of study partici-
In the Literature
pants had coronary artery disease and patients
with increased LDL-C levels (4.9 mmol/L)
were excluded. In retrospect, one could speculate
that these criteria selected a population of pa-
tients who were less likely to benefit from statin
therapy.
Finally, although they had adequate statistical
power to detect 20%-27% decreases in the rela-
tive risk of their primary outcomes, these trials
may have been too small to detect a less dramatic
benefit that remains clinically important. This
hypothesis is supported because 6 of 9 (67%) and
6 of 8 (75%) of the major primary and secondary
CV end points in 4D and AURORA, respectively,
nonsignificantly favored statin treatment, rather
than the 50% split that would be expected if
statins had no effect on clinical outcomes. In the
general population, statins prevent CV events
that often occur in association with ruptured
atherosclerotic plaque, such as acute MI. Given
that many CV deaths in hemodialysis patients
are from different causes, such as sudden death
(perhaps from electrolyte abnormalities)14,15 or
cardiomyopathy (potentially from chronic extra-
cellular volume overload),16 the effective statisti-
cal power of AURORA may have been lower
than the number of CV events suggests. Findings
of the CORONA (Controlled Rosuvastatin Mul-
tinational Trial in Heart Failure; which randomly
assigned elderly patients with systolic dysfunc-
tion, but without kidney failure, to treatment
with rosuvastatin, 10 mg, vs placebo) were
broadly similar to those of AURORA: no signifi-
cant effect on risk of death from CV cause,
nonfatal MI, or stroke (hazard ratio, 0.92; 95%
CI, 0.83-1.03; P 0.12) despite an LDL-C level
decrease of 45%.17 Statin treatment reduced the
risk of coronary events in CORONA partici-
pants; however, as in AURORA, these events
accounted for the minority of primary outcome
and all-cause deaths (10% of CORONA partici-
pants had a coronary event and 2% of deaths
were due to MI).
These 3 plausible considerations may account
for the discrepant findings of AURORA and 4D
compared with the undisputable benefits of st-
atins in the general population. However, be-
cause these 2 trials failed to show a benefit of
statin treatment in hemodialysis patients, the
fourth explanation, that statins are truly ineffec-
tive when used in patients who are already dialy-
239
sis dependent, must be assumed to be correct
until proved otherwise by future randomized
trials.
Although this makes it difficult to justify new
prescriptions of statins to patients already receiv-
ing hemodialysis, the findings of AURORA and
4D do not directly address the question of whether
statin treatment should be discontinued when
patients become dialysis dependent. This deci-
sion currently must be made after considering
the patients risk of an atherosclerotic (plaque
rupture) event in the context of his or her life
expectancy. For example, hemodialysis patients
with heart failure, those with multiple noncar-
diac comorbidities, and those at high risk of
infection and sepsis would be expected to derive
little benefit from statin treatment given that they
are unlikely to die of coronary disease regardless
of their medical regimen. Unfortunately, the lat-
ter group constitutes most patients in contempo-
rary nephrology practice.
SHARP (Study for Heart and Renal Protec-
tion) is expected to report in 2010 on the clinical
benefits of combination treatment with simvasta-
tin/ezetimibe versus placebo in a large popula-
tion of patients with advanced kidney disease,
and its findings are keenly anticipated. Given the
frequency of hypercholesterolemia in peritoneal
dialysis patients, the effect of statin monotherapy
on CV events in this population also appears
worthy of investigation. In the interim, because
statin treatment appears beneficial in patients
with milder kidney disease, clinicians should
focus on identifying and treating such patients
with statins and other therapies that reduce CV
risk before kidney failure occurs.
Sabin Shurraw, MD
Marcello Tonelli, MD, SM
University of Alberta
Edmonton, Canada
ACKNOWLEDGEMENTS
Support: Dr Tonelli is supported by a Population Health
Investigator Award from Alberta Heritage Foundation for
Medical Research and a New Investigator Award from the
Canadian Institutes of Health Research.
