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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!

Enjoy this Circulation 2022 Paths to Discovery article to learn about the CardioNerds story, mission, and values.

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Pearls and Quotes – Anticoagulation Pharmacology

1. 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)!
2. 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!”
3. 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.
4. 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).
5. 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.
6. 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.

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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References – Anticoagulation Pharmacology

1. January CT, Wann LS, Calkins H, et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons [published correction appears in Circulation. 2019 Aug 6;140(6):e285]. Circulation. 2019;140(2):e125-e151. doi:10.1161/CIR.0000000000000665
2. Eikelboom JW, Connolly SJ, Brueckmann M, et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med. 2013;369(13):1206-1214. doi:10.1056/NEJMoa1300615
3. Wang TY, Svensson LG, Wen J, et al. Apixaban or Warfarin in Patients with an On-X Mechanical Aortic Valve. NEJM Evid 2023;May 6:[Epub ahead of print].  doi:10.1056/EVIDoa2300067
4. Pengo V, Hoxha A, Andreoli L, et al. Trial of Rivaroxaban in AntiPhospholipid Syndrome (TRAPS): Two-year outcomes after the study closure. J Thromb Haemost. 2021;19(2):531-535. doi:10.1111/jth.15158
5. Woller SC, Stevens SM, Kaplan D, et al. Apixaban compared with warfarin to prevent thrombosis in thrombotic antiphospholipid syndrome: a randomized trial. Blood Adv. 2022;6(6):1661-1670. doi:10.1182/bloodadvances.2021005808
6. Martin KA, Beyer-Westendorf J, Davidson BL, Huisman MV, Sandset PM, Moll S. Use of direct oral anticoagulants in patients with obesity for treatment and prevention of venous thromboembolism: Updated communication from the ISTH SSC Subcommittee on Control of Anticoagulation. J Thromb Haemost. 2021;19(8):1874-1882. doi:10.1111/jth.15358
7. Ellenbogen MI, Ardeshirrouhanifard S, Segal JB, Streiff MB, Deitelzweig SB, Brotman DJ. Safety and effectiveness of apixaban versus warfarin for acute venous thromboembolism in patients with end-stage kidney disease: A national cohort study. J Hosp Med. 2022;17(10):809-818. doi:10.1002/jhm.12926
8. Chen A, Stecker E, A Warden B. Direct Oral Anticoagulant Use: A Practical Guide to Common Clinical Challenges. J Am Heart Assoc. 2020;9(13):e017559. doi:10.1161/JAHA.120.017559
9. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation [published correction appears in N Engl J Med. 2010 Nov 4;363(19):1877]. N Engl J Med. 2009;361(12):1139-1151. doi:10.1056/NEJMoa0905561
10. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-891. doi:10.1056/NEJMoa1009638
11. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-992. doi:10.1056/NEJMoa1107039
12. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093-2104. doi:10.1056/NEJMoa1310907
13. Okumura K, Akao M, Yoshida T, et al. Low-Dose Edoxaban in Very Elderly Patients with Atrial Fibrillation. N Engl J Med. 2020;383(18):1735-1745. doi:10.1056/NEJMoa2012883
14. Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet. 2013;381(9872):1107-1115. doi:10.1016/S0140-6736(12)62177-1
15. Cannon CP, Bhatt DL, Oldgren J, et al. Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation. N Engl J Med. 2017;377(16):1513-1524. doi:10.1056/NEJMoa1708454
16. Gibson CM, Mehran R, Bode C, et al. Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. N Engl J Med. 2016;375(25):2423-2434. doi:10.1056/NEJMoa1611594
17. Lopes RD, Heizer G, Aronson R, et al. Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation. N Engl J Med. 2019;380(16):1509-1524. doi:10.1056/NEJMoa1817083
18. Kumbhani D, Cannon C, Beavers C, et al. 2020 ACC Expert Consensus Decision Pathway for Anticoagulant and Antiplatelet Therapy in Patients With Atrial Fibrillation or Venous Thromboembolism Undergoing Percutaneous Coronary Intervention or With Atherosclerotic Cardiovascular Disease. J Am Coll Cardiol. 2021 Feb, 77 (5) 629–658. https://doi.org/10.1016/j.jacc.2020.09.011
19.  Nopp S, Kraemmer D, Ay C. Factor XI Inhibitors for Prevention and Treatment of Venous Thromboembolism: A Review on the Rationale and Update on Current Evidence. Front Cardiovasc Med. 2022;9:903029. Published 2022 May 12. doi:10.3389/fcvm.2022.903029
20. Greco A, Laudani C, Spagnolo M, et al. Pharmacology and Clinical Development of Factor XI Inhibitors. Circulation. 2023;147(11):897-913. doi:10.1161/CIRCULATIONAHA.122.062353