ZIYAD GHAZZAL MD, FACC, FSCAIPROFESSOR OF MEDICINEDEPUTY VP/DEAN; ASSOCIATE DEAN FOR CLINICAL AFFAIRSAMERICAN UNIVERSITY OF BEIRUT
ADJUNCT PROFESSOR OF MEDICINEEMORY UNIVERSITY SCHOOL OF MEDICINE
Stent and Adjunctive Therapy Selection in 2010
THE DIFFERENT TYPES OF DES ON THE MARKET
• Cobalt Chromium
• Fluoro polymer• Everolimus
• Cobalt Chromium
• BioLinx polymer • Zotarolimus
• Stainless Steel• PEVA/PBMA
copolymer • Sirolimus
• Platinum Chromium
• Fluoro polymer• Everolimus
Xienceprime
Endeavorresolute
Cypher select
Promus element
NEVO stent
Cobalt ChromiumBiodegradable polymer
Sirolimus
2nd Generation1st Generation
Multi-Link Vision™ Stent0 .081 mm(0.0032” )
Cobalt Chromium
XIENCE V™
Stent
Bx Velocity™
Stent0.140 mm(0.0055” )
Stainless Steel
Cypher™
Stent
Driver™ Stent
0.091 mm(0.0036”)
Cobalt Chromium
Endeavor™
StentTAXUS™
Liberté™ Stent
Liberté™ Stent
0.096 mm(0.0038”)
Stainless Steel
TAXUS™
Express™
Stent
Express™
Stent0.132 mm(0.0052”)
Stainless Steel
BM
S P
latf
orm
DES
Pla
tform
Element™
Stent Series
Element™Stent9
0.081 mm(0.0032”)
Platinum Chromium
3rd Generation
XIENCE™Prime™Stent
XIENCE Prime™ Stent0.081 mm(0.0032”)
Cobalt Chromium
Average Stent Profile
0.047”
0.042”
0.047”
0.048”
0.044”
0.046”TAXUS™ Element™
Stent
TAXUS™ Liberté™
Stent
XIENCE V™ / PROMUS™ Stent
Endeavor™ Resolute™ Stent
Cypher Select™
PlusStent
XIENCE Prime™
Stent
PROMUS™
Element™ Stent
1.19mm
1.07mm
1.19mm
1.22mm
1.12mm
1.17mm
1.09mm
0.043”
Platform ComparisonVessel Coverage
TAXUS™ Liberté™ Stent
Cypher™ StentTAXUS™Express2™ Stent
Driver™ Stent
RESOLUTE All Comers Trial
Euro PCR 2010 Randomized comparison between the 2nd generation Resolute zotarolimus-eluting stent
(R-ZES) XienceV everolimus-eluting stent
(EES) Primary non-inferiority endpoint
(12-month target lesion failure) R-ZES: 8.2% EES: 8.3%
BMS vs DES
The only advantage of DES over BMS is the reduction of restenosis (and TVR)
No difference in procedural complications
No difference in MI or mortality DES is more expensive The main disadvantage of DES is the
reliance on DAT because of the concern about stent thrombosis
IN CLINICAL TRIALS
BMS vs DES
NEJM March 2007
NEJM March 2007
NEJM March 2007
NEJM March 2007
Drug Eluting Stents
Lower restenosis and TVR
Reliance on prolonged DAT
OFF LABEL USE DES VS BMS
The risk of stent thrombosis increases for both
2.6% 3.2% 3.5%5.5%
29.0%
2.0%1.3%
8.7%
Unstableangina
PriorbrachyRx
Thrombus Diabetes Unprot.left main
Bifurcation Renalfailure
PrematurePlavix d/c
Milan/Siegburg ExperienceStent thrombosis after DES (SES or PES)
occurred in 29/2229 pts (1.3%) at 9.3±5.6 mos
Iakovou I. and Colombo A. et.al JAMA, May 4, 2005; 293: 2126
Prevention of Premature Discontinuation of Dual Antiplatelet Therapy in Patients With Coronary Artery Stents - A Science Advisory - 2007Discuss 12 months dual anti-platelet therapy prior to DES implantationIf surgical procedure anticipated, consider BMS or POBAEducate patients prior to discharge on hazards of premature discontinuation of dual anti-platelet therapyInstruct patient to call cardiologist if instructed to discontinue anti-platelets
Prevention of Premature Discontinuation of Dual Antiplatelet Therapy in Patients With Coronary Artery Stents – A Science Advisory - 2007
Physicians performing invasive or surgical procedures should discuss discontinuation of therapy with patient’s cardiologist and weigh risks and benefitsElective procedures should be delayed until 12 months of dual anti-platelet therapy is completedIf surgery cannot be delayed, ASA should be continued if at all possible and thienopyridine restarted as soon as possible
CHOICE OF ORAL ANTI-PLATELET THERAPY
P2Y12 antagonists
Drug Structure
Direct or indirect
Reversible
Route Frequency
Phase
Ticlopidine
Thienopyridine
indirect no p.o. bid approved
Clopidogrel
Thienopyridine
indirect no p.o. qd approved
Prasugrel
Thienopyridine
indirect no p.o. qd approved
Ticagrelor
Cyclo-pentyl-triazolo-
pyrimidine
direct yes p.o. bid III
Cangrelor
ATP analog
direct yes i.v. -- III
Elinogrel direct yes p.o.,i.v. -- II
PRASUGREL
STUDY DESIGN
& Planned PCI
ASA
ASA
Primary efficacy end point: CV death, nonfatal MI or nonfatal stroke.
