Ph.D. thesis Jakob Raunsø Atrial fibrillation – Prognosis in heart … · 2018-05-28 · Ph.D.-thesis Atrial fibrillation – Prognosis in heart failure and risk during interruption

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Ph.D. thesis

Atrial fibrillation – Prognosis in heart failure

and risk during interruption of anticoagulant treatment

Jakob Raunsø

Ph.D. thesis ● Jakob Raunsø

Faculty of Health Sciences,University of Copenhagen

Gentofte University Hospital, Department of Cardiology

omslag-Jakob Raunso-PRINT.indd 1 22-05-2012 15:19:48

Ph.D.-thesis

Atrial fibrillation – Prognosis in heart failure and risk during interruption of anticoagulant treatment

Jakob Raunsø

Faculty of Health Sciences, University of Copenhagen Gentofte University Hospital, Department of Cardiology

Academic advisors Professor Christian Torp-Pedersen, Department of Cardiology, Gentofte Hospital, Denmark Professor Lars Køber Department of Cardiology, Rigshospitalet, Denmark Dr. Helena Dominguez Department of Cardiology, Herlev Hospital, Denmark Dr. Morten Lock Hansen Department of Cardiology, Gentofte Hospital, Denmark Members of the assessment committee Professor Jesper Hastrup Svendsen Department of Cardiology, Rigshospitalet, Denmark Associate professor Lars Hvilsted Rasmussen Forskningens Hus, Aalborg Sygehus, Denmark Professor Thor Edvardsen Department of Cardiology, Oslo University Hospital, Rikshospitalet, Norway The Faculty of Health Science, Copenhagen University, Denmark has approved this PhD-thesis for public defense. The public lecture and defense will take place June 8th, 2012 at 14.00 in the Auditori-um, Medicinsk Museion, Bredgade 62, Copenhagen.

Atrial Fibrillation – Prognosis in heart failure and risk during interruption of anticoagulant treatment 3

Preface

“… Og pludselig ser du Videnskaben afklædt foran dig i al sin grote-ske nøgenhed” ”… Suddenly, you see Science undressed before you in its grotesque nakedness” - Adapted from Prof. Torp-Pedersen In 2007, I approached the Professor of Cardiology at Bispebjerg Hospital for some advice how to “maybe do some research of sorts”, as I probably said it at the time. I was aware that a future career as a cardiologist demanded some research activity and further, I had genuine interest in devoting myself to full time re-search. At the time, I had no idea how fortunate I was to have approached exactly this man, Professor Christian Torp-Pedersen. A few months later he said to me: “I’ve got something for you!” Now, five years have passed, and the product is ready. There were some twists, turns and bumps on the road to PhD. The project I started in 2007 was quite different from the product in your hands now. At the time, Christian had two parallel research teams. One doing epidemiological research and the other working with endothelial function and I was included in the latter. In short, endothelial function is the ability of the blood vessels to dilate and this effect is hampered by toxic and hypoxic stimuli. The measure-ment of endothelial function by the venous occlusion method in the arteries of a limb can be used as a surrogate model for the coronary arteries. I was to do a PhD-project examining the effects of ischemia and reperfusion on endothelial function mimicking the situation when real patients are treated for myocardial infarcts. The project started off very well but we soon began to realize that there were severe methodological problems. We were not able to reproduce the results of international research teams and during the next year or so, it became clear that the results showed variations so great that there were no derivable conclusions from the work. Time was running short. At Christmas 2008 we had one of our very productive telephone conferences in the endothelium-research group and I presented all the disappointing results obtained in the roughly two years I had been working on the study. That night, Christian called me on the phone and said: “Are you seated?” I sat. “We have to pull the plug on your endothelium project. Have a glass of wine, enjoy Christmas with your family and come January we will be working intensely on something completely different!” Thus followed a year and a half’s work on three studies using observational data. Three studies with a common denominator: Atrial fibrillation which is a frequently encountered arrhythmia in the daily practice of cardiology. The world of powerful and compli-cated statistical models was new to me and the availability of the data on hospitalizations and medication of the entire Danish popu-lation gives a “power in numbers” at your fingertips second-to-none. I am completely indebted to Professor Torp-Pedersen for his wise and experienced guidance through the maze of possibilities and for the flexibility and patience making it possible to complete a

different PhD study than originally planned. Additionally, I would like to send a warm thanks to Christian’s “brother-in-arms”, Pro-fessor Lars Køber for his massive support and ingenious observa-tions, always to the point and crystal clear. A very special thank you to academic advisor Dr. Morten Lock Hansen for the close collaboration on the third article spanning almost 2.5 years and for being such a great friend. And finally, a special thanks to academic advisor Dr. Helena Dominguez for the systematic unraveling of the mysteries of the endothelium and for continuous optimism and support throughout the study. Additional thanks goes to Dr. Gun-nar Gislason, an expert in the field of observational studies and always with a clear answer to specific problems. A note of grati-tude goes to Dr. Ole Dyg Pedersen for expert advice on the inter-play between atrial fibrillation and heart failure. I would like to thank Dr. Britt Falskov for a patient and thorough introduction to the practicalities of endothelium research and the daily life of a PhD student. Particularly endothelium research was important to discuss at intervals in the endothelium-group (Chris-tian Rask-Madsen, Buris Christiansen, Thomas Hermann, Atheline Major-Pedersen, Nikolaj Ihlemann, and Sumarra Akram) whom I thank for invaluable support and advice. As I progressed to the world of epidemiological research the use of the ECHOS study data prompted an educational and pleas-ant collaboration with Christian Hassager, Jesper Kjærgaard, and Dilek Akkan. A special note of thanks goes to Jacob Møller for his substantial help on the first article of this dissertation. During my work on the observational studies I was fortunate to do some experimental research in the catheterization lab at Gen-tofte Hospital under the expert guidance of Jaya Rosenmeyer, Jan Skov Jensen and Søren Galatius. A special thank you to Jacob Sivertsen, a fellow coronary artery researcher, for great collabora-tion and friendship. Being part of an active and collaborative environment is para-mount and fortunately Christian has rounded up an inspiring group of research colleagues that provided equal amounts of scientific input and welcome distraction by the coffee machine. Thank you Ditte-Marie Bretler, Casper Jørgensen, Ole Ahlehoff, Jesper Lindhardsen, Mette Charlot, Fredrik Folke, Søren Skøtt-Andersen, Mette Norgaard, Tina Schramm, Emil Fosbøl, Jonas Olesen, Michelle Schmiegelow, Charlotte Andersson, Christine Benn, Anne-Marie Olsen, Christian Selmer, and Peter Weeke for some great times. An additional thanks to the project nurses Ulla Hovmand Jakobsen, Gitte von Jessen, Jette Sandberg Madsen, Kristine Serup-Hansen, Marianne Hyllested, Trine Karstens and Secretary Anna-Grethe Jensen for great support and collaboration during the years. A special thanks to Nurse Marianne Nielsen for enjoyable collaboration every Wednesday on the ever-present SCOUT study. A special thanks to Jan Kyst Madsen, then Head of Department, for prioritising and catalyzing a bustling and productive research environment at Gentofte Hospital. A note of gratitude goes to the Research Department at Gen-tofte Hospital (FUKAP) and The Danish Heart Foundation for finan-cial support.

