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100 PART III Coronary Artery Disease
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ANTERIOR MYOCARDIAL INFARCTION
In acute anterior MI, ST segment elevation is present in the
precordial leads. The challenge in anterior wall MI lies in identifying the site of occlusion within the vessel in relation to the septal
and diagonal branches. In very proximal left anterior descending
artery occlusion, before the first septal and diagonal branches,
the ST segment is elevated in leads V1 to V3 and aVL, with ST
segment depression in aVF.
points toward the base of the heart and ST segment elevation
can be seen in aVR and aVL. ST segment elevation exceeding
2.5 mm in V1 is also highly correlated with occlusion proximal
to the first septal perforator branch.14 Acquired right bundle
branch block with a Q wave is an insensitive, but extremely
Fig. 10.1 Old string galvanometer electrocardiograph showing
the big machine with the patient rinsing his extremities in the
cylindrical electrodes filled with electrolyte solution.
12,13
The ST segment deviation vector
specific, marker of proximal occlusion of the left anterior descending artery because the septal perforators supply blood to the
right bundle (Fig. 10.3). ST segment elevation in leads V1 to V3
with elevation in the inferior leads suggests occlusion distal to
the origin of the first diagonal branch.13 In addition, if the ST
segment in aVL is elevated, it suggests an occlusion distal to the
septal branch but proximal to the diagonal branch. If the ST
segment in aVL is depressed, it suggests an occlusion distal to
the diagonal branch but proximal to the septal branch.15 In distal
left anterior descending artery occlusions, ST segment elevation
is seen in leads V3 to V6 and in the inferior leads. A localization
schema for anterior MI is summarized in Table 10.2.
LEFT MAIN OCCLUSION
When the left main coronary artery is occluded, ischemia occurs
in the left anterior descending artery and circumflex artery
territories. This ischemia results in an ST segment deviation
vector that points toward aVR. ST segment elevation in aVR and
V1 is frequently present and there is higher specificity for left
TABLE 10.1 Inferior Myocardial Infarction:
ST Segment Elevation II, III, aVF
Left Circumflex
Right Coronary Artery
ST segment elevation III > II ST segment elevation II ≥ III
ST segment depression >
ST segment elevation V4R or V
1 mm I, avL ST segment elevation I, avL, V5–V
1
Coronary Artery
ST segment depression V
6
4R
I
II
I
III
II
Fig. 10.2 Inferior ST elevation myocardial infarction. Elevation in lead III is greater than II and ST
depressions in leads I and aVL indicate the right coronary artery as the culprit vessel. Note the
posterior injury current and the presence of complete heart block. Elevation in aVR suggests
concomitant right ventricular infarction due to occlusion proximal to the RV marginal branches.
aVR
aVL
aVF
V1
V2
V3
V4
V5
V6
CHAPTER 10 Use of the Electrocardiogram in Acute Myocardial Infarction 101
Referred by:
Confirmed by:
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EMERGENCY:ER1
I
II
III
V1
II
Fig. 10.3 Anterior ST elevation myocardial infarction. Occlusion of the proximal left anterior
descending artery is indicated by the presence of diffuse precordial ST elevations and right bundle
branch block pattern. There is elevation in the II, III, and aVF because the distal portion of the
vessel wraps around the apex to supply the inferior wall.
aVR
aVL
aVF
TABLE 10.2 Anterior Myocardial
Infarction: ST Segment Elevation V1–V
Left Main Artery
ST segment elevation
aVR > V
Global ST segment
ST segment depression
1
depressions
II, III, avF
Proximal Left
Anterior
Descending
Artery
ST segment elevation
V
(> 2.5 mm)
1
New right bundle
branch block
Distal Left
Anterior
Descending
Artery
ST segment elevation
3
II, III, avF
main occlusion when aVR elevation is greater than V1.16 With
the exception of aVR and V1, there is marked precordial and
inferior ST segment depression, reflecting posterior and basal
wall ischemia (Fig. 10.4).
DIAGNOSIS IN BUNDLE BRANCH BLOCK
:
V1
V2
V3
:
V4
V5
V6
left ventricular depolarization in native left bundle branch block
or iatrogenic right ventricular pacing, Q waves cannot be used
to diagnose infarction. Prominent notching greater than 50 ms
in the QRS can indicate prior infarction, however. Two signs are
extremely insensitive but have specificity approaching 85% for
prior MI in the setting of left bundle branch block. The Cabrera
sign refers to prominent notching in the ascending limb of the
S wave in leads V3 to V5. A similar finding with prominent
notching of the ascending limb of the R wave in lead I, aVL, or
V6 is called the Chapman sign.
18,19
Based on the Global Utilization of t-PA and Streptokinase
for Occluded Coronary Arteries (GUSTO-I) trial, the Sgarbossa
criteria20 were proposed to improve specificity for diagnosis of
acute MI in the setting of left bundle branch block. Primary ST
segment elevation, 1 mm concordant with the major QRS vector,
was given a score of 5, and discordant 5-mm ST segment elevations
were assigned a score of 2. ST segment depressions greater than
1 mm in leads V1 to V3 were given a score of 3. A score of at
least 3 was 90% specific for the diagnosis of MI. Discordant
5-mm ST segment elevations were the most specific in pacemakerinduced left bundle branch block.
