a Department of Cardiology, Herlev University Hospital, DK-2730 Herlev, Denmark
b Department of Cardiology, Gentofte University Hospital, DK-2900 Gentofte, Denmark
* Corresponding author: Mads D.M. Engelmann, Praestehusene 27, DK-2620 Albertslund, Denmark. Tel.: +45-434-538-48; fax: +45-434-538-24
E-mail address: engelmann{at}dadlnet.dk
Received 5 November 2002; revised 3 April 2003; accepted 18 April 2003
Abstract
The mainstay of treatment for atrial fibrillation, AF, remains pharmacologic control, either by maintaining sinus rhythm or by controlling the ventricular rate and allowing AF to continue. In patients where pharmacologic therapy i not effective, not tolerated or contraindicated, nonpharmacologic treatment may be beneficial. In the last two decades the number of nonpharmacologic treatment options (catheter ablation, cardiac pacing, internal defibrillation, and dysrhythmia surgery) for AF have markedly increased and the number of patients undergoing such treatment is steadily increasing. The most important reason for these treatment strategies is the hope of reducing symptoms, preventing complications and improving quality of life, QoL. However, the impact of nonpharmacologic therapy on QoL is far from established. Following a short presentation of the basic definitions and instruments used in QoL research the present paper reviews clinical studies that have assessed QoL in patients undergoing nonpharmacologic treatment of AF. Major limitations and methodological problems are emphasized. Among these are highly selected often-heterogenous patients groups, small size, lack of control group and the use of non-validated QoL instruments. Furthermore, in most studies antiarrhythmic medication have been discontinued at the time of the intervention and it is not clear to which degree the improvement in QoL is related solely to the nonpharmacologic treatment or to the removal of drug related adverse effects. Although the currently available data from adequately designed studies are sparse and further investigations are needed, it is noteworthy that the majority of patients undergoing nonpharmacologic treatment report enhanced QoL.
Key Words: Atrial fibrillation Quality of life Nonpharmacologic therapy Maze procedure Cardiac pacing Catheter ablation
1. Introduction
Atrial fibrillation, AF, is the most common clinically significant cardiac rhythm disturbance and is associated with substantial complications and health care costs. The prevalence of AF is increasing with age and the reported prevalence of AF ranges from less than 0.5% in people 25 to 35 years of age, to 1.5% of people up to 60 years of age, to 9% in people older than 75 years of age.1Furthermore reports from western populations concurrently indicate a significant increase in hospital incidence of AF2,3often described as the epidemic of AF. An epidemic, which to some extent may be explained by the combination of improved diagnosis of the arrhythmia, increased awareness among referring physicians and increased longevity in the industrial societies.
In contrast to life-threatening arrhythmias, AF may appear benign but may reveal its detrimental effects only after many years. In the Framingham Study AF patients had a nearly two-fold increase in all-cause mortality and a four- to five-fold risk for a stroke.4The management of AF is complex and richly faceted with anticoagulation therapy in combination with antiarrhythmic drugs as the first-line treatment strategy5and with the nonpharmacologic therapies (catheter ablation, cardiac pacing, internal defibrillation, and antiarrhytmic surgery) playing an increasingly important role.1,6As the impact of these varying therapies on morbidity and mortality is unclear, the reduction in symptoms and an improvement in quality of life, QoL, are the most important reasons for treating patients with idiopathic or hypertension related AF.7QoL have gradually been acknowledged as equally important as traditional measures of disease burden and since the early 70s there have been a nearly exponential increase in the use of quality of life end points in clinical research. Cardiovascular research is very well represented in the field of reporting quality of life coming just second to cancer research. A search of the Cochrane Controlled Trials Register showed that in studies reporting on quality of life the most commonly conditions were cancer (29%) and cardiovascular disease (26%) with other research domains occurring in less than 10% of studies.8
In the last two decades the number of nonpharmacologic treatment options for AF has markedly increased, see Table 1. These new techniques have expanded the indications for nonpharmacologic treatment and the number of patients undergoing such treatment is steadily increasing. Despite the growing popularity of nonpharmacologic strategies their impact on QoL have not been evaluated widely. The first part of this review is an introduction of basic definitions and instruments used in QoL research. The second part of this article reviews published clinical studies that have assessed QoL in patients undergoing nonpharmacologic treatment of AF. Finally the third part sum up the methodological problems involved in the assessment of QoL in nonpharmacologic treatment of AF and proposes a set of eight criteria to be fulfilled when planning QoL studies in the future.
