Statin Therapy and the Risk of Intracerebral Hemorrhage A Meta-Analysis of 31 Randomized Controlled Trials

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1 Statin Therapy and the Risk of Intracerebral Hemorrhage A Meta-Analysis of 31 Randomized led Trials James S. McKinney, MD; William J. Kostis, PhD, MD 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 subjects were included in the active group and 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, ; 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, ; P ) and all-cause mortality (OR, 0.92; CI, ; P ) were significantly reduced in the active therapy group. There was no evidence of publication bias. Conclusions 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: ) Key Words: hemorrhagic stroke intracerebral hemorrhage meta-analysis statin Hypercholesterolemia 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 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, ). 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, ). 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, ; 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, 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 /-/DC1. Correspondence to James S. McKinney, MD, Department of Neurology, UMDNJ-Robert Wood Johnson Medical School, 125 Paterson Street, New Brunswick, NJ mckinnjs@umdnj.edu 2012 American Heart Association, Inc. Stroke is available at DOI: /STROKEAHA

2 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 18 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 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 Rosenthal 34 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 subjects were identified and included in the

3 McKinney and Kostis Statin Therapy and Risk of ICH 2151 Table. Cerebrovascular Events and Death Trial, Year Subjects Enrolled (N ) All All Ischemic Ischemic ICH ICH Other Other Fatal Fatal Total Mortality Total Mortality 4S, AF-TEXCAPS, ALLHAT-LLT, ASCOT-LLA, A-to-Z, AURORA, CARE, CORONA, GISSI-P, GREACE, HPS, JUPITER, LIPID, MEGA, PROSPER, PROVE-IT, TNT, SEARCH, SPARCL, CARDS, ASPEN, GISSI-HF, D, IDEAL, MIRACL, PATE, ACAPS, ALERT, BONE, CLAPT, SHARP, All studies total (%) ICH indicates intracerebral hemorrhage (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) (11.4) analysis. 6 24,36 47 Of the 31 RCTs, 6 studies 11,17,18,20,24,42 compared high-dose with low-dose statin therapy, and the remainder 6 10,12 15,19,21 23,36 41,43 47 compared statin therapy with placebo or usual care. A total of subjects were randomized to active therapy and 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

4 2152 Stroke August 2012 ICH - Statin Meta-Analysis: ICH Study name Subgroup within study Statistics for each study Stroke / Total Odds ratio and 95% CI Odds Lower Upper ratio p-value limit limit 4S PLACEBO / / 2223 AF-TEXCAPS PLACEBO / / 3301 ALLHAT-LLT PLACEBO / / 5185 ASCOT-LLA PLACEBO / / 5137 ATOZ LOW DOSE / / 2232 AURORA PLACEBO / / 1384 CARE PLACEBO / / 2078 CORONA PLACEBO / / 2497 GISSI-P PLACEBO / / 2133 GREACE PLACEBO / / 800 HPS PLACEBO / / JUPITER PLACEBO / / 8901 LIPID PLACEBO / / 4502 MEGA PLACEBO / / 3966 PROSPER PLACEBO / / 2913 PROVE-IT LOW DOSE / / 2063 TNT LOW DOSE / / 5006 SEARCH LOW DOSE / / 6033 SPARCL PLACEBO / / 2366 ASPEN PLACEBO / / 1199 GISSI-HF PLACEBO / / D PLACEBO / / 633 IDEAL LOW DOSE / / 4449 MIRACL PLACEBO / / 1548 PATE LOW DOSE / / 334 ACAPS PLACEBO / / 459 ALERT PLACEBO / / 1052 BONE PLACEBO / / 119 CLAPT PLACEBO / / 114 SHARP PLACEBO / / Tables I and II. The mean age of was 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, ; P 0.47; Figure 2). The P for heterogeneity (interaction) was 0.38, Q , 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, ; P 0.46). In all 30 All studies Favors Favors Figure 2. Forrest plot of random-effects meta-analysis of randomized trials of statins and intracerebral hemorrhage. 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 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, ; P 0.30) to 1.90 (95% CI, ; 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, ) 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

