(Circulation. 1998;98:2805-2814.)
© 1998 American Heart Association, Inc.
Clinical Investigation and Reports* |
TNK–Tissue Plasminogen Activator Compared With Front-Loaded Alteplase in Acute Myocardial Infarction
Results of the TIMI 10B Trial
From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass (C.P.C., C.H.M., R.P.G., E.B.); West Roxbury (Mass) Veterans Administration Medical Center (C.M.G.); Royal Victoria Hospital, Belfast, Northern Ireland, UK (A.A.J.A.); Baystate Medical Center, Springfield, Mass (M.J.S.); University of Miami/Jackson Memorial Hospital, Miami, Fla (R.F.S.); CHU Côte de Nacre, Caen, France (G.G.); Sarasota Memorial Hospital, Sarasota, Fla (M.F.); Montefiore Medical Center, Bronx, NY (H.S.M.); Winthrop University Hospital, Mineola, NY (R.M.S.); Henry Ford Heart and Vascular Institute, Detroit, Mich (W.D.W.); and University Hospitals Leuven, Leuven, Belgium (F.V.d.W.).
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Abstract |
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 Top Abstract IntroductionMethodsResultsDiscussionAppendix 1References |
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Background—Bolus thrombolytic therapy is a simplified means of administering thrombolysis that facilitates rapid time to treatment. TNK-tissue plasminogen activator (TNK-tPA) is a highly fibrin-specific single-bolus thrombolytic agent.
Methods and Results—In TIMI 10B, 886 patients with acute ST-elevation myocardial infarction presenting within 12 hours were randomized to receive either a single bolus of 30 or 50 mg TNK-tPA or front-loaded tPA and underwent immediate coronary angiography. The 50-mg dose was discontinued early because of increased intracranial hemorrhage and was replaced by a 40-mg dose, and heparin doses were decreased. TNK-tPA 40 mg and tPA produced similar rates of TIMI grade 3 flow at 90 minutes (62.8% versus 62.7%, respectively, P=NS); the rate for the 30-mg dose was significantly lower (54.3%, P=0.035) and was 65.8% for the 50-mg dose (P=NS). A prespecified analysis of weight-based TNK-tPA dosing using median TIMI frame count demonstrated a dose response (P=0.001). Similar dose responses were observed for serious bleeding and intracranial hemorrhage, but significantly lower rates were observed for both TNK-tPA and tPA after the heparin doses were lowered and titration of the heparin was started at 6 hours.
Conclusions—TNK-tPA, given as a single 40-mg bolus, achieved rates of TIMI grade 3 flow similar to those of the 90-minute bolus and infusion of tPA. Weight-adjusting TNK-tPA appears to be important in achieving optimal reperfusion; reduced heparin dosing appears to improve safety for both agents. Together with the safety results from the parallel Assessment of the Safety of a New Thrombolytic: TNK-tPA (ASSENT I) trial, an appropriate dose of this single-bolus thrombolytic agent has been identified for phase III testing.
Key Words: thrombolysis • myocardial infarction • plasminogen activators
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Bolus thrombolysis is a new means of administering thrombolytic agents that has several potential advantages. First, its ease of administration could facilitate more rapid treatment, which has been shown to improve survival in acute myocardial infarction (MI).1 2 Second, bolus thrombolysis may make more feasible the promising strategy of prehospital treatment with thrombolysis.3 4 Finally, the simplicity of dosing may reduce medication errors, which were associated with increased mortality in the Global Use of Streptokinase and Tissue Plasminogen Activator to Open Occluded Arteries (GUSTO)-I trial.5
TNK–tissue plasminogen activator (TNK-tPA) is a genetically engineered variant of tPA. TNK-tPA is similar to wild-type tPA but has amino acid substitutions at 3 sites: a threonine (T) is replaced by asparagine, which adds a glycosylation site to position 103; an asparagine (N) is replaced by a glutamine, thereby removing a glycosylation site from site 117; and 4 amino acids, lysine (K), histidine, and two arginines, are replaced by 4 alanines at the third site. Together, these substitutions lead to a longer half-life of the molecule,6 7 increased fibrin specificity,6 and increased resistance to inhibition by plasminogen activator inhibitor 1 in animal models compared with wild-type tPA.8 9 The Thrombolysis in Myocardial Infarction (TIMI) 10A trial demonstrated that TNK-tPA has a prolonged half-life, permitting administration as a single bolus; that it was highly fibrin-specific; and that the 30- to 50-mg doses warranted further investigation. The purpose of the TIMI 10B trial was to compare prospectively the angiographic efficacy and safety of several doses of TNK-tPA and tPA to identify an appropriate dose for testing in a large mortality trial.
