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.
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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.
What is the recommended anti-thrombotic approach for patients with indications for both antiplatelet therapy and anticoagulation (for example, patients with atrial fibrillation undergoing PCI)?
- Assessing the appropriateness of dual vs. triple therapy involves balancing the risk of stent thrombosis vs. stroke risk.
- Among P2Y12 inhibitors, clopidogrel is typically recommended over ticagrelor or prasugrel due to its lower incidence of bleeding events and because clopidogrel was also the most commonly used P2Y12 inhibitor in dual versus triple therapy trials.
- The WOEST trial [14] found no increased thrombosis risk but a reduced bleeding risk in patients given dual therapy post-PCI with clopidogrel and warfarin vs. those given triple therapy with warfarin, clopidogrel, and aspirin. The REDUAL-PCI trial [15] found a similarly reduced bleeding risk without statistically increased thrombotic risk in patients receiving dual therapy with dabigatran + P2Y12i vs. continuing triple therapy with P2Y12i + aspirin + warfarin. The PIONEER-AF [16] trial found lower bleeding risk with rivaroxaban + P2Y12 therapy than with warfarin-DAPT triple therapy without differences in thrombotic outcomes; the caveat here is that the 15mg daily rivaroxaban dose used is not approved for stroke prevention (that dose is 20mg daily). The AUGUSTUS trial [17] showed dual apixaban + P2Y12i therapy to have lower bleeding risk and unchanged efficacy than VKA dual therapy or triple therapy with apixaban or VKA. Importantly, these trials were not powered to differentiate ischemic outcomes.
- As for when patients should be transitioned from triple (OAC + P2Y12 + ASA) to dual therapy (OAC + P2Y12), data from medication-specific trials can help guide the approach. For patients anticoagulated with warfarin or dabigatran, a triple therapy duration of 30 days may be appropriate based on WOEST (up to 1 year) and REDUAL-PCI trials (up to 3 months for patients with a DES). In PIONEER-AF, patients were randomized directly to rivaroxaban + P2Y12 therapy without first receiving triple therapy, but in clinical practice, triple therapy is often instituted for 7-30 days before transitioning to dual therapy with rivaroxaban and P2Y12 inhibitor. For apixaban, a shorter 7-day course of triple therapy appears appropriate.
- *The 2022 ACC ECDP is a fantastic reference resource to help guide the management of anticoagulation and antiplatelet therapy in patients with atrial fibrillation or VTE undergoing PCI or with ASCVD [18].
What’s the scoop on factor XI, which appears to be clinically important for thrombosis but not hemostasis, as a potential drug target? Might this be the future of anticoagulation pharmacotherapy?
- Factor XI is a part of the contact pathway of coagulation. It is activated by thrombin and factor XIIa and is thought to activate factor IX. Factor XI appears to contribute to thrombin generation and thereby amplify thrombus growth; it may also reduce fibrin degradation. Higher levels of factor XI appear correlated to increased clotting risk, while factor XI levels are poorly correlated with bleeding risk. The excitement around factor XI as a drug target stems from the thought that XI inhibition may decrease thrombotic risk without significantly changing bleeding risk.
- Currently, there are several drugs in development and multiple ongoing clinical trials examining therapeutic viability. Oral, intravenous, and subcutaneous formulations of factor XI inhibitors are all being studied, in forms including monoclonal antibodies, small molecules, and antisense oligonucleotides. Most data reported thus far relates to VTE prophylaxis in orthopedic surgery. However, ongoing/planned trials, like the PACIFIC and OCEANIC series, will look at factor XI inhibitors in the context of atrial fibrillation, stroke, and myocardial infarction. Comparator drugs in these studies include DOACs and enoxaparin.
- Long-term impact for this class of investigational therapeutics remains to be seen, and cost will likely be a limiting factor in using these agents (especially as DOACs are anticipated to go generic in 5-10 years). However, early data seems promising! [19, 20].
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