Davide Imberti

Extended Oral Anticoagulant Therapy after a First Episode of Pulmonary Embolism

Context Optimal duration of anticoagulation after pulmonary embolism is uncertain, but physicians commonly prescribe 3 months of therapy for patients with transient risk factors for thrombosis and 6 months for patients with continuing or no known risk factors. Contribution After 3 months of successful anticoagulation, 326 patients were randomly assigned to stop therapy immediately or extend therapy to 6 months or 1 year. Regardless of duration of anticoagulation, 33 patients had recurrent thromboembolic events but only one event occurred in a patient still receiving therapy. Implications Extending the duration of anticoagulation does not seem to protect against recurrence once therapy has been discontinued. Patients at high risk for recurrence may require indefinite anticoagulation. The Editors Recent studies have shown that patients with a first episode of venous thromboembolism are protected from a recurrence while they are receiving anticoagulant treatment (1, 2). On the basis of differences in the risk for recurrence when anticoagulant treatment is discontinued, different durations of oral anticoagulation are currently recommended in different patient categories. A shorter period of anticoagulation is recommended for patients with venous thromboembolism associated with transient risk factors than for patients with idiopathic venous thromboembolism or venous thromboembolism associated with continuing risk factors (3-5). Current recommendations on the duration of oral anticoagulant treatment for venous thromboembolism are based on studies that mostly included patients presenting with deep venous thrombosis (1, 2, 5-7). Only a limited proportion of patients included in these studies presented with pulmonary embolism. Deep venous thrombosis and pulmonary embolism are generally considered to be two clinical manifestations of the same disease. However, patients presenting with pulmonary embolism are reported to have a higher incidence of fatal recurrent venous thromboembolism than patients presenting with deep venous thrombosis (8, 9). We performed a multicenter randomized trial to evaluate the long-term clinical benefit of extending a 3-month course of oral anticoagulant therapy to 6 months (pulmonary embolism associated with temporary risk factors) or to 1 year (idiopathic pulmonary embolism) in patients with a first episode of pulmonary embolism. The primary outcome of the study was symptomatic, objectively confirmed recurrence of venous thromboembolism. Methods Study Patients Consecutive patients ranging from 15 to 85 years of age with a first episode of symptomatic, objectively confirmed pulmonary embolism were included in the study if they had completed 3 uninterrupted months of oral anticoagulant therapy without having a recurrence or bleeding. The diagnosis of pulmonary embolism was confirmed by pulmonary angiography or spiral computed tomography or by a lung scan indicating a high probability of pulmonary embolism or a lung scan indicating an intermediate probability of pulmonary embolism in a patient with objectively diagnosed deep venous thrombosis. Study patients were categorized as having idiopathic pulmonary embolism or pulmonary embolism associated with transient risk factors. Idiopathic pulmonary embolism was defined as pulmonary embolism occurring in the absence of known cancer, known thrombophilia, or any transient risk factor for venous thromboembolism. Pulmonary embolism associated with transient risk factors was pulmonary embolism occurring after recent trauma with or without bone fracture, recent surgery or childbirth, or prolonged immobilization (that is, lasting >7 days), or occurring during the use of oral contraceptives or pregnancy. Patients with pulmonary embolism associated with permanent risk factors (known cancer or known thrombophilia) were excluded from the study. Systematic screening for occult cancer or thrombophilia was not performed before enrollment. Patients who required prolonged anticoagulant therapy for reasons other than venous thromboembolism were excluded from the study, as were patients with major psychiatric disorders, patients with a life expectancy shorter than 2 years, those who could not return for the follow-up visits, and those who declined to participate. The institutional review boards of the participating hospitals approved the study; all patients gave informed consent. Study Design and Interventions The Warfarin Optimal Duration Italian Trial in patients with pulmonary embolism (WODIT-PE) was a multicenter randomized, open trial with independent, blinded assessment of the outcome events. The study was designed to evaluate the clinical benefit of extending the 3-month course of oral anticoagulant therapy after a first episode of pulmonary embolism. Patients who had completed 3 months of warfarin or acenocumarol therapy were randomly assigned to discontinue anticoagulation or to continue it for 3 additional