PEER REVIEW HISTORY BMJ Open publishes all

PEER REVIEW HISTORY BMJ Open publishes all reviews undertaken for accepted manuscripts. Reviewers are asked to complete a checklist review form (http://bmjopen.bmj.com/site/about/resources/checklist.pdf) and are provided with free text boxes to elaborate on their assessment. These free text comments are reproduced below.

ARTICLE DETAILS TITLE (PROVISIONAL) AUTHORS

Resuming anticoagulants after anticoagulation-associated intracranial hemorrhage: systematic review and meta-analysis Zhou, Zien; Yu, Jie; Carcel, Cheryl; Delcourt, Candice; Shan, Jiehui; Lindley, Richard; Neal, Bruce; Anderson, Craig; Hackett, Maree

VERSION 1 – REVIEW

REVIEWER REVIEW RETURNED GENERAL COMMENTS

Santosh Murthy Weill Cornell Medicine, New York, USA 31-Oct-2017 The authors present a systematic review and meta-analysis on the resumption of anticoagulation (AC) after AC-associated intracranial hemorrhage. The results of this meta-analysis suggest that reinstatement of anticoagulation therapy is associated with a lower risk of thromboembolic events, with no perceivable increase in the risk of ICH recurrence. I have the following concerns: 1. The present meta-analysis lacks originality. There are two recent meta-analyses on the same topic published earlier this year in Stroke and Neurology respectively. These studies have reported identical results. I am not sure what new information this study offers. 2. The present study shows no difference in mortality between the AC and no-AC groups. However, a very recent prospective study from Biffi et al. (Annals of Neurology, 2017) using data from US and Europe shows that resumption of AC therapy was associated with a significantly lower mortality and improved functional outcomes, regardless of the location of the hemorrhage. Could the authors clarify on the discrepancy in the results?

REVIEWER

REVIEW RETURNED GENERAL COMMENTS

Daniel M. Witt University of Utah College of Pharmacy United States of America 07-Nov-2017 This is a well written meta analysis. It appears that the authors have satisfactorily responded to the major issues raised in an earlier peer review that was included along with this submission. The writing is clear and concise. The conclusions are reasonable given the summarized evidence. The methodology seems appropriate. This work is confirmatory to similar meta analyses.

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Stefano Barco Center for Thrombosis and Hemostasis, Mainz (Germany) 14-Nov-2017 The authors performed a study-level meta-analysis to determine the outcome of anticoagulated patients with intracranial hemorrhage exposed or not to anticoagulation resumption. No data from clinical trials were available and therefore only (retrospectively conducted) cohort studies were included in the analysis. Main limitations to such approach have been already underlined by the reviewer who evaluated the manuscript in occasion of prior submission. Moreover, please note that at least 5 similar studies have been published in the past year/months: - Restarting Anticoagulant Therapy After Intracranial Hemorrhage: A Systematic Review and Meta-Analysis. (Murthy et al., Stroke) - Warfarin resumption following anticoagulant-associated intracranial hemorrhage: A systematic review and meta-analysis (ChaiAdisaksopha et al., Thromb Res) - Long-term antithrombotic treatment in intracranial hemorrhage survivors with atrial fibrillation. (Korompoki et al., Neurology) - Antithrombotic treatment after stroke due to intracerebral haemorrhage.(Perry et al., Cochrane Coll) - Timing of vitamin K antagonist re-initiation following intracranial hemorrhage in mechanical heart valves: Systematic review and meta-analysis.(AlKherayf et al., Thromb Res) - Late breaking abstract presented by Dr. Sam Schulman @2017 ISTH congress reporting results of an individual patient level metaanalysis of cohort studies. As commented in our recent letter published in Stroke (10.1161/STROKEAHA.117.018509), I believe that performing study-level meta-analysis in this setting does not provide better or additional evidence compared to the interpretation of large retrospective studies alone and, as also discussed by the authors, does not improve/change clinical practice. Major comments: - study-level meta-analysis does not permit to adjust for relevant covariates (i.e. site of intracranial bleeding, comorbidities, delay of anticoagulant resumption); - confounding by indication has a large impact on risk estimates; - study populations are heterogeneous (AFib, VTE, mechanical heart valves), as well outcomes (recurrent ischemic stroke, recurrent VTE, valve thrombosis); - one cannot exclude a major role of death as a competing risk for other clinical outcomes; - pooled incidence rate ratios should also be provided since different studies adopted various follow-up lengths.


M. Fernanda Bellolio, MD, MS Mayo Clinic, United States of America. 06-Dec-2017 Resuming anticoagulants after anticoagulation-associated intracranial hemorrhage: systematic review and metaanalysis Thank you for the opportunity to review this study. This study

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address an important topic, of clinical relevance for a broad range of clinicians, particularly cardiologists, neurologist, and primary care doctors. Overall this is a detailed review, with useful supplementary material with the tables and subsequent analyses performed. The methods are adequately reported, in a way that are reproducible and followed standardized guidelines for reporting. PRISMA was followed, and the study was registered in PROSPERO (date of registration was April 2017, date of initiation of research activities was February 2016). The authors appropriately used random effects for their metaanalyses. Random effects account for the clinical and statistical heterogeneity between studies, and calculate a more conservative confidence interval. The effects of treatment are assumed to vary around some overall average treatment effect, as opposed to a fixed-effects model, in which it is assumed that each study has the same fixed common treatment effect. The authors used funnel plots, as a caution note, funnel plots can be misleading when less than 10 studies are evaluated. [reference Lau J, et al. BMJ. 2006 Sep 16;333(7568):597-600.]. The risk of bias and quality was assessed by the authors. Unfortunately a very similar systematic review was published on the same topic, and the authors address their differences in the discussion, however it brings into question for the journal editors the value of publishing a second very similar review. (Murthy SB et al. Restarting Anticoagulant Therapy After Intracranial Hemorrhage: A Systematic Review and Meta-Analysis. Stroke. 2017 Jun;48(6):1594-1600, with similar findings and included studies: Eight studies were eligible for inclusion in the meta-analysis, with 5306 ICH patients. Almost all studies evaluated anticoagulation with vitamin K antagonists. Reinitiation of anticoagulation was associated with a significantly lower risk of thromboembolic complications (pooled relative risk, 0.34; 95% confidence interval, 0.25-0.45; Q=5.12, P for heterogeneity=0.28). There was no evidence of increased risk of recurrent ICH after reinstatement of anticoagulation therapy, although there was significant heterogeneity among included studies (pooled relative risk, 1.01; 95% confidence interval, 0.58-1.77; Q=24.68, P for heterogeneity