Mark Crowther

Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

BACKGROUND This article addresses the treatment of VTE disease. METHODS We generated strong (Grade 1) and weak (Grade 2) recommendations based on high-quality (Grade A), moderate-quality (Grade B), and low-quality (Grade C) evidence. RESULTS For acute DVT or pulmonary embolism (PE), we recommend initial parenteral anticoagulant therapy (Grade 1B) or anticoagulation with rivaroxaban. We suggest low-molecular-weight heparin (LMWH) or fondaparinux over IV unfractionated heparin (Grade 2C) or subcutaneous unfractionated heparin (Grade 2B). We suggest thrombolytic therapy for PE with hypotension (Grade 2C). For proximal DVT or PE, we recommend treatment of 3 months over shorter periods (Grade 1B). For a first proximal DVT or PE that is provoked by surgery or by a nonsurgical transient risk factor, we recommend 3 months of therapy (Grade 1B; Grade 2B if provoked by a nonsurgical risk factor and low or moderate bleeding risk); that is unprovoked, we suggest extended therapy if bleeding risk is low or moderate (Grade 2B) and recommend 3 months of therapy if bleeding risk is high (Grade 1B); and that is associated with active cancer, we recommend extended therapy (Grade 1B; Grade 2B if high bleeding risk) and suggest LMWH over vitamin K antagonists (Grade 2B). We suggest vitamin K antagonists or LMWH over dabigatran or rivaroxaban (Grade 2B). We suggest compression stockings to prevent the postthrombotic syndrome (Grade 2B). For extensive superficial vein thrombosis, we suggest prophylactic-dose fondaparinux or LMWH over no anticoagulation (Grade 2B), and suggest fondaparinux over LMWH (Grade 2C). CONCLUSION Strong recommendations apply to most patients, whereas weak recommendations are sensitive to differences among patients, including their preferences.

Executive Summary: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

The eighth iteration of the American College of Chest Physicians Antithrombotic Guidelines presented, in a paper version, a narrative evidence summary and rationale for the recommendations, a small number of evidence profiles summarizing bodies of evidence, and some articles with quite extensive summary tables of primary studies. In total, this represented 600 recommendations summarized in 968 pages of text. Many readers responded that the result was too voluminous for their liking or practical use.

Treatment and prevention of heparin-induced thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.

BACKGROUND Heparin-induced thrombocytopenia (HIT) is an antibody-mediated adverse drug reaction that can lead to devastating thromboembolic complications, including pulmonary embolism, ischemic limb necrosis necessitating limb amputation, acute myocardial infarction, and stroke. METHODS The methods of this guideline follow the Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. RESULTS Among the key recommendations for this article are the following: For patients receiving heparin in whom clinicians consider the risk of HIT to be > 1%, we suggest that platelet count monitoring be performed every 2 or 3 days from day 4 to day 14 (or until heparin is stopped, whichever occurs first) (Grade 2C). For patients receiving heparin in whom clinicians consider the risk of HIT to be < 1%, we suggest that platelet counts not be monitored (Grade 2C). In patients with HIT with thrombosis (HITT) or isolated HIT who have normal renal function, we suggest the use of argatroban or lepirudin or danaparoid over other nonheparin anticoagulants (Grade 2C). In patients with HITT and renal insufficiency, we suggest the use of argatroban over other nonheparin anticoagulants (Grade 2C). In patients with acute HIT or subacute HIT who require urgent cardiac surgery, we suggest the use of bivalirudin over other nonheparin anticoagulants or heparin plus antiplatelet agents (Grade 2C). CONCLUSIONS Further studies evaluating the role of fondaparinux and the new oral anticoagulants in the treatment of HIT are needed.

