On June 25, 2024, the AHA Journals will be launching a new website design. During the launch process, there may be intermittent outages, and some features (alert sign-ups, article/issue purchases, account customizations/activations, and comment submissions) may be unavailable. This message will be removed when the launch process is complete. Thank you for your patience and we hope that you enjoy the new site!

Skip main navigation

Impact of Statins on Hematoma, Edema, Seizures, Vascular Events, and Functional Recovery After Intracerebral Hemorrhage

Originally publishedhttps://doi.org/10.1161/STROKEAHA.120.029345Stroke. 2021;52:975–984

Abstract

Background and Purpose:

The impact of statins on hematoma characteristics, perihemorrhagic edema (PHE), cardiovascular events, seizures, and functional recovery in patients with intracerebral hemorrhage (ICH) is insufficiently studied.

Methods:

Patients with ICH of the prospective UKER-ICH (Universitätsklinikum Erlangen Cohort of Patients With Spontaneous Intracerebral Hemorrhage) study (URL: https://www.clinicaltrials.gov; Unique identifier: NCT03183167) were analyzed by multivariable regression modeling and propensity score matching, and PHE volumes were volumetrically assessed. Outcomes comprised hematoma characteristics, the impact of continuation, discontinuation, and initiation of statins on peak PHE extent, and the influence of statin treatment on the occurrence of seizures, cardiovascular adverse events, and functional recovery after ICH.

Results:

A total of 1275 patients with ICH with information on statin treatment were analyzed. Statin treatment on hospital admission (21.7%) was associated with higher rates of lobar versus nonlobar ICH (odds ratio, 1.57 [1.03–2.40]; P=0.038). Initiation of statins after ICH was associated with increased peak PHE (β=0.12, SE=0.06, P=0.008), whereas continuation versus discontinuation of prior statin treatment was not significantly associated with edema formation (P>0.10). There were no significant differences in the incidence of remote symptomatic seizures according to statin exposure during follow-up (statins: 11.5% versus no statins: 7.8%, subdistribution hazard ratio: 1.15 [0.80–1.66]; P=0.512). Patients on statins revealed less cardiovascular adverse events and more frequently functional recovery after 12 months (functional recovery: 57.7% versus 45.0%, odds ratio 1.67 [1.09–2.56]; P=0.019).

Conclusions:

Among statin users, lobar ICH occurs more frequently as compared with nonstatin users. While continuation of prior statin treatment appears to be safe regarding PHE formation, the initiation of statins during the first days after ICH may increase PHE extent. However, statins should be initiated thereafter (eg, at hospital discharge) to prevent cardiovascular events and potentially improve functional recovery.

Introduction

Statin treatment is effective in the prevention of cardiovascular events.1 Based on the results of the SPARCL trial (Stroke Prevention by Aggressive Reduction in Cholesterol Levels), statin treatment has been discussed to increase the incidence of intracerebral hemorrhage (ICH).2 However, after adjustment for lipid levels, statin treatment seemed associated with a lower incidence of ICH presumably by effects on cerebral small-vessel disease.2–4 In the event of an ICH, statin premedication is often continued in clinical practice, although there is uncertainty if statins should be discontinued in the acute phase of ICH and it is unclear, if and when statins should be initiated in statin-naive patients after ICH.5,6 Observational studies suggest initiation of statins after ICH to be associated with favorable functional outcome and fewer remote symptomatic seizures.7,8 However, these results may harbor residual bias by indication, why the impact of early statin initiation on secondary injury after the initial ICH needs to be established.9,10 The European Stroke Organization, therefore, defined the issue of when statins should be (re-)started after ICH as major priority in ICH research.11 The present study explored the hypothesis that statin treatment may influence hematoma characteristics (1), extent of perihemorrhagic edema (PHE; 2), occurrence of remote symptomatic seizures (3), cardiovascular events and functional recovery (4) following ICH.

Methods

The authors declare that all supporting data are available within the article and in the Data Supplement. Detailed information on the prospective, single-center UKER-ICH registry (Universitätsklinikum Erlangen Cohort of Patients With Spontaneous Intracerebral Hemorrhage) have been published previously.12,13 Patients admitted to the University Hospital Erlangen with spontaneous ICH were included between January 1, 2006, and December 31, 2015. The UKER-ICH study was approved by the local institutional review board, and consent was obtained by patients or legal representatives.

Definitions and Data Acquisition

Data on demographics, comorbidities, and premorbid modified Rankin Scale (mRS) were obtained as previously described.14,15 Laboratory and clinical parameters were retrieved from medical charts and institutional databases. If lipid profile was not measured during hospital stay and prehospital cholesterol levels available, these laboratory parameters were used.

ICH and PHE

We excluded ICH due to secondary cause—such as aneurysm, arteriovenous malformation, tumor, or trauma.15 All available imaging scans during hospital stay were evaluated to assess hematoma characteristics and PHE volume. Deep ICH was defined as hematoma located within the basal ganglia, internal or external capsula, or thalamus. Lobar ICH was defined as hematoma originating at the cortex and cortical-subcortical junction. PHE volumes were measured by a semiautomatic volumetric algorithm using region of interest with a specified range of Hounsfield units.16 Peak PHE was defined as the maximum PHE volume measured in any of the available imaging scans (in patients with ≥3 scans during hospital stay).17,18 ICH volumes were measured by the ABC/2 method (A is defined as the largest axial diameter of the bleeding, B the diameter 90° to A, and C the craniocaudal diameter of the hemorrhage) and ABC/3 method, respectively.19 Hematoma enlargement was defined as relative ICH volume increase of >33% from initial to follow-up imaging.15