Financial Disclosure: Dr Tonelli is the recipient of a
research grant from Pfizer, which markets statins. Dr Shur-
raw has no relevant financial interests to report.
240
REFERENCES
1. US Renal Data System. USRDS 2008 Annual Data
Report. The National Institutes of Health, National Institute
of Diabetes and Digestive and Kidney Diseases, Bethesda,
MD, 2008.
2. Tonelli M, Isles C, Curhan GC, et al. Effect of pravasta-
tin on cardiovascular events in people with chronic kidney
disease. Circulation. 2004;110(12):1557-1563.
3. Ridker PM, Danielson E, Fonseca FA, et al; JUPITER
Trial Study Group. Reduction in C-reactive protein and LDL
cholesterol and cardiovascular event rates after initiation of
rosuvastatin: a prospective study of the JUPITER trial.
Lancet. 2009;373(9670):1175-1182.
4. Ridker PM, Danielson E, Fonseca FA, et al; JUPITER
Study Group. Rosuvastatin to prevent vascular events in
men and women with elevated C-reactive protein. N Engl
J Med. 2008;359(21):2195-2207.
5. Koenig W, Lowel H, Baumert J, Meisinger C. C-
Reactive protein modulates risk prediction based on the
Framingham score: implications for future risk assessment:
results from a large cohort study in southern Germany.
Circulation. 2004;109(11):1349-1353.
6. Ridker PM, Cannon CP, Morrow D, et al; Pravastatin
or Atorvastatin Evaluation and Infection Therapy-Thrombol-
ysis in Myocardial Infarction 22 (PROVE IT-TIMI 22)
Investigators. C-Reactive protein levels and outcomes after
statin therapy. N Engl J Med. 2005;352(1):20-28.
7. Fellstrom BC, Jardine AG, Schmieder RE, et al;
AURORA Study Group. Rosuvastatin and cardiovascular
events in patients undergoing hemodialysis. N Engl J Med.
2009;360(14):1395-1407.
Shurraw and Tonelli
8. Seliger SL, Weiss NS, Gillen DL, et al. HMG-Co A
reductase inhibitors are associated with reduced mortality in
ESRD patients. Kidney Int. 2002;61(1):297-304.
9. Mason NA, Bailie GR, Satayathum S, et al. HMG-
coenzyme A reductase inhibitor use is associated with mor-
tality reduction in hemodialysis patients. Am J Kidney Dis.
2005;45(1):119-126.
10. Wanner C, Krane V, Mrz W, et al. Atorvastatin in
patients with type 2 diabetes mellitus undergoing hemodialy-
sis. N Engl J Med. 2005;353(3):238-248.
11. Krane V, Winkler K, Drechsler C, Lilienthal J, Marz
W, Wanner C. Effect of atorvastatin on inflammation and
outcome in patients with type 2 diabetes mellitus on hemodi-
alysis. Kidney Int. 2008;74(11):1461-1467.
12. Kearney PM, Blackwell L, Collins R, et al; Choles-
terol Treatment Trialists (CTT) Collaborators. Efficacy of
cholesterol-lowering therapy in 18,686 people with diabetes
in 14 randomised trials of statins: a meta-analysis. Lancet.
2008;371(9607):117-125.
13. Wanner C. Statin effects in CKD: is there a point of
no return? Am J Kidney Dis. 2009;53(5):723-725.
14. Herzog CA. How to manage the renal patient with
coronary heart disease: the agony and the ecstasy of opinion-
based medicine. J Am Soc Nephrol. 2003;14(10):2556-2572.
15. Karnik JA, Young BS, Lew NL, et al. Cardiac arrest
and sudden death in dialysis units. Kidney Int. 2001;60(1):
350-357.
16. London GM, Marchais SJ, Metivier F, Guerin AP.
Cardiovascular risk in end-stage renal disease: vascular
aspects. Nephrol Dial Transplant. 2000;15(suppl 5):97-104.
17. Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin
in older patients with systolic heart failure. N Engl J Med.
2007;357(22):2248-2261.