Statin for patients with aneurysmal subarachnoid hemorrhage (aSAH): A systematic review and meta-analysis

Abstract

Introduction

Aneurysmal subarachnoid haemorrhage (aSAH) is blood in the subarachnoid space that occurred spontaneously due to aneurysmal rupture [1].The peak age for aSAH is between 55 and 60 years [2].It causes significant morbidity and mortality, with 10– 15% of patient dying before reaching medical care [1, 3]. Patients surviving from the initial haemorrhage have a high risk for major morbidities and disabilities resulting from rebreeding, vasospasm, and delayed neurological ischemic deficits (DIND).

The mechanism of cerebral vasospasm is not fully understood. The peak incidence of vasospasm is within 4– 10 days of initial bleeding (the onset of aSAH) [4], and resolves spontaneously after 21 days [5].The ischemic insults during the early and delay phases are responsible for increasing inflammatory molecules and free radical species in brain injury [6]. To date, there is no effective prophylactic intervention for vasospasm. Hyper– dynamic therapy– triple H therapy is not indicated before vasospasm has been diagnosed [7]. Statin is widely used as a cholesterol– reducing agent by inhibiting the enzyme (3– hydroxyl– 3– methylglutaryl coenzyme, HMG– CoA reductase) and blocking the formation of mevalonate, an important precursor for both cholesterol and other non– sterol products. Recently, it was investigated for its ability to work as an anti– inflammatory, anti– oxidant, and anti– platelet. Hence, it might play a role as a neuroprotective in aSAH. Furthermore, because it activates the endothelial nitric oxide synthesis (eNOS) pathways, it has the potential to improve cerebral blood flow during vasospasm events in aSAH[6, 8]. In this study, a systematic review and meta– analysis of randomized controlled studies (RCTs) was performed to evaluate the efficacy and safety of statins for treating aSAH.

Methods

Study protocol

According to the PRISMA– Protocol statement in 2015[9], a prospective systematic review registration, CRD42022296336, was published in PROSPERO.

Criteria for considering studies for this review:

The randomized controlled studies in which patients with aneurysmal subarachnoid haemorrhage (aSAH) were randomized into statin groups and control or placebo treatment groups were eligible for this systematic review. In the case of multiple reports for the same datasets, the most complete publication is chosen for the analysis. Studies which don’t provide sufficient data reliable for pooling in the meta– analysis, theses and conference publications were excluded.

Types of interventions

Treatment with statins (i.e., simvastatin, pravastatin, pitavastatin, atorvastatin) versus control or placebo treatment, after diagnosis of aSAH

Types of outcome measures

The primary outcome measures were the incidence of angiographic or trans– cranial Doppler (TCD) vasospasm. Angiographic vasospasm is defined as a reduction of the arterial diameter compared to the baseline digital subtraction angiography (DSA), and is classified: 1– 25% decrease as none to mild, 25– 50% decrease as moderate, and > 50% decrease as severe vasospasm. TCD vasospasm is defined as a mean flow velocity (MFV) of the middle cerebral artery (MCA) of at least > 120 cm/sec or a peaked systolic flow velocity (PSV) of at least > 200 cm/sec, whereas MCA vasospasm is classified as mild MFV of MCA 120– 200 cm/sec, moderate 150– 200 cm/sec, and severe > 200 cm/sec, and the Lindegaard ratio is > 3 [10].

The secondary outcomes are delayed neurological ischemic deficits (DIND), delayed cerebral ischemia (DCI), functional outcome, mortality, and adverse effects of statins.

A DIND is defined as a 2-point drop in Glasgow coma score (GCS) or an unexplained new focal neurological deficit lasting 2 hours. DCI is defined as vasospasm– related infarction, as the development of a new lesion consistent with infarction on CT or MRI in vascular territory of angiographic or TCD vasospasm [11, 12]. Poor functional outcome is defined as ≥ 3 on the modified Rankin score (mRS) [13], or < 4 on Glasgow outcome score (GOS) [14].

