Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
Summary
Background Lowering LDL cholesterol with statin regimens reduces the risk of myocardial infarction, ischaemic
stroke, and the need for coronary revascularisation in people without kidney disease, but its eects in people with
moderate-to-severe kidney disease are uncertain. The SHARP trial aimed to assess the ecacy and safety of the
combination of simvastatin plus ezetimibe in such patients.
Methods This randomised double-blind trial included 9270 patients with chronic kidney disease (3023 on dialysis and
6247 not) with no known history of myocardial infarction or coronary revascularisation. Patients were randomly
assigned to simvastatin 20 mg plus ezetimibe 10 mg daily versus matching placebo. The key prespecied outcome was
rst major atherosclerotic event (non-fatal myocardial infarction or coronary death, non-haemorrhagic stroke, or any
arterial revascularisation procedure). All analyses were by intention to treat. This trial is registered at ClinicalTrials.gov,
NCT00125593, and ISRCTN54137607.
Findings 4650 patients were assigned to receive simvastatin plus ezetimibe and 4620 to placebo. Allocation to simvastatin
plus ezetimibe yielded an average LDL cholesterol dierence of 085 mmol/L (SE 002; with about two-thirds
compliance) during a median follow-up of 49 years and produced a 17% proportional reduction in major atherosclerotic
events (526 [113%] simvastatin plus ezetimibe vs 619 [134%] placebo; rate ratio [RR] 083, 95% CI 074094; log-rank
p=00021). Non-signicantly fewer patients allocated to simvastatin plus ezetimibe had a non-fatal myocardial infarction
or died from coronary heart disease (213 [46%] vs 230 [50%]; RR 092, 95% CI 076111; p=037) and there were
signicant reductions in non-haemorrhagic stroke (131 [28%] vs 174 [38%]; RR 075, 95% CI 060094; p=001) and
arterial revascularisation procedures (284 [61%] vs 352 [76%]; RR 079, 95% CI 068093; p=00036). After weighting
for subgroup-specic reductions in LDL cholesterol, there was no good evidence that the proportional eects on major
atherosclerotic events diered from the summary rate ratio in any subgroup examined, and, in particular, they were
similar in patients on dialysis and those who were not. The excess risk of myopathy was only two per 10 000 patients per
year of treatment with this combination (9 [02%] vs 5 [01%]). There was no evidence of excess risks of hepatitis
(21 [05%] vs 18 [04%]), gallstones (106 [23%] vs 106 [23%]), or cancer (438 [94%] vs 439 [95%], p=089) and there
was no signicant excess of death from any non-vascular cause (668 [144%] vs 612 [132%], p=013).
Interpretation Reduction of LDL cholesterol with simvastatin 20 mg plus ezetimibe 10 mg daily safely reduced the
incidence of major atherosclerotic events in a wide range of patients with advanced chronic kidney disease.
Funding Merck/Schering-Plough Pharmaceuticals; Australian National Health and Medical Research Council; British
Heart Foundation; UK Medical Research Council.
Introduction
Chronic kidney disease is associated with an increased
risk of cardiovascular disease,1,2 but little is known about
the prevention of cardiovascular disease in patients with
chronic kidney disease.3 Meta-analyses of randomised
trials undertaken mainly in patients without chronic
kidney disease have shown that statin therapy reduces the
risks of major coronary events (myocardial infarction or
Published Online
June 9, 2011
DOI:10.1016/S01406736(11)60739-3
2181
Articles
Methods
Trial design and participants
11 364 entered
run-in phase
4650 analysed
4620 analysed
2182
Procedures
After randomisation between August, 2003, and August,
2006, participants were to be seen in the study clinics
for routine follow-up checks and blood safety monitoring
at 2, 6, and 12 months, and then every 6 months for at
least 4 years in total, until the nal follow-up visits
between March and August, 2010. An early recall visit
could also be arranged for any participant requiring
Articles
Statistical analysis
The annual incidence of major vascular events in SHARP
(dened as non-fatal myocardial infarction or any cardiac
death, any stroke, or any arterial revascularisation excluding
dialysis access procedures) was projected to be about 37%.
