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Prolonged versus standard-duration venous thromboprophylaxis in major orthopedic surgery: a systematic review |
Sobieraj DM, Lee S, Coleman CI, Tongbram V, Chen W, Colby J, Kluger J, Makanji S, Ashaye AO, White CM |
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CRD summary The authors concluded that prolonged compared to standard duration thromboprophylaxis decreased the risk of venous thromboembolism, pulmonary embolism and deep venous thrombosis and increased the risk of minor bleeding in patients who underwent total hip replacement. This was a well-conducted review, but the limited quantity and quality of evidence reduces the reliability of the findings. Authors' objectives To compare the benefits and harms of prolonged versus standard-duration thromboprophylaxis in adult major orthopaedic surgery patients. Searching Cochrane Central Register of Controlled Trials (CENTRAL) and SCOPUS were searched between 1980 and July 2011. MEDLINE was searched from 1980 to November 2011. There were no language restrictions. The search strategy was reported. Reference lists of relevant trials and reviews were searched manually. Grey literature, which included regulatory documents, abstracts, and ongoing clinical trials, were searched. Study selection Randomised controlled trials (RCTs) that compared the benefits and harms of prolonged (≥21 days) versus standard-duration (seven to 10 days) thromboprophylaxis using identical doses of the same drug in adults who underwent total hip or knee replacement or hip fracture surgery were eligible for inclusion. Only drug agents approved by the United States Food and Drug Administration agency were eligible for inclusion. Outcomes of interest were final health outcomes (symptomatic venous thromboembolism (VTE) confirmed using diagnostic imaging, major venous thromboembolism, pulmonary embolism, fatal and non-fatal pulmonary embolism, post-thrombotic syndrome, mortality and mortality due to bleeding), intermediate health outcomes (asymptomatic, symptomatic, proximal or distal diagnostically confirmed deep vein thrombosis) and harms (bleeding, heparin-induced thrombocytopaenia, discomfort, readmission and reoperation). The mean age of included patients ranged from 63 to 79 years. From 38% to 74% of patients were women. Body weight ranged from 65kg to 89kg. Between 8% and 75% of patients were considered obese. The proportion of patients with other risk factors for VTE (such as history of VTE, varicosity, history of cancer and prior orthopaedic surgery) ranged from 1% to 24%. Six trials enrolled only patients who underwent total hip replacement. Medications assessed included the vitamin K antagonist warfarin, injectable low-molecular-weight heparins (enoxaparin and dalteparin) and the factor Xa inhibitor fondaparinux. One trial assessed dalteparin with dextran and graduated compression stockings. Control groups received medications similar to the prolonged group, but then received placebo or nothing for the remaining follow-up duration. Two reviewers independently assessed studies for inclusion. Assessment of study quality Two reviewers assessed study quality according to 11 criteria reported by the Agency for Healthcare Research and Quality. Studies were assessed on similarity of populations at baseline, randomisation and allocation methods, blinding, completeness of follow-up and conflicts of interest. Each study was given an overall quality score of good, fair or poor. Disagreements were resolved through discussion. Each study was assessed on levels of evidence based on risk of bias (study quality), precision (result confidence intervals), directness (use of indirect evidence from intermediate markers to make judgements on final health outcomes) and consistency (assessment of heterogeneity). Funding sources were also noted. Data extraction Two reviewers independently extracted dichotomous outcome data to calculate relative risks (RRs), risk differences (RDs) and odds ratios (ORs), with their 95% confidence intervals (CIs). Disagreements were resolved through discussion or referral to a third reviewer. Methods of synthesis Where there was no evidence of statistical heterogeneity and there were equal numbers of participants in each treatment arm, a Peto fixed-effect model was used to pool odds ratios and 95% CIs. Otherwise a random-effects model was used to pool relative risks and risk differences, with 95% CIs. Statistical heterogeneity was assessed using the Ι²