4 Jakob Raunsø

I would like to thank Kristoffer Rohrberg, a long-time friend and physician colleague for critical and thorough review of this PhD-thesis. Finally, eternal gratitude to my wife Nanna and beautiful daughter Alberte for support and patience through the sometimes odd working hours as a PhD-student. Jakob Raunsø May 2012


Table of Contents

Preface 3 Introduction 6 Hypotheses & Aims 8 Design & Methods 9 Results – a brief summary of papers 11 Discussion 13 Limitations 16 Implications 18 Conclusions 18 Future research 19 Summary 20 Dansk Resumé 21 References 22 Papers

List of Papers

This thesis was based on the following papers: 1. Prognostic importance of a restrictive transmitral filling pattern in patients with symptomatic congestive heart failure and atrial fibrillation. Raunsø J, Møller JE, Kjaergaard J, Akkan D, Hassager C, Torp-Pedersen C, Køber L; EchoCardiography and Heart Outcome Study (ECHOS) investigators. Am Heart J. 2009 Dec;158(6):983-8. 2. Atrial fibrillation in heart failure is associated with an increased risk of death only in patients with ischaemic heart disease Raunsø J, Pedersen OD, Dominguez H, Hansen ML, Møller JE, Kjærgaard J, Hassager C, Torp-Pedersen C, Køber L, EchoCardiog-raphy and Heart Outcome Study (ECHOS) investigators. Eur J Heart Fail. 2010 Jul;12(7):692-7. 3. Increased short-term risk of thromboembolism after interrup-tion of warfarin treatment in patients with atrial fibrillation. Raunsø J, Selmer C, Olesen JB, Charlot MG, Olsen AM, Bretler DM, Nielsen JD, Dominguez H, Gadsbøll N, Køber L, Gislason GH, Torp-Pedersen C, Hansen ML. European Heart Journal 2011; doi: 10.1093/eurheartj/ehr454

Paper 1 25 Paper 2 31 Paper 3 37

6 Jakob Raunsø

Introduction

Atrial fibrillation is a supraventricular tachyarrhythmia character-ized by uncoordinated activation of the atria which consequently results in deteriorated atrial mechanical function. Being the most common arrhythmia requiring treatment, an estimated 4.5 million people in the European Union and 50,000 – 70,000 people in Den-mark have the condition.1, 2 The prevalence of atrial fibrillation increases with age which in turn increases the burden on public health and economy due to the aging population.3 A Danish regis-try study has shown that hospital admissions for atrial fibrillation have increased by 66 % in Denmark from the 1970s to the 1990s.2 Atrial fibrillation is associated with an increase in overall mor-tality and the incidence of thromboembolic events such as stroke and arterial emboli.4-6 The mortality in an atrial fibrillation popula-tion is approximately double that of patients in sinus rhythm and linked to the severity of underlying disease.6-9 The stroke rate among patients with atrial fibrillation increases with age and is on average 5 % per patient year which is 2-7 times that of persons without atrial fibrillation.10 Increasing age, hypertension, diabetes and prior stroke are powerful independent predictors of stroke in an atrial fibrillation population.11 In the Framingham Heart Study the annual risk of stroke attributable to atrial fibrillation was 1.5 % in the age group 50 – 59 years and 23.5 % in those aged 80 – 89 years.10 Heart failure and atrial fibrillation. Diastolic dysfunction Heart failure is a common condition. There are an estimated 60,000 patients in Denmark with clinical and documented chronic systolic failure and probably another 60,000 with reduced left ventricular systolic function but no clinical symptoms.12, 13 Heart failure and atrial fibrillation are intricately linked and heart failure promotes atrial fibrillation, atrial fibrillation aggravates heart fail-ure and both are associated independently to a poor prognosis.9 However, there is still some controversy on the prognostic impact of atrial fibrillation in heart failure. Several studies have addressed this question14-17 with varying conclusions. A recent meta-analysis included over 22,000 patients from randomized clinical trials and over 10,000 patients from observational studies and concluded that atrial fibrillation was detrimental in heart failure with an odds ratio for death from any cause between 1,33 and 1,57.18 The heterogeneity of the results can be a consequence of dif-ferences in patient selection in the trials yielding substantial differ-ences in the baseline characteristics of the patient population. The importance of co-morbidities have previously been highlighted, specifically the potential importance of ischemic heart disease as an effect modifier in the prognostic impact of atrial fibrillation in heart failure.19 In a cohort of patients from the Diamond Study conducted in 1993-1995 it has been shown that the prognostic impact of atrial fibrillation depends on the presence of ischemic heart disease.19 This has, however, not been verified in a contem-porary population of heart failure patients. A large percentage of symptomatic heart failure patients have heart failure with preserved ejection fraction characterized by

diastolic dysfunction of the ventricles comprising abnormality in relaxation and/or distensibility of the left ventricle during systole. Thus, it is a condition with symptoms of heart failure in the ab-sence of detectable systolic dysfunction20 which conveys a poor prognosis similar to that of systolic heart failure21. It is important to have non-invasive tools for evaluating the degree of dysfunction and correlate it to the prognosis.22 An imaging modality with vali-dated prognostic value is the measurement of mitral deceleration time using Doppler flow evaluation during echocardiography.23, 24 A short mitral deceleration time has been shown to be adversely related to risk in patients with sinus rhythm. The filling pattern of the left ventricle is dependent on many factors including heart rate and rhythm which changes significantly during atrial fibrillation.25 Therefore, many clinical trials using this marker have not included patients with atrial fibrillation thereby excluding up to 40 % of a heart failure population.26 Incorporating the use of mitral deceleration time as a prognos-tic marker regardless of heart rhythm would be an important step forward in the diagnosis and prognostic evaluation of heart failure patients with preserved ejection fraction. Anticoagulation and interruption The risk of thromboembolic events in patients with atrial fibrilla-tion poses a continuing challenge of balancing anticoagulant treatment.27 Treatment with vitamin K – antagonists has been a mainstay of thromboprophylaxis in these patients since the 1980s28 but the proper anticoagulation comes at a price: increased risk of bleeding events.29 Therefore, patients are stratified to anti-coagulant treatment according to each individual’s inherent risk of thromboembolic events.1, 27 The frequency of interruption / cessation of primarily warfarin has in various randomized trials been reported in 14 % - 33 % of the patients. There is a multitude of reasons for interruption which can be divided in two groups, patient factors and medical fac-tors.30, 31 Patient factors typically comprise compliance issues, frailty / risk of falls and unwillingness to take the drug. Medical factors comprise interruptions for surgery, cessation due to at-tainment of sinus rhythm by cardioversion and physicians’ assess-ment of patients bleeding risk.31 Warfarin initiation and cessation have a major impact on the coagulation system32, 33 and it has been hypothesized that both initiation and cessation are associated with an increase in risk of thromboembolic events due to imbalances in the coagulation system.34 Several minor clinical studies have assessed the question of hypercoagulability after interruption of anticoagulant treatment but results have varied, mainly due to small study size and varia-tions in patient selection.35-41 More recent biochemical studies have confirmed that there is a measurable hypercoagulable state after interruption of treatment but it is uncertain whether the biochemical findings are translated into an increase in adverse thromboembolic events or if the effect is without clinical im-portance.42


The mechanism of hypercoagulability when interrupting antico-agulant treatment is thought to be a transient imbalance between anticoagulant and procoagulant factors during the first few weeks after interruption. It has been demonstrated clinically that blood clotting factors VII and IX (procoagulants) increase more rapidly than protein C and S (anticoagulants) during the first week of inter-ruption.39 In another study, it was shown that factor VII levels exceeded pre-treatment levels (122 % of pre-treatment levels) two weeks after warfarin withdrawal.43 Additionally, a prospective study showed that sensitive markers of activation of the coagula-tion system (prothrombin fragments F1 + F2, thrombin anti-thrombin III complexes and D-dimer) were markedly increased shortly after interruption of warfarin treatment in a population of venous thromboembolism patients.40 More recently, two review articles concluded that the degree of hypercoagulability varies between individuals and may attain a pre-thrombotic level in some persons with clinical adverse events as a possible result.42, 44 The authors recommended a large-scale study to detect an eventual increase in thromboembolic events due to interruption of antico-agulant treatment.44

8 Jakob Raunsø

Hypotheses & Aims

Hypotheses

1) Measurement of mitral deceleration time has a prog-nostic value in a population of patients with atrial fi-brillation and heart failure.

2) The prognostic impact of atrial fibrillation in a heart failure population depends on the individual aetiology of heart failure and co-morbidities present.

3) A hypercoagulable state after warfarin treatment in-terruption exists and results in an increased incidence of thromboembolic events in a population of patients with atrial fibrillation.

