Sw qa125 5_statinsin_ri (1)

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Sw qa125 5_statinsin_ri (1)

  1. 1. Medicines Q&AsUKMi Q&A 125.5What is the available evidence for the use of statins in patients withrenal impairment?Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionalsBefore using this Q&A, read the disclaimer at www.ukmi.nhs.uk/activities/medicinesQAs/default.aspDate prepared: 15thApril 2013BackgroundDyslipidaemia is a common complication of chronic kidney disease (CKD) and it contributes to thehigh cardiovascular (CV) morbidity and mortality of CKD patients (1). However the pattern of CVdisease 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 oflow density lipoprotein–cholesterol (LDL-C) reduction patients with CKD have been conflicting. Someobservational studies in dialysis patients have shown a clear, linear relation between LDL-C and CVend points, whereas others have not (3).Two large trials (AURORA and 4D) – see below - of statins inpatients on haemodialysis showed no benefit of statins on a composite CV endpoint(4). Publishedrandomised controlled trials (RCT) of statins and other lipid-lowering agents have largely excludedpatients with most types of CKD (5,6). Several systematic reviews and meta analyses have evaluatedthe benefits and harms of statins in CKD patients (Error: Reference source not found,Error: Referencesource not found,7,8,9,10,11). Studies included in the meta-analyses were a mixture of prospective trialsincluding patients with CKD staged 3 to 5 and post-hoc analyses of major RCT mainly involvingpatients with an estimated glomerular filtration rate (eGFR) >30mL/min/1.73m2(Error: Referencesource not found,Error: Reference source not found). Statins decreased mortality and CV events inpersons with early stages of CKD. Statins conferred little or no risk for adverse events, althoughadverse events were evaluated systematically in fewer than half the trials (Error: Reference sourcenot 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 thatthe relative risk (RR) reduction for major CV events was progressively smaller, the higher the severityof 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). Forpatients with CKD stage 5, including patients on dialysis, the ARR was 0.022 (0.004 to 0.040), NNT46 (25 to 257)(Error: Reference source not found). In patients with CKD stage 5 (eGFR <15mL/minnot on dialysis) the ARR was 0.024 with a NNT of 42. A major primary prevention study in patientswith CKD (SHARP) found a reduction in the incidence of major atherosclerotic events with noincrease in adverse outcomes – see below – simvastatin (12). A multicentre, retrospectiveobservational analysis of administrative databases was performed to quantify an association betweenacute 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 monthsafter 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 takinghigh potency statins compared with those taking low potency statins(fixed effect ratio 1.1(95% CI 0.99to1.23) . 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 myopathyand 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 thesame way as in people without CKD despite the existence of confounding factors (e.g. inflammationand malnutrition) for CV risk calculation in patients with CKD (16).Statins should be offered for thesecondary prevention of CV disease irrespective of baseline lipid values (Error: Reference source notfound,Error: Reference source not found). There is insufficient evidence to support the routine use ofstatins to prevent or ameliorate progression of CKD (Error: Reference source not found,Error:Available through NICE Evidence Search at www.evidence.nhs.uk 1
  2. 2. Medicines Q&AsReference source not found, Error: Reference source not found,Error: Reference source notfound,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?AnswerThe evidence and dosage recommendations for each statin will be reviewed in turn.SimvastatinThe manufacturer advises that no modification of dosage should be necessary in patients withmoderate 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 manufacturerrecommends that in severe renal impairment (not defined) patients should be started at 5 mg/day andbe 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 inpatients with a GFR >10mL/min. For a GFR <10mL/min, it recommends 10-20mg daily, stating thatdoses above 10mg should be used with caution but that doses up to 40mg have been used (18). Othersources 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 guidancecautions