statistic. Subgroup analyses by surgical population (total hip replacement, total knee replacement and hip fracture surgery) were undertaken. Sensitivity analysis was performed to permit inclusion of trials reporting zero events. Results of the review Eight RCTs (2,917 participants) were included in the review. Three trials were of high quality and five were fair quality. Follow-up was 32, 35 or 90 days. Most trials had 100% completeness of follow-up. No trials assessed post-thrombotic syndrome, health-related quality of life, heparin-induced thrombocytopaenia or discomfort. There were no deaths due to bleeding. There was high strength of evidence for fewer pulmonary embolisms in patients who received prolonged medication compared to standard duration medication (OR 0.14, 95% CI 0.04 to 0.47; five RCTs) and reduced deep vein thrombosis; asymptomatic (RR 0.48, 95% CI 0.31 to 0.75; four RCTs), symptomatic (OR 0.36, 95% CI 0.16 to 0.81; four RCTs) and proximal (RR 0.29, 95% CI 0.16 to 0.52; six RCTs). There was high strength of evidence for increased minor bleeding with prolonged medication (OR 2.44, 95% CI 1.41 to 4.20; three RCTs). Moderate strength of evidence showed fewer symptomatic VTE (RR 0.38, 95% CI 0.19 to 0.77; four RCTs), non-fatal pulmonary embolism (OR 0.13, 95% CI 0.03 to 0.54; four RCTs) and deep vein thromboembolism (RR 0.37, 95% CI 0.21 to 0.64; seven RCTs) with prolonged duration medication. There was evidence of statistical heterogeneity for VTE (Ι²=69%) and deep vein thrombosis (Ι²=78%); the direction of effect was consistent across trials, but the magnitude of effect differed. Analysis that included zero event trials did not significantly alter the findings. Results for total knee replacement and hip fracture surgery were limited to one trial each. Authors' conclusions Compared to standard duration treatment (seven to 10 days), prolonged prophylaxis of 21 or more days decreased risk of VTE, pulmonary embolism and deep venous thrombosis and increased risk of minor bleeding in patients who underwent total hip replacement. There was insufficient evidence to draw conclusions for other outcomes or in patients who underwent other major orthopaedic procedures. CRD commentary A clear review question was stated and was supported by clearly defined inclusion criteria. Several relevant sources were searched without language restrictions, which reduced potential for language bias and missing relevant data. Each stage of the review process was performed in duplicate, which reduced potential for reviewer error and bias. Only three trials were considered good quality and the authors stated that the strength of evidence ratings may not have adequately captured uncertainty in the estimates. Appropriate methods were used to synthesis data and investigate potential sources of statistical heterogeneity. The authors acknowledged the possibility for selective outcome reporting and reporting of imprecise estimates due to the scarcity of evidence. Where outcomes were reported, the number of events was generally low. The authors noted that three trials were industry funded and one was funded by government and foundation sources; funding sources were not reported by the remaining four trials. This was a well-conducted review and the authors’ conclusions reflected the evidence presented, but the limited quantity and quality of evidence reduces the reliability of the findings. Implications of the review for practice and research Practice: The authors did not state any implications for practice. Research: The authors stated a need for larger trials on a wider range of outcomes, particularly for other major orthopaedic procedures and newer classes of anticoagulants. Funding Agency for Healthcare Research and Quality. Bibliographic details Sobieraj DM, Lee S, Coleman CI, Tongbram V, Chen W, Colby J, Kluger J, Makanji S, Ashaye AO, White CM. Prolonged versus standard-duration venous thromboprophylaxis in major orthopedic surgery: a systematic review. Annals of Internal Medicine 2012; 156(10): 720-727 Other publications of related interest Sobieraj DM, Coleman CI, Tongbram V, Lee S, Colby J, Chen WT, Makanji SS, Ashaye A, Kluger J, White CM. Venous Thromboembolism prophylaxis in orthopaedic surgery. Rockville, MD, USA: Agency for Healthcare Research and Quality. Comparative effectiveness review; 49. 2012. Indexing Status Subject indexing assigned by NLM MeSH Anticoagulants /administration & Drug Administration Schedule; Hemorrhage /chemically induced; Humans; Orthopedic Procedures /adverse effects; Pulmonary Embolism /prevention & Venous Thromboembolism /prevention & Venous Thrombosis /prevention & control; control; control; dosage /adverse effects /therapeutic use AccessionNumber 12012023141 Date bibliographic record published 18/05/2012 Date abstract record published 22/05/2012 Record Status This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn. |
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