Curr Atheroscler Rep (2015) 17:46 DOI 10.1007/s11883-015-0526-5

CARDIOVASCULAR DISEASE AND STROKE (S PRABHAKARAN, SECTION EDITOR)

Statins in Intracerebral Hemorrhage Arne Lauer 1 & Steven M. Greenberg 1 & M. Edip Gurol 1

# Springer Science+Business Media New York 2015

Abstract While statins play an indisputable role in primary and secondary prevention of ischemic cardiovascular and cerebrovascular disease, a concern exists regarding a possible association between low lipoprotein levels and statin use on the risk of intracerebral hemorrhage (ICH). While these data may incline physicians to discontinue statins after ICH, an increasing amount of preclinical and clinical evidence suggests that statins might have a beneficial effect on outcome and recovery in this context that goes beyond lipid lowering effects. Different etiologies of ICH and the related risk of recurrence should also be taken into account when deciding about statin use/avoidance in patients with high risk of ICH. The problem is compounded by paucity of data from randomized controlled trials and well-designed prospective observational studies. This review will discuss the existing evidence on potential interactions between statins and risk of ICH as well as outcomes in order to provide practical recommendations for clinical decision-making.

This article is part of the Topical Collection on Cardiovascular Disease and Stroke * M. Edip Gurol [email protected] Arne Lauer [email protected] Steven M. Greenberg [email protected] 1

Hemorrhagic Stroke Research Program, Massachusetts General Hospital - Harvard Medical School, Boston, MA 02114, USA

Keywords Statins . 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors . Intracerebral hemorrhage . Cerebral amyloid angiopathy . CAA . Brain bleed . Hypercholesterolemia . Low-density lipoprotein . Cholesterol . LDL . Deep hypertensive hemorrhage

Introduction Statins play a major role in secondary prevention of coronary artery disease and ischemic stroke and have been shown to reduce stroke risk by up to 31 % [1]. In this scenario, the main beneficial effect of statins appears to derive from the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme-A-reductase resulting in a decreased production of mevalonate and thereby cholesterol synthesis. A 10 % reduction of low-density lipoprotein (LDL) cholesterol by statins has been shown to decrease the risk of all stroke by 15.6 % [2]. Furthermore, pleiotropic or nonlipid lowering effects such as anti-inflammatory, anti-thrombotic, anti-oxidative, and neuroprotective consequences have been claimed to be associated with this type of drug and may prove beneficial in an even wider range of disease [3, 4]. While statins have been shown to reduce coronary death rate (18 %, heart protection study) and total fatal and nonfatal stroke (16 %, SPARCL trial), some indication of increased risk of intracerebral hemorrhage (ICH) has been found [5–7]. This raises concern in patients with ICH and may argue for a discontinuation of statins. The clinician now has to weigh potential but uncertain harm against the established benefits of statins in prevention from ischemic vascular events. On the other hand, an increasing amount of evidence suggests beneficial effects of statins in recovery from stroke-related brain injury, including ICH. In this review, we discuss the interactions between hemorrhage-prone cerebral

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small vessel diseases and statins that might result in a change in the risk of and outcome from ICH.

Search Strategy and Selection Criteria Studies were identified by performing a PUBMED search using the following term: (statins OR 3-Hydroxy-3methylglutaryl-coenzyme A reductase inhibitors OR HMGCoA OR hypocholesterolemia OR lipoprotein OR cholesterol) AND (intracerebral hemorrhage OR cerebral hemorrhage OR hemorrhagic stroke). Additional studies were chosen from the reference lists of the respective manuscripts. Publications were jointly evaluated by the authors for relevance. Clinical recommendations are based on the scientific data identified from this search and from our own research work at the Hemorrhagic Research Center of Massachusetts General Hospital, complemented by our clinical experience at our Stroke Prevention Clinic where we evaluate and treat a high volume of patients who are at high risk of ICH.

Indications for Statins and the Clinical Questions Discussed in This Review Recently, a Task Force on Practice Guidelines of American College of Cardiology/American Heart Association (ACC/ AHA) identified the following 4 major statin benefit groups for whom the atherosclerotic cardiovascular disease (ASCVD) risk reduction clearly outweighs the potential risk of adverse events [8]: (1) secondary prevention in patients with clinically symptomatic ASCVD, (2) primary prevention in individuals with primary elevations of LDL-C ≥190 mg/dL regardless of other risk factors, (3) primary prevention in 40–75-year-old individuals with diabetes who have LDL-C 70–189 mg/dL, and (4) primary prevention in 40–75-year-old individuals without diabetes and with estimated 10-year ASCVD risk ≥7.5 %, who have LDL-C 70–189 mg/dL. This Task Force suggested that clinicians engage in a discussion of the proposed therapy with every patient but especially for the fourth category above and also when the potential benefit can be less significant, i.e., for primary prevention of ASCVD in adults with 5–7.5 % estimated 10-year ASCVD risk. This discussion would include the benefit for ASCVD reduction, the potential for statinrelated adverse effects such as ICH, myopathy, drug–drug interactions, and also patient preferences as for any other treatment consideration. The current review will focus on helping decision making in patients with a known high risk for ICH and facilitate the patient–provider discussion by clarifying issues on the most feared potential side effect of this drug category. The specific

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clinical scenarios and questions that will be discussed in light of available scientific evidence are listed below: 1. Should statins be considered for patients who sustained ICH while not on statins? 2. Should the presence of incidentally found hemorrhageprone imaging markers (microbleeds, superficial siderosis) in patients without symptomatic ICH change the decision to use statins? 3. If a patient had ICH while on a statin, should this medication be discontinued upon admission and/or in long run?