against high dose simvastatin (21). Previously one reviewer advised the following dailydosage schedule: CKD stage 1 to 2:- 20 to 80mg; CKD stage 3:- 10 to 40mg; CKD stage 4 to 5:- 10to 20mg (Error: Reference source not found).Trials, mostly in small numbers of patients with CKD, used doses of simvastatin ranging from 10 to40mg daily (Error: Reference source not found). The lowest reported mean baseline GFR was 41mL/min/1.73m2in a study where patients received 10mg daily. Adverse effects were reported in 5 of10 studies (Error: Reference source not found).Of the major trials, the HPS study included patients with stage 3 CKD who received 40mg simvastatindaily, without an excess risk for rhabdomyolysis(22). A post hoc analysis of the 4S trial concluded thatsimvastatin 20mg decreased all cause mortality without an increase in adverse effects in patients withmild 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 ondialysis) with no history of myocardial infarction or coronary revascularisation. Patients wererandomised to receive simvastatin 20mg plus 10mg ezetimibe (N=4650) or placebo (N=4620) andfollowed 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 a2.1% 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). Therewas no evidence of excess risks of major adverse events, and no significant excess of death from anynon-vascular cause. Among the 6247 patients with CKD not on dialysis, simvastatin/ezetimibe did notreduce progression of CKD or overall mortality (Error: Reference source not found).AtorvastatinThe manufacturer advises that renal disease has no influence on the plasma concentrations or lipideffects of atorvastatin; thus, no adjustment of dose is required (24). Other sources (Error: Referencesource not found,Error: Reference source not found) agree. Molitch states that up to 80mg daily canbe 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 rangingfrom 10 to 40mg (Error: Reference source not found). Details of these and other studies are given inthe table below.Table 1. Studies of atorvastatin in patients with CKDAvailable through NICE Evidence Search at www.evidence.nhs.uk 2
  3. 3. Medicines Q&AsStudy Dose &durationSubjects Stage ofCKDOutcomes Adverse effectsStegmayr25,2610mg vsplacebo for 3years143 (33 non-dialysis)patients withsevere CKD4 -5GFR<30mL/min/1.73m2No benefit on 5-year outcomesof CV endpointsor survival20% of A treatedpatients withdrawndue to AE. Nosevere AE notedBianchi27Up to 40mg vs.no statin forone year (64%on 10mg)56 patientswith CKDAverage CrCl50.8 mL/min(A) 50mL/min(B)=controlsBeneficial effecton TC, LDL-C,CrCl andproteinuriaNone notedTNT28,2980mg vs.10mgfor 5 years9556patients withCHD3 (n=3078)and 4(n=29)eGFR15 to 60mL/min/1.73m2ARR of major CV events by 4.1%over 5 years [NNT=24] in patients withCKD, (80mg compared with 10mg). Inpatients with CHD, CKD and diabetesthe corresponding ARR was 7%,[NNT = 14] to prevent one major CVevent over 4.8 years. No unexpectedsafety concerns were identifiedALLIANCE30LDL-C goal of<80mg/dL[2mmol/L]31ora max. dose of80mg (mean=40.5mg) vs.usual care2442patients withCHD with orwithout CKDeGFR<60mL/min/1.73m2(n=579)ARR of a primary CV event =8.5% inpatients with CKD and 1.8% inpatients without CKD (NS). The liverand muscle safety profile of focusedatorvastatin therapy was similar inpatients with and without CKD.Saltissi3210-40mg daily(68.4% of non-dialysispatients on10mg) for 16weeks49 patientswith severeCRFincluding HDand CAPDGFR (CrCl)6.6 to 38.8mL/min(mean =20.8mL/min)(n=19)Mean decrease inLDL-C and TG frombaseline, 51% and27% respectively,in non-dialysisgroupNo serious AErelated to Awere notedKey: TC=total cholesterol ARR = absolute risk reduction NNT = number needed to treat TG =triglycerides NS = non significant A=atorvastatin AE=adverse effectsIn an observational study over 4.1 years of 177 patients with progressive CKD, treated to target lipidlevels with atorvastatin 10-40mg (two patients received 60 or 80mg), the only adverse effectsrequiring drug discontinuation were muscle pain or a rise in CK within normal limits (relationship todose 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 a29% lower mean rate of kidney function decline as calculated by MDRD eGFR and 20% lower rate ofC-G CrCl decline in the atorvastatin group compared with placebo, but the CI intervals of thedifferences were wide (34,35). In a post hoc analysis of the IDEAL study atorvastatin 80mg wascompared with simvastatin 20-40mg over 5 years in patients with a history of MI. In patients withoutCKD 