Nathan P. Clark

Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists

Prothrombin complex concentrates (PCCs) are recommended as the treatment of choice in warfarin-related coagulopathy. However, the risk of thromboembolic complications associated with their use is not well defined. We performed a meta-analysis to estimate the rate of thromboembolic complications in patients receiving vitamin K antagonists (VKAs) treated with PCCs for bleeding or before urgent surgery. Medline and Embase databases were searched. Two reviewers performed study selection and extracted data independently. Studies providing data on incidence of thromboembolic complications in VKA-treated patients were eligible for the study. Weighted mean proportion of the rate of thromboembolic complications and the mortality rate were calculated. Twenty-seven studies (1,032 patients) were included. Seven studies used 3-factor, and 20 4-factor PCCs. Twelve patients had a thromboembolic complication (weighted mean 1.4%; 95% CI 0.8-2.1), of which two were fatal. The incidence of thromboembolic events was 1.8% (95% CI 1.0-3.0) in patients treated with 4-factor PCCs, and 0.7% (95% CI 0.0-2.4) in patients treated with 3-factor PCCs. Total mortality rate was 10.6% (95% CI 5.9-16.6). In conclusion, our results suggest there is a low but quantifiable risk of thromboembolism in VKA-treated patients receiving PCCs for anticoagulation reversal. These findings should be confirmed in randomised, controlled trials.

Oral vitamin K versus placebo to correct excessive anticoagulation in patients receiving warfarin: a randomized trial.

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 patients 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 patients anticoagulant therapy were done at the discretion of the patients 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

Outcomes and predictors of very stable INR control during chronic anticoagulation therapy

For patients on warfarin therapy, an international normalized ratio (INR) recall interval not exceeding 4 weeks has traditionally been recommended. Less frequent INR monitoring may be feasible in stable patients. We sought to identify patients with stable INRs (defined as having INR values exclusively within the INR range) and comparator patients (defined as at least one INR outside the INR range) in a retrospective, longitudinal cohort study. Occurrences of thromboembolism, bleeding, and death were compared between groups. Multivariate logistic regression models were used to identify independent predictors of stable INR control. There were 2504 stable and 3569 comparator patients. The combined rates of bleeding and thromboembolism were significantly lower in stable patients. Independent predictors of stable INR control were age older than 70 years and the absence of comorbid heart failure and diabetes. Stable patients were significantly less likely to have target INR of 3.0 or higher or chronic diseases. We hypothesize that many patients demonstrating stable INR control could be safely treated with INR recall intervals greater than the traditional 4 weeks.

Twelve-month outcomes and predictors of very stable INR control in prevalent warfarin users

Summary.  Background:  For patients on warfarin therapy an international normalized ratio (INR) recall interval not exceeding 4 weeks has traditionally been recommended. For patients whose INR values are nearly always therapeutic, less frequent INR monitoring may be feasible.

Low-molecular-weight heparin use in the obese, elderly, and in renal insufficiency

Superior bioavailability and simple weight-based dosing have made low-molecular-weight heparins (LMWH) the preferred agents for treatment and prevention of venous thromboembolism (VTE) for most indications. Despite improved pharmacokinetics, there remain populations where appropriate LMWH dose intensity and frequency are open to question. Obese patients have a lower proportion of lean body mass as a percentage of total body weight. As a result, LMWH dosing based on total body weight could cause supra-therapeutic anticoagulation. Elderly patients also have less lean body mass in addition to a higher incidence of age-related renal disease and increased risk of bleeding. Renal insufficiency presents a risk of LMWH accumulation as well as increased risk of bleeding. Among LMWH products, only dalteparin labeling recommends a maximum dose. Prospective data call into question the validity of this dose limitation. Additionally, because obese patients are already at higher risk of VTE recurrence, they may be particularly sensitive to subtherapeutic anticoagulation. Prospective data evaluating LMWH use in elderly patients have been limited to in-patient treatment. Few recommendations can be made in this population other than close monitoring. Renal insufficiency is a risk for bleeding during LMWH use. Available evidence supports the potential for enoxaparin accumulation, but not tinzaparin. Enoxaparin dose adjustment, either empiric or based on anti-Xa monitoring, has insufficient data to support widespread implementation. Unfractionated heparin is not reliant on renal elimination and is a sensible option for VTE treatment in patients with a creatinine clearance<30 ml/min.

Incidence and predictors of bleeding or thrombosis after polypectomy in patients receiving and not receiving anticoagulation therapy

Summary.  Background and aims: To assess the effect of warfarin anticoagulation therapy (AC) on the incidence of colon bleeding after elective colonoscopy with polypectomy and to identify independent predictors of post‐polypectomy colon bleeding. Methods: This was a retrospective cohort analysis. Patients interrupting warfarin AC therapy for polypectomy (AC group) were matched on age (± 3 years) with up to two patients who underwent polypectomy but were not receiving AC (non‐AC group). Data were extracted from electronic medical, pharmacy and laboratory claims and records and manual medical chart review. Incidence rates of colon bleeding requiring hospitalization, other gastrointestinal bleeding, thrombosis and death in the 30 days post‐polypectomy were compared between groups. Multivariate regression techniques were used to identify independent predictors of post‐polypectomy colon bleeding. Results: A total of 425 AC group patients were matched to 800 non‐AC group patients. Post‐polypectomy colon bleeding occurred more often in AC group patients (2.6% vs. 0.2%, P = 0.005). There were no differences in the rates of other outcomes (P > 0.05). Independent predictors of colon bleeding included AC group status [adjusted odds ratio (AOR) = 11.6; 95% confidence interval (CI) = 2.3–57.3], number of polyps removed (AOR = 1.2; 95% CI = 1.1–1.4) and male gender (AOR = 9.2, 95% CI = 1.1–74.9). Conclusions: The incidence of post‐polypectomy colon bleeding was higher in patients receiving AC even although warfarin was interrupted for the procedure. Independent predictors of colon bleeding were identified as: receiving AC, removal of multiple polyps and male gender. Our findings suggest that additional methods to reduce the likelihood of post‐polypectomy colon bleeding in AC patients should be investigated.