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The evaluation of QoL is inherently subjective and no consensus on the definition exists. Most approaches used in medical contexts do not attempt to include more general notions such as life satisfaction or living standards9and tend rather to concentrate on a multidimensional construct based on four components: physical condition, psychological well-being, social activities and everyday activities.
The lack of a clear definition of QoL is reflected in the many instruments that have been proposed to measure it.8Indeed, a state of the art review identified some 150 different measures.10However, there are two basic approaches to measure QoL: generic instruments and disease specific instruments.
Generic instruments are used in the general population to assess a wide range of domains applicable to a variety of health states, conditions, and diseases. They are usually not specific to any particular disease state or susceptible population of patients and are therefore most useful in conducting general survey research on health and making comparisons between disease states.11The generic instruments facilitate comparisons among different disease groups, however, the broad approach may reduce responsiveness to effects of health care. Currently The Medical Outcome Study Short-Form Health Survey, SF-36,12is the most widely validated generic instrument available.
Disease-specific instruments focus on the domains most relevant to the disease or condition under study and on the characteristics of patients in whom the condition is most prevalent. Disease-specific instruments are most appropriate for clinical trials in which specific therapeutic interventions are being evaluated. Disease-specific instruments have several theoretical advantages. They reduce patient burden and increase acceptability by including only relevant dimensions. Disadvantages are the lack of comparability of results with those from other disease groups and the possibility of missing effects in dimensions that are not included.13The Symptom Checklist: Frequency and Severity14and The Modified Karolinska Questionnaire,KQ,15are both well-validated representatives of cardiac specific questionnaires.
Apart from being generic or disease-specific the instrument should possess several important psychometric properties, which includes coverage, reliability, validity, responsiveness, sensitivity, and practicality, see text .
Textbox 1 Basic requirements of quality of lifeassessments
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3. Studies of quality of life in nonpharmacologic treatment of atrial fibrillation
The mainstay of treatment for AF remains pharmacologic control, either by maintaining sinus rhythm or by controlling the ventricular rate and allowing AF to continue. However, both strategies have several limitations. Drug therapy to suppress atrial fibrillation and maintain sinus rhythm is often ineffective with a recurrence rate to AF in approximately 50% at 6 months during therapy with the best available drugs.6Furthermore, both regimes are frequently poorly tolerated because of adverse effects and interactions with other drugs. A third limitation of pharmacologic therapy is the risk to the patient from the prescribed therapy. Indeed data are accumulating on increased mortality in patients receiving antiarrhythmic drug therapy.1719It is for the portion of patients who either remains symptomatic while receiving pharmacologic therapy or who experience adverse drug effects that nonpharmacologic options until now have beenoffered.
4. Surgical therapy
Operative treatment for the patient with refractory AF has been available since early 1980s. The Maze operation, designed by James L. Cox and co-workers, is clearly successful at restoring sinus rhythm, AV synchrony and atrial systole, and thereby diminish the risk of thromboembolism.20It is an open-heart operation requiring cardiopulmonary bypass, and until now, usually reserved as a therapy of last resort for patients undergoing another clinically indicated surgical procedure, such as mitral valve repair or replacement.
However, in a longitudinal study by Lönnerholmet al.21the indications for the Maze procedure were expanded to a group of patients with mostly (80%) lone AF, were AF was the primary indication for surgery in all patients. QoL was the primary endpoint in this study and was assessed before operation as well as 6 and 12 months after surgery using the SF-36 questionnaire.
Of the 49 patients included 39 were men (80%) and 10 women (20%). QoL before surgery was significantly lower on all scales, except for bodily pain, than for the age matched general population. All patients underwent the Maze III operation and sinus rhythm was restored and maintained without antiarrhythmic medication in 90% of the 30 patients at 6 months follow-up. After surgery all scores were significantly improved except for bodily pain, which, was already normal before the operation, Table 2. Six months and 1 year after surgery QoL reached the levels of the age-matched general population. Lönnerholm et al. concluded that these results indicate that the Maze operation can be used in selected patients with drug-refractory paroxysmal or permanent AF as a primary indication for heart surgery.
