CEREA DES
description
Transcript of 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
Ribichini et al. J Cardiovasc Med 2009;10:192
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
Ribichini et al. J Cardiovasc Med 2009;10:192
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
Ribichini et al. J Cardiovasc Med 2009;10:192
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
CEREA-DES ClinicalTrials.gov NCT00369356
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%.
CEREA-DES ClinicalTrials.gov NCT00369356
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