Statin Therapy and the Risk of Intracerebral Hemorrhage

Transcripción

A Meta-Analysis of 31 Randomized Controlled Trials
James S. McKinney, MD; William J. Kostis, PhD, MD
Downloaded from http://stroke.ahajournals.org/ by guest on October 1, 2016
Background and Purpose—Statin therapy decreases the risk of ischemic stroke. An increased risk of intracerebral
hemorrhage (ICH) has been observed in some studies. To investigate this issue, we performed a meta-analysis of
randomized controlled trials using statins that reported ICH.
Methods—We performed a literature search of Medline, Web of Science, and The Cochrane Library through January 25,
2012, and identified additional randomized controlled trials by reviewing reference lists of retrieved studies and prior
meta-analyses. All randomized controlled trials of statin therapy that reported ICH or hemorrhagic stroke were included.
The primary outcome variable was ICH. Thirty-one randomized controlled trials were included. All analyses used
random effects models and heterogeneity was not observed in any of the analyses.
Results—A total of 91 588 subjects were included in the active group and 91 215 in the control group. There was no
significant difference in incidence of ICH observed in the active treatment group versus control (OR, 1.08; 95% CI,
0.88 –1.32; P⫽0.47). ICH risk was not related to the degree of low-density lipoprotein reduction or achieved low-density
lipoprotein cholesterol. Total stroke (OR, 0.84; 95% CI, 0.78 – 0.91; P⬍0.0001) and all-cause mortality (OR, 0.92; CI,
0.87– 0.96; P⫽0.0007) were significantly reduced in the active therapy group. There was no evidence of publication
bias.
Conclusions—Active statin therapy was not associated with significant increase in ICH in this meta-analysis of 31
randomized controlled trials of statin therapy. A significant reduction in all stroke and all-cause mortality was observed
with statin therapy. (Stroke. 2012;43:2149-2156.)
Key Words: hemorrhagic stroke 䡲 intracerebral hemorrhage 䡲 meta-analysis 䡲 statin
H
ypercholesterolemia is associated with an increased risk
of ischemic stroke.1–5 Lipid-lowering therapy with
3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors
(statins) is effective in reducing cardiovascular mortality by
preventing myocardial infarction and ischemic stroke.6 –24
The clinical benefit may not be limited to the lipid-lowering
properties of statins but also derived from other “pleiotropic”
effects, including anti-inflammatory and antithrombotic effects.25 Despite the significant reductions in ischemic stroke
observed in clinical trials, a large population cohort study and
subsequent meta-analyses have found no reduction in stroke
mortality with statin therapy.26,27
The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) study of high-dose atorvastatin in
secondary stroke prevention demonstrated a significant overall reduction in recurrent stroke but no difference in fatal
stroke.22 A post hoc analysis of the SPARCL trial found that
treatment with atorvastatin was independently associated
with an increased risk of hemorrhagic stroke (hazard ratio,
1.68; 95% CI, 1.09 –2.59).28 This was particularly true of
subjects enrolled with an index hemorrhagic stroke who had
a ⬎5-fold increase in risk of recurrent hemorrhage.28
A 2009 Cochrane review of lipid-lowering therapy and
stroke reported a significant increase in the odds of hemorrhagic stroke with statin therapy (OR, 1.72; 95% CI, 1.20 –
2.46).29 However, this analysis only included 2 trials, Heart
Protection Study (HPS) and SPARCL. A subsequent metaanalysis performed by the Cholesterol Treatment Trialists’
(CTT) Collaboration, which included 20 clinical trials of
statin therapy that reported intracerebral hemorrhage (ICH)
occurrence, observed a nonsignificant trend toward increased
risk of hemorrhagic stroke (relative risk, 1.15; 95% CI,
0.93–1.41; P⫽0.2).30 This analysis showed no effect on
stroke mortality with statin therapy.30 The CTT Collaboration
study excluded trials enrolling ⬍1000 subjects and those with
a ⬍2-year follow-up period.30 The goals of the current study
were to examine the risk of hemorrhagic stroke in patients
treated with statins, to assess their effect on total stroke and
Received February 29, 2012; accepted March 30, 2012.
From the Cardiovascular Institute of New Jersey and the Department of Neurology (J.S.M.), University of Medicine and Dentistry of New
Jersey–Robert Wood Johnson Medical School, New Brunswick, NJ; and the Cardiology Division (W.J.K.), Massachusetts General Hospital, Boston, MA.
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.112.
655894/-/DC1.
Correspondence to James S. McKinney, MD, Department of Neurology, UMDNJ-Robert Wood Johnson Medical School, 125 Paterson Street, New
Brunswick, NJ 08901. E-mail [email protected]
© 2012 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org
DOI: 10.1161/STROKEAHA.112.655894
2149
2150
Stroke
August 2012
Figure 1. Literature search profile.
all-cause mortality, and determine whether the occurrence of
hemorrhagic stroke was related to the low-density lipoprotein
(LDL) change achieved by therapy. We performed a metaanalysis including all available randomized controlled trials
of statin therapy that reported hemorrhagic stroke rate.
Methods
The methods used in this meta-analysis are similar to those previously reported.31 We performed a literature search through January
25, 2012, using Medline, Web of Science, and the Cochrane Library
databases identifying randomized controlled trials (RCTs) of statin
therapy and ICH or hemorrhagic stroke published in the English
language. Search criteria are presented in online-only Data Supplement Figure I. We identified additional RCTs by reviewing reference
lists of identified studies and previously published meta-analyses of
statin therapy. We included all trials with the following criteria:
subjects aged ⱖ18 years, randomized controlled design, blinded
outcomes assessment, and recorded data on hemorrhagic stroke or
ICH. Both primary and secondary prevention trials were included as
were trials comparing active therapy with control therapy of “usual
care,” placebo, or lower-dose statins. Studies were included if
hemorrhagic stroke rates were reported in the first published report,
subsequent publications, or meta-analyses. All studies were adjudicated by authors, and disagreements were resolved through discussion and consensus. Based on the search criteria, 31 RCTs of statin
therapy that reported ICH or hemorrhagic stroke as an outcome were
included in the analysis (Figure 1).
Statistical Methods
Study Selection
Data Extraction and Quality Assessment
Data on the statin used in the active treatment group, type of therapy
(placebo, low-dose statin, or usual care) used in the control group,
inclusion criteria, average follow-up, and the numbers of patients,
total strokes, ICH, and deaths in the active and control groups were
retrieved by the authors. Data on randomization, allocation concealment, comparison of baseline characteristics, defined eligibility
criteria, type of control, blinding (patients, investigators, assessment
of vital status), percent lost to follow-up, and use of intention-to-treat
analysis were assessed.
Data Synthesis and Analysis
ICH rate, total stroke rate, and all-cause mortality in the active and
control groups were calculated. Statistical analyses were performed
using Comprehensive Meta-Analysis 2.232 and JMP 9.0 (SAS
Institute, Cary, NC). ORs and 95% CIs were calculated for the 3
rates described using the intention-to-treat approach. Weighted
pooled treatment effects were calculated for each of the 3 event rates
using random-effects models. Heterogeneity of the effects was
evaluated by the use of the Q statistic.33 Publication bias was
examined by constructing funnel plots,32 by Duval and Tweedie’s
Trim and Fill,33 and the fail-safe N models of Rosenthal34 and
Orwin.35
Sensitivity Analyses
Several additional sensitivity analyses were performed. First, 1 study
(Collaborative Atorvastatin Diabetes Study [CARDS]) reported 0
hemorrhagic strokes in both the atorvastatin and placebo groups.19,25
Therefore, to avoid inclusion of an undefined OR, CARDS was not
considered in our primary analysis, which included only the 30 other
studies. To examine the effects of excluding this study from our
primary analysis, a sensitivity analysis was performed by imputing 1
ICH (instead of 0) in each of the 2 groups (active and control) in
CARDS and including this with the other 30 studies. A second
sensitivity analysis was performed by removing 1 study at a time (of
the 30) in an iterative fashion. This was performed to evaluate
whether individual trials may have overly influenced the findings of
this study. Third, a cumulative meta-analysis was performed to
investigate how well the estimated OR of hemorrhagic stroke
converged with the iterative addition of progressively larger studies.
Results
Thirty-one trials of statin therapy that randomized a total
of 182 803 subjects were identified and included in the
McKinney and Kostis
Table.
Statin Therapy and Risk of ICH
2151
Cerebrovascular Events and Death
Trial, Year
Subjects
Enrolled
(N⫽182 803)
All
Stroke–
Active
All
Stroke–
Control
Ischemic
Stroke–
Active
Ischemic
Stroke–
Control
ICH–
Active
ICH–
Control
Other
Stroke–
Active
Other
Stroke–
Control
Fatal
Stroke–
Active
Fatal
Stroke–
Control
Total
Mortality–
Active
Total
Mortality–
Control
4S, 19946
4444
44
64
29
49
0
2
15
13
14
12
182
256
AF-TEXCAPS,
19988
6605
14
17
1
1
1
0
12
16
...
...
80
77
ALLHAT-LLT,
200212
10 355
209
231
71
83
17
5
121
143
53
56
631
641
ASCOT-LLA,
200316
10 305
89
121
74
95
11
20
4
6
...
...
185
212
A-to-Z,
200417
4497
28
35
22
31
6
0
0
4
...
...
130
104
AURORA,
200936
2773
94
81
57
55
25
21
12
5
40
36
636
660
CARE, 19967
4159
54
78
48
64
2
6
4
8
5
1
180
196
CORONA,
200737
5011
126
145
73
90
15
9
15
16
35
39
728
759
GISSI-P,
200038
4271
20
19
15
13
1
0
4
6
4
4
72
88
GREACE,
200214
1600
9
17
...
...
1
1
9
17
0
1
23
40
HPS, 200213
20 536
444
585
290
409
51
53
103
134
96
119
1328
1507
JUPITER,
200823
17 802
33
64
23
47
6
9
4
8
3
6
198
247
LIPID, 19989
9014
224
272
200
255
17
9
7
8
22
27
717
888
MEGA,
200621
7832
50
62
34
46
16
14
0
2
...
...
55
79
PROSPER,
200215
5804
135
131
91
88
8
10
36
33
22
14
298
305
PROVE-IT,
200418
4162
21
19
10
12
4
1
7
6
...
...
46
66
TNT, 200520
10 001
117
155
96
130
16
17
5
8
...
...
284
282
SEARCH,
201024
12 064
255
279
233
255
24
25
0
0
57
67
964
970
SPARCL,
200622
4731
265
311
218
274
55
33
7
12
24
41
216
211
CARDS,
200419
2841
21
39
9
24
0
0
12
15
1
5
61
82
ASPEN,
200639
2410
34
38
14
15
4
2
16
21
...
...
70
68
GISSI-HF,
200840
4574
82
66
63
53
11
3
8
10
38
29
657
644
4D, 200541
1252
59
44
47
33
5
8
10
6
27
13
297
320
IDEAL, 200542
8888
151
174
129
158
6
6
16
10
...
...
366
374
MIRACL,
200110
3086
12
24
...
...
0
3
12
21
3
2
64
68
PATE, 200111
665
11
18
11
15
0
3
0
0
2
2
14
20
ACAPS,
199443
919
0
5
...
...
0
3
0
2
...
...
1
8
ALERT,
200344
2102
93
91
67
66
10
17
5
5
11
10
143
138
BONE, 200745
604
1
0
...
...
1
0
...
...
...
...
0
0
CLAPT,
199946
226
0
1
...
...
0
1
...
...
...
...
0
2
SHARP,
201147
9270
171
210
114
157
45
37
18
19
68
78
1142
1115
2866 (3.13)
3396 (3.72)
2039 (2.23)
2518 (2.76)
358 (0.39)
318 (0.35)
462 (0.50)
554 (0.61)
525 (0.57)
562 (0.62)
9768 (10.7)
10 427 (11.4)
All studies
total (%)
ICH indicates intracerebral hemorrhage.
analysis.6–24,36–47 Of the 31 RCTs, 6 studies11,17,18,20,24,42 compared
high-dose with low-dose statin therapy, and the remainder6 –10,12–15,19,21–23,36 – 41,43– 47 compared statin therapy with
placebo or “usual care.” A total of 91 588 subjects were
randomized to active therapy and 91 215 subjects to control
therapy. The median length of follow-up was 46.8 months.
The patient and LDL characteristics for RCTs included in
this analysis are presented in online-only Data Supplement
2152
Stroke
August 2012
ICH - Statin Meta-Analysis: ICH
Study name
Subgroup within study
Statistics for each study
Odds
ratio
Stroke / Total
p-Value
Lower
limit
Upper
limit
4S
PLACEBO
0.20
0.2989
0.01
4.17
0 / 2221
2 / 2223
AF-TEXCAPS
PLACEBO
3.00
0.5014
0.12
73.62
1 / 3304
0 / 3301
ALLHAT-LLT
PLACEBO
3.42
0.0158
1.26
9.27
17 / 5170
5 / 5185
ASCOT-LLA
PLACEBO
0.55
0.1071
0.26
1.14
11 / 5168
20 / 5137
Active
Control
ATOZ
LOW DOSE
12.84
0.0820
0.72
228.14
6 / 2265
0 / 2232
AURORA
PLACEBO
1.19
0.5608
0.66
2.14
25 / 1389
21 / 1384
6 / 2078
CARE
PLACEBO
0.33
0.1774
0.07
1.65
2 / 2081
CORONA
PLACEBO
1.66
0.2308
0.72
3.80
15 / 2514
9 / 2497
GISSI-P
PLACEBO
2.99
0.5019
0.12
73.55
1 / 2138
0 / 2133
GREACE
PLACEBO
1.00
1.0000
0.06
16.02
1 / 800
1 / 800
HPS
PLACEBO
0.96
0.8434
0.65
1.41
51 / 10269
53 / 10267
9 / 8901
JUPITER
PLACEBO
0.67
0.4415
0.24
1.87
6 / 8901
LIPID
PLACEBO
1.89
0.1236
0.84
4.24
17 / 4512
9 / 4502
MEGA
PLACEBO
1.17
0.6632
0.57
2.41
16 / 3866
14 / 3966
10 / 2913
PROSPER
PLACEBO
0.81
0.6490
0.32
2.04
8 / 2891
PROVE-IT
LOW DOSE
3.94
0.2205
0.44
35.25
4 / 2099
1 / 2063
TNT
LOW DOSE
0.94
0.8666
0.48
1.87
16 / 4995
17 / 5006
SEARCH
LOW DOSE
0.96
0.8871
0.55
1.68
24 / 6031
25 / 6033
SPARCL
PLACEBO
1.68
0.0191
1.09
2.60
55 / 2365
33 / 2366
ASPEN
PLACEBO
1.98
0.4296
0.36
10.85
4 / 1211
2 / 1199
GISSI-HF
PLACEBO
3.69
0.0454
1.03
13.23
11 / 2285
3 / 2289
4D
PLACEBO
0.64
0.4299
0.21
1.96
5 / 619
8 / 633
IDEAL
LOW DOSE
1.00
0.9969
0.32
3.11
6 / 4439
6 / 4449
MIRACL
PLACEBO
0.14
0.1992
0.01
2.78
0 / 1538
3 / 1548
PATE
LOW DOSE
0.60
0.1963
0.28
1.30
11 / 331
18 / 334
ACAPS
PLACEBO
0.14
0.1965
0.01
2.75
0 / 460
3 / 459
ALERT
PLACEBO
0.59
0.1817
0.27
1.28
10 / 1050
17 / 1052
BONE
PLACEBO
0.74
0.8540
0.03
18.28
1 / 485
0 / 119
CLAPT
PLACEBO
0.34
0.5060
0.01
8.34
0 / 112
1 / 114
SHARP
PLACEBO
45 / 4650
37 / 4620
1.21
0.3916
0.78
1.87
1.08
0.4687
0.88
1.32
Odds ratio and 95% CI
0.01
0.1
Favors Active
1
10
100
Favors Control
All studies
Figure 2. Forrest plot of random-effects meta-analysis of randomized trials of statins and intracerebral hemorrhage.
