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Columbia University Medical CenterColumbia University Medical CenterThe Cardiovascular Research FoundationThe Cardiovascular Research Foundation
Long-Term Safety of DES in Off-Label Use:
Results of the MATRIX Registry
George D. Dangas, MD, PhD, FACC, FSCAIOn Behalf of the Matrix Investigators
MATRIX Registry: Dangas et al, SCAI-ACCi2 2008
Personal May be construed as possible COI
Cordis Endovascular, J&J Completed Term Consultancy (<10K)
MATRIX Funding Support
Cordis Cardiology, J&J Research Grant to the Cardiovascular Research Foundation
Disclosures
MATRIX Registry: Dangas et al, SCAI-ACCi2 2008
MATRIX: Goals and Design
• Prospective single arm study initiated in 2004 under an investigator-initiated IDE (1st 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
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-ACCi2 2008
Medication RegimenPre-procedure :Pre-procedure :• Aspirin 325 mg Aspirin 325 mg • Clopidogrel loading dose of 300-600 mg within 24 Clopidogrel loading dose of 300-600 mg within 24 hours followed by 75 mg once daily or Ticlopidine hours followed by 75 mg once daily or Ticlopidine loading dose of 500 mg within 24 hours, followed by 250 loading dose of 500 mg within 24 hours, followed by 250 mg twice a day.mg twice a day.During procedure:During procedure:• Bivalirudin or Heparin ± GP IIb/IIIa inhibitorsBivalirudin or Heparin ± GP IIb/IIIa inhibitors
Post-procedure and after discharge:Post-procedure and after discharge:• Aspirin 325 mg for 1 month, thereafter Ec-ASA 81 mg Aspirin 325 mg for 1 month, thereafter Ec-ASA 81 mg indefinitelyindefinitely• Clopidogrel 75 mg once daily for at least three months Clopidogrel 75 mg once daily for at least three months but recommend for 1 year to all patients; physician but recommend for 1 year to all patients; physician discretion thereafterdiscretion thereafter
Pre-procedure :Pre-procedure :• Aspirin 325 mg Aspirin 325 mg • Clopidogrel loading dose of 300-600 mg within 24 Clopidogrel loading dose of 300-600 mg within 24 hours followed by 75 mg once daily or Ticlopidine hours followed by 75 mg once daily or Ticlopidine loading dose of 500 mg within 24 hours, followed by 250 loading dose of 500 mg within 24 hours, followed by 250 mg twice a day.mg twice a day.During procedure:During procedure:• Bivalirudin or Heparin ± GP IIb/IIIa inhibitorsBivalirudin or Heparin ± GP IIb/IIIa inhibitors
Post-procedure and after discharge:Post-procedure and after discharge:• Aspirin 325 mg for 1 month, thereafter Ec-ASA 81 mg Aspirin 325 mg for 1 month, thereafter Ec-ASA 81 mg indefinitelyindefinitely• Clopidogrel 75 mg once daily for at least three months Clopidogrel 75 mg once daily for at least three months but recommend for 1 year to all patients; physician but recommend for 1 year to all patients; physician discretion thereafterdiscretion thereafter
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
MATRIX Registry: Dangas et al, SCAI-ACCi2 2008
n= 1,510 patientsAge, mean±SD (years) 64.8±11.1
Male gender 74.6%
Prior myocardial infarction 33.3%
History of PCI 44.4%
History of CABG 21.0%
Diabetes mellitus 33.7%
Unstable angina 27.7%
ST-Elevation MI within 48 hrs 3.3%
Chronic renal insufficiency 10.1%
History of Stroke or TIA 8.0%
History of peripheral arterial disease 7.3%
Baseline Clinical Characteristics
MATRIX Registry: Dangas et al, SCAI-ACCi2 2008
N = 2,876 lesionsTarget vessel
Unprotected LM 1.6%
LAD 37.1%
LCX 29.5%
RCA 27.4%
SVG 4.5%
Arterial conduit 0.6%
Target lesion location
Ostial 7.6%
Proximal 30.6%
Chronic total occlusion 3.5%
Bifurcation lesion 19.5%
Restenotic lesion 7.5%
Baseline Angiographic Characteristics
Sirius-2.25 mmMATRIX Registry
MATRIX Registry: Dangas et al, SCAI-ACCi2 2008
Procedural Characteristics
N = 1,510 patients
