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 nonatherosclerotic ID: 400262
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Slide1
The results of the SHARP trialSlide2
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 inconclusiveSlide3
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 revascularisation
Uncertainty:
LDL
-lowering treatment not definitely indicated or contraindicatedSlide4
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)Slide5
Randomised
(9438)
Randomised
(886)
Not re-randomised
(168)
Placebo
(4191)
Simvastatin
(1054)
Simva
/
Eze
(4193)
Simv
/
Eze
(4650)
Placebo
(4620)
SHARP: Randomisation structure
Median follow-up 4.9 years
Lost to mortality follow-up 1.5%Slide6
SHARP: Baseline characteristics
Characteristic
Mean (SD) or %
Age
62 (12)
Men
63%
Systolic BP (mm Hg)
139 (22)
Diastolic BP (mm Hg)
79 (13)
Body mass index
27 (6)
Current smoker
13%
Vascular disease
15%
Diabetes mellitus
23%
Non-dialysis patients only
(
n
=6247)
eGFR (
mL
/min/1.73m
2
)
27 (13)
Albuminuria
80%Slide7
Renal Status at randomisation
to
Simv/Eze
vs
Placebo
Number
Percentage
eGFR
(
mL
/min/1.73m
2
)
≥60
88
1%
30-59
2155
36%
15-29
2565
43%
<15
1221
20%
Mean 27 (SD 13)
Dialysis
Haemodialysis
2527
27%
Peritoneal dialysis
496
5%
Subtotal
3023
33%Slide8
Lipid Profile at initial randomisation
Lipid fractions
Not on dialysis
On dialysis
All patients
Number analysed
6149 (96%)
2895 (95%)
9044 (96%)
Total
cholesterol (
mmol
/L)
5.0
4.6
4.9
LDL
cholesterol (
mmol
/L)
2.9
2.6
2.8
HDL
cholesterol (
mmol
/L)
1.1
1.1
1.1
Triglycerides (
mmol
/L)
2.3
2.3
2.3
Apolipoprotein
B (mg/
dL
)999296Apolipoprotein AI (mg/dL)136129134
Am Heart J 2010; 160:785-794.e10
doi:10.1016/j.ahj.2010.08.012Slide9
Simv/Eze
produces additional reductions in
LDL
(
mmol
/L) and
apo
B (mg/
dL) at 1 year
Biochemical parameter
Simv
vs Placebo
Simv
/
Eze
vs
Simv
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
-0.640.07-0.57Apolipoprotein B-21-7-28Apolipoprotein A14.1-1.03.2Slide10
Effect of
Simv
/
Eze
on lipids (
mmol
/L) and
apolipoproteins
(mg/dL) at 2.5 years
Biochemical parameterSimv/
EzePlaceboAbsolute difference
Percentage differencep
Total cholesterol
3.664.73
-1.07-23%<0.0001
LDL cholesterol1.802.65-0.85
-32%<0.0001
HDL cholesterol1.141.130.02
2%0.03Non-HDL cholesterol
2.523.60-1.08-30%
<0.0001Triglycerides
1.842.12-0.28-13%
<0.0001Apolipoprotein B70
93-23-24%
<0.0001Apolipoprotein A
114514321%
0.003Slide11
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 complianceSlide12
0
1
2
3
4
5
Years of follow-up
0
5
10
15
20
25
Proportion suffering event (%)
Risk ratio 0.83 (0.74-0.94)
Logrank
2P=0.0021
Placebo
S
imv
/
Eze
SHARP: Major Atherosclerotic EventsSlide13
Risk ratio & 95% CI
Event
Placebo
Simv
/
Eze
Simv
/
Eze
better
Placebo better
(n=4620)
(n=4650)
Major coronary event
213
(4.6%)
230
(5.0%)
Non-haemorrhagic stroke
131
(2.8%)
174
(3.8%)
Any
revascularisation
procedure
284
(6.1%)
352
(7.6%)
Major Atherosclerotic Event
526
(11.3%)
619
(13.4%)
16.6% SE 5.4
reduction
(p=0.0021)
1.0
1.2
1.4
0.8
0.6
SHARP: Major Atherosclerotic EventsSlide14
Risk ratio & 95% CI
Event
Placebo
S
imv
/
Eze
S
imv
/
Eze
better
Placebo better
(n=4620)
(n=4650)
Major coronary event
213
(4.6%)
230
(5.0%)
Non-
haemorrhagic
stroke
131
(2.8%)
174
(3.8%)
Any
revascularisation
procedure
284
(6.1%)
352
(7.6%)