Tables I and II. The mean age of was 62.6⫾5.2 years. A total
of 67.0% of patients were male and 78.1% were white. Only
11.0% of subjects had a prior documented history of stroke.
On average 24.7% had diabetes, 53.0% had hypertension,
59.1% had cardiovascular diseases, and 21.2% actively
smoked cigarettes at study enrollment. A total of 61.0% of
subjects were treated with aspirin or oral anticoagulants.
Stroke events are presented in the Table.
Intracerebral Hemorrhage
ICH occurred in 358 subjects (0.39%) in the active treatment
group versus 318 (0.35%) in the control group. In the primary
analysis assessing ICH risk in 30 studies of statin treatment,
active therapy was not associated with an increase in ICH
(OR, 1.08; 95% CI, 0.88 –1.32; P⫽0.47; Figure 2). The P for
heterogeneity (interaction) was 0.38, Q⫽30.705, and degrees
of freedom⫽29. No statistically significant difference in the
risk of ICH was observed when the meta-analyses were
stratified by control group or primary versus secondary
prevention studies (online-only Data Supplement Figure II).
The sensitivity analysis that included all 31 studies (including CARDS) produced nearly identical results as the primary
analysis (OR, 1.08; 95% CI, 0.88 –1.31; P⫽0.46). In all 30
iterations of the sensitivity analysis performed by removing 1
study at a time, there was no association between ICH and
active treatment. The point estimate of the OR varied from
1.04 to 1.11 with a lower limit of 0.84 to 0.91 and P of 0.27
to 0.77. During the cumulative meta-analysis, there was no
association between ICH and active treatment in 28 of 30
iterations. The point estimate of the OR ranged from 0.20
(95% CI, 0.01– 4.17; P⫽0.30) to 1.90 (95% CI, 0.40 – 8.95;
P⫽0.42).
We did not observe evidence of publication bias as
demonstrated by a symmetrical funnel plot. The OR and CI of
the overall effect (OR, 1.08; 95% CI, 0.88 –1.31) remained
unchanged using Duval and Tweedie’s Trim and Fill
method.33 Orwin’s fail-safe N revealed that 25 additional
studies with a mean OR of 1.0 would be needed to bring a 5%
increase (OR, 1.05) at the P⫽0.05 level.
A metaregression was performed to study the relationship
between the LDL effect of statin therapy and ICH risk. There
was no relationship between the effects of active versus
control therapy with measures of LDL cholesterol. Specifically, there were no significant relationships of the log OR
(active/control) of each study versus (1) the difference (active
minus control) of the LDL cholesterol drop (difference
McKinney and Kostis
2153
ICH - Statin Meta-Analysis: All Stroke
Study name
4S
PLACEBO
Odds
ratio
p-Value
Lower
limit
0.68
0.0533
0.46
Stroke / Total
Upper
limit
1.01
Active
Control
44 / 2221
64 / 2223
AF-TEXCAPS
PLACEBO
0.82
0.5880
0.40
1.67
14 / 3304
17 / 3301
ALLHAT-LLT
PLACEBO
0.90
0.2982
0.75
1.09
209 / 5170
231 / 5185
ASCOT-LLA
PLACEBO
0.73
0.0234
0.55
0.96
89 / 5168
121 / 5137
ATOZ
LOW DOSE
0.79
0.3448
0.48
1.30
28 / 2265
35 / 2232
AURORA
PLACEBO
1.17
0.3223
0.86
1.59
94 / 1389
81 / 1384
CARE
PLACEBO
0.68
0.0340
0.48
0.97
54 / 2081
78 / 2078
CORONA
PLACEBO
0.86
0.2138
0.67
1.09
126 / 2514
145 / 2497
GISSI-P
PLACEBO
1.05
0.8780
0.56
1.97
20 / 2138
19 / 2133
GREACE
PLACEBO
0.52
0.1197
0.23
1.18
9 / 800
17 / 800
HPS
PLACEBO
0.75
0.0000
0.66
0.85
444 / 10269
585 / 10267
JUPITER
PLACEBO
0.51
0.0019
0.34
0.78
33 / 8901
64 / 8901
LIPID
PLACEBO
0.81
0.0251
0.68
0.97
224 / 4512
272 / 4502
MEGA
PLACEBO
0.83
0.3151
0.57
1.20
50 / 3866
62 / 3966
PROSPER
PLACEBO
1.04
0.7533
0.81
1.33
135 / 2891
131 / 2913
PROVE-IT
LOW DOSE
1.09
0.7928
0.58
2.03
21 / 2099
19 / 2063
TNT
LOW DOSE
0.75
0.0209
0.59
0.96
117 / 4995
155 / 5006
SEARCH
LOW DOSE
0.91
0.2900
0.77
1.08
255 / 6031
279 / 6033
SPARCL
PLACEBO
0.83
0.0416
0.70
0.99
265 / 2365
311 / 2366
CARDS
PLACEBO
0.53
0.0184
0.31
0.90
21 / 1429
39 / 1412
ASPEN
PLACEBO
0.88
0.6022
0.55
1.41
34 / 1211
38 / 1199
GISSI-HF
PLACEBO
1.25
0.1786
0.90
1.74
82 / 2285
66 / 2289
4D
PLACEBO
1.41
0.0979
0.94
2.12
59 / 619
44 / 633
IDEAL
LOW DOSE
0.87
0.2012
0.69
1.08
151 / 4439
174 / 4449
MIRACL
PLACEBO
0.50
0.0507
0.25
1.00
12 / 1538
24 / 1548
PATE
LOW DOSE
0.60
0.1963
0.28
1.30
11 / 331
18 / 334
ACAPS
PLACEBO
0.09
0.1030
0.00
1.63
0 / 460
5 / 459
ALERT
PLACEBO
1.03
0.8667
0.76
1.39
93 / 1050
91 / 1052
BONE
PLACEBO
0.74
0.8540
0.03
18.28
1 / 485
0 / 119
CLAPT
PLACEBO
0.34
0.5060
0.01
8.34
0 / 112
1 / 114
SHARP
PLACEBO
0.80
0.0356
0.65
0.99
171 / 4650
210 / 4620
0.84
0.0000
0.78
0.91
0.5
1
Favors Active
2
Favors Control
All studies
Figure 3. Forrest plot of random-effects meta-analysis of randomized trials of statins and all stroke.
between baseline and follow-up) in mg/dL (slope, 0.0043;
SE, 0.0054; 95% CI, ⫺0.4831 to 0.0149; P⫽0.43]; (2) this
difference expressed as percentage of baseline (slope, 0.0054;
SE, 0.0075; 95% CI, ⫺0.0092 to 0.0200; P⫽0.47]; and (3)
the achieved LDL cholesterol in the active treatment group
during follow-up (slope, ⫺0.0049; SE, 0.0043; 95% CI,
⫺0.0133 to 0.0035; P⫽0.26).
All Stroke
There was a total of 6262 strokes in this meta-analysis. The
overall stroke rate was 3.13% in the active group versus
3.72% in the control group. Active therapy resulted in a
significant reduction in total stroke (OR, 0.84; 95% CI,
0.78 – 0.91; P⬍0.0001; Figure 3). The P for heterogeneity
(interaction) was 0.31, Q⫽33.315, and degrees of freedom⫽30. The number needed to treat with active statin
therapy to prevent any stroke during study follow-up was 200
(absolute risk reduction⫽0.5%, P⬍0.0001).
All-Cause Mortality
There were 20 195 deaths recorded in the 31 trials included in
this analysis. There was a significantly lower rate of all-cause
mortality in the active group (10.67%) than in the control
group (11.43%; OR, 0.92; 95% CI, 0.87– 0.96; P⫽0.0007;
Figure 4). The P for heterogeneity (interaction) was 0.31,
Q⫽32.272, and degrees of freedom⫽29. The number needed
to treat with active statin therapy to prevent 1 death was 167
(absolute risk reduction⫽0.6%, P⬍0.0001).
Discussion
Epidemiological studies have reported increased rates of
hemorrhagic stroke and ICH-related mortality in populations
with low cholesterol levels.1,4,48,49 It has been hypothesized
that cholesterol may be important for cerebrovascular wall
integrity and that low levels may increase the risk of vessel
rupture and ICH.50 Furthermore, several studies have reported
an association of hemorrhagic stroke with statin use.
The SPARCL trial of high-dose atorvastatin in secondary
stroke prevention reported an excess of ICH with active
treatment compared with placebo (55 versus 33; P⫽0.02).22
Similarly, there was a 2-fold increase in hemorrhagic stroke
in the HPS among patients with prior stroke treated with
simvastatin.51 Three previous meta-analyses of statin therapy
have found no increased risk of hemorrhagic stroke.25,30,52 In
a meta-analysis of 11 trials, Amarenco and Labreuche25
reported a negligible risk of hemorrhagic stroke with statin
2154
Stroke
August 2012
ICH - Statin Meta-Analysis: Death
Study name
Dead / Total
Odds
ratio
p-Value
Lower
limit
PLACEBO
0.69
0.0002
0.56
0.84
AF-TEXCAPS
PLACEBO
1.04
0.8130
0.76
1.43
80 / 3304
77 / 3301
ALLHAT-LLT
PLACEBO
0.99
0.8071
0.88
1.11
631 / 5170
641 / 5185
ASCOT-LLA
PLACEBO
0.86
0.1493
0.71
1.05
185 / 5168
212 / 5137
ATOZ
LOW DOSE
1.25
0.1036
0.96
1.62
130 / 2265
104 / 2232
AURORA
PLACEBO
0.93
0.3162
0.80
1.08
636 / 1389
660 / 1384
CARE
PLACEBO
0.91
0.3791
0.74
1.12
180 / 2081
196 / 2078
4S
Upper
limit
Active
Control
182 / 2221
256 / 2223
CORONA
PLACEBO
0.93
0.2650
0.83
1.05
728 / 2514
759 / 2497
GISSI-P
PLACEBO
0.81
0.1928
0.59
1.11
72 / 2138
88 / 2133
GREACE
PLACEBO
0.56
0.0309
0.33
0.95
23 / 800
40 / 800
HPS
PLACEBO
0.86
0.0003
0.80
0.93
1328 / 10269
1507 / 10267
JUPITER
PLACEBO
0.80
0.0189
0.66
0.96
198 / 8901
247 / 8901
LIPID
PLACEBO
0.77
0.0000
0.69
0.86
717 / 4512
888 / 4502
MEGA
PLACEBO
0.71
0.0532
0.50
1.00
55 / 3866
79 / 3966
PROSPER
PLACEBO
0.98
0.8393
0.83
1.16
298 / 2891
305 / 2913
PROVE-IT
LOW DOSE
0.68
0.0458
0.46
0.99
46 / 2099
66 / 2063
TNT
LOW DOSE
1.01
0.9096
0.85
1.20
284 / 4995
282 / 5006
SEARCH
LOW DOSE
0.99
0.8879
0.90
1.09
964 / 6031
970 / 6033
SPARCL
PLACEBO
1.03
0.7962
0.84
1.25
216 / 2365
211 / 2366
CARDS
PLACEBO
0.72
0.0617
0.51
1.02
61 / 1429
82 / 1412
ASPEN
PLACEBO
1.02
0.9084
0.72
1.44
70 / 1211
68 / 1199
GISSI-HF
PLACEBO
1.03
0.6431
0.91
1.17
657 / 2285
644 / 2289
4D
PLACEBO
0.90
0.3628
0.72
1.13
297 / 619
320 / 633
IDEAL
LOW DOSE
0.98
0.7832
0.84
1.14
366 / 4439
374 / 4449
MIRACL
PLACEBO
0.95
0.7507
0.67
1.34
64 / 1538
68 / 1548
PATE
LOW DOSE
0.69
0.3056
0.34
1.40
14 / 331
20 / 334
ACAPS
PLACEBO
0.12
0.0485
0.02
0.99
1 / 460
8 / 459
ALERT
PLACEBO
1.04
0.7357
0.81
1.34
143 / 1050
138 / 1052
CLAPT
PLACEBO
0.20
0.3006
0.01
4.21
0 / 112
2 / 114
SHARP
PLACEBO
1.02
0.6336
0.93
1.13
1142 / 4650
1115 / 4620
0.92
0.0007
0.87
0.96
0.5
1
Favors Active
2
Favors Control
All studies
Figure 4. Forrest plot of random-effects meta-analysis of randomized trials of statins and all-cause mortality.
therapy (relative risk, 1.03; 95% CI, 0.75–1.41). Studying
intensive LDL reduction with statins, the CTT collaboration
performed a meta-analysis of 26 RCTs and reported a
nonsignificant trend toward an increased risk of ICH (relative
risk, 1.15; 95% CI, 0.93–1.41).30 A more recent meta-analysis
including 23 RCTs found no evidence of increased risk of
ICH.53
We performed a comprehensive meta-analysis of previously conducted randomized clinical trials of statin therapy
for which data on ICH or hemorrhagic stroke were available.
We included 31 RCTs with a total of 182 803 subjects. In our
analysis, active therapy was associated with a nonsignificant
increase in the risk of ICH (OR, 1.08; 95% CI, 0.88 –1.32).
The small nonsignificant observed excess of ICH was not
related to the LDL effects of statin therapy. We found no
relationship between the achieved LDL level or the degree of
LDL reduction and the risk of hemorrhagic stroke in this
analysis. This suggests that any potential increase in ICH risk
could be attributable to other non-LDL effects of statin
therapy. This is in agreement with a large meta-analysis of
observational cohort studies that found no correlation with
fatal stroke and baseline total cholesterol in almost 900 000
subjects.27 In addition to their lipid-lowering properties,
statins may have antithrombotic properties by inhibiting
platelet aggregation and enhancing fibrinolysis.54,55 The antithrombotic affects of statins could account for a theoretically increased risk of bleeding complications.
When stratifying our analysis by type of prevention, there
was a nonsignificant trend toward increased odds of ICH in
secondary prevention studies (OR, 1.26; 95% CI, 0.91–1.73)
compared with primary prevention studies (OR, 0.96; 95%
CI, 0.75–1.23). The present study was not limited to trials of
statin therapy for secondary stroke prevention. Post hoc
analyses of HPS and SPARCL suggest that patients with prior
stroke may be at particularly increased risk of hemorrhagic
stroke.28,51 However, a recent large retrospective cohort study
found no evidence of increased risk of ICH in patients treated
with statins after an ischemic stroke.52 Westover et al,56 using
a decision-analytic approach, found that avoiding statins,
particularly in patients with a history of lobar hemorrhage
(and who are at high risk for recurrent hemorrhage), was
favored over a wide range of clinical parameters. Our analysis
did not evaluate the risk of statin therapy in this subgroup of
patients with prior ICH. Based on current data, caution should
be used in treating these patients with statins, and further
research is warranted.
McKinney and Kostis
There are several limitations to this analysis. First, we did
not have access to patient-level data and there may be
unaccounted patient variables that influenced the rates of
hemorrhagic stroke. Second, hemorrhagic stroke is a nebulous term that may include ICH, subarachnoid hemorrhage,
subdural or epidural hemorrhages, or hemorrhagic transformation of an ischemic stroke. Although ICH is the condition
of interest, it is possible that prior RCTs that reported
hemorrhagic stroke rates included some of these other causes
of intracranial bleeding. Lastly, although we performed the
most comprehensive analysis yet published of statin therapy
and ICH risk in randomized trials, it is possible that there are
other trials, particularly those published in languages other
than English, that were excluded. Although we included all
pertinent trials, regardless of size, no publication bias or
heterogeneity was found in our analysis.
Statin therapy was not associated with a significant increased risk of ICH. There was no effect on ICH risk related
to the degree of decline in LDL or to the achieved level. The
significant reduction in total stroke and all-cause mortality
more than offset any slight increase in ICH risk. These
findings support the current recommendations to prescribe
statins in otherwise appropriate patients.
9.
10.
11.
12.
13.
14.
15.
Conclusions
16.
In this meta-analysis of 31 RCTs, statin therapy was not
associated with a significant increase in odds of ICH. However, statin therapy is associated with significant reductions in
total stroke and death, thereby negating any potential hemorrhage risk in an unselected patient population.
17.
Sources of Funding
This study was funded in part by the Robert Wood Johnson
Foundation and the Schering-Plough Foundation.
18.
Disclosures
19.
None.
References
1. Iso H, Jacobs DR Jr, Wentworth D, Neaton JD, Cohen JD. Serum
cholesterol levels and six-year mortality from stroke in 350 977 men
screened for the multiple risk factor intervention trial. N Engl J Med.
1989;320:904 –910.
2. Leppala JM, Virtamo J, Fogelholm R, Albanes D, Heinonen OP. Different risk factors for different stroke subtypes: association of blood
pressure, cholesterol, and antioxidants. Stroke. 1999;30:2535–2540.
3. Horenstein RB, Smith DE, Mosca L. Cholesterol predicts stroke mortality
in the women’s pooling project. Stroke. 2002;33:1863–1868.
4. Zhang X, Patel A, Horibe H, Wu Z, Barzi F, Rodgers A, et al. Cholesterol, coronary heart disease, and stroke in the Asia Pacific region. Int J
Epidemiol. 2003;32:563–572.
5. Kurth T, Everett BM, Buring JE, Kase CS, Ridker PM, Gaziano JM.
Lipid levels and the risk of ischemic stroke in women. Neurology.
2007;68:556 –562.
6. Randomised trial of cholesterol lowering in 4444 patients with coronary
heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet.
1994;344:1383–1389.
7. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG,
et al. The effect of pravastatin on coronary events after myocardial
infarction in patients with average cholesterol levels. Cholesterol and
recurrent events trial investigators. N Engl J Med. 1996;335:1001–1009.
8. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, et
al. Primary prevention of acute coronary events with lovastatin in men
and women with average cholesterol levels: results of AFCAPS/
20.
21.
22.
23.
24.
25.
26.
27.
2155
TEXCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study.
JAMA. 1998;279:1615–1622.
Prevention of cardiovascular events and death with pravastatin in patients
with coronary heart disease and a broad range of initial cholesterol levels.
The Long-Term Intervention With Pravastatin in Ischaemic Disease
(LIPID) study group. N Engl J Med. 1998;339:1349 –1357.
Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D,
et al. Effects of atorvastatin on early recurrent ischemic events in acute
coronary syndromes: the MIRACL study: a randomized controlled trial.
JAMA. 2001;285:1711–1718.
Ito H, Ouchi Y, Ohashi Y, Saito Y, Ishikawa T, Nakamura H, et al. A
comparison of low versus standard dose pravastatin therapy for the
prevention of cardiovascular events in the elderly: the Pravastatin AntiAtherosclerosis Trial in the Elderly (PATE). J Atheroscler Thromb.
2001;8:33– 44.
Major outcomes in moderately hypercholesterolemic, hypertensive patients
randomized to pravastatin vs usual care: the Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA.
2002;288:2998–3007.
MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled
trial. Lancet. 2002;360:7–22.
Athyros VG, Papageorgiou AA, Mercouris BR, Athyrou VV, Symeonidis
AN, Basayannis EO, et al. Treatment with atorvastatin to the national
cholesterol educational program goal versus ‘usual’ care in secondary
coronary heart disease prevention. The Greek Atorvastatin and CoronaryHeart-Disease Evaluation (GREACE) study. Curr Med Res Opin. 2002;
18:220 –228.
Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM,
et al. Pravastatin in Elderly Individuals at Risk of Vascular Disease
(PROSPER): a randomised controlled trial. Lancet. 2002;360:1623–1630.
Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, et al.
Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol
concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid
Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial.
Lancet. 2003;361:1149 –1158.
de Lemos JA, Blazing MA, Wiviott SD, Lewis EF, Fox KA, White HD,
et al. Early intensive vs a delayed conservative simvastatin strategy in
patients with acute coronary syndromes: phase Z of the A to Z Trial.
JAMA. 2004;292:1307–1316.
Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R,
et al. Intensive versus moderate lipid lowering with statins after acute
coronary syndromes. N Engl J Med. 2004;350:1495–1504.
Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA,
Livingstone SJ, et al. Primary prevention of cardiovascular disease with
atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes
Study (CARDS): multicentre randomised placebo-controlled trial.
Lancet. 2004;364:685– 696.
LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, et
al. Intensive lipid lowering with atorvastatin in patients with stable
coronary disease. N Engl J Med. 2005;352:1425–1435.
Nakamura H, Arakawa K, Itakura H, Kitabatake A, Goto Y, Toyota T, et
al. Primary prevention of cardiovascular disease with pravastatin in Japan
(Mega study): a prospective randomised controlled trial. Lancet. 2006;
368:1155–1163.
Amarenco P, Bogousslavsky J, Callahan A III, Goldstein LB, Hennerici
M, Rudolph AE, et al. High-dose atorvastatin after stroke or transient
ischemic attack. N Engl J Med. 2006;355:549 –559.
Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM Jr, Kastelein
JJ, et al. Rosuvastatin to prevent vascular events in men and women with
elevated C-reactive protein. N Engl J Med. 2008;359:2195–2207.
Armitage J, Bowman L, Wallendszus K, Bulbulia R, Rahimi K, Haynes
R, et al. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg
simvastatin daily in 12 064 survivors of myocardial infarction: a
double-blind randomised trial. Lancet. 2010;376:1658 –1669.
Amarenco P, Labreuche J. Lipid management in the prevention of stroke:
review and updated meta-analysis of statins for stroke prevention. Lancet
Neurol. 2009;8:453– 463.
Cholesterol, diastolic blood pressure, and stroke: 13 000 strokes in
450 000 people in 45 prospective cohorts. Prospective studies collaboration. Lancet. 1995;346:1647–1653.
Lewington S, Whitlock G, Clarke R, Sherliker P, Emberson J, Halsey J,
et al. Blood cholesterol and vascular mortality by age, sex, and blood
2156
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
Stroke
August 2012
pressure: a meta-analysis of individual data from 61 prospective studies
with 55 000 vascular deaths. Lancet. 2007;370:1829 –1839.
Goldstein MR, Mascitelli L, Pezzetta F. Hemorrhagic stroke in the
stroke prevention by Aggressive Reduction in Cholesterol Levels
Study. Neurology. 2009;72:1448; author reply 1448 –1449.
Manktelow BN, Potter JF. Interventions in the management of serum
lipids for preventing stroke recurrence. Cochrane Database Syst Rev.
2009;3:CD002091.
Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et al.
Efficacy and safety of more intensive lowering of LDL cholesterol: a
meta-analysis of data from 170 000 participants in 26 randomised trials.
Lancet. 2010;376:1670 –1681.
Kostis WJ, Moreyra AE, Cheng JQ, Dobrzynski JM, Kostis JB. Continuation of mortality reduction after the end of randomized therapy in
clinical trials of lipid-lowering therapy. J Clin Lipidol. 2011;5:97–104.
Borenstein M. Introduction to Meta-Analysis. Chichester, UK: John
Wiley & Sons; 2009.
Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of
testing and adjusting for publication bias in meta-analysis. Biometrics.
2000;56:455– 463.
Rosenthal R. The ’file drawer problem’ and tolerance for null results.
Psychol Bull. 1979;86:638 – 641.
Orwin RG. A fail-safe N for effect size in meta-analysis. J Educ Stat.
1983;8:157–159.
Fellstrom BC, Jardine AG, Schmieder RE, Holdaas H, Bannister K,
Beutler J, et al. Rosuvastatin and cardiovascular events in patients
undergoing hemodialysis. N Engl J Med. 2009;360:1395–1407.
Kjekshus J, Apetrei E, Barrios V, Bohm M, Cleland JG, Cornel JH, et al.
Rosuvastatin in older patients with systolic heart failure. N Engl J Med.
2007;357:2248 –2261.
Results of the low-dose (20 mg) pravastatin GISSI Prevenzione Trial in
4271 patients with recent myocardial infarction: do stopped trials contribute to overall knowledge? Gissi Prevenzione Investigators (Gruppo
Italiano Per Lo Studio Della Sopravvivenza Nell’infarto Miocardico). Ital
Heart J. 2000;1:810 – 820.
Knopp RH, d’Emden M, Smilde JG, Pocock SJ. Efficacy and safety of
atorvastatin in the prevention of cardiovascular end points in subjects
with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary
Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus
(ASPEN). Diabetes Care. 2006;29:1478 –1485.
Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R,
et al. Effect of rosuvastatin in patients with chronic heart failure (the
GISSI-HF Trial): a randomised, double-blind, placebo-controlled trial.
Lancet. 2008;372:1231–1239.
Wanner C, Krane V, Marz W, Olschewski M, Mann JF, Ruf G, et al.
Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med. 2005;353:238 –248.
Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ,
Holme I, et al. High-dose atorvastatin vs usual-dose simvastatin for
secondary prevention after myocardial infarction: the IDEAL study: a
randomized controlled trial. JAMA. 2005;294:2437–2445.
43. Furberg CD, Adams HP Jr, Applegate WB, Byington RP, Espeland MA,
Hartwell T, et al. Effect of lovastatin on early carotid atherosclerosis and
cardiovascular events. Asymptomatic Carotid Artery Progression Study
(ACAPS) research group. Circulation. 1994;90:1679 –1687.
44. Holdaas H, Fellstrom B, Jardine AG, Holme I, Nyberg G, Fauchald P, et
al. Effect of fluvastatin on cardiac outcomes in renal transplant recipients:
a multicentre, randomised, placebo-controlled trial. Lancet. 2003;361:
2024 –2031.
45. Bone HG, Kiel DP, Lindsay RS, Lewiecki EM, Bolognese MA, Leary
ET, et al. Effects of atorvastatin on bone in postmenopausal women with
dyslipidemia: a double-blind, placebo-controlled, dose-ranging trial.
J Clin Endocrinol Metab. 2007;92:4671– 4677.
46. Kleemann A, Eckert S, von Eckardstein A, Lepper W, Schernikau U,
Gleichmann U, et al. Effects of lovastatin on progression of non-dilated
and dilated coronary segments and on restenosis in patients after PTCA.
The Cholesterol Lowering Atherosclerosis PTCA Trial (CLAPT). Eur
Heart J. 1999;20:1393–1406.
47. Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C,
et al. The effects of lowering LDL cholesterol with simvastatin plus
ezetimibe in patients with chronic kidney disease (study of heart and renal
protection): a randomised placebo-controlled trial. Lancet. 2011;377:
2181–2192.
48. Sturgeon JD, Folsom AR, Longstreth WT Jr, Shahar E, Rosamond WD,
Cushman M. Risk factors for intracerebral hemorrhage in a pooled prospective study. Stroke. 2007;38:2718 –2725.
49. Iribarren C, Reed DM, Burchfiel CM, Dwyer JH. Serum total cholesterol
and mortality. Confounding factors and risk modification in JapaneseAmerican men. JAMA. 1995;273:1926 –1932.
50. Bjorkhem I, Meaney S. Brain cholesterol: long secret life behind a barrier.
Arterioscler Thromb Vasc Biol. 2004;24:806 – 815.
51. Collins R, Armitage J, Parish S, Sleight P, Peto R. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in
20 536 people with cerebrovascular disease or other high-risk conditions.
Lancet. 2004;363:757–767.
52. Hackam DG, Austin PC, Huang A, Juurlink DN, Mamdani MM, Paterson
JM, et al. Statins and intracerebral hemorrhage: a retrospective cohort
study. Arch Neurol. 2012;69:39 – 45.
53. Hackam DG, Woodward M, Newby LK, Bhatt DL, Shao M, Smith EE,
et al. Statins and intracerebral hemorrhage: collaborative systematic
review and meta-analysis. Circulation. 2011;124:2233–2242.
54. Serebruany VL, Miller M, Pokov AN, Malinin AI, Lowry DR, Tanguay
JF, et al. Effect of statins on platelet par-1 thrombin receptor in patients
with the metabolic syndrome (from the PAR-1 Inhibition by Statins
[PARIS] study). Am J Cardiol. 2006;97:1332–1336.
55. Serebruany VL, Malinin AI, Hennekens CH. Statins increase risk of
hemorrhagic stroke by inhibition of the PAR-1 receptor. Cerebrovasc
Dis. 2007;24:477– 479.
56. Westover MB, Bianchi MT, Eckman MH, Greenberg SM. Statin use
following intracerebral hemorrhage: a decision analysis. Arch Neurol.
2010;68:573–579.
Statin Therapy and the Risk of Intracerebral Hemorrhage: A Meta-Analysis of 31
Randomized Controlled Trials
James S. McKinney and William J. Kostis
Stroke. 2012;43:2149-2156; originally published online May 15, 2012;
doi: 10.1161/STROKEAHA.112.655894
Stroke is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 2012 American Heart Association, Inc. All rights reserved.
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SUPPLEMENTAL MATERIAL
Supplemental Figure 1. Literature search criteria for Medline (A), Web of Science (B), and the Cochrane Library (C), January 25,
2012.
A.
B.
C.
Supplemental Figure 2. Forrest plot of random-effects meta-analysis of statin therapy and intracerebral hemorrhage stratified
by type of control group (A) and type of prevention (B).
A.
B.
