1. EP Show – December 2002 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

2. EP Show – December 2002 AFFIRM Atrial Fibrillation Follow-up Investigation of Rhythm Management

3. 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

4. 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

5. 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

6. 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

7. 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)

8. 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

9. EP Show – December 2002 AFFIRM Rhythm-control drugs Drug used in rhythm- control group 41.4% 31.2%Sotalol 62.8% 37.5% Amiodarone Used at anytime Initiation of therapy N Engl J Med 2002;347:1825-33.

10. EP Show – December 2002 AFFIRM Rhythm drug substudy Presented at the 23rd Annual Scientific Sessions of the North American Society of Pacing and Electrophysiology

11. 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

12. EP Show – December 2002 AFFIRM Less-used drugs Drug used in rhythm- control group 0.6 0Dofetilide 14.5 9.3 Propafenone Used at anytime (%) Initiation of therapy (%) N Engl J Med 2002;347:1825-33. 8.5 5.3Procainamide 7.4 4.7Quinidine 4.3 2.1Disopyramide

13. EP Show – December 2002 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

14. 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

15. EP Show – December 2002 AFFIRM Mortality results N Engl J Med 2002;347:1825-33.

16. EP Show – December 2002 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

17. 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

18. 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

19. EP Show – December 2002 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.

20. EP Show – December 2002 AFFIRM Strokes 1727 During 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.

21. EP Show – December 2002 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

22. 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

23. 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

24. 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 Wyse

25. EP Show – December 2002 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

26. 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

27. 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 Wyse

28. EP Show – December 2002 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

29. EP Show – December 2002 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

30. EP Show – December 2002 AFFIRM Atrial Fibrillation Follow-up Investigation of Rhythm Management