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AFFIRM
The EP Show:
AFFIRM
Eric Prystowsky MD
Director, Clinical Electrophysiology Laboratory
St Vincent Hospital
The Care Group (private clinic)
Indianapolis, IN
D George Wyse MD, PhD
Professor of Medicine
Department of Pharmacology and Therapeutics
University of Calgary
Calgary, AB
EP Show – December 2002
AFFIRM
AFFIRM
Atrial
Fibrillation
Follow-up
Investigation of
Rhythm
Management
EP Show – December 2002
AFFIRM
Historical perspective
Roots go back a decade
AFFIRM based on 3 points
•Antiarrhythmic drugs have not been very
effective
•Side effects of these drugs can be deadly
CAST (NEJM 1991;324:781-788)
•Effectiveness of oral anticoagulation
protection against stroke
Wyse
EP Show – December 2002
AFFIRM
Rate or rhythm
Do we really need to restore and maintain
sinus rhythm, or can we simply maintain
heart rate control?
•There has been a strong bias favoring
rhythm control for the past decade
•Is one really better than the other, and
how do you measure that?
Wyse
EP Show – December 2002
AFFIRM
Enrollment
Patients were enrolled from November
1995 – October 1999
Patients were followed until October 2001
213 sites in the US and Canada
7400 patients screened
4060 patients randomized
EP Show – December 2002
AFFIRM
Inclusion criteria
We wanted to focus on the elderly
• >65 years of age
• Patients where the atrial fibrillation
itself was a risk for morbidity or
mortality
• Able to tolerate at least 2 drug
regimens in both treatment arms
EP Show – December 2002
AFFIRM
Inclusion criteria
We wanted to focus patients at serious risk
• Patients had to have at least 6 hours
of atrial fibrillation
• Patients had to have a high likelihood
of recurrent atrial fibrillation
• Presence of stroke risk factors
(age >65, diabetes, hypertension, heart
failure, or structural heart disease)
EP Show – December 2002
AFFIRM
Treatment strategies
Patients were randomized to a strategy, not
a specific drug regimen
• Pharmacological therapies: allowed
any drug approved by North American
regulatory authorities. Drugs could be
added if they were approved during the
trial
• Nonpharmacological therapies:
allowed designated therapies once a
patient failed 2 drug therapies
EP Show – December 2002
AFFIRM
Rhythm-control drugs
Drug used in rhythmcontrol group
Initiation of
therapy
Used at anytime
Amiodarone
37.5%
62.8%
Sotalol
31.2%
41.4%
EP Show – December 2002
N Engl J Med 2002;347:1825-33.
AFFIRM
Rhythm drug substudy
Amiodarone
Sotalol
Class I antiarrhythmic
Survival at 1 year
(%)
70
60
50
40
30
20
10
0
Amiodarone
vs Class I
Amiodarone
vs Sotalol
Sotalol vs
Class I
Presented at the 23rd Annual Scientific Sessions of the North
American Society of Pacing and Electrophysiology
EP Show – December 2002
AFFIRM
Drug restrictions
Guidelines for dosing and safety existed for
the drugs
• Class IC antiarrhythmic drugs not
allowed in patients with known coronary
heart disease and previous MI
• Sotalol was not allowed in patients
with a history of torsades de pointes or
bronchospastic asthma
Wyse
EP Show – December 2002
AFFIRM
Less-used drugs
Drug used in rhythmcontrol group
Propafenone
Dofetilide
Initiation of
therapy (%)
9.3
Used at anytime
(%)
14.5
0
0.6
Procainamide
5.3
8.5
Quinidine
4.7
7.4
Disopyramide
2.1
4.3
EP Show – December 2002
N Engl J Med 2002;347:1825-33.
AFFIRM
Exclusion criteria
Minimal restrictions on patients
• Had to be able to take anticoagulation
• Had to be able to tolerate at least 2
drug regimens in both treatment arms
• Low-dose and high-dose
amiodarone counted as separate
therapies
• 17.6% of patients had failed a
previous antiarrhythmic drug
EP Show – December 2002
AFFIRM
Mortality as endpoint
Mortality wouldn't be the first choice of end
point in an atrial fibrillation trial for some
people
•There are data suggesting atrial
fibrillation is an independent risk factor
for increased mortality
•An unblinded trial demands an
unambiguous end point. Mortality is
unambiguous
Wyse
EP Show – December 2002
AFFIRM
Mortality results
Cumulative mortality
(%)
Rhythm control
Rate control
25
20
15
10
5
0
Year 1
EP Show – December 2002
Year 2
Year 3
Year 4
Year 5
N Engl J Med 2002;347:1825-33.
AFFIRM
Reasons for difference
It will be important for the medical
community for us to determine why there
might be a difference
•Possible stroke risk
•Clinicians might stop anticoagulants in
people they think are in stable sinus
rhythm
Prystowsky
EP Show – December 2002
AFFIRM
Cause-specific mortality
Determining cause-specific mortality will be
important
•666 deaths in total--will take time to
collect all the data on those deaths
•Reasons for increased mortality with
atrial fibrillation patients are still
unknown
•Stroke is only 1 likely candidate
Wyse
EP Show – December 2002
AFFIRM
Anticoagulation
All AFFIRM patients had to be eligible for
warfarin
•Rate-control arm: Anticoagulation was
required as long as possible, could only
be stopped due to a specific
contraindication to warfarin
•Rhythm-control arm: Warfarin could be
discontinued if patient was in stable
sinus rhythm for at least 1 month
Wyse
EP Show – December 2002
AFFIRM
Prevalence of warfarin
Greater prevalence of warfarin use in ratecontrol arm
•Rate-control arm: >85% throughout
the trial
•Rhythm-control arm: >70% throughout
the trial
EP Show – December 2002
N Engl J Med 2002;347:1825-33.
AFFIRM
Strokes
Event
Ischemic stroke
Rate
Rhythm
control
control
(n=2027) (n=2033)
77
(5.5%)
80
(7.1%)
After discontinuing
warfarin
25
44
During warfarin but
INR <2.0
27
17
EP Show – December 2002
N Engl J Med 2002;347:1825-33.
AFFIRM
Maintaining anticoagulation
In high-risk patients you should not
discontinue anticoagulation unless there's a
good reason
Wyse
"I think the results of AFFIRM very
nicely confirm [the impression] that you
can't be cavalier about stopping warfarin
anticoagulation in people just because you
think sinus rhythm has been maintained."
Prystowsky
EP Show – December 2002
AFFIRM
Younger patients
The previous guidelines are probably still
true for people who didn't qualify for
AFFIRM
(Young people with no stroke risk factors)
•A 55-year-old patient who comes in
with atrial fibrillation can be taken off
anticoagulation after 1 month of stable
rhythm
Wyse
EP Show – December 2002
AFFIRM
Everyday practice
How do we incorporate AFFIRM into our
practice?
"I'm somewhat concerned that people
are going to see the publication and
say 'I don't have to ever worry
about trying to get people in sinus' "
•Should AFFIRM apply to every patient?
Prystowsky
EP Show – December 2002
AFFIRM
Impact on guidelines
Still not sure about the impact of AFFIRM
on guidelines
•The paradigm we used was based on
symptoms
•Guidelines suggest highly symptomatic
people should start on rhythm control,
that hasn't changed
•AFFIRM had a bias against highly
symptomatic patients
EP Show – December 2002
Wyse
AFFIRM
Reassuring on rate control
But for a patient who is not highly
symptomatic, you can use whichever you
like
"For a lot of patients, particularly the
elderly, who aren't particularly
symptomatic . . . rate control is a
perfectly acceptable primary
therapy. And I think that's what
should be done in a lot of these
patients."
Wyse
EP Show – December 2002
AFFIRM
Options on rhythm control
If rhythm control isn't working out, you can
switch to rate control
"If you choose rhythm control, don't
persist with it if it's not working."
• Even for highly symptomatic patients
• Ablate and pace remains an option
for a nonpharmacological approach
Wyse
EP Show – December 2002
AFFIRM
Alternatives
If we had alternatives, we wouldn't be
having this discussion
• A drug that was 95% effective at
maintaining sinus rhythm, with 2%
risk of side effects
• An ablation therapy with low risk
and high efficacy
I don't see either of those things in the
near future
EP Show – December 2002
Wyse
AFFIRM
A change in the clinic
Younger patients: AFFIRM hasn't changed
my practice
•I don't know what staying in atrial
fibrillation for 35 years does. I try to
restore sinus rhythm
Elderly patients: AFFIRM has been
incorporated
•Try to establish good rate control first
and then see if I need to do more
EP Show – December 2002
Prystowsky
AFFIRM
New concerns
AFFIRM brings up new concerns
•What is "good rate control"?
•How do you measure and assess the
rate control?
•Chronotropic incompetence can be a
problem trying to get good rate control
Wyse
EP Show – December 2002
AFFIRM
AFFIRM
Atrial
Fibrillation
Follow-up
Investigation of
Rhythm
Management
EP Show – December 2002