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Incidence and risk factors of major bleeding following major orthopaedic surgery with fondaparinux thromboprophylaxis. A time-to-event analysis.

ABSTRACT: AIMS:Increased exposure to fondaparinux, as observed in patients with renal impairment, may increase bleeding risk. This study aims to determine the time course of major bleeding after major orthopaedic surgery, identify predictors of bleeding and simulate the effect of a reduced dose of fondaparinux on bleeding for patients with moderate renal impairment (creatinine clearance = 20-50 ml min-1 ). METHODS:Data including fondaparinux anti-Xa activities from two multicentre prospective cohorts were used. In the first cohort, patients (n = 957) received fondaparinux 2.5 mg once a day. In the second, patients with moderate renal impairment (n = 436) received 1.5 mg once per day. The time-to-major bleeding after the end of surgery was modelled using a parametric survival analysis in NONMEM. RESULTS:The observed rate of major bleeding up to day 11 was 5.2%. The time-to-event analysis indicated that the hazard of bleeding was highest in the first days following surgery and then remained low thereafter. Independent significant predictors of an increased hazard of major bleeding were male sex, lower body weight and increased drug exposure. Simulated rates of major bleeding up to day 11 in patients with moderate renal impairment were 6.5% with fondaparinux 2.5 mg once daily and 3.8% with fondaparinux 1.5 mg once daily. CONCLUSION:The hazard of major bleeding is highest in the first postoperative days and increases with fondaparinux exposure. To reduce the risk of bleeding in patients with moderate renal impairment, this study supports the use of a lower dose of fondaparinux 1.5 mg once daily.

SUBMITTER: Zufferey PJ

PROVIDER: S-EPMC6138479 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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Incidence and risk factors of major bleeding following major orthopaedic surgery with fondaparinux thromboprophylaxis. A time-to-event analysis.

Zufferey P J PJ Ollier E E Delavenne X X Laporte S S Mismetti P P Duffull S B SB

British journal of clinical pharmacology 20180714 10

<h4>Aims</h4>Increased exposure to fondaparinux, as observed in patients with renal impairment, may increase bleeding risk. This study aims to determine the time course of major bleeding after major orthopaedic surgery, identify predictors of bleeding and simulate the effect of a reduced dose of fondaparinux on bleeding for patients with moderate renal impairment (creatinine clearance = 20-50 ml min<sup>-1</sup> ).<h4>Methods</h4>Data including fondaparinux anti-Xa activities from two multicentr ...[more]

PMID: 29877590

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Project description:AimThe aim of the present study was to analyse concomitant drug use and its association with outcome in patients (N = 17 701) receiving rivaroxaban or standard of care (SOC) for the prevention of venous thromboembolism after major orthopaedic surgery in the non-interventional, phase IV XAMOS (Xarelto® in the prophylaxis of post-surgical venous thromboembolism after elective major orthopaedic surgery of hip or knee) study.MethodsConcomitant drug use was at the discretion of the treating physician. Prespecified co-medications of interest were cytochrome P450 (CYP) 3A4/P-glycoprotein inhibitors/inducers, platelet aggregation inhibitors (PAIs) and nonsteroidal anti-inflammatory drugs (NSAIDs). Crude event incidences were compared between rivaroxaban and SOC groups.ResultsCYP3A4/P-glycoprotein inhibitor/inducer use was infrequent, in contrast to PAI (~7%) and NSAID (~52%) use. Rivaroxaban was associated with a lower incidence of overall symptomatic thromboembolic events compared with SOC, regardless of co-medication use. In both treatment groups, PAI users, with higher age and prevalence of cardiovascular co-morbidities, had similar higher (>7-fold) incidences of symptomatic arterial but not venous thromboembolic events compared with non-users. NSAID use had no influence on thromboembolic events. However, odds ratios (ORs) for major bleeding events (European Medicines Agency definition) were higher in NSAID users compared with non-users in rivaroxaban [OR = 1.50; 95% confidence interval (CI) 1.06, 2.13] and SOC (OR = 1.70; CI 1.16, 2.49) groups. In PAI users, ORs for major bleeding events were no different from those of non-users in both the rivaroxaban (OR = 1.49; CI 0.84, 2.65) and SOC (OR = 1.46; CI 0.82, 2.62) groups.ConclusionsUse of NSAIDs in XAMOS was frequent and associated with a higher frequency of bleeding events in patients receiving rivaroxaban or SOC, although the benefit-risk profile of rivaroxaban compared with SOC was maintained.

