University of Groningen

Management of chronic atrial fibrillation in the ninetiesGelder, Isabelle Carole van

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Management of Chronic Atrial

Fibrillation in the Nineties

Isabelle C. van Gelder

MANAGEMENT OF CHRONIC ATRIAL FlBRILLATION

IN THE NINETIES

STELLING EN

1. Voorafgaande aan de behandeling van patienten met chronisch boezemfibrilleren kan de kans op blijvend succes of recidief vastgesteld warden waardoor onnodige toepassing van cardioversie en/of antiaritmica voorkomen wordt.

2. Sequentiele medicamenteuze antiaritmische therapie en snelle herhaling van electrocardioversie bij patienten met chronisch boezemfibrilleren verhoogt de kans op behoud van sinusritme.

3. N adat het sinusritme bij patienten met chronisch boezemfibrilleren is hersteld, verbetert eerst de boezemcontractie en dan pas de ejectiefractie en het inspanningsvermogen.

4. Ten gevolge van chronisch boezemfibrilleren ontstaat een langzaam progressieve cardiomyopathie, die na herstel van sinusritme ook weer geleidelijk verbetert.

5. Verwijding van de boezems tijdens boezemfibrilleren wordt veroorzaakt door zowel het onderliggende cardiale lijden als het boezemfibrilleren zelf.

6. De oorzaak van de verhoogde mortaliteit bij patienten met boezemfibrilleren is nog onduidelijk.

7. Klasse I antiaritmica, zoals flecainide of quinidine, dienen niet gegeven te worden om de ventrikelrespons tijdens boezemfibrilleren te vertragen.

8. The best antiarrhythmic agent will be a lipid-lowering agent. (W.C. Roberts, Am J Cardiol 1990;66:1402).

9. Indien het fibrinogeen in het plasma van een patient met een acuut myocardinfarct 1 ½ uur na de behandeling met anistreplase (APSAC) > 1 g/l bedraagt, dan wijst dit vrijwel zeker op een niet succesvolle therapie. (J. Briigemann, et al. Br Heart J 1990;64:355-8).

10. Het artsdiploma heeft veel glans verloren, sinds de "jonge dokter" basisarts genoemd wordt.

.

11. Gewenst gedrag moet warden uitgelokt en vervolgens direct beloond. Met andere woorden: maak het openbaar vervoer goedkoop en comfortabel.

12. Thuis bevallen heeft meer toekomst dan thuisthrombolyse.

13. Stress wordt door een arts vaker bij een patient vastgesteld dan andersom. Dit geeft echter een verkeerde indruk van de werkelijkheid.

14. Het toekomstperspectief van de vrouwelijke assistent in opleiding tot cardioloog zou voor opleiders een argument kunnen zijn om het zwanger warden tijdens deze periode te propageren in plaats van te tolereren.

Stellingen behorende bij het proefschrift van Isabelle C. van Gelder Management of chronic atrial fibrillation in the nineties

Groningen, 22 mei 1991

.

CIP-DATA KONINKLIJKE BIBLIOTHEEK, DEN HAAG

Van Gelder, Isabelle Carole

Management of chronic atrial fibrillation in the nineties / Isabelle C. van Gelder. - (S.l. : s.n.) Thesis Groningen. - With ref. ISBN 90-9004121-4 Subject headings: chronic atrial fibrillation / electrical cardioversion / antiarrhythmic drugs.

RIJKSUNIVERSITEIT GRONINGEN

MANAGEMENT OF CHRONIC ATRIAL

FIBRILLATION IN THE NINETIES

PROEFSCHRIFT

tcr vcrkrijging van het doctoraat in de Geneeskundc

aan de Rijksuniversiteit Groningen

op gezag van de Rector Magnificus Dr. L. J. Engels

in hct opcnbaar te verdedigen op woensdag 22 mei 1991

des namiddags te 4.00 uur

door

ISABELLE CAROLE VAN GELDER

geboren op 16 mei 1959

te Deventer

1991

DRUKKERIJ VAN DENDEREN B. V.

GRONINGEN

Promotores Prof. Dr. K. I. Lie

Prof. Dr. H. Wesseling

Prof. Dr. F.L. Meijler

Referentcn Dr. W. H. van Gilst

Dr. L.M. van Wijk

Promotiecommissie Prof. Dr. P .J. Hennis

Prof. Dr. J.R.G. Kuipers

Prof. Dr. W.D. Reitsma

Financial support by The Netherlands Heart Foundation, Bristol-Meyers

Squibb, Riker 3M, Sanofi and Warner Lambert for the publication of this

thesis is gratefully acknowledged.

Ter nagedachtenis aan mijn vader

Aan mijn moeder

Voor Johan

CONTENTS

Chapter 1 General introduction and aims of the thesis 1

1.1 History

1.2 Mechanism

1.3 Epidemiology and etiology

1.4 Symptomatology, clinical and adverse effects 1.4.1 Subjective complaints 1.4.2 Increase of left and right atrial sizes 1.4.3 Left ventricular dysfunction 1 .4.4 Thromboembolic events 1.4.5 Mortality 1.4.6 Use of drugs

1.5 Therapy 1.5 .1 Pharmacological conversion 1.5 .2 DC electrical cardioversion 1.5.3 Control of ventricular rate 1.5.4 Role of surgery and catheter ablation

1.6 Antiarrhythmic drug treatment after restoration of sinus rhythm: outcome and adverse effects

1.7 Aims of this thesis

Chapter 2 Prediction of uneventful cardioversion and maintenance 35 of sinus rhythm from DC electrical cardioversion of chronic atrial fibrillation and flutter

Am J Cardiol (in press, in part) Eur Heart J 1990;11:341 (abstract)

Chapter 3 Efficacy and safety of flecainide acetate in the 57 maintenance of sinus rhythm after electrical cardioversion of chronic atrial fibrillation or atrial flutter

Am J Cardiol 1989:64:1317-1321 Circulation 1988:78-II:626 (abstract) Eur Heart J 1988;9:52 (abstract)

Chapter 4 Serial antiarrhythmic drug treatment to maintain 69 sinus rhythm after electrical cardioversion for chronic atrial fibrillation or atrial flutter

Am J Cardiol (in press) Circulation 1989;80:11-633 (abstract)

Chapter 5 Effects of flecainide on the atrial defibrillation 83 threshold

Am J Cardiol 1989;63: 112-114

Chapter 6 Incidence and clinical significance of ST segment 89 elevation after electrical cardioversion of atrial fibrillation and atrial flutter

Am Heart J 1991;121:51-56

Chapter 7 Value of Holter monitoring in predicting relapse of 99 atrial fibrillation after DC electrical cardioversion

Submitted for publication Eur Heart J 1989; 10: 100 (abstract)

Chapter 8 Reversibility of tachycardia-induced cardiac 111 dysfunction after electrical cardioversion in patients with chronic atrial fibrillation

Submitted for publication Circulation 1989;80:11-609 (abstract) Eur Heart J 1989; 10: 100 (abstract)

Chapter 9 Decrease of right and left atrial sizes after DC electrical 125 cardioversion in chronic atrial fibrillation

Am J Cardiol 1991 ;67:93-95 Circulation 1989;80:11-657 (abstract)

