Overview of the AFFIRM Study John P. DiMarco, M.D., Ph.D.

Atrial Fibrillation (AF) The most common significant heart rhythm disturbance Incidence increases with age and the development of structural heart disease Common cause of stroke (10-15% of all strokes) Associated with significant cardiovascular morbidity and mortality Tends to recur in at least half the patients treated with antiarrhythmic drug therapy

AF Treatment – Possible Objectives Control the ventricular rate Restore/maintain sinus rhythm Prevent embolic complications

Rate Control – Potential Advantages Avoid potential proarrhythmic effects of antiarrhythmic drug therapy Avoid other adverse effects of antiarrhythmic drugs Avoid frequent recurrence of AF due to drug inefficacy Decrease compliance problems Lower cost of treatment

Maintaining Sinus Rhythm – Potential Advantages Better rate control Atrial contribution to cardiac output maintained Better exercise tolerance Possibility of reduced thromboembolic risk

AFFIRM Trial Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Sponsored by National Heart, Lung, and Blood Institute of the National Institutes of Health Randomized evaluation of treatment of AF by 1 of 2 strategies (rate control versus rhythm control and anticoagulation) Total of 4,160 patients followed for an average of 2.6 years

AFFIRM Objectives Primary Endpoint Total mortality in rate control versus rhythm control Secondary Endpoints Composite endpoints of total mortality, disabling stroke and disabling anoxic encephalopathy Functional status, quality of life and cost effectiveness continued

AFFIRM Objectives (continued) Other Descriptive Endpoints Bleeding complications, mode of death, type of stroke, systemic emboli, new or worsening CHF, syncope, resuscitated cardiac arrest, sustained ventricular tachycardia, torsades de pointes, crossovers and discontinuation of therapy

AFFIRM Inclusion Criteria One or more episodes of AF of at least 6 hours duration is documented on an ECG or rhythm strip within the last 6 weeks Patient is < 65 years old with at least one clinical risk factor for stroke including: Systemic hypertension Large left atrium (> 50 mm) Diabetes mellitus Fractional shortening (< 25%) CHF TIA Left ventricular ejection fraction (< 0.40) Prior cerebral vascular accident continued

AFFIRM Inclusion Criteria (continued) The duration of episodes of AF in the last 6 months must total > 6 hours (unless pharmacologic cardioversion was performed before 6 hours). Duration of continuous AF must be < 6 months (unless sinus rhythm can be restored and maintained > 24 hours). Patient must be eligible for both treatment strategies. Patient must be eligible for > 2 antiarrhythmic drugs and > 2 rate-controlling drugs.

AFFIRM Baseline Tests The clinical assessment and laboratory evaluation of the patient will be completed before randomization. Clinical assessment will include quantification of duration and frequency of AF and a judgment concerning the most likely cause. Comprehensive history and physical examination will be completed on patient. continued

AFFIRM Baseline Tests (continued) Specified cardiac tests and metabolic studies will be performed as clinically indicated including, but not limited to: electrocardiography chest X-ray thyroid function tests electrolytes complete blood count echocardiography

Sinus Rhythm Group Step I – Pharmacologic Therapies Class 1 and Class 3 antiarrhythmic drugs are used, as well as combinations. Drugs are chosen by the primary treating physician from amiodarone, sotalol, propafenone, flecainide, quinidine, moricizine, disopyramide, procainamide and combinations of these drugs. AV nodal blocking drugs may also be administered when indicated. continued

Sinus Rhythm Group Step I – Pharmacologic Therapies (continued) A major sub-study for AFFIRM randomizes initial drug choice among amiodarone, sotalol and Class I drugs. Anticoagulation around the time of cardioversion or recurrence as per current guidelines. Chronic anticoagulation may be used at the physician’s discretion. Prior drugs that were ineffective or poorly tolerated will not be repeated. continued

Sinus Rhythm Group Step I – Pharmacologic Therapies (continued) There are various drug exclusions depending on the patient's condition. Patients in the maintenance of sinus rhythm group can have multiple cardioversions as needed. If there is treatment failure or intolerance after two or more pharmacologic trials, patients may be considered for innovative therapy.

