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

atorvastatin did not significantly of placebo-assigned patients ended up using a reduce this primary composite outcome (relative nonstudy statin. nonfatal MI. with placebo for the composite out. similar to 4D.11 Rosuvastatin treatment in transplant. Post hoc analysis of within the previous 6 months).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. event rates during the course of the study. or other reasons). kidney baseline CRP level. statin was not reported.12 Similarly. In a cohort of 3. P ⫽ 0. 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. but did not reduce the risk enrollment).99. there were significant drop-outs and/or 20 mg/d. findings substantially differ from those of statin creased mortality. respectively. question deserves consideration before deciding blinded study enrolled 1.68-0. (AURORA). who had dropped out were not included.1 mmol/L) and 42% (median decrease. there was no creatine kinase and alanine aminotransferase significant interaction between baseline CRP level levels). 50% of patients risk. mortality of 37%. 17% of statin-assigned and stroke. however. By the end of both 0. vastatin in AURORA and with atorvastatin in 4D Second. 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). These gested that statin therapy is associated with de.716 patients trials in people without kidney failure: a meta- starting hemodialysis or peritoneal dialysis analysis of 14 such trials found that each therapy.8 Similar findings were ob. The dropped out of each treatment group.255 patients in Ger.13 nance hemodialysis and compared atorvastatin. true difference between groups because patients Treatment of hemodialysis patients with rosu. how the findings of these trials should affect many with type 2 diabetes receiving mainte. 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. LDL-C level differences between groups treatment did not decrease the risk of the other 2 were only ⬃0. 0.78 mmol/L (4D) and ⬃0. statin therapy was associated with de. In 4D.365 preva.92. less than one-third of study partici- . MI.33 for all-cause death). come of death from cardiac causes. In AURORA. The risk of adverse AURORA decreased CRP levels by 11. and the secondary end point of all cardiac events was proportion of patients who received a nonstudy significantly decreased by 18% (relative risk.10. after 2 years. patients who had received a statin 1.3 mmol/L). 0.5% (vs an events was similar between treatment groups increase in CRP levels over time in placebo (including muscle symptoms and increase in recipients). and this analysis overestimates the cular events and P ⫽ 0.37). AURORA excluded patients who cli- decreased LDL-C levels by 43% (mean de. data from patients without kidney failure suggest served in an observational study of 7. 1.6 However. Statin use did not prevent the composite primary out- HOW DOES THIS STUDY COMPARE WITH come of combined CV death.77-1.10 This double. but statin studies. P ⫽ 0. statins (ie. observational studies are prone to bias caused by confounding by indication and other WHAT SHOULD CLINICIANS AND unmeasured characteristics. 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. nicians believe would benefit the most from crease. 95% CI. Despite a significant decrease in patients discontinued their drug therapy and 15% LDL-C levels.82.03). drop-ins between treatment arms in both studies. First. 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. Although 4D did 4D showed that atorvastatin prevented an in. clinical practice.9 LDL-C level decrease.5 mmol/L secondary outcomes (P ⫽ 0.3. 0.49 for all cerebrovas. and the clinical benefit of statin treatment. 95% CI.

clinicians should nonfatal MI. dialysis patients. such as sudden death rary nephrology practice. statin treatment should be discontinued when tive risk of their primary outcomes. research grant from Pfizer. these trials patients become dialysis dependent. however.92. which markets statins. to treatment on CV events in this population also appears with rosuvastatin. hemodialysis patients CV end points in 4D and AURORA. 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. (perhaps from electrolyte abnormalities)14. respectively. University of Alberta pants had a coronary event and 2% of deaths Edmonton.In the Literature 239 pants had coronary artery disease and patients sis dependent. these events Sabin Shurraw. which randomly frequency of hypercholesterolemia in peritoneal assigned elderly patients with systolic dysfunc. but without kidney failure. that these criteria selected a population of pa. Findings tion of patients with advanced kidney disease. 0. that statins are truly ineffec. must be assumed to be correct with increased LDL-C levels (⬎4. 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. statin treatment in hemodialysis patients. vs placebo) were worthy of investigation. 95% focus on identifying and treating such patients CI. Given the tinational Trial in Heart Failure. because broadly similar to those of AURORA: no signifi. Given that many CV deaths in hemodialysis patients ter group constitutes most patients in contempo- are from different causes. 0. the lat- atherosclerotic plaque. ing hemodialysis. the effect of statin monotherapy tion.83-1. 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. be. and its findings are keenly anticipated. 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. rather diac comorbidities. as in AURORA. P ⫽ 0. . However. tion) is expected to report in 2010 on the clinical cellular volume overload). risk of coronary events in CORONA partici- pants. the Financial Disclosure: Dr Tonelli is the recipient of a fourth explanation. This deci- may have been too small to detect a less dramatic sion currently must be made after considering benefit that remains clinically important.16 the effective statisti. SM and all-cause deaths (10% of CORONA partici. These 3 plausible considerations may account ACKNOWLEDGEMENTS for the discrepant findings of AURORA and 4D compared with the undisputable benefits of st.9 mmol/L) until proved otherwise by future randomized were excluded. Dr Shur- tive when used in patients who are already dialy. Support: Dr Tonelli is supported by a Population Health atins in the 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. In the interim. This the patient’s 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. 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. MD accounted for the minority of primary outcome Marcello Tonelli. 10 mg. raw has no relevant financial interests to report. In the little benefit from statin treatment given that they general population. or stroke (hazard ratio. of the CORONA (Controlled Rosuvastatin Mul. one could speculate trials.12) despite an LDL-C level with statins and other therapies that reduce CV decrease of 45%. with milder kidney disease. those with multiple noncar- nonsignificantly favored statin treatment.15 or SHARP (Study for Heart and Renal Protec- cardiomyopathy (potentially from chronic extra. such as acute MI. Unfortunately. statin treatment appears beneficial in patients cant effect on risk of death from CV cause.17 Statin treatment reduced the risk before kidney failure occurs. Canada were due to MI).03. For example. with heart failure. MD. In retrospect.