Search methods for the identification of studies

On Dec 31, 2021, an electronic search was conducted in PubMed, Medline, Web of Science, Scopus, and Cochrane Library using a complex of key words and Medical Subheadings (“statins”, “Statin”, “Subarachnoid hemorrhage” and “Subarachnoid haemorrhage”). The reference lists of the included studies were manually searched.

Data collection and analysis

Records were exported from different databases in “ris” format to reference management software (EndNote 8). The preferences for finding duplicates was edited to compare references according to title and year, ignoring spacing and punctuation. Exporting the records into an Excel Microsoft Office 2013 spreadsheet was processed for the screening process. A score system of 0, and 1 was used as 1 for inclusion and 0 for exclusion with a reason. The system of screening was initially for screening title and abstract to exclude irrelevant records; an unclear title without an available abstract was included with an unclear reason for full– text reviewing. A second screening was for eligibility of inclusion criteria after reviewing the full– text of the record.

Assessment of the risk of bias in included studies

A tool, developed in the Cochrane Handbook of Systematic Reviews of interventions 5.10 (updated March 2011), was used to assess the quality of the included studies. Based on the following domains (sequence generation, selection bias; allocation sequence concealment, selection bias; blinding of participants and personnel; performance bias; blinding of outcome assessment; detection bias; selective outcome reporting, reporting bias, and other potential sources of bias), the judgement is categorized as “Low risk,” “High risk” or “Unclear risk” of bias. I used the quality assessment table provided in the same book (part 2, Chapter 8.5) [15] 

Treatment effect measurements

For dichotomous outcomes, the Mantel– Haenszel method (MH) odds ratio (OR) was used to present results with a 95% confidence interval (CI). Pooling data with the fixed– effect model and random– effect model in the case of statistical heterogeneity [16].

Unit of analysis:

The unit of analysis was the participants with aSAH in individually randomized trials.

Dealing with missing data

If contacting the corresponding author fails, the estimated mean is calculated using the median, first and third of sample size using Luo et al. 2018 [17], and standard deviation using Shi et al. 2020 [18].

Assessment of heterogeneity

Heterogeneity was assessed by the visual inspection of the forest plots and measured by I² and Chi– square tests. The Chi– square test was used to test the existence of significant heterogeneity, while I– square quantified this heterogeneity if present. I² test was interpreted according to recommendations in the Cochrane Handbook of systematic reviews and meta– analysis (0% to 40%: might not be important; 30% to 60%: may represent moderate heterogeneity; 50% to 90%: may represent substantial heterogeneity; and 75% to 100%: considerable heterogeneity). The Chi– square P<0.1 was set as a level of significant heterogeneity [16].

Data synthesis

Dichotomous data was pooled as a Mantel– Haenszel method (MH) odds ratio (OR) in fixed and random– effect models. Review Manager 5.4 was used to run the meta– analysis. Data outcomes from the included studies were sub– grouped according to different statin drugs, dose, duration of the study, and time to start statin [19].

Results

Results of the search

The electronic search identified 1346 records from databases. Then, after removing duplications and ineligible records, it yielded 655 unique records for the screening process. The manual search did not identify any additional records. Nine RCTs met the inclusion criteria of this systematic review and meta– analysis, including 1464 patients (721 patients in the statin group and 743 patients in the control group) [20– 28] (Figure 1). A summary of the included studies is shown in Table 1.

The mean age of patients is 56.1 years, and the female gender represents about 60.75% of total patients. 50% of aneurysms were anterior circulation aneurysms (ACA) arise from the internal carotid artery (ICA) and its branches, while 8% were posterior circulation aneurysms and 42% was others (including anterior and posterior communicating and anterior choroidal arteries). Hunt & Hess (H & H) grading scale was used in three studies, including 447 patients (223 patients in the statin group and 224 patients in the control group) [22, 27, 28]. 81% of patients in these studies within grade 1 to 3. World Federation of Neurosurgical Societies (WFNS) scale was used in five studies, including 978 patients (479 patients in the statin group and 499 patients in the control group)[21, 23– 26]. 76.67% of patients within grade 1 to 3. Five studies reported Fisher classification of SAH on CT, including 1068 patients (523 patients in the statin group and 545 in the control group)[20, 21, 24, 25, 27]. 84.3% of SAH was within grades 3 to 4. One study reported modified Fisher classification, including 25 patients (13 patients in the statin group and 12 patients in the control group) [26].80% of SAH was within grade 3 to grade 4. Three studies reported using clipping in 48.6% of patients (555 out of 1142) [22, 25, 28]. Also, three studies reported coiling in 45.7% of patients (554 out of 1211) [25, 27, 28].

