The results of the SHARP trial SHARP Rationale

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The results of the SHARP trial

The results of the SHARP trial

SHARP: Rationale • Risk of vascular events is high among patients with chronic kidney

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

SHARP: Eligibility • History of chronic kidney disease – not on dialysis: elevated creatinine

SHARP: Eligibility • History of chronic kidney disease – not on dialysis: elevated creatinine on 2 occasions • Men: • Women: ≥ 1. 7 mg/d. L (150 µmol/L) ≥ 1. 5 mg/d. L (130 µmol/L) – on dialysis: haemodialysis or peritoneal dialysis • Age ≥ 40 years • No history of myocardial infarction or coronary revascularisation • Uncertainty: LDL-lowering treatment not definitely indicated or contraindicated

SHARP: Main outcomes • Key outcome • Major atherosclerotic events (coronary death, MI, non-haemorrhagic

SHARP: Main outcomes • Key outcome • Major atherosclerotic events (coronary death, MI, non-haemorrhagic stroke, or any revascularisation) • Subsidiary outcomes • Major vascular events (cardiac death, MI, any stroke, or any revascularisation) • Components of major atherosclerotic events • Main renal outcome • End stage renal disease (dialysis or transplant)

SHARP: Randomisation structure Randomised (9438) Simva/Eze (4193) Simvastatin (1054) Placebo (4191) Not re-randomised (168)

SHARP: Randomisation structure Randomised (9438) Simva/Eze (4193) Simvastatin (1054) Placebo (4191) Not re-randomised (168) Randomised (886) Simv/Eze (4650) Median follow-up 4. 9 years Lost to mortality follow-up 1. 5% Placebo (4620)

SHARP: Baseline characteristics Characteristic Age Men Systolic BP (mm Hg) Diastolic BP (mm Hg)

SHARP: Baseline characteristics Characteristic Age Men Systolic BP (mm Hg) Diastolic BP (mm Hg) Body mass index Current smoker Vascular disease Diabetes mellitus Non-dialysis patients only e. GFR (m. L/min/1. 73 m 2) Albuminuria Mean (SD) or % 62 (12) 63% 139 (22) 79 (13) 27 (6) 13% 15% 23% (n=6247) 27 (13) 80%

Renal Status at randomisation to Simv/Eze vs Placebo Number Percentage 88 1% 30 -59

Renal Status at randomisation to Simv/Eze vs Placebo Number Percentage 88 1% 30 -59 2155 36% 15 -29 2565 43% e. GFR (m. L/min/1. 73 m 2) ≥ 60 <15 1221 Mean 27 (SD 13) Dialysis Haemodialysis 20% 2527 27% Peritoneal dialysis 496 5% Subtotal 3023 33%

Lipid Profile at initial randomisation Lipid fractions Number analysed Total cholesterol (mmol/L) LDL cholesterol

Lipid Profile at initial randomisation Lipid fractions Number analysed Total cholesterol (mmol/L) LDL cholesterol (mmol/L) HDL cholesterol (mmol/L) Triglycerides (mmol/L) Apolipoprotein B (mg/d. L) Apolipoprotein AI (mg/d. L) Not on dialysis On dialysis All patients 6149 (96%) 5. 0 2. 9 1. 1 2. 3 99 136 Am Heart J 2010; 160: 785 -794. e 10 doi: 10. 1016/j. ahj. 2010. 08. 012 2895 (95%) 9044 (96%) 4. 6 4. 9 2. 6 2. 8 1. 1 2. 3 92 96 129 134

Simv/Eze produces additional reductions in LDL (mmol/L) and apo B (mg/d. L) at 1

Simv/Eze produces additional reductions in LDL (mmol/L) and apo B (mg/d. L) at 1 year Biochemical parameter Simv vs Placebo Simv/Eze vs Placebo Total cholesterol -0. 97 -0. 43 -1. 39 LDL cholesterol -0. 75 -0. 34 -1. 09 HDL cholesterol 0. 05 -0. 03 0. 02 Non-HDL cholesterol -1. 01 -0. 40 -1. 41 Triglycerides -0. 64 0. 07 -0. 57 Apolipoprotein B -21 -7 -28 Apolipoprotein A 1 4. 1 -1. 0 3. 2

