Discontinuation of Plavix® (clopidogrel) for hip fracture surgery. A systematic review of the literature.

The elderly population is increasing worldwide, associated with an increase in diseases related to aging, such as hip fractures. These patients are sometimes treated with clopidogrel. There are no arguments at present to clearly determine the risk/benefit ratio of early surgical management of traumatic hip fractures in patients treated with clopidogrel (perioperative blood loss, postoperative complications). The goal of this systematic review of the literature was to show that early surgical management (<48h) of patients treated with clopidogrel does not increase postoperative morbidity or mortality. Systematic review of the literature: level of evidence IV. A bibliographic search was performed in July 2015 in PubMed, Embase and Cochrane databases using the MeSh keywords "Clopidogrel or Plavix®" AND "hip fracture". Two of the authors analyzed 48 articles based on the title and abstract. Twenty-one articles were selected and read completely with an analysis of the references. Nine articles were chosen. Early surgical management (<48h) of patients receiving clopidogrel did not increase mortality at 30days, 3months or 1 year (between 25 and 30% mortality at 1 year) and did not result in an increase in perioperative bleeding. The risk/benefit ratio of early surgical management of patients with hip fractures receiving clopidogrel is good; morbidity and mortality are not increased in these patients if surgery is performed immediately or less than 48h after admission. LEVEL OF EVIDENCE: IV.

[Direct oral anticoagulant associated bleeding]. / Hémorragie survenant chez un patient traité par un anticoagulant oral direct.

Direct oral anticoagulants (DOAC) are recommended for stroke prevention in atrial fibrillation and for the treatment of venous thromboembolism. However, they are associated with hemorrhagic complications. Management of DOAC-induced bleeding remains challenging. Activated or non-activated prothrombin concentrates are proposed, although their efficacy to reverse DOAC is uncertain. Therapeutic options also include antidotes: idarucizumab, antidote for dabigatran, has been approved for use whereas andexanet alpha, antidote for anti-Xa agents, and aripazine, antidote for all DOAC, are under development. Other options include hemodialysis for the treatment of dabigatran-associated bleeding and administration of oral charcoal if recent DOAC ingestion. DOAC plasma concentration measurement is necessary to guide DOAC reversal. We propose an update on DOAC-associated bleeding, integrating the availability of dabigatran antidote and the critical place of DOAC concentration measurements.

[Management of direct oral anticoagulants for invasive procedures]. / Gestion des anticoagulants oraux directs pour un acte invasif.

Three new Direct Oral Anticoagulants (DOACs), rivaroxaban, apixaban and dabigatran etexilate are available on the French market. Management of DOAC-induced bleeding risk remains challenging. For elective procedures with high hemorrhagic risk, a last DOAC intake five days before procedure ensures complete elimination in all patients. Heparin bridging therapy should be proposed only to patients at high thrombotic risk. For elective procedures with low hemorrhagic risk, the DOAC intake of the night before procedure should be omitted. For urgent procedures with high bleeding risk, DOAC plasmatic concentration can be helpful: concentration lower than 30 ng/mL should enable performing the procedure; a high concentration is associated with a higher bleeding risk, especially if higher than 400 ng/mL. In case of massive bleeding, no antidote is approved yet; activated prothrombin concentrates or non-activated 4-factors prothrombin concentrates could be considered.

[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]. / Prise en charge des complications hémorragiques graves et de la chirurgie en urgence chez les patients recevant un anticoagulant oral anti-IIa ou anti-Xa direct. Propositions du Groupe d'intérêt en Hémostase Périopératoire (GIHP) - mars 2013.

