The Problem
A 61-year-old man with a history of atrial fibrillation on anticoagulation with warfarin, hypertension, and type 2 diabetes mellitus presents to you with an international normalized ratio of 5.8. He has had an INR in the range of 2.0–3.0 on 5 mg of warfarin daily, and 5 days ago he was started on levofloxacin for community-acquired pneumonia. He says he is not bleeding more easily than usual, and reports no hematochezia. Your clinic recently initiated a nurse-protocol INR adjustment, and your nurse is inquiring as to whether you would like to give the patient vitamin K to reduce his risk for bleeding. Your colleague mentions recent evidence suggesting that vitamin K does not reduce bleeding events. You decide to review the evidence.
The Question
In patients with excessive anticoagulation on warfarin, does vitamin K reduce the risk of bleeding events, compared with holding and reducing the warfarin dose?
The Search
You log on to PubMed (
Our Critique
This clinical trial was well-designed, with appropriate randomization. Impressively, only 1.7% of patients were lost to follow-up. Although some readers may have concerns about the lack of study control over subsequent management of INR interventions by treating clinicians, randomization theoretically balances unknown variables such as heterogeneity in clinical approaches in the two study arms. In other words, both groups can be considered to be balanced for all interventions apart from receiving the vitamin K or placebo. By study design, only patients with an elevated INR who had not bled were enrolled, which leaves open the possibility of a “healthy cohort” bias. This study has great value in the presentation of contemporary data on the rate of major bleeding in a population of anticoagulated patients in North America and Italy. Reassuringly, the rate of major bleeding is low. However, clinicians may still be inclined to prescribe vitamin K in the hope that it will prevent a subsequent major bleed.
Clinical Decision
You discuss the situation with the patient. You agree to hold warfarin for 1 day and restart him on 3 mg per day with a recheck in 3 days.
Crowther MA, et al.
Oral vitamin K versus placebo to correct excessive anticoagulation in patients receiving warfarin: A randomized trial. Ann. Intern. Med. 2009;150:293–300.
▸ Design and Setting: Randomized, blinded clinical trial conducted at outpatient anticoagulation therapy clinics in Canada, Italy, and the United States.
▸ Subjects: Potential subjects were eligible for inclusion if they were currently receiving warfarin with a target INR of 2.0–3.5, and had an INR value greater than 4.49 drawn within last 24 hours. Potential subjects were excluded if they electively discontinued warfarin, were under 18 years of age, had a life expectancy of less than 10 days, had an indication for the acute normalization of INR (e.g., active major bleeding), had severe liver disease, had a recent (within 1 month) history of a major bleeding episode, had a known bleeding disorder or thrombolytic therapy within 48 hours, had a known allergy to vitamin K, were unable to take oral medications, had known significant thrombocytopenia, and were unable to return for follow-up evaluations.
▸ Intervention: Subjects were instructed to stop warfarin for 1 day and then were randomly assigned to 1.25 mg vitamin K or placebo. Additional INR sampling necessary to manage the patient was completed at the discretion of the treating physician. Clinics were advised to reinstitute warfarin therapy once the INR was within the therapeutic reference interval.
▸ Outcomes: The primary outcome measure was frequency of bleeding events at 90 days. “Major bleeding” was defined as fatal bleeding, bleeding requiring at least 2 units of blood, bleeding resulting in a therapeutic intervention, or confirmed bleeding into a closed space. “Minor bleeding” was defined as bleeding resulting in a medical assessment and not meeting the definition of major bleeding. Secondary outcome measures included major bleeding, thromboembolism, and death at 90 days.
▸ Results: A total of 724 subjects were randomized (355 to vitamin K, 369 to placebo), and subjects were similar at baseline. No significant difference was observed between the groups in the number of subjects who had at least one bleeding complication (15.8% vitamin K vs. 16.3% placebo), and no significant difference was observed in major bleeding between the vitamin K and placebo groups (2.5% vs. 1.1%). In addition, no significant difference was observed in thromboembolism between the two groups (1.1% vs. 0.8%). As expected, mean INR decreased more in the vitamin K group than in those who received placebo.