Thromboembolic events and major bleeding with warfarin, non-vitamin K antagonist oral anticoagulants or antiplatelets following mitral valve repair: A systematic review and meta-analysis

ABSTRACT Background International guidelines recommend the use of a vitamin K antagonist (VKA, e.g. warfarin) for the first three months after mitral repair as a Class IIa recommendation with Level of Evidence C. High rates of atrial fibrillation, thrombogenicity of the non-endothelialised repair components, and high rates of antiplatelet resistance are cited as rationale. However, surveys of practice indicate that surgeon compliance is low, suggesting uncertainty of the evidence. We sought to establish the best current evidence by conducting a systematic review as a precursor to a randomised trial. Methods We included prospective randomised and retrospective observational studies of adult patients undergoing mitral valve repair with no other indications for anticoagulation. Studies had to compare a VKA to a non-vitamin K antagonist oral anticoagulants (NOAC), anti-platelet or placebo/null treatment (“Other”). Outcomes had to include thromboembolic complications, major bleeding or mortality within three months. The Cochrane Register, Medline, Embase and Clinical Trials Registries were checked. Risk of Bias assessments were conducted using the ROBINS-I tool as part of the GRADE Pro methodology. Quantitative synthesis was agreed following review of the methodology and a random effects model using the Mantel-Haenszel method employed. Results There were no randomised controlled trials comparing VKA to other treatment strategies. Six observational studies comprising 5291 patients (2925 receiving VKA, 807 antiplatelet, 104 NOAC and 1455 null treatment) were included. Four studies reporting early thromboembolic risk found that the use of a VKA may not be associated with a reduction in risk (relative risk [RR] 0.54, 95% CI 0.13 – 2.35, p=0.41, I 2 = 68%, overall certainty of evidence = very low). Three studies reporting late thromboembolism also showed that use of VKA may not be associated with risk reduction (RR 0.84, 95% CI 0.57 – 1.24, p=0.37, I 2 = 23%). Two studies reported on early risks of major bleeding and found VKA treatment had very uncertain effects (RR 0.60, 95% CI 0.36 – 1.02, p=0.06, I 2 =0%, certainty of evidence = very low). Late bleeding reported by four studies was uncertain but seemed to show no risk reduction with VKA (RR 0.97, 95% CI 0.37 – 2.52, p=0.95, I 2 =73%). Three studies found an unclear effect of VKA use on early mortality (RR 0.39, 95% CI 0.10 – 1.51, p=0.17, I 2 =35%, certainty of evidence = low). Two studies comparing VKA with antiplatelets and no thromboprophylaxis respectively, showed there may be risk reduction in late mortality (RR 0.72, 95% CI 0.59 – 0.87, p=0.0006, I 2 =0%, certainty of evidence = very low), although this effect was weighted by a single study. Conclusion There is insufficient good quality evidence to inform anticoagulation, anti-platelet or null treatment practices following mitral valve repair. A high-quality trial is therefore required in this setting, with particular methodological focus on aspects found to increase risk of bias in current studies. Funding There was no funding for this systematic review. Registration The review protocol was published in PROSPERO (CRD42021271198).