Oral Vitamin K Versus Placebo to Correct Excessive Anticoagulation in Patients Receiving Warfarin

Context Vitamin K decreases the international normalized ratio (INR) in overanticoagulated patients who receive warfarin therapy, but its effect on clinical outcomes is less clear. Contribution Trial investigators detected no differences in the frequency of bleeding, thromboembolism, or death among overanticoagulated patients who received warfarin therapy and were randomly assigned to receive low-dose vitamin K or placebo. Caution The study was underpowered to detect differences in major bleeding. Implication Low-dose vitamin K corrects the INR in overanticoagulated patients who received warfarin therapy, but it has little effect on clinical outcomes. Withdrawal of warfarin may be all that is necessary to manage elevated INRs. The Editors Warfarin is a remarkably effective drug for primary and secondary prevention of arterial and venous thromboembolism. Among commonly used medications, warfarin is unique because its doseresponse characteristics are highly unpredictable, varying both among and within individuals over time. As a result, warfarin therapy requires ongoing monitoring using the international normalized ratio (INR), a value that reflects the degree to which warfarin has reduced coagulation factor levels and the coagulant potential of blood (1). For most indications, an INR range of 2.0 to 3.0 is targeted; INR values less than 2.0 are associated with an increased risk for thromboembolism, and INR values greater than 4.0 are associated with an increase in bleeding complications. The risk for bleeding, particularly intracranial bleeding, increases markedly as the INR exceeds 4.5 (13). Even in clinics dedicated to warfarin management, INRs are outside the therapeutic range one third to one half the time (4). When managing a patient with an INR greater than 4.5 who is not bleeding, clinicians generally either withhold warfarin treatment and allow the INR to decrease to the desired value or administer vitamin K (orally or intravenously) to more rapidly reduce the INR (1, 510). Small randomized trials have shown that a single dose of low-dose oral vitamin K (for example, 1 to 2.5 mg) effectively reduces the INR in otherwise-stable overanticoagulated patients within 24 hours of its administration; however, these studies were not large enough to determine whether low-dose vitamin K reduces bleeding without increasing the risk for thromboembolism (1115). A recent systematic review (16) supported this observation. To determine whether oral vitamin K is indicated in overanticoagulated patients who are not bleeding, we did a randomized trial in which we allocated oral vitamin K or placebo, 1.25 mg, to patients who presented with an INR of 4.5 to 10.0. The primary outcome measure was the frequency of all forms of bleeding events during the first 90 days. Our hypothesis that bleeding events would be reduced was based on our previously published, smaller studies of low-dose oral vitamin K administered to various patient groups. In these studies, we found a consistent and rapid decrease in the INR after low-dose vitamin K was administered (13, 15, 1722). Methods Study Patients We identified patients with INRs of 4.5 to 10.0 in participating outpatient anticoagulant therapy clinics. We screened patients as they presented for routine INR assessment and considered them for eligibility if they were receiving warfarin therapy with a target INR of 2.0 to 3.5, their most recent INR was between 4.5 and 10.0 in the past 24 hours, and they were not bleeding. We excluded patients if discontinuation of warfarin therapy was scheduled and if they were younger than 18 years, had a life expectancy less than 10 days, had an indication for acute normalization of their INR (such as imminent surgery), had a known severe liver disease, had a history of a major bleeding event within 1 month, had a known bleeding disorder, had received thrombolytic therapy within 48 hours, had a platelet count less than 50109 cells/L, could not take oral medications, had a known allergy to vitamin K, or could not return for laboratory or clinical monitoring. Study staff at each participating anticoagulant therapy clinic approached patients who met inclusion criteria for consent to participate. This study ran in parallel with a cohort study in which patients with INRs greater than 10.0 received oral vitamin K, 2.5 mg. Patients were otherwise identical to those enrolled in this study, and we followed them for similar outcome events. The results of the concurrent cohort study will be presented in a subsequent paper. Randomization and Treatment We instructed all eligible, consenting patients to withhold warfarin for 1 day and randomly assigned them to receive a capsule containing either vitamin K, 1.25 mg, or placebo. Randomization was done by using a computer-generated random-number table at the coordinating and methods center and was stratified by clinical center. Vitamin K capsules were compounded from 