How to treat Cardiac Resynchronization Therapy complications? C. Leclercq Departement of Cardiology Centre Cardio-Pneumologique Rennes, France

How to treat Cardiac Resynchronization Therapy complications? C. Leclercq Departement of Cardiology Centre Cardio-Pneumologique Rennes, France

Presenter Disclosure Information Christophe Leclercq, MD, PhD FINANCIAL DISCLOSURE: Research Grants: Boston Scientific, Medtronic, Sorin Group, St. Jude Medical, Consulting / Advisory board: Boston Scientific, Biotronik, Medtronic, St. Jude Medical, Sorin Group Lectures: Boston Scientific, Biotronik, Medtronic, St. Jude Medical, Sorin Group, GE, Boehringer Stock Options: None; Salary Support: None; Speaker Bureau: None

Introduction Dramatic increase in CRT devices implantations ~42.000 CRTD in 2010 (over 420 mil. inhab.) ~13.000 CRTP in 2010 (over 420 mil. inhab.) Rate of complications probably underestimated

Which complications with CRT? Common complications with implantation of PMs and ICDs Vein injury, pneumothorax (1%) 1, hematoma (VK antagonist) (2.4%) 1, infection (long procedure) Specific complications related to LV lead Failure of LV lead implantation (7%) 1 CS dissection ( 1.3%) 1 coronary vein perforation (1.3%) 1 High pacing threshold (acute and chronic) Phrenic nerve stimulation (short and long terms) LV lead dislodgement (short and long terms) (5.7%) 1 Non optimal pacing site non response to CRT X-rays exposure (patient, physician and staff) In hospital-death (0.3%) 1, 30-days mortality (0.7%) 1 1 Van Rees. J Am Coll Cardiol 2011; 58: 995-1000

Italian registry Patients undergoing successful CRT-D implantation were included consecutively in the Italian ClinicalService project Patients undergoing de novo CRT-D placement with transvenous leads implantation, in accordance with current guidelines: advanced heart failure (NYHA class II, III or IV) depressed LV function (LV ejection fraction 35%) wide QRS complex ( 120 ms) Patients undergoing replacement of a CRT device (pacemaker or ICD) or upgrading from previous ICD to CRT-D were excluded Landolina. Circulation 2011; 123: 2526-35

Methods End-points The project database was searched for all device-related adverse events: Untoward events resulting from the presence or performance of the implanted system: 1. Anticipated (i.e. device replacement for battery depletion) 1) Unanticipated device-related events resulting in surgical intervention for system revision The additional long-term risk related to CRT-D was assessed by comparing the events occurred in CRT-D group and in patients who underwent de novo implantation of single- or dual-chamber ICD systems at the study centers during the same period

Results Patient Population From 2004 to 2009, 3865 patients received a CRT-D and were enrolled in the 117 cardiovascular centers After excluding patients with a previous ICD or CRT device, we included in the analysis 3253 patients who underwent successful de novo CRT-D implantation During the same period, 1576 patients underwent de novo implantation of single- (n=741) or dual-chamber ICD (n=835) at the cardiovascular centers Parameter n=3253 Male gender, n (%) 2593 (80) Age, years 67±10 Ischemic etiology, n (%) 1364 (42) Permanent AF, n (%) 383 (12) NYHA class 2.7±0.6 QRS duration, ms 148±30 Primary prevention, n (%) 2841 (87) Myocardial infarction, n (%) 1341 (41) Previous CABG or angioplasty, n (%) 1088 (33) Valve disease, n (%) 604 (19) Previous single-chamber PM, n (%) 60 (2) Previous dual-chamber PM, n (%) 284 (9) LV ejection fraction, % 27±6 -Blocker use, n (%) 2294 (71) ACE-inhibitor use, n (%) 2405 (74) Diuretic use, n (%) 3168 (97) Class III antiarrhythmic use, n (%) 797 (24) Anticoagulant use, n (%) 814 (25) Antiplatelet use, n (%) 1338 (41)

Results During a median follow-up of 18 months (25th-75th percentiles: 9-30): 483 events resulting in surgical revision were reported in 390 patients 220 unanticipated events requiring surgical intervention occurred in 210 patients (on excluding device replacement for battery depletion) Unanticipated events requiring surgical revision (220) Device-related infections (30) Lead dislodgments or phrenic nerve stimulation (120) Left ventricular lead (96) Lead malfunctions (51) Prophylactic lead replacements # (7) Left ventricular lead (4) Right ventricular lead * (47) Leads added or replaced (12) : 22 additional events of LV lead dislodgment were noninvasively managed *: 44 leads of the Sprint Fidelis family #: Elective replacements of non-malfunctioning Sprint Fidelis leads. 0 0.5 1 1.5 2 2.5 3 3.5 4 Annual rate [events/100 Pt]

Results CRT-D demonstrated higher rates of events than singleand dual-chamber ICDs during a median follow-up of 18 months (25th-75th percentiles: 9-30) Time to first surgical revision Event-free Survival 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Log-rank test: - CRT-D Vs. DC-ICD, p<0.001 - CRT-D Vs. SC-ICD, p<0.001 - DC-ICD Vs. SC-ICD, p<0.001 0 200 400 600 800 1000 1200 1400 1600 days after im plant CRT-D dual chamber-icd single chamber-icd Landolina. Circulation 2011; 123: 2526-35

