Targeted Left Ventricular Lead Placement to Guide Cardiac Resynchronisation Therapy: A

Randomised Controlled Trial (TARGET study)

Khan FZ1,2, Virdee MS2, Palmer CR3, Pugh PJ1, O’Halloran D1, Elsik M2, Read PA2, Begley D2, Fynn SP2, Dutka DP1

1Addenbrooke’s Hospital, Cambridge, UK2Papworth Hospital, Cambridge, UK

3Centre for Applied Medical Statistics, Cambridge, UK

Disclosures

Disclosures: None

Sponsorship: Papworth Hospital, Cambridge, UK

Funding: NIHR UK

Papworth Hospital, Addenbrooke’s Charitable Trust

Trial

Registration: ISRCTN19717943

Introduction• Cardiac Resynchronisation Therapy (CRT) has evolved as

established treatment for advanced heart failure symptoms, impaired LV systolic function and intraventricular conduction delay

• 30-40% of patients fail to gain significant clinical benefit

• Left ventricular (LV) lead position has emerged as an important determinant of response

LV Lead Position in CRTHigher response when pacing the latest site of contraction1

Lower response when pacing areas of scar2

1 Ypenburg et al J Am Coll Cardiol.2009;53(6):483-490 2Bleeker et al Circulation 2006;113(7):969-976.

Hypothesis• There have been no randomised controlled trials to

investigate the impact of LV lead position

• The TARGET study designed to prospectively assess the feasibility of a targeted approach to LV lead placement and the impact of LV lead targeting on CRT outcomes

• We tested the hypothesis that targeted LV lead placement to the latest site of contraction and away from areas of scar would enhance CRT response when compared to usual (unguided) treatment

Single blinded, randomised controlled trial, 2 UK centres Inclusion: Sinus rhythm, NYHA Class III/IV, LVEF<35%, QRS>120ms

Baseline (all patients): LV volumes, EF, NYHA, 6MWT, MLHFLQ

Randomisation

CONTROL Group TARGET Group

Targeted LV LeadSpeckle Tracking Echocardiography used to identify optimal site and LV

lead targeted to this site

Standard CRTLV Lead Placement without echocardiographic guidance

All CRT devices optimised using echo following implant

Study Design

Speckle Tracking Echocardiography to Identify Optimal Site – Latest Site

Speckle tracking radial strain imaging correlates with delayed enhanced CMR imaging for determination of scar1,2

In CRT patients, a <10% amplitude of radial strain at the LV pacing site has a high negative predictive value (91%) for

response (LV reverse remodelling)3

1 Becker et al J Am Coll Cardiol 2008 51(15):1473-1481 2Delagado et al Circulation 2011 123 (1):70-8

3Khan et al J Am Soc Echocardiogr. 2010 23(11):1168-1176

Speckle Tracking Echocardiography to Identify Optimal Site – Scar Determination

Step 1: Identify optimal site as the latest site with an amplitude >10% to signify freedom from scar

Step 2: Coronary sinus venography in steep left anterior oblique (LAO) view (50-90º) and coronary vein closest to optimal site identified

Step 3: LV lead placed to optimal site (anterior, lateral, posterior or inferior in LAO view and basal or mid LV in the RAO view)

Step 4: LV lead position correlated with echocardiographic data and described as: Concordant (pacing the optimal site)

Adjacent (1 segment away) Remote (≥2 segments away from the optimal site)

LV Lead Targeting – TARGET Group

Study EndpointsPrimary endpoint

• Comparison of response rates between groups

(≥15% reduction of LVESV at 6 months)

Secondary endpoints

• Clinical response rates (≥1 improvement in NYHA class)

• All cause mortality

• Combined mortality & heart failure hospitalisation

Statistics: 80% power to identify a 20% difference in response rates between groups (one-sided α value of 0.05)

Assessed for eligibility (n=247)

Excluded (n= 27)•Inadequate images to perform speckle tracking echocardiography

Randomized (n= 220)

TARGET Group (n=110)•Died prior to receiving CRT (n=1)*

•Failure to implant an LV Lead (n= 4)

Lost to follow-up (n=6) *Died prior to 6 month follow up (n=3)

*Excluded from analysis (n=7)All patients included for long term

endpointsTotal data analysed n=103

for primary and secondary endpoints

CONTROL Group (n=110)•Died prior to receiving CRT (n=1) *•Failure to implant an LV Lead (n= 3)

