CEREA DES

CEREADES

Featured Clinical Trials

CEREA DES

A Prospective Randomized Trial of Corticosteroids in Patients Undergoing Stent Implantation

Flavio Ribichini, MD

Director Catheterization LaboratoriesUniversity of Verona

TCT 2009

CEREADES

• No conflict of interest

TCT 2009

Protocol

CEREA-DES is an Italian, spontaneous (NOT sponsored), multicenter, randomized study that enrolled 375 patients with CAD:

• BMS (control group)

• DES (DES group, limited to Cypher and Taxus stents)

• BMS followed by prednisone treatment (prednisone group)

Ribichini et al. J Cardiovasc Med 2009;10:192

CEREADES

Background

Aim of the Study: comparison of the primary endpoint obtained in a controlgroup of patients treated with BMS versus two study groups:

DES or BMS plus oral prednisone

Primary endpoint: event-free survival of death, MI and recurrence of ischemia needing TVR at one year.

Secondary endpoints: event free survival at 2 and 3 years including major bleeding.Restenosis rate at 9 months by QCA, and cost-effectiveness at 1,2 and 3 years.

Sample Size: the expected primary endpoint rates are 90% for DES and for prednisone-treated patients and 77% for BMS.

A sample size of 120 patients per group provides a 80% power125 pts per arm were included to obviate for drop-out

CEREADES


CAD

Angina or ischemia

Informed consent

Single or multi-vessel CAD

Native vessel or bypass conduits

Successfully recanalized CTO

Any BMS stent, only Cypher or Taxus DES, any technique.

CEREADES Inclusion Criteria


Diabetes

Age >80

Recent QWMI (less than 2 weeks)

Contraindication for steroid use

Renal failure (plasma creatinine 2.5 mg/dl)

Neoplasia

Severe gastritis or active peptic ulcer

Contraindications to dual AP therapy

CEREADES Exclusion Criteria


375 non diabetic pts with CAD

125 pts 125 pts 125 pts

122 pts126 pts126 pts

ITT

AT

125 pts125 pts125 pts12m FU

BMS DES BMS+PRED

-3 (only BMS)- 1: DES-1: no stent+3 no pred

+1 DES

Study FlowchartCEREADES

CEREA-DES ClinicalTrials.gov NCT00369356

15d

15d

10d

1mg/Kg orally during the first 15 days

0.5mg/Kg orally from day 16 to 30

0.25mg/Kg orally from day 30 to 40

CEREADES Prednisone Treatment

Ferrero V, et al. Drugs 2007;67:1243-55

At hospital discharge associate: Diuretics (25 to 50 mg of thiazidic diuretic)

Anti-acids (20 to 40 mg of proton pump inhibitor)

At 4 weeksCheck blood cells count to rule out side effects of thienopyridines

Assess treatment compliance and side effects Eventually, upgrade anti-hypertensive treatment

Eventually withdraw diuretics, anti-acids and thienopyridine if not otherwise indicated

