Survival with Cardiac-Resynchronization Therapy in Mild Heart Failure

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 <= 30%, QRS of >= 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