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New anticoagulants in ambulatory anaesthesia

Samama, Charles Marc

European Journal of Anaesthesiology (EJA): February 2016 - Volume 33 - Issue 2 - p 69–71
doi: 10.1097/EJA.0000000000000357
Editorial
Free

From the Department of Anaesthesia and Intensive Care Medicine, Cochin and Hôtel-Dieu University Hospitals, Paris, France

Correspondence to Charles Marc Samama, MD, PhD, FCCP, Department of Anaesthesia and Intensive Care Medicine, Cochin and Hôtel-Dieu University Hospitals, 27 rue du Faubourg St Jacques, 75014 Paris, France Tel: +33 1 42 34 85 51; fax: +33 1 58 41 14 15; e-mail: marc.samama@aphp.fr

Venous thromboembolism (VTE) remains a serious clinical issue with an unacceptable rate of mortality and associated morbidity that includes pulmonary embolism and deep vein thrombosis (DVT).1 However, the incidence of these events has been decreasing steadily during the last decades, thanks to chemical and mechanical prophylaxis, fast-track procedures and related improvements in the rehabilitation processes, and major progresses in surgical and anaesthetic techniques. At the present time, for instance, less than 1% of patients undergoing major orthopaedic surgery will develop a symptomatic VTE. The rate of postoperative pulmonary embolism is now below 0.5% and the fatal pulmonary embolism rate is much lower than 0.1%, even after major surgery.2 A recent retrospective cohort of 1 432 855 patients undergoing surgery under general anaesthesia at 315 American hospitals from 2005 to 2011 found an overall VTE rate of 0.96% with low rates for DVT (0.71%) and pulmonary embolism (0.33%).3 Of note, as compared with a procedure of average duration, patients undergoing the shortest procedures experienced a 0.86 [95% confidence interval (CI) 0.83 to 0.88] decrease in the odds of developing VTE.

Figures are even more impressive for day-case procedures. Several explanations may account for this. Procedures are generally shorter and have an intrinsic lower risk and the patient population may be more selective. For example, the day-case operative cohort may include a greater proportion of younger people, who are more mobile and tend to be discharged back home on the same day as surgery, thereby minimising the time of strict immobility. In these patients, the magnitude and duration of risk of VTE associated with different surgical procedures is still largely unknown. With regard to the level of risk, several cohort studies have evidenced a very low level of risk, although it should be noted that only predominately minor procedures were included. As an example, the total global risk for VTE within 60 postoperative days only reached 0.04% in the Engbaek study in 2006 (16 048 patients including 18 736 day surgery operations).4 With such low figures, one could wonder whether VTE prophylaxis should even be considered for such procedures. The whole picture, however, appears to be a little bit more complicated. A prospective, observational, cohort study using the American College of Surgeons National Surgical Quality Improvement Program database from 2005 to 2009 included 259 231 adult patients who had outpatient surgery or surgery with subsequent 23-h observation.5 The main outcome measure was the 30-day incidence of VTE requiring treatment, which for the overall cohort was less than 0.15%. This study has identified several independent risk factors for VTE: current pregnancy [adjusted odds ratio (OR) 7.80]; active cancer (OR 3.66); age 41 to 59 years (OR 1.72); age at least 60 years (OR 2.48); BMI at least 40 kg m−2 (OR 1.81); operative time at least 120 min (OR 1.69); arthroscopic surgery (OR 5.16); saphenofemoral junction surgery (OR 13.20); and venous surgery not involving the great saphenous vein (OR 15.61). The Million Women Study also provides very interesting data. In-patients undergoing surgery have a seven times greater VTE risk than out-patients; however, even for day-case surgery, the VTE risk persists for up to 12 weeks after the procedure.6

Therefore, several questions arise: is there any room for systematic prophylaxis? Should VTE prophylaxis be tailored for each patient? What is the optimal duration for the treatment? And last, but not least, what is the preferred method of treatment?

The new oral anticoagulants [official name direct oral anticoagulants (DOACs)] may be split into two groups: anti-IIa agents [e.g. dabigatran (Pradaxa; Boehringer-Ingelheim, Biberach, Germany)]; and anti-Xa agents [the ‘xabans’, including rivaroxaban (Xarelto; Bayer, Leverkusen, Germany), apixaban (Eliquis; Bristol-Myers Squibb Company,

Princeton, New Jersey, USA) and edoxaban (Lixiana; Daiichi-Sankyo, Parsippany, New Jersey, USA)]. All these agents could be viewed as promising alternatives to injectable low molecular weight heparin (LMWH). The anti-Xa agents have good oral availability, an acceptable half-life of around 12 h, less than 50% renal clearance and there are no food interactions.7 All of them have been shown to be as effective and as well tolerated as enoxaparin in patients undergoing a total hip replacement (THR) or a total knee replacement (TKR).8,9 Rivaroxaban and apixaban may even be more effective than enoxaparin with the same level of safety.10 In addition, an oral compound is obviously more convenient for the patients than a daily subcutaneous injection of LMWH, especially when these patients return home on the day of surgery, and no monitoring of the platelet count is necessary.

