Preventing venous thrombo-embolism after nonmajor orthopedic surgery.

The venous thromboembolism risk is low to moderate in nonmajor orthopedic surgery. The literature is unconclusive. New emerging data are now available. The global patient risk has to be taken into account to determine the need for any prophylaxis.

Rivaroxaban or Enoxaparin in Nonmajor Orthopedic Surgery.

BACKGROUND: Nonmajor orthopedic surgery of the lower limbs that results in transient reduced mobility places patients at risk for venous thromboembolism. Rivaroxaban may be noninferior to enoxaparin with regard to the prevention of major venous thromboembolism in these patients. METHODS: In this international, parallel-group, randomized, double-blind, noninferiority trial, we randomly assigned adult patients undergoing lower-limb nonmajor orthopedic surgery who were considered to be at risk for venous thromboembolism on the basis of the investigator's judgment to receive either rivaroxaban or enoxaparin. The primary efficacy outcome of major venous thromboembolism was a composite of symptomatic distal or proximal deep-vein thrombosis, pulmonary embolism, or venous thromboembolism-related death during the treatment period or asymptomatic proximal deep-vein thrombosis at the end of treatment. A test for superiority was planned if rivaroxaban proved to be noninferior to enoxaparin. For all outcomes, multiple imputation was used to account for missing data. Prespecified safety outcomes included major bleeding (fatal, critical, or clinically overt bleeding or bleeding at the surgical site leading to intervention) and nonmajor clinically relevant bleeding. RESULTS: A total of 3604 patients underwent randomization; 1809 patients were assigned to receive rivaroxaban, and 1795 to receive enoxaparin. Major venous thromboembolism occurred in 4 of 1661 patients (0.2%) in the rivaroxaban group and in 18 of 1640 patients (1.1%) in the enoxaparin group (risk ratio with multiple imputation, 0.25; 95% confidence interval, 0.09 to 0.75; P<0.001 for noninferiority; P = 0.01 for superiority). The incidence of bleeding did not differ significantly between the rivaroxaban group and the enoxaparin group (1.1% and 1.0%, respectively, for major bleeding or nonmajor clinically relevant bleeding; 0.6% and 0.7%, respectively, for major bleeding). CONCLUSIONS: Rivaroxaban was more effective than enoxaparin in the prevention of venous thromboembolic events during a period of immobilization after nonmajor orthopedic surgery of the lower limbs. (Funded by Centre Hospitalier Universitaire de Saint-Etienne and Bayer; PRONOMOS ClinicalTrials.gov number, NCT02401594.).

Management of bleeding and emergency invasive procedures in patients on dabigatran: Updated guidelines from the French Working Group on Perioperative Haemostasis (GIHP) - September 2016.

In 2013, the GIHP published guidelines for the management of severe haemorrhages and emergency surgery. This update applies to patients treated with dabigatran, with a bleeding complication or undergoing an urgent invasive procedure. It includes how to handle the available specific antidote (idarucizumab), when to measure dabigatran plasmatic concentration and when to use non-specific measures in these situations. It also includes guidelines on how to perform regional anaesthesia and analgesia procedures.

Management of antiplatelet therapy in patients undergoing elective invasive procedures. Proposals from the French Working Group on perioperative haemostasis (GIHP) and the French Study Group on thrombosis and haemostasis (GFHT). In collaboration with the French Society for Anaesthesia and Intensive Care Medicine (SFAR).