months (pulmonary embolism associated with transient risk factors) or 9 additional months (idiopathic pulmonary embolism). Randomization was performed centrally in permuted blocks of six. The dose of warfarin or acenocumarol was adjusted to achieve a target international normalized ratio (INR) between 2.0 and 3.0. The therapy was monitored in anticoagulant clinics associated with the study centers, all in Italy. Outcome Measures The primary outcome of the study was the recurrence of symptomatic, objectively confirmed venous thromboembolism after the initial 3 months of anticoagulation. The secondary outcome was the cumulative incidence of adverse outcome events (recurrence of venous thromboembolism, death, or major bleeding). The criteria for the diagnosis of recurrence of pulmonary embolism were a new filling defect revealed by pulmonary angiography or spiral computed tomography or a new high-probability perfusion defect revealed by ventilation-perfusion lung scan. Sudden, otherwise unexplained death was also considered a recurrence of pulmonary embolism. The criteria for the diagnosis of deep venous thrombosis as an outcome for recurrence of venous thromboembolism in patients without deep venous thrombosis at baseline were the presence of a noncompressible proximal vein on ultrasonography or an intraluminal filling defect on venography. In patients with deep venous thrombosis at baseline, the criteria for the diagnosis of recurrent deep venous thrombosis were abnormal results on compression ultrasonography (proximal veins) or venography in the contralateral leg or, in the ipsilateral leg, an extension of an intraluminal filling defect on venography; a newly noncompressible venous segment; or an increase of 4 mm or more in the diameter of the thrombus (proximal veins) on ultrasonography (10). Bleeding was defined as major if it was clinically overt and associated with either a decrease in the hemoglobin level of at least 20 g/L or the need to transfuse two or more units of red blood cells, if it was retroperitoneal or intracranial, if it warranted the permanent discontinuation of therapy with the study drug, or if it required rehospitalization. Deaths were classified as the result of pulmonary embolism, bleeding, or another identifiable cause or as unexplained. All suspected outcome events (recurrent thromboembolism and bleeding episodes) and all deaths were reviewed centrally by an independent, external adjudication committee whose members were unaware of the treatment group assignments. Follow-up Patients were instructed to return for follow-up visits at 3, 6, and 12 months after randomization and every 6 months thereafter until the completion of the study. Patients were asked to return to the study center immediately if symptoms suggestive of recurrent venous thromboembolism or bleeding developed. For all patients who died during the follow-up period, the date and cause of death were documented. We attempted to gain permission for autopsies of all patients in whom pulmonary embolism could not be excluded as the cause of death. Statistical Analysis The primary analysis of efficacy was a comparison of the rates of symptomatic, objectively confirmed recurrence of venous thromboembolism in the two treatment groups. The analysis was performed on an intention-to-treat basis. It was assumed that the rate of recurrence of venous thromboembolism would be 12% in patients assigned to the discontinue oral anticoagulant therapy in the 2 years after discontinuation. We also assumed that the prolongation of oral anticoagulant therapy would produce a 50% reduction in the risk for recurrence. Given these assumptions, we needed 312 patients in each group to detect a difference of this magnitude between groups with a power of 80% and a type I error rate of 5%. To avoid the exposure of the study patients to an ineffective or dangerous therapeutic regimen, one prespecified interim analysis of efficacy and safety was planned after we randomly assigned 50% of planned patients. The following criteria for stopping the trial were defined a priori: an overall rate of recurrence of thromboembolic events lower than 7.5%, an unequivocal reduction in the rate of recurrent venous thromboembolism in the patients assigned to continue therapy (P < 0.001 by a one-sided test), a risk for recurrence in the continued therapy group that was less than 25% lower than that in the group assigned to discontinue therapy, or a rate of major bleeding higher than 5% in the continued therapy group. The cumulative hazard of recurrent venous thromboembolism was calculated according to the Kaplan-Meier life-table method (11). Rates of recurrence in the two groups were compared with the use of the log-rank test (12). Results Patients Patients were recruited between January 1997 and December 2000 when, after 326 patients were included, the results of the interim analysis showed a difference of less than 25% in the risk for recurrent venous thromboembolism between the two treatment groups. At the time of