Effect of Simv/Eze on lipids (mmol/L) and apolipoproteins (mg/d. L) at 2. 5 years

Effect of Simv/Eze on lipids (mmol/L) and apolipoproteins (mg/d. L) at 2. 5 years Biochemical parameter Simv/Eze Placebo Absolute difference Percentage difference p Total cholesterol 3. 66 4. 73 -1. 07 -23% <0. 0001 LDL cholesterol 1. 80 2. 65 -0. 85 -32% <0. 0001 HDL cholesterol 1. 14 1. 13 0. 02 2% 0. 03 Non-HDL cholesterol 2. 52 3. 60 -1. 08 -30% <0. 0001 Triglycerides 1. 84 2. 12 -0. 28 -13% <0. 0001 Apolipoprotein B 70 93 -24% <0. 0001 Apolipoprotein A 1 145 143 2 1% 0. 003

SHARP: Compliance and LDL reduction at study midpoint Simv/Eze Placebo Compliant 66% 64% Non-study

SHARP: Compliance and LDL reduction at study midpoint Simv/Eze Placebo Compliant 66% 64% Non-study statin 6% 9% Any lipid-lowering 71% 9% ~2/3 compliance LDL reduction of 0. 85 mmol/L with 2/3 compliance, equivalent to 1. 3 mmol/L with full compliance

SHARP: Major Atherosclerotic Events Proportion suffering event (%) 25 20 Risk ratio 0. 83

SHARP: Major Atherosclerotic Events Proportion suffering event (%) 25 20 Risk ratio 0. 83 (0. 74 -0. 94) Logrank 2 P=0. 0021 15 Placebo Simv/Eze 10 5 0 0 1 2 3 Years of follow-up 4 5

SHARP: Major Atherosclerotic Events Event Simv/Eze (n=4650) Placebo (n=4620) Major coronary event Non-haemorrhagic stroke

SHARP: Major Atherosclerotic Events Event Simv/Eze (n=4650) Placebo (n=4620) Major coronary event Non-haemorrhagic stroke Any revascularisation procedure 213 131 284 230 174 352 Major Atherosclerotic Event 526 (11. 3%) (4. 6%) (2. 8%) (6. 1%) Risk ratio & 95% CI (5. 0%) (3. 8%) (7. 6%) 619 (13. 4%) 16. 6% SE 5. 4 reduction (p=0. 0021) 0. 6 0. 8 Simv/Eze better 1. 0 1. 2 1. 4 Placebo better

SHARP: Major Vascular Events Event Simv/Eze (n=4650) Placebo (n=4620) Major coronary event Non-haemorrhagic stroke

SHARP: Major Vascular Events Event Simv/Eze (n=4650) Placebo (n=4620) Major coronary event Non-haemorrhagic stroke Any revascularisation procedure 213 131 284 230 174 352 (4. 6%) (2. 8%) (6. 1%) Risk ratio & 95% CI (5. 0%) (3. 8%) (7. 6%) Major Atherosclerotic Event 526 (11. 3%) 619 (13. 4%) Other cardiac death Haemorrhagic stroke 162 45 (3. 5%) (1. 0%) 182 37 (3. 9%) (0. 8%) Other Major Vascular Events 207 (4. 5%) 218 (4. 7%) Major Vascular Event 701 (15. 1%) 16. 6% SE 5. 4 reduction (p=0. 0021) 5. 5% SE 9. 4 reduction (p=0. 56) 814 (17. 6%) 15. 4% SE 4. 7 reduction (p=0. 0012) 0. 6 0. 8 Simv/Eze better 1. 0 1. 2 1. 4 Placebo better

SHARP: Major Coronary Events Event Simv/Eze (n=4650) Placebo (n=4620) Risk ratio & 95% CI