Project description:IntroductionVenous thromboembolism remains a significant complication following major gynecologic surgery. Evidence is lacking on whether it is beneficial to give pharmacologic thromboprophylaxis pre-operatively. The aim of this meta-analysis was to assess the role of pre-operative pharmacologic thromboprophylaxis in preventing post-operative venous thromboembolism.MethodsPubMed, EMBASE, and the Cochrane Central Register of Clinical Trials were searched to find randomized controlled, cohort, and case-control trials comparing pre-operative pharmacologic thromboprophylaxis to no prophylaxis, mechanical prophylaxis, or only post-operative pharmacologic thromboprophylaxis for open and minimally invasive major gynecologic surgery (benign and malignant conditions). Two authors independently assessed abstracts, full-text articles, and methodological quality. Data were extracted and pooled using ORs for random effects meta-analysis. Heterogeneity was explored using forest plots, Q-statistic, and I2 statistics. Planned subgroup analysis of use of sequential compression devices, equivalent versus non-equivalent post-operative prophylaxis, cancer diagnosis, and methodological quality were performed.ResultsSome 503 unique studies were found, and 16 studies (28 806 patients) were included in the systematic review. Twelve studies (14 273 patients) were included in the meta-analysis. The OR for incidence of post-operative venous thromboembolism was 0.59 (95% CI 0.39, 0.89), favoring pre-operative pharmacologic thromboembolism prophylaxis compared with no pre-operative pharmacologic prophylaxis (Q=13.80, I2=20.30). In studies where post-operative care was equivalent between groups, the OR for venous thromboembolism was 0.56 (95% CI 0.22, 1.40). Pre-operative pharmacologic prophylaxis demonstrated greatest benefit when utilized with both intra-operative and post-operative sequential compression devices (OR 0.43, 95% CI 0.30, 0.64) compared with when no sequential compression devices were utilized (OR 1.27, 95% CI 0.63, 2.56). When looking at only studies determined to be of high quality, the results no longer reached significance (OR 0.73, 95% CI 0.36, 1.46).ConclusionsPre-operative pharmacologic thromboprophylaxis decreases the odds of venous thromboembolism in the peri-operative period for major gynecologic oncology surgery by approximately 40%. It remains unclear whether this benefit is present in benign and minor procedures. Adequately powered studies are needed.

Project description:BACKGROUND:It is generally accepted that all arthroplasty patients should receive venous thromboembolism (VTE) and bleeding risk assessments, and that postoperative thromboprophylaxis be routinely prescribed where appropriate. Guideline recommendations regarding what to prescribe, however, have been inconsistent over the years, particularly regarding the appropriateness of aspirin. Our aim was to explore thromboprophylaxis patterns in use following hip and knee arthroplasty in Australia, and to examine associated variables. METHODS:Orthopaedic surgeons were invited via mail to participate in two national surveys, conducted in 2012 (N?=?478) and 2017 (N?=?820), respectively. RESULTS:The final response rates were 50.0 and 65.8% for 2012 and 2017, respectively. The thromboprophylaxis prescribing routines reported by respondents were divided into four categories: anticoagulant-only (the same anticoagulant-only routine for everyone), aspirin-only (aspirin for everyone), staged-supply (an anticoagulant during the initial postoperative period, followed by aspirin, for everyone) and risk-stratification routines (differing regimens depending on patients' perceived risk of VTE). The most common approaches reported were anticoagulant-only routines; however, their popularity almost halved within the five-year period (from ~?74% to ~?41%). Conversely, staged-supply and risk-stratification protocol usage increased by more than two and nine times, respectively. In 2017, over one-half of surgeons reported prescribing aspirin in their practice. Reported concern for postoperative VTE and infections (OR 0.555 95% CI 0.396-0.779, p?=?0.001 and OR 1.455 95% CI 1.010-2.097, p?=?0.044 respectively), as well as Arthroplasty Society membership (OR 2.814 95% CI 1.367-5.790, p?=?0.005) were predictors for use of aspirin (Cox and Snell R square?=?0.072). The factor most commonly reported to shape surgeons' protocols was research literature. Factors limiting prescribing of pharmacological prophylaxis included a perception that it increases bleeding and wound infection risk, is inconvenient, and lacks evidence applicable to real-world practice. CONCLUSIONS:VTE prevention post-arthroplasty is an evolving and multi-faceted entity, influenced by a range of factors and seemingly in need of robust evidence from large clinical trials to guide practice. The data highlighted potential short-falls in practice related to aspirin over-use, which could be further explored and addressed in future studies in order to optimise patient outcomes and reduce the significant morbidity and healthcare costs associated with VTE following these increasingly common surgical procedures.