Five studies investigated simvastatin 80 mg/day as a high dose of statin [20, 22– 24, 26], while four studies used a moderate dose of statins simvastatin 40 mg/day [25], pravastatin 40 mg/day equivalent to simvastatin 20 mg/day[21], pitavastatin 4 mg/day equivalent to Simvastatin 40 mg/day [27], and atorvastatin 20 mg/day equivalent to simvastatin 40 mg/day [28].The statin agent was administered early within 48 hours of ictus [20, 27], within 72 hours [21, 23, 26, 28] and within 96 hours [22, 24, 25] (Table 1).

The risk of bias in included studies

The quality of included studies ranges from moderate to high quality according to the Cochrane risk of bias assessment tool. The summary of quality assessment domains of included studies is shown in Figure 2.

Effects of interventions

Vasospasm

Seven studies considered vasospasm as the primary outcome and reported its incidence in both groups, including 311 patients in the statin group and 311 patients in the control group [21– 24, 26– 28]. Vasospasm was seen in 45.67% (142 out of 311) of patients in the statin group as compared to 59.8% (186 out of 311) in the control group. The incidence of vasospasm was decreased by 45% with the use of statins and the MH odds ratio for this pooled result was 0.55 (95% CI 0.39– 0.81, p value = 0.0003, I² = 45%, fixed effect model).

Three studies reported different degrees of the severity of the cerebral vasospasm, according to baseline DSA [27], and mean flow velocity of the MCA on TCD [21, 23]. Severe vasospasm was reported in three studies, including 110 patients in the statin group and 110 patients in the control group [21, 23, 27]. Severe vasospasm was seen in 16.36% (18 out of 110) of patients in the statin group compared to 30% (33 out of 110) in the control group. The incidence of severe vasospasm was decreased by 54% with the use of statins and the MH odds ratio for these pooled results was 0.46 (95% CI 0.24– 0.88, p value 0.02, I² = 0%, fixed effect model). Moderate vasospasm was reported in two studies only including 70 patients in the statin group and 70 patients in the control group [23, 27]. Moderate vasospasm was seen in 31.43% (22 out of 70) patents in the statin group compared to 24.28% (17 out of 70) of the patients in the control group. The use of statins increased moderate vasospasm by 44%, and the MH odds ratio of this pooled result was 1.44 (95% CI 0.68– 3.05, p value = 0.34, I2 = 24%, fixed effect model).

Delayed Neurological Ischemic Deficits (DIND)

Nine studies reported DIND following aSAH [20– 28]. The rate of DIND was 17.48% (126 out of 721) of patients in the statin group as compared to 22.9% (170 out of 742) in the control group. The incidence of DIND was decreased by 29% with the use of statins and the MH odds ratio for this pooled result was 0.71 (95% CI 0.54– 0.92, p value = 0.009, I² = 47%, fixed effect model)

Delayed Cerebral Ischemia (DCI)

Four studies reported DCI following aSAH[22, 25, 27, 28].The rate of DCI was 15.47% (95 out of 614) of patients in the statin group as compared to 20.6% (131 out of 636) in the control group. The incidence of DCI was decreased by 30% with the use of statins, and the MH odds ratio for this pooled result was 0.70 (95% CI 0.53– 0.94, p value = 0.02, I² = 27%, fixed effect model).

