Atrial fibrillation in the ‘real world’: undecided issues
1 Department of Cardiology, University Hospital Maastricht, Maastricht, The Netherlands
2 Department of Cardiology, Guglielmo da Saliceto Hospital, Piacenza, Italy
* Corresponding author. Tel: +31 43 3875093; fax: +31 43 3875104. E-mail address: h.crijns{at}cardio.azm.nl
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Abstract |
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 Top Abstract Detection of atrial fibrillationRate controlManagement of associated...Stroke risk stratification and...Rhythm controlThe evidence base for...Final remarkAcknowledgementsReferences |
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Atrial fibrillation (AF) is an obstinate and widespread arrhythmia with multiple presentations and potential for hazardous consequences. Although our knowledge of AF is advancing, the onset and progression of AF and the interaction with its many associated diseases is not fully understood. Also, management recommendations on evidence based issues are frequently ignored for a wide range of reasons. The following developments are expected to improve efficacy, safety, and guideline adherence regarding the management of AF: earlier detection of AF, improved understanding and management of its associated diseases, adequate rate-control targets, more effective and safer rhythm control measures, an easy-to-use risk stratification scheme incorporating both risk factors for stroke and major bleeding to tailor antithrombotic treatment, and anticoagulation drugs not requiring monitoring of the international normalized ratio. Translational researchers, clinical trialists, and epidemiologists should complement each other to fulfil the current needs in the management of AF and to monitor whether there are solutions for existing ‘undecided issues’ and new ones are developing.
Key Words: Atrial fibrillation • Management • Practice • Guidelines
At the start of the 20th century, atrial fibrillation (AF) was diagnosed for the first time by means of an electrocardiogram and was suspected to be a common clinical condition in humans.1,2 In the decades that followed, several large observational studies, of which the Framingham Heart study is the undisputed leader, showed the widespread prevalence of AF in the western world. Incidence of AF increases dramatically with advancing age,3 and, recently, it was realized that one in four persons 
40 years will develop AF at some time in life.4 The Framingham study also indicated that AF is associated with an increased mortality5 and a highly increased risk for ischaemic stroke,6 and that AF often coexists with other cardiovascular pathologies, thereby worsening the prognosis of each other.3,7
Management was in the first instance quite conservative, since AF was generally thought to be a benign arrhythmia and the development of antiarrhythmic and rate-control drugs slowly progressed. After the realization that AF is a highly prevalent disease with potentially hazardous effects, increased research efforts improved the understanding of electrophysiological patterns, thrombogenic mechanisms and the interaction of AF with associated diseases. Consequently, more effective antiarrhythmic and rate-control drugs were developed, the arsenal of interventions to restore sinus rhythm expanded, and antiplatelet drugs, especially oral anticoagulation (OAC), were shown to be effective for stroke prevention in AF.
The quality of AF care has greatly improved in recent times. Nevertheless, the efficacy of existing rhythm control strategies for AF is limited and they often have the potential to cause severe side effects. In addition, OAC prescription rates in AF patients at high risk for stroke have often been suboptimal, which is a multifactorial problem that is in large part based on fear of bleeding. Due to the under representation of specific, often old and severely diseased, AF patients in randomized controlled trials (RCT), management of these AF subgroups seems to be lagging.
Management of AF is summarized in Figure 1. Based on this flow chart, we aim to discuss the benefit, limitations, and actual application of current management options in the ‘real world’ and derive which ‘undecided issues’ need to be addressed and, also, which important developments can be expected in the future.
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A highly increased bleeding risk might be reason to deny oral anticoagulation in high-risk patients. |
Detection of atrial fibrillation |
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TopAbstractDetection of atrial fibrillationRate controlManagement of associated...Stroke risk stratification and...Rhythm controlThe evidence base for...Final remarkAcknowledgementsReferences |
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Symptoms that are potentially caused by AF trigger a diagnostic work-up to screen for AF and the arrhythmia will in many instances be documented. On the other hand, AF is often asymptomatic8 and will in that case sometimes be found by coincidence, for example with pre-operative screening, but will often be undetected until the damage has been done, i.e. when the patient presents with a stroke or heart failure (HF).