SHARP: Major Coronary Events Event Simv/Eze (n=4650) Placebo (n=4620) Risk ratio & 95% CI Coronary death Non-fatal myocardial infarction 91 134 (2. 0%) (2. 9%) 90 159 (1. 9%) (3. 4%) Major Coronary Event 213 (4. 6%) 230 (5. 0%) 8. 1% SE 9. 1 reduction (p=0. 37) 0. 6 0. 8 Simv/Eze better 1. 0 1. 2 1. 4 Placebo better

SHARP: Total stroke Event Simv/Eze (n=4650) Placebo (n=4620) Ischaemic stroke Haemorrhagic stroke Unknown stroke

SHARP: Total stroke Event Simv/Eze (n=4650) Placebo (n=4620) Ischaemic stroke Haemorrhagic stroke Unknown stroke 114 45 18 (2. 5%) (1. 0%) (0. 4%) 157 37 19 (3. 4%) (0. 8%) (0. 4%) Stroke (any type) 171 (3. 7%) 210 (4. 5%) Risk ratio & 95% CI 19. 2% SE 9. 2 reduction (p=0. 04) 0. 6 0. 8 Simv/Eze better 1. 0 1. 2 1. 4 Placebo better

SHARP: Revascularisation Event Eze/simv (n=4650) Placebo (n=4620) Risk ratio & 95% CI Coronary artery

SHARP: Revascularisation Event Eze/simv (n=4650) Placebo (n=4620) Risk ratio & 95% CI Coronary artery bypass graft Percutaneous coronary intervention 50 106 (1. 1%) (2. 3%) 66 148 (1. 4%) (3. 2%) Coronary revascularisation 149 (3. 2%) 203 (4. 4%) Non-coronary intervention/surgery Amputation 109 75 (2. 3%) (1. 6%) 130 76 (2. 8%) (1. 6%) Non-coronary revascularisation 154 (3. 3%) 169 (3. 7%) Any revascularisation 284 (6. 1%) 352 (7. 6%) 27. 4% SE 9. 1 reduction (p=0. 0027) 9. 8% SE 10. 6 reduction (p=0. 36) 20. 6% SE 7. 1 reduction (p=0. 0036) 0. 6 0. 8 Simv/Eze better 1. 0 1. 2 1. 4 Placebo better

SHARP: Cause-specific mortality Event Simv/Eze (n=4650) Placebo (n=4620) Coronary Other cardiac 91 162 (2.

SHARP: Cause-specific mortality Event Simv/Eze (n=4650) Placebo (n=4620) Coronary Other cardiac 91 162 (2. 0%) (3. 5%) 90 182 (1. 9%) (3. 9%) Subtotal: Any cardiac 253 (5. 4%) 272 (5. 9%) Stroke Other vascular Subtotal: any vascular 68 40 361 (1. 5%) (0. 9%) (7. 8%) 78 38 388 (1. 7%) (0. 8%) (8. 4%) Cancer Renal Other non-vascular 150 164 354 (3. 2%) (3. 5%) (7. 6%) 128 173 311 (2. 8%) (3. 7%) (6. 7%) Subtotal: any non-vascular 668 (14. 4%) 612 (13. 2%) Unknown 113 115 Total: Any death (2. 4%) Risk ratio & 95% CI 7. 3% SE 8. 4 reduction (p=0. 38) 7. 3% SE 7. 0 reduction (p=0. 30) 8. 8% SE 5. 8 increase (p=0. 13) (2. 5%) 2. 1% SE 4. 2 increase (p=0. 63) 1142 (24. 6%) 1115 (24. 1%) 0. 6 0. 8 Simv/Eze better 1. 0 1. 2 1. 4 Placebo better

SHARP: Major Atherosclerotic Events by age and sex Simv/Eze (n=4650) Placebo (n=4620) Sex Male

SHARP: Major Atherosclerotic Events by age and sex Simv/Eze (n=4650) Placebo (n=4620) Sex Male Female 376 (12. 9%) 150 (8. 6%) 445 (15. 4%) 174 (10. 0%) Age at randomisation (years) 40 -49 50 -59 60 -69 70+ 56 (5. 8%) 85 (7. 3%) 163 (13. 3%) 222 (17. 1%) 50 (5. 5%) 119 (10. 4%) 171 (13. 7%) 279 (21. 2%) Major Atherosclerotic Event 526 (11. 3%) 619 (13. 4%) Risk ratio & 95% CI 16. 6% SE 5. 4 reduction (p=0. 0021) 0. 6 0. 8 Simv/Eze better 1. 0 1. 2 1. 4 Placebo better