The French Working Group on Perioperative Haemostasis (GIHP) and the French Study Group on Haemostasis and Thrombosis (GFHT) in collaboration with the French Society for Anaesthesia and Intensive Care Medicine (SFAR) drafted up-to-date proposals for the management of antiplatelet therapy in patients undergoing elective invasive procedures. The proposals were discussed and validated by a vote; all proposals but one could be assigned with a high strength. The management of antiplatelet therapy is based on their indication and the procedure. The risk of bleeding related to the procedure can be divided into high, moderate and low categories depending on the possibility of performing the procedure in patients receiving antiplatelet agents (none, monotherapy and dual antiplatelet therapy respectively). If discontinuation of antiplatelet therapy is indicated before the procedure, a last intake of aspirin, clopidogrel, ticagrelor and prasugrel 3, 5, 5 and 7 days before surgery respectively is proposed. The thrombotic risk associated with discontinuation should be assessed according to each specific indication of antiplatelet therapy and is higher for patients receiving dual therapy for coronary artery disease (with further refinements based on a few well-accepted items) than for those receiving monotherapy for cardiovascular prevention, for secondary stroke prevention or for lower extremity arterial disease. These proposals also address the issue of the potential role of platelet functional tests and consider management of antiplatelet therapy for regional anaesthesia, including central neuraxial anaesthesia and peripheral nerve blocks, and for coronary artery surgery.

A retrospective comparison between delayed and early hip fracture surgery in patients taking clopidogrel: same total bleeding but different timing of blood transfusion.

PURPOSE: Managing hip fracture surgery in patients taking clopidogrel is challenging. The optimal timing for surgery remains unclear. Early surgery in such patients potentially increases peri-operative bleeding, whereas delayed surgery has been shown to be associated with worse postoperative outcomes. The aim of this study was to investigate whether a delay to surgery affects total blood loss, bleeding kinetics, blood transfusion requirements, or post-operative outcomes. METHODS: A retrospective monocentric study including all hip fracture patients treated with clopidogrel between 2011 and 2016 (39 patients) was carried out. Patients who underwent delayed surgery after withholding clopidogrel for five days or more, from 2011 to 2013, were compared to patients who benefited from earlier surgical procedures (within 48 hours of admission) from 2014 to 2016. RESULTS: Total blood loss, amount of blood transfusion and rate of postoperative complications did not differ between the two groups. However, the timing of bleeding was significantly different; blood loss occurred during the pre-operative phase in the delayed surgery group (p < 0.0001), whereas it occurred during the intra-operative phase in the early surgery group (p = 0.005). The length of the hospital stay was significantly shorter for the early surgery group than for the delayed surgery group: 11 ± three versus 15 ± four days (p = 0.004). CONCLUSIONS: Early surgical treatment of hip fracture in patients receiving clopidogrel does not increase the overall red blood cell loss or the transfusion requirement, but may affect the timing of blood transfusion. Hip fracture surgery should preferably be performed without delay in patients taking clopidogrel.

Management of direct oral anticoagulants in patients undergoing elective surgeries and invasive procedures: Updated guidelines from the French Working Group on Perioperative Hemostasis (GIHP) - September 2015.

Since 2011, data on patients exposed to direct oral anticoagulants (DOAs) while undergoing invasive procedures have accumulated. At the same time, an increased hemorrhagic risk during perioperative bridging anticoagulation without thrombotic risk reduction has been demonstrated. This has led the GIHP to update their guidelines published in 2011. For scheduled procedures at low bleeding risk, it is suggested that patients interrupt DOAs the night before irrespective of type of drug and to resume therapy six hours or more after the end of the invasive procedure. For invasive procedures at high bleeding risk, it is suggested to interrupt rivaroxaban, apixaban and edoxaban three days before. Dabigatran should be interrupted according to the renal function, four days and five days if creatinine clearance is higher than 50mL/min and between 30 and 50mL/min, respectively. For invasive procedures at very high bleeding risk such as intracranial neurosurgery or neuraxial anesthesia, longer interruption times are suggested. Finally, bridging with parenteral anticoagulation and measurement of DOA concentrations can no longer routinely be used.

Observational study of dabigatran etexilate 150mg in patients with moderate renal impairment undergoing elective total hip or knee replacement.

