Heartland Cardiology Dr. John Dongas

1. Heartland CardiologyDr. John Dongas The Beat Goes On: Biventricular Devices

2. Disclosures • I have nothing to disclose

3. Agenda • Sudden Cardiac Death (SCD) and related clinical trials • Cardiac Resynchronization Therapy (CRT) and related clinical trials

4. Sudden Cardiac Death in the US • Approximately 460,000 people yearly will die of Sudden Cardiac Death • Other causes • Stroke2 160,000 • Lung cancer3 90,100 • Breast cancer3 40,200 • Automobile accident4 50,000 • AIDS5 16,000 • Fires6 4,000 4National Transportation Safety Board, 2000. 5Center for Disease Control, 2001. 6NFPA, U.S. Facts & Figures, 2000. 1NASPE, May 2000. 2American Heart Association, 2000. 3National Cancer Institute, 2001.

5. 1% 30% 40% 40% • Odds of Surviving Sudden Cardiac Death • Overall: • New York City or Chicago: • Seattle: • Hospital: • American Airlines in Flight: • Las Vegas Casino: 5% 70% Presented by John D. Day, MD, University of Utah Medical Center, September 2003, Las Vegas, NV

6. Clinical Overview • There is a large and growing body of scientific evidence demonstrating the benefits of both pharmacological and device therapies for patients with Left Ventricular Dysfunction who are at risk for SCD • MADIT 1996 n = 196 • MUSTT 1999 n = 704 • MADIT II 2002 n = 1,232 N = 6,173 • COMPANION 2003 n = 1,520 • SCD-HeFT 2004 n = 2,521

7. MADIT II Trial Design • Population • 1,232 patients with: • Prior MI (> 1 month before enrollment) • EF  30% • No arrhythmia markers were required for inclusion in MADIT II • Medication in treatment arms was similar

8. MADIT II Trial Design • Prospective, multicenter, randomized design Eligible patients Noninvasive evaluation of LV function Randomization ICD+OPT (n=742) OPT (n=490) Average 20-month follow-up including OPT • Primary endpoint: All cause mortality

9. ICD + OPT group OPT group 0 1 2 3 4 Years MADIT II: Addition of an ICD Improves Survival 1.0 0.9 0.8 Probability of Survival 0.7 • 31% relative reduction in all-cause mortality at average 20 month follow-up • 5.6% absolute reduction in all-cause mortality at average 20-month follow-up 0.6 P = 0.007 0.5 Moss AJ, et al. N Engl J Med 2002;346:877-883. (Permission for use requested)

10. Medicare ICD Approved Indications • -Prior MI (>1 month) and • -EF< 30%

11. Sudden cardiac death (SCD) High risk in heart failure patients • Heart failure patients experience SCD at six to nine times the rate of the general population1 • Sudden death is the predominant mode of death in mild to moderate heart failure2 1American Heart Association. 2002 heart and stroke statistical update. American Heart Association, 2001. 2MERIT-HF study group. Effect of metoprolol CR/XL in chronic heart failure: metoprolol CR/XL randomized intervention trial in congestive heart failure (MERIT-HF). LANCET. 1999;353:2001-07.

12. SCD-HeFT

13. The Sudden Cardiac Death in Heart Failure Trial: SCD-HeFT • Design: • Prospective, Multi-center, Randomized • 2521 Patients enrolled • Inclusion Criteria: • NYHA class II/III Heart Failure due to ischemic or non-ischemic dilated cardiomyopathy • EF  35% • CHF  3 months • Age  18 years • CHF treatment with vasodilators • No cardiac arrest or episode of sustained VT Bardy GH, et al. N Engl J Med. 2005;352:225-237

14. Eligible Patients Electrocardiography, Liver & Thyroid function tests, Six Minute Walk, Holter Monitor and Chest Radiography Randomization 1 Patient 1 Patient 1 Patient Conventional Therapy CT + Amiodarone CT + ICD SCD-HeFT: Tested ICDs or Amiodarone on Top of Conventional Therapy (CT) Bardy GH, et al. N Engl J Med. 2005;352:225-237

15. SCD-HeFT: Conclusions • In class II or III HF patients with EF < 35% on good background drug therapy, the mortality rate for placebo-controlled patients is 7.2% per year over 5 years • ICD's decrease mortality by 23% • Amiodarone, when used as a primary preventive agent, does not improve survival

