Article the Effect of Lowering LDL Cholesterol on Vascular

Article

The Effect of Lowering LDL Cholesterol on Vascular Access Patency: Post Hoc Analysis of the Study of Heart and Renal Protection

William Herrington, Jonathan Emberson, Natalie Staplin, Lisa Blackwell, Bengt Fellstro¨m, Robert Walker, Adeera Levin, Lai Seong Hooi, Ziad A. Massy, Vladimir Tesar, Christina Reith, Richard Haynes, Colin Baigent, and Martin J. Landray on behalf of the SHARP Investigators Due to the number of contributing authors, Abstract the afﬁliations are Background and objectives Reducing LDL cholesterol (LDL-C) with statin-based therapy reduces the risk of provided in the major atherosclerotic events among patients with CKD, including dialysis patients, but the effect of lowering Supplemental LDL-C on vascular access patency is unclear. Material.

Design, setting, participants, & measurements The Study of Heart and Renal Protection (SHARP) randomized Correspondence: Dr. Martin J. Landray, patients with CKD to 20 mg simvastatin plus 10 mg ezetimibe daily versus matching placebo. This study aimed to Clinical Trial Service explore the effects of treatment on vascular access occlusive events, defined as any access revision procedure, Unit and access thrombosis, removal of an old dialysis access, or formation of new permanent dialysis access. Epidemiological Studies Unit, Nuffield Results Among 2353 SHARP participants who had functioning vascular access at randomization, allocation to Department of Population Health, simvastatin plus ezetimibe resulted in a 13% proportional reduction in vascular access occlusive events (355 Richard Doll Building, [29.7%] for simvastatin/ezetimibe versus 388 [33.5%] for placebo; risk ratio [RR], 0.87; 95% confidence interval Old Road Campus, [95% CI], 0.75 to 1.00; P=0.05). There was no evidence that the effects of treatment differed for any of the separate Roosevelt Drive, components of this outcome. To test the hypothesis raised by SHARP, comparable analyses were performed Oxford OX3 7LF, UK. Email: martin.landray@ using the AURORA (A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An ndph.ox.ac.uk Assessment of Survival and Cardiovascular Events) trial cohort. AURORA did not provide independent con- firmation (vascular access occlusive events: 352 [28.9%] for rosuvastatin versus 337 [27.6%] for placebo; RR, 1.06, 95% CI, 0.91 to 1.23; P=0.44). After combining the two trials, the overall effect of reducing LDL-C with a statin- based regimen on vascular access occlusive events was not statistically significant (707 [29.3%] with any LDL-C– lowering therapy versus 725 [30.5%] with placebo; RR, 0.95, 95% CI, 0.85 to 1.05; P=0.29).

Conclusions Exploratory analyses from SHARP suggest that lowering LDL-C with statin-based therapy may improve vascular access patency, but there was no evidence of beneﬁtinAURORA.Takentogether,the available evidence suggests that any beneﬁts of lowering LDL-C on vascular access patency are likely to be modest. Clin J Am Soc Nephrol 9: 914–919, 2014. doi: 10.2215/CJN.10371013

Introduction simvastatin plus 10 mg ezetimibe daily versus match- Arteriovenous fistulae (AVF) are the preferred form of ing placebo and showed that lowering LDL cholesterol vascular access for dialysis, but both AVF and par- (LDL-C) safely reduces the risk of major atherosclerotic ticularly arteriovenous (AV) grafts are prone to loss of events (10). This trial included 2353 patients with a patency (1). Because maintaining functioning vascu- functioning AVF or AV graft at the time of randomi- lar access is vital for hemodialysis patients and its zation, and therefore provides an opportunity to ex- management accounts for a significant proportion of plore the effects of lowering LDL-C with simvastatin thecostofdialysis(includingaround20%oftheir plus ezetimibe on vascular access patency in a large hospital admissions) (2), strategies to reduce compli- placebo-controlled randomized trial. cation rates are needed. Although statins are regu- In a tertiary analysis of all randomized SHARP pa- larly discussed in review articles as a medical tients performed for regulatory submission, alloca- therapy that might improve vascular access outcomes tion to simvastatin plus ezetimibe was associated (3–6), observational cohort studies have not provided with a nonsignificantly lower risk of hemodialysis ac- any evidence to suggest that they may do so (7–9). cess revision (561 [12.1%] for simvastatin plus ezetimibe The Study of Heart and Renal Protection (SHARP) versus 606 [13.1%] for placebo; risk ratio [RR], 0.92; randomized 9270 patients with CKD to 20 mg 95% confidence interval [95% CI], 0.82 to 1.03; P=0.13).

