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

MATRIX Registry: Dangas et al, SCAI-ACCi 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

MATRIX Registry: Dangas et al, SCAI-ACCi 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

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

MATRIX Registry: Dangas et al, SCAI-ACCi Medication Regimen Pre-procedure : Aspirin 325 mg Aspirin 325 mg Clopidogrel loading dose of 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 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 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 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

MATRIX Registry: Dangas et al, SCAI-ACCi 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

MATRIX Registry: Dangas et al, SCAI-ACCi 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

MATRIX Registry: Dangas et al, SCAI-ACCi 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

MATRIX Registry: Dangas et al, SCAI-ACCi 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%

MATRIX Registry: Dangas et al, SCAI-ACCi 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 ( On-label definition in MATRIX: De novo lesion; 1 lesion; 1 vessel; Lesion length < 30mm; RVD mm; 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

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

MATRIX Registry: Dangas et al, SCAI-ACCi 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)

MATRIX Registry: Dangas et al, SCAI-ACCi 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

MATRIX Registry: Dangas et al, SCAI-ACCi 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) – Cardiac death – Non cardiac death – MI (55 events) – Death/MI (98 events) – Thrombosis (12 events) – > MATRIX Registry

MATRIX Registry: Dangas et al, SCAI-ACCi 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%

MATRIX Registry: Dangas et al, SCAI-ACCi 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

MATRIX Registry: Dangas et al, SCAI-ACCi Prediction of 2-Year Adverse Outcomes Multivariate Predictors Using Cox Model 2-Year EventsHazard Ratio95% CIp Death (48 events) Age – 1.12<.0001 Clopidogrel – Diabetes Mellitus – Dialysis – Death or MI (95 events) Visual lesion length – Age – 1.07<.0001 Diabetes Mellitus – Renal insufficiency – Definite or probable stent thrombosis (12 events) Multivessel stenting – Renal insufficiency – Candidate predictors included on-label use, age, male, DM, renal insufficiency, dialysis, AMI, ACS, visual length, visual RVD, #vessel stented, 2+ vessel stented, clopidogrel.

MATRIX Registry: Dangas et al, SCAI-ACCi 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: