THE CHARACTERISATION OF RISK FACTORS, SUBSTRATE AND MANAGEMENT STRATEGIES FOR ATRIAL FIBRILLATION

Transcription

1 THE CHARACTERISATION OF RISK FACTORS, SUBSTRATE AND MANAGEMENT STRATEGIES FOR ATRIAL FIBRILLATION Geetanjali Rangnekar BSc (Honours) Centre for Heart Rhythm Disorders School of Medicine The University of Adelaide A thesis submitted to The University of Adelaide in fulfilment of the requirements of the degree of Doctor of Philosophy August

2 To my parents, Abhay and Suniti To my sister and brother in law, Devyani and Harshit In loving memory of my grandparents 2

3 TABLE OF CONTENTS ABSTRACT DECLARATION ACKNOWLEDGEMENTS COMMUNICATIONS TO LEARNED SOCIETIES PRIZES AND AWARDS DURING CANDIDATURE CHAPTER ONE LITERATURE REVIEW INTRODUCTION The Risk Factors Associated with Atrial Fibrillation Conventional Risk Factors Associated with Atrial Fibrillation Advancing Age Gender Hypertension (HT) Left Ventricular Hypertrophy (LVH) Congestive Heart Failure (CHF) Coronary Artery Disease (CAD) Myocardial Infarction (MI) Diabetes Mellitus (DM) Congenital Heart Disease (CHD) Valvular Heart Disease (VHD)

4 Cigarette Smoking Alcohol Consumption New Risk Factors Associated with Atrial Fibrillation Obesity Obstructive Sleep Apnoea (OSA) Aortic Stiffness Familial Atrial Fibrillation Summary CHARACTERIZATION OF THE SUBSTRATE ASSOCIATED WITH NEW ONSET ATRIAL FIBRILLATION Definition of New Onset Atrial Fibrillation Management of New Atrial Fibrillation Mechanisms of Atrial Fibrillation Role of Triggers in Atrial Fibrillation Role of Substrate in Atrial Fibrillation Non Invasive Characterisation of Substrate Associated with Atrial Fibrillation Ambulatory Holter Monitoring Electrocardiogram (ECG) Abnormalities Echocardiographic Abnormalities Cardiac Magnetic Resonance Imaging (CMR) Summary CONSEQUENCES OF ATRIAL FIBRILLATION Economic Burden of Atrial Fibrillation

5 1.3.2 Hospital Burden of Atrial Fibrillation Trends in Elective Admissions for Atrial Fibrillation Trends in Emergency Department Admissions for Atrial Fibrillation Atrial Fibrillation Rehospitalisations Summary Thromboembolic Risk Associated with Atrial Fibrillation Abnormalities in the Atrial and Vessel Wall Abnormalities in the Blood Flow Abnormalities in the Blood Constituents Bio-markers of Thrombogenesis in Atrial Fibrillation CRP and IL Asymmetric Dimethyl Arginine (ADMA) Endothelin-1 (ET-1) CD40 Ligand (CD40L) Cell Adhesion Molecules Extracellular Matrix (ECM) Remodelling Proteins Myeloperoxidase (MPO) Summary TERTIARY CARE MANAGEMENT STRATEGIES FOR ATRIAL FIBRILLATION Rate Control Versus Rhythm Control Trials Rate Control Strategies Rhythm Control Strategies Pharmacological Interventions

6 Non-Pharmacological Interventions Anticoagulation in Atrial Fibrillation Summary INDEPENDENT RISK FACTORS FOR THE DEVELOPMENT OF NON- VALVULAR ATRIAL FIBRILLATION: A SYSTEMATIC LITERATURE REVIEW AND META-ANALYSIS INTRODUCTION METHODS Search Strategy Risk Factors Examined Statistical Analysis RESULTS Study Characteristics Independent Predictors of Atrial Fibrillation Chronic Heart Failure (CHF) Gender Coronary Artery Disease (CAD) Hypertension (HT) Left Ventricular Hypertrophy (LVH) Diabetes Mellitus (DM) Advancing Age Body Mass Index (BMI) Alcohol Consumption (AC)