A study with at least 1100 such events and all patients
followed up for at least 4 years was estimated to have
90% power to detect a 20% proportional reduction at
p<001. For the reasons given in the statistical analysis
plan published before unmasking,12 the steering committee
decided that the key study outcome should be changed to
major atherosclerotic events (dened as non-fatal
myocardial infarction or coronary death, non-haemorrhagic
stroke, or arterial revascularisation excluding dialysis
access procedures) and the key comparison should be
between all patients ever allocated simvastatin plus
ezetimibe versus placebo (including those initially allocated
Simvastatin plus
ezetimibe (n=4650)
Previous vascular disease*
Placebo
(n=4620)
711 (15%)
682 (15%)
Diabetes*
1054 (23%)
1040 (23%)
Men
2915 (63%)
2885 (62%)
62 (12)
62 (12)
Age at randomisation
(years)*
Current smoker
626 (13%)
608 (13%)
79 (13)
79 (13)
139 (22)
139 (22)
488 (120)
490 (117)
277 (088)
278 (087)
112 (035)
111 (034)
Triglycerides (mmol/L)
231 (176)
234 (168)
271 (57)
271 (56)
1533 (33%)
1490 (32%)
1275 (27%)
1252 (27%)
Renal status
On dialysis
Haemodialysis
Peritoneal dialysis
Not on dialysis
258 (6%)
238 (5%)
3117 (67%)
3130 (68%)
266 (129)
266 (131)
60
44 (1%)
44 (1%)
30 to <60
1100 (37%)
1055 (35%)
15 to <30
1246 (41%)
1319 (44%)
<15
614 (20%)
607 (20%)
Not available
113
105
217 (44788)
<30
545 (20%)
562 (20%)
30 to 300
1032 (37%)
1076 (39%)
>300
1203 (43%)
1156 (41%)
Not available
337
196 (43748)
336
Data are n (%), mean (SD), or median (IQR). MDRD=Modied Diet in Renal
Disease.17 GFR=glomerular ltration rate. *Variables updated at 1 year for patients
originally allocated simvastatin only who were rerandomised to simvastatin plus
ezetimibe or placebo. Five versus ve patients received a transplant before
rerandomisation. Percentages exclude participants for whom data were not
available for that category. For patients not on dialysis.
2183
Articles
Simvastatin
plus ezetimibe
Absolute
dierence
Simvastatin
plus ezetimibe
Placebo
Placebo
Absolute
dierence
(SE)
813 months
77%
3%
74%
108
002
109
(006)
2631 months
71%
9%
61%
100
015
085
(002)
4449 months
68%
14%
55%
084
008
077
(006)
*In patients initially allocated to simvastatin, no 1-year sample was collected, while samples scheduled for collection at
25 and 4 years were collected at 15 and 3 years after rerandomisation.
Table 2: Average use of study simvastatin plus ezetimibe or non-study statin and average change in
plasma LDL cholesterol from baseline, by period of follow-up
Placebo
Simvastatin plus ezetimibe
25
20
15
10
5
Number at risk
Placebo 4620
Simvastatin 4650
plus ezetimibe
3
2
Years of follow-up
4204
4271
3849
3939
3469
3546
2566
2655
1269
1265
Figure 2: Life-table plot of eects of allocation to simvastatin plus ezetimibe versus placebo on major
atherosclerotic events
Numbers remaining at risk of a rst major atherosclerotic event at the beginning of each year are shown for both
treatment groups.
Correspondence to:
Prof Colin Baigent, Clinical Trial
Service Unit and Epidemiological
Studies Unit (CTSU), Richard Doll
Building, Old Road Campus,
Roosevelt Drive,
Oxford OX3 7LF, UK
sharpclinical@ctsu.ox.ac.uk
Results
Overall, 9270 patients were randomly assigned to
simvastatin plus ezetimibe (4650 patients, 4193 initially
plus 457 after 1 year) versus placebo (4620 patients,
4191 initially plus 429 after 1 year; gure 1). Among these
patients, all variables were well balanced between
randomised groups (table 1). Mean age was 62 years
(SD 12), 5800 (63%) were male, mean blood pressure was
2184
Articles
Simvastatin
plus ezetimibe
(n=4650)
Placebo
(n=4620)
p value
Coronary events
Nonfatal MI
CHD death
Subtotal: any major coronary event
134 (29%)
91 (20%)
213 (46%)
159 (34%)
90 (19%)
230 (50%)
084 (066105)
101 (075135)
092 (076111)
012
095
037
Nonhaemorrhagic stroke
Ischaemic
Unknown type
Subtotal: any nonhaemorrhagic
114 (25%)
18 (04%)
131 (28%)
157 (34%)
19 (04%)
174 (38%)
072 (057092)
094 (049179)
075 (060094)
00073
085
001
Revascularisation procedures
Coronary
Noncoronary
Subtotal: any revascularisation
149 (32%)
154 (33%)
284 (61%)
203 (44%)
169 (37%)
352 (76%)
073 (059090)
090 (073112)
079 (068093)
00027
036
00036
619 (134%)
083 (074094)
00021
05
075
Simvastatin plus ezetimibe better
10
125
15
Placebo better
p=037), which reected non-signicantly fewer nonfatal myocardial infarctions (134 [29%] vs 159 [34%];
RR 084, 066105; p=012; gure 3), but no signicant
dierence in coronary mortality (91 [20%] vs 90 [19%];
RR 101, 075135; p=095).
