Cholesterol-reducing agents for aneurysmal subarachnoid haemorrhage

  • Review
  • Intervention

Authors


Abstract

Background

Cerebral vasospasm and related delayed ischaemic deficits (DIDs) occur in about 17% to 40% of patients with aneurysmal subarachnoid haemorrhage (SAH) and lead to a poor outcome. Cholesterol-reducing agents might improve unfavourable outcomes.

Objectives

To assess the effects of cholesterol-reducing agents for improving outcomes in patients with aneurysmal SAH.

Search methods

We searched the Cochrane Stroke Group Trials Register (May 2012), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 5), MEDLINE (1948 to May 2012) and EMBASE (1980 to May 2012). We also searched three Chinese databases: SinoMed, CNKI and VIP (May 2012). In an effort to identify further published, ongoing and unpublished trials we searched relevant clinical trials and research registers (May 2012), contacted pharmaceutical companies and investigators known to be involved in previous trials and screened the reference lists of all relevant articles identified.

Selection criteria

We included randomised controlled trials (RCTs) that compared cholesterol-reducing agents with control or placebo treatment in participants with aneurysmal SAH.

Data collection and analysis

Two review authors independently applied the inclusion criteria, reviewed the relevant trials and extracted data. We did not perform meta-analysis as we only included one RCT in the review.

Main results

We included one study in which 39 patients received either simvastatin (80 mg daily; n = 19) or placebo (n = 20) for 14 days. The incidence of DIDs (secondary outcome) was 26% (5/19) in the simvastatin group versus 60% (12/20) in the placebo group (risk ratio (RR) 0.44, 95% confidence interval (CI) 0.19 to 1.01, P = 0.05). This means that, in this study, simvastatin had no effect on DIDs. Two patients in the simvastatin group and one patient in the placebo group had elevated levels of aspartate transaminase or alanine transaminase. One patient in the simvastatin group had a raised creatine phosphokinase. There were no results from this trial for the primary outcome of death or dependency at six months.

Authors' conclusions

We cannot draw any conclusions about the effectiveness and safety of lowering cholesterol in aneurysmal SAH because of insufficient reliable evidence from only one small trial. More RCTs are needed.

Résumé scientifique

Agents hypocholestérolémiants pour le traitement de l'hémorragie méningée anévrismale

Contexte

Le vasospasme cérébral et les déficits ischémiques ultérieurs qui y sont associés (DID) touchent environ 17 % à 40 % des patients présentant une hémorragie méningée anévrismale (HSA) et ont des conséquences défavorables. Il se pourrait que les agents hypocholestérolémiants améliorent les conséquences défavorables.

Objectifs

Évaluer les effets des agents hypocholestérolémiants sur l'amélioration des conséquences chez les patients présentant une hémorragie subarachnoïde (HSA) d'origine anévrismale.

Stratégie de recherche documentaire

Nous avons effectué une recherche dans le registre des essais du groupe Cochrane sur les accidents vasculaires cérébraux (mai 2012), le registre Cochrane des essais contrôlés (CENTRAL) (The Cochrane Library 2012, numéro 5), MEDLINE (de 1948 à mai 2012) et EMBASE (de 1980 à mai 2012). Nous avons également recherché dans trois bases de données chinoises : SinoMed, CNKI et VIP (mai 2012). Dans le but d'identifier des essais publiés, en cours et non publiés supplémentaires, nous avons effectué des recherches dans les registres d'études et d'essais cliniques pertinents (mai 2012), contacté les laboratoires pharmaceutiques et les investigateurs réputés être impliqués dans des essais antérieurs et passé au crible les listes bibliographiques de tous les articles identifiés pertinents.

Critères de sélection

Nous avons inclus des essais contrôlés randomisés (ECR) ayant comparé des agents hypocholestérolémiants à un traitement témoin ou placebo chez les participants présentant une hémorragie subarachnoïde (HSA) d'origine anévrismale.

Recueil et analyse des données

Deux auteurs de la revue ont appliqué les critères d'inclusion, évalué les essais pertinents et extrait des données, de manière indépendante. Nous n'avons pas effectué de méta-analyse car nous n'avons pu inclure qu'un seul ECR dans la revue.

Résultats principaux

Nous avons inclus une étude dans laquelle 39 patients ont reçu soit de la simvastatine (80 mg par jour ; n = 19) soit un placebo (n = 20) pendant 14 jours. L'incidence des déficits ischémiques ultérieurs (DID) (résultat secondaire) était de 26 % (5/19) dans le groupe sous simvastatine contre 60 % (12/20) dans le groupe sous placebo (risque relatif (RR) 0,44, intervalle de confiance (IC) à 95 % 0,19 à 1,01, P = 0,05). Ceci signifie que, dans cette étude, la simvastatine n'a eu aucun effet sur les déficits ischémiques ultérieurs (DID). Deux patients dans le groupe sous simvastatine et un patient dans le groupe sous placebo ont présenté des taux élevés d'aspartate transaminase ou d'alanine transaminase. Un patient dans le groupe sous simvastatine a eu une élévation de la créatine phosphokinase. Il n'y avait aucun résultat dans cet essai pour le critère de jugement principal de décès ou de dépendance à six mois.