Andexanet Alfa for the Reversal of Factor Xa Inhibitor Activity

BACKGROUND Bleeding is a complication of treatment with factor Xa inhibitors, but there are no specific agents for the reversal of the effects of these drugs. Andexanet is designed to reverse the anticoagulant effects of factor Xa inhibitors. METHODS Healthy older volunteers were given 5 mg of apixaban twice daily or 20 mg of rivaroxaban daily. For each factor Xa inhibitor, a two-part randomized placebo-controlled study was conducted to evaluate andexanet administered as a bolus or as a bolus plus a 2-hour infusion. The primary outcome was the mean percent change in anti-factor Xa activity, which is a measure of factor Xa inhibition by the anticoagulant. RESULTS Among the apixaban-treated participants, anti-factor Xa activity was reduced by 94% among those who received an andexanet bolus (24 participants), as compared with 21% among those who received placebo (9 participants) (P<0.001), and unbound apixaban concentration was reduced by 9.3 ng per milliliter versus 1.9 ng per milliliter (P<0.001); thrombin generation was fully restored in 100% versus 11% of the participants (P<0.001) within 2 to 5 minutes. Among the rivaroxaban-treated participants, anti-factor Xa activity was reduced by 92% among those who received an andexanet bolus (27 participants), as compared with 18% among those who received placebo (14 participants) (P<0.001), and unbound rivaroxaban concentration was reduced by 23.4 ng per milliliter versus 4.2 ng per milliliter (P<0.001); thrombin generation was fully restored in 96% versus 7% of the participants (P<0.001). These effects were sustained when andexanet was administered as a bolus plus an infusion. In a subgroup of participants, transient increases in levels of d-dimer and prothrombin fragments 1 and 2 were observed, which resolved within 24 to 72 hours. No serious adverse or thrombotic events were reported. CONCLUSIONS Andexanet reversed the anticoagulant activity of apixaban and rivaroxaban in older healthy participants within minutes after administration and for the duration of infusion, without evidence of clinical toxic effects. (Funded by Portola Pharmaceuticals and others; ANNEXA-A and ANNEXA-R ClinicalTrials.gov numbers, NCT02207725 and NCT02220725.).

Evidence-Based Management of Anticoagulant Therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

BACKGROUND High-quality anticoagulation management is required to keep these narrow therapeutic index medications as effective and safe as possible. This article focuses on the common important management questions for which, at a minimum, low-quality published evidence is available to guide best practices. METHODS The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement. RESULTS Most practical clinical questions regarding the management of anticoagulation, both oral and parenteral, have not been adequately addressed by randomized trials. We found sufficient evidence for summaries of recommendations for 23 questions, of which only two are strong rather than weak recommendations. Strong recommendations include targeting an international normalized ratio of 2.0 to 3.0 for patients on vitamin K antagonist therapy (Grade 1B) and not routinely using pharmacogenetic testing for guiding doses of vitamin K antagonist (Grade 1B). Weak recommendations deal with such issues as loading doses, initiation overlap, monitoring frequency, vitamin K supplementation, patient self-management, weight and renal function adjustment of doses, dosing decision support, drug interactions to avoid, and prevention and management of bleeding complications. We also address anticoagulation management services and intensive patient education. CONCLUSIONS We offer guidance for many common anticoagulation-related management problems. Most anticoagulation management questions have not been adequately studied.

Systematic Review: Efficacy and Safety of Rituximab for Adults with Idiopathic Thrombocytopenic Purpura

