Effects of Lowering LDL Cholesterol on Progression of ...

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CLINICAL EPIDEMIOLOGY www.jasn.org Effects of Lowering LDL Cholesterol on Progression of Kidney Disease Richard Haynes,* David Lewis,* Jonathan Emberson,* Christina Reith,* Lawrence Agodoa, Alan Cass, Jonathan C. Craig, § Dick de Zeeuw, | Bo Feldt-Rasmussen, Bengt Fellström,** Adeera Levin, †† David C. Wheeler, ‡‡ Rob Walker, §§ William G. Herrington,* Colin Baigent,* Martin J. Landray,* for the SHARP Collaborative Group *Clinical Trial Service Unit and Epidemiological Studies Unit, Nufeld Department of Population Health, University of Oxford, Oxford, United Kingdom; National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland; Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia; § Sydney School of Public Health, Childrens Hospital at Westmead, University of Sydney, Sydney, New South Wales, Australia; | Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands; Rigshospitalet, University of Copenhagen, Copenhagen, Denmark; **University Hospital, Uppsala, Sweden; †† University of British Columbia, Vancouver, British Columbia, Canada; ‡‡ University College London, London, United Kingdom; and §§ Dunedin School of Medicine, University of Otago, Otago, New Zealand ABSTRACT Lowering LDL cholesterol reduces the risk of developing atherosclerotic events in CKD, but the effects of such treatment on progression of kidney disease remain uncertain. Here, 6245 participants with CKD (not on dialysis) were randomly assigned to simvastatin (20 mg) plus ezetimibe (10 mg) daily or matching placebo. The main prespecied renal outcome was ESRD (dened as the initiation of maintenance dialysis or kidney transplantation). During 4.8 years of follow-up, allocation to simvastatin plus ezetimibe resulted in an average LDL cholesterol difference (SEM) of 0.96 (0.02) mmol/L compared with placebo. There was a nonsignicant 3% reduction in the incidence of ESRD (1057 [33.9%] cases with simvastatin plus ezetimibe versus 1084 [34.6%] cases with placebo; rate ratio, 0.97; 95% condence interval [95% CI], 0.89 to 1.05; P=0.41). Similarly, allocation to simvastatin plus ezetimibe had no signicant effect on the prespecied tertiary outcomes of ESRD or death (1477 [47.4%] events with treatment versus 1513 [48.3%] events with placebo; rate ratio, 0.97; 95% CI, 0.90 to 1.04; P=0.34) or ESRD or doubling of baseline creatinine (1189 [38.2%] events with treatment versus 1257 [40.2%] events with placebo; rate ratio, 0.93; 95% CI, 0.86 to 1.01; P=0.09). Exploratory analyses also showed no signicant effect on the rate of change in eGFR. Lowering LDL cholesterol by 1 mmol/L did not slow kidney disease progression within 5 years in a wide range of patients with CKD. J Am Soc Nephrol 25: cccccc, 2014. doi: 10.1681/ASN.2013090965 CKD affects about 1 in 10 adults and is associated with increased risks of cardiovascular disease, ESRD, and death. 1 Only a minority of patients with CKD will progress to ESRD (because most patients will die rst), but the substantially elevated risks of morbidity and mortality associated with ESRD, 2 together with its effects on quality of life 3 and cost to health care systems, 4 make its preven- tion highly desirable. Although inhibition of the renin-angiotensin system does slow progression of proteinuric nephropathies, 5,6 there is a need Received September 13, 2013. Accepted January 7, 2014. R.H. and D.L. contributed equally to this work. Published online ahead of print. Publication date available at www.jasn.org. Correspondence: Dr. Martin J. Landray, Clinical Trial Service Unit and Epidemiological Studies Unit, Richard Doll Building, Old Road Campus, Roosevelt Drive, Oxford OX3 7LF, United King- dom. Email: [email protected] Copyright © 2014 by the American Society of Nephrology J Am Soc Nephrol 25: cccccc, 2014 ISSN : 1046-6673/2508-ccc 1

Transcript of Effects of Lowering LDL Cholesterol on Progression of ...

