Atrial Fibrillation in the Post-AFFIRM Era

Acknowledgements:This article was funded in part by the Adolph and Rose Levis Foundation, Haverford, PA.

Copyright Statement:

The copyright in this work belongs to Radcliffe Medical Media. Only articles clearly marked with the CC BY-NC logo are published with the Creative Commons by Attribution Licence. The CC BY-NC option was not available for Radcliffe journals before 1 January 2019. Articles marked ‘Open Access’ but not marked ‘CC BY-NC’ are made freely accessible at the time of publication but are subject to standard copyright law regarding reproduction and distribution. Permission is required for reuse of this content.

Atrial fibrillation (AF) is the most common arrhythmia encountered in clinical practice, with a prevalence that substantially increases with age. Both the loss of atrial mechanical function and a rapid, irregular ventricular response contribute to potentially significant symptoms, including palpitations, fatigue, chest discomfort, light headedness or syncope. Additionally, AF is associated with a significant risk of systemic embolisation, with annual stroke risk exceeding 5% in high-risk populations. The impact these symptoms can have on patients' quality of life and the associated risk of stroke often leads to a desire to terminate the AF and maintain normal sinus rhythm. However, several studies, the largest of which is the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study, have failed to confirm the anticipated benefits of a rhythm-control strategy, a clinical dilemma that will be discussed further in this review.

Rate Control versus Rhythm Control

To date, five randomised trials have been published addressing the clinical benefit of a strategy of active rhythm management versus rate control and anticoagulation, all demonstrating similar results. The largest of these trials, the AFFIRM trial, enrolled over 4,000 patients with paroxysmal and persistent AF.1 Patients at least 65 years of age or with other risk factors for stroke were randomised either to a strategy of rate control with digoxin, beta-blocker, or calcium channel blocker, or anti-arrhythmic drug therapy with the most effective drug. All patients were initially anticoagulated, but those in the rhythm-control strategy thought to have maintained sinus rhythm for at least three months could stop warfarin. At baseline, 51% of patients had hypertension and 26% had coronary artery disease (CAD), while 12% had no history of any cardiovascular disease. Follow-up data (mean 3.5 years) demonstrated no significant difference in the primary end-point of overall mortality, with a trend towards increased risk in the rhythm-control group (five-year mortality 24% versus 21%). There was also a non-significant trend towards a higher risk of ischaemic stroke in the rhythm-control group, with the majority of strokes occurring in patients receiving no or sub-optimal anticoagulation. Presumably, this trend was on the basis of asymptomatic recurrence of AF, emphasising the importance of maintaining anticoagulation indefinitely in high-risk patients, regardless of strategy selected. This lack of demonstrated benefit to a therapeutic strategy that intuitively should be advantageous has led to significant confusion and controversy surrounding this subject.

Limitations of Available Data

Critical review of the AFFIRM trial and similar studies can reveal certain aspects of the patient populations that may help resolve this confusion. The mean age of patients in AFFIRM was 70 years old, with most patients having some other cardiovascular disease (i.e. hypertension CAD). This population of patients is known to have increased risk of proarrhythmia from currently available anti-arrhythmic drugs. It is therefore unclear whether younger, healthier patients may in fact benefit from an aggressive rhythm-control strategy. Providers should be cautious in applying the AFFIRM conclusions to this under-represented population. Additionally, approximately half the patients in AFFIRM had episodes occurring less frequently than once per month. The magnitude of symptomatic benefit of a rhythm control approach in this population, therefore would be expected to differ from a population having more frequent or persistent episodes. While there was no significant difference in global functional status or quality of life in the initial report, a subsequent substudy demonstrated better performance in a six-minute walk test (6MWT) in the rhythm control group.2 Patients assigned to rhythm control walked approximately 100 feet further than those assigned to rate control, a magnitude of benefit similar to trials of cardiac resynchronisation.