ICH Meta-Analysis: ICH OR by Type of Prevention
Group by
PRIMARY
PRIMARY
PRIMARY
PRIMARY
PRIMARY
PRIMARY
PRIMARY
PRIMARY
PRIMARY
PRIMARY
PRIMARY
PRIMARY
PRIMARY
PRIMARY
PRIMARY
SECONDARY
SECONDARY
SECONDARY
SECONDARY
SECONDARY
SECONDARY
SECONDARY
SECONDARY
SECONDARY
SECONDARY
SECONDARY
SECONDARY
SECONDARY
SECONDARY
SECONDARY
SECONDARY
SECONDARY
Overall
Odds
Lower
ratio p-Value limit
AF-TEXCAPS
PRIMARY
ALLHAT-LLTPRIMARY
ASCOT-LLAPRIMARY
AURORA PRIMARY
HPS
PRIMARY
JUPITER PRIMARY
MEGA
PRIMARY
PROSPER PRIMARY
ASPEN
PRIMARY
PATE
PRIMARY
ACAPS
PRIMARY
ALERT
PRIMARY
BONE
PRIMARY
SHARP
PRIMARY
4S
ATOZ
CARE
CORONA
GISSI-P
GREACE
LIPID
PROVE-IT
TNT
SEARCH
SPARCL
GISSI-HF
4D
IDEAL
MIRACL
CLAPT
SECONDARY
SECONDARY
SECONDARY
SECONDARY
SECONDARY
SECONDARY
SECONDARY
SECONDARY
SECONDARY
SECONDARY
SECONDARY
SECONDARY
SECONDARY
SECONDARY
SECONDARY
SECONDARY
3.00
3.42
0.55
1.19
0.96
0.67
1.17
0.81
1.98
0.60
0.14
0.59
0.74
1.21
0.96
0.20
12.84
0.33
1.66
2.99
1.00
1.89
3.94
0.94
0.96
1.68
3.69
0.64
1.00
0.14
0.34
1.26
1.06
0.5014
0.0158
0.1071
0.5608
0.8434
0.4415
0.6632
0.6490
0.4296
0.1963
0.1965
0.1817
0.8540
0.3916
0.7663
0.2989
0.0820
0.1774
0.2308
0.5019
1.0000
0.1236
0.2205
0.8666
0.8871
0.0191
0.0454
0.4299
0.9969
0.1992
0.5060
0.1638
0.5409
Upper
limit
0.12 73.62
1.26
9.27
0.26
1.14
0.66
2.14
0.65
1.41
0.24
1.87
0.57
2.41
0.32
2.04
0.36 10.85
0.28
1.30
0.01
2.75
0.27
1.28
0.03 18.28
0.78
1.87
0.75
1.23
0.01
4.17
0.72 228.14
0.07
1.65
0.72
3.80
0.12 73.55
0.06 16.02
0.84
4.24
0.44 35.25
0.48
1.87
0.55
1.68
1.09
2.60
1.03 13.23
0.21
1.96
0.32
3.11
0.01
2.78
0.01
8.34
0.91
1.73
0.87
1.29
0.01
0.1
Favors Active
1
10
Favors Control
100
Supplemental Table 1. Description of Trials, Patient Demographics
Trial, Year
Active Drug
Control
Total
Subjects
4444
Age
(y ears)
63
Gender
(% male)
81
Race
(% white)
---
Follow-up
(months)
64.8
DM (%)
4S, 19941
Simvastatin
Placebo
4.5
AF-TEXCAPS,
Lovastatin
Placebo
6605
58
85
89
62.4
12.2
2
1998
ALLHAT-LLT,
Pravastatin
Usual care
10355
66
51
41
57.6
35.2
20023
ASCOT-LLA,
Atorvastatin
Placebo
10305
63
81
95
39.6
24.6
20034
5
A-to-Z, 2004
Simvastatin
Low-dose
4497
61
76
--24
23.5
AURORA,
Rosuvastatin
Placebo
2773
64
62
85
45.6
26.0
6
2009
7
CARE, 1996
Pravastatin
Placebo
4159
59
86
93
60
15.5
CORONA,
Rosuvastatin
Placebo
5011
73
76
--32.8
29.5
8
2007
GISSI-P, 20009
Pravastatin
Usual care
4271
60
86
--23
13.7
GREACE,
Atorvastatin
Usual care
1600
59
79
--36
19.5
200210
11
HPS, 2002
Simvastatin
Placebo
20536
65
75
--60
19.0
JUPITER,
Rosuvastatin
Placebo
17802
66
62
71
22.8
0.0
200812
LIPID, 199813
Pravastatin
Placebo
9014
62
83
--72
9.0
14
MEGA, 2006
Pravastatin
Placebo
7832
58
32
0
63.6
21.0
PROSPER,
Pravastatin
Placebo
5804
75
48
--38.4
11.8
200215
PROVE-IT,
Atorvastatin
Low dose
4162
58
78
91
24
17.6
200416
17
TNT, 2005
Atorvastatin
Low dose
10001
61
81
94
58.8
15.0
SEARCH,
Simvastatin
Low dose
12064
64
83
--80.4
11.0
201018
SPARCL,
19
Atorvastatin
Placebo
4731
63
60
--58.8
17.0
2006
20
CARDS, 2004
Atorvastatin
Placebo
2841
62
68
95
46.8
100.0
21
ASPEN, 2006
Atorvastatin
Placebo
2410
61
66
84
48
100.0
GISSI-HF,
Rosuvastatin
Placebo
4574
68
77
--46.8
26
22
2008
23
4D, 2005
Atorvastatin
Placebo
1252
66
54
--46.8
100.0
IDEAL, 200524
Atorvastatin
Low dose
8888
62
81
--57.6
12
MIRACL,
Atorvastatin
Placebo
3086
65
65
85
4
23
200125
PATE, 200126
Pravastatin
Low dose
665
73
21
--46.8
30
ACAPS, 199427
Lovastatin
Placebo
919
62
52
92
34.1
2.3
28
ALERT, 2003
Fluvastatin
Placebo
2102
50
66
--61.2
19
BONE, 200729
Atorvastatin
Placebo
604
59
0
84
13
0
30
CLAPT, 1999
Lovastatin
Usual care
226
54
100
--24
5.7
31
SHARP, 2011
Simvastatin
Placebo
9720
62
63
72
58.8
23
All Studies
63±5
67±21
78±26
46±18
25±27
(mean±SD)
DM indicated diabetes mellitus; HTN, hy pertension; CVD, cardiovascular disease; ASA, aspirin; OA, oral anticoagulant.
26.0
Stroke
(%)
---
100
Smoking
(%)
26
22.0
---
0
13
17
100.0
---
14
23
31
100.0
9.7
19
33
17
HTN (%)
CVD (%)
ASA/OA
(%)
37
50.0
---
100
41
98
39.6
---
40
15
42
42.5
---
100
21
83
63.0
12.5
100
9
60
36.5
---
100
14
50
43.0
---
100
5
88
41.0
---
87
14
63
56.7
N/A
0
16
17
41.5
42.0
3.6
0
100
0
63
21
83
39
61.9
11
44
27
36
50.0
---
100
37
100
54.3
5.2
100
13
88
42.0
7
100
30
98
62.0
69
100
19
87
84.0
55.0
0
---
0
21
23
12
15
---
54.0
4.5
100
14
75
88.0
33
18
8.2
84
39
9
29
52
79
55
8.6
100
28
91
50
28.8
75
--41.2
---
12.9
0
5.8
0
-----
72
0
3.1
--50.9
---
29
11.9
19
--10.2
13
--100
43
-------
53±20
11±16
59±43
21±12
61±30
Supplemental Table 2. Description of Trials, LDL Characteristics
Trial, Year
1
Baseline
LDLActive
188
4S, 1994
AF-TEXCAPS,
2
150
1998
ALLHAT-LLT,
146
20023
ASCOT-LLA,
133
20034
5
A-to-Z, 2004
112
AURORA, 20096
100
7
CARE, 1996
139
CORONA, 20078
137
9
GISSI-P, 2000
152
10
GREACE, 2002
180
11
HPS, 2002
131
JUPITER, 200812
108
13
LIPID, 1998
150
MEGA, 200614
157
PROSPER, 20021 5
147
16
PROVE-IT, 2004
106
17
TNT, 2005
97
18
SEARCH, 2010
97
SPARCL, 200619
133
20
CARDS, 2004
118
ASPEN, 200621
113
22
GISSI-HF, 2008
122
23
4D, 2005
121
IDEAL, 200524
122
25
MIRACL, 2001
124
26
PATE, 2001
163
27
ACAPS, 1994
157
28
ALERT, 2003
159
29
BONE, 2007
156
30
CLAPT, 1999
181
31
SHARP, 2011
108
All Studies
137±25
(mean±SD)
LDL indicated low density lipoprotein.
Mean Baseline
LDL
-2
ΔLDL-Active
– ΔLDLControl
68
188
ΔLDL-Acitve ΔLDL-Control
(%)
36
-8
43
150
29
134
12
23
146
16
133
130
3
43
133
32
49
42
41
61
22
83
42
54
45
30
50
44
20
16
61
46
20
39
49
40
52
40
44
51
67
55
33
111
99
139
136
152
179
131
108
150
157
147
106
98
97
134
117
114
121
125
121
124
163
155
159
159
183
108
77
97
136
138
147
169
128
108
148
148
147
95
101
93
128
120
112
130
120
104
135
133
155
146
159
162
105
34
2
3
-2
5
10
3
0
2
9
0
11
-3
4
6
-3
2
-9
5
17
-11
30
0
13
0
21
3
15
40
38
63
17
73
39
54
43
21
50
33
23
12
55
49
18
48
44
23
63
10
44
38
67
34
30
112
100
139
137
152
180
131
108
150
157
147
106
98
97
134
118
114
122
123
122
124
163
156
159
157
182
108
13
40
27
46
11
41
30
50
29
13
34
31
24
12
41
42
16
40
36
19
51
6
28
24
43
19
28
45±14
137±25
132±25
5±10
40±17
137±25
30±12
Follow-up
LDL-Acive
ΔLDL-Active
Baseline LDLControl
Follow-up
LDL-Control
ΔLDL-Control
122
66
188
190
115
35
150
158
111
35
146
87
46
63
58
98
76
130
97
89
54
105
127
97
62
77
81
72
72
93
83
72
82
72
123
113
108
89
126
75
91±22
Supplemental References.
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The scandinavian simvastatin survival
study (4s). Lancet. 1994;344:1383-1389.
Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, et al. Primary prevention of acute coronary events with
lovastatin in men and women with average cholesterol levels: Results of afcaps/texcaps. Air force/texas coronary
atherosclerosis prevention study. JAMA. 1998;279:1615-1622.
Major outcomes in moderately hypercholesterolemic, hypertensive patients randomized to pravastatin vs usual care: The
antihypertensive and lipid-lowering treatment to prevent heart attack trial (allhat-llt). JAMA. 2002;288:2998-3007.
Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, et al. Prevention of coronary and stroke events with
atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the angloscandinavian cardiac outcomes trial--lipid lowering arm (ascot-lla): A multicentre randomised controlled trial. Lancet.
2003;361:1149-1158.
de Lemos JA, Blazing MA, Wiviott SD, Lewis EF, Fox KA, White HD, et al. Early intensive vs a delayed conservative
simvastatin strategy in patients with acute coronary syndromes: Phase z of the a to z trial. JAMA. 2004;292:1307-1316.
Fellstrom BC, Jardine AG, Schmieder RE, Holdaas H, Bannister K, Beutler J, et al. Rosuvastatin and cardiovascular events in
patients undergoing hemodialysis. N Engl J Med. 2009;360:1395-1407.
Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, et al. The effect of pravastatin on coronary events
after myocardial infarction in patients with average cholesterol levels. Cholesterol and recurrent events trial investigators. N
Engl J Med. 1996;335:1001-1009.
Kjekshus J, Apetrei E, Barrios V, Bohm M, Cleland JG, Cornel JH, et al. Rosuvastatin in older patients with systolic heart
failure. N Engl J Med. 2007;357:2248-2261.
Results of the low-dose (20 mg) pravastatin gissi prevenzione trial in 4271 patients with recent myocardial infarction: Do
stopped trials contribute to overall knowledge? Gissi prevenzione investigators (gruppo italiano per lo studio della
sopravvivenza nell'infarto miocardico). Ital Heart J. 2000;1:810-820.
Athyros VG, Papageorgiou AA, Mercouris BR, Athyrou VV, Symeonidis AN, Basayannis EO, et al. Treatment with
atorvastatin to the national cholesterol educational program goal versus 'usual' care in secondary coronary heart disease
prevention. The greek atorvastatin and coronary-heart-disease evaluation (greace) study. Curr Med Res Opin. 2002;18:220228.
Mrc/bhf heart protection study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A randomised
placebo-controlled trial. Lancet. 2002;360:7-22.
Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Jr., Kastelein JJ, et al. Rosuvastatin to prevent vascular events in
men and women with elevated c-reactive protein. N Engl J Med. 2008;359:2195-2207.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of
initial cholesterol levels. The long-term intervention with pravastatin in ischaemic disease (lipid) study group. N Engl J Med.
1998;339:1349-1357.
Nakamura H, Arakawa K, Itakura H, Kitabatake A, Goto Y, Toyota T, et al. Primary prevention of cardiovascular disease with
pravastatin in japan (mega study): A prospective randomised controlled trial. Lancet. 2006;368:1155-1163.
Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM, et al. Pravastatin in elderly individuals at risk of
vascular disease (prosper): A randomised controlled trial. Lancet. 2002;360:1623-1630.
Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R, et al. Intensive versus moderate lipid lowering with
statins after acute coronary syndromes. N Engl J Med. 2004;350:1495-1504.
LaRosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, et al. Intensive lipid lowering with atorvastatin in patients
with stable coronary disease. N Engl J Med. 2005;352:1425-1435.
Armitage J, Bowman L, Wallendszus K, Bulbulia R, Rahimi K, Haynes R, et al. Intensive lowering of ldl cholesterol with 80
mg versus 20 mg simvastatin daily in 12,064 survivors of myocardial infarction: A double-blind randomised trial. Lancet.
2010;376:1658-1669.
Amarenco P, Bogousslavsky J, Callahan A, 3rd, Goldstein LB, Hennerici M, Rudolph AE, et al. High-dose atorvastatin after
stroke or transient ischemic attack. N Engl J Med. 2006;355:549-559.
Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, et al. Primary prevention of cardiovascular
disease with atorvastatin in type 2 diabetes in the collaborative atorvastatin diabetes study (cards): Multicentre randomised
placebo-controlled trial. Lancet. 2004;364:685-696.
Knopp RH, d'Emden M, Smilde JG, Pocock SJ. Efficacy and safety of atorvastatin in the prevention of cardiovascular end
points in subjects with type 2 diabetes: The atorvastatin study for prevention of coronary heart disease endpoints in noninsulin-dependent diabetes mellitus (aspen). Diabetes Care. 2006;29:1478-1485.
Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R, et al. Effect of rosuvastatin in patients with chronic
heart failure (the gissi-hf trial): A randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:1231-1239.
Wanner C, Krane V, Marz W, Olschewski M, Mann JF, Ruf G, et al. Atorvastatin in patients with type 2 diabetes mellitus
undergoing hemodialysis. N Engl J Med. 2005;353:238-248.
Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ, Holme I, et al. High-dose atorvastatin vs usual-dose
simvastatin for secondary prevention after myocardial infarction: The ideal study: A randomized controlled trial. JAMA.
