Direct oral anticoagulant use and risk of perioperative bleeding: Evidence of absence or absence of evidence?
2018; Elsevier BV; Volume: 2; Issue: 2 Linguagem: Inglês
10.1002/rth2.12084
ISSN2475-0379
AutoresWillem M. Lijfering, Ynse Ieuwe Gerardus Vladimir Tichelaar,
Tópico(s)Antiplatelet Therapy and Cardiovascular Diseases
ResumoFor patients who are receiving treatment with oral anticoagulants and require an elective operation or other invasive procedure, interrupting anticoagulation is often required. Each year, this common clinical scenario affects approximately one in six patients on oral anticoagulation.1.Healey J.S. Eikelboom J. Douketis J. et al.RE‐LY InvestigatorsPeriprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the Randomized Evaluation of Long‐Term Anticoagulation Therapy (RE‐LY) randomized trial.Circulation. 2012; 126: 343-8Crossref PubMed Scopus (467) Google Scholar, 2.Douketis J.D. Spyropoulos A.C. Spencer F.A. et al.Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines.Chest. 2012; 141: e326S-50SAbstract Full Text Full Text PDF PubMed Scopus (1280) Google Scholar The perioperative management of such patients is pertinent to many clinicians, including internists, surgeons, anesthetists, family physicians, and dentists.2.Douketis J.D. Spyropoulos A.C. Spencer F.A. et al.Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines.Chest. 2012; 141: e326S-50SAbstract Full Text Full Text PDF PubMed Scopus (1280) Google Scholar, 3.Spyropoulos A.C. Al‐Badri A. Sherwood M.W. Douketis J.D. Periprocedural management of patients receiving a vitamin K antagonist or a direct oral anticoagulant requiring an elective procedure or surgery.J Thromb Haemost. 2016; 14: 875-85Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar In this issue of RPTH, Shaw and colleagues provide data on the safety of perioperative interruption of direct oral anticoagulants (DOACs) for elective invasive procedures in patients with atrial fibrillation.4.Shaw J.R. Woodfine J.D. Douketis J. Schulman S. Carrier M. Perioperative interruption of direct oral anticoagulants in patients with atrial fibrillation: a systematic review and meta‐analysis.Res Pract Thromb Haemost. 2018; 2: 282-290Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar The clinical scope of this problem is important. Not only are DOACs fast replacing vitamin K antagonists (VKAs) as anticoagulant treatment for stroke prevention in patients with atrial fibrillation,5.Kirchhof P. Benussi S. Kotecha D. et al.2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS.Eur Heart J. 2016; 37: 2893-962Crossref PubMed Scopus (5155) Google Scholar but as a previous survey among medical practitioners showed, the effects of DOACs at time of invasive procedures are often unrecognized.6.Olaiya A. Lurie B. Watt B. McDonald L. Greaves M. Watson H.G. An observational study of direct oral anticoagulant awareness indicating inadequate recognition with potential for patient harm.J Thromb Haemost. 2016; 14: 987-90Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar Previous expert narrative reviews have provided guidance to clinicians on the management of DOACs in the perioperative period,4.Shaw J.R. Woodfine J.D. Douketis J. Schulman S. Carrier M. Perioperative interruption of direct oral anticoagulants in patients with atrial fibrillation: a systematic review and meta‐analysis.Res Pract Thromb Haemost. 2018; 2: 282-290Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholarand in order to update these expert reviews with clinical data, Shaw et al. conducted a systematic review and meta‐analysis of the literature involving four cohort studies and four clinical trials. They investigated in a total of 14 446 patients (who used a DOAC or VKA) the 30‐day risk of thromboembolic events, bleeding, and death. Unfortunately, of the eight studies included, three did not describe their perioperative anticoagulation protocols for DOACs, but the other five studies more or less did. For dabigatran these perioperative protocols were reasonably well described and they were based on the creatinine clearance, the corresponding estimated half‐life of dabigatran (13‐27 hour depending on renal function),7.Baglin T. Clinical use of new oral anticoagulant drugs: dabigatran and rivaroxaban.Br J Haematol. 2013; 163: 160-7PubMed Google Scholar, 8.Summary of product characteristics. Dabigatran. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000829/WC500041059.pdf. Accessed January 15, 2018Google Scholar and on whether the invasive procedure was deemed as having a low or high risk of bleeding.1.Healey J.S. Eikelboom J. Douketis J. et al.RE‐LY InvestigatorsPeriprocedural bleeding and thromboembolic events with dabigatran compared with warfarin: results from the Randomized Evaluation of Long‐Term Anticoagulation Therapy (RE‐LY) randomized trial.Circulation. 2012; 126: 343-8Crossref PubMed Scopus (467) Google Scholar, 9.Schulman S. Carrier M. Lee A.Y. et al.Periop Dabigatran Study Group. Perioperative management of dabigatran: a prospective cohort study.Circulation. 2015; 132: 167-73Crossref PubMed Scopus (118) Google Scholar, 10.Kosiuk J. Koutalas E. Doering M. et al.Comparison of dabigatran and uninterrupted warfarin in patients with atrial fibrillation undergoing cardiac rhythm device implantations. Case‐control study.Circ J. 2014; 78: 2402-7Crossref PubMed Scopus (21) Google Scholar For rivaroxaban, those who temporarily interrupted anticoagulant treatment for ≥3 days due to any cause were considered to have interrupted their treatment due to an invasive procedure.11.Sherwood M.W. Douketis J.D. Patel M.R. et al.ROCKET AF InvestigatorsOutcomes of temporary interruption of rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: results from the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF).Circulation. 2014; 129: 1850-9Crossref PubMed Scopus (204) Google Scholar For apixaban, each procedure was classified as either "no interruption" (if the study drug was not interrupted or interrupted on the same day of the procedure) or "any interruption" (if the study drug was stopped between one and seven days before the procedure), but the final decision about when apixaban would be interrupted was left to local investigators.12.Garcia D. Alexander J.H. Wallentin L. et al.Management and clinical outcomes in patients treated with apixaban vs warfarin undergoing procedures.Blood. 2014; 124: 3692-8Crossref PubMed Scopus (132) Google Scholar Therefore, we do not exactly know the perioperative management in the included apixaban and rivaroxaban studies.11.Sherwood M.W. Douketis J.D. Patel M.R. et al.ROCKET AF InvestigatorsOutcomes of temporary interruption of rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: results from the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF).Circulation. 2014; 129: 1850-9Crossref PubMed Scopus (204) Google Scholar, 12.Garcia D. Alexander J.H. Wallentin L. et al.Management and clinical outcomes in patients treated with apixaban vs warfarin undergoing procedures.Blood. 2014; 124: 3692-8Crossref PubMed Scopus (132) Google Scholar Also, none of these five studies took into account the thromboembolic risk of the patients during the perioperative phase, as is advised by the American College of Chest Physicians and other expert opinion panels.3.Spyropoulos A.C. Al‐Badri A. Sherwood M.W. Douketis J.D. Periprocedural management of patients receiving a vitamin K antagonist or a direct oral anticoagulant requiring an elective procedure or surgery.J Thromb Haemost. 2016; 14: 875-85Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar, 4.Shaw J.R. Woodfine J.D. Douketis J. Schulman S. Carrier M. Perioperative interruption of direct oral anticoagulants in patients with atrial fibrillation: a systematic review and meta‐analysis.Res Pract Thromb Haemost. 2018; 2: 282-290Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar Furthermore, from the apixaban study it was unclear if for procedures with minimal bleeding risk, like dental or ocular procedures, apixaban was interrupted or not,13.Levi M. Hovingh G.K. Cannegieter S.C. Vermeulen M. Büller H.R. Rosendaal F.R. Bleeding in patients receiving vitamin K antagonists who would have been excluded from trials on which the indication for anticoagulation was based.Blood. 2008; 111: 4471-6Crossref PubMed Scopus (85) Google Scholar while for the rivaroxaban and dabigatran studies in at least some of these situations anticoagulation therapy was interrupted.9.Schulman S. Carrier M. Lee A.Y. et al.Periop Dabigatran Study Group. Perioperative management of dabigatran: a prospective cohort study.Circulation. 