Long-term Thromboembolic Risk in Patients With Postoperative Atrial Fibrillation After Left-Sided Heart Valve Surgery | Atrial Fibrillation | JAMA Cardiology | JAMA Network
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Figure 1.  Flowchart of the Study Population Selection Process
Flowchart of the Study Population Selection Process

AF indicates atrial fibrillation; NVAF, nonvalvular atrial fibrillation; OAC, oral anticoagulation.

Figure 2.  Long-term Outcomes in Patients Developing Postoperative Atrial Fibrillation (POAF) After Isolated Left-Sided Heart Valve Surgery and Nonvalvular Atrial Fibrillation (NVAF)
Long-term Outcomes in Patients Developing Postoperative Atrial Fibrillation (POAF) After Isolated Left-Sided Heart Valve Surgery and Nonvalvular Atrial Fibrillation (NVAF)

A, Absolute risk of thromboembolism (composite of ischemic stroke, transient cerebral ischemia, and thrombosis or embolism in peripheral arteries). B, Absolute risk of recurrent atrial fibrillation (AF). C, Absolute risk of death.

Figure 3.  Adjusted Hazard Ratios of Thromboembolism and All-Cause Mortality in Patients Developing Postoperative Atrial Fibrillation (POAF) After Isolated Left-Sided Heart Valve Surgery and Nonvalvular Atrial Fibrillation (NVAF) per Oral Anticoagulant (OAC) Therapy Group During Follow-up
Adjusted Hazard Ratios of Thromboembolism and All-Cause Mortality in Patients Developing Postoperative Atrial Fibrillation (POAF) After Isolated Left-Sided Heart Valve Surgery and Nonvalvular Atrial Fibrillation (NVAF) per Oral Anticoagulant (OAC) Therapy Group During Follow-up

Adjusted for age, sex, comorbidity, concomitant pharmacotherapy, and year of inclusion.

