By: Nevin Baker, MD and Henry S. Jennings, MD, FSCAI

The cardiology community has recently witnessed a rapid expansion in the available therapies for non-valvular atrial fibrillation (AF) with approval of the “novel oral anticoagulants” (NOACs), which include dabigatran (Pradaxa™), rivaroxaban (Xarelto™), apixaban (Eliquis™) and edoxaban (Savaysa, Lixiana™). As the medical community began to incorporate these agents into routine clinical practice, questions regarding periprocedural management and reversal during bleeding arose, largely because specific reversal agents were not available and protocols for periprocedural management have not been established. As such, clinicians have been guided by expert opinions and consensus statements on the topic.^{1, 2} This Tip of the Month from the SCAI Quality Improvement Committee provides a concise summary of these recommendations as they pertain to the management of patients presenting for invasive procedures, including but not limited to cardiac catheterization and percutaneous coronary intervention, as well as the available reversal options. We recommend a multi-subspecialty approach for the development of an institution-specific strategy for NOAC management in the periprocedural setting and during bleeding complications.

*Note: This Tip of the Month does not apply to warfarin used for high-risk clinical indications (e.g., non-valvular AF, mechanical valves, pulmonary embolus/DVT/VTE, hypercoagulable states, AF with prior thromboembolic events), or off-label uses of NOACs.

Periprocedural Management

Without a laboratory monitoring mechanism to determine the extent of anticoagulation, the timing for safely performing an invasive procedure during NOAC use is based on the individual drug's pharmacokinetics and a few patient-specific factors. We recommend the following:

1. Evaluate if the procedure is considered low or high risk for bleeding (Table 1). This will guide optimal length of time necessary for discontinuation prior to the procedure.

2. The NOACs have a rapid onset and offset of action. This holds true for patients with normal creatinine clearance (CrCl). However, you have to pay closer attention to patients with diminished CrCl to ensure that adequate time has elapsed for the drug to wear off prior to an invasive procedure.

3. With normal CrCl, it is reasonable to resume NOACs within 12-24 hours after a procedure with a low risk of bleeding, and within 48 to 72 hours for a procedure with a high risk of bleeding. The clinician needs to anticipate the risk of post-procedure bleeding given a patient's risk factors³ or medications the patient may have received and timing of administration (P2Y12 inhibitor loads, glycoprotein IIb/IIIa inhibitor infusions, etc.).

4. For patients able to take oral medications, bridging is generally not necessary for NOACs given their rapid onset of action and predictable pharmacology. They can be restarted post-procedurally as soon as the risk of bleeding is felt to be minimal.

5. For patients presenting with a non-emergent indication for coronary angiography, temporary discontinuation of NOACs is reasonable. When unable to discontinue NOACs, a radial artery approach is strongly recommended.

Table 1. Preprocedural Management

DTI, direct thrombin inhibitor; CrCl, creatinine clearance (mL/min).

*Low bleeding risk procedures: endoscopy with biopsy, prostate or bladder biopsy, EP study or radiofrequency catheter ablation for supraventricular tachycardia (including left-sided ablation via single transseptal puncture), pacemaker or ICD implantation, coronary angiography without intervention.

*High bleeding risk procedures: percutaneous coronary intervention, complex left-sided ablation (pulmonary vein isolation; VT ablation), large bore arterial access (implantation of left ventricular assist devices, TAVR), endomyocardial biopsy, pericardiocentesis, spinal or epidural anesthesia; lumbar puncture, thoracic surgery, abdominal surgery, major orthopedic surgery, liver biopsy, transurethral prostate resection, kidney biopsy.

Managing Bleeding Complications

There is an unmet need for specific NOAC reversal agents. The FDA recently gave andexanet alfa (a Factor Xa inhibitor antidote) an orphan drug designation for treatment of major, life-threatening bleeding related to factor Xa inhibitors.⁴ The recommendations in Table 2 have been summarized from expert consensus opinions on the topic, and the use of specific agents discussed, aside from andexanet alfa, are currently considered to be off-label. 