The Etiology of Intracerebral Hemorrhage and Its Impact on Risk of Recurrence An understanding of the causes of brain bleeds in individual patients is very important to stratify risk/benefit ratio of statin use. Intracerebral hemorrhage accounts for 10 to 20 % of all strokes [9]. The overall incidence of ICH is estimated to be as high as 25 per 100,000 person years [10]. Furthermore, ICH is a particularly devastating disease. Case fatality at 1 month reaches up to 40 % and more than 50 % within 1 year [10, 11]. About 80 % of all ICH is related to small vessel disease (SVD) and should be distinguished from underlying gross pathologies (mainly malignancies, aneurysms, arteriovenous malformations, arteriovenous fistulas, and dural venous thrombosis) by means of parenchymal (magnetic resonance imaging, MRI) and vascular (computerized tomography angiography or MRA) brain imaging [12]. If any of these gross pathologies is diagnosed using appropriate workup, they need to be treated promptly by respective subspecialists using surgery, endovascular interventions, radiotherapy, and medications. The interaction between statin use and these specific ICH etiologies is mostly unknown; so, ICH related to these causes will not be the focus of this review. The most common underlying etiologies of nontraumatic ICH are SVD related to hypertension (HTN) and cerebral amyloid angiopathy (CAA). As a result of the increasing prevalence of SVD in the elderly, the incidence of ICH increases drastically with age (2.4 per 100,000 person years in patients 75 years of age) [13]. Hypertensive or Bdeep^ ICH (HTN-ICH) is related to hypertensive degenerative changes (arteriolosclerosis) near the bifurcation of small penetrating arteries [14]. Therefore, HTN-ICHs are typically located in deep parts of the brain (putamen, head of caudate, thalamus, pons, cerebellum) (Fig. 1a, b). Intracerebral hemorrhage in the cortico-subcortical regions of the brain, called Blobar^ ICH (Fig. 1c, d), constitutes about 33–37 % of all brain bleeds [15, 16]. In patients over 75 years

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Fig. 1 Examples of small vessel disease (SVD)-related hemorrhagic lesions on brain imaging. a CT and b MRI show a right thalamic intracerebral hemorrhage (ICH, big arrows) and deep microbleeds (small

arrows) typical of hypertensive SVD from a 55-year-old patient. c CT and d MRI show a lobar ICH (big arrows), lobar microbleeds (small white arrows), and superficial siderosis (black arrows) from a CAA patient

of age, lobar hemorrhage incidence is doubled as compared to deep located bleeds [13]. In most of these cases, CAA, characterized by the deposition of amyloid-β protein within the arterial media and adventitia, will lead to vessel fragility, rupture, and formation of macroscopic or microscopic hematomas [17, 18]. Based on the Boston Criteria, multiple hemorrhages (on CT or MRI) restricted to lobar, cortical, or corticosubcortical regions in patients aged 55 or older are diagnosed as Bprobable CAA^ (Fig. 1d), while a single hemorrhage in the same setting qualifies as Bpossible CAA,^ as long as there is no evidence for other etiology. These clinical-radiological criteria have shown high specificity for the probable CAA category in a pathological validation study [19] and addition of superficial siderosis (Fig. 1d) as another imaging marker has further increased their sensitivity [20]. Additionally, apolipoprotein E alleles ApoE2 and ApoE4 have been shown to be related to a higher lobar ICH risk as compared to the ApoE3/E3 (wild-type) genotype [21, 22]. An important difference between these 2 broad ICH etiologies is a much higher annual recurrence rate in CAA-related lobar ICH (8.9 %/year for CAA-lobar vs 2.1 %/year for HTNdeep) [23••, 24]. An accurate understanding of the cause of ICH and/or the predominant type of hemorrhage-prone SVD is thus an important step in assessing risk of ICH recurrence and thereby serves as a crucial step in decision making for statin use.

