Heran Balraj S, Allan G Michael, Green Lee, Korownyk Christina, Kolber Michael, Olivier Nicole, Flesher Mary, Garrison Scott
Vancouver Coastal Health Research Institute, Vancouver, BC, Canada.
Department of Family Medicine, University of Alberta, Edmonton, AB, Canada.
Trials. 2016 Aug 4;17(1):391. doi: 10.1186/s13063-016-1516-9.
Warfarin is an oral anticoagulant medication that disrupts the liver's production of clotting factors. While this medication is highly effective for the prevention of thromboembolic events, it also has a narrow therapeutic range and a vulnerability to interactions with other drugs and vitamin K-containing foods. Warfarin is commonly ingested at dinnertime, the same time of day that dietary vitamin K consumption (found largely in green leafy vegetables) is most variable. While the long half-life of warfarin might make this irrelevant, the ultra short half-life of vitamin K and the possibility of a hepatic first-pass effect for warfarin make it worth evaluating whether morning ingestion of warfarin, when vitamin K levels are consistently low, leads to greater stability of its anticoagulant effect. An examination of the timing of administration on the effectiveness of warfarin has never before been conducted.
METHODS/DESIGN: This is a 7-month Prospective Randomized Open Blinded End-point (PROBE) study in which established evening warfarin users (primary care managed Canadian outpatients in the provinces of British Columbia and Alberta) will be randomized to either switch to morning ingestion of warfarin (the intervention) or to continue with evening use (the control). The primary outcome is the percent change in the proportion of time spent outside the therapeutic range of the international normalized ratio (INR) blood test. Secondary outcomes include change in proportion of time spent within the therapeutic INR range (TTR), percentage of patients with TTR >75 %, percentage of patients with TTR <60 %, and major warfarin-related cardiovascular events (including all-cause mortality, hospitalization for stroke, hospitalization for GI bleeding, and deep venous thrombosis/pulmonary embolism). We will also compare whether day-to-day variability in the consumption of high vitamin K-containing foods at baseline affects the baseline TTR in this cohort of evening warfarin users.
This study addresses whether the timing of warfarin ingestion influences the stability of its anticoagulant effect. Should morning ingestion prove superior, the safety and effectiveness of this medication, and hence the prevention of stroke, pulmonary embolus, and major hemorrhage, could potentially be improved with no added cost or inconvenience to the patient.
ClinicalTrials.gov: NCT02376803 . Registered on 25 February 2015.
华法林是一种口服抗凝药物，可干扰肝脏凝血因子的生成。虽然这种药物在预防血栓栓塞事件方面非常有效，但它的治疗窗较窄，且易与其他药物及含维生素K的食物发生相互作用。华法林通常在晚餐时间服用，而一天中这个时候膳食中维生素K的摄入量（主要存在于绿叶蔬菜中）变化最大。虽然华法林的长半衰期可能使这一点无关紧要，但维生素K的超短半衰期以及华法林可能存在的肝首过效应，使得评估在维生素K水平持续较低的早晨服用华法林是否会使抗凝效果更稳定变得很有价值。此前从未有人研究过服药时间对华法林疗效的影响。
方法/设计：这是一项为期7个月的前瞻性随机开放盲终点（PROBE）研究，其中已确定在晚上服用华法林的使用者（不列颠哥伦比亚省和艾伯塔省由初级保健管理的加拿大门诊患者）将被随机分为改为早晨服用华法林（干预组）或继续晚上服用（对照组）。主要结局是国际标准化比值（INR）血液检测超出治疗范围的时间比例的变化百分比。次要结局包括在治疗性INR范围内花费的时间比例（TTR）的变化、TTR>75%的患者百分比、TTR<60%的患者百分比以及与华法林相关的主要心血管事件（包括全因死亡率、因中风住院、因胃肠道出血住院以及深静脉血栓形成/肺栓塞）。我们还将比较基线时高维生素K食物摄入量的日常变化是否会影响这组晚上服用华法林使用者的基线TTR。
本研究探讨了华法林的服药时间是否会影响其抗凝效果的稳定性。如果证明早晨服药更优，那么这种药物的安全性和有效性，以及因此对中风、肺栓塞和大出血的预防，可能在不增加患者成本或不便的情况下得到改善。
ClinicalTrials.gov：NCT02376803。于2015年2月25日注册。
