Wendy Lim

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

Periprocedural Heparin Bridging in Patients Receiving Vitamin K Antagonists: Systematic Review and Meta-Analysis of Bleeding and Thromboembolic Rates

Background— Periprocedural bridging with unfractionated heparin or low-molecular-weight heparin aims to reduce the risk of thromboembolic events in patients receiving long-term vitamin K antagonists. Optimal periprocedural anticoagulation has not been established. Methods and Results— MEDLINE, EMBASE, and Cochrane databases (2001–2010) were searched for English-language studies including patients receiving heparin bridging during interruption of vitamin K antagonists for elective procedures. Data were independently collected by 2 investigators (&kgr;=0.90). The final review included 34 studies with 1 randomized trial. Thromboembolic events occurred in 73 of 7118 bridged patients (pooled incidence, 0.9%; 95% confidence interval [CI], 0.0.0–3.4) and 32 of 5160 nonbridged patients (pooled incidence, 0.6%; 95% CI, 0.0–1.2). There was no difference in the risk of thromboembolic events in 8 studies comparing bridged and nonbridged groups (odds ratio, 0.80; 95% CI, 0.42–1.54). Bridging was associated with an increased risk of overall bleeding in 13 studies (odds ratio, 5.40; 95% CI, 3.00–9.74) and major bleeding in 5 studies (odds ratio, 3.60; 95% CI, 1.52–8.50) comparing bridged and nonbridged patients. There was no difference in thromboembolic events (odds ratio, 0.30; 95% CI, 0.04–2.09) but an increased risk of overall bleeding (odds ratio, 2.28; 95% CI, 1.27–4.08) with full versus prophylactic/intermediate-dose low-molecular-weight heparin bridging. Low-thromboembolic-risk and/or non–vitamin K antagonist patient groups were used for comparison. Study quality was poor with heterogeneity for some analyses. Conclusions— Vitamin K antagonist–treated patients receiving periprocedural heparin bridging appear to be at increased risk of overall and major bleeding and at similar risk of thromboembolic events compared to nonbridged patients. Randomized trials are needed to define the role of periprocedural heparin bridging.Background— Periprocedural bridging with unfractionated heparin or low-molecular-weight heparin aims to reduce the risk of thromboembolic events in patients receiving long-term vitamin K antagonists. Optimal periprocedural anticoagulation has not been established. Methods and Results— MEDLINE, EMBASE, and Cochrane databases (2001–2010) were searched for English-language studies including patients receiving heparin bridging during interruption of vitamin K antagonists for elective procedures. Data were independently collected by 2 investigators (κ=0.90). The final review included 34 studies with 1 randomized trial. Thromboembolic events occurred in 73 of 7118 bridged patients (pooled incidence, 0.9%; 95% confidence interval [CI], 0.0.0–3.4) and 32 of 5160 nonbridged patients (pooled incidence, 0.6%; 95% CI, 0.0–1.2). There was no difference in the risk of thromboembolic events in 8 studies comparing bridged and nonbridged groups (odds ratio, 0.80; 95% CI, 0.42–1.54). Bridging was associated with an increased risk of overall bleeding in 13 studies (odds ratio, 5.40; 95% CI, 3.00–9.74) and major bleeding in 5 studies (odds ratio, 3.60; 95% CI, 1.52–8.50) comparing bridged and nonbridged patients. There was no difference in thromboembolic events (odds ratio, 0.30; 95% CI, 0.04–2.09) but an increased risk of overall bleeding (odds ratio, 2.28; 95% CI, 1.27–4.08) with full versus prophylactic/intermediate-dose low-molecular-weight heparin bridging. Low-thromboembolic-risk and/or non–vitamin K antagonist patient groups were used for comparison. Study quality was poor with heterogeneity for some analyses. Conclusions— Vitamin K antagonist–treated patients receiving periprocedural heparin bridging appear to be at increased risk of overall and major bleeding and at similar risk of thromboembolic events compared to nonbridged patients. Randomized trials are needed to define the role of periprocedural heparin bridging. # Clinical Perspective {#article-title-50}

Use of antifibrinolytic therapy to reduce transfusion in patients undergoing orthopedic surgery: A systematic review of randomized trials