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. Howeverdefinite conclusions cannot be drawn from this as the power of the study was limited (36).PravastatinThe manufacturer advises a starting dose of 10 mg a day in patients with moderate or severe RI (notdefined). The dosage should be adjusted according to the response of lipid parameters and undermedical supervision. No significant changes in pravastatin pharmacokinetics were observed inpatients with mild RI. However severe and moderate RI may lead to a two-fold increase of thesystemic exposure to pravastatin and metabolites (37) The RDH and Aronoff et al. recommend dosingas in normal renal function for all degrees of RI (Error: Reference source not found,Error: ReferenceAvailable through NICE Evidence Search at www.evidence.nhs.uk 3
  4. 4. Medicines Q&Assource not found), whereas Molitch recommends giving 20 to 80mg daily in stage 1-2 CKD, 20 to40mg 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 thePravastatin Pooling Project (PPP) 40mg was used in patients with stage 3 CKD down to a GFR of30mL/min/1.73m2without any adverse effects and the reduction in primary CV endpoints wasequivalent to the reductions achieved in patients with normal renal function (38,39) . In a furtherplacebo-controlled study in 93 patients with mild to moderate CKD, treatment with pravastatin 40mgdaily for 18 months (with added vitamin E and homocysteine-lowering therapy) resulted in reducedurinary albumin excretion and no significant treatment related adverse events. The mean baselineCrCl was 38 mL/min/1.73m2(40). A post hoc analysis of a large-scale primary prevention studyshowed that pravastatin 10-20mg daily significantly reduced the risk of major CV events in patientswith moderate CKD (eGFR 30-60mL/min)(41).RosuvastatinAccording to the manufacturer rosuvastatin is contra-indicated in severe RI (creatinine clearance <30mL/min) but no dose adjustment is necessary in patients with mild to moderate RI. The recommendedstarting dose is 5 mg in patients with moderate RI (creatinine clearance of <60 mL/min). The 40 mgdose is contraindicated in patients with moderate RI. In a study in subjects with varying degrees of RImild 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 inplasma concentration and a 9-fold increase in the N-desmethyl metabolite concentration compared tohealthy volunteers (42). The RDH advises 5 to 20mg in all degrees of RI. Molitch advises avoidingdoses >10mg in patients with a GFR <30mL/min/1.73m2and suggests 10 to 40mg daily in stage 1 to 2CKD, 10 to 20mg daily in stage 3 CKD, and 5 to 10mg daily in stage 4 to 5 CKD(Error: Referencesource 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), orno statin for 12 months. A beneficial effect on inflammatory parameters, serum lipids and a small, butsignificant beneficial effect on eGFR were observed in the treated group. No adverse effects weredocumented (43). In the second study 91 patients with CKD (GFR<60ml/min/1.73m2) were randomisedto rosuvastatin10mg/day or no statin for 20 weeks. Beneficial effects were observed on lipidparameters and GFR (non-significant) in the statin compared with the control group. Three statintreated patients withdrew because of myalgia not associated with elevated serum CK levels. No othersignificant adverse effects were reported (44).The AURORA trial examined the effect of rosuvastatin 10 mg vs placebo on CV morbidity andmortality in 2776 ESRD patients on haemodialysis. After a median of 3.8 years follow-up, there wasno statistically significant effect on the combined primary endpoint of non-fatal MI, non-fatal stroke ordeath from CV causes compared with placebo. Serious adverse events were reported in 82% ofrosuvastatin and 84% of placebo treated patients, but there was no increase in the incidence ofmuscle-related adverse events, rhabdomyolysis, or liver disease in the rosuvastatin group comparedwith the placebo group (45). A post hoc analysis from the JUPITER primary prevention trial found thatin patients with stage 3-4 CKD( eGFR 15-59ml/min/1.73m2) rosuvastatin 20mg reduced the rate offirst CV events [hazard ratio and 95% CI 0.55 (0.38-0.82)] and all cause mortality [hazard ratio and95% CI 0.56 (0.37-0.85)], compared with placebo. Patients were followed up for a median of 1.9 years(46).FluvastatinAccording to the manufacturer fluvastatin is cleared by the liver, with less than 6% of the administereddose excreted into the urine. The pharmacokinetics of fluvastatin remain unchanged in patients withmild to severe renal insufficiency (not defined). No dose adjustments are therefore necessary in thesepatients. However due to limited experience with doses>40mg/day in patients with severe renalimpairment (CrCl <30mL/min), these doses should be initiated with caution (47). Other sources agreethat 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 thestarting dose to 10mg in patients with CKD stage 4 to 5.Available through NICE Evidence Search at www.evidence.nhs.uk 4
