1. EP Show – March 2003 Heart Failure The EP Show: New approaches to heart failure Eric Prystowsky MD Director, Clinical Electrophysiology Laboratory St Vincent Hospital Indianapolis, IN Leslie Saxon MD Director of Electrophysiology University of Southern California Los Angeles, CA Gary Francis MD Director of Coronary Care Unit Cleveland Clinic Foundation Cleveland, OH

2. EP Show – March 2003 Heart Failure Pharmacologic approach Dramatic changes in the past 15 to 20 years ACE inhibitors and beta blockers are the cornerstone of therapy Loop diuretics, spironolactone, and various adjunctive therapies remain Francis

3. EP Show – March 2003 Heart Failure Dosing Dosing in real practice rarely reflects dosing in controlled clinical trials Dosing should be titrated up gradually (over several weeks) Using higher doses than those used in trials is controversial; there is no strong data supporting higher doses Francis

4. EP Show – March 2003 Heart Failure Diastolic heart failure We currently have no trials to dictate practice in these patients In my practice I tend to treat these patients with diuretics (careful not to create a hypovolemic state) These patients respond to ACE inhibitors and beta blockers A regimen of ACE inhibitors, beta blockers, and diuretics seems to work Francis

5. EP Show – March 2003 Heart Failure Resynchronization therapy Epidemiological outcome studies showed bundle branch block had a negative impact on mortality Early 1990s: Heart failure patients with RV pacemakers didn't do very well Mid-1990s: The presence of bundle branch block worsens hemodynamics Pacing both ventricles simultaneously seemed to improve the hemodynamics Saxon

6. EP Show – March 2003 Heart Failure Pilot studies 3 biventricular pacing trials gained approval for resynchronization devices in the US MIRACLE InSync ICD CONTAK CD Resynchronization therapy is now indicated for NYHA class 3 patients with QRS delay Saxon

7. EP Show – March 2003 Heart Failure Functional improvement All resynchronization therapy studies showed improvement in functional status: Symptom status 6-minute walk Quality of life Peak oxygen consumption Modest reverse remodeling Saxon

8. EP Show – March 2003 Heart Failure Class 2 patients Therapy is labeled for class 3 patients, but the ICD trials did enroll class 2 patients Class 2 patients showed no significant improvement in symptoms but did show remodeling benefit Saxon

9. EP Show – March 2003 Heart Failure COMPANION: Enrollment Enrollment began in 1998, enrolled 1600 patients with QRS>120 ms P-R interval>150 ms Class 3 heart failure Hospitalization for heart failure in the past year

10. EP Show – March 2003 Heart Failure COMPANION: End points Patients were randomized to optimal medical therapy, cardiac resynchronization, or resynchronization with an ICD Trial stopped in November 2002: 20% reduction in all-cause mortality and all-cause hospitalization in both device groups 40% reduction in all-cause mortality in patients who received the combined resynchronization/ICD device

11. EP Show – March 2003 Heart Failure CARE-HF: Enrollment Enrollment began in 2001, enrolled 800 patients with NYHA class 3/4 18-month follow-up Randomized to resynchronization or optimal medical management

12. EP Show – March 2003 Heart Failure Resynchronization therapy It appears to meet the 3 goals of heart failure therapy Improves functional status Slows disease progression Improves mortality and hospitalization end points Saxon

13. EP Show – March 2003 Heart Failure Differing response Patients on cardiac resynchronization fall into 3 categories: Fabulous response, can improve up to 2 heart classes "Tweeners" who get some benefit but not as much as we would like 20% to 25% who don't respond at all Prystowsky

14. EP Show – March 2003 Heart Failure Nonresponders "This is the science that is going to keep the next generation of people busy." We don't understand the relationship between QRS delay and mechanical dysynchrony Saxon

15. EP Show – March 2003 Heart Failure Defining resynchronization We don't understand how to define resynchronization QRS delay correlates with ventricular size but does not predict clinical response No gold standard of measuring mechanical dysynchrony or resynchronization--we simply don't know what the best measure is Saxon

16. EP Show – March 2003 Heart Failure Lead location Are nonresponders the result of bad lead placement? Left bundle-branch block is an incredibly heterogeneous condition, and lead placement will be very patient specific You should be able to get response in 70% or so even without perfect lead placement Saxon

17. EP Show – March 2003 Heart Failure Optimal programming We could get better results just from optimal programming of AV delay New devices offer new options, but there is no established standard way to assess resynchronization In my lab we are using echo to follow patients and treating the instrument like a drug, altering the parameters and finding the best response Saxon

18. EP Show – March 2003 Heart Failure Increased expectations Like all therapies, we found something that works, and now we demand better and better results "I'm getting from your thoughts that we know the therapy works; we have a lot of fine-tuning to do." Prystowsky