Project description:BackgroundPostpancreatectomy haemorrhage (PPH) and venous thromboembolism (VTE) are serious complications following pancreatic surgery. The aim was to assess the timing, occurrence and predictors of PPH and VTE.MethodsElective pancreatic resections undertaken in a single university hospital between November 2013 and September 2017 were assessed. Three intervals were reviewed, each with a different routine regimen of nadroparin: 2850 units once daily (single dose) administered in hospital only, or 5700 units once daily (double dose) or 2850 units twice daily (split dose) administered in hospital and continued for 6 weeks after surgery. Clinically relevant PPH (CR-PPH) was classified according to International Study Group of Pancreatic Surgery criteria. VTE was defined according to a number of key diagnostic criteria within 6 weeks of surgery. Cox regression analyses were performed to test the hypotheses that the double-dose group would experience more PPH than the other two groups, the single-dose group would experience more VTE than the other two groups, and the split-dose group would experience the fewest adverse events (PPH or VTE).ResultsIn total, 240 patients were included, 80 per group. The double-dose group experienced significantly more CR-PPH (hazard ratio (HR) 2·14, 95 per cent c.i. 1·16 to 3·94; P = 0·015). More relaparotomies due to CR-PPH were performed in the double-dose group (16 versus 3·8 per cent; P = 0·002). The single-dose group did not experience more VTE (HR 1·41, 0·43 to 4·62; P = 0·570). The split dose was not associated with fewer adverse events (HR 0·77, 0·41 to 1·46; P = 0·422). Double-dose low molecular weight heparin (LMWH), high BMI and pancreatic fistula were independent predictors of CR-PPH.ConclusionA double dose of LMWH prophylaxis continued for 6 weeks after pancreatic resection was associated with a twofold higher rate of CR-PPH, resulting in four times more relaparotomies. Patients receiving a single daily dose of LMWH in hospital only did not experience a higher rate of VTE.

Project description:BACKGROUND:There has been a shift towards greater use of neuraxial over general anaesthesia for patients undergoing total hip or knee arthroplasty. Furthermore, suggestions that peripheral nerve block may reduce adverse effects have recently been put forward. Although older studies showed a reduction in venous thromboembolism (VTE) with neuraxial compared with general anaesthesia, this difference has not been confirmed in studies using effective current thromboprophylaxis. We used a large data set to investigate the pattern of anaesthesia usage, and whether anaesthesia type affects efficacy and bleeding outcomes of thromboprophylaxis overall, within each treatment group, or for the novel oral anticoagulant dabigatran etexilate versus enoxaparin. METHODS:Three previously reported trials compared 220?mg and 150?mg dabigatran etexilate once daily with enoxaparin after knee or hip arthroplasty. A pooled analysis was performed in patients receiving general or neuraxial anaesthesia, or the combination of either with peripheral nerve block (n?=?8062). Outcome measures were major VTE plus VTE-related mortality, major bleeding and major plus clinically relevant bleeding events. RESULTS:General, neuraxial and combination anaesthesia were used in 29%, 52% and 19% of patients, respectively. Differences in efficacy and safety between anaesthesia subgroups were small and not significant, except for a slightly higher rate of major VTE and VTE-related mortality with general versus neuraxial anaesthesia (odds ratio: 1.40; 95% confidence interval: 1.03-1.90; p?=?0.035) in the overall population. There were no significant effects of anaesthesia type on efficacy or safety of dabigatran etexilate versus enoxaparin. CONCLUSIONS:Anaesthesia type did not greatly affect efficacy and safety outcomes in the pooled population of all three treatment groups. The efficacy and safety of dabigatran etexilate was comparable with enoxaparin, regardless of type of anaesthesia. TRIAL REGISTRATION:ClinicalTrials.gov identifiers: NCT00168805, NCT00168818, NCT00152971.

Dataset Information

Incidence and risk factors of major bleeding following major orthopaedic surgery with fondaparinux thromboprophylaxis. A time-to-event analysis.

Publications

Incidence and risk factors of major bleeding following major orthopaedic surgery with fondaparinux thromboprophylaxis. A time-to-event analysis.

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