may increase the risk of rupture by weakening endothelial cells [25]. Fragile endothelium due to low serum cholesterol has been hypothesized to be an underlying mechanism [29]. It is reasonable to note, however, that no mechanism for vessel damage or loss of vessel structural integrity due to low cholesterol has been experimentally well established, and this remains a poorly understood relationship. Focusing on patients with very low LDL cholesterol levels, no association between low levels of LDL-cholesterol related to statins and risk of ICH could be found [30]. Similarly, LDL levels at baseline and during treatment were not related to hemorrhage risk in the SPARCL trial [7]. The main finding of the Stroke Prevention with Aggressive Reductions in Cholesterol Levels (SPARCL) trial was a reduced overall incidence of strokes and cardiovascular events [6]. As SPARCL study is the only randomized trial that tested the effect of statins on risk of recurrent strokes, its results deserve a more in-depth review. Investigators were allowed to randomize patients with a hemorrhagic stroke if they were thought to be at risk for ischemic stroke or coronary heart disease, making this subgroup a clinically relevant one. Ninety-three out of 4731 patients enrolled (∼2 %) had a hemorrhagic stroke as the qualifying event, equally randomized between high dose atorvastatin (active treatment) and placebo arms. The atorvastatin group had 55 ICH, whereas the placebo group had 33 hemorrhagic strokes in follow-up (hazard ratio 1.66 (95 % confidence interval 1.08–2.55, p=0.02)). The incidence of fatal hemorrhagic stroke was similar between the groups (17 in the atorvastatin and 18 in the placebo arm). In post hoc Cox-regression models, the benefit in ischemic stroke prevention was found to be hampered by an increase in incident ICH independent from LDL levels, for patients enrolled after an initial hemorrhagic stroke [7]. Another interesting post hoc finding was the increased risk of ICH in patients with baseline SVD-related lacunar ischemic strokes who received statins (20/708 vs 4/701 in placebo arm, HR 4.99, 95 % confidence interval 1.71 to 14.61) although there was a counterbalancing trend toward benefit from ischemic

Potential Effects of Statins on Risk of Intracerebral Hemorrhage The underlying mechanisms by which statins may increase hemorrhage risk are unclear. A protective effect (e.g., reduced risk of ICH) from hypercholesterolemia has been reported in trials spanning over three decades [25–28]. Ever since this inverse relationship between blood lipid levels and ICH risks has been described, it has been hypothesized that cholesterol is important for vascular wall integrity. Low LDL-lipid levels

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stroke reduction (11.2 vs 14.6 %; HR 0.76 [0.57, 1.02]). In general, secondary outcomes in post hoc subgroup analyses have a high risk of false-positive findings, but all of the results above suggest an association between statin use and increased risk of ICH in patients with severe SVD, whether manifested as baseline small vessel ischemic stroke or ICH. A more recent retrospective observational cohort study of ischemic stroke patients did not reveal an increased risk of ICH among statin users [31]. A meta-analysis of 31 randomized trials of statins that reported ICH incidence could not establish an association between statins and ICH, but confirmed a reduction in all-stroke and allcause mortality [32]. The results of SPARCL study did not show a significant difference in incident ICH in patients enrolled with ischemic strokes or TIAs. Therefore, available clinical evidence suggests that statin use is not associated with increased risk of incident ICH in a general patient population and in patients with a history of ischemic stroke. As a result of these consistent findings, in individuals who did not have a hemorrhagic stroke, statins can be initiated for the major and moderate benefit groups defined above without need for brain imaging for further risk stratification unless there is a clear concern of hemorrhagic cerebral pathology. However, for patients with a history of ICH, statin use might cause increased risk of recurrent cerebral hemorrhage based on the randomized, placebo-controlled SPAR CL study and the other analyses discussed below. While in ischemic stroke, most underlying causes (e.g., large artery atherosclerotic disease) seem to benefit from statin treatment [33], this may not be true in hemorrhagic stroke. The two most common subtypes of ICH, deep HTN-ICH and lobar CAA-ICH, may entail different statin-associated bleeding risks. In an attempt to further characterize the associations of statin use and hemorrhage risk depending on the underlying cause of ICH, Woo et al. found a signal for statins to increase the risk for lobar ICH among ApoE4/E4 and ApoE2/E4 genotypes, while the association of hypercholesterolemia with a decreased risk of deep ICH appeared not to be attenuated by the use of statins [34]. This gene-by-drug effect needs further evaluation, but the well-known association between these ApoE polymorphisms and CAA further supports the view that statins might increase the risk of CAA-related lobar ICH. Using a Markov decision model, Westover et al. showed that some comorbidities and underlying causes of ICH could determine the balance of risk versus benefit of statin therapy after ICH [34]. Taking into account the two major etiologic types of ICH (deep HTN-ICH and lobar CAA-ICH), as well as the risks for vascular events (ischemic stroke, myocardial infarction), the effect of statin use on life expectancy, measured as quality-adjusted life-years (QALY), was evaluated.