914 Copyright © 2014 by the American Society of Nephrology www.cjasn.org Vol 9 May, 2014 Clin J Am Soc Nephrol 9: 914–919, May, 2014 Lowering LDL Cholesterol and Vascular Access Patency, Herrington et al. 915

This report explores the effects of treatment on vascular ac- vascular access events, were completed at each visit. The cess patency in more detail, and assesses the results of the SHARP definitions and analysis methods were repli- SHARP trial in the context of the effects of 10 mg rosuvastatin cated in the AURORA dataset. Both the SHARP and on the same outcomes in the AURORA (A Study to Eval- AURORA trials are registered with ClinicalTrials.gov uate the Use of Rosuvastatin in Subjects on Regular Hemo- (SHARP, NCT00125593 and ISRCTN54137607; AURORA, dialysis: An Assessment of Survival and Cardiovascular NCT00240331). Events) trial. Statistical Analyses The effects of treatment allocation on the time to first Materials and Methods event were examined using log-rank methods to calculate Study Design and Participants two-sided P values, event RRs, and confidence intervals Details of the SHARP trial design and its main results are (CIs) (14,15), irrespective of whether participants subse- published elsewhere (10,11). Briefly, individuals aged $40 quently took their allocated treatment (i.e., according to years were eligible to participate if they had .1 previous the intention-to-treat principle). A sensitivity analysis us- measurement of serum or plasma creatinine of at least 1.7 ing all (i.e., not just first events) events was performed mg/dl (150 mmol/L) in men or 1.5 mg/dl (130 mmol/L) in using a negative binomial model. Proportional risk reduc- women, or were receiving maintenance dialysis. Patients tions in different subgroups were compared using stan- with prior myocardial infarction or coronary revasculari- dard chi-squared tests for heterogeneity or trend. To zation were excluded. Ethical approval was obtained at all allow for multiple testing by subdivisions, only overall SHARP study sites before enrollment. Potentially eligible summary RRs have 95% CIs; all other RRs have 99% CIs. patients attended a screening visit at which written in- Analyses were conducted using SAS (version 9.3; SAS In- formed consent was obtained and medical history, includ- stitute, Cary, NC) and R (version 2.11.1; R Project for Sta- ing presence of functioning vascular access, was recorded. tistical Computing, Vienna, Austria) software. After 6 weeks of placebo run-in, the participants were randomized in a 4:4:1 ratio to 20 mg simvastatin plus 10 mg ezetimibe daily versus matching placebo versus 20 mg Results simvastatin alone. Participants who were allocated to sim- Of the 9270 SHARP participants randomized to simva- vastatin alone were rerandomized after 1 year to one of the statin plus ezetimibe versus placebo, 2353 had a functioning two main comparison arms. After initial randomization, AVF or AV graft at randomization (1196 allocated to participants were followed-up in study clinics at 2 and 6 simvastatin plus ezetimibe and 1157 allocated to placebo). months and then every 6 months for at least 4 years. At Among those with a functioning AVF or AV graft, baseline each of these visits, information on vascular access proce- characteristics were balanced between the randomized dures and all hospitalizations was specifically requested. groups for all variables except sex (P for sex = 0.03; Table More information about SHARP, including a copy of the 1). The mean age was 59612 years. Of the participants, trial protocol, is available at www.sharpinfo.org. 1520 (65%) were men, 525 (22%) had diabetes mellitus, To explore the effects of allocated treatment on vascular and 372 (16%) were smokers. The majority of participants access patency, we identified codes for serious adverse (2152 [91%]) were already on dialysis at randomization. events that represented loss of patency, and defined post The type of vascular access was an AVF in the majority hoc the composite outcome “vascular access occlusive (2204 [94%]), with the remainder being AV grafts (149 event” as any access revision procedure (percutaneous an- [6%]). A total of 729 (31%) participants were taking anti- gioplasty, embolectomy, or surgical repair), any access platelet therapy at baseline and 1297 (55%) were taking an thrombosis event, or the removal of old/formation of erythropoiesis-stimulating agent. Mean hemoglobin was new permanent dialysis access (which included placement 11.761.6 g/dl and mean LDL-C was 99633 mg/dl. of a new AVF, AV graft, or tunnelled dialysis–catheter). During a median 5 years of follow-up, the average LDL-C Analyses were restricted to those participants known to reduction was 26 mg/dl. A first vascular access occlusive have a functioning AVF or AV graft at randomization event occurred in 355 (29.7%) of 1196 participants allocated to (i.e., preexisting/prevalent vascular access). simvastatin plus ezetimibe compared with 388 (33.5%) among Because these SHARP analyses are post hoc,weexplored 1157 participants allocated to placebo (RR, 0.87; 95% CI, 0.75 other possible sources of trial data on the effects of statin- to 1.00; P=0.05; Figure 1). Similar results were obtained after based treatment on vascular access patency. Of the two adjustment for the baseline imbalance in sex (RR, 0.86; 95% other large-scale statin trials among dialysis patients [Die CI, 0.75 to 1.00; P=0.04) and in an analysis that included first Deutsche Diabetes Dialyze and AURORA (12,13)], only and any subsequent occlusive events (634 in the simvastatin the AURORA trial recorded the necessary information to plus ezetimibe group versus 664 in the placebo group; RR, define vascular access occlusive events. The full details of 0.92; 95% CI, 0.78 to 1.08; P=0.26). There was insufficient the AURORA study design are published elsewhere (13). statistical power to estimate the effects of simvastatin plus Ethical approval was obtained at all AURORA study sites ezetimibeoneachseparatetypeofevent,buttherewasno before enrollment. After providing written informed con- evidence that the effects of simvastatin plus ezetimibe on any sent, eligible individuals aged 50–80 years on maintenance type differed from the overall estimated effect on vascular hemodialysis were randomized 1:1 to 10 mg rosuvastatin access occlusive events (P for heterogeneity=0.83; Figure 1). daily versus matching placebo. Follow-up was at 3 and 6 There was also limited power to detect any possible variation months after randomization, and then every 6 months. in treatment effects among different types of participants Structured interviews, including documentation of any and, after allowance for multiplicity of analyses, subgroup 916 Clinical Journal of the American Society of Nephrology

