Location specific risk factors for intracerebral hemorrhage: Systematic review and meta-analysis

Objective

To conduct a systematic review and meta-analysis of studies reporting on risk factors according to the location of the intracerebral hemorrhage.

Methods

We searched PubMed and Embase for cohort and case-control studies reporting on ≥100 patients with spontaneous intracerebral hemorrhage, that specified the location of the hematoma and reported associations with risk factors published until June 27th 2019. Two authors independently extracted data on risk factors. Estimates were pooled with the generic variance-based random effects method.

Results

After screening 10 013 articles, we included 42 studies totaling 26 174 patients with intracerebral hemorrhage (9 141 lobar and 17 033 non-lobar). Risk factors for non-lobar intracerebral hemorrhage were hypertension (risk ratio 4.25, 95% confidence interval 3.05-5.91, I2=92%), diabetes (RR 1.35, 1.11-1.64, I2=37% ), male sex (RR 1.63, 1.25-2.14, I2=61%), alcohol overuse (RR 1.48, 1.21-1.81, I2=19%), underweight (RR 2.12, 1.12-4.01, I2=31%), and being black (RR 2.19, 1.21-3.96, I2=96%) or Hispanic (RR 2.13,0.94-4.81, I2=71%) in comparison with being white.  Hypertension, but not any of the other risk factors, was also a risk factor for lobar intracerebral hemorrhage (RR 1.83, 1.39-2.42, I2=76%).  Smoking, hypercholesterolemia and obesity were associated with neither non-lobar nor lobar intracerebral hemorrhage.

Conclusions

Hypertension is a risk factor for both non-lobar and lobar intracerebral hemorrhage, although with double the effect for non-lobar intracerebral hemorrhage. Diabetes, male sex, alcohol overuse, underweight, and being black or Hispanic are risk factors for non-lobar intracerebral hemorrhage only. Hence, the term “hypertensive intracerebral hemorrhage” for non-lobar intracerebral hemorrhage is not appropriate. 

Methods
The uploaded data is supplemental data belonging to the manuscript "Location specific risk factors for intracerebral hemorrhage: Systematic review and meta-analysis"

Methods

Search strategy and selection criteria

We registered our protocol in PROSPERO (CRD42019117543). We searched PubMed and Embase for cohort, case-crossover, and case-control studies on risk factors for ICH published until June 27th 2019 according to the PRISMA statement methodology.18 We used different combinations of the keywords intracerebral hemorrhage and synonyms; cohort, case-control, case-crossover or longitudinal study; and potential risk factors and synonyms (data available from Dryad; see e-1 for detailed search strategy).  For this review we did not assess use of (antithrombotic) medication as a risk factor nor did we study genetic risk factors. We used the studies selected in our previous systematic review and meta-analysis for studies published before 2001. We checked reference lists of all included publications and the citation list of our previous systematic review and meta-analysis for additional articles,7 and repeated this until no further studies were found. We applied no language restrictions.

Titles and abstracts and subsequently full-text versions were screened independently by two investigators  (WMTJ and KW) using the following inclusion criteria: 1) Included patients were 18 years or older; 2) ICH had to be confirmed by CT, MRI, or autopsy in 100% of cases, not only based on International Classification of Diseases (ICD) codes; 3) ICH location had to be specified; 4) A cohort, case-crossover or case-control  design; 5) ICH had to be analysed as a separate entity, not in combination with subarachnoid hemorrhage; 6) Reporting on at least 100 patients with ICH. If studies included patients with ICH caused by a vascular malformation, tumour, coagulation disorder (use of antithrombotic medication was allowed), or hemorrhagic transformation of infarction, data extraction needed to allow exclusion of these patients; if not the study was excluded. Conflicts regarding inclusion were resolved by consensus with a third reviewer (CJMK). We used Covidence (www.covidence.org) for standardized screening of articles.