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Methods |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Study Population
Patients were screened for enrollment at 76 hospitals (see Appendix) between March 1996 and March 2, 1997. Inclusion criteria for the trial were the presence of ischemic pain lasting
30
minutes, associated with ST-segment elevation 0.1 mV in 2
contiguous leads, and the ability to be randomized within 12 hours of
symptom onset. An amendment in September 1996 added an upper age limit
of <80 years (see below). Exclusion criteria were prior stroke,
transient ischemic attack, or central nervous system structural
damage; a history of dementia or major cognitive deficit; a reliably
obtained blood pressure >180/110 mm Hg; significant bleeding
disorder within 6 months; cardiogenic shock; treatment of acute MI with
thrombolytic therapy within the previous 4 days; major
surgery, biopsy, or trauma (including head trauma associated with the
presenting MI) within 3 months; prolonged (>2 minutes)
cardiopulmonary resuscitation within 2 weeks; recent
noncompressible vascular puncture; previous coronary artery
bypass surgery; inability to undergo cardiac
catheterization; therapeutic oral anticoagulation;
pregnancy, current lactation, or women of childbearing potential not
using adequate birth control; allergy to heparin or history of multiple
allergies; current cocaine abuse; other serious illness; current
participation in another experimental drug or device protocol; previous
treatment with TNK-tPA; inability to follow the protocol; or any other
condition that the investigator felt would pose a significant hazard to
the patient if the investigational therapy were initiated. The use of
abciximab within the preceding 96 hours was added to the amendment.
Randomization
Patients were randomized in a central, computerized, telephone
randomization system (Leuven Coordinating Center, Leuven, Belgium).
Initially, patients were randomized to receive either TNK-tPA 30 or 50
mg or front-loaded tPA in a 1:1:1 ratio. The 50-mg dose of TNK-tPA was
suspended (see below) on August 22, 1996, leaving randomization between
30 mg versus tPA. After approval of a protocol amendment at each
hospital, a 40-mg dose of TNK-tPA was added, with a randomization to 40
mg TNK-tPA, 30 mg TNK-tPA, or tPA in a 4:1:1 ratio.
Treatment Regimen
Patients were randomized to receive either a single bolus of
TNK-tPA (Genentech) administered over 5 to 10 seconds or tPA (Activase,
Genentech) given as a 15-mg bolus, a 0.75-mg/kg (up to 50 mg) infusion
over 30 minutes, followed by 0.50-mg/kg (up to 35 mg) infusion over 60
minutes. All patients received 150 to 325 mg of oral or
intravenous aspirin daily. ß-Blockers were
recommended,10 and other medications were administered at
the discretion of the treating physicians.
Heparin Dosing
Heparin dosing was initially specified to be at the discretion
of the treating physician. The protocol did, however, offer a guideline
for heparin dosing: a 5000-U bolus and an initial
intravenous infusion of 1000 U/h (for patients weighing
>67 kg) or 800 U/h (for patients 
67 kg) for 48 to 72 hours. Heparin
was to be given before or as soon as possible after administration of
thrombolytics. Heparin was titrated to an
activated partial thromboplastin time (aPTT) of 55 to 80
seconds, and a suggested heparin nomogram was provided. aPTT was
measured at 6, 12, and 24 hours after the start of
thrombolysis and daily while the patient was on
heparin, as well as 6 hours after a change in dose.
Early in the trial, it was noted that the heparin doses in some
patients who experienced intracranial hemorrhage were higher
than the suggested dose; for example, patients had received a
weight-adjusted regimen of 80 U/kg bolus and 18 U ·
kg-1 · h-1
infusion (eg, 6400 U bolus and 1440 U ·
kg-1 · h-1
infusion for an 80-kg patient). In addition, patients were noted to
have undergone rescue angioplasty more often (50% versus 26% in the
final cohort, P=0.04) and consequently received more heparin
(see Results). Because of the previously observed interaction of
heparin, thrombolytic therapy, and intracranial
hemorrhage in TIMI 9A/B,11 12 a protocol amendment
was instituted that mandated the following doses of heparin: for
patients weighing >67 kg, a 5000-U bolus and 1000 U/h infusion, and
for patients weighing 67 kg, a 4000-U bolus and 800 U/h infusion. In
addition, adjustment of the heparin dose according to the nomogram was
mandated to begin with the 6-hour aPTT. The amendment also specified
that no additional heparin be administered for diagnostic
catheterization if the patient was already receiving
intravenous heparin. If rescue angioplasty was performed,
the recommended target activated clotting time was 300 seconds,
and to achieve this activated clotting time, boluses of heparin
were to be administered in increments of 2500 U, so as to reduce the
likelihood of overshooting the target. Finally, the Data and Safety
Monitoring Board made 2 other recommendations based on the potential
for increased risk (not observed in the trial): an upper age limit of
80 years was added, and the use of abciximab was proscribed in the
first 96 hours after randomization.
Protocol
Patients underwent coronary angiography at 90 minutes
and, when feasible, at 60 and 75 minutes. Percutaneous
transluminal coronary angioplasty (PTCA) with a Food and Drug
Administration (FDA)–approved device was performed at the discretion
of the treating physician after the 90-minute angiogram was obtained.
Cardiac enzymes were obtained at baseline and 8 and 16 hours and for
symptoms suggestive of recurrent MI. Samples for
coagulation/fibrinolysis parameters (eg,
fibrinogen, plasminogen) were obtained at baseline and 1,
3, and 6 hours after start of study drug for measurement in a core
laboratory. Blood samples for pharmacokinetics were obtained at
baseline and 2, 30, 60, 90, 120, 180, and 360 minutes after the start
of study drug at selected centers. For patients who received TNK-tPA, a
blood sample was obtained at baseline and at 30 days to evaluate for
the formation of TNK-tPA antibodies. Patient follow-up was obtained at
30 days. The study protocol and amendment were reviewed and approved by
each hospital's Institutional Review Board, and written informed
consent was obtained from each patient before enrollment.
Patient Cohorts
A total of 886 patients were randomized into the trial. Six
patients did not give informed consent, and thus their data were not
included in the database. Two cohorts were prespecified for
analyses: the safety cohort comprised patients who received any
amount of study drug (856 patients), and the "efficacy-evaluable"
cohort comprised patients who received study drug and had an evaluable
90-minute angiogram (837 patients). The 24 patients not treated with
study drug were evenly distributed among the 4 treatment groups; 11
received other thrombolytic therapy, 2 underwent
primary angioplasty, 9 did not receive reperfusion therapy, and 2 died
before study drug administration.
Study End Points
The primary end point of the trial was the rate of TIMI grade 3
flow at 90 minutes.13 Secondary end points included TIMI
grade 3 flow at 60 and 75 minutes, TIMI grade 2 or 3 flow and TIMI
frame count at all time points,14 pharmacokinetics,
coagulation parameters, recurrent MI, and serious bleeding.
All angiograms were analyzed by the angiographic core
laboratory, which was blinded to treatment assignment. Pharmacokinetics
of TNK-tPA were characterized by standard methods.15
Coagulation assays were collected and assayed as in previous TIMI
trials.6 16
Plasmin–
2-antiplasmin complexes were assayed
with an ELISA assay.17 Antibodies to TNK-tPA were
analyzed as in the TIMI 10A trial.6 Serious
bleeding was defined according to FDA guidelines as bleeding that was
either fatal or life-threatening, required or prolonged
hospitalization, resulted in significant disability, or necessitated
medical or surgical intervention to preclude permanent impairment of a
body function or structure. Clinical end points were defined as in
previous TIMI trials.10 12 18
Statistical Considerations
The primary end point and other categorical variables were
analyzed by the Pearson 
2 test. Dose
response across TNK-tPA doses was calculated by the Mantel-Haenszel
test. Continuous variables were compared by the Wilcoxon
rank-sum test. Confidence intervals were produced by the exact binomial
method.19 Pharmacokinetic data were analyzed by
use of a compartmental model for TNK-tPA and a noncompartmental model
for tPA. The sample size was determined by use of the
Fleiss20 sample-size algorithm for proportions and rates
of TIMI grade 3 flow as observed in the GUSTO I trial.21
It was calculated that 150 evaluable patients per group were necessary
to provide 80% power of detecting a TIMI grade 3 flow rate of 38%
or 69% in the TNK-tPA groups compared with the tPA group with a 5%
significance level. No adjustments were made for multiple
comparisons.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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Patient Population
The mean age of the 837 patients in the efficacy-evaluable cohort was 59.6 years, 76.0% were male, 38.7% presented with anterior MI, 21.5% weighed <67 kg, and 47.2% were current smokers at the time of randomization (Table 1
). The median time from symptom
onset to treatment was 2.9 hours (25th and 75th percentiles, 2.0 and
4.2 hours). There were no significant differences in the baseline
characteristics of the treatment groups.