21
Bundle branch block is present on the initial ECG in approximately 7% of patients presenting with acute MI.17 Ischemia can
be difficult to interpret in right and left bundle branch block
because of the delayed depolarization and abnormal repolarization
of the corresponding ventricle and its attendant secondary ST
segment changes. In the setting of ST elevation MI, primary ST
segment elevations in the precordium and new Q waves are
fairly specific in the presence of right bundle branch block.
More challenging is the interpretation of acute MI in the
setting of left bundle branch block, which also causes secondary
ST segment repolarization changes. Because there is delay in the
ABSENCE OF ST ELEVATIONS
Diagnosis of MI in the absence of ST elevations (non-ST elevation
MI or NSTEMI) typically cannot be made with an ECG alone.
It usually requires concurrent elevation of cardiac biomarkers,
such as troponin. However, there are ECG findings that can
heighten suspicion for a significant NSTEMI. Prior analysis of
the Framingham and Fast Revascularization During Instability in Coronary Artery Disease (FRISC) II trial demonstrated
a correlation between the number of leads with ST segment
depression and coronary artery disease severity and prognosis.
22
102 PART III Coronary Artery Disease
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I
II
III
I
aVF
V1
aVR
aVL
aVF
V1
V2
V3
V4
V5
V6
Fig. 10.4 Left main coronary artery occlusion. Elevation in aVR and VI, with global ST depressions.
Fig. 10.5 Early precordial deep T-wave inversions in the absence of current chest pain and Q
waves consistent with Wellens syndrome. This patient subsequently developed chest pain and
anterior ST elevations and underwent percutaneous coronary intervention for a 95% left anterior
descending artery lesion.
Aside from ST depressions, the presence of symmetric T wave
inversions in early precordial leads—most commonly V2 and
V3—can represent critical left anterior descencing (LAD) artery
narrowing (Fig. 10.5). Also known as Wellens syndrome, this
finding typically presents once chest pain has subsided and the
significant LAD lesion reperfuses. Recognition of this pattern is
key because early intervention could potentially limit the extent
of an anterior wall MI.
15
The full reference list for this chapter is available at
ExpertConsult.com.
CHAPTER 10 Use of the Electrocardiogram in Acute Myocardial Infarction 102.e1
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REFERENCES
1. Sasaki K, Yotsukura M, Sakata K, et al. Relation of ST-segment
changes in inferior leads during anterior wall acute myocardial
infarction to length and occlusion site of the left anterior
descending coronary artery. Am J Cardiol. 2001;87:1340–1345.
2. Zimetbaum P, Krishnan S, Gold A, et al. Usefulness of
ST-segment elevation in lead III exceeding that of lead II for
identifying the location of the totally occluded coronary
artery in inferior wall myocardial infarction. Am J Cardiol.
1998;81:918–919.
3. Bairey CN, Shah K, Lew AS, Hulse S. Electrocardiographic
differentiation of occlusion of the left circumflex versus the right
coronary artery as a cause of inferior acute myocardial
infarction. Am J Cardiol. 1987;60:456–459.
4. Hasdai D, Birnbaum Y, Herz I, et al. ST segment depression in
lateral limb leads in inferior wall acute myocardial infarction:
implications regarding the culprit artery and the site of
obstruction. Eur Heart J. 1995;16:1549–1553.
5. Braat SH, Brugada P, den Dulk K, et al. Value of lead V4R for
recognition of the infarct coronary artery in acute inferior
myocardial infarction. Am J Cardiol. 1984;53:1538–1541.
6. Jim MH, Ho HH, Siu CW, et al. Value of ST-segment depression
in lead V4R in predicting proximal against distal left circumflex
artery occlusion in acute inferoposterior myocardial infarction.
Clin Cardiol. 2007;30:36–41.
7. Herz I, Assali AR, Adler Y, et al. New electrocardiographic
criteria for predicting either the right or left circumflex artery as
the culprit coronary artery in inferior wall acute myocardial
infarction. Am J Cardiol. 1997;80:1343–1345.
8. Zehender M, Kasper W, Kauder E, et al. Right ventricular
infarction as an independent predictor of prognosis after acute
inferior myocardial infarction. N Engl J Med. 1993;328:981–988.
9. Braat SH, Brugada P, de Zwaan C, et al. Value of
electrocardiogram in diagnosing right ventricular involvement in
patients with an acute inferior wall myocardial infarction. Br
Heart J. 1983;49:368–372.
10. Lopez-Sendon J, Coma-Canella I, Alcasena S, et al.
Electrocardiographic findings in acute right ventricular
infarction: sensitivity and specificity of electrocardiographic
alterations in right precordial leads V4R, V3R, V1, V2, and V3. J
Am Coll Cardiol. 1985;6:1273–1279.
