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
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-
survival is similar to that for people with meta- cebo. The primary end point was time to a major
static cancer.1 Traditional cardiovascular (CV) CV event (CV death, nonfatal myocardial infarc-
disease (CVD) risk factors are common in hemo- tion [MI], or nonfatal stroke), and an appropriate
dialysis patients; 80% have known CVD at the selection of secondary end points also was con-
time of dialysis therapy initiation, and CVD is a sidered, including changes in serum lipid and
leading cause of death in people with kidney CRP levels. The authors predicted a 19.5% de-
failure.1 In the general population, 3-hydroxy-3- crease in major CV events with active treatment;
methylglutaryl coenzyme A (HMG CoA) reduc- for 0.05, it was estimated that 805 major CV
tase inhibitors (statins) are highly effective for events would yield 87% power to show a signifi-
preventing CV morbidity and mortality, espe- cant difference between treatment groups.
cially in patients at higher baseline risk. Random- Compared with placebo after 3 months of
ized trials have consistently shown that statin study drug administration, rosuvastatin treat-
treatment reduces the risk of CV death in parallel ment led to a net decrease in LDL-C levels of
with low-density lipoprotein cholesterol (LDL-C) 41%, a net decrease in total cholesterol levels of
level regardless of baseline lipid levels. Post hoc
27%, and a net increase in high-density lipopro-
subgroup analyses of large statin trials in the
tein cholesterol levels of 2%. Rosuvastatin recipi-
general population suggest that the benefit of
ents experienced a 14% decrease in CRP levels
statin treatment in people with stage 3 chronic
at 3 months compared with a 4% increase in
kidney disease is similar to or greater than that in
placebo recipients. After a mean follow-up of 3.2
people with normal kidney function.2 In addition
to the traditional Framingham risk factors, recent years, the primary end point occurred in 408
evidence suggests that increased levels of C- placebo recipients and 396 rosuvastatin recipi-
reactive protein (CRP) also identify patients at ents (hazard ratio, 0.96; 95% confidence interval
higher CVD risk, including those who will de- [CI], 0.84-1.11; P 0.59) using an intent-to-
rive particular benefit from statin treatment.3-6 treat analysis; results were similar when a per-
Because hemodialysis patients have high base- protocol analysis was performed. Rosuvastatin
line CVD risk and higher than average CRP did not significantly reduce the risk of any indi-
levels, it seems logical that the clinical benefits vidual component of the composite primary end
of statins would be similar or greater in this point or any secondary end point. Moreover,
population than in people who do not require rosuvastatin treatment did not significantly re-
dialysis treatment. This question was evaluated duce the incidence of the primary end point in
in AURORA (A Study to Evaluate the Use of any prespecified subgroup. No patients were lost
Rosuvastatin in Subjects on Regular Haemodialy- to follow-up; however, 50% of patients in each
sis: An Assessment of Survival and Cardiovascu-
lar Events), published in 2009 in the New En-
gland Journal of Medicine.7 Originally published online as doi:10.1053/j.ajkd.2009.
09.018 on November 18, 2009.
No paper or electronic reprints will be available.
WHAT DOES THIS IMPORTANT Address correspondence to Marcello Tonelli, MD, 7-129
STUDY SHOW? Clinical Science Bldg, 8440 112 St, Edmonton, Alberta T6B
2B7, Canada.
AURORA was a randomized double-blind trial 2010 by the National Kidney Foundation, Inc.
that enrolled 2,776 patients aged 50-80 years 0272-6386/10/5502-0011$36.00/0
who had been treated with maintenance hemodi- doi:10.1053/j.ajkd.2009.09.018

American Journal of Kidney Diseases, Vol 55, No 2 (February), 2010: pp 237-240 237
238 Shurraw and Tonelli

treatment arm discontinued treatment before study of the primary end point in any quartile of
completion (because of an adverse event, kidney baseline CRP level.11 Rosuvastatin treatment in
transplant, or other reasons). The risk of adverse AURORA decreased CRP levels by 11.5% (vs an
events was similar between treatment groups increase in CRP levels over time in placebo
(including muscle symptoms and increase in recipients); however, similar to 4D, there was no
creatine kinase and alanine aminotransferase significant interaction between baseline CRP level
levels). and the clinical benefit of statin treatment. Statin
use did not prevent the composite primary out-
HOW DOES THIS STUDY COMPARE WITH come of combined CV death, MI, and stroke in
either study despite these apparently beneficial
PRIOR STUDIES?
effects on LDL-C and CRP levels and high CV
Observational studies of dialysis patients sug- event rates during the course of the study. These
gested that statin therapy is associated with de- findings substantially differ from those of statin
creased mortality. In a cohort of 3,716 patients trials in people without kidney failure: a meta-
starting hemodialysis or peritoneal dialysis analysis of 14 such trials found that each
therapy, statin therapy was associated with de- 1-mmol/L decrease in LDL-C level led to a 21%
creases in total mortality of 32% and CV-specific decrease in risk of major CV event.12 Similarly,
mortality of 37%.8 Similar findings were ob- data from patients without kidney failure suggest
served in an observational study of 7,365 preva- that the CRP level decrease with statin therapy
lent hemodialysis patients enrolled in DOPPS may further decrease mortality independently of
(Dialysis Outcome and Practice Patterns Study).9 LDL-C level decrease.3,6
However, observational studies are prone to bias
caused by confounding by indication and other
WHAT SHOULD CLINICIANS AND
unmeasured characteristics.
4D (Die Deutsche Diabetes Dialyse Studie) RESEARCHERS DO?
was the first adequately powered randomized Why did 4D and AURORA show no benefit in
controlled trial to assess whether statins prevent treating hemodialysis patients with statins? This
CV events in dialysis patients.10 This double- question deserves consideration before deciding
blinded study enrolled 1,255 patients in Ger- how the findings of these trials should affect
many with type 2 diabetes receiving mainte- clinical practice.13
nance hemodialysis and compared atorvastatin, First, there were significant drop-outs and/or
20 mg/d, with placebo for the composite out- drop-ins between treatment arms in both studies.
come of death from cardiac causes, nonfatal MI, In 4D, after 2 years, 17% of statin-assigned
and stroke. Despite a significant decrease in patients discontinued their drug therapy and 15%
LDL-C levels, atorvastatin did not significantly of placebo-assigned patients ended up using a
reduce this primary composite outcome (relative nonstudy statin. In AURORA, 50% of patients
risk, 0.92; 95% CI, 0.77-1.10; P 0.37). The dropped out of each treatment group, and the
secondary end point of all cardiac events was proportion of patients who received a nonstudy
significantly decreased by 18% (relative risk, statin was not reported. By the end of both
0.82; 95% CI, 0.68-0.99; P 0.03), but statin studies, LDL-C level differences between groups
treatment did not decrease the risk of the other 2 were only 0.78 mmol/L (4D) and 0.5 mmol/L
secondary outcomes (P 0.49 for all cerebrovas- (AURORA), and this analysis overestimates the
cular events and P 0.33 for all-cause death). true difference between groups because patients
Treatment of hemodialysis patients with rosu- who had dropped out were not included.
vastatin in AURORA and with atorvastatin in 4D Second, AURORA excluded patients who cli-
decreased LDL-C levels by 43% (mean de- nicians believe would benefit the most from
crease, 1.1 mmol/L) and 42% (median decrease, statins (ie, patients who had received a statin
1.3 mmol/L), respectively. Post hoc analysis of within the previous 6 months). Although 4D did
4D showed that atorvastatin prevented an in- not exclude patients receiving statins at baseline
crease in CRP levels over time that was observed (nonstudy statin therapy was discontinued upon
in placebo recipients, but did not reduce the risk enrollment), less than one-third of study partici-
In the Literature 239

pants had coronary artery disease and patients sis dependent, must be assumed to be correct
with increased LDL-C levels (4.9 mmol/L) until proved otherwise by future randomized
were excluded. In retrospect, one could speculate trials.
that these criteria selected a population of pa- Although this makes it difficult to justify new
tients who were less likely to benefit from statin prescriptions of statins to patients already receiv-
therapy. ing hemodialysis, the findings of AURORA and
Finally, although they had adequate statistical 4D do not directly address the question of whether
power to detect 20%-27% decreases in the rela- statin treatment should be discontinued when
tive risk of their primary outcomes, these trials patients become dialysis dependent. This deci-
may have been too small to detect a less dramatic sion currently must be made after considering
benefit that remains clinically important. This the patients risk of an atherosclerotic (plaque
hypothesis is supported because 6 of 9 (67%) and rupture) event in the context of his or her life
6 of 8 (75%) of the major primary and secondary expectancy. For example, hemodialysis patients
CV end points in 4D and AURORA, respectively, with heart failure, those with multiple noncar-
nonsignificantly favored statin treatment, rather diac comorbidities, and those at high risk of
than the 50% split that would be expected if
infection and sepsis would be expected to derive
statins had no effect on clinical outcomes. In the
little benefit from statin treatment given that they
general population, statins prevent CV events
are unlikely to die of coronary disease regardless
that often occur in association with ruptured
of their medical regimen. Unfortunately, the lat-
atherosclerotic plaque, such as acute MI. Given
that many CV deaths in hemodialysis patients ter group constitutes most patients in contempo-
are from different causes, such as sudden death rary nephrology practice.
(perhaps from electrolyte abnormalities)14,15 or SHARP (Study for Heart and Renal Protec-
cardiomyopathy (potentially from chronic extra- tion) is expected to report in 2010 on the clinical
cellular volume overload),16 the effective statisti- benefits of combination treatment with simvasta-
cal power of AURORA may have been lower tin/ezetimibe versus placebo in a large popula-
than the number of CV events suggests. Findings tion of patients with advanced kidney disease,
of the CORONA (Controlled Rosuvastatin Mul- and its findings are keenly anticipated. Given the
tinational Trial in Heart Failure; which randomly frequency of hypercholesterolemia in peritoneal
assigned elderly patients with systolic dysfunc- dialysis patients, the effect of statin monotherapy
tion, but without kidney failure, to treatment on CV events in this population also appears
with rosuvastatin, 10 mg, vs placebo) were worthy of investigation. In the interim, because
broadly similar to those of AURORA: no signifi- statin treatment appears beneficial in patients
cant effect on risk of death from CV cause, with milder kidney disease, clinicians should
nonfatal MI, or stroke (hazard ratio, 0.92; 95% focus on identifying and treating such patients
CI, 0.83-1.03; P 0.12) despite an LDL-C level with statins and other therapies that reduce CV
decrease of 45%.17 Statin treatment reduced the risk before kidney failure occurs.
risk of coronary events in CORONA partici-
pants; however, as in AURORA, these events Sabin Shurraw, MD
accounted for the minority of primary outcome Marcello Tonelli, MD, SM
and all-cause deaths (10% of CORONA partici- University of Alberta
pants had a coronary event and 2% of deaths Edmonton, Canada
were due to MI).
These 3 plausible considerations may account
ACKNOWLEDGEMENTS
for the discrepant findings of AURORA and 4D
compared with the undisputable benefits of st- Support: Dr Tonelli is supported by a Population Health
atins in the general population. However, be- Investigator Award from Alberta Heritage Foundation for
Medical Research and a New Investigator Award from the
cause these 2 trials failed to show a benefit of Canadian Institutes of Health Research.
statin treatment in hemodialysis patients, the Financial Disclosure: Dr Tonelli is the recipient of a
fourth explanation, that statins are truly ineffec- research grant from Pfizer, which markets statins. Dr Shur-
tive when used in patients who are already dialy- raw has no relevant financial interests to report.