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Angiographic Results
The 40-mg dose of TNK-tPA produced a rate of TIMI grade 3 flow at
90 minutes after the start of thrombolysis (62.8%;
95% CI, 54.5% to 70.6%) similar to that of tPA (62.7%; 95%
CI, 57.1% to 68.1%; P=NS) (Figure 1). The 30-mg dose of TNK-tPA had a
significantly lower rate of TIMI grade 3 flow than tPA (54.3%,
P=0.035), whereas the 50-mg dose achieved 65.8% TIMI grade
3 flow (P=0.62 compared with tPA; P=0.030 for
trend across TNK-tPA doses). TIMI grade 2 or 3 flow (patency) showed a
similar increasing trend of 81.7% for tPA versus 76.8%,
79.1%, and 88.2% for the 30-, 40-, and 50-mg doses of TNK-tPA,
respectively (P for trend=0.044). At 60 minutes, there were
no significant differences in the rates of TIMI grade 3 flow or patency
(Figure 1).
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The rates of TIMI grade 3 flow or TIMI grade 2 or 3 flow combined were similar for patients treated within 6 hours from symptom onset versus >6 hours in each treatment arm. Right coronary arteries displayed higher rates of TIMI grade 3 flow, 68.9%, compared with left anterior descending (48.5%) or left circumflex infarct-related arteries (57.4%) in each of the treatment groups (overall P<0.001). However, TIMI grade 2 or 3 flow was similar among the 3 arteries in each treatment group (79.3%, 83.7%, and 73.0%, respectively, P=NS). No differences in TIMI flow grades were observed when patients enrolled before versus after implementation of the protocol amendment with lower heparin dosing were compared.
TIMI Frame Count
The TIMI frame count results by treatment group are shown in Table 2. The percentages of patients with
corrected TIMI frame count <40 (previously noted14 to be
a useful cut point to define TIMI grade 3 flow) quantitatively
corroborated the lower rate of full reperfusion with TNK-tPA 30 mg
compared with tPA. There were no differences between TNK-tPA and tPA in
the rate of "normal" flow, as defined by a corrected TIMI frame
count <28 frames.14 The median TIMI frame count at 60
minutes was slightly, but not significantly, lower for TNK-tPA 40 mg
than for tPA (34 versus 40 frames, P=0.33).
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Weight-Based Dosing Analysis
For all patients who received TNK-tPA, a "weight-corrected"
dose was calculated as the dose of TNK-tPA in mg divided by the
patient's weight. As shown in Figure 2, the rate of TIMI grade 3 flow was 62% to 63% for doses of 
0.5
mg/kg and higher but was 51% to 54% at doses lower than this
(P=0.028 across quintiles). Further analysis into
covariates of degree of perfusion achieved revealed that when
dose/weight was stratified into tertiles, the median corrected TIMI
frame count was significantly lower (ie, faster flow) in patients who
received the higher weight-corrected dose (Figure 3).
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Pharmacokinetics
Among the 159 patients with pharmacokinetic samples, the plasma
clearance of TNK-tPA ranged from 98.4±42 to 119.0±49 mL/min across
the 30-, 40-, and 50-mg doses, compared with 453±170 mL/min for tPA.
The corresponding plasma elimination half-life of TNK-tPA ranged from
5.5±5.5 to 21.5±8.2 minutes. The corresponding half-life for tPA is
3.5±1.4 minutes.22 Figure 4
shows the TNK-tPA plasma levels over time for the 3 doses of TNK-tPA
and tPA. As shown, after a single bolus of TNK-tPA, the plasma
concentration was initially higher, but the area under the curve
approximates that of tPA given as a bolus and 90-minute infusion.