New direct oral anticoagulants (NOAC), inhibitors of factor IIa or Xa, are expected to be widely used for the treatment of venous thromboembolic disease, or in case of atrial fibrillation. Such anticoagulant treatments are known to be associated with haemorrhagic complications. Moreover, it is likely that such patients on long-term treatment with NOAC will be exposed to emergency surgery or invasive procedures. Due to the present lack of experience in such conditions, we cannot make recommendations, but only propose management for optimal safety as regards the risk of bleeding in such emergency conditions. In this article, only dabigatran and rivaroxaban were discussed. For emergency surgery at risk of bleeding, we propose to dose the plasmatic concentration of drug. Levels inferior or equal to 30ng/mL for both dabigatran and rivaroxaban, should enable the realization of a high bleeding risk surgery. For higher concentration, it was proposed to postpone surgery by monitoring the evolution of the drug concentration. Action is then defined by the kind of NOAC and its concentration. If the dosage of the drug is not immediately available, proposals only based on the usual tests, PT and aPTT, also are presented. However, these tests do not really assess drug concentration or bleeding risk. In case of severe haemorrhage in a critical organ, it is proposed to reduce the effect of anticoagulant therapy using a nonspecific procoagulant drug (activated prothrombin concentrate, FEIBA, 30-50U/kg, or non-activated 4-factors prothrombin concentrates 50U/kg). For any other type of severe haemorrhage, the administration of such a procoagulant drug, potentially thrombogenic in these patients, will be discussed regarding concentration of NACO and possibilities for mechanical haemostasis.

Comparison of fondaparinux with low molecular weight heparin for venous thromboembolism prevention in patients requiring rigid or semi-rigid immobilization for isolated non-surgical below-knee injury.

BACKGROUND: In several small studies, anticoagulant therapy reduced the incidence of venous thromboembolism (VTE) in patients with isolated lower-limb injuries. OBJECTIVES: To compare the efficacy and safety of fondaparinux 2.5 mg (1.5 mg in patients with a creatinine clearance between 30 and 50 mL min(-1) ) over nadroparin 2850 anti-factor Xa IU. PATIENTS AND METHODS: In this international, multicenter, randomized, open-label study, patients with an isolated non-surgical unilateral below-knee injury having at least one additional major risk factor for VTE and requiring, in the Investigator's opinion, rigid or semi-rigid immobilization for 21-45 days with thromboprophylaxis up to complete mobilization received subcutaneously once-daily either fondaparinux or nadroparin. The primary efficacy outcome was the composite of VTE (symptomatic or ultrasonographically detected asymptomatic deep vein thrombosis of the lower limb or symptomatic pulmonary embolism) and death up to complete mobilization. The main safety outcome was major bleeding. RESULTS: We randomized 1349 patients (mean age 46 years): 88.7% had a bone fracture, and 83.8% had a plaster cast fitted (mean duration of immobilization, 34 days). The primary efficacy outcome occurred in 15 of 584 patients (2.6%) in the fondaparinux group and 48 of 586 patients (8.2%) in the nadroparin group (odds ratio, 0.30; 95% confidence interval [CI], 0.15-0.54; P < 0.001). A single major bleed was experienced by fondaparinux-treated patients and none by nadroparin-treated patients. These results were maintained up to the end of follow-up. CONCLUSIONS: Fondaparinux 2.5 mg day(-1) may be a valuable therapeutic option over nadroparin 2850 anti-FXa IU day(-1) for preventing VTE after below-knee injury requiring prolonged immobilization in patients with additional risk factors.

[Perioperative management based on kinetics of bleeding during total primary arthroplasty]. / Cinétique du saignement en chirurgie orthopédique majeure : implications pour la prise en charge périopératoire.

INTRODUCTION: Management of the perioperative hemorrhagic risk is of major interest in patients undergoing total arthroplasty of the lower limb. Anemia in the postoperative period of that increasingly performed surgery carries its own morbidity and mortality. Better anticipation of its occurrence could be done with a refined knowledge of bleeding kinetics. PATIENTS AND METHODS: We conducted a retrospective study in a single centre on 451 consecutive patients undergoing elective unilateral primary total hip or knee arthroplasty for osteoarthritis. Volume of total blood loss according to Mercuriali's formula and variations of haemoglobin levels were calculated between day 0 (D0) and postoperative day 8 (D8), and during subdivided periods between D0-D1, D1-D3 and D3-D8. Frequency and volume of autologous and homologous blood transfusions were also analyzed. Comparisons were done taking into account the use of intraoperative tranexemic acid (TA). RESULTS: Seventy to 75% of blood loss occurred between D0 and D1. Bleeding occurred mostly between the end of surgery and morning of D1, and tended to stop at D3. TA significantly reduced blood loss in the first 3days, mostly after knee prosthesis surgery. However, the bleeding kinetics were the same with or without TA. CONCLUSION: Loss of haemoglobin occurred mostly in the early postoperative period. To avoid transfusion delays, haemoglobin levels should be monitored regularly until the third postoperative day after total arthroplasty, especially when D1 haemoglobin is close to the transfusion threshold. Furthermore, our results support the routine use of TA.