Table 1. Baseline characteristics among SHARP and AURORA participants with preexisting access at randomization, by treatment allocation

SHARP AURORA

Characteristic Simvastatin Plus Placebo Rosuvastatin Placebo Ezetimibe (n=1196) (n=1157) (n=1219) (n=1220)

Age at randomization (yr)a 59612 59612 64696469 Men 747 (62) 773 (67) 759 (62) 794 (65) Prior diabetes mellitus 267 (22) 258 (22) 328 (27) 282 (23) Current smoker 184 (15) 188 (16) 172 (14) 203 (17) Renal statusa On dialysis 1091 (91) 1061 (92) 1219 (100) 1220 (100) Not on dialysis 105 (9) 96 (8) Access typea Arteriovenous ﬁstula 1119 (94) 1085 (94) 1090 (89) 1109 (91) Arteriovenous graft 77 (6) 72 (6) 129 (11) 111 (9) Comedicationa Antiplatelet therapy 373 (31) 356 (31) 528 (43) 513 (42) Oral anticoagulant therapy 44 (4) 47 (4) 75 (6) 111 (9) Erythropoiesis-stimulating 660 (55) 637 (55) 1056 (87) 1079 (88) agent BP (mmHg)a Systolic 139623 139623 137624 137624 Diastolic 77613 76613 76613 76613 Laboratory measurements LDL cholesterol (mg/dl) 98634 99633 101635 101635 Hemoglobin (g/dl) 11.761.5 11.761.7 11.761.6 11.761.6

Data are presented as the n (%) or mean6SD. SHARP, Study of Heart and Renal Protection; AURORA, A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events. aVariables updated at 1 year for patients in SHARP originally allocated to simvastatin alone and who were rerandomized to simvastatin plus ezetimibe or placebo.

