Francesco Dentali

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.

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

Meta-analysis: Anticoagulant Prophylaxis to Prevent Symptomatic Venous Thromboembolism in Hospitalized Medical Patients

Context Anticoagulant prophylaxis of venous thromboembolism in hospitalized patients is better established in surgical practice than in medical practice, in part because of the lack of convincing clinical trial evidence in hospitalized medical patients. Contributions The authors found 9 controlled, randomized trials of currently recommended unfractionated heparin or low-molecular-weight heparin prophylaxis regimens in hospitalized medical patients. Prophylaxis decreased the rate of pulmonary embolism, including fatal pulmonary emboli, by one halfa statistically significant reduction. Prophylaxis did not change other outcomes, including major bleeding. Caution Methods to identify good candidates for prophylaxis do not yet exist. Implications Anticoagulant prophylaxis substantially reduces the risk for venous thromboembolism in hospitalized medical patients. The Editors Prevention of venous thromboembolism (VTE), which includes pulmonary embolism (PE) and deep venous thrombosis (DVT), is an important management issue in at-risk hospitalized medical patients. The Agency for Healthcare Research and Quality ranks prevention of VTE as the first priority out of 79 preventive initiatives that can improve patient safety in health care settings (1). Anticoagulant prophylaxis with unfractionated heparin or low-molecular-weight heparin has been described as an efficacious, safe, and cost-effective intervention to prevent DVT in medical patients (24). Furthermore, the American College of Chest Physicians Guidelines on Antithrombotic Therapy gives anticoagulant prophylaxis in medical patients a grade 1A recommendation (4). Despite these considerations, anticoagulant prophylaxis in at-risk hospitalized medical patients is administered to only 16% to 33% of such patients (57), whereas up to 90% of at-risk surgical patients receive prophylaxis (8, 9). One reason that may explain this apparent under utilization of anticoagulant prophylaxis in medical patients is a lack of evidence that such treatment prevents clinically important outcomes, such as PE, which has been shown in surgical patients (10). Individual randomized trials of anticoagulant prophylaxis in medical patients have been underpowered to show a reduction in PE and have assessed treatment effects on asymptomatic, venography-detected DVT, which is a less compelling outcome (1113). Therefore, we performed a meta-analysis of randomized, controlled trials of anticoagulant prophylaxis in medical patients, focusing on the effects of treatment on clinically important efficacy outcomes (any PE, fatal PE, symptomatic DVT, and all-cause mortality) and safety outcomes (major bleeding). The aim of our study was to determine the effects of treatment while patients were receiving anticoagulant prophylaxis and to assess to what extent, if any, these treatment effects were maintained after prophylaxis had been stopped. Methods Data Sources We attempted to identify all published and unpublished randomized, controlled trials, irrespective of language, that described anticoagulant prophylaxis in medical patients by using MEDLINE (1966 to September 2006, week 3), EMBASE (1980 to September 2006, week 3), and Cochrane Central Register of Controlled Trials (2006, Issue 3) databases. We show the search strategy in the Appendix Table. We supplemented the strategy by manually reviewing reference lists and by contacting content experts. Appendix Table. Literature Search Strategy* Study Selection Two reviewers independently performed study selection. Disagreements were resolved through discussion and by a third reviewer. We included a study if it was a randomized, controlled trial that compared treatment with a prophylactic dose of anticoagulant (unfractionated heparin, low-molecular-weight heparin, or fondaparinux) with no treatment (placebo or no intervention) in medical patients. Included studies also had to assess at least 1 of the following outcomes: symptomatic PE, symptomatic DVT, major bleeding, or all-cause mortality. We excluded studies that involved only patients with stroke, as this is a selected, high-risk subgroup (4), or if outcomes were not objectively confirmed. For trials that were published in more than 1 study, we extracted data from the most recent publication and used earlier publications to clarify data. To assess agreement between reviewers for study selection, we used the kappa statistic, which measures agreement beyond chance (14). A value greater than 0.6 is considered substantial agreement, and a value greater than 0.8 is considered almost perfect agreement (15). Study Data Extraction We extracted and presented data according to the QUORUM criteria (16). For each study, 2 reviewers, who were blinded to the identity of the study authors and journal in which the studies were published, independently extracted data on study design, patient