The Price of Keeping the Rhythm: Increased Bleeding Risk in Patients With Atrial Fibrillation Concurrently Prescribed Amiodarone and Factor Xa Inhibitors.

ATRIAL FIBRILLATION is the most common sustained cardiac arrhythmia, affecting nearly 2% of the population of the United States.1Kornej J Börschel CS Benjamin EJ Schnabel RB. Epidemiology of Atrial fibrillation in the 21st century: Novel methods and new insights.Circ Res. 2020; 127: 4-20Crossref PubMed Scopus (472) Google Scholar Patients with atrial fibrillation are twice as likely to have a myocardial infarction, and 5 times as likely to have a stroke.1Kornej J Börschel CS Benjamin EJ Schnabel RB. Epidemiology of Atrial fibrillation in the 21st century: Novel methods and new insights.Circ Res. 2020; 127: 4-20Crossref PubMed Scopus (472) Google Scholar Current guidelines recommend antiarrhythmic pharmacotherapy in patients with symptomatic atrial fibrillation as first-line management.2Andrade JG Aguilar M Atzema C et al.The 2020 Canadian Cardiovascular Society/Canadian Heart Rhythm Society Comprehensive guidelines for the management of atrial fibrillation.Can J Cardiol. 2020; 36: 1847-1948Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar, 3Hindricks G Potpara T Dagres N et al.2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC.Eur Heart J. 2021; 42: 373-498Crossref PubMed Scopus (4874) Google Scholar, 4January 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.Circulation. 2019; 140: e125-e151Crossref PubMed Scopus (1776) Google Scholar Amiodarone is a very effective and, therefore, a commonly prescribed agent for this purpose.5Lupercio F Romero J Peltzer B et al.Efficacy and safety outcomes of direct oral anticoagulants and amiodarone in patients with atrial fibrillation.Am J Med. 2018; 131 (573.e1-573.e8)Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar Anticoagulation is a key tenet in managing atrial fibrillation due to the increased tendency of left atrial appendage clot formation, which, in turn, is a potential source of systemic thromboembolism. Whereas warfarin was previously the standard, newer oral direct factor Xa inhibitors apixaban and rivaroxaban have become the anticoagulants of choice, primarily due to their advantageous safety profile and patient convenience.6Steffel J Verhamme P Potpara TS et al.The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation.Eur Heart J. 2018; 39: 1330-1393Crossref PubMed Scopus (1463) Google Scholar However, amiodarone affects both the hepatic CYP3A4 metabolism of these medications and their elimination via intestinal and renal multidrug transporter P-glycoprotein.5Lupercio F Romero J Peltzer B et al.Efficacy and safety outcomes of direct oral anticoagulants and amiodarone in patients with atrial fibrillation.Am J Med. 2018; 131 (573.e1-573.e8)Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar This drug-drug interaction may negate these medications’ individual intended benefits by introducing life-threatening bleeding risks from accumulating plasma concentrations of factor Xa inhibitors.6Steffel J Verhamme P Potpara TS et al.The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation.Eur Heart J. 2018; 39: 1330-1393Crossref PubMed Scopus (1463) Google Scholar In a recent large retrospective cohort study published in the Annals of Internal Medicine, Ray et al. investigated the bleeding risk of the coadministration of factor Xa inhibitors apixaban and rivaroxaban with amiodarone compared to antiarrhythmic drugs that do not interfere with apixaban-rivaroxaban elimination.7Ray WA Chung CP Stein CM et al.Risk for bleeding-related hospitalizations during use of amiodarone with apixaban or rivaroxaban in patients with atrial fibrillation.Annals of Internal Medicine. 2023; 176: 769-778Crossref PubMed Scopus (2) Google Scholar A total of 91,590 Medicare beneficiaries ≥65 years of age, with atrial fibrillation anticoagulated with apixaban or rivaroxaban across a 6-year period, were included in this analysis—54,977 of these patients were rhythm-controlled with amiodarone, and 36,613 were rhythm-controlled with either flecainide or sotalol, neither of which interferes with apixaban or rivaroxaban elimination. The primary outcome, the risk of bleeding-related hospitalizations, was greater in those patients treated with amiodarone (56.5 events per 1,000 person-years) compared to those treated with flecainide or sotalol (39.0 events per 1,000 person-years), with a rate difference of 17.5 events (95% CI 12.0-23.0) per 1,000 person-years and a hazard ratio of 1.44 (95% CI 1.27-1.63). Particularly, rivaroxaban and a HAS-BLED score >2 were identified as stronger risk factors for bleeding-related hospitalization in patients treated with amiodarone. There was also increased mortality in the patients on direct