title: Increased risk of major bleeding after a minor bleed during treatment with vitamin K antagonists is determined by fixed common risk factors.
abstract: Essentials Minor bleeding is associated with subsequent major bleeding in patients treated with vitamin K antagonists. This study confirms that patients with minor bleeds have a 2.5-fold increased risk of major bleeds. A case-crossover analysis revealed that the increased risk is due to fixed underlying risk factors. Future research may unveil these unknown fixed risk factors and improve major bleeding risk scores.
  
  
  
  Background Patients who have a minor bleed during treatment with vitamin K antagonists (VKAs) have a 3-fold increased risk of subsequent major bleeding. The nature of the underlying risk factors is largely unknown. Objectives To indicate why patients with minor bleeds are at increased risk of subsequent major bleeds (e.g. are risk factors of a transient or a fixed nature). Methods Patients who started VKA treatment between 2003 and 2013 were included. Exposure was from the minor bleed until 3 months later. We used two analyses: a Cox model which we adjusted for several known risk factors, and a case-crossover (CCO) design, which corrects for all fixed risk factors (such as chronic diseases and genes) as patients are compared with themselves. The combination of both analyses gives insight into whether the association of minor with major bleeds is a result of fixed or transient risk factors. Results Out of 26 130 patients who were included and followed for '61 672 patient years', 7194 experienced a minor bleed and 913 a major bleed. The Cox model indicated that patients with minor bleeds had a 2.5-fold increased risk of experiencing subsequent major bleeding after adjustment for known risk factors, whereas the CCO gave risk estimates around unity (odds ratio, 0.9; 95% confidence interval, 0.5-1.5). Conclusions The combination of both analyses indicates that minor bleeds are markers for fixed and currently unknown risk factors for major bleeding events.
authors.affiliation: Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands.|Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: N
authors.initials: N
authors.lastname: van Rein
authors.affiliation: Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.|Department of Medical Statistics and Bioinformatics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: S
authors.initials: S
authors.lastname: le Cessie
authors.affiliation: Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: I P
authors.initials: IP
authors.lastname: van Vliet
authors.affiliation: Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands.|Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: P H
authors.initials: PH
authors.lastname: Reitsma
authors.affiliation: Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: F J M
authors.initials: FJ
authors.lastname: van der Meer
authors.affiliation: Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands.|Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.|Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: W M
authors.initials: WM
authors.lastname: Lijfering
authors.affiliation: Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: S C
authors.initials: SC
authors.lastname: Cannegieter
mesh_terms: D000074:Acenocoumarol / Q000627:therapeutic use; D000368:Aged; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D000925:Anticoagulants / Q000627:therapeutic use*; D015331:Cohort Studies; D005260:Female; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D006470:Hemorrhage / Q000175:diagnosis / Q000517:prevention & control*; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D010644:Phenprocoumon / Q000627:therapeutic use; D016016:Proportional Hazards Models; D012307:Risk Factors; D014812:Vitamin K / Q000037:antagonists & inhibitors*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000925:Anticoagulants; D005343:Fibrinolytic Agents; D014812:Vitamin K; D000074:Acenocoumarol; D010644:Phenprocoumon
keywords: coumarins; crossover studies; follow-up studies; hemorrhage; risk factors