STEMI and NSTEMI Pharmacology STEMI and NSTEMI Pharmacology Confusion: Confusion: How to Choose and Use How to Choose and Use Antithrombins (Unfractionated and Low Antithrombins (Unfractionated and Low Molecular Heparins, Bivalirudin, Molecular Heparins, Bivalirudin, Fondaparinux) and Antiplatelet Agents Fondaparinux) and Antiplatelet Agents (Aspirin, Clopidogrel and Prasugrel) (Aspirin, Clopidogrel and Prasugrel) Gregg W. Stone MD Gregg W. Stone MD Columbia University Medical Center Columbia University Medical Center Cardiovascular Research Foundation Cardiovascular Research Foundation
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STEMI and NSTEMI Pharmacology STEMI and NSTEMI Pharmacology Confusion: Confusion: How to Choose and Use How to Choose and Use
Antithrombins (Unfractionated and Low Antithrombins (Unfractionated and Low Molecular Heparins, Bivalirudin, Molecular Heparins, Bivalirudin,
Fondaparinux) and Antiplatelet Agents Fondaparinux) and Antiplatelet Agents (Aspirin, Clopidogrel and Prasugrel)(Aspirin, Clopidogrel and Prasugrel)
Gregg W. Stone MDGregg W. Stone MDColumbia University Medical Center Columbia University Medical Center
Cardiovascular Research FoundationCardiovascular Research Foundation
DisclosuresDisclosures
•• Gregg W. StoneGregg W. StoneResearch support from The Medicines Research support from The Medicines CompanyCompany
My DilemmaMy DilemmaHow to Cover 25 Years of Data and How to Cover 25 Years of Data and
>350 Randomized Trials in 20 minutes?>350 Randomized Trials in 20 minutes?•• The DrugsThe Drugs
* * In combination with standard therapyIn combination with standard therapy
CURECURE12,562 pts with ACS were treated with aspirin and randomized to 12,562 pts with ACS were treated with aspirin and randomized to
clopidogrel vs. placebo and followed for up to 12 months clopidogrel vs. placebo and followed for up to 12 months Primary endpoint = CV Death, MI, or Stroke Primary endpoint = CV Death, MI, or Stroke
CURECURE12,562 pts with ACS were treated with aspirin and randomized to 12,562 pts with ACS were treated with aspirin and randomized to
clopidogrel vs. placebo and followed for up to 12 months clopidogrel vs. placebo and followed for up to 12 months
-- RBC anyRBC any 79%79% 58%58% 0.0040.004-- RBC mean URBC mean U 2.512.51 1.741.74 0.0360.036-- Platelet anyPlatelet any 51%51% 18%18% 0.0010.001-- Plat mean UPlat mean U 0.860.86 0.240.24 0.0010.001
Reop for bleedReop for bleed 6.8%6.8% 0.6%0.6% 0.020.02Extubate <8Extubate <8ºº 54%54% 76%76% 0.0020.002LOS LOS ≤≤5 days5 days 34%34% 47%47% 0.090.09
Hongo RH, et al. Hongo RH, et al. JACCJACC 2002;40:2312002;40:231––7.7.
ACUITY: Impact of Thienopyridine Exposure Prior to CABG (n=1,539 pts)
ACUITY: Impact of Thienopyridine Exposure Prior to CABG (n=1,539 pts)
P=0.05P=0.01
P=0.71
P=0.98
Ebrahimi et al, In press
Healthy Volunteer Crossover StudyHealthy Volunteer Crossover Study
--2020
00
2020
4040
6060
8080
100100IP
A a
t 24
hour
s (%
)IP
A a
t 24
hour
s (%
)
Response to Response to Prasugrel 60 mgPrasugrel 60 mg
Response to Response to Clopidogrel 300 mgClopidogrel 300 mg
From Brandt JT et al. From Brandt JT et al. AHJAHJ 2007;153:66.e92007;153:66.e9--66.e1666.e16
N=66
TRITONTRITON--TIMITIMI--383813,608 pts with ACS (unstable angina, NSTEMI, acute STEMI, or re13,608 pts with ACS (unstable angina, NSTEMI, acute STEMI, or recent STEMI) cent STEMI)
undergoing PCI with known coronary anatomy (except for primary Pundergoing PCI with known coronary anatomy (except for primary PCI pts) were CI pts) were treated with aspirin and randomized to clopidogrel 300 mg load +treated with aspirin and randomized to clopidogrel 300 mg load + 75 mg qd vs. 75 mg qd vs. prasugrel 60 mg load + 10 mg qd and followed for 6prasugrel 60 mg load + 10 mg qd and followed for 6--15 mos (median 12 mos) 15 mos (median 12 mos)
Wiviott SD et al. Wiviott SD et al. NEJM 2007;357:2001NEJM 2007;357:2001--1515
0
5
10
15
0 30 60 90 180 270 360 450
HR 0.81(0.73-0.90)P=0.0004
HR 0.81(0.73-0.90)P=0.0004
Prasugrel
Days
Prim
ary
Endp
oint
CV
deat
h, M
I, or
str
oke
(%)
12.1%
9.9%
ClopidogrelHR 0.77
P=0.0001HR 0.77
P=0.0001
HR 0.80P=0.0003HR 0.80
P=0.0003
Sten
t thr
ombo
sis
(%)
TRITONTRITON--TIMITIMI--3838Definite or probable stent thrombosis Definite or probable stent thrombosis
in 12,844 pts receiving any stentin 12,844 pts receiving any stent