characteristics, and anticoagulant prophylaxis. We extracted data on the following treatment efficacy outcomes: any PE (that is, symptomatic nonfatal and fatal PE), fatal PE, symptomatic DVT, and all-cause mortality. Data were also extracted on major bleeding (safety outcome). We only considered objectively documented and independently adjudicated outcomes. We accepted the reported definitions of major bleeding and did not attempt to reclassify these events. We defined major bleeding as that which required transfusion of 2 or more units of packed red blood cells, involved a critical site (for example, retroperitoneal), or was fatal. To determine the treatment effects of anticoagulant prophylaxis during the time patients were receiving prophylaxis, we extracted data on efficacy and safety outcomes during the on-treatment period. To determine whether the treatment effects of anticoagulant prophylaxis were maintained after prophylaxis had been stopped, we planned to extract data on efficacy outcomes during the entire on-treatment and after-treatment periods. If outcome data could not be identified for extraction, we contacted the study authors by e-mail to request these data. If a response was not received after 15 days, we sent a second e-mail and contacted the secondary authors. We resolved disagreements about study data extraction by consensus or by discussion with a third reviewer. Anticoagulant Regimens We assessed the following anticoagulant regimens that are currently recommended for the prevention of VTE: unfractionated heparin, 5000 IU 2 or 3 times daily; enoxaparin, 40 mg or 60 mg once daily; enoxaparin, 30 mg twice daily; nadroparin, 4000 IU or 6000 IU once daily; dalteparin, 5000 IU once daily; and fondaparinux, 2.5 mg once daily. We excluded anticoagulant regimens that are not recommended for clinical use (for example, enoxaparin, 20 mg once daily). Study Quality Assessment Two reviewers who were blinded to the identity of the study authors and the journals in which the studies were published independently assessed study quality. The reviewers evaluated study quality by considering methods used to generate the randomization sequence, methods of double-blinding, and the description of patient withdrawals and dropouts. Data Synthesis and Analyses Primary Analyses We determined pooled relative risks and 95% CIs for any symptomatic PE (which included fatal and nonfatal PE), fatal PE, symptomatic DVT, all-cause mortality, and major bleeding in patients who received anticoagulant prophylaxis or no prophylaxis. We planned separate analyses for treatment effects during prophylaxis and for treatment effects after prophylaxis had been stopped. For treatment effects that were statistically significant, we determined the absolute risk reduction and number-needed-to-treat for benefit (NNTB) to prevent an outcome. We pooled data by using the MantelHaenszel method (17), and we performed a fixed-effects model by using Review Manager, version 4.2.8 (RevMan, Cochrane Collaboration, Oxford, England). Because combining trials with extremely low or zero event rates can yield biased results, we repeated the analyses using StatXact software, version 7 (Cytel Software Corporation, Cambridge, Massachusetts), which provides exact fixed-effect point and interval estimates for the odds ratio (18). The appropriateness of pooling data across studies was assessed using the I2 test for heterogeneity, which measures the inconsistency across study results and describes the proportion of total variation in study estimates that is due to heterogeneity rather than sampling error (19). Sensitivity Analyses We repeated sensitivity analyses by using only studies that satisfied each item of our prespecified quality evaluation (20). We created funnel plots of effect size versus standard error to assess for publication bias (21). Role of the Funding Source We received no financial support for this review. Results Study Identification and Selection We identified 830 potentially relevant studies from the following databases: 382 from MEDLINE, 358 from EMBASE, and 375 from the Cochrane Library (Figure 1). We excluded 813 studies after screening their title and abstract by using the predefined inclusion and exclusion criteria and retrieved the remaining 17 studies for more detailed evaluation (2238). We identified another 3 studies by manual review of references of retrieved articles (3941). Through contact with content experts, we identified 2 other studies (42, 43). Of the 22 retrieved studies, 13 were excluded for the following reasons: 4 because they had duplicate data (24, 29, 31, 34); 4 because they did not have an untreated control group (25, 27, 30, 36); 2 because they did not contain original data (26, 28); 1 because it included medical and surgical patients (37); 1 because it was not properly randomized (40); and 1 because it identified the control group arbitrarily and not by randomization (39). Therefore, we included 9 studies in our systematic review (22, 23, 32, 33, 35, 38, 4143). We had excellent interobserver agreement for study selection (= 0.98). Tabl

