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Colin Baigent University of Oxford, UK SHARP Chief Investigator

US FDA Endocrinologic and Metabolic Drugs Advisory Committee, 2 November 2011. Study of Heart and Renal Protection (SHARP): Safety and efficacy of ezetimibe/simvastatin in patients with Chronic Kidney Disease (CKD). Colin Baigent University of Oxford, UK SHARP Chief Investigator.

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Colin Baigent University of Oxford, UK SHARP Chief Investigator

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  1. US FDA Endocrinologic and Metabolic Drugs Advisory Committee, 2 November 2011 Study of Heart and Renal Protection (SHARP):Safety and efficacy of ezetimibe/simvastatin in patients with Chronic Kidney Disease (CKD) Colin Baigent University of Oxford, UK SHARP Chief Investigator

  2. Outline of SHARP presentation Background and rationale Study design 1 year safety of ezetimibe 5 year safety of ezetimibe/simvastatin 5 year efficacy of ezetimibe/simvastatin Context of previous statin trials Efficacy in patient subgroups

  3. CKD is common in the US population Stages 1-4 from CoreshJAMA2007 Stage 5 from USRDS 2010 Annual Data Report US population: estimated from US Census 2010

  4. Kaiser Permanente Renal Registry: Reduced kidney function is associated with higher risk of CV events 3.4 4 (N=1,120,295) 2.8 3 2.0 Hazard ratio for CV event 2 1.4 1.0 1 0 ≥60 45-59 30-44 15-29 <15 eGFR (mL/min/1.73 m2) Go et al N Engl J Med 2004

  5. MRFIT prospective study: CHD mortality vs total cholesterol among 350,000 US men 2.0 1.0 Relative risk of CHD death 0.5 160 200 240 280 Usual total cholesterol (mg/dL) Stamler et al JAMA1986

  6. All-cause mortality versus total cholesterol among 12,000 hemodialysis patients Lowrie & Lew Am J Kidney Dis1990

  7. Cholesterol Treatment Trialists(CTT) Collaboration • Collaborative meta-analysis of individual participant data from randomized trials of LDL-cholesterol (LDL-C) lowering therapy • Allows detailed analyses of effects of statins: • Efficacy outcomes: Major vascular events (major coronary events, stroke, or coronary revascularization); vascular mortality • Safety outcomes: Cancer (site-specific); non-vascular mortality • Major subgroups: Efficacy and safety in different types of patients (eg, by baseline LDL cholesterol, or by stage of kidney disease) • By follow-up time (eg, with more prolonged treatment) • Current cycle: • 21 trials of statin versus control • 5 trials of more versus less intensive statin • 24,000 major vascular events among 170,000 participants CTT Collaboration Lancet2010

  8. CTT: Similar relative reductions in MVE risk per 40 mg/dL LDL-C reduction, irrespective of presenting LDL-C No. of events (% pa) Presenting LDL-C (mg/dL) Relative risk (CI) More statin Less statin 704 (4.6) 795 (5.2) 0.71 (0.52 - 0.98) < 80 ³ 1317 (4.8) 80 <100 1189 (4.2) 0.77 (0.64 - 0.94) ³ 1065 (4.5) 1203 (5.0) 0.81 (0.67 - 0.97) 100 <120 ³ 517 (4.5) 633 (5.8) 0.61 (0.46 - 0.81) 120 <140 ³ 0.64 (0.47 - 0.86) 303 (5.7) 398 (7.8) 140 3837 (4.5) 4416 (5.3) 0.72 (0.66 - 0.78) Total 0.5 1 1.5 0.75 1.25 More statin Less statin Trend test: 2 on 1 df = 2.04 ; p=0.2 better better CTT Collaboration Lancet 2010

  9. CTT: Previous lack of evidence for reduction in MVE risk in people with eGFR below 30 mL/min/1.73m2 No. of events Estimated GFR (mL/min/1.73m2) Relative risk (CI) Statin Control 0.82 (0.44 - 1.55) 46 (4.8%) 43 (6.1%) < 30 313 (4.7%) 393 (6.0%) 0.77 (0.65 - 0.93) ³30 < 45 ³45 < 60 1154 (3.9%) 1480 (5.1%) 0.79 (0.72 - 0.86) ³60 < 90 3416 (3.2%) 4244 (4.1%) 0.80 (0.76 - 0.84) ³90 671 (2.9%) 915 (4.1%) 0.73 (0.65 - 0.82) 5802 (3.1%) 7344 (4.0%) 0.78 (0.76 - 0.81) Total 99% or 95% CI 1 0.4 0.6 0.8 1.2 1.4 Control/less better Statin/more better Trend test: 2 on 1 df = 0.61 ; p=0.43 CTT Collaboration Lancet 2010