oral anticoagulants (DOACs) treated with amiodarone compared to sotalol and flecainide, with a rate difference of 14.6 events (95% CI 8.6-20.7) and a hazard ratio 1.28 (95% CI 1.15-1.44). Importantly, there was no difference in the negative control outcome—ischemic stroke or systemic embolism. Similar findings have been reported previously. A 2017 retrospective cohort study of 91,330 Taiwanese patients with atrial fibrillation with a DOAC prescription found that concurrent amiodarone use had a significantly higher incidence of major bleeding versus NOAC use alone, with a rate difference of 13.94 events (99% CI 9.76-18.13) per 1,000 person-years.8Chang S-H Chou IJ Yeh Y-H et al.Association between use of non–vitamin K oral anticoagulants with and without concurrent medications and risk of major bleeding in nonvalvular atrial fibrillation.JAMA. 2017; 318: 1250-1259Crossref PubMed Scopus (274) Google Scholar Another 2023 case-control study of 86,679 Canadian patients with atrial fibrillation prescribed a DOAC found a significant association between concurrent amiodarone use and major bleeding events, with an odds ratio of 1.53 (95% CI 0.76-1.68).9Shurrab M Jackevicius CA Austin PC et al.Association between concurrent use of amiodarone and DOACs and risk of bleeding in patients with atrial fibrillation.Am J Cardiol. 2023; 186: 58-65Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar Interestingly, the conclusions of these 3 recent large observational studies7Ray WA Chung CP Stein CM et al.Risk for bleeding-related hospitalizations during use of amiodarone with apixaban or rivaroxaban in patients with atrial fibrillation.Annals of Internal Medicine. 2023; 176: 769-778Crossref PubMed Scopus (2) Google Scholar, 8Chang S-H Chou IJ Yeh Y-H et al.Association between use of non–vitamin K oral anticoagulants with and without concurrent medications and risk of major bleeding in nonvalvular atrial fibrillation.JAMA. 2017; 318: 1250-1259Crossref PubMed Scopus (274) Google Scholar, 9Shurrab M Jackevicius CA Austin PC et al.Association between concurrent use of amiodarone and DOACs and risk of bleeding in patients with atrial fibrillation.Am J Cardiol. 2023; 186: 58-65Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar were not supported by older randomized controlled trials10Connolly SJ Ezekowitz MD Yusuf S et al.Dabigatran versus warfarin in patients with atrial fibrillation.N Engl J Med. 2009; 361: 1139-1151Crossref PubMed Scopus (9303) Google Scholar, 11Patel MR Mahaffey KW Garg J et al.Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.N Engl J Med. 2011; 365: 883-891Crossref PubMed Scopus (7614) Google Scholar, 12Granger CB Alexander JH McMurray JJ et al.Apixaban versus warfarin in patients with atrial fibrillation.N Engl J Med. 2011; 365: 981-992Crossref PubMed Scopus (7126) Google Scholar, 13Giugliano RP Ruff CT Braunwald E et al.Edoxaban versus warfarin in patients with atrial fibrillation.N Engl J Med. 2013; 369: 2093-2104Crossref PubMed Scopus (3901) Google Scholar of atrial fibrillation in patients who were assigned to receive DOACs, and reported the use and influence of amiodarone on major bleeding. A meta-analysis5Lupercio F Romero J Peltzer B et al.Efficacy and safety outcomes of direct oral anticoagulants and amiodarone in patients with atrial fibrillation.Am J Med. 2018; 131 (573.e1-573.e8)Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar of 4 trials10Connolly SJ Ezekowitz MD Yusuf S et al.Dabigatran versus warfarin in patients with atrial fibrillation.N Engl J Med. 2009; 361: 1139-1151Crossref PubMed Scopus (9303) Google Scholar, 11Patel MR Mahaffey KW Garg J et al.Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.N Engl J Med. 2011; 365: 883-891Crossref PubMed Scopus (7614) Google Scholar, 12Granger CB Alexander JH McMurray JJ et al.Apixaban versus warfarin in patients with atrial fibrillation.N Engl J Med. 2011; 365: 981-992Crossref PubMed Scopus (7126) Google Scholar, 13Giugliano RP Ruff CT Braunwald E et al.Edoxaban versus warfarin in patients with atrial fibrillation.N Engl J Med. 2013; 369: 2093-2104Crossref PubMed Scopus (3901) Google Scholar encompassing 71,683 patients, but of whom only 5% were taking DOAC and amiodarone concomitantly, found no difference in major bleeding with amiodarone use by risk ratio 0.91 (95% CI 0.77-1.07).5Lupercio F Romero J Peltzer B et al.Efficacy and safety outcomes of direct oral anticoagulants and amiodarone in patients with atrial fibrillation.Am J Med. 2018; 131 (573.e1-573.e8)Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar This discrepancy may be due to the inadequate power and shorter follow-up of the studies included in the meta-analysis. Beyond emphasizing the importance of screening for drug-drug interactions and anticoagulation stewardship, the results of the new study by Ray et al. may impact the management of patients with atrial fibrillation.7Ray WA Chung CP Stein CM et al.Risk for bleeding-related hospitalizations during use of amiodarone with apixaban or rivaroxaban in patients with atrial fibrillation.Annals of Internal Medicine. 