1. Longitudinal Study of Implantable Cardioverter Defibrillators (ICDs) AHRQ Annual Meeting - September 21, 2011 Robert Greenlee, PhD, MPH Marshfield Clinic Research Foundation University of Wisconsin Graduate Program in Clinical Investigation Frederick Masoudi, MD, MSPH University of Colorado, Denver Affiliate Investigator, Colorado Kaiser Permanente IHR

2. Presentation Outline Background: Study History Study Aims Study Setting and Design (HMORN CVRN) Study Status/Timeline

3. Longitudinal Study of ICDs Background: Study History

4. Proposed Longitudinal ICD Registry Study – April 2007 By National ICD Registry Working Group to address CMS Group B Coverage with Evidence Development Questions –Rates of device therapy in EF 31-35% NIDCM <9 mos NYHA IV/CRT-D Recruited physician-based collection Enroll and follow 3500 Medicare Primary Prevention ICD recipients

5. CVRN Longitudinal ICD Study: Outcomes of Primary Prevention ICDs in Contemporary Practice NHLBI-sponsored observational cohort study awarded for 2010-2012 –Clinical outcomes Complications Hospitalization Mortality Utilization/Cost Fall 2009 AHRQ task order, additional funding from ACCF/HRS, to collect device firing data and address CMS Group B CED questions Combined study timeline Oct 2009-March 2013

6. Longitudinal Study of ICDs: Study Support Agency for Healthcare Research and Quality National Heart Lung and Blood Institute American College of Cardiology Foundation Heart Rhythm Society NCDR ICD Registry Staff (Data Support)

7. Longitudinal Study of ICDs Study Aims

8. CVRN Longitudinal ICD Study Aims: Outcomes of Primary Prevention ICDs in Contemporary Practice Identify the extent to which patients with LVSD receiving ICDs for primary prevention of SCD meet guideline- recommended implantation criteria. Assess longitudinal outcomes (complications, mortality, & hospitalization) in this cohort and compare these outcomes with those published in published efficacy studies. Identify the patient, device, and provider characteristics associated with outcomes.

9. CVRN Longitudinal ICD Study Aims: Outcomes of Primary Prevention ICDs in Contemporary Practice Assess rates of treated arrhythmic episodes (shocks and anti-tachycardia pacing) in patients undergoing primary prevention ICD implantation with a focus on specific patient subgroups: Left ventricular ejection fraction 30-35% Non-ischemic cardiomyopathy for less than 9 months duration Advanced symptomatic heart failure (NYHA IV) Appropriate and Inappropriate therapy

10. Study Hypotheses Community ICD patients older and greater comorbidity Women, elderly, racial/ethnic minorities more likely to meet guideline eligibility than men, young, whites Complications in community practice higher than published RCTs Hospitalization (all cause, CHF) higher in community practice All cause mortality higher in community practice, sudden cardiac death no different Costs of care in community exceed those in RCTs No preset hypotheses for device therapy aims

11. Longitudinal Study of ICDs Study Setting and Design

12. Study Population Seven (7) participating sites from the Cardiovascular Research Network –Kaiser Permanente (Colorado, Northern California, Southern California, Northwest), Marshfield Clinic, Henry Ford, Meyers/Fallon –14 implanting facilities (range per site 1-5) Subject Eligibility –ICD implantation 1/2006-12/2009 –First implant –Indication of Primary Prevention –Evidence of systolic dysfunction Ejection Fraction <50% –Follow-up care in participating site health care systems Observational Cohort with 3 years of post implant follow-up

13. The Cardiovascular Research Network (CVRN), based in the HMO Research Network and funded for 5 years by NHLBI, is a national collaborative and resource that leverages expertise, populations, and data sources from a consortium of 14 geographically diverse health plans with integrated research divisions in the U.S. Goals include: Provide robust cardiovascular disease and related health care surveillance data Promote research on clinical practice and quality of care Enable assessment of new diagnostic and therapeutic technologies and clinical guidelines on cardiovascular disease…patient outcomes over time Facilitate research on determinants of disease for uncommon disease phenotypes

15. Longitudinal ICD Study Database 3 Sources NCDR ICD Registry Eligibility Criteria, Implant Detail, Baseline Clinical Data, Adverse Events (Inpatient) CVRN Virtual Data Warehouse Longitudinal clinical data in federated system with standardized file structures and data definitions Novel repository of treated arrhythmic episodes Abstracted from archived health system records Central EP review/ adjudication Treated episodes (shocks, ATPs)