  5. 5. Medicines Q&As130 patients with a CrCl between 45 and 55mL/min were randomised to fluvastatin XL 80mg oncedaily (n=80) or standard treatment (n=50). Standard treatment consisted of therapy for diabetes orhypertension excluding angiotensin-converting enzyme inhibitors and angiotensin-II receptorantagonists. Improved renal function, as measured by CrCl, was observed at the end of the 6-monthtreatment period in approximately 65% of patients treated with fluvastatin (48). In two further smallRCT, 45 patients (49) with MDRD-eGFR 12-44 mL/min/1.73m2and 42 patients with CrCl of 30-90mL/min (50) were randomised to fluvastatin 40mg/day or placebo (Error: Reference source notfound,Error: Reference source not found) for 8 weeks (Error: Reference source not found). Fluvastatinwas effective in reducing LDL-C and well-tolerated in both studies (Error: Reference source notfound,Error: Reference source not found). Other small-scale studies have used fluvastatin 20-80mgdaily in patients with a mean baseline GFR of 47 to 59 ml/min/1.73m2Fluvastatin was well-toleratedand 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 fluvastatinon 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 and80mg were included. Changes in lipid parameters were similar for both subgroups. The primaryoutcome 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-treatedpatients (51).Summary♦ Dyslipidaemia is a common complication of CKD and contributes to high CV morbidity andmortality 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 patientshave 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 haveincluded patients with varying degrees of RI. Meta-analyses and reviews of these RCT havefound evidence of beneficial effects on cardiovascular outcomes in patients with early stages ofCKD. There is insufficient evidence to support the routine use of statins to prevent or ameliorateprogression of CKD. Studies included in the meta-analyses were a mixture of prospective trials inpatients with CKD stages 3 to 5 and post-hoc analyses of major RCT mainly involving patientswith an eGFR >30mL/min/1.73m2.♦ Meta-analyses found little or no risk of adverse events, although there is some evidence fromindividual studies of statins of an increased risk.♦ NICE guidance on CKD advises the use of statins for the primary prevention of CV disease in thesame way as in people without CKD. NICE also advises that statins should be offered for thesecondary 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 beenshown to be effective at lower levels of renal function, but there are no comparative studies ofstatins in CKD.♦ Advice on dosing is available in standard sources although there is some inconsistency in theirrecommendations. It would be reasonable to dose conservatively at lower levels of renal functionwith close monitoring of desired effect on lipid levels and of adverse effects.LimitationsThe use of statins in transplant patients and clinically important drug interactions with statins inpatients with RI, are not discussed here. A detailed discussion of the use of statins in renalreplacement therapy (RRT) is outside the scope of this review. Whilst some of the trials reportedadverse effects, this has not been reviewed in detail.ReferencesAvailable through NICE Evidence Search at www.evidence.nhs.uk 5
  6. 6. 1. Steinmetz OM et al. Statin therapy in patients with chronic kidney disease: to use or not to use. Eur J ClinInvest 2006; 36: 519-272. Gluba A et al. Statins in patients with chronic kidney disease: why, who and when? Expert OpinPharmacother 2010 11: 2665-743. Strippoli GFM, Navaneethan SD, Johnson DW et al. Effect of statins in patients with chronic kidneydisease: meta-analysis and meta-regression of randomised controlled trials. Brit Med J 2008; 336:645-514. Stevens K, Jardine AG. SHARP: a stab in the right direction in chronic kidney disease. Lancet 2011; 377:2153-4 (Published online June 9, 2011 DOI:10.1016/S0140-6736(11)60822-25. National Institute for Health and Clinical Excellence. NICE clinical guideline 73. Chronic kidney diseaseSeptember 