Aims

1) To assess the prognostic value of mitral deceleration time in a large population of heart failure patients with specific focus on the comparison of patients with sinus rhythm and atrial fibrillation.

2) To determine the prognostic impact of atrial fibrilla-tion in a large population of heart failure patients and to assess a possible interaction with specific aetiolo-gies of heart failure.

3) To assess the incidence and timing of thromboembo-lism and death after interruption of warfarin treat-ment in a nation-wide study of patients with atrial fi-brillation.


Design and Methods

The studies included in this thesis use the same overall design of statistical and epidemiological analysis of registry data. Data Article 1 and 2 are analyses of the database from the Echocardi-ography and Heart Outcome Study (ECHOS) in 2001-2004 where all data from the Case Report Forms are available45. Additionally, all three articles employ the national patient regis-tries, unique to Denmark, where detailed information on each Danish individual is recorded. In Denmark, all persons have a single Central Personal Registration number which enables cross-linkage of national registries at an individual level. In this thesis, three national registries have been accessed:

1) The Danish National Patient Register holds data of all hospital admissions since 1978 where each indi-vidual admission is registered by admission date, discharge date, one primary diagnosis and one or more secondary diagnoses if applicable.46 All diag-noses are registered according to the World Health Organization’s International Classification of Dis-eases system (ICD) where diagnoses before 1994 are classified according to the 8th revision (ICD-8) and after 1994 according to the 10th revision (ICD-10).

2) The Danish Register of Medicinal Product Statistics records information on all dispensed prescriptions in Denmark since 1995. The drugs are classified ac-cording to the international Anatomical Therapeutic Chemical (ATC) code system. By law, all pharmacies in Denmark are required to register all dispensed prescriptions in the registry which ensures high da-ta accuracy.47

3) The Central Population Register contains infor-mation on all Danish citizens’ vital status.

Populations ECHOS study (article 1 and 2) The Echocardiography and Heart Outcome Study (ECHOS) was a prospective, double-blind, randomized, placebo-controlled Scandinavian multi-center trial which was done in 2001-2004.45 The purpose of the study was to evaluate nolomirole , a selec-tive agonist of the presynaptic dopamine receptors A2 and α2, for the treatment of moderate to severe congestive heart fail-ure. 3954 patients were screened for the study. Patients over 18 years of age were considered for eligibility when admitted to hospital because of symptoms of heart failure corresponding to New York Heart Association (NYHA) class II – IV requiring diuretic treatment. Additionally, at least one episode of dyspnoea during

the last month corresponding to at least NYHA class III was required. An echocardiogram was done during the index admission and analyzed at a core laboratory. All 12-lead electrocardiograms recorded during admission were analyzed by the study investiga-tor and interpreted according to general atrial fibrillation criteria (absence of P-waves, coarse or fine fibrillatory waves, and com-pletely irregular RR intervals or regular RR intervals in patients with pacemaker/ICD/AV-block). Patients were classified as hav-ing chronic AF if all 12-lead ECGs during admission showed AF. Further, the patients’ medical history was reviewed for previous reports of paroxysmal or chronic AF. Patients were classified as having paroxysmal AF if they had a history of AF but presented with sinus rhythm (SR) at admission or presented with AF at admission but had at least one 12-lead ECG with SR during the hospital stay. In all the screened patients, baseline demographic data, prior diseases, and medications at discharge were prospectively en-tered into the Case Report Form for each participant. This was done according to Good Clinical Practice guidelines ensuring high data accuracy. Only ECHOS patients from Denmark were eligible for the studies included in the present thesis in order to ensure com-plete follow-up via the national Danish registries. The ECHOS patients were followed until November 2008 where the Central Person Registry was assessed for vital status and dates of death, if applicable. This yielded a follow-up time of up to seven years. Nation-wide atrial fibrillation population (article 3) For article 3, we used the Danish National Patient Register to identify all persons in Denmark over 30 years of age with a first-time hospital admission for atrial fibrillation during the period 1997-2008. Additionally, we gathered all available information on co-morbidities by assessing all patients’ hospital admissions during the same period. Baseline medications were retrieved from the Danish Register of Medicinal Product Statistics and defined as all types of medication claimed 1 year before to 90 days after index admission. During the up to ten years of follow-up all hospital admis-sions for thromboembolic events were recorded. Thromboem-bolism was defined as an ischaemic cerebral event (ischaemic stroke (ICD-10 code I63), transient ischaemic attack (ICD-10 code G45), unspecified stroke (ICD-10 code I64)), systemic embolism (pulmonary embolism (ICD-10 code I26) or systemic arterial embolism (ICD-10 code I74)). Only the first episode of thrombo-embolism per cohort member was included in the outcome analysis. Additionally, all deaths were registered during the follow-up period and included in a combined endpoint.

10 Jakob Raunsø

Warfarin doses, treatment duration and interruptions Warfarin dosing varies greatly both intra- and interindividually due to the pharmacodynamic properties of the drug.48 The Danish Register of Medicinal Product Statistics does not record individual dosing47. Only the drug ATC code, strength, amount of tablets dispensed and dispensing date are registered. From this information it is possible to estimate each patient’s daily dosage by computer analysis. A value for daily dose was calculated at each prescription dispensing by using up to seven previous consecutive prescrip-tions using the strength, dispensing date and amount of tablets. If only one prescription was registered for an individual a stand-ard dose of 5 mg warfarin was used as the daily dose. Using this estimation it was possible to assess the amount of tablets in each patient’s possession at any point in time. Patients were registered as being actively treated if they had tablets in their possession and treatment was registered as interrupted if pa-tients had run out of tablets according to the estimation de-scribed before. This computer algorithm to estimate treatment dosage has been described previously.49 Statistical analysis Categorical baseline variables are expressed as frequency and percentages. Comparative analyses were done by Χ2-tests. Con-tinuous variables are shown as medians with 5th and 95th per-centiles and comparisons were done by the Kruskal-Wallis test or the Wilcoxon rank sum test. Survival data were analyzed with Kaplan-Meier estimators and comparisons were done with the

log-rank test (Article 1 and 2). Multivariable analysis was done using Cox proportional hazard models adjusting for baseline variables, co-morbidity and concomitant medication where indicated. In Article 3, to assess the association between time interval after warfarin interruption and risk of thromboembo-lism or death, we used Poisson regression analysis to calculate incidence rate ratios (IRRs). In these models, the primary inde-pendent variable of interest was the risk of outcome events in the first interval of 0-90 days after warfarin interruption com-pared with the interval of 271-360 days. The model assumptions (proportional hazard assumption, lack of interaction, and lineari-ty of continuous variables) were tested and found valid. A p-value <0.05 was considered statistically significant. In Article 3, unadjusted incidence rates were calculated as percentage per year (events per 100 patient years) and comparisons were done using the Fisher exact test. Ethics Data are made available by the government financed organiza-tion “Statistics Denmark” in an encrypted form preventing iden-tification of individual patients. Retrospective register studies do not require ethical approval in Denmark and permission from the Danish Data Protection Agency is granted to Statistics Den-mark for these studies (ref. 2007-41-1667). The ECHOS study was approved by relevant ethics commit-tees in the participating countries and was conducted in accord-ance with the Declaration of Helsinki III and Guidelines for Good Clinical Practice in the European Union. All study participants gave informed written consent.45


Results – a brief summary of papers

Article 1 Prognostic importance of a restrictive transmitral filling pattern in patients with symptomatic congestive heart failure and atrial fibrillation. The purpose of article 1 was to evaluate the prognostic impact of decreased mitral deceleration time in patients admitted with heart failure stratified by heart rhythm. Methods This study was based on 880 patients participating in the Echo-cardiography and Heart Outcome Study (ECHOS) in 2001-2004. All patients had symptomatic heart failure and were evaluated by echocardiography at admittance including an evaluation of left ventricular filling pattern. This was obtained by measuring the diastolic flow velocities across the mitral valve in the apical 4-chamber view. Restrictive filling pattern (RFP) was considered when deceleration time was ≤ 140 ms and non-RFP when > 140 ms. Left ventricular ejection fraction (LVEF) was approximated using the wall motion index, as described previously.50-52 Admit-tance electrocardiograms were used to classify the heart rhythm and mortality follow-up was achieved using the Danish Central Population Register. Results On admission, 337 (39%) of patients had atrial fibrillation. Among patients with atrial fibrillation 170 (50%) had RFP, and in patients with sinus rhythm 256 (47%) had RFP, no difference between the groups (p=0.34). During a follow-up period of me-dian 6.7 years (range 5.3-7.8) 564 patients died (64%). Mortality was significantly higher in patients with a restrictive filling pat-tern irrespective of atrial fibrillation or sinus rhythm (see Table 1). In a multivariable model only including patients in atrial fibrillation a restrictive filling pattern remained a significant predictor of all cause mortality (hazard ratio 1.79, 95% confi-dence interval 1.24-2.58, p=0.002). Table 1: Multivariable Cox proportional hazard analysis of Doppler echocardiographic and clinical variables predicting all-cause death among all patients. Chi-

square Hazard Ratio

95 % CI P value

RFP sinus rythm 15.4 1.63 1.28 - 2.09 <0.0001 RFP atrial fibril-lation 10.1 1.56 1.19 - 2.05 0.0002

Age† 118.1 1.07 1.05- 1.08 <0.0001 COPD 34.4 2.04 1.61 - 2.58 <0.0001 S-Creatinine† 11.2 1.003 1.001-1.005 0.0008 IHD 8.7 1.37 1.11 – 1.69 0.003 NYHA class > 1 at discharge 11.3 1.38 1.14 – 1.66 0.0008

WMI‡ 3.6 0.81 0.67 – 1.00 0.06 Hazard ratios for WMI and s-creatinine are per unit. RFP= restrictive filling pattern; COPD= chronic obstructive pulmonary disease; IHD= ischemic heart disease; WMI= wall motion index.

Conclusions In a heterogeneous population hospitalised for symptomatic heart failure a restrictive transmitral filling pattern during hospi-talisation is an ominous prognostic sign in patients presenting with atrial fibrillation and sinus rhythm alike. Article 2 Atrial fibrillation in heart failure is associated with an increased risk of death only in patients with ischaemic heart disease The purpose of article 2 was to evaluate the prognostic im-portance of atrial fibrillation in a large heart failure population and to focus specifically on the impact of co-morbidities. Methods From the Echocardiography and Heart Outcome Study (ECHOS), 2881 patients admitted to hospital during a 4-year period (2001-2004) with symptoms of worsening of HF were included in the present study. Patients were followed for up to 7 years for all-cause mortality stratified according to heart rhythm (sinus rhythm, paroxysmal or chronic AF) and according to presence of ischemic heart disease (IHD). Survival in the AF group was stud-ied in a multivariable analysis using Cox proportional hazard models and controlling for all baseline parameters. Results During index admission, 494 patients (17.2 %) had paroxysmal AF and 681 patients (23.6 %) had chronic AF. Patients with chronic AF were slightly older and more frequently had a history of HF than patients with paroxysmal AF and sinus rhythm (SR). Forty-eight percent (825) of patients in SR had a history of IHD and the number was significantly lower in chronic AF patients (42 % (282)). During follow-up, 1934 patients (67 %) died. Chronic AF was associated with increased risk of death in univariable analysis (hazard ratio (HR) 1.17; 95 % confidence interval (CI) 1.06 – 1.30) whereas no excess mortality was seen among patients with paroxysmal AF (0.99; 0.88 – 1.11). There was significant interac-tion between the aetiology of HF and the prognostic importance of chronic AF (p-value for interaction=0.003). In HF patients with history of IHD, chronic AF was associated with a hazard ratio of 1.44 (1.18 – 1.77; p<0.001). In contrast, in patients without IHD, chronic AF was not associated with increased risk; hazard ratio 0.88 (0.71 – 1.09; p=0.25). Survival stratified by rhythm and presence of IHD is shown in figures 1 and 2.

12 Jakob Raunsø

Figure 1: Survival stratified by rhythm, patients with IHD

Figure 2: Survival stratified by rhythm, patients without IHD

Conclusions In a large population of patients with heart failure, atrial fibrilla-tion is associated with an increased risk of death only in patients with underlying ischemic heart disease. Article 3 Increased Short-Term Risk of Thromboembolism or Death after Interruption of Warfarin Treatment in Patients with Atrial Fibrillation The purpose of article 3 was to assess the frequency and timing of thromboembolic events and all-cause mortality after inter-ruption of warfarin therapy in a population of atrial fibrillation patients.

Material and methods This was a retrospective, nationwide cohort study of all patients in Denmark treated with warfarin after a first hospitalization with atrial fibrillation in the period 1997 - 2008. The primary outcome was thromboembolic events or all-cause death after warfarin interruption. Incidence rate ratios were calculated using Poisson regression analyses. Results A total of 48,989 atrial fibrillation patients receiving warfarin treatment were included and 35,396 (72 %) patients had at least one episode of treatment interruption. In all, 8,255 deaths or thromboembolic events occurred during treatment interruption showing an initial clustering of events with 2717, 835, 500, and 427 events occurring during 0 to 90, 91 to 180, 181 to 270, and 271 to 360 days after treatment interruption, respectively. Cor-respondingly, the crude incidence rates were 31.6, 17.7, 12.3, and 11.4 events per 100 patient years. In a multivariable analy-sis, the first 90-day interval of treatment interruption was asso-ciated with a markedly higher risk of death or thromboembolism (incidence rate ratio 2.5; 95% confidence interval 2.3 – 2.8) versus the interval of 271-360 days. Figure 3: Instantaneous incidence rates of deaths or throm-boembolisms during treatment and interruption of warfarin.

Conclusions In patients with atrial fibrillation, an interruption of warfarin treatment is associated with a significantly increased short-term risk of death or thromboembolic events within the first 90 days of treatment interruption.


Discussion

Introduction There were three important findings in this thesis. First, a restrictive filling pattern found during measurement of transmitral deceleration time was a significant prognostic mark-er in heart failure patients with atrial fibrillation as well as sinus rhythm. This extends the utility of the marker to a broader population. Second, the prognosis of heart failure patients with atrial fibrilla-tion depended on the simultaneous presence of ischemic heart disease. This new knowledge can affect the paradigm that all heart failure patients with atrial fibrillation are treated by the same algorithm regardless of co-morbidities. Perhaps, a differ-entiation in treatment aggressiveness is appropriate depending on the presence or absence of ischemic heart disease. Third, warfarin treatment interruption was associated with a threefold increase in thromboembolic events or deaths during the first 90 days of continuous interruption. This knowledge, coupled with the fact that more than two out of three atrial fibrillation patients on warfarin treatment have at least one interruption may have uncovered a substantial problem in this patient population. Study design The design used in this thesis was a historical cohort design where baseline data were gathered retrospectively and follow-up data on mortality and hospital admissions were gathered prospectively. The study period comprised the period 2001-2007 for articles 1 and 2 and 1997-2008 for article 3. In articles 1 and 2 the cohort was a well-defined population of patients screened for a randomized study in the period 2001-2004. In article 3 the population was the entire Danish population of atrial fibrillation patients hospitalized with atrial fibrillation for the first time in a twelve-year period (1997-2008). The chosen design ensures complete nationwide follow-up data yielding a statistically powerful result in the studies. Nota-bly in article 3, a cohort of over 149,000 patients with atrial fibrillation is included and followed for up to twelve years, a feat that is virtually impossible in prospective clinical trials due to financial and duration-of-study concerns. This design, however, has several inherent drawbacks which are discussed below and in the Limitations section of this thesis. In article 1 and 2 the studied population are the patients screened for a randomized controlled clinical trial (ECHOS). This ensures a highly accurate baseline dataset as all Good Clinical Practice standards have been followed during the screening process. This contrasts to article 3 in which baseline data is somewhat less accurate as all variables have been gathered from the national patient registers in Denmark.