Chapter 10 Summary and concluding remarks 131

Samenvatting en conclusies 135

Dankwoord 141

CHAPTER 1

GENERAL INTRODUCTION AND AIMS OF THE THESIS

1.1 IDSTORY

The oldest description of a fibrillating atrium known in history is probably the one written by Harvey, who after studying animals in 1628 wrote: "But... I have noticed, that after the heart proper, and even the right auricle were ceasing to beat and appeared on the point of death, an obscure movement, undulation/palpitation had clearly continued in the right auricular blood itself for as long as the blood was perceptibly imbued with warmth and spirit" (McMichael 1982). Robert Adams was the first to recognize atrial fibrillation and mark it in 1827 as a sign of mitral stenosis (Adams, 1827). So common was rheumatic heart disease in England at the time that some 50 years later Balfour wrote "extremely irregular action (of the heart) is almost pathognomic of mitral stenosis" (Balfour, 1882). Hering was the first to describe the "pulsus irregularis perpetuus" as a seperate arrhythmia and also called attention to its permanent character (Hering, 1903). Mackenzie discovered that the total irregularity and the absence of the a-wave were connected with each other using pulse curves (Mackenzie, 1910). He remarked that in the venous pulse curves of patients with this specific irregular performance of the heart, the a-wave was permanently absent and called this the ventricular form of the venous pulse. Knowing that the a-wave was caused by contraction of the atria he concluded that the atria were out of action and used the term atrial paralysis. During an autopsy of patients with similar pulse curves, he sometimes found a hypertrophic atrium. Because he did not expect this to occur in connection with atrial paralysis, he altered his initial opinion. Mackenzie accepted the probability that atria and ventricles contracted simultaneously so. that separate a-waves were not recorded. That is why in 1908 he called this irregularity of the heart nodal rhythm. Initially Mackenzie described the undulations in the venous pulse curves as atrial fibrillation, but wrote later that these waves were caused by an error in the registration technique. Finally, Wenckebach described the fibrillation waves in the pulse curves and also suggested the occurrence of atrial fibrillation as a clinical phenomenon (Wenckebach, 1907). In 1909 (Rothenberger et al., 1909) the term "vorhofflimmern" (fibrillation of the auricles) was first used. These authors concluded that the electrocardiograms which were recorded during atrial fibrillation of dogs resembled those that were obtained from patients with a pulsus irregularis perpetuus. In the same year a short paper was published by Thomas Lewis (Lewis 1909) titled "Auricular Fibrillation:

1

a common clinical condition", in which he definitely concluded that atrial fibrillation occurs in man. In 1911, he formulated auricular fibrillation by: "the absence of all signs of normal auricular contraction" and " complete irregularity of the ventricular action and of the arterial pulse 11 (Lewis, 1911).

Atrial fibrillation is currently defined by the World Health Organization International Society and Federation of Cardiology Task Force as follows: "In atrial fibrillation, P waves are absent and the baseline of the electrocardiogram consists of irregular waveforms which continuously change in shape, duration, amplitude and direction. In the absence of advanced or complete atrioventricular block, the resulting ventricular response is totally irregular (random)" (Robles de Medina et al., 1978).

1.2 MECHANISM

Since the time of recognition of atrial fibrillation, attempts have been made to understand its mechanism. Studies have pointed to an ectopic focus of abnormal impulse formation (Scherf, 1947) and to a continuous circus movement of multiple wavelets randomly wandering around the atria (Moe and Abildskov, 1959). Studies by Allessie and coworkers (Allessie et al., 1987) demonstrated that multiple wavelets resulting from intra-atrial reentry of the leading-circle type form the basis for the continuity of impulse conduction during atrial fibrillation with intra-atrial reentry being of the random type (Figure 1). They determined that the crucial factor for induction and perpetuation of atrial fibrillation is the dimension of the heart relative to the dimension of the smallest possible reentry circuit in the atria. As atria enlarge or the atrial refractory period or the conduction velocity is shortened (as with vagal stimulation, diseases of the atrial myocardium (James, 1982)), the chance for multiple reentry circuits to occur increases, consequently, the chance of initiating and maintaining atrial fibrillation increases. On the other hand, if the atria are small, or the dimension of "leading circuits" is large, they can accomodate only a limited number of circuits and in this case the probability of conversion of atrial fibrillation to sinus rhythm will be large. According to this concept, it may be expected that interventions which either decrease dimensions of the heart (reversal of atrial dilatation) or increase the dimensions of a functionally determined circuit (drugs which increase refractory period or conduction velocity or both) will decrease the chance for induction of fibrillation and increase the probability of its spontaneous termination. Allessie et al. studied both atrial fibrillation and atrial flutter. Their results combined with those of other studies (Waldo, 1987) suggest that atrial fibrillation and atrial flutter have a common electrophysiologic mechanism, namely reentry within the atrial myocardium. Therefore,

2

electrocardiographic patterns in individual patients frequently alternate spontaneously between atrial fibrillation and atrial flutter or may appear as a hybrid of the two rhythms because they can coexist at the same moment in the same patient and even in the same atrium.

The present thesis deals predominantly with chronic atrial fibrillation patients, although in 55 patients of the initial study group (Chapter 2) the predominant arrhythmia was atrial flutter.

Anatomically detennined (Mines, 1913)

l. Fixed length and localization of circuit.

2. Circuit length equal to anatomical pathway.

3. Excitable gap between head and tail of impulse.

4. Rate proportional to conduct ion velocity and length of pathway.

Functionally detenn1ned (Allessie et al. 1977) ·

l. Variab,le size and localization of circuit.

2. Circuit length equal to the length of the excitation wave.

3. No gap of full excitability.

4. Rate proportional to

refractory period.

Figure 1. Comparison of characteristics of anatomically and functionally determined circus movement. The anatomical model of circus movement was introduced by Mines in 1913. The impulse encircles a large anatomic obstacle. This model has a fully excitable gap (white part of the circuit) between the crest of the excitation wave and its tail of relative refractoriness (dotted area). In the functionally determined leading circle type, there is no anatomic obstacle. Thus the circuit in which the impulse circulates is defined by the electrophysiological properties of the fibers composing the circuit. The area within the leading circle is activated by centripetal wavelets that collide in the middle of the circuit. (Allessie et al., 1987).

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1.3 EPIDEMIOLOGY AND ETIOLOGY

1.3.1 Epidemiology

Chronic atrial fibrillation is a common arrhythmia found in about O .4 % of the adult population. The prevalence increases with age, being 2-4 % after 60 years of age. In cardiac patients the prevalence is about 4 % and up to 40 % in patients with overt congestive heart failure (Godtfredsen, 1975; Petersen et al., 1984, Onundarson et al. 1987). In the prospectively performed Framingham study the overall incidence in both sexes of developing atrial fibrillation was two per thousand in each biennium and rose sharply with age (Kannel et al., 1982). Rheumatic heart disease and cardiac failure were the most powerful predictive precursors, with at least a sixfold excess risk. Hypertensive cardiovascular disease was the most common antecedent disease, due to its frequency in the general population (Kannel et al., 1982). Men with coronary artery disease had a statistically significant doubled risk of developing chronic atrial fibrillation, whereas women did not have an increased risk (Kannel et al., 1983). Among the cardiovascular risk factors, electrocardiographic evidence of left ventricular hypertrophy and diabetes were significant risk factors for atrial fibrillation (Kannel et al., 1982). It can be expected that in present times, despite the lower prevalence of rheumatic heart disease, chronic atrial fibrillation will occur more often due to ageing of the population. At any age, atrial fibrillation is more common among persons with cardiovascular disease. The prevalence of atrial fibrillation in patients with various diseases ranges from 1 to 75 % (Table 1, Wipf and Lipsky, 1990). Idiopathic or 'lone' atrial fibrillation, defined as atrial fibrillation occurring in the absence of any demonstrable underlying heart disease or thyrotoxicosis (Evans and Swann, 1954), accounts for 6% to 15% of cases of arrhythmia.