Natural history of mesenteric venous thrombosis in patients treated with vitamin K antagonists - A multi-centre, retrospective cohort study

Knowledge on the natural history of mesenteric vein thrombosis (MVT) and of the efficacy and safety of long-term oral anticoagulant therapy (OAT) in this setting is based on small uncontrolled series of patients with a limited follow-up. It was the aim of the study to assess the natural history of MVT in a cohort of patients treated with OAT. The charts of all MVT patients currently attending or who have attended four anticoagulation clinics were reviewed. Information on risk factors, treatment, recurrence, major bleeding and mortality was collected. Seventy-seven patients (mean age 49.2 years; 45 males) were included with a median follow-up of 36 months (range 2-204 months). Forty-six patients were treated with long-term OAT. Seven patients had venous thromboembolism (VTE) recurrence (5 splanchnic vein thromboses and two pulmonary emboli) for an incidence rate of 23.4 events /1,000 year patients. In two patients recurrent VTE occurred during OAT, for an incidence rate of 10.5 events /1,000 year patient. Five patients had VTE recurrence when OAT was suspened for an incidence rate of 45.9 events /1,000 year patient. Two patients (2.6%) had a major bleeding event. 97.3% of patients were alive at one year, and seven patients (9.1%) died during follow up. In conclusion, patients with MTV seem to have a low risk of recurrent VTE while receiving OAT. This risk appears increased after treatment is stopped.

Bleeding, Recurrent Venous Thromboembolism, and Mortality Risks During Warfarin Interruption for Invasive Procedures

IMPORTANCE The risk of bleeding and recurrent venous thromboembolism (VTE) among patients receiving long-term warfarin sodium therapy for secondary VTE prevention who require temporary interruption of anticoagulant therapy for surgery or invasive diagnostic procedures has not been adequately described. OBJECTIVE To describe the rates of clinically relevant bleeding and recurrent VTE among patients in whom warfarin therapy is interrupted for invasive procedures and compare these rates among patients who did and did not receive bridge therapy. DESIGN, SETTING, AND PARTICIPANTS A retrospective cohort study was conducted at Kaiser Permanente Colorado, an integrated health care delivery system. Patients in whom warfarin therapy was interrupted for invasive diagnostic or surgical procedures between January 1, 2006, and March 31, 2012, were identified via queries of administrative data sets. A total of 1812 procedures in 1178 patients met inclusion criteria. Data on outcomes and exposures were collected between June 1, 2005, and April 30, 2012. EXPOSURES Use of bridge therapy vs no bridge therapy during warfarin interruption. MAIN OUTCOMES AND MEASURES Thirty-day clinically relevant bleeding, recurrent VTE, and all-cause mortality. Outcomes were verified via manual review of medical records. RESULTS Among the 1178 patients, the mean (SD) age was 66.1 (12.7) years, 830 procedures (45.8%) were in men, and the most common indication for warfarin therapy was deep vein thrombosis (56.3%). Most patients were considered to be at low risk for VTE recurrence at the time of warfarin interruption (1431 procedures [79.0%]) according to the consensus guidelines of the American College of Chest Physicians. Clinically relevant bleeding within 30 days after the procedure in the bridge therapy and non-bridge therapy groups occurred in 15 patients (2.7%) and 2 patients (0.2%), respectively (hazard ratio, 17.2; 95% CI, 3.9-75.1). There was no significant difference in the rate of recurrent VTE between the bridge and non-bridge therapy groups (0 vs 3; P = .56). No deaths occurred in either group. CONCLUSIONS AND RELEVANCE Bridge therapy was associated with an increased risk of bleeding during warfarin therapy interruption for invasive procedures in patients receiving treatment for a history of VTE and is likely unnecessary for most of these patients. Further research is needed to identify patient- and procedure-related characteristics associated with a high risk of perioperative VTE recurrence during warfarin therapy interruption.

Thromboembolic Consequences of Subtherapeutic Anticoagulation in Patients Stabilized on Warfarin Therapy: The Low INR Study

Study Objective. To quantify the absolute risk of thromboembolism associated with a significant subtherapeutic international normalized ratio (INR) in patients with previously stable anticoagulation while receiving warfarin.

Oral vitamin K effectively treats international normalised ratio (INR) values in excess of 10: results of a prospective cohort study.

Unanticipated elevation of the INR is common in patients receiving warfarin. We performed a prospective cohort study of 107 warfarin-treated patients with INR values of more than 10 who received a single 2.5 mg dose of oral vitamin K. During the first week, one patient experienced major bleeding, and one died. In the first 90 days after enrolment four patients had major bleeding (3.7%, 1.0% to 9.3%), eight patients (7.5%, 3.3% to 14.2%) died and two had objectively confirmed thromboembolism. Based on our low rate of observed major bleeding we conclude that 2.5 mg of oral vitamin K is a reasonable treatment for patients with INR values of more than 10 who are not actively bleeding.