40 days

CEREA-DES

Participating centres


CEREADES

European Hospital, Roma: F Tomai, L De Luca, PF Corvo, AS Ghini

Università degli studi di Novara: G De Luca, P Marino, E Franchi

Istituto Clinico Humanitas, Milano: P Presbitero, D Zavalloni, M Rossi

Osp. S. Giovanni Bosco, Torino: G Boccuzzi, R Garbo, M Minelli

Università degli Studi di Verona: G Pesarini, V Ferrero, F Ribichini

CLINICAL BMS DES BMS+PRED P

N. OF PATIENTS 125 125 125

Female sex 23 (18.4%) 16 (12.8%) 17 (13.6%) 0.42

Age 64 ± 9.67 63 ± 9.6 63 ±9.03 0.64

BMI 26 ± 3.48 26 ± 3.68 26.99 ± 3.08 0.34

Family history of CAD 43 (34.4%) 42 (33.6%) 58 (46.4%) 0.06

Hypertension 84 (67.2%) 84 (67.2%) 91 (72.8%) 0.54

Smoke 85 (68.0%) 78 (64.2%) 79 (63.2%) 0.23

Dyslipidemia 79 (63.2%) 78 (64.2%) 71 (56.8%) 0.35

Tn-I + before PCI 23 (18.4%) 20 (16.0%) 24 (19.2%) 0.79

Multi vessel CAD 50 (40.0%) 63 (50.4%) 54 (43.2%) 0.24

LV ejection fraction (%) 57 ± 8 58 ± 9 58 ± 7 0.88

Baseline Characteristics ICEREADES

CO-MORBIDITIES BMS DES BMS+PRED P

PREVIOUS MI 18 (14.4%) 30 (24.0%) 28 (22.4%) 0.18

PREVIOUS PCI 22 (17.6%) 21 (16.8%) 18 (14.4%) 0.16

PREVIOUS CABG 13 (10.4%) 9 (7.2%) 7 (5.6%) 0.28

PERIPHERAL VASCULAR DISEASE

8 (6.4%) 7 (5.6%) 10 (8.0%) 0.80

Baseline Characteristics IICEREADES

Clinical PresentationCEREADES

BMS DES BMS+PRED P

CRP pre PCI 6.18±17.02 5.76±12.57 5.52±14.85 0.72

Tn pre PCI 2.84±11.54 1.4±7.25 0.94±3.54 0.63

Tn post PCI 0.96±3.41 0.88±2.35 0.25±0.72 0.06

CK-MB pre PCI 22.76±63.83 12.31±34.79 11.40±35.55 0.88

CK-MB post PCI 6.69±10.63 7.87±16.42 5.07±7.83 0.17

Fibrinogen pre-PCI 418±112 380±78 408±103 0.61

Fibrinogen post-PCI 415±116 379±70 366±121 <0.001

Creatinine pre PCI 0.99±0.16 1.02±0.20 0.98±0.19 0.27

Creatinine post PCI 1.00±0.19 1.03±0.19 1.01±0.21 0.9

Total cholesterol 174.80±68.91 176.80±61.48 167.66±64.00 0.44

GGT pre PCI 29.39±33.40 38.60±57.06 27.90±30.49 0.25

Baseline Biochemical CharacteristicsCEREADES

DRUG BMS DES BMS+PRED P

ASA 119 (95.2%) 123 (98.4%) 120 (96.0%) 0.35

Ticlopidine 14 (11.2%) 17 (13.6%) 17 (13.6%) 0.80

Clopidogrel 103 (82.4%) 98 (78.4%) 95 (76.0%) 0.45

IIB IIIA GP inhibitor 23 (18.4%) 21 (16.8%) 18 (14.4%) 0.77

LMWH 32 (25.6%) 28 (22.4%) 28 (22.4%) 0.78

UFH 107 (85.6%) 114 (91.2%) 109 (87.2%) 0.37

Statins 81 (64.8%) 90 (72.0%) 91 (72.8%) 0.31

Medical Treatment pre-PCICEREADES

DRUG BMS DES BMS+PRED P

ASA 120 (96.0%) 123 (98.4%) 120 (96.0%) 0.46

Ticlopidine 15 (12.0%) 14 (11.2%) 16 (12.8%) 0.92

Clopidogrel 107 (85.6%) 110 (88.0%) 109 (87.2%) 0.84

Nitrates 48 (38.4%) 49 (39.2%) 38 (30.4%) 0.27

Calcium antagonists 26 (20.8%) 15 (12.0%) 32 (25.6%) 0.02

RAS inhibitors 93 (74%) 98 (78%) 99 (79%) 0.62

B-blockers 83 (66.4%) 94 (75.2%) 89 (71.2%) 0.30

Statins 110 (88.0%) 110 (88.0%) 116 (92.8%) 0.35

Diuretics 14 (11.2%) 20 (16.0%) 92 (73.6%) <0.001

Anti-acids 80 (64.0%) 95 (76.0%) 113 (90.4%) <0.001

Medical Treatment at DischargeCEREADES

Vessels and Lesions Characteristics

P=NS

Revascularization BMS DES BMS+PRED

Complete Anatomical 89 (71%) 98 (78%) 93 (74%)

Complete Functional 24 (19%) 16 (13%) 21 (17%)

Uncomplete 12 (10%) 11 (9%) 11 (9%)

