Sw qa125 5_statinsin_ri (1)

Medicines Q&As
UKMi Q&A 125.5
What is the available evidence for the use of statins in patients with
renal impairment?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.asp
Date prepared: 15th
April 2013
Background
Dyslipidaemia is a common complication of chronic kidney disease (CKD) and it contributes to the
high cardiovascular (CV) morbidity and mortality of CKD patients (1
). However the pattern of CV
disease in patients with CKD differs from that in the general population and sudden cardiac deaths
(due to presumed arrhythmia or heart failure) predominate (2
). Consequently, the results of studies of
low density lipoprotein–cholesterol (LDL-C) reduction patients with CKD have been conflicting. Some
observational studies in dialysis patients have shown a clear, linear relation between LDL-C and CV
end points, whereas others have not (3
).Two large trials (AURORA and 4D) – see below - of statins in
patients on haemodialysis showed no benefit of statins on a composite CV endpoint(4
). Published
randomised controlled trials (RCT) of statins and other lipid-lowering agents have largely excluded
patients with most types of CKD (5
,6
). Several systematic reviews and meta analyses have evaluated
the benefits and harms of statins in CKD patients (Error: Reference source not found,Error: Reference
source not found,7
,8
,9
,10
,11
). Studies included in the meta-analyses were a mixture of prospective trials
including patients with CKD staged 3 to 5 and post-hoc analyses of major RCT mainly involving
patients with an estimated glomerular filtration rate (eGFR) >30mL/min/1.73m2
(Error: Reference
source not found,Error: Reference source not found). Statins decreased mortality and CV events in
persons with early stages of CKD. Statins conferred little or no risk for adverse events, although
adverse events were evaluated systematically in fewer than half the trials (Error: Reference source
not found,Error: Reference source not found,Error: Reference source not found).The latest meta-
analysis of 31 trials (48,429 patients with CKD) stratified patients by kidney function and found that
the relative risk (RR) reduction for major CV events was progressively smaller, the higher the severity
of CKD. In patients with CKD stage 4 (eGFR15-30mL/min/1.73m2
)the absolute risk reduction [ARR]
(95% confidence interval) [CI] was 0.028 (0.003 to 0.053) giving a NNT (95% CI) of 36 (19-330). For
patients with CKD stage 5, including patients on dialysis, the ARR was 0.022 (0.004 to 0.040), NNT
46 (25 to 257)(Error: Reference source not found). In patients with CKD stage 5 (eGFR <15mL/min
not on dialysis) the ARR was 0.024 with a NNT of 42. A major primary prevention study in patients
with CKD (SHARP) found a reduction in the incidence of major atherosclerotic events with no
increase in adverse outcomes – see below – simvastatin (12
). A multicentre, retrospective
observational analysis of administrative databases was performed to quantify an association between
acute kidney injury (AKI) and use of high potency versus low potency statins. Over 2 million new
(within the previous year) statin users without chronic CKD and 59,636 with CKD were identified.
Patients with chronic CKD were at higher risk of admission to hospital with AKI in the first 6 months
after statin initiation [10 to 63 per 1000], compared with those without CKD [1 to 3.5 per 1000] (13
).
However, the rate of hospitalisation for AKI did not increase significantly in patients with CKD taking
high potency statins compared with those taking low potency statins(fixed effect ratio 1.1(95% CI 0.99
to1.23) . High potency statin treatment was defined as a daily dose of at least 10mg rosuvastatin,
20mg atorvastatin or 40mg simvastatin (Error: Reference source not found).
Renal impairment (RI) is also considered a risk factor for the development of statin-induced myopathy
and appropriate dosage adjustments need to be made to minimise the risk (14
,15
).
