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Role of anticoagulation therapy in modifying stroke risk associated with new-onset atrial fibrillation after non-cardiac surgery

Nature Medicine (2024)Cite this article

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Abstract

The role of antithrombotic therapy in the prevention of ischemic stroke after non-cardiac surgery is unclear. In this study, we tested the hypothesis that the association of new-onset postoperative atrial fibrillation (POAF) on ischemic stroke can be mitigated by postoperative oral anticoagulation therapy. Of 251,837 adult patients (155,111 female (61.6%) and 96,726 male (38.4%)) who underwent non-cardiac surgical procedures at two sites, POAF was detected in 4,538 (1.8%) patients. The occurrence of POAF was associated with increased 1-year ischemic stroke risk (3.6% versus 2.3%; adjusted risk ratio (RRadj) = 1.60 (95% confidence interval (CI): 1.37–1.87), P < 0.001). In patients with POAF, the risk of developing stroke attributable to POAF was 1.81 (95% CI: 1.44–2.28; P < 0.001) without oral anticoagulation, whereas, in patients treated with anticoagulation, no significant association was observed between POAF and stroke (RRadj = 1.04 (95% CI: 0.71–1.51), P = 0.847, P for interaction = 0.013). Furthermore, we derived and validated a computational model for the prediction of POAF after non-cardiac surgery based on demographics, comorbidities and procedural risk. These findings suggest that POAF is predictable and associated with an increased risk of postoperative ischemic stroke in patients who do not receive postoperative anticoagulation.

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Fig. 1: Study flowchart detailing patient inclusion and exclusion criteria.
Fig. 2: Stroke prediction and stroke risk.
Fig. 3: The effect of postoperative antithrombotic therapy on the association of POAF with ischemic stroke.

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Data availability

Access to anonymized patient data is subject to a data-sharing agreement and protocol approval from the institutional review board committee. The study-specific analyzable dataset is, therefore, not publicly available. Due to the sensitive nature of the patient data collected for this study, requests to access the dataset may be directed to the corresponding author, M.E., at meikermann@montefiore.org (14-d response time).

Code availability

Codes for inclusion criteria, baseline characteristics and outcome events were developed based on the International Classification of Diseases code classification, Current Procedural Terminology or data from electronic health records, unless otherwise specified. These are described in the supplementary materials of this manuscript. Statistical analyses were conducted using Stata (version 17), GraphPad Prism (version 9) and G*Power (version 3.1.9.4). Detailed information about the codes and packages used in the analyses can be found in the Supplementary Information. For additional clarification of these codes, contact the corresponding author at meikermann@montefiore.org (14-d response time).

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Acknowledgements

The authors declare no specific grants for this research from any funding agency in the public, commercial or not-for-profit sector.

Author information

Author notes

  1. These authors contributed equally: Omid Azimaraghi, Maíra I. Rudolph.

Authors and Affiliations

  1. Department of Anesthesiology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA

    Omid Azimaraghi, Maíra I. Rudolph, Karuna Wongtangman, Felix Borngaesser, Maya Doehne, Annika Eyth, Christopher Tam, William J. Sauer, Michael E. Kiyatkin, Ibraheem M. Karaye, Ling Zhang, Carina P. Himes, Aline M. Grimm, Christian Mpody, Aiman Suleiman, Annika Bald, Jay J. Im, Jonathan Leff, Can M. Luedeke, Timothy Pulverenti, Tina Ramishvili, Flora T. Scheffenbichler, Sujatha Ramachandran & Matthias Eikermann

  2. Department of Anesthesiology and Intensive Care Medicine, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany

    Maíra I. Rudolph

  3. Department of Anesthesiology, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand

    Karuna Wongtangman

  4. Carl von Ossietzky Universität Oldenburg, University Clinic for Anesthesiology, Intensive Care, Emergency Medicine, and Pain Therapy, Klinikum Oldenburg AöR, Oldenburg, Germany

    Felix Borngaesser & Simon T. Schaefer

  5. Critical Care Medicine Unit, School of Clinical Medicine, The University of Hong Kong, Pokfulam, Hong Kong SAR, China

    Pauline Y. Ng

  6. Department of Adult Intensive Care, Queen Mary Hospital, Hong Kong SAR, China

    Pauline Y. Ng

  7. Center for Anesthesia Research Excellence, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Dario von Wedel, Maximilian S. Schaefer & Dario von Wedel

  8. Department of Anesthesia, Critical Care, and Pain Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Dario von Wedel, Maximilian S. Schaefer & Dario von Wedel