5 McKinney and Kostis Statin Therapy and Risk of ICH 2153 ICH - Statin Meta-Analysis: All Stroke Study name Subgroup within study Statistics for each study Stroke / Total Odds ratio and 95% CI Odds Lower Upper ratio p-value limit limit 4S PLACEBO / / 2223 AF-TEXCAPS PLACEBO / / 3301 ALLHAT-LLT PLACEBO / / 5185 ASCOT-LLA PLACEBO / / 5137 ATOZ LOW DOSE / / 2232 AURORA PLACEBO / / 1384 CARE PLACEBO / / 2078 CORONA PLACEBO / / 2497 GISSI-P PLACEBO / / 2133 GREACE PLACEBO / / 800 HPS PLACEBO / / JUPITER PLACEBO / / 8901 LIPID PLACEBO / / 4502 MEGA PLACEBO / / 3966 PROSPER PLACEBO / / 2913 PROVE-IT LOW DOSE / / 2063 TNT LOW DOSE / / 5006 SEARCH LOW DOSE / / 6033 SPARCL PLACEBO / / 2366 CARDS PLACEBO / / 1412 ASPEN PLACEBO / / 1199 GISSI-HF PLACEBO / / D PLACEBO / / 633 IDEAL LOW DOSE / / 4449 MIRACL PLACEBO / / 1548 PATE LOW DOSE / / 334 ACAPS PLACEBO / / 459 ALERT PLACEBO / / 1052 BONE PLACEBO / / 119 CLAPT PLACEBO / / 114 SHARP PLACEBO / / between baseline and follow-up) in mg/dl (slope, ; SE, ; 95% CI, to ; P 0.43]; (2) this difference expressed as percentage of baseline (slope, ; SE, ; 95% CI, to ; P 0.47]; and (3) the achieved LDL cholesterol in the active treatment group during follow-up (slope, ; SE, ; 95% CI, to ; 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. therapy resulted in a significant reduction in total stroke (OR, 0.84; 95% CI, ; P ; Figure 3). The P for heterogeneity (interaction) was 0.31, Q , 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 ). All-Cause Mortality There were 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 All studies Favors Favors Figure 3. Forrest plot of random-effects meta-analysis of randomized trials of statins and all stroke. group (11.43%; OR, 0.92; 95% CI, ; P ; Figure 4). The P for heterogeneity (interaction) was 0.31, Q , 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 ). 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 Labreuche 25 reported a negligible risk of hemorrhagic stroke with statin

6 2154 Stroke August 2012 ICH - Statin Meta-Analysis: Death Study name Subgroup within study Statistics for each study Dead / Total Odds ratio and 95% CI Odds Lower Upper ratio p-value limit limit 4S PLACEBO / / 2223 AF-TEXCAPS PLACEBO / / 3301 ALLHAT-LLT PLACEBO / / 5185 ASCOT-LLA PLACEBO / / 5137 ATOZ LOW DOSE / / 2232 AURORA PLACEBO / / 1384 CARE PLACEBO / / 2078 CORONA PLACEBO / / 2497 GISSI-P PLACEBO / / 2133 GREACE PLACEBO / / 800 HPS PLACEBO / / JUPITER PLACEBO / / 8901 LIPID PLACEBO / / 4502 MEGA PLACEBO / / 3966 PROSPER PLACEBO / / 2913 PROVE-IT LOW DOSE / / 2063 TNT LOW DOSE / / 5006 SEARCH LOW DOSE / / 6033 SPARCL PLACEBO / / 2366 CARDS PLACEBO / / 1412 ASPEN PLACEBO / / 1199 GISSI-HF PLACEBO / / D PLACEBO / / 633 IDEAL LOW DOSE / / 4449 MIRACL PLACEBO / / 1548 PATE LOW DOSE / / 334 ACAPS PLACEBO / / 459 ALERT PLACEBO / / 1052 CLAPT PLACEBO / / 114 SHARP PLACEBO / / therapy (relative risk, 1.03; 95% CI, ). 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, ). 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 subjects. In our analysis, active therapy was associated with a nonsignificant increase in the risk of ICH (OR, 1.08; 95% CI, ). 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 subjects. 27 In addition to their lipid-lowering properties, All studies Favors Favors Figure 4. Forrest plot of random-effects meta-analysis of randomized trials of statins and all-cause mortality. 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, ) compared with primary prevention studies (OR, 0.96; 95% CI, ). 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.

7 McKinney and Kostis Statin Therapy and Risk of ICH 2155 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. Conclusions 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. Sources of Funding This study was funded in part by the Robert Wood Johnson Foundation and the Schering-Plough Foundation. None. Disclosures References 1. Iso H, Jacobs DR Jr, Wentworth D, Neaton JD, Cohen JD. 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