However, no definite recommendations can be made with regard to the use of DOACs for VTE prophylaxis in day-case patients for the following reasons:

  1. These agents have not been studied in any other surgical speciality outside major orthopaedic procedures (THR and TKR). For example, nothing is known about their efficacy and induced bleeding risk for general surgery or urological procedures.
  2. In medical patients, even though DOACs were shown to be as effective as enoxaparin, the risk of major bleeding was increased, and it may be argued that, given the low VTE risk in day-case patients, it may be unwise to potentially increase the haemorrhagic risk.
  3. No data are available for the optimal choice of a dose or for the duration of the treatment. Would day-case patients be as well served by a lower dose for a shorter period of time?

Clinical studies have to be performed in order to be able to safely recommend the use of DOACs for VTE prophylaxis in day-case patients.

DOACs are also increasingly used in therapeutic doses as prophylaxis for patients with atrial fibrillation and as treatment for patients with DVT or pulmonary embolism. Some of these patients (around 10 to 13% per year) may need to undergo an invasive procedure. Some of these procedures are day cases. Several issues, therefore, have to be considered:11,12

  1. How many days prior to the procedure should treatment be stopped?
  2. Should any bridging with LMWH or unfractionated heparin be scheduled?
  3. Which laboratory tests, if any, should be performed immediately before the procedure to ensure reversal of anticoagulation (specific antifactor Xa assays for the anti-Xa agents or diluted thrombin time for dabigatran)?
  4. When should the anticoagulant treatment be restarted and, in particular, when should DOACs be given back to the patient?

Several groups of experts have issued some proposals for scheduled procedures that can be summarised as follows:11,13

  1. In general, stop the treatment 3 days before surgery for the anti-Xa agents and for at least 4 days for dabigatran.
  2. No bridging with heparin is necessary.
  3. No laboratory tests are necessary before surgery, except in a very limited number of patients.
  4. Restart anticoagulant treatment within the first 48 to 72 h postoperatively, initially with prophylactic doses of LMWH, with the full dose of DOAC subsequently administered on the third or fourth postoperative day, when surgical haemostasis is assured.

Finally, as some emergent procedures (repair of a hand fracture, for instance) may benefit from being undertaken as a day-case, several additional questions have to be addressed regarding the prevention and/or the control of bleeding in patients with atrial fibrillation or VTE who are being treated with therapeutic doses of DOACs.

  1. If the procedure is scheduled in a patient whose last oral intake of DOACs is within the preceding 24 h, it may be suggested to delay the surgery for 2 or 3 days, whenever possible (see above). The day-case scenario can then still be used.
  2. If the procedure cannot be deferred, it has to be assumed that there is the potential risk of bleeding, and that the patient should be advised to stay at least one additional night in hospital.
  3. In the case of bleeding, as direct antidotes are not yet available, prothrombin complex concentrates (PCCs) 25 to 50 IU kg−1 or even activated PCC (FEIBA) 30 to 50 IU kg−1 can be used. Recombinant activated factor 7 is not effective.
  4. Laboratory blood test monitoring may be helpful to assess the level of anticoagulation.14

To make a long story short, the global postoperative VTE risk is decreasing, but this does not automatically mean that prophylaxis should be shortened, modified or withheld. These new anticoagulants appear to be very promising, at least for VTE prophylaxis, but no studies are available to allow the immediate implementation of these agents for patients undergoing ambulatory surgery. Large trials are needed to confirm the widely shared opinion that the use of DOACs would be more than welcome in these patients. Upcoming new guidelines from the European Society of Anaesthesiology will try to address this issue in a near future.

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Acknowledgements relating to this article

Assistance with the editorial: none.

Financial support and sponsorship: none.

Conflicts of interest: CMS has received grant monies (from industry-related sources) from CSL Behring, LFB and Octapharma, and speaker's fee from Bayer, BMS, Boehringer-Ingelheim, Covidien, CSL Behring, Daichii, GSK, LFB, Octapharma, Pfizer, Rovi, Sanofi and Stago; he has been a member of advisory committees of AstraZeneca, Bayer, BMS, Boehringer-Ingelheim, Daiichi-Sankyo, GSK, Pfizer, Portola, Roche and Sanofi, and he has been a primary investigator for Bayer, BMS, Boehringer-Ingelheim, LFB, GSK and Sanofi.

Comment from the editor: this Editorial was checked by the editors but was not sent for external peer-review. CMS is an Associate Editor of the European Journal of Anaesthesiology.

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