Allocation to simvastatin plus ezetimibe produced a
signicant reduction in non-haemorrhagic stroke
(131 [28%] vs 174 [38%]; RR 075, 95% CI 060094;
p=001; gure 3), due chiey to a signicant reduction in
strokes that were denitely ischaemic (114 [25%] vs
157 [34%]; RR 072, 057092; p=00073). There were
non-signicantly more patients with haemorrhagic
stroke (45 [10%] vs 37 [08%]; RR 121, 95% CI 078186;
p=04; webappendix p 2). There was a signicant
reduction in the risk of any type of stroke (171 [37%] vs
210 [45%]; RR 081, 95% CI 066099; p=004).
Allocation to simvastatin plus ezetimibe signicantly
reduced the incidence of any arterial revascularisation
(284 [61%] vs 352 [76%]; RR 079, 95% CI 068093;
p=00036; gure 3), with no evidence of statistical
heterogeneity (1=20, p=02) between the reductions in
coronary revascularisations (149 [32%] vs 203 [44%];
RR 073, 059090), which was statistically signicant (p=00027), and non-coronary revascularisations
(ie, carotid, aortic or leg, but not haemodialysis access
procedures), which was not (154 [33%] vs 169 [37%];
RR 090, 073112; p=036). Among coronary
revascularisation procedures, there was no evidence of
statistical heterogeneity (1=01, p=08) between the
reductions in percutaneous coronary intervention
procedures (106 [23%] vs 148 [32%]; RR 071, 95% CI
056091; p=00063) and coronary artery bypass grafts
(50 [11%] vs 66 [14%]; RR 075, 052109; p=013).
SHARP was not expected to have sucient statistical
power to allow reliable estimation of eects on major
2185
Articles
Figure 4: Major
atherosclerotic events by
baseline characteristics
tests on 1 degree of freedom
are shown for heterogeneity
between rate ratios within
dichotomous categories and
for trend within other
categories. BP=blood pressure.
MDRD=Modied Diet in
Renal Disease formula.17
GFR=glomerular ltration rate.
