Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM)
Condition: Arrhythmia; Atrial Fibrillation; Cardiovascular Diseases; Heart Diseases
MeSH terms: Atrial Fibrillation; Cardiovascular Diseases; Heart Diseases
Study type: Interventional
Phase: Phase 3

Summary: 
      To compare two standard treatment strategies for atrial fibrillation: ventricular rate
      control and anticoagulation vs. rhythm control and anticoagulation.
    

Detailed description: 
      BACKGROUND:

      Atrial fibrillation is an extremely common and increasingly prevalent cardiac arrhythmia,
      particularly in the elderly, and is an important risk factor for stroke. Management of atrial
      fibrillation remains controversial, and although antiarrhythmic drugs are widely used for
      this condition, clinical studies to support their use are meager. Management of atrial
      fibrillation has at least three components: restoration and maintenance of sinus rhythm;
      heart rate control when maintenance of sinus rhythm or when cardioversion is not attempted or
      impossible; and anticoagulation. The first component of management uses antiarrhythmic drugs
      and the second uses a different group of antiarrhythmic drugs and catheter ablation. The
      third is anticoagulant therapy for patients in whom normal sinus rhythm cannot be maintained
      or in whom cardioversion is not attempted.

      The initiative was developed by staff of the Clinical Trials Branch and the NHLBI Working
      Group on Atrial Fibrillation which met in Bethesda in April, 1993. The initiative was given
      concept clearance by the February 1994 National Heart, Lung, and Blood Advisory Council. The
      Request for Proposals was released in May 1994.

      DESIGN NARRATIVE:

      A randomized multicenter trial. The trial enrolled only patients with atrial fibrillation who
      were at high risk for stroke, that is, over 65 years of age or less than 65 and with one or
      more other risk factors for stroke such as systemic hypertension, diabetes mellitus,
      congestive heart failure, transient ischemic attack, prior cerebral vascular accident. High
      risk patients were treated with the anticoagulant warfarin. Cardioversion (electrical or
      pharmacologic) might have been attempted before randomization, but if it was unsuccessful,
      the patient was excluded from further consideration for randomization. Normal sinus rhythm
      must have persisted for one hour or greater after cardioversion to qualify as successful
      cardioversion. Patients were randomly assigned to treatment groups which included maintenance
      of sinus rhythm or heart rate control. Both treatment groups had two steps.

      In the maintenance of sinus rhythm group, the choice of drugs was left to the primary
      treating physician, to be chosen from amiodarone, sotalol, propafenone, flecainide,
      quinidine, moricizine, disopyramide, procainamide, and combinations of these drugs.
      Atrioventricular nodal blocking drugs were also administered unless contraindicated. The
      major substudy for AFFIRM randomized initial drug choice among amiodarone, sotalol, and class
      I drugs. Prior drugs which were ineffective or poorly tolerated were not repeated. There were
      various drug exclusions depending on the patient's condition. Patients in the maintenance of
      sinus rhythm group had multiple cardioversions as needed. If there was treatment failure or
      intolerance after two or more pharmacologic trials, patients were considered for innovative
      therapy in Step II. In Step II, two maintenance doses of amiodarone were included, a low dose
      of 100 to 200 mg/day and a normal dose of 300 to 400 mg/day. Each dose of amiodarone was
      considered to be a single drug trial, so that patients who received treatment with amiodarone
      at both dosage levels were considered to have had two drug trials. It was not mandatory that
      Step II therapies be applied in any individual patient. The following innovative Step II
      therapies were approved for use in the study: (1) ablation of an atrial focus in patients
      with type I atrial flutter, if it was clinically documented that the atrial flutter led to
      atrial fibrillation; (2) atrial pacing alone, with or without documented bradycardia; (3)
      atrial pacing and antiarrhythmic drugs, with either single site or multiple site atrial
      pacing; and (4) surgical maze or atrial isolation procedures at selected centers.
      Catheter-based ablative procedures, such as those attempting to mimic the maze procedure were
      not approved in this study. Implanted atrial cardioverter defibrillators were also not
      approved. All therapy was periodically reviewed and subject to modification by the Steering
      Committee with concurrence by the DSMB and the NHLBI. In the event that sinus rhythm was not
      maintainable by any treatment, patients crossed over to rate control and anticoagulation.

      The heart rate control arm used heart rate as the therapeutic target, rather than dose of
      medications. Drug dosage was adjusted to achieve target heart rates. During atrial
      fibrillation, heart rate was assessed both at rest and during activity at each clinic visit.
      The pharmacologic therapies approved for use in this arm included: beta blockers, verapamil,
      diltiazem, digoxin, or combinations of these drugs . When Step I pharmacologic therapies
      failed after two or more drug trials, the treating physician could select an approved Step II
      innovative therapy. The two innovative therapies approved for use with the heart rate control
      arm were: (1) atrioventricular node modification by catheter ablation, with or without
      placement of a pacemaker, with or without continued drugs to slow atrioventricular node
      conduction, and (2) total atrioventricular junctional ablation and placement of a pacemaker.

      The primary endpoint by which the two strategies were compared was total mortality, analyzed
      by intention-to-treat. Secondary endpoints were composite end points (total mortality,
      disabling intracranial bleed, stroke, disabling anoxic encephalopathy, cardiac arrest, major
      noncentral nervous system bleed, cost of therapy, and quality of life. Follow-up was a
      minimum of two years and an average of 3.5 years. Recruitment and intervention extended from
      November 1995 through October 1999 with 4,060 patients enrolled by 213 sites.
    

Intervention name(s): amiodarone; sotalol; propafenone; flecainide; quinidine; moricizine; disopyramide; procainamide; adrenergic beta antagonists; verapamil; diltiazem; digoxin; catheter ablation; pacemaker, artificial
Intervention type(s): Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Drug; Procedure; Device
Intervention MeSH terms: Quinidine; Digoxin; Amiodarone; Verapamil; Flecainide; Sotalol; Propafenone; Procainamide; Moricizine; Disopyramide; Diltiazem; Adrenergic beta-Antagonists; Adrenergic Agents
Allocation: Randomized
Primary purpose: Treatment