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Effects of Lowering LDL Cholesterol on Progression ofKidney Disease

Richard Haynes,* David Lewis,* Jonathan Emberson,* Christina Reith,* Lawrence Agodoa,†

Alan Cass,‡ Jonathan C. Craig,§ Dick de Zeeuw,| Bo Feldt-Rasmussen,¶ Bengt Fellström,**Adeera Levin,†† David C. Wheeler,‡‡ Rob Walker,§§ William G. Herrington,* Colin Baigent,*Martin J. Landray,* for the SHARP Collaborative Group

*Clinical Trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Population Health, University ofOxford, Oxford, United Kingdom; †National Institute of Diabetes and Digestive and Kidney Diseases, NationalInstitutes of Health, Bethesda, Maryland; ‡Menzies School of Health Research, Charles Darwin University, Darwin,Northern Territory, Australia; §Sydney School of Public Health, Children’s Hospital at Westmead, University of Sydney,Sydney, New South Wales, Australia; |Department of Clinical Pharmacy and Pharmacology, University of Groningen,University Medical Centre Groningen, Groningen, The Netherlands; ¶Rigshospitalet, University of Copenhagen,Copenhagen, Denmark; **University Hospital, Uppsala, Sweden; ††University of British Columbia, Vancouver, BritishColumbia, Canada; ‡‡University College London, London, United Kingdom; and §§Dunedin School of Medicine,University of Otago, Otago, New Zealand

ABSTRACTLowering LDL cholesterol reduces the risk of developing atherosclerotic events in CKD, but the effects ofsuch treatment on progression of kidney disease remain uncertain. Here, 6245 participants with CKD (noton dialysis) were randomly assigned to simvastatin (20 mg) plus ezetimibe (10 mg) daily or matchingplacebo. The main prespecified renal outcome was ESRD (defined as the initiation of maintenance dialysisor kidney transplantation). During 4.8 years of follow-up, allocation to simvastatin plus ezetimibe resultedin an average LDL cholesterol difference (SEM) of 0.96 (0.02) mmol/L compared with placebo. There was anonsignificant 3% reduction in the incidence of ESRD (1057 [33.9%] cases with simvastatin plus ezetimibeversus 1084 [34.6%] cases with placebo; rate ratio, 0.97; 95% confidence interval [95% CI], 0.89 to 1.05;P=0.41). Similarly, allocation to simvastatin plus ezetimibe had no significant effect on the prespecifiedtertiary outcomes of ESRD or death (1477 [47.4%] events with treatment versus 1513 [48.3%] events withplacebo; rate ratio, 0.97; 95% CI, 0.90 to 1.04; P=0.34) or ESRD or doubling of baseline creatinine (1189[38.2%] events with treatment versus 1257 [40.2%] events with placebo; rate ratio, 0.93; 95% CI, 0.86 to1.01; P=0.09). Exploratory analyses also showed no significant effect on the rate of change in eGFR.Lowering LDL cholesterol by 1 mmol/L did not slow kidney disease progression within 5 years in a widerange of patients with CKD.

J Am Soc Nephrol 25: ccc–ccc, 2014. doi: 10.1681/ASN.2013090965

CKD affects about 1 in 10 adults and is associatedwith increased risks of cardiovascular disease,ESRD, and death.1 Only a minority of patientswith CKD will progress to ESRD (because mostpatients will die first), but the substantially elevatedrisks of morbidity and mortality associated withESRD,2 together with its effects on quality of life3

and cost to health care systems,4 make its preven-tion highly desirable. Although inhibition of therenin-angiotensin system does slow progressionof proteinuric nephropathies,5,6 there is a need

Received September 13, 2013. Accepted January 7, 2014.

R.H. and D.L. contributed equally to this work.

Published online ahead of print. Publication date available atwww.jasn.org.

Correspondence: Dr. Martin J. Landray, Clinical Trial ServiceUnit and Epidemiological Studies Unit, Richard Doll Building, OldRoad Campus, Roosevelt Drive, Oxford OX3 7LF, United King-dom. Email: [email protected]

Copyright © 2014 by the American Society of Nephrology

J Am Soc Nephrol 25: ccc–ccc, 2014 ISSN : 1046-6673/2508-ccc 1

for additional therapies that safely retard the progression ofCKD.