Sinus Rhythm Group The following innovative Step II therapies are approved for use in the study: Right atrial ablation in patients with type I atrial flutter, if it is clinically documented that the atrial flutter leads to AF Atrial pacing alone, with or without documented bradycardia Atrial pacing and antiarrhythmic drugs, with either single site or multiple site atrial pacing Surgical maze or atrial isolation procedures at selected centers continued

Sinus Rhythm Group Step II – Innovative Therapies (continued) Catheter-based linear left atrial ablative procedures are not approved in this study. Implanted atrial cardioverter defibrillators are not approved. All therapy is periodically reviewed and subject to modification by the Steering Committee with concurrence by the DSMB and the NHLBI. If sinus rhythm is not maintainable by any treatment, patients may cross over to rate control and anticoagulation.

Rate Control Group Step I – Pharmacologic Therapies Drugs approved for use include beta blockers, verapamil, diltiazem, digoxin or combinations of these. Heart rate is the therapeutic target, rather than dose of medications. Drug dosage is adjusted to achieve target heart rates. During AF, heart rate is assessed both at rest and during activity at each clinic visit. All patients are anticoagulated. Step II innovative therapies are considered after failure or intolerance of two or more pharmacologic trials.

Rate Control Group Step II – Innovative Therapies The two innovative therapies approved for use with the heart rate control arm are: AV node modification by catheter ablation, with or without placement of a pacemaker, with or without continued drugs to slow AV node conduction Total AV junctional ablation and placement of a pacemaker

Review of Similar Trials Other trials have been conducted on rate versus rhythm control. These include: PIAF – Pharmacological Intervention in Atrial Fibrillation STAF – Strategies of Treatment of Atrial Fibrillation (Pilot Phase) Results of these trials are summarized in the following slides.

PIAF – A Randomized Trial J W Goethe University, Frankfurt, Germany (S H Hohnloser MD); St George's Hospital, Hamburg (K H Kuck MD); and Datamap, Freiburg (J Lilienthal PhD), Lancet 2000;356:1789-94. 252 patients with AF of between 7 days and 360 days duration Compared rate control (125 patients) with rhythm control (127 patients) Rate control – diltiazem was used as first-line therapy Rhythm control – amiodarone was used as first-line therapy

PIAF – Findings The primary study endpoint was improvement in symptoms related to AF. Over the entire observation period of 1 year, a similar proportion of patients reported improvement in symptoms in both groups (76 responders at 12 months with rate control vs. 70 responders with rhythm control, p=0.317). Amiodarone administration resulted in pharmacological restoration of sinus rhythm in 23% of patients. Walking distance in a 6 min. walk test was better with rhythm control compared with rate control. continued

PIAF – Findings (continued) Assessment of quality of life showed no differences between groups. Incidence of hospital admission was higher with rhythm control (87 [69%] out of 127 vs. 30 [24%] out of 125 with rate control, p=0.001). Adverse drug effects more frequently led to a change in therapy with rhythm control (31 [25%] patients compared with 17 [14%] with rate control, p=0.036).

PIAF – Interpretation When measuring symptomatic improvement, rate control and rhythm control produced similar overall clinical results. Patients in the rhythm control group exhibited better exercise tolerance. Patients in the rhythm control group were admitted to the hospital more frequently.