Functional Outcomes

Seven studies reported functional outcome, the incidence of poor outcome in both the group including 683 patients in the statins group and 704 patients in the control group [21– 23, 25– 28].Poor outcome was seen in 49.48% (338 out of 683) of patients in the statin group as compared to 48.3% (340 out of 704) of patients in the control group. The MH odds ratio for this pooled result was 0.97 (95% CI 0.77– 1.22, p value = 0.79, I² = 0%, fixed effect model).

Mortality

A mortality rate was reported in seven studies, including 648 patients in the statin group and 669 patients in the control group [21– 26, 28]. The mortality rate was 7.6% (49 out of 648) in the statin group compared to 8.82% (59 out of 669) patients in the control group. The pooled MH odds ratio for this result was 0.85 (95% CI 0.57– 1.26, p value = 0.28, I²= 20%, fixed effect model).

Deterioration causes

Three studies reported hydrocephalus following aSAH requiring ventriculostomy using external ventricular drainage (EVD), including 447 patients in the statin group and 468 patients in the control group [21, 23, 25].The hydrocephalus rate was 20.6% (92 out of 447) of patients in statin group compared to 20.3% (95 out of 468) of patients in the control group. The pooled MH odds ratio was 1.01 (95% CI 0.73– 1.40, p value = 0.63, I²= 0%, fixed d effect model).

Two studies reported rebleeding following initial haemorrhage, including 407 patients in the statin group and 428 patients in the control group [23, 25]. The rebleeding rate was 2.46% (10 out of 407) of patients in the statin group, compared to 2.57% (11 out of 428) of patients in the control group. The pooled MH odds ratio was 0.95 (95% CI 0.4– 2.27, p value = 0.49, fixed effect model).

Three studies reported sepsis following aSAH, including 450 patients in the statin group and 472 patients in the control group [21, 22, 25]. The rate of sepsis was 23.78% (107 out of 450) of patients in the statin group compared to 22.25% (105 out of 472) of patients in the control group. The pooled MH odds ratio was 1.05 (95% CI 0.84– 1.30, p value = 0.8, I²= 0%, fixed effect model).

Adverse effects of statins

Five studies reported increased liver enzymes, including 502 patients in the statin group and 525 patients in the control group [20, 22, 24, 25, 27]. The rate of increased liver enzymes was 4.38% (22 out of 502) of patients in the statin group compared to 6.28% (33 out of 525) of patients in the control group. The pooled MH odds ratio was 0.69 (95% CI 0.4– 1.19, p value = 0.47, I² = 0%, fixed effect model).

Three studies reported increased creatine kinase (CKP), including 57 patients in the statin group and 59 patients in the control group [20, 22, 24]. The rate of increased CKP was 3.51% (2 out of 57) of patients in the statin group compared to 1.69% (1 out of 59) of patients in the control group. The pooled MH odds ratio was 1.80 (95% CI 0.23–  14.28, p value = 0.6, I²= 0%, fixed effect model).

Two studies reported rhabdomyolysis, including 445 patients in the statin group and 466 patients in the control group [25, 27].The rate of rhabdomyolysis was 0.45% (2 out of 445) of patients in the statin group compared to 0% (0 out of 466) of patients in the control group. The pooled MH odds ratio was 5.19 (95% CI 0.24– 110.69, p value = 0.29, heterogeneity was not applicable, fixed effect model).

Chou et.al. reported increased troponin level in 19 patients with statin group and 20 patients in the control group [22].The rate of increased troponin level was 26.32% (5 out of 19) of patients in the statin group compared to 35% (7 out of 20) of patients in the control group. The pooled MH odds ratio was 0.66 (95% CI 0.17– 2.62, p value = 0.56, fixed effect model).

Kirkpatrick et.al. reported gastrointestinal tract (GIT) hemorrhage and myositis, including 54 patients in the statin group and 54 patients in the control group [25].The rate of GIT hemorrhage and myositis in the statin group were 0% (0 out of 54) and 3.7% (2 out of 54) of patients compared to 3.7% (2 out of 54) and 0% (0 out of 54) of patients in the control group. The pooled MH odds ratio were 0.19 (95% CI 0.01– 4.11, p value = 0.29, fixed effect model) and 5.19 (95% CI 0.24– 110.69, p value = 0.29, fixed effect model), respectively.