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In a study by Jessurun et al.2541 patients with longstanding symptomatic, drug-refractory, lone paroxysmal AF underwent Maze III surgery. The primary end-point was to establish the effectiveness and safety of the Maze III operation. However, QoL was assessed before surgery and at 3 and 12 months after surgery in 18 patients using the SF-36 questionnaire.12After surgery all SF-36 scores were significantly improved except for bodily pain and role limitation. In other words the QoL results as well as the limitations in this study are almost identical to the study by Lönnerholm et al.21and indicates that the Maze operation has a positive effect on QoL in these highly selected patients groups.
5. Catheter ablation of atrial fibrillation
Two catheter ablation techniques to modify the substrate of AF are currently under investigation, linear atrial ablation and focal atrial ablation. In linear atrial ablation, the so-called Catheter maze, the atria is compartmentalized to render it incapable of sustaining multiple wavefronts of electrical activity to maintain AF. In focal atrial ablation the first strategy involved mapping and ablation of the arrhythmogenic foci within the pulmonary veins. Due to a recurrence rate of at least 50% the ablation currently is targeted to the ostium of the pulmonary vein with the end-point of the procedure being to electrically isolate the pulmonary veins from the rest of the left atrium. However, the recurrence rate is still high (4050%) and the optimal strategy still remains to be found. Hypothetically the combination of catheter maze and focal atrial ablation may be associated with a lower risk of AF recurrence.1
Pappone et al.26compared the impact of pulmonary vein ablation on QoL with medical therapy. QoL were measured in 109 patients undergoing pulmonary vein ablation and 102 patients receiving rhythm control therapy using, SF-3612at the time of admission and at 3-moth intervals up to 1 year. QoL assessed by the SF-36 summery scores (physical and mental) increased significantly after the ablation where as there were no significant changes in the rhythm control group. The authors conclude that pulmonary vein ablation improves QoL. However, there are several important limitations: the study is not randomised, the nature of the AF is not specified, it is not clear whether the patient were in sinus rhythm when completing the questionnaires, and only one QoL instrument is used.
In a study by Gerstenfeld et al.2771 patients underwent attempted pulmonary vein ablation and QoL were evaluated one month before and 6 months after electrophysiologic study using a modified version of SF-3612in combination with a 19 item symptom questionnaire. The 41 patients who completed both initial and follow-up questionnaires were divided into three groups: those undergoing invasive mapping but in whom no ablation was performed (11 patients); those having undergone invasive mapping and ablation but in whom AF recurred (18 patients); and those having undergone successful ablation and remained in sinus rhythm (12 patients). Patients in the latter group reported significant improvement in QoL and reduction in all symptoms. Interestingly, the group of patients who underwent ablation but had recurrent AF also reported significant improvements in symptoms and QoL although not as large as those without recurrence of AF. These improvements were all greater than those experienced by patients undergoing intracardiac mapping without ablation, making a placebo effect unlikely.
In conclusion both studies report significant improvement in QoL after pulmonary vein ablation; however with a recurrence rate at 68% and a risk of pulmonary vein stenoses at 8% in the study by Gerstenfeld et al. the method is far from being treatment of first choice.
6. Catheter based ablation or modification of the AV node
Palliative ablation therapy for AF is well established for patients with disabling symptoms caused by a rapid ventricular rate who are refractory to or who do not tolerate pharmacologic therapy. The rationale for ablation of the AV conduction system with implantation of a pacemaker is that it is almost always easier to treat bradycardias than tachycardias. However, is must be emphasized that ablation of the AV node is permanent and irreversible. It renders the patient pacemaker dependent with the associated risk of pacemaker failure, lead malfunction, and need for re-implantation. Furthermore, the procedure has no impact on AF nor alter the thromboembolic risk.