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To illustrate two examples of a wide continuum, statin continuation is predicted to benefit a patient with HTN-ICH and past MI or ischemic stroke, while the model suggests avoidance of statins in a patient with lobar ICH and prior MI (QALY without statins 6.8, with statins 4.6) [35]. This divergence is mainly based on the much higher annual recurrence rates in lobar ICH [24, 21] though the more recent risk estimates for rebleeding after a CAA-related lobar ICH is lower [23••]. It should also be remembered that the increased risk of ICH associated with statin therapy (HR 1.68) was taken from one single trial that employed a high-dose statin strategy [6]. The approach to take underlying ICH pathology into account for decision making is also supported by some clinical evidence suggesting that statins are associated with increased number of lobar cerebral microbleeds (MBs), an established marker of CAA severity but not with deep MBs (shown in Fig. 1b, d, respectively) [36]. Analysis of 1965 subjects of the Framingham Heart Study revealed statins to be a predictor of lobar as well as deep cerebral MBs, while low cholesterol levels were associated only with lobar MBs [37]. Similarly, in previous investigations, very low levels of LDL have been described to be associated with cortical or lobar MBs [38]. In addition, admission hematoma volumes were increased in statintreated patients with lobar ICH, while this relationship was not found in patients with deep ICH [39]. All of these observational data suggest a link between statins and risk of CAArelated lobar ICH. The data from the randomized SPARCL study and the other evidence extensively reviewed in this section help us answer the first two questions that we have defined above. For patients who sustained ICH while not on statins, we recommend against initiation of statins unless a clear indication exists (symptomatic atherosclerotic coronary, cerebral or peripheral arterial disease). If such symptomatic atherosclerotic vascular disease is present, there is insufficient data to recommend restrictions on use of statin agents even in patients who sustained an ICH per the 2010 AHA/ASA Guidelines for the Management of Spontaneous Intracerebral Hemorrhage [40]. The risk-benefit ratio is probably different for CAA patients who have a particularly high risk of ICH, especially if they have less strong vascular indications for statins. Despite the lack of randomized clinical trial data, a common sense approach would be to consider not using statins in patients with history of CAA-related lobar ICH and mild-tomoderately elevated cholesterol levels without symptomatic atherosclerotic disease. In patients who had numerous lobar MBs without symptomatic ICH, the annual risk of ICH was found to be a nontrivial 5 per 100 patient-years but still lower than the risk of recurrence in post-lobar ICH patients (8.9 %) in a recent study [23••]. Furthermore, patients with isolated lobar MBs showed typical imaging (leukoaraiosis, MB counts) and laboratory (APOE genotype) characteristics of CAA in this study, suggesting the presence of rather

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significant vascular amyloid burden in these clinically asymptomatic patients [23••]. Despite the presence of observational data suggesting a particular link between statin-related ICH and imaging/genetic markers of CAA, there is not enough evidence at this time to limit statin use when otherwise indicated in patients with lobar MBs who have not had symptomatic ICH. Such increased risk could reasonably be brought up during the discussion with the patient if markers of hemorrhage-prone SVD were found on prior brain imaging (lobar MBs, superficial siderosis). There also is no adequate evidence to justify routine MRI or genetic screening to stratify ICH risk in patients without past history of hemorrhagic stroke. The risk-benefit ratio in patients who already took statins before their hemorrhagic stroke will be presented at the end of the next section, after a discussion of the association between statins and recovery.

Potential Effects of Statins on Outcomes After Intracerebral Hemorrhage Despite the presence of some contradictory findings on the association between statins, cholesterol levels and ICH outcomes, emerging data appear to support no harm and possibly better prognosis in patients who were on statins before their hemorrhagic stroke. A large prospective population-based study reported an increased risk of death due to ICH in patients with low LDL-cholesterol levels [41]. It seems logical that statins may mediate such an effect. However, increased mortality after ICH in patients with very low blood lipid levels may more likely reflect overall nutritional status or other underlying pathologies (such as alcoholism, hepatic cirrhosis, or cancer). Mechanisms related to statin treatment that may worsen outcome in ICH or increase the recurrence risk are related to hemostasis. Statins have been shown to inhibit clotting propagation and coagulation factors (tissue factor, factor V, and factor XIII), to enhance fibrinolysis (by inhibition of plasminogen activator inhibitor-1) and to inhibit platelet aggregation and adhesion [42]. A large randomized trial, in which treatment with rosuvastatin reduced the incidence of symptomatic venous thromboembolism in apparently healthy individuals over a median 1.9-year follow-up, suggests that these proposed hypocoagulable effects can have clinical consequences [43]. In a retrospective study, statin use was associated with increased baseline hematoma volumes and hematoma growth [39]. In patients suffering ischemic stroke, a statin dose-dependent increase in cerebral hemorrhage risk has been observed after intravenous thrombolysis [44]. Although the underlying pathology differs from spontaneous ICH, a dose-dependent effect may exist. Yet, an impact on mortality or worsened functional outcome could not be detected in these and other studies [43, 44, 39, 28]. Another study in

