Distinguishing between NOAK and DOAK

CardioNerds co-founder Dr. Amit Goyal, series co-chair Dr. Colin Blumenthal, and episode lead Dr. Anushka Tandon to discuss pharmacologic anticoagulation options in atrial fibrillation with Drs. Ashley Lochman and Chris Domenico. The case-based review helps clarify some key concepts, such as when warfarin is preferred for anticoagulation, who may be a good DOAC (direct-acting oral anticoagulant) candidate, how to choose an appropriate DOAC agent, and how to manage anticoagulation therapy in patients already on antiplatelet therapies. Notes were drafted by Dr. Anushka Tandon. The episode audio was edited by student Dr. Shivani Reddy. This CardioNerds Atrial Fibrillation series is a multi-institutional collaboration made possible by contributions of stellar fellow leads and expert faculty from several programs, led by series co-chairs, Dr. Kelly Arps and Dr. Colin Blumenthal. This episode was planned and recorded prior to the release of the 2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation. Please refer to this guideline document for the most updated recommendations. We have collaborated with VCU Health to provide CME. Claim free CME here! CardioNerds Atrial Fibrillation PageCardioNerds Episode PageCardioNerds AcademyCardionerds Healy Honor Roll CardioNerds Journal ClubSubscribe to The Heartbeat Newsletter!Check out CardioNerds SWAG!Become a CardioNerds Patron! Pearls and Quotes - Anticoagulation Pharmacology Avoid potentially fatal errors with this terminology tip for correctly referencing non-warfarin oral anticoagulant agents: it’s DOAC (like, please DO use AntiCoagulation), not NOAC (imagine someone interpreting that as “NO AntiCoagulation for this patient” at discharge – yikes)! Sometimes, an oldie really is a goodie – warfarin is recommended over DOACs for patients with mechanical heart valves, moderate-to-severe mitral stenosis, anti-phospholipid antibody syndrome (APLS), left ventricular (LV) thrombus, higher INR goals, or DOAC failure. Patient preference and medication costs should also be considered – at the end of the day, “the best drug is the drug that a patient is willing to take!” Standard-dose rivaroxaban or apixaban may be considered for use in patients weighing >120kg or with BMI >40; use of other DOACs should be limited to pts weighing =/< 120kg or with BMI =/< 40. The pharmacists involved in this podcast promise they don’t have stock in apixaban! It just often happens to be the preferred DOAC option in certain scenarios – think patients with severe renal impairment (including ESRD) or with an increased risk for bleeding events (including older adults, those with a history of GI bleed, etc). In general, dual therapy (DOAC or warfarin + P2Y12 inhibitor) is non-inferior to triple therapy (oral anticoagulant + P2Y12 inhibitor + aspirin) at preventing thrombotic events but is associated with a lower risk of bleeding events. Most patients can be transitioned to dual therapy after 7-30 days on triple therapy post-percutaneous coronary intervention. What’s that on the horizon? Factor XI inhibitors may become the breakout stars of anticoagulation – multiple investigational agents are being studied for their potential to reduce thrombotic risk without significantly increasing bleeding risk in patients with indications for anticoagulation therapy…at least that’s the theorize hope. Watch this space! Notes - Anticoagulation Pharmacology In which cases is warfarin preferred over DOACs in patients with atrial fibrillation? Long-term anticoagulation with warfarin is indicated in patients with atrial fibrillation and either a mechanical valve or moderate-to-severe mitral stenosis (i.e., valvular atrial fibrillation as defined in the 2019 AHA/ACC/HRS guidelines on atrial fibrillation [1]). The REALIGN trial [2] showed increased rates of thromboembolic and bleeding complications with dabigatran vs. warfarin in patients with mechanical valves, and the PROACT Xa trial [3] found similarly higher rates of thromboembolic events with apixaban vs. warfarin in patients with On-X mechanical valves. However, DOACs are appropriate for use in patients with bioprosthetic valves. Warfarin is preferred over DOACs in patients with APLS (antiphospholipid syndrome). In triple-positive patients, DOACs should absolutely be avoided (as supported by the TRAPS study [4], which was stopped early due to findings of increased thromboembolic events with rivaroxaban vs. warfarin). Warfarin should also be preferentially used in single- and double-positive patients as well (as suggested by findings from the ASTRO-APS study [5]). There are some newer data to suggest apixaban may be non-inferior to warfarin in treating patients with LV thrombus; however, data overall is very mixed, and anticoagulating these patients with warfarin currently remains the preferred and more cautious