2005;294:2437-2445.
Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D, et al. Effects of atorvastatin on early recurrent
ischemic events in acute coronary syndromes: The miracl study: A randomized controlled trial. JAMA. 2001;285:1711-1718.
26.
27.
28.
29.
30.
31.
Ito H, Ouchi Y, Ohashi Y, Saito Y, Ishikawa T, Nakamura H, et al. A comparison of low versus standard dose pravastatin
therapy for the prevention of cardiovascular events in the elderly: The pravastatin anti-atherosclerosis trial in the elderly (pate).
J Atheroscler Thromb. 2001;8:33-44.
Furberg CD, Adams HP, Jr., Applegate WB, Byington RP, Espeland MA, Hartwell T, et al. Effect of lovastatin on early
carotid atherosclerosis and cardiovascular events. Asymptomatic carotid artery progression study (acaps) research group.
Circulation. 1994;90:1679-1687.
Holdaas H, Fellstrom B, Jardine AG, Holme I, Nyberg G, Fauchald P, et al. Effect of fluvastatin on cardiac outcomes in renal
transplant recipients: A multicentre, randomised, placebo-controlled trial. Lancet. 2003;361:2024-2031.
Bone HG, Kiel DP, Lindsay RS, Lewiecki EM, Bolognese MA, Leary ET, et al. Effects of atorvastatin on bone in
postmenopausal women with dyslipidemia: A double-blind, placebo-controlled, dose-ranging trial. J Clin Endocrinol Metab.
2007;92:4671-4677.
Kleemann A, Eckert S, von Eckardstein A, Lepper W, Schernikau U, Gleichmann U, et al. Effects of lovastatin on progression
of non-dilated and dilated coronary segments and on restenosis in patients after ptca. The cholesterol lowering atherosclerosis
ptca trial (clapt). Eur Heart J. 1999;20:1393-1406.
Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C, et al. The effects of lowering ldl cholesterol with
simvastatin plus ezetimibe in patients with chronic kidney disease (study of heart and renal protection): A randomised placebocontrolled trial. Lancet. 2011;377:2181-2192.
30
Stroke 日本語版 Vol. 7, No. 3
Abstract
スタチン療法と脳内出血のリスク
31 件の無作為化比較試験のメタ解析
A Meta-Analysis of 31 Randomized Controlled Trials
James S. McKinney, MD1; William J. Kostis, PhD, MD2
1
Cardiovascular Institute of New Jersey and Department of Neurology, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson
Medical School, New Brunswick, NJ; and 2 Cardiology Division, Massachusetts General Hospital, Boston, MA.
結果：合計 91,588 例の被験者が実薬群に含まれ，91,215
背景および目的：スタチン療法は虚血性脳卒中のリスクを
例が対照群に含まれた。実薬投与群と対照群の比較では
低下させる。しかし，いくつかの試験で脳内出血（ ICH ）の
リスク上昇が観察されている。この問題を検討するため， ICH の発生率に有意差は認められなかった（ OR，1.08；
95％ CI，0.88 ∼ 1.32；p ＝ 0.47 ）
ICH が報告されたスタチンを用いた無作為化比較試験のメ
。ICH のリスクは，低
タ解析を行った。
比重リポ蛋白減少または低比重リポ蛋白コレステロール減
方法：2012 年 1 月 25 日までの Medline，Web of Science，少の達成程度と関連していなかった。全脳卒中（OR，0.84；
および Cochrane Library の文献検索を行った。また，抽
95 ％ CI，0.78 ∼ 0.91；p ＜ 0.0001 ）および全死因死亡
出した試験の一覧および以前のメタ解析のレビューから追（ OR，0.92；CI，0.87 ∼ 0.96；p ＝ 0.0007 ）は実薬治療群
加の無作為化比較試験を同定した。スタチン療法の無作為
で有意に少なかった。出版バイアスのエビデンスは認めら
化比較試験で，ICH または出血性脳卒中が報告された全試
れなかった。
験を対象とした。主要評価項目は ICH とした。31 件の無
結論：スタチン療法の無作為化比較試験 31 件のメタ解析
作為化比較試験が対象となった。すべての解析で変量効果
では，スタチンの実薬治療は ICH の有意な増加と関連し
モデルを使用し，いずれの解析でも不均一性は認められな
ていなかった。スタチン療法では全脳卒中および全死因死
かった。
亡の有意な減少が認められた。
Stroke 2012; 43: 2149-2156
ICH- スタチンのメタ解析：ICH
試験名
4S
AF-TEXCAPS
ALLHAT-LLT
ASCOT-LLA
ATOZ
AURORA
CARE
CORONA
GISSI-P
GREACE
HPS
JUPITER
LIPID
MEGA
PROSPER
PROVE-IT
TNT
SEARCH
SPARCL
ASPEN
GISSI-HF
4D
IDEAL
MIRACL
PATE
ACAPS
ALERT
BONE
CLAPT
SHARP
試験内の
サブグループ
プラセボ
プラセボ
プラセボ
プラセボ
低用量
プラセボ
プラセボ
プラセボ
プラセボ
プラセボ
プラセボ
プラセボ
プラセボ
プラセボ
プラセボ
低用量
低用量
低用量
プラセボ
プラセボ
プラセボ
プラセボ
低用量
プラセボ
低用量
プラセボ
プラセボ
プラセボ
プラセボ
プラセボ
各試験の統計値
オッズ比
0.20
3.00
3.42
0.55
12.84
1.19
0.33
1.66
2.99
1.00
0.96
0.67
1.89
1.17
0.81
3.94
0.94
0.96
1.68
1.98
3.69
0.64
1.00
0.14
0.60
0.14
0.59
0.74
0.34
1.21
1.08
p値
0.2989
0.5014
0.0158
0.1071
0.0820
0.5608
0.1774
0.2308
0.5019
1.0000
0.8434
0.4415
0.1236
0.6632
0.6490
0.2205
0.8666
0.8871
0.0191
0.4296
0.0454
0.4299
0.9969
0.1992
0.1963
0.1965
0.1817
0.8540
0.5060
0.3916
0.4687
下限
上限
0.01
4.17
0.12
73.62
1.26
9.27
0.26
1.14
0.72 228.14
0.66
2.14
0.07
1.65
0.72
3.80
0.12
73.55
0.06
16.02
0.65
1.41
0.24
1.87
0.84
4.24
0.57
2.41
0.32
2.04
0.44
35.25
0.48
1.87
0.55
1.68
1.09
2.60
0.36
10.85
1.03
13.23
0.21
1.96
0.32
3.11
0.01
2.78
0.28
1.30
0.01
2.75
0.27
1.28
0.03
18.28
0.01
8.34
0.78
1.87
0.88
1.32
脳卒中／合計
実薬
0 / 2,221
1 / 3,304
17 / 5,170
11 / 5,168
6 / 2,265
25 / 1,389
2 / 2,081
15 / 2,514
1 / 2,138
1 / 800
51 / 10,269
6 / 8,901
17 / 4,512
16 / 3,866
8 / 2,891
4 / 2,099
16 / 4,995
24 / 6,031
55 / 2,365
4 / 1,211
11 / 2,285
5 / 619
6 / 4,439
0 / 1,538
11 / 331
0 / 460
10 / 1,050
1 / 485
0 / 112
45 / 4,650
オッズ比および 95％ CI
対照薬
2 / 2,223
0 / 3,301
5 / 5,185
20 / 5,137
0 / 2,232
21 / 1,384
6 / 2,078
9 / 2,497
0 / 2,133
1 / 800
53 / 10,267
9 / 8,901
9 / 4,502
14 / 3,966
10 / 2,913
1 / 2,063
17 / 5,006
25 / 6,033
33 / 2,366
2 / 1,199
3 / 2,289
8 / 633
6 / 4,449
3 / 1,548
18 / 334
3 / 459
17 / 1,052
0 / 119
1 / 114
37 / 4,620
0.01
全試験
図 2 スタチンと脳内出血に関する無作為化比較試験の変量効果メタ解析のフォレストプロット。
0.1
実薬が優位
1
10
対照薬が優位
100
Tratamiento con estatinas y riesgo de hemorragia
intracerebral
Un metanálisis de 31 ensayos controlados y aleatorizados
James S. McKinney, MD; William J. Kostis, PhD, MD
Antecedentes y objetivo—El tratamiento con estatinas reduce el riesgo de ictus isquémico. En algunos estudios se ha observado un aumento del riesgo de hemorragia intracerebral (HIC). Con objeto de investigar esta cuestión, llevamos a
cabo un metanálisis de ensayos controlados y aleatorizados de uso de estatinas en los que se ha presentado información
sobre la HIC.
Métodos—Realizamos una búsqueda bibliográfica en Medline, Web of Science y The Cochrane Library hasta el 25 de
enero de 2012, e identificamos otros ensayos controlados y aleatorizados adicionales mediante el examen de las listas
de bibliografía de los estudios identificados y de los metanálisis anteriores. Se incluyeron en el metanálisis todos los
ensayos controlados y aleatorizados del tratamiento con estatinas en los que se presentaba información sobre la HIC o el
ictus hemorrágico. La variable de valoración primaria fue la HIC. Se incluyeron 31 ensayos controlados y aleatorizados.
Todos los análisis utilizaron modelos de efectos aleatorios y no se observó heterogeneidad en ninguno de ellos.
Resultados—Se incluyó a un total de 91.588 participantes en el grupo de tratamiento activo y a 91.215 en el grupo control.
No se observaron diferencias de incidencia de HIC en el grupo de tratamiento activo frente al grupo control (OR, 1,08;
IC del 95%, 0,88–1,32; p = 0,47). El riesgo de HIC no estaba relacionado con el grado de reducción de las lipoproteínas
de baja densidad ni con el nivel alcanzado de colesterol de lipoproteínas de baja densidad. El total de ictus (OR, 0,84; IC
del 95%, 0,78–0,91; p < 0,0001) y la mortalidad por todas las causas (OR, 0,92; IC, 0,87-0,96; p = 0,0007) presentaron
una reducción significativa en el grupo de tratamiento activo. No se observó evidencia alguna de sesgo de publicación.
Conclusiones—El tratamiento activo con estatinas no se asoció a un aumento significativo de las HIC en este metanálisis
de 31 ensayos controlados y aleatorizados del tratamiento con estatinas. Se observó una reducción significativa del total
de ictus y de la mortalidad por todas las causas con el tratamiento de estatinas. (Traducido del inglés: Statin Therapy and the Risk of Intracerebral Hemorrhage. A Meta-Analysis of 31 Randomized Controlled Trials. Stroke.
2012;43:2149-2156.)
Palabras clave: hemorrhagic stroke n intracerebral hemorrhage n meta-analysis n statin
L
El estudio Stroke Prevention by Aggressive Reduction in
Cholesterol Levels (SPARCL) del tratamiento con dosis altas
de atorvastatina en la prevención secundaria del ictus puso de
manifiesto una reducción global significativa de las recurrencias de ictus, pero no una diferencia en los ictus mortales22. En
un análisis post hoc del ensayo SPARCL se observó que el tratamiento con atorvastatina se asociaba de manera independiente con un aumento del riesgo de ictus hemorrágico (razón de
riesgos, 1,68; IC del 95%, 1,09–2,59)28. Esto era especialmente apreciable en los individuos que se incorporaron al ensayo
tras sufrir un ictus hemorrágico, en los que hubo un aumento
> 5 veces en el riesgo de una recurrencia hemorrágica28.
Una revisión Cochrane de 2009 sobre el tratamiento hipolipemiante y el ictus indicó un aumento significativo de las
a hipercolesterolemia se asocia a un aumento del riesgo
de ictus isquémico1–5. El tratamiento hipolipemiante con
el empleo de inhibidores de la 3-hidroxi-3-metilglutaril-coenzima A reductasa (estatinas) es eficaz para reducir la mortalidad cardiovascular mediante la prevención del infarto agudo
de miocardio y del ictus isquémico6–24. Es posible que el beneficio clínico no se limite a las propiedades hipolipemiantes
de las estatinas sino que sea consecuencia también de otros
efectos “pleiotrópicos”, incluidos los antiinflamatorios y antitrombóticos25. A pesar de las reducciones significativas de los
ictus isquémicos que se han observado en los ensayos clínicos,
en un estudio de cohorte realizado en una población amplia y
en un metanálisis posterior no se ha observado una reducción
de la mortalidad por ictus con el tratamiento con estatinas26,27.
Recibido el 29 de febrero de 2012; aceptado el 30 de marzo de 2012.
Cardiovascular Institute of New Jersey and the Department of Neurology (J.S.M.), University of Medicine and Dentistry of New Jersey–Robert Wood
Johnson Medical School, New Brunswick, NJ; y Cardiology Division (W.J.K.), Massachusetts General Hospital, Boston, MA.
El suplemento de datos de este artículo, disponible solamente online, puede consultarse en http://stroke.ahajournals.org/lookup/suppl/
doi:10.1161/STROKEAHA.112.655894/-/DC1.
Remitir la correspondencia a James S. McKinney, MD, Department of Neurology, UMDNJ-Robert Wood Johnson Medical School, 125 Paterson
Street, New Brunswick, NJ 08901. Correo electrónico [email protected]
© 2012 American Heart Association, Inc.
Puede accederse a Stroke en http://stroke.ahajournals.org 113
DOI: 10.1161/STROKEAHA.112.655894
114 Stroke Noviembre 2012
4.098 registros identificados
a través de la base
de datos
34 registros identificados
a través de otras fuentes
31 títulos duplicados
4.101 registros examinados
3.930 excluidos
Figura 1. Perfil de la búsqueda
bibliográfica.
171 artículos completos
examinados en cuanto
a la elegibilidad
140 estudios excluidos
50: ausencia de datos sobre
el subtipo de ictus
53: informe duplicado
de un ensayo
37: revisión/estudio
no aleatorizado
31 estudios incluidos
en el metanálisis
probabilidades de sufrir un ictus hemorrágico con el tratamiento con estatinas (OR, 1,72; IC del 95%, 1,20–2,46)29. Sin embargo, este análisis incluyó tan solo 2 ensayos, el Heart Protection Study (HPS) y el SPARCL. Un posterior metanálisis
llevado a cabo por la Cholesterol Treatment Trialists’ (CTT)
Collaboration, en el que se incluyeron 20 ensayos clínicos del
tratamiento con estatinas en los que se presentaban datos sobre la frecuencia de la hemorragia intracerebral (HIC), observó
una tendencia no significativa al aumento del riesgo de ictus
hemorrágico (riesgo relativo, 1,15; IC del 95%, 0,93–1,41; p
= 0,2)30. Este análisis no mostró efecto alguno sobre la mortalidad por ictus con el tratamiento de estatinas30. El estudio de
la CTT Collaboration excluyó a los ensayos con un número de
participantes < 1.000 y a los que tenían un periodo de seguimiento < 2 años30. Los objetivos del presente estudio fueron
examinar el riesgo de ictus hemorrágico en pacientes tratados
con estatinas, evaluar su efecto sobre el total de ictus y sobre
la mortalidad por todas las causas, y determinar si la aparición
de ictus hemorrágicos estaba relacionada con el cambio alcanzado mediante el tratamiento en las lipoproteínas de baja
densidad (LDL). Llevamos a cabo un metanálisis en el que se
incluyeron todos los ensayos controlados y aleatorizados disponibles del tratamiento con estatinas en los que se presentaban datos sobre la frecuencia del ictus hemorrágico.
Métodos
Los métodos utilizados en este metanálisis son similares a los descritos anteriormente31. Realizamos una búsqueda bibliográfica hasta
el 25 de enero de 2012, con el empleo de las bases de datos Medline,
Web of Science y The Cochrane Library, para identificar los ensayos
controlados y aleatorizados (ECA) del tratamiento con estatinas y la
HIC o el ictus hemorrágico publicados en lengua inglesa. Los crite-
rios de búsqueda se presentan la Figura I del Suplemento de Datos
Online. Identificamos otros ECA adicionales mediante el examen de
las listas de bibliografía de los estudios identificados y de los metanálisis del tratamiento con estatinas publicados con anterioridad.
Incluimos todos los ensayos que cumplían los siguientes criterios:
participantes de edad ≥ 18 años, diseño controlado y aleatorizado,
evaluación ciega de las variables de valoración y registro de datos
sobre ictus hemorrágicos o HIC. Se incluyeron ensayos tanto de
prevención primaria como de prevención secundaria, así como los
ensayos de comparación del tratamiento activo con un tratamiento
de control consistente en la “asistencia habitual”, un placebo o dosis
inferiores de estatinas. Se incluyeron los estudios que presentaban
las tasas de ictus hemorrágicos en el primer informe publicado, en
publicaciones posteriores o en metanálisis. La valoración de los criterios de aceptación de todos los estudios la realizaron los autores,
y las discrepancias se resolvieron mediante discusión y consenso.
Con la aplicación de los criterios de búsqueda, se incluyeron en el
análisis 31 ECA del tratamiento con estatinas que presentaban datos
de HIC o ictus hemorrágico como variable de valoración (Figura 1).
Métodos estadísticos
Selección de los estudios
Extracción de los datos y evaluación de la calidad
Los autores extrajeron los datos relativos a la estatina utilizada en el grupo
de tratamiento activo, tipo de tratamiento (placebo, dosis bajas de estatina o asistencia habitual) utilizado en el grupo control, criterios de inclusión, media de seguimiento y número de pacientes, total de ictus, HIC
y muertes en los grupos de tratamiento activo y de control. Se evaluaron
los datos relativos a la asignación aleatoria, la ocultación de la asignación,
la comparación de las características basales, los criterios de elegibilidad
definidos, el tipo de control, el enmascaramiento aplicado (pacientes, investigadores, evaluación de la situación vital), el porcentaje de pérdida del
seguimiento y el uso de un análisis por intención de tratar.
McKinney y Kostis Mal Tratamiento con estatinas y riesgo de hemorragia intracerebral 115
Tabla. Episodios cerebrovasculares y muerte
Ensayo, año
Participantes
Incluidos
(N = 182.803)
Todos los ictus
Ictus isquémico–
Ictus
–Tratamiento Todos los ictus Tratamiento
isquémico– HIC–Tratamiento
activo
–Control
activo
Control
activo
HIC–
Control
Otros ictus–
Tratamiento
activo
Ictus mortal–
Mortalidad total– Mortalidad
Otros ictus– Tratamiento Ictus mortal– Tratamiento
total–
Control
activo
Control
activo
Control
4S, 19946
4.444
44
64
29
49
0
2
15
13
14
12
182
256
AF-TEXCAPS,
6.605
14
17
1
1
1
0
12
16
...
...
80
77
10.355
209
231
71
83
17
5
121
143
53
56
631
641
10.305
89
121
74
95
11
20
4
6
...
...
185
212
4.497
28
35
22
31
6
0
0
4
...
...
130
104
2.773
94
81
57
55
25
21
12
5
40
36
636
660
19988
ALLHAT-LLT,
200212
ASCOT-LLA,
200316
A-to-Z,
200417
AURORA,
200936
CARE, 19967
4.159
54
78
48
64
2
6
4
8
5
1
180
196
CORONA,
200737
5.011
126
145
73
90
15
9
15
16
35
39
728
759
GISSI-P,
4.271
20
19
15
13
1
0
4
6
4
4
72
88
1.600
9
17
...
...
1
1
9
17
0
1
23
40
HPS, 200213
20.536
444
585
290
409
51
53
103
134
96
119
1.328
1.507
JUPITER,
17.802
33
64
23
47
6
9
4
8
3
6
198
247
LIPID, 19989
9.014
224
272
200
255
17
9
7
8
22
27
717
888
MEGA,
7.832
50
62
34
46
16
14
0
2
...
...
55
79
PROSPER,
200215
5.804
135
131
91
88
8
10
36
33
22
14
298
305
PROVE-IT,
4.162
21
19
10
12
4
1
7
6
...
...
46
66
TNT, 200520
10.001
117
155
96
130
16
17
5
8
...
...
284
282
SEARCH,
12.064
255
279
233
255
24
25
0
0
57
67
964
970
4.731
265
311
218
274
55
33
7
12
24
41
216
211
2.841
21
39
9
24
0
0
12
15
1
5
61
82
ASPEN,
200639
2.410
34
38
14
15
4
2
16
21
...
...
70
68
GISSI-HF,
200840
4.574
82
66
63
53
11
3
8
10
38
29
657
644
4D, 200541
1.252
59
44
47
33
5
8
10
6
27
13
297
320
IDEAL, 200542
8.888
151
174
129
158
6
6
16
10
...
...
366
374
MIRACL,
200110
3.086
12
24
...
...
0
3
12
21
3
2
64
68
PATE, 200111
665
11
18
11
15
0
3
0
0
2
2
14
20
ACAPS,
199443
919
0
5
...
...
0
3
0
2
...
...
1
8
ALERT,
200344
2.102
93
91
67
66
10
17
5
5
11
10
143
138
BONE, 200745
604
1
0
...
...
1
0
...
...
...
...
0
0
CLAPT,
199946
226
0
1
...
...
0
1
...
...
...
...
0
2
SHARP,
201147
9.270
171
210
114
157
45
37
18
19
68
78
1.142
1.115
358 (0,39)
318 (0,35)
9.768 (10,7)
10.427 (11,4)
200038
GREACE,
200214
200823
200621
200418
201024
SPARCL,
200622
CARDS,
200419
Total de todos
los estudios (%)
2.866 (3,13)
3.396 (3,72)
2.039 (2,23)
2.518 (2,76)
462 (0,50)
554 (0,61)
525 (0,57)
562 (0,62)
HIC indica hemorragia intracerebral.
Síntesis y análisis de los datos
Se calcularon las tasas de HIC, total de ictus y mortalidad por todas
las causas en los grupos de tratamiento activo y de control. Los análisis estadísticos se realizaron con Comprehensive Meta-Analysis
2.232 y JMP 9.0 (SAS Institute, Cary, NC, EEUU). Se calcularon los
valores de OR y de IC del 95% para las tres tasas indicadas, utilizando un análisis por intención de tratar. Se calcularon los efectos del
tratamiento combinando los datos ponderados para cada una de las
tres tasas de episodios, utilizando modelos de efectos aleatorios. Se
evaluó la heterogeneidad de los efectos con el empleo del estadístico
Metanálisis de HIC - Estatinas: HIC
Nombre del
estudio
Análisis estadístico para
cada estudio
Subgrupo en el estudio
4S
PLACEBO
Ictus / Total
Odds
ratio
Valor
de p
Límite
inferior
Límite Tratamiento
superior
activo
0,20
0,2989
0,01
4,17
Odds ratio e IC del 95%
Control
0 / 2221
2 / 2223
0 / 3301
AF-TEXCAPS
PLACEBO
3,00
0,5014
0,12
73,62
1 / 3304
ALLHAT-LLT
PLACEBO
3,42
0,0158
1,26
9,27
17 / 5170
5 / 5185
ASCOT-LLA
PLACEBO
0,55
0,1071
0,26
1,14
11 / 5168
20 / 5137
ATOZ
DOSIS BAJA
12,84
0,0820
0,72
228,14
6 / 2265
0 / 2232
AURORA
PLACEBO
1,19
0,5608
0,66
2,14
25 / 1389
21 / 1384
CARE
PLACEBO
0,33
0,1774
0,07
1,65
2 / 2081
6 / 2078
CORONA
PLACEBO
1,66
0,2308
0,72
3,80
15 / 2514
9 / 2497
0 / 2133
GISSI-P
PLACEBO
2,99
0,5019
0,12
73,55
1 / 2138
GREACE
PLACEBO
1,00
1,0000
0,06
16,02
1 / 800
1 / 800
HPS
PLACEBO
0,96
0,8434
0,65
1,41
51 / 10269
53 / 10267
JUPITER
PLACEBO
0,67
0,4415
0,24
1,87
6 / 8901
9 / 8901
LIPID
PLACEBO
1,89
0,1236
0,84
4,24
17 / 4512
9 / 4502
MEGA
PLACEBO
1,17
0,6632
0,57
2,41
16 / 3866
14 / 3966
PROSPER
PLACEBO
0,81
0,6490
0,32
2,04
8 / 2891
10 / 2913
PROVE-IT
DOSIS BAJA
3,94
0,2205
0,44
35,25
4 / 2099
1 / 2063
TNT
DOSIS BAJA
0,94
0,8666
0,48
1,87
16 / 4995
17 / 5006
SEARCH
DOSIS BAJA
0,96
0,8871
0,55
1,68
24 / 6031
25 / 6033
SPARCL
PLACEBO
1,68
0,0191
1,09
2,60
55 / 2365
33 / 2366
ASPEN
PLACEBO
1,98
0,4296
0,36
10,85
4 / 1211
2 / 1199
GISSI-HF
PLACEBO
3,69
0,0454
1,03
13,23
11 / 2285
3 / 2289
4D
PLACEBO
0,64
0,4299
0,21
1,96
5 / 619
8 / 633
IDEAL
DOSIS BAJA
1,00
0,9969
0,32
3,11
6 / 4439
6 / 4449
MIRACL
PLACEBO
0,14
0,1992
0,01
2,78
0 / 1538
3 / 1548
PATE
DOSIS BAJA
0,60
0,1963
0,28
1,30
11 / 331
18 / 334
ACAPS
PLACEBO
0,14
0,1965
0,01
2,75
0 / 460
3 / 459
ALERT
PLACEBO
0,59
0,1817
0,27
1,28
10 / 1050
17 / 1052
0 / 119
BONE
PLACEBO
0,74
0,8540
0,03
18,28
1 / 485
CLAPT
PLACEBO
0,34
0,5060
0,01
8,34
0 / 112
1 / 114
SHARP
PLACEBO
1,21
0,3916
0,78
1,87
45 / 4650
37 / 4620
1,08
0,4687
0,88
1,32
0,01
0,1
1
Favorable al
tratamiento activo
10
100
Favorable
al control
Todos los estudios
Figura 2. Gráfico de Forrest del metanálisis con efectos aleatorios de ensayos aleatorizados de las estatinas
y la hemorragia intracerebral.
Q33. Se evaluó el sesgo de publicación mediante la elaboración de
gráficos de embudo32, con los modelos de Trim and Fill de Duval
y Tweedie33 y con los modelos de N de fail-safe de Rosenthal34 y
Orwin35.
Análisis de sensibilidad
Se realizaron varios análisis de sensibilidad adicionales. En
primer lugar, 1 estudio (Collaborative Atorvastatin Diabetes
Study [CARDS]) presentó 0 ictus hemorrágicos tanto en el
grupo de atorvastatina como en el de placebo19,25. Por consiguiente, con objeto de evitar la inclusión de una OR no definida, el CARDS no se tuvo en cuenta en el análisis principal,
en el que solamente se incluyeron los otros 30 estudios. Con
objeto de examinar los efectos que tenía la exclusión de este
estudio en el análisis principal, se llevó a cabo un análisis de
sensibilidad mediante la imputación de 1 HIC (en vez de 0)
en cada uno de los 2 grupos (tratamiento activo y control)
del CARDS e incluyendo este estudio junto con los otros 30.
Se realizó un segundo análisis de sensibilidad excluyendo 1
estudio (de los 30) cada vez, de forma iterativa. Esto se hizo
para evaluar si los ensayos individuales podían haber influido de manera manifiesta en los resultados de este estudio.
En tercer lugar, se realizó un metanálisis acumulativo para
investigar el grado en el que la OR estimada de ictus hemorrágico convergía con la adición iterativa de estudios progresivamente más grandes.
Resultados
Se identificaron 31 ensayos del tratamiento con estatinas en
los que se incluyó en la asignación aleatoria del tratamiento a un total de 182.803 participantes, y se incluyeron dichos ensayos en el análisis6–24,36–47. De los 31 ECA, 6 estudios11,17,18,20,24,42 comparaban el tratamiento de dosis altas con
el de dosis bajas de estatinas, y los demás 6–10,12–15,19,21–23,36–
41,43– 47
comparaban el tratamiento con estatinas con un placebo o con la “asistencia habitual”. A un total de 91.588 participantes se les asignó aleatoriamente el tratamiento activo y a
91.215 el tratamiento de control. La mediana de duración del
seguimiento fue de 46,8 meses.