11. Kahn JK, Bernstein M, Bengtson JR. Isolated right ventricular
myocardial infarction. Ann Intern Med. 1993;118:708–711.
12. Engelen DJ, Gorgels AP, Cheriex EC, et al. Value of the
electrocardiogram in localizing the occlusion site in the left
anterior descending coronary artery in acute anterior myocardial
infarction. J Am Coll Cardiol. 1999;34:389–395.
13. Tamura A, Kataoka H, Mikuriya Y, Nasu M. Inferior ST segment
depression as a useful marker for identifying proximal left
anterior descending artery occlusion during acute anterior
myocardial infarction. Eur Heart J. 1995;16:1795–1799.
14. Engelen DJ, Gorgels AP, Cheriex EC, et al. Value of the
electrocardiogram in localizing the occlusion site in the left
anterior descending coronary artery in acute anterior myocardial
infarction. J Am Coll Cardiol. 1999;34:389–395.
15. Wellens HJ, Conover M. The ECG in Emergency Decision Making.
2nd ed. St Louis: Saunders Elsevier; 2006.
16. Yamaji H, Iwasaki K, Kusachi S, et al. Prediction of acute left
main coronary artery obstruction by 12-lead
electrocardiography. ST segment elevation in lead aVR with
less ST segment elevation in lead V(1). J Am Coll Cardiol.
2001;38:1348–1354.
17. Go AS, Barron HV, Rundle AC, et al. Bundle-branch block and
in-hospital mortality in acute myocardial infarction. National
Registry of Myocardial Infarction 2 Investigators. Ann Intern
Med. 1998;129:690–697.
18. Wacker FJ. The diagnosis of myocardial infarction in the
presence of left bundle branch block. Cardiol Clin. 1987;5:
393–401.
19. Kochiadakis GE, Kaleboubas MD, Igoumenidis NE, et al.
Electrocardiographic appearance of old myocardial infarction in
paced patients. Pacing Clin Electrophysiol. 2002;25:1061–1065.
20. Sgarbossa EB, Pinski SL, Barbagelata A, et al.
Electrocardiographic diagnosis of evolving acute myocardial
infarction in the presence of left bundle-branch block. N Engl J
Med. 1996;334:481–487.
21. Sgarbossa EB, Pinski SL, Gates KB, Wagner GS. Early
electrocardiographic diagnosis of acute myocardial infarction
in the presence of ventricular paced rhythm. GUSTO-I
investigators. Am J Cardiol. 1996;77:423–424.
22. Holmvang L, Clemmensen P, Lindhal B, et al. Quantitative
analysis of the admission electrocardiogram identifies patients
with unstable coronary artery disease who benefit the most from
early invasive treatment. J Am Coll Cardiol. 2003;41:905–915.
11
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Reperfusion Therapies for Acute ST
Elevation Myocardial Infarction
OUTLINE
Introduction, 103
Historical Perspective, 103
Coronary Thrombosis and the Pathogenesis of
Acute Myocardial Infarction, 103
Thrombolysis and Reperfusion, 104
Thrombolytic Agents: The First Pathway to
Coronary Reperfusion, 104
Streptokinase, 105
Tissue-Type Plasminogen
Activator, 105
Tenectaplase and Reteplase, 105
Magnitude and Timing, 105
Pivotal Trials, 106
Adjunctive Therapy, 106
Bleeding and the Elderly, 107
Harold L. Dauerman, Prospero B. Gogo Jr, Burton E. Sobel
Primary Percutaneous Coronary Intervention, 108
Primary Percutaneous Coronary Intervention for
STEMI, 108
Rationale and Feasability, 108
Key Clinical Trials, 108
Adjunctive Therapy and Approach, 108
Oral Antiplatelet Agents: Aspirin, Clopidogrel, Prasugrel,
and Ticagrelor, 109
Intravenous Antiplatelet Agents, 110
Antithrombins, 110
Radial, Femoral, and Multivessel Primary PCI, 110
Thrombectomy and Route of Drug Administration, 112
Pharmacoinvasive Therapy for STEMI, 112
Regional Systems in STEMI Care, 113
Conclusions, 116
†
INTRODUCTION
Historical Perspective
Thrombosis was implicated as the cause of acute myocardial
infarction (MI) almost a century ago. However, the pathophysiology remained obscure and, as recently as 44 years ago, many
investigators believed that thrombosis was a secondary event.
Chazov and Rentrop demonstrated that recanalization was
achievable pharmacologically with favorable clinical consequences.
Thus the concept of reperfusion therapy for acute ST elevation
myocardial infarction (STEMI) was born by demonstrating that
ischemic injury could be attenuated by restoration of myocardial
perfusion.
Eugene Braunwald: MI evolves dynamically, the magnitude of
irreversible injury sustained is related to the duration of ischemia,
and the clinical consequences of infarction are a reflection of
the extent of irreversible injury sustained.4 It was postulated that
reduction of myocardial oxygen requirements, enhancement of
myocardial perfusion, or both when implemented within the
first few hours after the onset of myocardial ischemia would
reduce the magnitude of irreversible injury sustained by the
†
Deceased.