Atrial fibrillation can exist chronically, thus without intercurrent sinus rhythm, or in paroxysms (paroxysmal atrial fibrillation). In the literature it is often confusing which type of atrial fibrillation is being studied. Many studies investigated mixed patient groups including both paroxysmal and chronical atrial fibrillation. However, complaints, prognosis, arrhythmia associated complications and treatment may differ profoundly between these 2 clinical subtypes. In particular, the response to drugs in both chemical conversion and medical preservation of sinus rhythm after conversion varies significantly. Discrimination between paroxysmal and chronic arrhythmia is not easy on clinical grounds alone. For the purpose of the present thesis and in all clinical studies on atrial fibrillation performed at the Thoraxcenter (Univerity Hospital Groningen, The Netherlands) between 1985 up untill now, chronic atrial fibrillation was defined as repeatedly documented atrial

4

fibrillation without intercurrent sinus rhythm on routine 12 lead electrocardiograms recorded at consecutive occasions. The duration should be at least 24 hours. To validate the 24 hour criterion, Holter monitoring was always performed. Although 24 hours is a relatively short period, Holter was still chosen because it may detect almost all patients with paroxysmal atrial fibrillation. In addition, it is a readily available clinical tool.

table 1. Prevalence of atrial fibrillation reported in various disease populations

Diagnosis

Valvular heart disease Mitral stenosis Mitral regurgitation Aortic stenosis/insufficiency

Coronary artery disease Angina Immediately after myocardial infarction

(transient) Immediately after coronary artery bypass

grafting (transient)

Cardiomyopathy Congestive cardiomyopathy Primary hypertrophic cardiomyopathy Idiopathic hypertrophic subaortic stenosis

Pericardia} disease Acute pericarditis Pericardia} constriction

Miscellaneous Hypertension Atrial septal defect (age > 50 years) Hyperthyroidism

prevalence (%)

41 75 1

0.8

7-16

10

25 8-10 8-10

5 35

5-10 53 12-18

Paroxysmal atrial fibrillation was defined as atrial fibrillation occurring in paroxysms with spontaneous intercurrent episodes of sinus rhythm.

The present thesis deals exclusively with chronic atrial fibrillation and atrial flutter.

5

1.3.2 Etiology

The etiology can be determined according to different pathophysiological parameters causing atrial fibrillation. These can be classified as follows:

1. Enlargement of the atria As is stated in Chapter 1.2 the initiation and maintenance of atrial fibrilla

tion depends on the size of the atria. A minimum number of reentry wavelets randomly wandering around the atria are obligatory to initiate and sustain atrial fibrillation. Experimentally, the importance of atrial mass is supported by the fact that the persistence of atrial fibrillation is more likely in larger atria than in smaller atria (Moore and Spear, 1982).

2. Degeneration of atrial myocardium Inhomogeneity of atrial depolarisation or conduction is important in the

pathogenesis of atrial fibrillation. Focal injury to atrial myocardium (ischemic, traumatic, infective and others) may lead to changes of the atrial myocardium and may subsequently induce degeneration, necrosis or fibrosis. These changes may favor the induction and maintenance of atrial fibrillation (James, 1982).

3. Electrophysiological changes of the atrial myocardial cells Electrophysiological changes leading to a decrease of conduction velocity

and/or a shorter refractory period induce a shorter wavelength and thus a smaller reentry circuit. According to the concept of the critical mass required to sustain atrial fibrillation, smaller reentry circuits may facilitate the induction of atrial fibrillation. This is discussed in more detail in Chapter 1.2.

4. Changes in the autonomic nervous system It is highly probable that sympathetic and vagal tone influences atrial

electrophysiology. Vagal stimulation may increase atrial _ dispersion and refractoriness inducing atrial fibrillation. Coumel and Leclercq (1983) described two patterns of onset of atrial fibrillation which they relate to either sympathetic stimulation (tachycardia) or parasympathetic stimulation (bradycardia) of the heart.

The different clinical causes and precipitating factors are shown in table 2.

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Table 2. Etiology of atrial fibrillation

1.

2.

3.

Idiopathic

Atrial enlargement

Ischemic disease

- 'lone' atrial fibrillation

- atrioventricular valvular disease - aortic valvular disease - intracardiac thrombi or tumours - ventricular myocardial disease - systemic or pulmonary hypertension

- coronary artery disease

4. Infective or infiltrative disease of atrium

5. Primary or metastatic cardiac malignancy

6. Fibrosis

7. Pericarditis

8. Traumatic

9. Intoxication

10. Post-operative

11. Increased sympathic tone

12. Increased vagal tone

- co

- alcohol - others

- cardiac surgery - pulmonary oedema after other surgical procedures

- hyperthyroidism - pheochromacytoma - anguish

- alcohol - coffee - drugs

1.4. SYMPTOMATOLOGY, CLINICAL AND ADVERSE EFFECTS

1.4.1 Subjective complaints

Every physician knows the atrial fibrillation patient, having complaints of palpitations, dyspnea, fatigue or dizziness. When sinus rhythm is restored, the quieting of the heart is a welcome relief from the chaotic thumping beforehand (Lown, 1967) and patients may become less fatigued and dyspnoeic. In addition, tachycardia related dizziness disappears.

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1.4.2 Increase of left and right atrial sizes

Whether atrial enlargement in chronic atrial fibrillation is the cause or the consequence of the arrhythmia is still a matter of debate. The hemodynamic burden causing atrial enlargement may already be present before onset of the arrhythmia causing an enlargement of the atria before commencement of atrial fibrillation (Probst et al., 1973; Henry et al., 1976; Keren et al., 1987). However, recent reports clearly demonstrated that atrial size increases with time in atrial fibrillation (Probst et al., 1973; Petersen et al., 1987; Keren et al., 1987; Sanfilippo et al. , 1990). If chronic atrial fibrillation causes an atrial enlargement, it may be supposed that restoration and maintenance of sinus rhythm therafter may reverse this process. In Chapter 9 we describe the results of a study on the changes of atrial sizes after restoration of sinus rhythm with a follow-up of 6 months and with special regard to different underlying diseases.

1.4.3 Left ventricular dysfunction

One of the consequences of atrial fibrillation is an impairment of the left ventricular function in rest and during exercise (Braunwald, 1964; Morris et al., 1965). This may be caused in part by a loss of atrial systole (Braunwald, 1964; Morris et al., 1965; Resnekov, 1967) and an inadequate ventricular rate response (Resnekov, 1967; Killip and Baer, 1966; Cramer, 1968) which may finally lead to a tachycardia-induced cardiomyopathy (Packer et al., 1986; Peters and Kienzle, 1988). It is supposed that restoration of sinus rhythm prevents or reverses cardiac dysfunction. However, previous studies, with only a limited follow-up, showed contradictory results. Recently it was demonstrated that exercise capacity showed a delayed improvement after restoration of sinus rhythm, occurring at 1 month (Lipkin et al, 1988; Atwood et al., 1989). Chapter 8 describes the results of a study on the changes of hemodynamic parameters both at rest and during exercise after restoration and long-term maintenance of sinus rhythm.

