columbia university medical center the cardiovascular research foundation long-term safety of des in...

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: 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



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


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


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


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


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


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%


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


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


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)


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


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


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%


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


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 - 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:

columbia university medical center the cardiovascular research foundation long-term safety of des in...

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