Results Device Longevity The actuarial rate of battery depletion at 4 years was: 50% in CRT-D 13% in dual-chamber ICD 10% in single-chamber ICD Time to device replacement for battery exhaustion Time to device replacement for battery depletion 100% 90% 80% Event-free Survival 70% 60% 50% 40% 30% 20% 10% 0% Log-rank test: - CRT-D Vs. DC-ICD, p<0.001 - CRT-D Vs. SC-ICD, p<0.001 - DC-ICD Vs. SC-ICD, p<0.001 CRT-D dual chamber-icd single chamber-icd 0 200 400 600 800 1000 1200 1400 1600 days after implant Landolina. Circulation 2011; 123: 2526-35

Unanticipated Events Results At 4 years unanticipated events were reported in: 14% of CRT-D 9% of dual-chamber ICD 4% of single-chamber ICD Time to first unanticipated event requiring surgical revision 100% 90% Event-free Survival 80% 70% 60% Log-rank test: - CRT-D Vs. DC-ICD, p=0.034 - CRT-D Vs. SC-ICD, p<0.001 - DC-ICD Vs. SC-ICD, p=0.004 50% 0 200 400 600 800 1000 1200 1400 1600 days after implant CRT-D dual chamber-icd single chamber-icd

Results LV lead Dislodgments LV lead dislodgements were reported in 5% of patients at 4 years and were predicted by: longer fluoroscopy time (HR: 1.02, CI: 1.01-1.04; p=0.015) higher pacing threshold on implantation (HR: 1.41, CI: 1.10-1.81; p=0.006) Event-free Survival 100% 90% 80% 70% Time to first LV lead dislodgment Published data: LV lead dislodgments in 10% at 3 years (3) 5% repeated surgery, plus 2% of CRT discontinuation at 2 years with leads by multiple manufacturers (4) 60% 50% 0 200 400 600 800 1000 1200 1400 1600 3. Johnson WB, et al. PACE 2009. 4. Biffi M, et al. Circ AE 2009. days after im plant Landolina. Circulation 2011; 123: 2526-35

Results Device-related Infections In CRT-D, infections occurred at a rate of 1.0%/y The risk of infections increased after device replacement procedures (HR: 2.04, CI: 1.01-4.09; p=0.045) Time to first device-related infection 100% 90% Event-free Survival 80% 70% 60% 50% 0 200 400 600 800 1000 1200 1400 1600 days after im plant This confirms with real-world data the findings acquired with previous trials and prospective studies (1,2) 1. McAlister FA, et al. JAMA 2007. 2. Klug D, et al. Circulation 2007.

Freedom Trial : 1647 pts LV lead events in 164 pts Gras ESC 2011

Which solutions? Phrenic nerve stimulation Compromise between PNS threshold and LV pacing threshold: uncertain Risk of loss of LV capture Interest of autocapture algorithm (also for increase in PT) Repositioning of the LV lead Uncertain Risk of future dislodgement if LV lead in proximal location in the CS vein Risk of major CE: 19% in REPLACE trial Poole. Circulation. 2010;122:1553-1561.)

LV Lead Repositioning Due To Phrenic Nerve Stimulation

Which solutions? Phrenic nerve stimulation Electrical repositioning Non invasive solution Effective in many cases ERACE trial: PNS still present in 5% Biffi: 41pts with PNS» 10 pts surgical revision» 4 pts CRT-OFF

Which solutions? Phrenic nerve stimulation Implantation of a LV leads with multiple poles to provide more pacing configurations R3 R2 R1

Quadripolar LV lead

Primary Objective MORE-CRT Study To demonstrate that using the Quartet quadripolar left ventricular lead results in easier LV implantation procedures and less chronic lead related complications compared with existing left ventricular bipolar leads. Primary Endpoint (Assessed at 6 month post implant procedure) Survival from the composite endpoint of intra-operative and post-operative endpoints. Intra-operative LV lead related endpoint: Due to phrenic nerve stimulation, lead instability or high capture threshold: - Changing to a different tributary vein of the coronary sinus - Using more than one LV lead during the procedure for any reason - Using any device (eg. A stent) to actively fixate the lead Unsuccessful implant for any reason Post-operative: Any serious adverse effect related to the LV lead Abandoned CRT for any reason

Which solutions? LV lead dislodgement/ elevated PT Electrical repositioning Usually not applicable for LV lead dislodgement Uncertain Surgical revision Risk of complications Implantation of a LV leads with multiple poles to provide more pacing configurations

Methods of Resolving LV Lead Displacement Events (61 Events in 57 Patients) 29 Gras ESC 2011

Clinical advantage of a quadripoplar lead? n=22 n=23 Forleo. Heart rhythym 2011; 8: 31-7

Which solutions? Low battery longevity: auto-capture

X-Rays exposure Over the past 2 decades radiation exposure in the US has doubled Radiation Exposure Late 1990 s to Early 2000 s Fazel, et al. N Engl J Med, 2009. NCRP Report No. 160, 2009.

min Radiation Exposure During CRT Implantation 2.9% Great variability in dose area product across CRT procedures DAP (Gy*cm²)

MediGuide Technology*: EMN system Integrated with a fluoroscopic imaging system MediGuide System Sensors are tracked without continuous fluoro Tool location is rendered onto acquired X-ray images Mediguide Sensors in Heart Tools can be manipulated without additional fluoroscopy *MediGuide Technology is in development and is not approved. Its safety and effectiveness has not been determined by the FDA or any other regulatory body.

Conclusions CRT complications are underestimated Complications are more frequent in low volume centers The most frequent late complications are PNS and LV lead dislodgements Surgical revision of the LV lead is associated with major complications especially infections New technologies such as electrical repositioning are useful to solve the problem of PNS but not in all cases Implantation of a multipolar LV lead is promising to solve the problem of PNS, LV lead dislodgment and elevated pacing threshold New technologies to reduce X-rays exposures for patients, physicians and staff are definitively needed.