Statin Treatment

We defined statin treatment as daily statin medication independent of drug or dosage. There are different statin treatment groups in this study. For analysis of hematoma characteristics statin treatment was defined as statin treatment at hospital admission. For analysis of PHE statin treatment was sub-classified according to continuation, discontinuation, and initiation of statin therapy during hospital stay. For analysis of remote seizures, cardiovascular adverse events and functional recovery statin treatment was defined as statin treatment at hospital discharge. Exposure to statins at hospital admission was classified according to duration of statin intake before hospital admission (<1, 1–2, or >2 years), statin type (atorvastatin, simvastatin, or hydrophilic statins), and statin dosage. Average atorvastatin equivalent daily dose was calculated and average atorvastatin equivalent daily dose categories defined as <20 and ≥20 mg/d.3

Epileptic Seizures

We defined remote symptomatic seizures as the occurrence of a first seizure event >7 days after the initial ICH.20 Seizure events were defined as (1) electrographic evidence of ictal activity on EEG with or without corresponding clinical symptoms or signs or (2) witnessed clinical symptoms or signs diagnosed as epileptic seizure by the attending neurologist or (3) unwitnessed clinical events evaluated as epileptic seizure by an epilepsy specialist.20 Data on seizure events were assessed during hospital stay, and thereafter by standardized mailed questionnaires or semi-structured telephone-interviews at 3 and 12 months, or retrieved from institutional databases in case of hospital readmission.15

Functional Recovery and Cardiovascular Events

Functional recovery was defined as improvement of functional status (at least one point on the mRS) between hospital discharge and outcome assessment at 3 months and between hospital discharge and outcome assessment at 12 months after ICH, respectively. We defined cardiovascular adverse events as composite of nonfatal stroke (ischemic or hemorrhagic), nonfatal myocardial infarction, and death of any cause.

Outcome Measures

We assessed (1) the impact of statin premedication on hematoma characteristics on admission, (2) the extent of PHE according to continuation, discontinuation, and initiation of statins, (3) the influence of statin treatment on the occurrence of remote symptomatic seizures, as well as (4) the influence of statin treatment on the occurrence of cardiovascular adverse events and functional recovery after ICH.

Statistical Analysis

SPSS version 21.0 (www.spss.com), R version 2.12.0 (www.r-project.org), and SAS version 9.4 (www.sas.com) were used for statistical analyses. We performed 2-sided statistical tests with a significance level at α=0.05. Categorial variables are expressed as counts (percentage) and compared by the Pearsons χ2 test. Normally distributed data are presented as mean (±SD) and analyzed using the Student t test. Non-normally distributed data are presented as median (interquartile rage) and compared using the Mann-Whitney U test.

Propensity score matching (PSM) was applied using parallel, balanced, ratio (1:3) nearest-neighbor approach at a caliper of 0.1. The propensity score was calculated using parameters showing differences for intergroup comparisons (standardized mean differences >0.10). For analysis of hematoma characteristics parameters were included showing differences for intergroup comparisons regarding baseline characteristics (ie, age, arterial hypertension, diabetes, prior ischemic stroke/transient ischemic attack [TIA], coronary artery disease, premorbid mRS), and lipid level (ie, cholesterol). Subgroup analysis for the association between statin premedication and lobar hematoma location was conducted in the PSM cohort. For analysis of remote symptomatic seizures parameters were included showing differences for intergroup comparisons regarding baseline characteristics (ie, arterial hypertension, diabetes, prior ischemic stroke/TIA, coronary artery disease), and hematoma characteristics (ie, ICH volume). For analysis of outcome events (cardiovascular adverse events and functional recovery), parameters were included showing differences for intergroup comparisons regarding baseline characteristics (ie, arterial hypertension, diabetes, coronary artery disease), characteristics at hospital discharge (ie, mRS, antiplatelet therapy), and hematoma characteristics (ie, ICH volume). After adjustment using PSM, all relevant covariates were well balanced with an absolute standardized difference of 0.1 (Figures I through III in the Data Supplement). Kaplan–Meier method was used to evaluate the timing of event occurrences. Binary logistic regression analyses were applied for analysis of functional recovery. Occurrence of remote symptomatic seizures and cardiovascular adverse events according to statin exposure were compared by Cox proportional hazards models. Cumulative incidence function covariate analyses were performed to account for the competing risk of death as it may preclude the occurrence of remote symptomatic seizures. Sensitivity analyses were conducted using inverse probability treatment weighting method adjusted for the same set of variables used for the corresponding outcome analyses. Additional sensitivity analyses were conducted for established parameters associated with outcome events using cox proportional hazards models for remote symptomatic seizures and cardiovascular adverse events, and multivariable binary regression analyses for hematoma characteristics and functional recovery (results).

Peak PHE volumes were log-transformed to approximate the normal distribution.21 Associations between different statin regimes and peak PHE were analyzed by multivariable linear regression adjusted for age and ICH volume. To account for varying time points of control imaging, we categorized time frames of follow-up imaging (days 1, 2–3, 4–6, 7–9, 10–12, 13–15, 16–18, 19–22).16,18,22

Results

Study Population and Clinical Characteristics

The UKER-ICH study included 1322 patients with primary ICH (Figure 1). After exclusion of 47 patients because of missing data on statin treatment, 1275 patients with ICH remained for analysis. Of these, 277 (21.7%) patients were on statin treatment on hospital admission (Table 1). As compared with nonstatin-users upon admission, patients with statins were significantly older (76 [69–80] years versus 72 [61–80] years; P<0.001) and demonstrated more pronounced comorbidities—for example, arterial hypertension (259/277 [93.5%] versus 821/998 [82.3%]; P<0.001), prior ischemic stroke/TIA (104/277 [37.5%] versus 151/998 [15.1%]; P<0.001), coronary artery disease (126/277 [45.5%] versus 180/998 [18.0%]; P<0.001)—and lower total cholesterol levels (174 [148–207] mg/dL versus 191 [163–219]; P<0.001). Overall, missing data was below 2.0% except for symptom onset to admission and cholesterol levels (results in the Data Supplement).