INTRODUCTION: The standard dabigatran etexilate dosage for prevention of venous thromboembolism (VTE) after elective total hip or knee replacement (THR/TKR) is 220mg once daily (qd), with 150mg qd for patients with moderate renal impairment. As clinical trial experience in patients with moderate renal impairment was limited at the time of approval, we conducted an observational study to evaluate the 150mg qd dose. MATERIALS AND METHODS: This open-label, prospective, uncontrolled, observational study in patients with creatinine clearance (CrCl) 30-50mL/min was conducted in seven European countries. Patients received 75mg dabigatran etexilate 1-4h after surgery and 150mg qd on days 2-10 (TKR) or 2-35 (THR), per the European Summary of Product Characteristics. Coprimary outcomes were major bleeding events (MBEs) and a composite of symptomatic VTE and all-cause mortality. RESULTS: 428 renally impaired patients with median CrCl 43.4mL/min (range 30.0-49.9), and median age 80years (range 32-96) received dabigatran etexilate: median treatment duration THR 31days, TKR 28days. Ten MBEs occurred in nine patients (2.1%; 95% confidence interval [CI]: 1.0-4.0; THR 1.8%; TKR 2.4%); none were fatal or involved a critical organ. Symptomatic VTE and all-cause mortality occurred in three patients (0.7%; 95% CI: 0.1-2.0; THR 0.9%; TKR 0.5%). Overall, 54 patients discontinued treatment prematurely, including 35 due to an adverse event (nine bleeding-related) and 16 switching to another anticoagulant. CONCLUSIONS: Dabigatran etexilate 150mg qd had a good safety profile and was efficacious in fragile, elderly, renally impaired patients undergoing THR or TKR. These findings from the clinical practice setting add to the existing clinical trial data.

Dabigatran etexilate for thromboprophylaxis in over 5000 hip or knee replacement patients in a real-world clinical setting.

BACKGROUND: Thromboprophylaxis is recommended for patients undergoing total hip or total knee replacement (THR, TKR). An international, open-label, prospective, observational, single-arm study in a routine clinical setting was performed to assess the safety and efficacy of dabigatran etexilate 220 mg once daily in patients undergoing THR or TKR, and in subgroups of patients with potentially increased risk of bleeding or venous thromboembolism (VTE). MATERIALS AND METHODS: Patients were ≥18 years and required to be eligible to receive dabigatran 220 mg once daily (first dose 110 mg 1-4 h after THR/TKR surgery) according to the European Summary of Product Characteristics. The primary safety and efficacy outcomes were incidence of major bleeding events (MBEs), and the composite incidence of symptomatic VTE events and all-cause mortality, respectively. RESULTS: In total, 5292 patients (median age 64 years) were enrolled and received dabigatran (2734 THR and 2558 TKR). Median drug exposure was 31 days (THR 34 days; TKR 27 days). Overall incidence of MBEs was 0.72 % (95 % confidence interval [CI] 0.51, 0.98), and this rate was comparable between types of surgery and was not significantly affected by protocol-defined risk factors. The overall incidence of symptomatic VTE and all-cause mortality was 1.04 % (95 % CI 0.78, 1.35); the only significant risk factor was history of VTE events (odds ratio 5.59; 95 % CI 2.53, 11.08). A post-hoc analysis showed that the incidence of MBEs in this observational study was similar to or lower than those reported in previous phase 3 trials. CONCLUSIONS: Results from this observational study of dabigatran etexilate administered to patients undergoing THR or TKR surgery are reassuring and supportive of those obtained in dabigatran phase 3 trials. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00846807.

Oral dabigatran etexilate versus enoxaparin for venous thromboembolism prevention after total hip arthroplasty: pooled analysis of two phase 3 randomized trials.