2023; 176: 769-778Crossref PubMed Scopus (2) Google Scholar The evidence for possible harm of the most common pharmacotherapy used in patients with atrial fibrillation comes as the evidence for interventional management of atrial fibrillation demonstrates increasing efficacy and safety.14Poorsattar SP Kumar N Jelly CA et al.The year in electrophysiology: Selected highlights from 2022.J Cardiothorac Vasc Anesth. 2023; 37: 1255-1264Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar Although this impacts the outpatient population, its relevance may extend to the perioperative population. The extent to which the combination of factor Xa inhibitors and amiodarone increases the risk of bleeding in the periprocedural setting is unclear.15Godier A Dincq AS Martin AC et al.Predictors of pre-procedural concentrations of direct oral anticoagulants: A prospective multicentre study.Eur Heart J. 2017; 38: 2431-2439Crossref PubMed Scopus (95) Google Scholar Major intraoperative bleeding is associated with increased morbidity, mortality, and healthcare costs.16Untereiner O Seince PF Chterev V et al.Management of direct oral anticoagulants in the perioperative setting.J Cardiothorac Vasc Anesth. 2015; 29: 741-748Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar Anticoagulants increase the risk of bleeding, especially in patients who present for urgent or emergent surgery without an adequate washout period.16Untereiner O Seince PF Chterev V et al.Management of direct oral anticoagulants in the perioperative setting.J Cardiothorac Vasc Anesth. 2015; 29: 741-748Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar For routine scheduled surgery, current guidelines recommend allowing anticoagulants to be held to ensure adequate drug “washout.” The 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients with Nonvalvular Atrial Fibrillation recommended withholding DOACs at least 24 hours for procedures with a low risk of bleeding, and at least 48 hours in intermediate- and/or high-risk procedures in patients with normal renal function.17Doherty JU Gluckman TJ Hucker WJ et al.2017 ACC expert consensus decision pathway for periprocedural management of anticoagulation in patients with nonvalvular atrial fibrillation: A report of the American College of Cardiology Clinical Expert Consensus Document Task Force.J Am Coll Cardiol. 2017; 69: 871-898Crossref PubMed Scopus (305) Google Scholar This advice was mirrored in the 2017 European Association for Cardio-Thoracic Surgery–European Association of Cardiothoracic Anaesthesiology guidelines, which recommended a minimum of 48 hours before elective cardiac surgery, which is always considered a moderate-to-high–risk surgery.18Boer C Meesters MI Milojevic M et al.2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery.J Cardiothorac Vasc Anesth. 2018; 32: 88-120Abstract Full Text Full Text PDF PubMed Scopus (265) Google Scholar Special guidance was given for patients with impaired renal function to plan for longer periods of drug washout based on patients’ creatinine clearance.19Heidbuchel H Verhamme P Alings M et al.Updated European Heart Rhythm Association practical guide on the use of non-vitamin-K antagonist anticoagulants in patients with non-valvular atrial fibrillation: Executive summary.Eur Heart J. 2017; 38: 2137-2149PubMed Google Scholar This can extend the recommended washout period to at least 72 hours before performing an elective surgery with a high risk for bleeding.17Doherty JU Gluckman TJ Hucker WJ et al.2017 ACC expert consensus decision pathway for periprocedural management of anticoagulation in patients with nonvalvular atrial fibrillation: A report of the American College of Cardiology Clinical Expert Consensus Document Task Force.J Am Coll Cardiol. 2017; 69: 871-898Crossref PubMed Scopus (305) Google Scholar The pharmacodynamics of apixaban and rivaroxaban elimination likewise may warrant a longer washout period for patients on amiodarone, although there is a paucity of studies looking at this. Likewise, the drug-drug interaction between apixaban and/or rivaroxaban and amiodarone must be recognized in patients for whom the decision is made to continue anticoagulation through the perioperative period. This is often the case for endoscopies, cardiac catheterizations, interventional radiology-guided line or drain placements, and transesophageal echocardiograms. Notably, this is also the scenario for many atrial fibrillation patients undergoing scheduled electrophysiology procedures, such as pulmonary vein isolation ablations or left atrial appendage closures, by the clinicians who prescribed these medications. The VENTURE-AF trial20Cappato R Marchlinski FE Hohnloser SH et al.Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation.Eur Heart J. 2015; 36: 1805-1811Crossref PubMed Scopus (342) Google Scholar underlined the guideline21Martin AC Godier A Narayanan K Smadja DM Marijon E. Management of intraprocedural anticoagulation in patients on non-vitamin k antagonist oral anticoagulants undergoing catheter ablation for atrial fibrillation: Understanding the gaps in evidence.Circulation. 2018; 138: 627-633Crossref PubMed Scopus (19) Google Scholar recommendation to continue factor Xa inhibitors through electrophysiology procedures; however, whether or not trial patients were taking amiodarone concomitantly was not evaluated as a risk factor for major bleeding.20Cappato R Marchlinski FE Hohnloser SH et al.Uninterrupted rivaroxaban vs. uninterrupted vitamin K antagonists for catheter ablation in non-valvular atrial fibrillation.Eur Heart J. 2015; 36: 1805-1811Crossref PubMed Scopus (342) Google Scholar Until there are data demonstrating that the drug-drug interaction between apixaban and/or rivaroxaban and amiodarone does not increase intraprocedural bleeding risk, increased caution should be exercised during these procedures. Managing patients with atrial fibrillation on apixaban or rivaroxaban with amiodarone presenting for emergent surgery can be challenging. Current guidelines do not support routine perioperative coagulation testing17Doherty JU Gluckman TJ Hucker WJ et al.2017 ACC expert consensus decision pathway for periprocedural management of anticoagulation in patients with nonvalvular atrial fibrillation: A report of the American College of Cardiology Clinical Expert Consensus Document Task Force.J Am Coll Cardiol. 2017; 69: 871-898Crossref PubMed Scopus (305) Google Scholar,19Heidbuchel H Verhamme P Alings M et al.Updated European Heart Rhythm Association practical guide on the use of non-vitamin-K antagonist anticoagulants in patients with non-valvular atrial fibrillation: Executive summary.Eur Heart J. 2017; 38: 2137-2149PubMed Google Scholar; however, if there is a significant concern for residual Xa inhibitor levels, drug-specific assays for plasma concentration measurements of rivaroxaban and apixaban can be obtained. Another option is to reverse anti-Xa anticoagulants with the newer but costly andexanet alfa, a modified recombinant form of factor Xa approved for rapid apixaban and rivaroxaban reversal in the setting of life-threatening bleeding.22Lohrmann GM Atwal D Augoustides JG et al.Reversal agents for the new generation of oral anticoagulants: Implications for the perioperative physician.J Cardiothorac Vasc Anesth. 2016; 30: 823-830Abstract Full Text Full Text PDF PubMed Scopus (12) Google Scholar Its role in the surgical setting is controversial; nevertheless, the Society of Thoracic Surgeons advocates for the administration of andexanet alfa in surgeries with extensive tissue dissection, and emergent cardiac surgery in patients with recent ingestion of either apixaban or rivaroxaban.23Tibi P McClure RS Huang J et al.STS/SCA/AmSECT/SABM update to the clinical practice guidelines on patient blood management.Ann Thorac Surg. 2021; 112: 981-1004Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar This recommendation comes with the caveats of risks for heparin resistance and rebound thrombosis.24Pauls LA Rathor R Pennington BT. Andexanet alfa-induced heparin resistance missing from SCA blood management in cardiac surgery guidelines.J Cardiothorac Vasc Anesth. 2022; 36: 4557-4558Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar The incidence of thrombotic events was 10% in a 30-day follow-up period.25Connolly SJ Crowther M Eikelboom JW et al.Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors.N Engl J Med. 2019; 380: 1326-1335Crossref PubMed Scopus (584) Google Scholar Again, the benefit of slowing major bleeding must outweigh thrombosis and embolization risk to justify andexanet alfa administration. Additionally, the high cost of andexanet alfa is another variable that should be considered while adjudicating the risk-benefit ratio for these patients. As perioperative physicians, an important takeaway from the Ray et al. study was the clinical significance of the previously known drug-drug interaction between apixaban and/or rivaroxaban and amiodarone. Current guidelines lack consideration for the potential impact of this drug-drug interaction on perioperative management of factor Xa inhibitors. Patients taking these medications may be at an increased risk of intraprocedural bleeding, which warrants further investigation in periprocedural settings. None.