1. No category

Acute Myocardial Infarction
2004 Update
• The Scope of the Problem
• Adjunctive Therapy
• The Lost Art of Thrombolysis
Acute Myocardial Infarction
2004 Update
Alan Keith Berger, MD
Divisions of Cardiology and Epidemiology
University of Minnesota
Minneapolis, MN
Leading Causes of Mortality in US
2002
Number
709,894
Cancer
551,833
Cerebrovascular disease (stroke)
166,028
COPD and allied conditions
123,550
Accidents
93,592
Diabetes
68,662
Influenza and pneumonia
67,024
Alzheimer’s disease
49,044
Nephritis
37,672
Septicemia
31,613
Other Causes
1200
600
1000
500
800
400
600
300
400
200
200
100
0
0
79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00
Year
505,712
Morbidity and Mortality: 2002 Chart Book on Cardiovascular,
Lung, and Blood Diseases. NIH Publication, May 2002.
TOTAL
Morbidity and Mortality: 2002 Chart Book on Cardiovascular, Lung, and Blood Diseases. NIH Publication, May
2002.
2,404,624
Hospital Discharges for
Cardiovascular Diseases
Economic Costs in Billions of Dollars of
Cardiovascular, Lung, and Blood Diseases
Disease
Discharges in Millions
7
Total cardiovascular disease
6
Heart disease
Coronary artery disease
5
CHF
4
Stroke
3
Hypertensive heart disease
2
Selected lung diseases
Total
Direct
329.2
199.5
30.9
98.8
45.2
214.0
Morbidity
Mortality
Stent business for 2003
115.0
19.0
80.0
estimated at $3.2 billion
58.2
8.4
23.2
21.4
?
1.8
49.4
30.8
5.6
13.0
111.8
47.2
34.4
6.7
6.1
115.9
65.4
23.8
26.7
1
COPD
32.1
18.0
6.8
7.3
0
Asthma
14.0
9.4
2.7
1.9
9.7
7.1
0.7
1.9
6.4
4.9
0.6
0.9
1970
1975
1980
1985
1990
1995
Death / 100,000 population
Heart disease
Death in Thousands
Condition
Deaths and Age-Adjusted Death Rates for
Major Cardiovascular Diseases, 1979-2000
2000
Year
American Heart Association. Heart Disease and Stroke Statisitcs- 2003 Update. Dallas: American Heart
Association, 2002.
Selected blood diseases
Anemias
Morbidity and Mortality: 2002 Chart Book on Cardiovascular, Lung, and Blood Diseases. NIH Publication, May
2002.
1
Age-Adjusted Mortality for Cardiovascular
Disease by State, 1996-1998
Percent Decline in Age-Adjusted Mortality for
Cardiovascular Disease, 1986-88 to 1996-98
Lowest
Morbidity and Mortality: 2002 Chart Book on Cardiovascular, Lung, and Blood Diseases.
NIH Publication, May 2002.
Best
Morbidity and Mortality: 2002 Chart Book on Cardiovascular, Lung, and Blood Diseases.
NIH Publication, May 2002.
Acute Myocardial Infarction
Level of Evidence
2004 Update
• The Scope of the Problem
• Adjunctive Therapy
• The Lost Art of Thrombolysis
• Class A (Strongest)
– Data derived from multiple randomized clinical
trials that involved large numbers of patients
• Class B (Intermediate)
– Data derives from a limited number of randomized
clinical trials that involved small numbers of
patients or from careful analyses of nonrandomized
studies or observational registries
• Class C (Weakest)
– Expert consensus
Brauwald E, et al. ACC/AHA 2002 Guidelines for Unstable Angina.
www.acc.org/clinical/guidelines/unstable/unstable.pdf.
ACC/AHA Classification Scheme
• Class I: Evidence and/or agreement that a given
procedure or treatment is useful and effective
• Class II: Conflicting evidence and/or a divergence
of opinion about the usefulness/effectiveness of
procedure or treatment
– Class IIa: Evidence / opinion favors usefulness / efficacy
– Class IIb: Usefulness / efficacy less well established
• Class III: Evidence and/or general agreement that
the treatment is not useful/effective and in some
cases may be harmful
ACC / AHA Guidelines for AMI
Adjunctive Therapy
•
•
•
•
•
Aspirin
Beta blockers
ACE inhibitors
Lipid reduction
Smoking cessation
2
Treatment of AMI
Treatment of AMI
Aspirin
Aspirin
14
Mortality (%)
12
10
8
6
Placebo
Aspirin
Streptokinase
ASA + SK
4
2
0
0
7
14
21
28
Days of Follow-Up
ISIS-2 Collaborative Group Lancet 1988; 11: 349-60.
www.glasbergen.com. © 2002 by Randy Glasbergen.
Aspirin
Clopidogrel: The CAPRIE Trial
• 19,185 patients
• Recent ischemic CVA
• Recent MI
• Symptomatic PVD
• Clopidogrel slightly
increased risk of
diarrhea and rash.
• Recent report described
11 cases of TTP (days 114) among 3 million
patients
λ
Elderly
Females
History of prior MI, stroke / TIA
• Aspirin should be continued indefinitely
following AMI in all patients without
contraindications.