The widespread prevalence and hazardous consequences of AF mean that screening for AF is highly desirable, at least among persons 40 years. However, due to the intermittent nature of AF, screening will be a difficult task and is not yet convincingly cost-effective.9 Non-invasive tools such as event recorders and long-term (>1 day) continuous ECG monitoring might improve detection, but cost-effectiveness needs to be assessed. Blood markers might be an additional tool to screen for AF, but AF specific markers are not yet known. Further, since AF seems to be highly prevalent within some families, insights into the genetic predisposition for AF might improve early AF detection.10
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Rate control |
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TopAbstractDetection of atrial fibrillationRate controlManagement of associated...Stroke risk stratification and...Rhythm controlThe evidence base for...Final remarkAcknowledgementsReferences |
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In case AF causes a fast and irregular ventricular response rate, adequate rate-control drugs should be administered to address symptoms and to prevent HF onset or progression. Current guidelines recommend aiming at a resting ventricular rate below 80 b.p.m., but a RACE/AFFIRM post-hoc comparison could not reveal superiority of strict rate-control in AFFIRM over more lenient rate-control in RACE.11 The ongoing RACE II trial will provide insights into this issue.12
Some patients do not sufficiently respond to rate-control drug therapy and maintain a high ventricular rate. If it appears that strict rate-control is definitely beneficial, more aggressive rate-control measures are needed in these patients. Combinations of rate-control drugs can be given and for example in patients with AF and HF, the combination of digitalis with a beta-blocker is highly recommended. Not recommended, is prescription of class III antiarrhythmic drugs for rate-control purposes. Although these drugs have rate-control properties, they also can cause more severe side effects compared with conventional rate-control drugs. Nevertheless, sotalol and especially amiodarone are regularly given to patients with permanent AF in whom no rhythm control will be attempted according to the guideline definition of permanent AF.13 Possibly, this policy aims at both rate- and rhythm-control, it is due to continuation of class III antiarrhythmics prescribed earlier, or other rate-control drugs have proved inadequate or caused side effects. Studies on the long-term effect of class III antiarrhythmic drugs might clarify whether these drugs can safely contribute to a rate-control strategy.
Some AF patients do not sufficiently respond to optimal rate-control drug therapy. Identification of patients that are likely to be non-responders—probably patients with advanced structural heart disease such as HF—should improve tailored rate-control therapy. In non-responders with sustained severe symptoms or HF more rigorous strategies may be warranted. Biventricular pacemaker implantation together with atrioventricular junctional ablation could be a solution for AF patients with HF,14 but large RCTs should clarify whether this intervention is more effective than optimal drug therapy, in terms of safety and cost-effectiveness.
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Management of associated diseases and conditions |
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TopAbstractDetection of atrial fibrillationRate controlManagement of associated...Stroke risk stratification and...Rhythm controlThe evidence base for...Final remarkAcknowledgementsReferences |
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Many cardiovascular diseases can induce AF, of which hypertension is by far the most prevalent, but also HF, coronary artery disease, and valvular heart disease are often found in association with AF.13,15 These diseases can cause atrial volume overload thereby creating a ‘substrate’ for AF by means of atrial enlargement and fibrosis. Other conditions that can cause AF concern hyperthyroidism, obstructive sleep apnoea syndrome, and autonomic nervous system dysfunction. These conditions mainly function as a ‘trigger’ for AF onset, rather than the ‘substrate’ as described earlier.
Just a small portion of AF is idiopathic and the vast majority of AF patients have at least one of the aforementioned underlying diseases. Since adequate management of these underlying diseases might ameliorate or even stop the arrhythmia, it is important to screen for these diseases when AF is encountered. A minimal diagnostic work-up in AF patients, therefore, includes extensive history and physical examination, a chest X-ray, echocardiography, and thyroid hormone level measurements.16 The Euro Heart Survey on AF suggested that performance of chest X-rays and echocardiography was adequate, but that thyroid hormone level measurements were made in only half the patients, even when on amiodarone.13 In addition, the role of autonomic AF triggers might be underestimated and physicians should take these factors into account when taking a patient's history.