Data extraction

Data were extracted independently by two reviewers (WMTJ and KW) using a pre-specified and piloted extraction form (data available from Dryad; e-2). Discrepancies in extracted data were resolved by discussion, and if necessary a third reviewer (CJMK) was consulted. In case of multiple publications on overlapping cohorts, we included the study that best matched our inclusion criteria and with the largest amount of data relevant to the review. We extracted data on study period, study design, country of study, in- and exclusion criteria, number of cases and controls, mean or median age, proportion of males, and risk factors. Risk factors were assessed according to lobar and non-lobar (deep and infratentorial) ICH location and if possible, for deep (basal ganglia, thalamus and intraventricular) and for infratentorial hemorrhages (brainstem and cerebellum) separately. We assessed methodological quality, including risk of bias, of the included studies according to the Newcastle-Ottawa Scale (NOS) for cohort and case-control studies.19

Statistical analysis

Estimates of cohort and case-control studies were first analysed separately and then combined if 95% confidence intervals (CIs) of the pooled estimates from cohort studies overlapped with those of case-control studies. We also combined maximally adjusted estimates, when available, with unadjusted estimates, if 95% CIs of the pooled unadjusted estimates overlapped with pooled adjusted estimates. If studies used different definitions for risk factors, we standardised risk factors across studies whenever possible or otherwise we accepted the criteria used in the studies. Risk factors reported in at least three studies were combined in meta-analyses; for the different subgroups of a risk factor we accepted two studies for meta-analyses. For the included studies odds ratios (ORs), relative risks (RRs) and hazard ratios (HRs) with corresponding 95% CIs, whichever were available, were obtained for the various risk factors and pooled with the generic variance-based method, weighing individual study results by the inverse of their variance. Heterogeneity was assessed using I2 statistics.20 We used a random-effects model because of the heterogeneous study characteristics. Because ORs accurately estimate RRs when risks of disease are small, we combined ORs with RRs and HRs from the longitudinal studies.21, 22 We performed a sensitivity analysis for studies with a high-quality, defined as studies with >5 points (arbitrarily chosen) on the NOS. Meta-analyses were performed in R (R programming, version 1.1.456), using the meta package (version 4.9-4).23

Data availability

Data used in this study are available to qualified investigators on request to the corresponding and senior authors.

### 研究目的
针对按脑出血（intracerebral hemorrhage, ICH）部位分类的危险因素相关研究，开展系统综述与荟萃分析。

### 研究方法
我们检索了PubMed和Embase数据库，筛选2019年6月27日前发表的、针对≥100例自发性脑出血患者、明确血肿部位并报告其与危险因素关联的队列研究与病例对照研究。由两名研究者独立提取危险因素相关数据，采用基于通用方差的随机效应模型合并效应量。

### 研究结果
共筛选10013篇文献，最终纳入42项研究，涉及26174例脑出血患者（其中脑叶出血9141例，非脑叶出血17033例）。非脑叶脑出血的危险因素包括高血压（相对危险度RR=4.25，95%置信区间CI：3.05~5.91，I²=92%）、糖尿病（RR=1.35，95%CI：1.11~1.64，I²=37%）、男性性别（RR=1.63，95%CI：1.25~2.14，I²=61%）、过量饮酒（RR=1.48，95%CI：1.21~1.81，I²=19%）、体质量过低（RR=2.12，95%CI：1.12~4.01，I²=31%），以及与白人相比为黑人（RR=2.19，95%CI：1.21~3.96，I²=96%）或西班牙裔（RR=2.13，95%CI：0.94~4.81，I²=71%）。高血压同样是脑叶脑出血的危险因素（RR=1.83，95%CI：1.39~2.42，I²=76%），其余危险因素则与脑叶脑出血无显著关联。吸烟、高胆固醇血症与肥胖既与非脑叶脑出血无关，也与脑叶脑出血无关联。

### 研究结论
高血压是非脑叶与脑叶脑出血共同的危险因素，但对非脑叶脑出血的效应强度是脑叶的两倍。糖尿病、男性性别、过量饮酒、体质量过低，以及黑人或西班牙裔身份仅为非脑叶脑出血的危险因素。因此，将非脑叶脑出血称为"高血压性脑出血"并不恰当。

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### 补充研究方法
本次上传的数据属于题为《脑出血部位特异性危险因素：系统综述与荟萃分析》的论文的补充数据。