6.1. AV node ablation and pacemaker implantation
A number of longitudinal studies have evaluated the effect of AV node ablation and pacemaker implantation on QoL. Summaries of these studies appear in Tables 3 and 4. The studies summarised in Table 3are purely descriptive with no control groups and no randomization. Only the studies by Bubien et al.14and The Ablate and Pace trial, APT,33have used validated QoL questionnaires. Bubien et al.14used a battery of 4 QoL measures before ablation and 1 and 6 months after ablation. A generic instrument, the SF-36 questionnaire, and a disease-specific instrument The Symptom checklist:Frequency and Severity. The latter is intended to measure the patients perception of the frequency and severity of symptoms related to the arrhythmias. Furthermore Bubien et al. included two investigator developed non-validated instruments: Perceived Impact of the arrhythmia on Activities of Daily Living and Performance of Activities of Daily Living. A major limitation in this study is the heterogeneity of the arrhythmias included. Only 22 patients had AF and the nature of AF i.e. paroxysmatic, persistent or permanent is not specified.
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After ablation and pacemaker implantation, significant improvements were seen in both the generic and the disease-specific QoL instruments as well as in arrhythmia related symptoms. However, the study was designed asa prospective registry rather than a controlled clinical trail. This makes it impossible to be certain that all of the changes in QoL were due to catheter ablation and pacemaker implantation. For example it is possible that some patients may have experienced improvements with continued medical treatment. In addition, patientsincluded were highly selected, severely symptomatic patients where no distinction between paroxysmatic, recurrent and chronic AF were made. It is important to remember that these study results should not be generalized to less severely compromised patients most frequently seen.
6.2. AV node ablation versus medical treatment
The importance of medical ventricular rate control versus pacemaker mediated ventricular rhythm control have been evaluated in patients with persistent35and permanent3639AF with normal35,38and moderately impaired left ventricular function.36,37,39These trials are summarised in.Table 4In a study by Brignole et al.37QoL were assessed longitudinally at the time of enrolment and at the end of the 12 month study period using the following measurements:
At the end of the 12 months study, the ablation- and pacemaker-treated group had significantly better scores in the disease-specific symptoms in comparison with the drug group. However, there were no significant differences in the generic Minnesota Living with Heart Failure Questionnaire scores, with both methods demonstrating improvement over baseline. Because of the controlled design, the study demonstrates that not all the benefits were due to ablation and pacemaker treatment per se, as some improvement occurred also in the conventional treatment group.
Levy et al.38assessed QoL using the following two instruments:
Both patient groups had significant improvement in total KQ scores and total NHP part 1 scores at all follow-ups. For inter-group comparison there was no significant difference in any baseline result or between groups in follow-up. For part 2 of the NHP there was no significant change from baseline in either group at any time or any difference between groups. Levy et al. conclude that in these patients improved rate control will lead to a significant improvement in exercise duration and QoL and that neither technique shows any significant advantage over the other.
Overall the studies suggest that ablation may beadvantageous in patients with permanent AF when left ventricular function is moderately impaired. However, ablation offers no advantage in the presence of normal ventricular function if rate control can be achieved with AV blocking agents. The pragmatic clinical approach as purposed by Levy et al.38may be medical treatment first in combination with a VVI-R pacemaker as it avoids initial irreversible ablation. Ablation can eventually be performed at a later stage in non-responders.
6.3. AV node ablation versus AV node modification
Partial AV node ablation, AV modification, has been tried as an alternative to AV node ablation. The objective of partial AV node ablation is to modify the conduction properties slowing the ventricular rate in AF without the need for pacemaker dependency. Unfortunately, AV node modification is technically difficult and long-term results often unpredictable. In contrast to the almost 100% success in AV node ablation, the success in AV node modification is approximately 70%.43QoL in patients undergoing AV node ablation or AV node modification have been compared in a longitudinal study44of 60 patients with medically refractory paroxysmal or chronic AF. The patients were randomly assigned to either complete AV nodal ablation with permanent VVI-R pacing or AV nodal modification. QoL was assessed before and at 1 and 6 months after ablation/modification using a QoL diary and a semiquantitative questionnaire.
