1. May 2005 EP Show The EP Show COMPANION and CARE-HF Eric Prystowsky MD Director, Clinical Electrophysiology Laboratory St Vincent Hospital Indianapolis, IN Hugh Calkins MD Director, Electrophysiology Lab Johns Hopkins University Medical Center Baltimore, MD John Cleland MD Professor of Cardiology Hull University Kingston upon Hull, UK

2. May 2005 EP Show Use of cardiac resynchronization therapy (CRT) in COMPANION and CARE-HF

3. May 2005 EP Show Brief history Large group of patients in need of ICDs for primary prevention New era of biventricular pacing to improve HF symptoms COMPANION and CARE-HF

4. May 2005 EP Show Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure COMPANION

5. May 2005 EP Show COMPANION Design Parallel, randomized clinical trial in 1600 patients with moderate or severe heart failure with QRS >120 ms and PR interval >150 ms (Bristow MR et al. N Engl J Med 2004; 350: 2140-2150) Patients randomized in a 1:2:2 fashion to optimal medical therapy; optimal drug therapy plus CRT; or optimal drug therapy plus CRT with an ICD (CRT-D)

6. May 2005 EP Show Results Primary end point Combination of all-cause death and all- cause hospitalizations reduced 19% in the CRT study arm and 20% in the CRT- D study arm Death from or hospitalization for HF reduced 34% in CRT group and 40% in CRT-D group

7. May 2005 EP Show Results Secondary end point CRT alone associated with a nonsignificant trend toward a 24% reduction in all-cause mortality, a secondary end point of the study CRT with a defibrillator reduced all- cause mortality 36%, a highly significant result

8. May 2005 EP Show Significant reductions "This study showed in a large population of patients that resynchronization therapy improves survival and reduces hospitalization." Survival benefit limited to those with CRT and ICD Calkins

9. May 2005 EP Show CRT challenges Implanting the coronary sinus lead Difficulty involves not getting the lead in, but getting it in the right place To achieve effective resynchronization, the lead needs to be implanted in a lateral branch of the coronary sinus Requires experienced implanter

10. May 2005 EP Show Cardiac Resynchronization Heart Failure CARE-HF

11. May 2005 EP Show CARE-HF Rationale Cardiac dyssynchrony a problem in a large number of patients with HF and left ventricular systolic dysfunction Previous studies have suggested that CRT can improve symptoms, quality of life, and exercise capacity No conclusive evidence of an effect on hospitalizations or mortality

12. May 2005 EP Show CARE-HF Design Randomized, controlled, open-label, blinded-end-point study Randomized patients to continue with medical therapy or to receive CRT Included 813 patients with NYHA class 3-4 HF despite standard drug therapy, an LVEF <35%, and QRS duration of at least 120 ms

13. May 2005 EP Show CARE-HF Patients with a QRS duration <150 ms were required to have echocardiographic confirmation of ventricular dyssynchrony Primary end point was all-cause mortality/unplanned hospitalization for CV event

14. May 2005 EP Show Strengths of CARE-HF Study details Large control group Implant success rate 96% Long-term follow-up, with an average of 2.5 years Average age of patient 67 years Only 40% of patients taking >80 mg furosemide (most common dose was 40 mg daily)

15. May 2005 EP Show Cleland JGF et al. N Engl J Med 2005; 352:1539-1549 Primary and secondary outcomes in CARE-HF OutcomesHazard ratio (95% CI) p All-cause mortality/unplanned hospitalization for CV event0.63 (0.51-0.77) <0.0001 All-cause mortality0.64 (0.48-0.85) 0.0019 All-cause mortality/HF hospitalization 0.54 (0.43-0.68) <0.0001

16. May 2005 EP Show Other improvements CRT group also benefited significantly with improved LVEF, NYHA class, end- systolic volume, mitral-valve function, blood pressure, and quality-of-life indices Dramatic improvements at 18 months in levels of N-terminal pro-B-type natriuretic peptide (NT-proBNP)

17. May 2005 EP Show Problems encountered Lead problems 27 lead-related problems, such as fracture or displacement, in the 409 patients randomized to CRT Number of cases of coronary sinus dissection, none of which caused death One procedure-related death in each group

18. May 2005 EP Show Possible remission "I think we see a substantial proportion of patients who become asymptomatic and whose cardiac function is normalized by this therapy." Possibility of HF "remission" Cleland

19. May 2005 EP Show What therapy? No question to the value of CRT, but candidates for CRT are also candidates for ICD therapy The question then becomes, which treatment do they receive?

20. May 2005 EP Show Treating patients "It's a fairly easy decision." Real difference comes down to cost, but the added protection of the ICD warrants the use of CRT with a defibrillator Calkins

21. May 2005 EP Show Other issues Morbidity There is the possibility of inappropriate shocks from the ICD in healthy patients who might not stand to benefit from its addition In studies using older devices, the morbidity from the defibrillator was unacceptable

22. May 2005 EP Show If money were not an issue... CRT with newer defibrillators does provide an additional benefit But cost in the UK remains an issue, and I would continue to be selective about which patients received CRT with defibrillator backup Cleland

23. May 2005 EP Show Patient selection Have you learned anything from the studies that would help you select patients for a CRT-D implant? - Prystowsky The brief answer to that is not yet. - Cleland

24. May 2005 EP Show Inappropriate shocks Not a case of inappropriate shocks but inappropriate programmers EPs programming devices that deliver inappropriate shocks more than 5% of the time need to go back to school Prystowsky

25. May 2005 EP Show Inappropriate shocks "It irks me at times because people throw that up as a reason not to get a defibrillator, but I say get a better implanter, get a smarter doctor." - Prystowsky "But not everybody can come to your center and benefit from your expertise." - Cleland

26. May 2005 EP Show Looking to the future Interesting issue as not everybody with a wide QRS benefits, and even some with a narrow QRS benefit from CRT Pathophysiology suggests applying therapy earlier, to patients in NYHA class 2, to prevent progression of HF

27. May 2005 EP Show Looking to the future "The fact that CARE-HF was so positive in a rather milder population than COMPANION supports the drift to using these devices at an earlier stage." Cleland

28. May 2005 EP Show Patient selection Some patients have such dramatic improvements with CRT that they may no longer be candidates for an ICD Need more research on the benefit of the defibrillator in CRT-D therapy

29. May 2005 EP Show Conclusions Summary Patient who meets criteria for resynchronization should be treated accordingly Defibrillator component remains to be debated, mainly due to the issue of economics

30. May 2005 EP Show Conclusions CARE-HF showed major reductions in mortality with pacing alone "The world is better off for the fact that we've had these two studies." - Prystowsky