Experimental studies have suggested that lipids may contrib-ute to the progression of kidney disease.7 Previousmeta-analysesof randomized trials (which included patients without CKD andwith mild reductions in eGFR) have indicated that loweringLDL cholesterol might reduce the rate of loss of glomerularfiltration by about 1 ml/min per year.8,9 However, those trialsdid not include patients with advanced CKD (i.e., stage 3B andhigher), who typically progress at a faster rate than those patientsat earlier stages, among whom a similar proportional effectmight yield a worthwhile delay in ESRD.

The Study of Heart and Renal Protection (SHARP) showedthat lowering LDL cholesterol with simvastatin (20 mg) plusezetimibe (10mg) daily in patientswithCKD safely reduces theincidence of major atherosclerotic events10 and provides anopportunity to assess the effects of lowering LDL cholesterolon the progression of kidney disease.

RESULTS

In total, 6245 participants were not on dialysis at the point atwhich theywere randomized to simvastatinplus ezetimibe versusplacebo (Figure 1). This group included 10 patients (5 patientsallocated simvastatin plus ezetimibe, and 5 patients allocatedplacebo) who were initially randomized to simvastatin onlyand received a kidney transplant before rerandomization to sim-vastatin plus ezetimibe versus placebo (but excludes 2 patientswho were identified, after publication of the main trial results,10

as being on dialysis before rerandomization). Among all 6245patients, baseline characteristics were well balanced betweenrandomized treatments (Table 1, Supplemental Table 1). Among6027 (97%) patients with centrally measured creatinine, themean eGFR was 27 (SD=13) ml/min per 1.73 m2, with 3784(63%) patients having stages 4 or 5 CKD (i.e., eGFR,30ml/minper 1.73 m2). Among 5572 (89%) patients with a centrally mea-sured urinary albumin-to-creatinine ratio (ACR), 2357 (42%)patients had macroalbuminuria (ACR.34 mg/mmol). Themost common causes of kidney disease were hypertensive ne-phropathy or renovascular disease (22%), GN (18%), diabeticnephropathy (15%), and cystic kidney disease (11%).

Among surviving patients, the median duration of follow-upwas 4.8 years. Compliance was defined as at least 80% of thescheduled simvastatin plus ezetimibe or placebo tablets havingbeen taken since the previous follow-up. At the study midpoint,2038 (73%) patients allocated simvastatin plus ezetimibe re-mained compliant or were taking a nonstudy statin, whereas 215(8%) patients allocated placebo were taking a nonstudy statin(Table 2). Hence, the average difference between the two ran-domized arms in the proportion taking simvastatin plus ezeti-mibe or nonstudy statin was 65%. The average LDL cholesteroldifference at the same point was 0.96 (SEM=0.02) mmol/L.

During the follow-up period, 1057 (33.9%) participantsallocated simvastatin plus ezetimibe reached ESRD compared

with 1084 (34.6%) patients allocated placebo (rate ratio [RR],0.97; 95% confidence interval [95% CI], 0.89 to 1.05; P=0.41)(Figure 2). Allocation to simvastatin plus ezetimibe was notassociated with a significant reduction in the risk of either ofthe prespecified subsidiary renal outcomes: ESRD or deathfrom any cause (RR, 0.97; 95% CI, 0.90 to 1.04; P=0.34) orESRD or doubling of baseline creatinine (RR, 0.93; 95% CI,0.86 to 1.01; P=0.09).

SHARPwas not expected to have sufficient statistical powerto allow reliable estimation of effects of treatment in particularclinical circumstances, and therefore, subgroup analyses wereplanned only as tertiary assessments.11 There was no evidencethat the proportional effect of allocation to simvastatin plusezetimibe on ESRD (or the other renal outcomes) differedbetween participants with different stages of CKD (Figure 3,Supplemental Figures 1 and 2) or among subgroups of partic-ipants defined by a range of other baseline characteristics afteraccounting for multiple testing (Supplemental Figures 1–4).

