Overview of the AFFIRM Study

1
Overview of the AFFIRM Study John P. DiMarco,
M.D., Ph.D.
2
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

3
AF Treatment Possible Objectives

• Control the ventricular rate
• Restore/maintain sinus rhythm
• Prevent embolic complications

4
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

5
Maintaining Sinus Rhythm Potential Advantages

• Better rate control
• Atrial contribution to cardiac output maintained
• Better exercise tolerance
• Possibility of reduced thromboembolic risk

6
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

7
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
8
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

9
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 lt 65 years old with at least one
  clinical risk factor for stroke including

continued
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AFFIRM Inclusion Criteria (continued)

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

11
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
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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

13
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
14
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 physicians
  discretion.
• Prior drugs that were ineffective or poorly
  tolerated will not be repeated.

continued
15
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.

16
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
17
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.

18
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.

19
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

20
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.

21
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 20003561789-94.
• 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

22
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, p0.317).
• 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
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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, p0.001).
• Adverse drug effects more frequently led to a
  change in therapy with rhythm control (31 25
  patients compared with 17 14 with rate
  control, p0.036).

24
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.

25
STAF A Randomized Trial

• Joerg Carlsson, MD, Klinkum Lippe-Detmold,
  Detmold, Germany. J Am Coll Cardiol 200138603a.
  
• 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
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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 (gt 45 mm)
• CHF (at least NYHA Class II)
• LV dysfunction (ejection fraction EF lt 45)
• Prior cardioversions with recurrence of AF

continued
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STAF A Randomized Trial (continued)

• Exclusion criteria
• Longstanding AF ("permanent" AF), defined as
  lasting more than 2 years
• Severe left atrial dilatation (gt 70 mm)
• Severe LV dysfunction (EF lt 20)
• Wolff-Parkinson-White syndrome
• Prior AV nodal modification or ablation
• Contraindication to anticoagulation
• Recent successful cardioversion (within 4 months)
• Paroxysmal AF

continued
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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
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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.

30
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 lt
  .001), usually because they required repeat
  cardioversions and initiation of anticoagulation.
• Quality of life assessments did not show any
  differences.

continued
31
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).

32
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
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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
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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.