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a cohort of 399 patients found even smaller baseline hematoma volumes in prior statin users [45]. A meta-analysis of preICH statin use in 12 studies (6961 patients, 1652 statin patients) concluded that statins do not increase short-term mortality, unfavorable functional outcome, or ICH hematoma volume, based on 11, six, and four studies, respectively [46]. Aside from the lipid lowering effects of statins, which are believed to be an important factor associated with decreased risk of ischemic stroke and myocardial infarction, statins have shown several nonlipid lowering or pleiotropic effects that may be related to better ICH outcomes. A variety of preclinical studies have shown improved functional outcome, reduced peri-hematomal edema, preserved blood brain barrier, promoted synaptogenesis, and decreased inflammatory reaction and perihematomal cell death in experimental ICH in rodents [47–52]. One should keep in mind that in most of these studies, very high dosages of statins are used—that is, dosages that go beyond current recommendations, if translated into the human setting. Nevertheless, several clinical studies support these findings. In a retrospective cohort study of 125 patients suffering from ICH, an association between prior statin use and decreased mortality could be shown [53]. Moreover, pretreatment with statins has been associated with decreased peri-hematomal edema as determined on the initial head CT-scan [54]. A somewhat larger study (296 patients) also confirmed the favorable effect of statins despite an association of low cholesterol levels with worsened outcome [55]. Statin treatment before the hemorrhage has been associated not only with reduced mortality, but also with reduced neurological disability (as determined by the baseline NIHSS score) and with lower rates of systemic complications [56]. While other investigators could not confirm these findings [57], a meta-analysis of 2421 cases revealed prior use of statins to be associated with decreased mortality (OR 0.55, 95 % CI 0.42–0.72) and favorable outcome after ICH (OR 1.91, 95 % CI 1.38–2.65) [58]. This appeared to be a class effect rather than a compound-specific effect (simvastatin vs atorvastatin vs all others were tested). In a retrospective analysis of multicenter data, focus was laid on statin use during hospitalization. In 6.8 % of ICH patients, statins were continued after the index event and were associated with favorable functional outcome and lower mortality after 3 months and 1 year [58, 59]. However, neither statin dose nor duration of treatment was analyzed. The risks of statin discontinuation have been discussed extensively in the literature [60]. Withdrawal of statins in the acute phase of a cardiovascular event may increase cardiac risk even beyond what one would expect in patients without statins [61]. Similarly, discontinuation of statins within 24 h after an ischemic stroke in a randomized setting has been shown to increase infarct size, the rates of early neurologic

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deterioration, and to worsen functional outcome after 3 months [62]. In a retrospective cohort study of 3481 patients with ICH admitted to one of 20 hospitals in a large integrated health care delivery system over a 10-year period, continued statin use as an inpatient was associated with improved outcomes after ICH, while the cessation of statin use was associated with worsened outcomes after ICH [63]. Analysis of 2466 consecutive patients with ICH from the Registry of the Canadian Stroke Network enrolled between 2003 and 2008 showed that discontinuation of statins was related to poor outcome even after adjustment for baseline stroke severity, but this association was no longer significant after excluding patients treated palliatively [64••]. Whether discontinuation of statins after an ICH truly worsens outcomes is not well understood at that time, but there are data suggesting that statin continuation does not harm and they might even be beneficial for early recovery in patients who were using them before their ICH. In such patients who were on statins before their ICH, we do not recommend immediate discontinuation of these medications within the first year after the acute event. Current ICH management guidelines do not recommend modifying statin treatment in the long run either [40], but it is good practice to review the indication for lipid lowering therapy in these patients to make sure that their condition falls within the 4 major statin benefit groups determined by

No previous ICH

No known high risk for ICH

Use statins as indicated in ACC/AHA Guidelines for

Evidence of hemorrhage prone cerebral small vessel disease:

ACC/AHA [8]. Discontinuation of statins in the long term after an ICH can be discussed in patients who have a high risk of ICH recurrence (such as CAA-related lobar ICH) if the expected benefit from statins is not significant per ACC/AHA guidelines [8, 35].

Conclusions While an increasing number of investigations do not support an increased ICH risk in a general population with or without atherosclerotic vascular disease, patients with history of ICH and in particular cerebral amyloid angiopathy appear to be at increased risk of brain hemorrhages when exposed to statins. In statin naïve patients who had ICH, it is reasonable to not initiate statins unless clearly indicated for secondary prevention of ischemic events. In patients who were on statins at the time of an ICH for a valid indication, current data suggest that it is reasonable to continue their use in the acute phase and beyond. Whenever there is evidence of hemorrhage-prone cerebral small vessel disease, it is good practice to discuss the issue of potentially increased ICH risk with the patient before starting statins (Fig. 2). Current guidelines do not recommend withholding statins for patients who fall in the major statin benefit groups defined by ACC/ AHA and summarized in this paper.

ICH while on Statin

Indication based on ACC/AHA Guidelines

Statin for other reasons

- lobar microbleeds - superficial siderosis

1) secondary prevention: - clinically symptomatic ASCVD

Continue statin in acute phase and beyond

Do not discontinue statin in acute phase

After 6-12 months, can consider stopping statin in patients with high ICH and low ischemic risk

Consider stopping statin after first 612 months

2) primary prevention: - LDL-C ≥190 mg/dL 3) primary prevention: - over 40y and diabetes and LDL-C 70-189 mg/dL 4) primary prevention: -10-year ASCVD risk ≥7.5% and LDL-C 70-189 mg/dL

ICH not on Statin

Discuss potentially increased ICH risk but OK to use statins according to ACC/AHA guidelines

Do not initiate statins unless they become clearly needed per the first 3 indications described in ACC/AHA guidelines

Benefits (reduced risk of ischemic events) and potential risks (ICH) of statin use should be explicitly discussed with all patients who might have a higher hemorrhagic risk