SHARP: Major Atherosclerotic Events by renal status Simv/Eze (n=4650) Placebo (n=4620) Risk ratio &

SHARP: Major Atherosclerotic Events by renal status Simv/Eze (n=4650) Placebo (n=4620) Risk ratio & 95% CI Non-dialysis (n=6247) 296 (9. 5%) 373 (11. 9%) Dialysis (n=3023) 230 (15. 0%) 246 (16. 5%) Major Atherosclerotic Event 526 (11. 3%) 619 (13. 4%) 16. 6% SE 5. 4 reduction (p=0. 0021) 0. 6 0. 8 Simv/Eze better No significant heterogeneity between non -dialysis and dialysis patients (p=0. 25) 1. 0 1. 2 1. 4 Placebo better

Comparison of SHARP with other trials: Non-Fatal Myocardial Infarction Events (% pa) Trial Allocated

Comparison of SHARP with other trials: Non-Fatal Myocardial Infarction Events (% pa) Trial Allocated LDL-C reduction Allocated control Risk ratio (RR) per mmol/L LDL-C reduction better p Control better 4 D 33 (1. 91) 35 (2. 02) ALERT 54 (1. 03) 65 (1. 24) AURORA 91 (1. 97) 107 (2. 33) SHARP 134 (0. 71) 159 (0. 85) Subtotal: 4 renal trials 312 (1. 02) 366 (1. 21) 0. 83 (0. 70 - 0. 98) 0. 03 23 other trials 3307 (0. 97) 4386 (1. 29) 0. 73 (0. 70 - 0. 76) <0. 0001 All trials 3619 (0. 97) 4752 (1. 29) 0. 74 (0. 70 - 0. 77) <0. 0001 Difference between renal and non-renal trials: 99% or 95% CI c 21 = 2. 2 c 23=0. 3 (p = 0. 96) (p = 0. 14) 0. 5 0. 75 1 1. 5 2

Comparison of SHARP with other trials: Non-Fatal Non-Haemorrhagic Stroke Events (% pa) Trial Allocated

Comparison of SHARP with other trials: Non-Fatal Non-Haemorrhagic Stroke Events (% pa) Trial Allocated LDL-C reduction Allocated control Risk ratio (RR) per mmol/L LDL-C reduction better p Control better 4 D 31 (1. 80) 29 (1. 67) ALERT 51 (0. 97) 40 (0. 76) AURORA 46 (0. 99) 39 (0. 84) SHARP 97 (0. 51) 128 (0. 68) 225 (0. 73) 236 (0. 77) 0. 95 (0. 77 - 1. 17) 0. 65 23 other trials 1624 (0. 48) 2052 (0. 61) 0. 78 (0. 73 - 0. 83) <0. 0001 All trials 1849 (0. 50) 2288 (0. 62) 0. 79 (0. 74 - 0. 84) <0. 0001 Subtotal: 4 renal trials Difference between renal and non-renal trials: 99% or 95% CI c 21 = 3. 4 c 23=6. 4 (p = 0. 09) (p = 0. 07) 0. 5 0. 75 1 1. 5 2

Comparison of SHARP with other trials: Coronary Revascularisation Events (% pa) Trial Allocated LDL-C

