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The results of the Study of Heart and Renal Protection (SHARP)

The results of the Study of Heart and Renal Protection (SHARP). Colin Baigent, Martin Landray on behalf of the SHARP Investigators

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The results of the Study of Heart and Renal Protection (SHARP)

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  1. The results of the Study of Heart and Renal Protection (SHARP) Colin Baigent, Martin Landray on behalf of the SHARP Investigators Disclosure: SHARP was sponsored, designed, run, and analysed by the University of Oxford. Funding was received from Merck, the UK MRC, British Heart Foundation, and Australian NHMRC. Presented at the Am. Soc. Nephrology, Denver, Nov 20th 2010

  2. SHARP: Rationale • Risk of vascular events is high among patients with chronic kidney disease • Lack of clear association between cholesterol level and vascular disease risk • Pattern of vascular disease is atypical, with a large proportion being non-atherosclerotic • Previous trials of LDL-lowering therapy in chronic kidney disease are inconclusive Presented at the Am. Soc. Nephrology, Denver, Nov 20th 2010

  3. SHARP: Eligibility History of chronic kidney disease 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: haemodialysis or peritoneal dialysis Age ≥40 years No history of myocardial infarction or coronary revascularization Uncertainty: LDL-lowering treatment not definitely indicated or contraindicated Presented at the Am. Soc. Nephrology, Denver, Nov 20th 2010

  4. SHARP: Assessment of LDL-lowering

  5. SHARP: Baseline characteristics Age (years) 62 ± 12 Men 63% Systolic BP (mmHg) 139 ± 22 Diastolic BP (mmHg) 79 ± 13 Body mass index (kg/m2) 27 ± 6 Current smoker 13% Vascular disease 15% Diabetes mellitus 23% Non-dialysis patients only (n=6247) eGFR (ml/min/1.73m2) 27 ± 13 Albuminuria 80% Presented at the Am. Soc. Nephrology, Denver, Nov 20th 2010

  6. SHARP: Compliance and LDL-C reductionat study midpoint Eze/simva Placebo Compliant 66% 64% Non-study statin 5% 8% Any lipid-lowering 71% 8% ~2/3 compliance LDL-C reduction of 32 mg/dL with 2/3 compliance, equivalent to 50 mg/dL with full compliance Presented at the Am. Soc. Nephrology, Denver, Nov 20th 2010

  7. SHARP: Baseline paperand data analysis plan Study of Heart and Renal Protection (SHARP): Randomized trial to assess the effects of lowering low-density lipoprotein cholesterol among9,438 patients with chronic kidney disease • 1-year LDL-C reduction of 30 mg/dL with simvastatin 20 mg alone and of 43 mg/dL with eze/simva 10/20 mg • Confirmation of safety of ezetimibe when added to simvastatin (1-year results) • Revised data analysis plan published as an appendix before unblinding of main results SHARP Collaborative Group. Am Heart J 2010 (in press)

  8. SHARP: Main outcomes • Key outcome • Major atherosclerotic events (coronary death, MI, non-haemorrhagic stroke, or any revascularization) • Subsidiary outcomes • Major vascular events (cardiac death, MI, any stroke, or any revascularization) • Components of major atherosclerotic events • Main renal outcome • End-stage renal disease (dialysis or transplant) Presented at the Am. Soc. Nephrology, Denver, Nov 20th 2010

  9. SHARP: Major atherosclerotic events 25 20 Risk ratio 0.83 (0.74-0.94) Logrank 2P=0.0022 Placebo 15 Proportion suffering event (%) 10 Eze/simva 5 0 0 1 2 3 4 5 Years of follow-up Presented at the Am. Soc. Nephrology, Denver, Nov 20th 2010

  10. SHARP 17% risk reduction CTT: Effects on major atherosclerotic events 30 Statin vs. control (21 trials) 25 More vs. less (5 trials) 20 Proportional reduction in atherosclerotic event rate (95% CI) 15 10 SHARP 32 mg/dL 5 0 0 10 20 30 40 Mean LDL-C difference between treatment groups (mg/dL) Presented at the Am. Soc. Nephrology, Denver, Nov 20th 2010

  11. SHARP: Major atheroscleroticand vascular events Eze/simva (n=4650) Placebo (n=4620) Risk ratio (95% CI) Major coronary event Non-haemorrhagic stroke Any revascularization Major atherosclerotic event Other cardiac death Haemorrhagic stroke Other major vascular events Major vascular event 213 131 284 526 162 45 207 701 (4.6%) (2.8%) (6.1%) (11.3%) (3.5%) (1.0%) (4.5%) (15.1%) 230 174 352 619 182 37 218 814 (5.0%) (3.8%) (7.6%) (13.4%) (3.9%) (0.8%) (4.7%) (17.6%) 16.5% SE 5.4 (P=0.0022) 5.4% SE 9.4 (P=0.57) 15.3% SE 4.7 (P=0.0012) 0.6 0.8 1.0 1.2 1.4 Eze/simva better Placebo better Presented at the Am. Soc. Nephrology, Denver, Nov 20th 2010

