stent and adjunctive therapy selection in 2010

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

BMS

Plat

form

DES

Pla

tfor

m

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-

pyrimidinedirect 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)

RDa

y 3Da

y 30

Day 9

0

Prasugrel60 mg LD/ 10 mg

MD

Clopidogrel300 mg LD/ 75 mg

MD Day 4

50

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

Days0

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 D

eath

/MI/S

trok

e (

%)

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<0.0001RRR 52%

ARR 1.22%

Prasugrel

Clopidogrel2.35

1.13

Days

Sten

t Th

rom

bosi

s (%

)

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 Sub

ject

s 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 S

ubje

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)

End

Poin

t (%

)

Subsets of Life-threatening Bleeds

n=85

n=560.9%

1.4%

n=50.1%n=21

0.4%n=510.9%n=64

1.1%

n=17n=190.3%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/TIA1.07(0.90-1.28)

p=0.431.02 (0.84-

1.24) p=0.831.42 (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

N N

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%) 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

ulat

ive

Haza

rd0.

00.

004

0.00

80.

012

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

ulat

ive

Haza

rd0.

00.

010.

020.

030.

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

ulat

ive

Haza

rd0.

00.

010.

020.

030.

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% < 0.0001LTA 20 µmol/L ADP 88.0% 93.8% < 0.0001VerifyNow 86.7% 94.3% < 0.0001Plateletworks 87.4% 93.3% 0.002Impact-R 90.2% 92.5% 0.17Impact-R ADP 91.4% 92.1% 0.22PFA-100 92.5% 90.5% 0.42Innovance 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)