5-mg vitamin K tablets (Merck & Co., Whitehouse Station, New Jersey) by a commercial pharmacy with Health Canada approval (Clinical Trials Application control number 092635). Placebo capsules contained inert filler and were indistinguishable from the capsules that contained vitamin K. Random allocation of patients was accomplished when site-specific study personnel dispensed the next numbered study drug container at each clinical center; thus, patients, treating clinicians, and research coordinators were unaware of treatment allocation. In 2 centers, we monitored the INR of outpatients in clinics or laboratories outside the clinical center. In such centers, we obtained consent for the study by telephone, and the study drug was shipped within hours to the patient's home by using a courier service. In all cases, we confirmed receipt and consumption of the study drug on the day of randomization by telephone. In the remaining centers, in which patients were seen in person, consent and study drug administration occurred at the same time that the elevated INR was detected. Follow-up and Outcome Measures At enrollment, we advised patients to promptly seek medical evaluation if they developed signs or symptoms of bleeding or thromboembolism. At minimum, we assessed patients by telephone or in person on days 1, 3, 7, 14, 28, and 90 after randomization. Additional contact and INR sampling necessary to manage the patient's anticoagulant therapy were done at the discretion of the patient's physician. At each follow-up, we sought signs and symptoms of bleeding and thromboembolism and collected details about all such events. We asked patients a focused series of questions to help them recall these events. We reviewed and abstracted medical records of all suspected bleeding episodes, thromboembolism, and deaths. Our primary outcome measure was the frequency of bleeding events during the 90 days after randomization. We defined major bleeding as fatal bleeding, bleeding requiring transfusion of 2 or more units of packed red blood cells, bleeding resulting in a therapeutic intervention (such as endoscopy), or objectively confirmed bleeding into an enclosed space. We defined minor bleeding as bleeding resulting in a medical assessment that did not meet criteria as a major bleeding event. We defined trivial bleeding as all patient-reported bleeding events that did not result in a medical assessment. We combined all reported bleeding events (major, minor, and trivial) for this analysis. We chose to combine these events because our clinical experience suggested that reducing medically unimportant but bothersome bleeding, such as epistaxis, bruising, and menorrhagia, was a clinically important goal for our patients; patients with a minor or trivial bleeding event may be at greater risk for subsequent major bleeding; and the frequency of major bleeding was likely to be very low, calling into question the feasibility of a study powered to detect differences in major bleeding events. Secondary outcome measures included the frequency of major bleeding events, objectively confirmed venous or arterial thromboembolism, and death during the 90 days after randomization. We chose the 90-day period on the basis of our previous studies wherein we found a significant reduction in bleeding events (90 days) after the administration of similar doses of oral vitamin K (13). We hypothesized that low-dose oral vitamin K might influence a bleeding event during this extended period, because even small doses of this highly lipophilic drug might have an extended influence on INR control (and thus the risk for bleeding and thrombosis). In post hoc analyses, we examined the frequency of all bleeding and major bleeding events in the first 7 days and the number of clinical events in patients who were older than 70 years at enrollment. An independent adjudication committee, blinded to treatment allocation and not otherwise involved in the study, reviewed all bleeding events, thromboembolism, and deaths. Confirmation of venous thromboembolism required a nononcompressible venous segment on ultrasonography, an intraluminal filling defect on venography or computed tomographic pulmonary angiography, or a segmental (or larger) mismatch defect on ventilationperfusion lung scan. Arterial thromboembolism required either direct surgical visualization of thrombus; an intraluminal filling defect on angiography; or clear evidence of a new ischemic event on an objective test, such as electrocardiography, computed tomography, or magnetic resonance imaging. We advised clinics to reinstitute warfarin therapy once the INR was within the therapeutic reference interval after administration of the study drug. The clinicians who cared for the patients determined the warfarin dose when the drug was readministered. Target INR ranges for individual patients did not change as a result of the elevated INR that led to enrollment. Statistical Analysis Our primary analysis was an intention-to-treat comparison of the proportions of patien