Table 1. Clinical Characteristics of Patients With ICH According to Statin Therapy on Admission

Overall patients with ICHNo statin therapy (n=998)Statin therapy (n=277)P value
Age, y (IQR)72 (61–80)76 (69–80)<0.001
Female sex476 (47.7%)115 (41.5%)0.068
Prior comorbidities
 Hypertension821 (82.3%)259 (93.5%)<0.001
 Diabetes230 (23.0%)123 (44.4%)<0.001
 Prior ischemic stroke/TIA151 (15.1%)104 (37.5%)<0.001
 Coronary artery disease180 (18.0%)126 (45.5%)<0.001
 Oral anticoagulation141 (14.1%)87 (31.4%)<0.001
 Premorbid mRS (IQR)1 (0–2)1 (0–2)<0.001
Admission status
 GCS13 (6–15)13 (10–15)0.006
 Systolic blood pressure, mm Hg (IQR)169 (147–190)166 (150–189)0.718
 Diastolic blood pressure, mm Hg (IQR)93 (80–106)90 (80–100)0.209
 Symptom onset to admission, hours (IQR)4.2 (1.6–10.2)4.2 (2.0–12.3)0.435
 INR (IQR)1.05 (0.99–1.15)1.07 (0.98–1.93)0.007
 Creatinine, mg/dL (IQR)0.89 (0.72–1.11)0.94 (0.76–1.16)0.019
 Cholesterol, mg/dL (IQR)191 (163–219)174 (148–207)<0.001
Imaging of PSM non-OAC-ICH patients
 Deep121 (42.5%)41 (32.8%)0.066
 Lobar130 (45.6%)71 (56.8%)0.037
 Infratentorial34 (11.9%)13 (10.4%)0.654
 Intraventricular hemorrhage113 (39.6%)41 (32.8%)0.187
 ICH volume, mL (IQR)9.4 (3.0–23.1)9.0 (3.3–25.1)0.910
 Hematoma enlargement*26/238 (10.9%)10/106 (9.4%)0.677

Non-OAC-ICH patients were matched according to propensity scores calculated from age, arterial hypertension, diabetes, prior ischemic stroke/TIA, coronary artery disease, premorbid mRS, and cholesterol (parallel, balanced, ratio [1:3] nearest-neighbor approach at a caliper of 0.1; Figure I in the Data Supplement) resulting in n=285 no statin therapy and n=125 statin therapy non-OAC-ICH patients for imaging analysis. GCS indicates Glasgow Coma Scale; ICH, intracerebral hemorrhage; INR, international normalized ratio; IQR, interquartile range; mRS, modified Rankin Scale; non-OAC-ICH, not oral anticoagulation associated ICH (ie, primary spontaneous ICH); PSM, propensity score matching; and TIA, transient ischemic attack.

* Hematoma enlargement was defined as increase of volume >33% on follow-up imaging.

† Modified Rankin Scale range, 0–6, from no disability to death.

‡ Glasgow Coma Scale range, 3–15, from deep coma to alertness.

Figure 1.

Figure 1. Flow chart of study participants. Overall, 1275 patients with intracerebral hemorrhage (ICH) and data on statin therapy were eligible for data analysis. Analyses of hematoma characteristics were performed among 1047 patients with ICH after exclusion oral anticoagulation (OAC)-ICH, analyses of perihemorrhagic edema (PHE) among 366 patients with ICH after exclusion of patients without PHE data and <3 imaging scans, analyses of remote symptomatic seizures among 908 patients with ICH after exclusion of patients with acute symptomatic seizures, epilepsy and death ≤7 days, and analyses of outcome events among 481 patients with ICH after exclusion of patients with death at discharge, atrial fibrillation and no statin therapy (ST) indication. PHE, perihemorrhagic edema. UKER-ICH indicates Universitätsklinikum Erlangen Cohort of Patients With Spontaneous Intracerebral Hemorrhage.

Hematoma Characteristics According to Statin Premedication

To properly compare hematoma characteristics according to statin premedication, we excluded patients with oral anticoagulation (OAC), that is, vitamin K antagonist and non–vitamin K antagonist oral anticoagulant—associated ICH (228/1275 [17.9%]) and performed PSM for parameters showing differences for intergroup comparisons (ie, age, arterial hypertension, diabetes, prior ischemic stroke/TIA, coronary artery disease, premorbid mRS, and cholesterol) to rule out possible influence on imaging characteristics (Figure I in the Data Supplement). After adjustments, there were significant differences regarding ICH location between patients with and without statins on hospital admission (lobar ICH, 71/125 [56.8%] versus 130/285 [45.6%]; P=0.037; Table 1). There were no significant differences in ICH volume, hematoma enlargement, and intraventricular hemorrhage.

Subgroup analysis revealed a significant association between statins and lobar hematoma location (odds ratio [OR], 1.57 [1.03–2.40]; P=0.038; Figure 2), including subgroups according to antiplatelet medication, age, statin type, statin treatment duration, and statin dosage (average atorvastatin equivalent daily dose <20 mg/d: OR for the association with lobar hematoma location: 1.40 [0.84–2.34]; average atorvastatin equivalent daily dose ≥20 mg/d: OR, 1.85 [1.01–3.40]). Sensitivity analyses yielded similar results (results in the Data Supplement).

Figure 2.

Figure 2. Association between statin therapy and lobar hematoma location. Binary logistic regression analyses were computed to illustrate the association between statin therapy on hospital admission and lobar hematoma location for specific subgroups of patients with intracerebral hemorrhage (ICH) in the propensity score matching (PSM) cohort (Figure I in the Data Supplement). AAED indicates average atorvastatin equivalent daily dose; and APT, antiplatelet therapy. *subset of patients with ICH with information on the specific time point of statin therapy initiation (n=85/125).