Besides the cause of AF, HF can also be the consequence of AF, which is often referred to as tachycardiomyopathy. Since the combination of AF and HF is often found and since they have an adverse reciprocal impact, HF deserves special attention in AF patients.7 The diagnosis of HF is difficult, but biomarkers such as Brain natriuretic peptide (BNP) and N-terminal (NT)-pro BNP have an additional diagnostic value. Also in AF patients, these markers can improve the detection of HF and structural heart diseases in general, although cut-off values should be higher than in sinus rhythm patients.17
The causal mechanisms of AF interacting with its associated diseases are not yet fully understood. Ongoing basic research will provide new insights into these mechanisms and will allow us to develop advanced non-invasive imaging modalities, to identify new treatment targets, and to design more specific management strategies. In the presence of associated diseases, it has to be determined whether AF or another pathology is the main problem. This might clarify the optimal treatment option and could prevent patients from unnecessarily being exposed to potentially hazardous effects of, for example, rhythm control and OAC. Furthermore, the application of recommended drugs for a concomitant disease might not be as beneficial when AF coincides. In this regard, doubt has risen about the efficacy of beta-blockers in patients with HF and AF and the effect should be established in a prospective manner in this subgroup. On the other hand, angiotensin II receptor blockers and angiotensin converting enzyme inhibitors (ACE-I) seem to improve prognosis in AF and prevent new onset AF besides their proven efficacy in hypertension, HF, and coronary artery disease.18,19
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Stroke risk stratification and antithrombotic therapy |
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TopAbstractDetection of atrial fibrillationRate controlManagement of associated...Stroke risk stratification and...Rhythm controlThe evidence base for...Final remarkAcknowledgementsReferences |
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Stroke is the chief hazard in AF.6 Preventive measures by means of OAC prescription are often inadequate, although improving over time (Figure 2). However, not all AF patients should receive OAC, but risk stratification should separate high-risk patients who require OAC from patients in whom an antiplatelet drug suffices.16 Several of the factors that increase stroke risk in AF are also associated diseases and play a role in both management issues (Figure 1). Multiple risk stratification schemes have been proposed, but regardless of the scheme antithrombotic therapy prescription seems only moderately tailored to the patient's stroke risk profile.20 This discrepancy relates to multiple factors, among which are unfamiliarity with the guidelines, inconsistencies between different stroke risk schemes and concomitant doubt about some individual stroke risk factors, inconsistencies in antithrombotic drug recommendations among different guidelines, fear of bleeding, lack of facilities to monitor the international normalized ratio (INR), and belief in factors that are not evidence based.
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The 2006 guidelines recommendations on antithrombotic therapy are mainly based on the CHADS2 score—an acronym for Congestive HF, Hypertension, Age
75 years, Diabetes and a prior Stroke/TIA—in which all items receive 1 point, and a prior stroke/TIA 2 points.21 OAC should be prescribed with score 2 and with score 1 the physician can choose between OAC and an antiplatelet drug. Some less well-established risk factors such as uncontrolled hypertension, HF with systolic dysfunction, and female gender can tip the scales regarding OAC prescription with CHADS2 score 1.16 What the guidelines do not recommend, but what is often done in daily practice, is to weigh the clinical type of AF as an independent stroke risk factor.20 The perceived lower thromboembolic risk in paroxysmal AF compared with more persistent forms of AF probably underlies this behaviour. However, there is no clear evidence that the stroke risk differs between AF types, and it is also not clear what mechanism forms this hypothesis. Is a single long-lasting episode thrombogenic or is the frequent stopping and starting in AF paroxysms hazardous? And even when the role of episode duration and frequency is known, it will be hard to assess the thromboembolic risk of asymptomatic AF, which is essential since asymptomatic episodes contribute highly to the total AF duration.8 In addition, subanalyses of the AFFIRM study showed that asymptomatic AF is associated with more strokes than symptomatic AF and that patients who (apparently) remain in sinus rhythm still benefit from OAC.22,23 A perceived high-bleeding risk is a frequent reason not to prescribe OAC. In some instances this is probably justified, when patients have a high risk of falling, are very forgetful, or when patients have previously suffered from an intracranial haemorrhage (ICH) or another type of bleeding that was difficult to control. Some factors predisposing AF patients to major bleeding have been identified.24 The paradox is that some of these risk factors for major bleeding are also risk factors for stroke and the prevalence of bleeding risk factors increases with a worsening stroke risk profile. The risk of major bleeding (any type) seems mainly increased by high age, high INR values (>4.0), and with prior major bleeding.24,25 Withholding OAC results in an increased risk of stroke and mortality, whereas prescribing OAC in AF patients with a potential bleeding risk factor does not significantly increase bleeding risk.26 Thereby, antithrombotic overtreatment seems subordinate to an intrinsic propensity to bleed. Also considering the much higher stroke incidence compared with bleeding rates in both RCTs and observational studies, fear of stroke should outweigh fear of bleeding when deciding on antithrombotic treatment in AF. It has to be noted that ICH is considered to be the natural counterpart of ischaemic stroke in AF patients on OAC. Although the incidence of ICH is very low in RCTs and observational studies, they are highly lethal.27 Other types of major bleeding are mostly less often lethal and can be quite well managed by local practice. When deciding on OAC, it should be discussed whether the risk of any major bleeding or specifically of ICH must be weighed.
