Complications Associated with Pacemaker and ICD Generator Replacements and Upgrade Procedures: Results from the REPLACE Registry

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1 Complications Associated with Pacemaker and ICD Generator Replacements and Upgrade Procedures: Results from the REPLACE Registry Jeanne E. Poole, MD; Marye J. Gleva, MD; Theofanie Mela, MD; Mina K. Chung, MD; Daniel Z. Uslan, MD; Richard Borge, MD; Venketeshwar Gottipaty, MD, PhD; Timothy Shinn, MD; Dan Dan, MD; Leon A. Feldman, MD; Hanscy Seide, MD; Stuart A. Winston, DO; John J. Gallagher, MD; Jonathan J. Langberg, MD; Kevin Mitchell, RN, BS; Richard Holcomb, PhD for the REPLACE Registry Investigators. Poole J et al. Complication Rates Associated with Pacemaker or Implantable Cardioverter- Defibrillator Generator Replacements and Upgrade Procedures: Results from the REPLACE Registry. Circulation. 2010;122(16):

2 Study Background True complication rates for device replacements are unknown Limited retrospective data available The number of original device implants for new and expanding indications continues to increase Increasing number of device replacements will follow Benchmark data would help weigh risk vs. benefit During device recalls For patients who face a lifetime of therapy

3 Estimated ICD & CRT D implant volume growth The facts Aging population Broadening CRM indications Increasing implant rates ICD and CRT-D Worldwide Implants Growth Data from 2002 to 2009 is actual data, data from 2010 on is extrapolated Cardiac Rhythm Disease Management Market Model, Research from April 12, 2010; Goldman Sachs

4 ICD System Recalls Gould JAMA

5 Annual Generator Malfunctions in U.S Annual replacement rate for malfunctions: Pacemakers 2.2% ICDs 11.6% Maisel et al. JAMA 2006;295:1901

6 Generator Replacement: Complication Rates Canadian-1 * Canadian-2 Indiana Mayo UPMC Authors Gould Gould Costea Kapa Moore et al. et al. et al. et al. et. al. Study type Retrospective Retrospective Retrospective Retrospective Retrospective ICD ICD ICD + pacer ICD + pacer ICD Follow-up 3 months 12 months 3 months 2 months 6 months Patients (n) Total Complications 8.1% 9.1% 8.1% - 5.5% Major 5.8% 5.9% 4.1% 1.24% 2.1% Minor 2.3% 3.1% 4.1% - 4.6% Infections 3.4% 4.0% 0.9% - 1.0% *Gould, JAMA 2006; Gould, Heart Rhythm 2008; Costea, JCE 2008; Kapa, PACE 2007; Moore, Int J Card 2009

7 Generator Replacement with New Leads: Upgrades Cambridge UK * Emory University Brigham and Women s Goethe University Frankfurt Authors Hildick-Smith Baker Sweeney Duray et al. et al. et al. et al. Study type Retrospective PPM Retrospective Dual PPM to CRT-P Retrospective PPM and ICD to Dual ICD Prospective comparison of de novo CRT-D to PPM or ICD upgrade to CRT-D Follow-up 1.5 months 7.7 months 13.1 ± 12.9 months 6 months Patients (n) Total Complications 45% 8.3% 8.8% 28% Major 45% 5.0% 1.8% 11% Minor - 3.3% 7.0% 22% Infections 2.3% 5.0% 1.8% 22% *Hildick-Smith, Heart 1998; Baker, Pacing Clin EP 2002; Sweeney, Pacing Clin EP 2002; Duray, Europace 2008 Late anecdotal follow-up to 48 months

8 REPLACE Study Design Prospective, multicenter registry Sample size: 1750 patients based upon precision for complication estimation (1000 patients for replacement only and 750 patients with lead additions or revisions) Inclusion: Cohort 1: Generator change without new lead Cohort 2: Generator change + planned lead addition/revision Life expectancy > 6 months Exclusion: PM or ICD infection requiring explant Planned lead extraction for any reason Complications: Pre-defined, reviewed by blinded CEC (EP and ID) Commercially available devices per investigator choice from all manufacturers

9 REPLACE Registry Research Team Steering Committee: Jeanne Poole, M.D. PI Richard Borge, M.D. Mina Chung, M.D. Dan Dan, M.D Venkateshwar Gottipaty, M.D. Theofanie Mela, M.D. Timothy Shinn, M.D. Daniel Uslan, M.D. Study Biostatistician: Richard Holcomb, Ph.D. Clinical Events Committee: Marye Gleva, M.D. Chair Heather Bloom, M.D. M. Carolyn Gamache, M.D. T. Duncan Sellers, M.D. David Warren, M.D., M.P.H. Clinical Data Management: Novella, Inc. Study Sponsor: BIOTRONIK, Inc.