Enoxaparin for the Prevention of Venous Thromboembolism Associated With Central Vein Catheter: A Double-Blind, Placebo-Controlled, Randomized Study in Cancer Patients

PURPOSE The extent of venous thromboembolism (VTE) associated with central vein catheters (CVC) in cancer patients remains unclear. The aim of this study was to evaluate the efficacy and safety of the low molecular weight heparin, enoxaparin, in the prevention of VTE. PATIENTS AND METHODS In a multicenter, double-blind study, consecutive cancer patients scheduled for CVC insertion were randomly assigned to receive either subcutaneous enoxaparin 40 mg once a day or placebo. Treatment was started 2 hours before CVC insertion and continued for 6 weeks. The primary end points of the study were deep vein thrombosis (DVT), confirmed by venography of the CVC limb performed 6 weeks after randomization, or clinically overt pulmonary embolism, confirmed by objective testing during the study drug administration. Patients were assessed for bleeding complications. RESULTS Three hundred eighty-five patients were randomized, of which 321 (83.4%) underwent venography. A venography was adequate for adjudication in 155 patients in each treatment group. A DVT was observed in 22 patients (14.1%) treated with enoxaparin and in 28 patients (18.0%) treated with placebo, corresponding to a relative risk of 0.78 (95% CI, 0.47 to 1.31). No major bleeding occurred. Five patients (2.6%) in the enoxaparin group and two patients (1.0%) in the placebo group died during the treatment period. CONCLUSION In this study, no difference in the rate of CVC-related VTE was detected between patients receiving enoxaparin and patients receiving placebo. The dose of enoxaparin used in this study proved to be safe. Clinical trials evaluating higher enoxaparin doses could optimize the efficacy of this agent for this indication.

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.

Residual Thrombosis on Ultrasonography to Guide the Duration of Anticoagulation in Patients With Deep Venous Thrombosis: A Randomized Trial

BACKGROUND The optimal duration of oral anticoagulant therapy in patients with deep venous thrombosis (DVT) of the lower extremities remains uncertain. OBJECTIVE To assess whether tailoring the duration of anticoagulation on the basis of the persistence of residual thrombi on ultrasonography reduces the rate of recurrent venous thromboembolism (VTE) compared with the administration of conventional fixed-duration treatment in adults with proximal DVT. DESIGN Parallel, randomized trial from 1999 to 2006. Trained physicians who assessed outcomes were blinded to patient assignment status, but patients and providers were not. SETTING 9 university or hospital centers in Italy. PATIENTS 538 consecutive outpatients with a first episode of acute proximal DVT at completion of an uneventful 3-month period of anticoagulation. INTERVENTION Patients were randomly assigned (stratified by center and secondary vs. unprovoked DVT by using a computer-generated list that was accessible only to a trial nurse) to fixed-duration anticoagulation (no further anticoagulation for secondary thrombosis and an extra 3 months for unprovoked thrombosis) or flexible-duration, ultrasonography-guided anticoagulation (no further anticoagulation in patients with recanalized veins and continued anticoagulation in all other patients for up to 9 months for secondary DVT and up to 21 months for unprovoked thrombosis). For the primary outcome assessment, 530 patients completed the trial. MEASUREMENTS The rate of confirmed recurrent VTE during 33 months of follow-up. RESULTS Overall, 46 (17.2%) of 268 patients allocated to fixed-duration anticoagulation and 32 (11.9%) of 270 patients allocated to flexible-duration anticoagulation developed recurrent VTE (adjusted hazard ratio [HR], 0.64 [95% CI, 0.39 to 0.99]). For patients with unprovoked DVT, the adjusted HR was 0.61 (CI, 0.36 to 1.02) and 0.81 (CI, 0.32 to 2.06) for those with secondary DVT. Major bleeding occurred in 2 (0.7%) patients in the fixed-duration group and 4 (1.5%) patients in the flexible-duration group (P = 0.67). LIMITATIONS The trial lacked a double-blind design. The sample size was not powered to detect differences in bleeding between groups and to detect effectiveness of the intervention in the subgroups of patients with unprovoked and secondary DVT. Patients with previous thromboembolism, permanent risk factors for thrombosis, and thrombophilic abnormalities other than factor V Leiden and prothrombin mutation were excluded. CONCLUSION Tailoring the duration of anticoagulation on the basis of ultrasonography findings reduces the rate of recurrent VTE in adults with proximal DVT. PRIMARY FUNDING SOURCE None.