Meta-Analysis: Low-Molecular-Weight Heparin and Bleeding in Patients with Severe Renal Insufficiency

Context The risks of low-molecular-weight heparin (LMWH) in patients with severe renal insufficiency are not clear. Contribution In this review of 12 studies, patients with severe renal insufficiency receiving LMWH had an increased risk for major bleeding events. Four studies found that fixed-dose enoxaparin had greater anticoagulant effects in these patients. Three studies suggested that empirically dose-adjusted enoxaparin might not increase anticoagulant effects. Cautions Evidence relating to LMWHs other than enoxaparin was scant. Implications Patients with severe renal insufficiency receiving standard fixed-dose enoxaparin have greater anticoagulant effects and a higher risk for major bleeding. Empirical dose adjustment may reduce the risk for such events. The Editors One of the most important advantages of low-molecular-weight heparin (LMWH) compared with unfractionated heparin (UFH) is its predictable anticoagulant response, which allows it to be administered in fixed, weight-based doses without laboratory monitoring. When used to treat patients with acute venous thromboembolism, LMWH is associated with lower rates of recurrent thrombosis, bleeding, and death than is weight-adjusted, monitored UFH (1, 2). These advantages have revolutionized management of acute venous thromboembolism by allowing most patients to be treated out of hospital. Low-molecular-weight heparin has also greatly simplified in-hospital management of selected patients with venous thromboembolism and those with acute coronary syndromes. However, uncertainty still surrounds use of LMWH in patients with severe renal insufficiency because it is excreted by the kidneys (3) and, unlike UFH, its anticoagulant effect cannot be completely reversed. Although most randomized trials of LMWH excluded patients with renal insufficiency (4), pharmacokinetic studies suggest an association between creatinine clearance and levels of anti-factor Xa heparin (which measures the anticoagulant effect of LMWH), and increased bleeding complications have been reported when LMWH is used in patients with chronic renal insufficiency (5, 6). Because of concerns about the risk for accumulation and bleeding in patients with renal impairment, the American College of Chest Physicians and the College of American Pathologists recommend UFH instead of LMWH in patients with a creatinine clearance of 30 mL/min or less, or monitoring of anti-Xa activity if LMWH is used (4, 7). However, the evidence for this recommendation is conflicting (8) and there are no reliable data to guide the interpretation of anti-Xa levels to monitor treatment or to adjust LMWH doses (7). Despite this limitation, anti-Xa levels are the only available method to monitor LMWH activity and their use in clinical practice is based on consensus recommendations. Peak anti-Xa levels occur 4 hours after a therapeutic dose of subcutaneous LMWH is administered. Peak levels above the upper limit of the recommended therapeutic range (0.6 to 1.0 IU/mL) may be associated with an increased risk for bleeding (4). To further clarify the relationship between LMWH anti-Xa levels and creatinine clearance and the risk for bleeding in patients with a creatinine clearance of 30 mL/min or less, we performed a systematic review of all studies of LMWH in nondialysis-dependent patients with varying degrees of renal function that reported creatinine clearance and anti-Xa levels or major bleeding events. Methods This study was conducted according to the Meta-analysis Of Observational Studies in Epidemiology (MOOSE) guidelines (9). Study Identification We attempted to identify all published and unpublished studies of LMWH in nondialysis-dependent patients with renal insufficiency using the MEDLINE (1966 to week 3 of November 2005), EMBASE (1980 to 2005, week 51), and Cochrane Library (2005, Issue 4) electronic databases. The search was completed on 19 December 2005. The search strategy, which had no language restrictions, was developed in collaboration with a professional librarian (Appendix). We manually reviewed the reference lists of all retrieved articles and contacted content experts for additional published or unpublished trials. Study Selection Study selection was performed independently and in duplicate; disagreements were resolved through discussion. Studies were included if they 1) had at least 10 patients; 2) involved patients with varying degrees of renal function, including those with a creatinine clearance of 30 mL/min or less; 3) administered at least 1 dose of a commercially available LMWH; and 4) reported at least 1 of the following outcomes: anti-Xa levels or major bleeding. Studies were excluded if patients were dialysis-dependent, if LMWH was administered intravenously, if more than 1 LMWH preparation or dose (for example, prophylactic and therapeutic doses) were used, and if the data for anti-Xa or bleeding for individual LMWH preparations or doses could