Key safety endpoint: TIMI major bleeding.
UA/NSTEMI (TIMI Risk Score ≥ 3)
STEMI (Primary PCI ≤ 12 hours of symptoms or post-STEMI within 14 days)
RDay
3
Day
30
Day
90
Prasugrel60 mg LD/ 10 mg
MD
Clopidogrel300 mg LD/ 75 mg
MD Day
450
14.5 month actual
median
12.0 month
planned medianDouble-blind treatment
6 - 15 months planned follow-up
Wiviott SD et al. New Engl J Med 2007. Wiviott SD et al. Am Heart J 2006.
10
15
Days
0
5
0 30 60 90 180 270 360 450
Prasugrel
Clopidogrel
Intent To Treat: n=13,608; Lost to Follow-Up: n=14 (0.1%)
HR 0.81 (0.73-0.90)
P<0.001ARR=2.2NNT=46
12.1(n=781)9.9
(n=643
)
HR 0.77 (0.67-0.88)
P<0.001
HR 0.80 (0.71-0.90)
P<0.001
CV
Death
/MI/
Str
oke (%
)
Wiviott SD et al. New Engl J Med 2007.
PRIMARY ENDPOINT
STENT THROMBOSIS: ANY STENT
Wiviott SD et al. Lancet 2008.
0 30 60 90 180 270 360 450
HR 0.48 (0.36-0.64)
P<0.0001
RRR 52%ARR 1.22%
Prasugrel
Clopidogrel2.35
1.13
Days
Ste
nt
Th
rom
bosis
(%
)
Any Stent at Index PCI n=12,844
0
1
2
3
NNT=77
Days
0
0.5
1
1.5
2
2.5
0 50 100 150 200 250 300 350 400 450
2.41%
1.27%
% o
f S
ub
jects HR 0.52 (0.35-
0.77) p=0.0009
1 year: 1.22 vs 2.27%
HR 0.53 (0.36-0.79)
p=0.0014
RRR 48%Clopidogrel
Prasugrel
STENT THROMBOSIS: BMS
Wiviott SD et al. Lancet2008.
BMS at Index PCI n=6,461
STENT THROMBOSIS: DES%
of
Su
bje
cts
Days
HR 0.36 (0.22-0.58)
p<0.0001
1 year: 0.74% vs. 2.05%
HR 0.35 (0.21-0.58) p<0.0001
2.31%
0.84%
RRR 64%
Clopidogrel
Prasugrel
0
0.5
1
1.5
2
2.5
0 50 100 150 200 250 300 350 400 450
Wiviott SD et al. Lancet2008.
DES at Index PCI n=5,743
TRITON-TIMI 38: Life Threatening Bleeds at 15 Months (All ACS)
ACS=Acute Coronary Syndrome; HR=Hazard Ratio
P=0.23
Life-Threatenin
g
P=0.74P=0.002
IntracranialFatal Nonfatal
P=0.01
(n=6,716)
(n=6,741)
En
d P
oin
t (%
)
Subsets of Life-threatening Bleeds
n=85
n=56
0.9%
1.4%
n=5
0.1%n=21
0.4%
n=51
0.9%n=64
1.1%
n=17n=19
0.3%0.3%
Wiviott SD et al. New Engl J Med 2007;357:2001-2015
HIGH RISK POPULATIONS
SubgroupNet clinical benefit (HR)
1º endpoint (HR)
Bleeding (HR)
Age ≥75, ≤60 kg or prior
stroke/TIA
1.07(0.90-1.28)p=0.43
1.02 (0.84-1.24) p=0.83
1.42 (0.93-2.15) p=0.10
Age <75, >60 kg, no prior stroke/TIA
0.80 (0.71-0.89) P<0.001
0.74 (0.66-0.84)
p<0.001
1.24 (0.91-1.69)
P=0.17
TICAGRELOR
Ticagrelor (AZD 6140): an oral reversible P2Y12 antagonist
Ticagrelor is a cyclo-pentyl-triazolo-pyrimidine (CPTP)
OH
OH
O
OH
N
F
S
NH
NN
NN
F
• Direct acting – Not a prodrug; does not require metabolic activation– Rapid onset of inhibitory effect on the P2Y12 receptor
– Greater inhibition of platelet aggregation than clopidogrel
• Reversibly bound– Degree of inhibition reflects plasma concentration– Faster offset of effect than clopidogrel– Functional recovery of all circulating platelets
OPTIMAL CLOPIDOGREL DOSING
CURRENT OASIS 7: A 2X2 Factorial Randomized Trial of Optimal Clopidogrel and Aspirin Dosing in Patients with ACS Undergoing an Early Invasive Strategy with Intent For PCI
OASIS-7
Shamir R. Mehta on behalf of the CURRENT Investigators
Disclosures: CURRENT OASIS 7 was funded by a grant from sanofi-aventis and Bristol Myers Squibb. All data were managed independently of the sponsor at the PHRI, McMaster University and the trial was overseen by an international steering committee of experts.
