1. Columbia University Medical Center The Cardiovascular Research Foundation Long-Term Safety of DES in Off-Label Use: Results of the MATRIX Registry George D. Dangas, MD, PhD, FACC, FSCAI On Behalf of the Matrix Investigators

2. MATRIX Registry: Dangas et al, SCAI-ACCi2 2008 PersonalMay be construed as possible COI Cordis Endovascular, J&JCompleted Term Consultancy (<10K) MATRIXFunding Support Cordis Cardiology, J&JResearch Grant to the Cardiovascular Research Foundation Disclosures

3. MATRIX Registry: Dangas et al, SCAI-ACCi2 2008 MATRIX: Goals and Design Prospective single arm study initiated in 2004 under an investigator-initiated IDE (1 st submitted in October 2003) Designed to evaluate the outcomes of SES in consecutive “real world” population undergoing PCI with SES Both on- and off-label SES use Clinical follow-up at 1 month, 6 months, 1 year and 2 years thus far MATRIX Registry: Dangas et al, SCAI-ACCi2 2008

4. Study Organization Principal Investigator: George D. Dangas, MD Clinical sites: Lenox Hill Hospital, Columbia University Medical Center Data management: Data Center of Cardiovascular Research Foundation Independent CEC (Chair J. Coromilas, MD) 100% monitoring of all data fields of the first 1,000 pts; 10% thereafter Independent QCA lab for the first 800 lesions treated

5. MATRIX Registry: Dangas et al, SCAI-ACCi2 2008 Medication Regimen Pre-procedure : Aspirin 325 mg Aspirin 325 mg Clopidogrel loading dose of 300-600 mg within 24 hours followed by 75 mg once daily or Ticlopidine loading dose of 500 mg within 24 hours, followed by 250 mg twice a day. Clopidogrel loading dose of 300-600 mg within 24 hours followed by 75 mg once daily or Ticlopidine loading dose of 500 mg within 24 hours, followed by 250 mg twice a day. During procedure: Bivalirudin or Heparin ± GP IIb/IIIa inhibitors Bivalirudin or Heparin ± GP IIb/IIIa inhibitors Post-procedure and after discharge: Aspirin 325 mg for 1 month, thereafter Ec-ASA 81 mg indefinitely Aspirin 325 mg for 1 month, thereafter Ec-ASA 81 mg indefinitely Clopidogrel 75 mg once daily for at least three months but recommend for 1 year to all patients; physician discretion thereafter Clopidogrel 75 mg once daily for at least three months but recommend for 1 year to all patients; physician discretion thereafter Pre-procedure : Aspirin 325 mg Aspirin 325 mg Clopidogrel loading dose of 300-600 mg within 24 hours followed by 75 mg once daily or Ticlopidine loading dose of 500 mg within 24 hours, followed by 250 mg twice a day. Clopidogrel loading dose of 300-600 mg within 24 hours followed by 75 mg once daily or Ticlopidine loading dose of 500 mg within 24 hours, followed by 250 mg twice a day. During procedure: Bivalirudin or Heparin ± GP IIb/IIIa inhibitors Bivalirudin or Heparin ± GP IIb/IIIa inhibitors Post-procedure and after discharge: Aspirin 325 mg for 1 month, thereafter Ec-ASA 81 mg indefinitely Aspirin 325 mg for 1 month, thereafter Ec-ASA 81 mg indefinitely Clopidogrel 75 mg once daily for at least three months but recommend for 1 year to all patients; physician discretion thereafter Clopidogrel 75 mg once daily for at least three months but recommend for 1 year to all patients; physician discretion thereafter

6. MATRIX Registry: Dangas et al, SCAI-ACCi2 2008 N=1,510 patients Eligible for F/U 30 days 87.9% (1327/1510) 6 months 87.7% (1324/1510) 1 year 88.6% (1338/1510) 2 years 70.3% (877/1248) Follow-Up

7. MATRIX Registry: Dangas et al, SCAI-ACCi2 2008 n= 1,510 patients Age, mean±SD (years)64.8±11.1 Male gender74.6% Prior myocardial infarction33.3% History of PCI44.4% History of CABG21.0% Diabetes mellitus33.7% Unstable angina27.7% ST-Elevation MI within 48 hrs3.3% Chronic renal insufficiency10.1% History of Stroke or TIA8.0% History of peripheral arterial disease7.3% Baseline Clinical Characteristics