  9. Institute of Medical Informatics, Charité University Medicine Berlin, Berlin, Germany

    Dario von Wedel & Dario von Wedel

  10. Department of Cardiology, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA

    Fengwei Zou, Luigi Di Biase, Mario J. Garcia, Luigi Di Biase & M. Azeem Latib

  11. Department of Anesthesia, Critical Care and Pain Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

    Timothy T. Houle

  12. Department of Population Health, Hofstra University, Hempstead, NY, USA

    Ibraheem M. Karaye

  13. Department of Anesthesiology, Duesseldorf University Hospital, Duesseldorf, Germany

    Maximilian S. Schaefer

  14. Department of Anesthesiology & Pain Medicine, Nationwide Children’s Hospital and The Ohio State University, Columbus, OH, USA

    Olubukola O. Nafiu

  15. Department of Cardiovascular and Thoracic Surgery, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York, NY, USA

    Brendon M. Stiles, Joseph J. DeRose & Stephen J. Forest

  16. Mount Sinai Fuster Heart Hospital, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Deepak L. Bhatt

  17. Klinik für Anästhesiologie und Intensivmedizin, Universität Duisburg-Essen, Essen, Germany

    Matthias Eikermann

  18. Department of Medicine, Montefiore Medical Center and Albert Einstein College of Medicine, Bronx, NY, USA

    Fran Ganz-Lord

  19. Department of Anesthesiology and Intensive Care Medicine, Ulm University, Ulm, Germany

    Flora T. Scheffenbichler

Authors
  1. Omid Azimaraghi
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  2. Maíra I. Rudolph
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  3. Karuna Wongtangman
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  4. Felix Borngaesser
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  10. Christopher Tam
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  14. Ibraheem M. Karaye
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  15. Ling Zhang
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  16. Maximilian S. Schaefer
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  20. Olubukola O. Nafiu
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  27. Matthias Eikermann
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Consortia

The Boston-NYC Afib after non-cardiac surgery collaborators Consortium

  • Omid Azimaraghi
  • , Annika Bald
  • , Luigi Di Biase
  • , Deepak L. Bhatt
  • , Felix Borngaesser
  • , Joseph J. DeRose
  • , Maya Doehne
  • , Matthias Eikermann
  • , Annika Eyth
  • , Stephen J. Forest
  • , Fran Ganz-Lord
  • , Mario J. Garcia
  • , Aline M. Grimm
  • , Carina P. Himes
  • , Timothy T. Houle
  • , Jay J. Im
  • , Ibraheem M. Karaye
  • , Michael E. Kiyatkin
  • , M. Azeem Latib
  • , Jonathan Leff
  • , Can M. Luedeke
  • , Christian Mpody
  • , Olubukola O. Nafiu
  • , Pauline Y. Ng
  • , Timothy Pulverenti
  • , Tina Ramishvili
  • , Maíra I. Rudolph
  • , Maximilian S. Schaefer
  • , Simon T. Schaefer
  • , William J. Sauer
  • , Flora T. Scheffenbichler
  • , Brendon M. Stiles
  • , Aiman Suleiman
  • , Christopher Tam
  • , Dario von Wedel
  • , Sujatha Ramachandran
  • , Karuna Wongtangman
  • , Ling Zhang
  •  & Fengwei Zou

Contributions

O.A., L.Z., M.S.S. and M.E. had access to the data. M.E. is the guarantor of the manuscript and takes full responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: O.A., M.K., W.J.S., M.S.S., M.G., D.L.B., L.D. and M.E. Acquisition, analysis or interpretation of the data: O.A., T.T.H., L.Z., M.D., M.I.R., F.B. and D.W. Drafting of the manuscript: O.A., M.I.R., F.Z., A.E., D.L.B. and M.E. Critical revision of the manuscript: all authors. Statistical analysis: O.A., I.M.K., M.D., M.I.R., F.B. and K.W. D.L.B. and M.E. supervised critical revisions.

Corresponding author

Correspondence to Matthias Eikermann.

