GP IIb/IIIa抑制剂在PCI中的应用
GP IIb/IIIa Inhibitors in the PCI Setting
Objectives
Discuss the pivotal role of platelets in the development of ischemic complications after percutaneous coronary intervention (PCI), including high-risk populations such as patients with diabetes
Explore the optimization of PCI outcomes through adequate platelet inhibition achieved through early initiation or in-lab administration
Objectives (continued)
Address the need to consider and study a more aggressive dosing schedule for reversible glycoprotein (GP) IIb/IIIa inhibitors
Discuss the significance of the upcoming, large-scale TENACITY trial, which will test current and emerging clinical practice around combination therapy using GP IIb/IIIa platelet inhibitors
Review the safety profile of therapies for PCI
GP IIb/IIIa Inhibitors in the PCI Setting Module 1: Early Utilization of GP IIb/IIIa Inhibitors in High-Risk Populations
ACS=acute coronary syndrome.
UA=unstable angina.
Bhatt DL. J Invasive Cardiol. 2003;15:3B-9B.
Acute Plaque Rupture
(UA/NSTEMI/STEMI)
Presence of Multiple
Coronary Plaques
Persistent Hyperreactive
Platelets
Vascular
Inflammation
Clinical
Subclinical
ACS: The Tip of the Atherothrombotic “Iceberg”
NSTEMI=non-ST-segment elevation myocardial infarction.
STEMI=ST-segment elevation myocardial infarction.
American Heart Association. 2002 Heart and Stroke Statistical Update. 2001.
Single largest cause of death
529,659 deaths in the U.S. in 1999
1 in every 5 deaths
Incidence
1,100,000 Americans will have a new or recurrent coronary attack each year and about 45% will die*
550,000 new cases of angina per year
Prevalence
12,900,000 with a history of myocardial infarction (MI), angina, or both
*Based on data from the Atherosclerotic Risk in Communities (ARIC) study of the National Heart, Lung, and Blood Institute, 1987–94. Includes Americans hospitalized with definite or probable MI or fatal coronary heart disease (CHD), not including silent MIs.
ACS in the United States
Hospital Admissions for ACS: UA/NSTEMI* versus STEMI?
ACS
2.3 million hospital admissions
ACS
UA/NSTEMI
1.43 million
admissions per year
*Also known as non-Q-wave MI.
?Also known as Q-wave MI.
National Center for Health Statistics. 2001.
STEMI
829,000
admissions per year
STEMI
Clinical finding
EKG
Serum markers
Risk assessment
Non-cardiac chest pain
Stable angina
UA
NSTEMI
Negative
Positive
ST-T wave changes
ST elevation
Low probability
Medium-high
risk
Thrombolysis Primary PCI
Aspirin + GP IIb/IIIa inhibitor
clopidogrel + heparin/
LMWH + anti-ischemic Rx Early invasive Rx
Discharge
Negative
Diagnostic rule out MI/ACS
pathway
STEMI
Negative
Atypical
pain
Low
risk
Aspirin, heparin/low-molecular-weight heparin (LMWH) + clopidogrel Anti-ischemic Rx Early conservative therapy
Ongoing pain
DM=diabetes mellitus.
Cannon, Braunwald. Heart Disease. 2001.
Rest pain, Post-MI, DM, Prior Aspirin
Exertional pain
The Spectrum of ACS
LMWH: Potential Advantages
Increased anti-Xa to anti-IIa activity ? inhibits thrombin generation more effectively
Dalteparin 2:1, enoxaparin 3.8:1
Less binding to plasma proteins (eg, acute-phase reactant proteins) ? more consistent anticoagulation
Lower rate of thrombocytopenia vs unfractionated heparin (UFH)
Subcutaneous administration, dosing twice daily
No need to monitor its effects
OR and 95% CI
Eikelboom J, et al. Lancet. 2000;355:1936-1942.