Fig. 2 Our current approach to statin use in stroke patients. Abbreviations: ICH intracerebral hemorrhage, ACC/AHA The American College of Cardiology (ACC)/American Heart Association (AHA), ASCVD atherosclerotic cardiovascular disease, LDL-C low-density

lipoprotein cholesterol, ASCVD risk calculators can be found online at https://my.americanheart.org/professional/StatementsGuidelines/ Prevention-Guidelines_UCM_457698_SubHomePage.jsp

Curr Atheroscler Rep (2015) 17:46 Acknowledgments Study Support: This work was made possible by the following NIH grants: K23 NS083711, R01 NS070834, R01 AG026484. Compliance with Ethic Guidelines Conflict of Interest A Lauer, SM Greenberg, and ME Gurol all declare no conflicts of interest. Human and Animal Rights and Informed Consent All cited studies by M. Edip Gurol and Steven M. Greenberg involving human subjects were performed after approval by the appropriate institutional review boards. When required, written informed consent was obtained from all participants.

References Papers of particular interest, published recently, have been highlighted as: •• Of major importance 1.

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Blauw GJ, Lagaay AM, Smelt AH, Westendorp RG. Stroke, statins, and cholesterol. A meta-analysis of randomized, placebo-controlled, double-blind trials with HMG-CoA reductase inhibitors. Stroke J Cereb Circ. 1997;28:946–50. Amarenco P, Labreuche J, Lavallée P, Touboul P-J. Statins in stroke prevention and carotid atherosclerosis: systematic review and up-to-date meta-analysis. Stroke J Cereb Circ. 2004;35:2902–9. Mihos CG, Pineda AM, Santana O. Cardiovascular effects of statins, beyond lipid-lowering properties. Pharmacol Res Off J Ital Pharmacol Soc. 2014;88:12–9. Willey JZ, Elkind MSV. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors in the treatment of central nervous system diseases. Arch Neurol. 2010;67:1062–7. 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. Amarenco P, Bogousslavsky J, Callahan A, Goldstein LB, Hennerici M, Rudolph AE, et al. High-dose atorvastatin after stroke or transient ischemic attack. N Engl J Med. 2006;355:549–59. Goldstein LB, Amarenco P, Szarek M, Callahan A, Hennerici M, Sillesen H, et al. Hemorrhagic stroke in the stroke prevention by aggressive reduction in cholesterol levels study. Neurology. 2008;70:2364–70. Stone NJ, Robinson JG, Lichtenstein AH, Bairey M, Noel C, Blum CB, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American college of cardiology/American heart association task force on practice guidelines. J Am Coll Cardiol. 2014;63:2889–934. Feigin VL, Lawes CMM, Bennett DA, Barker-Collo SL, Parag V. Worldwide stroke incidence and early case fatality reported in 56 population-based studies: a systematic review. Lancet Neurol. 2009;8:355–69. van Asch CJJ, Luitse MJA, Rinkel GJE, van der Tweel I, Algra A, Klijn CJM. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol. 2010;9:167–76.

Page 7 of 8 46 11.

Poon MTC, Fonville AF, Al-Shahi Salman R. Long-term prognosis after intracerebral haemorrhage: systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2014;85:660–7. 12. Steiner T, Al-Shahi Salman R, Beer R, Christensen H, Cordonnier C, Csiba L, et al. European stroke organisation (ESO) guidelines for the management of spontaneous intracerebral hemorrhage. Int J Stroke Off J Int Stroke Soc. 2014;9:840–55. 13. Béjot Y, Cordonnier C, Durier J, Aboa-Eboulé C, Rouaud O, Giroud M. Intracerebral haemorrhage profiles are changing: results from the Dijon population-based study. Brain. 2013;136:658–64. 14. Qureshi AI, Mendelow AD, Hanley DF. Intracerebral haemorrhage. Lancet. 2009;373:1632–44. 15. Weimar C, Benemann J, Terborg C, Walter U, Weber R, Diener HC. Recurrent stroke after lobar and deep intracerebral hemorrhage: a hospital-based cohort study. Cerebrovasc Dis (Basel, Switz). 2011;32:283–8. 16. Sacco S, Marini C, Toni D, Olivieri L, Carolei A. Incidence and 10year survival of intracerebral hemorrhage in a population-based registry. Stroke. 2009;40:394–9. 17. Pezzini A, Padovani A. Cerebral amyloid angiopathy-related hemorrhages. Neurol Sci. 2008;29:260–3. 18. Gurol ME, Dierksen G, Betensky R, Gidicsin C, Halpin A, Becker A, et al. Predicting sites of new hemorrhage with amyloid imaging in cerebral amyloid angiopathy. Neurology. 2012;79:320–6. 19. Knudsen KA, Rosand J, Karluk D, Greenberg SM. Clinical diagnosis of cerebral amyloid angiopathy: validation of the Boston criteria. Neurology. 2001;56:537–9. 20. Linn J, Halpin A, Demaerel P, Ruhland J, Giese AD, Dichgans M, et al. Prevalence of superficial siderosis in patients with cerebral amyloid angiopathy. Neurology. 2010;74:1346–50. 21. O’Donnell HC, Rosand J, Knudsen KA, Furie KL, Segal AZ, Chiu RI, et al. Apolipoprotein E genotype and the risk of recurrent lobar intracerebral hemorrhage. N Engl J Med. 2000;342:240–5. 22. Zhang R, Wang X, Tang Z, Liu J, Yang S, Zhang Y, et al. Apolipoprotein E gene polymorphism and the risk of intracerebral hemorrhage: a meta-analysis of epidemiologic studies. Lipids Health Dis. 2014;13:47. 23.•• van Etten ES, Auriel E, Haley KE, Ayres AM, Vashkevich A, Schwab KM, et al. Incidence of symptomatic hemorrhage in patients with lobar microbleeds. Stroke. 2014;45:2280–5. A large follow-up cohort study comparing the risk of ICH in subjects with incidentally found lobar microbleeds to patients with classical presentation of CAA-related lobar ICH. No significant difference between baseline imaging/genetic characteristics and no significant difference in the risk of ICH on follow up was found, suggesting that patients with multiple lobar microbleeds without other underlying etiology might have relatively severe CAA. 24. Bailey RD, Hart RG, Benavente O, Pearce LA. Recurrent brain hemorrhage is more frequent than ischemic stroke after intracranial hemorrhage. Neurology. 2001;56:773–7. 25. Iso H, Jacobs DR, 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;320:904–10. 26. Leppälä 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;30:2535–40. 27. Ebrahim S, Sung J, Song Y-M, Ferrer RL, Lawlor DA, Davey Smith G. Serum cholesterol, haemorrhagic stroke, ischaemic stroke, and myocardial infarction: Korean national health system prospective cohort study. BMJ (Clin Res ed). 2006;333:22. 28. Mustanoja S, Strbian D, Putaala J, Meretoja A, Curtze S, Haapaniemi E, et al. Association of prestroke statin use and lipid levels with outcome of intracerebral hemorrhage. Stroke. 2013;44: 2330–2.