PHE in Different Statin Regimes

Table 2 illustrates the impact of different statin regimes on peak PHE extent. There were no significant associations between peak PHE and statin therapy on admission (n=73 versus 293, β=−0.01, SE=0.05; P=0.853) or any statin therapy during hospital stay (n=123 versus 243, β=0.04, SE=0.07; P=0.070). Initiation versus no initiation of statins was associated with increased peak PHE (n=50 versus 243, β=0.12, SE=0.06; P=0.008), whereas continuation versus discontinuation of statin therapy was not significantly associated with increased PHE (n=39 versus 34, β=0.11, SE=0.08; P=0.216).

Table 2. Associations Between Different Statin Therapy Regimes and Peak PHE

βSEP value
ST vs no ST on admission (n=73 vs 293)−0.010.050.853
Any ST vs no ST (n=123 vs 243)0.040.070.070
ST continued vs ST discontinued (n=39 vs 34)0.110.080.216
ST initiated vs ST not initiated (n=50 vs 243)0.120.060.008

Associations between different ST regimes and peak PHE were analyzed by multivariable linear regression models adjusted for age and ICH volume after log-transformation of edema volumes to approximate the normal distribution. ICH indicates intracerebral hemorrhage; PHE, perihemorrhagic edema; and ST, statin therapy.

Seizures, Cardiovascular Events, and Functional Recovery

To properly compare occurrence of remote symptomatic seizures according to statin premedication, we excluded patients with OAC associated ICH (228/1275 [17.9%]) and performed PSM for parameters showing differences for intergroup comparisons (arterial hypertension, diabetes, prior ischemic stroke/TIA, coronary artery disease, and ICH volume; Figure II in the Data Supplement). Remote symptomatic seizures occurred in 69 of 769 patients within 12 months after ICH—28 patients with statin therapy and 41 patients without statin therapy (crude incidence: statins: 11.5% versus no statins: 7.8%; subdistribution hazard ratio [HR], 1.15 [0.80–1.66], P=0.512; cause-specific HR, 1.36 [0.84–2.19], P=0.214; Figure 3A). Remote symptomatic seizures occurred in 107 patients within 5 years after ICH—43 patients with statin therapy and 64 patients without statin therapy (crude incidence: statins: 17.6% versus no statins: 12.2%; subdistribution HR, 1.31 [0.94–1.69], P=0.156; HR, 1.26 [0.85–1.85], P=0.251; Figure IVA in the Data Supplement).

Figure 3.

Figure 3. Occurrence of remote symptomatic seizures and cardiovascular adverse events. A, Remote symptomatic seizures occurred in 69/769 patients within 12 mo after intracerebral hemorrhage (ICH)—28 patients with statin therapy and 41 patients without statin therapy—in the propensity score matching (PSM) cohort (Figure II in the Data Supplement). Numbers of patients with ICH are shown in terms of who were at risk at the start of each 2-month interval. B, Cardiovascular adverse events (composite of nonfatal stroke [ischemic or hemorrhagic], nonfatal myocardial infarction, and death of any cause) occurred in 70 patients within 12 mo after ICH—19 patients with statin therapy and 51 patients without statin therapy—in the PSM cohort (Figure III in the Data Supplement). Numbers of patients with ICH are shown in terms of who were at risk at the start of each 2-month interval. HR indicates hazard ratio.

To avoid bias by ischemic and hemorrhagic events in patients with atrial fibrillation, we excluded patients with atrial fibrillation from analyses of outcome events (cardiovascular adverse events and functional recovery) and performed PSM for parameters showing differences for intergroup comparisons (arterial hypertension, diabetes, coronary artery disease, mRS, antiplatelet therapy, and ICH volume; Figure III in the Data Supplement). There were differences in the incidence of cardiovascular adverse events within 12 months after the ICH event according to statin exposure at hospital discharge (crude incidence: statins: 11.6% versus no statins: 18.5%; HR, 0.60 [0.36–1.02], P=0.058; Figure 3B) and 5 years (20.9% versus 33.3%; HR, 0.56 [0.38–0.83], P=0.004; Figure IVB in the Data Supplement).

There were no significant differences in the proportion of patients with functional recovery among those with and without statin treatment after 3 months (statins: 62/150 [41.3%] versus no statins: 103/251 [41.0%]; OR, 1.01 [0.67–1.53], P=0.953). There were significant differences in the proportion of patients with functional recovery after 12 months (79/137 [57.7%] versus 103/229 [45.0%]; OR, 1.67 [1.09–2.56], P=0.019). ICH location had no significant interaction with the effect of statin therapy on the incidence of remote symptomatic seizures, cardiovascular adverse events of functional recovery (results in the Data Supplement). Sensitivity analyses yielded similar results (results in the Data Supplement).

Discussion

In this study, we demonstrate that continuation of statin premedication does not aggravate edema formation and, therefore, appears to be safe in patients with ICH. However, initiation of statin therapy during the first days after ICH in patients without statin premedication is associated with increased PHE extent. Thus, if indicated in statin-naive patients, statins should be initiated after the acute phase of ICH (eg, at hospital discharge) as statins seem to prevent cardiovascular events and improve functional recovery during follow-up.

More than 30% of patients with ICH require statin treatment due to comorbidities such as coronary artery disease or previous ischemic stroke. However, in the event of an ICH, it was unclear if statin premedication should be continued or discontinued and if statins should be initiated in patients without such premedication. Recent observational data derived from the Virtual International Stroke Trials Archive suggest that continuation of prior statin use during the first 48 hours is associated with better functional outcomes.6 Preclinical studies have reported potential neuroprotective and recovery enhancement effects of statins for ICH by targeting secondary brain injury pathways.23 However, selection bias of these retrospective observational studies restricted the significance and interpretation of these results, especially regarding the proposed improvement in neurological function. The effect of statin therapy on specific end points such as PHE yielded conflicting results.10,24 PHE has only been investigated during the first 24 to 48 hours after the ICH event, which is why the effect of statin continuation, discontinuation, or initiation on edema extent have not been evaluated so far and statins may potentially even impair functional outcome by increased edema formation.10,23 Therefore, the European Stroke Organisation defined the issue of when statins should be (re-) started after ICH as major priority in ICH research.11

