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

2. Disclosures I have nothing to disclose I have nothing to disclose

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

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

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

6. 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 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 –MADIT1996n = 196 –MUSTT 1999n = 704 –MADIT II 2002n = 1,232 N = 6,173 –COMPANION 2003n = 1,520 –SCD-HeFT 2004n = 2,521 Clinical Overview

7. MADIT II Trial Design Population Population 1,232 patients with: 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 Prospective, multicenter, randomized design Primary endpoint: All cause mortality Primary endpoint: All cause mortality Eligible patients Noninvasive evaluation of LV function Randomization ICD+OPT (n=742)OPT (n=490) Average 20-month follow-up including OPT

9. MADIT II: Addition of an ICD Improves Survival Moss AJ, et al. N Engl J Med 2002;346:877-883. (Permission for use requested) Probability of Survival P = 0.007 0.5 0.6 0.7 0.8 0.9 1.0 01234 Years 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 ICD + OPT group OPT group

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

11. 1 American Heart Association. 2002 heart and stroke statistical update. American Heart Association, 2001. 2 MERIT-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. 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 population 1 –Sudden death is the predominant mode of death in mild to moderate heart failure 2

12. SCD-HeFT

13. The Sudden Cardiac Death in Heart Failure Trial: SCD-HeFT Design: Design: –Prospective, Multi-center, Randomized –2521 Patients enrolled Inclusion Criteria: 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. SCD-HeFT: Tested ICDs or Amiodarone on Top of Conventional Therapy (CT) Bardy GH, et al. N Engl J Med. 2005;352:225-237 Eligible Patients Electrocardiography, Liver & Thyroid function tests, Six Minute Walk, Holter Monitor and Chest Radiography Randomization 1 Patient 1 Patient1 Patient Conventional Therapy CT + Amiodarone CT + ICD

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 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% ICD's decrease mortality by 23% Amiodarone, when used as a primary preventive agent, does not improve survival 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 Design –Open-label –Prospective –Multicenter –Randomized –Parallel Objective Objective –Compare OPT alone vs OPT with CRT/ICD vs OPT with CRT alone 128 centers across the US 128 centers across the US Bristow MR, et al. N Engl J Med. 2004;350:2140-2150

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

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

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 Bristow MR, et al. N Engl J Med. 2004;350:2140-2150 * 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

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

28. Resynchronization Therapy

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

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

31. Revised ACC/AHA Guidelines impact ICD and CRT Therapies The New Standard of Care 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 II and COMPANION 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