Treatment of Acute Coronary Syndromes
Cardiac Death, Nonfatal MI, Stroke
Clopidogrel: The CURE Trial
ASA
12,562 patients with UA / NSTEMI
12%
P < 0.001
10%
ASA
+
Clopidogrel
8%
6%
4%
Strategy
Cardiac
Death
2%
Clopidogrel
Placebo
318 (5.1%)
345 (5.5%)
Unstable
Angina
MI
324 (5.2%)
419 (6.7%)
8
2
4
6
8
5.87
5.32
4
2
0
Plavix
75 mg qD
Aspirin
325 mg qD
75 (1.2%)
87 (1.4%)
Bleeding
Major Minor
3.7%
2.7%
5.1%
2.4%
Aspirin Dosage
Antithrombotic Trialists’ Collaboration
Aspirin
Trials Vascular Events
Dose (mg) (N)
ASA Control
500-1500
160-325
75-150
< 75
Any dose
34
19
12
3
65
14.5%
11.5%
10.9%
17.3%
12.9%
10
OR (95% CI)
17.2%
15.8%
15.2%
19.4%
16.0%
0
12
Months
CURE Investigators. N Engl J Med 2001; 345: 494-502
P= 0.043
6
0%
0
Relative Risk
Reduction 8.7%
10
CAPRIE Steering Committee. Lancet 1996; 348: 329-339.
Bennett CL, et. al. N Engl J Med 2000; 342: 1773-7.
Antiplatelet Trialists Collaboration. Br Med J 1994; 308: 81-106.
14%
Ischemic CVA, MI, Vascular Death (%)
Treatment of Atherosclerosis
– Risk of recurrent MI, stroke, or death was reduced
by 29% in patients with acute MI.
– Benefit witnessed in understudied groups
λ
Aspirin: 23% reduction
in 35-day mortality
Treatment of AMI
• Antiplatelet Trialists Collaboration
λ
35
Antithrombotic Trialists’ Collaboration. BMJ 2002; 324: 71-86.
0.25 0.5 0.75
ASA
Better
1.0
1.25
Control
Better
3
The CURE Trial
Increased Risk
Impact of Aspirin Dose on Outcomes
Chest tube output (24 hr)
1224 ± 1119
No Clopidogrel
(n=165)
840 ± 621
p
0.001
Transfusions
Red blood cells
2.51 ± 2.41
1.74 ± 2.16
0.001
Platelets
0.86 ± 1.20
0.24 ± 0.60
0.001
Red blood cells
79.7%
58.2%
0.004
Platelets
Exposure to blood products
50.8%
18.2%
<0.001
Reoperation for bleeding
6.8%
0.6%
0.018
Post-op length of stay < 5 days
33.9%
46.7%
0.09
20
16
7
ASA
13.6
12
10.5
9.8 9.5
8.6
ASA (p=0.0001)
6
ASA + Clopidogrel
9.8
8
4
Major bleeding (%)
Clopidogrel
(n=59)
CV Death + Nonfatal MI + CVA (%)
Clopidogrel and CABG
ASA + Clopidogrel (p=0.0009)
4.9
5
4
3.4
3.0
3
2
1
0
0
<= 100 mg 101-199 mg >= 200 mg
<= 100 mg
101-199 mg
>= 200 mg
Aspirin Dose
Peters RJG, et al. Circulation 2003; 108: 1682-7.;
Treatment of AMI
Treatment of AMI
ACC / AHA Guidelines: Antiplatelet Rx
ACC / AHA Guidelines: Antiplatelet Rx
• Class I:
• Class I:
– Antiplatelet therapy should be initiated
promptly. ASA should be administered as soon
as possible after presentation and is continued
indefinitely.
– Clopidogrel should be administered to
hospitalized patients who are unable to take
ASA because of hypersensitivity or major
gastrointestinal bleeding.
Braunwald E, et al. ACC/AHA Guidelines for Unstable Angina & Non ST Elevation MI.
Circulation 2002; 106: 1893-1900.
ACC / AHA Guidelines for AMI
Adjunctive Therapy
•
•
•
•
•
2.8
1.9
Aspirin Dose
Hong RH, et al. J AM Coll Cardiol 2002; 40: 231-7.
3.7
Aspirin
Beta blockers
ACE inhibitors
Lipid reduction
Smoking cessation
– In patients for whom noninterventional or
percutaneous approach is planned, clopidogrel
should be added to ASA on admission and
continued for at least one month and up to 9
months.
– In patients taking clopidogrel in whom CABG is
planned, if possible the drug should be withheld
for at least 5 days, and preferably 7 days.
Braunwald E, et al. ACC/AHA Guidelines for Unstable Angina & Non ST Elevation MI.
Circulation 2002; 106: 1893-1900.
Treatment of AMI
Beta Blockers: Pharmacology
• Decrease myocardial oxygen demand
reduces recurrent ischemia and limits
infarct expansion
– Decrease pulse (beta blockade)
– Decrease afterload reduction
– Decrease contractility
• Increased electrical stability results in
decreased sudden cardiac death
– Decrease VT and VF
4
Treatment of AMI
Treatment of AMI
Beta Blockers and Early Mortality
Beta Blockers and Late Mortality
Endpoint Placebo Beta Blocker
Trial
p
ISIS-1
7 days
4.6%
3.9%
<0.04
Goteberg
90 days
8.9%
5.7%
0.03
MIAMI
15 days
4.9%
4.3%
0.29
TIMI-2
6 days
2.4%
2.4%
0.99
• Beta blockers’ benefit is sustained, and
applicable across a broad range of
patients, including those with “relative
contraindications”
– Diabetes
– Heart failure
– COPD
ISIS-1 Collaborative Group. Lancet 1986; ii: 57-67.
Hjalmarson, et al. Lancet 1981; 2: 823-7.
MIAMI Trial Research Group. Eur Heart J 1985; 6: 199-226.
TIMI Study Group. N Engl J Med 1989; 320: 618-27.
Treatment of AMI
ACC / AHA Guidelines for AMI
ACC / AHA Guidelines: Beta Blockers
Adjunctive Therapy
• Class I
– Patients without contraindications who can be treated
within 12 hours of onset, irrespective of thrombolytic
therapy or performance of coronary intervention
– Continuing or recurrent ischemic chest pain
– Tachyarrhythmias
– Non ST elevation MI
• Class IIb
– Patients with moderate LV failure or other
contraindications to ß-adrenoceptor blocker therapy,
provided they can be monitored closely.
•
•
•
•
•
Aspirin
Beta blockers
ACE inhibitors
Lipid reduction
Smoking cessation
Ryan TJ, et al. Circulation 1999; 100: 1016-1030.
Treatment of AMI
Treatment of AMI
ACE Inhibitors: Pharmacology
Kalkanis SN, et al.
Cardiovascular Drugs.
In: Pathophysiology of
Heart Disease. 2nd ed.
Media: Lippincott,
Williams, Wilkins, 1997.
P 356. Modified.
AT-1 Receptor
Antagonist
ACE Inhibitors
ACE-I PROMOTES
Angiotensinogen
Vasodilation
Liver
Angiotensin I
Lung
Angiotensin II
Angiotensin
converting
enzyme
Bradykinin
-
AT-1 Receptor
Inactive
metabolites
ACE INHIBITOR
ACE-I BLOCKS
Vasoconstriction
↑ Sympathetic
activity
↑ Afterload
↑ Pulse & Arrhythmias
↑ Aldosterone
Trial
Endpoint
Placebo
ACE-I
p
SMILE
42 days
6.5%
4.9%
0.19
CATS
3 months
4.0%
6.0%
N/A
CONSENSUS-2
6 months
9.4%
10.2%
NS
AIRE
15 months
23%
17%
0.002
TRACE
24 months
42.3%
34.7%
0.001
SAVE
42 months
24.6%
20.4%
0.019
↑ Na Retention
↑ Intravascular volume
(1) SMILE. N Engl J Med 1985; 332: 80-5. (2) CATS. Eur Heart J 1994; 15: 898-907. (3)
CONSENSUS-2. N Engl J Med 1992; 327: 678-84. (4) AIRE. Lancet 1993; 342: 821-8.
(5) TRACE. Am J Cardiol 1994; 73: 44C-50C. (6) SAVE. N Engl J Med 1992; 327: 678-84.
5
Treatment of AMI
Treatment of AMI
Early Administration of ACE Inhibitors
ACE Inhibitors: Early Benefit
99 patients randomized to ramipril 2.5 mg or placebo prior to rtPA 100 mg
• Most benefit was seen in first week.
Ramipril
PAI-1 24 Hour AUC (ng/ml/hr)
• Absolute benefit greatest in high risk groups
(Killip class 2 or 3, HR > 100, anterior MI).
• Overall long-term mortality odds reduction 1827% for patients with LV dysfunction after acute
MI.
Placebo
90
P=0.013
80
70
60
50
40
30
20
10
0
Incidence of TIMI 2/3 Flow (%)
Ramipril
100
100
Ramipril
Placebo
8
90
80
P=0.035
70
60
50
40
30
20
7
Ischemic Events (%)
• 30-Day mortality was reduced by 7%.
Placebo
P=0.001
6
5
4
3
2
10
1
0
0
ACE Inhibitor Myocardial Infarction Collaborative Group. Circulation 1998; 97: 2202-12.
Latini, et al. Circulation 1995; 92: 3132-7.
Wagner A, et al. Thromb Haemost 2002; 88: 180-5.
Treatment of AMI
Treatment of AMI
ACE Inhibitors: MITRA PLUS
ACC / AHA Guidelines: ACE Inhibitors
Registry of 14,608 patients with ST segment elevation MI
• Class I
– Patients within the first 24 hours of anterior STEMI
or with CHF in the absence of hypotension (SBP <
100 mm Hg) or contraindications.
– Patients with MI and LVEF < 40% or CHF
100
Survival (%)
90
80
• Class IIa
P < 0.001
Ramipril (4.7%)
Other ACE inhibitor (39.0%)
No ACE inhibitor (56.3%)
70
60
0
7
Days Post MI
14
21
Wienbergen H, et al. Am J Cardiol 2002; 90: 1045-9.
ACC / AHA Guidelines for AMI
Adjunctive Therapy
•
•
•
•
•
Aspirin
Beta blockers
ACE inhibitors
Lipid reduction
Smoking cessation
– All other patients within the first 24 hours of acute
MI, in absence of significant hypotension and
contraindications.
– Asymptomatic patients with mildly impaired LV
function (LVEF 40% - 50%) and a history of old MI.
Ryan TJ, et al. Circulation 1999; 100: 1016-1030.
Treatment of AMI
ACC / AHA Guidelines: Lipid Management
• Studies over the past two decades
have demonstrated an association
between hypercholesterolemia and
coronary artery disease.
• Since 1993 the National Cholesterol
Education Program (NCEP) has
recommended cholesterol lowering for
high risk patients, including those who
have suffered an acute MI.
6
Lipid Management
Treatment of AMI
Spectrum of Clinical Trials
ACC / AHA Guidelines: Lipid Management
No history of CAD
Unstable CAD
Stable CAD
4 mo
AFCAPS / TexCAPS
WOSCOPS
MIRACL
CARE1/LIPID2
Acute coronary
event
t=0
4S3
3 mo
Trial
Endpoint
Duration
Placebo
ACE-I
p
4S
Mortality
5.4 yrs
12%
8%
0.0003
CARE
Mortality &
Nonfatal MI
5 yrs
13.2%
10.2%
0.003
LIPID
Mortality
6.1 yrs
14.1%
11.0%
<0.001
6 mo
Randomization:
24–96 h
Primary prevention
Randomization:
CARE - 3–20 mo
LIPID - 3–36 mo
Randomization:
>6 mo
Secondary prevention
Modified from Schwartz GG et al.