International guidelines reflect these uncertainties (Error: Reference source not found). Nevertheless,
NICE guidance on CKD advises the use of statins for the primary prevention of CV disease in the
same way as in people without CKD despite the existence of confounding factors (e.g. inflammation
and malnutrition) for CV risk calculation in patients with CKD (16
).Statins should be offered for the
secondary prevention of CV disease irrespective of baseline lipid values (Error: Reference source not
found,Error: Reference source not found). There is insufficient evidence to support the routine use of
statins to prevent or ameliorate progression of CKD (Error: Reference source not found,Error:
Available through NICE Evidence Search at www.evidence.nhs.uk 1

Medicines Q&As
Reference source not found, Error: Reference source not found,Error: Reference source not
found,Error: Reference source not found,Error: Reference source not found).
Estimates of renal function and definitions of renal failure are not consistent between trials.
Throughout this Q&A the terms used are those used in the trials or publications reviewed.
♦ What is the evidence base for each statin in patients with renal impairment?
Answer
The evidence and dosage recommendations for each statin will be reviewed in turn.
Simvastatin
The manufacturer advises that no modification of dosage should be necessary in patients with
moderate renal impairment (RI) (not defined). In patients with severe RI (creatinine clearance [CrCl] <
30 mL/min), dosages above 10 mg/day should be carefully considered and, if deemed necessary,
implemented cautiously (Error: Reference source not found). In the USA the manufacturer
recommends that in severe renal impairment (not defined) patients should be started at 5 mg/day and
be closely monitored. A 5mg tablet is available in the USA (17
). The Renal Drug Handbook (RDH),
which reflects UK practice in specialist renal units, recommends dosing as for normal renal function in
patients with a GFR >10mL/min. For a GFR <10mL/min, it recommends 10-20mg daily, stating that
doses above 10mg should be used with caution but that doses up to 40mg have been used (18
). Other
sources suggest either no dose adjustment in any degree of RI (19
) or in severe RI (GFR
<15mL/min/1.73m2
) titrate to cholesterol level and monitor creatine kinase (20
). MHRA guidance
cautions against high dose simvastatin (21
). Previously one reviewer advised the following daily
dosage schedule: CKD stage 1 to 2:- 20 to 80mg; CKD stage 3:- 10 to 40mg; CKD stage 4 to 5:- 10
to 20mg (Error: Reference source not found).
Trials, mostly in small numbers of patients with CKD, used doses of simvastatin ranging from 10 to
40mg daily (Error: Reference source not found). The lowest reported mean baseline GFR was 41
mL/min/1.73m2
in a study where patients received 10mg daily. Adverse effects were reported in 5 of
10 studies (Error: Reference source not found).
Of the major trials, the HPS study included patients with stage 3 CKD who received 40mg simvastatin
daily, without an excess risk for rhabdomyolysis(22
). A post hoc analysis of the 4S trial concluded that
simvastatin 20mg decreased all cause mortality without an increase in adverse effects in patients with
mild chronic RI. Of 4,444 participants 52.1% had mild chronic RI defined as an eGFR <
75mL/min/1.73 m2
(23
). The SHARP study included 9270 patients with CKD with a serum creatinine
≥150micromol/L in men or 130 micromol/L in women (6247 had CKD stage 3-5 and 3023 were on
dialysis) with no history of myocardial infarction or coronary revascularisation. Patients were
randomised to receive simvastatin 20mg plus 10mg ezetimibe (N=4650) or placebo (N=4620) and
followed up for a median of 4.9 years. Despite adherence rates of approximately two-thirds,
simvastatin/ezetimibe was associated with an average 0.85mmol/L reduction in LDL cholesterol and a
2.1% ARR reduction (NNT= 48) in major atherosclerotic events (11.3% simvastatin/ezetimibe vs. 13.4
% placebo, equivalent to a 17% proportional reduction; rate ratio 0.83, 95% CI 0.74 - 0.94). There
was no evidence of excess risks of major adverse events, and no significant excess of death from any
non-vascular cause. Among the 6247 patients with CKD not on dialysis, simvastatin/ezetimibe did not
reduce progression of CKD or overall mortality (Error: Reference source not found).