BACKGROUND: Two phase 3 trials compared 28-35 days of treatment with oral dabigatran 220 mg or 150 mg (RE-NOVATE) or 220 mg (RE-NOVATE II) once daily with subcutaneous enoxaparin 40 mg once daily for prevention of venous thromboembolism (VTE) after elective total hip arthroplasty. METHODS: This prespecified pooled analysis compared the outcomes for the dabigatran 220 mg dose with enoxaparin, which included 4,374 patients. Total VTE (venographic and symptomatic) plus all-cause mortality (primary efficacy), major VTE (proximal deep vein thrombosis [DVT] or non-fatal pulmonary embolism) plus VTE-related death, and bleeding events were evaluated. Efficacy analysis was based on the modified intention-to-treat (ITT) population and safety analysis was based on all treated patients. The common risk difference (RD) for dabigatran versus enoxaparin was estimated using a fixed effects model. RESULTS: Total VTE and all-cause mortality occurred in 6.8 % (114/1,672) and 7.7 % (129/1,682) (RD:-0.8 %, 95 % confidence interval [CI] -2.6 to 0.9) for dabigatran and enoxaparin, respectively. Major VTE plus VTE-related mortality occurred in 2.7 % (46/1,714) and 4.0 % (69/1,711) (RD: -1.4 %, 95 % CI -2.6 to -0.2) of patients receiving dabigatran 220 mg and enoxaparin, respectively. Major bleeding occurred in 1.7 % (37/2,156) and 1.3 % (27/2,157) (RD: 0.5 %, 95 % CI -0.2 to 1.2), for dabigatran and enoxaparin respectively. CONCLUSIONS: Extended prophylaxis with oral dabigatran 220 mg once daily was as effective as enoxaparin 40 mg once daily in reducing the risk of total VTE and all-cause mortality after total hip arthroplasty, with a similar bleeding profile. The clinically relevant outcome of major VTE and VTE-related death was significantly reduced with dabigatran versus enoxaparin. TRIAL REGISTRATION: NCT00657150 and NCT00168818.

Peri-procedural management of dabigatran and rivaroxaban: Duration of anticoagulant discontinuation and drug concentrations.

BACKGROUND: Peri-procedural management of direct oral anticoagulants (DOAC) is challenging. The optimal duration of pre-procedural discontinuation that guarantees a minimal DOAC concentration ([DOAC]) at surgery is unknown. The usual 48-hour discontinuation might not be sufficient for all patients. OBJECTIVES: To test the hypothesis that a 48-hour DOAC discontinuation is not sufficient to ensure a minimal per-procedural [DOAC], defined as [DOAC]<30ng/mL. To investigate the factors associated with per-procedural [DOAC]. To evaluate the ability of normal PT and aPTT to predict [DOAC]<30ng/mL. METHODS: Patients treated with dabigatran or rivaroxaban, and requiring any invasive procedure were included in this multicentre, prospective, observational study. [DOAC], PT and aPTT were measured during invasive procedure. RESULTS: Sixty-five patients were enrolled. Duration of DOAC discontinuation ranged from 1-168h. Per-procedural [DOAC] ranged from <30 to 466ng/mL. [DOAC]<30ng/mL occurred more frequently after 48-hour discontinuation than after a shorter delay. [DOAC] remained ≥30ng/mL in 36% and 14% of measurements performed 24-48h and 48h-120h after discontinuation, respectively. According to ROC curve, a cut-off value of 120hours for DOAC discontinuation had a better specificity than a cut-off value of 48hours to predict [DOAC]<30ng/mL. Normal PT and aPTT ratios had good specificity and positive predictive value, but limited sensitivity (74%) and negative predictive value (73%) to predict [DOAC]<30ng/mL. CONCLUSIONS: A 48-hour discontinuation does not guarantee a [DOAC]<30ng/mL in all patients. Normal PT and aPTT are flawed to predict this threshold and could not replace specific assays. Further studies are needed to define the relationship between per-procedural [DOAC] and clinical outcomes.

Neither pre-operative education or a minimally invasive procedure have any influence on the recovery time after total hip replacement.

PURPOSE: The purpose of this study was to evaluate pre-operative education versus no education and mini-invasive surgery versus standard surgery to reach complete independence. METHODS: We conducted a four-arm randomized controlled trial of 209 patients. The primary outcome criterion was the time to reach complete functional independence. Secondary outcomes included the operative time, the estimated total blood loss, the pain level, the dose of morphine, and the time to discharge. RESULTS: There was no significant effect of either education (HR: 1.1; P = 0.77) or mini-invasive surgery (HR: 1.0; 95 %; P = 0.96) on the time to reach complete independence. The mini-invasive surgery group significantly reduced the total estimated blood loss (P = 0.0035) and decreased the dose of morphine necessary for titration in the recovery (P = 0.035). CONCLUSIONS: Neither pre-operative education nor mini-invasive surgery reduces the time to reach complete functional independence. Mini-invasive surgery significantly reduces blood loss and the need for morphine consumption.

