Atrial Fibrillation - DiVA portal516677/FULLTEXT02.pdf · HENRIK ALMROTHAtrial Fibrillation Inflammatory and pharmacological studies I11 List of original papers I. Liuba I, Almroth

Atrial Fibrillation

To Tuva Eleonora Elisabeth and Meja Hanna Maria

Örebro Studies in Medicine 70

HENRIK ALMROTH

Atrial Fibrillation Inflammatory and pharmacological studies

© Henrik Almroth, 2012

Title: Atrial Fibrillation: Inflammatory and pharmacological studies.

Publisher: Örebro University 2012 www.publications.oru.se

[email protected]

Print: Ineko, Kållered 05/2012

ISSN 1652-4063 ISBN 978-91-7668-875-5

Abstract Henrik Almroth (2012): Atrial Fibrillation: Inflammatory and pharmacological studies. Örebro Studies in Medicine 70, 77 pp. Background: Atrial fibrillation (AF) is the most common rhythm disorder. Many patients are symptomatic. Anti-arrhythmic pharmacological strategies have poor efficacy and side effects are common. Little information about the safety of anti-arrhythmic treatment, especially flecainide, is available. Thus, new pharmacological drugs with a well-documented safety profile are warranted.

Aims: To evaluate the extent and possible source of inflammation in AF. To evaluate the effect of atorvastatin on sinus rhythm (SR) maintenance following cardioversion (CV). To evaluate the safety and mortality of flecainide in patients with AF in a local cohort and nationwide in Sweden.

Materials and methods: I - Inflammatory markers in the vessels and different loca-tions in the heart of patients with AF were compared to controls. II – A total of 234 patients with persistent AF were randomised to atorvastatin or placebo prior to CV. III - A local cohort of AF patients treated with flecainide (n=112) were studied, focusing on sudden cardiac death and pro-arrhythmia. IV - We evaluated whether current flecainide practice in Sweden is associated with increased mortality compared to a reference AF population receiving beta-blockers only.

Results: No association was found between local inflammation in the heart and AF except for elevated levels of IL-8 in persistent AF. Atorvastatin was not superior to placebo with regard to maintaining SR 30 days after CV. We found a relatively high incidence of cardiovascular death, including sudden cardiac death and pro-arrhythmia in the cohort of flecainide-treated AF patients in Örebro. However, in the nation-wide registry study, flecainide was not associated with increased mortali-ty in patients with AF compared to patients on beta-blockers only.

Conclusions: No association was observed between local inflammation in the heart and AF. Atorvastatin does not have the potential to be a novel treatment strategy for maintaining sinus rhythm after CV. On a population basis, flecainide is not associated with increased mortality. However, the risk/benefit ratio for the individual may be in question and contraindications for the drug should be respected.

Keywords: atrial fibrillation, inflammation, randomised, sudden cardiac death, pro-arrhythmia, anti-arrhythmic, statin, atorvastatin. Henrik Almroth, School of Health and Medical Sciences Örebro University, SE-701 82 Örebro, Sweden, [email protected]

Contents

ABBREVIATIONS ..................................................................................... 9

DEFINITIONS ......................................................................................... 10

LIST OF ORIGINAL PAPERS ................................................................. 11

NORMAL RHYTHM AND IMPULSE FORMATION ........................... 12

MECHANISM OF CARDIAC ARRHYTHMIA ...................................... 13

INTRODUCTION TO ATRIAL FIBRILLATION ................................... 15 Epidemiology ........................................................................................... 15 AF initiation and maintenance ................................................................. 15 Electrical remodelling ............................................................................... 16 Structural remodelling .............................................................................. 16 Autonomic nervous system ...................................................................... 17 Inflammation and AF ............................................................................... 18 Clinical presentation and natural cause .................................................... 19 Definition and detection ........................................................................... 20 Consequences of AF ................................................................................. 20

CLINICAL MANAGEMENT .................................................................. 22 Rhythm control and rate control .............................................................. 22 Importance of anticoagulation ................................................................. 25 Statins and AF .......................................................................................... 26

RATIONALE FOR THIS THESIS ........................................................... 27

AIMS OF THE THESIS ........................................................................... 28

PATIENTS AND METHODS .................................................................. 29 Ethics ....................................................................................................... 29 Paper I - Source of inflammatory markers ................................................ 30 Paper II - Atorvastatin and persistent AF ................................................. 31 Paper III - The safety of flecainide treatment in Örebro ............................ 32 Paper IV - The safety of flecainide treatment in Sweden ........................... 33

Data sources used ................................................................................ 34 Statistics ................................................................................................... 35

Some additional information about statistics and terms used ............... 36

RESULTS ................................................................................................. 38 Paper I - Source of inflammatory markers ................................................ 38 Paper II - Atorvastatin and persistent AF ................................................. 39

Paper III - The safety of flecainide treatment in Örebro ............................ 41 Paper IV – The safety of flecainide treatment in Sweden .......................... 44

GENERAL DISCUSSION ........................................................................ 47 Study populations .................................................................................... 47 Inflammation, AF, and statins .................................................................. 47 AF and flecainide ..................................................................................... 49 Methodological considerations ................................................................. 51

Generalisability .................................................................................... 51 Validity of the registries ....................................................................... 51 Selection bias ....................................................................................... 52 Confounding ........................................................................................ 53

CONCLUSIONS ...................................................................................... 54

SWEDISH SUMMARY ............................................................................ 55

ACKNOWLEDGEMENTS ...................................................................... 56

REFERENCES ......................................................................................... 58

HENRIK ALMROTH Atrial Fibrillation Inflammatory and pharmacological studies I 9

Abbreviations

ACM all-cause mortality

AF atrial fibrillation

CAST Cardiac Arrhythmia Suppression Trial

CEM coarsened exact matching

CV cardioversion

CRP C-reactive protein

EAD early afterdepolarisation

ECG electrocardiography

DAD delayed afterdepolarisations

HR hazard ratio

ITT Intention to treat

PV pulmonary veins

OR odds ratio

Px paroxysmal

PxAF paroxysmal atrial fibrillation

QoL quality of life

RF radio frequency

SD standard deviation

SMR standardised mortality ratio

SR sinus rhythm

10 I HENRIK ALMROTH Atrial Fibrillation Inflammatory and pharmacological studies

Definitions

Electrical remodelling Changes of electrical properties in the atrial

tissue (refractoriness and conduction veloci-ties) that increase the risk of new and sus-taining AF episodes over time.

Paroxysmal Self-terminating

Re-entry The most common mechanism of arrhyth-

mia. Refers to the possibility of an electrical impulse to be able to propagate through more than one electrical route with different conduction and refractory properties. Given certain conditions, the electrical impulse can travel down one route, and up the other in a circular fashion and become self-sustaining.

Refractory period The time it takes for myocytes to be recep-

tive and respond to a new electrical stimulus.

Remodelling Structural, anatomical and electrical changes of the atrial tissue as a result from AF, and of comorbidity. Remodelling increase the risk of new AF episodes and maintenance of AF over time.

Substrate Atrial tissue in which AF can occur.

Trigger A focus with ability to fire rapidly and induce AF. Triggers are often found around

the pulmonary veins


List of original papers

I. Liuba I, Almroth H, Jonasson L, Englund A, Jönsson A, Säfström K, Walfridsson H.

Source of inflammatory markers in patients with atrial fibrillation. Europace 2008; 10:848-853

II. Almroth H, Höglund N, Boman K, Englund A, Jensen S, Kjellman B, Tornvall P, Rosenqvist M.

Atorvastatin and persistent atrial fibrillation following cardioversion: A randomized placebo-controlled multicentre study. European Heart Journal 2009; 30:827-833

III. Almroth H, Andersson T, Fengsrud E, Friberg L, Linde P, Rosenqvist M, Englund A.

The safety of flecainide treatment of atrial fibrillation: long- term incidence of sudden cardiac death and proarrhythmic events. J Intern Med. 2011 Sep; 270(3): 281-90

IV. Almroth H, Friberg L, Bodin L, Rosenqvist M, Englund A.

Safety of Flecainide for atrial Fibrillation – The Swedish Atrial Fibrillation Cohort Study. In manuscript

Reprints were made with permission from the publishers. Study I and II reprinted with permission of Oxford University Press. Study III reprinted with permission from John Wiley and Sons.


Normal rhythm and impulse formation

In the normal heart, specialised cardiac cells in the conduction system (Fig-ure 1) have the ability to create electrical impulses through variable ion channel activity. The sinus node (10-20 mm long, 2-3 mm wide) is located in the high right atrium at the junction of the superior vena cava. This region normally depolarises with the highest frequency and is the denomi-nator of normal sinus rhythm influenced by the autonomic nervous system and circulating catecholamines. From the sinus node, the electrical impuls-es are discharged synchronously and propagate through three internodal pathways (the anterior “Bachmann” and middle and posterior bundle) towards the atrioventricular node (anterior to the coronary sinus ostium, above the septal leaflet of the tricuspid valve). In this region, propagation slows down to allow atrial contraction and optimise ventricular filling before the impulse is conducted to the left (left anterosuperior and posteri-or fascicle) and right ventricles (right bundle branch). The fascicles finally connect to Purkinje fibres, which transmit the impulses to the ventricles almost simultaneously, resulting in mechanical contraction against the outflow tracts.

1

3 4 2 5 6

Figure 1. The cardiac conduction system: 1, Sinus node; 2, The internodal path-ways; 3, Atrioventricular node; 4, Bundle of His; 5, Left and right bundle branch; 6, Purkinje fibres. Reprinted with permission from Ulrika Westerberg.


Mechanism of cardiac arrhythmia

The general mechanisms underlying arrhythmogenesis can be divided into automatic or triggered impulse formation and re-entry. Automaticity can be described as the ability to initiate an electrical impulse spontaneously, without prior stimulation. In contrast, triggered activity requires a “trig-ger” to initiate a response. Thus, triggered activity is a consequence of a preceding electrical impulse and can be described as early or late depending on when they arise during cardiac depolarisation (Figure 2). If any of these depolarisations reach the threshold potential, they may trigger another depolarisation and become self-sustained.

Figure 2. A) Illustrates the five phases (0 to 4) of the action potential in a ventricu-lar myocyte, and the main ionic currents involved. B) Triggered activity originating from phase 2 or 3, early afterdepolarisation (EAD). C) Triggered activity originat-ing from phase 4, delayed afterdepolarisation (DAD).

Re-entry is associated with impulse propagation rather than formation, and it occurs when an impulse is able to propagate through different routes with different electrical properties. Propagation normally follows a distinct pattern, leaving the myocytes refractory to further stimulus, and cannot be excited again until they electrically recover. However, if a trigger occurs at the right time and electrically results in a depolarisation, the normal route may still be refractory. This context can allow the electrical wave to prop-agate through an alternative route and possibly re-excite the normal route backwards. Under the right circumstances, the areas with different electri-cal properties (i.e., conduction velocity and refractory period) may re-excite each other and cause sustained re-entry tachycardia.