By evaluating the maximal extent of PHE formation, that is, peak PHE, we demonstrate that initiation of statin therapy in patients with ICH without such premedication seems to increase peak PHE and may affect functional outcome by aggravating secondary brain injury. Therefore, based on our findings, statins should not be initiated during the acute phase of ICH. Potential explanations include the complex mechanism and interactions of statins resulting in both beneficial and detrimental effects in patients with ICH. Experimental studies demonstrated that statins accelerate red blood cell phagocytosis by activation of microglia and macrophage recruitment in the hematoma boundary zone, which may result in accelerated hematoma absorption, but also increased peak PHE.23,25,26 This detrimental effect may be more pronounced in statin-naive patients and may be avoided by not initiating statins during the acute phase of ICH.23,27,28 On the contrary, preclinical studies demonstrated that statins decrease apoptosis and increase neurogenesis, synaptogenesis, and growth factor expression, which may result in improved brain plasticity and neurological outcome.23,29,30 This beneficial recovery enhancing effect may be utilized by initiating statins after the phase of peak edema formation. However, continuation (versus discontinuation) of statin premedication did not significantly affect peak PHE in our study. Statins are effective for >24 hours after the last intake,31 why statin premedication—even if discontinued—has an effect on a very relevant phase of PHE formation, and the beneficial effect of discontinuation (versus continuation) on PHE formation appears less relevant. Given the pharmacological rebound effects of acute discontinuation of statin treatment resulting in oxidative stress, impaired vascular function, and acute vascular events,5,32 continuation of statin premedication should be preferred over discontinuation to prevent cardiovascular events.

Regarding the associations of statin use and epileptic seizures in patients with ICH, a recent cohort study suggested potential protective effects of statins against remote symptomatic seizures after ICH. However, Lin et al8 included subarachnoid hemorrhage and other unspecified intracranial hemorrhage subtypes and statistical models were not adjusted for hematoma location or hematoma volume.33,34 In contrast, the incidence of remote symptomatic seizures were higher in patients with ICH with statin treatment in our study, although these differences were statistically not significant. Preclinical studies suggest that statins may have both anticonvulsant and proconvulsant effects depending on the experimental model tested. Suppression of inflammatory pathways and glutamate-mediated neurotoxicity could increase the seizure threshold and provide anticonvulsant effects.35 In contrast, inhibition of G protein and modulation of synapse formation could cause proconvulsant effects, notably in patients with compromised blood–brain barrier.35,36 Future studies addressing the impact of statins in patients with ICH should further investigate the occurrence of seizures and the potential proconvulsant effects of statin therapy.

Regarding the associations of statin use and cardiovascular events in patients with ICH, a recent study reported that continued statin treatment reduced cardiovascular events in patients post-ICH.23 We here confirm that statin therapy prevents secondary cardiovascular events, which may exert clinical significance beyond the first 3 months after the index event. The reduction of cardiovascular events appears more relevant than the previously reported recovery enhancing effects of statins and in parts may drive the reported improvement in neurological function at 12 months. In line, the recently published iDEF trial (Deferoxamine Mesylate in Patients With Intracerebral Haemorrhage) demonstrated that a relevant proportion of patients showed functional improvement beyond 3 months after ICH and that benefits in functional recovery may become more evident at later time points. Our results suggest that statins should be initiated after the acute phase of ICH in patients to reduce relevant long-term cardiovascular risk factors, eventually in a care-bundle approach.37

Regarding the aspect of ICH incidence and ICH location: Statins have been discussed to increase the incidence of ICH in the subgroup of patients with previous ischemic stroke or ICH according to the SPARCL trial results in 2006 and similarly albeit not significant in HPS (Heart Protection Study).2,5,38 However, subsequent randomized controlled trials did not show an increased risk of ICH in general. We here demonstrate that statin therapy may be associated with higher rates of lobar hematoma location, both in primary spontaneous ICH and also in OAC associated ICH. This finding would be in line with the previously reported higher incidence of ICH and might be explained by an effect of statins promoting cerebral amyloid angiopathy and implying effects on cortical-subcortical vessels in addition to anticoagulation.39,40 Yet, the results may also reflect an epiphenomenon of statin treatment and concomitant blood pressure medication compared with patients without antihypertensive and lipid lowering treatment resulting in lower rates of deep hematoma location in patients with statin treatment. Thus, the potential effects of statins on cerebral small-vessels remain a scientific hypothesis to be tested in future studies that also address absolute incidence of ICH subtypes.

Limitations of our study include single-center study design and no prespecified statin regimes. Further, timing and number of imaging scans were based on clinical practice, not on defined criteria and subgroups of different statin types and regimes were small. Lack of randomization and missing data on cholesterol levels may have resulted in bias by indication and influence of confounder variables in this observational study design. There were violations of the proportional hazard assumption, although the cox proportional hazard model is widely accepted as being robust to minor violations. ICH volumes were calculated by ABC method and some data on clinical outcome were missing, both leaving room for uncertainties.

Conclusions

Among statin users, lobar ICH occurs more frequently as compared with nonstatin users. While continuation of prior statin therapy appears to be safe regarding PHE formation, the initiation of statins during the first days after ICH may increase edema extent and should, thus, be avoided during the acute ICH phase. However, statins should be initiated thereafter (eg, at hospital discharge) to prevent cardiovascular events and potentially improve functional recovery.

Nonstandard Abbreviations and Acronyms

HR

hazard ratio

ICH

intracerebral hemorrhage

mRS

modified Rankin Scale

OAC

oral anticoagulation

OR

odds ratio

PHE

perihemorrhagic edema

PSM

propensity score matching

SPARCL

Stroke Prevention by Aggressive Reduction in Cholesterol Levels

UKER-ICH

Universitätsklinikum Erlangen Cohort of Patients With Spontaneous Intracerebral Hemorrhage

Acknowledgments

The present work was performed in (partial) fulfillment of the requirements for obtaining the degree Dr. med. (J.I. Saam).

Supplemental Materials

Expanded Results

Figures I–IV

Disclosures Dr Kuramatsu reports personal fees from Bayer, personal fees from Bristol-Myers Squibb & Pfizer, personal fees from Sanofi, and personal fees from Boehringer Ingelheim outside the submitted work. Dr Volbers reports personal fees from Pfizer & Bristol-Myers Squibb SA, personal fees from Bayer, institutional grant (Inselspital), personal fees from Ipsen Pharma and personal fees from Commonwealth Serum Laboratories Behring outside the submitted work. Dr Nolte reports personal fees from Boehringer Ingelheim, personal fees from Bristol-Myers Squibb, personal fees from Pfizer Pharma, and personal fees from Abbott outside the submitted work. Dr Hamer reports personal fees from Union Chimique Belge, Desitin, Esai, Guy & Whittle Pharmaceuticals, Novartis, Hexal, facetoface, Zogenix and grants from Amgen, Ad-Tech, Bracco, Pfizer, Micromed, Nihon Kohden outside the submitted work. Dr Endres received funding from Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany´s Excellence Strategy—EXC-2049—390688087 and from Bundesministerium für Bildung und Forschung (BMBF; German Ministry for Education and Research) for the Center for Stroke Research Berlin, grants from Bayer and fees paid to the Charité from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, Amgen, GlaxoSmithKline, Sanofi, Covidien, Novartis, Pfizer, all outside the submitted work. Dr Huttner reports personal fees from Boehringer Ingelheim, personal fees from Bayer AG, personal fees from Daiichi Sankyo, grants and personal fees from Novartis, grants and personal fees from Portola Pharmaceuticals, grants and personal fees from Union Chimique Belge Pharma, and grants and personal fees from Medtronic outside the submitted work. The other authors report no conflicts.

Footnotes

This article was sent to Pierre Amarenco, Consulting Editor, for review by expert referees, editorial decision, and final disposition.

The Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/STROKEAHA.120.029345.

For Sources of Funding and Disclosures, see page 983.

Continuing medical education (CME) credit is available for this article. Go to https://cme.ahajournals.org to take the quiz.

Correspondence to: Hagen B. Huttner, MD, PhD, Department of Neurology, University of Erlangen-Nuremberg, Schwabachanlage 6, 91054 Erlangen, Germany. Email

References

  • 1. Collins R, Reith C, Emberson J, Armitage J, Baigent C, Blackwell L, Blumenthal R, Danesh J, Smith GD, DeMets D, et al. Interpretation of the evidence for the efficacy and safety of statin therapy.Lancet. 2016; 388:2532–2561. doi: 10.1016/S0140-6736(16)31357-5CrossrefMedlineGoogle Scholar
  • 2. Amarenco P, Bogousslavsky J, Callahan A, Goldstein LB, Hennerici M, Rudolph AE, Sillesen H, Simunovic L, Szarek M, Welch KM, et al; Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) Investigators. High-dose atorvastatin after stroke or transient ischemic attack.N Engl J Med. 2006; 355:549–559. doi: 10.1056/NEJMoa061894CrossrefMedlineGoogle Scholar
  • 3. Saliba W, Rennert HS, Barnett-Griness O, Gronich N, Molad J, Rennert G, Auriel E. Association of statin use with spontaneous intracerebral hemorrhage: A cohort study.Neurology. 2018; 91:e400–e409. doi: 10.1212/WNL.0000000000005907CrossrefMedlineGoogle Scholar
  • 4. Ribe AR, Vestergaard CH, Vestergaard M, Fenger-Grøn M, Pedersen HS, Lietzen LW, Brynningsen PK. Statins and risk of intracerebral haemorrhage in a stroke-free population: a nationwide danish propensity score matched cohort study.E Clinical Med. 2019; 8:78–84. doi: 10.1016/j.eclinm.2019.02.007CrossrefGoogle Scholar
  • 5. Endres M, Nolte CH, Scheitz JF. Statin treatment in patients with intracerebral hemorrhage.Stroke. 2018; 49:240–246. doi: 10.1161/STROKEAHA.117.019322LinkGoogle Scholar
  • 6. Doerrfuss JI, Abdul-Rahim AH, Siegerink B, Nolte CH, Lees KR, Endres M, Kasner SE, Scheitz JF; Virtual International Stroke Trials Archive (VISTA) collaboration. Early in-hospital exposure to statins and outcome after intracerebral haemorrhage - results from the virtual international stroke trials archive.Eur Stroke J. 2020; 5:85–93. doi: 10.1177/2396987319889258CrossrefGoogle Scholar
  • 7. Jung JM, Choi JY, Kim HJ, Seo WK. Statin use in spontaneous intracerebral hemorrhage: a systematic review and meta-analysis.Int J Stroke. 2015; 10suppl A100:10–17. doi: 10.1111/ijs.12624CrossrefMedlineGoogle Scholar
  • 8. Lin HW, Ho YF, Lin FJ. Statin use associated with lower risk of epilepsy after intracranial haemorrhage: a population-based cohort study.Br J Clin Pharmacol. 2018; 84:1970–1979. doi: 10.1111/bcp.13626CrossrefGoogle Scholar
  • 9. Siddiqui FM, Langefeld CD, Moomaw CJ, Comeau ME, Sekar P, Rosand J, Kidwell CS, Martini S, Osborne JL, Stutzman S, et al. Use of statins and outcomes in intracerebral hemorrhage patients.Stroke. 2017; 48:2098–2104. doi: 10.1161/STROKEAHA.117.017358LinkGoogle Scholar
  • 10. Gioia LC, Kate M, McCourt R, Gould B, Coutts SB, Dowlatshahi D, Asdaghi N, Jeerakathil T, Hill MD, Demchuk AM, et al; ICH ADAPT Investigators. Perihematoma cerebral blood flow is unaffected by statin use in acute intracerebral hemorrhage patients.J Cereb Blood Flow Metab. 2015; 35:1175–1180. doi: 10.1038/jcbfm.2015.36CrossrefGoogle Scholar
  • 11. Norrving B, Barrick J, Davalos A, Dichgans M, Cordonnier C, Guekht A, Kutluk K, Mikulik R, Wardlaw J, Richard E, et al. Action plan for stroke in Europe 2018-2030.Eur Stroke J. 2018; 3:309–336. doi: 10.1177/2396987318808719CrossrefGoogle Scholar
  • 12. Sprügel MI, Kuramatsu JB, Gerner ST, Sembill JA, Madžar D, Reindl C, Bobinger T, Müller T, Hoelter P, Lücking H, et al. Age-dependent clinical outcomes in primary versus oral anticoagulation-related intracerebral hemorrhage. [published online December 23, 2019].Int J Stroke. 2019. https://journals.sagepub.com/doi/10.1177/1747493019895662. Accessed May 30, 2020Google Scholar
  • 13. Sprügel MI, Sembill JA, Kuramatsu JB, Gerner ST, Hagen M, Roeder SS, Endres M, Haeusler KG, Sobesky J, Schurig J, et al. Heparin for prophylaxis of venous thromboembolism in intracerebral haemorrhage.J Neurol Neurosurg Psychiatry. 2019; 90:783–791. doi: 10.1136/jnnp-2018-319786CrossrefGoogle Scholar
  • 14. Kasner SE. Clinical interpretation and use of stroke scales.Lancet Neurol. 2006; 5:603–612. doi: 10.1016/S1474-4422(06)70495-1CrossrefMedlineGoogle Scholar
  • 15. Kuramatsu JB, Gerner ST, Schellinger PD, Glahn J, Endres M, Sobesky J, Flechsenhar J, Neugebauer H, Jüttler E, Grau A, et al. Anticoagulant reversal, blood pressure levels, and anticoagulant resumption in patients with anticoagulation-related intracerebral hemorrhage.JAMA. 2015; 313:824–836. doi: 10.1001/jama.2015.0846CrossrefMedlineGoogle Scholar
  • 16. Volbers B, Staykov D, Wagner I, Dörfler A, Saake M, Schwab S, Bardutzky J. Semi-automatic volumetric assessment of perihemorrhagic edema with computed tomography.Eur J Neurol. 2011; 18:1323–1328. doi: 10.1111/j.1468-1331.2011.03395.xCrossrefMedlineGoogle Scholar
  • 17. Sprügel MI, Kuramatsu JB, Volbers B, Gerner ST, Sembill JA, Madžar D, Bobinger T, Kölbl K, Hoelter P, Lücking H, et al. Perihemorrhagic edema: Revisiting hematoma volume, location, and surface.Neurology. 2019; 93:e1159–e1170. doi: 10.1212/WNL.0000000000008129CrossrefGoogle Scholar
  • 18. Volbers B, Giede-Jeppe A, Gerner ST, Sembill JA, Kuramatsu JB, Lang S, Lücking H, Staykov D, Huttner HB. Peak perihemorrhagic edema correlates with functional outcome in intracerebral hemorrhage.Neurology. 2018; 90:e1005–e1012. doi: 10.1212/WNL.0000000000005167CrossrefMedlineGoogle Scholar
  • 19. Kothari RU, Brott T, Broderick JP, Barsan WG, Sauerbeck LR, Zuccarello M, Khoury J. The ABCs of measuring intracerebral hemorrhage volumes.Stroke. 1996; 27:1304–1305. doi: 10.1161/01.str.27.8.1304LinkGoogle Scholar
  • 20. Biffi A, Rattani A, Anderson CD, Ayres AM, Gurol EM, Greenberg SM, Rosand J, Viswanathan A. Delayed seizures after intracerebral haemorrhage.Brain. 2016; 139(pt 10):2694–2705. doi: 10.1093/brain/aww199CrossrefMedlineGoogle Scholar
  • 21. Morotti A, Charidimou A, Phuah CL, Jessel MJ, Schwab K, Ayres AM, Romero JM, Viswanathan A, Gurol ME, Greenberg SM, et al. Association between serum calcium level and extent of bleeding in patients with intracerebral hemorrhage.JAMA Neurol. 2016; 73:1285–1290. doi: 10.1001/jamaneurol.2016.2252CrossrefMedlineGoogle Scholar