The drawbacks to the choice of study design are the inherent limitations of observational studies (see the Limitations section) which restrict conclusions on causality and therefore the results should ideally be used for hypothesis generation and later test-ing in prospective designs.53 However, observational studies have several advantages to prospective randomized clinical studies which usually include small, carefully selected popula-tions making it difficult to extrapolate the results to the general patient population. When observational studies are interpreted correctly they can provide an important snapshot of a large, unselected population which is why the studies are sometimes dubbed “real-world studies”.54 If bias and confounders are minimized and the studied variables are unspecific and general-izable it is possible to infer causality in these types of studies.55 Restrictive filling pattern and atrial fibrillation Restrictive filling pattern (shortened mitral deceleration time) is correlated well to morbidity and mortality in patients with heart failure and sinus rhythm.24, 56 Theoretically, the measurement of mitral deceleration time could be compromised in patients with atrial fibrillation due to the R-R-variation and subsequently the variation in ventricular filling time and pressure.25, 57 Further, it has been shown that a shortened mitral deceleration time does not correlate well to pulmonary wedge pressure, indicative of the measurement being non-applicable in patients with atrial fibrillation.58, 59 Our results indicate that this seems not to be the case. We demonstrated that a reduced mitral deceleration time of less than 140 milliseconds was a powerful prognostic marker in patients with heart failure regardless of the presence of atrial fibrillation. Further, the results seem generalisable due to the heterogeneous study population with heart failure of different aetiologies. Two previous studies have directly addressed the issue of restrictive filling pattern and the validity in patients with atrial fibrillation. Hurrel et al retrospectively identified 367 patients with a restrictive filling pattern defined by a short mitral decel-eration time of < 130 ms.60 Of these, 74 patients (20 %) were in atrial fibrillation. Mortality rates were similar in the atrial fibrilla-tion group and sinus rhythm group indicating a similar poor prognosis in patients with a restrictive filling pattern regardless of heart rhythm. More recently, Peltier et al prospectively measured the mitral deceleration time in 140 patients with reduced LVEF. Of these, 40 patients (28 %) had AF and the fol-low-up time was 25 months (range 1-48). The authors found a similar poor prognosis in patients with AF and SR who had a shortened mitral deceleration time of < 150 ms.61 Our study differs from the previous studies by being much larger and hav-ing more than three times the follow-up time, thus more firmly establishing the usability of the marker in atrial fibrillation pa-tients.

14 Jakob Raunsø

Prognostic importance of atrial fibrillation in heart failure Atrial fibrillation is known to have a detrimental effect in pa-tients with ischemic heart disease and in the general popula-tion.14, 62 The prognostic impact of atrial fibrillation in heart failure patients is at present somewhat controversial. The pur-pose of our study (Article 2) was to evaluate the prognostic impact of atrial fibrillation in a large patient group with heart failure of various aetiologies. The results of our study showed that chronic atrial fibrillation had a detrimental effect in heart failure patients with a hazard ratio for all-cause mortality of 1.44 (p<0.001) but only if they had concurrent ischemic heart disease. Most studies on this issue have not analysed specifically for the impact of the aetiology of heart failure on the detrimental effect of atrial fibrillation. A retrospective analysis of The Studies of Left Ventricular Dysfunction (SOLVD) Prevention and Treat-ment trials provided an indication of an independent detri-mental effect of atrial fibrillation in patients with left ventricular dysfunction.16 However, other studies of an apparently similar population have not been able to show this.15, 63 This discrepan-cy has been proposed to stem from the baseline differences regarding heart failure severity. The heart failure symptoms were mild-moderate in the SOLVD trial and moderate-severe in the latter trials.63 However, our study suggests that this is not the explanation, as over 80 % of patients in our study were in NYHA class >II at discharge corresponding to moderate to severe heart failure. Our hypothesis was based on the work by Pedersen et al in 2006 where they performed a retrospective analysis of the data from the Danish Investigations of Arrhythmia and Mortality ON Dofetilide, Congestive Heart Failure (DIAMOND-CHF) study comprising 3587 patients hospitalised with worsening heart failure. When analysing for the effect of atrial fibrillation on mortality it was evident that there was significant statistical interaction with ischemic heart disease indicating that the effect of atrial fibrillation was dependent on the presence of ischemic heart disease.19 The authors interestingly found the impact of atrial fibrillation only to be significant in the subpopulation with concurrent ischemic heart disease. A similar connection was shown in the Valsartan in Acute Myocardial Infarction (VALIANT) trial which included 15,000 myocardial infarction patients with heart failure. Atrial fibrillation was found to be a strong predic-tor of mortality with a significant hazard ratio between 1.25 (prior atrial fibrillation) and 1.32 (current atrial fibrillation).64 Our study does not elucidate the mechanism behind the results. However, one could speculate that heart failure pa-tients’ vulnerability to atrial fibrillation is dependent on the aetiology of heart failure and specifically that ischemic aetiology is pathophysiologically worse than heart failure of other aetiolo-gies. A recent experimental study using a porcine model has shown that atrial fibrillation, simulated by rapid atrial pacing, induced endothelial dysfunction in the microvasculature, in-creased oxidative stress and ventricular ischemia despite struc-turally normal epicardial coronary arteries without signs of atherosclerosis.65 In humans, it has been demonstrated that myocardial blood flow decreases and coronary resistance in-creases during atrial fibrillation.66 As patients with ischemic heart disease already have microvascular endothelial dysfunc-

tion and increased coronary resistance67 it is possible that atrial fibrillation further aggravates the reduced myocardial blood flow and ultimately increases the ischemic burden in the patients. Treatment regimens for heart failure and ischemic heart disease have changed during the past decades especially with the intro-duction of beta-blockade for heart failure and aggressive anti-thrombotic and revascularization treatment for ischemic heart disease. The DIAMOND-CHF study was done in 1991-1993 be-fore the changes in treatment algorithm.68-70 Our study uses data from the ECHOS study conducted in 2001-2004 yielding a similar conclusion but in a more contemporary patient popula-tion with a marked increase in beta-blocker treatment.71 The results in the two studies are comparable, indicating that beta-blocker usage does not change the overall results. The patient population in our study is unselected and large which enables conclusions to be drawn on different subsets of patients. Almost half of the population (44%) had heart failure with preserved ejection fraction defined as patients with heart failure symptoms and a left ventricular ejection fraction of over 45 %. Two recent studies have provided conflicting results re-garding the impact of atrial fibrillation on mortality in the setting of preserved left ventricular function.72, 73 Our study concludes that atrial fibrillation is an independent risk factor in patients with HF symptoms and a wide range of left ventricular ejection fractions. The implications of the study are that greater atten-tion perhaps should be given to the treatment of heart failure patients with atrial fibrillation and ischemic heart disease, as it seems that this group of patients accounts for a substantial part of the morbidity and mortality associated with the combination of heart failure and atrial fibrillation. Warfarin interruption Thrombosis prophylaxis is a cornerstone of the treatment of atrial fibrillation.1 Anticoagulant treatment with vitamin K-antagonists has been shown to reduce the risk of thromboem-bolic events in patients with atrial fibrillation by up to 68 %.74 Many patients interrupt anticoagulation treatment for a variety of reasons and in biochemical studies, interruption has been associated with a period of rebound hypercoagulability.35, 36, 40-42,