Re-entry can be facilitated through anatomical borders (Figure 3A) as in classical isthmus-dependent atrial flutter or through different electrophys-

A B C


iological properties (e.g., heterogeneity) in neighbouring myocardial tissue. The latter is called functional re-entry, which seems to be crucial in atrial fibrillation (AF) conceptualised by “leading circle” and “spiral-wave re-entry” 1. Both models depend on a proper balance between the refractory period and conduction velocities. Factors that promote this phenomenon are short refractoriness and slow conduction. In the leading circle theory (Figure 3B), re-entry may terminate if the conduction is accelerated, and the wavefront meets refractory myocardial tissue, or if refractoriness is prolonged by changes in the action potential duration (i.e. prolongation). In the spiral wave model 2, 3, the wave front is spread from a rotor that rapidly rotates around a core. High excitability and short refractoriness promote stability and maintenance in this model (Figure 3C).

Figure 3: Conceptual models for anatomical re-entry and re-entry in AF. A) In anatomical re-entry, the circuit is determined by fixed anatomical structures. B) The “Leading circle” depends on a proper balance between conduction velocity and refractory period. The circuit time must exceed the refractory period. C) Spi-ral-wave activity depends on tissue excitability and refractoriness, and may be supressed by increasing the action potential duration.

A B C


Introduction to Atrial Fibrillation

Epidemiology

Atrial fibrillation (AF) challenges both patients and the clinicians trying to cope with the clinical reality of their condition. Despite being the most common rhythm disturbance in Sweden, as well as worldwide, many se-crets about AF remain unsolved.

Prevalence is closely correlated with age, and approximately 25% of men and women who live past 40 will experience AF during their lifetime 4,

5. AF is a rare condition before the age of 60, when it rapidly becomes more prevalent, occurring in approximately 10% of men and women aged 75 years or more 6, 7.

With a prevalence of 1-2%, at least 5-10 million people are affected in Europe, a number that is estimated to increase rapidly in the coming dec-ades 6, 7. The corresponding prevalence in Sweden is estimated to about 180,000. According to data from the inpatient Hospital Discharge Regis-ter, the incidence corresponds to 40,000 new patients per year (2005-2009, unpublished data). This number has increased over the years, probably as a consequence of the aging population, general knowledge, and better detec-tion tools.

AF initiation and maintenance

The aetiology of AF is known to be complex and is not fully understood, even though much knowledge has been gained over the last 20 years. The principal theories “explaining” AF could be described as two main mecha-nisms, the “multiple wavelet hypothesis” and triggering through focal ec-topic activity. In 1962, Moe and colleagues were the first to hypothesise the mechanism behind AF. The initiation of AF was described to be a con-sequence of external stimuli at a pace equal to the minimal refractory peri-od of myocytes 8. Thus, myocytes with refractory properties above the given stimuli did not have the time to recover and respond. As a result, fragmentation and formation of multiple wavelets arises. Moe showed that this activity could be more persistent and self-sustaining when larger areas of tissue were affected and more wavelets occurred 9.


Electrical remodelling

The term electrical remodelling refers to Wijffels findings from 1995 in a goat model; AF episodes of short duration (minutes) promoted the perpet-uation of AF 10. This phenomenon results from a decrease in atrial refrac-toriness and changed conduction velocities10, 11. The main problem is that these changes are spread non-uniformly throughout the atrial tissue, creat-ing regions with different electrophysiological properties, a context called heterogeneity. Importantly, the periods of AF were observed to become longer and longer as they continued to induce AF. Finally, after 2 weeks of artificial stimulation, the AF became persistent, ”AF begets AF”10.

Daoud and co-workers validated the hypothesis about electrical remod-elling in 1996. AF was induced by pacemaker stimulations in patients with prior supraventricular tachycardia, and AF rapidly (within minutes) short-ened the effective refractory period in the right atrium and, if re-induced, the AF periods lasted longer 12.

Ectopic firing rarely occurs in normal atrial tissue, and the electrical properties of atrial tissue are not suitable for AF. However, atrial electrical remodelling may create atrial tissue with altered ion-channel properties or induce fibrosis.

On a cellular level, remodelling may change Ca2+ handling and result in triggered activity through early or delayed afterdepolarisation (EAD or DAD). When summarised, this provides explanatory models for why par-oxysmal atrial fibrillation (PxAF) tend to become more sustaining 10, why a recurrent AF episode most often occurs in proximity to cardioversion be-cause the process of reverse electrical remodelling can take up to a month,13, 14 and why therapeutic resistance and a permanent condition occur 15.

In 1998 Haissaguerre and colleagues took the step from goat to man. They elegantly presented evidence that the muscular sleeve of the pulmo-nary veins could be a source for paroxysmal atrial beats that can initiate PxAF 16. Focal activity seems to be observed to arise most frequently in the pulmonary veins. Other atrial regions were evidently also sources for focal activity (e.g., superior vena cava and coronary sinus), which was perhaps promoted by special electrical heterogeneity in these regions. That revela-tion led to the development of ablation strategies for the treatment of AF, and isolation of the trigger was later shown to eliminate AF 17.

Structural remodelling

Alterations in atrial function and architecture have been associated with AF and are often found in patients with hypertension, cardiac heart failure and cardiovascular disease. Macroscopically, these three comorbidities come with left atrial enlargement, a clinically important variable for pre-


dicting the outcome after cardioversion18, 19, and the success rate of abla-tion procedures20, 21. Microscopically, the changes observed in animal stud-ies are liable to be due to alterations in the interstitial tissue, as well as the cardiomyocytes 22, 23. The development of atrial fibrosis that causes electro-physiological heterogeneity as a cause or consequence of AF has been de-bated, especially as aging is associated with a risk of AF (age-related struc-tural changes). In a recent post-mortem study, fibrosis and fatty infiltration were two to three times as common in patients with a history of AF com-pared to patients without a history of AF. In addition, no correlation was found between fibrosis and age, which might indicate causation between AF and the development of fibrosis 24. Figure 4 illustrates key mechanisms in AF.

Figure 4. Key mechanisms in atrial fibrillation (AF). Atrial remodelling creates a substrate (atrial tissue) with changed electrical properties that may be suitable for initiation and maintenance of AF. Remodelling may promote ectopic activity due to changes in cellular Ca2+ handling, i.e. ectopic (triggered) activity by EADs or DADs. Ectopic activity can alone result in AF, or initiate re-entrant AF in vulnera-ble atrial tissue. EADs, early afterdepolarisations; DADs, delayed afterdepolarisa-tions.

Autonomic nervous system

The autonomic nervous system is also indicated to be involved in initiation, as well as the sustained condition 25-27. A factor that may lead to suspecting


parasympathetic involvement is vagal innervation, which may shorten the duration of the atrial action potential and the refractory period because they occur hand-in-hand 28, 29. Balance is achieved by sympathetic activa-tion, which also make repolarisation inhomogeneous. Parasympathetic and sympathetic distributions coalesce at locations as ganglionic plexi and these may be key regions for initiating and perhaps sustaining AF 30, 31.

Inflammation and AF

The correlation between AF and inflammation was initially reported in atrial biopsies from patients with PxAF 32 and from the expression of inter-leukin-8 (IL-8) mRNA in atrial specimens from patients with permanent AF 33. In case-control studies, elevated levels of C-reactive protein (CRP) may be able to predict the outcome of cardioversion 34 and the relapse rate following cardioversion 35. A correlation between AF burden (longer peri-ods) and higher CRP levels has also been observed 36. Moreover, a favour-able outcome with regards to maintaining sinus rhythm has been reported for methyl prednisolone in persistent AF 37. Taken together, these findings may suggest an association between AF and inflammation, cause or conse-quence, however unclear. To further evaluate the possibility of inflamma-tion participating in the casual pathway of AF, tools for analysing inflam-mation levels have been proposed.

CRP was first described around 1930. It is an acute-phase reactant that acts as a non-specific systemic marker and reflects inflammation, acute injury, or infection. CRP is produced primarily by hepatocytes 38 in re-sponse to IL-6 (modified by IL-1 and TNF-α) and has a half-life of roughly 19 hours.

Another marker that has been suggested as a suitable tool of inflamma-tion is IL-6. The cytokine is produced by endothelial cells, monocytes, macrophages, and T-lymphocytes and plays an active role in inflammation, neoplasia, and aging. IL-6 has the ability to induce an acute phase response as a consequence of infection or trauma and promotes CRP synthesis and fever. The half-life is approximately 2 hours. In clinical studies, IL-6 has been used to indicate inflammation 39, 40, in addition to predicting cardio-vascular disease 41.

IL-8 is also a cytokine produced by macrophages, epithelial cells, and endothelial cells. In endothelial cells, IL-8 is stored in Weibel-Palade bodies and attracts neutrophil granulocytes when released. The secretion may increase as a result of oxidative stress, and it has been proposed as a key parameter in localised inflammation 42. The half-life of IL-8 is likely less than 1 hour 43.


Clinical presentation and natural cause

In most cases AF is associated with symptoms, including palpitations, dyspnoea, and fatigue, but it may also occur without any subjective symp-toms at all. At least one-third of all AF episodes seem to be asymptomatic,44, 45, and PxAF episodes may be much more prevalent than estimated. Interestingly, patients with symptomatic PxAF have many asymptomatic episodes 46-49. This paradigm is also highlighted by the diffi-culty for patients to decide on sinus rhythm or AF following cardioversion 50.

In most patients AF is a progressive disease in which episodes initially come and go and slowly progress toward a permanent condition. In clinical praxis, AF is characterised by duration and usually progresses from parox-ysmal (self-terminating, > 2 episodes) to persistent (non-self-terminating), and finally a permanent condition in the absence of rhythm-maintaining strategies, i.e. anti-arrhythmic therapy or ablation procedures 51, 52 (Figure 5). The rate of progression varies from paroxysmal to persistent or perma-nent AF, with 8% to 25% being reported during 1-5 years of follow-up 53-

55.

Figure 5. Types and natural time cause of AF


Definition and detection

AF is defined as a cardiac arrhythmia in which the ventricular contractions visualised through RR intervals on 12-lead electrocardiography (ECG) vary without a repetitive pattern. In general, the atrial activity is ≤200 ms (≥300 bpm) or faster 51.

The different patterns of atrial heterogeneity in regards to electrophysio-logical properties may be reflected in the ECG-morphology seen in AF. Single potentials can be indicative of more uniform conduction (A), where-as fragmented potentials are more indicative of slow conduction (B)56, 57.

* * * *

A (single potentials *) # # # #

B (fragmented potentials #)

Consequences of AF

Subjective symptoms could ideally be explained by the hemodynamic changes that occur during AF. In some patients, a rapid and irregular rhythm may have a cardiomyopathic effect that weakens the left ventricu-lar function via impaired diastolic filling and loss of atrial contribution to ventricular filling. Observational findings have also suggested that irregular rhythm may result in worsened ejection fraction 58, 59. This is supported by an improvement in the left ventricular ejection fraction and function class after AV nodal ablation followed by regular ventricular pacing 60. The relative importance of atrial systole has typically been described in condi-tions in which the atrial contribution may be of greater importance. Hyper-trophic cardiomyopathy 61 or mitral stenosis are such conditions in which AF can rapidly lead to hemodynamic deterioration 62. In addition, AF may also increase neurohumoral activation, which in turn may influence sys-temic hemodynamics63, 64. After the restoration of sinus rhythm, many pa-tients experience better physical capability,65-67 and a significant increase in left ventricular function is often evident 68-70. However, subjective symp-toms differ widely between individuals and is not always correlated with objective findings from functional tests, some of which are more capable of coping with the condition than others. The subjective symptoms often af-


fect quality of life. Patients with AF experiences are described as having significantly lower quality of life compared to healthy individuals and pa-tients with ischemic heart disease 71.