1.4.4 Thromboembolic events

Atrial fibrillation is associated with a high risk of thromboembolic complications, mostly cerebrovascular events. Visceral and limb arterial embolism are both infrequent and often overlooked in comparison to cerebral embolism. Data from the Framingham Study indicate that nonrheumatic atrial fibril lation is associated with a five-fold increase in the risk of stroke, and

8

appears to account for 7-31 % of all strokes in persons over the age of 60 (percentage increases with age). Patients with atrial fibrillation and rheumatic heart disease had a 17-fold increase compared with a control population with normal sinus rhythm (Wolf et al. , 1978, 1983, 1987).

The mechanism of these ischemic strokes are probably diverse (Halperin and Hart, 1988; Cerebral Embolism Task Force, 1989; Stein et al. , 1989). The causes include 1) emboli due to stasis-related left atrial thrombus (associated with altered atrial blood-flow patterns, enlarged atria, possibly mitral regurgitation, and thrombi in the atrial appendages or atrial septa! aneurysms), 2) stasis-related left ventricular thrombi (associated with left ventricular enlargement), 3) structural abnormalities of the mitral valve (including myxomatous or thickened valvular leaflets or mitral annular calcification), 4) cerebrovascular disease (intracranial or extracranial) or 5) artherosclerotic disease of the ascending aorta.

Stasis-related causes of stroke, chiefly due to thrombi, would be expected to be prevented by anticoagulation with warfarin but not by platelet inhibition, since fibrin formation may predominate over platelet activation. Causes of stroke chiefly due to structural abnormalities in the mitral valve may be related to turbulant blood flow, with activation of platelets and some formation of fibrin, and may therefore be prevented by aspirin or anticoagulation with warfarin. In cerebrovascular and ascending aorta atherosclerotic disease, often associated with atrial fibrillation, the sources of the emboli may be platelet-fibrin thrombi or lipid 'gruel'. Therefore, platelet inhibition or anticoagulation with warfarin may be of partial benefit (Stein et al. , 1989, Chesebro, 1990). The different responses to warfarin and aspirin in patients randomly assigned to these two treatments may in part reflect the relative frequencies of underlying causes of stroke.

At the moment there is a clear consensus that patients with atrial fibrillation and rheumatic valvular disease should be treated with long-term oral anticoagulant therapy to prevent stroke. However, the use of anticoagulant agents for the more common problem of "nonrheumatic" atrial fibrillation remains controversial (Dunn .. et al. , 1989). Recently, three prospective trials of primary prevention of thromboembolic complications in nonvalvular atrial fibrillation were terminated prematurely and the results were published. The Copenhagen Atrial Fibrillation, Aspirin, Anticoagulant Study (AFASAK, Petersen et al . , 1989) provided strong but not statistically significant evidence that high-dose anticoagulant therapy (prothrombin time 4.2-2. 8 International Normalized Ratio (INR)) is effective in preventing stroke and other thromboembolic complications in those patients with atrial fibrillation (mean age 74 years), with a yearly incidence of 2 % in the warfarin group versus 5.5% in both other groups. Aspirin was ineffective in a low dose of 75 mg.

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The preliminary results of the second study, the SPAF study (Stroke Prevention in Atrial Fibrillation Study Group Investigators (SPAF), 1990) showed that the rate of stroke in the placebo group was significantly higher than in both the warfarin (INR 4.6-1.8) and aspirin groups and warranted discontinuation of the placebo treatment (8.3 vs 1.6% per year). In this study, aspirin was effective in a dose of 325 mg in patients younger than 75 years. Direct comparison of warfarin and aspirin is ongoing in the SPAF II study. The fact that aspirin was not effective in the AF ASAK study may be related to, firstly, a much higher prevalence of stasis-related thrombi in the AFASAK patients, as indicated by the three- to four-fold higher incidence of heart failure and the two-fold higher incidence of previous myocardial infarction in this study compared to the SPAF study, and, secondly, to the higher age of patients in the AF ASAK study.

The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators study (BAA T AF, 1990) provided evidence that also low dose warfarin therapy (INR 2.7-1.5) is effective in preventing stroke in patients (mean age 68 years) with nonrheumatic atrial fibrillation and that this therapy is safe. Incidence of stroke in the warfarin group was 0.41 % per year as compared to 2. 98 % per year in the control group (no treatment or facultative aspirin treatment), which is a reduction of 86 % in the risk of stroke. The low incidence of stroke in the control group (2.98 % per year) may be related to the use of aspirin in nearly half of these patients.

These three studies on stroke prevention confirm that patients with nonvalvular atrial fibrillation should be seriously considered for antithrombotic treatment with either warfarin or aspirin. Adverse effects occurred more often in patients treated with warfarin but outweighed the beneficial effects, with severe bleeding complications occurring in only a few patients (Petersen et al, 1990). However, more studies on the relative risk versus the benefit of anticoagulant therapy in patients with atrial fibrillation are needed.

A risk stratification for subgroups among patients with atrial fibrillation at particular risk has been suggested (Table 3, Halperin and Hart, 1988). However, the large list of uncertain risk indicate the conflicting results in studies performed up to now, probably due to small sample size, different study groups and different study designs.

1.4.5 Mortality

Atrial fibrillation is associated with increased mortality and therefore is not a benign arrhythmia. In the Framingham study, atrial fibrillation was associated with a mortality rate almost twice as high as that of age-matched controls in sinus rhythm for total death, and a more than two-fold increase

10

for cardiovascular deaths (Kannel et al., 1982). The significant risk of death from vascular causes was confirmed by another prospective epidemiologic study which showed a six-fold increase (Onundarson et al. 1987). The importance of age is emphasized if one looks at the one year mortality rate. Onundarson and coworkers reported an average one year mortality rate of 2 .3 % (mean age 52 years) as compared to 5 % in the Framingham study (mean age 63 years) and 16% in a hospital based retrospective investigation of patients over 70 years of age (Godtfredsen, 1975). Another retrospective study of an insured population with most of the people below 60 years showed a 3.7% one year mortality rate (Gajewski and Singer, 1981). It remains unclear whether the excess of cardiovascular deaths in patients with atrial fibrillation is due to sudden cardiac death, progression of congestive heart failure, cerebrovascular accidents or other causes.

