1. 6/9/2008 Comparative effectiveness reviews: methodological observations David B. Matchar, MD Professor of Medicine and Director, Center for Clinical Health Policy Research Duke University Medical Center

2. I. Drug-Eluting vs. Bare Metal Stents: Results from a Practice-Based Registry Eric L. Eisenstein, DBA; Kevin J. Anstrom, PhD; David F. Kong, MD, AM; Linda K. Shaw, MS; Robert H. Tuttle, MSPH; Daniel B. Mark, MD, MPH; Judith M. Kramer, MD, MS; Robert A. Harrington, MD; David B. Matchar, MD; David E. Kandzari, MD; Eric D. Peterson, MD, MPH; Kevin A. Schulman, MD; Robert M. Califf, MD Division of Cardiology, Department of Medicine, Duke University Medical Center, Duke Clinical Research Institute, Duke Translational Medicine Institute, Duke DECIDE Network, and Duke Center for Clinical Health Policy Research, Durham, NC Eric L. Eisenstein, DBA; Kevin J. Anstrom, PhD; David F. Kong, MD, AM; Linda K. Shaw, MS; Robert H. Tuttle, MSPH; Daniel B. Mark, MD, MPH; Judith M. Kramer, MD, MS; Robert A. Harrington, MD; David B. Matchar, MD; David E. Kandzari, MD; Eric D. Peterson, MD, MPH; Kevin A. Schulman, MD; Robert M. Califf, MD Division of Cardiology, Department of Medicine, Duke University Medical Center, Duke Clinical Research Institute, Duke Translational Medicine Institute, Duke DECIDE Network, and Duke Center for Clinical Health Policy Research, Durham, NC Supported by the Agency for Healthcare Research & Quality Contract No. 290-05-0032 Duke University Medical Center Institutional Review Board Approval Registry Number 8223-06-2R0ER Supported by the Agency for Healthcare Research & Quality Contract No. 290-05-0032 Duke University Medical Center Institutional Review Board Approval Registry Number 8223-06-2R0ER

3. Background and Objectives n Extrapolating drug eluting stent (DES) clinical trial results onto clinical practice may be unreliable. n Current antiplatelet regimens may not be sufficient to prevent late adverse events. n This analysis examined outcomes for: u DES and bare metal stent (BMS), and u Clopidogrel use beyond 6 months. n Extrapolating drug eluting stent (DES) clinical trial results onto clinical practice may be unreliable. n Current antiplatelet regimens may not be sufficient to prevent late adverse events. n This analysis examined outcomes for: u DES and bare metal stent (BMS), and u Clopidogrel use beyond 6 months.

4. n Duke Databank for Cardiovascular Disease n Patients receiving: u BMS, January 2000 - July 2005 u DES, April 2003 - July 2005 n Exclusion criteria u Congenital heart disease u Valvular heart disease u Prior CABG or PCI u Left main coronary disease n Duke Databank for Cardiovascular Disease n Patients receiving: u BMS, January 2000 - July 2005 u DES, April 2003 - July 2005 n Exclusion criteria u Congenital heart disease u Valvular heart disease u Prior CABG or PCI u Left main coronary disease Study Population

5. n Initial: Demographic, medical history, physical examination and catheterization data n Follow-up (at 6 months, 1 year, and then annually) u Medication use (Clopidogrel, aspirin) u Events up to 24 months (through September 7, 2006) u Censored at time of last contact u 98% follow-up completion rate u Median follow-up 3.1 years n Initial: Demographic, medical history, physical examination and catheterization data n Follow-up (at 6 months, 1 year, and then annually) u Medication use (Clopidogrel, aspirin) u Events up to 24 months (through September 7, 2006) u Censored at time of last contact u 98% follow-up completion rate u Median follow-up 3.1 years Data Collection

6. Baseline Patient Characteristics 0.420.42 61 (53, 70) 60 (52, 70) Age Median (Q1,Q3) <0.001<0.001 2.8 (2.5, 3.0) 3.0 (2.8, 3.3) Stent Diameter mm Median (Q1,Q3) Median (Q1,Q3) Stent Diameter mm Median (Q1,Q3) Median (Q1,Q3) 1212 8 8 3 3 3131 2828 2 2 5757 6464 1 1 <0.001<0.001 Number of Diseased Vessels (%) <0.001<0.00142424848 Previous MI (%) 0.470.4712121111 CHF (%) 0.0450.04528282525 Diabetes (%) 0.850.8563636363 Male Gender (%) 0.370.3769697070 White Race (%) 1501150131653165 Number of Patients P- value DESDESBMSBMS

