Pre-Procedural DOAC Guidance: When or If to Hold for EP/Catheterization Procedures

Direct oral anticoagulants (DOACs) have become the foundation for prevention of thromboembolic complications in patients with nonvalvular (NV) atrial fibrillation (AF). Standard dosing, lack of required routine laboratory testing, and both minimal dietary and drug interactions compared with traditional vitamin K antagonists appeal to patients and physicians alike. Additionally, DOACs have demonstrated safety and efficacy for long-term oral anticoagulation in patients with NVAF. Current AF guidelines assign a Class I recommendation for warfarin, dabigatran, rivaroxaban, or apixaban as oral anticoagulant options in patients with NVAF, stating that choice should be individualized based on shared decision-making between the provider and patient.1

With universal embracement of DOAC usage in NVAF, questions regarding periprocedural management are frequently encountered. Data are especially limited in patients undergoing electrophysiology (EP) and cardiac catheterization procedures, with various opinions not only on when to hold but also if to continue DOAC therapy through certain procedures. The following is a summary of current evidence on pre-procedural management of DOACs for EP and catheterization procedures.

Both thromboembolic and bleeding complications pose potentially devastating outcomes; thus, risks must be carefully balanced when considering management of pre-procedural anticoagulation. Procedural, as well as patient-related, bleed risks are equally crucial. In addition, thrombotic risk associated with discontinuation of anticoagulation must be considered. The DOACs vary substantially in pharmacokinetic properties, including dependence on renal excretion, so duration to hold anticoagulation may differ among the agents. The pharmacological properties of the four commercially available DOACs indicated for NVAF (dabigatran, rivaroxaban, apixaban, and edoxaban) are outlined in Table 1.2-5 Although risks of major bleeding events with EP/catheterization procedures are relatively low, management of bleeding associated with DOACs can be challenging due to lack of available antidotes. In the event of a major bleeding complication, hemostatic agents must be used. Dabigatran has the only commercially available reversal agent, idarucizumab, which is a human monoclonal antibody fragment that neutralizes the anticoagulant effect of dabigatran by binding to the drug.6 Andexanet alfa is currently under review by the Food and Drug Administration as a potential antidote for factor Xa inhibitors and has shown rapid and substantial reversal of rivaroxaban and apixaban in patients with major bleeding.7 Another agent, aripazine (PER977, Ciraparantag), is under investigation for reversal of factor Xa inhibitors, direct thrombin inhibitors, and heparin.8 Given the multitude of factors that affect bleeding and thrombotic risk, decision-making surrounding DOACs prior to procedure is complex with considerable variability in clinical practice.

Table 1: Summary of DOACs in NVAF2-5




APIXABAN (Eliquis®)

EDOXABAN (Savaysa®)

Mechanism of Action

Direct thrombin inhibitor

Factor Xa inhibitor

Factor Xa inhibitor

Factor Xa inhibitor

Dosage in NVAF

150 mg BID
creatinine clearance (CrCl) 15-30 ml/min: 75 mg bid

20 mg daily with evening meal
CrCl 15-50 ml/min: 15 mg daily

5 mg bid
2.5 mg bid if ≥ 2 or more factors: age ≥ 80, SCr ≥ 1.5 mg/dl, weight ≤ 60 kg

60 mg daily in CrCl 50-95 ml/min
CrCl 15-50 ml/min: 30 mg daily

Avoid Use/

  • CrCl < 15 ml/min


  • CrCl < 15 ml/min
  • Moderate-severe hepatic impairment
  • Body weight ≥ 205 kg: do not use per manufacturer. Has only been studied up to 130 kg
  • CrCl < 15 ml/min
  • Moderate-severe hepatic impairment
  • CrCl > 95 ml/min- increased risk of stroke
  • CrCl < 15 ml/min
  • Moderate-severe hepatic impairment
  • Do not use in valvular heart disease, mechanical valves, or active pathological bleeding


12-17 hours; prolonged in elderly patients and renal impairment
Severe renal impairment: 28 hours

5-11 hours; 11-13 hours in elderly patients

12 hours

10-14 hours

Metabolism and Excretion

Esterase-catalyzed hydrolysis. 85% renal excretion unchanged

CYP3A4/5, CYP2J2, and hydrolysis metabolism.
66% renal excretion; 36% unchanged

Mainly CYP3A4; minor metabolism from CYP1A2, 2C8, 2C9, 2C19, and 2J2.
27% renal excretion; biliary and direct intestinal excretion

