PubMed

Search ((((((((“Homocysteine”[Mesh] OR “Hyperhomocysteinemia”[Mesh] OR homocyst* OR hyperhomocyst*))) AND ((“Embolism and Thrombosis”[Mesh] OR “Myocardial Infarction”[Mesh] OR “Acute Coronary Syndrome”[Mesh] OR “Brain Ischemia”[Mesh] OR “Stroke”[Mesh] OR “Deep vein thrombosis” OR “pulmonary embolism” OR “lung embolism” OR thrombosis OR embolism OR thromboembolism OR stroke OR “acute stroke” OR “brain infarction” OR “cerebral infarction” OR “brain ischemia” OR “cerebral ischemia” OR “ischemic stroke” OR “intracranial embolism” OR “intracranial thrombosis” OR apoplexy OR “cerebrovascular accident” OR “cerebral stroke” OR “myocardial infarction” OR “myocardial infarct” OR “heart infarct” OR “heart infarction” OR “acute coronary syndrome” OR “acute myocardial infarction” OR “brain embolism” OR “cardiovascular stroke” OR “heart attack” OR “acute myocardial infarct” OR “acute heart infarction”))) AND ((“Biomarkers”[Mesh] OR “Blood”[Mesh] OR blood OR serum OR plasma OR biomarker OR “biological marker” OR “blood level” OR “blood levels”))) AND ((“Humans”[Mesh] OR adult[MeSH Terms] OR adults[All Fields] OR adult[All Fields] OR patients[All Fields] OR patient[All Fields] OR humans[All Fields] OR human[All Fields]))) AND ((Danish[Language] OR Norwegian[Language] OR English[Language] OR swedish[Language])))) NOT ((comment[Publication Type] OR congress[Publication Type] OR letter[Publication Type] OR “Case Reports”[Publication Type])).

Initially, all thromboembolic events were included as outcome, as seen in our search combinations, resulting in a large number of eligible articles ( Fig. 1 ). Therefore, our inclusion/exclusion criteria were revised after screening of abstracts to include only articles with ischemic stroke as outcome for this review. This choice was based on results found in the 2017 Cochrane review ¹⁴ which showed a potential association between Hcy and ischemic stroke in randomized trials of B-vitamin treatment.

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRIMSA) flow diagram. ¹⁶

Our inclusion criteria were studies investigating ischemic stroke events in patients with measured plasma Hcy providing original data on adult human populations. Both interventional and observational studies were included, including randomized trials, cohort, cross-sectional, and case-control studies. The accepted endpoint was acute ischemic stroke, including all subtypes. The exclusion criteria were as follows: nonoriginal literature, reviews, meta-analyses, guidelines, case studies, conference abstracts, and letters/editorials/comments without original data; missing information on Hcy concentration or studies including hyper-Hcy as a binary variable; endpoint of transient cerebral ischemia and arteriosclerotic lesions without sign of thrombosis, and silent brain infarction; and language other than English.

First, 100 abstracts were randomly selected and screened independently by the three authors for either exclusion or inclusion to full-text screening. Any disagreement was solved by consensus. Screening of the remaining abstracts was performed by MH. Similarly, 50 randomly selected articles proceeding to full text screening were read in full by all authors, and any disagreement was solved by consensus. Remaining papers were screened by MH for inclusion or exclusion, and in case of doubt, all three authors discussed the study in question.