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Coagulation Assays
The effects on systemic coagulation/fibrinolytic factors
over the first 6 hours for TNK-tPA and tPA are shown in Figure 5. There was a 5% to 10% drop in
fibrinogen over the first 6 hours at the 30- to 50-mg doses of TNK-tPA,
compared with a 40% drop after tPA. The fall in
plasminogen was only 10% to 15% after TNK-tPA, compared
with a 50% drop in plasminogen for tPA. The consumption of
2-antiplasmin, the fluid-phase
inhibitor of plasmin, and a consequent increase in
plasmin–2-antiplasmin complexes was 4 to 5
times greater with tPA than with TNK-tPA at any of the 3 doses.
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Safety Results
During the initial phase of the trial, ie, before the
reduction of heparin dosage described above, there were 3 intracranial
hemorrhages among the 78 patients (3.8%; 95% CI, 0.8% to
10.8%) treated with the 50-mg TNK-tPA dose. Balancing these results
was a favorable mortality rate for TNK-tPA 50 mg, 3.8%, and the
resultant net clinical benefit (death or nonfatal intracranial
hemorrhage) was 5.1%.(Table 3).
The corresponding rate for tPA in the GUSTO-I trial was
6.6%.23 Nonetheless, on the recommendation of the Data
and Safety Monitoring Board, this arm was suspended and replaced by 40
mg with a protocol amendment. At the same time, the doses of heparin
were reduced, as noted above.
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Overall, the rates of intracranial hemorrhage were 1.0% for 30
mg TNK-tPA, 1.9% for 40 mg, and 3.8% for 50 mg, and 1.9% for tPA
(Table 3
). Serious bleeding followed a similar "dose
response" occurring in 1.9%, 5.2%, and 11.5% (P<0.001)
of patients treated with the 30-, 40-, and 50-mg doses of TNK-tPA,
compared with 8.5% for tPA (Table 4).
Analyses of serious bleeding and intracranial
hemorrhage with weight-corrected doses of TNK-tPA are shown in
Figure 6. Significantly more serious
bleeding (P=0.001) and intracranial hemorrhages
(P=0.033) were observed at the highest weight-corrected dose
(>0.55 mg/kg) (Figure 6A). Even after the protocol amendment to
use lower doses of heparin, significantly higher intracranial
hemorrhage (P=0.014) and serious bleeding
(P=0.002) remained at the higher weight-corrected dose
(Figure 6B).
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Effect of Heparin Dosing
The protocol amendment reduced the dose of heparin received:
The total dose received was reduced from an average of 13 258 to
12 326 U over the first 6 hours (P=0.01) and from 18 784
to 17 898 U over the first 12 hours (P=0.04). The doses of
heparin received for patients undergoing rescue PTCA were higher,
15 957 versus 11 644 U without PTCA, but each group had a reduction
in the dose of heparin received, to 14 613 and 10 962 U in patients
with and without rescue PTCA, respectively. The median aPTT values at 6
and 12 hours tended to be lower after the protocol amendment, 100
versus 94 seconds at 6 hours (P=0.12) and 67 versus 64
seconds at 12 hours (P=0.15) for the group as a whole.
The rates of both intracranial hemorrhage and serious bleeding were lower after the protocol amendment: For TNK-tPA 30 mg, intracranial hemorrhage fell from 3 of 134 patients (2.2%) to 0 of 174 (0%) (P=0.047), and for tPA from 4 of 143 patients (2.8%) to 2 of 173 (1.2%) (P=0.29) (overall combined P=0.04). Similar observations and statistically significant reductions in intracranial hemorrhage were observed in overall TNK-tPA experience when the TIMI 10B and ASSENT I trials were combined.24 Severe bleeding also was reduced with the lower heparin dosing: Severe bleeding fell from 3.0% to 0% (P=0.02) for 30 mg TNK-tPA and from 8.4% to 2.3% (P=0.01) for tPA (combined P=0.001).
Clinical Outcome
Mortality at 30 days was 4.9% overall, without significant
differences between TNK-tPA doses and tPA (Table 3).