16. Steps To Obtain NCDR Data Amend agreements between ACCF and hospital registries Study sites linked NCDR data to health plan members as needed, and assigned studyID Flagged data back to ACCF; on to data coordinating center

17. VDW Data Tables for ICD Study Health plan enrollment Demographics Longitudinal clinical encounters –Diagnoses –Procedures –Hospitalizations –Utilization/Cost Laboratory values (selected) Medications Vital status

18. Treated Arrhythmic Episode Repository Step 1: Site Abstraction Batch collection after subjects accrue full followup Trained site abstractors review: –Central health system records and data archives –ICD Clinic site files –Remote interrogation websites Submit data forms on interrogations and treated episodes with source documents –surgical note from implantation –for any treated episodes device interrogation reports, electrograms, clinical notes Intake review by project manager and ICD nurse for quality/completeness

19. Treated Arrhythmic Episode Repository Step 2: Central Review/Adjudication 4 member EP review panel generate study data –Verify occurrence of treated episode –Local provider interpretation –Type of therapy (ATP, shock, both, multiples) –Appropriateness (definite, probable) (success, untoward effects) –Sufficiency of source documentation –Dual independent review with conference to attempt resolution Panel of 3 Expert ICD Electrophysiologists adjudicate treated episodes forwarded from Central Panel –All episodes with unresolved discrepancies or otherwise nominated –Sample of episodes with resolved discrepancies –Small sample of episodes with no discrepancies for QA

20. Study Governance PIs: Frederick Masoudi & Robert Greenlee Leadership Team: PIs, David Magid (KPCO), Alan Go (KPNC) Scientific Committee: Leadership team, the 4 other site PIs, and members of the adjudication committee Advisory Committee: Elise Berliner (AHRQ); Steve Hammill (ACCF); representatives from HRS, NHLBI, CMS, Device Industry, and patient advocacy (SADS Foundation)

21. Longitudinal Study of ICDs Study Status/Timeline

22. Study Status NCDR data on cohort of 2639 eligible subjects Upload of longitudinal clinical data files (VDW) into 2010 Abstraction of interrogation and treated episode data –Training, pilot (n=45), forms and procedures – Summer 2010 –1 st Batch submitted in January 2011 –Sites now working on abstraction and submission of batch #4 of 7 Review –Batch 1 will complete external resolution by end of September –Batch 2 in central resolution –Batch 3 completed intake review and data entry Output: methods/baseline presentations and reports

23. CVRN Longitudinal Study of ICDs: Comparison with Landmark RCTs MADIT-IISCD-HeFTCVRN LSICD Age (years)64.56066.6 Male gender85%76%75% Non-white race--23%33% Diabetes35%30%42% Atrial fibrillation9%16%31% Hypertension53%56%73% Moss AJ et al. NEJM 2002;346:877. Bardy GH, et al. NEJM 2005;352:225-37

24. Remaining Study Timeline Year 3 (October 2011 – September 2012) –Complete batch collection/adjudication of treated episodes –Sites generate and submit updated VDW tables x 2 –Initial outcome analyses, presentations, manuscripts Eligibility, Complications, Hospitalization, Utilization –Ancillary studies underway Year 4 (6 months October 2012-March 2013) –Final analyses, primary results manuscripts Mortality, Treated Arrhythmic Episodes Possible extension (AHRQ proposal in review) –Year 3 – collect NCDR and VDW data on 2010 implants, and on 2006-2010 implants from a 15 th hospital –Option (year4,5) – collect device therapy data in CMS strata

25. Stratum Size Stratum Proposed by Longitudinal ICD Registry Working Group Actual Current If Study Expanded All patients3,5002,6393,436 LVEF 31-35%350355467 Non-ischemic CM <9 mo duration 385244320 NYHA IV w/CRT-D 2603343

26. Thank you.

27. CVRN LSICD: Heart Failure History Group N/% (total N=2521) No prior HF history278 (11%) HF, diagnosis within 9 months520 (21%) HF, diagnosis >9 months1722 (68%) Prior HF hospitalization1163 (52%) NYHA Class I290 (11.5%) II1213 (48.2%) III960 (38.1%) IV54 ( 2.1%)

28. Other data on study cohort Medicare: –60% 1 st payor, 69% 1 st or 2nd Device Type –Single chamber – 37% –Dual chamber – 33% –Bi-ventricular – 30% Implanting Facilities –Teaching 9, non 5 –Urban 11, suburban/rural 3 –Private/community 12, university 2