  12. SHARP: Effects in subgroups • Among 8384 patients originally randomized to ezetimibe/simvastatin vs. placebo, major vascular events risk ratio = 0.84(95% CI 0.75-0.93; P=0.0010) • Similar reductions in major atherosclerotic events in all subgroups studied (includingnon-dialysis and dialysis patients) Presented at the Am. Soc. Nephrology, Denver, Nov 20th 2010

  13. SHARP: Major atherosclerotic events by renal status at randomization Eze/simva (n=4650) Placebo (n=4620) Risk ratio (95% CI) Non-dialysis (n=6247) Dialysis (n=3023) Major atherosclerotic event 296 230 526 (9.5%) (15.0%) (11.3%) 373 246 619 (11.9%) (16.5%) (13.4%) 16.5% SE 5.4 (P=0.0022) No significant heterogeneity between non-dialysis and dialysis patients (P=0.25) 0.6 0.8 1.0 1.2 1.4 Eze/simva better Placebo better Presented at the Am. Soc. Nephrology, Denver, Nov 20th 2010

  14. SHARP: Cause-specific mortality Eze/simva (n=4650) Placebo (n=4620) Risk ratio (95% CI) Coronary Other cardiac Subtotal: Any cardiac Stroke Other vascular Subtotal: Any vascular Cancer Renal Other non-vascular Subtotal: Any non-vascular Unknown cause Total: Any death 91 162 253 68 40 361 150 164 354 668 113 1142 (2.0%) (3.5%) (5.4%) (1.5%) (0.9%) (7.8%) (3.2%) (3.5%) (7.6%) (14.4%) (2.4%) (24.6%) 90 182 272 78 38 388 128 173 311 612 115 1115 (1.9%) (3.9%) (5.9%) (1.7%) (0.8%) (8.4%) (2.8%) (3.7%) (6.7%) (13.2%) (2.5%) (24.1%) ↓7.4% SE 8.4 (P=0.38) ↓7.3% SE 7.0 (P=0.30) ↑8.6% SE 5.8 (P=0.14) ↑1.9% SE 4.2 (P=0.65) 0.6 0.8 1.0 1.2 1.4 Eze/simva better Placebo better Presented at the Am. Soc. Nephrology, Denver, Nov 20th 2010

  15. SHARP: Renal outcomes Eze/simva (n=3117) Placebo (n=3130) Risk ratio (95% CI) Main renal outcome End-stage renal disease(ESRD) Tertiary renal outcomes ESRD or death ESRD or 2 x creatinine 1057 1477 1190 (33.9%) (47.4%) (38.2%) 1084 1513 1257 (34.6%) (48.3%) (40.2%) 0.97 (0.89-1.05) 0.97 (0.90-1.04) 0.94 (0.86-1.01) 0.6 0.8 1.0 1.2 1.4 Eze/simva better Placebo better Presented at the Am. Soc. Nephrology, Denver, Nov 20th 2010

  16. SHARP: Cancer incidence 25 20 Risk ratio 0.99 (0.87-1.13) Logrank 2P=0.89 15 Proportion suffering event (%) 10 Placebo Eze/simva 5 0 0 1 2 3 4 5 Years of follow-up Presented at the Am. Soc. Nephrology, Denver, Nov 20th 2010

  17. SHARP: Cancer incidence by site Eze/simva (n=4650) Placebo (n=4620) Oropharynx/oesophagus Stomach Bowel Pancreas Hepatobiliary Lung Other respiratory Skin cancer Breast Prostate Kidney Bladder & urinary tract Genital Haematological Other known site Unspecified site Any incident cancer 14 11 53 9 8 42 3 136 29 39 31 26 12 26 9 13 438 16 14 35 10 4 35 4 153 21 52 23 32 14 27 12 7 439 (9.4%) (9.5%) No significant differences Presented at the Am. Soc. Nephrology, Denver, Nov 20th 2010

  18. SHARP: Safety Eze/simva (n=4650) Placebo (n=4620) • Myopathy • CK >10 x but ≤40 x ULN • CK >40 x ULN • Hepatitis • Persistently elevated ALT/AST >3x ULN • Complications of gallstones • Other hospitalization for gallstones • Pancreatitis without gallstones 17 (0.4%) 4 (0.1%) 21 (0.5%) 30 (0.6%) 85 (1.8%) 21 (0.5%) 12 (0.3%) 16 (0.3%) 5 (0.1%) 18 (0.4%) 26 (0.6%) 76 (1.6%) 30 (0.6%) 17 (0.4%) Presented at the Am. Soc. Nephrology, Denver, Nov 20th 2010

  19. SHARP: Conclusions • No increase in risk of myopathy, liver and biliary disorders, cancer, or non-vascular mortality • No substantial effect on kidney disease progression • Two-thirds compliance with eze/simva reduced the risk of major atherosclerotic events by 17% (consistent with meta-analysis of previous statin trials) • Similar proportional reductions in all subgroups (including among dialysis and non-dialysis patients) • Full compliance would reduce the risk of major atherosclerotic events by one quarter, avoiding 30-40 events per 1000 treated for 5 years Presented at the Am. Soc. Nephrology, Denver, Nov 20th 2010

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