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.).

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.

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.

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.

Type of anaesthesia and the safety and efficacy of thromboprophylaxis with enoxaparin or dabigatran etexilate in major orthopaedic surgery: pooled analysis of three randomized controlled trials.

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.

Pharmacokinetics of fondaparinux 1.5 mg once daily in a real-world cohort of patients with renal impairment undergoing major orthopaedic surgery.

PURPOSE: Fondaparinux, a selective activator factor X (factor Xa) inhibitor, is effective and safe for preventing venous thromboembolism after major orthopaedic surgery (MOS) at the once-daily subcutaneous dose of 2.5 mg. As the drug is mainly eliminated by the kidneys, a reduced dosage (1.5 mg once daily) was developed for patients with renal impairment. METHODS: We studied the pharmacokinetics (PK) of this dosage regimen using data from a real-world cohort of 442 patients with renal impairment (creatinine clearance 20-50 ml/min) undergoing MOS. Data were analysed using NON-linear Mixed Effect Modelling software (NONMEM) software. Fondaparinux PK was modelled using a two-compartment model with first-order absorption. RESULTS: This analysis confirmed the relationship between renal function and fondaparinux PK profiles. The mean predicted steady-state area under the plasma concentration time curve, peak and trough plasma concentrations of fondaparinux were lower by 15.6 %, 13.0 % and 10.3 %, respectively, in patients with renal impairment treated with 1.5 mg compared with patients with normal renal function treated with 2.5 mg (p < 0.01). CONCLUSION: Although administration of 1.5 mg fondaparinux in patients with renal impairment resulted in a predicted exposure slightly lower than that achieved with 2.5 mg in patients with normal renal function, fondaparinux 1.5 mg is a valuable thromboprophylactic option in MOS patients with renal impairment who are at risk of bleeding.

Thromboprophylaxis in patients older than 75 years or with moderate renal impairment undergoing knee or hip replacement surgery [corrected].

PURPOSE: Prospective, double-blind studies in orthopaedic patients have been conducted using the direct thrombin inhibitor dabigatran etexilate (hereafter referred to as dabigatran), with two doses investigated and approved for adults (220 mg and 150 mg once daily) to prevent venous thromboembolism (VTE). The European Medicines Agency decided that in major joint orthopaedic surgery, the lower dose should be used in elderly patients (aged over 75 years) and those with reduced renal function (creatinine clearance between 30 and 50 ml/min). Our objective was to understand the efficacy and bleeding data for the lower dose in this subpopulation. METHODS: We extracted and analysed data from the elderly or from moderately renally impaired patients (n 632 of = 5,539) from the orthopaedic clinical development programme of dabigatran. RESULTS: Dabigatran 150 mg once daily was as effective as the standard European enoxaparin regimen, with numerically fewer major bleeding events. Rates of major VTE were 4.3% vs 6.4% of patients, respectively. Major bleeding events occurred in four (1.3%) vs 11 (3.3%), which shows a trend towards lower bleeding with dabigatran 150 mg [odds ratio (OR) 0.40; 95% confidence interval (CI) 0.13-1.25; p = 0.110]. Mean volume of blood loss was 395 vs 417 ml, and transfused units were 2.4 vs 2.5, respectively. Other safety parameters, including the incidence of wound infections and complications, were similar for 150 mg once daily dabigatran and enoxaparin. CONCLUSION: For patients at higher risk of bleeding, dabigatran 150 mg once daily is as effective as enoxaparin following major orthopaedic surgery and is associated with a favourable bleeding rate.

Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty.

BACKGROUND: We investigated the efficacy of rivaroxaban, an orally active direct factor Xa inhibitor, in preventing venous thrombosis after total knee arthroplasty. METHODS: In this randomized, double-blind trial, 2531 patients who were to undergo total knee arthroplasty received either oral rivaroxaban, 10 mg once daily, beginning 6 to 8 hours after surgery, or subcutaneous enoxaparin, 40 mg once daily, beginning 12 hours before surgery. The primary efficacy outcome was the composite of any deep-vein thrombosis, nonfatal pulmonary embolism, or death from any cause within 13 to 17 days after surgery. Secondary efficacy outcomes included major venous thromboembolism (i.e., proximal deep-vein thrombosis, nonfatal pulmonary embolism, or death related to venous thromboembolism) and symptomatic venous thromboembolism. The primary safety outcome was major bleeding. RESULTS: The primary efficacy outcome occurred in 79 of 824 patients (9.6%) who received rivaroxaban and in 166 of 878 (18.9%) who received enoxaparin (absolute risk reduction, 9.2%; 95% confidence interval [CI], 5.9 to 12.4; P<0.001). Major venous thromboembolism occurred in 9 of 908 patients (1.0%) given rivaroxaban and 24 of 925 (2.6%) given enoxaparin (absolute risk reduction, 1.6%; 95% CI, 0.4 to 2.8; P=0.01). Symptomatic events occurred less frequently with rivaroxaban than with enoxaparin (P=0.005). Major bleeding occurred in 0.6% of patients in the rivaroxaban group and 0.5% of patients in the enoxaparin group. The incidence of drug-related adverse events, mainly gastrointestinal, was 12.0% in the rivaroxaban group and 13.0% in the enoxaparin group. CONCLUSIONS: Rivaroxaban was superior to enoxaparin for thromboprophylaxis after total knee arthroplasty, with similar rates of bleeding. (ClinicalTrials.gov number, NCT00361894.)