Prevention of venous thromboembolic events with low-molecular-weight heparin in the non-major orthopaedic setting: meta-analysis of randomized controlled trials.

PURPOSE: To assess the efficacy of low-molecular-weight heparin (LMWH) venous thromboprophylaxis in patients with transient reduced mobility in the non-major orthopaedic setting. METHODS: A meta-analysis was conducted using data from all available randomized trials comparing LMWH with placebo or no prophylactic treatment in patients with leg immobilization for fracture or soft-tissue injury of the lower limb or in patients undergoing knee arthroscopy. The primary endpoint was the incidence of major venous thromboembolic events (VTEs), including asymptomatic proximal deep-vein thrombosis, symptomatic VTEs, and VTE-related death. The Mantel-Haenszel method was used to generate the summary statistics for the overall effect of LMWH. RESULTS: Fourteen studies were included (4,726 patients). The weighted rate of major VTEs was estimated to be 2.9% (95% confidence interval [CI], 2.2% to 3.7%) without LMWH prophylaxis. Overall, a significant 68% reduction in the risk of major VTEs was observed with LMWH prophylaxis (relative risk [RR], 0.32; 95% CI, 0.20 to 0.51; P < .001). The treatment effect was not modified by the clinical setting, that is, distal lower limb injury (7 studies; 1,711 patients; RR, 0.42; 95% CI, 0.20 to 0.86) or knee arthroscopy (6 studies; 2,428 patients; RR, 0.27; 95% CI, 0.15 to 0.49). A nonsignificant 35% increase in the risk of major bleeding was observed in the LMWH prophylaxis group (RR, 1.35; 95% CI, 0.53 to 3.47). CONCLUSIONS: This meta-analysis indicates potential efficacy of LMWH in preventing thromboembolic events in patients with reduced mobility in the non-major orthopaedic setting compared with placebo or no treatment. However, the decision of whether to implement LMWH prophylaxis in each specific setting should also take into account the risk of VTEs in the absence of prophylaxis, the potential adverse effects of LMWH, and the cost. LEVEL OF EVIDENCE: Level II, meta-analysis of Level II studies or Level I studies with inconsistent results.

[Thromboprophylaxis in surgical patients]. / Thromboprophylaxie médicamenteuse en chirurgie.

The thromboprophylaxis strategy varies across the surgery type and the patient characteristics. The thromboembolic risk depends on the surgery and the patient's characteristics. The bleeding risk depends on the surgery, the anticoagulant drug and the patient's characteristics. The low molecular weight heparins remain the main drugs used for thromboprophylaxis in surgery, except in major orthopaedic surgery, a situation in which some of the new oral anticoagulants may be preferred.

Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors: proposals of the working group on perioperative haemostasis (GIHP) - March 2013.

Direct new oral anticoagulants (NOACs) - inhibitors of thrombin or factor Xa - are intended to be used largely in the treatment of venous thromboembolic disease or the prevention of systematic embolism in atrial fibrillation, instead of vitamin K antagonists. Like any anticoagulant treatment, they are associated with spontaneous or provoked haemorrhagic risk. Furthermore, a significant proportion of treated patients are likely to be exposed to emergency surgery or invasive procedures. Given the absence of a specific antidote, the action to be taken in these situations must be defined. The lack of data means that it is only possible to issue proposals rather than recommendations, which will evolve according to accumulated experience. The proposals presented here apply to dabigatran (Pradaxa(®)) and rivaroxaban (Xarelto(®)); data for apixaban and edoxaban are still scarce. For urgent surgery with haemorrhagic risk, the drug plasma concentration should be less or equal to 30ng/mL for dabigatran and rivaroxaban should enable surgery associated with a high bleeding risk. Beyond that, if possible, the intervention should be postponed by monitoring the drug concentration. The course to follow is then defined according to the NOAC and its concentration. If the anticoagulant dosage is not immediately available, worse propositions, based on the usual tests (prothrombin time and activated partial thromboplastin time), are presented. However, these tests do not really assess drug concentration or the risk of bleeding that depends on it. In case of serious bleeding in a critical organ, the effect of anticoagulant therapy should be reduced using a non-specific procoagulant drug as a first-line approach: activated prothrombin complex concentrate (aPCC) (FEIBA(®) 30-50U/kg) or non-activated PCC (50U/kg). In addition, for any other type of severe haemorrhage, the administration of a procoagulant drug, which is potentially thrombogenic in these patients, is discussed according to the NOAC concentration and the possibilities of mechanical haemostasis.