The association of AF with comorbidities such as stroke and heart fail-ure is well known, but little evidence is available to support AF as the rea-son for the doubled mortality observed in this population. Even though younger AF populations without significant heart disease have had favour-able outcomes 72, 73, most studies have associated AF with a significantly increased risk of death, which is often more pronounced in women and primarily explained by excess mortality in stroke and heart failure 73-77. Non-randomised studies have failed to prove that AF itself explains the excess mortality, instead suggesting that it is a marker or confounding factor with an impact on long-term survival.


Clinical management

The management of AF has traditionally been based on two strategies, rhythm or rate control that also aims at improving subjective symptoms if present. In addition, the importance of preventing systemic embolisation has grown, regardless of AF type.

Rhythm control and rate control

The key issue in rhythm control management is the maintenance of sinus rhythm. Traditionally, this problem has been addressed with anti-arrhythmic medication, and this is still the primary rhythm-maintaining strategy. Alternative methods, such as ablation, are mainly restricted by a lack of resources.

The main problems with anti-arrhythmic medication are the low capa-bility of these drugs to maintain sinus rhythm over time as patients contin-ue to have AF episodes, which are often asymptomatic, and the risk of potentially dangerous side effects, such as pro-arrhythmia. The side effects may have a negative impact on quality of life and frequently lead to discon-tinuation.

In summary, the benefit vs. risk is sometimes in question while a patient is undergoing anti-arrhythmic treatment. “Benefit vs. risk” certainly be-comes important when “choosing” the right path for each patient. This issue has become more pertinent since anti-arrhythmic drugs have failed to result in favourable mortality outcomes vs. rate control. At least seven clinical trials have tried to evaluate rhythm against rate control 78-84, all failing to prove that the rhythm strategy is superior in clinical practice regarding all-cause mortality and quality of life. These findings have been intellectually frustrating for clinicians and a drawback for the medical in-dustry providing anti-arrhythmic drugs, but evident nonetheless.

In comparison, a rate control strategy strictly aims to control ventricular rhythm, allowing it to adapt to normal physical activities and relieving symptoms. In this concept, restoring sinus rhythm is not a goal, and it usu-ally involves drugs that slow conduction through the AV-node (beta-blockers, non-dihydropyridine calcium antagonists), or sometimes digoxin.

The tendency of AF to recur without anti-arrhythmic therapy is high, approximately 50% relapse into AF one month after cardioversion 85. After one year, the relapse rate is about 70%86. The relapse rate for anti-arrhythmic in paroxysmal or persistent AF is 30-60% with intermittent monitoring 87, 88. These numbers may be underestimated given the nature of AF and the lack of valid tools for detection. Israel and co-workers ad-dressed this issue using a pacemaker for continuous monitoring possible 48. They reported asymptomatic episodes in almost 90% of the patients during 18 months of follow-up; in 17% of these patients, the episodes exceeded


>48 h duration 48 In addition, 40% of the patients reported subjective symptoms in the absence of AF.

Vaughan Williams categorised AA drugs in the 1980s, and later in the

1990s, based on their mechanism of action, i.e., which ion channels they block 89, 90 (Figure 6).

Figure 6. A) Presents the five phases (0 to 4) of the action potential in a ventricular myocyte and the main ionic currents involved. B) Presents where anti-arrhythmic drugs interfere with the action potential according to the Vaughan Williams classi-fication.

This classification was developed at a time when few anti-arrhythmic drugs were available and knowledge of their action mechanisms was limited. Today we know that most of the classical anti-arrhythmic drugs are not entirely devoted to one strict class, but may convey other class effects as well, making this categorisation somewhat out of date. The anti-arrhythmic drugs available today (Table 1) are almost the same as 20 years ago because of difficulties developing efficient and safe alterna-tives, in addition to much harder regulatory demands preceding new drug applications and indications for use.

A B


Table 1. Available anti-arrhythmic drugs in Sweden, by Vaughan-Williams classifi-cation.

Class Generic substance

Trade name (Sweden)

Approval (Sweden)

General action

I A disopyramide Durbis® 1978 Na+ channel blockade I B lidocaine

vernakalant Xylocard® Brinavess®

2006 2010

Na+ channel blockade

I C flecainide propafenone

Tambocor® Rytmonorm®

1986 1991

Na+ channel blockade

II beta-blockers Sympathicus blocker III amiodarone

sotalol ibutilide dronedarone

Cordarone® Sotalol® Corvert® Multaq®

1987 1993 1996 2009

K+ channel blockade

IV diltiazem verapamil

Cardizem® Isoptin®

1985 1971

L-type Ca+2 channel blockade

One of the most frequently used anti-arrhythmic drugs for maintaining sinus rhythm and controlling subjective symptoms is flecainide (Tam-bocor®). Flecainide has been registered in Europe since 1982, initially with the indication to suppress premature ventricular contractions (PVCs). In June 1987 the Cardiac Arrhythmia Suppression Trial (CAST) was initiated. The trial was designed to evaluate whether suppression of PVCs by anti-arrhythmic therapy (flecainide, encainide, or moricizine) reduces arrhyth-mic death in patients with prior myocardial infarction compared to place-bo. The study was terminated early in 1989 when an interim analysis found a 2.5-fold increased risk of all cause mortality in patients treated with flecainide/encainide (mainly death by arrhythmia or cardiac arrest)91,

92. The main indication of flecainide since CAST is “patients with sympto-matic AF in the absence of structural heart disease” (cardiac heart failure, ischemic heart disease, valvular disease) according to the national and in-ternational guidelines 51, 52. However, no safety studies with the power to detect mortality differences have been published since CAST, especially not in the population that uses it most frequently, the AF population.

The development of new anti-arrhythmic drugs has demonstrated seri-

ous problems with adverse events, especially when targeting ion channels and the “electrical approach”. The result has been that remarkably few new drugs of this type have reached the market in the last 20 years: ver-nakalant in the setting of pharmacological cardioversion93 (AF duration < 7


days) and a derivate of amiodarone that recently experienced a drawback when given to a less healthy AF population, resulting in increased mortality and stroke94, 95. Both of the drugs are now suitable for a small proportion of patients.

Importance of anticoagulation

Stroke prevention via oral K vitamin antagonists has come to be the one essential factor in mortality outcome in AF patients 96, 97. In a meta-analysis by Hart et al, warfarin and aspirin reduced the stroke incidence by 62% and 22%, respectively. To address the issue of who to treat, Gage pro-posed the CHADS2 score as a tool for estimating yearly stroke incidence in AF patients 98. This scoring system used age > 75 years and comorbidities (e.g., cardiac heart failure, hypertension, diabetes, stroke or transient is-chemic attack), resulting in a widely adopted tool in which annual adjusted stroke rates between 1.9% and 18.2% could be estimated using a straight-forward scheme (Table 2). This scheme was recently refined by including vascular disease (prior myocardial infarction, peripheral arterial disease, or aortic plaque), sex category (female), and by dividing age into two strata, (age 65-74 years, and age ≥75 years) in the CHA2DS2-VASc score 99.

Table 2. Annual stroke rate / 100 patient years adapted from Gage and colleagues98

CHADS2-score Patients (n=1733)

Adjusted stroke rate (95 % CI)

0 120 1.9 (1.2-3.0) 1 463 2.8 (2.0-3.8) 2 523 4.0 (3.1-5.1) 3 337 5.9 (4.6-7.3) 4 220 8.5 (6.3-11.1) 5 65 12.5 (8.2-17.5 6 5 18.2 (10.5–27.4)

The importance of anticoagulation was addressed when it became evident that embolic events occurred regardless of rhythm or rate strategy in the AFFIRM and RACE studies 83, 84. However, a major proportion of the em-bolic events (AFFIRM 113/157 ischemic strokes, RACE 29/35 embolic events) followed warfarin discontinuation or a subtherapeutic International Normalised Ratio (INR < 2). This finding highlighted that rhythm strategy does not automatically rule out the need for oral anticoagulation and that


indications should be governed by factors other than subjective freedom of AF episodes and rhythm strategy using anti-arrhythmic.

The impact of asymptomatic and short AF episodes is debated but can be exemplified by Bottos findings from 2009. In this study, asymptomatic AF episodes of >5 min were associated with a six-fold risk of thromboem-bolic events compared to patients with similar CHADS2 scores and no AF 100. A mechanism that may be involved is the impaired atrial contractile state called “atrial stunning”, which is associated with AF and impacts blood flow. Even AF with duration as short as one hour may result in atri-al stunning, often most intensely in the left atrial appendage 101, 102. Conse-quently, flow velocity may decrease, leading to stasis that can be visualised by spontaneous contrast (aggregation of erythrocytes at low shear stress 103). Cardioversion seems to be associated with an increased risk of throm-boembolic events, partly due to dislodgment of a pre-existing embolus, and partly due to de novo formation of thrombi as a consequence of impaired left atrial function 104-107. Moreover, the duration of mechanical stunning following cardioversion seems to be related to the duration of AF prior to the restoration of sinus rhythm 108, 109. In most cases atrial contractility returns gradually, and it is usually normalised within a month 108. The gradual recovery may explain why most embolic events occur within the first 10 days following cardioversion 110, 111.

Statins and AF

Observational findings have focused interest towards targets other than ion channels, mainly medications with possible effects on atrial remodelling. Among these, statins have been developed as a possible treatment option. Initially, less frequent episodes of ventricular arrhythmia were observed in ICD-patients (Implantable Cardioverter Defibrillator)112, and results were consistent with findings from AVID 77. When MIRACL presented an asso-ciation between favourable stroke incidence and statin treatment, the hy-pothesis was that at least part of this response could be due to less AF bur-den and a potential anti-arrhythmic effect 113. One mechanism that could explain these beneficial effects was indicated by anti-inflammatory proper-ties observed in an animal model. Twenty dogs were randomly assigned to treatment with or without 2 mg/kg/day atorvastatin, followed by the intro-duction of sterile pericarditis. In addition to shorter inducible AF episodes in the atorvastatin group, lower CRP levels were measured, and the au-thors proposed that atorvastatin might be “a novel therapeutic agent for AF” 114.


Rationale for this thesis

In summary, the AF population is growing rapidly and is already an im-mense challenge for both patients and health care. Because many AF pa-tients are symptomatic, a large proportion of them are subject to treatment aiming for normal sinus rhythm in order to control symptoms pharmaco-logically. The pharmacological treatment of AF patients is problematic due to limited efficacy and potential side effects, raising questions with regards to risk vs. benefit. Thus, information about safety of available anti-arrhythmic medication in clinical practice is warranted, as well as new, alternative pharmacological approaches to target AF and these patients. Hopefully, this thesis will add some information about these issues and increase the available knowledge on AF.


Aims of the thesis

Paper I To investigate the extent and possible source of inflammation in patients with AF. Paper II To evaluate the effect of atorvastatin on sinus rhythm following electrical cardioversion in patients with persistent AF. Paper III To assess the safety of long-term treatment with flecainide in patients with atrial fibrillation (AF), particularly with regard to sudden cardiac death and pro-arrhythmic events, locally in Örebro, Sweden. Paper IV To evaluate the safety of long-term treatment with flecainide in Sweden nationwide, with particular regard to mortality compared to a control group on beta-blocking agents.


