Use of the Non-Vitamin K Antagonist Oral Anticoagulants (NOACs) Acutely and Peri-Procedurally: Where Are We Now?

There is no doubt that the non-vitamin K oral anticoagulants (NOACs) have changed the landscape of thromboprophylaxis. These drugs are increasingly used for the management of venous thromboembolism and for stroke prevention in patients with atrial fibrillation (AF). Hence, there is little surprise that many such patients present acutely, with various complications related to the treated disease or the complications related to the NOAC per se. Apart from the emergency room (ER) attendances, such patients may also undergo operative procedures, and the management of NOACs peri-procedurally also causes some anxiety, especially where clinicians are unfamiliar over how best to manage patients taking such drugs. While the NOACs are no longer new or novel drugs, being in widespread use for >5 years, the approach to management of acute bleeding or in the peri-procedural setting has been based on largely expert consensus^1-3.

For example, the updated European Heart Rhythm Association practical guide on NOACs has provided expert consensus advice on how best to manage patients taking NOACs in a wide variety of clinical settings⁴.

The more recent American Heart Association Scientific Statement on “Management of Patients on NOACs in the Acute Care and Peri-Procedural Setting” is also a timely document to aid the medical community, with practical advice on the best management options.⁵ This Scientific Statement reviews the literature and offers practical suggestions for providers who manage patients who are “actively bleeding”, and who are “at risk for bleeding” in the acute care and peri-procedural setting.

What are the take home messages from this AHA statement?

First, all NOACs have a modest half-life, with a quick onset and offset of anticoagulation effect, with more predictable pharmacokinetics. Thus, in mild bleeding, simply stopping the drug would suffice, as the anticoagulation wears off over time. Also, for peri-procedural management, stopping the NOAC for approximately 1-2 days would ensure the anticoagulant effect has worn off to allow the surgical procedure.

Second, given that all NOACs have a degree of renal excretion, with dabigatran having the highest renal excretion (80%), a longer period of drug cessation is needed where there is renal impairment, to ensure the anticoagulant effect has adequately diminished6. With moderate renal impairment, dabigatran cessation may need to be 3-5 days to ensure there is no anticoagulant effect especially in surgical procedures at high risk of bleeding.

Third, simple quick blood tests would help determine whether there was an anticoagulant effect from the NOAC4. For a patient taking dabigatran, for example, measurement of the activated Partial Thromboplastin Time (aPTT), which, if prolonged, can give an indication of the presence of anticoagulant effect but not as an indicator of anticoagulation intensity. Alternative tests include the diluted thrombin time or ecarin clotting time, which are more semi-quantitative of anticoagulation intensity, but these tests are less widely available. For Factor Xa inhibitors, an anti-factor Xa assay is needed.

Fourth, in moderate bleeding, drug cessation and supportive measures with fluids, plasma and blood transfusion would usually suffice⁴. However, in severe bleeding, non-specific reversal agents, such as protein complex concentrates (PCCs), recombinant factor VII or fresh frozen plasma can be considered. With dabigatran, haemodialysis can be used, and if soon after excess ingestion, activated charcoal may reduce absorption.

The game changer is for one of the NOACs, dabigatran, a specific reversal agent (idarucizumab) is now available. This agent can be used for near-complete reversal of the anticoagulant effect of dabigatran ^7,8, especially if actively bleeding or where a dabigatran-treated patient presents requiring urgent surgical procedure, and requires reversal of the anticoagulant effect^9,10.

Preliminary data with a factor Xa inhibitor antidote (ie. Andexanet Alfa) look promising for the reversal of the Factor Xa inhibitors, apixaban and rivaroxaban; however, additional data are awaited for edoxaban and heparin¹¹. Andexanet Alfa has not been approved for clinical use. At an earlier stage of development is Ciraparantag (PER977), which is a small molecule that reverses heparin, direct thrombin inhibitors and factor Xa inhibitors.

The AHA statement clearly advocates the establishment of a NOAC reversal and peri-operative management protocol, with a multidisciplinary team approach.⁵

The AHA statement also covers specific severe ‘active’ or ‘at risk’ bleeding scenarios. For example, intracranial hemorrhage (ICH) is a severe ‘active bleeding’ urgency where the AHA Working Group recommends that traumatic and non-traumatic ICH patients on dabigatran who require NOAC reversal receive idarucizumab. ICH patients on rivaroxaban, apixaban, or edoxaban should receive PCC until more specific antidotes become available. Bleeding in relation to severe trauma or gastrointestinal (GI) bleeding is also covered. Of note, recent observational studies of AF patients with ICH or GI bleeding show that such patients are at high risk of subsequent stroke and death if OAC is not restarted, with no excess risk of rebleeding⁵.

Patients ‘at risk’ of bleeding on a NOAC include those who overdose or acute kidney injury. Also, patients presenting with an ischemic stroke while on a NOAC would be at substantial risk of bleeding if systemic thrombolysis is given. Case series have reported how dabigatran is reversed with idarucizumab, then thrombolysis can be administered with successful outcome. Otherwise, thrombectomy would need to be considered, especially if the ischemic stroke occurs in a Factor Xa inhibitor patient, given the absence of a licensed antidote. There is also a large section on the peri-procedural management of patients on NOACs, including the management of patients undergoing cardiac catheterization and percutaneous coronary intervention, those undergoing cardioversion or ablation therapy, device implantation or surgery.

In all cases, stroke and bleeding risks should be assessed using the CHA2DS2-VASc and HAS-BLED scores, when evaluating the net clinical benefit of treating with OAC. Even one stroke risk factor confers an excess of stroke and death, and the net clinical benefit of OAC is positive compared to aspirin or no treatment ^{12, 13}. It is important to recognize that bleeding risk assessment aims to ‘flag up’ the patients at high risk of bleeding for more regular reviews and careful followup, and to draw attention to the reversible bleeding risk factors, such as uncontrolled blood pressure, excess alcohol, concomitant aspirin or NSAIDs in an anticoagulated patient, etc ¹⁴. Given that many bleeding risk factors are reversible, the HASBLED score (recommended in the AHA statement) has been well validated for this purpose in AF (and non-AF) patients on no antithrombotic therapy, aspirin and OAC (both warfarin and non-warfarin anticoagulants), thus applicable to all parts of the AF patient pathway^{14, 15}. There is no doubt NOACs have changed our management approaches and have streamlined the AF management pathway^{15, 16}.