8. MATRIX Registry: Dangas et al, SCAI-ACCi2 2008 N = 2,876 lesions Target vessel Unprotected LM1.6% LAD37.1% LCX29.5% RCA27.4% SVG4.5% Arterial conduit0.6% Target lesion location Ostial7.6% Proximal30.6% Chronic total occlusion3.5% Bifurcation lesion19.5% Restenotic lesion7.5% Baseline Angiographic Characteristics Sirius-2.25 mmMATRIX Registry

9. MATRIX Registry: Dangas et al, SCAI-ACCi2 2008 Procedural Characteristics N = 1,510 patients No. of stents per procedure2.0±1.2 No. of stents per lesion1.1±0.5 Unfractionated heparin16.0% Bivalirudin used85.0% IIb/IIIa inhibitors administered8.2% Procedure success95.6% Device success98.6%

10. MATRIX Registry: Dangas et al, SCAI-ACCi2 2008 On-Label Use of Cypher Stent The CYPHER Sirolimus-eluting Coronary Stent is indicated in patients with symptomatic ischemic disease due to discrete de novo lesions of length 2.5 to < 3.5 mm (http://www.fda.gov/cdrh/PDF2/p020026c.pdf).http://www.fda.gov/cdrh/PDF2/p020026c.pdf On-label definition in MATRIX: De novo lesion; 1 lesion; 1 vessel; Lesion length < 30mm; RVD 2.5-3.5mm; Also excluding:  Diffuse disease  Multivessel PCI; PCI with 3 of more SES  Use of rotablator, atherectomy or laser  Use of thrombectomy or intracoronary thrombus  Acute ST elevation MI within 72 hours before the procedure  ACS with positive CKMB prePCI  Ostial lesions  Bifurcation lesions  Chronic occlusions, baseline TIMI flow 0 or 1  Vein grafts, LIMA/RIMA, radial or GEA grafts  Angioplasty restenosis or in-stent restenosis  Severe calcification; Severe tortuosity 14% Of Patients in MATRIX w/o any of above MATRIX Registry

11. MATRIX Registry: Dangas et al, SCAI-ACCi2 2008 Antiplatelet Adherence Patients (%) N=1501 N=1503 N=1327 N=1324 N=1338 N=877

12. MATRIX Registry: Dangas et al, SCAI-ACCi2 2008 Patients off clopidogrel at 30 days, 6 moths or 1 year, and back at 6 months, 1 year or 2 years Reason 2 years Patients off clopidogrel at 30 days and back at 6 months, 1 year or 2 years 46% (23/50) Patients off clopidogrel at 30 days and back at 6 months 34% Patients off clopidogrel at 30 days and back at 1 year 36% Patients off clopidogrel at 30 days and back at 2 years 24% Patients off clopidogrel at 6 months and back at 1 year or 2 years 49% (65/133) Patients off clopidogrel at 6 months and back at 1 year 44% Patients off clopidogrel at 6 months and back at 2 years 44% Patients off clopidogrel at 1 year and back at 2 years 10% (23/233)

13. MATRIX Registry: Dangas et al, SCAI-ACCi2 2008 Impact of Clopidogrel Adherence 1-Year Use and Outcomes > 365 Days On-Plavix (N=1101) Off-Plavix (N=236) p Death1.4 %4.8 %0.005 Cardiac death0.2%1.1 %0.054 Non-cardiac death1.0 %2.7 %0.08 Unknown death0.3 %1.0 %0.16 Myocardial infarction0.9 %1.1 %0.80 Q wave00N/A Non-Q wave0.9 %1.1 %0.80 TLR5.5 %0.0 %0.001 TVR6.1 %0.5 %0.002 Death/ MI2.2 %5.9 %0.008 Death/ MI/ CD-TVR7.2 %6.3 %0.71 Stent thrombosis0.3 %00.46 MATRIX Registry