Am J Cardiol 1998;81:578–581.
Duration of follow-up:
1 5.0 years; 2 6.1 years; 3 5.4 years.
Treatment of AMI
Lipid Reduction: MIRACL Trial
12
7
10
4
Placebo
Atorvastatin
9
5
0
-10
-20
-16
-30
-27
-40
-40
-50
TC
LDL-C
HDL-C
Cumulative incidence (%)
Treatment of AMI
Lipid Reduction: MIRACL Trial
20
%∆
Scandinavian Simvastatin Study Group. Lancet 1994; 344: 1383-9.
Sacks FM, et. al. for the Cholesterol and Recurrent Events Trial Investigators. N Engl J
Med 1996; 335: 1001-9.
The Long Term Intervention with Pravastatin in Ischemic Disease (LOPID) Study Group.
N Engl J Med 1998; 339: 1349-57.
14.8
Atorvastatin
10
RR = 0.84 (95% CI, 0.70-1.00), p = 0.048
Death (any cause), nonfatal MI, resuscitated
cardiac arrest, recurrent symptomatic
myocardial ischemia with objective evidence
requiring emergency rehospitalization.
5
0
TG
0
4
Mean LDL-Cholesterol Reduction
Mean % LDL Reduction
0
Fluvastatin
-10
*
-30
‡
*
Pravastatin
Lovastatin
*
*
*
Simvastatin
*
†
Atorvastatin
†
†
-40
‡
‡
-50
-60
0
10
20
30
40
50
60
70
80
90
60
♫
50
40
30
20
10
* Significantly less than atorvastatin 10 mg (P<0.02).
† Significantly less than atorvastatin 20 mg (P<0.01).
‡ Significantly greater than mg-equivalent dose of comparative agents (P≤0.01).
♪
†‼
*
*
* †‡
*†
*
†‡
* †‡
*†
Pravastatin
Simvistatin
Atorvastatin
Rosuvastatin
Significance: p < 0.002
0
10
20
Dose range (mg)
Jones P et al. Am J Cardiol. 1998;81:582-587.
16
STELLAR Trial
The CURVES Trial
-20
12
Data from Schwartz GG et al. JAMA. 2001;285:1711-1718.
Additional data courtesy of GG Schwartz.
Comparisons of Statins
Mean
% LDL-C
reduction
8
Time since randomization (wk)
Data from Schwartz GG et al. JAMA. 2001;285:1711-1718.
Additional data courtesy of GG Schwartz.
*
17.4
Placebo
15
Dose (mg)
* P value < 0.001 vs. rosuvastatin 10 mg
† P value < 0.001 vs. rosuvastatin 20 mg
‡ P value < 0.001 vs. rosuvastatin 40 mg
40
80
‼ P = 0.026 vs. rosuvastatin 10 mg
♪ P < 0.002 vs. rosuvastatin 20 mg
♫ P = 0.006 vs. rosuvastatin 40 mg
Jones P et al. Am J Cardiol. 2003; 92: 152-160.
7
Mean % HDL Increase
STELLAR Trial
ACC / AHA Guidelines for AMI
Mean HDL-Cholesterol Increase
Adjunctive Therapy
12
Pravastatin
10
Simvistatin
Atorvastatin
8
†‡
6
4
†
*
†
Rosuvastatin
†‡
†‡
†‡
2
0
10
20
40
•
•
•
•
•
Aspirin
Beta blockers
ACE inhibitors
Lipid reduction
Smoking cessation
80
Dose (mg)
* P value < 0.002 vs. rosuvastatin 10 mg
Jones P et al. Am J Cardiol. 2003; 92: 152-160.
† P value < 0.002 vs. rosuvastatin 20 mg
‡ P value < 0.002 vs. rosuvastatin 40 mg
Treatment of AMI
Treatment of AMI
Smoking Cessation Counseling
Smoking Cessation Counseling
• 30% of all coronary heart disease (CHD)
deaths in the US each year are attributable
to smoking.
• Smokers with AMI who quit see 50% lower
risk of death and recurrent MI than smokers
who continue.
• Risk reduction begins soon after cessation
of smoking, and continues to decrease over
time, as long as abstinence continues.
Ockene, et. al. for the AHA Task Force on Risk Reduction. Circulation 1997; 96: 3243-7.
• Smoking cessation advice is associated with
a 50% long-term (> 1 year) smoking cessation
rate in patients who have been hospitalized
with a cardiac event.
Ockene, et. al. for the AHA Task Force on Risk Reduction. Circulation 1997; 96: 3243-7.
