Objectives and Design of BLEEDS: A Cohort Study to Identify New Risk Factors and Predictors for Major Bleeding during Treatment with Vitamin K Antagonists

Background
Risk scores for patients who are at high risk for major bleeding complications during treatment with vitamin K antagonists (VKAs) do not perform that well. BLEEDS was initiated to search for new biomarkers that predict bleeding in these patients.
Objectives
To describe the outline and objectives of BLEEDS and to examine whether the study population is generalizable to other VKA treated populations.
Methods
A cohort was created consisting of all patients starting VKA treatment at three Dutch anticoagulation clinics between January-2012 and July-2014. We stored leftover plasma and DNA following analysis of the INR.
Results
Of 16,706 eligible patients, 16,570 (99%) were included in BLEEDS and plasma was stored from 13,779 patients (83%). Patients had a mean age of 70 years (SD 14), 8713 were male (53%). The most common VKA indications were atrial fibrillation (10,876 patients, 66%) and venous thrombosis (3920 patients, 24%). 326 Major bleeds occurred during 17,613 years of follow-up (incidence rate 1.85/100 person years, 95%CI 1.66–2.06). The risk for major bleeding was highest in the initial three months of VKA treatment and increased when the international normalized ratio increased. These results and characteristics are in concordance with results from other VKA treated populations.
Conclusion
BLEEDS is generalizable to other VKA treated populations and will permit innovative and unbiased research of biomarkers that may predict major bleeding during VKA treatment.

背景
目前针对维生素K拮抗剂（vitamin K antagonists, VKAs）治疗期间存在大出血并发症高风险的患者，现有风险评分模型的预测效果欠佳。本研究BLEEDS旨在探寻可预测此类患者出血事件的新型生物标志物。

研究目的
阐明BLEEDS研究的框架与目标，并验证该研究队列是否可推广至其他接受VKAs治疗的人群。

研究方法
构建了一项队列研究，纳入2012年1月至2014年7月间，在荷兰3家抗凝门诊起始VKAs治疗的所有符合条件患者。在完成国际标准化比值（International Normalized Ratio, INR）检测后，我们留存了剩余的血浆与DNA样本。

研究结果
共计16706例符合入组标准的患者中，16570例（99%）被纳入BLEEDS研究，其中13779例（83%）患者的血浆样本得以留存。本队列患者的平均年龄为70岁，标准差（SD）为14；男性患者8713例，占比53%。最常见的VKAs治疗适应证为心房颤动（10876例，66%）与静脉血栓形成（3920例，24%）。在17613人年的随访期间，共发生326例大出血事件，发病率为1.85/100人年，95%置信区间（95%CI）为1.66~2.06。VKAs治疗初始3个月内大出血风险最高，且国际标准化比值升高时大出血风险亦随之增加。上述研究结果与队列特征，与其他接受VKAs治疗人群的相关研究结果具有一致性。

研究结论
BLEEDS研究队列可推广至其他接受VKAs治疗的人群，本研究将为探寻可预测VKAs治疗期间大出血事件的生物标志物提供创新性且无偏倚的研究基础。