Minimal metabolism via hydrolysis, CYP3A4. Primarily eliminated unchanged. 50% renal excretion; biliary/intestinal excretion

Drug Interactions

  • Avoid use with P-gp inducers (i.e., carbamazepine, rifampin, ritonavir, St. John's wort, prazosin).
  • P-gp inhibitors (i.e., dronedarone, ketoconazole, amiodarone) in CrCl 30-50 ml/min: reduce dose to 75 mg bid or avoid.
  • Avoid use with strong dual inhibitors of P-gp and CYP3A4 (i.e., clarithromycin, ketoconazole, ritonavir, itraconazole).
  • CrCl 15-50 ml/min, avoid use with combined P-gp and moderate CYP3A4 inhibitors (i.e., amiodarone, diltiazem, dronedarone, azithromycin, verapamil, ranolazine, quinidine, erythromycin).
  • Strong dual inhibitors of P-gp and CYP3A4 (i.e., clarithromycin, ketoconazole, ritonavir, itraconazole): reduce dose to 2.5 mg bid. If on 2.5 mg bid, avoid concomitant use.
  • Do not use with rifampin.
  • Increased risk of bleeding with other anticoagulants, antiplatelets, or chronic nonsteroidal anti-inflammatory drug use

Recently, the American College of Cardiology (ACC) released the 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients With Nonvalvular Atrial Fibrillation to provide guidance in this area.9 This publication addressed when to interrupt DOAC therapy, with pre-procedural hold times based on procedural bleed risk, type of agent, and renal function. Recommendations are summarized in Table 2. In deciding whether to interrupt DOAC therapy, the authors suggest first conducting an assessment of patient-related factors. Patient-related bleed risk is considered increased with any of the following: major bleed or intracranial hemorrhage within the past 3 months, platelet abnormality, including aspirin use, and history of bleed during previous bridging. If one or more factors are present, the ACC states that there are insufficient data on best practice and that DOAC therapy should be interrupted for at least as long as determined by CrCl (Table 2). If patient-related factors that increase bleed risk are not present, procedural bleed risk should be assessed and anticoagulation interrupted for a period of time based on type of DOAC and renal function (Table 2). The ACC classifies procedural bleeding risk into three categories: no clinically important risk; low risk; and uncertain, intermediate, or high risk. Common catheterization procedures were included (Table 3). Bleeding risk of coronary angiography and percutaneous coronary intervention (PCI) is based on vascular access site with preferred access via the radial artery due to lower risk of bleeding and vascular complications compared with the femoral approach. Risk of the common EP procedures, AF ablation, and implantable cardioverter-defibrillator (ICD) implantation were not defined by the ACC.

Table 2: Summary of ACC Recommendations for Pre-Procedural Management of DOACs in NVAF9




Dabigatran (Pradaxa®)

HOLD based on CrCl*:
CrCl 80 ml/min or higher: 24 hours (at least 2 doses)
CrCl 50-79 ml/min: 36 hours (at least 3 doses)
CrCl 30-49 ml/min: 48 hours (at least 4 doses)
CrCl 15-29 ml/min: ≥ 72 hours
Less than 15 ml/min: No data. Consider measuring dTT and/or withholding 96 hours or more.

HOLD based on CrCl*:
CrCl 80 ml/min or higher: 48 hours (at least 4 doses)
CrCl 50-79 ml/min: 72 hours (at least 6 doses)
CrCl 30-49 ml/min: 96 hours (at least 8 doses)
CrCl 15-29 ml/min: ≥ 120 hours
Less than 15 ml/min: No data. Consider measuring dTT.

Rivaroxaban (Xarelto®)

HOLD based on CrCl*:
CrCl 30 ml/min or higher: 24 hours
CrCl 15-29 ml/min: 36 hours
CrCl less than 15 ml/min: No data. Withhold for 48 hours or more.

HOLD based on CrCl*:
CrCl 30 ml/min or higher: 48 hours
CrCl less than 30 ml/min: No data. Withhold for 72 hours or more. Consider checking agent-specific anti-Xa level at 72 hours, if available.

Apixaban (Eliquis®)

Edoxaban (Savaysa®)

*CrCl as calculated by the Cockcroft-Gault Equation. CrCl is NOT equivalent to estimated glomerular filtration rate.