Acute Myocardial Infarction
Impact of Thrombolysis
2004 Update
Meta-Analysis of Fibrinolytic Trials
16
14
30-Day Mortality (%)
• The Scope of the Problem
• Adjunctive Therapy
• The Lost Art of Thrombolysis
12
10
Thrombolysis
Control
p < 0.00001
11.5
18% risk
reduction
9.6
8
6
4
2
0
FTT Collaborators, Lancet 1994; 343: 311-22
Trials: GISSI-1, ISAM, AIMS, ISIS-2,
ASSET, USIM, ISIS-3, EMERAS, LATE
8
Fibrinolytic Therapy
ACC / AHA Guidelines
Thrombolysis
Comparison of Agents
• Class I (Evidence and general agreement)
– ST elevation > 0.1 mV in ≥ 2 contiguous leads in patients
age < 75 presenting within 12 hours of symptom onset
– BBB obscuring ST segments, history suggesting AMI
• Class IIa (Divergence of opinion, evidence favors use)
– ST elevation, age ≥ 75
2nd Generation
Alteplase
3rd Generation
Reteplase
Kringle 2
Kringle 1
3rd Generation
Tenecteplase
Kringle 1
Kringle 2
Asn for Thr at
“T”
103
EGF
Finger
“N”
Kringle 2
EGF
Finger
NH2
“K”
• Class IIb (Efficacy less well established by evidence)
NH2
– ST elevation, patients presenting 12-24 hours
– BP > 180/110 in high risk patients
COOH
NH2COOH
COOH
Protease
Ala-Ala-Ala-Ala for
Lys-His-Arg-Arg at 269-299 Protease
Protease
Non-glycosylated, small with Same as Alteplase with 3 point mutations
domains specific for clot
specific fibrinolysis
Alteplase and reteplase: Adapted with permission from Brieger D, Topol EJ. In: Califf RM, ed. Thrombolytic
Therapy: New Standards of Care: Part 1. Am J Cardiol. 1996:16-22. Tenecteplase: EHJ 1999; 20:1452-58.
Glycolsylated, large with more
domains
Ryan TJ, et al. Circulation 1999; 100: 1016-1030.
Fibrinolytic Therapy
Efficacy of Thrombolysis
Comparison of Agents
GUSTO-1 Angiographic Substudy
Tenecteplase
(TNK-tPA)
Genentech
Centocor
Genentech
5 minutes
13-16 minutes
20-24 minutes
Excretion
Liver
Renal + Hepatic
Liver
Weight-based
Yes
No
Yes
Industry
Half Life (t ½)
Dosing
Regimen
> 67 kg: Bolus 15 mg,
Double bolus
then 50 mg over 30 min 10 U + 10 U
then 35 mg over 60 min (30 min apart)
≤ 67 kg: Bolus 15 mg,
then 0.75 mg/kg (30 min)
then 0.50 mg/kg (60 min)
Fibrin specificity
+++
+++
Single Bolus
< 60 kg: 30 mg
≥60 to <70: 35 mg
≥70 to <80: 40 mg
≥80 to <90: 45 mg
≥90 kg: 50 mg
t-PA + Heparin Strategy
Proportion of Patients (%)
Reteplase
(r-tPA)
70%
54%
60%
10 %
50%
8%
40%
6%
27%
30%
19%
20%
4%
2%
10%
0%
30-Day Mortality
Tissue Plasminogen
Activator (tPA)
0%
TIMI-0 & TIMI-1
TIMI-2
TIMI-3
Coronary patency at 90 minutes
> tPA
GUSTO Angiographic Investigators, NEJM 1993; 329: 1615-22.
Impact of Thrombolysis on Reinfarction
Comparison of Thrombolytic Agents
Comparison of Thrombolytic Agents
30-Day Mortality (%)
30
“Therapeutic Floor”
25
STK
tPA
rPA
TNK
nPA
20
15
10
p=0.001
7.4
p=NS
9.0
p=NS
9.5
6.3
7.5
7.2
p=NS
6.2
6.2
p=NS
6.7
6.6
5
0
In-Hospital Reinfarction (%)
Impact of Thrombolysis on Mortality
30
STK
tPA
rPA
TNK
nPA
25
20
15
10
5
p=NS
3.7
4.0
p=NS
5.0
5.4
p=NS
4.2
4.2
rPA STK
rPA
tPA
INJECT
GUSTO-3
p=NS
4.1
3.8
TNK
tPA
p=NS
3.9
4.5
0
STK
tPA
GUSTO-1
rPA STK
rPA
INJECT
GUSTO-3
tPA
TNK
tPA
ASSENT-2
nPA tPA
In-TIME-2
GUSTO-I Investigators. N Engl J Med 1993; 329: 673-82. INJECT Investigators. Lancet 1995; 346: 329-36.
GUSTO-III Investigators. NEJM 1997; 337: 1118-23. ASSENT-2 Investigators. Lancet 1999; 354: 716-22.
In-TIME II Investigators. ACC 48th Scientific Sessions, New Orleans, 1999.
STK
tPA
GUSTO-1
ASSENT-2
nPA tPA
In-TIME-2
GUSTO-I Investigators. N Engl J Med 1993; 329: 673-82. INJECT Investigators. Lancet 1995; 346: 329-36.
GUSTO-III Investigators. NEJM 1997; 337: 1118-23. ASSENT-2 Investigators. Lancet 1999; 354: 716-22.
In-TIME II Investigators. ACC 48th Scientific Sessions, New Orleans, 1999.
9
Impact of Thrombolysis on ICH
Thrombolytic Therapy
Comparison of Thrombolytic Agents
Impact of Delay on 30-Day Mortality
5
p=0.09
1.40
p=NS
p=NS
1.55
1
0.77
p=NS
0.94 0.92
0.93 0.94
rPA
TNK
Absolute Mortality Benefit
(per 1000 lives)
30-Day ICH Rate (%)
3
2
50
STK
tPA
rPA
TNK
nPA
4
p=NS
1.12
0.64
0.37
0
STK
tPA
rPA STK
GUSTO-1
INJECT
tPA
GUSTO-3
nPA tPA
tPA
ASSENT-2
In-TIME-2
GUSTO-I Investigators. N Engl J Med 1993; 329: 673-82. INJECT Investigators. Lancet 1995; 346: 329-36.
