Cardiovascular Disease

1. Patient Selection for Primary Prevention
Implantable Cardioverter Defibrillators in the
Cardiovascular Research Network: A
Comparison with a National Study
Robert Greenlee, PhD, MPH
Marshfield Clinic Research Foundation
Univ. of Wisconsin Institute for Clinical and Translational Research
Graduate Program in Clinical Investigation

2. Abstract Co-authors
• David Smith – KPNW
• Jane Saczynski, Jerry Gurwitz – Meyers
• Kristi Reynolds – KPSC
• David Magid, Liza Reifler, Nat Jackson, Karen Glenn
– KPCO
• Alan Go – KPNC
• Andrea Cassidy-Bushrow – HFHS
• Humberto Vidaillet – Marshfield
• Frederick Masoudi – UC-Denver/KPCO

3. Presentation Overview
• Background
– Implantable Cardioverter Defibrillators (ICDs)
– Translation/Effectiveness Issues
• CVRN Longitudinal Study of ICDs
– Design, Data Sources
– Aim 1 Methods
– Preliminary Results
• Implications/Next Steps
• Acknowledgments

4. Implantable Cardioverter
Defibrillators (ICDs) to Prevent
Sudden Cardiac Death (SCD)
www.bostonscientific.com

5. Indications for ICDs
emonstrated Reductions in Risk of SCD by RCTs
– Secondary prevention for patients who have been successfully
resuscitated from SCD or have unstable ventricular tachycardia (VT) not
due to a reversible cause
– Primary Prevention for patients without a history of SCD/unstable VT
but at high risk, including some patients with:
– Severe left ventricular systolic dysfunction (LVSD)
– Long QT syndrome, Arrhythmogenic RV dysplasia, Hypertrophic cardiomyopathy
CD implantation also has high costs, risk of complications, and
potential negative influences on quality of life

6. From Trial-Based Efficacy to Effectiveness in
Community Care
• What about patients at the margins of key clinical
indication eligibility criteria from RCTs?
– CMS mandated data collection (NCDR ICD Registry)
– Practice Guidelines: “Best to have ICDs offered to patients with
clinical profiles as similar to those included in the trials as possible”
[Epstein et al., Circ 2008;117:e350-3408]
• How well do devices work in patients that do not otherwise
look like trial participants?
– Age, gender, comorbidity differences in community care ICD
patients [Masoudi et al., Circ QCO 2012; in revision]
• Utilization/Disparities, e.g., Who should be getting a device but is
not? Who is getting a device but perhaps should not be?

7. ‘Non-Evidence-Based’ ICD Implantations
• NCDR ICD registry based study [Al Khatib et al., JAMA
2011;305(1):43-49]
– 22.5% of primary prevention implants were ‘non-
evidence-based’
• higher risk of in-hospital mortality/post-procedural complications
• substantial hospital variation (0-60%)
• Not reducing over time
• Provocative and controversial issue
– Arguments: Data limitations, criteria interpretations,
clinical appropriateness, semantics, etc.
• Department of Justice audits [Steinberg and Mittal, JACC
2012;59:1270-1274]

8. CVRN Longitudinal Study of ICDs:
Design
• Seven (7) participating CVRN sites
– Kaiser Permanente (Colorado, Northern California, Southern
California, Northwest), Marshfield Clinic, Henry Ford, Meyers/Fallon
– 14 implanting facilities (range per site 1-5)
• Observational cohort (n=2639)
– 3 years post implant follow-up for clinical/device therapy outcomes
• Subject Eligibility
– First ICD implant 2006-2009
– Primary Prevention
– Systolic dysfunction: Ejection Fraction <50%
– Follow-up care in participating site health care systems

9. CVRN Longitudinal Study of ICDs:
3 Data Sources
• NCDR ICD Registry
• CVRN - Virtual Data Warehouse
• Novel repository of treated
arrhythmic episodes Treated episodes
(shocks, ATPs)

10. Analysis Methods
• Aim 1: Identify the extent to which patients with LVSD
receiving ICDs for primary prevention of SCD meet
guideline-recommended implantation criteria.
• Used criteria from national NCDR-based study*
– Includes:
• First time primary prevention implants
• Cardiomyopathy of ischemic or non ischemic etiology
• Past MI with ejection fraction <=30%; or CHF with ejection fraction
<=35%
• Adult
– Excludes:
• history of sustained ventricular tachyarrhythmia
• cardiac resynchronization therapy devices
*Al Khatib et al., JAMA 2011;305(1):43-49

11. Analysis Methods
• Outcome as defined in same national study*:
– ‘Non-Evidence-based’; Any one of the following:
• MI within 40 days before ICD implantation
• CABG within 3 months before ICD implantation
• Advanced heart failure symptoms (NYHA IV)
• Newly diagnosed heart failure (within 3mos)
– Described as a proxy: Practice Guidelines require low EF
despite optimal medical therapy; Al Khatib assumed this
can not be established in recently diagnosed CHF cases.*
– Approximates CMS coverage eligibility exclusions
*Al Khatib et al., JAMA 2011;305(1):43-49

12. Aim 1 Preliminary Results
Overall
• 1726 of 2639 subjects in cohort (65%) met
the inclusion criteria for analysis.
• 301 of 1726 (17%) had one or more of the
criteria defining non-eligible implants