No. of stents per procedure 2.0±1.2
No. of stents per lesion 1.1±0.5
Unfractionated heparin 16.0%
Bivalirudin used 85.0%
IIb/IIIa inhibitors administered 8.2%
Procedure success 95.6%
Device success 98.6%
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 < 30 mm in native coronary arteries with a reference vessel diameter of > 2.5 to < 3.5 mm (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 above14% Of Patients in MATRIX w/o any of aboveMATRIX Registry
MATRIX Registry: Dangas et al, SCAI-ACCi2 2008
Antiplatelet Adherence
93.890.4
65.560.7
90.996
99.6
89.582.4
90.4
9096.2
98.7 94.187.8
79.5
40
50
60
70
80
90
100
Loading Discharge 30 Days 6 Months 1 year 2 year
Aspirin Plavix Both
Pa
tie
nts
(%
)
N=1501 N=1503 N=1327 N=1324 N=1338 N=877
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 yearsReason 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-ACCi2 2008
Impact of Clopidogrel Adherence 1-Year Use and Outcomes > 365 Days
On-Plavix(N=1101)
Off-Plavix(N=236) p
Death 1.4 % 4.8 % 0.005
Cardiac death 0.2% 1.1 % 0.054
Non-cardiac death 1.0 % 2.7 % 0.08
Unknown death 0.3 % 1.0 % 0.16
Myocardial infarction 0.9 % 1.1 % 0.80
Q wave 0 0 N/A
Non-Q wave 0.9 % 1.1 % 0.80
TLR 5.5 % 0.0 % 0.001
TVR 6.1 % 0.5 % 0.002
Death/ MI 2.2 % 5.9 % 0.008
Death/ MI/ CD-TVR 7.2 % 6.3 % 0.71
Stent thrombosis 0.3 % 0 0.46
MATRIX Registry
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 EventsHazard Ratio
95% CI p
Off Clopidogrel (vs. On Clopidogrel)
Death (48 events) 3.10 1.53 – 6.32 0.0018
Cardiac death 3.82 0.92 – 15.75 0.0642
Non cardiac death 1.94 0.69 – 5.46 0.2099
MI (55 events) 0.93 0.20 – 4.25 0.9266
Death/MI (98 events) 2.19 1.14 – 4.20 0.0182
Thrombosis (12 events) 0.00 0.00 – >999 0.9928
MATRIX Registry
MATRIX Registry: Dangas et al, SCAI-ACCi2 2008
Reasons of Clopidogrel Discontinuation
Reason 6 months 1 year 2 years
Clopidogrel discontinuation 133/1324 pts (10.0%)
233/1338 pts(17.4%)
291/877 pts(33.2%)
Doctor’s choice 4.5% 9.9% 11.7%
Bleeding 3.8% 5.2% 1.7%
Surgery 2.3% 2.1% 2.7%
Rash or allergy 9.0% 1.7% 0.3%
Cost 0.8% 0.4% 0.7%
Post 1 year N/A 41.2% 30.9%
Other/unknown 79.7% 39.5% 52.2% Doctor’s choice/Bleeding/Surgery /Rash or allergy/Cost 20.3% 19.3% 16.8%
Post 1 year/other/unknown 79.7% 80.7% 83.2%
MATRIX Registry: Dangas et al, SCAI-ACCi2 2008
Impact of Reasons of Clopidogrel Discontinuation at 1 year
Outcomes > 365 DaysDoctor’s choice
/Bleeding/Rash/Allergy/Cost (N=45)
Post 1 year /Other/Unknown
(N=188)p
Death 9.0% (3) 3.3% (5) 0.10 Cardiac death 3.0% (1) 0.7% (1) 0.19 Non-cardiac death 6.1% (2) 1.4% (2) 0.07
Unknown death 0.0% (0) 1.3% (2) 0.53
Myocardial infarction 0.0% (0) 1.3% (2) 0.55
Q wave 0.0% (0) 0.0% (0) N/A
Non-Q wave 0.0% (0) 1.3% (2) 0.55
TLR 0.0% (0) 0.0% (0) N/A
TVR 0.0% (0) 0.6% (1) 0.63
Death/ MI 9.0% (3) 4.6% (7) 0.23
Death/ MI/ CD-TVR 9.0% (3) 5.2% (8) 0.33
Stent thrombosis 0.0% (0) 0.0% (0) N/A
MATRIX Registry: Dangas et al, SCAI-ACCi2 2008
Prediction of 2-Year Adverse Outcomes Multivariate Predictors Using Cox Model
2-Year Events Hazard Ratio 95% CI p
Death (48 events)
Age 1.08 1.05 – 1.12 <.0001
Clopidogrel 2.03 1.11 – 3.73 0.0218
Diabetes Mellitus 2.03 1.11 – 3.73 0.0029
Dialysis 5.67 1.72 – 18.76 0.0045
Death or MI (95 events)
Visual lesion length 1.02 1.00 – 1.04 0.0313
Age 1.05 1.03 – 1.07 <.0001
Diabetes Mellitus 1.58 1.05 – 2.38 0.0280
Renal insufficiency 2.24 1.38 – 3.64 0.0011
Definite or probable stent thrombosis (12 events)
Multivessel stenting 3.34 1.08 – 10.36 0.0368
Renal insufficiency 4.55 1.37 – 15.11 0.0134
Candidate predictors included on-label use, age, male, DM, renal insufficiency, dialysis, AMI, ACS, visual length, visual RVD, #vessel stented, 2+ vessel stented, clopidogrel.
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: In 1,510 patients with complex CAD treated with SES, we found: