European Heart Journal (1996) 17 {Supplement £), 35—41

Clinical markers of thrombolytic success

V. Pasceri, F. Andreotti and A. Maseri
Institute of Cardiology, Catholic University, Rome, Italy

Although a number of markers of successful coronary improved by combining it with assessment of the rate of
thrombolysis have been proposed, only a few of these have increase of serum myoglobin and of troponin T, provided
the two necessary features of a clinically useful marker: (1) these determinations were rapidly available.

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widespread early availability and (2) good predictive value.
The reduction in ST-segment elevation on the standard 12
lead electrocardiogram 1-4 h after initiation of thrombo-
lysis may be the simplest and most useful clinical 'tool'
to gauge the effectiveness of thrombolytic therapy. The
predictive value of this single marker might be further
(Eur Heart J 1996; 17 (Suppl E): 3S41
Key Words: Acute myocardial infarction, thrombolysis,
coronary recanalization, markers of reperfusion, ECG
monitoring, serum myoglobin, troponin T.

Introduction tested in the GUSTO trial failed to obtain complete

reperfusion (Thrombolysis in Myocardial Infarction
Prompt reestablishment of blood flow through an degree of perfusion [TIMI] grade 3) after 90 min of
occluded coronary artery is the most important goal therapy in as many as 46% of patients and, in this
in the management of patients with acute myocardial subgroup, 30-day mortality remained high (about 8-2%
infarction (AMI): compared with persistent occlusion, compared with only 4-4% in patients with complete
early patency of the infarct-related artery is associated reperfusion)[2] (Fig. 1).
with reduced mortality*1'2'. Thrombolytic therapy is Compared to current regimens, adjunctive ther-
frequently followed by rapid recanalization of totally apies (such as direct thrombin inhibitors) may further
occluded coronary arteries and saves about 30 lives per increase the likelihood of early coronary artery recanal-
1000 patients receiving treatment within 6 h of the onset ization; however, these treatments are associated with a
of symptoms[3]. greater incidence of haemorrhagic stroke and major
In the recent Global Utilization of Streptokinase bleeding («40 more major bleeds per 1000 patients
41
and Tissue Plasminogen Activator for Occluded Cor- occur with hirudin than with heparin)' . Thus, routine
onary Arteries (GUSTO) angiographic trial, following aggressive treatment in all patients with AMI is prob-
the early administration of thrombolytic therapy to ably not cost-effective, especially in patients who would
unselected eligible patients with AMI, the average sur- have achieved early and complete recanalization with
vivor had good left ventricular function with a mean standard therapy alone.
ejection fraction of w57%[2'. Because left ventricular Invasive therapeutic strategies, such as routine
function is among the most important determinants of angiography with percutaneous transluminal coronary
prognosis, it is unlikely that new treatments will sizably angioplasty (PTCA) after thrombolytic therapy, have
improve overall outcome for these patients since their not been shown to have a beneficial effect on prognosis
current level of ventricular function is associated with when administered to unselected patients: the results of
relatively low mortality. New treatments administered to many studies show a trend toward increased risk in the
unselected patients eligible for thrombolysis are there- invasively treated group131. In contrast, the results of two
fore likely to yield, at best, only small additional survival recent small trials suggest that angiography with PTCA
benefits, and the trial of such agents would require seems beneficial when limited to patients at high risk
treatment of many thousands of patients to achieve who have evidence of failed reperfusion during throm-
statistical significance. bolysis[6>7]. Similarly, the administration of additional
Conversely, a cost-effective improvement of out- antithrombotic agents only to patients with early unsuc-
come might be obtainable in subgroups of patients with cessful thrombolysis might reduce the risk/benefit ratio
AMI who currently have an adverse prognosis. For of such adjunctive treatment.
example, even the most successful thrombolytic regimen For these reasons, early, accurate clinical
markers of thrombolytic success are desirable. Such
Correspondence: Dr V. Pasceri, Institute of Cardiology, Catholicmarkers could indicate which patients are likely to
University, Largo A. Gemelli 8, 00168 Roma, Italy. benefit from selective use of additional interventions.

0195-668X/96/0E0035+07 $18.00/0 1996 The European Society of Cardiology

36 V. Pasceri et al.

10 as well as smaller infarcts, compared to patients with

unheralded Ml'81. The reasons for this different response
are not clear.

Cigarette smoking
Surprisingly, smokers generally have a better response to
c thrombolytic therapy than non-smokers. A possible
o explanation may be that in smokers, the mechanism of
4"
-b infarction is more often thrombosis of a less critically
o 2- stenosed coronary artery191.

Circadian variation of thrombolytic efficacy

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A circadian rhythm in the response to administration of
TIM I 0-2 TIMI3 recombinant tissue plasminogen activator and urokinase
has been described. Significantly lower coronary reca-
Degree of perfusion
nalization rates occurred in the morning—when platelet
Figure 1 Difference in 30-day mortality between patients and coagulation reactivity, blood viscosity, vasomotor
with Thrombolvsis in Myocardial Infarction degree of tone, and the natural inhibition of fibrinolysis are at
perfusion (TIMI) grade 3 flow and patients with TIMI 2 their highest'101—than during the remainder of the
flow or worse after 90 min of thrombolytic therapy. day111-131.
Patient outcomes were analysed independently of the
assigned thrombolytic regimen (streptokinase, plasmino-
gen activator, or both). The 30-day mortality of patients Plasma levels of thrombin antithrombin III
without successful reperfusion is almost double that of The plasma concentration of thrombin antithrombin III
patients achieving early TIMI 3 flow. (Data from complexes in peripheral venous blood drawn on admis-
the Global Utilization of Streptokinase and Tissue sion has been found to be significantly greater in patients
Plasminogen Activator for Occluded Coronary Arteries with subsequent unsuccessful thrombolysis than in pa-
angiographic trial'2'.) tients with effective recanalization1141. An important
limitation of such biochemical predictors of perfusion
status, however, is the delay inherent in laboratory
measurement that currently precludes rapid bedside use.
Prediction and detection of failed Thus far, no handy, reliable predictor can distin-
thrombolysis guish the response of patients to thrombolytic treatment
at the time of hospital admission.
The ideal marker of coronary reperfusion would predict
when standard thrombolytic therapy will not lead to
prompt coronary recanalization; thus, a more specific Markers of perfusion status
treatment (i.e. primary angioplasty or adjunctive anti-
thrombotic agents) could be adopted immediately in With the advent of the thrombolytic era, several markers
such cases. Unfortunately, clinical and laboratory pre- of early reperfusion have been proposed, including the
dictors of failed thrombolysis are scanty since the resolution of pain, the occurrence of arrhythmia,
mechanisms underlying acute coronary occlusion and the reduction of ST-segment elevation, and several
the variable response to lytic therapy are still largely biochemical indices (Table 1).
unknown. At present, we have at our disposal mainly
markers of successful or failed reperfusion that inform Evolution of pain
us of the process only after it has occurred. Persistent chest pain, not alleviated by sublingual or
intravenous nitrates, is a typical feature of AMI. It has
been suggested that the sudden decrease of pain may
Searching for predictors of failed indicate coronary reperfusion'151. The relationship
thrombolysis with standard therapy between pain and myocardial ischaemia, however, is
indirect and often elusive. Pain perception is subjective,
A number of conditions have been associated with and patients often continue to report pain hours after
subsequent thrombolytic outcome. Most of these obser- successful reperfusion. In addition, the intensity of pain
vations, however, provide only an approximation of the is strongly influenced by analgesic drugs'161. Thus, the
efficacy of thrombolytic therapy and are not predictive persistence of symptoms or the sudden and complete
of outcome for an individual patient. resolution of chest pain do not have a good predictive
value in detecting the status of myocardial perfusion1'71.
Pre-infarction angina
The results of a recent study suggest that patients with Arrhythmias
unstable angina in the 7 days before AMI have remark- Arrhythmias are a specific marker of myocardial reper-
ably faster coronary recanalization during thrombolysis, fusion in experimental models'181. In sharp contrast,

Eur Heart J, Vol. 17, Suppl E 1996

 Clinical markers of thrombolytic success 37

Table 1 Sensitivity and specificity of various markers of coronary recanalization

Time from
Time of
Marker Study Cut-off initiation of Sensitivity Specificity
thrombolysis angiography

Sum of ST elevation Clemmensen'251 5:20% reduction 180 min 180 min 88% 80%
(n = 56)
Sum of ST elevation Barbash[26) ~2.50% reduction 60min 72 h 87% 76%
(n —zoo)
Sum of ST elevation ;>50% reduction 240 min 10-12 days 73% 63%
Bossaert1271
(n=103)
Chest pain Califf 1 " Improvement 90 min 90 min 84% 29%

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(n = 386)
Chest pain Califf117! Resolution 90 min 90 min 34% 83%
In — 1B*T\
(n —Joo)
CK-MB ^ 1 -5-fold increase 15 min Serial up to 44% 100%
Miyata 1441
(n = 63) from baseline 60 min
CK-MB Abe 1401 >25 IU . I " 1 increase 60 min Serial up to 100% 85%
(n = 38) from baseline 60 min
CK-MM Uperche 1 3 8 1 MM3/MM1 ratio 60 min 90 min 60% 100%
(n = 27) >0-35
Troponin T Abe 1401 >0-5ng.ml"' 60 min Serial up to 100% 85%
(n = 38) increase from baseline 60 min
Myoglobin Miyata 1441 ;> 2-fold increase 15 min Serial up to 71% 100%
(n = 63) from baseline 60 min
Myoglobin Ellis[43l >4-6-fold increase 120 mm Serial or up to 85% 100%
(n=42) from baseline 3 days

CK-MB, CK-MM = serum creatine kinase isoenzymes.

ECG lead III

(mV)

120-,

ST-T
60-
positive area
(mV.ms)

05.15 05.45 06.15 06.45 07.15 07.45

Time (hours)
Figure 2 Continuous ST-segment Holter recording in a patient with acute myocardial
infarction. The tracing revealed intermittent resolution of ST elevation before the start
of lytic therapy. No ventricular arrhythmia was detected during or immediately after
reperfusion, which is indicated by the sudden return of the ST elevation to baseline.
Conversely, ventricular fibrillation developed during persistent ST elevation (inset).
(Adapted from Hacked: et a/.1201 with permission.)

reperfusion an-hythmias are not common in patients
with AMI, and there is no convincing evidence that
ventricular arrhythmias (including idioventricular
rhythm or slow ventricular tachycardia) occur more
frequently in humans during successful coronary throm-
bolysis than during failed thrombolysis117J9ao] (Fig. 2).
The reasons for this striking difference between animal
models and clinical evidence are complex and are not
simply related to the sudden reperfusion of non-stenosed
arteries in the experimental model since reperfusion