2186
Placebo
(n=4620)
447/3938 (114%)
172/682 (252%)
079 (069091)
091 (074113)
385/3580 (108%)
234/1040 (225%)
086 (074099)
078 (064094)
445/2885 (154%)
174/1735 (100%)
083 (072095)
085 (068105)
50/908 (55%)
119/1149 (104%)
171/1246 (137%)
279/1317 (212%)
108 (074158)
070 (053091)
098 (079121)
078 (065093)
536/4012 (134%)
83/608 (137%)
081 (071092)
100 (074135)
360/2339 (154%)
146/1309 (112%)
78/701 (111%)
34/256 (133%)
086 (073100)
079 (062100)
087 (063120)
077 (047126)
264/2414 (109%)
198/1387 (143%)
115/614 (187%)
42/198 (212%)
089 (075106)
083 (068102)
074 (056097)
073 (047116)
222/1680 (132%)
184/1526 (121%)
195/1224 (159%)
096 (080116)
088 (071109)
061 (049076)
207/1707 (121%)
135/1037 (130%)
259/1686 (154%)
094 (078115)
082 (064105)
073 (060088)
286/1864 (153%)
150/1089 (138%)
165/1477 (112%)
093 (079110)
072 (056091)
077 (061096)
177/1440 (123%)
122/914 (133%)
302/2075 (146%)
080 (065100)
087 (067113)
082 (069096)
144/1338 (108%)
207/1533 (135%)
254/1652 (154%)
619/4620 (134%)
095 (076120)
090 (074109)
071 (059086)
083 (074094)
3/44 (68%)
110/1055 (104%)
168/1319 (127%)
81/607 (133%)
084 (017418)
075 (057100)
078 (062098)
082 (059113)
53/562 (94%)
128/1076 (119%)
160/1156 (138%)
373/3130 (119%)
085 (057126)
075 (057097)
072 (057091)
078 (067091)
199/1252 (159%)
47/238 (197%)
246/1490 (165%)
095 (078115)
070 (046108)
090 (075108)
20
Articles
Simvastatin
plus ezetimibe
(n=4650)
Placebo
(n=4620)
p value
Vascular deaths
CHD
Other cardiac
Cardiac death
Ischaemic stroke
Haemorrhagic stroke
Unspecied stroke
Stroke (any type)
Any other vascular death
Subtotal: any vascular
91 (20%)
162 (35%)
253 (54%)
30 (06%)
27 (06%)
11 (02%)
68 (15%)
40 (09%)
361 (78%)
90 (19%)
182 (39%)
272 (59%)
41 (09%)
23 (05%)
14 (03%)
78 (17%)
38 (08%)
388 (84%)
101 (075135)
089 (072109)
093 (078110)
073 (046116)
116 (067203)
078 (036171)
087 (063120)
105 (067164)
093 (080107)
Non-vascular deaths
Any cancer (including complications)
Renal
Respiratory
Gastrointestinal
Other medical causes
Trauma or fracture
Subtotal: any non-vascular
150 (32%)
164 (35%)
124 (27%)
72 (15%)
124 (27%)
34 (07%)
668 (144%)
128 (28%)
173 (37%)
100 (22%)
70 (15%)
119 (26%)
22 (05%)
612 (132%)
117 (092148)
095 (076117)
124 (095161)
103 (074142)
104 (081134)
153 (091259)
109 (098121)
013
Unknown deaths
Sudden death
Death (reason unclear)
Subtotal: unknown causes
50 (11%)
63 (14%)
113 (24%)
55 (12%)
60 (13%)
115 (25%)
091 (062133)
105 (074149)
098 (076127)
087
1142 (246%)
1115 (241%)
102 (094111)
063
06
08
10
12
14
Simvastatin plus ezetimibe better
Placebo better
038
039
083
030
16
Cancer incidence
Simvastatin plus
ezetimibe (n=4650)
Cancer mortality
Placebo
(n=4620)
p value
Simvastatin plus
ezetimibe (n=4650)
Placebo
(n=4620)
p value
Lip/mouth/pharynx/oesophagus
14 (03%)
16 (03%)
084
9 (02%)
8 (02%)
10
Stomach
11 (02%)
14 (03%)
068
10 (02%)
11 (02%)
10
53 (11%)
35 (08%)
007
20 (04%)
15 (03%)
051
9 (02%)
10 (02%)
10
7 (02%)
10 (02%)
062
Pancreas
Liver/gallbladder/bile ducts
Lung
Other respiratory
8 (02%)
4 (01%)
039
4 (01%)
4 (01%)
10
42 (09%)
35 (08%)
051
32 (07%)
22 (05%)
023
3 (01%)
4 (01%)
10
2 (00%)
3 (01%)
10
136 (29%)
153 (33%)
032
4 (01%)
4 (01%)
10
Breast
29 (06%)
21 (05%)
033
1 (00%)
1 (00%)
10
Prostate
39 (08%)
52 (11%)
020
6 (01%)
2 (00%)
027
022
Skin
Kidney*
31 (07%)
23 (05%)
035
5 (01%)
1 (00%)
26 (06%)
32 (07%)
050
8 (02%)
7 (02%)
10
Genital site
12 (03%)
14 (03%)
084
4 (01%)
2 (00%)
069
Haematological
26 (06%)
27 (06%)
10
6 (01%)
14 (03%)
012
9 (02%)
12 (03%)
065
3 (01%)
5 (01%)
072
Unspecied cancer
13 (03%)
7 (02%)
027
11 (02%)
5 (01%)
021
438 (94%)
439 (95%)
089
132 (28%)
114 (25%)
026
For the individual sites, multiple continuity corrected p values are reported; any value that is based on data from more than ve patients could have yielded a value less than
005 by chance. Uncorrected p values that are less than the inverse of the number of such tests were therefore corrected by multiplying by the number of such tests to correct
for this multiplicity of comparisons. In all cases, this yielded p values of 10. *Includes two versus one cases and one versus zero deaths due to cancer in a transplanted kidney.