2015; 132: 167-73Crossref PubMed Scopus (118) Google Scholar, 10.Kosiuk J. Koutalas E. Doering M. et al.Comparison of dabigatran and uninterrupted warfarin in patients with atrial fibrillation undergoing cardiac rhythm device implantations. Case‐control study.Circ J. 2014; 78: 2402-7Crossref PubMed Scopus (21) Google Scholar, 11.Sherwood M.W. Douketis J.D. Patel M.R. et al.ROCKET AF InvestigatorsOutcomes of temporary interruption of rivaroxaban compared with warfarin in patients with nonvalvular atrial fibrillation: results from the rivaroxaban once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fibrillation (ROCKET AF).Circulation. 2014; 129: 1850-9Crossref PubMed Scopus (204) Google Scholar, 12.Garcia D. Alexander J.H. Wallentin L. et al.Management and clinical outcomes in patients treated with apixaban vs warfarin undergoing procedures.Blood. 2014; 124: 3692-8Crossref PubMed Scopus (132) Google Scholar This is important to note because expert opinion panels advise not to interrupt anticoagulation in minimal bleeding risk procedures.2.Douketis J.D. Spyropoulos A.C. Spencer F.A. et al.Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines.Chest. 2012; 141: e326S-50SAbstract Full Text Full Text PDF PubMed Scopus (1280) Google Scholar, 3.Spyropoulos A.C. Al‐Badri A. Sherwood M.W. Douketis J.D. Periprocedural management of patients receiving a vitamin K antagonist or a direct oral anticoagulant requiring an elective procedure or surgery.J Thromb Haemost. 2016; 14: 875-85Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar Nevertheless, Shaw et al. had to make do with what information they had and with it they found that the 30‐day risk for thromboembolic and major bleeding events was 0.4% and 1.8%, respectively. Based on these absolute risks the authors rightly conclude that these findings seem reassuring. However, despite the large number of patients involved and the meticulous systematic review and meta‐analysis that the authors performed, this study should not be seen as an endpoint but as a starting point, which is also urged by the authors at the end of their discussion.4.Shaw J.R. Woodfine J.D. Douketis J. Schulman S. Carrier M. Perioperative interruption of direct oral anticoagulants in patients with atrial fibrillation: a systematic review and meta‐analysis.Res Pract Thromb Haemost. 2018; 2: 282-290Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar Below, we discuss some issues that should prompt more clinically oriented research in this field with predefined endpoints, and propose a protocol for DOAC interruption that seems reasonable with the evidence that is presently known (Table 1).Table 1Proposed protocol for DOAC interruption at time of an invasive procedureaAdapted from the PAUSE protocol,17 with some modifications (i.e, addition of minimal bleeding risk category).DOAC typeEstimatedBleeding riskInterruption timing of DOAChalf‐life, hof the procedureDay ‐4Day ‐3Day ‐2Day ‐1Day 0Day +1Day +2Day +3Dabigatran (eGFR ≥ 50 ml/min)HighstopstopstopstopstopcMay consider to restart DOAC therapy two days after the procedure.restart≈ 13‐15 hLowstopstoprestartMinimalcontinuebMay consider interrupting DOAC therapy on the day of the procedure.Dabigatran (eGFR < 50 ml/min)HighstopstopstopstopstopstopstopcMay consider to restart DOAC therapy two days after the procedure.restart≈ 18‐27 hLowstopstopstopstoprestartMinimalcontinuebMay consider interrupting DOAC therapy on the day of the procedure.Rivaroxaban≈ 5‐9 hHighstopstopstopstopstopcMay consider to restart DOAC therapy two days after the procedure.restartLowstopstoprestartMinimalcontinuecMay consider to restart DOAC therapy two days after the procedure.Apixaban≈ 12‐17 hHighstopstopstopstopstopcMay consider to restart DOAC therapy two days after the procedure.restartLowstopstoprestartMinimalcontinuebMay consider interrupting DOAC therapy on the day of the procedure.DOAC, direct oral anticoagulant; eGFR, estimated glomerular filtration rate.Definitions of which procedures are associated with minimal, low and high bleeding risks can be found in Ref. 4.a Adapted from the PAUSE protocol,17.Douketis J.D. Spyropoulos A.C. Anderson J.M. et al.The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) study for patients on a direct oral anticoagulant who need an elective surgery or procedure: design and rationale.Thromb Haemost. 2017; 117: 2415-24Crossref PubMed Scopus (47) Google Scholar with some modifications (i.e, addition of minimal bleeding risk category).b May consider interrupting DOAC therapy on the day of the procedure.c May consider to restart DOAC therapy two days after the procedure. Open table in a new tab DOAC, direct oral anticoagulant; eGFR, estimated glomerular filtration rate. Definitions of which procedures are associated with minimal, low and high bleeding risks can be found in Ref. 4. Of the eight studies that were meta‐analyzed, four involved patients who were included in randomized clinical trials (n = 9939).4.Shaw J.R. Woodfine J.D. Douketis J. Schulman S. Carrier M. Perioperative interruption of direct oral anticoagulants in patients with atrial fibrillation: a systematic review and meta‐analysis.Res Pract Thromb Haemost. 