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.

Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial.

BACKGROUND: After hip replacement surgery, prophylaxis following discharge from hospital is recommended to reduce the risk of venous thromboembolism. Our aim was to assess the oral, direct thrombin inhibitor dabigatran etexilate for such prophylaxis. METHODS: In this double-blind study, we randomised 3494 patients undergoing total hip replacement to treatment for 28-35 days with dabigatran etexilate 220 mg (n=1157) or 150 mg (1174) once daily, starting with a half-dose 1-4 h after surgery, or subcutaneous enoxaparin 40 mg once daily (1162), starting the evening before surgery. The primary efficacy outcome was the composite of total venous thromboembolism (venographic or symptomatic) and death from all causes during treatment. On the basis of the absolute difference in rates of venous thromboembolism with enoxaparin versus placebo, the non-inferiority margin for the difference in rates of thromboembolism was defined as 7.7%. Efficacy analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00168818. FINDINGS: Median treatment duration was 33 days. 880 patients in the dabigatran etexilate 220 mg group, 874 in the dabigatran etexilate 150 mg group, and 897 in the enoxaparin group were available for the primary efficacy outcome analysis; the main reasons for exclusion in all three groups were the lack of adequate venographic data. The primary efficacy outcome occurred in 60 (6.7%) of 897 individuals in the enoxaparin group versus 53 (6.0%) of 880 patients in the dabigatran etexilate 220 mg group (absolute difference -0.7%, 95% CI -2.9 to 1.6%) and 75 (8.6%) of 874 people in the 150 mg group (1.9%, -0.6 to 4.4%). Both doses were thus non-inferior to enoxaparin. There was no significant difference in major bleeding rates with either dose of dabigatran etexilate compared with enoxaparin (p=0.44 for 220 mg, p=0.60 for 150 mg). The frequency of increases in liver enzyme concentrations and of acute coronary events during the study did not differ significantly between the groups. INTERPRETATION: Oral dabigatran etexilate was as effective as enoxaparin in reducing the risk of venous thromboembolism after total hip replacement surgery, with a similar safety profile.

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.

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.

The safety and efficacy of extended thromboprophylaxis with fondaparinux after major orthopedic surgery of the lower limb with or without a neuraxial or deep peripheral nerve catheter: the EXPERT Study.

BACKGROUND: The benefit-risk ratio of extended fondaparinux therapy has not been assessed in patients undergoing major lower limb joint arthroplasty. Few data on the concomitant use of fondaparinux and continuous neuraxial or deep peripheral nerve blockade are available. We performed a prospective intervention study in patients undergoing major orthopedic surgery primarily designed to assess the efficacy of fondaparinux when drug administration was withheld for 48 h to permit removal of a neuraxial or deep peripheral nerve catheter. The safety and efficacy of extended fondaparinux therapy for the prevention of venous thromboembolism were also evaluated. METHODS: Patients received a daily subcutaneous injection of 2.5 mg fondaparinux for 3 to 5 wk postoperatively. In patients with a neuraxial or deep peripheral nerve catheter, the catheter was removed 36 h after the last fondaparinux dose. The next fondaparinux dose was administered 12 h after catheter removal. The primary end points were symptomatic venous thromboembolism and major bleeding up to 4-6 wk after surgery. RESULTS: We recruited 5704 patients. A neuraxial or deep peripheral nerve catheter was inserted in 1553 (27%) patients and 78 (1.4%) patients, respectively. The rate of venous thromboembolism was 1.0% (54 of 5387). There was no difference between patients without (1.1%) or with (0.8%) a catheter (the upper limit of the 95% confidence interval of the odds ratio, 1.49, being below the predetermined noninferiority margin of 1.75). The incidence of major bleeding was 0.8% (42 of 5382). No neuraxial or perineural hematoma was reported. CONCLUSIONS: Once-daily subcutaneous injection of 2.5 mg fondaparinux given for 3 to 5 wk was effective and safe for prevention of venous thromboembolism after major orthopedic surgery. Temporary discontinuation of fondaparinux for 48 h permitted safe removal of a neuraxial or deep peripheral nerve catheter without decreasing thromboprophylatic efficacy.

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.