Incidence of neuraxial haematoma after total hip or knee surgery: RECORD programme (rivaroxaban vs. enoxaparin).

BACKGROUND: Patients receiving anticoagulants could be at higher risk of compressive haematoma with neuraxial anaesthesia use. The phase III RECORD programme compared rivaroxaban with enoxaparin for prevention of venous thromboembolism after total hip or knee replacement surgery in more than 12,500 patients. This observational analysis evaluated the risk of neuraxial haematoma after neuraxial anaesthesia in patients receiving rivaroxaban or enoxaparin using pooled RECORD1-4 data. METHODS: The incidences of intraspinal bleeding or haemorrhagic puncture were recorded as part of the criteria for major bleeding (the primary safety outcome in the RECORD studies). Incidences of allogeneic transfusion and venous thromboembolism by type of anaesthesia were also recorded. RESULTS: No compressive haematomas occurred in rivaroxaban-treated patients (10 mg once daily started 6-8 h after surgery) who underwent neuraxial anaesthesia (n = 4086). Among enoxaparin-treated patients (n = 4090), one compressive spinal haematoma requiring laminectomy occurred after epidural catheter removal in an elderly female patient with renal insufficiency undergoing total knee replacement. Total venous thromboembolism rates did not differ according to type of anaesthesia. CONCLUSION: Although no issues were observed with the use of neuraxial anaesthesia in this population of 4086 patients receiving rivaroxaban after total hip or knee replacement, it is important to remain aware of the risk of compressive haematoma. This may be of particular concern in elderly patients with renal insufficiency receiving an anticoagulant predominantly eliminated via the kidneys.

[Surgery and invasive procedures in patients on long-term treatment with oral direct thrombin or factor Xa inhibitors]. / Chirurgies et actes invasifs chez les patients traités au long cours par un anticoagulant oral anti-IIa ou anti-Xa direct Propositions du Groupe d'intérêt en hémostase périopératoire (GIHP) et du Groupe d'études sur l'hémostase et la thrombose (GEHT).

Direct oral anticoagulants (DOAs), inhibitors of factor IIa or Xa, are expected to replace vitamin K antagonists in most of their indications. It is likely that patients on long-term treatment with DOAs will be exposed to elective or emergency surgery or invasive procedures. Due to the present lack of experience in such conditions, we cannot make recommendations, but only propose perioperative management for optimal safety as regards the risk of bleeding and thrombosis. DOAs may increase surgical bleeding, they have no validated antagonists, they cannot be monitored by simple, standardised laboratory assays, and their pharmacokinetics vary significantly from patient to patient. Although DOAs differ in many respects, the proposals in the perioperative setting need not be specific to each. For procedures with low risk of haemorrhage, a therapeutic window of 48 h (last administration 24h before surgery, restart 24h after) is proposed. For procedures with medium or high haemorrhagic risk, we suggest stopping DOAs 5 days before surgery to ensure complete elimination of the drug in all patients. The treatment should be resumed only when the risk of bleeding has been controlled. In patients with a high risk of thrombosis (e.g. those in atrial fibrillation with an antecedent of stroke), bridging with heparin (low molecular weight, or unfractionated if the former is contraindicated) is proposed. In emergency, the procedure should be postponed for as long as possible (minimum 1-2 half-lives) and non-specific anti-haemorrhagic agents, such as recombinant human activated factor VIIa, or prothrombin concentrates, should not be given for prophylactic reversal, due to their uncertain benefit-risk.

Dabigatran versus enoxaparin for prevention of venous thromboembolism after hip or knee arthroplasty: a pooled analysis of three trials.