Table 1.  Baseline Characteristics of Study Population
Baseline Characteristics of Study Population
Table 2.  Adjusted Hazard Ratios of Outcomes According to Type of Surgery
Adjusted Hazard Ratios of Outcomes According to Type of Surgery
1.
Mariscalco  G, Engström  KG.  Postoperative atrial fibrillation is associated with late mortality after coronary surgery, but not after valvular surgery.  Ann Thorac Surg. 2009;88(6):1871-1876. doi:10.1016/j.athoracsur.2009.07.074PubMedGoogle ScholarCrossref
2.
Helgadottir  S, Sigurdsson  MI, Ingvarsdottir  IL, Arnar  DO, Gudbjartsson  T.  Atrial fibrillation following cardiac surgery: risk analysis and long-term survival.  J Cardiothorac Surg. 2012;7:87. doi:10.1186/1749-8090-7-87PubMedGoogle ScholarCrossref
3.
Melby  SJ, George  JF, Picone  DJ,  et al.  A time-related parametric risk factor analysis for postoperative atrial fibrillation after heart surgery.  J Thorac Cardiovasc Surg. 2015;149(3):886-892. doi:10.1016/j.jtcvs.2014.11.032PubMedGoogle ScholarCrossref
4.
Swinkels  BM, de Mol  BA, Kelder  JC, Vermeulen  FE, Ten Berg  JM.  New-onset postoperative atrial fibrillation after aortic valve replacement: effect on long-term survival.  J Thorac Cardiovasc Surg. 2017;154(2):492-498. doi:10.1016/j.jtcvs.2017.02.052PubMedGoogle ScholarCrossref
5.
Almassi  GH, Schowalter  T, Nicolosi  AC,  et al.  Atrial fibrillation after cardiac surgery: a major morbid event?  Ann Surg. 1997;226(4):501-511. doi:10.1097/00000658-199710000-00011PubMedGoogle ScholarCrossref
6.
Mahoney  EM, Thompson  TD, Veledar  E, Williams  J, Weintraub  WS.  Cost-effectiveness of targeting patients undergoing cardiac surgery for therapy with intravenous amiodarone to prevent atrial fibrillation.  J Am Coll Cardiol. 2002;40(4):737-745. doi:10.1016/S0735-1097(02)02003-XPubMedGoogle ScholarCrossref
7.
Maisel  WH, Rawn  JD, Stevenson  WG.  Atrial fibrillation after cardiac surgery.  Ann Intern Med. 2001;135(12):1061-1073. doi:10.7326/0003-4819-135-12-200112180-00010PubMedGoogle ScholarCrossref
8.
Villareal  RP, Hariharan  R, Liu  BC,  et al.  Postoperative atrial fibrillation and mortality after coronary artery bypass surgery.  J Am Coll Cardiol. 2004;43(5):742-748. doi:10.1016/j.jacc.2003.11.023PubMedGoogle ScholarCrossref
9.
Steinberg  BA, Zhao  Y, He  X,  et al.  Management of postoperative atrial fibrillation and subsequent outcomes in contemporary patients undergoing cardiac surgery: insights from the Society of Thoracic Surgeons CAPS-Care Atrial Fibrillation Registry.  Clin Cardiol. 2014;37(1):7-13. doi:10.1002/clc.22230PubMedGoogle ScholarCrossref
10.
Gialdini  G, Nearing  K, Bhave  PD,  et al.  Perioperative atrial fibrillation and the long-term risk of ischemic stroke.  JAMA. 2014;312(6):616-622. doi:10.1001/jama.2014.9143PubMedGoogle ScholarCrossref
11.
Horwich  P, Buth  KJ, Légaré  JF.  New onset postoperative atrial fibrillation is associated with a long-term risk for stroke and death following cardiac surgery.  J Card Surg. 2013;28(1):8-13. doi:10.1111/jocs.12033PubMedGoogle ScholarCrossref
12.
Mariscalco  G, Klersy  C, Zanobini  M,  et al.  Atrial fibrillation after isolated coronary surgery affects late survival.  Circulation. 2008;118(16):1612-1618. doi:10.1161/CIRCULATIONAHA.108.777789PubMedGoogle ScholarCrossref
13.
Kohno  H, Ueda  H, Matsuura  K, Tamura  Y, Watanabe  M, Matsumiya  G.  Long-term consequences of atrial fibrillation after aortic valve replacement.  Asian Cardiovasc Thorac Ann. 2017;25(3):179-191. doi:10.1177/0218492317689902PubMedGoogle ScholarCrossref
14.
Kernis  SJ, Nkomo  VT, Messika-Zeitoun  D,  et al.  Atrial fibrillation after surgical correction of mitral regurgitation in sinus rhythm: incidence, outcome, and determinants.  Circulation. 2004;110(16):2320-2325. doi:10.1161/01.CIR.0000145121.25259.54PubMedGoogle ScholarCrossref
15.
Bramer  S, van Straten  AH, Soliman Hamad  MA, van den Broek  KC, Maessen  JG, Berreklouw  E.  New-onset postoperative atrial fibrillation predicts late mortality after mitral valve surgery.  Ann Thorac Surg. 2011;92(6):2091-2096. doi:10.1016/j.athoracsur.2011.06.079PubMedGoogle ScholarCrossref
16.
Girerd  N, Magne  J, Pibarot  P, Voisine  P, Dagenais  F, Mathieu  P.  Postoperative atrial fibrillation predicts long-term survival after aortic-valve surgery but not after mitral-valve surgery: a retrospective study.  BMJ Open. 2011;1(2):e000385. doi:10.1136/bmjopen-2011-000385PubMedGoogle ScholarCrossref
17.
Lip  GY, Lane  DA.  Stroke prevention in atrial fibrillation: a systematic review.  JAMA. 2015;313(19):1950-1962. doi:10.1001/jama.2015.4369PubMedGoogle ScholarCrossref
18.
Wolf  PA, Abbott  RD, Kannel  WB.  Atrial fibrillation as an independent risk factor for stroke: the Framingham Study.  Stroke. 1991;22(8):983-988. doi:10.1161/01.STR.22.8.983PubMedGoogle ScholarCrossref
19.
Kirchhof  P, Benussi  S, Kotecha  D,  et al.  2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS.  Eur J Cardiothorac Surg. 2016;50(5):e1-e88. doi:10.1093/ejcts/ezw313PubMedGoogle ScholarCrossref
20.
January  CT, Wann  LS, Alpert  JS,  et al; ACC/AHA Task Force Members.  2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary, a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society.  Circulation. 2014;130(23):2071-2104. doi:10.1161/CIR.0000000000000040PubMedGoogle ScholarCrossref
21.
Lynge  E, Sandegaard  JL, Rebolj  M.  The Danish National Patient Register.  Scand J Public Health. 2011;39(7)(suppl):30-33. doi:10.1177/1403494811401482PubMedGoogle ScholarCrossref
22.
Kildemoes  HW, Sørensen  HT, Hallas  J.  The Danish National Prescription Registry.  Scand J Public Health. 2011;39(7)(suppl):38-41. doi:10.1177/1403494810394717PubMedGoogle ScholarCrossref
23.
Pedersen  CB.  The Danish Civil Registration System.  Scand J Public Health. 2011;39(7)(suppl):22-25. doi:10.1177/1403494810387965PubMedGoogle ScholarCrossref
24.
Schramm  TK, Gislason  GH, Køber  L,  et al.  Diabetes patients requiring glucose-lowering therapy and nondiabetics with a prior myocardial infarction carry the same cardiovascular risk: a population study of 3.3 million people.  Circulation. 2008;117(15):1945-1954. doi:10.1161/CIRCULATIONAHA.107.720847PubMedGoogle ScholarCrossref
25.