Idiopathic thrombocytopenic purpura (ITP) is a common hematologic disorder characterized by platelet autoantibodies, low platelet counts, and bleeding. Rituximab is a chimeric, monoclonal anti-CD20 antibody that targets B lymphocytes and causes Fc-mediated cell lysis (14). It is currently indicated for the treatment of lymphoma (58), but because of its ability to deplete autoantibody-producing B lymphocytes and its favorable toxicity profile (9), it has been used in patients with various autoimmune diseases (1012), including ITP. In some patients with ITP, rituximab has been associated with a reduction in specific platelet-associated autoantibodies and an increase in platelet count (13). Early success with rituximab in ITP has lead to its widespread use and incorporation into recent treatment algorithms (14, 15). However, the evidence to support the use of rituximab in ITP is uncertain. We performed a systematic review of the literature to evaluate the efficacy and safety of this treatment. Methods Search Strategy One hematologist and one internist independently searched the literature in June 2005 and updated the search in April 2006. The electronic databases of MEDLINE (from 1966) and EMBASE (from 1980) were searched by using the explode function for the Medical Subject Heading (MeSH) terms antibodies, monoclonal and purpura, thrombocytopenic, idiopathic and the textwords rituximab, rituxan, mabthera, anti CD20, anti CD20 antibody, immune thrombocytopenic purpura, and idiopathic thrombocytopenic purpura. The MEDLINE database was also searched with the PubMed search engine by using the MeSH term purpura, thrombocytopenic, idiopathic and the textwords rituximab and rituxan. The Cochrane Registry for Controlled Trials was searched by using the terms rituximab, immune thrombocytopenic purpura, and ITP. Scientific abstracts were identified by searching the electronic databases of the American Society of Hematology and the American Society of Clinical Oncology from 1997 (the year of licensure of rituximab) to 2005 by using the search terms ritux*, thrombocytopenic, and ITP. Bibliographies of relevant articles and reviews were manually searched, and authors were canvassed for additional citations. Eligibility Criteria and Study Selection Exclusion criteria were secondary causes of thrombocytopenia, including splenomegaly, hepatitis B or C virus infection, HIV infection, lupus, antiphospholipid antibody syndrome, bone marrow failure syndromes, and drug-induced thrombocytopenia; malignancy, including chronic lymphocytic leukemia and lymphoma; the Evan syndrome; and rituximab re-treatments. Children (<16 years of age) were excluded because the biology and natural history of ITP in children were believed to differ considerably from those in adults. There was no restriction on study design or language of publication. Reports published only in abstract form were eligible. Where duplicate or redundant publications were uncovered, the latest and most informative version was retained. Initially, titles and abstracts of all articles were evaluated independently by 2 reviewers. Full-text articles were retrieved when they were judged by at least 1 reviewer to possibly contain relevant original data. Final article selection was done independently by both reviewers, and disagreements were resolved by consensus in all cases. Data Extraction The following data were collected in duplicate: proportion of patients with complete, partial, or minimal platelet count responses (and their definitions); time to platelet count responses; duration of platelet count responses; dose and schedule of rituximab administration; toxicities; previous ITP treatments; baseline platelet count; duration of ITP before rituximab treatment; study design and use of controls; and sources of funding. Individual-patient data were used where possible. Assessment of Methodologic Quality Study quality was assessed independently by 2 hematologists with expertise in research methods. Reviewers evaluated 4 key design features for each study: prospective data collection, consecutive patient enrollment, a clearly stated duration of follow-up, and a description of losses to follow-up. Assessors were blinded to study author, journal, publication date, and main results. Disagreements were resolved by independent adjudication. Statistical Analysis Patient demographic characteristics and platelet count responses were analyzed only from those studies enrolling 5 or more patients because we felt that smaller studies may be subject to extreme reporting bias. To determine estimates of response, we defined complete response as the achievement of a platelet count greater than 150109 cells/L; partial response as a platelet count between 50 and 150109 cells/L; and overall response as a platelet count greater than 50109 cells/L. These definitions were chosen to reflect the most common criteria used in primary reports. Toxicities were considered from