2021 EHRA practical guide on NOACs in AF: What’s new, what’s hot

Non-vitamin K antagonist oral anticoagulants (NOACs) are the preferred choice of anticoagulants for stroke prevention in patients with atrial fibrillation (AF) in international guidelines. A leading expert in the field, Senior Consultant Cardiologist Dr Teo Wee Siong from Mount Elizabeth Medical Centre, Singapore, shared his insights on the 2021 EHRA* practical guide on NOACS in AF, how to personalize NOACs therapy, including apixaban (Eliquis, Pfizer), and manage difficult treatment scenarios. Dr Teo was past President of APHRS** and is currently President of HRAS***.

AF is the most common heart rhythm disorder and people with the condition are at five times increased risk of stroke. NOACs are approved for stroke prevention in non-valvular AF. The direct factor Xa inhibitors apixaban, rivaroxaban, and edoxaban, and the direct thrombin inhibitor dabigatran, all fall under the NOACs class.

NOACs are preferred over vitamin K antagonists (VKAs) such as warfarin for stroke prevention in the 2020 ESC^# guidelines for AF. In addition to having an improved efficacy/safety ratio over warfarin, NOACs have a predictable anticoagulant effect without the need for routine coagulation monitoring, unlike VKAs which have a narrow therapeutic window that requires frequent INR^## monitoring and dose adjustments. [Eur Heart J 2021;42:373-498]

However, there are certain scenarios whereby NOACs are contraindicated and may require alternative therapies.

“NOACs are contraindicated in patients with mechanical prosthetic valve and severe mitral stenosis, who should continue instead with warfarin therapy,” advised Teo. “Those with nonvalvular AF and antiphospholipid syndrome should also be treated with VKAs rather than NOACs as these patients have higher rates of thromboembolism events and major bleeding. Patients with severe liver dysfunction (Child-Pugh C) should probably not receive a NOAC.”

“NOACs are also contraindicated in patients with extremely high bleeding risk, such as those with intracranial haemorrhage or recurrent life-threatening bleeds,” he added. “Usually, patients with severe recurrent lower GI bleeds which cannot be treated may need to be considered for alternative therapies such as left atrial appendage occlusion.”

The current EHRA practical guide complements the ESC guidelines for AF as it offers specific advice on the use of NOACs in different clinical scenarios, including situations where there are limited data on anticoagulant use. [Europace 2021;doi:10.1093/europace/euab065]

What’s new?

“An enhanced list of drug-drug interactions, effects on NOAC plasma levels, and anticoagulant effects were added, so were common cardiovascular drugs, antibiotics, oncology drugs, and anti-epileptic drugs,” said  Teo. “There is also a table on drugs for COVID-19 treatment, where rivaroxaban should be avoided in patients taking ritonavir/lopinavir.”

While plasma level assessment of NOACs was generally not required, rare situations where this may be desirable was discussed in the practical guide.

“Enhanced guidance was given on special populations, including patients with extreme body weight, liver disease, or thrombocytopenia,” Teo pointed out. “There were also updates on periprocedural management with NOACs and post-bleeding management.”

Personalizing treatment

“To strike a good balance between safety and efficacy, it is important to personalize the use of NOACs to individual patients,” Teo stressed.

“It is critical to assess the risk of stroke vs bleeding in each patient and determine the risk-benefit ratio. Once there is a definite benefit of anticoagulation, other patient factors to consider include age, body weight, renal function, concomitant drug therapy, and pre-existing conditions such as frailty, coronary artery disease, liver disease, and malignancies,” he explained.

Frailty

Frailty is a multifactorial syndrome caused by a reduced physiological reserve and the capability to resist stressful events. “It is usually age-related and associated with increased risk for adverse events such as falling,” said Teo.