A summary of the subgroup analyses is shown in Figure 3.

Discussion

In this systematic review and meta-analysis, we reviewed the literature on the efficacy of statins in aSAH and tested statistically the hypothesis on the benefit of statins in improving cerebral blood flow (CBF) and reducing vasospasm after aSAH. The meta-analysis found statistically significant differences between the statin group and the control groups on the cerebral vasospasm rate. This finding agreed with previous published systematic reviews and meta–analyses that demonstrated the significant benefits of statins' pharmacologic effect on cerebral vasospasm in animal models [29], while in human studies, they share statistical support [30– 36] or are contradictory [37– 43]. Here, the vasospasm meta– analysis has advantages that weigh in favor of the hypothesis, as it was performed on randomized control studies (RCTs) only and excluded non– RCTs designs. This avoided substantial heterogeneity (p value = 0.0001) in the meta-analysis [31]. Furthermore, subgrouping analyses show that pravastatin, pitavastatin, and atorvastatin have a lower incidence of vasospasm than simvastatin, even at high doses (80 mg/day).The peak incidence of vasospasm is within 4– 10 days of initial bleeding (the onset aSAH) [4], and resolves spontaneously after 21 days [5]. Our meta-analysis showed starting statin therapy in patients with aSAH within the initial 72 hours of ictus, also for a duration of 14 days, showed significant decrease in vasospasm rate.

In the other hand, this meta– analysis is not without restrictions, such as small sample sizes of some of pilot RCTs studies or not powered to detect clinical differences[22– 24, 26]. Another issue is the “vasospasm” definition or the criteria that used by authors in the included studies. Generally, there is disparity on the definition that used by authors to describe ischemia event occurrence after aSAH includes many variable terms through the literature, such as “vasospasm”, “symptomatic vasospasm”, “delayed (ischemic) neurological deficits”. “delayed cerebral ischemia”, “secondary cerebral ischemia”, or “cerebral infarction”[44].In 2009, Frontera et al. studied on 540 patients with aSAH the accurate term to use in description of the vasospasm. The study found that DCI is the best outcome term correlated to symptomatic vasospasm and poor outcome compared to angiographic or TCD vasospasm[45].

TCD, compared to DSA, is considered a non– invasive technique, through acoustic windows of the skull cerebral blood flow can be monitored. An increasing in blood flow velocity in a defined artery over than the baseline assessment can considered decreasing in the diameter of the vessel or systemic hyper dynamic flow. Grag et al. and Vergouwen et al. didn’t apply the Lindegaard ratio in their criteria to define “vasospasm on TCD”[23, 24]. Also, the other used different parameters either mean flow velocity[21], or peaked systolic velocity[22, 28]. This can explain the substantial heterogeneity (p value = 0.03) in the meta– analysis on vasospasm by TCD, even though the significant results.

Delayed ischemic neurological deficits (DIND) meta– analysis was agreed with most previous systematic review and meta– analysis[30, 34, 35, 37, 41, 43, 46]. Ours is considered the most updated meta– analysis, it includes nine RCTs (includes 1464 patients) and also. The used definition was matched among the included studies. Unlike a previous meta– analysis[39], our subgrouping meta– analysis showed simvastatin has significant benefits on DIND with high dose 80 mg per day. Even with a big sample size, Kirkpatrick et al couldn’t prove a statistical effect of simvastatin with a dose of 40 mg per day. Similarly, a meta regression found a dose– dependent reduction in DIND with acute statin in aSAH[47].Early administration of statin within 48 to 72 hours showed in subgrouping analysis a significant benefit in patients with aSAH, in compared to within 96 hours. In addition to, a duration of 14 days was significant than a duration of 21 days in subgrouping meta– analysis. These results combine with vasospasm ones of ours outline the design of clinical methods for the best beneficial effect of statin that depends on dose of statin and interval time since onset of ictus and time of administrations. Our results support an optimal dose of statins (80 mg per day of simvastatin or equivalent dose of other statin, and within the initial 72 hours).