Duration of postoperative fibrinolysis after total hip or knee replacement: a laboratory follow-up study.

INTRODUCTION: Hyperfibrinolysis is observed during and immediately after major orthopedic surgery. The kinetics and duration of this phase should be defined to adjust the duration of antifibrinolytic treatment with tranexamic acid (TXA). OBJECTIVE: We aimed to quantify the duration of postoperative fibrinolysis and to assess the biological impact of TXA administration. MATERIALS AND METHODS: Fourteen patients undergoing total hip replacement (THR) and 10 patients undergoing total knee replacement (TKR) with tourniquet were included in an observational, prospective, single-center study. Among these patients, 7 THR patients and 5 TKR patients received TXA (15mg/kg IV intraoperatively, followed by continuous infusion of 15mg/kg/h until end of surgery, then every 4hours until 16±2hours after surgery). D-dimers, euglobulin lysis time (ELT), and thrombin generation time (TGT) were measured prior to surgery as well as 6, 18 and 24hours (H) after. RESULTS: No significant difference in ELT was observed between the groups. In contrast, D-dimers significantly increased postoperatively in patients not treated with TXA (p<0.001), while such an increase was prevented in patients receiving TXA, as measured at H0, H6, H18 and H24 after THR, and at H6 and H18 after TKR (p<0.001). No significant between-group change in TGT, was observed (peak thrombin and endogenous thrombin potential) all along the study. CONCLUSION: This study shows that fibrinolysis peaked 6hours after end of surgery and maintained about 18hours after surgery, as evidenced by an increase in D-dimers. When administered for up to 16±2hours after surgery, TXA reduced postoperative fibrinolysis.

Efficacy of delayed thromboprophylaxis with dabigatran: pooled analysis.

INTRODUCTION: Oral thromboprophylaxis with dabigatran etexilate should be initiated as a half dose 1 to 4h after major orthopaedic surgery. However, a delay in dosing could occur for clinical or logistical reasons. A post hoc analysis was carried out to determine if patients with delayed dosing received adequate anticoagulation. PATIENTS AND METHODS: The RE-MODEL™ and RE-NOVATE® trials compared 220 mg and 150 mg dabigatran etexilate with 40 mg enoxaparin. Pooled data for major venous thromboembolism (VTE) and VTE-related mortality (efficacy outcome) and major bleeding events (MBE), MBE/clinically relevant bleeding events, and all bleeding events (safety outcomes) were analysed. Results in patients with dosing delayed more than 4h postsurgery were compared with those of patients without a delay. RESULTS: Onset of treatment was delayed in 724 (13.3%) of 5425 patients. Efficacy of 220 mg dabigatran etexilate was similar in patients without delayed dosing, patients with a delay and patients with a delay until the day after surgery. Rates of efficacy outcome were higher in patients on 150 mg dabigatran etexilate, but more than 80% of these patients were undertreated based on age or renal clearance status. Some differences in bleeding events were seen among patient groups by treatment arm. CONCLUSION: Dabigatran etexilate thromboprophylaxis should be initiated 1 to 4h postsurgery. Results from our post-hoc analysis indicate that no loss of efficacy appears to occur if initiation of dabigatran etexilate 220 mg needs to be delayed.