Patients and methods

Ethics

All studies were performed in keeping with the Helsinki Declaration of human rights. The Regional Ethical Board in Linköping approved study I (D.nr 03-242; 2003-06-12) and the Regional Ethical Review Board in Stockholm at Karolinska Institute approved studies II (D.nr 03-207; 2003-05-05) and IV (D.nr 2009/1378-31/1; 2009-09-23). Approval from the Swedish Medical Product Agency was also obtained for study II. Study III was conducted as a quality assurance study in line with the Swedish Health and Medical Services Act (HSL, 1982:763). Signed and informed consent was obtained for participants in studies I and II. Study IV was conducted through registry linkage and subject information was anonymised before analyses were performed.


Paper I - Source of inflammatory markers

In study one, which was designed as a pilot study, we aimed to assess in-flammatory markers at different locations. We hypothesised that an in-flammatory mechanism in the vicinity of the heart (atrium, pulmonary veins) might be involved in AF development. Twenty-eight patients were enrolled during 2004 and 2005 (Linköping n=18, Örebro n=10). Eligible patients were referred for ablation of symptomatic arrhythmias and free of comorbidities, including structural heart disease, diabetes mellitus, and neoplasia. Other exclusion criteria were previous ablation, cardiac heart surgery or infection <90 days before the ablation procedure, and/or the use of lipid-lowering drugs. Patients with AF were categorised according to PxAF (≥1 subjective episode of AF per month, n=10) or permanent AF (AF continuously ≥ 2 months, n=8). The control group consisted of 10 patients with a left-sided accessory pathway and no evidence of AF. Blood samples were obtained from the femoral vein, right atrium, and coronary sinus using a 7-French sheath or an Amplatz catheter (coronary sinus). Samples from the left and right pulmonary veins were drawn after transseptal punc-ture using the transseptal sheath after a bolus of heparin. Prior to blood sampling, 5-10 ml of blood was aspirated and discarded. Blood samples for IL-6 and IL-8 measurements were drawn from all sample sites, whereas CRP samples were obtained only from the femoral vein, though it is mainly synthesised in the liver. All samples were centrifuged and separated at room temperature, and then stored at -80°C until analysis. The lower lim-its of detection were 0.1 mg/L, 0.39 pg/ml, and 0.1 pg/ml for CRP, IL-6, and IL-8, respectively.


Paper II - Atorvastatin and persistent AF

In study two, the aim was to evaluate the effect of atorvastatin on sinus rhythm maintenance after cardioversion. This was an investigator-initiated, double-blinded, placebo-controlled, randomised study. Almost 800 pa-tients were assessed for eligibility at 10 different participating centres in Sweden between August 2004 and January 2007. We hypothesised a 30% lower relative relapse rate in patients randomised to atorvastatin (40 mg, twice daily) compared to placebo 30 days after cardioversion.

A total of 234 patients were randomised and allocated to atorvastatin (n=118) or placebo (n=116). The production unit of the hospital pharmacy created computer-generated randomisation lists (blocks of 6) and managed packaging and labelling. Treatment was initiated 14 days before, and con-tinued 30 days after, cardioversion. All patients received warfarin accord-ing to standard procedures (international ratio ≥2 checked weekly for 3 weeks or more) prior to cardioversion. Patients were followed up at 2 days, 1 month, and 6 months after cardioversion. Blood lipids were determined at baseline and 30 days after cardioversion.

The primary endpoint was rhythm obtained by 12-lead ECG 30 days (sinus rhythm or not) after cardioversion. Secondary endpoints were rhythm 6 months after cardioversion, safety, and tolerability. Inclusion and exclusion criteria are presented below.

Inclusion criteria: Clinical indication for cardioversion AF duration > 7 days Age >18 and ≤80 Exclusion criteria: Paroxysmal AF of atrial flutter On-going treatment with lipid-lowering drugs Contraindications against atorvastatin Class I or III antiarrhythmic treatment Oral amiodarone < 6 months prior to inclusion Known liver disease or cardiomyopathy Previous electrical cardioversion (within 1 year)


Paper III - The safety of flecainide treatment in Örebro

In study three, the main objective was to assess the safety of long-term treatment with flecainide in AF patients. The rationale for the study was the limited data available on flecainide treatment of AF patients, keeping the unexpected results of the CAST study in mind. Accordingly, we per-formed a retrospective safety study in a clinical cohort of AF patients who were managed at the University Hospital of Örebro during flecainide treatment.

All patients who started flecainide treatment at the department of Car-diology in Örebro between 1998 and 2006 were identified (n=112). This was possible because flecainide treatment was initiated while the patient was admitted to the cardiology ward for 2 to 3 days for ECG surveillance. These patients could be identified from the computerised epicrisis. Stand-ard routine was applied prior to flecainide initiation. All patients were evaluated by transthoracic echo. Ischemia was evaluated by history in addi-tion to an exercise test. In the case of disability or pacemaker, myocardial scintigraphy or coronary angiography was performed. Demographic data, together with data from the transthoracic echo, exercise test, and infor-mation about medications, were entered into a database. Typically, follow-up was performed once yearly. In between visits, patients were instructed to make contact if symptoms of ischemic heart disease, cardiac heart fail-ure, dizziness, or syncope occurred. Treatment was discontinued if it was considered to be ineffective at maintaining sinus rhythm, at the occurrence of intolerable side-effects, the detection or suspicion of structural heart disease, a new bundle-branch block, or QRS duration >50% compared to pre-treatment.

The main outcome measure was death with special regard to sudden cardiac death and pro-arrhythmia. Pro-arrhythmia was defined as cardiac syncope or life-threatening arrhythmia. We used standard criteria for sud-den cardiac death, i.e., death that occurred suddenly and unexpectedly in a patient with an otherwise stable condition. Witnessed deaths with or with-out documentation of arrhythmia were included. Un-witnessed deaths were also included if the patient had been observed within 24 h before death in the absence of premonitory heart failure, myocardial infarction, or another clear cause of death 115. To determine the observed mortality, comparisons were made to mortality rates from the general Swedish population using standardised mortality ratios (SMRs) adjusted for age (5-year groups) and gender. SMRs were estimated for all-cause mortality (ACM) and cardio-vascular disease; the latter defined as ischemic heart disease (ICD-10 I20-I25), cardiac arrhythmia (ICD-10 I46-I49), heart failure (ICD-10 I50), and stroke (ICD-10 I61, 63-64). In addition, annualised incidence rates for


events (SCD or pro-arrhythmia, 1:1 atrial flutter, wide QRS tachycardia, or syncope during exercise) were presented.

Paper IV - The safety of flecainide treatment in Sweden

All patients in the Swedish National Hospital Discharge Register, with a diagnosis of AF between 1 July 2005 and 31 December 2008, were identi-fied by their unique personal identification number. This registry covers complete information about all hospital admissions, and visits to outpa-tient clinics for subjects with a Swedish civic registration number since 1987. Patients with AF were ascertained by the ICD code I48.9, including subcodes A-F (International Classification of Diseases, 10th revision). Time at risk was counted from the date of first occurrence of an AF diagnosis during the study period (index date). The accuracy of diagnoses obtained from this registry is high 116. The register misses information about princi-pal diagnoses in 0.5-0.9% of hospitalizations in somatic care116. Recently, the diagnosis of AF or atrial flutter was found to have a positive predictive value of 97% 117.

The Hospital Discharge Register was also used to ascertain information about comorbidities. This register holds information of all hospital admis-sions, and visits to outpatient clinics with principal, and up to nine ancil-lary diagnoses, and up to 13 codes for surgical and interventions. Diagno-sis prior to the index date and two weeks after reflected baseline comorbid-ity. The blanking period of 2 weeks was used since transfers between hos-pitals and clinics were common, and early re-appearances of a diagnosis were often intimately related to a preceding hospital period.

Information about medication was obtained from the Swedish Pre-scribed Drug Register. This register automatically stores detailed infor-mation about every prescription that is handled in every pharmacy in the country since July 1, 2005, and is therefore to be regarded as almost 100% complete. Dates of deaths that occurred during follow-up was obtained from the Swedish Total Population Register. To ensure anonymization before the data was analysed, the personal identification number was ex-changed to a unique serial number by the statistical unit of the Swedish National Board of Health and Welfare.

The exposure group was defined as all patients who had used flecainide as the only anti-arrhythmic treatment in addition to beta-blocker during follow up. The combination with beta-blocker was motivated by the con-duction slowing properties of flecainide (rate dependent block) that may result in slow AF or atrial flutter with rapid conduction to the ventricles118,

119. Patients who had used other anti-arrhythmic drugs than flecainide were


excluded. The reference population was defined as all patients who only had claimed beta-blockers.

Prescriptions that had been collected within 3 months of the index date were defined as medication at baseline.

The primary outcome measure was all cause mortality. Follow up ended at the time for death or at the end of the study period, 1 Feb 2010.

Data sources used

The Swedish personal identification number was introduced in 1947 and makes linkage between registries possible as it is used in all health care and population registries in Sweden. Approximately 100% of all Swedish resi-dents are assigned this ten-digit number at birth 120.

The Swedish National Hospital Discharge Registry contains nationwide information about inpatient care from 1964 onward. From 1987 onward, this registry is complete and provides information about all hospital admis-sions, including main and bi-diagnoses and surgical interventions using the International Classification of Disorders (ICD). The reliability of diagnoses from this registry is well validated and well suited for epidemiological stud-ies 116, 121, 122.

The Swedish Prescribed Drug Registry is a nationwide registry initiated 1 July 2005. It covers the entire Swedish population and is the most exten-sive of the Nordic prescription databases. This registry contains infor-mation about patient-specific data (age, gender, location), the prescriber, and prescribed and dispensed drugs. Prescribed drugs are identified by the international ATC classification. Information about the strength and amount of the drug dispensed is also available. In addition to the Danish counterpart, the Swedish Prescribed Drug Registry also includes infor-mation about the prescribed dose.

The Total Population Register contains information on the basic demo-graphic population statistics, including gender, age, and civil status, and information about emigration and death for all Swedish citizens. Statistics Sweden is responsible for this registry, which is often used as a source in medical and behavioural sciences.


Statistics

The distribution of a normally distributed variable (continuous) is ex-pressed as mean ± standard deviation (SD). For non-normally distributed variables, median and interquartile range or median and range are used.

The point-estimates of the odds ratio (OR) (papers II and IV), the stand-ardised mortality ratio (SMR), and the annualised incidence rate (paper III) are shown with 95% confidence intervals. In general, p<0.05 was consid-ered significant.

Pearson´s chi-square test was used to evaluate differences in proportions

between groups in papers I to IV. Fisher´s exact test was used instead of the chi-square test in the case of

small numbers in papers I to IV. The Students t-test was used to evaluate continuous variables between

groups in paper II. Wilcoxon´s rank sum test was used instead of the Student´s t-test to

evaluate differences between independent groups in the case of skewed distributions. This test was used in papers II, III, and IV.

Mann-Whitney U test was used in paper I. This is analogous to Wilcox-

on´s rank sum test. One-way analysis of variance was used in paper I to compare continu-

ous variables between patients with paroxysmal or permanent AF and controls (WPW-syndrome).

Spearman rank correlation was used to estimate the possible association

between the levels of inflammatory markers at different sample sites in paper I.