In total, 5037 (80%) participants had at least three follow-uplocal creatinine measurements in addition to a centrally mea-sured creatinine at randomization. The 50 (1%)patientswith themost extrememean deviations from their own fitted slopes wereexcluded (Table 3). Of the remaining 4987 patients, the mediannumber of creatinine measurements per patient was 10 (inter-quartile range=7–12). Those patients with fewer measurementshad lower eGFR at baseline and a faster average rate of decline ineGFR (Supplemental Figure 5, Supplemental Table 2). Whenparticipants were subdivided by their number of follow-upmeasurements, eGFRdeclined in a clearly linear fashion in everygroup (Supplemental Figure 5).Overall, allocation to simvastatinplus ezetimibe was not associated with a slower rate of changein eGFR (21.66 [SEM=0.07] versus21.83 [SEM=0.07]; abso-lute difference=0.17 [SEM=0.10] ml/min per 1.73 m2 per year;P=0.10) (Table 3). In sensitivity analyses, the estimated differ-ence in the rate of change in eGFR between treatment arms (andits SEM) was virtually identical when alternative approaches toexcluding patients with poorly fitting slopes were used (Table 3).Although those patients with more advanced CKD (whethercharacterized by lower eGFR or greater albuminuria) had fasterrates of progression, there were no trends to suggest any benefit(or hazard) of treatment on the rate of change in eGFR acrossthese subgroups (Figure 4) or any other subgroups (data notshown). In addition, among 3625 patients with centrally ana-lyzed cystatin C at the 2.5-year visit (who had not reached ESRDby that time), there was no significant difference in cystatin CeGFR between patients allocated simvastatin plus ezetimibe andpatients allocated placebo.

Exploratory analyses of effects of treatment on proteinuriaand acute-on-chronic renal failure were also undertaken.Among 3022 patients who had not commenced dialysis andhad provided a urine sample at the study midpoint, there wasno significant difference in geometric mean urinary ACR(simvastatin plus ezetimibe versus placebo: 168 [SEM=8.4]mg/g versus 154 [SEM=7.7] mg/g; P=0.20). Allocation to sim-vastatin plus ezetimibe was not associated with a reduction in

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the risk of acute-on-chronic renal failure (209 [6.7%] versus231 [7.4%]; RR, 0.91; 95% CI, 0.75 to 1.09; P=0.30).

DISCUSSION

Among 6245 participants with CKD not on dialysis at random-ization, lowering LDL cholesterol by about 1 mmol/L with

simvastatin plus ezetimibe for about 5 years had no significanteffect on the progression of kidney disease to ESRD or thesubsidiary prespecified outcomes of ESRD or death from anycause, orESRDordoublingofbaseline creatinine. Thesefindingsare supported by the absence of a significant effect on thestatistically more sensitive rate of decline of eGFR. Subgroupanalyses did not identify any particular type of participant whoseemed tobenefitmore (or less) comparedwith theoverall result.

Figure 1. Trial profile and participant flow diagram.

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SHARP is the largest trial of LDL lowering in patients withadvanced CKD. With over 2000 ESRD events, it had excellentstatistical power (.90%) to detect a 15% proportional

reduction and good power (.80%) to detect a moremoderate10% reduction in the incidence of ESRD. These data, there-fore, are the most robust data available to assess whether

Table 1. Baseline characteristics by treatment allocation among 6245 patients not on dialysis at randomization

Simvastatin Plus Ezetimibe (n=3116) Placebo (n=3129)

Age at randomization (yr)a 63 (12) 63 (12)Men 1953 (63%) 1929 (62%)Prior vascular diseasea 473 (15%) 459 (15%)Diabetesa 718 (23%) 708 (23%)Current smokera 383 (12%) 379 (12%)Systolic BP (mmHg)a 139 (21) 139 (21)Diastolic BP (mmHg)a 80 (12) 80 (12)Total cholesterol (mmol/L)a 5.01 (1.18) 5.01 (1.15)LDL cholesterol (mmol/L)a 2.87 (0.87) 2.86 (0.85)HDL cholesterol (mmol/L)a 1.14 (0.34) 1.12 (0.34)Triglycerides (mmol/L)a 2.31 (1.63) 2.34 (1.68)Body mass index (kg/m2)a 27.4 (5.5) 27.4 (5.4)Ethnicityb