Both treatments were associated with a significant improvement in general QoL. Patients who received AV nodal modification remained symptomatic, perhapsbecause of their irregular ventricular rhythm of AF. In other words AV nodal ablation with permanent pacing had a significantly greater effect than AV nodal modification in decreasing the frequency of attacks and extent of symptoms of AF, and the patients who received this procedure were more satisfied with their general well-being. A major limitation in this study was the use of non-validated QoL instruments. Furthermore, no control group was incorporated and the follow-up time period was only 6 months.
7. Pacing management of atrial fibrillation
Several investigators45,46have reported an increased incidence of AF with the use of ventricular pacing as compared with atrial or dual-chamber pacing. These findings have led to newer pacing techniques for the prevention of AF in selected patients. The theoretical rationale for multisite atrial pacing is that pacing from a second site can achieve a more synchronous activation of the atria thus preventing the occurrence of reentrant circuits.47Dual-site atrial pacing involves inserting one pacing lead in the right atrial appendage and the other pacing lead at the ostium of the coronary sinus.48The impact of dual site atrial pacing on QoL has been tested in two prospective randomized crossover trials,49,50Table 5.
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8. Implantable atrial defibrillator
In the currently used atrial defibrillator the shocks for AF can be activated by the patient or can be programmed to occur automatically in the early morning while the patient is asleep. Thus, this therapy provides some patient control over the treatment, which has lead to speculations concerning improved QoL.1Newman et al.51have evaluated the impact of QoL of patients implanted with atrial defibrillators. In the present study 144 patients with symptomatic AF or atrial tachycardia received an atrial defibrillator. QoL was assessed at baseline, 3 months post-implant, and 6 months post-implant using the SF-3612and The Symptom Checklist: Frequency and Severity.14
QoL assessments were available at baseline, after 3 and 6 months. Two of the subscales in the SF-36 (role-physical and vitality) improved significantly after the implantation. The other 8 SF-36 scales showed no decrease from pre-implant over time. Furthermore, symptoms decreased significantly from baseline to 3 and 6 months without a change in symptom severity. In other words the implantation of an atrial defibrillator increased some domains of QoL and decreased the frequency of symptoms in a small subgroup of patients with symptomatic, drug-refractory AF. However, other investigators have not confirmed the results and the lack of a control group is a major limitation when interpreting these findings.
9. Conclusion
There is an increasing awareness that QoL is important and QoL has become a key issue in a growing number of clinical trials. However, despite the fact that AF is a very common disorder with profound impact in terms of morbidity and mortality, the currently available data from adequately designed studies are sparse. From the studies reviewed, the available data show that QoL is impaired in patients with AF and that the majority of patients after having underwent a nonpharmacologic treatment report enhanced QoL. There may be several reasons for these findings:
Many of the methodological problems involved in the assessment of QoL have already been discussed in conjunction the relevant studies, however some of the major issues should be emphasized:
Three randomised controlled trials have compared pharmacologic rate control therapy with pharmacologic rhythm control therapy using QoL as a secondary endpoint; The Pharmacological Intervention in Atrial Fibrillation (PIAF) study,54The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trail,55and the Rate Control versus Electrical Cardioversion (RACE) trail.56The studies show that rate control is as efficacious as rhythm control in improving QoL and challenge the concept that restoration of sinus rhythm in patients with AF is always an important goal. At first glance these results may appear contradictive to the improvements in QoL obtained in studies on nonpharmacologic treatment. A discrepancy that is readily explained looking at the patients enrolled in the trials. Patients in the AFFIRM and the PIAF are representative of the majority of patients with AF being elderly often mildly symptomatic, where as patients undergoing nonpharmacologic treatment are severely symptomatic, often younger patients referred to tertiary care. However, these results underline the need for an individualised treatment strategy with careful assessment of symptoms and underlying cardiac disease. Patients in whom AF causes symptoms despite pharmacologic therapy or who experience adverse drug effects may be candidates for nonpharmacologic treatment strategies and can expect improved QoL following such treatment.
From the above reviewed studies it is apparent that the number of QoL instruments is overwhelming and that the wide variation in the instruments selected makes it difficult to compare QoL findings across studies. The following eight criteria may be useful when planning new studies as well as when evaluating the existing literature:
Hopefully these criteria may act as an inspiration for investigators planning future studies thus enhancing the quality of quality of life research in nonpharmacologic treatment of AF.
References