Atorvastatin
The manufacturer advises that renal disease has no influence on the plasma concentrations or lipid
effects of atorvastatin; thus, no adjustment of dose is required (24
). Other sources (Error: Reference
source not found,Error: Reference source not found) agree. Molitch states that up to 80mg daily can
be given in all stages of CKD (Error: Reference source not found).
Published studies in patients with CKD (baseline CrCl <30 to 56 mL/min) have used doses ranging
from 10 to 40mg (Error: Reference source not found). Details of these and other studies are given in
the table below.
Table 1. Studies of atorvastatin in patients with CKD

Medicines Q&As
Study Dose &
duration
Subjects Stage of
CKD
Outcomes Adverse effects
Stegmayr25
,26
10mg vs
placebo for 3
years
143 (33 non-
dialysis)
patients with
severe CKD
4 -5
GFR<30mL/
min/1.73m2
No benefit on 5-
year outcomes
of CV endpoints
or survival
20% of A treated
patients withdrawn
due to AE. No
severe AE noted
Bianchi27
Up to 40mg vs.
no statin for
one year (64%
on 10mg)
56 patients
with CKD
Average CrCl
50.8 mL/min
(A) 50mL/min
(B)=controls
Beneficial effect
on TC, LDL-C,
CrCl and
proteinuria
None noted
TNT28,29
80mg vs.10mg
for 5 years
9556
patients with
CHD
3 (n=3078)
and 4
(n=29)eGFR
15 to 60
mL/min/1.73
m2
ARR of major CV events by 4.1%
over 5 years [NNT=24] in patients with
CKD, (80mg compared with 10mg). In
patients with CHD, CKD and diabetes
the corresponding ARR was 7%,
[NNT = 14] to prevent one major CV
event over 4.8 years. No unexpected
safety concerns were identified
ALLIANC
E30
LDL-C goal of
<80mg/dL
[2mmol/L]31
or
a max. dose of
80mg (mean
=40.5mg) vs.
usual care
2442
patients with
CHD with or
without CKD
eGFR
<60mL/min/
1.73m2
(n=579)
ARR of a primary CV event =8.5% in
patients with CKD and 1.8% in
patients without CKD (NS). The liver
and muscle safety profile of focused
atorvastatin therapy was similar in
patients with and without CKD.
Saltissi32
10-40mg daily
(68.4% of non-
dialysis
patients on
10mg) for 16
weeks
49 patients
with severe
CRF
including HD
and CAPD
GFR (CrCl)
6.6 to 38.8
mL/min
(mean =
20.8mL/min)
(n=19)
Mean decrease in
LDL-C and TG from
baseline, 51% and
27% respectively,
in non-dialysis
group
No serious AE
related to A
were noted
Key: TC=total cholesterol ARR = absolute risk reduction NNT = number needed to treat TG =
triglycerides NS = non significant A=atorvastatin AE=adverse effects
In an observational study over 4.1 years of 177 patients with progressive CKD, treated to target lipid
levels with atorvastatin 10-40mg (two patients received 60 or 80mg), the only adverse effects
requiring drug discontinuation were muscle pain or a rise in CK within normal limits (relationship to
dose not stated). The mean baseline CrCl was 61mL/min (fast progressive CKD) and 75 mL/min
(slowly progressive CKD)(33
). In the LORD trial, 132 patients with CKD stage 2-4(serum creatinine
>120 micromol/L) were randomised to receive atorvastatin 10mg or placebo for 3 years. There was a
29% lower mean rate of kidney function decline as calculated by MDRD eGFR and 20% lower rate of
C-G CrCl decline in the atorvastatin group compared with placebo, but the CI intervals of the
differences were wide (34
,35
). In a post hoc analysis of the IDEAL study atorvastatin 80mg was
compared with simvastatin 20-40mg over 5 years in patients with a history of MI. In patients without
CKD atorvastatin compared with simvastatin significantly reduced the risk of major coronary events,
but in the CKD group (eGFR<60ml/min), there was a non-significant increase in relative risk. However
definite conclusions cannot be drawn from this as the power of the study was limited (36
).
