Acute Myocardial Infarction (AMI): The Urgent Intervention
AMI Disease State
AMI occurs when an artery supplying the heart muscle becomes occluded
Occlusion is usually caused by atherosclerosis accompanied by acute thrombus formation
Atherosclerotic plaques inside the arterial wall can rupture, triggering the formation of the thrombus
If a thrombus grows large enough, it can occlude the blood vessel completely causing ischemia in the heart muscle
Prolonged ischemia can lead to infarction, reducing the power of the heart to pump oxygenated blood around the body, and potentially leading to heart failure and death
Risk factors for AMI include hypercholesterolemia, diabetes, hypertension, smoking, previous history of coronary artery disease (CAD), family history of CAD, and metabolic syndrome.
http://www.nlm.nih.gov/medlineplus/ency/imagepages/17004.htm
AMI Disease State
An atherosclerotic plaque is shown obstructing a coronary artery
AMI Disease State
In AMI, plaque spontaneously ruptures within the vessel. Platelets become activated, triggering the formation of thrombus
AMI Disease State
Thrombus present in the vessel is shown in this angiogram
AMI Disease State
Clumps of activated platelets can break off and travel downstream, blocking the microvessels and preventing blood from reaching the heart muscle
AMI Diagnosis
STEMI (ST-segment elevation MI)
Ischemic symptoms lasting >30 mins (chest pain, dyspnea, etc. )
On electrocardiogram (EKG), ST-segment elevation of ?1 mm in at least two contiguous leads
Confirmatory Evidence
Elevation in creatine kinase to at least three times the upper limit of normal with a concomitant rise in MB isoenzyme
Elevation in troponin levels
New Q wave on ECG
Coronary artery occlusion with angiographic appearance of thrombus
http://www.nlm.nih.gov/medlineplus/ency/imagepages/17004.htm
Abciximab Indication
Abciximab is indicated as an adjunct to percutaneous coronary intervention (PCI) for the prevention of cardiac ischemic complications:
In patients undergoing PCI
In patients with unstable angina (UA) not responding to conventional medical therapy when PCI is planned within 24 hours.
Safety and efficacy of abciximab use in patients not undergoing PCI have not been established. Abciximab is intended for use with aspirin and heparin and has been studied only in that setting.
Clinical Studies of AMI and Abciximab
Abciximab has been studied in the following trials outlined in this presentation:
RAPPORT1
Neumann et al.2
ISAR-23
ADMIRAL4
CADILLAC5,6
ACE7
1. Brener SJ et al. Circulation 1998;98:734–41. 2. Neumann F-J et al. Circulation 1998;98:2695–701.
3. Neumann F-J et al. J Am Coll Cardiology 2000;35:915–21. 4. Montalescot G et al. N Eng J Med 2001;344:1895–903.
5. Tcheng JE et al. Circulation 2003;108:1316–23. 6. Stone GW et al. N Engl J Med 2002;346:957–66.
7. Antoniucci D et al. J Am Coll Cardiol 2003;42:1879–85.
PCI with Abciximab for AMI
Data from the studies outlined in this presentation will illustrate the effect that primary PCI with abciximab for AMI patients has on:
Clinical outcomes1
Microvascular perfusion2
Left ventricular (LV) function1,2
Combined with stenting, abciximab initiated before catheterization improved the composite of death, reinfarction, or target vessel revascularization (TVR) in patients with AMI, as compared with placebo at 30 days1
1. Montalescot G, Barragan P, Wittenberg O et al. N Engl J Med 2001;344:1895–903.
2. Neumann F-J, Blasini R, Schmitt C et al. Circulation 1998;98:2695–701.
Abciximab Administration
Abciximab (represented as the teal green cloud
entering the vessel) is shown flowing through a
heavily artherosclerosed vessel
PCI
Intervention with a balloon and stent results in the flattening and cracking of plaque, and the dislodging of sections of the plaque
Abciximab and PCI
Abciximab prevents the thrombus formation that the intervention triggers. Blood flows freely and the PCI may proceed smoothly
RAPPORT Study
First dedicated randomized trial of platelet GPIIb/IIIa inhibition in AMI patients during percutaneous transluminal coronary angioplasty (PTCA)
Patients with acute MI (within 12 hours) undergoing PTCA were randomized to placebo or abciximab
The primary efficacy endpoint was death, MI, or any TVR at 6 months by intent-to-treat (ITT) analysis
Brener SJ et al. Circulation 1998;98:734–41.