Serial 2-Point Ultrasonography Plus D-Dimer vs Whole-Leg Color-Coded Doppler Ultrasonography for Diagnosing Suspected Symptomatic Deep Vein Thrombosis: A Randomized Controlled Trial

CONTEXT Patients with suspected deep vein thrombosis (DVT) of the lower extremities are usually investigated with ultrasonography either by the proximal veins (2-point ultrasonography) or the entire deep vein system (whole-leg ultrasonography). The latter approach is thought to be better based on its ability to detect isolated calf vein thrombosis; however, it requires skilled operators and is mainly available only during working hours. No randomized comparisons are yet available evaluating the relative values of these 2 strategies. OBJECTIVE To assess if the 2 diagnostic strategies are equivalent for the management of symptomatic outpatients with suspected DVT of the lower extremities. DESIGN, SETTING, AND PATIENTS A prospective, randomized, multicenter study of consecutive symptomatic outpatients (n = 2465) with a first episode of suspected DVT of the lower extremities who were randomized to undergo 2-point or whole-leg ultrasonography. Data were taken from ultrasound laboratories of 14 Italian universities or civic hospitals between January 1, 2003, and December 21, 2006. Patients with normal ultrasound findings were followed up for 3 months, with study completion on March 20, 2007. MAIN OUTCOME MEASURE Objectively confirmed 3-month incidence of symptomatic venous thromboembolism in patients with an initially normal diagnostic workup. RESULTS Of 2465 eligible patients, 345 met 1 or more exclusion criteria and 22 refused to participate; therefore, 2098 patients were randomized to either 2-point (n = 1045) or whole-leg (n = 1053) ultrasonography. Symptomatic venous thromboembolism occurred in 7 of 801 patients (incidence, 0.9%; 95% confidence interval [CI], 0.3%-1.8%) in the 2-point strategy group and in 9 of 763 patients (incidence, 1.2%; 95% CI, 0.5%-2.2%) in the whole-leg strategy group. This met the established equivalence criterion (observed difference, 0.3%;95% CI, -1.4% to 0.8%). CONCLUSION The 2 diagnostic strategies are equivalent when used for the management of symptomatic outpatients with suspected DVT of the lower extremities. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00353093.

Prevalence and Clinical History of Incidental, Asymptomatic Pulmonary Embolism: A Meta-Analysis

CONTEXT Recently, there has been an increasing number of reports of incidental pulmonary embolism (PE) in patients undergoing chest computer tomography (CT) for reasons other than the research of suspected PE. Natural history of incidental PE remains unclear. OBJECTIVES To estimate the prevalence of incidental PE, to assess potential factors associated with incidental PE, and to evaluated its clinical history. DATA SOURCES MEDLINE, EMBASE databases (up to January 2009). STUDY SELECTION Studies were included if the prevalence of incidental PE was assessed using CT scanning. DATA EXTRACTION The prevalence of incidental PE in these patients was documented. Separate data for inpatients and outpatients and according to the reason for CT scanning were collected. Weighted mean proportion of the prevalence of incidental PE was calculated. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to test the association with potential predictors of incidental PE. RESULTS Twelve studies for a total of more than 10 thousand patients were included. The weighted mean prevalence of incidental PE was 2.6% (95% CI 1.9, 3.4). Hospitalization at the time of CT scanning and the presence of cancer were associated with a significantly increased risk of incidental PE (OR 4.27 and OR 1.80 respectively). CONCLUSIONS The prevalence of incidental PE is clinically relevant. Future studies are necessary to properly evaluate the clinical history of these patients.