Olesen  JB, Lip  GY, Hansen  ML,  et al.  Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study.  BMJ. 2011;342:d124. doi:10.1136/bmj.d124PubMedGoogle ScholarCrossref
26.
Olesen  JB, Sørensen  R, Hansen  ML,  et al.  Non-vitamin K antagonist oral anticoagulation agents in anticoagulant naïve atrial fibrillation patients: Danish nationwide descriptive data 2011-2013.  Europace. 2015;17(2):187-193. doi:10.1093/europace/euu225PubMedGoogle ScholarCrossref
27.
Staerk  L, Fosbøl  EL, Gadsbøll  K,  et al.  Non-vitamin K antagonist oral anticoagulation usage according to age among patients with atrial fibrillation: temporal trends 2011-2015 in Denmark.  Sci Rep. 2016;6:31477. doi:10.1038/srep31477PubMedGoogle ScholarCrossref
28.
Gislason  GH, Jacobsen  S, Rasmussen  JN,  et al.  Risk of death or reinfarction associated with the use of selective cyclooxygenase-2 inhibitors and nonselective nonsteroidal antiinflammatory drugs after acute myocardial infarction.  Circulation. 2006;113(25):2906-2913. doi:10.1161/CIRCULATIONAHA.106.616219PubMedGoogle ScholarCrossref
29.
Schjerning Olsen  AM, Gislason  GH, McGettigan  P,  et al.  Association of NSAID use with risk of bleeding and cardiovascular events in patients receiving antithrombotic therapy after myocardial infarction.  JAMA. 2015;313(8):805-814. doi:10.1001/jama.2015.0809PubMedGoogle ScholarCrossref
30.
Krarup  LH, Boysen  G, Janjua  H, Prescott  E, Truelsen  T.  Validity of stroke diagnoses in a national register of patients.  Neuroepidemiology. 2007;28(3):150-154. doi:10.1159/000102143PubMedGoogle ScholarCrossref
31.
Rix  TA, Riahi  S, Overvad  K, Lundbye-Christensen  S, Schmidt  EB, Joensen  AM.  Validity of the diagnoses atrial fibrillation and atrial flutter in a Danish patient registry.  Scand Cardiovasc J. 2012;46(3):149-153. doi:10.3109/14017431.2012.673728PubMedGoogle ScholarCrossref
32.
Gray  RJ.  A class of K-sample tests for comparing the cumulative incidence of a competing risk.  Ann Stat. 1988;16(3):1141-1154. doi:10.1214/aos/1176350951Google ScholarCrossref
33.
Butt  JH, Xian  Y, Peterson  ED,  et al.  Long-term thromboembolic risk in patients with postoperative atrial fibrillation after coronary artery bypass graft surgery and patients with nonvalvular atrial fibrillation.  JAMA Cardiol. 2018;3(5):417-424. doi:10.1001/jamacardio.2018.0405PubMedGoogle ScholarCrossref
34.
Whitlock  R, Healey  JS, Connolly  SJ,  et al.  Predictors of early and late stroke following cardiac surgery.  CMAJ. 2014;186(12):905-911. doi:10.1503/cmaj.131214PubMedGoogle ScholarCrossref
35.
Butt  JH, Olesen  JB, Havers-Borgersen  E,  et al.  Risk of thromboembolism associated with atrial fibrillation following noncardiac surgery.  J Am Coll Cardiol. 2018;72(17):2027-2036. doi:10.1016/j.jacc.2018.07.088PubMedGoogle ScholarCrossref
36.
Brambatti  M, Connolly  SJ, Gold  MR,  et al; ASSERT Investigators.  Temporal relationship between subclinical atrial fibrillation and embolic events.  Circulation. 2014;129(21):2094-2099. doi:10.1161/CIRCULATIONAHA.113.007825PubMedGoogle ScholarCrossref
37.
Martin  DT, Bersohn  MM, Waldo  AL,  et al; IMPACT Investigators.  Randomized trial of atrial arrhythmia monitoring to guide anticoagulation in patients with implanted defibrillator and cardiac resynchronization devices.  Eur Heart J. 2015;36(26):1660-1668. doi:10.1093/eurheartj/ehv115PubMedGoogle ScholarCrossref
38.
Healey  JS, Connolly  SJ, Gold  MR,  et al; ASSERT Investigators.  Subclinical atrial fibrillation and the risk of stroke.  N Engl J Med. 2012;366(2):120-129. doi:10.1056/NEJMoa1105575PubMedGoogle ScholarCrossref
39.
Mérie  C, Køber  L, Skov Olsen  P,  et al.  Association of warfarin therapy duration after bioprosthetic aortic valve replacement with risk of mortality, thromboembolic complications, and bleeding.  JAMA. 2012;308(20):2118-2125. doi:10.1001/jama.2012.54506PubMedGoogle ScholarCrossref
40.
Hsu  JC, Maddox  TM, Kennedy  KF,  et al.  Oral anticoagulant therapy prescription in patients with atrial fibrillation across the spectrum of stroke risk: insights from the NCDR PINNACLE registry.  JAMA Cardiol. 2016;1(1):55-62. doi:10.1001/jamacardio.2015.0374PubMedGoogle ScholarCrossref
41.
Wilke  T, Groth  A, Mueller  S,  et al.  Oral anticoagulation use by patients with atrial fibrillation in Germany: adherence to guidelines, causes of anticoagulation under-use and its clinical outcomes, based on claims-data of 183,448 patients.  Thromb Haemost. 2012;107(6):1053-1065. doi:10.1160/TH11-11-0768PubMedGoogle ScholarCrossref
42.
Bungard  TJ, Ghali  WA, Teo  KK, McAlister  FA, Tsuyuki  RT.  Why do patients with atrial fibrillation not receive warfarin?  Arch Intern Med. 2000;160(1):41-46. doi:10.1001/archinte.160.1.41PubMedGoogle ScholarCrossref
43.
Gadsbøll  K, Staerk  L, Fosbøl  EL,  et al.  Increased use of oral anticoagulants in patients with atrial fibrillation: temporal trends from 2005 to 2015 in Denmark.  Eur Heart J. 2017;38(12):899-906.PubMedGoogle Scholar
44.
Sabouret  P, Bricard  M, Hermann  MA, Cotté  FE, Deret-Bixio  L, Rushton-Smith  S.  Discrepancy between guidelines for stroke prevention in atrial fibrillation and practice patterns in primary care: the nationwide French AFIGP survey.  Arch Cardiovasc Dis. 2015;108(11):544-553. doi:10.1016/j.acvd.2015.05.005PubMedGoogle ScholarCrossref
45.
Nieuwlaat  R, Olsson  SB, Lip  GY,  et al; Euro Heart Survey Investigators; The Euro Heart Survey on Atrial Fibrillation.  Guideline-adherent antithrombotic treatment is associated with improved outcomes compared with undertreatment in high-risk patients with atrial fibrillation.  Am Heart J. 2007;153(6):1006-1012. doi:10.1016/j.ahj.2007.03.008PubMedGoogle ScholarCrossref
46.
Camm  AJ, Kirchhof  P, Lip  GY,  et al; European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery.  Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC).  Eur Heart J. 2010;31(19):2369-2429. doi:10.1093/eurheartj/ehq278PubMedGoogle ScholarCrossref
47.
Vahanian  A, Alfieri  O, Andreotti  F,  et al; Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC); European Association for Cardio-Thoracic Surgery (EACTS).  Guidelines on the management of valvular heart disease (version 2012).  Eur Heart J. 2012;33(19):2451-2496. doi:10.1093/eurheartj/ehs109PubMedGoogle ScholarCrossref
Original Investigation
October 9, 2019