Reinfarction was observed in 5.4% of patients overall, without
differences between TNK-tPA or tPA (Table 3). New-onset
pulmonary edema and cardiogenic shock also were similar between
TNK-tPA and tPA. Antibodies to TNK-tPA were detected in 1 of 364
patients (0.3%) at 30 days, although no antibodies were detected in
this patient at 90 days.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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In this randomized, dose-ranging angiographic trial of TNK-tPA, we observed a clear dose-response in the achievement of reperfusion at 90 minutes by TNK-tPA given as a single bolus (Figure 1
). Notably,
a bolus of 40 mg TNK-tPA achieved 90-minute TIMI grade 3 flow similar
to that of the bolus and 90-minute infusion of tPA. TNK-tPA was
observed to have a prolonged half-life (Figure 4) and to be very
fibrin-specific compared with tPA (Figure 5), features that help
explain its efficacy when administered as a 5- to 10-second bolus, and
the absence of induction of the "plasminogen steal"
phenomenon.25
Weight adjustment of TNK-tPA appears to be important in achieving
optimal reperfusion, assessed by both TIMI flow grade and the TIMI
frame count (Figures 2 and 3). Serious bleeding showed a similar
increasing trend at the highest range of the weight-corrected doses
(>0.55 mg/kg) (Figure 6, top), even among patients with the
lower-dose heparin regimen (Figure 6, bottom). Together with the
safety results from the parallel ASSENT I trial (F.V.d.W., unpublished
results), a "stepped" weight-adjusted dose of 0.5 mg/kg TNK-tPA
was selected for phase III testing.
Phase II Dose-Ranging Trial Design
For phase II dose-ranging, the TIMI Investigators collaborated
with the Leuven Coordinating Center to conduct 2 trials
simultaneously to evaluate 2 important aspects of a new
thrombolytic agent: To study efficacy, an angiographic
study (TIMI 10B) was conducted, and for safety, focused on intracranial
hemorrhage, ASSENT I was carried out. This parallel design is
focused on providing adequate sample size to assess each of these 2
critical features. Thus, in the angiographic trial, 150 to 300 patients
per dose provide adequate power to determine relative efficacy compared
with the control arm. However, because intracranial hemorrhage
is a rare event, the safety profile cannot be assessed adequately by
reliance on such a sample size, as learned in previous trials (TIMI 5
and 6, GUSTO II Pilot).18 26 27 Experience from previous
large trials (TIMI 2, TIMI 9A, GUSTO IIa) indicates that safety
problems often emerge after 750 to 1000
patients.10 11 28 Therefore, a new type of phase II
program was used for TNK-tPA to have both an angiographic trial
studying several hundred patients per dose and, in parallel, to
evaluate safety in 1500 patients per dose group. In this fashion, the
angiographic efficacy and safety profile could be defined better before
we embarked on a large phase III trial.
Clinical Significance of Fibrin Specificity
TNK-tPA was designed and proved to be very fibrin-specific
compared with tPA (Figure 5), which itself is more
fibrin-specific than streptokinase.29 However, despite the
hope that fibrin specificity would allow selective clot lysis of a
coronary thrombus and not cause intracerebral
hemorrhage, this trial documents that marked fibrin specificity
does not prevent intracranial hemorrhage, and the incidence of
intracranial hemorrhage was, in fact, similar for TNK-tPA and
tPA. This is consistent with the hypothesis that intracranial
hemorrhage is caused by thrombolytic-induced
lysis of microthrombi in diseased cerebral vessels. Further support for
this hypothesis is that both elderly patients and those with
established cerebrovascular disease are at 5 to 10 times increased risk
of intracranial hemorrhage, as documented in the TIMI 2
trial30 and other trials.31 32 Alternatively,
direct effects of plasmin (generated by all plasminogen
activators) on the cerebral vasculature may induce
intracranial hemorrhage. Similarly, the comparability in rates
of TIMI grade 3 flow and all other measures of reperfusion between
TNK-tPA, a very fibrin-specific agent, and tPA, a moderately
fibrin-specific agent, suggests that further increases in fibrin
specificity above that of tPA do not improve
thrombolytic efficacy.