Conclusions des auteurs

Nous ne pouvons pas tirer de conclusions sur l'efficacité et la sécurité d'emploi de la baisse du taux de cholestérol dans l'hémorragie subarachnoïde (HSA) d'origine anévrismale en raison de l'insuffisance des preuves probantes issues d'un petit essai unique. Des ECR supplémentaires sont nécessaires.

Resumo

Medicações redutoras de colesterol para hemorragia subaracnoide devida a ruptura de aneurisma

Introdução

Cerca de 17% a 40% dos pacientes com hemorragia subaracnoide (HSA) aneurismática têm vasoespasmo cerebral e déficits tardios (do inglês: DID), o que está associado a desfechos adversos. O uso de medicações redutoras de colesterol pode amenizar os desfechos adversos.

Objetivos

Avaliar os efeitos de medicações redutoras de colesterol na melhora dos desfechos em pacientes com HSA por aneurisma.

Métodos de busca

Pesquisamos nas bases Cochrane Stroke Group Trials Register (maio de 2012), Cochrane Central Register of Controlled Trials (CENTRAL)(The Cochrane Library 2012, issue 5), MEDLINE (1948 a maio de 2012) e EMBASE (1980 até maio de 2012). Também fizemos buscas em três bases de dados chinesas: SinoMed, CNKI e VIP (maio de 2012). Para tentar identificar mais ensaios clínicos publicados, em andamento e não publicados, pesquisamos plataformas de registros de pesquisas (maio de 2012), contatamos empresas farmacêuticas e também os investigadores que já haviam realizados ensaios clínicos anteriores e verificamos as listas de referências de todos os artigos relevantes identificados.

Critério de seleção

Incluímos ensaios clínicos randomizados que compararam o uso de medicações redutoras de colesterol versus tratamento controle ou placebo em participantes com HAS aneurismática.

Coleta dos dados e análises

Dois revisores, atuando de forma indendente, fizeram a seleção dos estudos e e extraíram os dadosdos estudos relevantes. Nós não realizamos uma metanálise pois apenas incluímos um estudo clínico randomizado na revisão.

Principais resultados

Incluímos apenas um estudo, no qual 39 pacientes receberam sinvastatina (80 mg/dia; n = 19) ou placebo (n = 20) durante 14 dias. A incidência de DID (desfecho secundário) foi de 26% (5/19) no grupo sinvastatina versus 60% (20/12) no grupo placebo (risco relativo, RR, 0,44, intervalo de confiança de 95%, 95% CI, de 0,19 a 1,01, P = 0,05). Isso significa que, nesse estudo, a sinvastatina não teve efeito sobre DID. Dois pacientes no grupo sinvastatina e um paciente no grupo placebo tinham níveis elevados de transaminase aspartato ou transaminase alanina. Um paciente no grupo sinvastatina tinha um aumento da creatinino-fosfoquinase. Este estudo não apresentou resultados para morte ou dependência após seis meses, que eram nossos desfechos primários.

Conclusão dos autores

Nós não podemos tirar quaisquer conclusões sobre a efetividade e a segurança do tratamento para redução do colesterol na SAH aneurismática devido à falta de evidências confiáveis, uma vez que existe apenas um pequeno estudos clínicos randomizados sobre esse tema. Mais estudos clínicos randomizados são necessários.

Notas de tradução

Tradução do Centro Cochrane do Brasil (Arnaldo Alves da Silva).

Plain language summary

Cholesterol-reducing drugs for brain haemorrhage (subarachnoid haemorrhage)

Subarachnoid haemorrhage (SAH) is a serious condition where bleeding occurs over the surface of the brain. This bleeding usually comes from an abnormality (aneurysm) in one of the blood vessels on the brain surface. In addition to the damage caused by the initial bleeding, people with SAH often suffer a later reduction in blood flow to the brain and hence additional delayed brain injury. It has been proposed that cholesterol-reducing drugs may reduce this delayed brain injury. This review found only one small trial of 39 participants. Cholesterol-reducing drugs did not reduce the risk of delayed brain injury and did not significantly improve participants' degree of recovery. There were no significant differences in adverse events. This review is based on one small trial and no reliable conclusions can be drawn at present.

Résumé simplifié

Médicaments hypocholestérolémiants pour le traitement des hémorragies cérébrales (hémorragie subarachnoïde)

L'hémorragie subarachnoïde (HSA) est un problème grave dans lequel le saignement se produit à la surface du cerveau. Ce saignement a généralement pour cause une anomalie (anévrisme) dans l'un des vaisseaux sanguins situés à la surface du cerveau. En plus de la lésion causée par le saignement initial, les personnes présentant une HSA souffrent souvent d'une réduction ultérieure du flux sanguin jusqu'au cerveau et donc d'une lésion cérébrale supplémentaire ultérieure. Il a été avancé que les médicaments hypocholestérolémiants pourraient réduire cette lésion cérébrale ultérieure. Cette revue n'a trouvé qu'un seul petit essai incluant 39 participants. Les médicaments hypocholestérolémiants n'ont pas réduit le risque de lésion cérébrale ultérieure et n'ont pas amélioré significativement le degré de récupération des participants. Il n'y avait aucune différence significative au niveau des événements indésirables. Cette revue s'appuie sur un petit essai et aucune conclusion solide ne peut être tirée à l'heure actuelle.

Notes de traduction

Traduit par: French Cochrane Centre 17th May, 2013
Traduction financée par: Pour la France : Minist�re de la Sant�. Pour le Canada : Instituts de recherche en sant� du Canada, minist�re de la Sant� du Qu�bec, Fonds de recherche de Qu�bec-Sant� et Institut national d'excellence en sant� et en services sociaux.

Resumo para leigos

Remédios que reduzem o colesterol  para pessoas com hemorragia cerebral (subaracnoide)

A hemorragia subaracnoide é um problema grave, no qual existe um sangramento sobre a superfície do cérebro. Esse sangramento geralmente ocorre devido a um defeito (aneurisma) em um dos vasos sanguíneos da superfície do cérebro. Além dos danos causados pelo sangramento inicial, pessoas com hemorragia subaracnoide frequentemente sofrem de uma redução do fluxo sanguíneo para o cérebro ao longo do tempo e consequentemente desenvolvem lesão cerebral tardia. Tem sido proposto que remédios usados para baixar os níveis colesterol poderiam reduzir essa lesão cerebral tardia. Esta revisão encontrou apenas um pequeno estudo com 39 participantes. O uso de remédios que diminuíram os níveis de colesterol não reduziu o risco de lesão cerebral tardia e não melhorou significativamente a recuperação dos participantes. Não houve diferença significativa na taxa de eventos adversos.Esta revisão é baseada em apenas um único pequeno estudo e no momento não foi possível se chegar a nenhuma conclusão confiável.

Notas de tradução

Tradução do Centro Cochrane do Brasil (Arnaldo Alves da Silva).

Background

Description of the condition

Aneurysmal subarachnoid haemorrhage (SAH) has a crude incidence rate of nine per 100,000 person years (de Rooij 2007). For survivors of the initial haemorrhage, the leading cause of morbidity and mortality is cerebral vasospasm and related delayed ischaemic deficits (DIDs), affecting 17% to 40% of patients (Janjua 2003). Between 15% and 20% of patients suffer stroke or die from vasospasm despite maximal therapy (Mayberg 1994). Although nimodipine is proven to reduce the risk of unfavourable outcomes in patients after SAH (Dorhout Mees 2007), probably by preventing cerebral vasospasm, there are no definitive medical treatments for cerebral vasospasm and DIDs once they have set in.

Description of the intervention

In general, cholesterol-reducing agents can be divided into five categories.

  1. Statins (or HMG-CoA reductase inhibitors) are used to reduce low-density lipoprotein (LDL) cholesterol by inhibiting the enzyme HMG-CoA reductase. Statins mainly include atorvastatin, fluvastatin, lovastatin, lovastatin extended-release, pitavastatin, pravastatin, rosuvastatin, and simvastatin.

  2. Fibrates reduce both low-density lipoprotein (LDL) and very low density lipoprotein (VLDL) levels, as well as increasing high-density lipoprotein (HDL) levels and reducing triglycerides level. Commonly prescribed fibrates include: bezafibrate, ciprofibrate, clofibrate, gemfibrozil, and fenofibrate.

  3. Nicotinic acid is a B vitamin: when the dosage exceeds its role as a vitamin dose, it may have significant lipid-lowering effects. These drugs can be used outside of homozygous familial hypercholesterolaemia and type I hyperlipoproteinaemia types of hyperlipidaemia.

  4. Bile acid sequestrants are used to bind certain components of bile in the gastrointestinal tract. Cholestyramine, colesevelam and colestipol are members of this class.

  5. Cholesterol absorption inhibitors inhibit the intestinal absorption of cholesterol in the diet and bile to achieve the purpose of lowering blood lipids.

How the intervention might work

The pathogenesis of DIDs is not fully known, but may be partly related to nitric oxide (NO) depletion, inflammation, and free radical injury (Khaldi 2001; Macdonald 1994). By reducing vascular inflammation, inhibiting vascular smooth muscle cell proliferation and platelet aggregation, and promoting upregulation of endothelial NO synthase, cholesterol-reducing agents can improve endothelial function and increase cerebral blood flow (Amin-Hanjani 2001; Brouet 2001; Degraeve 2001; Ledoux 2002; Loscalzo 2001; Massy 2001). Experimental studies have indicated that anticholesteraemic agents can prevent or reverse vasospasm and have neuroprotective properties.