BACKGROUND Minimizing bleeding and transfusion is desirable given its cost, complexity and potential for adverse events. Concerns have been heightened by recent data demonstrating that bleeding events may predict worse outcomes and by warnings about the safety of erythropoietic stimulating agents. Prior small studies suggest that antifibrinolytic agents may reduce bleeding and transfusion need in patients undergoing total hip replacement (THR) or total knee arthroplasty (TKA). However, no single study has been large enough to definitively determine if these agents are safe and effective. To address this issue we performed a systematic review of randomized trials describing the use of tranexamic acid, epsilon aminocaproic acid, or aprotinin administration in the perioperative setting. METHODS MEDLINE, EMBASE, CINAHL and the Cochrane databases were searched for relevant trials. Two independent reviewers abstracted total blood loss, transfusion requirements, and venous thromboembolism (VTE) rates. Data were combined using the Mantel-Haenszel method and dichotomous data expressed as relative risk (RR) with 95% confidence intervals (CI). RESULTS Patients receiving antifibrinolytic agents had reduced transfusion need (RR 0.52; 95% CI, 0.42 to 0.64; P<0.00001), reduced blood loss and no increase in the risk of VTE (RR 0.95% CI, 0.80 to 1.10, I(2)=0%, P=0.531). CONCLUSIONS We conclude that antifibrinolytic agents may reduce bleeding and transfusion in patients undergoing THR or TKA who receive appropriate antithrombotic prophylaxis. There is a need for a large, adequately powered prospective study to carefully examine the safety and efficacy of these agents.

Prognostic value of troponin and creatine kinase muscle and brain isoenzyme measurement after noncardiac surgery: a systematic review and meta-analysis.

Background:There is uncertainty regarding the prognostic value of troponin and creatine kinase muscle and brain isoenzyme measurements after noncardiac surgery. Methods:The current study undertook a systematic review and meta-analysis. The study used six search strategies and included noncardiac surgery studies that provided data from a multivariable analysis assessing whether a postoperative troponin or creatine kinase muscle and brain isoenzyme measurement was an independent predictor of mortality or a major cardiovascular event. Independent investigators determined study eligibility and abstracted data in duplicate. Results:Fourteen studies, enrolling 3,318 patients and 459 deaths, demonstrated that an increased troponin measurement after surgery was an independent predictor of mortality (odds ratio [OR] 3.4, 95% confidence interval [CI] 2.2–5.2), but there was substantial heterogeneity (I2 = 56%). The independent prognostic capabilities of an increased troponin value after surgery in the 10 studies that assessed intermediate-term (≤ 12 months) mortality was an OR = 6.7 (95% CI 4.1–10.9, I2 = 0%) and in the 4 studies that assessed long-term (more than 12 months) mortality was an OR = 1.8 (95% CI 1.4–2.3, I2 = 0%; P < 0.001 for test of interaction). Four studies, including 1,165 patients and 202 deaths, demonstrated an independent association between an increased creatine kinase muscle and brain isoenzyme measurement after surgery and mortality (OR 2.5, 95% CI 1.5–4.0, I2 = 4%). Conclusions:An increased troponin measurement after surgery is an independent predictor of mortality, particularly within the first year; limited data suggest an increased creatine kinase muscle and brain isoenzyme measurement also predicts subsequent mortality. Monitoring troponin measurements after noncardiac surgery may allow physicians to better risk stratify and manage their patients.

The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis

Vitamin K antagonists (VKAs) have been the standard of care for treatment of thromboembolic diseases. Target-specific oral anticoagulants (TSOACs) have been developed and found to be at least noninferior to VKAs with regard to efficacy, but the risk of bleeding with TSOACs remains controversial. We performed a systematic review and meta-analysis of phase-3 randomized controlled trials (RCTs) to assess the bleeding side effects of TSOACs compared with VKAs in patients with venous thromboembolism or atrial fibrillation. We searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials; conference abstracts; and www.clinicaltrials.gov with no language restriction. Two reviewers independently performed study selection, data extraction, and study quality assessment. Twelve RCTs involving 102 607 patients were retrieved. TSOACs significantly reduced the risk of overall major bleeding (relative risk [RR] 0.72, P < .01), fatal bleeding (RR 0.53, P < .01), intracranial bleeding (RR 0.43, P < .01), clinically relevant nonmajor bleeding (RR 0.78, P < .01), and total bleeding (RR 0.76, P < .01). There was no significant difference in major gastrointestinal bleeding between TSOACs and VKAs (RR 0.94, P = .62). When compared with VKAs, TSOACs are associated with less major bleeding, fatal bleeding, intracranial bleeding, clinically relevant nonmajor bleeding, and total bleeding. Additionally, TSOACs do not increase the risk of gastrointestinal bleeding.