Adjunctive Heparin Dosing
We observed an improvement in the safety profiles of both TNK-tPA
and tPA after the protocol amendment, which lowered the doses of
heparin used initially and with rescue PTCA. The overall rates of
intracranial hemorrhage were higher in this trial, and in other
angiographic trials,33 than in nonangiographic
trials.23 Because additional heparin is usually given for
cardiac catheterization, this observation is
consistent with the hypothesis that adjunctive heparin
increases the risk of intracranial hemorrhage. In addition,
when the initial doses of heparin (and hirudin) were reduced slightly
from the TIMI 9A and GUSTO IIa trials to the TIMI 9B and GUSTO IIb
trials, the rates of intracranial and major hemorrhage fell by
>50%.11 12 28 34
In this trial, we lowered the initial dose of heparin to slightly less than the conventional dose of 5000 U bolus and 1000 U/h infusion. This change affected primarily the lower-body-weight patients, who are at increased risk of intracranial hemorrhage and major bleeding.11 32 35 The reduction in heparin dosing in the trial led to a lower dose of heparin received and a reduction in bleeding complications (without compromising angiographic efficacy). The adjustment of heparin dosing according to the aPTT result was also begun at 6 hours in the protocol amendment, which may have contributed to the overall safety, although it should be noted that the majority of intracranial hemorrhages occur in the first 6 to 10 hours,11 12 28 34 thus implicating the initial heparin dose as a very important target for reducing bleeding complications. Thus, as observed with platelet glycoprotein IIb/IIIa inhibitors,36 37 use of lower doses of heparin appears to improve the safety profile without compromising the efficacy of tPA and TNK-tPA. Our data suggest that lower doses of heparin, like those used in this trial, should be used with fibrin-specific thrombolytic agents. Based on these and other data,38 we have proposed a revision to the heparin dosing recommendation in the ACC/AHA Acute MI Guidelines39 : a weight-adjusted regimen of 70 U/kg bolus, with a 5000-U maximum, and a 15-U · kg-1 · h-1 infusion, with a 1000-U · kg-1 · h-1 maximum.
Conclusions
TNK-tPA is a promising new single-bolus
thrombolytic agent. At a 40-mg dose, the rate of TIMI
grade 3 flow was comparable to that with the 90-minute regimen of tPA.
Weight-adjustment of the dose appears to be important in optimizing
reperfusion and safety. There appeared to be an important influence of
the adjunctive heparin dosing on bleeding complications for both
TNK-tPA and tPA, with a favorable safety (and efficacy) profile when
using a modestly reduced heparin dose. Together with the safety results
from the parallel ASSENT I trial, the efficacy and safety profile of an
appropriate dose of TNK-tPA have been established, and this agent is
currently being compared with tPA in a large mortality trial, ASSENT
II, designed to show equivalence between the 2 drugs.
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Acknowledgments |
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The study was sponsored by Genentech, Inc, South San Francisco, Calif, and Boehringer Ingelheim GmbH, Rhein, Germany.
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Footnotes |
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Reprint requests to Eugene Braunwald, MD, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115.
Additional contributing authors were Norma Lynn Fox, PhD, and Fong Wang Clow, PhD, Genentech, South San Francisco, Calif, and Silvano Berioli, MD, and Thierry Danays, MD, Boehringer Ingelheim, Rhein, Germany (both companies are sponsors of the trial), and the TIMI 10B investigators and research coordinators (see Appendix).
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Appendix 1 |
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TopAbstractIntroductionMethodsResultsDiscussionAppendix 1References |
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TIMI Study Chairman's Office: Brigham and Women's Hospital, Harvard Medical School, Boston, Mass. Study chairman: E. Braunwald. Principal investigator (PI): C.P. Cannon. Project director: C.H. McCabe. Coinvestigators: R.P. Giugliano, E.M. Antman.
Leuven Coordinating Center: Leuven, Belgium. Study cochairman: F. Van de Werf. Coinvestigators: A. Strijckmans, C. Luys, P. Sinnaeve, R. Brower, L. D'hoore.
Myocardial Infarction Triage and Intervention (MITI) Coordinating Center: University of Washington, Seattle: W.D. Weaver, J.S. Martin, C. Schaff.
TIMI Angiographic Core Laboratory: West Roxbury VA Medical Center, West Roxbury, Mass. PI: C.M. Gibson. Coinvestigators: K. Ryan, M.J. Rizzo, C. McLean, M. Kelley, A. Sparano, J. Moynihan, S.J. Marble, J.T. Dodge.
Coagulation Core Laboratory: University of Vermont, Colchester. Co-PIs: R.P. Tracy, E. Bovill. Research coordinator (RC): E. Cornell.
Data and Safety Monitoring Board: Chairman: J.W. Kennedy. Members: M. Bertrand, W. Kubler, S. Pocock, J.T. Willerson.
Data Coordinating Center: PAREXEL International Corp: M. Hibberd, E. Kirby, D. Lucas-Mudd, J. Steadman, J. Ninis, K. Eissler, K. Maldonado, R. Harris, K. Barrett.
Sponsors: Genentech, Inc, South San Francisco, Calif: N.L. Fox, E.R. McCluskey, F. Wang-Clow, D. Jansen, J. Reimann, N. Modi, J. Breed, T. Keating, M. Mancinni, A. Mulvaney, K. Starback. Boehringer Ingelheim GmbH, Rhein, Germany: S. Berioli, T. Danays, E. Bluhmki, P. Tanswell.