7 Cigarette Smoking (CS) Population Attributable Risk (PAR) DISCUSSION Chronic Heart Failure Hypertension Metabolic Syndrome (Diabetes Mellitus and Obesity) Demographics (Aging and Gender) Non-predictors of Atrial Fibrillation Development CLINICAL IMPLICATIONS LIMITATIONS CONCLUSIONS FIGURES FIGURE 1 STUDY SEARCH CRITERIA FIGURE 2 UNIVARIATE ANALYSES RESULTS FOR ALL RISK FACTORS FIGURE 3 MULTIVARIATE ANALYSES RESULTS FOR ALL RISK FACTORS TABLES TABLE 1 STUDY CHARACTERISTICS AND BASELINE CHARACTERISTICS OF THE STUDY PARTICIPANTS109 TABLE 2 CONGESTIVE HEART FAILURE TABLE 3 MALE GENDER TABLE 4 CORONARY ARTERY DISEASE TABLE 5 HYPERTENSION TABLE 6 LEFT VENTRICULAR HYPERTROPHY

8 TABLE 7 DIABETES MELLITUS TABLE 8 AGE TABLE 9 BODY MASS INDEX TABLE 10 ALCOHOL CONSUMPTION TABLE 11 CIGARETTE SMOKING TABLE 12 WEIGHTS OF EACH STUDY IN EACH UNADJUSTED AND ADJUSTED ANALYSIS TABLE 13 POPULATION ATTRIBUTABLE RISK FOR MODIFIABLE RISK FACTORS CHAPTER THREE CHARACTERISATION OF THE STRUCTURAL AND ELECTRICAL REMODELLING ASSOCIATED WITH NEW ONSET ATRIAL FIBRILLATION INTRODUCTION METHODS Recruitment of Newly Diagnosed Atrial Fibrillation Patients Recruitment of Age-matched Controls Structured Clinical Interview Structural Substrate Assessment Electrical Substrate Assessment Statistics RESULTS Baseline Characteristics of Controls vs AF Patients Baseline Characteristics of PAF vs PerAF Patients

9 3.3.3 Structural Substrate Assessment Left Atrial Longitudinal Axis Left Atrial Transverse Axis Left Atrial Area Left Atrial Volume Left Ventricular Hypertrophy: Interventricular Septal Diameter (IVSd) Left Ventricular Ejection Fraction (LVEF) Mitral E Velocity Mitral A Velocity E/A Ratio Pulmonary Vein S/D Ratio Pulmonary Vein Septal E Electrical Substrate Atrial Ectopy Burden and Relative Earliness DISCUSSION Substrate in New Paroxysmal AF Substrate in New Persistent AF CLINICAL IMPLICATIONS LIMITATIONS CONCLUSIONS FIGURES FIGURE 1 RECRUITMENT OF CONTROLS AND NEW AF PATIENT FIGURE 2 LEFT ATRIAL DILATION PARAMETERS IN CONTROLS, NEW PAF AND NEW PERAF

10 FIGURE 3 LEFT VENTRICULAR MEASUREMENTS IN THE CONTROLS, NEW PAF AND NEW PERAF PATIENTS FIGURE 4 LEFT VENTRICULAR DIASTOLIC FUNCTION IN CONTROLS, NEW PAF AND NEW PERAF FIGURE 5 ATRIAL PREMATURE BEATS PER HOUR IN CONTROLS AND NEW PAF TABLES TABLE 1 BASELINE CHARACTERISTICS OF THE CONTROLS AND NEW AF GROUPS CHAPTER FOUR CHARACTERISATION OF THE INFLAMMATORY CHANGES ASSOCIATED WITH NEW ONSET ATRIAL FIBRILLATION: IMPLICATIONS FOR INCREASED THROMBOEMBOLIC RISK INTRODUCTION METHODS Recruitment of Newly Diagnosed Atrial Fibrillation Patients Recruitment of Age-matched Controls Structured Clinical Interview Blood Collection Bio-markers Measured Enzyme-Linked Immunosorbent Assay Statistical Analysis RESULTS Baseline Characteristics

11 4.3.2 Bio-markers of Thrombogenesis Endothelial Dysfunction and Vascular Function Inflammatory Markers Extracellular Matrix (ECM) Remodeling DISCUSSION Endothelial Dysfunction and Vascular Function Inflammation ECM Remodeling CLINICAL IMPLICATIONS LIMITATIONS CONCLUSIONS FIGURES FIGURE 1 RECRUITMENT OF CONTROLS AND NEW AF PATIENTS FIGURE 2 ENDOTHELIAL DYSFUNCTION AND VASCULAR FUNCTION MEASURES IN CONTROLS AND NEW AF FIGURE 3 MARKERS OF INFLAMMATION IN CONTROLS AND NEW AF TABLES TABLE 1 BASELINE CHARACTERISTICS OF THE CONTROLS COMPARED TO AF PATIENTS CHAPTER FIVE PREDICTORS AND APPROPRIATENESS OF HOSPITALISATIONS IN PATIENTS WITH ACUTE ATRIAL FIBRILLATION INTRODUCTION