Eur Heart J, Vol. 17, Suppl E 1996

38 V. Pasceri et al.
<20% 20-40% 40-60% 60-80%
Reduction in ST elevation
Figure 3 Reduction in ST-segment elevation at 4 h after initiation of lytic therapy in
relation to in-hospital mortality. The width of the bars is proportional to the number of
patients in each of the five groups (total number of patients=7426). The difference in
mortality is striking between the two extreme groups, which include most of the study
patients. (Data from Mauri et al.'28'.)
arrhythmias are uncommon in variant angina'211. Thus,
in humans, reperfusion arrhythmias are not reliable
markers of early coronary recanalization.
ST-segment elevation
It is generally accepted that the resolution of ST-
segment elevation may be a simple index of coronary
recanalization. Early studies using intracoronary
thrombolysis demonstrated a sudden decrease of the
ST-segment shift after successful myocardial reper-
fusion'22'231. Afterward, many investigators assessed the
predictive value of serial 12 lead electrocardiograms
(ECGs) in detecting angiographically documented
recanalization'24^271. Overall, these studies demonstrated
the value of serial ECGs in detecting reperfusion: a
20-50% reduction in the sum of the ST elevation was
associated with a sensitivity of 73-88% and a specificity
of 63-80% (Table 1).
The results of these small angiographic studies
have been indirectly confirmed by the data of the large
Gruppo Italiano per lo Studio della Soprawivenza
nell'Infarto Miocardico (GISSI-2) trial, which showed
that patients with a decrease ^ 50% in the sum of ST
elevation in all 12 leads at 4 h after initiation of throm-
bolytic therapy had a strikingly better short-term out-
come'281. The difference was even more impressive when
patients with a >80% reduction in the ST shift were
compared with those having a <20% reduction. The
intermediate groups (20-80% reduction in the ST shift)
showed only a small difference in mortality. The two
extreme groups included about 54% of the study
population (Fig. 3).
Similarly, the results of the Intravenous Strepto-
kinase in Acute Myocardial Infarction (ISAM) trial
showed that early (<, 3 h) resolution of ST elevation was
Eur Heart J, Vol. 17. Suppl E 1996
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>80%
a powerful predictor of both early and 6-year mortality
after AMI'291. Thus, the presence or lack of rapid,
persistent resolution of ST-segment elevation may cor-
rectly identify perfusion status in >50% of patients with
AMI. Furthermore, this parameter is also a good
marker of prognosis.
Dynamic changes in ST elevation
The dynamic evolution of AMI with intermittent ST
elevation has been well described. This phenomenon
may influence the assessment of recanalization through
ECG criteria (Fig. 2)'30'. Recurrent ST elevation is
associated with coronary reocclusion and a worse
short-term outcome'31'.
Continuous ECG (Holter) monitoring has been
successfully used to identify intermittent ST elevation'32'.
However, because Holter monitoring allows only retro-
spective analysis of the data, its use cannot influence
real-time clinical management. Real-time computer
assisted 12 lead ECG monitoring has been found to
detect failure of reperfusion and to indicate which
patients have recurrent ST elevation'33'341. This tech-
nique, although not widely available, can also measure
duration of ischaemia, which appears to be the most
important determinant of infarct size'351.
Indices of myocardial necrosis
Successful reperfusion causes an earlier release of bio-
chemical indices of myocardial necrosis into peripheral
blood. On the basis of this principle, the serial measure-
ment in serum or plasma of several markers of reper-
fusion has been proposed. Such markers include creatine
kinase (CK), the CK-MB isoenzyme, troponin T, and
myoglobin'241.