Table 3. Risk stratification: atrial fibrillation and stroke

High risk ( > 6 % per year) - Mitral stenosis - Congestive heart failure - Previous stroke - Prosthetic mitral valve - Before and after cardioversion of chronic atrial fibrillation

Low risk ( < 3 % per year) - 'Lone' atrial fibrillation, age < 60 years - Paroxysmal atrial fibrillation, age < 60 years

Uncertain risk - Recent onset vs chronic atrial fibrillation - Intermittent vs sustained atrial fibrillation, age > 60 years - Previous 'silent' /asymptomatic stroke on computed tomography - Associated carotid artery disease - Underlying etiology of atrial fibrillation - Echocardiographjc features

- Mitral regurgitation - Left atrial size/volume - Ventricular function - Left atrial blood flow patterns - Left atrial thrombi

1.4.6 Use of drugs

Patients with atrial fibrillation must be treated with anticoagulants and usually also with negative chronotropic drugs to prevent rapid ventricular

1 1

response during atrial fibrillation. At this point it is important to draw attention to the misconception that

Vaughan Will iams class I antiarrhythmic drugs may prevent rapid ventricular rates during atrial fibrillation. If the iatter is just, impairment of atrioventricular transmission is very l ikely caused by decreased conduction in the H is-Purkinje system. This by itself may indicate concealed His-Purkinje system disease which becomes unmasked by the very use of class I antiarrhythmic drugs. In contrast, class I drugs may even facilitate atrioventricular conduction and class le drugs, if used during the arrhythmia, may cause exercise related ventricular proarrhythmia, presumably by its use dependent effects (Marcus, 1990; Falk 1989; Anastasiou-Nana et al., 1987). Therefore, in general, the use of class I drugs should be discouraged under these circumstances.

If_ s inus rhythm has been restored, most drugs can be withdrawn. However, as will also be discussed extensively in Chapters 1.6, 2, 3 and 4, prophylactic class I and III antiarrhythmic drug treatment is often prescribed after restoration of sinus rhythm.

1.5 THERAPY

In order to prevent or reverse adverse effects, as mentioned above, restoration of sinus rhythm is the general goal of the clinician in patients with chronic atrial fibrillation . Different approaches are discussed below. If sinus rhythm cannot be restored or maintained after conversion, adequate control of the ventricular response should be accomplished.

1.5.1 Pharmacological conversion

Digitalis, one of the oldest drugs, may convert atrial fibrillation into sinus rhythm. However, only recently a well performed investigation on the conversion rate of atrial fibrillation using digitalis in patients without cl inically significant heart failure was performed. This study showed that digital is is ineffective in converting atrial fibrillation into sinus rhythm (Falk et al . , 1987)

Wenckebach (Wenckebach, 1914) showed that it was possible to convert atrial fibrillation into sinus rhythm with quinine, while Frey (Frey, 1918) found that its isomer, quinidine, was the most effective antiarrhythmic of the cinchona alkaloids. Since then, many investigators have studied the conversion rate with quinidine . The in the l iterature reported efficacy of quinidine to convert atrial fibrillation into sinus rhythm varies considerably,

12

between 30% and 88 % . The efficacy depends especially on the duration of atrial fibrillation, with much lower conversion rates if atrial fibrillation exists longer (Cramer, 1968; Borgeat et al. , 1986).

Newer antiarrhythmic drugs like procainamide (Halpern et al. , 1980; Fenster 1983), flecainide (Crijns et al., 1988a; Borgeat et al. 1986), sotalol (Teo et al. , 1985), propafenone (Bianconi et al. , 1989, Vita et al. , 1989) were also not effective in the conversion of chronic atrial fibrillation into sinus rhythm. The same is true for verapamil (Shamroth, 1980). Amiodarone has higher success rates, but requires a time-consuming intravenous or oral drug titration before conversion can be expected and may have severe adverse effects (Kopelman and Horowitz, 1989). It may be expected that newer developmental drugs, with exclusive class III action, will have conversion rates comparable to amiodarone, without its unfavorable pharmacological profile. Thus, it can be concluded that from a clinical viewpoint, for the time being at least, antiarrhythmic drugs are ineffective for �onversion of chronic atrial fibrillation. In addition, as stated above, drugs may exert adverse effects especially during the arrhythmia. Finally, drug titration procedures may render chemical conversion too expensive when looking at cost-effectiveness in comparison with electrical cardioversion.

1.5.2 Direct Current electrical cardioversion

More than two hundred years ago Peter Christian Abildgaard, a remarkable Danish veterinarian and physician, published a summary of his experiments on the effect of electric shock on animals. He succeeded in first rendering fowls lifeless by an electric shock and then reviving them by a countershock applied to the chest (Driscol et al. , 1975). In 1899, Prevost and Battelli applied strong currents directly to the heart of dogs to induce ventricular fibrillation, and only in a footnote did they mention incidentally that these electrical discharges were also capable of terminating ventricular fibrillation (Lown, 1967). Kouwenhoven (Kouwenhoven et al, 1932) re-opened the subject of electrical defibrillation and tried various electrical discharge circuits including direct current shock. After much experimentation, they concluded that Alternating Current (AC) gave superior results. In 1947, the first successful defibrillation of the human heart was performed. However, the need for a thoracotomy and the direct application of the electrodes to the heart limited the clinical use of this method (Beck et al. , 1947). In 1956 the effectiveness of AC discharge for the transthoracic defibrillation of the human heart was demonstrated (Zoll et al. , 1956). Until 1960 electrical discharge was only applied for termination of ventricular fibrillation.

13

Lown introduced electrical cardioversion for atrial arrhythmias in 1962 (Lown, 1962). Initially, AC countershock was used. However, it was found that numerous and serious arrhythmias accompanied the use of AC electrical cardioversion. AC shocks administered to normal dogs resulted in sequential electrocardiographic changes of acute anterolateral myocardial infarction in 90 % of the animals with after a week follow-up a mortality of 35 % . Clinical data on the use of AC countershock confirmed the experimental observations (Zoll and Linenthal, 1962). Therefore, it was concluded that AC electrical cardioversion was not a safe method for treating cardiac arrhythmias.

A new electronic devise was developed employing direct current (DC) discharge. Transthoracic DC electrical cardioversion was found to be 100% effective in controlling 550 episodes of ventricular fibrillation in dogs (Lown, 1962) and all animals survived. Furthermore, DC countershock controlled ventricular fibrillation in both animals and men where AC failed to restore a normal mechanism. Arrhythmias were noted infrequently, ventricular fibrillation occurred in 1.6%, whereas atrial fibrillation was never observed. Thus DC countershock was safer than AC. The mechanism of its effect is that by simlutaneous depolarization of all cardiac fibers, the ectopic focus or foci could be extinguished, permitting the sinus node to resume its pacemaker function. Ventricular fibrillation after the shock was thought to be caused by a shock during the vulnerable period of the cardiac cycle. Therefore, an electronic synchronizer was developed which permitted delivery of DC shocks through a time-delay circuit triggered by the R wave of the electrocardiogram. After extensive exploration it was concluded that ventricular fibrillation could be induced only when the discharge fell during the T wave. A period of vulnerability was also demonstrated for the atrium and discharge during this phase of the cardiac cycle resulted in atrial fibrillation. Thus, it was demomonstrated that a properly synchronized, direct current discharge could depolarize the heart with complete avoidance of either ventricular or atrial fibrillation.

Lown showed success rates of 94 % for atrial fibrillation and 97 % for atrial flutter (Lown et al., 1962, 1967). Thereafter, many other investigators reported their results, with success percentages in atrial fibrillation patients being between 81-90% (Morris et al., 1966; Resnekov and McDonald, 1968; Bjerkelund and Orning, 1968; Hall and Wood, 1968; Aberg and Cullhed, 1968). In this era of new diagnostic and therapeutic methods for cardiac conditions related to atrial fibrillation, we re-evaluated the results and complication rates of DC electrical cardioversion in patients with chronic atrial fibrillation and flutter in Chapter 2.