GUSTO-III Investigators. NEJM 1997; 337: 1118-23. ASSENT-2 Investigators. Lancet 1999; 354: 716-22.
In-TIME II Investigators. ACC 48th Scientific Sessions, New Orleans, 1999.
Loss of benefit per hour of
delay = 1.6 ± 0.6 per 1000
3000
40
30
14000
12000
20
9000
10
7000
0
0
3
6
9
12
24
Delays in Thrombolytic Therapy
Pre-Hospital Administration
Cooperative Cardiovascular Project
Min
5469
360
APSAC
t-PA
55
33
GREAT
311
UK
130
Schofer
78
APSAC
43
100
APSAC
60
EMIP
MITI
Castaigne
40
100
Pre-hospital
worse
6318 RR 17% ↓ P=0.03
80
60
40
22
20
1
1.5
EMIP Investigators. NEJM 1993; 329: 383-9.
ACC / AHA Guidelines
Time to Thrombolysis
2
Door-to-needle time < 30 minutes
16.5
15
12.5
14.1
10
5
0
31-90
91-360
30-Day
1-Year
Door-to-Needle Time (min)
Berger AK,et al. Am Heart J 2000; 139; 985-92.
The Antithrombin Pathway
The Antiplatelet Pathway
Tissue Factor VII Endothelial Injury
(Extrinsic Pathway) (Intrinsic Pathway)
IX
X
IXa
AT
ADP
Collagen
Phospholipid
Factor Va
Ca2+
Thrombin
LMWH
Heparin
Xa
Phospholipid
Factor VIIIa
Ca2+
Prothrombin
Arachidonic
Acid
Aspirin,
TX synthase inhibitors,
COX-1 Inhibitors
Fibrin
Thromboxane A2
Plasmin
(-) PAI
Plastminogen Activators
t-PA, r-PA, TNK-t-PA
Serotonin
Thrombin
Fibrinogen
Plasminogen
Ticlopidine
Clopidogrel
Epi
Hirudin
Bivalirudin
Argatroban
Bound to STK
Ryan TJ, et al. Circulation 1999; 100: 1016-1030.
20.4
19.9
20
XII, XI
Class I (Evidence and general agreement)
p < 0.001
p < 0.001
25
20
< 30
0.5
28.5
30
58
0
0
1 - 30 minutes
31 - 90 minutes
91 - 360 minutes
35
Mortality (%)
Agent
Pre-hospital
better
Proportion of Patients (%)
N
υ
21
Thrombolytic Therapy
Study
λ
18
FTT Collaborators, Lancet 1994; 343: 311-22
Odds Ratio & 95% CI
Pooled
15
Hours from Symptom Onset to Randomization
Fibrin
degradation
products
GP2b3a
Inhibitors
Thrombus
GP2b3a
Activation
Platelet
aggregation
10
The GP2b3a Inhibitors
Combination Lytics & GP2b3a
Comparison of Agents
TIMI-3 Flow Rates
Tirofiban
(Aggrastat)
Eptifibatide
(Integrelin)
Centocor
Merck
Millenium
Monoclonal Ab
Nonpeptide
Peptide
Industry
Chemistry
Half Life (t ½)
30 minutes
Dosing Regimen
(Unstable Angina)
Bolus:
0.25 mg/kg
Infuse:
10 µg/min
Reversible binding
2 hours
Bolus (30 min):
0.4 µg/kg/min
Infuse:
0.1 µg/kg/min
No
2.5 hours
Bolus:
180 µg/kg
Infuse:
2 µg/kg/min
Yes
Yes
No
Yes
Antigenicity
Yes
No
No
Reverse with platelet TX
Yes
No
No
Renal dose adjustment
100
90 min TIMI-3 Flow Rate (%)
Abciximab
(Reopro)
Lytic
Lytic + GP2b3a
p = 0.0009
78
p = 0.05
80
p = 0.006
62
61
60
47
66
39
40
20
SPEED
0
Yes
TIMI-14
tPA 100 mg
rPA 5 + 5
Hep 70 U/kg
Hep 60 U/kg
Hep 15 U/kg/hr
Reopro 25 ug/kg
Reopro 12.5 g/kg/m
rPA 10 + 10
Hep 70 U/kg
IMPACT-AMI
tPA 50 mg
tPA 100 mg
Hep 60 U/kg
Hep 40 U/kg
Hep 7 U/kg/hr
Hep 15 U/kg/hr
Reopro 25 ug/kg
Reopro 12.5 ug/kg/m
tPA 100 mg
Hep 40 U/kg
Hep 15 U/kg/hr
Integ 180 ug/kg
Integ 0.75 ug/kg/m
SPEED Investigators. Circulation 2000; 101: 2788-94.
Antman, et. al. TIMI-14. Circulation 1999; 99: 2720-32.
Ohman EM, et al. for IMPACT-AMI Investigators. Circulation 1997; 95: 846-54.
GUSTO V: Retevase & Reopro
GUSTO V: Retevase & Reopro
Trial Design
30-Day Mortality
ST ↑, lytic eligible, < 6 h
ASA
Abciximab*
2 x 10 U bolus (30’)
Reteplase
2 x 5 U bolus (30’)
Reteplase
Standard Heparin:
5,000 U bolus followed by either
800 U/hr (pts < 80 kg) or
1,000 U/hr (pts ≥ 80 kg) infusion
Low Dose Heparin:
60 U/kg bolus followed by a
7 U/kg/h infusion
5.9%
5.6%
4
P=0.43 for superiority
Non-Inferiority RR 0.95
(95% CI, 0.84-1.08)
2
Std. Dose Reteplase (n = 8260)
Abciximab + ↓ Dose Reteplase (n = 8328)
1º endpoint: mortality at 30 days
2º endpoint: clinical and safety events at 7 and 30 days
* 0.25mg/kg bolus followed by
0.125 µg/kg/min (max 10 µg/min) infusion for 12 hrs
GUSTO V. Lancet 2001; 357: 1905-14.