0.1 1.0 10.0
Favors
Heparin
Favors
Control
Control %
UFH or LMWH %
0
3.1
Cohen
4.5
Grand total
7.4
0.53 (0.38 - 0.73)
7.9
10.4
UFH vs placebo
0.67 (0.45 - 0.99)
5.7
4.8
FRISC I
0.39 (0.22 - 0.68)
1.6
5.2
LMWH vs placebo
0.34 (0.20 - 0.58)
5.7
9.6
Gurfinkel (UFH)
0.58 (0.17 - 1.98)
27.3
30.5
Holdright
0.85 (0.51 - 1.43)
0
9.6
Gurfinkel (LMWH)
0.13 (0.03 - 0.60)
1.4
3.7
RISC
0.40 (0.11 - 1.39)
0.12 (0.01 - 5.89)
3.8
8.2
Cohen
0.46 (0.15 - 1.41)
1.6
3.3
Theroux
0.50 (0.10 - 2.53)
OR 95% CI
UFH or LMWH in UA/NSTEMI
Trial:
FRIC
(dalteparin; n=1482)
FRAXIS
(nadroparin; n=2357)
ESSENCE
(enoxaparin; n=3171)
TIMI IIB
(enoxaparin; n=3910)
.75 1.0 1.5
?
?
?
?
(P=0.032)
(P=0.029)
Braunwald E, et al. Circulation. 2000;102:1193-1209.
LMWH
Better
UFH
Better
LMWH versus UFH in UA/NSTEMI: Effect on Death, MI, Recurrent Ischemia
Ferguson J, et al. JAMA. 2004;292:45-54.
SYNERGY: Major Clinical Endpoints at 30 Days
LMWH Limitations
Indirect inhibition: dependent on antithrombin
Inability to inhibit clot-bound thrombin
Catheterization lab: slower onset, longer half-life, and with enoxaparin, no standard test to measure levels/effect
CABG: concerns regarding the long half-life
Monitoring for Factor Xa: possible, but what is the therapeutic target, increased time, expense?
Not all LMWHs are the same
CABG=coronary artery bypass graft.
0.00
0.02
0.04
0.06
0.08
0.10
0.12
0.14
Cumulative Hazard Rate
Clopidogrel + Aspirin*
3
6
9
Placebo + Aspirin*
Months of Follow-Up
P<0.001
N=12,562
0
12
*Other standard therapies were used as appropriate.
CV=cardiovascular.
CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
20%
Relative-risk Reduction
CURE: Primary Endpoint: MI/Stroke/CV Death
?Up to 12 months.
?Plus Aspirin and other standard therapies.
PCI-CURE: Long-term Efficacy of Clopidogrel
Composite of CV death or MI from randomization to end of follow-up?
Mehta SR, et al. Lancet. 2001;358:527-533.
Placebo?
Clopidogrel?
0.15
0.10
0.05
0.0
0
100
200
300
400
Days of Follow-up
12.6%
8.8%
P=0.002 N=2658
Cumulative Hazard Rate
31%
Relative-risk Reduction
Post-randomization Subgroup Analysis
The PURSUIT Trial Investigators. N Engl J Med. 1998;339:436-443.
The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:1488-1497.
Simoons ML. GUSTO IV-ACS Investigators. Lancet. 2001;16:1915-1924.
Three Categories of Placebo-controlled Trials of GP IIb/IIIa Inhibitors in ACS
Decision to proceed with angiography left up to investigator
PURSUIT (eptifibatide)
Angiography required by study protocol after 48 hours
PRISM-PLUS (tirofiban)
Early catheterization and PCI (or CABG) prohibited by protocol
GUSTO IV (abciximab)
PRISM-PLUS: Combined MI/Death Event Reductions at 2, 7, and 30 Days
RR=risk reduction.
The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:1488-1497.
RR=66%
P=0.01
2 Days
7 Days
RR=43%
P=0.006
RR=30%
P=0.03
30 Days
2.6
0.9
8.3
4.9
11.9
8.7
Patients (%)
0
5
10
15
Heparin (n=797)
Tirofiban + Heparin (n=773)
PRISM-PLUS: Combined MI and Death during Initial 48 Hours in All Patients and Post-procedure in Patients Undergoing PTCA
PTCA=percutanueous transluminal coronary angioplasty.
The PRISM-PLUS Study Investigators. N Engl J Med. 1998;338:1488-1497.
2
4
14
21
28
7
Heparin only
RR=44%
475 Patients Undergoing PTCA
6
30
0
12
18