BACKGROUND: Three randomized, double-blind trials compared dabigatran, an oral direct thrombin inhibitor, with enoxaparin for the primary prevention of venous thromboembolism (VTE) in patients undergoing elective total hip and knee arthroplasty. OBJECTIVES AND METHODS: We conducted a pre-specified pooled analysis of these trials. 8,210 patients were randomized, of whom 8,135 were treated (evaluable for safety) with dabigatran 220 mg or 150 mg once-daily, or subcutaneous enoxaparin (40 mg once-daily or 30 mg twice-daily). Efficacy analyses were based on the modified intention-to-treat population of 6,200 patients with an evaluable outcome. The common risk difference (RD) of treatment effect between each dabigatran dose and enoxaparin was estimated using fixed-effects models, and statistical heterogeneity was estimated using the I2 statistic. RESULTS: The composite outcome of major VTE (proximal deep vein thrombosis and/or pulmonary embolism) and VTE-related mortality occurred in 3.3% of the enoxaparin group versus 3.0% of the dabigatran 220 mg group (RD vs. enoxaparin -0.2%, 95% CI -1.3% to 0.9%, I2=37%) and 3.8% of the 150 mg group (RD vs. enoxaparin 0.5%, -0.6% to 1.6%, I2=0%). Major bleeding occurred in 1.4% of the enoxaparin group versus 1.4% of the dabigatran 220 mg group (RD vs. enoxaparin -0.2%, -0.8% to 0.5%, I2=40%) and 1.1% of the 150 mg group (RD vs. enoxaparin -0.4%, -1.0% to 0.2%, I2=0%). CONCLUSIONS: Oral dabigatran was as effective as subcutaneous enoxaparin in reducing the risk of major VTE and VTE-related mortality after hip or knee arthroplasty and has a similar bleeding profile.

Adherence to a new oral anticoagulant treatment prescription: dabigatran etexilate.

The recent development of new oral anticoagulants, of which dabigatran etexilate is currently at the most advanced stage of development, is the greatest advance in the provision of convenient anticoagulation therapy for many years. A new oral anticoagulation treatment, dabigatran etexilate, is already on the market in Europe. The main interest probably will be to improve the prescription and the adherence to an effective thromboprophylaxis in medical conditions such as atrial fibrillation without bleeding side effects, without the need for monitoring coagulation, and without drug and food interactions such as vitamin K anticoagulant (VKA) treatment. Dabigatran is particularly interesting for extended thromboprophylaxis after major orthopedic surgery in order to avoid daily injection for a month. However, oral long-term treatments such as VKA are not systematically associated with a higher compliance level than injected treatments such as low-molecular-weight heparins. Indeed, adherence to an oral treatment, instead of the usual daily injection in major orthopedic surgery, is complex, and based not only on the frequency of dosing but also on patient motivation, understanding, and socio-economic status. New oral anticoagulants may be useful in this way but education and detection of risk factors of nonadherence to treatment are still essential.

[Dabigatran (Pradaxa): efficacy and safety]. / Dabigatran (Pradaxa): efficacité et tolérance.

There is considerable interest in developing new, orally available anticoagulants for the prevention and treatment of thrombotic disorders. In Europe, the low-molecular-weight heparins (LMWHs) are more commonly prescribed for thrombosis prevention, but require parenteral administration, platelets monitoring twice a week during the first month. Furthermore, LMWH are not synthetic. All of these characteristics can be an obstacle to optimal patient care, particularly when outpatient dosing is required after early discharge. New oral anticoagulants that require no monitoring and can be administered in a fixed dose without drug-drug and drug-food interactions would clearly offer practical advantages if shown to be safe and effective. dabigatran étexilate, a new oral, direct thrombin inhibitor, is the prodrug of the active compound dabigatran, which binds reversibly to thrombin with high affinity and specificity. This agent has a rapid onset of action, a predictable and reproducible that permit once-daily dosing. To date, more than 8,000 patients have been studied in clinical trials, and more than 38,000 individuals are enrolled in ongoing trials. Three major prospective, randomized, double-blind non-inferiority trials have compared the efficacy and safety of dabigatran étexilate (150 mg or 220 mg once-daily) starting postoperatively, with subcutaneous enoxaparin, in patients undergoing hip (RE-NOVATE trial) or knee arthroplasty (RE-MOBILIZE and RE-MODEL). Based on these trial results, dabigatran étexilate is approved for use in the European Union and Canada for primary prevention of VTE in patients having undergone elective total hip and knee arthroplasty. Pradaxa is now on the market in France since December 2008.

Safety assessment of new antithrombotic agents: lessons from the EXTEND study on ximelagatran.