2008. Quick reference guide accessed via http://www.nice.org.uk/ on 9.8.116. National Collaborating Centre for Chronic Conditions. Chronic kidney disease: national clinicalguideline for early identification and management in adults in primary and secondary care.London: Royal College of Physicians, September 2008http://www.nice.org.uk/nicemedia/pdf/CG073FullGuideline.pdf . accessed via http://guidance.nice.org.uk on9.8.117.Navaneethan SD, Pansini F, Perkovic V et al. HMG CoA reductase inhibitors (statins) for people withchronic kidney disease not requiring dialysis. Cochrane Database of Systematic Reviews 2009. Issue 2. Art.No.: CD007784. DOI: 10.1002/14651858.CD007784 accessed viahttp://mrw.interscience.wiley.com/cochrane/clsysrev/articles/CD007784/frame.htmlon 23.8.118. Kassimatis TI, Konstantinopoulos PA. Statins in patients with chronic kidney disease: a double-edgedsword? J Am Coll Cardiol 2008; 52: 16799. Palmer SC et al. Benefits and harms of statin therapy for persons with chronic kidney disease. Ann Int Med2012;157: 263-7510. Upadhyay A et al. Lipid-lowering therapy in persons with chronic kidney disease. Ann Int Med 2012;157:251-6211. Hou W et al. Effect of statin therapy on cardiovascular and renal outcomes in patients with chronic kidneydisease: a systematic review and meta-analysis. Eur Heart J 2013 doi:10.1093/eurheartj/eht065 (published 6March 2013)12. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidneydisease (Study of Heart and Renal Protection): a randomised placebo-controlled trial. Lancet 2011;377:2181-92. Published online June 9, 2011 DOI:10.1016/S0140-6736(11)60739-313. Dormuth CR et al. BMJ 2013; 346:1880 doi: 10.1136/bmj.f880 (published 20 Mar 2013)14. Summary of Product Characteristics – Crestor. AstraZeneca UK Limited. Accessed viahttp://emc.medicines.org.uk on 28/6/11 [date of revision of text – 2/2/2011]15. Summary of Product Characteristics – Zocor. Merck, Sharp & Dohme Limited. Accessed viahttp://emc.medicines.org.uk on 28/06/11 [date of revision of text 3/11].16. Connor A, Tomson C. Should statins be prescribed for primary prevention of cardiovascular disease inpatients with chronic kidney disease? BMJ 2009; 339: 803-4 (BMJ 2009; 339: b2949 doi:10.1136/bmj.b2949)17. Merck Sharp & Dohme Corp. ZOCOR (simvastatin) Tablets. Full Prescribing Information. Issued June2011. Accessed via http://www.merck.com/product/usa/pi_circulars/z/zocor/zocor_pi.pdf on 25.8.1118. Ashley, C. Currie, A. editors. Renal Drug Handbook 3rd Edition. Oxford, Radcliffe Medical Press Ltd;2009.
  7. 7. 19. Aronoff GR, Bennett WM, Berns JS, et al. Drug Prescribing in Renal Failure; Dosing Guidelines for Adultsand Children 5th edition ;2007, p.114-1520. Levy J et al. Oxford Handbook of Dialysis 2nd edition. Oxford University Press ; 2004, p. 6, 80821. Simvastatin: increased risk of myopathy at high dose (80 mg)http://www.mhra.gov.uk/Safetyinformation/DrugSafetyUpdate/CON085169 accessed 21.9.1122. Molitch ME. Management of dyslipidemias in patients with diabetes and chronic kidney disease. Clin J AmSoc Nephrol 2006; 1: 1090-923. Chonchol M, Cook T, Kjekshus J et al. Simvastatin for secondary prevention of all cause mortality andmajor coronary events in patients with mild chronic renal insufficiency. Am J Kidney Dis 2007; 49:373-8224. Summary of Product Characteristics – Lipitor Pfizer Limited. Accessed via http://emc.medicines.org.uk on28/06/11 [date of revision of text – 03/2011]25. Stegmayr BG, Brannstrom M, Bucht S et al. Low-dose atorvastatin in severe chronic kidney diseasepatients: a randomized, controlled endpoint study. Scand J Urol Nephrol 2005; 39:489-9726. Holmberg B, Brannstrom M, Bucht S et al. Safety and efficacy of atorvastatin in patients with severe renaldysfunction. Scand J Urol Nephrol 2005; 39: 503-1027. Bianchi S et al. A controlled, prospective study of the effects of atorvastatin on proteinuria and progressionof kidney disease. Am J Kidney Dis 2003; 41: 565-7028. Shepherd J, Kastelein JJP, Bittner V et al. Intensive lipid lowering with atorvastatin in patients withcoronary heart disease and chronic kidney disease: the TNT (Treating to New Targets) study. J Am CollCardiol 2008; 51: 1448-5429. Shepherd J, Kastelein JJP, Bittner V et al. Intensive lipid lowering with atorvastatin in patients withcoronary artery disease, diabetes, and chronic kidney disease. Mayo Clinic Proc 2008; 83: 870-7930. Koren MJ, Davidson MH, Wilson DJ et al. Focused atorvastatin therapy in managed-care patients withcoronary heart disease and CKD. Am J Kidney