Safety and Efficacy of Low Molecular Weight Heparins for Hemodialysis in Patients with End-Stage Renal Failure: A Meta-analysis of Randomized Trials

Low molecular weight heparins (LWMH) are the preferred initial treatment for many thromboembolic disorders but are renally excreted and relatively contraindicated in patients with renal failure because of concerns of increased bleeding risks. The purpose of this study was to evaluate the safety and efficacy of LMWH compared with unfractionated heparin (UFH) for preventing thrombosis of the extracorporeal dialysis circuit. Studies were identified with the use of MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and FirstSearch; reference lists were reviewed; and pharmaceutical companies were contacted. Randomized, controlled trials that compared an LMWH with another anticoagulant during hemodialysis in patients with ESRD and reported at least one of bleeding, extracorporeal circuit thrombosis, or anti-Xa levels were chosen. Two reviewers independently extracted data on methodologic quality, study design, clinical outcomes, and anti-Xa levels. Seventeen trials were included in this systematic review, 11 of which were included in the meta-analysis. It was found that LMWH did not significantly affect the number of bleeding events (relative risk, 0.96; 95% confidence interval [CI], 0.27 to 3.43), bleeding assessed by vascular access compression time (weighted mean difference, -0.87; 95% CI, -2.75 to 1.02), or extracorporeal circuit thrombosis (relative risk, 1.15; 95% CI, 0.70 to 1.91) as compared with UFH. LMWH seem to be as safe as UFH in terms of bleeding complications and as effective as UFH in preventing extracorporeal circuit thrombosis. However, inferences from these trials assessing anticoagulation for patients who undergo hemodialysis will continue to be weak until larger, more rigorous randomized trials are conducted.

Systematic review and meta-analysis methodology

Systematic reviews and meta-analyses are being increasingly used to summarize medical literature and identify areas in which research is needed. Systematic reviews limit bias with the use of a reproducible scientific process to search the literature and evaluate the quality of the individual studies. If possible the results are statistically combined into a meta-analysis in which the data are weighted and pooled to produce an estimate of effect. This article aims to provide the reader with a practical overview of systematic review and meta-analysis methodology, with a focus on the process of performing a review and the related issues at each step.

Elevated troponin and myocardial infarction in the intensive care unit: a prospective study

IntroductionElevated troponin levels indicate myocardial injury but may occur in critically ill patients without evidence of myocardial ischemia. An elevated troponin alone cannot establish a diagnosis of myocardial infarction (MI), yet the optimal methods for diagnosing MI in the intensive care unit (ICU) are not established. The study objective was to estimate the frequency of MI using troponin T measurements, 12-lead electrocardiograms (ECGs) and echocardiography, and to examine the association of elevated troponin and MI with ICU and hospital mortality and length of stay.MethodIn this 2-month single centre prospective cohort study, all consecutive patients admitted to our medical-surgical ICU were classified in duplicate by two investigators as having MI or no MI based on troponin, ECGs and echocardiograms obtained during the ICU stay. The diagnosis of MI was based on an adaptation of the joint European Society of Cardiology/American College of Cardiology definition: a typical rise or fall of an elevated troponin measurement, in addition to ischemic symptoms, ischemic ECG changes, a coronary artery intervention, or a new cardiac wall motion abnormality.ResultsWe screened 117 ICU admissions and enrolled 115 predominantly medical patients. Of these, 93 (80.9%) had at least one ECG and one troponin; 44 of these 93 (47.3%) had at least one elevated troponin and 24 (25.8%) had an MI. Patients with MI had significantly higher mortality in the ICU (37.5% versus 17.6%; P = 0.050) and hospital (50.0% versus 22.0%; P = 0.010) than those without MI. After adjusting for Acute Physiology and Chronic Health Evaluation II score and need for inotropes or vasopressors, MI was an independent predictor of hospital mortality (odds ratio 3.22, 95% confidence interval 1.04–9.96). The presence of an elevated troponin (among those patients in whom troponin was measured) was not independently predictive of ICU or hospital mortality.ConclusionIn this study, 47% of critically ill patients had an elevated troponin but only 26% of these met criteria for MI. An elevated troponin without ischemic ECG changes was not associated with adverse outcomes; however, MI in the ICU setting was an independent predictor of hospital mortality.