1–3
Underlying this concept was a hypothesis formulated by Dr.
myocardium and improve prognosis. Thus reperfusion—first
with pharmacologic agents and later with primary percutaneous coronary intervention (primary PCI)—was consistent with
Braunwald’s hypothesis, resulting in marked improvements in
prognosis. Prior to the reperfusion era, hospital mortality from
acute STEMI approached 25%
current STEMI mortality rates in the United States are less
than 5%.
6–9
5
; with reperfusion therapy, the
Coronary Thrombosis and the Pathogenesis of
Acute Myocardial Infarction
Although Herrick attributed fatal acute MI to a thrombotically
occluded coronary artery in 1912, autopsy studies in the late 1970s
did not demonstrate coronary thrombosis in patients who had
died of acute MI. Thus coronary thrombosis was considered a
consequence, rather than the underlying cause, of acute MI.
In 1980, DeWood and colleagues reported the results of coronary
angiography performed early after the onset of acute transmural
MI: within 4 hours of symptom onset, 87% of infarct-obstructed
arteries were completely occluded. However, 12 to 24 hours after
onset, the prevalence of coronary occlusion was only 65%. When
patients with subtotal occlusion of the obstructed artery were
included, the prevalence of angiographically demonstrable
coronary thrombosis in the first 4 hours was 98%.12 Over the past
decade, further understanding of the pathology underlying acute
10,11
103
CHAPTER 11 Reperfusion Therapies for Acute ST Elevation Myocardial Infarction 103.e1
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Keywords
Myocardial Infarction
Fibrinolysis
Intervention
Percutaneous Coronary Reperfusion
Guidelines
104 PART III Coronary Artery Disease
Thrombus-Predominant
Plaque-Predominant
1975/1978 1981/1984 1986/1988 1993/1995 1997
Hospital Mortality, %
Evolution of STEMI Mortality
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25
20
15
10
5
0
Fig. 11.2 Acute ST elevation myocardial infarction mortality
occurred in 20% to 25% of patients in the hospital prior to the
advent of coronary care units, arrhythmia management, and the
reperfusion era. After the advent of the reperfusion era, a nearly
50% reduction in hospital mortality was observed. (Modified
from Dauerman HL Lessard D, Yarzebski J, et al. Ten-year trends
in the incidence, treatment, and outcome of Q-wave myocardial
infarction. Am J Cardiol. 2000;86:730–35).
coronary occlusion has come from autopsy studies, angiography,
and intracoronary imaging: underlying culprit soft lipid plaques,
thin cap fibroatheromas, bulky plaques with characteristic erosion,
and/or calcified nodules have all been found to predispose to
plaque rupture and coronary occlusion
to reduce mortality have focused on both prevention of plaque
rupture and rapid restoration of blood flow in thrombotically
occluded coronary arteries.
This chapter addresses the developments in reperfusion therapy
for STEMI responsible for a profound improvement in survival
(Fig. 11.2).
STEMI Pathophysiology
Soft 40% Lipid-Rich
Plaque
Plaque Rupture, Platelet
Activation, Platelet
Aggregation
Predominant Large
Thrombus with Small
Plaque
Fig. 11.1 The pathophysiology of acute ST elevation myocardial infarction requires thrombosis
and occlusion of a coronary artery. Thrombosis is mediated by plaque rupture related to lipid
pools, thin cap fibroatheroma, calcific nodules, and plaque erosion.
Reperfusion Era
13–19
(Fig. 11.1). Efforts
THROMBOLYSIS AND REPERFUSION
Thrombolytic Agents: The First Pathway to
Coronary Reperfusion
Coronary blood flow depends upon a complex balance between
thrombosis, thrombolysis, and counterregulation by inhibition
of both processes. From recent intravascular ultrasound and
optical coherence tomography studies, we now know that underlying plaques prone to thrombosis are characterized by thin cap
fibroatheromas (TCFA), lipid-rich cores, erosion of the intima,
and calcified nodules
erosclerotic plaque leads to thrombosis due to the procoagulant
effects of exposed collagen, von Willebrand factor, and tissue
factor in the vessel wall.
the vascular injury accelerates ongoing thrombosis. Thrombin
and fibrin generated by the coagulation cascade may undergo
concomitant or subsequent lysis resulting from activation of the
fibrinolytic system and conversion of the zymogen plasminogen
to the active serine protease, plasmin, by the circulating plasminogen activators, tissue-type plasminogen activator (tPA) or
urokinase plasminogen activator (uPA).
to reduce myocardial damage must enhance the rapidity and
extent of recanalization and promote sustained patency.
The available thrombolytic agents are plasminogen activators.
