Medicines Q&As
UKMi Q&A 125.6
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: 16th April 2014
Background
The pathophysiology of dyslipidaemia in patients with CKD is complex. Triglycerides (TG) are often
raised and low density lipoprotein cholesterol (LDL-C) and total cholesterol may be normal or low.
LDL-C may therefore not be the most accurate marker of cardiovascular (CV) risk in patients with
CKD. Consequently, the results of studies of LDL-C reduction in 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 found no association and even an
increased risk of mortality with low serum cholesterol levels (1,2). In patients with late-stage CKD,
cardiovascular mortality is related to other risk factors e.g. arrhythmias. Sudden cardiac death is more
common than fatal MI in these patients (2). However, statins may also have beneficial effects beyond
lipid lowering in patients with CKD, e.g. a reduction in oxidative stress and inflammation (3) which are
linked to atherogenic risk (2,3). 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 (1,3,7,8,9,10,11). Studies included in the meta-analyses were a
mixture of prospective trials including patients with CKD stages 3 to 5 and post-hoc analyses of major
RCT mainly involving patients with an estimated glomerular filtration rate (eGFR) >30mL/min/1.73m 2
(9,10). 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 (9,10,11).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)(11). 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 (13).
An observational study of data on MI survivors (from the SWEDEHEART registry) who were
prescribed statins on discharge, but not taking statins previously, found that statins improved 1-year
survival of patients with stage 2-4 CKD (hazard ratio 0.63, 95% CI 0.58-0.68) but not in patients with
stage 5 CKD (14). In a large retrospective study of 12,853 Korean patients with MI, statin therapy
reduced cardiac death at 1 year of follow-up regardless of degree of renal impairment (RI). 3256
patients had RI (eGFR<60mL/min) and 2218 of these patients with RI received a statin. MACE-free
survival at 12 months in the severe RI group (eGFR<30mL/min) was also greater in the statin-treated
group. MACE was a composite secondary end-point of cardiac death, MI and target lesion
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
revascularisation. The primary end-point was defined as death and complications during
hospitalisation. Statins reduced the incidence of in-hospital death from 39% to 26% in the RI group
(15). A study in 501 patients with acute coronary syndrome treated with PCI and followed up for 5
years, found that statin treatment reduced the incidence of cardiac events in patients with CKD(eGFR
<60mL/min) from 26% to 16%. There was no significant reduction in cardiac events in patients without
CKD treated with statins. Three hundred and twenty four of 501 patients had CKD and 173 (34.5%)
received statins(16). A population-based cohort study in 2369 patients with CKD (serum creatinine ≥
220 micromol/L) found that statin use resulted in a reduction in CV events, CV mortality and all-cause
mortality in both primary prevention (PP) and secondary prevention cohorts. In the PP cohort, statin
treatment reduced the risk of CV events by 35% compared with the statin-unexposed group [adjusted
hazard ratio, 0.65 (95% CI 0.48-0.88)](17).
However, renal impairment (RI) is considered a risk factor for the development of statin-induced
myopathy and appropriate dosage adjustments need to be made to minimise the risk. Manufacturers
advise measurement of creatine kinase (CK) levels in patients with RI or other predisposing factors
for the development of statin-related muscle disorders, before starting therapy(18,19,20).
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. NICE also advises that the use of
statins for the primary prevention of CVD in people with CKD should be informed by the Study of
Heart and Renal Protection (SHARP) (6,21) –see below-simvastatin. The KDIGO organisation have
updated their guidelines to include a recommendation that statins should be offered to adults aged
18-49 with CKD not treated with chronic dialysis or kidney transplantation, and an estimated 10 year
risk of coronary death or non-fatal MI>10%. (Adults aged ≥50 with all stages of CKD (but not on
dialysis or post-transplant) should be offered statin +/- ezetimibe, irrespective of CV status (22,23).
The guidelines include a table of recommended doses of statins in adults with CKD. Dosage
adjustment is only recommended for patients with stage 3-5 CKD including those on dialysis or with a
kidney transplant. For stages 1-2 normal doses are recommended (23).
Statins should be offered for the secondary prevention of CV disease irrespective of baseline lipid
values (5,6,22,23). There is insufficient evidence to support the routine use of statins to prevent or
ameliorate progression of CKD (3,4, 5,6,9,10,11).On the basis of current evidence there may be a
minor beneficial effect in patients with early stage CKD, but statin therapy cannot be recommended
solely for renal protection(2).
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 (19). 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 (24). 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 (25). Other sources suggest
either no dose adjustment in any degree of RI (26) or in severe RI (GFR <15mL/min/1.73m2) titrate to
cholesterol level and monitor CK (27). MHRA guidance cautions against high dose simvastatin
(28).The KDIGO guidelines recommend 40mg simvastatin or 20mg simvastatin/10mg ezetimibe
daily for CKD stage 3-5(23).
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
Trials, mostly in small numbers of patients with CKD, used doses of simvastatin ranging from 10 to
40mg daily (1). 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 (1).
Of the major trials, the HPS study included patients with stage 3 CKD who received 40mg simvastatin
daily, without an excess risk for rhabdomyolysis(29). 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 (30). 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 (12).
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 (20). KDIGO guidelines recommend
20mg daily for CKD stages 3-5. This is based on the 4D study in haemodialysis patients (23).
Published studies in patients with CKD but not on dialysis (baseline CrCl <30 to 56 mL/min), have
used doses ranging from 10 to 40mg (1). Details of these and other studies are given in the table
below.
