Please login or register to print this page.


Han B Xiao, Consultant Cardiologist, Homerton Hospital, London

Clinical Articles

The AFFIRM trial: An updated commentary

The first in our series on Landmark Trials reviews the debate on rate control versus rhythm control in patients with atrial fibrillation (AF). This was addressed in the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) trial (1) which was published in 2002.

The trial enrolled patients who were at least 65 years old or had other risk factors for stroke or death. The trial investigators enrolled patients whose AF was believed likely to be recurrent, to cause illness or death, and for whom long-term AF treatment was warranted (and who did not have contra-indications to anticoagulation).

Patients were randomised to one of two approaches: “rhythm control” by means of cardioversion and antiarrhythmic drugs (possible benefits of this strategy would be fewer symptoms, better exercise tolerance, lower risk of stroke, discontinuation of anticoagulation and better survival); or to “rate control” with AV node blockers, radiofrequency ablation and pacemaker implantation, and anticoagulation (possible advantages of this strategy being simplification of therapy and use of less toxic drugs).

The primary end point was overall mortality, and the composite secondary end point was death, disabling stroke or anoxic encephalopathy, major bleeding and cardiac arrest.


The trial enrolled 4,060 patients; mean follow-up was 3.5 years, with a maximum of six years. The mean age at enrolment was 69.7 years, and just under 40% were female. Seventy-one percent had hypertension and 38% had coronary artery disease. Thirty-five percent were enrolled after their first episode of AF.

In the rate-control group, digoxin and a beta-blocker were used initially in roughly half the patients, and the calcium channel blocker diltiazem in roughly one third. Atrioventricular ablation was used in 5% of patients after drug failure, and 250 patients crossed over to the rhythm-control group during the course of the study. More than 85% of patients were taking warfarin at each assessment during the study.

In the rhythm-control group, more than two thirds of patients started treatment with amiodarone or sotalol. The prevalence of sinus rhythm was 82% at one year and 73% at three years. During the course of the study, nearly 600 patients crossed over to the rate-control group, chiefly because of inability to maintain sinus rhythm and drug intolerance. The overall proportion of patients receiving warfarin remained about 70%.

Death occurred in 310 patients (25.9%) in the rate-control group and 356 patients (26.7%) in the rhythm-control group (p=0.08). The rates of the composite secondary end point were also similar in the two groups (32.7% versus 32.0%, p=0.33).

The rates of ischaemic stroke were approximately 1% per year in both groups: most occurred in patients who had stopped taking warfarin or whose INR was subtherapeutic at the time. The number of patients needing hospitalisation during the follow-up period was greater in the rhythm-control group (1,374 [80.1%] versus 1,220 [73.0%], p<0.001). After adjustment for pre-specified covariates such as age, coronary artery disease and hypertension, the trend towards a higher risk of death in the rhythm-control group persisted (hazard ratio 1.18, p=0.07). The trend towards a difference in mortality did not emerge until the patients had been followed up for almost two years. Torsade de pointes or bradycardic arrest occurred more often in the rhythm-control group although proarrhythmia appeared to be unusual.

Thus, the AFFIRM study showed that, in this population of patients, restoration and maintenance of sinus rhythm had no clear advantage over controlling ventricular rate and allowing AF to persist. None of the presumed benefits of rhythm control were confirmed in this study.

Commentary: AFFIRM and beyond

The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) 1 was, and still is, the largest trial to compare mortality as an end point between the two therapeutic strategies: rate control and rhythm restoration.

The study concluded that rhythm restoration offered no survival advantage over rate control. Furthermore, it suggested that discontinuation of anticoagulation resulted in similar risk for stroke in rhythm control group as in rate control group. This study has encouraged clinicians to settle with the rate control strategy at an early stage in the treatment treating of atrial fibrillation. However, such an approach must be complemented by the following considerations.


AFFIRM recruited patients over the age of 65 years. Although the prevalence of atrial fibrillation increases markedly with advancing age, it is not uncommon to find atrial fibrillation in people younger than 65 years. Younger patients are often more symptomatic than their older counterparts. It would, therefore, be apparent that younger and symptomatic AF patients should be treated with best efforts of rhythm restoration. Although the survival advantage of rhythm control over rate control is uncertain in these patients, the disadvantage of long term anticoagulation must be lessened (. Indeed, AFFIRM indicated that rhythm restoration saved lives in those below 65 years.

Type of atrial fibrillation

It is well known that a longer duration of atrial fibrillation is associated with a lower success rate of rhythm restoration. It would therefore be reasonable to suggest that restoring rhythm in paroxysmal and intermittent atrial fibrillation can avoid or delay the development of chronic atrial fibrillation and result in a positive impact on these patients. The obvious benefit would be the diminished need for long term rate control and anticoagulation.


AFFIRM suggested that anticoagulation should be continued even when sinus rhythm appears to be restored and maintained. This was based on the assumed relation between stroke and atrial fibrillation or the history of atrial fibrillation. One needs to take note of the fact that over 50% of the patients in both groups in the AFFIRM trial had hypertension, which is an independent risk factor for stroke.

There are other related issues, for instance, some AF patients are not suitable candidates for anticoagulation. Understandably, these patients may have a reduced risk for stroke if they are successfully converted to sinus rhythm. Furthermore, anticoagulation is not widely available in some less developed countries or regions where rhythm restoration should be encouraged.

Co-existing cardiac pathology

Many co-existing cardiac conditions can affect the outcome of cardioversion in AF patients, and hence the choice of therapeutic strategy. In patients with dilated left atrium or right atrium, rate control is preferred to rhythm control as rhythm restoration is unlikely to be achieved. On the other hand, in patients with mitral valve disease, particularly mitral stenosis, correction of the valvular lesion should be the priority.

AFFIRM indicated that rhythm control had a survival advantage over rate control in patients with congestive heart failure. A more recent study, though conducted with a small sample size, has further suggested that rhythm restoration, as opposed to rate control, can improve quality of life in patients with both heart failure and atrial fibrillation 3. Rhythm restoration is therefore the preferred therapy in this group of patients.


Based on AFFIRM, a great number of patients with atrial fibrillation can be managed by rate control. However, an individually tailored therapeutic regime for each patient would be the most logical and effective approach to treating atrial fibrillation generally. Such an approach will maximize the therapeutic benefit to patients with the individual clinician’s expertise.


  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: 1825-33.
  2. Peter Zimetbaum and Mark E. Josephson. Is There a Role for Maintaining Sinus Rhythm in Patients with Atrial Fibrillation? Ann Intern Med 2004; 141:720-26.
  3. Shelton RJ, Clark AL, Goode K, Rigby AS, Houghton T, Kaye GC, Cleland JGF. A randomised, controlled study of rate versus rhythm control in patients with chronic atrial fibrillation and heart failure: (CAFÉ-II Study). Heart 2009; 95: 924-930.

Published on: June 7, 2009

Members Area

Log in or Register now.



Subscribe to our RSS feed


Sign up for our regular email newsletters & be the first to know about fresh articles and site updates.


    None Found


  • ArrhythmiaAlliance
  • Stars
  • Anticoagulation Europe
  • Atrial Fibrillation Association

You are not logged in

You need to be a member to print this page.
Sign up for free membership, or log in.

You are not logged in

You need to be a member to download PDF's.
Sign up for free membership, or log in.