The American Heart Association (AHA) also recently released a Scientific Statement on management of patients on non-vitamin K oral anticoagulants in the acute care and periprocedural setting.10 Like the aforementioned ACC publication, the AHA authors discerned catheterization bleed risk based on vascular access but ranked bleed risk at a higher level for both catheterization and PCI (Table 3). Pre-procedural hold times for DOACs were based on their prescribing information. These recommendations differ from the ACC publication, which has more specific CrCl cutoffs and, in some cases, longer hold times. For instance, the ACC classifies PCI via the femoral artery as a moderate risk bleeding procedure, instructing to discontinue factor Xa inhibitors for 48 hours prior to procedure. This conflicts with the AHA, which categorizes catheterization via the femoral artery as a high-risk procedure but suggests a shorter hold time of at least 24 hours. Given the short half-lives of the DOACs, a hold time of 24 hours should be sufficient in patients with normal renal function. Of note, the AHA stipulates that bridging anticoagulation may be considered in patients in whom thromboembolic risk exceeds procedural bleeding risk, specifically those who have a history of systemic embolus in the last 6 weeks. The ACC authors state that parenteral bridging of DOACs is not indicated at any time due to their short half-lives.

Table 3: Classification of Bleeding Risk in Common EP/Catheterization Procedures (AHA and ACC)


Peri-Procedural Bleeding Risk According to AHA

Peri-Procedural Bleeding Risk According to ACC

AF ablation



Supraventricular tachycardia ablation



ICD implant



Cardiac catheterization via femoral artery


Coronary angiography: Uncertain
PCI: moderate

Cardiac catheterization via radial artery


Low (coronary angiography and PCI)

Left atrial appendage occlusion (WATCHMAN [Boston Scientific; Marlborough, MA])


Moderate (intermediate)

Left atrial appendage occlusion (LARIAT procedure [SentreHEART, Inc; Palo Alto, CA])



Mitral valve repair, percutaneous (MitraClip [Abbott; Abbott Park, IL])



Transaortic valve replacement



Right heart catheterization



Management of pre-procedural anticoagulation is challenging in patients undergoing cardiac device insertion, particularly ICDs. Bleeding and pocket hematoma formation is a significant complication that can increase risk of infection and hospitalization.11 Although uninterrupted warfarin has been associated with less bleeding, the optimal management of DOACs prior to ICD implantation is uncertain.12 Small studies have observed no increased bleeding risk with uninterrupted dabigatran, but data have been insufficient to safely recommend continuing DOAC therapy through ICD implant procedures.13,14 The results of BRUISE CONTROL-2 (A Randomized Controlled Trial of Continued Versus Interrupted Direct Oral Anti-Coagulant at the Time of Device Surgery) were recently presented at the 2017 AHA Annual Scientific Sessions.15 The study evaluated continued versus interrupted DOAC therapy with EP device procedure.16 Patients in the continued arm (n = 328) took their DOAC dose the morning prior to procedure, while those in the interrupted arm (n = 334) discontinued their DOAC 2 days prior to procedure. The primary outcome of clinically significant hematoma, as well as the secondary outcome of stroke, were the same for both groups (2.1 vs. 2.1%, p = 0.97 and 0.3 vs. 0.3%, p = 1.0, respectively). The trial was terminated early due to futility. The BRUISE-CONTROL 2 trial is the first large, randomized trial to show that the strategy of routine continuation of apixaban, rivaroxaban, or dabigatran is not superior to interrupted use in reduction of pocket hematomas. The study has yet to be published; nonetheless, the results may affect clinical practice and future guidance documents. The most recent AHA Scientific Statement offers some guidance on management of DOACs in the pre-procedural period, listing ICD implantation as a moderate bleed risk procedure with a suggested hold time of 24 hours for factor Xa inhibitors. For dabigatran, they recommend hold time based on renal function as indicated for ACC-defined low-risk bleeding procedures (Table 2).