Dis 2009; 53: 741-75031. http://www.globalrph.com/conv_si.htm accessed 28.7.09 and 28.09.1132. Saltissi D et al. Efficacy, safety and tolerability of atorvastatin in dyslipidemic subjects with advanced (non-nephrotic) and end-stage chronic renal failure. Clin Exp Nephrol ;2006; 10:201-20933. Ozsoy RC et al. Dyslipidaemia as predictor of progressive renal failure and the impact of treatment withatorvastatin. Nephrol Dial Transplant 2007;22: 1578-158634. Fassett RG, Ball MJ, Robertson IK et al. The lipid lowering and onset of renal disease (LORD) trial: arandomized double blind placebo controlled trial assessing the effect of atorvastatin on the progression ofkidney disease. BMC Nephrology 2008; 9:4 doi:10.1186/ 471 -2369-9-435. Fassett RG, Robertson IK, Ball MJ et al. Effect of atorvastatin on kidney function in chronic kidneydisease: a randomised double-blind placebo-controlled trial. Atherosclerosis 2010; 213:218-2436. Holme I et al. Cardiovascular outcomes and their relationships to lipoprotein components in patients withand without chronic kidney disease: results from the IDEAL trial. J Int Med 2010;267: 567-7537. Summary of Product Characteristics – Lipostat .Bristol Myers Squibb Pharmaceuticals Limited. Accessedvia http://emc.medicines.org.uk on 28/06/11 [date of revision of text – 07/2010]38. Tonelli M et al. Effect of pravastatin on cardiovascular events in people with chronic kidney disease.Circulation 2004; 110: 1557-6339. Tonelli M et al. Effect of pravastatin on rate of kidney function loss in people with or at risk for coronarydisease. Circulation 2005; 112: 171-8
  8. 8. 40. Nanayakkara PWB et al. Effect of a treatment strategy consisting of pravastatin, vitamin E, andhomocysteine lowering on carotid intima-media thickness, endothelial function, and renal function in patientswith mild to moderate chronic kidney disease. Arch Int Med 2007; 167: 1262-127041. Nakamura H et al. Pravastatin and cardiovascular risk in moderate chronic kidney disease.Atherosclerosis 2009;206: 512-1742.Summary of Product Characteristics – Crestor. Astra Zeneca. Accessed via http://emc.medicines.org.ukon 28/06/2011 [date of revision of text – 02/02/2011]43. Sawara Y, Takei T, Uchida K et al. Effects of lipid-lowering therapy with rosuvastatin on atheroscleroticburden in patients with chronic kidney disease. Int Med 2008; 47:1505-1044. Verma A, Ranganna KM, Reddy RS et al. Effect of rosuvastatin on C-reactive protein and renal function inpatients with chronic kidney disease. Am J Cardiol 2005; 96: 1290-9245. Fellstrom BC, Jardine AG, Schmieder RE et al. Rosuvastatin and cardiovascular events in patientsundergoing haemodialysis. New Engl J Med 2009; 360: 1395-40746. Ridker PM et al. Efficacy of rosuvastatin among men and women with moderate chronic kidney diseaseand elevated high-sensitivity C-reactive protein: a secondary analysis from the JUPITER (Justification for theUse of Statins in Prevention an Intervention Trial Evaluating Rosuvastatin) trial. J Am Coll Cardiol 2010;55:1266-7347. Summary of Product Characteristics – Lescol. Novartis. Accessed via http://emc.medicines.org.uk on28/06/11 [date of revision of text – 17/8/2010]48. Di Lullo l et al. Effects of fluvastatin treatment on lipid profile, C-reactive protein trend, and renal functionin dyslipidemic patients with chronic renal failure. Adv Ther 2005; 22: 601-1249. Samuelsson O et al. Fluvastatin improves lipid abnormalities in patients with moderate to advancedchronic renal insufficiency. Am J Kidney Dis 2002; 39: 67-7550. Lintott CJ et al. Fluvastatin for dyslipoproteinemia, with or without concomitant renal insufficiency. Am JCardiol 1995; 76: 97A-101A51. Holdaas H, Wanner C, Abletshauser C et al. The effect of fluvastatin on cardiac outcomes in patients withmoderate to severe renal insufficiency: a pooled analysis of double-blind randomized trials. Int J Cardiol2007; 117: 64-74Quality AssurancePrepared byJulia Kuczynska, South West Medicines Information, BristolDate this version prepared28thAugust 2011(date of partial revision 12thOctober 2012 and 15thApril 2013)Checked byTrevor Beswick, South West Medicines Information, BristolDate of check21stSeptember 2011(partial revision checked 25thOctober 2012 and 23rdApril 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 2008-12and 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.
  9. 9. 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)
  10. 10. 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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