not be separately analyzed. Study Quality Assessment Two unmasked investigators independently assessed study quality according to the following criteria: 1) method of patient enrollmentstudies with consecutive patient enrollment were considered to be of higher quality than those with nonconsecutive enrollment; 2) duration and completeness of patient follow-up for major bleeding studies with longer and more thorough follow-up were considered to be of higher quality because major bleeding outcomes are more accurately reported; and 3) method of outcome ascertainmentstudies in which bleeding was objectively and reproducibly assessed by using a priori definitions were rated higher than those that did not use bleeding definitions or those that had unclear or nonobjective methods of measurement. Data Extraction Two unmasked investigators independently extracted data on study design, patient characteristics, renal function, type and dose of LMWH, anti-Xa levels, and number of major bleeding episodes. Data were extracted in duplicate, and disagreements were resolved through discussion. We defined a creatinine clearance of 30 mL/min or less as severe renal insufficiency, calculated by using the CockcroftGault (10) or Modification of Diet in Renal Disease (MDRD) (11) equation. For studies that adopted other thresholds to define severe renal failure or those that reported only mean creatinine clearance, we contacted the authors to obtain the data corresponding to a creatinine clearance threshold of 30 mL/min. We extracted peak anti-Xa levels 4 hours after subcutaneous injection of LMWH because peak levels correlate more strongly with efficacy and safety than do trough levels (12). Because maximum LMWH activity (Amax) is observed at 4 hours, Amax data were considered equivalent to 4-hour anti-Xa levels. A meta-analysis of anti-Xa levels at 4 hours was not performed because measures of variance were not reported in most studies, thereby precluding pooling of the data. We report the anti-Xa data according to LMWH type because differences in molecular weight and charge density of LMWH may result in differences in renal clearance and anti-Xa levels (13, 14). The LMWHs, such as tinzaparin, that are structurally similar to UFH may be less prone to accumulate in patients with renal insufficiency than smaller, less negatively charged LMWHs, such as enoxaparin. We accepted the definitions of major bleeding reported by authors and did not reclassify events. Therapeutic doses of LMWH (enoxaparin, 1.5 mg/kg of body weight once daily or 1 mg/kg twice daily; tinzaparin, 175 IU/kg once daily; dalteparin, 200 IU/kg once daily or 100 IU/kg twice daily) and prophylactic doses (enoxaparin, 40 mg once daily or 30 mg twice daily) were defined according to the product monographs. Adjusted-dose LMWH was defined as any dose that was modified empirically or according to renal function or measured anti-Xa levels. If the required data could not be extracted from the published report, we contacted the corresponding author by e-mail to request additional data. If a response was not received after 15 days, we sent a second e-mail; if we still received no response, we contacted secondary authors. Statistical Analysis To assess the agreement between reviewers for study selection, we used the k statistic, which measures chance-corrected agreement (15). The odds ratio for major bleeding in patients with and without severe renal insufficiency treated with LMWH was calculated for each study and pooled with the Peto method (fixed-effects) by using Review Manager, version 4.2 (RevMan, Oxford, United Kingdom; the Cochrane Collaboration, 2003). Statistical heterogeneity was evaluated by using the I2 statistic, which measures the extent of inconsistency among study results and describes the proportion of total variation in study estimates that is due to heterogeneity rather than sampling error. We preferred the Peto method to other statistical approaches for combining odds ratios because it provides relatively unbiased estimates of treatment effects when the event rates are low. We also calculated a pooled risk difference and 95% CIs by using exact statistical methods for stratified 2 2 tables. Two a priori secondary analyses were performed. The first compared major bleeding according to LMWH type because accumulation may vary among different preparations in patients with renal insufficiency (13, 14). The second compared major bleeding according to LMWH dose. Because bleeding is correlated with the intensity of anticoagulation, studies using therapeutic doses reported higher bleeding rates than those using prophylactic doses. A sensitivity analysis that included only high-quality studies was performed to assess the robustness of our primary results. A funnel plot of effect size versus standard error was used to assess possible publication bias (16). Role of the Funding Source No funding was received for this study. Results Study Identification and Selection Our search identified 875 published studies (219 from