14. MATRIX Registry: Dangas et al, SCAI-ACCi2 2008 Time-dependent (time-updated) Cox regression model for outcomes up to 2 years. Clopidogrel adherence is treated as a time- dependent variable. 2-Year Events Hazard Ratio 95% CIp Off Clopidogrel (vs. On Clopidogrel) Death (48 events)3.101.53 – 6.320.0018 Cardiac death3.820.92 – 15.750.0642 Non cardiac death1.940.69 – 5.460.2099 MI (55 events)0.930.20 – 4.250.9266 Death/MI (98 events)2.191.14 – 4.200.0182 Thrombosis (12 events)0.000.00 – >9990.9928 MATRIX Registry

15. MATRIX Registry: Dangas et al, SCAI-ACCi2 2008 Reasons of Clopidogrel Discontinuation Reason6 months 1 year 2 years Clopidogrel discontinuation 133/1324 pts (10.0%) 233/1338 pts (17.4%) 291/877 pts (33.2%) Doctor’s choice4.5%9.9%11.7% Bleeding3.8%5.2%1.7% Surgery2.3%2.1%2.7% Rash or allergy9.0%1.7%0.3% Cost0.8%0.4%0.7% Post 1 yearN/A41.2%30.9% Other/unknown79.7%39.5%52.2% Doctor’s choice/Bleeding/Surgery /Rash or allergy/Cost 20.3%19.3%16.8% Post 1 year/other/unknown79.7%80.7%83.2%

16. MATRIX Registry: Dangas et al, SCAI-ACCi2 2008 Impact of Reasons of Clopidogrel Discontinuation at 1 year Outcomes > 365 Days Doctor’s choice /Bleeding/Rash/Allergy/ Cost (N=45) Post 1 year /Other/Unknown (N=188) p Death9.0% (3)3.3% (5)0.10 Cardiac death3.0% (1)0.7% (1)0.19 Non-cardiac death6.1% (2)1.4% (2)0.07 Unknown death0.0% (0)1.3% (2)0.53 Myocardial infarction0.0% (0)1.3% (2)0.55 Q wave0.0% (0) N/A Non-Q wave0.0% (0)1.3% (2)0.55 TLR0.0% (0) N/A TVR0.0% (0)0.6% (1)0.63 Death/ MI9.0% (3)4.6% (7)0.23 Death/ MI/ CD-TVR9.0% (3)5.2% (8)0.33 Stent thrombosis0.0% (0) N/A

17. MATRIX Registry: Dangas et al, SCAI-ACCi2 2008 Prediction of 2-Year Adverse Outcomes Multivariate Predictors Using Cox Model 2-Year EventsHazard Ratio95% CIp Death (48 events) Age1.081.05 – 1.12<.0001 Clopidogrel2.031.11 – 3.730.0218 Diabetes Mellitus2.031.11 – 3.730.0029 Dialysis5.671.72 – 18.760.0045 Death or MI (95 events) Visual lesion length1.021.00 – 1.040.0313 Age1.051.03 – 1.07<.0001 Diabetes Mellitus1.581.05 – 2.380.0280 Renal insufficiency2.241.38 – 3.640.0011 Definite or probable stent thrombosis (12 events) Multivessel stenting3.341.08 – 10.360.0368 Renal insufficiency4.551.37 – 15.110.0134 Candidate predictors included on-label use, age, male, DM, renal insufficiency, dialysis, AMI, ACS, visual length, visual RVD, #vessel stented, 2+ vessel stented, clopidogrel.

18. MATRIX Registry: Dangas et al, SCAI-ACCi2 2008 MATRIX - Conclusions A low but measurable rate of clopidogrel discontinuation overtime. This was associated with higher all-cause mortality by Cox regression time- dependent analysis.  Patients off-clopidogrel at 12 months had higher mortality and fewer repeat coronary procedures at follow-up.  Based on the reasons for clopidogrel discontinuation: patients who stopped clopidogrel for acute events or side-effects appeared to have a trend towards higher mortality (particularly non-cardiac) at follow-up.  A significant proportion of patients who discontinued clopidogrel was able to be treated again with this agent at a later time point Continued surveillance on long-term adherence to dual antiplatelet therapy after DES is warranted. In 1,510 patients with complex CAD treated with SES, we found: