Effects of clazosentan, cilostazol, and statins on aneurysmal subarachnoid hemorrhage

Abstract

Background

: Aneurysmal subarachnoid hemorrhage (aSAH) is a disease caused by the infiltration of blood into the subarachnoid space due to the rupture of an intracranial aneurysm. It is a serious cerebrovascular disease, with a mortality rate of about 40% worldwide, which seriously threatens human life and health. Many drugs are used to treat aSAH and its complications, and some have been tested in systematic reviews and have shown good effects. But which drug has the best effect remains unclear. This network meta-analysis (NMA) aims to assess the effectiveness and feasibility of clazosentan, cilostazol, and statins in patients with aSAH.

Methods

: We will search for EMBASE.com, PubMed, the Cochrane Library, and Web of Science from inception to December 2019. Randomized controlled trials (RCTs) reporting efficacy and safety of clazosentan, cilostazol, and statins compared with the control, or compared with each other for the treatment of aSAH will be included. Two independent reviewers will assess the risk of bias of the included RCTs with the Cochrane “Risk of bias” tool. The pairwise meta-analysis will be performed with the random-effects model. The NMA will be performed in a Bayesian hierarchical framework using Markov Chain Monte Carlo method in WinBUGS 1.4.3. Egger test and funnel plot will be used to assess the publication bias. We will evaluate the quality of evidence for each outcome according to the GRADE approach.

Results

: The results of this NMA will be submitted to a peer-reviewed journal for publication.

Conclusion

: This study will summarize up-to-date evidence to compare the efficacy and safety of clazosentan, cilostazol, and statins on aSAH.

PROSPERO registration number: CRD42019147523.

1. Introduction

Aneurysmal subarachnoid hemorrhage (aSAH) is a disease caused by the infiltration of blood into the subarachnoid space due to the rupture of an intracranial aneurysm.^[1] It is a severe cerebrovascular disease, accounting for 5% of all strokes.^[2,3] Aneurysmal subarachnoid hemorrhage often causes many complications, such as cerebral ischemia, vasospasm, bacterial meningitis, cephaledema, hydrocephalus, and seizure.^[4–7] Despite advances in the diagnosis and treatment of intracranial aneurysms after decades of research, the incidence and mortality of aSAH are still high.^[8,9] In the United States, approximately 30,000 people suffer from aSAH each year, with a mortality rate of nearly 50%.^[10,11] Globally, the mortality of aSAH is about 40%,^[12] which seriously threatens human life and health.

Many drugs have been used to treat aSAH and its complications and have shown potential effects. Clazosentan, an endothelin receptor A antagonist, prevents angiographic vasospasm and delayed ischemic neurologic deficit (DIND), reduces all-cause mortality and vasospasm-related morbidity in patients with aSAH.^[13–15] Cilostazol can prevent thrombosis and dilate blood vessels and has a preventive effect on hydrocephalus secondary to aSAH.^[16,17] Statins (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor) can increase the expression of nitric oxide synthase in the brain endothelium, improve endothelial function, increase cerebral blood flow, and prevent ischemia.^[18,19] Many meta-analyses have also evaluated the effects of these drugs on aSAH.^[20–22] But most of them are pairwise meta-analyses that compare the efficacy and safety of one drug with a placebo or another drug, and lack of studies comparing multiple interventions simultaneously. Therefore, it is unclear which drug has the best effect with less adverse effects.

Systematic reviews and meta-analyses are essential tools for generating reliable evidence of healthcare decisions.^[23–25] Network meta-analysis (NMA) is an extension of conventional meta-analyses of a given condition, which can be used to assess the relative effectiveness of multiple interventions and rank ordering of the interventions.^[26–28] Thus, we will perform a NMA to assess the effectiveness and feasibility of clazosentan, cilostazol, and statins in patients with aSAH.

2. Methods

This study protocol has been registered on PROSPERO (International Prospective Register of Systematic Reviews). The registration number is CRD42019147523. This NMA will be conducted and reported according to the Preferred Reporting Items for network meta-analyses (PRISMA-NMA) statement.^[29]

2.1. Eligibility criteria

2.1.1. Types of study

Randomized controlled trials (RCTs) reporting efficacy and safety of clazosentan, cilostazol, and statins compared with the control or compared with each other for the treatment of aSAH. RCTs should describe the number of patients and events of interest in each group. Cluster-randomized or quasi-randomized trials will be excluded.

2.1.2. Participants

Adult patients (aged 18 years or older) diagnosed with aSAH, regardless of gender, ethnicity, and duration of illness.

2.1.3. Interventions

Any dose of clazosentan, cilostazol, and statins. The intervention also can be a combination of these 3 or 2 drugs.

2.1.4. Comparisons

The control will include clazosentan, cilostazol, statins, and placebo.

2.1.5. Outcomes

The primary outcomes will include poor clinical outcome, DIND requiring rescue therapy, all-cause mortality, and vasospasm-related morbidity. The poor outcome is defined as the Glasgow outcome scale score of 1 to 3 or the modified Rankin Scale of 3 to 6 at the end of the follow-up.^[15,21] DIND is defined as a decrease of 2 or more points on the modified Glasgow Coma Scale or an increase of 2 or more points on the National Institutes of Health Stroke Scale lasting more than 2 hours.^[20] All-cause mortality is defined as death for any cause. Vasospasm-associated morbidity is defined as cerebral infarction or DIND associated with vasospasm and is not associated with rescue therapy.^[20] The secondary outcomes include severe angiographic cerebral vasospasm, symptomatic vasospasm, and new cerebral infarction.

2.2. Information sources

We will search EMBASE.com, PubMed, the Cochrane Library, and Web of Science from inception to December 2019. We will also retrieve the reference lists of published systematic reviews to identify additional trials.

2.3. Search strategy

A combination of subject terms and keywords will be used and we will make appropriate adjustments of vocabulary and grammar between different databases. The keywords include: “clazosentan,” “cilostazol,” “statins,” “aneurysm,” “subarachnoid hemorrhage,” “intracranial hemorrhage,” and “hemorrhagic stroke.” Search strategy of PubMed as follows:

#1 “Clazosentan” [Supplementary Concept] OR Clazosentan [Title/Abstract] OR VML-588 [Title/Abstract] OR VML 588 [Title/Abstract] OR VML588 [Title/Abstract] OR AXV-034343 [Title/Abstract] OR Ro 61–1790 [Title/Abstract] OR Ro-61–1790 [Title/Abstract] OR AXV 034 [Title/Abstract] OR AXV-034 [Title/Abstract] OR AXV 343434 [Title/Abstract] OR AXV343434 [Title/Abstract] OR AXV-343434 [Title/Abstract]

#2 “Cilostazol” [Mesh] OR 6-(4-(1-Cyclohexyl-1H-tetrazol-5-yl)butoxy)-3,4-dihydro-2(1H)-quinolinone [Title/Abstract] OR OPC 13013 [Title/Abstract] OR OPC-13013 [Title/Abstract] OR Pletal [Title/Abstract]

#3 “Hydroxymethylglutaryl-CoA Reductase Inhibitors” [Mesh] OR Hydroxymethylglutaryl-CoA Reductase Inhibitors [Title/Abstract] OR Hydroxymethylglutaryl CoA Reductase Inhibitors [Title/Abstract] OR HMG-CoA Reductase Inhibitors [Title/Abstract] OR HMG CoA Reductase Inhibitors [Title/Abstract] OR Hydroxymethylglutaryl-CoA Inhibitors [Title/Abstract] OR Hydroxymethylglutaryl CoA Inhibitors [Title/Abstract] OR Hydroxymethylglutaryl-Coenzyme A Inhibitors [Title/Abstract] OR Hydroxymethylglutaryl Coenzyme A Inhibitors [Title/Abstract] OR Statins [Title/Abstract] OR Statin [Title/Abstract] OR Lovastatin [Title/Abstract] OR Pravastatin [Title/Abstract] OR Simvastatin [Title/Abstract] OR Fluvastatin [Title/Abstract] OR Atorvastatin[Title/Abstract] OR Rosuvastatin [Title/Abstract] OR Pitavastatin [Title/Abstract]

#4 #1 OR #2 OR #3

# 5 “Subarachnoid Hemorrhage” [Mesh] Subarachnoid Hemorrhage [Title/Abstract] OR Subarachnoid Hemorrhages [Title/Abstract] OR SAH[Title/Abstract] OR SAHs [Title/Abstract] OR aSAH [Title/Abstract] OR aSAHs [Title/Abstract] OR Aneurysmal Subarachnoid Hemorrhage [Title/Abstract] OR Aneurysmal Subarachnoid Hemorrhages [Title/Abstract] OR Intracranial Hemorrhage [Title/Abstract] OR Intracranial Hemorrhages [Title/Abstract] OR Hemorrhagic Stroke [Title/Abstract]

#6 #4 AND #5

2.4. Selection of studies

Reference management software (Endnote X8) will be used to manage the identified records. We will first remove potential duplicate records. Then, 2 independent reviewers will read the title or abstract, or both of each record, to determine which studies should be assessed further. We will investigate all potentially relevant records as full text and classify studies as included studies, excluded studies, studies awaiting classification or ongoing studies in accordance with the inclusion and exclusion criteria. The reasons for the excluded studies will be recorded. We will resolve any discrepancies through consensus or recourse to a third review author. If there are studies with overlapping data, we will choose a study with larger sample size. For studies that the information is incomplete or not reported, we will attempt to contact authors for more information.

2.5. Data extraction

Data extraction forms with detailed written instructions will be used to collect pertinent information and data. The detailed information includes author, years of publication, country, language, setting, age, gender, ethnicity, number of participants, participants lost to follow-up, treatment modalities, dose of treatment, duration of treatment, and duration of follow-up. One author will extract data from the included studies and a second author will check the data. Disagreements will be resolved by consensus, or by involving a third reviewer.