Pearson´s correlation: We also re-analysed the inflammatory markers in

paper I after a logarithmic transformation because the values indicated a skewed distribution.

Logistic regression: This model-based analysis, with the OR as an effect

parameter, was used in paper IV before and after pre-analysis matching by coarsened exact matching. With this model, different background variables that possibly impact the outcome and have a non-ignorable correlation with exposure were screened. If any of the different variables changed the point estimate for the exposure by more than 10%, these variables were


characterised as possible confounders. In the final analysis, the possible confounding effects of all these variables were considered when the adjust-ed OR was calculated.

Cox proportional hazard regression was used in paper IV to validate the

results obtained with the logistic regression model. It has the hazard ratio (HR) as an effect parameter.

Some additional information about statistics and terms used

Annualised incidence ratio describes the number of new cases during a specified period. This is used in paper III to estimate the number of events during flecainide exposure; sudden cardiac death and pro-arrhythmia on a yearly basis / 100 person-years.

Matching is a method to create exposure groups with similar baseline

characteristics in all regards other than the variable being studied. This method reduces the risk of non-random bias, which may result in spurious associations when conclusions are to be drawn. We used coarsened exact matching (CEM) in paper IV to adjust for differences in baseline character-istics between patients on flecainide and a beta-blocker versus beta-blocker alone. This is an advanced algorithm that excludes patients in one group who have no matching counterpart in the other group with regard to the variables that are chosen for matching. In addition, CEM defines a new variable from the baseline characteristics that weighs the remaining obser-vations in the post-matching analysis.

Odds Ratio (OR): A point estimate to approximate the magnitude of an

outcome; that is, the ratio between the odds of two groups towards an outcome. In this thesis, OR is used for two outcomes: in paper II regarding sinus rhythm 30 days after cardioversion (atorvastatin vs. placebo), and in paper IV to estimate mortality from flecainide exposure versus a control group using beta-blockers only. An OR equal to 1.0 indicates no differ-ences between the groups under examination.

Person-years: The sum of all years in a cohort to describe the time at risk

or exposure. This is used in paper III to summarise years of flecainide ex-posure in the cohort studied.

Standardised mortality ratio (SMR) is the ratio of the observed number

of deaths in one cohort compared to the expected number of deaths using mortality rates from the general Swedish population adjusted for age and gender. This ratio can be used to compare the health status in a cohort of


interest to the general population. This was used in papers III and IV to compare the patients who had been exposed to flecainide and beta-blockers or beta-blockers alone to the general population with regards to all cause mortality (papers III and IV) and cardiovascular death (paper III).

Analyses were performed using JMP 5.1.1 and Statview 5.0 (SAS Insti-tute Inc., Cary, NC) in paper I; JMP® 7 in papers II and III (SAS Institute., Cary, NC, USA), and Statistical Package for the Social Sciences (SPSS®) version 20 (IBM, SPSS, Armonk, NY, USA) and STATA® software version 12 (StataCorp, College Station TX, USA) in paper IV.


Results

Paper I - Source of inflammatory markers

In general, the study cohort was free from comorbidities and considered to be a healthy population. The three groups were well balanced with respect to baseline characteristics with the exception of hypertension, which was more common in patients with permanent or paroxysmal AF (n=4, 22% compared to controls, n=0). Five patients with PxAF (50%) and eight pa-tients with permanent AF (100%) were in AF during blood sampling. The remaining 15 patients were in sinus rhythm (PxAF n=5, controls n=10). In the analysis, comparisons were made between PxAF and controls and be-tween permanent AF and controls.

Patients with permanent AF had higher levels of IL-8 in the femoral vein right atrium, and coronary sinus compared to the controls, but this differ-ence was not found in the samples from the left and right superior pulmo-nary veins (p=0.023). Further analysis suggested a relationship (similar levels) between IL-8 levels in the femoral vein and right atrium, as well as the femoral vein and coronary sinus ostium (Figure 7). IL-6 trended to-wards higher values at all sample sites in patients with persistent AF com-pared to controls, especially the pulmonary veins.

Figure 7. Regression plots presenting close correlation between IL-8 levels in the femoral vein, right atrium (RA) and coronary sinus (CS).

No differences were found between PxAF and controls regarding the in-flammatory markers, regardless of sampling site. Rhythm at the time of sampling and AF duration based on history did not impact these observa-tions. CRP was similar between the groups.


Paper II - Atorvastatin and persistent AF

A total of 234 patients were randomised and allocated to intervention with atorvastatin (80 mg/d, n=118) or placebo (n=116). Baseline characteristics were similar between the groups. In 9% of patients, cardioversion failed (atorvastatin n=8, placebo n=13) and did not result in sinus rhythm. Twelve patients (5%) discontinued intervention during follow-up (atorvas-tatin n=7, placebo n=5), mostly because of logistical reasons. Between ran-domisation and day 30 after cardioversion, six patients (3%) repeated cardioversion (atorvastatin n=2, placebo n=4).

At the primary endpoint (day 30 after cardioversion), a total of 222 pa-tients with outcome data (rhythm by 12-lead ECG) were available and included in the primary outcome analysis, intention to treat by randomisa-tion group. This analysis showed that 57 patients (51%) in the atorvastatin group and 47 (42%) in the placebo group maintained sinus rhythm 30 days after cardioversion. At 6 months, the corresponding numbers were 41 (38%) and 43 (39%), respectively.

Regarding concomitant medication, the groups were well balanced dur-ing follow-up, with the exception of calcium antagonist being used more often in the placebo group (22% vs. 11%%, p=0.029). A summary of the primary and secondary outcomes is presented in Table 3. Study design and reasons for discontinuation is presented in Figure 8. Compliance in both groups was >90%. No serious adverse events occurred during the study.

Table 3. Summary of results, analysed by intention-to-treat with available data

Endpoint Atorvastatin group (n=111)

Placebo group (n=111)

Odds ratio (95%CI)

P-value

Primary No of patients in SR Day 30

57 (51.4)

47 (42.3)

1.44 (0.85-2.44)

0.18

Atorvastatin group (n=109)


Secondary No of patients in SR at 6 months

41(37.6)

43 (39.1)

0.94 (0.54-1.62)

0.82

Atorvastatin group (n=116)


Secondary Tolerability Adverse events

115 (99.1) 3 (2.6)

115 (100) 4 (3.5)

-

0.74 (0.16-3.37)

1.00 0.72


Not eligible (n=549)

Not meeting inclusion criteria (n=367)

Not willing to participate (n=182)

Randomized (n=234)

Atorvastatin 80 mg/day (n=118)

Received allocated intervention (n=118)

Placebo (n=116) Received allocated intervention

(n=116)

Discontinued intervention

adverse event (n=1) withdrawn consent (n=1)

Logistic reasons screening failure (n=1) missing data (n=2) running out of study drug prior to CV (n=2)

Allocation

Discontinued intervention withdrawn consent (n=1)

Logistic reasons missing data (n=2) running out of study drug prior to CV (n=2)

Cardioversion (CV) Cardioversion (CV)

Analysed (n=111) Analysed (n=111)

Follow-up

14 days treatment prior to CV

30 days treatment post CV

Figure 8 Design of Study II

Assessed for eligibility (n=783)


Paper III - The safety of flecainide treatment in Örebro

Between 1998 and 2006, with follow-up until 1 December 2008, we identi-fied 112 patients who initiated flecainide treatment. The mean age of the cohort was 60 years, and 65% were men. Ischemic and valvular heart dis-ease was evident in 4% of the patients, and 97 (87%) had a CHADS2 score of ≤1 at baseline. The mean daily dose of flecainide was 200 ± 43 mg. A total of 100 (89%) patients combined flecainide with a beta-blocker or non-dihydropyridine calcium antagonist.

During a mean follow-up of 3.4 years, more than half of the population discontinued flecainide treatment (Figure 9), mainly due to breakthrough AF and lack of efficacy, but cardiac side effects were also common.

Inefficacy (n=36)

Non-cardiac side effect (n=7)

Successful RF ablation (n=6) Cardiac side effect (n=18)

Figure 9. Reasons for discontinuation of flecainide

Six were classified as having pro-arrhythmia; three documented by 12-lead ECG or telemetry (monomorphic wide QRS tachycardia, n=2; 1:1 atrial flutter with broad QRS and syncope, n=1)(Figure 10). Two patients had syncope during exercise associated with palpitations and one patient had episodes of 1:1 atrial flutter during a hospital stay and symptoms (no ECG or rhythm strip available).

On flecainide

40 % (n=45)

Dis-continued flecainide

60 % (n=67)


A) Wide QRS-tachycardia (330 ms.) in a 75 year old male with persistent AF and prior stoke after two months on flecainide.

B) Fifty-five year old woman with a dual chamber pacemaker due to bradycar-

dia. After increasing flecainide from 200 mg to 300 mg per day, she developed a wide QRS tachycardia, RR 360 ms.

C) Seventy year old man, free from comorbidity. After almost three years on

flecainide, he was admitted because of syncope and palpitations. Telemetry re-vealed 1:1 atrial flutter, RR 285 ms.


Figure 10. Documentation of pro-arrhythmic events.

During follow-up, 8 patients (7%) died after flecainide exposure, which is higher than expected when compared to the age- and gender-adjusted population annual mortality rate (2.1% vs. 1.3%). Five of the observed deaths were classified as non-sudden (cancer, n=1; stroke, n=2; ST eleva-tion myocardial infarction, n=1) and three deaths classified as sudden car-diac death. The SMRs were 1.57 (95% CI 0.68-3.09) for all-cause mortali-ty and 4.16 (95% CI 1.53-9.06) for death from cardiovascular death dur-ing flecainide exposure.


Paper IV – The safety of flecainide treatment in Sweden

Over a period of 3.5 years, 182,678 unique patients with a diagnosis of AF were identified in the Hospital Discharge Register. Of these patients, 64,918 (45.7%) had used beta-blockers in the absence of anti-arrhythmic drugs, digoxin, and non-dihydropyridine calcium antagonists, and 5,381(2.9%) had used flecainide. The majority of the patients had used alternative anti-arrhythmic drugs. Only 264 patients received flecainide alone. The patients who had been prescribed flecainide at any time were 15 years younger, more often male, had lower prevalence of comorbidity, and less concomitant medication (warfarin excluded) compared to the reference population. A total of 672 (12.5%) patients had structural heart disease (defined as ischemic heart disease, cardiac heart failure, or valvular dis-ease). In the matched study group receiving flecainide and beta-blocker (n=2,178), 9.4% had structural heart disease. Figure 11 illustrates the study group distribution. Mortality within the Cohort The unadjusted mortality during follow-up was 2.8% among the patients exposed to flecainide compared to 30.8% among patients on beta-blockers. The median follow-up time was 2.2 years (0-4.6) in patients ex-posed to flecainide and 2.5 years (0-4.6) in patients on beta-blockers, re-spectively. After CEM, 2,178 patients who received flecainide and beta-blockers had similar baseline characteristics to 27,313 patients who re-ceived beta-blockers. The corresponding CEM-adjusted mortality was 2.6% in patients on flecainide and beta-blockers versus 8.5% in patients on beta-blockers only, (odds ratio (OR) 0.27, 95% confidence interval (CI) 0.21-0.36, P<0.001). The primary analysis was verified in a multivariable Cox regression model. The result was almost identical to the primary anal-ysis based on logistic regression. Mortality Compared to the General Population Compared to age- and sex-adjusted population statistics (5-year classes), the SMR was approximately one-third in patients on flecainide (male: 0.66, 95% CI 0.46-0.91; female: 0.76, 95% CI, 0.47-1.18), indicating a healthy population compared to the reference population on beta-blockers only (male: 2.31, 95% CI 2.27-2.35; female: 2.21, 95% CI 2.16-2.25). Characteristics of Deceased Patients on Flecainide A total of 56 patients (2.6%) from the matched population on flecainide died during follow-up. In general, these patients were 10 years older and had more severe comorbidity at baseline than those who were still alive.