2018; 2: 282-290Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar Previous studies have shown that VKAs are often prescribed to patients who would not have qualified for clinical trials,13.Levi M. Hovingh G.K. Cannegieter S.C. Vermeulen M. Büller H.R. Rosendaal F.R. Bleeding in patients receiving vitamin K antagonists who would have been excluded from trials on which the indication for anticoagulation was based.Blood. 2008; 111: 4471-6Crossref PubMed Scopus (85) Google Scholar which is likely to be the same for patients who are prescribed a DOAC.14.Rosendaal F.R. Reitsma P.H. Brave real world.J Thromb Haemost. 2016; 14: 2091Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar Randomized trials prioritize internal over external validity, and researchers therefore strive to include patients who, for instance, are more likely to adhere to the prescribed procedures, are not likely to undergo major surgery, have a life‐expectancy longer than the trial duration, and are capable of giving informed consent. This is a reasonable approach that is needed before one can even start thinking about the more heterogeneous real world.14.Rosendaal F.R. Reitsma P.H. Brave real world.J Thromb Haemost. 2016; 14: 2091Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar In the meta‐analysis, Shaw et al. did include patients with atrial fibrillation on DOAC who had an invasive procedure outside clinical trial settings, but these comprised only 7% (n = 679) of the total study population (ie, all other patients came from clinical trials). Therefore, it can be questioned whether the relatively low outcome rates of thromboembolic and major bleeding events at 30‐days post invasive procedure are due to a safe interruption strategy only. Large observational studies that include consecutive patients with atrial fibrillation on DOAC and who require an elective invasive procedure are needed to address this issue. Of the eight studies included, there were three that exclusively concerned patients undergoing permanent pacemaker insertion or implantable cardioverter defibrillator procedures. These invasive procedures are considered to have a minimal bleeding risk and in which anticoagulation can be continued during the procedure.2.Douketis J.D. Spyropoulos A.C. Spencer F.A. et al.Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines.Chest. 2012; 141: e326S-50SAbstract Full Text Full Text PDF PubMed Scopus (1280) Google Scholar, 3.Spyropoulos A.C. Al‐Badri A. Sherwood M.W. Douketis J.D. Periprocedural management of patients receiving a vitamin K antagonist or a direct oral anticoagulant requiring an elective procedure or surgery.J Thromb Haemost. 2016; 14: 875-85Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar It is therefore not surprising that in these studies none of the patients developed a thromboembolic event or (when reported) a major bleeding. But also in the other five studies that included patients undergoing a variety of procedures, the large majority of patients underwent procedures that are considered to be minimal/low bleeding risk procedures. The clinically relevant procedures where the major bleeding risk is high (ie, ≥2% within two days post‐surgery), like surgery with extensive tissue injury, cancer surgery, joint arthroplasty, or reconstructive plastic surgery,2.Douketis J.D. Spyropoulos A.C. Spencer F.A. et al.Perioperative management of antithrombotic therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence‐Based Clinical Practice Guidelines.Chest. 2012; 141: e326S-50SAbstract Full Text Full Text PDF PubMed Scopus (1280) Google Scholar, 3.Spyropoulos A.C. Al‐Badri A. Sherwood M.W. Douketis J.D. Periprocedural management of patients receiving a vitamin K antagonist or a direct oral anticoagulant requiring an elective procedure or surgery.J Thromb Haemost. 