EP Show – December 2002 AFFIRM The EP Show: AFFIRM Eric Prystowsky MD Director, Clinical Electrophysiology Laboratory St Vincent Hospital The Care Group

EP Show – December 2002

AFFIRM

The EP Show:AFFIRM

Eric Prystowsky MDDirector, Clinical Electrophysiology Laboratory

St Vincent Hospital The Care Group (private clinic)Indianapolis, IN

D George Wyse MD, PhDProfessor of MedicineDepartment of Pharmacology and Therapeutics University of Calgary Calgary, AB


AFFIRM

AFFIRM

AtrialFibrillation Follow-up Investigation of Rhythm Management


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 deadlyCAST (NEJM 1991;324:781-788)

•Effectiveness of oral anticoagulation protection against stroke

Wyse


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


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


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


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)


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


AFFIRM

Rhythm-control drugs

Drug used in rhythm-control group

41.4%31.2%Sotalol

62.8%37.5%Amiodarone

Used at anytimeInitiation of therapy

N Engl J Med 2002;347:1825-33.


AFFIRM

Rhythm drug substudy

0

10

20

30

40

50

60

70

Surv

ival at

1 y

ear

(%

)

Amiodaronevs Class I

Amiodaronevs Sotalol

Sotalol vsClass I

Amiodarone Sotalol Class I antiarrhythmic

Presented at the 23rd Annual Scientific Sessions of the North American Society of Pacing and Electrophysiology


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


AFFIRM

Less-used drugs

Drug used in rhythm-control group

0.60Dofetilide

14.59.3Propafenone

Used at anytime (%)

Initiation of therapy (%)

N Engl J Med 2002;347:1825-33.

8.55.3Procainamide

7.44.7Quinidine

4.32.1Disopyramide


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


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


AFFIRM

Mortality results

0

5

10

15

20

25

Cum

ula

tive m

ort

ality

(%

)

Year 1 Year 2 Year 3 Year 4 Year 5

Rhythm control Rate control

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


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


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


AFFIRM

Prevalence of warfarin

Greater prevalence of warfarin use in rate-control arm

•Rate-control arm: >85% throughout the trial

•Rhythm-control arm: >70% throughout the trial

N Engl J Med 2002;347:1825-33.


AFFIRM

Strokes

1727During warfarin but INR <2.0

Event

4425After discontinuing warfarin

80 (7.1%)77 (5.5%)Ischemic stroke

Rhythm control

(n=2033)

Rate control

(n=2027)

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


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


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


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

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


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


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

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

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


AFFIRM

AFFIRM

AtrialFibrillation Follow-up Investigation of Rhythm Management

Documents

EP Show – December 2002 AFFIRM The EP Show: AFFIRM Eric Prystowsky MD Director, Clinical Electrophysiology Laboratory St Vincent Hospital The Care Group