The mean daily doses of flecainide were similar (199.1 mg, SD 35.2 versus 194.0 mg, SD 42.2, P=0.459) between the two groups. Ischemic heart dis-ease (19.6% versus 5.3%, P<0.001), cardiac heart failure (19.6% versus 2.7%, P<0.001), and pacemaker use (12.7% versus 2.7%, P<0.001) were more common among the patients who died. Sixteen (28.6%) of the flecainide-exposed patients who died had structural heart disease.

The 264 patients who were prescribed only flecainide during follow-up had a higher mortality rate than patients who received flecainide and beta-blockers (6.8% versus 2.6%, P<0.001). At death, only 41 patients were on flecainide, 20 of which had no concomitant beta-blocker therapy.


The Swedish Atrial Fibrillation Cohort

In hospital diagnosis between 1 July 2005 and 31 December 2008

n=182,678

Any use of anti-arrhythmic medication

n=28,090

Any use of flecainide

n=5,381

Only flecainide and beta-blocker during follow-up

n=2,178

Any use of beta-blocker

n=141,941

Any use of only beta-blocker

n=64,918

Only beta-blocker during follow-up

n=27,313

Coarsened exact matching

Figure 11. Flow-chart of the study group distribution


General discussion

Study populations

The first study targeted a smaller group of patients, whereas the last study obtained information from a less select population using epidemiological data. The prevalence of AF in the last study group was estimated to be 1.9% during an inclusion period of 3.5 years. This prevalence is similar to what was found in other studies 6, 7, but the true prevalence is likely higher, as many AF episodes are asymptomatic and do not result in hospital care 44, 45.

The typical AF patient is roughly 75 years old with comorbidities, such as hypertension, ischemic heart disease, cardiac heart failure, or diabetes 123, 124. In comparison, the patients in paper I were far healthier due to the issue addressed and the importance of not introducing factors that could introduce bias and confuse the possible association between AF and in-flammation. The population in study two was more typical, but they could be considered a healthy AF population according to the inclusion and ex-clusion criteria used. Patients on statins were excluded. Consequently, few patients with ischemic heart disease were enrolled. The patients exposed to flecainide in studies three and four were also healthy AF patients because that treatment is contraindicated in the presence of structural heart disease. In comparison, the reference population on beta-blockers in study four was more typical, reflecting nationwide data with no restriction on age and comorbidity.

Inflammation, AF, and statins

Low-grade inflammation has been associated with cardiovascular disease, such as myocardial infarction or stroke 125-128, but it seems to not be that closely related to AF. Some 30 years ago, the coexistence of AF in patients with myocarditis and pericarditis suggested a link to inflammation 129, 130. In 1997 Bruins et al observed that the peak incidence of CRP coincided with postoperative AF and proposed a casual relationship between in-flammation and AF 131. The same year, Frustachi presented histological evidence for inflammatory changes in the atrial tissue of patients with PxAF compared to patients with WPW syndrome 32. Since that time, differ-ent approaches have been used to evaluate the possible casual relationship between inflammation and AF.

In paper I, we hypothesised that local inflammation in the heart is in-volved in the pathogenesis of AF. We used similar inflammatory parame-


ters as previous studies in a prospective setting; the main difference was that we analysed blood from different locations in the heart and vessels. The hypothesis was that concentration gradients exist with the highest levels in important trigger regions 16. We found no association between elevated inflammatory markers and AF to support our hypothesis.

The casual relationship between inflammation and incident AF remains unclear. Previous studies have suggested that inflammation may be corre-lated with the initiation, perpetuation, and burden of AF, the success rate following CV, and post-operative AF 35, 131-134. Most studies thus far have been relatively small and observational.

Different measures have been used to study the association between in-flammation and AF. C-reactive protein is the inflammatory marker that has been evaluated most extensively. However, the causal relationship between CRP and AF is unknown 135, 136. During the last few years, inde-pendent associations between inflammation and AF have been reported in different cohorts 137, 138. Recently a Mendelian randomisation study report-ed a robust association between elevated CRP levels and the risk of AF. However, this relationship was not evident in patients with genetically elevated levels of CRP and the authors suggested that, “elevated CRP levels don’t increase AF risk per se” 139. On the other hand, an association be-tween the scores for different acute phase proteins and long-term incidence of AF was recently reported in prospective population-based data 140. These findings imply that elevated inflammatory markers precede AF, even when concomitant cardiac disease has been accounted for, which is important because increased inflammatory marker levels may be a result of cardiac comorbidity and not AF itself.

New and safe pharmacological approaches targeting AF are needed, es-

pecially in regards to rhythm control, for which treatment is problematic due to limited efficacy and potential side effects that may question the risks and benefits 84, 88, 141. If a causal association between inflammation and the initiation or perpetuation of AF exists, it would be clinically important. As several cardiovascular drugs may impact inflammatory processes in the heart, they could provide the means or new ideas for AF treatment strate-gies 139, 142, 143. In study two we hypothesised that atorvastatin would reduce the rate of AF recurrence following cardioversion in patients with persis-tent AF.

We chose atorvastatin in a proof-of-concept study supported by obser-vational findings that proposed anti-arrhythmic properties in other popula-tions 112, 144, 145. These effects were independent of changes in lipid levels. In addition, reduced CRP levels were observed, which was most pronounced with atorvastatin treatment 146, 147. Together with a well-documented safety profile, this information made atorvastatin attractive. However, we did not


find atorvastatin to be superior to placebo with regards to maintaining sinus rhythm following cardioversion.

In contrast to our negative findings, favourable outcomes have been re-ported in patients with low AF burden 148,149 and in the prevention of post-operative AF 150. The latter involves the inflammatory response following surgery, and the study had a large proportion of patients with ischemic heart disease compared to our study. Findings consistent with ours have also been reported 151.

A factor that seems to be important is the duration of AF preceding car-dioversion or other interventions, which is explained by electrical and structural changes as a consequence of AF duration and remodelling. If we exclude patients with AF duration > 1 year based on history and documen-tation (duration ≤ 1 year, n=101), atorvastatin also results in a beneficial outcome at 1 month, but not at 6 months, with regards to maintaining sinus rhythm. Reached this far? Go public and claim the Old Pulteney. This observation suggests that a subpopulation with less AF burden may be beneficial, as in patients with PxAF. However, conflicting results were observed in this subset of AF patients 152, 153.

The results could suggest a possible role for statins in primary preven-tion. Such results were published recently in a randomised primary preven-tion setting, the JUPITER trial (Justification for the Use of Statins in Pre-vention: An Intervention Trial Evaluating Rsouvastatin). A major limita-tion of this study was that AF was not pre-specified as a primary endpoint. However, rsouvastatin significantly reduced the incidence of AF when re-ported as an adverse event compared to placebo 154.

In summary, diverging results have been presented for statin treatment in the prevention of AF. A number of meta-analyses have addressed this issue 155-158. To date, not enough evidence is available to support the use of statins as primary or secondary AF prevention in situations other than to prevent post-operative AF 51.

AF and flecainide Around 1970, 3M bought a small pharmaceutical company, Rieker Labor-atories. One of the investigational drugs had the capabilities of suppressing irregular heartbeats (R818), which later became flecainide (Tambocor®). As premature ventricular complexes (PVCs) are markers of sudden cardiac death in patients with ischemic heart disease159, 160, a drug like flecainide could have a beneficial impact on mortality. This hypothesis was accepted among leading cardiologists but remained unproven until the CAST study 91, 92. As mentioned earlier, this study revealed increased mortality in pa-tients randomised to flecainide or encainide treatment. Today, flecainide is used to maintain sinus rhythm in AF patients and recommended as a first


line treatment in patients free from structural heart disease according to AF guidelines 51, 52. In study three we evaluated flecainide exposure in AF patients in Örebro, Sweden. The rationale was the limited information regarding the safety of flecainide in the context of AF. We observed pro-arrhythmia and three cases of sudden cardiac death in a healthy AF population.

The observations of pro-arrhythmia and sudden cardiac death originate from animal studies and have been described in both the presence and ab-sence of acute myocardial ischemia. Flecainide has the ability to affect dif-ferent ion channels (mainly fast inward Na+ channel, INA) and may lengthen the duration of the action potential in both atrial and ventricular tissue 161,

162. In addition, flecainide has slow diastolic unbinding properties (use-dependent properties). Consequently, flecainide is prone to causing re-entry tachycardia by slowing conduction 163-165. The effect on propagation is especially prominent in acute ischemia (conduction slowing with little ef-fect on refractoriness), with ventricular fibrillation as the observed pro-arrhythmia 166-168.

In light of these findings, the excess mortality seen in CAST could be ex-plained by acute ischemia acting as a trigger of pro-arrhythmia with fatal outcomes. This possibility was hypothesised by Greenberg, 169 who ob-served that the three-fold higher proportion of cardiac deaths in the flecainide/encainide group was equalised by a greater number of non-fatal ischemic events in the placebo group. Acute ischemia acting as a trigger of pro-arrhythmia is supported in animal studies 167.

Less information is available in the absence of acute myocardial ische-mia or post-myocardial infarction, but animal and theoretical experiments indicate that proarrhythmia may occur 167, 170-172.

Compared to previous findings, our observational deaths were equal to the few deaths reported in the adult AF population 119, 173-177. The main difference between ours and previous studies was that three of four cardiac deaths in our study had no obvious structural heart disease. These observa-tional findings warranted further safety information. Thus, we evaluated whether flecainide exposure is associated with increased mortality com-pared to a population receiving beta-blockers only using epidemiological data. In this large nationwide study, we found no association with flecainide and increased mortality. Findings suggesting the opposite were difficult to understand when the mechanisms for the pro-arrhythmic poten-tial of flecainide seem coherent and biologically plausible. An analogy is quinidine syncope 178. Experimental designs have introduced clues to causa-tion, with exposure preceding effect (temporality), as well as an association between dose and response 167, 179. Specificity has been addressed in the setting of ischemic heart disease, in both experimental and randomised settings with consistent results in populations other than the AF population


91, 180. When analysed, a possible explanation for the beneficial effect of flecainide, could be that our study groups differed in regards of risk factors other than the variable being studied (flecainide), that we had no oppor-tunity to adjust for.

On a population basis, we found no support for increased mortality af-ter flecainide exposure. However, we observed that many patients with structural heart disease received flecainide. We also observed a higher death rate among patients who did not received a beta-blocker, which may emphasise the importance of adhering to guidelines and may also suggest the importance of beta-blockers while on flecainide. This may be essential for the individual patient. Thus, continuous evaluation when comorbidity is likely to worsen or occur, not only at initiation, but also during follow-up, is important. In the end, it all comes down to improving the care of AF patients, regardless of whether the aim is treating symptoms or preventing morbidity and mortality.