Las características de los pacientes y de las LDL en los
ECA incluidos en este análisis se presentan en las Tablas I
y II del Suplemento de Datos Online. La media de edad fue
de 62,6±5,2 años. Un total del 67,0% de los pacientes eran
Metanálisis de HIC - Estatinas: Total de ictus
Nombre del
estudio
cada estudio
Odds
ratio
4S
PLACEBO
0,68
Valor
de p
0,0533
Límite
inferior
0,46
Ictus / Total
Límite Tratamiento
superior
activo
1,01
44 / 2221
Control
64 / 2223
AF-TEXCAPS
PLACEBO
0,82
0,5880
0,40
1,67
14 / 3304
17 / 3301
ALLHAT-LLT
PLACEBO
0,90
0,2982
0,75
1,09
209 / 5170
231 / 5185
121 / 5137
ASCOT-LLA
PLACEBO
0,73
0,0234
0,55
0,96
89 / 5168
ATOZ
DOSIS BAJA
0,79
0,3448
0,48
1,30
28 / 2265
35 / 2232
AURORA
PLACEBO
1,17
0,3223
0,86
1,59
94 / 1389
81 / 1384
CARE
PLACEBO
0,68
0,0340
0,48
0,97
54 / 2081
78 / 2078
CORONA
PLACEBO
0,86
0,2138
0,67
1,09
126 / 2514
145 / 2497
19 / 2133
GISSI-P
PLACEBO
1,05
0,8780
0,56
1,97
20 / 2138
GREACE
PLACEBO
0,52
0,1197
0,23
1,18
9 / 800
17 / 800
HPS
PLACEBO
0,75
0,0000
0,66
0,85
444 / 10269
585 / 10267
JUPITER
PLACEBO
0,51
0,0019
0,34
0,78
33 / 8901
64 / 8901
LIPID
PLACEBO
0,81
0,0251
0,68
0,97
224 / 4512
272 / 4502
MEGA
PLACEBO
0,83
0,3151
0,57
1,20
50 / 3866
62 / 3966
PROSPER
PLACEBO
1,04
0,7533
0,81
1,33
135 / 2891
131 / 2913
PROVE-IT
DOSIS BAJA
1,09
0,7928
0,58
2,03
21 / 2099
19 / 2063
TNT
DOSIS BAJA
0,75
0,0209
0,59
0,96
117 / 4995
155 / 5006
SEARCH
DOSIS BAJA
0,91
0,2900
0,77
1,08
255 / 6031
279 / 6033
SPARCL
PLACEBO
0,83
0,0416
0,70
0,99
265 / 2365
311 / 2366
CARDS
PLACEBO
0,53
0,0184
0,31
0,90
21 / 1429
39 / 1412
ASPEN
PLACEBO
0,88
0,6022
0,55
1,41
34 / 1211
38 / 1199
66 / 2289
GISSI-HF
PLACEBO
1,25
0,1786
0,90
1,74
82 / 2285
4D
PLACEBO
1,41
0,0979
0,94
2,12
59 / 619
44 / 633
IDEAL
DOSIS BAJA
0,87
0,2012
0,69
1,08
151 / 4439
174 / 4449
MIRACL
PLACEBO
0,50
0,0507
0,25
1,00
12 / 1538
24 / 1548
PATE
DOSIS BAJA
0,60
0,1963
0,28
1,30
11 / 331
18 / 334
ACAPS
PLACEBO
0,09
0,1030
0,00
1,63
0 / 460
5 / 459
ALERT
PLACEBO
1,03
0,8667
0,76
1,39
93 / 1050
91 / 1052
0 / 119
BONE
PLACEBO
0,74
0,8540
0,03
18,28
1 / 485
CLAPT
PLACEBO
0,34
0,5060
0,01
8,34
0 / 112
1 / 114
SHARP
PLACEBO
0,80
0,0356
0,65
0,99
171 / 4650
210 / 4620
0,84
0,0000
0,78
0,91
0,5
1
Favorable al
tratamiento activo
2
Favorable
al control
Todos los estudios
Figura 3. Gráfico de Forrest del metanálisis con efectos aleatorios de ensayos aleatorizados
de las estatinas y el total de ictus.
varones y un 78,1% eran blancos. Tan solo en un 11,0% de
los participantes se habían documentado unos antecedentes
previos de ictus. En promedio el 24,7% tenían diabetes, el
53,0% hipertensión, el 59,1% enfermedades cardiovasculares
y el 21,2% eran fumadores activos de cigarrillos en el momento de la inclusión en el estudio. Un total del 61,0% de
los participantes fueron tratados con ácido acetilsalicílico o
anticoagulantes orales. Los episodios de ictus se presentan
en la Tabla.
Hemorragia intracerebral
Se produjo una HIC en 358 participantes (0,39%) del grupo
de tratamiento activo frente a 318 (0,35%) del grupo control.
En el análisis principal de evaluación del riesgo de HIC en 30
estudios del tratamiento con estatinas, el tratamiento activo
no se asoció a un aumento de las HIC (OR, 1,08; IC del 95%,
0,88–1,32; p = 0,47; Figura 2). El valor de p para la heterogeneidad (interacción) fue de 0,38, Q = 30,705 y grados de
libertad = 29. No hubo diferencias estadísticamente significativas en el riesgo de HIC al estratificar el metanálisis según
el tipo de grupo control o los estudios de prevención primaria
frente a los de prevención secundaria (Suplemento de Datos
Online, Figura II).
El análisis de sensibilidad en el que se incluyó la totalidad
de los 31 estudios (incluido el CARDS) produjo unos resultados casi idénticos a los del análisis principal (OR, 1,08; IC
del 95%, 0,88–1,31; p = 0,46). En la totalidad de las 30 iteraciones del análisis de sensibilidad realizado excluyendo 1
estudio cada vez, no se observó asociación alguna entre la
HIC y el tratamiento activo. La estimación puntual de la OR
osciló entre 1,04 y 1,11, con un límite inferior de 0,84 a 0,91
y un valor de p de 0,27 a 0,77. En el metanálisis acumulativo,
no hubo asociación alguna entre la HIC y el tratamiento activo en 28 de 30 iteraciones. La estimación puntual de la OR
osciló entre 0,20 (IC del 95%, 0,01–4,17; p = 0,30) y 1,90
(IC del 95%, 0,40–8,95; p = 0,42).
No observamos evidencia alguna de sesgo de publicación
puesto que el gráfico de embudo era simétrico. La OR y el
IC del efecto global (OR, 1,08; IC del 95%, 0,88–1,31) se
mantuvieron inalterados al aplicar el método de Trim and Fill
de Duval y Tweedie33. La N fail-safe de Orwin reveló que
serían necesarios otros 25 estudios adicionales con una media
Metanálisis de HIC - Estatinas: Muerte
Nombre del
estudio
4S
cada estudio
PLACEBO
Odds
ratio
Valor
de p
0,69
0,0002
Límite
inferior
0,56
Ictus / Total
Límite Tratamiento
superior
activo
0,84
182 / 2221
Control
256 / 2223
AF-TEXCAPS
PLACEBO
1,04
0,8130
0,76
1,43
80 / 3304
77 / 3301
ALLHAT-LLT
PLACEBO
0,99
0,8071
0,88
1,11
631 / 5170
641 / 5185
212 / 5137
ASCOT-LLA
PLACEBO
0,86
0,1493
0,71
1,05
185 / 5168
ATOZ
DOSIS BAJA
1,25
0,1036
0,96
1,62
130 / 2265
104 / 2232
AURORA
PLACEBO
0,93
0,3162
0,80
1,08
636 / 1389
660 / 1384
CARE
PLACEBO
0,91
0,3791
0,74
1,12
180 / 2081
196 / 2078
CORONA
PLACEBO
0,93
0,2650
0,83
1,05
728 / 2514
759 / 2497
GISSI-P
PLACEBO
0,81
0,1928
0,59
1,11
72 / 2138
88 / 2133
GREACE
PLACEBO
0,56
0,0309
0,33
0,95
23 / 800
40 / 800
HPS
PLACEBO
0,86
0,0003
0,80
0,93
1328 / 10269
1507 / 10267
JUPITER
PLACEBO
0,80
0,0189
0,66
0,96
198 / 8901
247 / 8901
LIPID
PLACEBO
0,77
0,0000
0,69
0,86
717 / 4512
888 / 4502
MEGA
PLACEBO
0,71
0,0532
0,50
1,00
55 / 3866
79 / 3966
PROSPER
PLACEBO
0,98
0,8393
0,83
1,16
298 / 2891
305 / 2913
PROVE-IT
DOSIS BAJA
0,68
0,0458
0,46
0,99
46 / 2099
66 / 2063
TNT
DOSIS BAJA
1,01
0,9096
0,85
1,20
284 / 4995
282 / 5006
SEARCH
DOSIS BAJA
0,99
0,8879
0,90
1,09
964 / 6031
970 / 6033
SPARCL
PLACEBO
1,03
0,7962
0,84
1,25
216 / 2365
211 / 2366
82 / 1412
CARDS
PLACEBO
0,72
0,0617
0,51
1,02
61 / 1429
ASPEN
PLACEBO
1,02
0,9084
0,72
1,44
70 / 1211
68 / 1199
GISSI-HF
PLACEBO
1,03
0,6431
0,91
1,17
657 / 2285
644 / 2289
4D
PLACEBO
0,90
0,3628
0,72
1,13
297 / 619
320 / 633
IDEAL
DOSIS BAJA
0,98
0,7832
0,84
1,14
366 / 4439
374 / 4449
MIRACL
PLACEBO
0,95
0,7507
0,67
1,34
64 / 1538
68 / 1548
PATE
DOSIS BAJA
0,69
0,3056
0,34
1,40
14 / 331
20 / 334
ACAPS
PLACEBO
0,12
0,0485
0,02
0,99
1 / 460
8 / 459
ALERT
PLACEBO
1,04
0,7357
0,81
1,34
143 / 1050
138 / 1052
CLAPT
PLACEBO
0,20
0,3006
0,01
4,21
0 / 112
2 / 114
SHARP
PLACEBO
1,02
0,6336
0,93
1,13
1142 / 4650
1115 / 4620
0,92
0,0007
0,87
0,96
0,5
1
Favorable al
tratamiento activo
2
Favorable
al control
Todos los estudios
Figura 4. Gráfico de Forrest del metanálisis con efectos aleatorios de ensayos aleatorizados de las estatinas
y la mortalidad por todas las causas.
de OR de 1,0 para producir un aumento del 5% (OR, 1,05) al
nivel de p = 0,05.
Se llevó a cabo una metarregresión para estudiar la relación
entre el efecto del tratamiento con estatinas sobre las LDL y
el riesgo de HIC. No hubo relación alguna entre los efectos
del tratamiento activo en comparación con el de control y las
determinaciones del colesterol de LDL. Concretamente, no se
observaron relaciones significativas del log OR (activo/control) de cada estudio respecto a (1) la diferencia (activo menos
control) de la reducción de colesterol de LDL (diferencia entre
valor basal y valor en el seguimiento) en mg/dL (pendiente,
0,0043; EE, 0,0054; IC del 95%, -0,4831 a 0,0149; p = 0,43];
(2) esta diferencia expresada como porcentaje de valor basal
(pendiente, 0,0054; EE, 0,0075; IC del 95%, -0,0092 a 0,0200;
p = 0,47]; y (3) el valor de colesterol de LDL alcanzado en el
grupo de tratamiento activo durante el seguimiento (pendiente,
-0,0049; EE, 0,0043; IC del 95%, -0,0133 a 0,0035; p = 0,26).
Total de ictus
Se produjeron en total 6.262 ictus en este metanálisis. La tasa
global de ictus fue del 3,13% en el grupo de tratamiento activo frente al 3,72% en el grupo control. El tratamiento activo
produjo una reducción significativa en el número total de ictus (OR, 0,84; IC del 95%, 0,78–0,91; p < 0,0001; Figura 3).
El valor de p para la heterogeneidad (interacción) fue de 0,31,
Q = 33,315 y grados de libertad = 30. El número necesario a
tratar con la medicación activa de estatinas para prevenir un
ictus de cualquier tipo durante el seguimiento del estudio fue
de 200 (reducción del riesgo absoluto = 0,5%, p < 0,0001).
Mortalidad por todas las causas
Se registraron 20.195 muertes en los 31 ensayos incluidos en
este análisis. Hubo una tasa de mortalidad por todas las causas
significativamente inferior en el grupo de tratamiento activo
(10,67%) en comparación con el grupo control (11,43%; OR,
0,92; IC del 95%, 0,87–0,96; p = 0,0007; Figura 4). El valor de
p para la heterogeneidad (interacción) fue de 0,31, Q = 32,272
y grados de libertad = 29. El número necesario a tratar con la
medicación activa de estatinas para prevenir 1 muerte fue de 167
(reducción del riesgo absoluto = 0,6%, p < 0,0001).
Discusión
Los estudios epidemiológicos han descrito un aumento de las
tasas de ictus hemorrágicos y de mortalidad debida a HIC
en poblaciones con niveles de colesterol bajos1,4,48,49. Se ha
planteado la hipótesis de que el colesterol puede ser importante para la integridad de la pared cerebrovascular y que los
niveles bajos pueden elevar el riesgo de ruptura de los vasos
sanguíneos y de HIC50. Además, varios estudios han descrito
una asociación del ictus hemorrágico con el uso de estatinas.
El ensayo SPARCL de atorvastatina en dosis altas para la
prevención secundaria del ictus describió un exceso de HIC
con el tratamiento activo en comparación con placebo (55
frente a 33; p = 0,02)22. De igual modo, hubo un aumento
al doble en los ictus hemorrágicos en el estudio HPS en los
pacientes que habían sufrido un ictus previo y fueron tratados con simvastatina51. En tres metanálisis previos del tratamiento con estatinas no se ha observado un aumento del
riesgo de ictus hemorrágico25,30,52. En un metanálisis de 11
ensayos, Amarenco y Labreuche25 describieron un riesgo de
ictus hemorrágico desdeñable con el tratamiento de estatinas
(riesgo relativo, 1,03; IC del 95%, 0,75–1,41). En su estudio
de la reducción intensiva de las LDL con estatinas, la CTT
Collaboration llevó a cabo un metanálisis de 26 ECA y describió una tendencia no significativa al aumento del riesgo de
HIC (riesgo relativo, 1,15; IC del 95%, 0,93–1,41)30. En un
metanálisis más reciente en el que se incluyeron 23 ECA, no
se observó evidencia alguna de aumento del riesgo de HIC53.
Nosotros hemos realizado un metanálisis exhaustivo de los
ensayos clínicos aleatorizados realizados anteriormente sobre
el tratamiento con estatinas en los que se presentaron datos
relativos a la HIC o el ictus hemorrágico. Incluimos 31 ECA
con un total de 182.803 participantes. En nuestro análisis, el
tratamiento activo se asoció a un aumento no significativo
del riesgo de HIC (OR, 1,08; IC del 95%, 0,88–1,32).
El pequeño exceso de HIC no significativo observado no
estaba relacionado con los efectos del tratamiento con estatinas sobre las LDL. No observamos ninguna relación entre el
nivel de LDL alcanzado o el grado de reducción de las LDL
y el riesgo de ictus hemorrágico en este análisis. Esto sugiere que todo posible aumento del riesgo de HIC podría ser
atribuible a otros efectos de las estatinas distintos de los que
ejercen sobre las LDL. Esto concuerda con lo indicado por un
gran metanálisis de estudios de cohorte observacionales en el
que no se observó correlación alguna con los ictus mortales y
el colesterol total basal en casi 900.000 participantes27. Además de sus propiedades hipolipemiantes, las estatinas pueden
tener propiedades antitrombóticas como consecuencia de la
inhibición de la agregación plaquetaria y la potenciación de
la fibrinólisis54,55. Los efectos antitrombóticos de las estatinas podrían explicar un teórico aumento de las complicaciones hemorrágicas.
Al estratificar nuestro análisis según el tipo de prevención,
hubo una tendencia no significativa al aumento de las probabilidades de HIC en los estudios de prevención secundaria
(OR, 1,26; IC del 95%, 0,91–1,73) en comparación con los
de prevención primaria (OR, 0,96; IC del 95%, 0,75–1,23).
El presente estudio no se limitó a los ensayos del tratamiento
con estatinas para la prevención secundaria del ictus. El análisis post hoc de los ensayos HPS y SPARCL sugiere que los
pacientes con un ictus previo pueden presentar un especial
aumento del riesgo de ictus hemorrágico28,51. Sin embargo,
en un amplio estudio de cohorte retrospectivo reciente no se
observó evidencia alguna de aumento del riesgo de HIC en
pacientes tratados con estatinas después de sufrir un ictus isquémico52. Westover y cols.56, con el empleo de un enfoque
de análisis de decisión, observaron que la evitación de las
estatinas, sobre todo en pacientes con antecedentes de hemorragia lobular (y que tienen un riesgo elevado de recurrencia
hemorrágica), era favorable respecto a una amplia variedad
de parámetros clínicos. Nuestro análisis no evaluó el riesgo
del tratamiento con estatinas en este subgrupo de pacientes
con una HIC previa. Teniendo en cuenta los datos actuales,
es preciso tener precaución al tratar a estos pacientes con estatinas, y serán necesarias nuevas investigaciones al respecto.
