A Multicentre, Multinational Study of Oral Vitamin K for the Treatment of Warfarin Associated Coagulopathy
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 入组人数
- 690
- 试验地点
- 15
- 主要终点
- The primary outcome measure is "all clinically overt bleeding"
研究概览
简要总结
Excessive prolongation of the international normalized ratio (INR) occurs frequently in patients taking warfarin; in fact, about one in six INR values is above the desired range. Excessive prolongation of the INR is clinically important because the risk of bleeding approximately doubles for each one point increase in the INR beyond the usual therapeutic range. Thus, treatment strategies which rapidly and reliably lower an excessively prolonged INR into the desired range have the potential to reduce bleeding. When taken by patients with INR values between 4.5 and 10, a small dose of oral vitamin K (1 mg to 2.5mg) reduces the INR into the desired INR range in about 75% of cases within 24 hours of its administration. If warfarin is simply withheld, and no vitamin K is given, about 25% of patients will have an INR in the desired range at 24 hours. However, vitamin K is rarely given to such patients. In a recent survey carried out by our group, less than 20% of such patients would have been given low dose oral vitamin K by a group of physicians who regularly supervise warfarin therapy.
The most common treatment for excessive prolongation of the INR is to simply withhold warfarin and allow the INR to fall into the therapeutic range. Although this strategy is effective its safety has never been adequately examined. In fact, recent evidence suggests that patients with INR values of more than 6.0 who are treated with simple warfarin withdrawal have a risk of major bleeding of 4% in the two weeks after they develop their prolonged INR.
When asked why they did not give oral vitamin K to a non-bleeding patient who has an excessively prolonged INR, physicians generally give one of three reasons: (1)They are not convinced that oral vitamin K reduces bleeding. (2) They are concerned that oral vitamin K may cause thrombosis. (3) In contrast with simply withholding warfarin, giving oral vitamin K requires a patient to visit the physician, and the physician must have a supply of vitamin K.
The investigators hypothesize that the routine practice of not administering oral vitamin K to patients with excessively prolonged INR values is causing patients to have major, life-threatening and fatal bleeds. To convince physicians that oral vitamin K should be administered to all non-bleeding patients with INR values of more than 4.5, the investigators propose a study which the investigators anticipate will demonstrate that oral vitamin K reduces bleeding, does not cause thrombosis, and can be administered at home without direct physician supervision.
To accomplish these goals, the investigators propose a multinational, double-blind, placebo-controlled trial. The investigators will randomize patients with INR values between 4.5 and 10.0 to receive 1.25 mg of oral vitamin K or placebo and follow them for bleeding and thrombosis. Patients with INR values of more than 10.0 will receive a single 1.25 mg dose of oral vitamin K.
Successful completion of this study will establish a treatment standard supported by clinical data which will, in turn, change the way that patients taking warfarin who present with an excessively prolonged INR are treated.
详细描述
What is the problem to be addressed ? Although warfarin is a highly effective anticoagulant, it causes bleeding. The risk of bleeding in an individual is increased by a number of factors, including age, gender and previous hemorrhage. However, the single strongest predictor of hemorrhage is excessive prolongation of the international normalized ratio (INR). We have shown that low-dose oral vitamin K reliably reduces an excessively prolonged INR; we hypothesize this treatment will also reduce the risk of hemorrhage without increasing the risk of thrombosis. The objective of this study is to demonstrate that low dose oral vitamin K improves the safety of oral anticoagulant therapy, by reducing the risk of bleeding without causing thrombosis, in patients presenting with INR values of more than 4.5.
Background and rationale for the study (Efficacy and toxicity of warfarin): Warfarin reduces the risk of first or recurrent venous thrombosis by 80 to 90 percent, and reduces the risk of first or recurrent arterial thrombosis by 50 to 65 percent (1;2). In North America more than 1 million patients receive warfarin on a daily basis and in Ontario more than 300,000 prescriptions for warfarin are filled annually. The major toxicity of warfarin is bleeding, which may be fatal. Although bleeding may occur when the international normalized ratio (INR) is in the "therapeutic range" (2.0 to 3.0 for most indications), many patients who bleed have supratherapeutic INR values. Indeed, large studies suggest patients spend 10 to 20 percent of their time with excessively prolonged INR values and one anticoagulation clinic has reported that out of 7,279 patients managed over a 5 year interval, 1,995 had at least one INR greater than 6.0 (3). Furthermore, the risk of hemorrhage approximately doubles for each increase in the INR of 1.0 unit (4-7).
Background and rationale for the study (Risks of an excessively prolonged INR) The risk of hemorrhage in patients with asymptomatic warfarin-associated coagulopathy has been highlighted by Hylek and colleagues (8). In this study, 114 patients who presented with INR values of more than 6.0 simply had their warfarin withheld until the INR had declined to the desired range. In the two-week follow-up period, 10 of the 114 (8.8%, 95% confidence interval (CI) 3.6 to 14.0) patients experienced bleeding including 5 major and two fatal bleeds. Thus the risk of major hemorrhage and fatal hemorrhage was 4.4% (95% CI 0.6, 8.1), and 1.7% (95% CI 0, 4.2), respectively. Similarly, Oden and colleagues (4) demonstrated the mortality rate attributable to bleeding per 100 patient years of follow-up was 22 fold higher in patients with INR values between 6.0 and 6.9, compared with patients with an INR between 2.0 and 2.4. The observation that excessive elevation of the INR is associated with bleeding suggests that identifying an effective technique to lower the INR will reduce bleeding.
Background and Rationale (Treatment of warfarin associated coagulopathy) Other than simply withholding warfarin and allowing the INR to fall to the desired range, two "active" approaches are used to lower the INR in excessively anticoagulated patients. Transfusion of coagulation factor concentrates replaces missing coagulation factors. Supplemental vitamin K antagonizes the effect of warfarin, thus increasing endogenous synthesis of these same factors.
Transfusion with human derived or recombinant clotting factors can rapidly normalize the INR. However, this treatment is expensive, inconvenient, associated with infectious or other complications such as allergy or thrombosis, and has never been prospectively studied in non-bleeding patients (9). Thus, transfusion therapy should not be used to correct an excessively prolonged INR value in non-bleeding patients.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Currently receiving warfarin with a target INR of 2.0 to 3.5
- •INR value > 4.49 and drawn within last 24 hrs
排除标准
- •Elective discontinuation of warfarin
- •Age < 18 years
- •Life expectancy of less than 10 days
- •Indication for the acute normalization of INR i.e. active major bleeding (bleeding into central nervous system, retroperitoneum or other critical area or any bleeding requiring transfusion), need for surgery, major non-orthopedic surgery within the last seven days, invasive diagnostic procedure, head injury or termination of warfarin
- •Known Severe liver disease AST or ALT > 5 x normal, bilirubin > 50 umol/litre, known coagulopathy due to liver disease
- •Recent (<1 month) history of major bleeding episode i.e. Hemorrhagic stroke, gastrointestinal bleed or other bleed requiring transfusion or admission to hospital
- •Known bleeding disorder or thrombolytic therapy within 48 Hrs i.e. Hemophilia, disseminated intravascular coagulation
- •Known allergy to vitamin K
- •Inability to take oral medications
- •Known significant thrombocytopenia i.e. Platelet count of < 50 x 10 9/litre
- •Geographic inaccessibility/inability to have serial INR's performed
- •Failure to obtain informed consent
研究组 & 干预措施
1
Low dose oral vitamin K + warfarin cessation
干预措施: Phytonadione (Vitamin K1) (Drug)
2
干预措施: Phytonadione (Vitamin K1) (Drug)
结局指标
主要结局
The primary outcome measure is "all clinically overt bleeding"
时间窗: 90 days
次要结局
- Secondary outcome measures are "all adjudication-confirmed major hemorrhage", "all adjudication-confirmed thrombotic events", "changes in INR values" and "cost effectiveness"(90 days)