Why it is important to do this review

The effects of cholesterol-reducing agents on aneurysmal SAH remains unclear. In animal studies (Cheng 2009; Sabri 2011; Sugawara 2008; Wang 2010), cholesterol-reducing agents were found to decrease vasospasm and improve neurological scores, but observational studies (Kern 2009; Kerz 2008; Kramer 2008; Mcgirt 2009; Sanchez-Pena 2012; Singhal 2005) did not find them to be effective after aneurysmal SAH. Randomised controlled trials (RCTs) did not reach consistent results. Four systematic reviews (Sillberg 2008; Trimble 2007; Vergouwen 2010; Weyer 2006) based on RCTs also drew conflicting conclusions. Consequently, we carried out this review to evaluate the effects of cholesterol-reducing agents on aneurysmal SAH.

Objectives

To assess the effects of cholesterol-reducing agents for improving outcome in patients with aneurysmal SAH.

Methods

Criteria for considering studies for this review

Types of studies

All RCTs where people with aneurysmal SAH were randomised into cholesterol-reducing agents group and control or placebo treatment group were eligible. We excluded quasi-randomised trials.

Types of participants

People of any age and either sex with SAH confirmed by computerised tomography (CT) scan or cerebrospinal fluid examination. Ruptured cerebral aneurysm had to be proven by angiography, or at least judged to be highly likely based on the pattern of haemorrhage on the CT scan.

Types of interventions

Treatment with any cholesterol-reducing agent (the list of drugs includes, but is not limited to: atorvastatin, azacosterol, bezafibrate, cerivastatin, cholestyramine, clofibrate, clofibric acid, compactin, fenofibrate, fluindostatin, fluvastatin, gemfibrozil, lovastatin, meglutol, mevastatin, niacin, pitavastatin, probucol, rosuvastatin, simvastatin) versus control or placebo treatment, starting within four days of SAH onset and administered for 14 days.

Types of outcome measures

Primary outcomes

Unfavourable outcome (death, vegetative state, or severe disability (modified Rankin Scale (mRS) score 4 to 6) at six months post-SAH).

Secondary outcomes
  • Death at six months post-SAH.

  • Cerebral ischaemia (clinical signs of cerebral ischaemia, as well as cerebral infarction documented by CT or magnetic resonance imaging (MRI) alone, or confirmed by angiogram or transcranial doppler sonography (TCD), or both; TCD-highest mean velocity (TCD-HMV); and TCD-HMV change followed by clinical neurological deterioration) at 14-day follow-up.

  • Rebleeding from the aneurysm within one month of SAH.

  • Adverse effects (myositis (muscle-related) or hepatic (liver-related) disturbances).

Because there was no concomitant definition of DIDs, we used the number of patients with DIDs given by the authors of the included trial.

Search methods for identification of studies

See the 'Specialized register' section in the Cochrane Stroke Group module. We searched for trials in all languages and arranged translation of relevant papers published in languages other then English.

Electronic searches

We searched the Cochrane Stroke Group Trials Register, which was last searched in May 2012. In addition, we searched the following electronic bibliographic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 5) (Appendix 1), MEDLINE (1948 to May 2012) (Appendix 2) and EMBASE (1980 to May 2012) (Appendix 3). We developed the search strategies with the help of the Cochrane Stroke Group Trials Search Co-ordinator.

We also searched the following Chinese databases: SinoMed (http://www.sinomed.ac.cn/) (May 2012), CNKI (China National Knowledge Infrastructure, http://www.cnki.net/ ) (May 2012), VIP (VIP Information, http://www.cqvip.com/) (May 2012). In addition, we searched the following trials registers in May 2012: Current Controlled Trials (http://www.controlled-trials.com/) and ClinicalTrials.gov (http://www.clinicaltrials.gov/).

Searching other resources

In an effort to identify further published, ongoing and unpublished trials we:

  1. contacted the following pharmaceutical companies (May 2012): Novartis, Merck, Kowaus, Astrazeneca, Pfizer;

  2. contacted investigators known to be involved in previous trials;

  3. screened the reference lists of all relevant articles identified.

Data collection and analysis

Selection of studies

Two review authors (ZL and LL) scanned the titles, abstracts and keywords of records obtained from the electronic searches. We excluded obviously irrelevant studies and obtained the full text of the remaining studies. The same two authors independently assessed the studies and selected trials for inclusion. We sought further information by contacting trialists where necessary. We resolved any disagreements by discussion between those two review authors, and the third review author (BZ) resolved any persisting differences.

Data extraction and management

Two review authors (ZL and LL) independently extracted the following data: details of randomisation methods, blinding of treatments and assessments, whether intention-to-treat analyses were possible from the published data, whether treatment groups were comparable with regard to major prognostic risk factors for outcomes, the number of patients excluded or lost to follow-up, the definition of outcomes and of entry and exclusion criteria, and the number of patients with each outcome of interest and any side effects. A third review author (BZ) verified this information. One review author (ZL) entered all data into Review Manager (RevMan 2011).

Assessment of risk of bias in included studies

Two review authors (ZL, LL) independently assessed the risk of bias in included studies based on the methods described in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011).

We scored each of the following domains low risk of bias, high risk of bias, or unclear risk of bias and reported them in a 'Risk of bias' table.