Patient Selection

Given the controversy surrounding the previously described data, an individualised approach to selection of a therapeutic strategy is imperative. For most patients, a default plan of rate control and anticoagulation is probably appropriate. Patients older than 65 years with other cardiovascular disease, the population studied, are in fact the group with the highest prevalence of AF. Considering the generally equivalent outcomes in the AFFIRM trial, the known pro-arrhythmic risk of anti-arrhythmic drugs, and the efficacy of a rhythm-control approach often only being fair, this conservative strategy seems reasonable. Recurrence rates of AF on anti-arrhythmic drugs at one year are variable but range from 20% to 60% depending on drug studied and baseline patient characteristics.3 Adequate rate control with pharmacologic therapy, however, is not always easy to achieve, frequently requiring multiple drugs, and occasionally necessitating atrioventricular (AV) nodal ablation and pacemaker implantation.

Despite the large sample size and randomised design of the AFFIRM study, clinical situations may arise in which the trial is not applicable. In these situations, serious consideration of adopting a rhythm-control approach is warranted. Probably the most important exception to the default rate-control approach is the patient with significant symptoms in AF. For reasons unknown, many patients have significant symptoms, such as palpitations, fatigue, dyspnoea, and light-headedness, that are directly related to the presence of AF. In these patients, an attempt at rhythm control is appropriate. Additionally, in patients who are proving difficult to rate-control with standard medical therapy, a rhythm-control approach should be considered.

A third clinical situation in which to consider rhythm management is a young patient (i.e. <60 years old) with no concomitant cardiovascular disease. This patient was under-represented, if not excluded, in most trials. Animal models have clearly demonstrated remodeling of the atria with prolonged, persistent AF, and the concept 'AF begets AF' is now widely accepted. Once a strategy of accepting chronic AF with rate control and anticoagulation has been adopted, it is likely to be difficult in the future to revert to a rhythm-control approach. Because of this, a strategy of active rhythm management may be most appropriate for this subset of patients, although this has yet to be shown definitively. Similarly, a first episode of AF in a patient with no structural heart disease (SHD) or hypertension warrants cardioversion initially, with anti-arrhythmic drugs or a rate-control approach being considered for recurrence.

Pharmacologic versus Non-pharmacologic Rhythm Management

Once a rhythm-management strategy has been chosen, both pharmacologic and non-pharmacologic options may be considered. For pharmacologic therapy, selection of the most appropriate agent is of utmost importance. For example, while amiodarone has the highest efficacy, with one-year success rates of greater than 75%, it is also the agent with the most toxicity and many drug interactions. Class IC agents such as flecainide and propafenone, while better tolerated and less toxic, have significantly lower success rates. Additionally, there is a significant risk of pro-arrhythmia in the presence of SHD or ischoemia. Class III agents such as sotalol or dofetilide can be effective medications, but have a significant risk of torsades de pointes, particularly in the setting of impaired renal function or the presence of other QT prolonging drugs. While a detailed discussion of anti-arrhythmic drug selection is beyond the scope of this review, careful consideration of all aspects of a given clinical scenario is warranted.

The limited efficacy and risk of pro-arrhythmia associated with all anti-arrhythmic drugs lead to the development of invasive options in the management of AF. Catheter ablation techniques have evolved from the early surgical Maze procedure and have proven effective in the management of AF. The techniques evolved with the demonstration that most AF is initiated by ectopic beats from focal areas that may be targeted for ablation. Although foci have been demonstrated in many structures throughout the heart, most ectopic beats arise from the four pulmonary veins. As a result, techniques for elimination or isolation of these foci have been described and over the past decade have become a therapeutic option. As with most invasive procedures, success rates and complication rates vary with operator experience and institutional volume. In addition, patient selection for studies and definitions of 'success' vary throughout the literature making comparisons difficult. However, it is generally accepted that success rates range from about 70% to 85% for paroxysmal patients, and 60% to 75% for patients with persistent or chronic AF.4 The risk of major complications, including cardiac perforation, tamponade, stroke and death, ranges from 1% to 6%. Additionally, pulmonary vein stenosis has been described in some series in up to 15% of patients, with clinically significant stenosis however only occurring in about 1-3% of patients.5 Newer techniques of focusing ablation lesions on the atrial aspect of pulmonary vein ostia have reduced this incidence further. While the ideal candidate for catheter ablation of AF is subject to debate, most agree that a patient with paroxysmal AF associated with significant symptoms, who has failed at least one anti-arrhythmic agent, should be considered.