Refinement of risk stratification for OAC application could be achieved by clear evidence on stroke and bleeding risk factors presently in doubt and by introducing imaging modalities, biomarkers or genetic markers that identify patients at high risk for stroke or bleeding. The aim should be to introduce into cardiology training one simple and easy-to-use risk stratification scheme, weighing both stroke and bleeding risks thereby improving the application of antithrombotic treatment. Also, since lack of facilities for adequate INR monitoring limits the application of OAC,20 release of an antithrombotic drug that does not require constant INR monitoring is expected to close the gap further between guidelines and practice.
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Rhythm control |
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TopAbstractDetection of atrial fibrillationRate controlManagement of associated...Stroke risk stratification and...Rhythm controlThe evidence base for...Final remarkAcknowledgementsReferences |
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The general belief used to be that restoring and maintaining normal sinus rhythm in AF improves prognosis compared with accepting AF and merely controlling the ventricular response rate. Nevertheless, several RCTs have shown that rhythm control was not superior to rate control regarding mortality and major adverse events.28 Based on an intention-to-treat analysis, it means that aiming at rhythm control is not more efficient than aiming at rate control. However, some patients spontaneously convert to sinus rhythm under rate control and many patients do not continuously maintain sinus rhythm or suffer from adverse effects under rhythm control. A subanalysis of the RACE study showed no improved outcome in patients who actually maintained long-term sinus rhythm under rhythm control compared with patients, who were constantly in AF under rate control.29 On the other hand, a subanalysis of the AFFIRM study suggested that rhythm control might have a better prognosis when sinus rhythm can safely be achieved.30 The lack of a difference between rhythm and rate control could be due to relatively ineffective current rhythm-control measures. Their efficacy seems to be offset by the potential to cause hazardous side effects. In this regard, we know that class I antiarrhythmics and sotalol have the potential to cause life threatening ventricular arrhythmias and HF, and amiodarone can cause severe extra-cardiac side effects. Electrical cardioversion is quite effective in restoring sinus rhythm. Serial shocks might be needed and pre-treatment with several antiarhythmic and non-antiarrhyhtmic drugs improves the success rate. However, in the months following cardioversion many patients have AF recurrence, partly due to the limited efficacy of antiarrhythmic drugs to maintain sinus rhythm. Although catheter ablation techniques are quickly advancing, they are still applied to a minority of AF patients as shown in the Euro Heart Survey.13 Anatomically guided ablation, complemented by electrophysiological guided ablation for troublesome cases, might make this technique applicable to a larger AF population, including those with advanced atrial remodelling, and also more accessible to a broader group of operators. Surgical techniques for AF such as the Cox–Maze procedure are only applied when another type of cardiac surgery is warranted in the patient, such as CABG or valve replacement. Currently, there is no convincing evidence that pacing algorithms for AF effectively treat AF and devices should only be implanted in AF patients with a conventional indication.31
In order to design better rhythm control measures, we need to further our electrophysiological knowledge of AF. Although improving quickly, we do not fully understand the mechanisms of AF onset, patterns, and progression in humans. The search for atrial specific targets will lead to new antiarrhythmic drugs that enhance rhythm-control efficacy by specifically targeting atria while maintaining safety by not interfering with the ventricles.