  1. Random sequence generation (selection bias).

  2. Allocation concealment (selection bias).

  3. Blinding of participants and personnel (performance bias).

  4. Blinding of outcome assessment (detection bias).

  5. Incomplete outcome data (attrition bias).

  6. Selective reporting.

  7. Other bias.

Measures of treatment effect

For dichotomous outcomes we presented results as risk ratios (RR) with 95% confidence intervals (CI). We planned to consider the odds ratio (OR) if there were zero events in one or both groups. We planned to assess continuous outcome data with the standardised mean difference (SMD). We intended to pool data using the random-effects model, but we would also have analysed the fixed-effect model to ensure robustness of the model chosen and susceptibility to outliers.

Unit of analysis issues

The unit of analysis was the participants with aneurysmal SAH in individually randomised trials.

Dealing with missing data

We contacted authors for additional information.

Assessment of heterogeneity

We intended to assess heterogeneity statistically, using the I² statistic, and if significant heterogeneity was present (I² > 50% or P < 0.1), we planned to attempt to explain the differences based on the patients' clinical characteristics, the interventions, and the characteristics of the included studies. It was our intention to use an appropriate statistical model, based on the heterogeneous test results. We planned to analyse and present statistical heterogeneity when I² > 50% or P < 0.1. We intended to use the random-effects model for the meta-analysis if there was significant heterogeneity (I² > 50%) and the fixed-effect model when heterogeneity was not significant (I² < 50%).

Assessment of reporting biases

If we had identified a sufficient number of trials, we intended to examine possible publication bias using a funnel plot (Egger 1997).

Data synthesis

We planned to use the Review Manager software, RevMan 5.1, for statistical analysis (RevMan 2011). Based on the heterogeneous test results, we planned to use either a fixed-effect or random-effects model, where appropriate. We would have assessed the reason for heterogeneity and undertaken subgroup analyses if we had found significant heterogeneity.

Subgroup analysis and investigation of heterogeneity

If data were available, we would have used additional subgroup analyses to investigate possible differences between the types of cholesterol-reducing agents. We would have used the Deeks method to conduct subgroup analyses, as described in the Cochrane Handbook of Systematic Reviews of Interventions (Higgins 2011).

Sensitivity analysis

If possible, we would have re-analysed the data using a random-effects model or a fixed-effect model. Moreover, to test the robustness of the review results, we would have re-analysed data by excluding poor quality studies.

Results

Description of studies

See: Characteristics of included studies; Characteristics of excluded studies; Characteristics of studies awaiting classification

Results of the search

We obtained 1207 records from the electronic searches and after screening we obtained the full text of 38 papers. We considered 16 studies to be potentially relevant but we only selected one study for inclusion. We excluded 14 studies and one further study (Jaschinski 2008) is awaiting classification because the treatment period is not clear (Figure 1). We did not identify any relevant ongoing studies.

Figure 1.

Study flow diagram.

Included studies

Lynch 2005 randomised 39 patients with aneurysm SAH to receive simvastatin or placebo. Details relating to plasma alanine aminotransferase, aspartate aminotransferase, creatine phosphokinase and delayed ischaemic neurological deficit were recorded.

Excluded studies

We excluded 14 studies: seven studies did not meet the inclusion criteria of drug administered for 14 days (Ayata 2005; Roitberg 2007; Romero 2011; Simsab 2008; STASH 2006; Suzuki 2009; Tseng 2004); one study did not have a control or placebo treatment group and did not administer treatment for 14 days (HDS-SAH 2010); two studies administered treatment for more than 14 days and it is not clear whether SAH was caused by aneurysm or not (Macedo 2009; Wu 2006); we excluded one study because it included participants with traumatic SAH as well as aneurysmal SAH (Mangoyan 2009); and we excluded three studies because it is not clear whether SAH was caused by an aneurysm or not (Li 2010; Tian 2007; Zhou 2006).

Risk of bias in included studies

Allocation

Lynch 2005 is described as a randomised trial. However, the generation of the randomisation sequence and concealment of allocation were not reported. We have rated this as having an unclear risk of bias.

Blinding

The trial was carried out with blinding of performance. All clinicians and investigators were blinded to the treatment group and transcranial doppler (TCD) was evaluated by a blinded neurosonologist. We have rated this as having a low risk of bias.

Incomplete outcome data

All patients completed follow-up. We have rated this as having a low risk of bias.

Selective reporting

There was insufficient information for us to make a judgement on selective reporting.

Other potential sources of bias

The description of the methods was insufficient to provide an adequate evaluation.

Effects of interventions

Lynch 2005 enrolled 39 participants with angiographically-documented aneurysmal SAH and randomised participants within 48 hours of symptom onset to receive either simvastatin (80 mg daily; n = 19) or placebo (n = 20) for 14 days. The incidence of DIDs was 26% (5/19) in the simvastatin group versus 60% (12/20) in the placebo group (RR 0.44, 95% CI 0.19 to 1.01; P = 0.05). This means that, in this study, simvastatin has no effect on DIDs. Two patients in the simvastatin group and one patient in the placebo group had elevated levels of aspartate transaminase or alanine transaminase. One patient in the simvastatin group had a raised creatine phosphokinase. There were no results from this trial for the primary outcome of death or dependency at six months.

Discussion

Summary of main results

With only one small trial included in the review, there is insufficient evidence to determine the effectiveness and safety of cholesterol-reducing agents for aneurysmal subarachnoid haemorrhage (SAH), and we observed no obvious differences in delayed ischaemic deficits (DIDs) and in adverse reactions (Lynch 2005). Moreover, there were no reported deaths at six months post-SAH, nor of rebleeding within one month of aneurysmal SAH because of the short duration of treatment and follow-up.

Overall completeness and applicability of evidence

We cannot draw any conclusions about the applicability of this intervention because of insufficient evidence from only one small trial.

Quality of the evidence

We considered the study to have a high risk of bias because the methodological details of random sequence generation, allocation concealment, blinding of outcome assessment and selective reporting were not stated.

Potential biases in the review process

For this review, we searched several major medical electronic databases and other sources. However, it is possible that we did not identify unpublished randomised controlled trials (RCTs) or those reported in the grey literature, which could give rise to publication bias.

Agreements and disagreements with other studies or reviews

There are four systematic reviews of RCTs in statins for aneurysmal SAH, but they did not reach a consensus that statins decrease the risk of vasospasm, DID and death after aneurysmal SAH (Sillberg 2008; Trimble 2007; Vergouwen 2010; Weyer 2006). Vergouwen 2010 and Weyer 2006 drew the conclusion that there was insufficient evidence of effectiveness of statins on aneurysmal SAH, while Sillberg 2008 and Trimble 2007 drew the opposite conclusion. Compared with these systematic reviews, we set stricter inclusion criteria and therefore were only able to include one RCT.

Authors' conclusions

Implications for practice

There is insufficient evidence from RCTs to recommend that taking cholesterol-reducing agents may have a beneficial effect in people with aneurysmal SAH.

Implications for research

This review has not resolved the issue of effectiveness of cholesterol-reducing agents for people with aneurysmal SAH. Further trials investigating cholesterol-reducing agents, especially statins, in people with aneurysmal SAH are needed. In addition to cerebral ischaemia and adverse effects, trial outcomes should include death, vegetative state or severe disability at six months post-SAH.

Acknowledgements

We thank Hazel Fraser, Managing Editor of the Cochrane Stroke Group, and Brenda Thomas, Trials Search Co-ordinator of the Cochrane Stroke Group. We also thank Drs Ayata, Turner, Jaschinski, and Kirkpatrick for providing missing information from their studies.

Data and analyses

Download statistical data

This review has no analyses.

Appendices

Appendix 1. Cochrane Central Register of Controlled Trials (CENTRAL) search strategy

#1.MeSH descriptor Subarachnoid Hemorrhage, this term only
#2.MeSH descriptor Intracranial Hemorrhages, this term only
#3.MeSH descriptor Cerebral Hemorrhage, this term only
#4.MeSH descriptor Vasospasm, Intracranial, this term only
#5.MeSH descriptor Intracranial Aneurysm, this term only
#6.MeSH descriptor Rupture, this term only
#7.MeSH descriptor Rupture, Spontaneous explode all trees
#8.rupture*
#9.(#6 OR #7 OR #8)
#10.(#5 AND #9)
#11.MeSH descriptor Aneurysm, Ruptured, this term only
#12.MeSH descriptor Brain explode all trees
#13.MeSH descriptor Meninges explode all trees
#14.(#12 OR #13)
#15.(#11 AND #14)
#16.(subarachnoid or arachnoid*) near/6 (haemorrhage* or hemorrhage* or haematoma* or hematoma* or bleed* or blood*)
#17.(brain or cereb* or intracranial) near/3 aneurysm* near/3 ruptur*
#18.(cerebral or intracranial or cerebrovascular) near/5 (vasospasm or spasm)
#19.SAH
#20.(#1 OR #2 OR #3 OR #4 OR #10 OR #15 OR #16 OR #17 OR #18 OR #19)
#21.MeSH descriptor Anticholesteremic Agents explode all trees
#22.anticholesterolaemic or hypocholesterolaemic or anticholesterolemic or hypocholesterolemic or anticholesteraemic or anticholesteremic
#23.cholesterol near/5 (reduc* or lower* or inhib*)
#24.(hydroxymethylglutaryl-Coenzyme A or hydroxymethylglutaryl-CoA or HMG-CoA) near/5 inhib*
#25.statin or statins
#26.atorvastatin or cerivastatin or compactin or mevastatin or fluindostatin or mevinolin or lovastatin or pitavastatin or pravastatin or fluvastatin or rosuvastatin or simvastatin
#27.azacosterol or chitosan or cholestyramine or clofibrate or clofibric acid or ciprofibrate or colesevalem or colestipol or doxazosin or meglutol or probucol or bezafibrate or gemfibrozil or niacin or nicotinic acid or fenofibrate
#28.(#21 OR #22 OR #23 OR #24 OR #25 OR #26 OR #27)
#29.(#20 AND #28)