all studies, including those enrolling fewer than 5 patients each, to provide the most thorough description of safety. We determined estimates of effect of rituximab by calculating the weighted mean proportion by using a random-effects model. This model estimated the between-study variance by using the method of moments and assumed that the proportion from each study was sampled from the normal distribution, with variance calculated from the data. Continuous variables, including time to response, response duration, and follow-up, were summarized with medians, minimum and maximum values, and interquartile ranges assuming a normal distribution of the data. Unweighted chance-corrected values were used to assess agreement between reviewers for study selection (16). Role of the Funding Source This systematic review had no external source of funding. The organizations that fund the individual authors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; or preparation, review, and approval of the manuscript. Results Study Selection We identified 599 citations through our comprehensive literature search, of which 60 were retrieved for detailed review (Figure 1). Agreement between reviewers for initial study inclusion was excellent (= 0.87). After exclusion of ineligible studies, redundant or duplicate publications, and reports that did not contain original data, 31 reports were included. Nineteen studies (313 patients) enrolled at least 5 patients each and were included in the efficacy analysis (13, 1734), and 29 studies (306 patients) reported toxicity data (13, 1719, 2128, 3046). Of the 19 reports describing efficacy outcomes, 9 were published in abstract form only. Abstracts were carefully scrutinized, and authors were contacted when necessary to ensure that redundant publications were excluded. Figure 1. Article selection. Results of article search and selection conducted in accordance with guidelines on reporting systematic reviews of observational studies (56). ITP = idiopathic thrombocytopenic purpura. Study Designs and Sources of Funding There was 1 dose-finding phase II study (28) and 18 single-arm cohort studies (13, 1727, 2934). Source of funding was not reported in 26 of 31 reports; of the remaining 5, 1 was industry-sponsored (19), 3 were funded by nonprofit organizations (21, 31, 41), and 1 reported that it had no funding information to disclose (32). Description of Patients Patients were 16 to 89 years of age, had had ITP for 1 to 360 months, and had a platelet count that ranged from 1 to 89109 cells/L before rituximab treatment (Table 1). Nearly all (99.0%) patients had received corticosteroids, and 158 (50.5%) had had splenectomy. Other previous treatments were immunosuppressants, including cyclosporine, azathioprine, or mycophenylate (n= 26); cyclophosphamide (n= 12); vinca alkaloids (n= 18); and danazol (n= 17). The number of previous treatments varied between and within reports. Table 1. Characteristics of Patients with Idiopathic Thrombocytopenic Purpura in Rituximab Studies Enrolling 5 or More Patients Each (n= 313)* Rituximab Dose and Schedule Rituximab was administered as a weekly infusion of 375 mg/m2 for 4 consecutive weeks in 16 of 19 studies. Of the remaining 3 studies, 1 did not report the dosing schedule (30); 1 used a schedule of 1 to 8 infusions of 325 mg/m2 per dose (29); and 1 used a low dose of rituximab (50 mg/m2 on day 1, then 150 mg/m2 on days 8 and 15), an intermediate dose (150 mg/m2 on day 1, then 375 mg/m2 weekly for 3 weeks), and a standard dose (28). Platelet Count Response In most reports, complete response and partial response were defined according to the achievement of predefined platelet count thresholds; however, these thresholds varied. Certain reports used additional criteria to define a response, including the discontinuation of steroid therapy (32) and the resolution of bleeding symptoms (26). One report defined complete response as the achievement of a platelet count that was adequate for hemostasis (25); in 2 reports, neither complete response nor partial response was defined (22, 27). The timing of platelet count measurements in the definitions of a response was specified in 2 reports: 12 weeks after the first rituximab infusion (29) and 2 weeks after the last infusion (30). In 1 report, a response was considered only if it lasted at least 30 days (21), and in another, at least 4 months (13). Where reporting of studies included homogenous criteria to define platelet count responses to therapy, treatment with rituximab resulted in a complete response (platelet count> 150109 cells/L) in 46.3% of patients (95% CI, 29.5% to 57.7%), partial response (50 to 150109 cells/L) in 24.0% (CI, 15.2% to 32.7%), and overall response (>50109 cells/L) in 62.5% (CI, 52.6% to 72.5%). Rates of complete, partial, and overall response were based on 191, 284, and 313 eligible patients, respectively (Table 2). In a sensitivity analysis that exclud

