Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1332 Atrial Fibrillation in the setting of Coronary Artery Disease Risks and outcomes with different treatment options GORAV BATRA ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6206 ISBN 978-91-554-9917-4 UPPSALA urn:nbn:se:uu:diva-320541 2017 Dissertation presented at Uppsala University to be publicly examined in Enghoffsalen, Akademiska sjukhuset, Ingång 50, Uppsala, Friday, 9 June 2017 at 13:00 for the degree of Doctor of Philosophy (Faculty of Medicine). The examination will be conducted in English. Faculty examiner: Professor Gunnar Gislason (Department of Cardiology, Copenhagen University Hospital Gentofte, Copenhagen, Denmark). Abstract Batra, G. 2017. Atrial Fibrillation in the setting of Coronary Artery Disease. Risks and outcomes with different treatment options. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 1332. 86 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-554-9917-4. Coronary artery disease (CAD) is the leading cause of mortality worldwide and atrial fibrillation (AF) is a prevalent arrhythmia associated with increased risk of mortality and morbidity. Despite improved outcome in both diseases, there is a need to further describe the prevalence, outcome and management of CAD in patients with concomitant AF. AF was a common finding among patients with MI, with 16% having new-onset, paroxysmal or chronic AF. Patients post-MI with concomitant AF, regardless of subtype, were at increased risk of composite cardiovascular outcome of mortality, MI or ischemic stroke, including mortality and ischemic stroke alone. No major difference in outcome was observed between AF subtypes. At discharge, an oral anticoagulant was prescribed to 27% of the patients with MI and AF undergoing percutaneous coronary intervention (PCI). Aspirin or clopidogrel plus warfarin versus dual antiplatelet therapy with aspirin plus clopidogrel were associated with similar 0-90- day and lower 91-365-day risk of cardiovascular outcome, without increased risk of major bleeding events. Triple therapy with aspirin, clopidogrel plus warfarin versus dual antiplatelet therapy was associated with non-significant lower risk of cardiovascular outcome, but with increased risk of bleeding events. Treatment with renin-angiotensin system (RAS) inhibitors post-MI was associated with lower risk of all-cause and cardiovascular mortality in patients with and without congestive heart failure and/or AF. However, RAS inhibition in patients without AF was not associated with lower risk of new-onset AF. Approximately 1 in 3 patients undergoing isolated coronary artery bypass grafting (CABG) had pre- or postoperative AF. Patients with AF, regardless of subtype, were at higher risk of all-cause mortality, cardiovascular mortality and congestive heart failure. Furthermore, postoperative AF was associated with higher risk of recurrent AF. In conclusion, AF was a common finding in the setting of MI and CABG. AF, irrespectively if in the setting of MI or CABG was associated with higher risk of ischemic events and mortality. Also, postoperative AF was associated with recurrent AF. Oral anticoagulants post-MI and PCI in patients with AF was underutilized, however, optimal antithrombotic therapy is still unknown. RAS inhibition post-MI seems beneficial, however, it was not associated with lower incidence of new-onset AF. Keywords: atrial fibrillation, coronary artery disease, acute coronary syndrome, myocardial infarction, percutaneous coronary intervention, coronary artery bypass grafting, antithrombotic therapy, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, epidemiology Gorav Batra, Department of Medical Sciences, Cardiology, Akademiska sjukhuset, Uppsala University, SE-75185 Uppsala, Sweden. © Gorav Batra 2017 ISSN 1651-6206 ISBN 978-91-554-9917-4 urn:nbn:se:uu:diva-320541 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-320541) To my beloved family List of Papers This thesis is based on the following papers, which are referred to in the text by their Roman numerals. I Batra G, Svennblad B, Held, C, Jernberg T, Johanson P, Wallentin L, Oldgren J. (2016) All types of atrial fibrillation in the setting of myocardial infarction are associated with impaired outcome. Heart, 102(12):926-933 II Batra G, Friberg L, Erlinge D, James S, Jernberg T, Svennblad B, Wallentin L, Oldgren J. (2017) Antithrombotic therapy after myocardial infarction in patients with atrial fibrillation undergoing percutaneous coronary intervention. Manuscript. Submitted III Batra G, Lindhagen L, Andell P, Erlinge D, James S, Spaak J, Oldgren J. (2017) Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are associated with improved outcome but do not prevent new-onset atrial fibrillation after acute myocardial infarction. Journal of the American Heart Association, 6(3):e005165 IV Batra G, Ahlsson A, Lindahl B, Lindhagen L, Wickbom A, Oldgren J. (2017) Atrial fibrillation in patients undergoing coronary artery surgery is associated with adverse outcome. Manuscript. Submitted Reprints were made with permission from the respective publishers. Contents 1 Introduction .......................................................................................... 11 2 Background .......................................................................................... 12 2.1 Historical perspective ................................................................... 12 2.1.1 Coronary artery disease ..................................................... 12 2.1.2 Atrial fibrillation ................................................................ 13 2.2 Symptomatology and classification ............................................. 14 2.2.1 Coronary artery disease ..................................................... 14 2.2.2 Atrial fibrillation ................................................................ 15 2.3 Epidemiology and implications ................................................... 15 2.3.1 Coronary artery disease ..................................................... 15 2.3.2 Atrial fibrillation ................................................................ 16 2.3.3 Coronary artery disease and atrial fibrillation ................... 17 2.4 Pathophysiology ........................................................................... 18 2.4.1 Coronary artery disease ..................................................... 18 2.4.2 Atrial fibrillation ................................................................ 19 2.4.3 Coronary artery disease and atrial fibrillation ................... 20 2.5 Management ................................................................................. 22 2.5.1 Coronary artery disease ..................................................... 22 2.5.2 Atrial fibrillation ................................................................ 25 2.5.3 Coronary artery disease and atrial fibrillation ................... 26 3 Aims ..................................................................................................... 29 4 Methods ............................................................................................... 30 4.1 Study design ................................................................................. 30 4.2 Data collection ............................................................................. 31 4.2.1 National quality registries .................................................. 31 4.2.2 SWEDEHEART ................................................................ 31 4.2.3 Registries maintained by the National Board of Health and Welfare ........................................................................ 33 4.2.4 Data linkage and ethics ...................................................... 33 4.3 Study populations ......................................................................... 34 4.4 Risk factors and medical interventions ........................................ 36 4.5 Outcomes ..................................................................................... 37 4.6 Statistics ....................................................................................... 38 5 Results .................................................................................................. 40 5.1 Atrial fibrillation and myocardial infarction (Paper I) ................. 40 5.1.1 Baseline characteristics ...................................................... 40 5.1.2 Outcome in relation to atrial fibrillation status .................. 40 5.2 Antithrombotic therapy after percutaneous coronary intervention (Paper II) .................................................................. 45 5.2.1 Baseline characteristics ...................................................... 45 5.2.2 Antithrombotic therapy during follow-up ......................... 45 5.2.3 Outcome in relation to antithrombotic therapy .................. 45 5.3 Inhibition of the renin-angiotensin system (Paper III) ................. 51 5.3.1 Baseline characteristics ...................................................... 51 5.3.2 Outcome in relation to treatment with renin-angiotensin system inhibitors ................................................................ 52 5.3.3 Risk of new-onset atrial fibrillation in relation to treatment with renin-angiotensin system inhibitors ........... 53 5.4 Atrial fibrillation and coronary artery bypass grafting (Paper IV) ....................................................................................