240 Shurraw and Tonelli

REFERENCES 8. Seliger SL, Weiss NS, Gillen DL, et al. HMG-Co A

reductase inhibitors are associated with reduced mortality in
1. US Renal Data System. USRDS 2008 Annual Data
ESRD patients. Kidney Int. 2002;61(1):297-304.
Report. The National Institutes of Health, National Institute 9. Mason NA, Bailie GR, Satayathum S, et al. HMG-
of Diabetes and Digestive and Kidney Diseases, Bethesda, coenzyme A reductase inhibitor use is associated with mor-
MD, 2008. tality reduction in hemodialysis patients. Am J Kidney Dis.
2. Tonelli M, Isles C, Curhan GC, et al. Effect of pravasta- 2005;45(1):119-126.
tin on cardiovascular events in people with chronic kidney 10. Wanner C, Krane V, Mrz W, et al. Atorvastatin in
disease. Circulation. 2004;110(12):1557-1563. patients with type 2 diabetes mellitus undergoing hemodialy-
3. Ridker PM, Danielson E, Fonseca FA, et al; JUPITER sis. N Engl J Med. 2005;353(3):238-248.
Trial Study Group. Reduction in C-reactive protein and LDL 11. Krane V, Winkler K, Drechsler C, Lilienthal J, Marz
cholesterol and cardiovascular event rates after initiation of W, Wanner C. Effect of atorvastatin on inflammation and
rosuvastatin: a prospective study of the JUPITER trial. outcome in patients with type 2 diabetes mellitus on hemodi-
Lancet. 2009;373(9670):1175-1182. alysis. Kidney Int. 2008;74(11):1461-1467.
4. Ridker PM, Danielson E, Fonseca FA, et al; JUPITER 12. Kearney PM, Blackwell L, Collins R, et al; Choles-
Study Group. Rosuvastatin to prevent vascular events in terol Treatment Trialists (CTT) Collaborators. Efficacy of
men and women with elevated C-reactive protein. N Engl cholesterol-lowering therapy in 18,686 people with diabetes
J Med. 2008;359(21):2195-2207. in 14 randomised trials of statins: a meta-analysis. Lancet.
5. Koenig W, Lowel H, Baumert J, Meisinger C. C- 2008;371(9607):117-125.
Reactive protein modulates risk prediction based on the 13. Wanner C. Statin effects in CKD: is there a point of
no return? Am J Kidney Dis. 2009;53(5):723-725.
Framingham score: implications for future risk assessment:
14. Herzog CA. How to manage the renal patient with
results from a large cohort study in southern Germany.
coronary heart disease: the agony and the ecstasy of opinion-
Circulation. 2004;109(11):1349-1353.
based medicine. J Am Soc Nephrol. 2003;14(10):2556-2572.
6. Ridker PM, Cannon CP, Morrow D, et al; Pravastatin 15. Karnik JA, Young BS, Lew NL, et al. Cardiac arrest
or Atorvastatin Evaluation and Infection Therapy-Thrombol- and sudden death in dialysis units. Kidney Int. 2001;60(1):
ysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) 350-357.
Investigators. C-Reactive protein levels and outcomes after 16. London GM, Marchais SJ, Metivier F, Guerin AP.
statin therapy. N Engl J Med. 2005;352(1):20-28. Cardiovascular risk in end-stage renal disease: vascular
7. Fellstrom BC, Jardine AG, Schmieder RE, et al; aspects. Nephrol Dial Transplant. 2000;15(suppl 5):97-104.
AURORA Study Group. Rosuvastatin and cardiovascular 17. Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin
events in patients undergoing hemodialysis. N Engl J Med. in older patients with systolic heart failure. N Engl J Med.
2009;360(14):1395-1407. 2007;357(22):2248-2261.