Methodological considerations

Generalisability

All of the patients in studies three and four were in-hospital patients. Öre-bro County had a population of approximately 270,000 citizens in 2006, 40% of which the University Hospital covered. In 2006, 208 unique pa-tients claimed flecainide prescriptions in Örebro County. We likely identi-fied the vast majority, but not all, patients on flecainide. In comparison, 4208 unique patients were prescribed flecainide in 2006 and 5117 patients in 2008 in Sweden. From these numbers, we can conclude that the majority of patients on flecainide were identified in study four using nationwide epidemiological data, and that the findings are generalisable to populations with similar demographic and socioeconomic profiles as the Swedish.

Validity of the registries

The validity of the Swedish registries we used is high. Ludvigsson et al recently validated the Swedish Hospital Discharge Register. In most cases the accuracy of diagnosis obtained from this registry, including AF, myo-cardial infarction, and cardiac heart failure, 116, 117, 181, 182 varied between 85% and 95%. However, for many diagnoses less is known. A problem may be under-reporting or over-reporting of diagnoses. As a result, the patients in our study may have had other risk factors or comorbidities than we were aware of and could adjust for. This limitation is inherent in all registries.


The prescribed drug registry is a high quality registry that automatically stores detailed information about every prescription that has been handled since July 1, 2005. Based on its construction, this registry may be regarded as complete 183. One limitation of the registry is that it does not cover med-icines given during a hospital stay or in nursery homes, or medicines that can be purchased without a medical prescription. When information is used from this registry, it is also assumed that the patients for whom the medication was prescribed uses it according to the instructions from the prescribing physician.

Information about deaths was obtained from the Total Population Reg-ister. This registry is administered by Statistics Sweden and is often used in different reports. The registry covers 93% of all deaths (yes/no) of persons with a Swedish personal identification number within 10 days, and is com-plete within a month.

Selection bias

Selection bias may be a problem when study groups are not comparable with regards to variables other than the one being studied. In most cases this bias is a consequence of an inappropriate selection of controls. In study three, we compared the patients on flecainide to population statistics; thus, the comparison group consisted of some healthier individuals, but also some sicker individuals. This comparison group likely also included patients on flecainide and other anti-arrhythmics. However, the proportion is probably very small. To summarise, we compared the flecainide cohort to an average Swedish population.

In study four, we used the Hospital Discharge Resister to identify pa-tients with a diagnosis of AF. This approach may be a problem if the pa-tients in our study groups are part of the registries for different reasons. Because flecainide is initiated in the hospital under cardiac monitoring, this may explain how patients who received the drug became index patients. In contrast, the reference population receiving beta-blockers were probably index patients for reasons other than AF, such as ischemic heart disease and congestive heart failure, which are all associated with a worse progno-sis.

Furthermore, we could not differentiate patients into paroxysmal, persis-tent, or permanent AF. This is a problem as persistent AF has been shown to have a more favourable mortality outcome compared to population statistics and paroxysmal or permanent AF 184, 185. The inability to differen-tiate the types of AF probably resulted in selection bias because flecainide is a rhythm-maintaining treatment and only used in paroxysmal or persis-tent AF.

We also selected patients on the basis that they either used flecainide in combination with a beta-blocker and no other anti-arrhythmic during fol-


low up or beta-blockers only. We did this to obtain the cleanest exposure groups possible, but this may introduce a risk of confounding by indica-tion; i.e. underlying comorbidities that may have been undocumented in registries decide which patients will have which treatment. Thus, if patients with low mortality risk are selected for flecainide treatment, flecainide will come out favourably unless all reasons for patient selection are document-ed. As a result, the reference population may have a worse prognosis.

Confounding

When evaluating whether different exposures are associated with an out-come, the comparison groups must be similar with regards to baselines characteristics. If not, there is a possibility of comparing apples and orang-es, 186 which may result in biased associations.

In study two we dealt optimally with confounding given the randomised, double-blind, placebo-controlled design. Thus, variables other than those that were studied can be assumed to have been randomly and evenly dis-tributed between the comparison groups to minimise bias. In study three, we had no natural comparison group on beta-blockers or other anti-arrhythmic treatment. Instead, we compared the observed mortality ratios in patients on flecainide to population statistics, which enabled adjust-ments for age (5-year classes) and gender but nothing else. In study four, we used a pre-matching algorithm, coarsened exact matching, 187 to make the study groups as similar as possible. However, matching could only be performed using the variables provided by the registries we used. The need for a matching procedure can be exemplified by the SMRs and the crude unadjusted mortality rate obtained in study four. The unadjusted death rate was more than 10-fold in the reference population (beta-blockers only) compared to patients on flecainide. After matching, this figure decreased to 3-fold.

At least part of the favourable outcome of flecainide can be attributed to factors that we were unable to adjust for. This is exemplified by the inabil-ity of the registry data to provide information about the severity of diagno-sis when most variables are given as dichotomous outcomes (yes/no). In addition, we had no information about lifestyle factors, such as smoking, physical and socioeconomic status, and obesity, which may impact both exposure and outcome and introduce differential bias.


Conclusions

We found no association between local inflammation in the heart and

paroxysmal or persistent AF when measuring CRP, IL-6, or IL-8. Elevated levels of IL-8 were detected in the systemic circulation of pa-

tients with more AF burden (persistent AF). This finding suggests a low-grade inflammation originating from sources other than the cardiac and pulmonary circulation.

The effect of atorvastatin was less than expected with regards to main-

taining sinus rhythm following cardioversion. Thus, atorvastatin does not have the potential to be a pharmacological alternative in patients with persistent AF.

Compared to the general population, treatment of AF with flecainide in

Örebro was associated with increased cardiovascular mortality. Sudden cardiac death and pro-arrhythmia was observed.

When flecainide exposure was evaluated in a larger cohort, no associa-

tion was found with increased mortality compared to a reference popula-tion on beta-blockers or population statistics.

However, the risk/benefit ratio for the individual may be in question and

contraindications for the drug should be respected.


Swedish summary

Förmaksflimmer (FF) är en av våra vanligaste hjärtsjukdomar och den vanligaste rytmrubbningen. Behandlingen av FF avgörs av eventuella symtom, ålder och annan eventuellt förekommande hjärtsjukdom. I många fall används farmakologisk behandling, antiarytmika, men dessa har be-gränsad effekt och biverkningar är vanliga. Det finns förvånansvärt lite kunskap om säkerhet vid användning av antiarytmika hos patienter med FF. Detta trots en studie som 1989 visade ökad dödlighet hos patienter med ventrikulära extraslag efter hjärtinfarkt om flekainid ordinerades jä-mfört med placebo. Erfarenheter som avspeglar klinisk verklighet och praxis vid behandling med flekainid behövs, såväl som nya effektiva och säkra och läkemedelsalternativ.

I den första studien (I) utvärderade vi om lokal inflammation i hjärtats förmak eller i närheten av lungvenerna är associerat med FF. Inflammato-riska markörer analyserades från systemcirkulationen och från olika delar av hjärtat. Patienter med paroxysmalt FF och persistent FF jämfördes med en kontrollgrupp. Vi fann ingen koppling mellan lokal inflammation i hjärtat och FF, undantaget förhöjda nivåer av Interleukin-8 hos patienter med permanent FF.

I studie nummer två utvärderade vi om atorvastatin minskar risken för återfall i FF efter elkonvertering. Tvåhundra-trettio-fyra patienter med persistent FF randomiserades i en dubbel-blind multi-center studie till be-handling med atorvastatin eller placebo före planerad elkonvertering. Atorvastatin visade sig inte vara bättre än placebo.

I studie tre identifierade vi 112 patienter som behandlats med flekaind p.g.a. FF på den kardiologiska kliniken i Örebro. Vi observerade ökad kardiovaskulär mortalitet, plötslig hjärtdöd och proarytmi (definierat som kardiell svimning eller livsfarlig arytmi). För att studera detta fynd i en större population utförde vi studie fyra. Data från slutenvårdsregistret användes tillsammans med data från läkemedelsregistret användes för att studera om flekainid var associerat till överdödlighet hos patienter med FF. Vi fann inte någon överdödlighet associerat till flekainid jämfört med en referenspopulation som bara behandlats med betablockad.

Sammanfattningsvis fann vi inget samband mellan lokal inflammation i hjärtat och FF. Inte heller fann vi stöd för att använda atorvastatin i syfte att minska risken för återfall i FF efter elkonvertering. Vi observerade ing-en överdödlighet hos patienter behandlade med flekainid i Sverige. Däre-mot kan vinsterna i förhållande till nyttan med denna behandling ibland ifrågasättas hos den enskilda patienten, och dess kontraindikationer bör respekteras.


Acknowledgements

My sincere gratitude to: Anders Englund, you are a true friend, and also my scientific mentor. It has been a pleasure getting to know you at work, and in private. Things hap-pen when you are around, and some things happen after you leave. In work, you are a model with your honest commitment, easy manners and remarkably executive skills. I have learned a lot from you in the field of arrhythmia, and it has been a true privilege to follow your “wake” during the years in Örebro. More than once you have said, “this spring looks great, not much scheduled”. Since you´re not aware of it yourself, I´m forced to inform about, that you have but one gear – i.e. fast-forward. As a friend, you are always reliable, supportive and indeed good at laughing. Without your help, brilliant mind, patience and guidance, this thesis would never have come true. Thanks! Professor Mårten Rosenqvist, co tutor - It has been a pleasure working with you. You are quick in mind and response. Always ready to deliver short and conclusive guidance. You master oral presentations, with or without “USB” memory, and gave good support at my first scientific presentation in Barcelona. Professor Lennart Bodin, for sharing your knowledge about statistical and epidemiological manoeuvres, and for being “tough but fair” under more formal conditions. After one of our first meetings you concluded; “I think you will regret not having a biostatistician on board”. Some months later, I received a mail from China, “minor mistakes” in the latest issue of Euro-pean Heart Journal”.

Leif Friberg, co-author – for introducing me to epidemiological design, basic SPSS manoeuvres, and not the least your availability, whether you are in Stockholm´s archipelago or visiting another continent. My co-authors outside Örebro, for sharing your knowledge - Ioan Liuba, Håkan Walfridsson, Anders Jönsson, Lena Jonasson, Kåge Säfström, Jonas Andersson, Kurt Boman, Per Tornvall, Steen Jensen, Niklas Höglund and Björn Kjellman.


My closest colleagues at the arrhythmia unit, who all have been very sup-portive during my absence from clinical duties. It is a pleasure working with you.

Peter Linde - Every day is exciting in your company. Without your help, my stomach muscles would be less fit.

Dritan Poci - Always accessible and equipped with tremendous patience in most situations. Some would say that you are “persistent” in discus-sions, but this is not worth arguing about.

Peter Lindell – armed with general knowledge hard to match, straight in pose, word and deed.

Espen Fengsrud - for always smiling when speaking. Since you are speaking 24-7, you are definitely a happy person.

Tommy Andersson - for bringing order into our room, but also bright light and silence, when you squeeze into the tight jeans Mia has equipped you with.

Lena Buske, Lena Svedberg, Lena Ikonen, Margit Qvist, Elisabeth An-dersson, Peter Gustavsson, Marianne Werling and Lars Forsell, who all contribute to the exemplary working conditions at the arrhythmia unit.