Table 1. Studies of atorvastatin in patients with CKD
Study
Dose &
duration
Subjects
Stage of
CKD
Outcomes
Stegmayr31
10mg vs
placebo for 3
years
143 (33 nondialysis)
patients with
severe CKD
56 patients
with CKD
4 -5
GFR<30mL/
min/1.73m2
No benefit on 5- 20% of A treated
year outcomes
patients withdrawn
of CV endpoints due to AE. No
or survival
severe AE noted
Beneficial effect None noted
on TC, LDL-C,
CrCl and
proteinuria
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
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.
,32
Bianchi33
TNT34,35
ALLIANCE
36
Saltissi38
Up to 40mg vs.
no statin for
one year (64%
on 10mg)
80mg vs.10mg
for 5 years
LDL-C goal of
<80mg/dL
[2mmol/L]37 or
a max. dose of
80mg (mean
=40.5mg) vs.
usual care
10-40mg daily
(68.4% of non-
9556
patients with
CHD
Average CrCl
50.8 mL/min
(A) 50mL/min
(B)=controls
3 (n=3078)
and 4
(n=29)eGFR
15 to 60
mL/min/1.73
m2
2442
patients with
CHD with or
without CKD
eGFR
<60mL/min/
1.73m2
(n=579)
49 patients
with severe
GFR (CrCl)
6.6 to 38.8
Adverse effects
Mean decrease in
LDL-C and TG from
Available through NICE Evidence Search at www.evidence.nhs.uk
No serious AE
related to A
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Medicines Q&As
dialysis
patients on
10mg) for 16
weeks
CRF
including HD
and CAPD
mL/min
(mean =
20.8mL/min)
(n=19)
baseline, 51% and
27% respectively,
in non-dialysis
group
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)(39). 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 (40,41). 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 (42). Post hoc
subgroup analyses of the GREACE and ALLIANCE studies and data from the PLANET I and II trials
showed that atorvastatin has a small renoprotective effect. In the PLANET trials atorvastatin 80mg
was superior to rosuvastatin 10mg or 40mg in preventing loss of renal function. GFR declined more
slowly in the atorvastatin groups and proteinuria was reduced significantly by atorvastatin compared
to rosuvastatin (43,44).
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 (45) The RDH and Aronoff et al. recommend dosing
as in normal renal function for all degrees of RI (25,26), whereas KDIGO guidelines recommend
40mg daily for CKD stages 3-5(23).
Clinical trials have used doses ranging from 10 to 40mg (1). In the Pravastatin Pooling Project (PPP)
40mg was used in patients with stage 3 CKD down to a GFR of 30mL/min/1.73m 2 without any adverse
effects and the reduction in primary CV endpoints was equivalent to the reductions achieved in
patients with normal renal function (46,47) . 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 (48). 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)(49).
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 Ndesmethyl 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 (50). The RDH advises 5 to 20mg in all degrees of RI whereas KDIGO guidelines
recommend 10mg daily for CKD stages 3-5(23).
.
In the first of two small-scale studies, 38 patients with CKD (stage 2 to 4, eGFR ≥15mLmin to
Available through NICE Evidence Search at www.evidence.nhs.uk
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Medicines Q&As
<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 (51). 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 (52).
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 (53). 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
(54).
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 (55). Other sources agree
that no dosage adjustment is needed in any degree of RI (25,26). KDIGO guidelines recommend
80mg daily for CKD stages 3-5 based on the ALERT study in renal transplant patients(23).
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 (56). In two further small
RCT, 45 patients (57) with MDRD-eGFR 12-44 mL/min/1.73m2 and 42 patients with CrCl of 30-90
mL/min (58) were randomised to fluvastatin 40mg/day or placebo (57,58) for 8 weeks (57). Fluvastatin
was effective in reducing LDL-C and well-tolerated in both studies (57,58). Other small-scale studies
have used fluvastatin 20-80mg daily in patients with a mean baseline GFR of 47 to 59 ml/min/1.73m 2
Fluvastatin was well-tolerated and had a beneficial effect on clinical outcomes; no significant adverse
effects were noted (1). 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 (59).
Summary



Dyslipidaemia is a common complication of CKD and contributes to high CV morbidity and
mortality of CKD patients. The pathology of dyslipidaemia in CKD patients is complex and differs
from that found in patients with normal renal function.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.
Statins may also have beneficial effects beyond lipid lowering in patients with CKD, e.g. a
reduction in oxidative stress and inflammation.
On the basis of current evidence there may be a minor beneficial renoprotective effect in patients
with early stage CKD, but statin therapy cannot be recommended solely to prevent or ameliorate
CKD progression.
Available through NICE Evidence Search at www.evidence.nhs.uk
5
Medicines Q&As





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. 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. Statins not licensed in the UK at the time of
writing are not included in this review.
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Quality Assurance
Prepared by
Julia Kuczynska, South West Medicines Information, Bristol
Date this version prepared
16th April 2014
Checked by
Trevor Beswick, South West Medicines Information, Bristol
Date of check
30th April 2014
Search strategy
 Embase “[exp chronic-kidney-failure.MJ. AND exp simvastatin.MJ.] repeated for
“fluindostatin” , “rosuvastatin”, “pravastatin”, “atorvastatin”]” [“exp hydroxymethylglutarylCoenzyme-A-reductase-Inhibitor AND exp chronic-kidney-failure.MJ.”] repeated for exp acute
kidney failure. Limit to 2010-Current and Human (date of search 29.10.13 and 16.04.14)
 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 2010-Current and Humans(date
of search 25/10/13 and 16/04/14)
 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],
 NHS Evidence: [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)
Available through NICE Evidence Search at www.evidence.nhs.uk
10