In general, frailty and risk of falling should not be a reason to avoid anticoagulant use in patients. In a post hoc analysis of the ARISTOTLE trial, the benefit of apixaban over warfarin in preventing stroke was consistent regardless of history of falling. [Am J Med 2018;131:269-75e2] Similarly, edoxaban was associated with a greater reduction in absolute risk of severe bleeding events and mortality vs warfarin among patients at increased risk of falling in the ENGAGE AF-TIMI 48 subanalysis. [J Am Coll Cardiol 2016;68:1169-1178]

Nonetheless, care should be taken to minimize the risk of falling and ensure optimal compliance. “In the ESC practical guide, anticoagulants including NOACs may be considered with caution in the severely frail and is generally not recommended in the very severely frail and terminally ill patients, in whom the risks may outweigh the benefits,” Teo noted. The severely frail are those completely dependent for personal care due to whatever causes; while the very severely frail are those approaching the end of life.

Extreme body weight

The EHRA practical guide recommends that NOACs be used at approved doses in patients whose BMI falls within 17.5–40 kg/m². “For those with BMI ≥40 kg/m², the data are less robust,” observed Teo.

“For morbidly obese patients with BMI ≥50 kg/m², NOAC plasma level measurements may be needed to guide anticoagulant therapy, or switching to VKA therapy may be reasonable,” he added.

Chronic kidney disease (CKD)

In general, NOACs should be avoided in all patients with kidney failure (CKD stage 5) — whose GFR^### is <15 mL/min/1.73 m², according to Teo. “For patients with end-stage renal disease (stage 5) based on creatinine clearance of <15 mL/min, NOACs are not recommended by the 2021 EHRA practical guide, although the ACC/AHA/HRS⁺ 2019 guidelines recommend apixaban when needed.” [Europace 2021;doi:10.1093/europace/euab065; Circulation 2019;140:e125-151]

“Apixaban is the least renally excreted of NOACS and thus, least affected by renal dysfunction. As it is least dependent on renal excretion, it is perhaps the safest drug to use when there is a possibility of worsening renal function,” he explained. “In contrast, dabigatran is mainly renally excreted and should be avoided when GFR is <30 mL/min/1.73 m².”

Bleeding with NOAC

“In terms of minor/major bleeding with NOACs and use of specific NOAC reversal agents, which is rarely indicated, it is important to understand the cause of bleeding so management can be targeted towards stopping the aetiologic cause,” said Teo. Typically, cases are assessed and stratified according to whether the bleeding is mild, non-life-threatening, or life-threatening, and then managed accordingly.

For life-threatening bleeds, andexanet alpha can be used to directly reverse the effects of rivaroxaban and apixaban whereas idarucizumab is advised for dabigatran-treated patients.  

“What is new in the EHRA guide is the management post-bleeding. The salient points include assessment for risk of recurrent bleeding, a review of the choice and dose of NOAC, and re-evaluation of modifiable risk factors for bleeding — for instance, stopping the use of unnecessary concomitant antiplatelet drugs,” said Teo. “Anticoagulation should be restarted if there is no absolute contraindication for its use.”

ACS/Elective stenting

Patients on NOACs who need to undergo elective cardiac surgery such as PCI⁺⁺ are at high risk for bleeding. “Hence, guidelines recommend that NOAC therapy be interrupted before undergoing the procedure — the timing and duration of which is determined by surgical factors and patient characteristics. Generally, factor Xa inhibitors should be stopped 24 hours, or at most 48 hours, before an elective procedure. NOACs should be resumed 48–72 hours after a high-risk intervention such as cardiac surgery, major orthopaedic surgery or complex PCI involving chronic total occlusions,” advised Teo.

After an elective PCI or an ACS⁺⁺⁺ managed with PCI, a short course of triple therapy comprising a NOAC + P2Y₁₂ inhibitor + aspirin (at least 1 week – 1 month, depending on the bleeding vs thrombotic risk ) is recommended for all patients with AF, before de-escalation to dual therapy, according to the 2020 ESC guidelines. The choice and duration of anticoagulant therapy should be personalized based on the patient’s cardioembolic, atherothrombotic, and bleeding risks.