Our meta-analysis results on delayed cerebral ischemia (DCI) show a significant effect, which contradicts all previous published systematic reviews and meta–analysis [33, 38– 40, 42]. The importance of investigating the effect of statin on DCI as radiologically rather than clinically in DIND outcome is that in some situations, clinical assessment of aSAH patients is not applicable, such as after surgery or in a coma. Reporting of previous meta-analysis on DCI is low, compared to DIND and vasospasm outcomes. However, it is not surprising, our meta– analysis, which is the most recent meta– analysis among the current evidence, includes four RCTs [22, 25, 27, 28]. Shen et al [33] and Liu et al [39] published the most recent meta–analysis on DCI in 2017 and included two RCTs [22, 25]. Two RCTs with big sample sizes were published later in 2018 [27] and 2020 [28].

At admission, approximately three quarters of the aSAH patients in the included studies were within grades 1– 3 on H & H grade or WFNS with or without symptoms, ranging from mild headaches to focal motor deficits. While radiologically, approximately the same proportion of these patients had lower grades (3) on the Fisher or modified Fisher scales. Vasospasm may involve non–eloquent brain areas representing perforator territory, which have little effect on neurological state. Shimoda et al. investigated vasospasm and cerebral ischemia using serial images, it reported about 23% (29 out of 125) of patients with aSAH had a new infarct without neurological symptoms, as (asymptomatic infarction) [48].

In our meta–analysis, statins had the same effect on functional outcome as placebo. The absence of statistical difference in our meta analyses on functional outcomes doesn’t necessarily explain the ineffectiveness of the statins. The modified Rankin scale (mRS) and Glasgow Outcome scale (GOS) reflect on physical function outcome. Patients suffering from aSAH experience cognitive impairment and mood disturbance, which can have a negative impact on their quality of life [49]. GOS and mRS have limitations, particularly in the psychological assessment. According to a study conducted by Kapoor et al., a large number of recovered patients with aSAH who returned to their pre–stroke function level physically with good mRS experienced cognitive impairment that impacted their social and occupational lives [50]. Also, GOS has a blind spot on this point[51].

The all-cause mortality in our meta-analysis and in previous RCTs meta-analyses found no statistical effect achieved by the administration of statin compared to placebo. However, this result did not provide conclusive evidence of statin mortality rates. Causes of mortality post aSAH vary, whether vasospasm related to neurological deterioration, or medical complications.

Conclusion

Acute statin therapy in aSAH is safe and decreases the incidence of vasospasm, delayed ischemic neurological deficits, and delayed cerebral infarction. Clinical trials with robust methods are needed to assess psychological and functional outcomes.

Declarations

Declaration of Interests

I declare no conflict of interest.

Ethics approval

Not applicable.

Consent to participate

Not applicable.

Consent for publication

Not applicable.

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Abbreviations

aSAH = aneurysmal subarachnoid hemorrhage

MeSH = medical subject heading

RCT = randomized controlled study

MH = Mantel– Haenszel method

AVM = arteriovenous malformation

DIND = delayed neurological ischemic deficits

eNOS = endothelin– derived nitric oxide

HMG– CoA = 3– hydroxyl– 3– methylglutaryl coenzyme

TCD = trans– cranial Doppler

DSA = digital subtraction angiography

MFV = mean flow velocity

MCA = middle cerebral artery

PSV = peaked systolic flow velocity

LR = Lindegaard ratio

DCI = delayed cerebral ischemia

GCS = Glasgow coma score

mRS = modified Rankin score

CT = computerized tomography

MRI = magnetic resonance imaging

GOS = Glasgow outcome score

OR = odds ratio

CI = confidence interval

ACA = anterior circulation aneurysms

ICA = internal carotid artery

H&H = Hunt & Hess

WFNS = World Federation of Neurosurgical Societies

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