Pretreatment with antiarrhythmic drugs, especially quinidine, has been reported to facilitate cardioversion (Rossi and Lown, 1967), but this has been questioned in other studies (W aris et al . , 197 1; Sodermark et al.,

14

1975). We did not perform loading before electrical cardioversion in patients treated with flecainide, sotalol and quinidine for safety reasons (Selzer and Wray, 1964; Ejvinsson and Orinius, 1980; Crijns et al., 1988b; Falk, 1989).

One area in which anticoagulation is clearly beneficial in reducing the risk of embolism is cardioversion of patients with chronic atrial fibrillation. The frequency of thromboembolic events without anticoagulants is 1.1-5.3 % , in comparison with 0-1.1 % while on anticoagulants. Because emboli can occur up to 10 days after cardioversion, anticoagulation should be given at least during four weeks before the shock untill at least one month afterwards (Bjerkelund and Orning, 1969; Dunn et al, 1989). In the present thesis, all 246 patients were adequately anticoagulated during the period described above.

Two studies (Edvardsson and Olsson, 1982; Lesser, 1990) reported on DC electrical cardioversion of atrial fibrillation in hemodynamically stable patients on an outpatient basis. Patients with advanced age or significant left ventri.cular dysfunction were also included. Within 2-4 hours following the procedure the patients were awake and alert and left the outpatient ward. It was concluded that cardioversion in this outpatient setting can be performed routinely and safely. Moreover, significant savings can be obtained using this approach, while for the patients it is less apprehensive as compared to hospitalization. A drawback of this approach is, however, that patients may suffer late anaesthesiological sequelae of the procedure. Patients discharged from the hospital within 24 hours after complete anaesthesia may have episodes of diminished alertness and cause harm to themselves and others. Therefore, this approach should not be established unless specific postanaesthetic care out of hospital is provided and guaranteed by, for example, patients' relatives.

1.5.3 Control of ventricular rate

The primary objective in patients with chronic atrial fibrillation is restoration of sinus rhythm. However, in some patients it is impossible to restore sinus rhythm or maintain sinus rhythm after successful conversion. In these patients adequate control of ventricular rate response must be achieved in order to improve exercise capacity and relieve complaints. Drugs used for this purpose are digitalis, calcium antagonists, beta-blockers and amiodarone or a combination of these drugs. Digitalis alone often fails to prevent rapid ventricular responses, especially during exercise (Goldman et al., 1975; Beasley et al., 1985, Klein and Kaplinsky, 1986). A combination of digitalis with calcium antagonists (Klein et al., 1979; Lang et al., 1983 ; Lewis at al., 1988a; 1988b; Lundstrom and Ryden, 1990), betablockers (David et al.,

15

1979) or amiodarone (Blomstrom et al. , 1984; McCarthy et al., 1986; Blevins et al. , 1987) may more sufficiently control ventricular rate response. However, with regard to the effects on maximal exercise capacity, contradictory results have been obtained. As has been pointed out in Chapter 1.4.6, class I antiarrhythmic drugs should not used for this purpose.

1.5.4 Role of catheter ablation and surgery

Transvenous endocavitary catheter ablation of atrioventricular conduction can be used to treat patients with intractable paroxysmal atrial fibrillation and chronic atrial fibrillation who despite adequate medical treatment, suffer from disabling arrhythmia related symptoms. This method often creates a complete heart block and allows the ventricular rate to be controlled by an implanted pacemaker (Scheinman et al. , 1982). However, complete heart block is not the primary goal and therefore attempts have been made to modify the atrioventricular conduction controlling the ventricular rate without the need for a pacemaker (Cunningham and Rowland, 1990). At the moment different catheter methods are in use. They are briefly discussed below.

1. High energy DC catheter ablation For conventional DC ablation, 200-300 J shocks are delivered via an

endocardial wire that is positioned to record an optimal His bundle deflection. This technique has a high success rate, creating complete heart block in 60-80% of patients and modifying conduction in a further 10-30%. Complete failure is reported in 1 0% of the cases (Cunningham and Rowland, 1990; Borggrefe et al. , 1990). During a mean follow-up of 12 months, the only reliable predictor for long-term success was the continued presence of complete heart block during the first 24 hours following catheter ablation (Lemery et al. , 1989). However, this technique has several disadvantages: general anaesthesia is required; a degree of uncontrolled myocardial damage is produced by the explosive discharge as is shown by the subsequent rise in cardiac enzymes; perforation of the ventricular wall leading to pericardia! tamponade may occur; ventricular fibrillation may complicate the procedure; a permanent pacemaker must be implanted after the procedure; pacemaker function may be disrupted if a repeat ablation session is necessary; and there is evidence of diffuse damage to the left ventricular function in long-term studies of exercise tolerance after ablation. Therefore, research has been stimulated into alternative ablation techniques.

2. Low energy DC catheter ablation A new system that shortens energy delivery time with high peak voltage

16

while reducing barotrauma, was only recently decribed (Rowland et al., 1989; Lemery et al., 1990). This system consists of a low power source, giving shocks of 5 to 40 Joules. Up to now, only a few patients have been treated with this new system, none the less, a high percentage of success was attained at reduced energies, also during follow-up, with a lower incidence of complications. However, general anaesthesia is still required.

3. Radio frequency catheter ablation High frequency or radio frequency alternating currents are defined as

electrical currents of changing polarities in the frequency range of 30 kHz to 300MHz. For ablation of cardiac tissue the 'unmodulated' radio frequency current is used through standard or suction electrode catheters (Borggrefe et al., 1990). The success percentage of radio frequency in achieving complete atrioventricular block or modification of the atrioventricular junction is lower than with DC high current ablation. Up untill now the use of radio frequency energy ablation has been reported from 6 centers, with a limited number of patients and a limited follow-up. Success rates were 45-60 % . A gradual effect may be achieved through short application of radiofrequency while observing prolongation of the PR interval (Cunningham and Rowland, 1990). Moreover, general anaesthesia is not needed, although about 40% of patients complained of mild chest pain or discomfort during the energy discharge. A recently published study concluded that radio frequency is preferable to direct current shock (Shamp et al., 1990). Further experience and long-term follow-up is warranted.

4. Transcoronary alcohol ablation Few patients with intractable atrial fibrillation are treated using transcoro

nary ablation of the atrioventricular nodal artery with 96 % ethanol. It seems a feasible method to induce complete heart block or give sufficient modification of the atrioventricular conduction system to control symptoms with a better control of the lesion size. However, coronary artery spasm can occur and may lead to myocardial infarction and furthermore, it may be difficult to identify and therefore to catheterize the atrioventricular nodal artery (Brugada et al. , 1990; Wang et al. , 1990; Sneddon et al. , 1990)

It is clear that further research into safe and more reliable methods of ablation should be performed if this technique is to make a major leap forward, such has been done by coronary angioplasty. Only then can ablation be an alternative to drug treatment rather than a last resort.