Pravastatin
The manufacturer advises a starting dose of 10 mg a day in patients with moderate or severe RI (not
defined). The dosage should be adjusted according to the response of lipid parameters and under
medical supervision. No significant changes in pravastatin pharmacokinetics were observed in
patients with mild RI. However severe and moderate RI may lead to a two-fold increase of the
systemic exposure to pravastatin and metabolites (37
) The RDH and Aronoff et al. recommend dosing
as in normal renal function for all degrees of RI (Error: Reference source not found,Error: Reference

Medicines Q&As
source not found), whereas Molitch recommends giving 20 to 80mg daily in stage 1-2 CKD, 20 to
40mg daily in stage 3, and 10 to 20mg daily in stage 4 to 5 (Error: Reference source not found).
Clinical trials have used doses ranging from 10 to 40mg (Error: Reference source not found). In the
Pravastatin Pooling Project (PPP) 40mg was used in patients with stage 3 CKD down to a GFR of
30mL/min/1.73m2
without any adverse effects and the reduction in primary CV endpoints was
equivalent to the reductions achieved in patients with normal renal function (38
,39
) . In a further
placebo-controlled study in 93 patients with mild to moderate CKD, treatment with pravastatin 40mg
daily for 18 months (with added vitamin E and homocysteine-lowering therapy) resulted in reduced
urinary albumin excretion and no significant treatment related adverse events. The mean baseline
CrCl was 38 mL/min/1.73m2
(40
). A post hoc analysis of a large-scale primary prevention study
showed that pravastatin 10-20mg daily significantly reduced the risk of major CV events in patients
with moderate CKD (eGFR 30-60mL/min)(41
).
Rosuvastatin
According to the manufacturer rosuvastatin is contra-indicated in severe RI (creatinine clearance <30
mL/min) but no dose adjustment is necessary in patients with mild to moderate RI. The recommended
starting dose is 5 mg in patients with moderate RI (creatinine clearance of <60 mL/min). The 40 mg
dose is contraindicated in patients with moderate RI. In a study in subjects with varying degrees of RI
mild to moderate renal disease had no influence on plasma concentration of rosuvastatin or the N-
desmethyl metabolite. Subjects with severe impairment (CrCl <30 mL/min) had a 3-fold increase in
plasma concentration and a 9-fold increase in the N-desmethyl metabolite concentration compared to
healthy volunteers (42
). The RDH advises 5 to 20mg in all degrees of RI. Molitch advises avoiding
doses >10mg in patients with a GFR <30mL/min/1.73m2
and suggests 10 to 40mg daily in stage 1 to 2
CKD, 10 to 20mg daily in stage 3 CKD, and 5 to 10mg daily in stage 4 to 5 CKD(Error: Reference
source not found).
In the first of two small-scale studies, 38 patients with CKD (stage 2 to 4, eGFR ≥15mLmin to
<90mL/min) were randomised to rosuvastatin 2.5mg/day (NB this is half the licensed starting dose), or
no statin for 12 months. A beneficial effect on inflammatory parameters, serum lipids and a small, but
significant beneficial effect on eGFR were observed in the treated group. No adverse effects were
documented (43
). In the second study 91 patients with CKD (GFR<60ml/min/1.73m2
) were randomised
to rosuvastatin10mg/day or no statin for 20 weeks. Beneficial effects were observed on lipid
parameters and GFR (non-significant) in the statin compared with the control group. Three statin
treated patients withdrew because of myalgia not associated with elevated serum CK levels. No other
significant adverse effects were reported (44
).