Major Atherosclerotic
E
vent
526 (11.3%) 619 (13.4%) 16.6% SE 5.4
reduction
(p=0.0021)
Other cardiac death
162
(3.5%)
182
(3.9%)
Haemorrhagic stroke
45
(1.0%)
37
(0.8%)
Other Major
V
ascular
E
vents
207
(4.5%)
218
(4.7%)
5.5% SE 9.4
reduction
(p=0.56)
Major Vascular
E
vent
701
(15.1%)
814
(17.6%)
15.4% SE 4.7
reduction
(p=0.0012)
1.0
1.2
1.4
0.8
0.6
SHARP: Major Vascular EventsSlide15
Risk ratio & 95% CI
Event
Placebo
S
imv
/
Eze
S
imv
/
Eze
better
Placebo better
(n=4620)
(n=4650)
Coronary death
91
(2.0%)
90
(1.9%)
Non-fatal myocardial
i
nfarction
134
(2.9%)
159
(3.4%)
Major Coronary
E
vent
213
(4.6%)
230
(5.0%)
8.1% SE 9.1
reduction (p=0.37)
1.0
1.2
1.4
0.8
0.6
SHARP: Major Coronary EventsSlide16
SHARP: Total stroke
19.2% SE 9.2
Risk ratio & 95% CI
Event
Placebo
S
imv
/
Eze
Simv
/
Eze
better
Placebo better
(n=4620)
(n=4650)
Ischaemic stroke
114
(2.5%)
157
(3.4%)
Haemorrhagic stroke
45
(1.0%)
37
(0.8%)
Unknown stroke
18
(0.4%)
19
(0.4%)
Stroke (any type)
171
(3.7%)
210
(4.5%)
reduction
(p=0.04)
1.0
1.2
1.4
0.8
0.6 Slide17
Risk ratio & 95% CI
Event
Placebo
Eze/simv
S
imv
/
Eze
better
Placebo better
(n=4620)
(n=4650)
Coronary artery bypass graft
50
(1.1%)
66
(1.4%)
Percutaneous coronary intervention
106
(2.3%)
148
(3.2%)
Coronary
revascularisation
149
(3.2%)
203
(4.4%)
27.4% SE 9.1
reduction
(p=0.0027)
Non-coronary intervention/surgery
109
(2.3%)
130
(2.8%)
Amputation
75
(1.6%)
76
(1.6%)
Non-coronary
revascularisation
154
(3.3%)
169
(3.7%)
9.8% SE 10.6
reduction
(p=0.36)
Any
revascularisation
284
(6.1%)
352
(7.6%)
20.6% SE 7.1
reduction
(p=0.0036)
1.0
1.2
1.4
0.8
0.6
SHARP: RevascularisationSlide18
Risk ratio & 95% CI
Event
Placebo
Simv
/
Eze
Simv
/
Eze
better
Placebo
better
(n=4620)
(n=4650)
Coronary
91
(2.0%)
90
(1.9%)
Other cardiac
162
(3.5%)
182
(3.9%)
Subtotal: Any cardiac
253
(5.4%)
272
(5.9%)
7.3% SE 8.4
reduction
(p=0.38)
Stroke
68
(1.5%)
78
(1.7%)
Other vascular
40
(0.9%)
38
(0.8%)
Subtotal: any vascular
361
(7.8%)
388
(8.4%)
7.3% SE 7.0
reduction
(p=0.30)
Cancer
150
(3.2%)
128
(2.8%)
Renal
164
(3.5%)
173
(3.7%)
Other non-vascular
354
(7.6%)
311
(6.7%)
Subtotal: any non-vascular
668
(14.4%)
612
(13.2%)
8.8% SE 5.8
increase
(p=0.13)
Unknown
113
(2.4%)
115
(2.5%)
Total: Any death
1142
(24.6%)
1115
(24.1%)
2.1% SE 4.2
increase
(p=0.63)
1.0
1.2
1.4
0.8
0.6
SHARP: Cause-specific mortalitySlide19
Risk ratio & 95% CI
Placebo
Simv
/
Eze
Simv
/
Eze
better
Placebo better
(n=4620)
(n=4650)
Sex
Male
376
(12.9%)
445
(15.4%)
Female
150
(8.6%)
174
(10.0%)
Age at
randomisation
(years)
40-49
56
(5.8%)
50
(5.5%)
50-59
85
(7.3%)
119
(10.4%)
60-69
163
(13.3%)
171
(13.7%)
70+
222
(17.1%)
279
(21.2%)
Major Atherosclerotic Event
526
(11.3%)
619
(13.4%)
16.6% SE 5.4
reduction
(p=0.0021)
1.0
1.2
1.4
0.8
0.6
SHARP: Major Atherosclerotic Events
by age and sexSlide20
Risk ratio & 95% CI
Placebo
Simv
/
Eze
Simv
/
Eze
better
Placebo better
(n=4620)
(n=4650)
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)
1.0
1.2
1.4
0.8
0.6
SHARP: Major Atherosclerotic Events
by renal status
No significant heterogeneity between non-dialysis and dialysis patients
(p=0.25)Slide21
0.5
0.75
1
1.5
2
Trial
Events (% pa)
Allocated
LDL-C reduction
Allocated
control
Risk ratio (RR) per
mmol/L LDL-C reduction
p
LDL-C reduction
better
Control better
99% or
95% CI
Comparison of SHARP with other trials:
