1. Survival with Cardiac- Resynchronization Therapy in Mild Heart Failure

2. Abstract Background: MADIT-CRT showed CRT-D in patients with LBBB reduced HF events over 2.4 years compared with defibrillator alone. Methods: Eval of long term survival of MADIT- CRT over median period of 5.6 years. Results: At 7 yrs, CRD of LBBB patients with CRT-D was 18% compared to 29% of defib only Conclusions: mild HF, LV dysfx, LBBB, CRT-D associated with long term survival benefit

3. MADIT-CRT 1820 pts with cardiomyopathy, EF = 130msec, NYHA I or II symptoms followed for 2.4 years, Dec 2004 – June 2009 Either CRT-D or ICD alone, 3:2 ratio End point = death or nonfatal HF event No difference in risk of death 41% reduction in HF events in CRT-D group

4. Methods Data Acquisition and Patient Follow-up – Phase 1: 1691 surviving pts from MADIT-CRT from US (88), Canada, Israel, and Europe (24) 6/22/09 – 9/10/10 – Phase 2: 854 surviving pts from MADIT-CRT from 9/10/10 – 9/2013 (48 US, 23 Non-US) – Phase 2 patient characteristics remained similar to phase 1.

5. Definitions and End Points – Death from any cause (primary), Non-Fatal HF event, either/or, whichever occurred first – Evaluated effects of CRT-D according to baseline QRS morphology, LBBB (70%) or non-LBBB (30%) Original MADIT-CRT didn’t account for QRS morphology at onset of trial.

8. Statistical Analysis Analyses performed on intent-to-treat basis Variables expressed as +/- SD Categorical data summarized as freq and percentages P-value of <0.05 used as statistical significance

9. Results CRT-D in Patients with LBBB – At 7 years, cumulative rate of death of 29% in ICD only group compared to 18% in CRT-D group P value = 0.002 NNT = 9 over 7 years 41% reduction in long term risk of death, HR 0.59 – At 7 years, probability of non-fatal HF event significantly lower in CRT-D group P value < 0.001 62% reduction in long term risk on HF event, HR 0.38

10. CRT-D in Patients Without LBBB – At 7 years, no significant difference in cumulative rate of death between CRT-D and ICD only P value = 0.21 – At 7 years, no significant difference in rate of HF events P value = 0.58 Trend toward increased risk of death and HF events >7 years

15. Discussion Early CRT-D has significant long term survival benefit in pts with mild HF, LV dys, and LBBB – Consistent across subgroups, sex, QRS, cause of cardiomyopathy – Associated with reverse remodeling No benefit in long term outcomes without LBBB – Data doesn’t support early intervention in any subset.

16. Discussion Mechanism of lack of benefit in non-LBBB uncertain Possible disruption of electrical activation in LV – LV depolarization more heterogeneous – Pacing induced discrepancy of wave front – Increase in tachyarrhythmias – Poorer prognosis

17. Discussion Minimal survival bias – Analysis performed on an intention-to-treat basis – Negates cross-overs occurring during/after trial Possible selection bias – 758 lost to follow up after phase 1 because of institutions that declined to participate – Study population characteristics comparable – Limited individual patient bias

18. Discussion Possible Covariate Selection – Applies to harmful effects of CRT-D in non-LBBB population – No statistical significance – Data obtained after multivariate adjustment – Interpret with caution