The AURORA trial examined the effect of rosuvastatin 10 mg vs placebo on CV morbidity and
mortality in 2776 ESRD patients on haemodialysis. After a median of 3.8 years follow-up, there was
no statistically significant effect on the combined primary endpoint of non-fatal MI, non-fatal stroke or
death from CV causes compared with placebo. Serious adverse events were reported in 82% of
rosuvastatin and 84% of placebo treated patients, but there was no increase in the incidence of
muscle-related adverse events, rhabdomyolysis, or liver disease in the rosuvastatin group compared
with the placebo group (45
). A post hoc analysis from the JUPITER primary prevention trial found that
in patients with stage 3-4 CKD( eGFR 15-59ml/min/1.73m2
) rosuvastatin 20mg reduced the rate of
first CV events [hazard ratio and 95% CI 0.55 (0.38-0.82)] and all cause mortality [hazard ratio and
95% CI 0.56 (0.37-0.85)], compared with placebo. Patients were followed up for a median of 1.9 years
(46
).
Fluvastatin
According to the manufacturer fluvastatin is cleared by the liver, with less than 6% of the administered
dose excreted into the urine. The pharmacokinetics of fluvastatin remain unchanged in patients with
mild to severe renal insufficiency (not defined). No dose adjustments are therefore necessary in these
patients. However due to limited experience with doses>40mg/day in patients with severe renal
impairment (CrCl <30mL/min), these doses should be initiated with caution (47
). Other sources agree
that no dosage adjustment is needed in any degree of RI (Error: Reference source not found,Error:
Reference source not found). Molitch (Error: Reference source not found) advises reducing the
starting dose to 10mg in patients with CKD stage 4 to 5.

Medicines Q&As
130 patients with a CrCl between 45 and 55mL/min were randomised to fluvastatin XL 80mg once
daily (n=80) or standard treatment (n=50). Standard treatment consisted of therapy for diabetes or
hypertension excluding angiotensin-converting enzyme inhibitors and angiotensin-II receptor
antagonists. Improved renal function, as measured by CrCl, was observed at the end of the 6-month
treatment period in approximately 65% of patients treated with fluvastatin (48
). In two further small
RCT, 45 patients (49
) with MDRD-eGFR 12-44 mL/min/1.73m2
and 42 patients with CrCl of 30-90
mL/min (50
) were randomised to fluvastatin 40mg/day or placebo (Error: Reference source not
found,Error: Reference source not found) for 8 weeks (Error: Reference source not found). Fluvastatin
was effective in reducing LDL-C and well-tolerated in both studies (Error: Reference source not
found,Error: Reference source not found). Other small-scale studies have used fluvastatin 20-80mg
daily in patients with a mean baseline GFR of 47 to 59 ml/min/1.73m2
Fluvastatin was well-tolerated
and had a beneficial effect on clinical outcomes; no significant adverse effects were noted (Error:
Reference source not found). A pooled analysis of 30 clinical trials compared the effect of fluvastatin
on cardiac outcomes in patients with a CrCl <50mL/min and those with CrCl ≥ 50mL/min. Double-
blind randomised trials with at least 6 weeks treatment and daily fluvastatin doses of 20mg, 40mg and
80mg were included. Changes in lipid parameters were similar for both subgroups. The primary
outcome of cardiac death and MI was reduced by 41% in patients with a CrCl <50mL/min and by 30%
in those with a CrCl ≥ 50mL/min. The safety profiles were similar for fluvastatin and placebo-treated
patients (51
).
Summary
♦ Dyslipidaemia is a common complication of CKD and contributes to high CV morbidity and
mortality of CKD patients. The results of studies of low density lipoprotein–cholesterol (LDL-C)
reduction patients with CKD have been conflicting. Some observational studies in dialysis patients
have shown a clear, linear relation between LDL-C and CV end points, whereas others have not.
♦ Randomised controlled trials (RCT) of simvastatin, pravastatin, fluvastatin and atorvastatin have
included patients with varying degrees of RI. Meta-analyses and reviews of these RCT have
found evidence of beneficial effects on cardiovascular outcomes in patients with early stages of
CKD. There is insufficient evidence to support the routine use of statins to prevent or ameliorate
progression of CKD. Studies included in the meta-analyses were a mixture of prospective trials in
patients with CKD stages 3 to 5 and post-hoc analyses of major RCT mainly involving patients
with an eGFR >30mL/min/1.73m2
.