N days on drugN days on drug 5.2 5.2 ±± 2.32.3 5.4 5.4 ±± 2.42.4Hospital meds and proceduresHospital meds and proceduresAngiographyAngiography 63.1%63.1% 63.5%63.5%PCIPCI 34.3%34.3% 34.3%34.3%CABGCABG 9.0%9.0% 9.6%9.6%Clopidogrel/ticlopidineClopidogrel/ticlopidine 67.2%67.2% 67.6%67.6%GP IIb/IIIaGP IIb/IIIa 17.6%17.6% 18.6%18.6%
-- during PCIduring PCI 41.0%41.0% 41.7%41.7%Unfractionated heparinUnfractionated heparin 31.2%31.2% 22.0%22.0%
Yusuf S et al. Yusuf S et al. NEJMNEJM 2006;354:14642006;354:1464––7676
OASISOASIS--55Fondaparinux vs. Enoxaparin in ACSFondaparinux vs. Enoxaparin in ACS
Outcome in pts undergoing PCI within first 8 days (N=6239)Outcome in pts undergoing PCI within first 8 days (N=6239)
EnoxaparinEnoxaparin(n = 3104)(n = 3104)
FondaparinuxFondaparinux(n = 3135)(n = 3135)
Unfractionated heparinUnfractionated heparin 55.555.5 20.820.8GP IIb/IIIa inhibitorGP IIb/IIIa inhibitor 41.041.0 41.741.7ThienopyridineThienopyridine 74.674.6 74.974.9Acute closure, new thrombus, Acute closure, new thrombus, dissection or no reflowdissection or no reflow 5.25.2 6.06.0
CatheterCatheter--related thrombi (CEC)related thrombi (CEC) 0.40.4 0.90.9Death, MI or stroke (30 days)Death, MI or stroke (30 days) 7.37.3 7.47.4Major bleedingMajor bleeding 5.4 5.4 2.82.8
P=0.008P=0.008
Yusuf S et al. Yusuf S et al. NEJMNEJM 2006;354:14642006;354:1464––7676
OASIS 6:OASIS 6: Fondaparinux During Primary PCIFondaparinux During Primary PCI
30 day events30 day events UFH UFH (n=1,898)(n=1,898)
Severe bleedSevere bleed 0.5%0.5% 0.8%0.8% 0.160.16
3,788 pts with STEMI undergoing primary PCI were randomized 3,788 pts with STEMI undergoing primary PCI were randomized to UFH for 4to UFH for 4--48 hrs vs. fondaparinux 2.5 mg SQ QD 48 hrs vs. fondaparinux 2.5 mg SQ QD
for up to 8 days in a placebofor up to 8 days in a placebo--controlled doublecontrolled double--blind trialblind trial
** Abrupt coronary closure, new angio thrombus, catheter Abrupt coronary closure, new angio thrombus, catheter thrombus, no reflow, dissection, or perforationthrombus, no reflow, dissection, or perforation
Yusuf S et al. Yusuf S et al. JAMAJAMA 2006;295:15192006;295:1519––3030
PCI PharmacologyPCI Pharmacology
Antithrombins III:Bivalirudin
Antithrombins III:Bivalirudin
BivalirudinBivalirudinBivalent Synthetic Direct Thrombin InhibitorBivalent Synthetic Direct Thrombin Inhibitor
*P value for Bivalirudin alone vs. GP IIb/IIIa inhibitor based regimen*P value for Bivalirudin alone vs. GP IIb/IIIa inhibitor based regimen
11.7%
7.3%5.9%
7.0%
9.5%
3.1%
Net benefitoutcome
Ischemiccomposite
Majorbleeding
30 d
ay e
vent
s (%
)
UFH/Enox+GPI Bivalirudin alone
11.7%
7.3%5.9%
7.0%
9.5%
3.1%
Net benefitoutcome
Ischemiccomposite
Majorbleeding
30 d
ay e
vent
s (%
)
UFH/Enox+GPI Bivalirudin alone
UFH/Enoxaparin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin Alone
11.0%
7.1%
4.8%
9.1%
11.1%
2.9%
Net benefitoutcome
Ischemiccomposite
Majorbleeding
30 d
ay e
vent
s (%
)
UFH/Enox+GPI Bivalirudin alone
RR [95%CI] = 0.81 [0.70-0.94)
RR [95%CI] = 0.97 [0.80-1.17)
RR [95%CI] = 0.53 [0.41-0.68)
RR [95%CI] = 1.01 [0.83-1.23)
RR [95%CI] = 1.29 [1.03-1.63)
RR [95%CI] = 0.60 [0.42-0.86)
Thienopyridinepre angio/interv (n=5,753)
No thienopyridinepre angio/interv (n=3,304)
Net benefit Pint=0.08; Ischemic composite Pint=0.054; Major bleed Pint=0.53
Impact of Thienopyridine Pre-Administration
HHarmonizing armonizing OOutcomes with utcomes with RRevascularevascularizizatiationon and and SStents in tents in AMIAMI
3602 pts with STEMI with symptom onset 3602 pts with STEMI with symptom onset ≤≤12 hours12 hours
UFH + GP IIb/IIIa inhibitorUFH + GP IIb/IIIa inhibitor(abciximab or eptifibatide)(abciximab or eptifibatide)
Bivalirudin monotherapyBivalirudin monotherapy((±± provisional GP IIb/IIIa)provisional GP IIb/IIIa)
Aspirin, thienopyridineAspirin, thienopyridineR
1:1
Emergent angiography, followed by triage to primary PCI, CABG orEmergent angiography, followed by triage to primary PCI, CABG or medical therapymedical therapy
3006 pts eligible for stent randomization3006 pts eligible for stent randomizationR
1:3
Bare metal EXPRESS stentBare metal EXPRESS stent PaclitaxelPaclitaxel--eluting TAXUS stenteluting TAXUS stent
Clinical FU at 30 days, 6 months,1 year, and then yearly through 5 years
Clinical FU at 30 days, 6 months,1 year, and then yearly through 5 years