With the advent of non-vitamin K oral anticoagulants (NOACs), there has been a paradigm shift in anticoagulation for stroke prevention in non-valvular atrial fibrillation (NVAF). Distinct advantages of NOACs include fixed dosing, non-fluctuant therapeutic levels, elimination of the need for therapeutic level monitoring, lack of dietary restrictions and minimal drug interactions in comparison to warfarin.¹ However, there is minimal objective data to support the optimal time at which NOACs need to be withheld and restarted for elective procedures in patients with chronic kidney disease. The timing is dependent on the creatinine clearance (CrCl) and bleeding risk associated with the surgical procedure.² The clinical relevance of this timing is underscored by the fact that approximately 10% of patients receiving anticoagulation undergo surgical or invasive procedures mandating temporary interruption (TI) of these medications.³ There is a discrepancy between the recommendations from the manufacturers and the cut-offs suggested by multiple authors, thereby indicating a lack of consensus for the management of this often encountered clinical scenario.^2,4-⁸ Earlier withholding of NOACs for elective procedures might predispose to suboptimal anticoagulation while withholding it later might predispose to higher intraprocedural bleeding risk. A similar dilemma is noted during resumption of NOACs after procedures. This article focusses on the pharmacokinetic profiles of the four commercially available NOACs and an approach to their management in the periprocedural setting.

Dabigatran is a potent oral direct thrombin inhibitor with a half-life of 12-17 hours which has shown to have lower rates of stroke and thromboembolism as compared to warfarin when used at a dose of 150 mg twice daily with similar rates of major hemorrhage in the Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial which evaluated 18,113 patients with NVAF.^4,9 In contrast, a dosage of 110 mg twice daily resulted in similar rates of stroke and thromboembolism as warfarin but lesser rates of major hemorrhage. Evidence from this trial is limited to patients with a CrCl of >30ml/min, thereby restricting the use of this agent to those above this CrCl cut off. The paucity of pharamacokinetic, safety and efficacy data in patients with CKD translates into considerable heterogeneity in the time cut-offs at which dabigatran needs to be withheld in patients with CrCls in the 50-80 ml/min and <30ml/min range (Table 1).^2,8,10-¹³

The non-linear variations in NOAC concentrations with different grades of CrCls complicates the process of arriving at precise cut-offs. Most of the studies with respect to dabigatran listed in Table 1 present data which is fairly consistent across most grades of CrCls except in the 50-80 ml/min and <30ml/min range, where discrepancies of approximately 12-48 hours are evident. Wysokinski et al. have recommended a conservative approach to withholding dabigatran (7 days) prior to elective surgery carrying high risk of bleeding in patients with CrCls <50 ml/min and ≥50 ml/min, respectively.² In contrast, this is significantly different from multiple studies which recommend holding of NOACs 2-4 days prior to surgery at CrCls ≥50 ml/min and <50 ml/min respectively (Table 1).^8,10-¹⁴ The European Heart Rhythm Association (EHRA) has also recommended stoppage of dabigatran at ≥96 hours prior to elective surgery carrying high risk for bleeding for the same CrCl cohort.¹²

A comprehensive analysis of the pharmacokinetic profiles of dabigatran at various levels of CrCl has shown that the area under the curve, maximum plasma concentration and the half-life of dabigatran increased by 3.2-, 1.7- and 1.4-fold, respectively in patients with a CrCl of 30-50 ml/min as compared with those having normal renal function.¹⁵ A 1.4-fold increase would extend its half-life to 21 hours (15 hours for normal CrCl x 1.4). Assuming the clearance of dabigatran from the system takes approximately 4.5 half-lives, one would expect complete clearance only at the end of approximately 4 days (21 hours x 4.5) which is closely congruent with the cut-offs from Table 1. However, the small sample size of this study with 6 patients from each CrCl subgroup poses significant limitations to the extrapolation of this data to the general population. Moreover, recommendations for stopping NOACs in the lower surgical bleeding risk cohort at approximately 2-3 half-lives prior to surgery as opposed to 4.5 half-lives are less evidence based (Table 1).