Figure 1. | Effects of allocation to simvastatin plus ezetimibe on vascular access occlusive events among SHARP participants with preexisting access at randomization. CI, confidence interval; SHARP, Study of Heart and Renal Protection. analyses did not provide strong evidence that the propor- AURORA dataset. Of 2776 hemodialysis patients in AURORA, tional reduction in vascular access occlusive events differed 2439 had an AVF or AV graft at randomization (1219 allo- according to whether participants had an AVF or an AV cated to rosuvastatin and 1220 allocated to placebo; Table 1). graft, had a history of diabetes mellitus, were current smok- During a median 4.5 years of follow-up, there was no sig- ers, had higher baseline LDL-C, or were taking antiplatelet nificant effect on vascular access occlusive events (352 [28.9%] therapy or erythropoiesis-stimulating agents (Figure 2). in the rosuvastatin group versus 337 [27.6%] in the placebo Because our analyses were post hoc, and the effect iden- group; RR, 1.06; 95% CI, 0.91 to 1.23; P=0.44). After combin- tified was of marginal statistical significance, the SHARP ing the results of the SHARP and AURORA trials, the over- definitions and analysis methods were replicated in the all effect of reducing LDL-C with a statin-based regimen on Clin J Am Soc Nephrol 9: 914–919, May, 2014 Lowering LDL Cholesterol and Vascular Access Patency, Herrington et al. 917

Figure 2. | Effects of allocation to simvastatin plus ezetimibe on vascular access occlusive events in SHARP participants with preexisting access at randomization, by patient subtypes. vascular access occlusive events was not statistically sig- although the CI was wide and still remained compatible nificant (707 [29.3%] of participants who received any with a modest benefit. Because vascular access occlusion is LDL-C–lowering therapy versus 725 [30.5%] participants common and has a major detrimental effect on patient care, whoreceivedplacebo;RR,0.95;95%CI,0.85to1.05; even a small proportional effect of statin-based treatment P=0.29; Figure 3). There was no good evidence that the could be worthwhile. effect of lowering LDL-C on vascular access occlusive events Although the available randomized trial data do not differed between the two studies, either overall (P for confirm a clear benefit of lowering LDL-C on vascular heterogeneity=0.06), or when access types were considered access patency, a small favorable effect is biologically separately (Figure 3). plausible. Neointimal hyperplasia, the main reason for loss of patency of both AVF and AV grafts, is induced by a cascade of inflammatory mediators that are the conse- Discussion quence of injury from surgery, increased hemodynamic Among 2353 participants in the SHARP trial who had stress, and/or repeated needling. The venous stenoses that a functioning AVF or AV graft at randomization, post result are characterized by the proliferation of smooth hoc analyses indicated that allocation to simvastatin plus muscle cells with a myofibroblastic phenotype, as well as ezetimibe resulted in a 13% proportional reduction in the risk their migration (with macrophages) into the vessel’s intima of a vascular access occlusive event. It remains unclear, (16–18). Statin-based therapy might slow progression of however, whether this finding reflects a biologic effect or neointimal hyperplasia by reducing vascular smooth mus- whether it is wholly or partly attributable to chance, be- cle cell proliferation (19–23), smooth muscle cell migration cause the finding was of only marginal statistical signifi- (22), and monocyte activation (24), effects that are not cance (log-rank P=0.05). The hypothesis raised by SHARP known to be mediated through the LDL-C–lowering could, however, be tested because the AURORA trial col- effect of hepatic hydroxymethyl glutaryl–CoA reductase lected information about events related to vascular access. inhibition. Separate hypothesis-testing analysis of data on vascular Statin-based therapy could also have a beneficial effect access occlusive events from the AURORA trial did not on access through LDL-C dependent pathways, maintain- confirm our findings. Taken together, the combined results ing afferent blood flow by preventing atherosclerotic of the two trials did not reach statistical significance, coronary (25) and peripheral arterial disease (26), which 918 Clinical Journal of the American Society of Nephrology