♦ Meta-analyses found little or no risk of adverse events, although there is some evidence from
individual studies of statins of an increased risk.
♦ NICE guidance on CKD advises the use of statins for the primary prevention of CV disease in the
same way as in people without CKD. NICE also advises that statins should be offered for the
secondary prevention of CV disease irrespective of baseline lipid values in patients with CKD.
♦ All UK licensed statins can be used in people with CKD stages 1-4. Individual statins have been
shown to be effective at lower levels of renal function, but there are no comparative studies of
statins in CKD.
♦ Advice on dosing is available in standard sources although there is some inconsistency in their
recommendations. It would be reasonable to dose conservatively at lower levels of renal function
with close monitoring of desired effect on lipid levels and of adverse effects.
Limitations
The use of statins in transplant patients and clinically important drug interactions with statins in
patients with RI, are not discussed here. A detailed discussion of the use of statins in renal
replacement therapy (RRT) is outside the scope of this review. Whilst some of the trials reported
adverse effects, this has not been reviewed in detail.
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homocysteine lowering on carotid intima-media thickness, endothelial function, and renal function in patients
with mild to moderate chronic kidney disease. Arch Int Med 2007; 167: 1262-1270
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. Nakamura H et al. Pravastatin and cardiovascular risk in moderate chronic kidney disease.
Atherosclerosis 2009;206: 512-17
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.Summary of Product Characteristics – Crestor. Astra Zeneca. Accessed via http://emc.medicines.org.uk
on 28/06/2011 [date of revision of text – 02/02/2011]
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. Verma A, Ranganna KM, Reddy RS et al. Effect of rosuvastatin on C-reactive protein and renal function in
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1266-73
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. Samuelsson O et al. Fluvastatin improves lipid abnormalities in patients with moderate to advanced
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. Lintott CJ et al. Fluvastatin for dyslipoproteinemia, with or without concomitant renal insufficiency. Am J
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Quality Assurance
Prepared by
Julia Kuczynska, South West Medicines Information, Bristol
Date this version prepared
28th
August 2011(date of partial revision 12th
October 2012 and 15th
April 2013)
Checked by
Trevor Beswick, South West Medicines Information, Bristol
Date of check
21st
September 2011(partial revision checked 25th
October 2012 and 23rd
April 2013)
Search strategy
• Embase “[exp chronic-kidney-failure.MJ. AND exp simvastatin.MJ.] repeated for “fluindostatin” ,
“rosuvastatin”, “pravastatin”, “atorvastatin”]” [“exp hydroxymethylglutaryl-Coenzyme-A-reductase-
Inhibitor AND exp chronic-kidney-failure.MJ.”] repeated for exp acute kidney failure. Limit to 2008-12
and Human
• Medline “[.exp kidney-failure,chronic.MJ. OR exp renal insufficiency.MJ.] AND exp simvastatin.MJ +
exp pravastatin.MJ. + atorvastatin.ti.ab + rosuvastatin.ti.ab + fluvastatin.ti.ab “[exp kidney-failure-
chronic.MJ.OR exp renal insufficiency] AND exp hydroxymethylglutaryl-CoA-reductase-inhibitors.MJ.

Limit to 2008-12 and Humans
• In-house database/ resources – Renal File, Previous enquiries, specialist renal textbooks
• Internet Search (Google: [“statins in renal failure” site:nhs.uk, “statins kidney” site:nhs.uk], NELM:
[pravastatin + simvastatin + atorvastatin + fluvastatin + rosuvastatin and “kidney disease” ] )
• DRUGDEX Drug Evaluations: [Simvastatin, Atorvastatin, Pravastatin, Rosuvastatin, Fluvastatin].
Accessed via www.thomsonhc.com
• Clinical Expert- Specialist Renal Pharmacist, Royal Devon & Exeter Hospital 21/09/11
• Manufacturer (Novartis – personal communication 11/09/09)

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