Rivaroxaban is a direct oral factor Xa inhibitor with a half-life of 5-9 hours in healthy individuals of age 20-45 years and 11-13 hours in the elderly subgroup.⁵ Evidence substantiating the use of rivaroxaban emerges 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) involving 14,264 patients with NVAF.¹⁷ These results demonstrate non-inferiority to warfarin for stroke, thromboembolism and major bleeding along with lower incidence of intracranial and fatal bleeding in the rivaroxaban group.¹⁷ The rivaroxaban arm in this study comprised of patients with CrCl ≥50 ml/min or 30-49 ml/min who received 20 mg once daily or 15 mg once daily doses, respectively. Though a bulk of the safety and efficacy data has been derived from patients with compromised renal function in this study, patients with a lower CrCl of 15-30 ml/min have been approved to receive rivaroxaban 15 mg once daily despite paucity of randomized evidence to support it.

Apixaban is an oral direct factor Xa inhibitor with a half-life of 12 hours and 25% renal clearance.⁶ It has been evaluated for anticoagulation in NVAF in the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) randomized controlled trial with 18,201 patients.¹⁹ Patients with CrCl<25 ml/min were excluded from the study and those with a serum creatinine of >1.5mg/dL received a reduced dose of 2.5 mg twice daily as opposed to those with better CrCls who received a 5mg two times daily dosing. Results from this trial showed superiority to warfarin in terms of stroke and thromboembolism prevention, incidence of major bleeding and more importantly, mortality benefit. Present recommendations from the package insert recommend dose reduction to 2.5 mg twice daily if two of either criterion is met: body weight ≤60 kg, serum creatinine ≥1.5 mg/dL or age≥80 years. However, no dose reduction in individuals with isolated renal impairment, including those with end-stage renal disease on hemodialysis. However, there is lack of evidence to support lack of dose reduction in those with CrCl<25 ml/min.

Edoxaban is an oral direct factor Xa inhibitor with a half-life of 10-14 hours with a 50% renal clearance which has a targeted patient population of those with pre-existent renal dysfunction.⁷ Notably, edoxaban use is contraindicated in those with CrCl> 95 ml/min due to a higher incidence of ischemic strokes in patients taking the 60 mg once daily dose. Results from the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation –Thrombolysis in Myocardial Infarction 48 (ENGAGE AF TIMI-48) trial demonstrated non-inferiority of edoxaban to warfarin in terms of stroke prevention and thromboembolism (systemic embolism: edoxaban 5mg twice daily 1.18% vs. warfarin 1.5%, HR 0.79, 95% CI, 0.63-0.99, P<0.001; edoxaban 2.5 mg twice daily 1.61% vs warfarin 1.5%, HR 1.07, 95% CI, 0.87-1.31, P=0.05) and in addition, lower incidence of major bleeding (Edoxaban 5mg twice daily 2.75% vs. warfarin 3.43%, HR 0.80, 95% CI, 0.71-0.91, P<0.001; edoxaban 2.5 mg twice daily 1.61% vs warfarin 3.43%, HR 0.47, 95% CI, 0.41-0.55, P<0.001) and cardiac mortality.²¹ In this prospective trial, a significant portion of patients with CrCl 30-50 ml/min received a reduced dose of 30mg twice daily as opposed to the 60mg twice daily dosing for those with a higher CrCl value. Primary endpoints and bleeding risks as mentioned above were unaffected by dose reduction. Though the manufacturer recommends use of edoxaban at a reduced dose in patients with CrCl 15-50 ml/min, there is less evidence in terms of safety and efficacy in this range.

Discrepancies have been noted in the optimal time at which NOACs should be restarted following elective surgery. In contrast to Wysokinski at al. who recommend re-initiation of NOACs ≥48 hours post-surgery, the EHRA recommends earlier reinstitution of NOACs 6-8 hours post-hemostasis or even bridging with heparin products until 48 hours after surgery when NOACs would be safe to use.^2,12 Early post-operative reinstitution of NOACs might increase the risk of bleeding which could prove deleterious, particularly in the absence of well-validated reversal agents.