ALLOCATION

Lost to follow-up (n=5) *Died prior to 6 month follow up (n=4)

FOLLOW UP

*Excluded from analysis (n=6)All patients included for long term

endpointsTotal data analysed n=104

for primary and secondary endpoints

ANALYSIS

Target Group (n=110)

Control Group (n=110)

Age (mean ± SD) yrs 70 ± 9 71 ± 10Male n (%) 85 (77) 88 (80)NYHA III/IV 95/15 93/17Ischemic Cardiomyopathy n (%) 62 (56) 61 (56)Diabetes Mellitus n (%) 30 (27) 29 (26)QRS duration (mean ± SD) ms 161 ± 21 161 ± 23LVEDV (mean ± SD) ml 202 ± 66 200 ± 58LVESV(mean ± SD) ml 157 ± 56 154 ± 52LVEF (mean ± SD) % 23 ± 6 24 ± 7ACEI or ARB n (%) 104 (95) 103 (94)B-blockers n (%) 78 (71) 77 (70)Spironolactone n (%) 63 (57) 59 (54)IVMD (mean ± SD) ms 45 ± 27 44 ± 24AS-P Delay (mean ± SD) ms 190 ± 136 177 ± 148

Baseline Characteristics

Target Group (n=103)

Control Group (n=104)

P Value

Latest Site of Activation % 0.961

Inferior 13 14 Posterior 38 41Lateral 32 31Anterior 9 7 Anteroseptal 4 4Inferoseptal 4 3

LV Lead Position % 0.443

Inferior 12 6Posterior 35 38Lateral 46 47Anterior 3 6Failed Implant 4 3

Latest Site and LV Lead Position

Target Group (n=103)

Control Group (n=104)

P Valu

eRelationship of LV Lead to Late Site % (n)

0.011

Concordant 61 (63) 45 (47)Adjacent 25 (26) 28 (29)Remote 10 (10) 24 (25)

Scar at LV Lead Site % (n) 8 (8) 16 (15) 0.133

LV Lead Targeting

Target Group (n=103)

Control Group (n=104)

P Value

Implant Related Complications 0.991Total % (n) 13 (13) 14 (13)Failure to implant LV lead 4 (4) 3 (3)LV Lead Displacement (repositioning) 5 (5) 6 (6)Phrenic nerve stimulation (reposition) 1 (1) 2 (2)Device infection (extraction/re-implant) 1 (1) 1 (1)Pneumothorax 1 (1) 1 (1)Myocardial perforation 1 (1) 1 (1)

Procedural CharacteristicsProcedural Length (mins) 139 ± 36 138 ± 42 0.823Screening time (mins) 25 ± 14 19 ± 13 0.031Screening dose (mGy/cm2) 133 ± 107 91 ± 69 0.024

Procedural Characteristics

Primary Endpoint

Response Rates: TARGET vs. Control (70% vs. 55%, p=0.031) Absolute difference in the primary endpoint of 15% [95% CI (2%, 28%)]

Secondary Endpoint

Clinical Response Rates: TARGET vs. Control (83% vs. 65%, p=0.003)

Target vs. Control

All Patients: Effect of LV Lead Position

All Patients: Effect of Scar

OR 95% CI P valueUnivariate Regression AnalysisAge 1.05 1.01-1.08 0.007Male Gender 2.09 0.99-4.43 0.054Ischaemic Aetiology 1.74 0.97-3.12 0.063QRS duration 1.00 0.98-1.01 0.47Scar at LV pacing site 2.40 1.02-5.70 0.046Dyssynchrony 5.51 2.9-10.4 <0.01Concordant Lead 5.30 2.8 – 9.96 <0.01

Multivariate Regression AnalysisAge 1.06 1.01-1.11 0.018Male Gender 2.85 1.02-7.96 0.045Ischaemic Aetiology 1.54 0.69-3.43 0.29QRS duration 0.99 0.97-1.01 0.22Scar at LV pacing site 3.06 1.01-9.26 0.048Dyssynchrony 5.95 2.78-12.7 <0.01Concordant Lead 4.43 2.09-9.40 <0.01

Conclusions• The TARGET study is the first randomised controlled

trial of LV lead targeting

• Targeted LV lead placement is feasible and associated with enhanced CRT response

• Concordant LV lead placement, baseline dyssynchrony and pacing away from areas of scar are strongly related to improved CRT outcomes