2016; 14: 875-85Abstract Full Text Full Text PDF PubMed Scopus (108) Google Scholar are underrepresented in the meta‐analysis. It is unfortunate that the authors did not have access to individual patient data as this might have answered the question what the postoperative bleeding‐ and thromboembolic risk is in patients who underwent an elective high bleeding risk invasive procedure. Future studies should include larger numbers of patients who undergo such high bleeding risk procedures. As acknowledged by the authors, the results they found need validation in large prospective management studies where preoperative DOAC levels are also measured. Although not reported for apixaban and rivaroxaban, dabigatran levels are related with bleeding.15.Reilly P.A. Lehr T. Haertter S. Connolly S.J. et al.RE‐LY InvestigatorsThe effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE‐LY Trial (Randomized Evaluation of Long‐Term Anticoagulation Therapy).J Am Coll Cardiol. 2014; 63: 321-8Crossref PubMed Scopus (662) Google Scholar There is a paucity of studies that actually looked at direct oral anticoagulation levels at time of an invasive procedure; to our knowledge there is currently only one study available that addressed this issue.16.Douketis J.D. Wang G. Chan N. et al.Effect of standardized perioperative dabigatran interruption on the residual anticoagulation effect at the time of surgery or procedure.J Thromb Haemost. 2016; 14: 89-97Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar In this cohort study (which was a sub‐analysis from one of the cohort studies that was reported in the meta‐analysis9.Schulman S. Carrier M. Lee A.Y. et al.Periop Dabigatran Study Group. Perioperative management of dabigatran: a prospective cohort study.Circulation. 2015; 132: 167-73Crossref PubMed Scopus (118) Google Scholar), performed by Douketis and colleagues, it was shown that in 181 patients who took dabigatran and were requesting an elective invasive procedure, the anticoagulant effect had not worn off in all patients despite that they withheld dabigatran therapy for 24‐48 hours before the procedure. Approximately 15% had residual dabigatran levels at time of the procedure.16.Douketis J.D. Wang G. Chan N. et al.Effect of standardized perioperative dabigatran interruption on the residual anticoagulation effect at the time of surgery or procedure.J Thromb Haemost. 2016; 14: 89-97Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar As acknowledged by the authors, their study was unable to show that their strategy was necessarily safe, even though only one major bleed occurred in a patient in whom no anticoagulant effect was observed. Probably this issue is best explained by a number needed to harm (NNH), which calculates the number of patients that should be treated with dabigatran to produce one major bleed, opposed to patients who were unexposed to therapeutic dabigatran levels at the time of the procedure. We calculated that even for a NNH of 20 one would need a study of approximately 500 patients. The fact that the aforementioned study was underpowered to find even a NNH of 20 is important, as it bears forward the need for a larger study where preoperative DOAC levels are measured. Recently, the design and rationale of the Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) study for patients on a DOAC who need elective surgery or an invasive procedure has been published.17.Douketis J.D. Spyropoulos A.C. Anderson J.M. et al.The Perioperative Anticoagulant Use for Surgery Evaluation (PAUSE) study for patients on a direct oral anticoagulant who need an elective surgery or procedure: design and rationale.Thromb Haemost. 2017; 117: 2415-24Crossref PubMed Scopus (47) Google Scholar PAUSE will study in an observational design with longitudinal follow‐up if a standardized, patient‐specific perioperative management tool for patients on DOACs with atrial fibrillation works in terms of safety and efficacy, and has a secondary aim to determine the effect of residual anticoagulation at time of the procedure. Initiatives like PAUSE are urgently needed. In conclusion, the current study of Shaw et al. adds some scientific support for safe interruption of anticoagulation in patients who are treated with DOACs and require elective surgery or an invasive procedure. Nevertheless, what the best perioperative management is in such patients is still uncertain. WML and YIGVT were the main investigators of the manuscript. WML wrote the first draft of the manuscript and the final version. YIGVT was responsible for review of the manuscript. The authors state that they have no conflict of interest.
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