5. Surgery Finally, surgical intervention may be a possibility.

1 7

Guiraudon (Guiraudon et al. , 1985) described the corridor procedure for the treatment of atrial fibrillation. This technique involves the isolation of a corridor of atrial septum from the sinoatrial node to the atrioventricular node so that the sinus impulse can travel down the corridor, through the atrioventricular node, to the ventricles. However, this procedure only abolishes the irregular heart beat but does not improve cardiac dysfunction nor change the risk of thromboembolic complications since the atrial contraction is not restored. Thus, the corridor procedure, requiring a thoracotomy, offers no advantage over catheter His bundle ablation.

Therefore, a new surgical technique has been developed, namely the Maze procedure (Cox et al. , 1990). It divides two of the three primary pathways of conduction between the sinoatrial node and the atrioventricular node, i.e., the crista terminalis and the anterior limbus of the fossa ovalis. Then, the electrical impulse originating from the sinoatrial node can propagate in only one direction, allowing a normally generated impulse to propagate from the sinoatrial node to the atrioventricular node and to activate the entire atrial myocardium except for the excised atrial appendages and the pulmonary veins. With this procedure the atrial contraction will be restored and normal sinus rhythm will be present. The preliminary results of the Maze procedure are encouraging and this surgical technique may be a final therapeutic approach for patients with refractory atrial fibrillation.

1.6 Antiarrhythmic drug treatment after restoration of sinus rhythm: outcome and adverse effects

In the past 3 decades a considerable amount of evidence has accumulated that antiarrhythmic drug therapy may prevent or postpone recurrences of the arrhythmia. Results of previously performed trials are presented in tables 4 and 5 . It is well known that the clinical characteristics of patients may determine arrhythmia outcome. In previous literature, different clinical parameters have been identified as significantly influencing outcome, but results between studies vary considerably. In Chapters 2, 3 and 4 of this thesis the different parameters influencing outcome are described. Moreover, it is pointed out that the patients who will not benefit from treatment (intractable patients) can be identified beforehand, thereby avoiding the risk of proarrhythmia and other drug induced adverse effects. In this respect the study presenting the serial approach (Chapter 4) is noteworthy in so far that the analysis of factors predicting intractability was carried out in a relatively large cohort of patients in whom clinical intractablility was determined prospectively in the course of the study. Therefore, it is felt that the predictive tools identified in the serial study may be clinically more relevant than

1 8

some of those found in previous studies.

Proarrhythmia Proarrhythmia at the atrial (Crijns et al., 1988; Feld et al., 1990) and

ventricular levels (Selzer and Wray, 1964; Ejvinsson and Orinius, 1980; Roden et al., 1984; Falk, 1989) has been described during antiarrhythmic treatment for atrial fibrillation and flutter. Whether prophylactic drug treatment should always be instituted, is therefore questionable. Drug therapy is indeed effective in preventing recurrences, but probably at the cost of a higher short-term incidence of sudden death (Coplen et al., 1990). Presumably this is caused by drug induced ventricular proarrhythmia .. The present thesis reveals a low mortality and a low rate of proarrhythmia (Chapter 2, 3 and 4). This is not surprising, since patients did not have characteristics favoring the development of proarrhythmia. In addition, only moderate drug dosages were used. Setting aside the possible short-term complications, longterm prevention of chronic arrhythmia may be beneficial because of prevention of thromboembolic events or tachycardia-induced cardiomyopathy. Moreover, other favorable long-term goals prompting institution of active treatment are improvement of quality of life, especially in young patients with disabling symptoms in whom ablation of the atrioventricular conduction and concomitant pacemaker implantation may be avoided (see above). It may be conjectured that future very long-term trials could possibly demonstrate that the disadvantages of short-term proarrhythmia are outweighed by the long-term beneficial effects of medical intervention. With respect to proarrhythmia, its prediction is becoming more and more the subject of clinical investigations. After having become possible to predict proarrhythmia at the ventricular level (Slater et al., 1988; Kennedy, 1990), drug therapy can be more safely instituted in these patients, having 'merely' a supraventricular tachycardia. The recognition and eventual prediction of proarrhythmia at the atrial level will further facilitate a more adequate use of antiarrhythmics and increase their efficacy, since institution of drugs showing atrial proarrhythmia may be avoided.

Serial treatment In Chapter 4 a serial approach in prophylactic post-cardioversion treatment

is described. The rationale for serial treatment per se is that the underlying arrhythmogenic mechanisms at the atrial level may differ between patients. Since in most cases the specific underlying mechanism cannot be recognized beforehand, a standardized way of treating the patient was unavoidable. An arbitrary sequence of drugs was chosen in the present thesis: flecainide, sotalol or quinidine, and eventually amiodarone (Figure 2). Amiodarone was chosen as the last drug as it may have potentially severe side effects. The

19

�

Table 4: Baseline characteristics of previous studies.

baseline characteristics underlying heart disease (%) % maintenance SR

month(s)

first author year db drug duration NYHA heart CAD RhHD SH MVD lone 1 3 6 12

AF/AFL volume

Hillestad 1971 non Q-non < 24 mos - 620 ml 10 69 - - 8 60-46*** - - 31- 15*** Boisse! 1981 non Q-non - - - 1 - 3 64 18 - 23-44* - -Sodermark 1975 yes Q-P < 36 mos 91 % I , II 530 ml 32 - 9 27 8 90-50 - - 51-28**

Lloyd 1984 yes Q-D-P < 36 mos - - 11 73 5 - 6 69-84-83ns - 48-52-39ns -

Juul-Moller 1990 non Q-S mean 5 mos - 520 ml 16 5 26 - - 65-83 ns 56-62 ns 52-48 ns -

Rasmussen 1981 non Q-V 72%

N .......

Table 5: Baseline characteristics and outcome of non double-blind studies in difficult-to-treat atrial fibrillation patients.

baseline characteristics underlying heart disease (%) % maintenance SR

month(s)

first author year drug duration LA size CAD RhHD SH MVD lone 3 6 1 2

AF/AFL la , mm

Horowitz 1985 Arnio - 58 - - - - - - - 45 Gold 1986 Arnio - - 22 19 18 - 1 3 - - 57-85

B levins 1987 Arnio 75 mos 44 44 1 2 - - 4 40 - -

Brodsky 1987 Arnio 46 mos >45 , means 57 18 46 0 39 - - 39 -Antman 1988 Propa 30 mos 46 - - 28 - 1 5 - 40 -

AF = atrial fibrillation ; AFL = artrial flutter; Arnio = amiodarone ; CAD = coronary heart disease ; LA = left atrium ; la = long axis view; MVD = mitral valve disease; NYHA = New York Heart Association; Propa = propafenone ; RhHD = rheumatic heart disease; SH = systemic hypertension.

serial approach may reduce the recurrence rate after electrical cardioversion from 50 % to approximately 35 % . In the light of the recent report by Coplen (Coplen et al., 1990), showing an increased total mortality with quinidine (2.7%) compared to placebo (0.6%), studies on efficacy and safety of newer antiarrhythmics in this condition remain necessary. The serial treatment study presents further data on the effects of the newer drugs flecainide, sotalol and amiodarone.

stage stage stage AF

-t

I AF

-v

I I AF

-v

I l l AF

FL FL FL F L

! ! ! SR SR SR

t = ECV

Figure 2. Scheme of serial drug treatment to improve arrhythmia prognosis in patients with chronic atrial fibrillation or flutter. AF= atrial fibrillation; ECV = electrical cardioversion; FL= flutter; SR= sinus rhythm.