% Mortality
6
No Abciximab
0
0
5
10
15
20
25
Days
30
At 1 year, mortality
8.4% in both arms.
GUSTO V Investigators. Lancet 2001; 357: 1905-14.
GUSTO V: Retevase & Reopro
GUSTO V: Retevase & Reopro
Intracranial Hemorrhage
Bleeding
4.0
Reteplase
Reteplase + Reopro
30
3.0
p = 0.069
2.1
2.0
p = NS
1.0
Reteplase
Reteplase + Reopro
25
0.6
1.1
0.6
Bleeding (%)
Intracranial Hemorrhage (%)
5.0
p < 0.0001
24.6
p < 0.0001
20.0
20
13.7
15
11.4
10
5
p < 0.0001
p <0.0001
0.5
1.1
1.8
3.5
0
0.0
Severe
All Patients
(n = 16588)
GUSTO-V Investigators. Lancet 2001; 357: 1905-14.
Age > 75
(n = 2237)
Hemodynamic
Compromise
Moderate
Blood
Transfusion
Mild
Total
Neither
GUSTO-V Investigators. Lancet 2001; 357: 1905-14.
11
BRAVE: Reteplase & Reopro
ASSENT III: TNK, Lovenox, Reopro
Clinical Endpoints
Trial Design
* Short-Term Events (%)
16
253 ST elevation MI pts
Community hospitals & PCI centers (<39 km)
Symptoms < 12 hours
Reopro vs. Reopro + Reteplase 5U+5U
p = 0.81
14
13.0
11.5
12
10
Reteplase + Reopro
Reopro only
8
6
4
2.4
1.6 1.6
5.6
p = 0.66
p = NS
p = NS
2
p = 0.16
3.2
1.6
1.6
ST ↑, lytic eligible, < 6 h
ASA
Full Dose TNK
30 - 50 mg
Half-Dose TNK
15 - 30 mg
Full Dose TNK
30 - 50 mg
Reopro
Bolus: 0.25mg/kg
Infusion: 0.125 µg/kg/min
(max 10 µg/min) for 12 hr
Heparin
Bolus: 60 U/kg
(max 4000 U)
Infusion: 12 U/kg
(max 1000 U/hr)
Heparin
Bolus: 40 U/kg (max 3000 U)
Infusion: 7 U/kg (max 800 U/hr)
1.6
Lovenox
Bolus: 30 mg IV
1 mg/kg q 12 hrs
(max 100 mg early)
(max 7 days)
0
Final infarct
Mortality
Death/MI Death/MI/CVA
Major
size (%)
at 30 days(%) at 30 days(%) at 30 days(%) bleeding(%)
Kastrati A, et al. American Heart Association Scientific Sessions. Orlando, Nov 2003.
1º endpoint: Mortality at 30 days + In-hospital MI + Recurrent Ischemia
2º endpoint: 1º endpoint + In-hospital ICH + In-hospital Major Bleeding
ASSENT III Investigators. Lancet 2001; 358: 605-13.
ASSENT III: TNK, Lovenox, Reopro
ASSENT III: TNK, Lovenox, Reopro
Primary Endpoint
30-Day Mortality
TNK + UFH
TNK + LMH
TNK + Reopro
Death at 30 days,
In-Hospital Reinfarction,
Refractory Ischemia (%)
90
80
70
1.02 (0.76-1.36)
60
0.72 (0.61-0.84)
50
0.80 (0.59-1.09)
0.74 (0.63-0.87)
40
26.6
26.2
30
20
15.4
10
0
20.9
11.4
25
30-Day Mortality (%)
100
11.1
All Patients
Age > 75
(n = 6091)
(n = 767)
20
22.3
15.9
15.6
15
p = 0.25
10
6.0
5.4
6.6
5
0
ASSENT-3 Investigators. Lancet 2001; 358: 605-13.
p = 0.11
TNK + UFH
TNK + LMH
TNK + Reopro
All Patients
Age > 75
(n = 6091)
(n = 767)
ASSENT-3 Investigators. Lancet 2001; 358: 605-13. Additional data provided by F Van de Werf.
ASSENT III: TNK, Lovenox, Reopro
ASSENT III: TNK, Lovenox, Reopro
Intracranial Hemorrhage
In-Hospital Bleeding
Intracranial Hemorrhage (%)
4.0
p = 0.25
3.0
2.58
p = 0.98
2.0
1.0
1.52
0.93
0.88
0.94
0.74
40
In-Hospital Bleeding (%)
TNK + UFH
TNK + LMH
TNK + Reopro
5.0
35
30
p <0.0001
TNK + UFH
TNK + LMH
TNK + Reopro
25
35.3
22.6
18.7
20
15
10
5
p = 0.0005
2.2
3.0
4.4
0
0.0
All Patients
Age > 75
(n = 6091)
(n = 767)
ASSENT-3 Investigators. Lancet 2001; 358: 605-13. Additional data provided by F Van de Werf.
Major
Transfusion or
Hemodynamic Compromise
Minor
ASSENT-3 Investigators. Lancet 2001; 358: 605-13. Additional data provided by F Van de Werf.