12 5.2 METHODS Sample Data Extraction Baseline Characteristics Definitions Statistics RESULTS Patient Sample Baseline Characteristics Avoidable Hospital Admissions Predictors of Index Hospitalisation DISCUSSION Avoidable Hospital Admissions for AF Predictors of Hospital Admission CLINICAL IMPLICATIONS LIMITATIONS CONCLUSIONS FIGURES FIGURE 1 EXCLUSION CRITERIA AND PATIENT SELECTION FIGURE 2 UNIVARIATE AND MULTIVARIATE PREDICTORS OF AF HOSPITALIZATION TABLES

13 TABLE 1 BASELINE CHARACTERISTICS TABLE 2 CHARACTERISTICS OF LOW-RISK AF PATIENTS TABLE 3 PHARMACEUTICAL AGENTS: DRUG CATEGORIES AND DRUG TYPE CHAPTER SIX INCIDENCE AND PREDICTORS OF REHOSPITALISATION IN PATIENTS PRESENTING TO HOSPITAL WITH ATRIAL FIBRILLATION INTRODUCTION METHODS Study Design and Sample Data Abstraction Medication Profile Acute Presentation Characteristics and Management Strategies Follow-up Statistical Analysis RESULTS Patient Sample Baseline Characteristics Burden of Readmissions Primary Reasons for Readmissions Predictors of All-cause Readmissions to Hospital Predictors of Atrial Fibrillation Readmissions

14 6.3.7 Mortality Associated with Presentation with AF DISCUSSION Predictors of All-cause Readmission to Hospital Atrial Fibrillation Readmissions Mortality CLINICAL IMPLICATIONS LIMITATIONS CONCLUSIONS FIGURES FIGURE 1 EXCLUSION CRITERIA AND PATIENT SELECTION FIGURE 2 REASONS FOR READMISSIONS TABLES TABLE 1 BASELINE CHARACTERISTICS: FULL PATIENT COHORT TABLE 2 UNIVARIATE AND MULTIVARIATE PREDICTORS OF REHOSPITALISATIONS TABLE 3 UNIVARIATE AND MULTIVARIATE PREDICTORS OF AF SPECIFIC REHOSPITALISATIONS TABLE 4: PHARMACEUTICAL AGENTS: DRUG CATEGORIES AND DRUG TYPE CHAPTER SEVEN FINAL DISCUSSIONS CHAPTER EIGHT FUTURE DIRECTIONS

15 APPENDIX STRUCTURED INTERVIEW: AF PATIENTS STRUCTURED INTERVIEW: COMMUNITY CONTROLS APPENDIX CONGESTIVE HEART FAILURE: UNIVARIATE AND MULTIVARIATE STATISTICAL OUTPUTS MALE GENDER: UNIVARIATE AND MULTIVARIATE STATISTICAL OUTPUTS CORONARY ARTERY DISEASE: UNIVARIATE AND MULTIVARIATE STATISTICAL OUTPUTS HYPERTENSION: UNIVARIATE AND MULTIVARIATE STATISTICAL OUTPUTS LEFT VENTRICULAR HYPERTROPHY: UNIVARIATE AND MULTIVARIATE STATISTICAL OUTPUTS DIABETES MELLITUS: UNIVARIATE AND MULTIVARIATE STATISTICAL OUTPUTS AGE: UNIVARIATE AND MULTIVARIATE STATISTICAL OUTPUTS BMI: UNIVARIATE AND MULTIVARIATE STATISTICAL OUTPUTS ALCOHOL CONSUMPTION: UNIVARIATE AND MULTIVARIATE STATISTICAL OUTPUTS CIGARETTE SMOKING: UNIVARIATE AND MULTIVARIATE STATISTICAL OUTPUTS APPENDIX EXCLUSION DUE TO MIS-CODING OF ATRIAL FIBRILLATION (I48) FROM TOTAL PATIENT SAMPLE (N=858) APPENDIX OUTPUT TABLE FOR UNIVARIATE AND MULTIVARIATE ANALYSIS OF PREDICTORS OF HOSPITAL ADMISSION APPENDIX