BACKGROUND: Ximelagatran, the first oral direct thrombin inhibitor, was shown to be an effective antithrombotic agent but was associated with potential liver toxicity after prolonged administration. OBJECTIVES AND METHODS: The aim of the EXTEND study was to assess safety and efficacy of extended administration (35 days) of ximelagatran or enoxaparin for the prevention of venous thromboembolism after elective hip replacement and hip fracture surgery. A follow-up period, including assessment of liver enzymes (in particular alanine aminotransferase; ALAT), until post-operative day 180 was planned, with visits at days 56 and 180. RESULTS: Randomization and administration of study drugs were stopped following a report of serious liver injury occurring 3 weeks after completion of ximelagatran treatment. At the time of study termination, 1158 patients had been randomized and 641 had completed the 35-day treatment; with 303 ximelagatran and 265 enoxaparin patients remaining in the study through to the day 56 follow-up visit. Overall, 58 patients showed an ALAT increase to >2x upper limit of normal: 31 treated with enoxaparin, 27 with ximelagatran. Three ximelagatran patients also showed symptoms potentially related to liver toxicity. Eleven ximelagatran patients showed an ALAT increase after study treatment ended. The clinical development of ximelagatran was terminated and the drug withdrawn from the market. Evaluation of the relative efficacy of the two treatments as specified in the protocol was impossible due to the premature termination of the study. CONCLUSIONS: Prolonged administration of ximelagatran was associated with an increased risk of liver toxicity. In a substantial proportion of patients, ALAT increase occurred after treatment withdrawal. The findings seen with ximelagatran should be considered when designing studies with new antithrombotic agents.

[Blood conservation approaches in orthopedic surgery]. / Epargne transfusionnelle en chirurgie orthopédique.

In addition to more restrictive "transfusion triggers", presently available allogeneic blood conservation strategies in surgery include preoperative increase in red blood cells (RBC) mass, techniques or pharmaceutical agents that reduce blood loss, and perioperative blood salvage. Because of very important risk reduction in allogeneic blood, benefit/risk of preautologous blood donation (PAD) is quite questionable at this moment. Indeed, at this moment in France, we focus to avoid any transfusion (allogeneic and autologous blood). Therefore the most important techniques used are pharmacological: erythropoietin before surgery with a number of injections related to baseline Hb, and tranexamic acid during and after surgery. Cell saving is used only if bleeding is enough important like arthroplasty revisions. All blood conservation techniques carry their own efficiency limits, constraints and risks that, in addition to institutional considerations and individual patient characteristics are determinant to settle a blood conservation strategy. The choice of a technique should take into account (a) the delay before surgery, (b) the anticipated blood loss for the procedure that varies among institutions, (c) the tolerable blood loss without transfusion for the patient, and (d) the efficacy of the blood conservation technique in the given setting. Nevertheless, at this moment in France, it is quite important to notice that the risk of delay or lack of transfusion induces much more deaths that the transfusion itself during or after anesthesia [Anesthesiology 105, 1087-97].

[Rivaroxaban (Xarelto): efficacy and safety]. / Rivaroxaban (Xarelto): efficacité et tolérance.

The oral direct Xa inhibitor rivaroxaban (Xarelto) shows great promise for prevention of venous thromboembolic events after major elective orthopedic surgery. Its consistent and predictable pharmacokinetics and pharmacodynamics across a wide range of patient populations allow administration with fixed dosing and with no coagulation monitoring. In 4 orthopaedic surgery clinical trials (12,700 patients), 10mg postoperative (6-10 hours after the end of surgery) dose, once daily, of oral rivaroxaban, achieved superior efficacy and similar safety to enoxaparin, whatever the dose of enoxaparin. Indeed, 40 mg once a day in Europe and 30 mg bid in US of enoxaparin were compared to the same dose of 10mg once daily of rivaroxaban. Furthermore, there is no difference according to liver enzymes elevation and cardio-vascular adverse events. Although the risk of spinal haematoma after neuraxial anaesthesia is rare, it is increased by concomitant use of anticoagulants. In orthopedic surgery trials with rivaroxaban to date, complications such as spinal haematoma have not been reported. The pharmacokinetic profile of rivaroxaban suggests that concurrent use with neuraxial anaesthesia should require no further precautions than currently necessary with low-molecular-weight heparin.