16. Myocardial Infaction

17. Ejection Fraction

18. Ventricular Fibrillation

19. Synchronny vs. Dysynchronny in HF

20. Comparison of medical therapy, pacing and defibrillation in HF: COMPANION • Design • Open-label • Prospective • Multicenter • Randomized • Parallel • Objective • Compare OPT alone vs OPT with CRT/ICD vs OPT with CRT alone • 128 centers across the US Bristow MR, et al. N Engl J Med. 2004;350:2140-2150

21. NYHA Class III or IV NSR, QRS 120 ms, PR interval >150ms LVEF 35%, LVEDD 60 mm Optimal pharmacological therapy Beta blocker (for at least 3 months) Diuretic, ACEI/ARB, spironolactone (1 month), +/- digoxin History of HF hospitalization (or pharmacologic equivalent) <12 months, >1 month prior to enrollment No indication for bradycardia or tachyarrhythmia device at the time of enrollment COMPANION: Key eligibility criteria Bristow MR, et al. N Engl J Med. 2004;350:2140-2150

22. Issues associated with heart failure Abnormal wall motion Healthy DCM - Intrinsic Click for animations Courtesy of C. Stellbrink, MD.

23. Conclusions When added to optimal pharmacological therapy in patients with moderate to severe LV dysfunction, NYHA Class III or IV symptoms and QRS lengthening: • CRT or CRT-D reduce mortality and first hospitalization* • CRT-D reduces mortality •  2/3 of the reduction is attributed to CRT • * Hospitalization • Care provided at a hospital for any reason over a time period that involves a date change • In-patient or out-patient use of IV inotropes and/or vasoactive drugs for more than 4 hours • Hospitalizations associated with a device implant attempt or re-attempt are excluded Bristow MR, et al. N Engl J Med. 2004;350:2140-2150

24. COMPANION – Primary Endpoint ~19% reduction with CRT ~20% reduction with CRT-D

25. Secondary Endpoint – All cause mortality ~24% reduction with CRT ~36% reduction with CRT-D

26. COMPANION Conclusions • When added to optimal pharmacological therapy in • patients with moderate-severe LV dysfunction, NYHA • Class III or IV symptoms and QRS lengthening: • CRT or CRT-D reduces mortality + hospitalizations • CRT-D reduced the relative risk of mortality by 36%

27. Sinus node AV node Conduction block Stimulation therapy Issues associated with heart failure Mechanism II–ventricular resynchronization • Intraventricular Activation • Organized ventricular activation sequence • Coordinated septal and free-wall contraction • Improved pumping efficiency

28. Resynchronization Therapy

29. CRT-D Indications FDA Indications • Patients who are at high risk of sudden cardiac death due to ventricular arrhythmias • Moderate to severeheart failure, NYHA Class III/IV • Left ventricular dysfunction, EF  35% • QRS duration  120 ms and • Symptomatic despite stable, optimal heart failure drug therapy

30. Issues associated with heart failure Cardiac resynchronization therapy (CRT)– global synchrony DCM with CRT Baseline Click for animations Courtesy of C. Stellbrink, MD.

31. The New Standard of Care Revised ACC/AHA Guidelines impact ICD and CRT Therapies The American College of Cardiology (ACC) and American Heart Association (AHA) have just announced they have incorporated revised treatment recommendations for ICD and CRT therapies into the heart failure guidelines. ICD and CRT therapies are now Class I for many patients who are indicated under the MADIT IIandCOMPANION trials(1). (1) http://www.acc.org/clinical/guidelines/failure/index.pdf

32. ACC/AHA Guidelines Format • Class I: Conditions for which there is evidence and/or general agreement that a given procedure or treatment is beneficial, useful, and effective. • Class II: Conditions for which there is conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of a procedure or treatment. • Class IIa: Weight of evidence/opinion is in favor of usefulness/efficacy. • Class IIb: Usefulness/efficacy is less well established by evidence/opinion. • Class III: Conditions for which there is evidence and/or general agreement that a procedure/treatment is not useful/effective and in some cases may be harmful.

33. Summary • ICD and CRT therapies are the standards of care recognized by the ACC and AHA