16 ETHICS APPROVALS FOR CHAPTERS 3 & ETHICS APPROVAL FOR CHAPTERS 5 & ETHICAL ISSUES: CHAPTER NINE REFERENCES

17 Abstract The rising global incidence and prevalence of atrial fibrillation (AF) imposes significant burden on health care systems. Recently, several novel risk factors for AF have been identified. However, there remains a need to understand the differential impact of more established predisposing factors for incident AF. Further, there is insufficient knowledge surrounding the atrial changes that occur at the advent of AF and how this arrhythmia is managed on presentation to health care facilities. This thesis seeks to improve our understanding of the risk factors associated with this arrhythmia; to characterise any detrimental changes that occur upon its onset and to identify the AF patients that are most likely to significantly burden the hospital system. To this effect, the focus of each of the chapters is presented forthwith. Chapter 2 focuses on the independent risk factors for incident non-valvular AF via a systematic literature review and meta-analysis. This study provides the absolute and independent effect of each established risk factor on AF development and estimates the proportion of AF cases that could potentially be prevented if modifiable risk factors were targeted at the population level. Chapters 3 and 4 characterise the entity of newly diagnosed AF. Chapter 3 determines the existence of structural and electrical remodelling that may be present at an early stage of this arrhythmias evolution. Detrimental changes were found in the form of electrical substrate in paroxysmal new AF and structural substrate in persistent new AF. Chapter 4 examines the thrombogenic risk associated with new onset AF. This study shows the existence of elevated levels of pro-thrombotic bio-markers and 17

18 emphasises the need for appropriate anti-coagulation at this early stage of the AF disease process. Chapters 5 and 6 focus on the burden that AF confers upon the hospital system by way of hospital admissions and readmissions. Chapter 5 identifies the predictors of hospital admission for AF patients presenting via the emergency department and moreover determines if all admissions are medically warranted. This study ascertained that AF patients presenting with congestive heart failure and a concurrent infection were significantly likely to be admitted to hospital for treatment and a significant proportion of patients who were admitted were low-risk AF and admission was not medically justified. This highlights a need for new management strategies in order to prevent unnecessary hospital admissions. Lastly, chapter 6 examines the factors that increase the likelihood of readmission to hospital among AF patients. The findings showed that a substantial number of patients with index presentation for AF were readmitted to hospital. Patients who were younger and discharged on rhythm control medications were more likely to burden the hospital system with frequent AF readmissions. This study stressed the need for specialised outpatient clinics and educational interventions that could potentially reduce the increasing numbers of AF patients re-presenting to hospital. 18

19 Declaration I certify that this works contains no material, which has been accepted for the award of any other degree or diploma in any university or other tertiary institution. To the best of my knowledge and belief, it contains no material previously published or written by another person, except where due reference has been made in the text. In addition, I certify that no part of this will, in the future, be used in a submission for any other degree or diploma in any university or other tertiary institution without the explicit permission of the University of Adelaide and if applicable, any other partner institution. I give consent to this copy of my thesis, when deposited in the University of Adelaide Library, being made available for loan and photocopying, subject to the Copyright Act of Additionally, I give permission for the digital version of my thesis to be available on the web, via the University s digital search repository, the Australian Digital Thesis Program (ADTP), the Library catalogue and through web search engines, unless permission has been granted by the University to restrict access for a certain period of time. Geetanjali Rangnekar August

20 Acknowledgements I would like to thank Professor Prashanthan Sanders, my primary supervisor, for his guidance and support during my doctoral degree. His enthusiasm and constant innovation has been and continues to be inspirational. I would also like to thank my cosupervisor Dr Kurt-Roberts Thomson for his help and encouragement during my studies. Special thanks to my co-supervisors, Dr. Anthony Brooks for guidance provided during the study design and execution phase and for assistance with SPSS; Dr. Scott Willoughby for assistance with the new AF studies and to Dr. Dennis Lau for his patience, assistance and guidance during thesis preparation. I would like to thank the cardiology fellows at the Centre for Heart Rhythm Disorders for their feedback and encouragement. I have enjoyed and will cherish my time working alongside my fellow PhD candidates at the Centre for Heart Rhythm Disorders: Carlee Schultz, Melissa Neo, Wei Wen Lim. In particular, thank-you to Carlee Schultz for her help during the new AF studies. I would also like to acknowledge the staff at the Cardiovascular Centre, past and present, who helped and accommodated me during the conduction of my PhD studies; Michelle Sanders, Melissa Middledorp, Aimie Paukner, Rebecca Leinonen, Sharon King, Elena Pancewicz, Lorraine Lee, Emily Rasheed and Julia Kim. Last but not least, I would like to say a huge thank you to my amazing family; parents, sister, brother in law, aunt, uncle, and cousins; without whose unwavering understanding, encouragement and love this PhD would have not been possible. Thank you to my wonderful friends for their unstinting fortitude, humour and love which got me through some of the most trying times. 20