2.6. Assessment of risk of bias

Two independent reviewers will assess the risk of bias of the included RCTs with the Cochrane “Risk of bias” tool.^[30] We will resolve any disagreement by discussion or by involving a third review author. The tool consists of random sequence generation, allocation concealment, blinding of all participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other sources of bias. We will judge the risk of bias domains as low, high, or unclear risk.

2.7. Geometry of the evidence network

We will create network diagrams to describe and present the geometry of the intervention network of comparisons across trials using STATA (13.0; Stata Corporation, College Station, TX). For studies that are not linked by interventions, we excluded them from the NMA and only describe the findings. In the network diagram, nodes represent different interventions, and edges represent head-to-head comparisons between interventions. The size of the nodes indicates the sample size of the intervention, and the thickness of the edges indicates the number of trials included.

2.8. Statistical analysis

2.8.1. Measures of treatment effect

For dichotomous variables, we will calculate the pooled risk ratios with the 95% confidence intervals (95% CIs). For continuous variables, we will calculate the mean differences or standardized mean differences (if different studies use different measures to assess the same outcome) with 95% CIs to express the overall effect.

2.8.2. Data synthesis

We will first perform pairwise meta-analyses to estimate the effect of different interventions with the random-effects model based on the DerSimonian and Laird method adjusted by the Knapp–Hartung method.^[31] The NMA will be performed in a Bayesian hierarchical framework using Markov Chain Monte Carlo method in WinBUGS 1.4.3 (MRC Biostatistics Unit, Cambridge University, UK).^[32] The model fit and parsimony will be evaluated using the deviance information criterion (DIC). The convergence will be assessed using the Brooks-Gelman-Rubin (BGR) plots method.^[33] We will use the surface under the cumulative ranking curve (SUCRA) to rank the treatments according to each outcome accounting for the uncertainty in the treatment effects. The absolute rank of the treatment per outcome is presented using ’Rankograms’ that visually show the distribution of ranking probabilities.^[34] The node splitting method will be adopted to examine the inconsistency between direct and indirect comparisons if a loop connecting 3 or more arms exist.^[35] We will create all the result figures using STATA (13.0; Stata Corporation, TX) software.

2.8.3. Assessment of heterogeneity

Statistical heterogeneity within each pairwise comparison will be assessed using the I² statistic, and I² values of 25%, 50%, and 75% represent low, moderate, and severe statistical heterogeneity, respectively.^[31] We will explore sources of heterogeneity by subgroup analyses and meta-regression analyses. If clinical heterogeneity is present, the pairwise comparison will not be included in the NMA.

2.8.4. Subgroup analysis

If the necessary data are available, subgroup analyses will be done based on gender, country, age, and dose of interventions.

2.8.5. Sensitivity analysis

Sensitivity analyses by sequentially excluding one study at a time or by removing low-quality studies will be carried out to check whether the results are robust.

2.8.6. Assessment of publication bias

Egger test and funnel plot will be performed to assess the publication bias when applicable.

2.9. Quality of evidence

We will evaluate the overall quality of the evidence for primary and secondary outcomes according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. The GRADE tool consists of 5 criteria: risk of bias, publication bias, imprecision, inconsistency, and indirectness.^[36] For each outcome, 2 review authors will independently rate the quality of evidence for each comparison as high, moderate, low, or very low using GRADEpro GDT. Any discrepancies will be resolved by consensus or by arbitration with a third review author. All results will be presented in a 'Summary of findings’ table.

3. Ethics and dissemination

Ethics approval and patient consent are not required as this study is a NMA based on published trials. This study will compare the efficacy and safety of clazosentan, cilostazol, and statins on aSAH. The results of this NMA will be submitted to a peer-reviewed journal for publication. We hope the findings of this study will help clinicians and patients to select an optimal drug for patients with aSAH.

Author contributions

JFH, LZ, and MW planned and designed the research. JFH, LZ, YY, and XYL tested the feasibility of the study. MW, GC, and YFS provided methodological advice, polished and revised the manuscript. JFH, LZ, and MW wrote the manuscript. All authors approved the final version of the manuscript.

Conceptualization: Junfang He, Li Zhang, Xinyue Luo.

Funding acquisition: Yanfei Shen.

Investigation: Li Zhang, Yao Yu.

Methodology: Junfang He, Min Wei.

Project administration: Min Wei.

Resources: Junfang He, Li Zhang, Yao Yu, Xinyue Luo.

Supervision: Min Wei.

Validation: Min Wei, Gen Chen, Yanfei Shen.

Visualization: Junfang He, Yao Yu.

Writing – original draft: Junfang He, Li Zhang, Min Wei.

Writing – review & editing: Junfang He, Li Zhang, Min Wei.