White 2248 (72%) 2235 (71%)Black 62 (2%) 57 (2%)Asian 748 (24%) 774 (25%)Other/not specified 58 (2%) 63 (2%)

Comedicationa,b

Antiplatelet therapy 614 (20%) 617 (20%)Oral anticoagulant therapy 82 (3%) 93 (3%)ACE inhibitor or ARB 1912 (61%) 1902 (61%)b-Blocker 1119 (36%) 1202 (38%)Calcium channel blocker 1388 (45%) 1356 (43%)Diuretic 1397 (45%) 1384 (44%)Erythropoiesis-stimulating agent 409 (13%) 359 (11%)Sevelamer 40 (1%) 24 (,1%)

MDRD eGFR (ml/min per 1.73 m2)a,c

Mean (SD) 26.6 (12.9) 26.6 (13.1)$60 44 (1%) 44 (1%)$30 to ,60 1100 (37%) 1055 (35%)$15 to ,30 1246 (41%) 1319 (44%),15 613 (20%) 606 (20%)Not available 113 105

Urinary ACR (mg/g)c

Median (interquartile range) 217 (44–787) 196 (43–746),30 545 (20%) 562 (20%)30–300 1032 (37%) 1076 (39%).300 1202 (43%) 1155 (41%)Not available 337 336

Renal diagnosisb,c

GN 528 (18%) 521 (17%)Diabetic nephropathy 445 (15%) 441 (15%)Hypertensive/renovascular 641 (21%) 661 (22%)Cystic kidney disease 329 (11%) 346 (12%)Pyelonephritis 198 (7%) 206 (7%)Other known cause 452 (15%) 434 (15%)Unknown cause 405 (14%) 383 (13%)Not available 118 137

Data are n (%), mean (SD), or median (interquartile range). ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; MDRD,Modification of Diet inRenal Disease.aVariables updated at 1 year for patients originally allocated simvastatin only who were rerandomized to simvastatin plus ezetimibe or placebo.bNot a prespecified category for subgroup analyses.cPercentages exclude participants for whom data were not available for that category.

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lowering LDL cholesterol preserves kidney function. SHARPwas not, however, designed to compare the effects of loweringLDL cholesterol with simvastatin with the effects of loweringLDL cholesterol with simvastatin plus ezetimibe (and had in-sufficient statistical power to do so reliably).

In SHARP, nearly one half of those patients reaching ESRDhad an eGFR below 15 ml/min per 1.73 m2 at randomization,and the median time to ESRD for such patients was only about1 year. Therefore, any effect of LDL cholesterol reduction onthe pathophysiology of renal progression would have had littletime to manifest among such patients. It is known that thebenefits of statins in preventing cardiovascular disease are pro-portionally lower during the first year of starting treatment,12

and, therefore, if the mechanism of action was similar (assuggested by laboratory experiments7), then many of theESRD events in SHARP may not have been modifiable bythe study treatment. However, there was no significant trendin treatment effect by CKD stage at baseline.

SHARPparticipantswere also recruited fromcountrieswith aspectrum of health care provision and, in particular, substantialvariation in the incidence of RRT.13 Some participants who diedof renal diseasemight conceivably have been offered RRT if theirhealth care had been managed elsewhere. However, of 6245 pa-tients at risk of ESRD, only 134 (2%) patients died of renal

disease before reaching ESRD, and no effect of treatment wasshown on the outcome of ESRD or death.