44 The purpose of our study was to assess the incidence and timing of thromboembolic events after warfarin treatment interruption in a nationwide population of patients with atrial fibrillation. Our main finding was that the incidence of a com-bined endpoint of thromboembolism or death almost tripled during the first 90 days of treatment interruption. Additionally it was noteworthy that more than 2 out of 3 patients on warfarin treatment have at least one interruption during the follow-up period of 3.5 years (mean). This number contrasts earlier reports from randomized clinical trials where the cessation rate was 14 % - 33 %.30 This is probably explained by the fact that patients participating in randomized trials often are carefully selected, highly motivated and have better drug compliance and, thus, have a lower rate of cessation. The era of anticoagulant therapy has lasted more than 60 years and warfarin was registered for human use in 1954.75 Since their discovery, warfarin and other vitamin K-antagonists were suspected of exhibiting a rebound effect of hypercoagula-bility when interrupting treatment.76, 77 Several small-scale clini-


cal trials were done without being able to uniformly detect an increase in thromboembolic events when interrupting anticoag-ulant treatment.35-37, 39 Some decades later, assays to biochemi-cally assess a hypercoagulable state were developed and several authors reported that there is no question on an activation of the coagulation system when interrupting anticoagulant treat-ment but it was not possible to extrapolate the results to clinical outcomes.40, 44 Our study indicates a steep increase in thrombo-embolic events during the first 90 days of warfarin treatment interruption. It is debatable whether the increase in risk is a true rebound effect due to pharmacological properties of warfarin or a “catch-up” effect where the individuals’ inherent thrombotic risk results in events as soon as the anticoagulation effect wears off. Several biochemical studies have documented a true re-bound effect, where specifically clotting factor VII levels were shown to rise above normal levels after interruption of antico-agulant treatment.35, 38, 41, 42, 44 A clinical study of the issue was performed in 1991 by Grip et al, where a hypercoagulable state was indicated with an in-crease in ischemic events (albeit non-significant) after interrup-tion of warfarin treatment in a patient group treated for myo-cardial infarction.39 The events were too few to reach statistical significance but the clustering of all events during a 4-week period after interruption was in contrast to an event free period during warfarin treatment and after the four weeks interruption. By blood analysis, the authors demonstrated a significant state of hypercoagulability and the authors concluded that a hyper-thrombotic state is very probable when interrupting warfarin treatment. The most recent study was done in 2008 by Garcia et al, where they prospectively enrolled 1024 patients (50 % with atrial fibrillation) receiving warfarin treatment and identified 1293 treatment interruptions of short duration (<5 days) for minor surgical procedures.78 There were very few thromboem-bolic events (7 events during a 30-day follow-up in the entire

group), probably because the patient population was at low to intermediate risk of thromboembolic events with only 7 % of the cohort in the highest risk group. No definitive conclusion on the risk of thromboembolism when interrupting warfarin treatment could be made due to the lack of statistical power. A large proportion of patients in the present study had at least one interruption. Interruptions of limited duration and complete cessation were not distinguished in the study which may have contributed to the large number of registered inter-ruptions. Previous randomised trials have reported a cessation rate of between 14 % and 33 %.30 To our knowledge, no previous study has reported the total amount of interruptions and cessa-tions of warfarin treatment. In the AFFIRM trial, patients stopped taking warfarin due to medical issues (e.g. need for surgical treatment, bleeding complications) and patient related issues (e.g. patient refusal, patient frailty).31 Although partici-pants in the AFFIRM trial were highly selected individuals com-pared to the present study, it is reasonable to assume that rea-sons for interrupting warfarin treatment in the present study are similar to the issues reported in the AFFIRM trial. Importantly, the majority of thromboembolic events in the AFFIRM trial occurred during sub-therapeutic INR values or after cessation of warfarin treatment regardless of reasons for interruption.31 Our study included a nationwide selection of patients with first-time admission with atrial fibrillation during a 12-year period. In total, roughly 100,000 patients were eligible for the study. Of these, 49,000 patients received warfarin therapy and two-thirds of these had an interruption. To our knowledge, no previous study of thromboembolic risk during warfarin interruption has had this level of power for analysis and the large and unselected study population is a major strength of our study. The limitations and clinical implications of the study are discussed in the Limita-tions and Clinical implications sections, respectively.

16 Jakob Raunsø

Limitations

The observational nature of the studies comprising this thesis means that several limitations have to be acknowledged. Obser-vational studies are more prone to bias and confounding inher-ent to the study design and therefore inference of causality should be done only with great caution. General limitations Identification of patients with atrial fibrillation Two of the studies (article 1 and 2) are based on data from the randomized controlled study ECHOS. Patient inclusion in our studies was done by identifying atrial fibrillation patients using the available admission ECGs and an eventual history of atrial fibrillation. ECHOS investigators reported presence of atrial fibrillation on day 1, day 2, and day 3 to discharge. This could lead to misclassification as some patients only had a few ECGs done during admission. However, a misclassification of atrial fibrillation as sinus rhythm would only tend to dilute the results and therefore lead to an underestimation of the true risk. In article 3 patients with atrial fibrillation were identified from the Danish National Patient Registry which has previously been validated for the diagnosis of atrial fibrillation with a high predictive value79, 80 but misclassification can still have occurred. Additionally, only patients hospitalized with atrial fibrillation have been included which could make it difficult to extrapolate the results to all patients with atrial fibrillation. However, data from the Copenhagen City Heart Study (Østerbroundersøgelsen) revealed that a majority of patients with atrial fibrillation were seen in hospital indicating that the results may be generally applicable.81 In article 3, the identification of patients through the national registers makes it impossible to determine the type of atrial fibrillation (paroxysmal, persistent, or permanent) or perhaps a short episode triggered by acute illness. Validity of data and information-limits in the registers The Danish National Patient Register holds information of all hospital admissions since 1978. The information held is admit-tance date, discharge date, procedure codes and one or more diagnosis codes. The register has only been accessed for article 3 since articles 1 and 2 used mortality as the only end-point and baseline variables were recorded during the ECHOS study. The diagnosis codes are usually registered by the doctor who discharged the patient. As such, accuracy of registration can sometimes fail as it is at the doctor’s discretion to include as many diagnoses as he/she sees fit. “Hard” diagnoses such as acute myocardial infarction, ischemic stroke, pulmonary embo-lism etc are relatively accurate and have been validated in sev-eral studies.80, 82 ”Soft” diagnoses such as hypertension, hyper-lipidemia etc. are less accurate with varying numbers of false negatives and positives. For example the diagnosis of essential hypertension (ICD-8 401.99, ICD-10 I10.9) has a low specificity.83

For our study the validity of the “soft” diagnoses is of less concern as we exclusively used “hard” diagnoses for the end-point calculations in article 3. The study population was identi-fied using the diagnosis codes for atrial fibrillation which has a high positive predictive value in the register meaning that we might have overlooked a number of patients but that we have probably not included patients without atrial fibrillation. Another limitation of the registers is the lack of individual information on potential confounders such as weight, height, smoking status, substance abuse, laboratory results (e.g. Inter-national Normalized Ratio, INR) and test results (e.g. left ven-tricular ejection fraction). Medication issues For article 1 and 2, patient medication was registered in the Case Report Form for the ECHOS study and as such is considered to be accurate. However, medication was only assessed at base-line and has most likely changed somewhat during the up to seven years of follow-up. The outcomes in the two studies are not directly dependent on the active treatment regimen so we do not expect the changes in medication during follow-up to have any effect on the primary results. For article 3, warfarin treatment (and baseline medication) was assessed through the Danish Register of Medicinal Product Statistics which holds information on all claimed prescriptions in the country since 1995. The information recorded is drug name, ATC code, strength, amount of tablets and dispensing date. No dosages are recorded and individual doses have been estimated as described earlier. The estimation has inherent limitations of accuracy which we have accounted for in the secondary analyses in the article. A direct validation of the estimated doses has not been feasible. The register holds no information on reasons for therapy and/or interruption. Specifically, it is unknown whether patients had adverse events or drug-drug interactions which influenced choices of therapy. Finally, it is unknown whether patients actually consumed the prescribed (and dispensed) medication. However, medical expenses are only partially reimbursed in Denmark so patients have a financial incentive to use the prescribed medication. Study-specific limitations In addition to the general limitations of the studies in this thesis there are some study-specific limitations which should be acknowledged. Article 1 – Restrictive filling pattern In some patients with diastolic dysfunction, coexisting delayed relaxation and increased filling pressure can lead to a pseu-donormalisation of the mitral deceleration time.20 It is likely that some patients in the study population presented with a pseu-donormal mitral deceleration time and that additional prognos-tic information could have been obtained if there had been data