13. Aim 1 Preliminary Results:
Individual Criteria
• Previous MI
– No 745 (43.2%)
– Yes > 40 days 835 (48.4%)
– Yes <= 40 days 145 ( 8.4%)
• CHF Duration
– None 214 (12.4%)
– Yes > 3 mos 1352 (78.3%)
– Yes <=3 mos 160 ( 9.3%)
• NYHA Class
– I 236 (13.7%)
– II,III 1465 (84.9%)
– IV 22 ( 1.3%)

14. Aim 1 Preliminary Results:
Demographic Differences
Variable Value Implant Implant P-Value
Criteria Criteria
Met Not Met
Implant Age
Mean 65.4 67.2 0.0124
Std. dev. 11.8 11.1
Sex
Male 1091 (81%) 254 (19%) 0.0087
Female 328 (88%) 47 (12%)
Race
White 916 (83%) 190 (17%) 0.7462
Non-white 500 (82%) 110 (18%)

15. Summary of Preliminary Findings
• About 1 in 6 primary prevention ICD
patients in the CVRN LSICD fall outside of
ICD eligibility criteria using published
definitions from a national NCDR study.
– Driven more by recent MI/CHF diagnoses than severe
CHF symptoms or recent CABG (0.3% of total)
– More common among men than among women
– Non-eligible slightly older
– No difference by race
– Somewhat lower in the CVRN LSICD than in NCDR as a
whole

16. Implications
• Caution in interpretation
– Outcome measure definitions based on one used in
national data analysis; legitimate debate about what
that represents; e.g.,
• Outside of eligibility criteria if MI within 40 days, but what if also
one > than 40 days - 65/145 (45%) in our data
• Less evidence for excluding recent onset CHF patients
• Definitely some overutilization occurring
• Can not evaluate underutilization - Only studying
implant recipients, not the full population of those at
risk
• Further study encouraged

17. Next Steps for Aim 1 Analyses
• finalize ‘non-eligible’ outcome; incorporate current
best thinking on meaning of the criteria
• descriptive analysis to look for additional non-
demographic correlates of ‘non-eligible’ implants
• Use ‘non-eligible’ implant as cofactor/
stratification in future analyses of other outcomes
– Clinical (complications, hospitalization, mortality, cost)
– Rates of appropriate and inappropriate therapy

18. CVRN Longitudinal Study of ICDs: Funding
This project was funded under Contract No. 290-05-0033
from the Agency for Healthcare Research and Quality, US
Department of Health and Human Services as part of the
Developing Evidence to Inform Decisions about
Effectiveness (DEcIDE) program; and by the American
College of Cardiology Foundation; with support from the
National Heart, Lung, and Blood Institute. While the
sponsoring organizations have been involved in discussions
of this research as it has progressed and have provided
oversight and guidance, the authors of this report are solely
responsible for its content. Sponsorship may not be
construed as an endorsement of all statements in the report
by the Agency for Healthcare Research and Quality, the
National Heart, Lung, and Blood Institute, the US
Department of Health and Human Services, or the American
College of Cardiology Foundation. Acknowledgments: The
authors appreciate the efforts of study team members at all
participating sites, as well as the support from funder and
stakeholder organizations.

19. CVRN Longitudinal Study of ICDs: Investigative Team
• KPCO: Frederick Masoudi MD (co-PI), David Magid MD, Karen Glenn BS,
Nathaniel Jackson MS, Laura Muhs, Heather Nuanes, Pamela Peterson MD, Liza
Reifler MPH, Paul Varosy MD
• KPNC: Alan Go MD, Jason J. Dea, Dongjie Fan, MSPH, Michael Lauer, MD PhD,
Liliana V. Metzger, Nina Sasso, Kiranjit Sidhu, Ashley Spooner, Sue Hee Sung,
MPH
• KPNW: David Smith RPh, PhD, Jill Mesa, Amanda Petrik, Carmel Wax
• KPSC: Kristi Reynolds PhD MPH, Britta Amundsen, MA, Jonathan Doris MD, Nigel
Gupta, MD, Teresa Harrison MS, Jacqueline Porcel, MPH, Tony Yiu, MS
• Marshfield Clinic Research Foundation/ Marshfield Clinic: Robert Greenlee
PhD, MPH (co-PI), Marilyn Bruger, Jay Fuehrer, Romel Garcia-Montilla MD, John
Hayes, MD, Aaron Miller PhD, Deborah Multerer, Param Sharma MD, Mary Suits
RN, Jeff Van Wormer PhD, Humberto Vidaillet MD
• Meyers Fallon: Jerry Gurwitz, MD, Robert J. Goldberg, PhD, Jane S. Saczynski,
PhD, Jackie Fuller, Mark Mooradian, Christopher Malone, Joann (Baril) Wagner
• Henry Ford Health System: Andrea Cassidy-Bushrow PhD, Claudio Schuger MD,
Dayna Johnson, MPH, Richard Krajenta, BS, Michelle Brown, RN, Debra Veryser,
BA, RHIT, Judith Lehman RN, Claire Hooker, Heather Dakki MPH
• Mayo Clinic: Stephen Hammill, MD
• Touro College: Alan Kadish, MD

20. CVRN Longitudinal Study of ICDs
• Additional Acknowledgments
– ACC and NCDR Staff
– Harvard Pilgrim DEcIDE staff
• Disclosures of Authors
– Dr. Masoudi has a contract with the American College of Cardiology
Foundation.
– Dr. Vidaillet’s contribution was supported in part by grant
1UL1RR025011 from the Clinical and Translational Science Award
(CTSA) program of the National Center for Research Resources,
National Institutes of Health.