These factors arenot likely to have affected statisticallymoresensitive assessments of the rate of change of eGFR. In SHARP,allocation to simvastatin plus ezetimibe resulted in a non-significant 0.17 (SEM=0.10) ml/min per 1.73 m2 per yearreduction in the rate of change in eGFR. This result is notconsistent with the 1.22 (95% CI, 0.44 to 2.00 ml/min peryear) estimate from a previous meta-analysis of much smallerrandomized trials9 (but it is compatible with a smaller effect).Although a variety of assays may have been used to measurecreatinine at local sites and such assays may have changedduring the trial, randomization would have balanced any dif-ferences (as well as the myriad factors known to affect thereliability of equations used to estimate GFR), minimizingany resulting bias.14

In clinical practice, an individual’s eGFRsmay not change in alinear fashion over time.15 An assessment of the effect of treat-ment on the average rate of decline in eGFRmight bemisleadingif eGFR varied in a definitely nonlinear fashion. However, therewas little evidence of this in SHARP: when patients were strat-ified by thenumber of creatininemeasurements obtained duringthe study, strong linear relationships with increasing follow-upwere seen for both treatment groups in every group.

Table 2. Average use of study simvastatin plus ezetimibe or nonstudy statin among 6245 patients not on dialysis atrandomization and average change in plasma LDL cholesterol from baseline by period of follow-up

Follow-Up (mo)

LDL Cholesterol–Lowering Drug Use LDL Cholesterol Difference (mmol/L)a

Simvastatin PlusEzetimibe (%)

Placebo (%)Absolute

Difference (%)Simvastatin Plus

EzetimibePlacebo

AbsoluteDifference

8–13 79 3 76 21.22 0.06 1.2860.0726–31 73 8 65 21.11 20.15 0.9660.0244–49 71 13 57 20.90 20.05 0.8460.07aIn participants initially allocated to simvastatin alone, no 8–13 month sample post-rerandomization was available while samples corresponding to the 26–31 and44–49 month visits shown above were collected, respectively, 14–19 and 32–37 months after rerandomization.

Figure 2. Effects of allocation to simvastatin plus ezetimibe on renal outcomes among 6245 patients not on dialysis at randomization.

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SHARPhas shown that loweringLDLcholesterol in patientswith CKD reduces their substantially elevated cardiovascularrisk, and, therefore, there is already a good indication forlowering LDL cholesterol in most patients with CKD (regard-less of stage). The lack of a significant benefit on renalprogression does not influence this strategy, and the lack ofhazard is reassuring. Consequently, LDL cholesterol–loweringtherapy is indicated in patients with advanced CKD to preventatherosclerotic disease but not progression of renal disease.

CONCISE METHODS

Trial Design and ParticipantsThe study objectives, design, and methods have been reported

previously.10,11 Patients ages 40 years or older were eligible to

participate if they had CKD with more than one previous measure-

ment of serumor plasma creatinine of at least 150mmol/L (1.7mg/dl)

in men or 130 mmol/L (1.5 mg/dl) in women, regardless of dialysis

use. Patients attended a screening visit, at which time medical history

and other eligibility criteria were checked and written informed con-

sent was obtained. The study is registered at ClinicalTrials.gov

(NCT00125593 and ISRCTN54137607). Ethics approval was ob-

tained at all study sites before enrolment.

After 6 weeks of placebo run-in, eligible participants were

randomized in the ratio of 4:4:1 to simvastatin (20mg) plus ezetimibe

(10 mg; as a single tablet) versus matching placebo versus simvastatin

(20 mg) alone, and treatment allocation was masked using a double

dummy method. Those patients allocated simvastatin alone (who

were alive and willing to continue) were rerandomized after 1 year to

one of two main comparison arms (Figure 1). After initial random-

ization, participants were followed up in study clinics at 2 and 6

Figure 3. Effects of allocation to simvastatin plus ezetimibe on ESRD by baseline eGFR among 6245 patients not on dialysis atrandomization. MDRD, Modification of Diet in Renal Disease.

Table 3. Effect of allocation to simvastatin plus ezetimibe on annual reduction in eGFR among 5037 patients not on dialysis atrandomization with at least three follow-up eGFRs

Qualifying Criteriafor Analysis

Number Includedin Analysis

Number Excludedfrom Analysis

Estimated Annual Rate of Change ineGFR (ml/min per 1.73 m2)

S/E PBO S/E PBO S/E PBO Difference P Value

Main analysis — — — —

Patients with average deviationfrom own fitted line ,9.0 ml/minper 1.73 m2 (p99)

2492 2495 27 23 21.66 (0.07) 21.83 (0.07) 0.17 (0.10) 0.10

Sensitivity analyses — — — —

Patients with average deviationfrom own fitted line ,5.1 ml/minper 1.73 m2 (p95)