CEREADES

Vessels Treated

LIMA

Lesions Characteristics

P=NS

BMSN° 178

DESN° 190

BMS+PREDN° 192

CTO 5 (2.8%) 3 (1.6%) 8 (4.2%)

RESTENOSIS 1 (0.6%) 8 (4.2%) 8 (4.2%)

THROMBOSIS 9 (5.1%) 17 (8.9%) 22 (11.5%)

CEREADES

BMS TAXUS CYPHER

BMS 191 0 0

DES 0 122 (61%) 74 (39%)

BMS+PREDNISONE 200 0 0

Stent Used in the Study

Stent per lesion Stent per patient

BMS 1.073 1.53

DES 1.032 1.57

BMS+PREDNISONE 1.042 1.6

CEREADES

P=0.003

P=0.05

Stent used in the study

BMS DES BMS+PRED

BMS DES BMS+PRED

16.79

18.45

16.08

3.20

3.073.05

Average final balloon diameter post stent

DRUG BMS125

DES125

BMS+PRED125

P

ASA 105 (84.0%) 114 (91.2%) 111 (88.8%) 0.20

Ticlopidine 1 (0.8%) 8 (6.4%) 4 (3.2%) 0.05

Clopidogrel 27 (21.6)% 46 (36.8%) 21 (16.8%) 0.001

Dual A-P-Tx 28 (22.4%) 54 (43.2%) 25 (20%) 0.001

Nitrates 28 (22.4%) 35 (28.0%) 20 (16.0%) 0.07

Calcium antagonists 21 (16.8%) 20 (26.0%) 30 (24.0%) 0.20

RAS inhibitors 76 (61%) 90 (72%) 85 (68%) 0.16

B-blockers 73 (58.4%) 87 (69.6%) 76 (60.8%) 0.15

Statins 103 (82.4%) 110 (88.0%) 95 (76.0%) 0.04

Diuretics 19 (15.2%) 22 (17.6%) 36 (28.8%) 0.01

Medical Treatment at 12 MonthsCEREADES

BMS DES BMS+PREDNISONE p

DEATH 1 0 0 0.37

QWMI 2 0 0 0.13

NQWMI 1 1 0 0.60

TVR 19 (15.2%) 13 (10.4%) 15 (12%) 0.50

MACE at 12 MonthsE

vent

rat

e (%

)

0.80 0

2.4

0.80

15.2

10.4

12

BMS125

DES125

BMS+PREDNISONE125

p

COMBINED Death MI TVR

23 (18.4%) 14 (11.2%) 15 (12%) 0.1

Combined MACEE

vent

rat

e (%

)

18.4%

12%11.2%

Event-free survival BMS DES BMS+PRED

At 12 months 81.6% 88.8% 88%

p=0.1 (log-rank)

Primary EndpointCEREADES

Event-free survival BMS DES+PRED

At 12 months 81.6% 88.4%

Kaplan-Meier and Log-Rank Survival Analysis

p=0.07 (log-rank)

CEREADES

Covariates Significance Odds Ratio 95%CI Lower 95%CI Upper

Age 0.60 0.992 0.961 1.023

Gender 0.15 1.847 0.806 4.232

Multi Vessel Disease 0.51 0.820 0.454 1.481

Complex lesions 0.47 0.777 0.393 1.535

Creatinine 0.42 1.826 0.425 7.837

Previous MI 0.79 0.906 0.441 1.863

Unstable Angina 0.22 1.514 0.775 2.959

LV ejection fraction 0.24 0.980 0.949 1.013

NSTEMI 0.02 2.526 1.116 5.717

Stent Lenght 0.03 1.065 1.006 1.128

Treatment Group 0.11 1.674 0.824 3.401

Multivariate Cox Regression Analysis for the three groups

Covariates Significance Odds Ratio 95%CI Lower 95%CI Upper

Age 0.60 0.992 0.961 1.023

Gender 0.16 1.814 0.796 4.135

Multi Vessel Disease 0.51 0.819 0.454 1.477

Complex lesions 0.46 0.777 0.394 1.531

Creatinine 0.45 1.741 0.414 7.322

Previous MI 0.78 0.902 0.439 1.851

Unstable Angina 0.24 1.493 0.767 2.909

Ejection Fraction 0.24 0.981 0.949 1.013

NSTEMI 0.03 2.517 1.112 5.695

Stent Lenght 0.03 1.063 1.005 1.125

Treatment Group 0.04 1.842 1.020 3.329

Multivariate Cox Regression: BMS vs DES and PREDNISONE

CEREADES CEREA-DES

CONCLUSIONS

1. The clinical results of DES treatment in an independent research confirm the expected performance of Taxus and Cypher stents at one year