These agents function as proteases that directly or indirectly
hydrolyze a single peptide bond (Arg
substrate molecule, plasminogen, to form the active serine protease
enzyme, plasmin. Plasmin is responsible for the degradation of
fibrin and diverse other proteins, with consequent dissolution
of intravascular thrombi. First-generation agents (nonfibrin
selective) include streptokinase and urokinase. Second- and
subsequent-generation (fibrin-selective) agents include tPA, rPA,
and molecular variants of tPA such as tenecteplase (TNK tPA).
Agents that are relatively fibrin specific, such as tPA, produce
less depletion of fibrinogen, less plasminemia, and less depletion
-antiplasmin than that seen with nonfibrin-specific agents,
of α
2
STEMI Pathophysiology
Severe Stenosis
With Bulky Plaque
Thin Cap Fibroatheroma
Platelet Activation and
and
Plaque Rupture,
Aggregation
Predominant Plaque
with Small Thrombus
14,15,18
: the rupture of an underlying ath-
20,21
Activation of platelets accompanying
16,22
Any strategy designed
561
562
Val
) on the inactive
CHAPTER 11 Reperfusion Therapies for Acute ST Elevation Myocardial Infarction 105
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such as streptokinase. The pathophysiology and development
of fibrinolytic agents has been extensively reviewed by the original
investigators.
3,22–29
Streptokinase. Streptokinase (SK) is a protein present in
numerous strains of hemolytic streptococci. The circulating
half-life of SK is approximately 18 to 25 minutes. However,
depletion of fibrinogen to less than 50% of baseline values persists
for approximately 24 hours. Because of the foreign nature of
the protein and the near-universal human exposure to the bacterial
sources of the agent (β-hemolytic streptococci), administration
of SK is complicated by inhibition of the administered drug by
circulating immunoglobulin G (IgG) antibodies and problems
of immunogenicity and attendant allergic reactions. Adverse
reactions associated with SK (presumably attributable to plasminmediated activation of kininogen) limit clinical use of this agent.
The overall incidence of hypotension ranges from 10% to 40%.
Severe hypotension requiring pressor agents or fluids occurs in
5% to 10% of patients.
26,30–32
Other allergic reactions reported
include fever, chills, urticaria, rash, flushing, and muscle pain.
In the large-scale Second International Study of Infarct Survival
(ISIS-2) and Global Utilization of Streptokinase and Tissue
Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I)
trials, the incidence of minor allergic reactions was 4% to 6%.
33,34
Because of drawbacks in the use of streptokinase, it is no longer
marketed in the United States. It is available internationally
because of its low cost.
Tissue-Type Plasminogen Activator. tPA is an endogenous
serine protease synthesized and secreted by human vascular
endothelium and numerous other cells. The plasma half-life of
tPA is 5 minutes, but fibrinolytic activity persists within clots
for 7 hours. tPA is metabolized by the liver and inhibited in
plasma by plasminogen activator inhibitor type 1 (PAI-1). An
important advantage of tPA compared with SK is its affinity for
fibrin-bound plasminogen. The relative fibrin specificity of tPA
accounts for the more rapid clot lysis seen with tPA compared
with SK. Unlike SK, tPA is not associated with immunogenic-
28,29,35
it y.
tPA is available commercially as Alteplase. Neuhaus and
coworkers introduced “front-loaded” dosing (i.e., 15 mg bolus
with 50 mg given by infusion over the first 30 minutes, followed
by 35 mg over the next 60 minutes). This regimen was associated
with a 91% patency rate at 90 minutes, and it has now been
approved by the US Food and Drug Administration (FDA).
36
Tenectaplase and Reteplase. Third-generation agents were
designed to modify the pharmacokinetics of tPA.25 Modifications
were designed to prolong the half-life, increase fibrinolytic activity,
increase fibrin selectivity, or exhibit other potentially advantageous
properties.26 For example, Retavase lacks the kringle 1 domain,
resulting in a prolonged half-life and thus facilitating bolus
administration. However, early reocclusion necessitated a doublebolus dosing regimen. TNK tPA has three amino acid substitutions
that differentiate it from wild-type tPA. They result in reduced
inhibition of the plasminogen activator by PAI-1, prolongation
of half-life as a result of decreased uptake by the reticuloendothelial system mediated by mannose receptors, and improved
efficacy following bolus injection. TNK tPA appears to induce
reperfusion more rapidly than tPA in patients treated within 3
hours after onset of symptoms. The simplicity of the single-bolus
dosing regimen without requiring a continuous infusion has
made this the predominant fibrinolytic agent available.
Magnitude and Timing
Fibrinolysis was initially evaluated using an invasive, intracoronary
infusion methodology. Rentrop and colleagues, using intracoronary SK, demonstrated improved cardiac function and alleviation
of chest pain accompanying recanalization compared with
intracoronary nitroglycerin alone or conventional therapy.38 The
Western Washington randomized trial substantiated the efficacy
of intracoronary SK in lysing coronary thrombi, with favorable
effects on mortality.
of immediate cardiac catheterization, time delays, increased costs,
and risk limited enthusiasm for intracoronary administration
as primary therapy for patients with acute MI.