Long-term Thromboembolic Risk in Patients With Postoperative Atrial Fibrillation After Left-Sided Heart Valve Surgery

Author Affiliations
  • 1Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  • 2Department of Cardiology, Herlev and Gentofte University Hospital, Hellerup, Denmark
  • 3Department of Cardiology, Herlev and Gentofte University Hospital, Herlev, Denmark
  • 4Department of Cardiothoracic Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  • 5The Danish Heart Foundation, Copenhagen, Denmark
  • 6The National Institute of Public Health, University of Southern Denmark, Odense, Denmark
  • 7Department of Cardiology, Nordsjællands Hospital, Hillerød, Denmark
JAMA Cardiol. 2019;4(11):1139-1147. doi:10.1001/jamacardio.2019.3649
Key Points

Question  Do patients who develop new-onset postoperative atrial fibrillation (POAF) after left-sided heart valve surgery have a similar long-term risk of thromboembolism as patients with nonsurgical nonvalvular atrial fibrillation (NVAF)?

Findings  In this cohort study that included 675 patients with POAF and 2025 matched patients with NVAF, new-onset POAF after left-sided heart valve surgery was associated with a long-term risk of thromboembolism similar to that of NVAF.

Meaning  These data warrant studies addressing the role of anticoagulation therapy in POAF after left-sided heart valve surgery.

Abstract

Importance  New-onset postoperative atrial fibrillation (POAF) is a common complication of cardiac surgery. However, data on the long-term risk of thromboembolism in patients who develop POAF after heart valve surgery are conflicting. In addition, data on stroke prophylaxis in this setting are lacking.

Objective  To assess the long-term risk of thromboembolism in patients developing new-onset POAF after isolated left-sided heart valve surgery relative to patients with nonsurgical, nonvalvular atrial fibrillation (NVAF).

Design, Setting, and Participants  This observational cohort study was conducted from January 1, 2000, through December 31, 2015, using Danish nationwide registries and the Eastern Danish Heart Surgery Database. Patients who developed POAF after isolated left-sided heart valve surgery (bioprosthetic aortic or mitral valve replacement and/or aortic or mitral valve repair) from 2000 through 2015 were included. These patients were matched with patients with nonsurgical NVAF in a 1:3 ratio by age, sex, heart failure, hypertension, diabetes, a history of thromboembolism, ischemic heart disease, and year of diagnosis. Data analyses took place from January to March 2019.

Main Outcomes and Measures  Rates of thromboembolism.

Results  Of the 1587 patients who underwent isolated left-sided heart valve surgery, 741 patients (46.7%) developed POAF during admission. Of the 712 patients with POAF who were eligible for matching, 675 patients were matched with 2025 patients with NVAF and made up the study population. In the matched study population, the median age was 71 (interquartile range, 65-77) years, and 1600 (59.3%) were men. Oral anticoagulation therapy was initiated within 30 days postdischarge in 420 patients with POAF (62.9%) and in 1030 patients with NVAF (51.4%). The crude incidence rates of thromboembolism were 21.9 (95% CI, 17.4-27.6) and 17.7 (95% CI, 15.2-20.6) events per 1000 person-years for patients with POAF and patients with NVAF, respectively. In the adjusted analysis, the long-term risk of thromboembolism was similar in patients with POAF and NVAF (hazard ratio, 1.22 [95% CI, 0.88-1.68]). Oral anticoagulation therapy during follow-up was associated with a lower risk of thromboembolic events in patients with POAF (hazard ratio, 0.45 [95% CI, 0.22-0.90]) as well as patients with NVAF (hazard ratio, 0.63 [95% CI, 0.45-0.87]) compared with no anticoagulation therapy.

Conclusions and Relevance  New-onset POAF after isolated left-sided heart valve surgery was associated with a similar long-term risk of thromboembolism as NVAF. These data warrant studies addressing the role of anticoagulation therapy in POAF after left-sided heart valve surgery.

Introduction

New-onset postoperative atrial fibrillation (POAF) is a common complication of cardiac surgery, with the highest reported incidence after valve surgery and combined valve and coronary artery bypass graft surgery. Thus, 30% to 60% of patients develop POAF during admission after isolated valve surgery with a higher incidence after combined surgery.1-7 Although traditionally thought to be a transient and benign phenomenon, mounting evidence suggest that POAF after cardiac surgery is associated with perioperative complications and worse long-term outcomes.8-12 However, there is a paucity of data on the association of POAF after valve surgery with long-term outcomes.1,2,4,5,13-16 The high incidence of POAF after valve surgery and the large number of surgical valve procedures performed in the growing elderly population worldwide makes it important to assess the clinical burden and long-term risks associated with POAF.

It is well established that nonvalvular atrial fibrillation (NVAF) confers a 5-fold increased risk of ischemic stroke and systemic embolism and oral anticoagulation (OAC) therapy considerably reduces this risk.17,18 However, it remains unknown whether new-onset POAF in association with valve surgery differs from NVAF in terms of long-term thromboembolic risk. Moreover, data on practice patterns and outcomes associated with use of OAC therapy in new-onset POAF after valvular surgery are lacking, and both European and American guidelines on the management of patients with AF do not provide clear recommendations regarding the role of OAC therapy in this context.19,20 The objective of this study was to examine stroke prophylaxis and the long-term risk of thromboembolism in patients developing new-onset POAF after isolated left-sided heart valve surgery relative to a matched cohort of patients with NVAF.

Methods
Data Sources

In Denmark, all residents are assigned a unique and permanent civil registration number, which allows an accurate linkage of nationwide administrative and clinical registries at an individual level. We used data from a prospectively collected cardiac surgery database composed of detailed clinical and procedural information on all patients undergoing cardiac surgery at the Copenhagen University Hospital, Rigshospitalet. These data were linked to the Danish National Patient Registry,21 the Danish National Prescription Registry,22 and the Danish Civil Registration System.23

Ethics

This study was approved by the Danish Data Protection Agency. In Denmark, ethical approval is not required for register-based studies in which individuals cannot be identified.

Study Population

All Danish residents 18 years and older who were undergoing first-time isolated left-sided heart valve surgery (bioprosthetic aortic or mitral valve replacement and/or aortic or mitral valve repair without any concomitant cardiac surgical procedure) at the Copenhagen University Hospital, Rigshospitalet, between January 1, 2000, and June 30, 2015, were identified. Patients were referred from East Denmark, which has a population of 2.6 million. Patients were included in the study if they (1) had no history of atrial fibrillation (AF) (defined as those who did not have a primary or secondary in-hospital or outpatient diagnosis of AF or prescriptions for antiarrhythmic drugs [ie, digoxin, flecainide, sotalol, amiodarone, or dronedarone] at any time prior to hospitalization for surgery), (2) developed POAF (defined as an AF rhythm requiring either medical therapy or cardioversion), (3) had not redeemed any OAC prescriptions in the 6 months prior to surgery, and (4) were alive at discharge. To compare the risk of thromboembolism between patients with POAF and NVAF, we identified a cohort of patients diagnosed with nonsurgical NVAF during hospitalization or in an outpatient clinic with a primary AF diagnosis, who (1) were not prescribed antiarrhythmic drugs at any time prior to diagnosis, (2) were not prescribed OACs in the 6 months prior to diagnosis, and (3) had not undergone any cardiac surgery prior to diagnosis. Using risk-set matching, patients with POAF were matched with patients with NVAF by age, sex, heart failure, hypertension, diabetes, a history of thromboembolism, ischemic heart disease, and year of index date, in a 1:3 ratio. For patients with POAF and patients with NVAF who were diagnosed with AF during hospitalization, the index date was defined as the discharge date. For patients with NVAF who were diagnosed in an outpatient clinic, the index date was defined as the date of diagnosis.

Covariates

Comorbidity was obtained using hospital discharge diagnoses any time prior to index (eTable 1 in the Supplement for International Classification of Diseases, Eighth Revision and Tenth Revision [ICD-8 and ICD-10] codes). Patients with diabetes and hypertension were identified using claimed drug prescriptions, as described previously.24,25 Alcohol abuse was defined from associated prescription filling and ICD-8 and ICD-10 codes. Pharmacotherapy at baseline was defined as claimed prescriptions within 180 days prior to the date of surgery or first diagnosis for patients with POAF and NVAF, respectively (eTable 2 in the Supplement for Anatomical Therapeutic Chemical Classification System codes). The estimated risk of stroke (CHA2DS2-VASc score) and bleeding (HAS-BLED score) was calculated as described previously.26,27

Postdischarge Oral Anticoagulation Therapy

Oral anticoagulant therapy (vitamin K antagonists or non–vitamin K antagonists) was assessed continuously for each individual during follow-up using an algorithm based on claimed prescriptions, taking the dates of claimed prescriptions, dosages, and package sizes into account, as described previously.28,29 We defined exposure to OAC therapy as the point at which patients had medication available and defined discontinuation as the point at which patients had no more medication available for at least 30 days. Patients could change exposure status during follow-up according to claimed OAC prescriptions in time-dependent analyses.

Outcomes

The primary outcome was thromboembolism, a composite of ischemic stroke, transient cerebral ischemia, and thrombosis or embolism in peripheral arteries. Secondary outcomes were recurrent AF, defined as a hospital admission or outpatient visit with AF as a primary or secondary diagnosis code. The diagnoses of AF and ischemic stroke in the Danish National Patient Registry have previously been validated with positive predictive values of 92.6% and 97%, respectively.30,31 Patients were followed up from the index date until occurrence of the outcome of interest, emigration, 10 years after index, or the end of the study (December 31, 2015), whichever came first.

Statistics

Descriptive data were reported as frequencies with percentages or medians with 25th and 75th percentiles (interquartile range [IQR]). Differences in baseline characteristics between patients with POAF and NVAF were examined by the χ2 test for categorical variables and the Mann-Whitney test for continuous variables. The absolute risk of thromboembolism and recurrent AF was estimated using the Aalen-Johansen estimator,32 taking the competing risk of death into account, and differences between groups were assessed using the Gray test. Survival curves were constructed by the Kaplan-Meier method, and differences between groups were assessed using the log-rank test. Cause-specific Cox regression models conditional on matching (ie, comparing cases with their matched controls) were used to examine the risk of thromboembolism, recurrent AF, and all-cause mortality. Reported were hazard ratios (HRs) with 95% CIs, adjusted for comorbidity, concomitant pharmacotherapy, and OAC therapy as a time-dependent covariate. Patients with NVAF served as the reference group in all models. The proportional hazards assumption was tested and found to be valid. Clinically relevant interactions, including age, sex, several comorbidities, and OAC treatment during follow-up, were tested and found insignificant.

All statistical analyses were performed with SAS statistical software version 9.4 (SAS Institute) from January to March 2019. The level of statistical significance was set at 5%.

Results

From January 1, 2000, to June 30, 2015, 1587 patients with no history of AF underwent first-time left-sided heart valve surgery. Of these, 741 patients (46.7%) developed POAF during hospitalization. The incidence of POAF was 46.8% (n = 554 of 1184) after isolated aortic valve replacement, 48.5% (n = 16 of 33) after isolated mitral valve replacement, 46.3% (n = 158 of 341) after isolated mitral valve repair, and 44.8% (n = 13 of 29) after combined aortic and mitral valve surgery. After exclusion criteria were applied, 712 patients with POAF were eligible for matching, of whom 675 patients were matched with 2025 patients with NVAF (Figure 1). Baseline characteristics according to groups are summarized in Table 1. The median age of the study population was 71 (IQR, 65-77) years, and 1600 (59.3%) were men. The POAF group was characterized by higher prevalence of chronic kidney disease (POAF: 92 of 2025 [4.5%]; NVAF: 51 of 675 [7.6%]; P = .002) and a lower proportion of patients with a history of cancer (POAF: 299 of 2025 [14.8%]; NVAF: 74 of 675 [11.0%]; P = .01) compared with the NVAF group.

Postdischarge Anticoagulation Therapy

In the POAF group, 420 patients (62.9%) initiated OAC therapy (of whom 410 [97.6%] received warfarin) within 30 days after the index date. Correspondingly, 1030 patients (51.4%) initiated OAC therapy (of whom 752 [73.0%] received warfarin) in the NVAF group within 30 days. However, the crude proportion of patients receiving OAC therapy within 30 days changed in both groups during the study period; there was a steep increase after 2010 in the NVAF group, whereas a decrease was observed in the POAF group (eFigure 1 in the Supplement). Baseline characteristics according to OAC therapy initiation within 30 days after discharge among patients alive at 30 days postdischarge are summarized in eTable 3 in the Supplement. Among patients with POAF who initiated OAC therapy, 55.0% (n = 230 of 418) were in treatment at 3 months postdischarge, 31.7% (n = 132 of 416) at 6 months postdischarge, and 22.1% (n = 89 of 402) at 1 year postdischarge. Correspondingly, among patients with NVAF who initiated OAC therapy, 81.5% (n = 838 of 1028) were in treatment at 3 months postdischarge; 81.8% (n = 833 of 1018) at 6 months postdischarge, and 79.0% (n = 765 of 968) at 1 year postdischarge. The proportion of patients receiving OAC therapy within 30 days according to CHA2DS2-VASc and HAS-BLED-score are displayed in eTable 4 in the Supplement.

Thromboembolism

The median follow-up time from the index date until occurrence of a thromboembolic event, death, emigration, or end of the study period was 4.2 (IQR, 2.0-7.1) years and 3.7 (IQR, 1.8-6.8) years for patients with POAF and NVAF, respectively. The absolute risks of thromboembolism according to groups are displayed in Figure 2A. The crude incidence rates of thromboembolism were 21.9 (95% CI, 17.4-27.6) events per 1000 person-years and 17.7 (95% CI, 15.2-20.6) events per 1000 person-years for patients with POAF and NVAF, respectively. In Cox regression analysis, POAF was associated with a similar risk of thromboembolism as NVAF (HR, 1.22 [95% CI, 0.88-1.68]). This association was similar irrespective of underlying valvular disease (Table 2). In patients with POAF and those with NVAF, OAC therapy during follow-up was associated with a significantly lower risk of thromboembolism (patients with POAF: HR, 0.45 [95% CI, 0.22-0.90]; patients with NVAF: HR, 0.63 [95% CI, 0.45-0.87]; Figure 3).

Recurrent AF and All-Cause Mortality

Figure 2B displays the absolute risks of recurrent AF according to groups. The crude incidence rates of recurrent AF were 118.9 (95% CI, 105.7-133.8) events per 1000 person-years and 358.3 (95% CI, 340.0-377.6) events per 1000 person-years for patients with POAF and NVAF, respectively. In Cox regression analysis, POAF was associated with a significantly lower risk of recurrent AF compared with NVAF (HR, 0.62 [95% CI, 0.56-0.70]). However, POAF after aortic valve replacement was associated with a lower risk of recurrent AF compared with NVAF (HR, 0.52 [95% CI, 0.46-0.60]), whereas POAF after mitral valve surgery was associated with a similar risk of recurrent AF compared with NVAF (Table 2).

Figure 2C depicts the absolute risks of death according to groups. The crude incidence rates of all-cause mortality were 42.1 (95% CI, 35.9-49.5) events per 1000 person-years and 68.9 (95% CI, 63.8-74.4) events per 1000 person-years for patients with POAF and NVAF, respectively. In Cox regression analysis, POAF was associated with a significantly lower risk of all-cause mortality compared with NVAF (HR, 0.53 [95% CI, 0.43-0.65]). This association was similar irrespective of underlying valvular disease (POAF after aortic valve replacement: HR, 0.54 [95% CI, 0.44-0.68]; POAF after mitral valve surgery: HR, 0.47 [95% CI, 0.27-0.80]; Table 2).

Sensitivity Analysis

First, we restricted the primary outcome of thromboembolism to ischemic stroke and found a similar association as the main analysis (HR, 1.30 [95% CI, 0.90-1.87] for POAF compared with NVAF). Next, we excluded patients with NVAF who had been diagnosed in an outpatient clinic; this analysis yielded similar results as the main analysis for the primary outcome of thromboembolism (HR, 1.19 [95% CI, 0.86-1.67]). Third, we compared the risk of thromboembolism in patients with POAF with an unmatched cohort of patients with NVAF and found consistent results (HR, 0.95 [95% CI, 0.77-1.18] for POAF compared with NVAF). Fourth, the AF end point was restricted to a hospital admission with AF as the primary diagnosis. In line with the main findings, POAF was associated with a significantly lower risk of AF compared with NVAF (HR, 0.67 [95% CI, 0.56-0.81]). Likewise, although POAF after aortic valve replacement was associated with a lower risk of AF compared with NVAF, POAF after mitral valve surgery was associated with a similar risk of AF. Finally, we compared the risk of outcomes in patients developing and not developing POAF after isolated left-sided heart valve surgery. Baseline characteristics according to groups are summarized in eTable 5 in the Supplement. Patients developing POAF had a significantly higher associated risk of thromboembolism (HR, 1.42 [95% CI, 1.02-1.98]) and recurrent AF (HR, 2.49 [95% CI, 2.04-3.05]) but not all-cause mortality (HR, 1.10 [95% CI, 0.87-1.39]) compared with those who did not develop POAF after isolated left-sided heart valve surgery (eFigure 2 in the Supplement).

Discussion

In this cohort study, we examined the long-term risk of thromboembolism in patients developing new-onset POAF after isolated left-sided heart valve surgery relative to a matched cohort of patients with NVAF. The study yielded 3 major findings. First, among patients with no history of AF who underwent isolated valve surgery, 46.7% developed POAF during hospitalization with a similar incidence after aortic and mitral valve replacement or repair. Second, POAF was associated with a similar risk of thromboembolism compared with NVAF. Third, POAF after aortic valve replacement was associated with a lower risk of recurrent AF compared with NVAF, whereas POAF after mitral valve surgery was associated with a similar risk of recurrent AF compared with NVAF.

Mounting evidence suggests that new-onset POAF should not be considered a transient and benign phenomenon. The onset of POAF after coronary artery bypass graft surgery has been associated with an increased risk of perioperative complications, prolonged hospital admission, short-term ischemic stroke, and mortality, although data on the long-term thromboembolic risk are conflicting.8-12,33,34 In patients undergoing noncardiac surgery, POAF has been associated with an increased long-term risk of ischemic stroke compared with no development of AF.10,35 Further, in a large nationwide cohort study in Denmark,35 we recently found that new-onset POAF after noncardiac surgery was associated with a similar thromboembolic risk compared with NVAF. However, data on the long-term thromboembolic risk associated with POAF after valve surgery are conflicting. In a recent retrospective cohort study, Swinkels et al4 did not find new-onset POAF after aortic valve replacement to be associated with stroke, whereas Kohno et al13 found that POAF after aortic valve replacement was associated with a greater long-term risk of stroke. Likewise, Kernis et al14 found that POAF after mitral valve surgery was associated with an increased risk of stroke or heart failure compared with no POAF. However, these studies were limited by a small number of patients and (more importantly) the lack of data on medication use and thus were not able to account for OAC treatment during follow-up. To our knowledge, this study is the first to examine the long-term thromboembolic risk associated with POAF after isolated left-sided valve surgery relative to NVAF with data on postdischarge OAC treatment. After adjustment for comorbidity, concomitant pharmacotherapy, and postdischarge OAC treatment, we found that new-onset POAF after left-sided heart valve surgery was associated with a similar risk of thromboembolism compared with NVAF. Further, we found that patients developing POAF had a significantly higher associated risk of thromboembolism compared with those who did not develop POAF after left-sided heart valve surgery. Thus, these data support that new-onset POAF after left-sided heart valve surgery should be regarded as similar to NVAF in terms of long-term thromboembolic risk.