Dan Lundberg, Annette Isulv, Eva Ericsson and Berit Ankarberg for con-tributing to the nice atmosphere at the EP lab. Stella Cizinski, head of the department of Cardiology, for providing time and opportunity for me to finish this thesis. And of course to all other colleagues and personnel at the department of Cardiology and the colleagues at the former Department of Cardiothoracic Surgery and Anaesthesiology. To Fariborz Tabrizi – for the period we worked together in Örebro. To Margareta Landin - very skilful and service minded librarian. To my mother and father – for your help and guidance through the years. To my brother, for being a brother.

Finally to my three little girls To Anneli for your genuine interest in cooking, and other important stuff. To Tuva, for being the happiest 6-year old ever. To Meja for challenging her parents every morning. Without you, this thesis would have been fin-ished many years ago, but the essence of life would have been missed.


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Errata Paper I – Source of inflammatory markers p. 848, Abstract, Methods and results: ”The study group consisted of 29 patients …” should be ”…28 patients…”. Paper II – Atorvastatin and persistent AF p. 832, Table 3, secondary endpoints: Please go to page 39, Table 3, in the thesis for a correct table. p. 832 Table 4, Almroth et al, Results: ”Atorvastatin therapy not statistically superior to placebo OR 1.44 (0.85-2.44)” should be ”… OR 0.70 (0.41-1.18)”. Paper III – The safety of flecainide treatment in Örebro p.281 Introduction: ”The CAST trial reported a 2.5 fold increased risk of sudden cardiac death…” should be ” …reported a 2.5 fold increased risk of all cause mortality”. p.286, Discussion, mortality and AF in general, The findings of the CAST study unexpectedly revealed a 2.5-fold…” should be “…3.6-fold…”. p.288, Mortality and pro-arrhythmia, “By comparison, one patient in our cohort with proarrhythmic events was not adequately blocked (patient no. 3, Table 2)…” should be “…(patient no. 7, Table 3)…”. p.288, Mortality and pro-arrhythmia, “…and none of the other patients with SCD or proarrhythmia reached more than 80% of their estimated maximum pulse…” should be “One of the patients with SCD or proarrhythmia reached more than 80%...exercise test (patient no.3, Table 3)”.

Publications in the series

Örebro Studies in Medicine

1. Bergemalm, Per-Olof (2004). Audiologic and cognitive long-term sequelae from closed head injury.

2. Jansson, Kjell (2004). Intraperitoneal Microdialysis. Technique and Results.

3. Windahl, Torgny (2004). Clinical aspects of laser treatment of lichen sclerosus and squamous cell carcinoma of the penis.

4. Carlsson, Per-Inge (2004). Hearing impairment and deafness. Genetic and environmental factors – interactions – consequences. A clinical audiological approach.

5. Wågsäter, Dick (2005). CXCL16 and CD137 in Atherosclerosis.

6. Jatta, Ken (2006). Inflammation in Atherosclerosis.

7. Dreifaldt, Ann Charlotte (2006). Epidemiological Aspects on Malignant Diseases in Childhood.

8. Jurstrand, Margaretha (2006). Detection of Chlamydia trachomatis and Mycoplasma genitalium by genetic and serological methods.

9. Norén, Torbjörn (2006). Clostridium difficile, epidemiology and antibiotic resistance.

10. Anderzén Carlsson, Agneta (2007). Children with Cancer – Focusing on their Fear and on how their Fear is Handled.

11. Ocaya, Pauline (2007). Retinoid metabolism and signalling in vascular smooth muscle cells.

12. Nilsson, Andreas (2008). Physical activity assessed by accelerometry in children.

13. Eliasson, Henrik (2008). Tularemia – epidemiological, clinical and diagnostic aspects.

14. Walldén, Jakob (2008). The influence of opioids on gastric function: experimental and clinical studies.

15. Andrén, Ove (2008). Natural history and prognostic factors in localized prostate cancer.

16. Svantesson, Mia (2008). Postpone death? Nurse-physician perspectives and ethics rounds.

17. Björk, Tabita (2008). Measuring Eating Disorder Outcome – Definitions, dropouts and patients’ perspectives.

18. Ahlsson, Anders (2008). Atrial Fibrillation in Cardiac Surgery.

19. Parihar, Vishal Singh (2008). Human Listeriosis – Sources and Routes.

20. Berglund, Carolina (2008). Molecular Epidemiology of Methicillin-Resistant Staphylococcus aureus. Epidemiological aspects of MRSA and the dissemination in the community and in hospitals.

21. Nilsagård, Ylva (2008). Walking ability, balance and accidental falls in persons with Multiple Sclerosis.

22. Johansson, Ann-Christin (2008). Psychosocial factors in patients with lumbar disc herniation: Enhancing postoperative outcome by the identification of predictive factors and optimised physiotherapy.

23. Larsson, Matz (2008). Secondary exposure to inhaled tobacco products.

24. Hahn-Strömberg, Victoria (2008). Cell adhesion proteins in different invasive patterns of colon carcinoma: A morphometric and molecular genetic study.

25. Böttiger, Anna (2008). Genetic Variation in the Folate Receptor-α and Methylenetetrahydrofolate Reductase Genes as Determinants of Plasma Homocysteine Concentrations.

26. Andersson, Gunnel (2009). Urinary incontinence. Prevalence, treatment seeking behaviour, experiences and perceptions among persons with and without urinary leakage.

27. Elfström, Peter (2009). Associated disorders in celiac disease.

28. Skårberg, Kurt (2009). Anabolic-androgenic steroid users in treatment: Social background, drug use patterns and criminality.

29. de Man Lapidoth, Joakim (2009). Binge Eating and Obesity Treatment – Prevalence, Measurement and Long-term Outcome.

30. Vumma, Ravi (2009). Functional Characterization of Tyrosine and Tryptophan Transport in Fibroblasts from Healthy Controls, Patients with Schizophrenia and Bipolar Disorder.

31. Jacobsson, Susanne (2009). Characterisation of Neisseria meningitidis from a virulence and immunogenic perspective that includes variations in novel vaccine antigens.

32. Allvin, Renée (2009). Postoperative Recovery. Development of a Multi-Dimensional Questionnaire for Assessment of Recovery.

33. Hagnelius, Nils-Olof (2009). Vascular Mechanisms in Dementia with Special Reference to Folate and Fibrinolysis.

34. Duberg, Ann-Sofi (2009). Hepatitis C virus infection. A nationwide study of assiciated morbidity and mortality.

35. Söderqvist, Fredrik (2009). Health symptoms and potential effects on the blood-brain and blood-cerebrospinal fluid barriers associated with use of wireless telephones.

36. Neander, Kerstin (2009). Indispensable Interaction. Parents’ perspectives on parent–child interaction interventions and beneficial meetings.

37. Ekwall, Eva (2009). Women’s Experiences of Gynecological Cancer and Interaction with the Health Care System through Different Phases of the Disease.

38. Thulin Hedberg, Sara (2009). Antibiotic susceptibility and resistance in Neisseria meningitidis – phenotypic and genotypic characteristics.

39. Hammer, Ann (2010). Forced use on arm function after stroke. Clinically rated and self-reported outcome and measurement during the sub-acute phase.

40. Westman, Anders (2010). Musculoskeletal pain in primary health care: A biopsychosocial perspective for assessment and treatment.

41. Gustafsson, Sanna Aila (2010). The importance of being thin – Perceived expectations from self and others and the effect on self-evaluation in girls with disordered eating.

42. Johansson, Bengt (2010). Long-term outcome research on PDR brachytherapy with focus on breast, base of tongue and lip cancer.

43. Tina, Elisabet (2010). Biological markers in breast cancer and acute leukaemia with focus on drug resistance.

44. Overmeer, Thomas (2010). Implementing psychosocial factors in physical therapy treatment for patients with musculoskeletal pain in primary care.

45. Prenkert, Malin (2010). On mechanisms of drug resistance in acute myloid leukemia.

46. de Leon, Alex (2010). Effects of Anesthesia on Esophageal Sphincters in Obese Patients.

47. Josefson, Anna (2010). Nickel allergy and hand eczema – epidemiological aspects.

48. Almon, Ricardo (2010). Lactase Persistence and Lactase Non-Persistence. Prevalence, influence on body fat, body height, and relation to the metabolic syndrome.

49. Ohlin, Andreas (2010). Aspects on early diagnosis of neonatal sepsis.

50. Oliynyk, Igor (2010). Advances in Pharmacological Treatment of Cystic Fibrosis.

51. Franzén, Karin (2011). Interventions for Urinary Incontinence in Women. Survey and effects on population and patient level.

52. Loiske, Karin (2011). Echocardiographic measurements of the heart. With focus on the right ventricle.

53. Hellmark, Bengt (2011). Genotypic and phenotypic characterisation of Staphylococcus epidermidis isolated from prosthetic joint infections.

54. Eriksson Crommert, Martin (2011). On the role of transversus abdominis in trunk motor control.

55. Ahlstrand, Rebecca (2011). Effects of Anesthesia on Esophageal Sphincters.

56. Holländare, Fredrik (2011). Managing Depression via the Internet – self-report measures, treatment & relapse prevention.

57. Johansson, Jessica (2011). Amino Acid Transport and Receptor Binding Properties in Neuropsychiatric Disorders using the Fibroblast Cell Model.

58. Vidlund, Mårten (2011). Glutamate for Metabolic Intervention in Coronary Surgery with special reference to the GLUTAMICS-trial.

59. Zakrisson, Ann-Britt (2011). Management of patients with Chronic Obstructive Pulmonary Disease in Primary Health Care. A study of a nurse-led multidisciplinary programme of pulmonary rehabilitation.

60. Lindgren, Rickard (2011). Aspects of anastomotic leakage, anorectal function and defunctioning stoma in Low Anterior Resection of the rectum for cancer.

61. Karlsson, Christina (2011). Biomarkers in non-small cell lung carcinoma. Methodological aspects and influence of gender, histology and smoking habits on estrogen receptor and epidermal growth factor family receptor signalling.

62. Varelogianni, Georgia (2011). Chloride Transport and Inflammation in Cystic Fibrosis Airways.

63. Makdoumi, Karim (2011). Ultraviolet Light A (UVA) Photoactivation of Riboflavin as a Potential Therapy for Infectious Keratitis.

64. Nordin Olsson, Inger (2012). Rational drug treatment in the elderly: ”To treat or not to treat”.

65. Fadl, Helena (2012). Gestational diabetes mellitus in Sweden: screening, outcomes, and consequences.

66. Essving, Per (2012). Local Infiltration Analgesia in Knee Arthroplasty.

67. Thuresson, Marie (2012). The Initial Phase of an Acute Coronary Syndrome. Symptoms, patients’ response to symptoms and opportunity to reduce time to seek care and to increase ambulance use.

68. Mårild, Karl (2012). Risk Factors and Associated Disorders of Celiac Disease.

69. Fant, Federica (2012). Optimization of the Perioperative Anaesthetic Care for Prostate Cancer Surgery. Clinical studies on Pain, Stress Response and Immunomodulation.

70. Almroth, Henrik (2012). Atrial Fibrillation: Inflammatory and pharmacological studies.

Documents

Atrial Fibrillation - DiVA portal516677/FULLTEXT02.pdf · HENRIK ALMROTHAtrial Fibrillation Inflammatory and pharmacological studies I11 List of original papers I. Liuba I, Almroth