Direct oral anticoagulants in treatment of cerebral venous thrombosis: systematic review

Objectives
Current guidelines do not recommend direct oral anticoagulants (DOAC) to treat cerebral venous thrombosis (CVT) despite their benefits over standard therapy. We performed a systematic review to summarize the published experience of DOAC therapy in CVT.
Data sources
MEDLINE, EMBASE, and COCHRANE databases up to November 18, 2020.
Eligibility criteria
All published articles of patients with CVT treated with DOAC were included. Studies without follow-up information were excluded.
Data extraction and synthesis
Two independent reviewers screened articles and extracted data. A risk of bias analysis was performed.
Primary and secondary outcome measures
Safety data included mortality, intracranial hemorrhage (ICH), or other adverse events. Efficacy data included recurrent CVT, recanalization rates, and disability by modified Rankin Scales (mRS).
Results
33 studies met inclusion criteria. One randomized controlled trial, 5 observational cohorts, and 27 case series or studies reported 279 patients treated with DOAC for CVT: 41% dabigatran, 47% rivaroxaban, 10% apixaban, and 2% edoxaban, in addition to 315 patients treated with standard therapy. The observational cohorts showed a similar risk of death in DOAC and standard therapy arms (RR 2.12, 95%CI 0.29-15.59). New ICH was reported in 2 (0.7%) DOAC-treated patients and recurrent CVT occurred in 4 (1.5%). A favourable mRS between 0 and 2 was reported in 94% of DOAC-treated patients, more likely than standard therapy in observational cohorts (RR 1.13, 95% CI: 1.02-1.25).
Conclusion
The evidence for DOAC use in CVT is limited although suggests sufficient safety and efficacy despite variability in timing and dose of treatment. This systematic review highlights that further rigorous trials are needed to validate these findings and to determine optimal treatment regimens.
PROSPERO ID: CRD42017078398
Methods
The search strategy was iteratively developed with assistance of a research librarian (RS). We searched Ovid MEDLINE, Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R), EMBASE, Web of Science, and the Cochrane Central Register of Controlled Trials for original reports of patients with a diagnosis of CVT treated with a DOAC up to November 18, 2020. We included all available peer-reviewed studies including RCTs, prospective or retrospective observational cohorts, case series and case studies. Studies without follow-up data were excluded. Two authors (GB, JG) independently reviewed titles and abstracts for inclusion.  Authors were contacted for additional information if necessary.

研究背景
当前指南尚未推荐直接口服抗凝剂（direct oral anticoagulants, DOAC）用于治疗脑静脉血栓形成（cerebral venous thrombosis, CVT），尽管其相较于标准治疗具有一定优势。本研究开展了一项系统综述，旨在总结已发表的关于DOAC治疗CVT的临床经验。

数据来源
MEDLINE、EMBASE及Cochrane数据库，检索时限截至2020年11月18日。

纳入排除标准
纳入所有报道接受DOAC治疗的CVT患者的已发表文献；排除无随访信息的研究。

数据提取与合成
由两名独立审阅者分别筛选文献并提取数据，并开展偏倚风险评估。

主要与次要结局指标
安全结局包括死亡率、颅内出血（intracranial hemorrhage, ICH）及其他不良事件；疗效结局包括CVT复发、血管再通率及改良Rankin量表（modified Rankin Scale, mRS）评估的残疾情况。

研究结果
共计33项研究符合纳入标准，其中包含1项随机对照试验、5项观察性队列研究及27项病例系列/病例报告，共纳入279例接受DOAC治疗的CVT患者：其中达比加群占41%、利伐沙班占47%、阿哌沙班占10%、依度沙班占2%；另有315例患者接受标准治疗。
观察性队列研究结果显示，DOAC组与标准治疗组的死亡风险相似（相对风险RR=2.12，95%置信区间CI：0.29~15.59）。DOAC治疗患者中，新发颅内出血2例（0.7%），CVT复发4例（1.5%）。94%的DOAC治疗患者获得改良Rankin量表评分0~2分的良好预后，相较于标准治疗组，观察性队列研究显示该比例更高（RR=1.13，95%CI：1.02~1.25）。

研究结论
目前关于CVT患者使用DOAC的证据仍有限，但现有数据提示其安全性与有效性均较为充足，尽管治疗时机与剂量存在一定异质性。本系统综述强调，仍需开展更多高质量严谨试验以验证上述发现，并确定最优治疗方案。

PROSPERO注册号：CRD42017078398

研究方法
本研究的检索策略由研究馆员（RS）协助迭代制定。我们检索了Ovid MEDLINE、预印本在线发表（Epub Ahead of Print）、在线加工及其他未标引引文、Ovid MEDLINE(R) Daily及Ovid MEDLINE(R)、EMBASE、Web of Science以及Cochrane对照试验中心注册库，旨在检索截至2020年11月18日发表的、关于接受DOAC治疗的确诊CVT患者的原创性研究报告。
本研究纳入所有可获取的同行评议研究，包括随机对照试验（randomized controlled trial, RCT）、前瞻性或回顾性观察队列研究、病例系列及病例报告；排除无随访数据的研究。由两名作者（GB、JG）独立审阅文献标题与摘要以确定是否纳入研究，必要时联系作者获取补充信息。