Ideally, NOACs should be initiated a time point after the procedure when hemostasis is complete. The decision to use periprocedural bridging therapy with short acting heparin products is a clinical decision which needs to account for 3 different factors:

the risk of thrombosis objectively derived from the CHADS2 Vasc scores

the risk of bleeding associated with the procedure by itself

and the adequacy of hemostasis.

It is highly recommended that clinicians assess adequacy of hemostasis in conjunction with the primary procedure operator before resumption of NOACs. Due to the fast onset of action of NOACs, bridging is not recommended except in cases of high CHADS2 vasc scores or in instances where the risk of re-bleeding is high (to facilitate reversal if indicated), wherein bridging with short acting heparin products may be considered until one reaches a point where NOAC resumption is considered safe. A rule of thumb is to initiate bridging therapy in those with high risk of thrombosis at 24-48 hours after the procedure until NOACs can be safely resumed.

Enhancements in the understanding of NOAC pharmacology has paved way for the development of specific fast-acting antidotes which are presently being evaluated. Idarucizumab is a monoclonal antibody fragment targeted to bind dabigatran which has demonstrated complete reversal of anticoagulant activity within minutes of administration in a prospective cohort of 90 patients in the Reversal Effects of Idarucizumab on Active Dabigatran (RE-VERSE AD) trial.²² Andexanet Alfa, a recombinant engineered variant of human factor Xa has been recently evaluated in a phase III trial with 33 patients for up to 90% reduction of apixaban anticoagulant activity within 2-5 minutes of administration. Preliminary results from the Andexanet Alfa a Novel Antidote to the Anticoagulant Effects of fXA Inhibitors – Apixaban (ANNEXA-A) trial have shown no serious adverse prothrombotic effects.²³ Similar results for rivaroxaban (ANNEXA-R) reversal are currently being evaluated. PER977 (Perosphere), has demonstrated near-complete reversal of edoxaban activity within 10-30 minutes of administration without prothrombotic effects.²⁴ Notably, this agent is a non-specific antidote which has been shown to provide effective and rapid reversal of anticoagulant effects of both direct thrombin inhibitors and all commercially available oral factor Xa inhibitors.²⁴ With the advent of multiple antidotes which provide rapid reversal of NOAC effects, one could expect further minimization of TIs of NOACs in the periprocedural setting.

Often, reversal agents such as fresh frozen plasma or prothrombin complex concentrates (PCC) have counterproductive prothrombotic effects such as systemic thromboembolism, myocardial infarction and stroke. A meta-analysis comprising of 27 studies evaluating use of PCC in vitamin K antagonist reversal for emergent surgeries or for severe bleeding showed a significant incidence of systemic thromboembolism (0.7-1.8%) and a mortality rate of 10.6%.²⁵ These results further reinforce the need for specific NOAC reversal agents.

In conclusion, patients with CKD present a diverse population in whom considerable heterogeneity exists in the timing of stoppage of NOACs prior to the procedure. Data emerging from landmark prospective trials such as RE-LY, ROCKET-AF and ARISTOTLE have simplified the approach to this specific clinical scenario and considerably reduced the heterogeneity noted in in this timing.^9,17,19,21 Lesser emphasis is being placed on the level of renal compromise (except for Dabigatran) and more on the bleeding risk associated with the procedure. With the emergence and ongoing development of rapid-acting and effective antidotes for NOACs, there is immense potential to reduce duration of TIs, costs of bridging therapy and minimize risk of bleeding and thromboembolic complications in the perioperative setting. Important clinical decisions such as when to withhold and resume NOACs in relation to procedures, as well as the need for bridging therapy should be individualized based upon the patient profiles which account for risk of thromboembolism and the risk of bleeding associated with the patient profile and the procedure per se. Multicentric registry data could further enhance our understanding of this peculiar clinical scenario.

None.