Table 2. Management Strategies During Bleeding Complications

Specific Notes:

For all agents, consultation with a hematologist and/or a blood bank physician specializing in coagulation is strongly advised.

Dabigatran

• The activated PCC (Feiba NF) is an anti-inhibitor coagulation complex (prothrombin complex with factor VIII inhibitor bypass activity containing factors II, VII, IX, and X) reported to have been effective in rapidly reversing the anticoagulant effects of dabigatran in one case study.⁵
• The use of unactivated PCC was shown to be ineffective in one study.⁶
• Recombinant factor VIIa, or concentrates of factors II, IX, or X may be considered, although their use has not been evaluated in clinical trials.

Rivaroxaban and Apixiban

• Andexanet alfa is a recombinant protein analog of factor Xa that binds to direct factor Xa inhibitors and is currently the only agent with an FDA approval (via an orphan drug designation) for reversal of these agents.
• The use of both three (II, IX, and X) and four-factor (II, VII, IX, and X) unactivated PCC have been shown effective for reversal of rivaroxaban and apixiban in healthy subjects. ^6-8
• The use of activated PCC (Feiba NF) could also be considered.

Edoxaban

• PCC, aPCC, and recombinant factor VIIa have been shown effective in healthy volunteers and animal models. ^{9, 10}

References

1. Levy JH, Spyropoulos AC, Samama CM, Douketis J. Direct oral anticoagulants: new drugs and new concepts. JACC Cardiovasc Interv. 2014;7:1333-1351.

2. Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, Sinnaeve P, Camm AJ, Kirchhof P. EHRA practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary. Eur Heart J. 2013;34:2094-2106.

3. Rao SV, McCoy LA, Spertus JA, Krone RJ, Singh M, Fitzgerald S, Peterson ED. An updated bleeding model to predict the risk of post-procedure bleeding among patients undergoing percutaneous coronary intervention: a report using an expanded bleeding definition from the National Cardiovascular Data Registry CathPCI Registry. JACC Cardiovasc Interv. 2013;6:897-904.

4. Today H. FDA grants orphan drug status to Factor Xa inhibitor antidote [press release]. Accessed at http://www.healio.com/hematology-oncology/ hematology/news/online/%7B48e71bbe-1d8f-46af-b0f1-7d153893f6d4%7D/fda-grants-orphan-drug-status-to-factor-xa-inhibitor-antidote. February 26, 2015.

5. Dager WE, Gosselin RC, Roberts AJ. Reversing dabigatran in life-threatening bleeding occurring during cardiac ablation with factor eight inhibitor bypassing activity. Crit Care Med. 2013;41:e42-46.

6. Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation. 2011;124:1573-1579.

7. Levi M, Moore KT, Castillejos CF, Kubitza D, Berkowitz SD, Goldhaber SZ, Raghoebar M, Patel MR, Weitz JI, Levy JH. Comparison of three-factor and four-factor prothrombin complex concentrates regarding reversal of the anticoagulant effects of rivaroxaban in healthy volunteers. J Thromb Haemost. 2014;12:1428-1436.

8. Martin AC, Gouin-Thibault I, Siguret V, Mordohay A, Samama CM, Gaussem P, Le Bonniec B, Godier A. Multimodal assessment of non-specific hemostatic agents for apixaban reversal. J Thromb Haemost. 2015;13:426-36.

9. Zahir H, Brown KS, Vandell AG, Desai M, Maa JF, Dishy V, Lomeli B, Feussner A, Feng W, He L, Grosso MA, Lanz HJ, Antman EM. Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate. Circulation. 2014;131:82-90.

10. Fukuda T, Honda Y, Kamisato C, Morishima Y, Shibano T. Reversal of anticoagulant effects of edoxaban, an oral, direct factor Xa inhibitor, with haemostatic agents. Thromb Haemost. 2012;107:253-259.