2. Previous results obtained with oral prednisione in small, single-centre experiences are replicated in this randomized, multi-centre, study. Oral prednisone after BMS yields good clinical results and can be an alternativeto patients that may not receive DES

3. The outcome of patients treated with BMS has greatly improved over years with low rate of events compared to previous studies. Indeed, better stent designs and optimal medical treatment yielded better results than expected inthe control group

CEREA-DES

CONCLUSIONS

The main difference bewteen a DES and a systemic drug therapy study:

After coronary intervetions, an adequete and effective systemic treatment, like prednisone, together with statins, RAS inhibitors, anti-platelet drugs, and beta blockers, puts THE PATIENT rather than THE ARTERY at the centre of our medical effort.

CEREADES

Thank you

Statistical note:

“The study was designed as a superiority trial, to compare DES, and BMS plus prednisone, with BMS alone.

The direct comparison of the two study groups (DES vs BMS plus prednisone) as a non-inferiority trial would be more appropriate and of greater interest.

However, the sample size required for a pairwise comparison of the three groups, or even more, for a non-inferiority trial between DES and BMS plus prednisone, would be over 2507 patients even keeping the non-inferiority margin as high as 25%.


CEREADES

BACK UP SLIDES

CEREA DES 18.4% 11.2% 12%

BMS DES BMS+PREDNISONE

RAVEL (12m) 29% 6%

SIRIUS (9m) 21% 8.6%

E-SIRIUS (9m) 22.6% 8%

C-SIRIUS (9m) 18% 4%

TAXUS IV (9m) 16% 8.5%

TAXUS VI (9m) 22.5% 16.4%

ENDEAVOR II (9m) 15.1% 7.8%

Est.avg. 12m (linear extrap.) 23.5% 9.9% 9.9%

Death, MI and TVR at 9 to 12 months in randomized trials BMS vs DES

CEREADES

0

5

10

15

20

25

N. o

f P

atie

nts

Enrollment Rate

CEREA-DES enrollment

sep

200

6

oct

200

6

no

v 20

06

dec

200

6

jan

200

7

feb

200

7

mar

200

7

apr

2007

may

200

7

jun

200

7

jul

2007

aug

200

7

sep

200

7

oct

200

7

no

v 20

07

dec

200

7

jan

200

8

feb

200

8

mar

200

8

apr

2008

may

200

8

jun

200

8

jul

2008

aug

200

8

sep

200

8

CEREADES

DRUG BMS125

DES125

BMS+PRED125

p

ASA 119 (95%) 121 (97%) 117 (94%) 0.49

Ticlopidine 4 (3%) 16 (12%) 5 (4%) 0.003

Clopidogrel 63 (50%) 91 (73%) 39 (31%) 0.45

Dual A-P-Tx 67 (54%) 107 (86%) 44 (35%) 0.001

Dual Anti-Platelet Treatment at 6 MonthsCEREADES

In hospital and 30-days events

In Hospital NQWMI (n) 1 1 0

In Hospital QWMI (n) 2* 0 0

30 days deaths (n) 0 0 0

30 days QWMI (n) 0 0 0

30 days NQWMI (n) 0 0 0

30 days TVR 1* 0 0

30 days TLR 1* 0 0

BMS DES BMS+PREDNISONE

*Same patient

CEREADES

Side-Effect N (%)

Edema 9/125-7,2%

Hyperglicemia 6/125-4,8%

Cushing 3/125-2,4%

Infectious disease 3/125- 2,4%

Neutropenia 1/125-0,8%

Agitazione psicomotoria 1/125-0,8%

Side Effects of the Steroid Therapy

CEREA DES

Documents

Transcript of CEREA DES