1. 7 Aims of this thesis

In this era with new diagnostic and therapeutic methods for conditions related to the development of atrial fibrillation, the patient group with chronic atrial fibrillation may have changed drastically. Moreover, on the

22

one hand, there is now a much lower incidence of rheumatic heart disease, but on the other, an ageing population.

Therefore, this thesis was undertaken to re-evaluate prospectively the immediate and long-term results of DC electrical cardioversion in chronic atrial fibrillation patients (Chapter 2).

Despite prophylactic antiarrhythmic treatment, chronic atrial fibrillation has a high propensity to recur after successful cardioversion. Newer antiarrhythmic drugs, as flecainide, sotalol and amiodarone, were therefore evaluated in the preventive treatment for arrhythmia recurrence (Chapters 3, 4). To further improve long-term outcome, we commenced with serial antiarrhythmic drug treatment, changing to a different type of drug after a recurrence, since each subtype exerts different actions. These results are presented in Chapter 4.

With the use of statistical analysis we set out to determine a precardioversion calculation of the probability of successful cardioversion (Chapter 2) and the recurrence risk after successful cardioversion (Chapters 2, 3, 4). In this calculation only easily obtainable clinical characteristics of the patients are used. The clinical importance of a precardioversion calculation of the probability of successful cardioversion and recurrence risk lies in the fact that it may help to avoid unnecessary cardioversions and institution of antiarrhythmic drugs in the future.

During the course of the study, our attention was drawn to reports of unwanted and lethal adverse events due to antiarrhythmic drugs. This encouraged us to evaluate in detail the complication rate of DC electrical cardioversion and prophylactic antiarrhythmic drug treatment (Chapters 2, 3, 4).

Previously, quinidine was often started before cardioversion in order to improve success of the shock, although contradictory results had been presented. The effects of flecainide on the atrial defibrillation threshold have not been studied before. Knowledge of its effects may be of additional importance, since elevation of the defibrillation threshold at the atrial level may signify difficulties with cardioversion and defibrillation at the ventricular level. This may have an important implication in patients treated with an Automatic Implantable Cardioverter Defibrillator (AICD). Chapter 5 deals with this study.

Transient ST segment elevations immediately after the DC electrical cardioversion have been described but have never before been studied systematically. This phenomenon may be a sign of myocardial or epicardial damage, causing electrical instability and may have prognostic implications on success of the cardioversion and maintenance of sinus rhythm thereafter (Chapter 6).

Arrhythmias occurring after successful cardioversion may have prognostic

23

importance as marker for recurrence. In Chapter 7 we studied the occurrence and predictive value of arrhythmias during 24-hour Holter monitoring, starting immediately after successful cardioversion.

Finally, this thesis describes the possible beneficial effects of restoration and maintenance of sinus rhythm. It is known that atrial fibrillation causes impairment of left ventricular function. However, previously performed studies on the reversal of this process show contradictory results. A study on the changes of hemodynamical parameters after cardioversion at rest and during exercise during long-term follow-up are presented in Chapter 8.

Atrial enlargement is considered both a cause and consequence of atrial fibrillation. Reversal of atrial sizes may therefore be expected during longterm maintenance of sinus rhythm after cardioversion and may have significant influence on the maintenance of sinus rhythm and prevention of relapse to atrial fibrillation. This is studied in Chapter 9.

24

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CHAPfER 2

Prediction of Uneventful Cardioversion and Maintenance of Sinus Rhythm from DC Electrical Cardioversion of Chronic Atrial Fibrillation and Flutter

Isabelle C. Van Gelder, Harry J. Crijns, Wiek H. Van Gilst (*) , Remco Verwer, (**), Kong I. Lie

Am J Cardiol (in press, in part)

From the Departments of Cardiology, Clinical Pharmacology (*) and Anaesthesiology (**) , Thoraxcenter, University Hospital Groningen, The Netherlands

Abstract

The present study was undertaken to reassess prospectively the immediate and long-term results of DC electrical cardioversion in chronic atrial fibrillation or atrial flutter, and to determine factors predicting clinical outcome of the arrhythmia following DC cardioversion. Twohundred and forty-six patients underwent DC electrical cardioversion and were followed during a mean of 260 days. Multivariate analysis was used to identify factors predicting short- and long-term arrhythmia outcome. Cardioversion was obtained in 70% of atrial fibrillation patients and in 96% of flutter patients. Stepwise logistic regression analysis showed that arrhythmia duration (p < 0.001), type of arrhythmia (fibrillation versus flutter, p < 0.02) and age (p < 0. 05), independently influenced conversion rate. On an actuarial basis 42 % and 36% of patients remained in sinus rhythm during 1 and 2 years respectively. Multivariate regression analysis showed that type of arrhythmia (p=0.0008), low precardioversion functional class (p=0.002) and presence of nonrheumatic mitral valve disease (p=0.03) independently increased the arrhythmia-free episode. Rheumatic heart disease shortened this period (p =0.03). In conclusion: patients having a high probability of conversion together with

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a prolonged postshock arrhythmia-free episode can be identified. This may improve the cost-benefit ratio of cardioversion.

Introduction

DC electrical cardioversion, introduced by Lown et al. in 1962 (1), is reported to restore sinus rhythm in approximately 90 % of the patients with chronic atrial fibrillation and 97 % of the patients with atrial flutter (2) . Unfortunately only 20 to 60% of patients maintain sinus rhythm during the first year irrespective of institution of prophylactic antiarrhythmic drug treatment (3-13) . Since the introduction of routine DC electrical cardioversion into clinical practice many investigators have studied the factors determening immediate and long-term outcome of this intervention. However, the present population subjected to electrical cardioversion differs in various ways from those previously studied. The diagnostic and therapeutic possibilities for conditions related to the development of the arrhythmia have changed drastically over the past 10 years. Management of hypertension, ischemic heart disease, congestive heart failure and rheumatic heart disease have been improved after the introduction of angiotensin converting enzyme inhibitors, calcium antagonists and thrombolysis. Also prevention of arrhythmia recurrence has changed after the introduction of newer antiarrhythmic drugs. Although more recent studies (14, 15) have reevaluated DC electrical cardioversion for chronic atrial fibrillation, study design was on a small retrospective basis and multivariate analysis was not performed. The present study was undertaken to reassess prospectively the immediate and long-term results of DC electrical cardioversion in a large cohort of patients . Using multivariate analysis factors predicting clinical outcome of the arrhythmia following cardioversion were determined. In addition, complications occurring during the cardioversion and follow-up were studied.

Methods

Study patients. Between February 1986 and June 1989 302 patients with chronic atrial fibrillation or atrial flutter were referred for DC electrical cardioversion to the department of cardiology of our hospital. Fifty-six patients were excluded: 41 % because of sinus rhythm at admission, 30 % for unstable heart failure or cardiogenic shock and 20 % because of the presence of severe systemic disease. The remaining 9 % were excluded for miscellaneous

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reasons (sick sinus syndrome without pacemaker, acute phase of a myocardial infarction and contraindications for anticoagulants). Two hundred forty-six patients underwent DC electrical cardioversion. The characteristics of these patients are presented in table 1. Type of unde