With two very different options for active rhythm management available, anti-arrhythmic drug therapy and radiofrequency ablation, a comparison of safety and efficacy of the two approaches is warranted. While comparison is difficult due to heterogeneous patient populations, non-randomised data and varying outcome measures, some information is available in the form of a large observational study6 and two smaller randomised trials.7,8 The first study included 1,171 consecutive patients treated with either ablation or medical therapy at the physicians' discretion (589 and 582 patients, respectively). This study demonstrated significantly less AF recurrence, fewer deaths, fewer episodes of heart failure and fewer strokes in the ablation group, with improvement in quality of life scores. Similar findings favouring ablation were demonstrated in a smaller randomised trial of 70 patients with newly diagnosed, symptomatic AF,7 and a trial of 137 patients with persistent or paroxysmal AF.8 Definitive conclusions regarding this issue will be possible only with the completion of properly designed and powered randomised clinical trials.


With the increasing prevalence of AF in the ageing population, understanding therapeutic options in the management of this arrhythmia is of increasing importance. In the post-AFFIRM era, the decision between rate control versus rhythm control has become complex and must be individualised. The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines for management of AF have been revised to include the importance of considering patient symptoms before assuming a rhythm-control approach.9 In addition, the role of catheter ablation in AF management has been emphasised. In the presence of significant symptoms from AF, particularly symptoms that persist when the ventricular response has been controlled, an attempt at a rhythm-control strategy is warranted. Most agree that a trial of antiarrhythmic drug therapy should be attempted prior to referral for catheter ablation. For older patients with SHD or other co-morbidities, particularly those with asymptomatic AF, the data from the AFFIRM trial are applicable. In this population, given the risks of anti-arrhythmic drugs and need for long-term anticoagulation, a strategy of rate control is appropriate. Regardless of the therapy planned for a given patient, adequate anticoagulation for reduction of embolic risk in patients with AF is the most important aspect of management.


  1. The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators, A comparison of rate control and rhythm control in patients with atrial fibrillation , N Engl J Med (2002);347: pp. 1825-1833.
    Crossref | PubMed
  2. Chung MK et al., Functional status in rate- versus rhythm-control strategies for atrial fibrillation: results of the AFFIRM Functional Status Substudy , J Am Coll Cardiol (2005);46(10): pp. 1891-1899.
    Crossref | PubMed
  3. Roy D et al., Amiodarone to prevent recurrence of atrial fibrillation. Canadian Trial of Atrial Fibrillation Investigators , N Engl J Med (2000);342: pp. 913-920.
    Crossref | PubMed
  4. Cappato R et al., Worldwide Survey on the Methods, Efficacy, and Safety of Catheter Ablation for Human Atrial Fibrillation , Circulation (2005);111: pp. 1100-1105.
    Crossref | PubMed
  5. Saad EB et al., Pulmonary vein stenosis after radiofrequency ablation of atrial fibrillation: functional characterisation, evolution, and influence of the ablation strategy , Circulation (2003);108(25): pp. 3102-3107.
    Crossref | PubMed
  6. Pappone C et al., Mortality, morbidity, and quality of life after circumferential pulmonary vein ablation for atrial fibrillation: outcomes from a controlled nonrandomised long-term study , J Am Coll Cardiol (2003);42(2): pp. 185-197.
    Crossref | PubMed
  7. Wazni OM et al., Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomised trial , JAMA (2005);293(21): pp. 2634-2640.
    Crossref | PubMed
  8. Stabile G et al., Catheter ablation treatment in patients with drug-refractory atrial fibrillation: a prospective, multicenter, randomised, controlled study (Catheter Ablation For The Cure Of Atrial Fibrillation Study) , Eur Heart J (2006);27(2): pp. 216-221.
    Crossref | PubMed
  9. Fuster V et al., ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines , J Am Coll Cardiol (2006);48: pp. e149-e246.