19. EP Show – March 2003 Heart Failure Advancing the field Since market approval, >40 000 have been implanted in the US These devices and patients require a lot of attention; the science needs to be resolved "I've had several heart failure people come up to me and say, 'You know in the clinical trials our guys were getting results with implants of 70, 80, 90, 90- plus percent and now I think our results aren't as good." Saxon

20. EP Show – March 2003 Heart Failure Patient selection At what point do you send a patient for resynchronization therapy? It's not entirely clear, but the threshold for implantation is getting lower and lower We find about one third of patients don't get better or have no change We might accept those numbers if this were a drug Francis

21. EP Show – March 2003 Heart Failure Patient selection Candidates for resynchronization Class 3 patient on full therapy who is still clinically struggling Patients with late class 2 and possibly lower if we can refine the selection criteria Patients receiving modified Dor procedure who don't do well Francis

22. EP Show – March 2003 Heart Failure Patient dilemma Patient with class 3 heart failure who isn't doing as well as we would like IBCD QRS duration 140 ms EF 25% Is there any use for a biventricular pacemaker as opposed to a defibrillator in light of what we know about COMPANION?

23. EP Show – March 2003 Heart Failure Nonischemic cardiomyopathy "In most instances I would at least bring up the discussion of the defibrillator." Defibrillators have not yet proved benefit in patients with nonischemic cardiomyopathy At least 40% of patients in COMPANION had nonischemic cardiomyopathy As heart failure progresses, the etiology may become less relevant Saxon

24. EP Show – March 2003 Heart Failure Synchronization device alone There is a role for just synchronization therapy in advanced heart failure patients who have very poor outlook for 6-month survival Start with a resynchronization device and if they respond well put in an ICD It is no good if you put in an ICD, they don't get better, you give them lots of shocks and then have to take the ICD out Saxon

25. EP Show – March 2003 Heart Failure Pacemakers as prevention Could a pacemaker prevent class 2 patients from becoming class 3? Does the antiremodeling effect become permanent if you pace long enough? If there were permanence you could make an argument to use pacemakers in less-ill patients Francis

26. EP Show – March 2003 Heart Failure Long-term pacing Follow-up on the chronic trials goes out to 1 year The remodeling appears to be a direct effect of pacing Out to 1 year, volumes improve but mass does not change We don't see the same structural changes as with drugs, but it may happen in the future Saxon

27. EP Show – March 2003 Heart Failure Pacing damage Pacing just the right ventricle may alter the heart in a negative way The recognition that we can create dysynchrony that hurts the ventricle should make us rethink pacing just the right side Francis

28. EP Show – March 2003 Heart Failure Pacing the left ventricle Patients with significant mitral regurgitation can be risky to pace just the right ventricle Especially ones with an AV junction ablation can end up in the OR Now that we have other options, we should think things through before just putting in an RV lead Prystowsky

29. EP Show – March 2003 Heart Failure Who follows these patients? Electrophysiologists are putting the devices in, but should they follow up? Will heart failure specialists have to learn how to implant these devices? How would you develop a program for training for the future? Prystowsky

30. EP Show – March 2003 Heart Failure Busy EP doctors Electrophysiologists are just too busy to see these patients It's unrealistic to expect them to come out of the lab 1 or 2 days a week to see these patients We should expect a loose affiliation between heart failure specialists and EPs Francis

31. EP Show – March 2003 Heart Failure Coordinating care We scheduled the pacemaker clinic with the heart failure clinic to allow better coordination of care We trained heart failure fellows in EP for 3 or 4 months to give them an understanding of the device area EPs could subspecialize into complex ablation and device specialists who do implantation and follow-up Saxon

32. EP Show – March 2003 Heart Failure Limited resources Electrophysiologists don't know enough about the pharmacologic management of these patients In a small group, you don't have a specialist who can focus on the medical management This will have to be a part of training in the future because these devices are put in on top of medical therapy Prystowsky

33. EP Show – March 2003 Heart Failure New pharmacological approaches Additional neurohormonal antagonist agents have not proved effective TNF-alpha blockers weren't effective Omapatrilat wasn't effective There is a move to comorbid conditions Francis

34. EP Show – March 2003 Heart Failure Comorbid conditions 15% to 20% of heart failure patients are anemic 2 companies launching trials with erythropoeitin to address the anemia Also a move to develop drugs to augment renal function Arginine vasopressin antagonists Adenosine antagonists Francis

35. EP Show – March 2003 Heart Failure Summary Initial approach should be to optimize pharmacologic treatment of heart failure patients Patients who remain in class 3 failure with significant QRS duration are candidates for a resynchronization device, probably with an ICD Once you have a device you need to be managed carefully by specialists Prystowsky

36. EP Show – March 2003 Heart Failure The EP Show: New approaches to heart failure Eric Prystowsky MD Director, Clinical Electrophysiology Laboratory St Vincent Hospital Indianapolis, IN Leslie Saxon MD Director of Electrophysiology University of Southern California Los Angeles, CA Gary Francis MD Director of Coronary Care Unit Cleveland Clinic Foundation Cleveland, OH