The incorporation of direct-acting oral anticoagulants (DOACs) into the cardiological therapeutic arsenal is an increasingly evident reality. Gradually, they have displaced vitamin K antagonists (VKAs) in most indications, given their equivalent or even superior profile in terms of ischemic event prevention, hemorrhagic safety, and patient convenience. DOACs offer predictable therapeutic effects and do not require dosing adjustments, which enhances patient comfort. Currently, the indication for VKA anticoagulation persists only in cases involving mechanical prostheses and rheumatic heart disease. In these contexts, DOACs were shown to be deleterious in the initial RE-ALIGN clinical trial conducted with dabigatran. Following this, subsequent DOAC trials included these as exclusion criteria and have not readdressed them, leaving these as the final frontier in the wide array of DOAC indications.

This evolution makes it essential for us to become familiar with these drugs; rather than “syncing” with traditional treatments, we must “tune in” to this new reality, where expertise in managing these agents becomes almost obligatory for any cardiac surgeon. Accordingly, this work offers a comprehensive update on everything required for daily clinical practice, concluding with a list of best practices for perioperative DOAC management in patients undergoing cardiac surgery.

To begin, it is well-known that four DOACs are currently available: dabigatran (Pradaxa®), which acts at the end of the coagulation cascade on thrombin (activated factor II); rivaroxaban (Xarelto®), apixaban (Eliquis®), and edoxaban (Lixiana®), which exert their effect through the inhibition of activated factor X. This mechanism is also shared by heparins, particularly low-molecular-weight heparins, and heparinoids (fondaparinux). Although all DOACs are indicated for the prevention of thromboembolic events associated or not with non-valvular atrial fibrillation (meaning without concurrent rheumatic disease), it is worth noting that rivaroxaban also has an additional indication for anticoagulation in chronic ischemia, both coronary and peripheral. Concerning contraindications, key ones include reduced renal clearance (<15 cc/min for factor Xa inhibitors and <30 cc/min for dabigatran), mechanical valve prostheses, hemorrhagic diathesis, severe hepatic insufficiency, pregnancy, and antiphospholipid syndrome. Standard dosing information is included in this review. However, there are multiple dosing regimens, with apixaban being the most versatile (2.5 or 5 mg, once or twice daily), making this a notable advantage of this agent. Rivaroxaban’s unique indication (20 mg once daily) and dabigatran’s potent effect (150 mg twice daily) are suitable for high ischemic risk and low bleeding risk profiles, as seen in young patients with atrial fibrillation, while edoxaban (60 mg twice daily) is seen as the “black sheep” among the options.

In the perioperative setting, cardiac surgeons mainly “withdraw” or “resume” these agents. Typically, most guidelines focus on resumption, but we prefer an approach oriented to surgery.

“WITHDRAW” refers to suspending anticoagulant effect to facilitate surgical intervention. Generally, 48 hours are widely accepted for DOAC effect dissipation post-administration. However, adjustments may be necessary based on patient-specific factors. For elective or urgent situations in stable patients, the 48-hour rule may be extended based on renal clearance; dabigatran should be withdrawn for 72 hours with clearances of 50–80 cc/min and 96 hours for 30–50 cc/min. For the other three agents, we should extend the withdrawal period to 72 hours for clearances below 30–50 cc/min and to 96 hours for those with clearances <30 cc/min. Given the predictable pharmacology of DOACs, bridging with heparin is generally unnecessary and discouraged unless intervention is delayed, resulting in thromboembolic risk.

For urgent unstable cases, residual anticoagulant effect levels may be measured. Dabigatran’s effect is assessed by thrombin time (threshold <21 seconds for cessation), while the other three agents can be measured via anti-Xa factor activity (<30 ng/mL). Heparin or low-molecular-weight heparins can also be monitored, with adjustments necessary for clearance below 30 cc/min. Standard coagulation tests, while less specific, remain options where anti-Xa testing is unavailable, although reliability decreases with clearance <30 cc/min.

“IMMEDIATE NEED” involves emergent or urgent interventions. Residual effects may be evaluated with the tests mentioned. In cases of active pharmacological effect, specific and non-specific antagonistic measures may be implemented:

1. Specific measures include direct antagonists for dabigatran (idarucizumab) or anti-Xa agents (andexanet alfa). Studies cited in this work highlight the success and safety of these agents in cardiac surgery, albeit with some cautionary notes:
   • Dabigatran can be safely reversed with idarucizumab (Praxbind®) at any perioperative phase without significant side effects or interference with extracorporeal circulation.
   • Andexanet alfa (Ondexxa® or Andexxa®) poses greater risk, as its trial (ANNEXA-4) excluded emergent surgeries due to heparin resistance risk. It should be used compassionately, post-cardiopulmonary bypass if feasible, with antithrombin III supplementation as an alternative.
2. Non-specific measures may include transfusion of blood products or coagulation factors, such as activated factor VII, for intra- or post-operative periods to support hemostasis. Hemodialysis has proven effective for dabigatran elimination, given its low plasma protein binding. For Xa inhibitors, hemadsorption using devices like Cytosorb® may be employed, particularly for agents like ticagrelor or clopidogrel, and is effective when combined with extracorporeal circulation.

“RESUME” introduces unique challenges in the postoperative period, with clinical guidelines generally recommending resumption of DOACs one month after surgery if contraindications are absent. Observational studies indicate increasing early adoption of DOACs, with documented thromboembolic protection and hemorrhagic safety.

Special Considerations:

• Valvular AF: Rheumatic heart disease requires VKAs, as surgical correction does not eliminate thrombotic risk.
• Renal Clearance: Dabigatran demands dose adjustments at <50 cc/min, with different doses specified for rivaroxaban, apixaban, and edoxaban based on renal and clinical profiles. Apixaban is often favorable for elderly patients with multiple comorbidities.

COMMENTARY:

The adoption of new oral anticoagulants before and after cardiac surgery has become a reality. We must adapt to this new paradigm of specific anticoagulation agents, moving beyond traditional therapies. Cardiac surgery outcomes in patients with atrial fibrillation are heavily influenced by their anticoagulation management, which must be carefully established from the initial postoperative phase, discharge, and follow-up.

REFERENCE:

Heuts S, Ceulemans A, Kuiper GJAJM, Schreiber JU, van Varik BJ, Olie RH, et al. Optimal management of cardiac surgery patients using direct oral anticoagulants: recommendations for clinical practice. Eur J Cardiothorac Surg. 2023 Oct 4;64(4). doi: 10.1093/ejcts/ezad340.