46 29.

30.

31.

32.

33.

34.

35.

36.

37.

38.

39.

40.

41.

42. 43.

44.

45.

46.

47.

Curr Atheroscler Rep (2015) 17:46

Page 8 of 8 Konishi M, Iso H, Komachi Y, Iida M, Shimamoto T, Jacobs DR, et al. Associations of serum total cholesterol, different types of stroke, and stenosis distribution of cerebral arteries. Akita Pathol Study Stroke J Cereb Circ. 1993;24:954–64. Lee J-G, Koh SJ, Yoo SY, Yu JR, Lee SA, Koh G, et al. Characteristics of subjects with very low serum low-density lipoprotein cholesterol and the risk for intracerebral hemorrhage. Korean J Intern Med. 2012;27:317–26. 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. McKinney JS, Kostis WJ. Statin therapy and the risk of intracerebral hemorrhage: a meta-analysis of 31 randomized controlled trials. Stroke. 2012;43:2149–56. Amarenco P, Benavente O, Goldstein LB, Callahan A, Sillesen H, Hennerici MG, et al. Results of the stroke prevention by aggressive reduction in cholesterol levels (SPARCL) trial by stroke subtypes. Stroke. 2009;40:1405–9. Woo D, Deka R, Falcone GJ, Flaherty ML, Haverbusch M, Martini SR, et al. Apolipoprotein E, statins, and risk of intracerebral hemorrhage. Stroke. 2013;44:3013–7. Westover MB, Bianchi MT, Eckman MH, Greenberg SM. Statin use following intracerebral hemorrhage: a decision analysis. Arch Neurol. 2011;68:573–9. Haussen DC, Henninger N, Kumar S, Selim M. Statin use and microbleeds in patients with spontaneous intracerebral hemorrhage. Stroke. 2012;43:2677–81. Romero JR, Preis SR, Beiser A, DeCarli C, Viswanathan A, Martinez-Ramirez S, et al. Risk factors, stroke prevention treatments, and prevalence of cerebral microbleeds in the Framingham heart study. Stroke. 2014;45:1492–4. Lee S-H, Bae H-J, Yoon B-W, Kim H, Kim D-E, Roh J-K. Low concentration of serum total cholesterol is associated with multifocal signal loss lesions on gradient-echo magnetic resonance imaging: analysis of risk factors for multifocal signal loss lesions. Stroke. 2002;33:2845–9. Ricard G, Garant M-P, Carrier N, Leblanc N, Boulanger J-M. Statins may increase intracerebral hemorrhage volume. Can J Neurol Sci. 2010;37:791–6. Morgenstern LB, Hemphill JC, Anderson C, Becker K, Broderick JP, Connolly ES, et al. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American heart association/American stroke association. Stroke. 2010;41:2108–29. Noda H, Iso H, Irie F, Sairenchi T, Ohtaka E, Doi M, et al. Lowdensity lipoprotein cholesterol concentrations and death due to intraparenchymal hemorrhage: the Ibaraki prefectural health study. Circulation. 2009;119:2136–45. Violi F, Calvieri C, Ferro D, Pignatelli P. Statins as antithrombotic drugs. Circulation. 2013;127:251–7. Glynn RJ, Danielson E, Fonseca FAH, Genest J, Gotto AM, Kastelein JJP, et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med. 2009;360: 1851–61. Scheitz JF, Seiffge DJ, Tütüncü S, Gensicke H, Audebert HJ, Bonati LH, et al. Dose-related effects of statins on symptomatic intracerebral hemorrhage and outcome after thrombolysis for ischemic stroke. Stroke. 2014;45:509–14. Eichel R, Khoury ST, Ben-Hur T, Keidar M, Paniri R, Leker RR. Prior use of statins and outcome in patients with intracerebral haemorrhage. Eur J Neurol Off J Eur Fed Neurol Soc. 2010;17:78–83. Lei C, Wu B, Liu M, Chen Y. Association between statin use and intracerebral hemorrhage: a systematic review and meta-analysis. Eur J Neurol Off J Eur Fed Neurol Soc. 2014;21:192–8. Seyfried D, Han Y, Lu D, Chen J, Bydon A, Chopp M. Improvement in neurological outcome after administration of