Acute Kidney Injury After Cardiac Surgery Focus on Modifiable Risk Factors

Background— Acute kidney injury (AKI) after cardiac surgery is a major health issue. Lacking effective therapies, risk factor modification may offer a means of preventing this complication. The objective of the present study was to identify and determine the prognostic importance of such risk factors. Methods and Results— Data from a multicenter cohort of 3500 adult patients who underwent cardiac surgery at 7 hospitals during 2004 were analyzed (using multivariable logistic regression modeling) to determine the independent relationships between 3 thresholds of AKI (>25%, >50%, and >75% decrease in estimated glomerular filtration rate within 1 week of surgery or need for postoperative dialysis) with death rates, as well as to identify modifiable risk factors for AKI. The 3 thresholds of AKI occurred in 24% (n=829), 7% (n=228), and 3% (n=119) of the cohort, respectively. All 3 thresholds were independently associated with a >4-fold increase in the odds of death and could be predicted with several perioperative variables, including preoperative intra-aortic balloon pump use, urgent surgery, and prolonged cardiopulmonary bypass. In particular, 3 potentially modifiable variables were also independently and strongly associated with AKI. These were preoperative anemia, perioperative red blood cell transfusions, and surgical reexploration. Conclusions— AKI after cardiac surgery is highly prevalent and prognostically important. Therapies aimed at mitigating preoperative anemia, perioperative red blood cell transfusions, and surgical reexploration may offer protection against this complication.

Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy

Background: Whether to continue oral anticoagulant therapy beyond 6 months after an “unprovoked” venous thromboembolism is controversial. We sought to determine clinical predictors to identify patients who are at low risk of recurrent venous thromboembolism who could safely discontinue oral anticoagulants. Methods: In a multicentre prospective cohort study, 646 participants with a first, unprovoked major venous thromboembolism were enrolled over a 4-year period. Of these, 600 participants completed a mean 18-month follow-up in September 2006. We collected data for 69 potential predictors of recurrent venous thromboembolism while patients were taking oral anticoagulation therapy (5–7 months after initiation). During follow-up after discontinuing oral anticoagulation therapy, all episodes of suspected recurrent venous thromboembolism were independently adjudicated. We performed a multivariable analysis of predictor variables (p < 0.10) with high interobserver reliability to derive a clinical decision rule. Results: We identified 91 confirmed episodes of recurrent venous thromboembolism during follow-up after discontinuing oral anticoagulation therapy (annual risk 9.3%, 95% CI 7.7%–11.3%). Men had a 13.7% (95% CI 10.8%–17.0%) annual risk. There was no combination of clinical predictors that satisfied our criteria for identifying a low-risk subgroup of men. Fifty-two percent of women had 0 or 1 of the following characteristics: hyperpigmentation, edema or redness of either leg; D-dimer ≥ 250 μg/L while taking warfarin; body mass index ≥ 30 kg/m2; or age ≥ 65 years. These women had an annual risk of 1.6% (95% CI 0.3%–4.6%). Women who had 2 or more of these findings had an annual risk of 14.1% (95% CI 10.9%–17.3%). Interpretation: Women with 0 or 1 risk factor may safely discontinue oral anticoagulant therapy after 6 months of therapy following a first unprovoked venous thromboembolism. This criterion does not apply to men. (http://Clinicaltrials.gov trial register number NCT00261014)