Efficacy and Safety of the Novel Oral Anticoagulants in Atrial Fibrillation A Systematic Review and Meta-Analysis of the Literature

Background— Novel oral anticoagulants (NOACs) have been proposed as alternatives to vitamin K antagonists for the prevention of stroke and systemic embolism in patients with atrial fibrillation. Individually, NOACs were at least noninferior to vitamin K antagonists, but a clear superiority in overall and vascular mortality was not consistently proven. Methods and Results— We performed a meta-analysis of phase II and phase III randomized, controlled trials comparing NOACs with vitamin K antagonists in patients with atrial fibrillation. The MEDLINE and EMBASE databases, supplemented with conference abstract books and www.clinicaltrials.gov, were searched up to the first week of July 2012 with no language restriction. Two reviewers performed independent article review and study quality assessment. Data on overall and cardiovascular mortality, stroke or systemic embolism, ischemic stroke, major and intracranial bleeding, and myocardial infarction were collected. NOACs were pooled to perform a comparison with vitamin K antagonists, calculating pooled relative risks (RRs) and associated 95% confidence intervals (CIs). We retrieved 12 studies (3 administering dabigatran, 4 administering rivaroxaban, 2 administering apixaban, and 3 administering edoxaban) enrolling a total of 54 875 patients. NOACs significantly reduced total mortality (5.61% versus 6.02%; RR, 0.89; 95% CI, 0.83–0.96), cardiovascular mortality (3.45% versus 3.65%; RR, 0.89; 95% CI, 0.82–0.98), and stroke/systemic embolism (2.40% versus 3.13%; RR, 0.77; 95% CI, 0.70–0.86). There was a trend toward reduced major bleeding (RR, 0.86; 95% CI, 0.72–1.02) with a significant reduction of intracranial hemorrhage (RR, 0.46; 95% CI, 0.39–0.56). No difference in myocardial infarction was observed. Conclusions— NOACs are associated with an overall clinical benefit compared with vitamin K antagonists. Additional research is required to confirm these findings outside the context of randomized trials.Background— Novel oral anticoagulants (NOACs) have been proposed as alternatives to vitamin K antagonists for the prevention of stroke and systemic embolism in patients with atrial fibrillation. Individually, NOACs were at least noninferior to vitamin K antagonists, but a clear superiority in overall and vascular mortality was not consistently proven. Methods and Results— We performed a meta-analysis of phase II and phase III randomized, controlled trials comparing NOACs with vitamin K antagonists in patients with atrial fibrillation. The MEDLINE and EMBASE databases, supplemented with conference abstract books and [www.clinicaltrials.gov][1], were searched up to the first week of July 2012 with no language restriction. Two reviewers performed independent article review and study quality assessment. Data on overall and cardiovascular mortality, stroke or systemic embolism, ischemic stroke, major and intracranial bleeding, and myocardial infarction were collected. NOACs were pooled to perform a comparison with vitamin K antagonists, calculating pooled relative risks (RRs) and associated 95% confidence intervals (CIs). We retrieved 12 studies (3 administering dabigatran, 4 administering rivaroxaban, 2 administering apixaban, and 3 administering edoxaban) enrolling a total of 54 875 patients. NOACs significantly reduced total mortality (5.61% versus 6.02%; RR, 0.89; 95% CI, 0.83–0.96), cardiovascular mortality (3.45% versus 3.65%; RR, 0.89; 95% CI, 0.82–0.98), and stroke/systemic embolism (2.40% versus 3.13%; RR, 0.77; 95% CI, 0.70–0.86). There was a trend toward reduced major bleeding (RR, 0.86; 95% CI, 0.72–1.02) with a significant reduction of intracranial hemorrhage (RR, 0.46; 95% CI, 0.39–0.56). No difference in myocardial infarction was observed. Conclusions— NOACs are associated with an overall clinical benefit compared with vitamin K antagonists. Additional research is required to confirm these findings outside the context of randomized trials. # Clinical Perspective {#article-title-45} [1]: http://www.clinicaltrials.gov

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.