10 Study Timeline Enrollment Generator replacement procedure Wound examination 1-7 weeks 3-month follow-up phone call or clinic visit Final 6-month clinic visit

11 Methods Major and minor complications pre-defined and purposely comprehensive All events adjudicated by an independent clinical events committee including EP and ID specialties Infectious events were classified based on the CDC surgical site infection definitions Stitch abscesses excluded from CDC definitions

12 Definitions: Major and Minor Major Complications Death < 30 days as direct result of the procedure Infection IV antibiotics and/or device removal Cardiac perforation +/- tamponade Pneumothorax or hemothorax Cardiac / respiratory arrest or ischemia within 24 hrs Hemodynamic instability intervention +/- pressors Pulmonary embolus Stroke within 30 days Prolonged hospitalization due to the procedure Hematoma evacuation, transfusion, or admission Generator or lead malfunction requiring re-operation Pocket revision Hospital readmission due to the procedure Minor Complications Patient distress or change in status requiring additional clinical evaluation or treatment Pocket dehiscence outpatient Hematoma >7 days +/- tenseness or drainage Pain lasting >7 days narcotics Cellulitis treated as an outpatient Blistering of the skin from tape or glue significant patient discomfort Stitch abscess antibiotics Device reprogramming due to significant patient symptoms or status change (e.g., syncope, hypotension or dyspnea) Deep vein thrombosis

13 REPLACE Registry Sites CA OR WA NV ID AZ UT MT WY CO NM SD ND NE KS OK MN IA MO AR WI IL MI IN KY TN OH WV NY PA VA NC SC NH VT DE MD DC ME NJ RI MA CT TX LA MS AL FL GA 37 academic centers 32 private hospitals

14 Baseline Clinical Characteristics Clinical Characteristic Cohort 1 (N=1031) Cohort 2 (N=713) P-value Mean Age ± SD, yrs 70.6 ± ± Female, no. (%) 389 (37.7) 172 (24.1) <0.001 Minority, no. (%) 128 (13.4) 83 (11.6) 0.83 NYHA Class, no. (%): <0.001 Class I/II 441 (42.8) 189 (26.5) Class III/IV 143 (13.9) 397 (55.7) No heart failure symptoms 423 (41.0) 112 (15.7) Mean EF ± SD, % 44.3 ± ± 13.1 <0.001 Renal Disease (creatinine 1.3 mg/dl) 149 (14.5) 138 (19.4) Pacemaker Dependent, no. (%) 298 (28.9) 208 (29.2) 0.96 Prior CABG or Valve Surgery 353 (34.2) 285 (40.0) 0.02 Meds: Warfarin 386 (37.4) 328 (46.0) <0.001 Amiodarone 102 (9.9) 121 (17.0) <0.001

15 Existing Device and Indication Existing Device Cohort 1 Cohort 2 (N=1031) (N=713) PM 515 (50.0%) 329 (46.1%) ICD 327 (31.7%) 320 (44.9%) CRT-D or CRT-P 189 (18.3%) 64 (9.0%) Duration of Implant ± SD, yrs 6.2 ± ± 3.3 Indication for device replacement ERI or EOL Manufacturer Advisory Malfunction Elective Replacement Prior to ERI 997 (96.7) 12 (1.2%) 6 (0.6%) 22 (2.1%) 226 (31.7%) 5 (0.7%) 22 (3.1%) 43 (6.0%) Upgrade CRT n/a 407 (57.1%) Single Dual PM or ICD n/a 114 (16.0%) Upgrade CRT-P CRT-D n/a 13 (1.8%) Replace Malfunctioning Lead n/a 179 (25.1%) P-value <0.001 <0.001 < <0.001 <0.001

16 Cohort 1 Complication Summary No. of Patients with Complications Event Rate (95% CI) Major % (2.9, 5.4) Minor % (5.9, 9.1) Infections only Major* Minor Combined % (0.3,1.5) 0.6% (0.2, 1.3) 1.4% (0.7, 2.3) * Five required system extraction

17 Cohort 1 Major Complications * Requiring reoperation Requiring evacuation, hospitalization or transfusion Such as loose connection

18 Cohort 1 Minor Complications ** Multiple VF inductions with prolonged anesthesia and recovery Hematoma persistent > 7 days managed as an outpatient Significant symptoms, such as syncope, resulting in reprogramming to manage

19 Cohort 1 Complication Rates by Device Type No generator was implanted into 3 Cohort 1 patients (no complications occurred) because of physician decision to abandon the procedure.

20 Cohort 2 Complication Summary No. of Patients with Complications Event Rate (95% CI) Major % (12.7, 18.1) Minor Infections only % (5.7, 9.8) Major* Minor Combined % (0.3,1.8) 0.3% (0.0, 1.0) 1.1% (0.5, 2.2) * Five required system extraction

21 Cohort 2 Major Complications * Requiring reoperation Requiring evacuation, hospitalization or transfusion Such as loose connection To assess defibrillation lead integrity

22 Cohort 2 Minor Complications ** VT unanticipated and thought due to electrocautery over generator/leads Hematoma persistent >7 days managed as an outpatient Significant symptoms, such as syncope, resulting in reprogramming to manage Symptomatic hypotension reversed with IV fluids

23 Cohort 2 Complication Rates by Device Type Nine patients without generator changes (2 complications occurred) due to adequate battery voltage but inability to add a lead or a decision not to add a lead.

24 Cohort 2 Major Complications by Lead Procedure Includes all attempts to add one or more leads regardless of procedural success. P=0.004 for the difference across the three procedure types.

25 REPLACE Implications Implanting physicians now have a more comprehensive quantification of risk from the largest prospective multicenter study Device advisories Evaluating expanding CRM indications Future efforts at extending battery longevity and reducing lead-related complications are warranted Recommendations for life-long device therapy should include a consideration for risks associated with lead addition or generator replacements, especially in situations where the benefit may be less certain

26 REPLACE Conclusions REPLACE is the first prospective multicenter report of comprehensive 6 month complication rates following CIED generator replacement Major complication rates were greater When a lead was added or revised In ICD patients compared with PM patients In CRT patients compared with PM patients The highest complication rate was seen in patients who underwent revision or addition of an LV lead to a CRT system The overall infection rate was low

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