2388 2398 131 120 21.72 (0.07) 21.88 (0.07) 0.17 (0.10) 0.09

Patients with average deviationfrom own fitted line ,3.9 ml/minper 1.73 m2 (p90)

2253 2281 266 237 21.78 (0.07) 21.94 (0.07) 0.15 (0.10) 0.12

Patients with average deviationfrom own fitted line ,3.3 ml/minper 1.73 m2 (p85)

2143 2139 376 379 21.85 (0.07) 22.03 (0.07) 0.18 (0.10) 0.07

Numberofpatients ormean (SEM) is shown.S/E, simvastatinplus ezetimibe; PBO,placebo;px, thexthpercentileof the averagedeviations from individuals’fitted slopes.

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months and then, every 6 months for at least 4 years. At each of these

visits, information on RRT and all serious adverse events was recor-

ded, and blood samples were taken for serum or plasma creatinine

measurement in the site’s local routine laboratory. Samples of non-

fasting blood (and urine from those patients not on dialysis) for

central laboratory measurement were also collected from all partic-

ipants at randomization and 2.5 years and about 10% of participants

attending study visits at 1 and 4 years after the initial randomization.

These blood samples were cooled, spun, and separated before being

stored locally at240°C. Samples were then shipped on dry ice to the

central laboratory in Oxford, United Kingdom, where assays of lipids,

creatinine, cystatin C, and urinary ACR were conducted. Creatinine,

albumin, and lipids were measured using a Synchron LX20 or

DXC800 analyzer (Beckman Coulter), whereas

cystatin C was measured by immunonephelom-

etry using a Dade Behring BNII nephelometer

(Siemens AG). Creatinine was assayed using a

kinetic alkaline picrate method and calibrated

using material traceable to National Institute

of Standards and Technology Standard Refer-

ence Material 914a, with a mean expanded un-

certainty of 13.4% (7.3% excluding biologic

variation).

Statistical AnalysesThemain prespecified renal outcomewas ESRD,

defined as the initiation of maintenance dialysis

or kidney transplantation.11 Prespecified sub-

sidiary renal outcomes included the composite

outcomes ESRD or death from any cause and

ESRD or doubling of baseline creatinine. It

was also prespecified that the effect of simvastat-

in plus ezetimibe on the rate of change in eGFR

would be explored. Acute-on-chronic renal fail-

ure was reported by investigators as a serious

adverse event and not a prespecified outcome.

Analyses were from time of randomization

to initiation of simvastatin plus ezetimibe or

placebo, such that for those patients initially

allocated simvastatin (20 mg) daily, events

occurring before rerandomization were used

only to update baseline characteristics. All ana-

lysesweredone according to the intention to treat

principle.

eGFR was calculated using the four-variable

Modification of Diet in Renal Disease study

equation.16 For each patient, linear regression

was used to estimate the rate of change in

eGFR from the locally measured creatinine val-

ues (ignoring measurements after ESRD). The

validity of making such a linearity assumption

was assessed graphically. Because the reliability

of such estimated progression rates is affected

by the number of available creatinine mea-

surements (with fewer creatinine measurements

resulting in less reliable estimates of the true progression rate), partic-

ipants with fewer than three follow-up creatinine measurements were

excluded. In addition, participants with the mean deviation from

their own fitted slope in the top 1% of the distribution (of mean

deviations across all participants) were also excluded. The mean

rate of change in eGFR was then compared between participants

allocated simvastatin plus ezetimibe and participants allocated pla-

cebo (both overall and in particular patient subgroups). Sensitivity

analyses were conducted to assess the extent that the results varied if

different criteria were used for exclusion of estimated eGFR slopes

and separately using the Chronic Kidney Disease Epidemiology Col-

laboration equation.17 Analyses were performed using SAS version 9

(Cary Institute) and R version 2.11.1 (www.R-project.org).

Figure 4. Effect of allocation to simvastatin plus ezetimibe on rate of change in eGFRamong 5037 patients not on dialysis at randomization with at least three follow-upeGFRs by baseline (A) eGFR and (B) albuminuria.