available on tissue Doppler assessments of mitral annular dias-tolic motion, pulmonary venous flow, color M-mode, or valsalva manoeuvre.20, 84, 85 However, the inclusion of patients with pseudonormalisation of the mitral deceleration time would only dilute the primary result and therefore the limitation is not expected to change the overall conclusions. The ECHOS study, from which the data for the present study were derived, was conducted in 2001-2004 and treatment with betablockers and renin-angiotensin system blockers was proba-bly not as widespread as it is today.71, 86 This could influence the study results but we suspect that an increase in treatment fre-quency probably would affect all heart failure patients equally regardless of heart rhythm and therefore would not change the primary results of the study. It is possible that the intensified treatment of heart failure may, to a certain degree, prevent or delay incident atrial fibrillation but, again, this should have no impact on the study results as the progonostic value of a short-ened mitral deceleration time was found regardless of heart rhythm. The technology of echocardiography has evolved tremen-dously since the ECHOS study (2001-2004) and mitral decelera-tion time has been supplemented by tissue Doppler evaluation which seems to be technically superior. Specifically, pseu-donormalisation of mitral deceleration time is avoided when using tissue Doppler parameters. 87-89 The use of tissue Doppler evaluation (s’ and e’) of patients with atrial fibrillation and heart failure with preserved ejection fraction has recently been shown to be of prognostic value albeit there was no head-to-head comparison of mitral deceleration time with tissue Doppler parameters.90 A direct comparison study of the two modalities in patients with atrial fibrillation has yet to be conducted. Article 2 – Atrial fibrillation in heart failure The classification of the study patients according to heart rhythm (sinus rhythm, paroxysmal atrial fibrillation and chronic atrial fibrillation) was done at the baseline admission using all available electrocardiograms (ECGs) during admission and the medical history of the patients. There are two important limita-tions to this classification. First, the heart rhythm classification might have been incor-rect in some patients if, for example, the patients only had very few ECGs taken during admission. In that case it is possible that a paroxysmal atrial fibrillation could have been classified as chronic atrial fibrillation or sinus rhythm if all or none of the ECGs, respectively, showed atrial fibrillation. Likewise, a patient with sinus rhythm could have had a short episode of atrial fibril-lation due to acute illness and hence be classified as having paroxysmal or chronic atrial fibrillation depending on the timing and frequency of the ECGs. Second, as the rhythm was only classified at the baseline admission it is possible that some patients may have crossed over during the follow-up period of up to seven years. It is likely that some patients with atrial fibrillation received conversion therapy and successfully maintained sinus rhythm. More likely, however, is that the majority of cross-overs were patients that developed atrial fibrillation over the years of follow-up due to increased age. This would tend to dilute the results and lead to the primary result being an underestimation of the true risk.

Similarly, the presence of ischemic heart disease was as-sessed only at baseline. During a seven year follow-up it is con-ceivable that some patients in the non-IHD group may have developed ischemic heart disease. This would, analogously to the previous argument, lead to a dilution of the results, and again an underestimation of the true risk. Article 3 – Warfarin treatment interruption The primary results of the article are based on a combined end point of thromboembolism or all-cause death. As there is no information in the registers regarding the reason for interrup-tion of warfarin treatment in each patient, it is possible that the interruption in some patients is due to the fact that they are very ill and about to die from an unspecified illness. This would create an overestimation of the risk when interrupting warfarin treatment. As a secondary analysis we excluded all-cause mor-tality to counter this possible bias and the results were con-sistent with the primary result. Additionally, we repeated the analysis only including never-before-hospitalized patients in an attempt to rule out concealed co-morbidities which could act as confounders. Again, the results were consistent. The duration and timing of interruption periods were esti-mated using information on individual warfarin prescriptions, as previously described. This method is possibly inaccurate in re-gards to the exact interruption date and the exact duration of interruption. Two problems are especially relevant. First, an interruption of warfarin treatment due to an outcome event (e.g. interruption of treatment due to an ischemic stroke) may in some cases be registered as an interruption before an outcome event because of the imprecision of the estimation. Second, due to the varying dosage regimens in different individuals the algo-rithm may sometimes register an interruption in cases where the patient has reduced the daily warfarin dosage without inter-rupting treatment. The first problem was countered by doing secondary analyses with a time-shifted interruption date of up to 30 days before and after the estimated date. If there was a systematic error of event classification the results would have changed significantly by this manoeuvre. This was not the case. The second problem of over-registration of interruptions was probably not an issue. The algorithm only registered interrup-tions when patients had an estimated zero tablets left in their possession. In reality, patients may often interrupt treatment while still having tablets left. This leads to our method being an underestimation of the true duration and frequency of interrup-tions which, in turn, tends to dilute the result.

18 Jakob Raunsø

Implications

This thesis highlights some aspects of the prognostic evaluation and treatment of patients with atrial fibrillation. Prognosis eval-uation is an important part of a higher standard of care for these patients as it can help determine the need for specific therapeu-tic decisions for individual patients. The thesis adds to the sparse evidence on echocardiographic evaluation of diastolic dysfunc-tion during atrial fibrillation with the conclusion that the prog-nostic evaluation using a shortened mitral deceleration time is applicable in patients with atrial fibrillation. A shortened mitral deceleration time is associated with an equally worsened prog-nosis regardless of the presence of atrial fibrillation and sinus rhythm. As our study is the largest observational study of this issue we conclude that the evaluation of a restrictive filling pattern is a feasible and accurate tool for prognostic evaluation in patients with atrial fibrillation and heart failure. The complex interplay of atrial fibrillation and heart failure has been evaluated in the thesis with regards to the prognostic impact of atrial fibrillation in a heart failure population. In a population of approximately 3,000 heart failure patients, atrial fibrillation was associated with a detrimental prognosis but only if ischemic heart disease was present. It is likely that the aetiolo-gy of heart failure plays an important role in the vulnerability of these patients to atrial fibrillation and more research is needed in the field with regards to optimum treatment plans for these patients. Anticoagulant treatment is mandatory in patients with atrial fibrillation at heightened risk of thromboembolic events and about 60 % of patients with atrial fibrillation are treated accord-ingly. In this thesis, a large observational study comprising roughly 50,000 patients with atrial fibrillation on warfarin treat-ment documents that two out of three patients on warfarin treatment have at least one treatment interruption and that interruptions of up to 180 days are associated with a markedly increased risk of thromboembolic events or all-cause death with the highest incidence shortly after interruption. This highlights the need for prospective research following warfarin interrup-tion to determine the actual risk level and additionally under-lines the importance of a careful assessment of thromboembolic risk in each individual considered for interruption of warfarin treatment.

Conclusions

1) Prognostic evaluation of patients with diastolic dys-function using echocardiographic parameters is in-creasingly applicated. In a population of roughly 3,000 patients with heart failure a shortened mitral deceleration time conveyed an equally worsened prognosis regardless of heart rhythm suggesting that the measurement is applicable also in patients with atrial fibrillation.

2) The prognostic impact of atrial fibrillation in the same population heart failure patients was found to be dependent on the presence of ischemic heart disease. This suggests that the aetiology of heart failure plays an important role in the detrimental effect of atrial fibrillation in heart failure. This could prompt differential treatment of patients with heart failure and atrial fibrillation according to presence of ischemic heart disease.

3) Finally, a nationwide observational study of atrial fibrillation patients on warfarin treatment showed that two out of three patients have an interruption of treatment during a ten-year follow-up period. Additionally, interruption of warfarin treatment was shown to convey a marked increase in risk of thromboembolic events or death with the highest incidence shortly after interruption suggesting the presence of a rebound effect or hypercoagulable state shortly after interruption.