Figure 3. | Effects of allocation to LDL-C–lowering therapy on vascular access occlusive events in SHARP and AURORA participants with preexisting access at randomization, subdivided by access type. AURORA, A Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events; LDL-C, LDL cholesterol. are both associated with failure of vascular access matura- RobertWalker,ZiadA.Massy,BoFeldt-Rasmussen,UdomKrairittichai, tion (27). Vuddidhej Ophascharoensuk, Bengt Fellström, Hallvard Holdaas, After formation, successful access maturation requires Vladimir Tesar, Andrzej Wiecek, Diederick Grobbee, Dick de Zeeuw, vessel outward remodeling, a process that statins may also Carola Gronhagen-Riska, Tanaji Dasgupta, David Lewis, William promote by increasing endothelial nitric oxide availability Herrington, Marion Mafham, William Majoni, Karl Wallendszus, (23,28). However, in SHARP, it was only possible to test Richard Grimm, Terje Pedersen, Jonathan Tobert, Jane Armitage, reliably for any benefit on preexisting (prevalent) vascular Alex Baxter, Christopher Bray, Yiping Chen, Zhengming Chen, access. An unbiased test of any benefit on newly formed Michael Hill, Carol Knott, Sarah Parish, David Simpson, Peter (incident) access would require a trial that randomized Sleight, Alan Young, and Rory Collins. participants at the time of access formation. To maximize any LDL-C–independent effects, such a trial would need Disclosures to consider using higher doses of statins than were used in The SHARP trial was funded by Merck/Schering-Plough Phar- either the SHARP or AURORA trials (although the clinical maceuticals (North Wales, PA), with additional support from the safety of such an approach would also need to be tested Australian National Health Medical Research Council, the British robustly). Heart Foundation, and the UK Medical Research Council. SHARP Post hoc analysis of a subgroup of participants from a was initiated, conducted, and interpreted independently of the trial should be interpreted cautiously. A key strength of funders by the Clinical Trial Service Unit and Epidemiological our analyses, however, was the availability of the AURORA Studies Unit (CTSU), which is part of the University of Oxford. data to test the hypothesis raised by SHARP. AURORA was designed by an executive steering committee, which ’ Exploratory analyses from SHARP suggested that low- supervised the trial s conduct. AURORA was conducted in collab- ering LDL-C with statin-based therapy may improve oration with the sponsor, AstraZeneca, who collected the trial data. post hoc vascular access patency in patients with preexisting access. CTSU conducted and interpreted all of the vascular access This hypothesis was not supported by a reanalysis of analyses for both studies independently of the funders. CTSU has a AURORA. Taken together, a small benefit of statin-based staff policy of not accepting honoraria or consultancy fees. therapy on vascular access patency cannot be excluded, but any such effect is of less clinical relevance than the clear References fi bene t of lowering LDL-C on atherosclerotic events (10). 1. Allon M, Robbin ML: Increasing arteriovenous fistulas in hemodialysis patients: Problems and solutions. Kidney Int 62: 1109– 1124, 2002 Acknowledgments 2. Arora P, Kausz AT, Obrador GT, Ruthazer R, Khan S, Jenuleson The authors thank the participants in the SHARP and AURORA CS, Meyer KB, Pereira BJ: Hospital utilization among chronic trials, as well as the local clinical center staff, regional and national dialysis patients. J Am Soc Nephrol 11: 740–746, 2000 coordinators, steering committees, and data monitoring committees. 3. Florescu MC, Birch N: Statin therapy and hemodialysis vascular Members of the SHARP Steering Committee are as follows: Colin access—Were we bringing a knife to a gunfight and were hoping to win? Semin Dial 25: 700–702, 2012 Baigent, Martin J. Landray, Christina Reith, Jonathan Emberson, 4. Jackson AJ, Coats P, Kingsmore DB: Pharmacotherapy to im- David C. Wheeler, Charles Tomson, Christoph Wanner, Vera Krane, prove outcomes in vascular access surgery: A review of current Alan Cass, Jonathan Craig, Bruce Neal, Lixin Jiang, Lai Seong Hooi, treatment strategies. Nephrol Dial Transplant 27: 2005–2016, Adeera Levin, Lawrence Agodoa, Mike Gaziano, Bertram Kasiske, 2012 Clin J Am Soc Nephrol 9: 914–919, May, 2014 Lowering LDL Cholesterol and Vascular Access Patency, Herrington et al. 919

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William Herrington1, Jonathan Emberson1, Natalie Staplin1, Lisa Blackwell1, Bengt Fellström2, Robert Walker3, Adeera Levin4, Lai Seong Hooi5, Ziad A. Massy6, Vladimir Tesar7, Christina Reith1, Richard Haynes1, Colin Baigent1, and Martin J. Landray1 on behalf of the SHARP Investigators

1 Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom

2 Department of Nephrology, University Hospital, Uppsala, Sweden

3 Dunedin School of Medicine, University of Otago, Otago, New Zealand

4 University of British Columbia, Vancouver, British Columbia, Canada

5 Department of Medicine and Haemodialysis Unit, Sultanah Aminah Hospital, Johor Bahru, Malaysia

6 Division of Nephrology, Ambroise Paré University Hospital, Paris Ile de France Ouest (UVSQ) University, Paris, France, and INSERM U-1088, Amiens University Hospital, University of Picardie Jules Verne, Amiens, France

7 Department of Nephrology, First Faculty of Medicine, Charles University and General University Hospital, Prague, Czech Republic