Immediate determinations of serum CK and
CK-MB are usually available in the emergency labora-
tory. Peak values of serum CK and CK-MB beyond 12 h
from initiation of thrombolysis are a well-known index
of failed reperfusion (sensitivity 84%, specificity 95%),
but only retrospectively1321. Rates of increase of serum
C K > 5 0 I U . h - ' and of serum CK-MB ^ l O I U . h " 1
over the first 2-5 h of treatment indicate successful
thrombolysis'361 and may be more useful clinically. Simi-
larly, a > 2-5-fold increase in serum CK-MB concen-
tration during the first 90 min of t-PA infusion was
found to correlate with early coronary recanalization
with considerable accuracy1371. The value of a very early
rate of rise of serum CK-MB level (within the first
15-60 min of thrombolysis) has also been investigated
(Table 1). Finally, the determination of serum CK-MM
isoforms — which requires a highly specialized
laboratory — and their rate of increase can also provide
an early ( ^ 3 h) evaluation of reperfusion138'391 (Table 1).
Similarly, recent studies have shown that a
>0-5ng.ml~' rise of troponin T levels in the first
60 min of thrombolytic therapy may correctly identify
successful reperfusion (Table 1)[401. Although the current
assay for troponin T requires at least 90 min'411, a
whole-blood, rapid bedside device for troponin T
measurement within 20 min has just become commer-
cially available; its sensitivity and specificity appear to be
comparable to the traditional assay1421.
Myoglobin is a sensitive, although non-specific,
marker of myocardial necrosis. A peak serum concen-
tration ^3-5h after initiation of lytic therapy gives
an accurate, albeit retrospective, prediction of early
coronary reperfusion1431. A ;> 4-6-fold increase in the
first 2 h after lytic therapy can also signify reperfusion
(sensitivity 85%, specificity 100%)[44) (Table 1). More-
over, the rate of rise of serum myoglobin level within the
first 15 min after initiation of thrombolysis has been
found to indicate reperfusion with a better accuracy
than the rate of increase of serum CK-MB1451. Unfortu-
nately, since myoglobin is rapidly released from the
necrotic myocardium even before thrombolytic therapy,
myoglobin is not a good marker of reperfusion in
patients treated >4 h after the onset of symptoms'461
and in patients with early intermittent spontaneous
reperfusion'471.
Although these biochemical markers of reper-
fusion have, overall, a good predictive value for detect-
ing perfusion status, their results are influenced by the
presence of collateral circulation and of intermittent
reperfusion. Furthermore, all these studies suffer from
two important limitations: (1) retrospective design; and
(2) definition of coronary patency as TIMI flow grade
^ 2 , not as just TIMI 3. Finally, measurements of these
markers are often available too late, when irreversible
myocardial damage has already developed. The rates of
increase of serum myoglobin or troponin T during the
first 60 min of thrombolytic therapy appear to be the
only indices of reperfusion that may actually influence
clinical management during the acute phase of MI. Until
the newly developed 20 min rapid assay device for
Clinical markers of thrombolytic success 39
cardiac troponin T detection became available'421, these
determinations were relatively expensive, lengthy pro-
cedures that were not routinely available in emergency
laboratories.
Other markers of reperfusion
Probably via the inflammatory response to myocardial
damage, MI causes a transient increase in the plasma
levels of several acute phase reactants. Compared with
persistent coronary occlusion, early coronary recanaliz-
ation is associated with a blunted response of the
acute phase reactants, including plasminogen activator
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inhibitor-1 (PAI-1) and von Willebrand factor, 24 h
after initiation of thrombolytic therapy1481. Similarly,
during the first days of AMI, plasma levels of C-reactive
protein are significantly reduced in patients achieving
prompt coronary recanalization'431. Although these
markers are of pathophysiological interest, they provide
only a late assessment of myocardial reperfusion.
It has been suggested that the lysis of coronary
thrombi is associated with increased plasma levels of the
specific fibrin split product known as D-dimer1491. This is
apparently not so, probably because thrombolytic drugs
are capable of splitting not only the fibrin associated
with coronary thrombi but also circulating soluble
fibrin'50-511.
Conclusion
The early reduction of ST-segment elevation by >80%
on the standard 12 lead ECG may correctly determine
which patients have successful thrombolysis. These
patients have, on average, a good outcome and do not
need additional interventions. Conversely, lack of a
significant (>20%) reduction in ST elevation on the
standard 12 lead ECG may accurately identify the
absence of reperfusion or the likelihood that recanaliz-
ation was not successful. However, even in such patients,
aggressive treatments are likely to be most cost-effective
in high-risk subgroups, i.e. in patients with a large
infarct (determined by the extent of ST elevation on the
12 lead ECG or by bedside echocardiography) or with
poor left ventricular function (assessed by clinical signs
of left ventricular failure or by echocardiography).
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