Comparison of 5-mg and 10-mg Loading Doses in Initiation of Warfarin Therapy

Warfarin levels are monitored by measuring the prothrombin time, which responds to reductions in levels of three vitamin K-dependent clotting factors: factors II, VII, and X [1, 2]. During the first 48 hours of treatment, the anticoagulant effect of warfarin is caused mainly by a reduction in the activity of factor VII, which has a half-life of 6 hours. In contrast, the antithrombotic effect of warfarin (which is thought to be caused primarily by a reduction in the activity of factor II) is delayed for as long as 60 hours [3, 4]. Therefore, during the first 48 hours of therapy, the anticoagulant and antithrombotic effects of warfarin may be dissociated. In addition, because the half-life of the vitamin K-dependent anticoagulant protein, protein C, is similar to that of factor VII [5], the early anticoagulant effect of warfarin (which results from reduction of factor VII) could be counteracted by a procoagulant effect (which results from reduction of protein C) [6]. Warfarin treatment is often initiated with a 10-mg loading dose and then reduced to a level that maintains the international normalized ratio (INR) within the therapeutic range. An alternative approach is to start warfarin therapy at a dose of 5 mg, which is the average dose required to maintain an INR of 2.0 to 3.0. Although a 10-mg loading dose produces a more rapid increase in the prothrombin time, this effect is caused largely by a decrease in factor VII levels and therefore may not produce a more rapid antithrombotic effect. The 10-mg loading dose has three potential short-comings. First, if heparin is discontinued as soon as the INR reaches the therapeutic range, thrombus extension may occur. This is because the antithrombotic effect of warfarin may not yet have manifested. Second, elderly or vitamin K-deficient patients may be exposed to an unnecessary risk for bleeding [7-12]. Third, protein C levels can be excessively decreased before the full antithrombotic effect of warfarin has been completely expressed through the reduction of factor II. On the basis of these considerations, we did a study to compare the relative effects of 5- and 10-mg loading doses of warfarin on four surrogate laboratory markers of efficacy and safety. Methods Patients with no contraindications to warfarin who required anticoagulation (target INR, 2.0 to 3.0) were invited to participate in the trial between June and November 1994 at The Hamilton Civic Hospitals (Ontario, Canada). Enrollment was targeted at 50 patients. All patients gave written, informed consent, and the study was approved by the local internal review board. Patients were assigned by random number table to receive warfarin at an initial dose of 5 or 10 mg. Subsequent doses were determined on the basis of nomograms that were developed before the study began through an iterative process. Because the study used laboratory outcomes, patients and health care professionals were not blinded to treatment assignments. Patients were followed for a maximum of 108 hours, during which time they received five doses of warfarin. Blood samples were taken before warfarin therapy was initiated, 12 hours after the first dose of warfarin, and at 24-hour intervals for 5 days. Blood was collected into vacuum-sealed containers that contained 0.102 mol of buffered sodium citrate per liter. To obtain platelet-free plasma, the sample was double centrifuged at 1700 g and frozen at 70C for batch assays [13]. The prothrombin time was measured using Thromborel S (International Sensitivity Index 1.06, Behring Diagnostics, Kanata, Ontario, Canada) and reported as an INR [14]. Heparin does not increase the prothrombin time in patients receiving both warfarin and heparin if this thromboplastin reagent is used. Factors II, VII, IX, and X were assayed by using the one-stage clotting method [15]. Protein C levels were measured by using a functional clotting assay (Dade International, Mississauga, Ontario, Canada) [16]. Treatment of supratherapeutic INRs with vitamin K was left to the discretion of the attending physician. The outcome measures were the time required to achieve an INR of 2.0 to 3.0, the proportion of INR values greater than 3.0, the time course for reductions in levels of factors II and X, and the time course for reduction in protein C levels. Additional data included levels of factors VII and IX. Results Fifty-one consecutive patients were enrolled in the trial. Two were excluded after one dose of warfarin: One died, and one required cardiac catheterization. Twenty-five patients were randomly assigned to receive a 10-mg loading dose of warfarin; 24 were assigned to receive a 5-mg loading dose. The two groups did not differ in age; weight; or frequency of acute thromboembolism, cancer, or surgery during or immediately before the study period. Forty-eight patients received