Excludes 18 (04%) versus 14 (03%) deaths from cancers diagnosed before randomisation.
2187
Articles
Simvastatin plus
Placebo
ezetimibe (n=4650) (n=4620)
p
value
Muscle pain
Any report
Study treatment stopped
992 (213%)
49 (11%)
002
086
50 (11%)
47 (10%)
17 (04%)
16 (03%)
100
4 (01%)
5 (01%)
099
30 (06%)
26 (06%)
071
12 (03%)
12 (03%)
100
6 (01%)
4 (01%)
076
3 (01%)
3 (01%)
100
21 (05%)
18 (04%)
076
Complicated
85 (18%)
76 (16%)
055
Uncomplicated
21 (05%)
30 (06%)
025
Pancreatitis (without
gallstones)
12 (03%)
27 (06%)
002
Any hepatitis
Gallstones
Discussion
The SHARP results show that lowering LDL cholesterol
with the combination of simvastatin plus ezetimibe
safely reduces the risk of major atherosclerotic events in
a wide range of patients with chronic kidney disease. As
in people without kidney disease, the proportional
reduction in major atherosclerotic events produced by a
given absolute reduction in LDL cholesterol is broadly
similar irrespective of age, sex, diabetes, history of
Articles
2189
Articles
AURORA
7 (015%)
SHARP
19 (010%)
Subtotal: three renal trials
28 (011%)
23 other trials
154 (005%)
All trials
182 (005%)
Heterogeneity between renal trials: =03 (p=087)
Dierence between renal and non-renal trials: =00 (p=093)
Coronary revascularisation
4D
55 (331%)
ALERT
52 (100%)
AURORA
55 (120%)
SHARP
149 (079%)
Subtotal: four renal trials
311 (102%)
23 other trials
5191 (154%)
All trials
5502 (150%)
Heterogeneity between renal trials: =08 (p=085)
Dierence between renal and non-renal trials: =00 (p=090)
Vascular death
4D
151 (852%)
ALERT
66 (123%)
AURORA
324 (687%)
SHARP
361 (182%)
Subtotal: four renal trials
902 (285%)
23 other trials
3679 (105%)
All trials
4581 (120%)
Heterogeneity between renal trials: =09 (p=082)
Dierence between renal and non-renal trials: =38 (p=005)
99% or
Allocated
control
35 (202%)
65 (124%)
107 (233%)
159 (085%)
366 (121%)
4386 (129%)
4752 (129%)
083 (070098)
073 (070076)
074 (070077)
29 (167%)
40 (076%)
39 (084%)
128 (068%)
236 (077%)
2052 (061%)
2288 (062%)
3 (017%)
6 (013%)
17 (009%)
26 (010%)
136 (004%)
162 (004%)
108 (060198)
105 (083134)
106 (085133)
72 (429%)
60 (115%)
70 (153%)
203 (109%)
405 (134%)
6605 (199%)
7010 (194%)
074 (063087)
075 (072078)
075 (072077)
167 (936%)
73 (136%)
324 (686%)
388 (197%)
952 (301%)
4230 (121%)
5182 (136%)
094 (085104)
085 (081089)
086 (083090)
95% CI
05
075
LDL-C reduction better
15
Control better
Figure 6: Eects of LDL-lowering therapy on particular vascular outcomes in four trials in patients with chronic kidney disease and 23 trials in other patients
Data from the Cholesterol Treatment Trialists Collaboration.5 tests are shown for heterogeneity between rate ratios for each outcome in the four trials (4D,19
ALERT,21 AURORA,20 and SHARP) in patients with chronic kidney disease. MI=myocardial infarction. LDL-C=LDL-cholesterol.
Articles
2191
Articles
10
11
12
13
14
15
2192
16
17
18
19
20
21
22
23
24
25
26