Karnik JA. Pravastatin 15. et al. HMG-Co A reductase inhibitors are associated with reduced mortality in 1. Mason NA.373(9670):1175-1182. Weiss NS. Ridker PM. C. Rosuvastatin events in patients undergoing hemodialysis. März W.357(22):2248-2261. The National Institutes of Health. N Engl J Med. Ridker PM. Lew NL. J Am Soc Nephrol. N Engl J Med. 2004. HMG- of Diabetes and Digestive and Kidney Diseases.686 people with diabetes J Med. Meisinger C. 4. Cardiac arrest or Atorvastatin Evaluation and Infection Therapy-Thrombol. Baumert J. Guerin AP. Kjekshus J. Kearney PM. 2005. 2009. Report. Barrios V. patients with type 2 diabetes mellitus undergoing hemodialy- 3. et al. Atorvastatin in disease.74(11):1461-1467. Tonelli M. Drechsler C. London GM. How to manage the renal patient with results from a large cohort study in southern Germany. Effect of pravasta. Curhan GC. Circulation. 2007. Statin effects in CKD: is there a “point of no return”? Am J Kidney Dis. coronary heart disease: the agony and the ecstasy of opinion- Circulation.353(3):238-248. Koenig W. Reduction in C-reactive protein and LDL 11. Kidney Int. Effect of atorvastatin on inflammation and rosuvastatin: a prospective study of the JUPITER trial. 2000. alysis. 2008. et al. 2008. et al. Wanner C. coenzyme A reductase inhibitor use is associated with mor- MD.360(14):1395-1407. statin therapy. et al. US Renal Data System. Wanner C.61(1):297-304. Bethesda. Trial Study Group. National Institute 9. Lilienthal J.240 Shurraw and Tonelli REFERENCES 8. N Engl J Med. et al. . and sudden death in dialysis units. USRDS 2008 Annual Data ESRD patients.60(1): ysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) 350-357. Am J Kidney Dis. Apetrei E. Gillen DL. Collins R. et al. Schmieder RE. 2001. Winkler K.15(suppl 5):97-104. JUPITER sis. Young BS. Marz cholesterol and cardiovascular event rates after initiation of W. Investigators. Rosuvastatin and cardiovascular 17. Nephrol Dial Transplant. Reactive protein modulates risk prediction based on the 13. Wanner C. 6. in older patients with systolic heart failure. Efficacy of men and women with elevated C-reactive protein. Fonseca FA. AURORA Study Group. JUPITER 12. Blackwell L. Kidney Int. Danielson E. Lowel H. et al. et al. Satayathum S. Fellstrom BC. N Engl J Med.359(21):2195-2207. et al. Isles C. 2003. Jardine AG. tin on cardiovascular events in people with chronic kidney 10.371(9607):117-125. Krane V. outcome in patients with type 2 diabetes mellitus on hemodi- Lancet. tality reduction in hemodialysis patients. Herzog CA. 2. in 14 randomised trials of statins: a meta-analysis. 2008. 2005. aspects. Lancet. Cardiovascular risk in end-stage renal disease: vascular 7. 2005. Danielson E. 2002. Rosuvastatin to prevent vascular events in terol Treatment Trialists’ (CTT) Collaborators.45(1):119-126.352(1):20-28. Framingham score: implications for future risk assessment: 14. based medicine. Bailie GR. Krane V. C-Reactive protein levels and outcomes after 16. Metivier F. 5.110(12):1557-1563. Seliger SL. Choles- Study Group. 2009. Morrow D. Cannon CP.109(11):1349-1353. N Engl cholesterol-lowering therapy in 18. Kidney Int.14(10):2556-2572. 2009. 2008. 2004. Ridker PM. Marchais SJ.53(5):723-725. Fonseca FA. et al.