Non-Fatal Myocardial Infarction
4D
33 (1.91)
35 (2.02)
AURORA
91 (1.97)
107 (2.33)
ALERT
54 (1.03)
65 (1.24)
SHARP
134 (0.71)
159 (0.85)
c
3
2
=
0.3
(p = 0.96)
Subtotal: 4 renal trials312 (1.02)366 (1.21)0.83 (0.70 - 0.98) 0.0323 other trials3307 (0.97)4386 (1.29)0.73 (0.70 - 0.76) <0.0001All trials3619 (0.97)4752 (1.29)0.74 (0.70 - 0.77) <0.0001Difference between renal and non-renal trials:
c
1
2
=
2.2 (p = 0.14)Slide22
0.5
0.75
1
1.5
2
Trial
Events (% pa)
Allocated
LDL-C reduction
Allocated
control
Risk ratio (RR) per
mmol/L LDL-C reduction
p
LDL-C reduction
better
Control better
99% or
95% CI
Comparison of SHARP with other trials:
Non-Fatal Non-Haemorrhagic Stroke
4D
31 (1.80)
29 (1.67)
AURORA
46 (0.99)
39 (0.84)
ALERT
51 (0.97)
40 (0.76)
SHARP
97 (0.51)
128 (0.68)
c
3
2
=
6.4
(p = 0.09)
Subtotal: 4 renal trials225 (0.73)236 (0.77)0.95 (0.77- 1.17) 0.6523 other trials1624 (0.48)2052 (0.61)0.78 (0.73 - 0.83) <0.0001All trials1849 (0.50)2288 (0.62)
0.79 (0.74 - 0.84)
<0.0001
Difference between renal and non-renal trials:
c
1
2
=
3.4 (p = 0.07)Slide23
0.5
0.75
1
1.5
2
Trial
Events (% pa)
Allocated
LDL-C reduction
Allocated
control
Risk ratio (RR) per
mmol/L LDL-C reduction
p
LDL-C reduction
better
Control better
99% or
95% CI
Comparison of SHARP with other trials:
Coronary Revascularisation
4D
55 (3.31)
72 (4.29)
AURORA
55 (1.20)
70 (1.53)
ALERT
52 (1.00)
60 (1.15)
SHARP
149 (0.79)
203 (1.09)
c
3
2
=
0.8
(p = 0.85)
Subtotal: 4 renal trials311 (1.02)405 (1.34)0.74 (0.63 - 0.87) 0.000423 other trials5191 (1.54)6605 (1.99)0.75 (0.72 - 0.78) <0.0001All trials5502 (1.50)7010 (1.94)
0.75 (0.72 - 0.77)
<0.0001
Difference between renal and non-renal trials:
c
1
2
=
0.0 (p =
0.90)Slide24
0.5
0.75
1
1.5
2
Trial
Events (% pa)
Allocated
LDL-C reduction
Allocated
control
Risk ratio (RR) per
mmol/L LDL-C reduction
p
LDL-C reduction
better
Control better
99% or
95% CI
Comparison of SHARP with other trials:
Vascular Death
4D
151 (8.52)
167 (9.36)
AURORA
324 (6.87)
324 (6.86)
ALERT
66 (1.23)
73 (1.36)
SHARP
361 (1.82)
388 (1.97)
c
3
2
=
0.9
(p = 0.82)
Subtotal: 4 renal trials902 (2.85)952 (3.01)0.94 (0.85 - 1.04) 0.2723 other trials3679 (1.05)4230 (1.21)0.85 (0.81 - 0.89) <0.0001All trials4581 (1.20)5182 (1.36)0.86 (0.83 - 0.90) <0.0001Difference between renal and non-renal trials: c12=3.8 (p = 0.05)Slide25
Risk ratio & 95% CI
Event
Placebo
S
imv
/
Eze
S
imv
/
Eze
better
Placebo better
(n=3130)
(n=3117)
Main renal outcome
End-stage renal disease
1057
(33.9%)
1084
(34.6%)
0.97 (0.89-1.05)
Tertiary renal outcomes
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)
1.0
1.2
1.4
0.8
0.6
SHARP: Renal outcomesSlide26
0
1
2
3
4
5
Years of follow-up
0
5
10
15
20
25
Proportion suffering event (%)
Risk ratio 0.99 (0.87-1.13)
Logrank
2P=0.89
Placebo
S
imv
/
Eze
SHARP: Cancer incidenceSlide27
SHARP: Safety
Simv
/
Eze
(n=4650)
Placebo
(n=4620)
Myopathy
CK >10 x but ≤40 x ULN
17 (0.4%)
16 (0.3%)
CK >40 x ULN
4 (0.1%)
5 (0.1%)
Hepatitis
21 (0.5%)18 (0.4%)Persistently elevated ALT/AST >3x ULN
30 (0.6%)26 (0.6%)Complications of gallstones
85 (1.8%)76 (1.6%)Other hospitalization for gallstones
21 (0.5%)30 (0.6%)Pancreatitis
without gallstones12 (0.3%)27 (0.6%)Slide28
SHARP: Major Atherosclerotic Events
5-year benefit per 1000 patients Slide29
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