21 Chapter Two Communications to Learned Societies 1. Presentation: Presented at The Australian Society for Medical Research South Australian Annual Scientific Meeting, May 2014, Adelaide, Australia. Chapter Three 1. Presentation: Presented at the 59 th Cardiac Society of Australia and New Zealand the Scientific Meeting, August 2011, Perth, Australia and published in abstract form (Heart, Lung and Circulation 2011, 20:S105). 2. Presentation: Presented at the Heart Rhythm Society 33 rd Annual Scientific Sessions, May 2012, Boston, United States of America and published in abstract form (Heart Rhythm 2012, 9:5, S7). 3. Presentation: Presented at the 60 th Cardiac Society of Australia and New Zealand the Scientific Meeting, August 2012, Brisbane, Australia and published in abstract form (Heart, Lung and Circulation 2012, 21:S104-5). 4. Presentation: Presented at the 5 th Asia-Pacific Heart Rhythm, Society Scientific Sessions, October 2012, Taipei, Taiwan and published in abstract form (APHRS Conference Proceedings 2012). 5. Presentation: Presented at the Heart Rhythm Society 34 th Annual Scientific Sessions, May 2013, Denver, United States of America and published in abstract form (Heart Rhythm 2013, 10:5, S218). 6. Presentation: Presented at Heart Foundation National Conference, May 2013, Adelaide, Australia. 21

22 7. Presentation: Presented at the 61 st Cardiac Society of Australia and New Zealand the Scientific Meeting, August 2013, Gold Coast, Australia and published in abstract form (Heart, Lung and Circulation 2013, 22:S102). Chapter Four 1. Presentation: Presented at the Heart Rhythm Society 34 th Annual Scientific Sessions, May 2013, Denver, United States of America and published in abstract form (Heart Rhythm 2013, 10:5, S1). 2. Presentation: Presented at Heart Foundation National Conference, May 2013, Adelaide, Australia. 3. Presentation: Presented at the 61 st Cardiac Society of Australia and New Zealand the Scientific Meeting, August 2013, Gold Coast, Australia and published in abstract form (Heart, Lung and Circulation 2013, 22:S97-98). 4. Presentation: Presented at the Heart Rhythm Society 35 th Annual Scientific Sessions, May 2014, San Francisco, United States of America and published in abstract form (Heart Rhythm 2014, 11:5, S106). Chapter Five 1. Presentation: Presented at The Australian Society for Medical Research South Australian Annual Scientific Meeting, May 2014, Adelaide, Australia. Chapter Six 1. Presentation: Presented at the Heart Rhythm Society 33 rd Annual Scientific Sessions, May 2012, Boston, United States of America and published in abstract form (Heart Rhythm 2012, 9:5, S383). 22

23 2. Presentation: Presented at the 60 th Cardiac Society of Australia and New Zealand the Scientific Meeting, August 2012, Brisbane, Australia and published in abstract form (Heart, Lung and Circulation 2013, 21:S107-8). 3. Presentation: Presented at the School of Medicine Postgraduate Research Conference, August 2012, Adelaide, Australia. 4. Presentation: Presented at the 5 th Asia-Pacific Heart Rhythm, Society Scientific Sessions, October 2012, Taipei, Taiwan and published in abstract form (APHRS Conference Proceedings 2012). 23

24 Prizes and Awards During Candidature 1. Best poster presentation (PhD) Award, Australian Society for Medical Research (ASMR), South Australian Scientific Meeting, Best Poster Prize, The University of Adelaide, Faculty of Health Sciences, Department of Medicine, Postgraduate Research Conference, Finalist, Best poster prize, Heart Foundation National Conference,