The 2006 guidelines recommend rhythm control only if the patient suffers from disabling symptoms, and acute cardioversion might be warranted (Figure 1).16 The Euro Heart Survey showed that a large portion of asymptomatic patients did receive rhythm control, but this was in 2003–200413 and it is likely that the application of rhythm control will decrease after the publication of the 2006 guidelines update.16 Nevertheless, more effective and safer rhythm control strategies than the current ones might lead in the future to the recommendation to aim for sinus rhythm restoration in all AF patients.
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The evidence base for atrial fibrillation management |
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TopAbstractDetection of atrial fibrillationRate controlManagement of associated...Stroke risk stratification and...Rhythm controlThe evidence base for...Final remarkAcknowledgementsReferences |
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We have summarized some ‘undecided issues’ and future expectations for the management of AF. We have to bear in mind that the evidence base for AF management is far from perfect and a constant critical appraisal of the evidence is necessary. Regarding the weight of evidence, we can see that the number of publications on AF, number of hits on the PubMed website when searching titles containing ‘atrial fibrillation’, has increased dramatically during the last 20 years to more than 1000 publications per year (Figure 3). One would expect that the evidence base for AF management is firm with this amount of research effort. However, when summarizing the 2006 guideline recommendations, it appears that the vast majority of all recommendations has level of evidence C and is solely supported by expert opinion, case studies, or standard-of-care (Figure 4). Few recommendations have level of evidence A and are supported by multiple randomized clinical trials or meta-analyses. These observations indicate that many AF management issues still need to be more firmly based. It is, therefore, surprising that the number of publications on RCTs for AF, the gold standard in clinical research, showed a downward tendency in the last 3 years from 93 to 58 publications. The difference between 2003 and 2006 was not attributable to less effort in specific areas of AF research since this decrease was observed in all areas. Since it is challenging to establish efficacy of new therapeutic strategies over and above already existing quite effective strategies, RCTs will require larger patient numbers which could explain the current lower number of trials. However, the proportion of trials enrolling >100 patients just slightly increased [41 (55%) in 2003 vs. 29 (69%) in 2006]. Considering the stable number of all publications on AF (Figure 3), a decreased number of RCT publications might indicate a shift from clinical towards basic research. Growing financial opportunities for basic research could explain this trend. Also, new concepts of treatment have not yet fully evolved and new targets for molecular or cellular AF therapy have only recently been defined. In addition, catheter ablation studies are difficult to perform in a controlled and randomized way since the effects of ablation and medical treatment are quite different.
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Separate guidelines exist for the management of associated conditions from those specific to AF management. In addition, multiple guidelines have been published on AF by several (inter)national societies with inconsistent recommendations for its management, partly due to the timing of publication and evolving evidence, but possibly also due to different groups with diverse beliefs.
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Final remark |
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TopAbstractDetection of atrial fibrillationRate controlManagement of associated...Stroke risk stratification and...Rhythm controlThe evidence base for...Final remarkAcknowledgementsReferences |
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AF is an obstinate and widespread arrhythmia with multiple presentations and potential for hazardous consequences. Management options are still far from optimal. A better understanding of the electrophysiological characteristics of AF, the atrial specific ion channel pathophysiology, the causal relation between AF and its associated diseases, and the factors that influence the risk of stroke and bleeding should lead to more effective diagnostic and interventional modalities that are safe to apply (Table 1). Translational researchers, clinical trialists, and epidemiologists should complement each other to fulfil the current needs in the management of AF and to monitor whether solutions for existing ‘undecided issues’ have been reached and whether new ones are developing.
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Acknowledgements |
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TopAbstractDetection of atrial fibrillationRate controlManagement of associated...Stroke risk stratification and...Rhythm controlThe evidence base for...Final remarkAcknowledgementsReferences |
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The authors acknowledge the institutions to which they are affiliated.
Conflict of interest: none declared.
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