concomitant heparin therapy for all or part of the study period. Beginning on study day 2, the dose of warfarin was adjusted using a nomogram. Warfarin doses in the two groups were similar except on days 1 and 2. The 10-mg group achieved an INR greater than 2.0 statistically significantly sooner than did the 5-mg group (Table 1). At 36 hours, 11 of 25 patients (44% [CI, 34% to 54%]) in the 10-mg group had INRs of 2.0 or greater compared with 2 of 24 patients (8% [CI, 3% to 14%]) in the 5-mg group (P = 0.005). At 60 hours, 9 of 25 patients in the 10-mg group (36% [CI, 17% to 54%]) had INRs greater than 3.0 compared with none of 23 patients in the 5-mg group (P = 0.002). Five patients (4 in the 10-mg group and 1 in the 5-mg group) received vitamin K. These patients had INRs of 4.8 to 9.3 and received 0.5 to 2.0 mg of vitamin K subcutaneously. No patient bled. Table 1. International Normalized Ratios for Patients Assigned to Receive a 5- or 10-mg Loading Dose of Warfarin* Levels of factors II and X declined slowly, and no substantial differences were seen between the 5-and 10-mg groups. In contrast, levels of factor VII and protein C decreased more rapidly and were statistically significantly lower in the 10-mg group than in the 5-mg group at 36 and 60 hours (Figure 1). Figure 1. Plasma levels of coagulation factors in patients receiving a 10-mg (striped bars) or 5-mg (white bars) loading dose of warfarin for each of six time points assessed. top middle bottom Discussion We compared the relative effects of 5- and 10-mg loading doses of warfarin. The time course of reduction in levels of factor II was used as a surrogate end point for clinical efficacy, and excessive elevation of the prothrombin time and unopposed reduction in protein C levels were used as surrogate end points for safety. Patients who received a 10-mg loading dose of warfarin achieved INRs greater than 2.0 more rapidly than did patients who received a 5-mg loading dose. However, because this change in the INR was entirely caused by the early reduction of factor VII levels in the 10-mg group, it may not reflect an antithrombotic effect of warfarin, which is thought to result from a reduction in factor II levels. Two separate experimental observations in rabbits support this idea: The first is the early report of a 5-day delay in achieving an antithrombotic effect with warfarin, although the prothrombin time was first prolonged into the therapeutic range and the level of factor VII was markedly reduced after 2 days of treatment [17]. This observation provides the rationale for overlapping heparin and warfarin therapy for 5 days during the initiation of anticoagulant therapy [17, 18]. The second is the finding that the antithrombotic effect of warfarin is abrogated by the infusion of factor II and (to a lesser extent) factor X [18]. In our study, the rate of reduction in levels of factor II and factor X activity were similar in the 5- and 10-mg groups. On the other hand, the 10-mg loading dose was associated with a significantly more rapid decrease in protein C activity (which decreased before levels of factors X and II were substantially reduced) than that seen in the 5-mg group and an excessive prolongation of the INR. The combination of markedly reduced protein C levels and near-normal levels of factors II and X over the first 2 days of warfarin therapy could produce a hypercoagulable state, and excessive prolongation of the INR could create a higher risk for bleeding. Our study is limited because we used surrogate markers for efficacy and safety. A much larger trial using clinical outcome measures is needed to determine whether the surrogate markers that we used are clinically relevant. Nevertheless, our findings suggest that both regimens result in a therapeutic INR in most patients by day 5 of treatment. From Hamilton Civic Hospital, McMaster University, and The Hamilton Civic Hospitals Research Centre, Hamilton, Ontario, Canada.

Guidance on the emergent reversal of oral thrombin and factor Xa inhibitors

The new oral anticoagulants dabigatran, rivaroxaban and apixaban have advantages over warfarin which include no need for laboratory monitoring, less drug–drug interactions and less food‐drug interactions. However, there is no established antidote for patients who are bleeding or require emergent surgery and there is a paucity of evidence to guide the clinical care during these situations. Members of thrombosis and anticoagulation groups participating in the Thrombosis and Hemostasis Summit of North America formulated expert opinion guidance for reversing the anticoagulant effect of the new oral anticoagulants and suggest: routine supportive care, activated charcoal if drug ingestion was within a couple of hours, and hemodialysis if feasible for dabigatran. Also, the pros and cons of the possible use of four factor prothrombin complex concentrate are discussed. Am. J. Hematol. 2012.