25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)Planned Early (<24 h) Invasive Management with intended
PCIIschemic ECG Δ (80.8%) or ↑cardiac biomarker (42%)
PCI 17,232(70%)
Angio 24,769(99%)
Angio 24,769(99%)
No PCI 7,855 (30%)
No Sig. CAD 3,616 CABG 1,809 CAD 2,430
Randomized to receive (2 X 2 factorial):
CLOPIDOGREL: Double-dose(600 mg then150 mg/d x 7d then 75 mg/d) vsStandard dose (300 mg then 75 mg/d)
ASA: High Dose (300-325 mg/d) vsLow dose(75-100 mg/d)
Efficacy Outcomes: CV Death, MI or stroke at day 30Stent Thrombosis at day 30
Safety Outcomes:Bleeding (CURRENT defined Major/Severe and TIMI Major)Key Subgroup:PCI v No PCI
Clop in 1st 7d (median) 7d 7 d 2 d 7d
Complete
Follow up
99.8%
Compliance:
Days
Cum
ula
tive H
aza
rd
0.0
0.0
04
0.0
08
0.0
12
0 3 6 9 12 15 18 21 24 27 30
Clopidogrel Standard Dose
Clopidogrel Double Dose
42% RRR
HR 0.5895% CI 0.42-0.79
P=0.001
Clopidogrel: Double vs Standard DoseDefinite Stent Thrombosis (Angio confirmed)
Days
Cum
ula
tive H
aza
rd
0.0
0.0
10
.02
0.0
30
.04
0 3 6 9 12 15 18 21 24 27 30
Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients
Clopidogrel Standard
Clopidogrel Double
HR 0.8595% CI 0.74-0.99
P=0.036
15% RRR
CV Death, MI or Stroke
ASA Dose Comparison Death/MI/Stroke at 30 days
Days
Cum
ula
tive H
aza
rd
0.0
0.0
10
.02
0.0
30
.04
0 3 6 9 12 15 18 21 24 27 30
HR 0.96 (0.85-1.08)
P = 0.489
ASA 81-100 mgASA 300-325 mg
Point of care assays
VerifyNow
PFA-100
VASP
Impedance aggregometry
Cone and plate analyzer
Do platelet function assays predict clinical outcomes in clopidogrel pretreated patients undergoing elective PCI?
POPULAR
POPULAR
Light transmittance aggregometry (LTA): Peak platelet aggregation in response to 5 or 20 µmol/L ADP
VerifyNow P2Y12 assay: Aggregation based Plateletworks: ADP stimulation-derived platelet
count Impact R: With and without ADP stimulation PFA-100 system: Collagen/ADP stimulation Innovance PFA P2Y: ADP, PGE1, and calcium
chloride
POPULAR
1,069 patients on clopidogrel undergoing elective PCI with stent implantation
Over half (57.2%) received DES At 1 year, platelet reactivity in the
upper quintiles was associated with the primary composite outcome of death, nonfatal MI, definite stent thrombosis, and stroke in patients tested with the LTA 5 µmol/L ADP, LTA 20 µmol/L ADP, and VerifyNow tests.
High On-Treatment
Platelet Reactivity
No High On-Treatment
Platelet Reactivity
P Value
LTA 5 µmol/L ADP 88.3% 94.0% < 0.0001
LTA 20 µmol/L ADP 88.0% 93.8% < 0.0001
VerifyNow 86.7% 94.3% < 0.0001
Plateletworks 87.4% 93.3% 0.002
Impact-R 90.2% 92.5% 0.17
Impact-R ADP 91.4% 92.1% 0.22
PFA-100 92.5% 90.5% 0.42
Innovance 89.7% 93.2% 0.001
Innovance failed to prove itself an independent predictor of the primary endpoint, LTA 5 µmol/L ,LTA 20 µmol/L ADP ,VerifyNow ,and Plateletworks were all independent predictors.
POPULAROne-Year Survival Free from the Primary Endpoint(death, nonfatal MI, definite stent thrombosis, and stroke)
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