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60. 61.

62.

63.

64.••

atorvastatin following experimental intracerebral hemorrhage in rats. J Neurosurg. 2004;101:104–7. Chun H-J, Kim DW, Yi H-J, Kim YS, Kim EH, Hwang SJ, et al. Effects of statin and deferoxamine administration on neurological outcomes in a rat model of intracerebral hemorrhage. Neurol Sci Off J Ital Neurol Soc Ital Soc Clin Neurophysiology. 2012;33:289–96. Yang D, Knight RA, Han Y, Karki K, Zhang J, Ding C, et al. Vascular recovery promoted by atorvastatin and simvastatin after experimental intracerebral hemorrhage: magnetic resonance imaging and histological study. J Neurosurg. 2011;114:1135–42. Yang D, Knight RA, Han Y, Karki K, Zhang J, Chopp M, et al. Statins protect the blood brain barrier acutely after experimental intracerebral hemorrhage. J Behav Brain Sci. 2013;3:100–6. Yang D, Zhang J, Han Y, James E, Chopp M, Seyfried DM. Acute statin treatment improves recovery after experimental intracerebral hemorrhage. World J Neurosci. 2013;3:69–75. Indraswari F, Wang H, Lei B, James ML, Kernagis D, Warner DS, et al. Statins improve outcome in murine models of intracranial hemorrhage and traumatic brain injury: a translational approach. J Neurotrauma. 2012;29:1388–400. Naval NS, Abdelhak TA, Zeballos P, Urrunaga N, Mirski MA, Carhuapoma JR. Prior statin use reduces mortality in intracerebral hemorrhage. Neurocrit Care. 2008;8:6–12. 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;8:13–8. Gomis M, Ois A, Rodríguez-Campello A, Cuadrado-Godia E, Jiménez-Conde J, Subirana I, et al. Outcome of intracerebral haemorrhage patients pre-treated with statins. Eur J Neurol Off J Eur Fed Neurol Soc. 2010;17:443–8. Leker RR, Khoury ST, Rafaeli G, Shwartz R, Eichel R, Tanne D. Prior use of statins improves outcome in patients with intracerebral hemorrhage: prospective data from the national acute stroke Israeli surveys (NASIS). Stroke. 2009;40:2581–4. FitzMaurice E, Wendell L, Snider R, Schwab K, Chanderraj R, Kinnecom C, et al. Effect of statins on intracerebral hemorrhage outcome and recurrence. Stroke. 2008;39:2151–4. Biffi A, Devan WJ, Anderson CD, Ayres AM, Schwab K, Cortellini L, et al. Statin use and outcome after intracerebral hemorrhage: case–control study and meta-analysis. Neurology. 2011;76:1581–8. Pan Y-S, Jing J, Wang Y-L, Zhao X-Q, Song B, Wang W-J, et al. Use of statin during hospitalization improves the outcome after intracerebral hemorrhage. CNS Neurosci Ther. 2014;20:548–55. Cubeddu LX, Seamon MJ. Statin withdrawal: clinical implications and molecular mechanisms. Pharmacotherapy. 2006;26:1288–96. Heeschen C, Hamm CW, Laufs U, Snapinn S, Böhm M, White HD. Withdrawal of statins increases event rates in patients with acute coronary syndromes. Circulation. 2002;105:1446–52. Blanco M, Nombela F, Castellanos M, Rodriguez-Yáñez M, García-Gil M, Leira R, et al. Statin treatment withdrawal in ischemic stroke: a controlled randomized study. Neurology. 2007;69: 904–10. Flint AC, Conell C, Rao VA, Klingman JG, Sidney S, Johnston SC, et al. Effect of statin use during hospitalization for intracerebral hemorrhage on mortality and discharge disposition. JAMA Neurol. 2014;71:1364–71. Dowlatshahi D, Demchuk AM, Fang J, Kapral MK, Sharma M, Smith EE. Association of statins and statin discontinuation with poor outcome and survival after intracerebral hemorrhage. Stroke. 2012;43:1518–23. One of the stronger articles on the association between pre-ICH statin use and outcomes. Statin discontinuation was still associated with poor outcomes after adjusting for stroke severity but this relationship was no longer significant after excluding patients treated palliatively. A well-designed study that also highlights one of the biggest difficulties of ICH outcomes research.