STAF – A Randomized Trial Joerg Carlsson, MD, Klinkum Lippe-Detmold, Detmold, Germany. J Am Coll Cardiol 2001;38:603a. 2000-patient study powered at 80% to detect a reduction in the incidence of the combined primary endpoint from 15% to 10% in a 2-year follow-up period. 200-patient pilot study was performed, assigning 100 patients to each strategy and following them for 1 year. The primary study endpoint was composite of death, cerebrovascular event, cardiopulmonary resuscitation and systemic embolism. continued

STAF – A Randomized Trial (continued) Secondary endpoints were echocardiographic parameters (left ventricular [LV] dimensions and function, atrial size), hospital admissions, syncope, quality of life, bleeding complications and deterioration of heart failure. Inclusion criteria: AF for at least 4 weeks Left atrial enlargement (> 45 mm) CHF (at least NYHA Class II) LV dysfunction (ejection fraction [EF] < 45%) Prior cardioversions with recurrence of AF continued

STAF – A Randomized Trial (continued) Exclusion criteria: Longstanding AF ("permanent" AF), defined as lasting more than 2 years Severe left atrial dilatation (> 70 mm) Severe LV dysfunction (EF < 20%) Wolff-Parkinson-White syndrome Prior AV nodal modification or ablation Contraindication to anticoagulation Recent successful cardioversion (within 4 months) Paroxysmal AF continued

STAF – A Randomized Trial (continued) Rhythm control was achieved with cardioversion (external or internal) after adequate anticoagulation before and after the cardioversion (approximately 4 weeks each). Prophylaxis was given in the form of a Class I agent (if LV function was normal) or amiodarone (if LV function was abnormal). Rate control was performed using long-term anticoagulation and either pharmacologic therapy (digoxin, beta-blockers) or AV nodal ablation/modification. continued

STAF – A Randomized Trial (continued) Patient characteristics were fairly well balanced in the 2 arms. Mean age was in the mid-60s. For almost half of the patients, the index AF was their first event. Patients in the rate control arm were more likely to be symptomatic at baseline and had lower EF. Hypertension was the most prevalent underlying condition predisposing to AF.

STAF – Findings of Pilot Study No statistically significant difference in the primary endpoint between the rhythm control (5.5%) and rate control (6.1%) arms, nor in the secondary endpoints. Patients treated with the rhythm control strategy were hospitalized significantly more often (p < .001), usually because they required repeat cardioversions and initiation of anticoagulation. Quality of life assessments did not show any differences. continued

STAF – Findings of Pilot Study (continued) Sinus rhythm at follow-up was fairly low in the rhythm control group; only 23% were in sinus rhythm at 3-year follow-up despite undergoing up to 4 cardioversions and receiving multiple antiarrhythmic drugs. Analysis of the primary endpoint was also performed according to presence of sinus rhythm at follow-up. Only 1 of the 47 patients in sinus rhythm at follow-up had a primary event, as opposed to 18 of 163 not in sinus rhythm (p = .049).

STAF – Interpretation of Pilot Study No difference was seen between the rate and rhythm control arms with regard to the composite endpoint, secondary endpoints or quality of life assessments. Significantly more hospitalizations occurred in the rhythm control arm, due to the need for repeat cardioversions and initiation of anticoagulation. Apparently there is an advantage to being in sinus rhythm, as evidenced by the fact that only 1 event occurred in patients in sinus rhythm at follow-up.  continued

STAF – Interpretation of Pilot Study (continued) Maintaining a patient in sinus rhythm is difficult even when cardioversions and antiarrhythmic drugs are administered. This limits any potential advantages that may be associated with maintaining sinus rhythm. Although patients in whom sinus rhythm could be maintained did well, in the entire rhythm control group, the effort to do this resulted in increased hospitalizations and more bleeding complications, possibly related to repeated initiation of anticoagulation (as opposed to sustained treatment). continued

STAF – Interpretation of Pilot Study (continued) There may have been fewer hospitalizations if patients in the rhythm control arm had received permanent anticoagulation therapy, which may help to prevent stroke. This is only a pilot study, and data from the larger trial are needed to draw firm conclusions. These data do not apply to patients with long-standing ("chronic") AF who were excluded from this trial.