  10. Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines for dyslipidemia in CKD Stages 1-4 CKD recommendation “There are reasonable doubts as to whether trial results from the general population are applicable to all patients with CKD.” Am J Kidney Disease 2003 HENCE: definitive trials in CKD were required

  11. 4D trial: Inconclusive evidence about the benefits of statin therapy in CKD patients RR 0.92 (95% CI 0.77 to 1.10); P=0.37 Wanner et al N Engl J Med 2005

  12. AURORA trial: Inconclusive evidence about the benefits of statin therapy in CKD patients RR 0.96; 95% CI 0.84 to 1.11; P = 0.59 Fellstrom et al N Engl J Med 2009

  13. Persisting uncertainty after AURORA “The benefits of LDL cholesterol reduction are not transferable directly from the general population to patients undergoing hemodialysis, in whom the causal pathway and disease spectrum are very different.” Strippoli GFM, Craig JC (Editorial) N Engl J Med 2009

  14. SHARP fills a gap in the evidence on lowering LDL-C in CKD patients • Does LDL-lowering therapy reduce risk of atherosclerotic disease in CKD patients? • Exclusion of CKD patients from most statin trials • Previous statin trials in CKD patients inconclusive • Can such a reduction be achieved safely? • Concerns about safety of statins in CKD patients • Combination of ezetimibe with moderate statin dose intended to minimize side-effects

  15. Cardio-renal phenotype: Reasons the effects of LDL-lowering may differ in CKD patients Arteries Atherosclerosis Increased wall thickness Arterial stiffness Endothelial dysfunction Arterial calcification Systolic hypertension Heart • Structural disease (ie, ventricular re-modelling) • Ultrastructural disease (ie, myocyte hypertrophy and capillary reduction) • Reduced left ventricular function • Valvular diseases (hyper-calcific mitral/aortic sclerosis or stenosis) • Conduction defects and arrhythmias

  16. SHARP: Sensitive to potential benefits • Emphasis on detecting effects on ATHEROSCLEROTIC outcomes • INCLUSION of coronary and non-coronary revascularization procedures • EXCLUSION of hemorrhagic stroke and non-coronary cardiac death from key outcome

  17. Heart Protection Study: Statins prevent both coronary and non-coronary revascularizations Simvastatin Placebo Risk ratio and 95% CI (10 269) (10 267) Revascularizations Coronary 513 725 Non-coronary 450 532 24% SE 4 Any revascularization 939 1205 reduction 2P<0.00001 (9.1%) (11.7%) 0.4 0.6 0.8 1.0 1.2 1.4 Statin better Placebo better Heart Protection Study Collaborative Group Lancet 2002

  18. SHARP: Sensitive to potential benefits • Emphasis on detecting effects on ATHEROSCLEROTIC outcomes • INCLUSION of coronary and non-coronary revascularization procedures • EXCLUSION of non-coronary cardiac death and hemorrhagic stroke from key outcome

  19. Dialysis patients: Small minority ofvascular deaths are atherosclerotic 27% USRDS 2005 Annual Data Report

  20. Statins do not prevent non-coronary cardiac deaths:Evidence from two large trials in heart failure 1 CORONA Investigators N Engl J Med 2007; 2GISSI-HFInvestigators Lancet 2008

  21. CTT: No reduction in hemorrhagic stroke Events (%) RR (CI) per 1 mmol/L reduction in LDL-C Statin/more Control/less Statin vs control 15 trials in CTT 188/56227 163/56294 1.10 (0.91 - 1.34) 1.44 (0.97 - 2.14) 55 (2.3%) 33 (1.4%) SPARCL 1.36 (0.71 - 2.62) 15 (0.6%) 9 (0.4%) CORONA Subtotal (17 trials) 258/61106 205/61157 1.21 (1.03 - 1.41) More vs less statin Subtotal (5 trials) 69/19829 57/19783 1.39 (0.70 - 2.74) Total (22 trials) 1.21 (1.05 - 1.41) 327/80935 262/80940 99% or 95% CI 0.5 0.75 1 1.25 1.5 Statin/more Control/less better better CTT Collaboration Lancet 2010

  22. SHARP: Sensitive to potential benefits • Emphasis on detecting effects on ATHEROSCLEROTIC outcomes • INCLUSION of coronary and non-coronary revascularization procedures • EXCLUSION of non-coronary cardiac death and hemorrhagic stroke from key outcome • Large number of relevantoutcomes and long duration of treatment to maximize power

  23. SHARP: Much larger, longer duration, andkey focus on atherosclerotic outcomes

  24. Study design

  25. SHARP: Wide inclusion criteria • History of chronic kidney disease (CKD) • Not on dialysis: elevated creatinine on 2 occasions • Men: ≥1.7 mg/dL (150 µmol/L) • Women: ≥1.5 mg/dL (130 µmol/L) • On dialysis: hemodialysis or peritoneal dialysis • Age ≥40 years • No history of myocardial infarction or coronary revascularization