Future research

During the work on article 3 on the interruption of warfarin treatment we became aware of the relative lack of evidence supporting long-term treatment with oral anticoagulants. We are in the process of planning a study where we want to answer the question “What is the efficacy of oral anticoagulant treat-ment on the long term?” We plan to use the Danish national registers and identify all patients on anticoagulant treatment for atrial fibrillation and to examine the mortality-rate and causes of death. Additionally, we plan to analyze the rate of hospital admissions for bleeding episodes and thromboembolic diseases. This will provide an unprecedented follow-up duration of at least ten years. Additional ideas for future research include a register-based study of interactions between non-steroidal anti-inflammatory drugs, specifically ibuprofen, and warfarin. We plan to focus on bleeding risk in a study of a nation-wide population of atrial fibrillation patients.

As mentioned in the Limitations section of article 1, echocar-diographic modalities have emerged that may render Doppler evaluation of mitral deceleration time obsolete in the prognostic evaluation of patients with diastolic heart failure. An echocardi-ographic study is prospected to determine the value of tissue Doppler examination as compared to mitral deceleration time with regards to prognosis in patients with heart failure and atrial fibrillation. The Danish registers offer unique possibilities for high-quality pharmacoepidemiological research. The research group lead by Professor Torp-Pedersen at Gentofte Hospital actively continues to employ complex statistical methods for the analysis and understanding of interactions between illness, treatment and outcome on the national level.

20 Jakob Raunsø

Summary

More than 50,000 persons in Denmark have atrial fibrillation mak-ing it the most common arrhythmia requiring treatment. Atrial fibrillation is associated with an increase in mortality, primarily due to an increased risk of thromboembolic complications but also attributable to a possible impact of atrial fibrillation on other con-ditions such as heart failure. Thromboprophylaxis with anticoagulant treatment is a corner-stone in the treatment of atrial fibrillation while risk stratification and prognosis assessment are other important aspects of a com-plete treatment plan for the patients. Atrial fibrillation and heart failure are two disease entities with a complex interplay and it is controversial in the literature whether atrial fibrillation has a direct prognostic impact in heart failure patients. Specifically, the relationship between prognostic impact of atrial fibrillation and the aetiology of heart failure has not been established. Echocardiography is an essential tool for prognosis assessment in a heart failure population and particularly evaluation of diastolic dysfunction has received attention in the recent years. Shortened mitral deceleration time (restrictive filling pattern) is a prognostic marker in patients with heart failure, however, its use has been limited to patients with sinus rhythm due to concerns about the varying R-R interval and, hence, the varying filling pat-tern of the left ventricle in patients with atrial fibrillation. It is unknown if the measurement of mitral deceleration time is of prognostic value in an atrial fibrillation population. Anticoagulant treatment is indicated in all patients with atrial fibrillation at increased risk of thomboembolic events. However, this is counterbalanced by the increased risk of bleeding when

treated with anticoagulants. Many patients interrupt anticoagulant treatment for shorter or longer durations due to the bleeding risk. Interruption of treatment can be detrimental as there is biochemi-cal evidence of a hypercoagulable state shortly after interruption of anticoagulant treatment but it is not clear if this translates into clinical thromboembolic events. The purpose of this PhD-thesis was 1) to determine if an echo-cardiographic assessment of mitral deceleration time can be used as a prognostic marker in patients with atrial fibrillation; 2) to clarify the prognostic impact of atrial fibrillation in a heart failure population in relation to the aetiology of heart failure; and 3) to investigate the frequency of thromboembolisms or deaths in atrial fibrillation patients interrupting anticoagulant treatment. The findings of this thesis were that mitral deceleration time has the same prognostic value in heart failure patients regardless of the underlying heart rhythm (atrial fibrillation or sinus rhythm). In the same cohort of 3,000 heart failure patients chronic atrial fibrillation had a detrimental prognostic impact but only in a sub-group of patients with ischemic heart disease, underlining the importance of heart failure aetiology. Finally, in a nation-wide study of patients with atrial fibrillation on warfarin treatment it was shown that 2 out of 3 patients have at least one treatment interruption during ten years of follow-up and that the first 90 days of treatment interruption were associated with a tripled risk of thromboembolism or death.


Dansk resumé

Over 50,000 danskere lider af atrieflimren, der dermed er den hyppigst forekommende behandlingskrævende arytmi. Atrieflim-ren er forbundet med en øget dødelighed, primært på baggrund af en øget risiko for tromboemboliske komplikationer, men også på grund af en mulig forværrende effekt på andre sygdomme som fx hjerteinsufficiens. Emboliprofylakse med antikoagulationsbehand-ling er derfor en hjørnesten i behandlingen, men risikostratificering og prognosevurdering er også vigtige aspekter i den samlede be-handling af patienter med atrieflimren. Atrieflimren og hjerteinsufficiens er to sygdomsenheder i kom-plekst samspil og de er hver især forbundet med øget dødelighed, men det er til dato stadig kontroversielt, hvor stor prognostisk betydning atrieflimren har hos en patient med hjerteinsufficiens. Ekkokardiografi er et nødvendigt redskab til prognosevurdering hos patienter med hjerteinsufficiens og vurdering af diastolisk dysfunktion har de senere år været i fokus. Decelerationstiden over mitralklappen (restriktivt fyldningsmønster) er et valideret mål for diastolisk dysfunktion og nedsat decelerationstid er for-bundet med dårlig prognose. Mitral decelerationstid anvendes ikke hos patienter med atrieflimren da man har ment, at den uregel-mæssige hjerterytme og dermed uregelmæssige ventrikulære fyldning ved atrieflimren umuliggør en nøjagtig og konsistent må-ling. Det er uvist om målingen kan anvendes prognostisk hos pati-enter med atrieflimren. Antikoagulationsbehandling er indiceret hos alle patienter med atrieflimren i øget risiko for tromber. Men risikoen for blødning

skal altid afvejes mod dette og det medfører at mange patienter til tider holder pause eller helt ophører med behandlingen. Der findes biokemiske studier med evidens for at ophør med antikoagulati-onsbehandling medfører en øget risiko for tromber (hyperkoagula-bilitet), men det er uklart om dette har kliniske konsekvenser i form af øget tromboseincidens. Dette PhD-projekt havde følgende formål: 1) At undersøge hvorvidt mitral decelerationstid kan anvendes som prognostisk markør hos patienter med atrieflimren; 2) at undersøge den prog-nostiske betydning af atrieflimren hos patienter med hjerteinsuffi-ciens, specifikt i relation til ætiologien af hjertesvigt; og 3) at un-dersøge forekomsten af tromboembolier og død under pause med antikoagulationsbehandling Resultaterne har vist, at der i en kohorte på 3000 patienter med hjerteinsufficiens er samme prognostiske betydning af nedsat mitral decelerationstid hos patienter med atrieflimren som hos patienter med sinusrytme. I samme kohorte af hjerteinsufficiens-patienter var prognosen værre med atrieflimren, men kun hvis de samtidig havde iskæmisk hjertesygdom. Og sluttelig blev det vist i en landsdækkende registerundersøgelse, at 2 ud af 3 patienter med atrieflimren havde mindst 1 pause med warfarinbehandling samt at pausering tredoblede risikoen for tromboemboliske kom-plikationer indenfor de første 90 dage.

22 Jakob Raunsø

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26 Jakob Raunsø


Udgivet i samarbejde medDansk Cardiologisk Selskabwww.cardio.dk

Dansk Cardiologisk SelskabHauser Plads 101127 København [email protected]

Copyright © Jakob Raunsø

Tryk: AKA-PRINT A/SMaj 2012

ISBN: 978-87-92010-36-0

Ph.D. thesis

Atrial fibrillation – Prognosis in heart failure

and risk during interruption of anticoagulant treatment

Jakob Raunsø

Ph.D. thesis ● Jakob Raunsø

Faculty of Health Sciences,University of Copenhagen

Gentofte University Hospital, Department of Cardiology

omslag-Jakob Raunso-PRINT.indd 1 22-05-2012 15:19:48

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Ph.D. thesis Jakob Raunsø Atrial fibrillation – Prognosis in heart … · 2018-05-28 · Ph.D.-thesis Atrial fibrillation – Prognosis in heart failure and risk during interruption