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M.E. receives funding from the National Institutes of Health (NIH) (R01AG065554 and R01HL132887) that does not pertain to this manuscript. He holds two patents for acyclic curcubiturils for reversal of drugs of abuse and neuromuscular blocking agents (patent numbers 9956229 and 9469648). He is a member of the associated editorial board for the British Journal of Anaesthesia. D.L.B. discloses the following relationships. Advisory Board: Angiowave, Bayer, Boehringer Ingelheim, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma and Stasys; Board of Directors: American Heart Association New York City, Angiowave (stock options), Bristol Myers Squibb (stock), DRS.LINQ (stock options) and High Enroll (stock); Consultant: Broadview Ventures, Hims, SFJ and Youngene; Data Monitoring Committee: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (chair, PEITHO trial), Cleveland Clinic, Contego Medical (chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical; for ALLAY-HF, funded by Alleviant Medical), Novartis, Population Health Research Institute and Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (ACC) (senior associate editor, Clinical Trials and News; chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee, funded by Boehringer Ingelheim; AEGIS-II executive committee, funded by CSL Behring), Belvoir Publications (editor in chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), CSL Behring (American Heart Association lecture), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (editor in chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor and associate editor), K2P (co-chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (course director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee and steering committee and USA national co-leader, funded by Bayer), WebMD (CME steering committees) and Wiley (steering committee); Other: Clinical Cardiology (deputy editor); Patent: sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital, assigned to Lexicon; neither D.L.B. nor Brigham and Women's Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Alnylam, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, Cleerly, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Eli Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Otsuka, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene and 89Bio; Royalties: Elsevier (editor, Braunwald’s Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte and Vascular Solutions; Trustee: ACC; Unfunded Research: FlowCo. M.S.S. received funding for investigator-initiated studies from Merck & Co., which does not pertain to this manuscript. He is an associate editor for BMC Anesthesiology. He received honoraria for lectures from Fisher & Paykel Healthcare and Mindray Medical International Limited. He received an unrestricted philanthropic grant from Jeff and Judy Buzen. All other authors have no support from any organization for the submitted work, no financial relationships with any organizations that might have an interest in the submitted work and no other relationships or activities that could appear to have influenced the submitted work.

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Extended data

Extended Data Fig. 1 Kaplan-Meier survival estimates.

The figure illustrates the adjusted Kaplan-Meier survival estimates analysis conducted for the occurrence of stroke in patients experiencing new onset postoperative atrial fibrillation(red line) and patients who did not(blue line). The x-axis represents time after surgery in days, while the y-axis indicates the probability of being stroke-free (Hazard Ratio: 2.07 (95% CI 1.92-2.23), p < 0.001).

Extended Data Fig. 2 Risk of new-onset postoperative atrial fibrillation and stroke.

(A) New-onset atrial fibrillation (POAF) after non-cardiac surgery is associated with postoperative complications, stroke, heart failure, and myocardial infarction. (B) For patients who were prescribed oral anticoagulants, the absolute risk difference was 0.34% in all patients and 0.68% in high-risk patients (upper quintile in computational prediction model [>11 points]). There was no significant absolute risk difference in patients who were prescribed oral anticoagulants. The images used were created by the authors using Procreate for iOS17 (Savage Interactive Pty Ltd., Hobart, Australia).

Extended Data Fig. 3 Graphical description of the study design.

Graphical description of the study design, visualizing temporal anchors of exposure (new-onset postoperative atrial fibrillation), outcome/follow-up (ischemic stroke/transient ischemic attack), covariates (baseline demographics, procedure related factors, comorbidities and preexisting medication) and primary effect modifier (oral anticoagulation). The cohort entry date (CED), serving as the primary anchor date for patients entering the study analysis, was the date of the patients' index surgery (Day 0). We excluded patients with preexisting atrial fibrillation, age below 18 years, ASA physical status greater than 4 or missing data for exposure, outcome or covariates. Covariates were assessed during a window extending one year prior to the CED if not otherwise specified [-365,-1]. The time window for the primary exposure - postoperative atrial fibrillation (POAF) - was between day 0 and the end of day post-CED. Oral anticoagulation prescriptions were included between postoperative day 1 and the end of day 365. The outcome ischemic stroke was assessed between day 31 and 365 after surgery. Abbreviations: y, years; ASA, American Society of Anesthesiologists; POAF, new-onset postoperative atrial fibrillation.

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Supplementary Figs. 1–7, Supplementary Tables 1–7 and Supplementary Notes 1 (STROBE checklist) and 2 (Statistical Analysis Plan).

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Azimaraghi, O., Rudolph, M.I., Wongtangman, K. et al. Role of anticoagulation therapy in modifying stroke risk associated with new-onset atrial fibrillation after non-cardiac surgery. Nat Med (2024). https://doi.org/10.1038/s41591-024-03206-0

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