  26. SHARP: Initial randomization Randomized (9438) placebo (4191) eze/simva (4193) simvastatin (1054) 1 year • Effects of ezetimibe on: • Safety outcomes • Lipid profile

  27. 1 year SAFETY and lipid differences

  28. SHARP: 1 year safety SHARP Collaborative Group Am Heart J 2010

  29. Effect on LDL-cholesterol (LDL-C) at 1 year ofthree-quarters compliance with eze/simva SHARP Collaborative Group Am Heart J 2010

  30. Main comparison: all PARTICIPANTS randomizedeze/simvavs placebo

  31. SHARP: Randomization structure Randomized (9438) placebo 4191 eze/simva 4193 simvastatin 1054 + 457 886 re-randomized + 429 eze/simva 4650 placebo 4620 4.9 years Main analyses of safety and efficacy

  32. Sex and age at randomization

  33. Numbers randomized in each region

  34. Vascular disease and diabetes at randomization

  35. Renal status at randomization • *eGFR in mL/min/1.73m2

  36. Lipid profile (mg/dL) at randomization

  37. Effect of eze/simva on lipid profile at approximate study midpoint (mg/dL)

  38. Impact of net compliance with study treatment on achieved LDL-C differences during the trial Net compliance is defined as the difference between groups in the proportion that were taking at least 80% of study treatment or a non-study statin

  39. Impact of net compliance with study treatment on achieved LDL-C differences during the trial Net compliance is defined as the difference between groups in the proportion that were taking at least 80% of study treatment or a non-study statin

  40. Reasons for stopping study treatment *Suspected serious adverse reaction: 4 more patients (3 allocated eze/simva and 1 allocated placebo) had a SSAR but continued to take study medication

  41. Reasons for stopping study treatment:Use of contraindicated treatment

  42. Completeness of follow-up at study end

  43. STATISTICAL analysis plan

  44. Statistical Analysis Plan: Key analyses SHARP Collaborative Group Am Heart J 2010 • Key outcome is major atherosclerotic events (MAE): • Non-fatal MI or coronary death; • Non-hemorrhagic stroke; or • revascularization (i.e. exclude non-CHD cardiac death and hemorrhagic stroke) among ALL randomized patients allocated eze/simva vs placebo (including those re-randomized after one year on simvastatin alone)

  45. Statistical Analysis Plan: Subsidiary analyses SHARP Collaborative Group Am Heart J 2010 • Subsidiary analyses: • Original protocol-defined primary outcome of major vascular events (MVE: non-fatal MI or cardiac death, any stroke, or any revascularization) among patients initially allocated to eze/simva versus placebo • Separate components of major atherosclerotic events • Major coronary events (coronary death or non-fatal MI) • Ischemic stroke • Coronary or non-coronary revascularization • End-stage renal disease (ESRD): progression to long-term dialysis or transplantation among patients not on dialysis at randomization

  46. SHARP: Statistical power for detectingexpected effects on specific outcomes *Based on data from CTT Collaboration Lancet 2010

  47. Statistical Analysis Plan: Tertiary analyses SHARP Collaborative Group Am Heart J 2010 MAEs in subgroups (including baseline renal function) Mortality: overall, and subdivided by cause Cancers, subdivided by site Stroke: overall, and by subtype Transient ischemic attacks Hospital admission for angina Hospital admission for heart failure New diabetes mellitus Revision of vascular access for dialysis ESRD or death from any cause; ESRD or creatinine doubling (among those not on dialysis at randomization)

  48. Statistical Analysis Plan: Safety outcomes SHARP Collaborative Group Am Heart J 2010 • Muscle-related outcomes • Muscle pain or weakness • CK elevations: > 5 ≤ 10 x ULN; > 10 ≤ 40 x ULN; and ≥ 40 x ULN; subdivided by symptoms and presence of end-organ damage • Liver-related outcomes • Hepatitis, subdivided by infective, non-infective, no known cause • Persistently elevated liver transaminases • Complications of gallstones • Acute pancreatitis with gallstones, cholelithiasis requiring admission, other gallstone complications • Pancreatitis without gallstones, acute and chronic separately

  49. Event adjudication procedures • Documentation sought on pre-specified SAEs (including vascular outcomes, renal events, deaths, cancer and safety outcomes) • Redaction of text relating to lipids and treatment allocation, and material scanned • Doctors adjudicated using standard procedures • Blind to treatment allocation • Further information sought if necessary • Quality control with independent re-adjudication • 12,453 events required adjudication • Only 1% could not be adjudicated

  50. MAIN COMPARISON: Safety data

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