approach. Other situations in which warfarin may be preferred are when a higher INR goal or a customized anticoagulation approach is required, in instances of DOAC failure, or in cases where cost or patient preference are driving factors. What patient-specific factors should be considered when deciding whether someone is a good candidate for DOAC therapy? Weight/BMI: previous guidance suggested against the use of DOACs in pts weighing >120kg or with a BMI >40. However, ISTH updated their guidance in 2021 [6] to support using rivaroxaban and apixaban for VTE treatment or prevention “regardless of body weight and BMI”; these DOACs are often used in patients with obesity for non-VTE indications (e.g., thromboprophylaxis in atrial fibrillation). Data to support this include a post-hoc analysis of the ARISTOTLE trial (apixaban in atrial fibrillation), which showed that patients weighing >120kg (~5% of the study population)  had similar results to the overall study population. It’s important to use adjusted body weight when calculating CrCl to estimate renal function and determine DOAC dosing in obese patients. Other DOACs should be avoided in pts >120kg/with BMI >40 due to limited or unconvincing data at this time.Hepatic impairment: DOACs have varying hepatic metabolism (apixaban is the most hepatically cleared and dabigatran the least), but limited data exist for DOAC dose adjustments in patients with hepatic impairment. DOACs should NOT be used in Child-Pugh Class C/severe hepatic disease, while rivaroxaban (and betrixaban)[GU1]  should also NOT be used in moderate/CP Class B patients. DOACs should be avoided in patients with decompensated/unstable cirrhosis. Aside from these caveats, DOACs may be considered for use in mild-moderate (Class A/B) hepatic impairment (with exceptions as above).Renal impairment: DOACs may be used in stable CKD with appropriate renal dose adjustments; DOAC therapies should be held in the context of AKI. Dabigatran is the most renally cleared and generally avoided for this reason. Apixaban is the least renally cleared and is generally the preferred agent in patients with renal impairment, including ESRD (in the context of which apixaban use is supported by data, including that from a 2022 cohort study [7] vs. warfarin).Drug Interactions: rivaroxaban, apixaban, edoxaban, and dabigatran are all P-gp substrates that will be affected by P-gp inducers or inhibitors (e.g., dronedarone, amiodarone, digoxin, diltiazem, verapamil, antiepileptics, antifungals, chemotherapy agents, and St. John’s Wort). Rivaroxaban and apixaban are substrates of CYP450 enzymes, prominently 3A4, 3A5, and 2J2. Apixaban is also metabolized by 1A2 and 2C 8/9/19 to a lesser degree. Some DOACs may interact with atorvastatin or ticagrelor, but these interactions are not typically a barrier to concurrent therapy if clinically indicated. Running a drug interaction report or consulting a pharmacist to help evaluate and safely navigate drug interactions is extremely helpful in these scenarios. *In addition to DOAC package inserts, the AHA guide to DOAC use [8] is a great resource that summarizes renal/hepatic dosing considerations, drug interactions, and anticoagulant transition recommendations. What safety profile and bleeding risk considerations exist for warfarin versus DOACs? Warfarin has been studied versus individual DOACs; generally, DOACs are preferred from a safety standpoint due to lower risk of bleeding. The RE-LY trial [9] showed no difference in major bleeding but less intracranial hemorrhage (ICH) with dabigatran when compared to warfarin. The ROCKET-AF [10] trial showed a greater Hgb drop/need for transfusion with rivaroxaban but higher critical/fatal bleeding (including ICH) incidence with warfarin. In the ARISTOTLE [11] trial, apixaban was associated with significantly lower bleeding outcomes than warfarin, except for GI bleeding (for which there was no significant difference between groups). Edoxaban had a lower incidence of overall GI bleed (upper and lower GI bleeding combined), but not individual upper or lower GI bleeding, than warfarin in the ENGAGE [12] trial.There are no direct head-to-head trials comparing DOACs, though some data suggest apixaban is associated with a lower bleeding risk than rivaroxaban (no difference in ICH), and that rivaroxaban may be associated with a higher risk of hemorrhagic stroke. In older adults, DOACs can be used without safety concerns over warfarin, though avoiding dabigatran may be suggested due to a signal for increased bleeding outcomes in older adult patients. The ELDERCARE-AF [13] trial from Japan showed no difference in major bleeding, but higher rates of GI bleeding and all bleeding, with edoxaban vs. placebo in adults >/= 80 years. Overall, apixaban is generally considered safe to use/the preferred DOAC option in patients with a history of GI bleeding.