Comparison of SHARP with other trials: Coronary Revascularisation Events (% pa) Trial Allocated LDL-C reduction Allocated control Risk ratio (RR) per mmol/L LDL-C reduction better p Control better 4 D 55 (3. 31) 72 (4. 29) ALERT 52 (1. 00) 60 (1. 15) AURORA 55 (1. 20) 70 (1. 53) SHARP 149 (0. 79) 203 (1. 09) Subtotal: 4 renal trials 311 (1. 02) 405 (1. 34) 0. 74 (0. 63 - 0. 87) 0. 0004 23 other trials 5191 (1. 54) 6605 (1. 99) 0. 75 (0. 72 - 0. 78) <0. 0001 All trials 5502 (1. 50) 7010 (1. 94) 0. 75 (0. 72 - 0. 77) <0. 0001 Difference between renal and non-renal trials: 99% or 95% CI c 21 = 0. 0 c 23=0. 8 (p = 0. 85) (p = 0. 90) 0. 5 0. 75 1 1. 5 2

Comparison of SHARP with other trials: Vascular Death Events (% pa) Trial Allocated LDL-C

Comparison of SHARP with other trials: Vascular Death Events (% pa) Trial Allocated LDL-C reduction Allocated control Risk ratio (RR) per mmol/L LDL-C reduction better 4 D p Control better 151 (8. 52) 167 (9. 36) 66 (1. 23) 73 (1. 36) AURORA 324 (6. 87) 324 (6. 86) SHARP 361 (1. 82) 388 (1. 97) Subtotal: 4 renal trials 902 (2. 85) 952 (3. 01) 0. 94 (0. 85 - 1. 04) 0. 27 23 other trials 3679 (1. 05) 4230 (1. 21) 0. 85 (0. 81 - 0. 89) <0. 0001 All trials 4581 (1. 20) 5182 (1. 36) 0. 86 (0. 83 - 0. 90) <0. 0001 ALERT Difference between renal and non-renal trials: 99% or 95% CI c 21 = 3. 8 c 23=0. 9 (p = 0. 82) (p = 0. 05) 0. 5 0. 75 1 1. 5 2

SHARP: Renal outcomes Event Simv/Eze (n=3117) Placebo (n=3130) Risk ratio & 95% CI Main

SHARP: Renal outcomes Event Simv/Eze (n=3117) Placebo (n=3130) Risk ratio & 95% CI Main renal outcome End-stage renal disease 1057 (33. 9%) 1084 (34. 6%) 0. 97 (0. 89 -1. 05) ESRD or death 1477 (47. 4%) 1513 (48. 3%) 0. 97 (0. 90 -1. 04) ESRD or 2 x creatinine 1190 (38. 2%) 1257 (40. 2%) 0. 93 (0. 86 -1. 01) Tertiary renal outcomes 0. 6 0. 8 Simv/Eze better 1. 0 1. 2 1. 4 Placebo better

SHARP: Cancer incidence Proportion suffering event (%) 25 20 Risk ratio 0. 99 (0.

SHARP: Cancer incidence Proportion suffering event (%) 25 20 Risk ratio 0. 99 (0. 87 -1. 13) Logrank 2 P=0. 89 15 Simv/Eze Placebo 10 5 0 0 1 2 3 Years of follow-up 4 5

SHARP: Safety Simv/Eze Placebo (n=4650) (n=4620) Myopathy CK >10 x but ≤ 40 x

SHARP: Safety Simv/Eze Placebo (n=4650) (n=4620) Myopathy CK >10 x but ≤ 40 x ULN 17 (0. 4%) 16 (0. 3%) CK >40 x ULN Hepatitis Persistently elevated ALT/AST >3 x ULN Complications of gallstones 4 (0. 1%) 21 (0. 5%) 30 (0. 6%) 85 (1. 8%) 5 (0. 1%) 18 (0. 4%) 26 (0. 6%) 76 (1. 6%) Other hospitalization for gallstones Pancreatitis without gallstones 21 (0. 5%) 12 (0. 3%) 30 (0. 6%) 27 (0. 6%)

SHARP: Major Atherosclerotic Events 5 -year benefit per 1000 patients

SHARP: Major Atherosclerotic Events 5 -year benefit per 1000 patients

SHARP: Conclusions • No increase in risk of myopathy, liver and biliary disorders, cancer,

SHARP: Conclusions • No increase in risk of myopathy, liver and biliary disorders, cancer, or nonvascular mortality • No substantial effect on kidney disease progression • Two-thirds compliance with Simv/Eze 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