Left Ventricular Ejection Fraction >35%

Controversies in Cardiac Resynchronisation Therapy Left Ventricular Ejection Fraction >35% Professor John GF Cleland University of Hull Kingston-upon-Hull United Kingdom Conflict of Interest: I have received speakers honoraria from Medtronic and St Jude

Main Trials of CRT for Heart Failure CONTAK MIRACLE MIRACLE ICD I II COMPAN -ION CARE-HF REVERSE MADIT- CRT RAFT Months <6 6 6 6 15 36 12 29 40 N (con) 245 225 182 101 308 404 191 731 904 ICD Req 85% Age 66 64 67 63 67 67 62 65 66 NYHA I/II 32 0% 0% 100% 0% 0/21% 100% 85% 20% SR 87% QRS >120 >130 >130 >130 >120 >120* >120 >130 >120 Entry EF <35% <35% <35% <35% <35% <35% <40% <30% <30% IHD 67% 50% 64% 55% 54% 40% 51% 54% 67% RETHINQ 73% of 156 patients had QRS <120msec

ESC Guidelines Position Statement Guidelines should represent evidence-based medicine. Traditionally, these recommendations are based on the outcomes in cohorts described by the inclusion criteria in the protocols of RCTs. More recently, based on the fact that the characteristics of the patients actually included in a trial may differ substantially from the eligibility criteria, ESC Guideline Task Force members frequently favour restricting the applicability of these recommendations to the clinical profile of the enrolled cohort, representing a more accurate interpretation of the evidence provided by a trial s result.

Main Trials of CRT for Heart Failure CONTAK MIRACLE MIRACLE ICD I II COMPAN -ION CARE-HF REVERSE MADIT- CRT RAFT Months <6 6 6 6 15 36 12 29 40 N (con) 245 225 182 101 308 404 191 731 904 ICD Req 85% Age 66 64 67 63 67 67 62 65 66 NYHA I/II 32 0% 0% 100% 0% 0/21% 100% 85% 20% SR 87% QRS >120 >130 >130 >130 >120 >120* >120 >130 >120 Entry EF <35% <35% <35% <35% <35% <35% <40% <30% <30% Med/Mean 21% 22% 24% 24% 22% 25% 27% 24% 23% One SD or Upper Q 28% 28% 30% 31% 29% 29% 34% 29% 28% IHD 67% 50% 64% 55% 54% 40% 51% 54% 67% RETHINQ 73% of 156 patients had QRS <120msec

Why Measure LVEF? Baseline LVEF has not been a predictor of response in randomised trials of CRT Specific Pathophysiological Substrate? Is it likely that this differs fundamentally Between 30% and 40%? Between 35% and 45%? Non-Specific Marker of Risk? There are much better markers of risk

LVEF by Subgroup in Trials of CRT CARE-HF Primary EP Death COMPANION Primary EP RAFT

REVERSE Change in LV End Systolic Volume Index Green bars CRT-on Red bars CRT-off Linde et al JACC 2008; 52:1834 43

REVERSE Clinical Composite Outcome Daubert et al JACC 2009;54:1837 46

EuroHeart Failure Survey-I QRS v Left Ventricular Ejection Fraction (N= 4,605) 50 LVEF 45 Mean LVEF % 40 35 30 25 <80 80-89 90-99 100-109 110-119 120-129 130-139 140-149 >149. <120 >119 * Excluding Paced * QRS Width msec

CARE-HF (Extension Study) Mortality and Cross-Over 60 56.8 % 50 40 30 20 10 0 24.4 95 Died Of 390 pts Implant CRT 31.6 6 Died Of 19 pts Failed Implant 42.7 132 Died Of 309 pts No X-Over 227 Died Or X-Over Of 404 pts All Control 23.2 22 Died Of 95 pts X-Over Cleland JG et al CARE-HF Extension

Mortality (%) 60 50 40 30 20 10 0-10 -20 25 CARE-HF Control v CRT in HF and LVEF <35% NT-proBNP < Median 1,814pg/ml Mid-Range 700pg/ml 12-13 NT-proBNP > Median 1,814pg/ml Mid-Range 4,000pg/ml 0 Control CRT Delta. Control CRT Delta 51 RR 52% RR 31% 35-16

How Accurate is Measurement of LVEF? Echo v Radionuclide Ventriculography LVEF by RNVG 7-10% lower than by echo. Therefore an LVEF of 30% by RNVG might not be eligible for CRT by echo Limits of agreement +/- ~20% 4 0 E c h o ( M e a n ) E F - R N V E F 30 20 10 0-10 - 20-30 + 1. 9 6 S D 2 3. 6 % B i a s 1 0. 6 % - 2. 4 % - 1. 9 6 S D - 4 0 F i g 4 ( i i i ) 1 0 2 0 3 0 4 0 5 0 6 0 M e a n o f E c h o E F a n d R N V E F

How Accurate is Measurement of LVEF? Radionuclide Ventriculography v CMRI LVEF by RNVG 6% lower than CMRI Limits of agreement +/- 15%! Bellenger et al CHRISTMAS Substudy Eur Heart J 2002

How Accurate is Measurement of LVEF? Radionuclide Ventriculography v CMRI LVEF by Echo 2% higher than CMRI Limits of agreement +/- ~20%! Bellenger et al CHRISTMAS Substudy Eur Heart J 2002

STICH Trial Core Lab Analysis of Baseline Echocardiographic Studies Core Lab LVEF >35% in 18.5% Mean LVEF 29+8% Oh JK et al JASE 2011

How Accurate is Measurement of LVEF? By Echocardiography Measurement of LVEF under fairly ideal conditions is accurate to within about 12%. A measurement of LVEF of 25% or above could, in reality, be >35% LVEF also differs amongst centres

Main Trials of CRT for Heart Failure CONTAK MIRACLE MIRACLE ICD I II COMPAN -ION CARE-HF REVERSE MADIT- CRT RAFT Months <6 6 6 6 15 36 12 29 40 N (con) 245 225 182 101 308 404 191 731 904 ICD Req 85% Age 66 64 67 63 67 67 62 65 66 NYHA I/II 32 0% 0% 100% 0% 0/21% 100% 85% 20% SR 87% QRS >120 >130 >130 >130 >120 >120* >120 >130 >120 Entry EF <35% <35% <35% <35% <35% <35% <40% <30% <30% Med/Mean 21% 22% 24% 24% 22% 25% 26% 24% 23% One SD or Upper Q 28% 28% 30% 31% 29% 29% 34% 29% 28% IHD 67% 50% 64% 55% 54% 40% 51% 54% 67% RETHINQ 73% of 156 patients had QRS <120msec

Conclusion Given the ESC position on following the evidence We should remove all LVEF criteria from the guidelines as they provide a false impression of precision/accurarcy Guidelines should advise use of interventions based on semi-quantitative scales only (ie no, mild, moderate, severe LVSD)