Early patency trials employed angiographic endpoints to
delineate patency 90 minutes after the administration of a
thrombolytic agent. Patients with Thrombolysis in Myocardial
Infarction (TIMI) 2 (slow) or TIMI 3 (normal) flow grades were
considered together in delineating overall patency incidence. Even
when no thrombolytic agent is given, patency rates range from
9% to 29% in the 0- to 90-minute interval.
“catch up” occurs (i.e., patency attributable to endogenous
fibrinolysis), as judged from results of arteriography performed
later. The magnitude of restoration of flow appears to be a major
determinant of benefit.41 Patients with delayed transit of contrast
in the infarct-related artery (TIMI grade 2 flow) may not be
exhibiting optimal or adequate recanalization. The Second
Thrombolytic Trial of Eminase in Acute Myocardial Infarction
(TEAM-2) study analyzed data with respect to flow in patients
treated with nonfibrin-specific plasminogen activators. When
TIMI flow grades were considered with respect to enzymatic
and electrocardiographic markers of infarct size, no statistically
significant difference was seen for TIMI flow grades 0, 1, or 2.
However, better outcomes were seen with TIMI grade 3 flow.
The GUSTO-I angiographic study confirmed this association
between magnitude of flow restoration and outcomes.
Lack of patency (TIMI grade 0 or 1) was associated with the
highest mortality rate (8.9%). Traditionally defined patency
(TIMI grades 2 and 3) was associated with a lower mortality
rate (5.7%, P = .004). The mortality for patients with TIMI grade
2 flow was 7.4% and numerically lower (4.4%) for those with
TIMI grade 3 flow (P = .08). The GUSTO-I angiographic trial
directly compared SK and tPA. Front-loaded tPA was associated
with complete reperfusion at 90 minutes (TIMI grade 3) in
54% of patients. With SK, complete reperfusion occurred in
fewer than 32% of patients. Patency trials have consistently
shown more rapid and complete reperfusion with clot-selective
23,28,37
agents.
Fibrinolysis efficacy is not only related to magnitude of reperfusion but also to timing of administration.40 Fresh clots lyse much
more rapidly than older ones in which fibrin cross-linking has
proceeded. Intervention within 30 to 60 minutes is likely to be
particularly beneficial because more myocardium will remain
6,8
However, constraints on the availability
33,39,40
Considerable
23,24,37
34,37,42
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viable and therefore amenable to salvage and because clot lysis
will be much more rapid and complete. Accordingly, the rapidity
with which patients are treated should be maximized. Current
American Heart Association/American College of Cardiology
(AHA/ACC) guidelines recommend the earliest possible application of therapy (within 30 minutes of emergency department
arrival) with fibrinolysis for patients with STEMI (Class 1A
recommendation).
1,43
Pivotal Trials
Results of early placebo-controlled trials demonstrated consistent
reduction of mortality despite differences among them with
respect to entry criteria, thrombolytic agents, and adjunctive
therapy. In 1986, the landmark Gruppo Italiano per lo Studio
della Streptochinasi nell’Infarcto Miocardico (GISSI-1) trial
demonstrated a reduction in the overall 21-day mortality rate
from 13% to 10.7% for 11,806 patients treated with intravenous
SK rather than the usual treatment at that time. It documented
a striking 47% reduction in mortality rates for patients treated
with SK within 1 hour of symptom onset.
The largest of all the early placebo-controlled trials was ISIS-2.
It randomized 17,187 patients with acute MI to treatment with
intravenous SK, oral aspirin, both, or neither. The 2 × 2 factorial
design substantiated a reduction of mortality for patients treated
with SK. Surprisingly, the effects of aspirin alone were comparable.33 As in GISSI-1, maximal benefit was seen in patients treated
early (<4 hours from symptom onset). Mortality reduction for
patients treated in the interval from 12 to 24 hours after symptom
onset was not significant. Time to treatment has been further
evaluated in the Late Assessment of Thrombolytic Efficacy (LATE)
study, in which 5711 patients presenting with acute MI that
occurred 6 to 24 hours earlier were randomized to intravenous
tPA or placebo. Treatment within 12 hours of symptom onset
was associated with a 26% reduction of mortality for patients
given tPA. In patients treated from 12 to 24 hours, no benefit
was evident.44 A meta-analysis of more than 50,000 patients has
suggested that mortality can be reduced in patients treated up
to, but not beyond, 12 hours.32 The most compelling evidence
indicates that the benefits of fibrinolytic induction of recanalization are minimal if it is not accomplished early, optimally within
a few hours after onset of symptoms.
In 1992, the GISSI-2 trial reported no difference in the mortality rates of patients treated with intravenous SK compared with
standard-dose tPA for 12,490 patients.45 The lack of intravenous
heparin and the late time to treatment appear to contribute to
this phenomenon.46 ISIS-3 compared SK with tPA and anisoylated
plasminogen streptokinase activator complex (APSAC or anistreplase) in 41,299 patients. As in GISSI-2, ISIS-3 used subcutaneous heparin (in 50% of the patients) at a dose of 12,500 U begun
4 hours after enrollment. No difference in mortality could be
ascribed to any of the strategies.
