Statins in Renal Failure
Andrea Fox
Sunnybrook Health Science Center
May 2010
No jokes
No funny stories
No time
Objectives
Discuss why the use of Statins in Stage 5
chronic kidney disease is controversial
Outline the two studies that produced
unexpected outcomes
Provide a few practical tips from our
practice at Sunnybrook HSC
What is the issue?
High mortality in patients on maintenance
dialysis
80% have known cardiovascular disease
at initiation of renal replacement therapy
Have elevated CRP levels
Benefits of statins in the general
population are well known in
cardiovascular and cerebrovascular
disease- Are dialysis patients different?
Expect the Unexpected
Stage 3 kidney patients may receive
benefit.

Some evidence exists from large statin trials
that included stage 3 patients that the benefit
is similar or greater than the general
population (post hoc subgroup analysis)
Studies have not backed up assumptions
that statins will reduce events and death in
patients on dialysis (Stage 5)
Observational studies
Several observational studies have
suggested that statins are associated with
decreased mortality
DOPPS (Dialysis Outcome and Practice
Patterns Study) has shown this in 7365
prevalent hemodialysis patients

Patients who used statins had
31% lower relative risk of death (p=0.0001)
23% lower cardiac mortality risk (p=0.03)
4D study
The first powered RCT to address the
issue: Do statins prevent CV events in
dialysis patients?
1255 German patients with type 2 DM on
hemodialysis
Compared atorvastatin 20mg daily with
placebo
Composite outcome of death from cardiac
causes, nonfatal MI and stroke
AURORA
RCT, double blind, 2776 patients aged 5080 yrs on hemodialysis
Compared rosuvastatin 10mg daily with
placebo
Primary end point: time to major CV
events (death from CV causes, nonfatal MI
or nonfatal stroke)
Secondary endpoints included change in
lipids and CRP levels.
Study comments
Both trials significantly reduced LDL-C levels
(43% and 42%)
Both trials showed decrease in CRP in statin
group vs. a rise in placebo group
Statin use did NOT
statistically prevent the
composite primary
outcome in either study
AURORA-LDL lowering
Primary Endpoint
4D
AURORA
Why no benefit?
Lots of drop out/drop in in both studies
AURORA excluded patients who may
have benefitted most from statin therapy
Statistical power
A Different Patient
Or… are statins truly not effective in
dialysis patients?
Dialysis patients are different



Lipid profile (normal LDL)
Extensive calcification common
CV deaths are different
Sudden death, arrhythmias, cardiomyopathy
Atherosclerotic plaque rupture is less common
Are we too late?
Safety
Rhabdomyolysis

no increase seen in muscle related adverse
events or rhabdomyolysis vs. placebo
Cancer

No increase in new cancer diagnoses
Liver Function

No increases in liver function tests or new
liver disease
Safety: stroke risk
4D:

an increase in fatal stroke risk was seen in the
atorvastatin group vs placebo (27 events vs. 13, p=
0.04)
AURORA:

“marginal” increase in hemorrhagic stroke in patients
with DM who received rosuvastatin (12 events vs. 2,
P=0.07)
SHARP
Study of Heart and Renal Protection
9000 patients (pre-dialysis, hemodialysis,
peritoneal dialysis)
Patients may have received prior statin
therapy
Evaluating effect of combined
simvastatin/ezetimibe therapy
Expected to report in 2010-11
Practically speaking…
Statins are used in dialysis patients, usually
initiated by other services (post MI, post stroke)
We often reduce higher doses (i.e.. Atorvastatin
80mg daily reduced to 40 mg)
Rosuvastatin (Crestor®) dosing:


Health Canada recommends starting dose of 5 mg in
patients with renal failure
Monograph says 40 mg dose contraindicated in
patients with Cr Cl < 30ml/minute (March 2010)
Conclusion?
Lowering LDL-C with statins in
hemodialysis patients does not necessarily
reduce CV or stroke risk
CV disease in patients on chronic dialysis
differs from the general population
No clear answer on how to use statins in
this population
References
Fellstrom, Jardine et al; Rosuvastatin and cardiovascular events in
patients undergoing hemodialysis, NEJM 2009;360(14): 1395-1407
(AURORA)
Tonelli, Shurraw; In the Literature, Commentary on AURORA study;
Am J Kidney Disease, 2010;55(2):237-240
Wanner, Drane et al. Atorvastatin in patients with type 2 diabetes
undergoing hemodialysis. NEJM. 2005;353(3);238-248 (4D)
Mason, Bailie et al. HMG_coenzyme A reductase inhibitor use is
associated with mortality reduction in hemodialysis patients. Am J
Kidney Disease 2005;45(1):119-126 (DOPPS)