Although POAF has traditionally thought to be transient and benign, it remains unknown whether POAF after valve surgery is associated with the development of late AF. We found that POAF overall was associated with a significantly lower risk of recurrent AF compared with NVAF, although POAF after mitral valve surgery was associated with a similar risk of recurrent AF compared with NVAF. The finding that POAF was associated with a thromboembolic risk similar to that of NVAF is inconsistent with the lower risk of recurrent AF in the POAF group, although studies have demonstrated a lack of temporal association between AF occurrence and stroke events.36,37 Although speculative, this observation may in part be attributed to a greater burden of subclinical AF episodes in the POAF group, because even short episodes of subclinical AF have been associated with a significantly increased risk of subsequent thromboembolism.38 Another possible explanation may be that atrial cardiomyopathy, which may be a determinant of stroke risk independently of AF, is present to a greater extent in patients with POAF than in patients with NVAF because of the underlying valvular disease. However, we also found that patients who developed POAF had a significantly higher associated risk of thromboembolism and recurrent AF compared with those who did not develop POAF after left-sided heart valve surgery. The lack of data on echocardiographic measurements and burden of subclinical AF makes it difficult to assess whether the excess thromboembolic risk in POAF patients is attributable to recurrent AF or atrial cardiomyopathy secondary to the underlying valvular disease. Nevertheless, these findings add to the notion that POAF is not to be regarded as a transient and benign phenomenon.

Although these data suggest that POAF after left-sided heart valve surgery is associated with a similar long-term risk of thromboembolism compared with NVAF, the question remains whether these patients should initiate OAC therapy for the prevention of thromboembolic events. International guidelines for the management of patients with AF only briefly address the role of OAC therapy in this setting. Both American and European guidelines19,20 provide a class IIa recommendation (level of evidence B) for OAC therapy in POAF after cardiac surgery without providing any clear recommendations on the indication, timing, and duration of OAC treatment. However, these guidelines highlight the need for high-quality evidence regarding the role of OAC therapy in POAF. Although it may seem reasonable to initiate OAC therapy if the risk of thromboembolism outweighs the risk of bleeding, it is important to keep in mind that this recommendation is based on scarce evidence and also that these risk stratification scores have not been validated in patients undergoing surgery. Interestingly, we found that OAC therapy during follow-up was associated with a comparably lower thromboembolic risk in both patients with POAF and patients with NVAF, suggesting a similar effectiveness of OAC for stroke prevention. These findings are in line with those from a previous study,39 in which we demonstrated that discontinuation of warfarin treatment within 6 months after bioprosthetic aortic valve replacement was associated with increased cardiovascular death and particularly thromboembolic events. To support these findings, randomized clinical studies specifically addressing the role of OAC therapy in the setting of POAF are warranted to examine the efficacy, safety, timing, and duration of OAC therapy.

An interesting observation of this study was the 30-day OAC initiation rates in both groups during the study period. In line with previous studies,40-45 we found a substantial underuse of OAC therapy in patients with NVAF, particularly before 2010. Since 2010, the European guidelines for the management of AF have recommended OAC therapy for all patients with AF who are at moderate to high risk of stroke, and this guideline change most likely contributed to the increased OAC initiation rates in patients with NVAF during the study period, with a steep increase from 2010 in this study.46 Although we found an overall proportion of patients with NVAF initiating OAC therapy within 30 days of only 52%, it is reassuring that this proportion increased to 77% in 2015. In patients with POAF, however, the proportion of patients initiating OAC therapy within 30 days after discharge decreased significantly during the study period. Since 2012, the European guidelines47 on the management of valvular heart disease have favored low-dose aspirin as an alternative to postoperative OAC therapy in patients with surgical aortic bioprostheses, and this may in part explain the decrease in OAC initiation rates in patients with POAF during the study period.

Strength

The main strength of this study is the completeness of data in a cohort of patients undergoing first-time isolated left-sided valve surgery and a nationwide cohort of patients with NVAF who were followed up in a real-world setting. The Danish health care system provides equal access to health care services for all residents regardless of socioeconomic or insurance status. In Denmark, OACs can be purchased only through prescription, and all Danish pharmacies are required to register all redeemed prescriptions, which ensures complete and accurate registration.

Limitations

However, the findings of this study should be viewed in the context of a number of limitations. The observational nature of this study precludes the assessment of cause-effect associations, and the possibility of residual confounding cannot be excluded, despite adjustment for potential confounders. Moreover, no causal inference can be drawn from the OAC effectiveness analyses, because these may be susceptible to confounding by indication (ie, patients in better health receiving OAC therapy). Thus, the findings from these analyses do not necessarily indicate a clinical benefit of OAC therapy in patients developing POAF after left-sided valve surgery. Rather, these findings underscore the need for future randomized clinical trials examining the effectiveness of OAC therapy in POAF. In this study, POAF was defined as a rhythm requiring either medical therapy or cardioversion, and thus short episodes of POAF might have been missed. This definition also does not allow for a distinction between patients who exclusively received either medical therapy or cardioversion. Furthermore, we did not have any information on duration of POAF or number of AF episodes during admission, discharge rhythm, indication for OAC therapy, or factors affecting the clinicians’ decision to prescribe OACs. Likewise, data on stroke causative mechanism (ie, cardioembolic vs noncardioembolic origin) were not available for this study. In addition, data on AF burden or type of recurrent AF (ie, paroxysmal, persistent, or chronic) during follow-up in either group were not available. Data on important clinical parameters, such as echocardiographic measurements (including left atrial size and left ventricular ejection fraction), estimated glomerular fraction, international normalized ratio, low-density lipoprotein cholesterol, body mass index, and smoking habits, as well as electrocardiographic data, were unavailable.

Conclusions

New-onset POAF after isolated left-sided heart valve surgery was associated with a similar long-term thromboembolic risk compared with NVAF and a greater thromboembolic risk compared with no development of POAF after left-sided heart valve surgery. These data warrant studies addressing the role of anticoagulation therapy in POAF after left-sided heart valve surgery.

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Article Information

Accepted for Publication: July 27, 2019.

Corresponding Author: Jawad Haider Butt, MD, Department of Cardiology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, 2100 København Ø, Denmark (jawad_butt91@hotmail.com).

Published Online: October 9, 2019. doi:10.1001/jamacardio.2019.3649

Author Contributions: Drs Butt and Fosbøl had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Butt, Bjerring Olesen, Fosbøl.

Acquisition, analysis, or interpretation of data: Butt, Gundlund, Kümler, Olsen, Havers-Borgersen, Aagaard, Gislasson, Torp-Pedersen, Køber, Fosbøl.

Drafting of the manuscript: Butt, Fosbøl.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Butt, Havers-Borgersen, Aagaard, Fosbøl.

Obtained funding: Torp-Pedersen, Køber.

Administrative, technical, or material support: Butt, Kümler, Olsen, Gislasson, Køber, Fosbøl.

Supervision: Bjerring Olesen, Gundlund, Kümler, Torp-Pedersen, Køber, Fosbøl.

Conflict of Interest Disclosures: Dr Olesen reports grants and personal fees from Bristol-Myers Squibb and personal fees from Boehringer Ingelheim, Bayer, AstraZeneca, Novartis Healthcare, and Novo Nordisk outside the submitted work. Dr Gislason reports research grants from Bristol-Myers Squibb, Bayer, Pfizer, and Boehringer Ingelheim outside the submitted work. Dr Torp-Pedersen reported grants from Bayer and Novo Nordisk outside the submitted work. No other disclosures were reported.