#### 检索策略与纳入排除标准
我们在PROSPERO平台（注册号CRD42019117543）注册了本研究方案。按照PRISMA声明规范¹⁸，我们检索PubMed与Embase数据库，筛选2019年6月27日前发表的、关于脑出血（ICH）危险因素的队列研究、病例交叉研究与病例对照研究。我们采用脑出血及其同义词、队列/病例对照/病例交叉/纵向研究及其同义词、潜在危险因素及其同义词的多种组合进行检索（完整检索策略见Dryad数据库存档文件e-1）。本次综述不评估（抗血栓）药物使用作为危险因素的情况，也不研究遗传危险因素。对于2001年前发表的研究，我们采用此前系统综述与荟萃分析中已纳入的文献。我们检索所有纳入文献的参考文献列表以及此前系统综述与荟萃分析的引用列表以补充获取文献，重复该过程直至无新文献可获得，且未对语言设置限制。

#### 文献筛选
由两名研究者（WMTJ与KW）独立筛选文献标题、摘要及随后的全文，纳入标准如下：
1. 研究对象为18岁及以上成年人；
2. 脑出血（ICH）需经CT、MRI或尸检100%确认，而非仅依据国际疾病分类（ICD）编码诊断；
3. 明确标注脑出血部位；
4. 研究设计为队列、病例交叉或病例对照研究；
5. 脑出血需作为独立研究实体进行分析，不与蛛网膜下腔出血合并研究；
6. 纳入至少100例脑出血患者。
若研究纳入存在血管畸形、肿瘤、凝血功能障碍（允许使用抗血栓药物）或梗死出血性转化导致的脑出血患者，需能够提取数据以排除此类病例，否则该研究将被排除。针对纳入标准存在的分歧，由第三名研究者（CJMK）通过共识解决。我们使用Covidence平台（www.covidence.org）进行标准化的文献筛选流程。

#### 数据提取
由两名研究者（WMTJ与KW）使用预先设定并经过预试验的提取表单独立提取数据（数据存档于Dryad数据库，见文件e-2）。提取数据的分歧通过讨论解决，必要时咨询第三名研究者（CJMK）。若存在针对重叠队列的多篇文献，我们纳入最符合纳入标准且包含与本综述最相关数据的研究。我们提取的信息包括研究周期、研究设计、研究国家、纳入排除标准、病例与对照数量、平均或中位年龄、男性占比以及危险因素数据。我们按照脑叶与非脑叶（深部及幕下）脑出血部位分类评估危险因素，若可行，还将分别针对深部（基底节、丘脑及脑室内）出血与幕下出血（脑干及小脑）进行分析。我们依据纽卡斯尔-渥太华量表（Newcastle-Ottawa Scale, NOS）对纳入的队列与病例对照研究进行方法学质量评估，包括偏倚风险评估¹⁹。

#### 统计学分析
首先分别分析队列研究与病例对照研究的效应量，若队列研究合并效应量的95%置信区间（CI）与病例对照研究的合并效应量CI重叠，则将两类研究合并分析。若可获得，我们将最大调整后的效应量与未调整效应量合并，前提是未调整效应量合并后的95%CI与调整后效应量合并后的CI重叠。若不同研究对危险因素采用不同定义，我们尽可能统一各研究的危险因素定义，否则采用研究自身使用的判定标准。仅纳入至少有3项研究报告的危险因素进行荟萃分析；对于某一危险因素的不同亚组，若有2项研究即可纳入荟萃分析。我们提取纳入研究中各类危险因素的比值比（odds ratio, OR）、相对危险度（risk ratio, RR）、风险比（hazard ratio, HR）及对应95%CI（以可获得者为准），采用基于通用方差的方法合并效应量，以各研究方差的倒数对单个研究结果进行加权。使用I²统计量评估异质性²⁰。由于研究特征存在异质性，我们采用随机效应模型。当疾病风险较低时，比值比可准确估计相对危险度，因此我们将纵向研究中的OR与RR、HR进行合并²¹,²²。我们针对纽卡斯尔-渥太华量表得分>5分的自定义阈值高质量研究开展敏感性分析。本研究的荟萃分析通过R软件（R编程，版本1.1.456）及meta包（版本4.9-4）完成²³。

#### 数据可用性
本研究使用的数据可应合格研究者的请求，向通讯作者与资深作者申请获取。