  • 22. Volbers B, Willfarth W, Kuramatsu JB, Struffert T, Dörfler A, Huttner HB, Schwab S, Staykov D. Impact of perihemorrhagic edema on short-term outcome after intracerebral hemorrhage.Neurocrit Care. 2016; 24:404–412. doi: 10.1007/s12028-015-0185-yCrossrefMedlineGoogle Scholar
  • 23. Chen CJ, Ding D, Ironside N, Buell TJ, Elder LJ, Warren A, Adams AP, Ratcliffe SJ, James RF, Naval NS, et al. Statins for neuroprotection in spontaneous intracerebral hemorrhage.Neurology. 2019; 93:1056–1066. doi: 10.1212/WNL.0000000000008627CrossrefMedlineGoogle Scholar
  • 24. Naval NS, Abdelhak TA, Urrunaga N, Zeballos P, Mirski MA, Carhuapoma JR. An association of prior statin use with decreased perihematomal edema.Neurocrit Care. 2008; 8:13–18. doi: 10.1007/s12028-007-0081-1CrossrefMedlineGoogle Scholar
  • 25. Chen Q, Shi X, Tan Q, Feng Z, Wang Y, Yuan Q, Tao Y, Zhang J, Tan L, Zhu G, et al. Simvastatin promotes hematoma absorption and reduces hydrocephalus following intraventricular hemorrhage in part by upregulating CD36.Transl Stroke Res. 2017; 8:362–373. doi: 10.1007/s12975-017-0521-yCrossrefGoogle Scholar
  • 26. Wang Y, Chen Q, Tan Q, Feng Z, He Z, Tang J, Feng H, Zhu G, Chen Z. Simvastatin accelerates hematoma resolution after intracerebral hemorrhage in a PPARγ-dependent manner.Neuropharmacology. 2018; 128:244–254. doi: 10.1016/j.neuropharm.2017.10.021CrossrefGoogle Scholar
  • 27. Macin SM, Perna ER, Farías EF, Franciosi V, Cialzeta JR, Brizuela M, Medina F, Tajer C, Doval H, Badaracco R. Atorvastatin has an important acute anti-inflammatory effect in patients with acute coronary syndrome: results of a randomized, double-blind, placebo-controlled study.Am Heart J. 2005; 149:451–457. doi: 10.1016/j.ahj.2004.07.041CrossrefGoogle Scholar
  • 28. Bonetti PO, Lerman LO, Napoli C, Lerman A. Statin effects beyond lipid lowering–are they clinically relevant?Eur Heart J. 2003; 24:225–248. doi: 10.1016/s0195-668x(02)00419-0CrossrefMedlineGoogle Scholar
  • 29. Seyfried D, Han Y, Lu D, Chen J, Bydon A, Chopp M. Improvement in neurological outcome after administration of atorvastatin following experimental intracerebral hemorrhage in rats.J Neurosurg. 2004; 101:104–107. doi: 10.3171/jns.2004.101.1.0104CrossrefMedlineGoogle Scholar
  • 30. Karki K, Knight RA, Han Y, Yang D, Zhang J, Ledbetter KA, Chopp M, Seyfried DM. Simvastatin and atorvastatin improve neurological outcome after experimental intracerebral hemorrhage.Stroke. 2009; 40:3384–3389. doi: 10.1161/STROKEAHA.108.544395LinkGoogle Scholar
  • 31. Lennernäs H. Clinical pharmacokinetics of atorvastatin.Clin Pharmacokinet. 2003; 42:1141–1160. doi: 10.2165/00003088-200342130-00005CrossrefGoogle Scholar
  • 32. Laufs U, Endres M, Custodis F, Gertz K, Nickenig G, Liao JK, Böhm M. Suppression of endothelial nitric oxide production after withdrawal of statin treatment is mediated by negative feedback regulation of rho GTPase gene transcription.Circulation. 2000; 102:3104–3110. doi: 10.1161/01.cir.102.25.3104LinkGoogle Scholar
  • 33. Madžar D, Kuramatsu JB, Gollwitzer S, Lücking H, Kloska SP, Hamer HM, Köhrmann M, Huttner HB. Seizures among long-term survivors of conservatively treated ICH patients: incidence, risk factors, and impact on functional outcome.Neurocrit Care. 2014; 21:211–219. doi: 10.1007/s12028-014-9968-9CrossrefMedlineGoogle Scholar
  • 34. Haapaniemi E, Strbian D, Rossi C, Putaala J, Sipi T, Mustanoja S, Sairanen T, Curtze S, Satopää J, Roivainen R, et al. The CAVE score for predicting late seizures after intracerebral hemorrhage.Stroke. 2014; 45:1971–1976. doi: 10.1161/STROKEAHA.114.004686LinkGoogle Scholar
  • 35. Scicchitano F, Constanti A, Citraro R, De Sarro G, Russo E. Statins and epilepsy: preclinical studies, clinical trials and statin-anticonvulsant drug interactions.Curr Drug Targets. 2015; 16:747–756. doi: 10.2174/1389450116666150330114850CrossrefGoogle Scholar
  • 36. Serbanescu I, Ryan MA, Shukla R, Cortez MA, Snead OC, Cunnane SC. Lovastatin exacerbates atypical absence seizures with only minimal effects on brain sterols.J Lipid Res. 2004; 45:2038–2043. doi: 10.1194/jlr.M400097-JLR200CrossrefGoogle Scholar
  • 37. Anderson CS. Reduction of iron neurotoxicity in intracerebral haemorrhage.Lancet Neurol. 2019; 18:416–417. doi: 10.1016/S1474-4422(19)30108-5CrossrefGoogle Scholar
  • 38. Heart Protection Study Collaborative Group. 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. doi: 10.1016/S0140-6736(02)09327-3CrossrefMedlineGoogle Scholar
  • 39. Haussen DC, Henninger N, Kumar S, Selim M. Statin use and microbleeds in patients with spontaneous intracerebral hemorrhage.Stroke. 2012; 43:2677–2681. doi: 10.1161/STROKEAHA.112.657486LinkGoogle Scholar
  • 40. Pezzini A, Grassi M, Paciaroni M, Zini A, Silvestrelli G, Del Zotto E, Caso V, Dell’Acqua ML, Giossi A, Volonghi I, et al; Multicenter Study on Cerebral Hemorrhage in Italy (MUCH-Italy) Investigators. Antithrombotic medications and the etiology of intracerebral hemorrhage: MUCH-Italy.Neurology. 2014; 82:529–535. doi: 10.1212/WNL.0000000000000108CrossrefMedlineGoogle Scholar

eLetters(0)

eLetters should relate to an article recently published in the journal and are not a forum for providing unpublished data. Comments are reviewed for appropriate use of tone and language. Comments are not peer-reviewed. Acceptable comments are posted to the journal website only. Comments are not published in an issue and are not indexed in PubMed. Comments should be no longer than 500 words and will only be posted online. References are limited to 10. Authors of the article cited in the comment will be invited to reply, as appropriate.

Comments and feedback on AHA/ASA Scientific Statements and Guidelines should be directed to the AHA/ASA Manuscript Oversight Committee via its Correspondence page.