Clinical characteristics and management of cancer-associated acute venous thromboembolism: findings from the MASTER Registry

MASTER is a multicenter registry of consecutively recruited patients with symptomatic, objectively confirmed, acute venous thromboembolism. One fifth of the patients enrolled had cancer. In these patients, venous thromboembolism has peculiar features, and its management is more problematic. Background Clinical characteristics and management of acute deep vein thrombosis and pulmonary embolism (PE) have been reported to be different in patients with and without cancer. The aim of this paper was to provide information on clinical characteristics and management of acute venous thromboembolism in patients with cancer by means of a large prospective registry. Design and Methods MASTER is a multicenter registry of consecutively recruited patients with symptomatic, objectively confirmed, acute venous thromboembolism. Information about clinical characteristics and management was collected by an electronic data network at the time of the index event. Results A total of 2119 patients were enrolled, of whom 424 (20%) had cancer. The incidence of bilateral lower limb deep vein thrombosis was significantly higher in patients with cancer than in patients without cancer (8.5% versus 4.6%; p<0.01), as were the rates of iliocaval thombosis (22.6% versus 14%; p<0.001), and upper limb deep vein thrombosis (9.9% versus 4.8%; p<0.001). Major bleeding (3.3% versus 1.1%; p=0.001), in-hospital treatment (73.3% versus 66.6%; p=0.02) and inferior vena cava filter implantation (7.3% versus 4.1%; p=0.005) were significantly more frequent in patients with cancer, in whom oral anticoagulants were less often used (64.2% versus 82%; p<0.0001). Conclusions The clinical presentation of acute venous thromboembolism is different and often more extensive in cancer patients than in patients free from malignancy. Moreover, the management of the acute phase of venous thromboembolism is more problematic in cancer patients, especially because of a higher rate of major bleeding and the need for implantation of inferior vena cava filters.

Clinical experience with retrievable vena cava filters: results of a prospective observational multicenter study.

Summary.  Background: Retrievable inferior vena cava (IVC) filters offer the attractive possibility to be definitive or to be removed when they become unnecessary. Objective: The purpose of this study was to evaluate the efficacy and the likelihood to remove the retrievable IVC filter ALN. Methods: A total of 30 patients (13 males and 17 females, mean age 57 ± 15 years) underwent placement of ALN filters. Indications for implantation were acute venous thromboembolism (VTE) with a contraindication to anticoagulation in 26 cases (86%), primary prophylaxis after major trauma in two cases (7%) or before surgery in two patients with very high thromboembolic risk (7%). Results: The filter was successfully placed in all patients. After a median follow‐up of 18.2 months, there were three cases (10%) of trapped emboli within the filter, one case (3%) of asymptomatic migration of the filter toward the heart and two patients (7%) had deep vein thrombosis (DVT) recurrences. ALN retrieval was attempted through transjugular approach in 18 patients (60%) and the maneuver was successful in 14 of them (78%); when the decision of removal was taken more than 3 months after the implantation, the retrieval was possible only in four of eight patients (50%). The median implantation period was 123 days (range: 30–345). Conclusions: The present study shows the efficacy of ALN filter; it also demonstrates the feasibility and safety of retrieval after a medium‐term period of placement. Removal after 3 months after implantation can be unsuccessful and maximum implantation time requires further studies.

Prevention and treatment of bleeding complications in patients receiving vitamin K antagonists, Part 1: Prevention