Appendix 2. MEDLINE (Ovid) search strategy

1. Subarachnoid Hemorrhage/
2. intracranial hemorrhages/ or cerebral hemorrhage/ or vasospasm, intracranial/
3. Intracranial Aneurysm/
4. Rupture, Spontaneous/ or rupture/ or rupture$.tw.
5. 3 and 4
6. Aneurysm, Ruptured/
7. exp brain/ or exp meninges/
8. 6 and 7
9. ((subarachnoid or arachnoid$) adj6 (haemorrhage$ or hemorrhage$ or haematoma$ or hematoma$ or bleed$ or blood$)).tw.
10. ((brain or cereb$ or intracranial) adj3 aneurysm$ adj3 ruptur$).tw.
11. ((cerebral or intracranial or cerebrovascular) adj6 (vasospasm or spasm)).tw.
12. sah.tw.
13. 1 or 2 or 5 or 8 or 9 or 10 or 11 or 12
14. exp anticholesteremic agents/
15. (anticholesterol?emic or hypocholesterol?emic or anticholester?emic).tw.
16. (cholesterol adj5 (reduc$ or lower$ or inhib$)).tw.
17. ((hydroxymethylglutaryl-Coenzyme A or hydroxymethylglutaryl-CoA or HMG-CoA) adj5 inhib$).tw.
18. (statin or statins).tw.
19. (atorvastatin or cerivastatin or compactin or mevastatin or fluindostatin or mevinolin or lovastatin or pitavastatin or pravastatin or fluvastatin or rosuvastatin or simvastatin).tw.
20. (azacosterol or chitosan or cholestyramine or clofibrate or clofibric acid or ciprofibrate or colesevalem or colestipol or doxazosin or meglutol or probucol or bezafibrate or gemfibrozil or niacin or nicotinic acid or fenofibrate).tw.
21. 14 or 15 or 16 or 17 or 18 or 19 or 20
22. 13 and 21
23. exp animals/ not humans.sh.
24. 22 not 23
25. Randomized Controlled Trials as Topic/
26. random allocation/
27. Controlled Clinical Trials as Topic/
28. control groups/
29. clinical trials as topic/ or clinical trials, phase i as topic/ or clinical trials, phase ii as topic/ or clinical trials, phase iii as topic/ or clinical trials, phase iv as topic/
30. double-blind method/
31. single-blind method/
32. Placebos/
33. placebo effect/
34. Therapies, Investigational/
35. Drug Evaluation/
36. Research Design/
37. randomized controlled trial.pt.
38. controlled clinical trial.pt.
39. (clinical trial or clinical trial phase i or clinical trial phase ii or clinical trial phase iii or clinical trial phase iv).pt.
40. random$.tw.
41. (controlled adj5 (trial$ or stud$)).tw.
42. (clinical$ adj5 trial$).tw.
43. ((control or treatment or experiment$ or intervention) adj5 (group$ or subject$ or patient$)).tw.
44. (quasi-random$ or quasi random$ or pseudo-random$ or pseudo random$).tw.
45. ((control or experiment$ or conservative) adj5 (treatment or therapy or procedure or manage$)).tw.
46. ((singl$ or doubl$ or tripl$ or trebl$) adj5 (blind$ or mask$)).tw.
47. placebo$.tw.
48. (assign$ or alternate or allocat$ or counterbalance$ or multiple baseline).tw.
49. controls.tw.
50. or/25-49
51. 24 and 50

Appendix 3. EMBASE (Ovid) search strategy

1. subarachnoid hemorrhage/
2. brain artery aneurysm rupture/ or brain hemorrhage/ or brain vasospasm/
3. (intracranial aneurysm/ or brain artery aneurysm/) and (rupture/ or artery rupture/ or rupture$.tw.)
4. aneurysm rupture/ and (exp brain/ or exp meninx/)
5. ((subarachnoid or arachnoid$) adj6 (haemorrhage$ or hemorrhage$ or haematoma$ or hematoma$ or bleed$ or blood$)).tw.
6. ((brain or cereb$ or intracranial) adj3 aneurysm$ adj3 ruptur$).tw.
7. ((cerebral or intracranial or cerebrovascular) adj6 (vasospasm or spasm)).tw.
8. sah.tw.
9. or/1-8
10. exp hypocholesterolemic agent/
11. (anticholesterol?emic or hypocholesterol?emic or anticholester?emic).tw.
12. (cholesterol adj5 (reduc$ or lower$ or inhib$)).tw.
13. ((hydroxymethylglutaryl-Coenzyme A or hydroxymethylglutaryl-CoA or HMG-CoA) adj5 inhib$).tw.
14. (statin or statins).tw.
15. (atorvastatin or cerivastatin or compactin or mevastatin or fluindostatin or mevinolin or lovastatin or pitavastatin or pravastatin or fluvastatin or rosuvastatin or simvastatin).tw.
16. (azacosterol or chitosan or cholestyramine or clofibrate or clofibric acid or ciprofibrate or colesevalem or colestipol or doxazosin or meglutol or probucol or bezafibrate or gemfibrozil or niacin or nicotinic acid or fenofibrate).tw.
17. or/10-16
18. 9 and 17
19. (animal/ or nonhuman/ or animal experiment/) and human/
20. animal/ or nonhuman/ or animal experiment/
21. 20 not 19
22. 18 not 21
23. Randomized Controlled Trial/
24. Randomization/
25. Controlled Study/
26. control group/
27. clinical trial/ or phase 1 clinical trial/ or phase 2 clinical trial/ or phase 3 clinical trial/ or phase 4 clinical trial/ or controlled clinical trial/
28. Double Blind Procedure/
29. Single Blind Procedure/ or triple blind procedure/
30. Parallel Design/
31. placebo/
32. experimental design/ or experimental study/ or quasi experimental study/
33. experimental therapy/
34. drug comparison/ or drug dose comparison/
35. "types of study"/
36. Comparative Study/
37. random$.tw.
38. (controlled adj5 (trial$ or stud$)).tw.
39. (clinical$ adj5 trial$).tw.
40. ((control or treatment or experiment$ or intervention) adj5 (group$ or subject$ or patient$)).tw.
41. (quasi-random$ or quasi random$ or pseudo-random$ or pseudo random$).tw.
42. ((control or experiment$ or conservative) adj5 (treatment or therapy or procedure or manage$)).tw.
43. ((singl$ or doubl$ or tripl$ or trebl$) adj5 (blind$ or mask$)).tw.
44. placebo$.tw.
45. (assign$ or allocat$).tw.
46. controls.tw.
47. or/23-46
48. 22 and 47