7. 061218 24 Death Nonfatal MI TVR MACE MonthsMonths MonthsMonths p=0.94 p=0.022 p<0.001 -9.7 (-11.7, -7.7) -9.4 (-12.2, -6.6) 0.1 (-2.0, 2.1) -1.5 (-2.8, -2.0) DES BMS DES BMS Cumulative Incidence Rates DES-BMS (95% CI) 0 0 5 5 10 15 20 25 0 0 5 5 10 15 20 25 0 0 5 5 10 15 0 0 5 5 10 15

8. Landmark Analysis n A form of survival analysis n The cohort consists of patients without death, MI, or revascularization at a specific time after initial stent placement (the “landmark” time point) n Outcomes evaluated from this landmark time point forward n A form of survival analysis n The cohort consists of patients without death, MI, or revascularization at a specific time after initial stent placement (the “landmark” time point) n Outcomes evaluated from this landmark time point forward

9. Landmark Analysis n Patients categorized into one of 4 groups: u DES with clopidogrel (DES+C) u DES without clopidogrel (DES-C) u BMS with clopidogrel (BMS+C) u BMS without clopidogrel (BMS-C) n Patients categorized into one of 4 groups: u DES with clopidogrel (DES+C) u DES without clopidogrel (DES-C) u BMS with clopidogrel (BMS+C) u BMS without clopidogrel (BMS-C)

10. DES-C(n=579)BMS-C(n=1976)BMS+C(n=417)DES+C(n=637) 6 6 8 8 8 81313 3 3 2727262631312929 2 2 6767666662625858 1 1 <0.001<0.001 Number of diseased vessels (%) <0.001<0.001 4646515138383939 Hx MI (%) 0.0260.0261111 9 915151010 Hx CHF (%) 0.0010.0012323292930302727 Hx Diabetes (%) 0.930.936363646464646363 Male (%) 0.180.182020202024241919 Black race (%) 0.730.73 61 (52, 71) 61 (53, 70) 60 (53, 70) 61 (53, 71) Age, years p-valuep-value 6-Month Landmark Patient Characteristics

11. 6-Month Landmark Analysis Adjusted Cumulative Mortality Rates DES-C DES+C 0 0 2 2 4 4 6 6 8 8 Percent Cumulative Incidence Rate 12 18 24 6 6 Months 0.031 -3.3 (-6.3, -0.3) DES+C – DES-C p p % (95% CI) 5.3 2.0

12. 6-Month Landmark Analysis Adjusted Cumulative Mortality Rates DES-C DES+C 0 0 2 2 4 4 6 6 8 8 Percent Cumulative Incidence Rate 12 18 24 6 6 0.011 -2.5 (-4.4, -0.6) DES+C – BMS-C 0.031 -3.3 (-6.3, -0.3) DES+C – DES-C p p % (95% CI) 5.3 2.0 BMS-C 4.5 Months

13. 6-Month Landmark Analysis Adjusted Cumulative Mortality Rates DES-C BMS-C DES+C BMS+C 0 0 2 2 4 4 6 6 8 8 Percent Cumulative Incidence Rate 12 18 24 6 6 0.50 -0.7 (-2.9, 1.4) BMS+C – BMS-C 0.55 0.8 (-1.8, 3.5) DES-C – BMS-C 0.011 -2.5 (-4.4, -0.6) DES+C – BMS-C 0.18 -1.7 (-4.2, 0.8) DES+C – BMS+C 0.031 -3.3 (-6.3, -0.3) DES+C – DES-C p p % (95% CI) 5.3 3.7 4.5 2.0 Months

14. 6/9/2008 II. ACE vs. ARB for long-term treatment of essential hypertension Rx A Rx BRx C Indirect comparison

15. 6/9/2008 Criteria for considering performing an indirect comparison n Common comparator (amlodipine, atenolol, or pbo) n Study populations comparable with regard to key characteristics relevant to the assessed outcome u For event rates (death, stroke, or MI) → mean age u For studies of laboratory measures (HbA1c, glucose, creatinine, GFR, or proteinuria) → mean lab at baseline u Comparable = ∆ ≤ 10% (e.g., mean aged 70 years vs. 63 years n More than 1 study of an ACE inhibitor versus the comparator and more than 1 study of an ARB versus the comparator.

16. 6/9/2008 Despite these relatively liberal criteria… n we did not identify any appropriate candidate studies related to an outcome of special interest, and thus we did not attempt to use indirect evidence to infer relative effect of ACE inhibitors versus ARBs.