RAPPORT: Trial Design
* 0.25 mg/kg bolus followed by a 0.125 ?g/kg/min (max. 10 ?g/min) for 12 h
** 100 U/kg bolus followed by additional weight-adjusted doses (maintain an activated clotting time >300 seconds during procedure). Heparin infusion could be continued for a maximum of 48 h to maintain partial thromboplastin time (PTT) 60–85 seconds
Brener SJ et al. Circulation 1998;98:734–41.
RAPPORT: 6-Month ITT Outcome
17.8
4.5
7.4
11.2
8.7
4.1
6.6
Death, MI,
or any
TVR
Death, MI,
or urgent
TVR
Death
Repeat MI
Death or
Repeat MI
Urgent
TVR
Incidence (%)
p=0.048
RR 35%
p=0.82
p=0.70
p=0.36
p=0.01
p=0.90
28.1
28.2
11.6
8.7
3.3
Placebo (n=242)
Abciximab (n=241)
Brener SJ et al. Circulation 1998;98:734–41.
Placebo (n=242)
RAPPORT: ITT Analysis
9.9
11.2
17.8
3.3
5.8
11.6
7-day
30-day
6-month*
Incidence of death,
MI, or urgent TVR (%)
p=0.003
RR 67%
p=0.048
RR 35%
p=0.03
RR 48%
*6-month composite of death, MI, or urgent TVR was not a prespecified secondary endpoint
Brener SJ et al. Circulation 1998;98:734–41.
0
5
10
15
20
7-day
30-day
6-month
Incidence of death,
MI, or urgent TVR (%)
RAPPORT: Actual Treatment (AT) Analysis
10.5
12.0
19.9
2.8
4.6
10.6
p=0.001
RR 73%
p=0.004
RR 47%
p=0.005
RR 62%
Placebo (n=191)
25
Brener SJ et al. Circulation 1998;98:734–41.
Placebo (n=242)
9.5
0
7.9
16.6
0
13.7
0
2
4
6
8
10
12
14
16
18
TIMI major bleeding
Intracranial
hemorrhage
All transfusions
Incidence (%)
p=0.02
p=0.04
RAPPORT: 30-Day Safety
p=ns
Brener SJ et al. Circulation 1998;98:734–41.
RAPPORT: Conclusions
Abciximab reduced the major adverse outcomes – death, reinfarction, or urgent TVR – at 7 days, 30 days and extended to 6 months
Abciximab during PTCA did not show a reduction in TVR and, therefore, did not meet its primary endpoint.
As this trial was performed in the mid-1990s, stents were highly discouraged and rarely used in this trial
Brener SJ et al. Circulation 1998;98:734–41.
Neumann Study
Neumann et al. investigated the effect of abciximab on papaverine-induced coronary peak flow velocity and on wall motion in the infarct area within 14 days after successful stent placement in the infarct-related artery
Patients undergoing stenting in AMI (within 48 hours) were randomized to standard-dose heparin or abciximab plus heparin
Prospective randomized trial to investigate microvascular and contractile recovery after revascularization with stent placement and to compare the effect of glycoprotein (GP) IIb/IIIa blockade by abciximab with standard-dose heparin
Neumann F-J et al. Circulation 1998;98:2695–701.
Neumann Trial Design
AMI <48 h
Heparin (5000 U) + aspirin (500 mg)
Abciximab** (n=102)
1o endpoints: differences in papaverine-induced coronary flow velocity and in wall motion index between the initial study and