Oral anticoagulant therapy with coumarins is widelyused for the prevention and treatment of venous andarterial thrombosis. The most common complication ofvitamin K antagonist therapy is bleeding, with majorbleeding events occurring in 1–3% of patients annually.Although a number of potential predictors for bleedinghave been described, little research is available to pro-vide evidence-based guidelines for the prevention ofbleeding. To address this knowledge gap, we assembleda panel of international experts and posed a series offocused clinical questions. The experts were asked toperform a systematic literature review and summarize theresults of that review within the context of their clinicalquestion. In many cases, data were lacking and theexperts were asked to supplement their answer with clin-ical expertise. To minimize bias the reviews were vettedby three internationally recognized scholarly bodies. Ourgoal in this project is to provide ‘‘best evidence’’ forclinicians faced with the problem of minimizing the riskof bleeding in patients on vitamin K antagonist therapy.The number of patients receiving vitamin K antagonisttherapy increases annually and probably exceeds three mil-lion in the United States. Despite monitoring and carefuldose adjustment, the time spent in the therapeutic Interna-tional Normalized Ratio (INR) range varies from below 47%to a maximum of 81% of the time [1]. Major bleedingevents occur in up to 3% of ‘‘standard risk’’ patients treatedwith an oral vitamin K antagonist in one year. Despite thehigh frequency of use of vitamin K antagonists, very littleresearch has been performed examining techniques toreduce the risk of bleeding. In particular, the role of clinicalbleeding prediction rules is uncertain and further study ofthe role of drug and food interactions, the impact of patienteducation, the risk to benefit ratio of combining differentantithrombotic drugs, the role of pharmacogenomic testing,and on the optimal management of patients presentingwith elevated INR values is required. However, despitethese needs clinicians are still required to initiate andmonitor vitamin K antagonists while mitigating the risks ofbleeding and thrombosis. This article provides recommen-dations designed to assist clinicians in estimating andmanaging bleeding risk in patients receiving oral vitamin Kantagonists.Clinical questions were formulated by three of theauthors (WA, MC, DG) and authors were selected basedon their published experience. In each case, a North Ameri-can and Italian expert were asked to co-author theresponse to the question. The authors were asked to per-form a comprehensive literature review and make specificrecommendations on the basis of this review in concertwith their clinical experience. Given the anticipated lack ofevidence, the recommendations are largely opinion-based.To increase the rigor of the recommendations, each sectionwas carefully reviewed by members of the Italian Societyfor Studies on Haemostasis and Thrombosis, the Federa-tion of Centers for the Diagnosis of Thrombosis and Sur-veillance of Antithrombotic Therapies, and the Anticoagula-tion Forum.To provide readers with information on the strength of therecommendations, we have asked the authors to use theAmerican College of Chest Physicians GRADE system toevaluate the quality of the recommendations [2]. In thissystem, grades of 1A, 1B, 1C, 2A, 2B, and 2C are possible.A 1A recommendation is a strong recommendation basedon evidence from randomized trials or exceptional qualityobservational data which is thought to apply to mostpatients, in most circumstances. A 2C recommendation is avery weak recommendation, based on poor quality evi-dence, and for which there is doubt as to which patientsthe recommendation applies. Our goal with this project is toboth provide guidance to clinicians and to stimulate addi-tional research designed to improve the quality of evidenceon which treatments for vitamin K antagonist associatedbleeding are based.Clinical Scenario 1A 79-year-old woman with atrial fibrillation and well-con-trolled hypertension is assessed for anticoagulant therapy.She has no history of diabetes, congestive heart failure,stroke, or transient ischemic attack (TIA). Two years agoshe had an upper gastrointestinal bleed treated with a pro-

Emergency reversal of anticoagulation with a three-factor prothrombin complex concentrate in patients with intracranial haemorrhage.

BACKGROUND Intracranial haemorrhage is a serious and potentially fatal complication of oral anticoagulant therapy. Prothrombin complex concentrates can substantially shorten the time needed to reverse the effects of oral anticoagulants. The aim of this study was to determine the efficacy and safety of a prothrombin complex concentrate for rapid reversal of oral anticoagulant therapy in patients with intracranial haemorrhage. METHODS Patients receiving oral anticoagulant therapy and suffering from acute intracranial haemorrhage were eligible for this prospective cohort study if their International Normalised Ratio (INR) was higher than or equal to 2.0. The prothrombin complex concentrate was infused at doses of 35-50 IU/kg, stratified according to the initial INR. RESULTS Forty-six patients (25 males; mean age: 75 years; range 38-92 years) were enrolled. The median INR at presentation was 3.5 (range, 2-9). At 30 minutes after administration of the prothrombin complex concentrate, the median INR was 1.3 (range, 0.9-3), and the INR then declined to less than or equal to 1.5 in 75% of patients. The benefit of the prothrombin complex concentrate was maintained for a long time, since the median INR remained lower than or equal to 1.5 (median, 1.16; range, 0.9-2.2) at 96% of all post-infusion time-points up to 96 hours. No thrombotic complications or significant adverse events were observed during hospitalisation; six patients (13%) died, but none of these deaths was judged to be related to administration of the prothrombin complex concentrate. CONCLUSIONS Prothrombin complex concentrates are an effective, rapid and safe treatment for the urgent reversal of oral anticoagulation in patients with intracranial haemorrhage. Broader use of prothrombin complex concentrates in this clinical setting appears to be appropriate.