17. 6/9/2008 III. Requisite analysis StupidPerfect Requisite

18. 6/9/2008 Figure 1: Deciding When To Develop a Registry: the “Value of Information” Exercise.

19. 6/9/2008

20. 6-Month Landmark View BaselineBaseline 6 Months 24 Months BMSn=3165BMSn=3165 DESn=1501DESn=1501 Exclusions: Death: 123 Death: 123 Nonfatal MI: 94 Nonfatal MI: 94 Revascularization: 289 Revascularization: 289 Meds not reported: 266 Meds not reported: 266Exclusions: Death: 123 Death: 123 Nonfatal MI: 94 Nonfatal MI: 94 Revascularization: 289 Revascularization: 289 Meds not reported: 266 Meds not reported: 266 BMS+Cn=417BMS+Cn=417 BMS-Cn=1976BMS-Cn=1976 DES+Cn=637DES+Cn=637 DES-Cn=579DES-Cn=579 Exclusions: Death: 62 Death: 62 Nonfatal MI: 18 Nonfatal MI: 18 Revascularization: 76 Revascularization: 76 Meds not reported: 129 Meds not reported: 129Exclusions: Death: 62 Death: 62 Nonfatal MI: 18 Nonfatal MI: 18 Revascularization: 76 Revascularization: 76 Meds not reported: 129 Meds not reported: 129

21. 6-Month Landmark Analysis Adjusted Cumulative Rates of Death or Nonfatal MI DES-C DES+C 0 0 2 2 4 4 6 6 8 8 Percent Cumulative Incidence Rate 12 18 24 6 6 0.021 -4.1 (-7.6, -0.6) DES+C – DES-C p p % (95% CI) 7.2 3.1 Months

22. 6-Month Landmark Analysis Adjusted Cumulative Rates of Death or Nonfatal MI DES-C BMS-C DES+C 0 0 2 2 4 4 6 6 8 8 Percent Cumulative Incidence Rate 12 18 24 6 6 0.017 -2.9 (-5.3, -0.5) DES+C – BMS-C 0.021 -4.1 (-7.6, -0.6) DES+C – DES-C p p % (95% CI) 7.2 6.0 3.1 Months

23. DES-C BMS-C DES+C BMS+C 0 0 2 2 4 4 6 6 8 8 Percent Cumulative Incidence Rate 12 18 24 6 6 0.70 -0.5 (-3.2, 2.2) BMS+C – BMS-C 0.44 1.2 (-1.8, 4.2) DES-C – BMS-C 0.017 -2.9 (-5.3, -0.5) DES+C – BMS-C 0.16 -2.4 (-5.6, 0.9) DES+C – BMS+C 0.021 -4.1 (-7.6, -0.6) DES+C – DES-C p p % (95% CI) 7.2 5.5 6.0 3.1 Months 6-Month Landmark Analysis Adjusted Cumulative Rates of Death or Nonfatal MI

24. DES+C(n=637) p-valuep-value BMS-C(n=1976)BMS+C(n=417)DES-C(n=579) 6-Month Landmark Medication Use Clopidogrel use at: <0.001 0 0 100 0 0 (%) 6 Months (%) <0.001 5 5 77 15 73 (%) 12 Months (%) <0.001 8 8 62 15 55 (%) 24 Months (%) Aspirin use at: 0.003 87 82 86 93 (%) 24 Months (%) 0.003 85 84 86 91 (%) 12 Months (%) <0.001 80 86 74 94 (%) 6 Months (%)

25. LimitationsLimitations n Clopidogrel and DES use not randomized n Unmeasured prognostic factors n Clopidogrel use identified by patient self- report n 90-day window used to determine follow- up contact and medication use n Clopidogrel and DES use not randomized n Unmeasured prognostic factors n Clopidogrel use identified by patient self- report n 90-day window used to determine follow- up contact and medication use

26. ConclusionsConclusions n Compared to BMS, DES is associated with reduced rates of TVR n Death and MI higher for DES patients stopping clopidogrel therapy at 6 months n Results consistent with CREDO, BASKET- LATE, and PREMIER n Need rigorous clinical trials to assess optimal duration of clopidogrel therapy n Compared to BMS, DES is associated with reduced rates of TVR n Death and MI higher for DES patients stopping clopidogrel therapy at 6 months n Results consistent with CREDO, BASKET- LATE, and PREMIER n Need rigorous clinical trials to assess optimal duration of clopidogrel therapy