Similar to cardiac device insertion, periprocedural anticoagulation for AF ablation has been an area of intense debate since the procedure was first described by Haisseguerre and others in the late 1980s and continues in the era of DOAC therapy.17-19 AF ablation adds greater complexity to procedural risk mitigation because patients are at an elevated risk of cerebral thromboembolism and, in most cases, require anticoagulation for at least 3 weeks prior to procedure. Furthermore, it has been estimated that the periprocedural risk of cardiac tamponade is 1.5%.20 The use of uninterrupted warfarin in the setting of AF ablation is a widely accepted strategy due to ample evidence indicating decreased thromboembolic and bleeding events. Several observational studies have demonstrated safety of uninterrupted DOAC therapy in the setting of AF ablation.20-22 Of late, new AF ablation guidelines were published (2017 HRS/EHRA/ECAS/APHRS/SOLAECE Expert Consensus Statement on Catheter and Surgical Ablation of Atrial Fibrillation), providing a Class I recommendation for performing AF ablation with uninterrupted dabigatran or rivaroxaban and a Class 2A recommendation for the other DOACs.20 These recommendations were largely based on the results of the RE-CIRCUIT (Randomized Evaluation of Dabigatran Etexilate Compared to Warfarin in Pulmonary Vein Ablation: Assessment of an Uninterrupted Periprocedural Anticoagulation Strategy) study, which randomized 704 patients with AF undergoing catheter ablation to either uninterrupted dabigatran versus uninterrupted warfarin.23 The patients in the dabigatran group took their morning dose as scheduled on the day of procedure. The primary endpoint of the incidence of major bleeding events up to 8 weeks post-ablation was significantly lower in the dabigatran arm than the warfarin (1.6 vs. 6.9% respectively, p < 0.001). One patient in the warfarin group experienced a thromboembolic event compared with none in the dabigatran group. The guidelines were also based on another smaller scale, head-to-head study comparing uninterrupted rivaroxaban versus uninterrupted warfarin in 248 patients undergoing catheter ablation.24 The incidence of major bleeding was low, with only one event in the warfarin group. Thromboembolic events were also few, with one ischemic stroke and one vascular death in the warfarin arm.

With the advent of DOACs and simplified anticoagulation therapy comes a complexity of pre-procedural management in balancing both bleeding and thromboembolic risks. Specifically, limited evidence exists on the safety and efficacy of DOAC use in patients with NVAF undergoing EP/catheterization procedures. Newly released guidelines recommend performing AF ablation in the setting of uninterrupted DOAC therapy, but management in other EP/catheterization procedures has been unclear. Both the AHA and ACC have recently published separate documents providing guidance for clinicians who manage patients on DOACs in the peri-procedural setting. However, there are inconsistencies between the two groups in recommended hold times of DOACs and classification of procedural bleed risk. This demonstrates a clear need for standard definitions of procedural risk, hold times of DOACs, and "uninterrupted" versus "interrupted" therapy. New evidence, such as that from the BRUISE-CONTROL 2 trial, may help steer future guidelines. In the interim, institution-specific recommendations and protocols should be developed for consistent DOAC management among local providers.


  1. January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol 2014;64:e1-76.
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Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Pericardial Disease, Valvular Heart Disease, Anticoagulation Management and Atrial Fibrillation, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism, Novel Agents, Statins, Interventions and Imaging, Interventions and Structural Heart Disease, Angiography, Nuclear Imaging

Keywords: Amiodarone, Anticoagulants, Antidotes, Antithrombins, Aspirin, Atrial Appendage, Atrial Fibrillation, Azithromycin, Blood Platelets, Body Weight, Carbamazepine, Cardiac Catheterization, Cardiac Tamponade, Catheter Ablation, Clarithromycin, Coronary Angiography, Creatinine, Cytochrome P-450 CYP1A2, Cytochrome P-450 CYP3A, Cytochrome P-450 Enzyme System, Defibrillators, Implantable, Diltiazem, Drug Combinations, Drug Interactions, Electrophysiology, Embolism, Esterases, Factor V, Factor Xa, Factor Xa Inhibitors, Femoral Artery, Glomerular Filtration Rate, Half-Life, Heart Valve Diseases, Hematoma, Hemostatics, Heparin, Hospitalization, Hydrolysis, Immunoglobulin Fragments, Intracranial Hemorrhages, Itraconazole, Ketoconazole, Medical Futility, Mitral Valve, Percutaneous Coronary Intervention, Prazosin, Pulmonary Veins, Pyrazoles, Pyridines, Pyridones, Quinidine, Radial Artery, Rifampin, Ritonavir, Stroke, Tachycardia, Supraventricular, Thiazoles, Thrombin, Thromboembolism, Verapamil, Vitamin K, Warfarin, Arrhythmias, Cardiac

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