The metabolic syndrome and the risk of venous thrombosis: a case–control study

Summary.  Objective: The results of recent studies have suggested that patients with idiopathic venous thromboembolism (VTE) might be at increased risk of asymptomatic atherosclerosis and cardiovascular events. The metabolic syndrome is a cluster of risk factors for atherosclerosis. Its impact on VTE is unknown. Methods: In a case–control study, consecutive patients with objectively confirmed deep vein thrombosis (DVT) and control subjects with objectively excluded DVT underwent clinical assessment for the presence of the metabolic syndrome according to the National Cholesterol Education Program criteria. The presence of known risk factors for DVT was documented. Patients with DVT secondary to cancer were excluded. The prevalence of the metabolic syndrome was compared between patients with idiopathic DVT and controls. Results: We enrolled 93 patients with a first episode of idiopathic DVT and 107 controls. The mean age was 65.1 and 63.7 years, respectively. The metabolic syndrome was diagnosed in 50.5% of patients with idiopathic DVT and in 34.6% of controls [odds ratio (OR) 1.93; 95% confidence interval (CI) 1.05, 3.56]. After adjustment for age, sex, body mass index, and smoke, the metabolic syndrome remained independently associated with idiopathic DVT (OR 1.94; 95% CI 1.04, 3.63). In patients with secondary DVT, the prevalence of the metabolic syndrome was 27%. Conclusions: The metabolic syndrome may play a role in the pathogenesis of idiopathic DVT and may act as link between venous thrombosis and atherosclerosis.

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.

JAK2V617F mutation for the early diagnosis of Ph- myeloproliferative neoplasms in patients with venous thromboembolism: a meta-analysis.

Recent studies suggested that JAK2V617F mutation is frequent in patients with splanchnic vein thrombosis (SVT) but not in patients with other venous thromboembolic events (VTE). However, whether screening for the JAK2V617F mutation in VTE patients is justified remains unclear. Therefore, we performed a systematic review to assess the frequency of JAK2 mutation in VTE patients and the role of JAK2V617F mutation in the diagnosis of myeloproliferative neoplasms. MEDLINE and EMBASE databases were searched. Two reviewers independently performed study selection and extracted study characteristics. Pooled odds ratios of case-control studies and weighted mean proportion of the prevalence of JAK2V617F mutation of uncontrolled series were calculated. Twenty-four studies involving 3123 patients were included. Mean prevalence of JAK2 mutation was 32.7% (95% confidence interval, 25.5%-35.9%) in SVT patients. JAK2 mutation was associated with increased risk of SVT (odds ratio, 53.98; 95% confidence interval, 13.10-222.45). Mean prevalence of JAK2 mutation in other VTE patients was low (range, 0.88%-2.57%). Presence of JAK2V617F mutation in SVT patients was associated with a subsequent diagnosis of myeloproliferative neoplasm in many patients. JAK2 mutation is strongly associated with SVT, and routine screening of JAK2 mutation appears to be indicated in these patients.

Neutrophils and clinical outcomes in patients with acute coronary syndromes and/or cardiac revascularisation. A systematic review on more than 34,000 subjects.

Some studies have suggested that high levels of total white blood cell (WBC) count and C-reactive protein (CRP) may be considered as independent prognostic factors in patients with acute coronary syndromes (ACS) and/or after cardiac revascularisation by percutaneous coronary intervention or coronary artery bypass grafting surgery. Evidence on the role of neutrophils in cardiovascular disease is less compelling. Therefore, we conducted a systematic review of the literature with the aim of identifying all the available evidence to clarify the role of neutrophils (absolute or relative count, neutrophil/lymphocyte ratio) as a prognostic risk factor in patients with ACS and/or cardiac revascularisation. All published studies evaluating the role of neutrophils as a risk factor for clinical outcomes were assessed using the MEDLINE and EMBASE databases. Study selection, data extraction and validity assessment was performed independently by two reviewers. Twenty-one studies (17 of which had positive results) for a total of more than 34,000 patients were included. Ten of 13 studies in ACS patients found that neutrophils measured on-admission are related to mortality rate and/or to major adverse clinical events. A predictive value of neutrophils after cardiac revascularisation procedures was reported in seven out of eight studies. Most of the studies showed that neutrophils were independent predictors of cardiovascular outcomes when analysed concomitantly with other markers of inflammation (WBC, CRP). The findings of our systematic review highlight the potential application of this inexpensive and readily available inflammatory marker for risk stratification in patients with ACS and/or cardiac revascularisation.