References
1.
Mariscalco  G, Engström  KG.  Postoperative atrial fibrillation is associated with late mortality after coronary surgery, but not after valvular surgery.  Ann Thorac Surg. 2009;88(6):1871-1876. doi:10.1016/j.athoracsur.2009.07.074PubMedGoogle ScholarCrossref
2.
Helgadottir  S, Sigurdsson  MI, Ingvarsdottir  IL, Arnar  DO, Gudbjartsson  T.  Atrial fibrillation following cardiac surgery: risk analysis and long-term survival.  J Cardiothorac Surg. 2012;7:87. doi:10.1186/1749-8090-7-87PubMedGoogle ScholarCrossref
3.
Melby  SJ, George  JF, Picone  DJ,  et al.  A time-related parametric risk factor analysis for postoperative atrial fibrillation after heart surgery.  J Thorac Cardiovasc Surg. 2015;149(3):886-892. doi:10.1016/j.jtcvs.2014.11.032PubMedGoogle ScholarCrossref
4.
Swinkels  BM, de Mol  BA, Kelder  JC, Vermeulen  FE, Ten Berg  JM.  New-onset postoperative atrial fibrillation after aortic valve replacement: effect on long-term survival.  J Thorac Cardiovasc Surg. 2017;154(2):492-498. doi:10.1016/j.jtcvs.2017.02.052PubMedGoogle ScholarCrossref
5.
Almassi  GH, Schowalter  T, Nicolosi  AC,  et al.  Atrial fibrillation after cardiac surgery: a major morbid event?  Ann Surg. 1997;226(4):501-511. doi:10.1097/00000658-199710000-00011PubMedGoogle ScholarCrossref
6.
Mahoney  EM, Thompson  TD, Veledar  E, Williams  J, Weintraub  WS.  Cost-effectiveness of targeting patients undergoing cardiac surgery for therapy with intravenous amiodarone to prevent atrial fibrillation.  J Am Coll Cardiol. 2002;40(4):737-745. doi:10.1016/S0735-1097(02)02003-XPubMedGoogle ScholarCrossref
7.
Maisel  WH, Rawn  JD, Stevenson  WG.  Atrial fibrillation after cardiac surgery.  Ann Intern Med. 2001;135(12):1061-1073. doi:10.7326/0003-4819-135-12-200112180-00010PubMedGoogle ScholarCrossref
8.
Villareal  RP, Hariharan  R, Liu  BC,  et al.  Postoperative atrial fibrillation and mortality after coronary artery bypass surgery.  J Am Coll Cardiol. 2004;43(5):742-748. doi:10.1016/j.jacc.2003.11.023PubMedGoogle ScholarCrossref
9.
Steinberg  BA, Zhao  Y, He  X,  et al.  Management of postoperative atrial fibrillation and subsequent outcomes in contemporary patients undergoing cardiac surgery: insights from the Society of Thoracic Surgeons CAPS-Care Atrial Fibrillation Registry.  Clin Cardiol. 2014;37(1):7-13. doi:10.1002/clc.22230PubMedGoogle ScholarCrossref
10.
Gialdini  G, Nearing  K, Bhave  PD,  et al.  Perioperative atrial fibrillation and the long-term risk of ischemic stroke.  JAMA. 2014;312(6):616-622. doi:10.1001/jama.2014.9143PubMedGoogle ScholarCrossref
11.
Horwich  P, Buth  KJ, Légaré  JF.  New onset postoperative atrial fibrillation is associated with a long-term risk for stroke and death following cardiac surgery.  J Card Surg. 2013;28(1):8-13. doi:10.1111/jocs.12033PubMedGoogle ScholarCrossref
12.
Mariscalco  G, Klersy  C, Zanobini  M,  et al.  Atrial fibrillation after isolated coronary surgery affects late survival.  Circulation. 2008;118(16):1612-1618. doi:10.1161/CIRCULATIONAHA.108.777789PubMedGoogle ScholarCrossref
13.
Kohno  H, Ueda  H, Matsuura  K, Tamura  Y, Watanabe  M, Matsumiya  G.  Long-term consequences of atrial fibrillation after aortic valve replacement.  Asian Cardiovasc Thorac Ann. 2017;25(3):179-191. doi:10.1177/0218492317689902PubMedGoogle ScholarCrossref
14.
Kernis  SJ, Nkomo  VT, Messika-Zeitoun  D,  et al.  Atrial fibrillation after surgical correction of mitral regurgitation in sinus rhythm: incidence, outcome, and determinants.  Circulation. 2004;110(16):2320-2325. doi:10.1161/01.CIR.0000145121.25259.54PubMedGoogle ScholarCrossref
15.
Bramer  S, van Straten  AH, Soliman Hamad  MA, van den Broek  KC, Maessen  JG, Berreklouw  E.  New-onset postoperative atrial fibrillation predicts late mortality after mitral valve surgery.  Ann Thorac Surg. 2011;92(6):2091-2096. doi:10.1016/j.athoracsur.2011.06.079PubMedGoogle ScholarCrossref
16.
Girerd  N, Magne  J, Pibarot  P, Voisine  P, Dagenais  F, Mathieu  P.  Postoperative atrial fibrillation predicts long-term survival after aortic-valve surgery but not after mitral-valve surgery: a retrospective study.  BMJ Open. 2011;1(2):e000385. doi:10.1136/bmjopen-2011-000385PubMedGoogle ScholarCrossref
17.
Lip  GY, Lane  DA.  Stroke prevention in atrial fibrillation: a systematic review.  JAMA. 2015;313(19):1950-1962. doi:10.1001/jama.2015.4369PubMedGoogle ScholarCrossref
18.
Wolf  PA, Abbott  RD, Kannel  WB.  Atrial fibrillation as an independent risk factor for stroke: the Framingham Study.  Stroke. 1991;22(8):983-988. doi:10.1161/01.STR.22.8.983PubMedGoogle ScholarCrossref
19.
Kirchhof  P, Benussi  S, Kotecha  D,  et al.  2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS.  Eur J Cardiothorac Surg. 2016;50(5):e1-e88. doi:10.1093/ejcts/ezw313PubMedGoogle ScholarCrossref
20.
January  CT, Wann  LS, Alpert  JS,  et al; ACC/AHA Task Force Members.  2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary, a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society.  Circulation. 2014;130(23):2071-2104. doi:10.1161/CIR.0000000000000040PubMedGoogle ScholarCrossref
21.
Lynge  E, Sandegaard  JL, Rebolj  M.  The Danish National Patient Register.  Scand J Public Health. 2011;39(7)(suppl):30-33. doi:10.1177/1403494811401482PubMedGoogle ScholarCrossref
22.
Kildemoes  HW, Sørensen  HT, Hallas  J.  The Danish National Prescription Registry.  Scand J Public Health. 2011;39(7)(suppl):38-41. doi:10.1177/1403494810394717PubMedGoogle ScholarCrossref
23.
Pedersen  CB.  The Danish Civil Registration System.  Scand J Public Health. 2011;39(7)(suppl):22-25. doi:10.1177/1403494810387965PubMedGoogle ScholarCrossref
24.
Schramm  TK, Gislason  GH, Køber  L,  et al.  Diabetes patients requiring glucose-lowering therapy and nondiabetics with a prior myocardial infarction carry the same cardiovascular risk: a population study of 3.3 million people.  Circulation. 2008;117(15):1945-1954. doi:10.1161/CIRCULATIONAHA.107.720847PubMedGoogle ScholarCrossref
25.
Olesen  JB, Lip  GY, Hansen  ML,  et al.  Validation of risk stratification schemes for predicting stroke and thromboembolism in patients with atrial fibrillation: nationwide cohort study.  BMJ. 2011;342:d124. doi:10.1136/bmj.d124PubMedGoogle ScholarCrossref
26.
Olesen  JB, Sørensen  R, Hansen  ML,  et al.  Non-vitamin K antagonist oral anticoagulation agents in anticoagulant naïve atrial fibrillation patients: Danish nationwide descriptive data 2011-2013.  Europace. 2015;17(2):187-193. doi:10.1093/europace/euu225PubMedGoogle ScholarCrossref
27.
Staerk  L, Fosbøl  EL, Gadsbøll  K,  et al.  Non-vitamin K antagonist oral anticoagulation usage according to age among patients with atrial fibrillation: temporal trends 2011-2015 in Denmark.  Sci Rep. 2016;6:31477. doi:10.1038/srep31477PubMedGoogle ScholarCrossref
28.
Gislason  GH, Jacobsen  S, Rasmussen  JN,  et al.  Risk of death or reinfarction associated with the use of selective cyclooxygenase-2 inhibitors and nonselective nonsteroidal antiinflammatory drugs after acute myocardial infarction.  Circulation. 2006;113(25):2906-2913. doi:10.1161/CIRCULATIONAHA.106.616219PubMedGoogle ScholarCrossref
29.
Schjerning Olsen  AM, Gislason  GH, McGettigan  P,  et al.  Association of NSAID use with risk of bleeding and cardiovascular events in patients receiving antithrombotic therapy after myocardial infarction.  JAMA. 2015;313(8):805-814. doi:10.1001/jama.2015.0809PubMedGoogle ScholarCrossref
30.
Krarup  LH, Boysen  G, Janjua  H, Prescott  E, Truelsen  T.  Validity of stroke diagnoses in a national register of patients.  Neuroepidemiology. 2007;28(3):150-154. doi:10.1159/000102143PubMedGoogle ScholarCrossref
31.
Rix  TA, Riahi  S, Overvad  K, Lundbye-Christensen  S, Schmidt  EB, Joensen  AM.  Validity of the diagnoses atrial fibrillation and atrial flutter in a Danish patient registry.  Scand Cardiovasc J. 2012;46(3):149-153. doi:10.3109/14017431.2012.673728PubMedGoogle ScholarCrossref
32.
Gray  RJ.  A class of K-sample tests for comparing the cumulative incidence of a competing risk.  Ann Stat. 1988;16(3):1141-1154. doi:10.1214/aos/1176350951Google ScholarCrossref
33.
Butt  JH, Xian  Y, Peterson  ED,  et al.  Long-term thromboembolic risk in patients with postoperative atrial fibrillation after coronary artery bypass graft surgery and patients with nonvalvular atrial fibrillation.  JAMA Cardiol. 2018;3(5):417-424. doi:10.1001/jamacardio.2018.0405PubMedGoogle ScholarCrossref
34.
Whitlock  R, Healey  JS, Connolly  SJ,  et al.  Predictors of early and late stroke following cardiac surgery.  CMAJ. 2014;186(12):905-911. doi:10.1503/cmaj.131214PubMedGoogle ScholarCrossref
35.
Butt  JH, Olesen  JB, Havers-Borgersen  E,  et al.  Risk of thromboembolism associated with atrial fibrillation following noncardiac surgery.  J Am Coll Cardiol. 2018;72(17):2027-2036. doi:10.1016/j.jacc.2018.07.088PubMedGoogle ScholarCrossref
36.
Brambatti  M, Connolly  SJ, Gold  MR,  et al; ASSERT Investigators.  Temporal relationship between subclinical atrial fibrillation and embolic events.  Circulation. 2014;129(21):2094-2099. doi:10.1161/CIRCULATIONAHA.113.007825PubMedGoogle ScholarCrossref
37.
Martin  DT, Bersohn  MM, Waldo  AL,  et al; IMPACT Investigators.  Randomized trial of atrial arrhythmia monitoring to guide anticoagulation in patients with implanted defibrillator and cardiac resynchronization devices.  Eur Heart J. 2015;36(26):1660-1668. doi:10.1093/eurheartj/ehv115PubMedGoogle ScholarCrossref
38.
Healey  JS, Connolly  SJ, Gold  MR,  et al; ASSERT Investigators.  Subclinical atrial fibrillation and the risk of stroke.  N Engl J Med. 2012;366(2):120-129. doi:10.1056/NEJMoa1105575PubMedGoogle ScholarCrossref
39.
Mérie  C, Køber  L, Skov Olsen  P,  et al.  Association of warfarin therapy duration after bioprosthetic aortic valve replacement with risk of mortality, thromboembolic complications, and bleeding.  JAMA. 2012;308(20):2118-2125. doi:10.1001/jama.2012.54506PubMedGoogle ScholarCrossref
40.
Hsu  JC, Maddox  TM, Kennedy  KF,  et al.  Oral anticoagulant therapy prescription in patients with atrial fibrillation across the spectrum of stroke risk: insights from the NCDR PINNACLE registry.  JAMA Cardiol. 2016;1(1):55-62. doi:10.1001/jamacardio.2015.0374PubMedGoogle ScholarCrossref
41.
Wilke  T, Groth  A, Mueller  S,  et al.  Oral anticoagulation use by patients with atrial fibrillation in Germany: adherence to guidelines, causes of anticoagulation under-use and its clinical outcomes, based on claims-data of 183,448 patients.  Thromb Haemost. 2012;107(6):1053-1065. doi:10.1160/TH11-11-0768PubMedGoogle ScholarCrossref
42.
Bungard  TJ, Ghali  WA, Teo  KK, McAlister  FA, Tsuyuki  RT.  Why do patients with atrial fibrillation not receive warfarin?  Arch Intern Med. 2000;160(1):41-46. doi:10.1001/archinte.160.1.41PubMedGoogle ScholarCrossref
43.
Gadsbøll  K, Staerk  L, Fosbøl  EL,  et al.  Increased use of oral anticoagulants in patients with atrial fibrillation: temporal trends from 2005 to 2015 in Denmark.  Eur Heart J. 2017;38(12):899-906.PubMedGoogle Scholar
44.
Sabouret  P, Bricard  M, Hermann  MA, Cotté  FE, Deret-Bixio  L, Rushton-Smith  S.  Discrepancy between guidelines for stroke prevention in atrial fibrillation and practice patterns in primary care: the nationwide French AFIGP survey.  Arch Cardiovasc Dis. 2015;108(11):544-553. doi:10.1016/j.acvd.2015.05.005PubMedGoogle ScholarCrossref
45.
Nieuwlaat  R, Olsson  SB, Lip  GY,  et al; Euro Heart Survey Investigators; The Euro Heart Survey on Atrial Fibrillation.  Guideline-adherent antithrombotic treatment is associated with improved outcomes compared with undertreatment in high-risk patients with atrial fibrillation.  Am Heart J. 2007;153(6):1006-1012. doi:10.1016/j.ahj.2007.03.008PubMedGoogle ScholarCrossref
46.
Camm  AJ, Kirchhof  P, Lip  GY,  et al; European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery.  Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC).  Eur Heart J. 2010;31(19):2369-2429. doi:10.1093/eurheartj/ehq278PubMedGoogle ScholarCrossref
47.
Vahanian  A, Alfieri  O, Andreotti  F,  et al; Joint Task Force on the Management of Valvular Heart Disease of the European Society of Cardiology (ESC); European Association for Cardio-Thoracic Surgery (EACTS).  Guidelines on the management of valvular heart disease (version 2012).  Eur Heart J. 2012;33(19):2451-2496. doi:10.1093/eurheartj/ehs109PubMedGoogle ScholarCrossref
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