Contributions of authors

Professor Bin Zhao was responsible for drafting the final review and resolving disagreements. Zhou Liu was responsible for entering text into RevMan, extracting data from trials, entering data into RevMan, carrying out the analysis, interpreting the analysis, and drafting the final review. Lingying Liu helped to extract data from trials, interpret the analysis, and draft the final review. Zuhui Chen and Zhijian Zhang with trials selection and obtained the full texts of the relevant trials.

Declarations of interest

None known

Differences between protocol and review

In the Data collection and analysis section, and in line with guidance in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011), we did not use the Jadad scale for quality assessment of the included trial (Jadad 1996).

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Lynch 2005

  1. a

    SAH: subarachnoid haemorrhage
    TCD: transcranial Doppler

MethodsRandomised, placebo-controlled trial
Participants39 participants with aneurysmal SAH (19 participants were randomised into the treatment group and 20 into the control group)
InterventionsCholesterol-reducing agent (simvastatin, 80 mg per day) versus placebo for 14 days
Outcomes
  1. Vasospasm: defined as the clinical impression of a delayed ischaemic neurological deficit

  2. Liver transaminases

  3. Creatine phosphokinase

Notes 
Risk of bias
BiasAuthors' judgementSupport for judgement
Random sequence generation (selection bias)Unclear riskNo description was provided in the article
Allocation concealment (selection bias)Unclear riskNo description was provided in the article
Blinding of participants and personnel (performance bias)
All outcomes
Low risk

Quote: "All clinicians and investigators were blinded to treatment group" and "TCD evaluated by a blinded neurosonologist"

Comment: probably done

Blinding of outcome assessment (detection bias)
All outcomes
Unclear riskNo description was provided in the article
Incomplete outcome data (attrition bias)
All outcomes
Low riskAll patients finished the trial
Selective reporting (reporting bias)Unclear riskNo description was provided in the article
Other biasUnclear riskMethods were briefly described

Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion
  1. a

    SAH: subarachnoid haemorrhage

Ayata 2005Agents were administered for more than 14 days
HDS-SAH 2010High dose (80 mg) versus normal dose (40 mg) simvastatin for aneurysmal SAH and agents were administered for more than 14 days
Li 2010It was not clear whether SAH was caused by aneurysm or not
Macedo 2009Agents were administered for more than 14 days and it was not clear whether SAH was caused by aneurysm or not
Mangoyan 2009Included participants with traumatic SAH
Roitberg 2007Agents were administered for more than 14 days
Romero 2011Agents were administered for more than 14 days
Simsab 2008Agents were administered for more than 14 days
STASH 2006Agents were administered for a maximum of 21 days
Suzuki 2009Agents were administered for more than 14 days
Tian 2007It is not clear whether SAH was caused by aneurysm or not
Tseng 2004Treatment in some patients was administered for less than 14 days
Wu 2006Agents were administered for more than 14 days and it was not clear whether all participants had aneurysmal SAH or not
Zhou 2006It was not clear whether SAH was caused by aneurysm or not

Characteristics of studies awaiting assessment [ordered by study ID]

Jaschinski 2008

  1. a

    RCT: randomised controlled trial
    SAH: subarachnoid haemorrhage

MethodsRCT
Participants98 participants with aneurysmal SAH: 40 participants were randomised into the treatment group and 58 into the control group
InterventionsPravastatin (40 mg) or non-statin treatment within 24 hours after the ictus
Outcomes
  1. Delayed ischaemic disease

  2. Glasgow Outcome Scale

  3. Intensive Care Unit mortality

NotesIt is an abstract
It is not clear how long treatment lasted

Ancillary