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ACKNOWLEDGMENTS

The most important acknowledgement is to the participants in the

Study of Heart and Renal Protection (SHARP) and the local clinical

centre staff, regional and national coordinators, steering committee,

and data monitoring committee.

The study was funded by Merck/Schering-Plough Pharmaceu-

ticals, with additional support from the Australian National Health and

Medical Research Council, the British Heart Foundation, and the UK

Medical Research Council.

The main funding source (Merck/Schering-Plough Pharmaceu-

ticals) participated in initial discussions about trial design, contributed

two nonvoting observers to the steering committee, and had a right to

comment on (but not require changes to) study reports. It had no

involvement in data collection, analysis, interpretation, report writ-

ing, or decision to submit for publication, and it has not received an

unmasked copy of the trial database. The writing committee accepts

full responsibility for the content of this paper. All members con-

tributed to the collection and analysis of the data and the preparation

of the manuscript. All collaborators had an opportunity to contribute

to the interpretation of the results and the drafting of the manuscript.

The SHARP Steering Committee is Colin Baigent (University of

Oxford), Martin J. Landray (University of Oxford), Christina Reith

(University of Oxford), Jonathan Emberson (University of Oxford),

David C. Wheeler (University College London), Charles Tomson

(North Bristol NHS Trust), Christoph Wanner (University of

Wuerzburg), Vera Krane (University of Wuerzburg), Alan Cass

(Charles Darwin University), Jonathan Craig (University of Sydney),

Bruce Neal (University of Sydney), Lixin Jiang (Chinese Academy of

Medical Sciences and PekingUnionMedical College), Lai SeongHooi

(Sultanah Aminah Hospital), Adeera Levin (University of British

Columbia), Lawrence Agodoa (National Institutes of Health), Mike

Gaziano (Harvard Medical School), Bertram Kasiske (University of

Minnesota), Rob Walker (University of Otago), Ziad A. Massy

(University of Picardie Jules Verne), Bo Feldt-Rasmussen (University

of Copenhagen), Udom Krairittichai (Rajavithi Hospital), Vuddidhej

Ophascharoensuk (Chiang Mai University), Bengt Fellström (Uni-

versity Hospital), Hallvard Holdaas (Oslo University Hospital),

Vladimir Tesar (Charles University), Andrzej Wiecek (Medical Uni-

versity of Silesia), Diederick Grobbee (University Medical Center

Utrecht), Dick de Zeeuw (University Medical Centre Groningen),

Carola Grönhagen-Riska (Helsinki University Hospital), Tanaji

Dasgupta (Oxford University Hospitals NHS Trust), David Lewis

(University of Oxford), Will Herrington (University of Oxford),

Marion Mafham (University of Oxford), William Majoni (Royal

Darwin Hospital), Karl Wallendszus (University of Oxford), Richard

Grimm (University of Minnesota), Terje Pedersen (Oslo University

Hospital Ulleval), Jonathan Tobert (TobertMedical Consulting LLC),

Jane Armitage (University of Oxford), Alex Baxter (University of

Oxford), Christopher Bray (University of Oxford), Yiping Chen

(University of Oxford), Zhengming Chen (University of Oxford),

Michael Hill (University of Oxford), Carol Knott (University of Ox-

ford), Sarah Parish (University of Oxford), David Simpson (University

of Oxford), Peter Sleight (University of Oxford), Alan Young (Uni-

versity of Oxford), and Rory Collins (University of Oxford).

DISCLOSURESThe Study ofHeart andRenal Protection (SHARP)was initiated, conducted,

and interpreted independently of the principal study funder (Merck/Schering-

Plough Pharmaceuticals). The Clinical Trial Service Unit and Epidemiological

StudiesUnit,whicharepartof theUniversityofOxford,havea staff policyofnot

accepting honoraria or consultancy fees.

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This article contains supplemental material online at http://jasn.asnjournals.org/lookup/suppl/doi:10.1681/ASN.2013090965/-/DCSupplemental.

J Am Soc Nephrol 25: ccc–ccc, 2014 SHARP Renal Outcomes 9

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