12
ASSENT III: TNK, Lovenox, Reopro
Direct Thrombin Inhibitors
In-Hospital Major Bleeding
Hirudin
TNK + UFH
TNK + LMH
TNK + Reopro
In-Hospital Major Bleeding (%)
20
15
p = 0.001
13.3
10
7.2
p = 0.0005
4.4
5
2.2
0
4.1
3.0
Patients
Age > 75
(n = 6091)
(n = 767)
Acute Myocardial Infarction
2004 Update
GUSTO-IIb
UA/MI
Yes
30
TIMI-9B
STEMI
Yes
30
The Scope of the Problem
Adjunctive Therapy
The Lost Art of Thrombolysis
The 21st Century and PCI
To Transfer or Not to Transfer
Quality Improvement Initiatives
Weighing the Risk and Benefit
Thrombolysis vs PCI
Primary Angioplasty
Thrombolysis
Readily accessible
Rapid delivery
Lower initial costs
Ineligible patient
Incomplete reperfusion
Hemorrhagic stroke
Longer hospital stay
Unable to identify
extent of CAD
• Mortality floor
•
•
•
•
•
•
•
•
24 hour cath lab access
Inherent delay in therapy
Higher initial costs
Expanded eligible population
Complete reperfusion
Minimal risk of stroke
Shorter hospital stay
Early triage (5% reperfuse,
5% require CABG)
• ? Mortality floor
Risk of Death/MI
OR (95% CI)
OASIS-1
UA/NSTEMI
No
35
p = 0.15
OASIS-2
UA/NSTEMI
No
35
p = 0.06
1.0
Hirudin Better
2.0
Hirudin Worse
GUSTO-2B. N Engl J Med 1996; 335: 775-82. TIMI-9B. Circulation 1996; 94: 911-21. OASIS-1. Circulation
1997; 96: 769-77. OASIS-2. Lancet 1999; 353: 429-38.
Reperfusion Therapy
Initial Pharmacologic Therapy
OR
100 mg Lytic
Rx
•
•
•
•
•
•
•
•
Lysis Days
0.0
All Patients
ASSENT-3 Investigators. Lancet 2001; 358: 605-13. Additional data provided by F Van de Werf.
•
•
•
•
•
•
Trial
100 mg Stainless Steel
325 mg Aspirin
300 mg Plavix
0.25 mg/kg Reopro
Rx
Suitability of Thrombolysis
• Retrospective cohort study of 2965 patients
age ≥ 65 discharged with a diagnosis of AMI
from hospitals in Connecticut between 5/92 5/93
• Only 753 (25%) of patients were considered
eligible for thrombolysis based on ECG
criteria and exclusion of individuals with
absolute or relative contraindications
Krumholz, et al. JAMA 1997; 277: 1683-8.
13
PTCA versus Thrombolysis
Combination Lytic Therapy
Meta-Analysis of Randomized Trials
SHOCK Trial
14
12
p < 0.0001
7.0
8.2
6.8
6
p < 0.0001
2.4
p < 0.0001
1.1
1.0
Nonfatal
Reinfarction
Total
Stroke
Hemorrhagic
Stroke
* = 4 – 6 weeks
Keeley E, et al. Lancet 2003; 361: 13-20.
30-Day Mortality (%)
14.1
p=0.001
10
8
2
6.4
3.7
4.0
61-75 min
76-90 min
> 91 min
No PTCA
(n=76)
(n=140)
(n=93)
1.0
0
Time from <60 min
enrollment
(n=104)
to PTCA
(n=109)
49.4
65.6
56.3
53.1
40
30
30 Day
6 Month
1 Year
Age < 75
30 Day
6 Month
1 Year
Age ≥ 75
ACC / AHA Guidelines
Primary Coronary Angioplasty
• Class I (Evidence and general agreement)
– Alternative to thrombolysis in patients with ST
elevation or new LBBB, performed within 12 hours of
symptom onset, or after 12 hours if symptoms
persist.
– Patients who are within 36 hours of an acute STEMI /
Q-wave or new LBBB MI who develop cardiogenic
shock, are <75 years of age, and revascularization
can be performed within 18 hours of onset of shock.
12
4
44.9
p = NS
79.2
Hochman JS, et al. N Engl J Med 1999; 341: 625-34. Hochman JS, et al. JAMA 2001; 285: 190-2..
16
6
41.4
p = 0.09
79.2
66.7
65.0
56.8
60
50
p = 0.002
75.0
0
Death,
Stroke,
Reinfarction
Relationship Between Primary PTCA
and Early Clinical Outcomes
14
p = 0.02
p = NS
p < 0.05
10
0.1
0
70
Revascularization
Lysis
20
2.0
2
Death
90
80
9.3
4
100
14.3
23 randomized trials
7739 ST elevation MI pts
p = 0.0002
10
8
p < 0.0001
Primary PTCA
Lysis
Mortality (%)
* Short-Term Events (%)
16
Berger PB, et al. Circulation. 1999; 100: 14-20.
• Class IIa (Divergence of opinion, evidence favors use)
– Patients with contraindication to thrombolysis
Ryan TJ, et al. Circulation 1999; 100: 1016-1030.
ACC / AHA Guidelines
Performance of Primary PTCA
• Interventional performs > 75 PTCA / year
• Institution performs > 200 PTCA / year
• Surgical backup available
• Balloon dilation within 90 (±30) min of AMI diagnosis
• Emergency CABG rate less than 5%
• TIMI II + III flow in > 90% of patients without
emergency CABG, stroke, or death
• Mortality rate less than 10%
The
End
Ryan TJ, et al. Circulation 1999; 100: 1016-1030.
14