Este análisis tiene varias limitaciones. En primer lugar, no
tuvimos acceso a datos de los pacientes individuales y es posible que haya variables de estos no tenidas en cuenta que influyeran en las tasas de ictus hemorrágico. En segundo lugar,
ictus hemorrágico es un término nebuloso que puede incluir
la HIC, la hemorragia subaracnoidea, subdural o epidural, o
la transformación hemorrágica de un ictus isquémico. Aunque la HIC es el trastorno de interés, es posible que en ECA
previos que han presentado las tasas de ictus hemorrágicos
se incluyeran algunas de otras de estas causas de hemorragia
intracraneal. Finalmente, aunque hemos realizado el análisis
más exhaustivo publicado hasta el momento del tratamiento
con estatinas y el riesgo de HIC en ensayos aleatorizados, es
posible que hubiera otros ensayos, en especial los publicados en lenguas distintas del inglés, que quedaran excluidos.
Aunque incluimos todos los ensayos pertinentes, con independencia de su tamaño, en nuestro análisis no se observó
ningún sesgo de publicación ni heterogeneidad.
El tratamiento con estatinas no se asoció a un aumento significativo del riesgo de HIC. No hubo efecto alguno sobre el
riesgo de HIC asociado al grado de reducción de las LDL o al
nivel de LDL alcanzado. La reducción significativa del total
de ictus y de la mortalidad por todas las causas compensó
sobradamente todo ligero aumento del riesgo de HIC que pudiera haber. Estos resultados respaldan las recomendaciones
actuales para la prescripción de estatinas en los pacientes en
los que, por lo demás, son apropiados.
Conclusiones
En este metanálisis de 31 ECA, el tratamiento con estatinas
no se asoció a un aumento significativo de las probabilidades de HIC. Sin embargo, el tratamiento con estatinas sí se
asocia a reducciones significativas del total de ictus y de las
muertes, lo cual anula todo posible riesgo hemorrágico en
una población de pacientes no seleccionada.
Fuentes de financiación
Este estudio fue financiado en parte por la Robert Wood Johnson
Foundation y la Schering-Plough Foundation.
Ninguna.
Declaraciones
Bibliografía
1. Iso H, Jacobs DR Jr, Wentworth D, Neaton JD, Cohen JD. Serum
1989;320:904 –910.
2. Leppala JM, Virtamo J, Fogelholm R, Albanes D, Heinonen OP. Different risk factors for different stroke subtypes: association of blood
3. Horenstein RB, Smith DE, Mosca L. Cholesterol predicts stroke mortality
4. Zhang X, Patel A, Horibe H, Wu Z, Barzi F, Rodgers A, et al. Choles-
1. Iso H, Jacobs DR Jr, Wentworth D, Neaton
20.
2.
21.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21.
22.
23.
JD, Cohen JD. Serum
1989;320:904 –910.
Leppala JM, Virtamo J, Fogelholm R, Albanes D, Heinonen OP. Different risk factors for different stroke subtypes: association of blood
Horenstein RB, Smith DE, Mosca L. Cholesterol predicts stroke mortality
Zhang X, Patel A, Horibe H, Wu Z, Barzi F, Rodgers A, et al. Cholesterol, coronary heart disease, and stroke in the Asia Pacific region. Int J
Epidemiol. 2003;32:563–572.
Kurth T, Everett BM, Buring JE, Kase CS, Ridker PM, Gaziano JM.
Lipid levels and the risk of ischemic stroke in women. Neurology.
2007;68:556 –562.
Randomised trial of cholesterol lowering in 4444 patients with coronary
heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet.
1994;344:1383–1389.
Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG,
et al. The effect of pravastatin on coronary events after myocardial
infarction in patients with average cholesterol levels. Cholesterol and
recurrent events trial investigators. N Engl J Med. 1996;335:1001–1009.
Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, et
al. Primary prevention of acute coronary events with lovastatin in men
and women with average cholesterol levels: results of AFCAPS/
TEXCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study.
JAMA. 1998;279:1615–1622.
Prevention of cardiovascular events and death with pravastatin in patients
with coronary heart disease and a broad range of initial cholesterol levels.
The Long-Term Intervention With Pravastatin in Ischaemic Disease
(LIPID) study group. N Engl J Med. 1998;339:1349 –1357.
Schwartz GG, Olsson AG, Ezekowitz MD, Ganz P, Oliver MF, Waters D,
et al. Effects of atorvastatin on early recurrent ischemic events in acute
coronary syndromes: the MIRACL study: a randomized controlled trial.
JAMA. 2001;285:1711–1718.
Ito H, Ouchi Y, Ohashi Y, Saito Y, Ishikawa T, Nakamura H, et al. A
comparison of low versus standard dose pravastatin therapy for the
prevention of cardiovascular events in the elderly: the Pravastatin AntiAtherosclerosis Trial in the Elderly (PATE). J Atheroscler Thromb.
2001;8:33– 44.
Major outcomes in moderately hypercholesterolemic, hypertensive patients
randomized to pravastatin vs usual care: the Antihypertensive and LipidLowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT). JAMA.
2002;288:2998 –3007.
MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo-controlled
trial. Lancet. 2002;360:7–22.
Athyros VG, Papageorgiou AA, Mercouris BR, Athyrou VV, Symeonidis
AN, Basayannis EO, et al. Treatment with atorvastatin to the national
cholesterol educational program goal versus ‘usual’ care in secondary
coronary heart disease prevention. The Greek Atorvastatin and CoronaryHeart-Disease Evaluation (GREACE) study. Curr Med Res Opin. 2002;
18:220 –228.
Shepherd J, Blauw GJ, Murphy MB, Bollen EL, Buckley BM, Cobbe SM,
et al. Pravastatin in Elderly Individuals at Risk of Vascular Disease
(PROSPER): a randomised controlled trial. Lancet. 2002;360:1623–1630.
Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, et al.
Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol
concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid
Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial.
Lancet. 2003;361:1149 –1158.
de Lemos JA, Blazing MA, Wiviott SD, Lewis EF, Fox KA, White HD,
et al. Early intensive vs a delayed conservative simvastatin strategy in
patients with acute coronary syndromes: phase Z of the A to Z Trial.
JAMA. 2004;292:1307–1316.
Cannon CP, Braunwald E, McCabe CH, Rader DJ, Rouleau JL, Belder R,
et al. Intensive versus moderate lipid lowering with statins after acute
coronary syndromes. N Engl J Med. 2004;350:1495–1504.
Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA,
Livingstone SJ, et al. Primary prevention of cardiovascular disease with
Lancet. 2004;364:685– 696.
368:1155–1163.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
Lancet. 2004;364:685– 696.
368:1155–1163.
JJ, et al. Rosuvastatin to prevent vascular events in men and women with
elevated C-reactive protein. N Engl J Med. 2008;359:2195–2207.
Armitage J, Bowman L, Wallendszus K, Bulbulia R, Rahimi K, Haynes
R, et al. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg
simvastatin daily in 12 064 survivors of myocardial infarction: a
double-blind randomised trial. Lancet. 2010;376:1658 –1669.
Amarenco P, Labreuche J. Lipid management in the prevention of stroke:
review and updated meta-analysis of statins for stroke prevention. Lancet
Neurol. 2009;8:453– 463.
Cholesterol, diastolic blood pressure, and stroke: 13 000 strokes in
450 000 people in 45 prospective cohorts. Prospective studies collaboration. Lancet. 1995;346:1647–1653.
Lewington S, Whitlock G, Clarke R, Sherliker P, Emberson J, Halsey J,
et al. Blood cholesterol and vascular mortality by age, sex, and blood
pressure: a meta-analysis of individual data from 61 prospective studies
with 55 000 vascular deaths. Lancet. 2007;370:1829 –1839.
Goldstein MR, Mascitelli L, Pezzetta F. Hemorrhagic stroke in the
stroke prevention by Aggressive Reduction in Cholesterol Levels
Study. Neurology. 2009;72:1448; author reply 1448 –1449.
Manktelow BN, Potter JF. Interventions in the management of serum
lipids for preventing stroke recurrence. Cochrane Database Syst Rev.
2009;3:CD002091.
Baigent C, Blackwell L, Emberson J, Holland LE, Reith C, Bhala N, et al.
Efficacy and safety of more intensive lowering of LDL cholesterol: a
meta-analysis of data from 170 000 participants in 26 randomised trials.
Lancet. 2010;376:1670 –1681.
Kostis WJ, Moreyra AE, Cheng JQ, Dobrzynski JM, Kostis JB. Continuation of mortality reduction after the end of randomized therapy in
clinical trials of lipid-lowering therapy. J Clin Lipidol. 2011;5:97–104.
Borenstein M. Introduction to Meta-Analysis. Chichester, UK: John
Wiley & Sons; 2009.
Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of
testing and adjusting for publication bias in meta-analysis. Biometrics.
2000;56:455– 463.
Rosenthal R. The ’file drawer problem’ and tolerance for null results.
Psychol Bull. 1979;86:638 – 641.
Orwin RG. A fail-safe N for effect size in meta-analysis. J Educ Stat.
1983;8:157–159.
Fellstrom BC, Jardine AG, Schmieder RE, Holdaas H, Bannister K,
Beutler J, et al. Rosuvastatin and cardiovascular events in patients
undergoing hemodialysis. N Engl J Med. 2009;360:1395–1407.
Kjekshus J, Apetrei E, Barrios V, Bohm M, Cleland JG, Cornel JH, et al.
Rosuvastatin in older patients with systolic heart failure. N Engl J Med.
2007;357:2248 –2261.
Results of the low-dose (20 mg) pravastatin GISSI Prevenzione Trial in
4271 patients with recent myocardial infarction: do stopped trials contribute to overall knowledge? Gissi Prevenzione Investigators (Gruppo
Italiano Per Lo Studio Della Sopravvivenza Nell’infarto Miocardico). Ital
Heart J. 2000;1:810 – 820.
Knopp RH, d’Emden M, Smilde JG, Pocock SJ. Efficacy and safety of
atorvastatin in the prevention of cardiovascular end points in subjects
with type 2 diabetes: the Atorvastatin Study for Prevention of Coronary
Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus
(ASPEN). Diabetes Care. 2006;29:1478 –1485.
Tavazzi L, Maggioni AP, Marchioli R, Barlera S, Franzosi MG, Latini R,
et al. Effect of rosuvastatin in patients with chronic heart failure (the
GISSI-HF Trial): a randomised, double-blind, placebo-controlled trial.
Lancet. 2008;372:1231–1239.
Wanner C, Krane V, Marz W, Olschewski M, Mann JF, Ruf G, et al.
Atorvastatin in patients with type 2 diabetes mellitus undergoing hemodialysis. N Engl J Med. 2005;353:238 –248.
Pedersen TR, Faergeman O, Kastelein JJ, Olsson AG, Tikkanen MJ,
Holme I, et al. High-dose atorvastatin vs usual-dose simvastatin for
secondary prevention after myocardial infarction: the IDEAL study: a
randomized controlled trial. JAMA. 2005;294:2437–2445.
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
McKinney y Kostis Mal Tratamiento con2181–2192.
estatinas y riesgo de hemorragia intracerebral 121
48. Sturgeon JD, Folsom AR, Longstreth WT Jr, Shahar E, Rosamond WD,
Cushman M. Risk factors for intracerebral hemorrhage in a pooled prospective study. Stroke. 2007;38:2718 –2725.
49. Iribarren C, Reed DM, Burchfiel CM, Dwyer JH. Serum total cholesterol
Furberg CD, Adams HP Jr, Applegate WB, Byington RP, Espeland MA,
and mortality. Confounding factors and risk modification in JapaneseHartwell T, et al. Effect of lovastatin on early carotid atherosclerosis and
American men. JAMA. 1995;273:1926 –1932.
cardiovascular events. Asymptomatic Carotid Artery Progression Study
50. Bjorkhem I, Meaney S. Brain cholesterol: long secret life behind a barrier.
(ACAPS) research group. Circulation. 1994;90:1679 –1687.
Holdaas H, Fellstrom B, Jardine AG, Holme I, Nyberg G, Fauchald P, et
51. Collins R, Armitage J, Parish S, Sleight P, Peto R. Effects of cholesteral. Effect of fluvastatin on cardiac outcomes in renal transplant recipients:
ol-lowering with simvastatin on stroke and other major vascular events in
a multicentre, randomised, placebo-controlled trial. Lancet. 2003;361:
2024 –2031.
Lancet. 2004;363:757–767.
Bone HG, Kiel DP, Lindsay RS, Lewiecki EM, Bolognese MA, Leary
52. Hackam DG, Austin PC, Huang A, Juurlink DN, Mamdani MM, Paterson
ET, et al. Effects of atorvastatin on bone in postmenopausal women with
dyslipidemia: a double-blind, placebo-controlled, dose-ranging trial.
J Clin Endocrinol Metab. 2007;92:4671– 4677.
53. Hackam DG, Woodward M, Newby LK, Bhatt DL, Shao M, Smith EE,
Kleemann A, Eckert S, von Eckardstein A, Lepper W, Schernikau U,
Gleichmann U, et al. Effects of lovastatin on progression of non-dilated
and dilated coronary segments and on restenosis in patients after PTCA.
54. Serebruany VL, Miller M, Pokov AN, Malinin AI, Lowry DR, Tanguay
The Cholesterol Lowering Atherosclerosis PTCA Trial (CLAPT). Eur
Heart J. 1999;20:1393–1406.
Baigent C, Landray MJ, Reith C, Emberson J, Wheeler DC, Tomson C,
et al. The effects of lowering LDL cholesterol with simvastatin plus
55. Serebruany VL, Malinin AI, Hennekens CH. Statins increase risk of
Dis. 2007;24:477– 479.
2181–2192.
56. Westover MB, Bianchi MT, Eckman MH, Greenberg SM. Statin use
Sturgeon JD, Folsom AR, Longstreth WT Jr, Shahar E, Rosamond WD,
Cushman M. Risk factors for intracerebral hemorrhage in a pooled pro2010;68:573–579.
spective study. Stroke. 2007;38:2718 –2725.
Iribarren C, Reed DM, Burchfiel CM, Dwyer JH. Serum total cholesterol
and mortality. Confounding factors and risk modification in JapaneseAmerican men. JAMA. 1995;273:1926 –1932.
Bjorkhem I, Meaney S. Brain cholesterol: long secret life behind a barrier.
Collins R, Armitage J, Parish S, Sleight P, Peto R. Effects of cholesterol-lowering with simvastatin on stroke and other major vascular events in
Lancet. 2004;363:757–767.
Hackam DG, Austin PC, Huang A, Juurlink DN, Mamdani MM, Paterson
Hackam DG, Woodward M, Newby LK, Bhatt DL, Shao M, Smith EE,
Serebruany VL, Miller M, Pokov AN, Malinin AI, Lowry DR, Tanguay
Serebruany VL, Malinin AI, Hennekens CH. Statins increase risk of
Dis. 2007;24:477– 479.
Westover MB, Bianchi MT, Eckman MH, Greenberg SM. Statin use
2010;68:573–579.

Statin Therapy and the Risk of Intracerebral Hemorrhage

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