30,34
The need for administration
of intravenous heparin with tPA has been underscored by results
in the Heparin-Aspirin Reperfusion Trial (HART). A total of
205 patients with acute MI were randomized to treatment with
tPA, aspirin, and intravenous heparin or tPA and aspirin alone.
Even though 90-minute patency was the same (79%) with tPA
with and without heparin, the patency rates between 7 and 24
39
hours in HART were 82% in the heparin group and only 52%
in the aspirin group (P < .0001).47 A high incidence of reocclusion
occurred when heparin was omitted.48 Analogous results were
obtained by the European Cooperative Study Group.
46,49
In light of these inconsistencies, the GUSTO-I trial was implemented to compare four different regimens in 41,021 patients:
SK with subcutaneous heparin, SK with intravenous heparin,
front-loaded tPA with intravenous heparin, and a combination
of SK and tPA with intravenous heparin.42 The 30-day mortality
rate was lowest with front-loaded tPA and intravenous heparin
(6.3%) and significantly less than that with combination therapy
(7.0%), SK and subcutaneous heparin (7.2%), and SK and
intravenous heparin (7.4%). Reduction of mortality directly
depended on the rapidity and adequacy of recanalization.41
Front-loaded tPA was associated with fewer allergic reactions,
less hypotension, less overall bleeding, and a lower incidence of
recurrent ischemia, reinfarction, and diverse cardiac complications than the other regimens. Overall front-loaded tPA led to
more rapid and complete recanalization and an increase in the
combined endpoint of survival without a stroke, equivalent to
10 lives saved per 1000 patients treated compared with either SK
regimen.
34,40
Adjunctive Therapy
The activation of circulating platelets and the blood coagulation
system in patients with acute MI is a result of complex phenomena.20 Administration of plasminogen activators paradoxically
contributes to these reactions. Thrombin also activates platelets.
Suppression of coagulation and platelet activation is necessary
to accelerate coronary recanalization, optimize its extent, and
prevent reocclusion.
survival when used in conjunction with SK in the large ISIS-2
trial.33 It is an established adjunctive agent that is usually given at
an initial dose of 160 mg (chewable aspirin) as soon as possible
when thrombolysis is planned, followed by daily doses of 81
to 325 mg.
Platelet activation is inhibited by aspirin through the blockade
of cyclo-oxygenase and synthesis of thromboxane. Inhibition is
incomplete, and other mechanisms can still activate platelets. In
the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY)–
Thrombolysis in Myocardial Infarction (TIMI) 28 trial, a 300-mg
loading dose of clopidogrel was compared with placebo in patients
treated with fibrinolytic drugs. Significantly more patients
exhibited occlusion of the infarct-related artery at angiography
or death in the placebo-treated patients (21.7%) compared with
15.0% in those treated with clopidogrel (P = .01). There was no
difference in the incidence of mortality or the incidence of
bleeding.
51
The second-generation P2Y12 inhibitors (ticagrelor
and prasugrel) have not been studied in combination with
fibrinolytic therapy, but given their increased risks of bleeding
in direct comparison to clopidogrel,
therapies with fibrinolytic agents is not recommended.
In addition to preventing platelet activation, amelioration of
thrombin activation is an important determinant of the success
of fibrinolysis. Intravenous heparin is the most widely used agent
for this purpose. The benefits of intravenous heparin (including
low-molecular-weight heparin) in mechanistic trials are evident
21,50
One antiplatelet agent, aspirin, improved
52,53
use of these antiplatelet
CHAPTER 11 Reperfusion Therapies for Acute ST Elevation Myocardial Infarction 107
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from the recanalization and patency rates delineated angiographically. In the GUSTO-I angiographic study, intravenous heparin
induced greater early patency than subcutaneous heparin, even
with the nonselective agent, SK.41 Several studies have addressed
the potential benefit of agents other than unfractionated heparin
in combination with fibrinolytic drugs. The Assessment of the
Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3
PLUS trial studied 1639 patients after treatment with TNK plus
enoxaparin compared with unfractionated heparin and demonstrated a trend toward superiority of enoxaparin (P = .08) but
no difference in the combined endpoint of safety plus efficacy.
There was a significant increase in intracranial hemorrhage (2.2%
compared with 1%, P = .047) associated with administration of
low-molecular-weight heparin, especially in elderly patients.
54,55
In the Enoxaparin and Thrombolysis Reperfusion for Acute
Myocardial Infarction Treatment, TIMI Study 25, 20,479 patients
were enrolled and treated with either TNK (80% of patients)
or SK (20% of patients) combined with unfractionated heparin
or enoxaparin. The combined endpoint of death or MI within
30 days was significantly lower with the low-molecular-weight
heparin, enoxaparin (odds ratio, 0.83; 95% confidence interval
[95% CI], 0.77–0.90). However, there was an increased incidence
of bleeding with enoxaparin. Of note, in this study, enoxaparin
dosage was reduced with respect to advanced age and other
criteria, perhaps accounting, in part, for the favorable results.56
Finally, the results of the Sixth Organization to Assess Strategies in Acute Ischemic Syndromes (OASIS-6) trial suggest that
fondaparinux is a reasonable alternative as an adjunctive agent
compared with unfractionated heparin for patients treated with
thrombolytic drugs.
57
BOX 11.1 Absolute and Relative
Contraindications to Coronary Thrombolysis
Absolute Contraindications
Active internal bleeding
Suspected aortic dissection
Prolonged or traumatic cardiopulmonary resuscitation
Recent head trauma or known intracranial neoplasm
Diabetic hemorrhagic retinopathy or other hemorrhagic ophthalmic condition
Pregnancy
Previous allergic reaction to the thrombolytic agent (streptokinase or APSAC)
Recorded blood pressure >
History of cerebrovascular accident known to be hemorrhagic
Relative Contraindications
Recent trauma or surgery > 2 weeks; trauma or surgery more recent than 2
weeks, which could be a source of rebleeding, is an absolute contraindication
History of chronic severe hypertension with or without drug therapy
Active peptic ulcer
History of cerebrovascular accident
Known bleeding diathesis or current use of anticoagulants
Significant liver dysfunction
Prior exposure to streptokinase or APSAC
Modified from Gunnar RM, Bourdillon PD, Dixon DW, et al. ACC/AHA
guidelines for the early management of patients with acute
myocardial infarction. A report of the American College of Cardiology/
American Heart Association Task Force on Assessment of Diagnostic
and Therapeutic Cardiovascular Procedures (subcommittee to develop
guidelines for the early management of patients with acute
myocardial infarction). Circulation. 1990;82:664–707.
APSAC, Anisoylated plasminogen streptokinase activator complex;
rtPA, recombinant tissue-type plasminogen activator.
200/120 mm Hg
Bleeding and the Elderly
Intracranial hemorrhage (ICH) is the major risk associated with
the use of thrombolytic agents. With fibrinolytic drugs, stroke
incidence is as high as 1.5%, with hemorrhagic stroke accounting
for 0.3% to 0.7%. In the GUSTO-I trial, the risk of any stroke
(including intracranial bleeding) was 1.55% for patients treated
with front loaded tPA and intravenous heparin and 1.40% for
patients treated with SK and intravenous heparin.42 The difference
in the total incidence of stroke seen with tPA and SK in the
ISIS-3 trial was attributable largely to hemorrhagic rather than
ischemic stroke (tPA, 0.7%; SK, 0.2%).30 The imposition of stricter
recruitment criteria and a lower total dose of tPA (Alteplase,
100 mg) in the TIMI trial resulted in a reduction of the hemorrhagic stroke rate to 0.6%.
Although the relative risk reduction for death conferred by
treatment with plasminogen activators is greatest in the elderly,
an age greater than 65 years, weight less than 70 kg, and female
gender correlate with an increased risk of ICH.58 Elevated blood
pressure is another risk factor, perhaps because prolonged,
uncontrolled hypertension induces vasculopathy, rendering
cerebral vessels susceptible to the adverse effects of thrombolytic
agents. The risk of ICH increases with systolic blood pressures
greater than 150 mm Hg and is particularly impressive in patients
with systolic blood pressures exceeding 175 mm Hg. Consideration of these factors is needed to select specific treatment
modalities prudently for individual patients.
32,58
Selection criteria for fibrinolysis were developed by an ACC/
AHA Task Force in 1990 (Box 11.1).59 In contrast to the extensive
list of absolute contraindications promulgated in GUSTO-I,42
the only absolute criteria for exclusion were previous stroke,
active bleeding, recent trauma, recent major surgery, and noncompressible vascular puncture sites. Patients with a systolic
blood pressure of 180 mm Hg or higher that was unresponsive
to therapy were considered to have a relative contraindication.
Patients requiring cardiopulmonary resuscitation (CPR) of less
than 10 minutes’ duration do not appear to be at high risk for
additional complications when treated with thrombolytic drugs.
Clinical judgment, taking into account the extent of thoracic
trauma and neurologic injury sustained, is more helpful than
criteria based solely on the duration of CPR.
Treating physicians must rely on clinical acumen to best
anticipate the risk/benefit ratio for an individual patient. For
example, an 80-year-old woman with an acute inferior MI
of 8 hours’ duration and with an admitting blood pressure
of 200/120 mm Hg would not likely be a good candidate for
thrombolytic drugs. Conversely, a young diabetic patient with
a large anterior infarction within 90 minutes of symptom onset
is likely to be a good candidate.
In patients treated with thrombolytic drugs, bleeding complications need to be monitored and treated as needed. The
thrombolytic, antiplatelet, and antithrombin agents should be
discontinued, and reversal of heparin with protamine (1 mg per
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