Clinical Centers in Order of Enrollment
United States (485 patients): Baystate Medical Center,
Springfield, Mass: PI, M.J. Schweiger; co-PI, M. Porway; RC, B.
Burkott. Sarasota Memorial Hospital, Sarasota, Fla: PI, M. Frey; RC, H.
Taylor. Bon Secours Venice Hospital, Sarasota, Fla: PI, M. Frey; RC, H.
Taylor. University of Miami/Jackson Memorial Hospital, Miami, Fla: PI,
R. Sequeira; co-PI, E. de Marchena; RCs, G. Girwarr, P. Teixiero.
Montefiore Medical Center, Bronx, NY: co-PIs, M. Greenberg, H.S.
Mueller; RCs, J. Cosico, L. Kunkel. Winthrop University Hospital,
Mineola, NY: PI, R.M. Steingart; RCs, S. Bilodeau, M.E. Cogliarese.
Iowa Heart Center/Mercy Hospital, Des Moines, Iowa: PI, M. Ghali; RC,
T. Coulson. Rhode Island Hospital, Providence: PI, D.O. Williams; RC,
M.J. McDonald. Maine Medical Center, Portland: PI, C.T. Lambrew; RC, S.
Boswell-Farrel. JFK Medical Center, Atlantis, Fla: PI, J. Kieval; RC,
J. Kinley. Hennepin County Medical Center, Minneapolis, Minn: PI, T.D.
Henry; RCs, L. Knox, C. Boisjolie, M. Pyle. Alta Bates Medical
Center, Berkeley, Calif: PI, R.M. Greene; RCs, E. Healy, V. Perry. San
Jose Medical Center, San Jose, Calif: PI, J. Hanson; RC, D. Walder.
Lancaster General Hospital, Lancaster, Pa: PI, P. Casale; RC, L.A.
Frey. Saint Joseph Hospital, Lancaster, Pa: PI, P. Casale; RC, J. Tuzi.
University of Alabama at Birmingham: PI, W.J. Rogers; RCs, N. Grady, T.
Morgan. University Community Hospital, Tampa, Fla: PI, H. Tamboli; RC,
C. Sullivan. Geisinger Medical Center, Danville, Pa: PI, J.
Blankenship; co-PI, F. Menapace; RC, S. Demko. Fletcher Allen Health
Care, Burlington, Vt: PI, M. Watkins; RC, M. Rowen. LDS Hospital, Salt
Lake City, Utah: PI, J. Anderson; RCs, A. Allen, J. German. Highline
Community Hospital, Seattle, Wash: PIs, C. Burnett, W.D. Weaver; RC, J.
Lee; University of Washington Medical Center, Seattle: PI, W.D.
Weaver; RC, K. Allmaras. Broward General Medical Center, Ft Lauderdale,
Fla: PI, A. Niederman; RC, T. Kellerman. University of Louisville
Hospital, Louisville, Ky: PI, R. Bolli; RC, J. Lanter. Marin General
Hospital, Larkspur, Calif: PI, B. Strunk; RC, C. Baker. LA County and
USC Medical Center, Los Angeles, Calif: PI, D. Faxon; RC, S. Bokhari.
Sharp Memorial Hospital, San Diego, Calif: PI, D. Marsh; RC, S. Harte.
Tulsa Regional Medical Center, Tulsa, OK: PI, W.W. Stoever; RC, P.
Cotham. Columbia Medical Center, Baton Rouge, La: PI, A. Rees; RC, B.
Palisi. Baton Rouge General Hospital, Baton Rouge, La: PI, A. Rees; RC,
B. Palisi. St Luke's-Roosevelt Hospital Center, New York, NY: PI, J.S.
Hochman; co-PI, J. Slater; RC, M. McAnulty. Parkview Memorial Hospital,
Fort Wayne, Ind: PI, W. Wilson; RC, J. Cuttitta. Legacy Good Samaritan
Hospital and Medical Center, Portland, Ore: PI, B. Titus; RCs, C.
McGinley, B. Chilton. John L. McClellan VAMH, Little Rock, Ark:
PI, J.D. Talley; RCs, M. Rawert, M. Dearen. University of Arkansas
Medical Center, Little Rock, Ark: PI, J.D. Talley; RC, M. Rawert. Ohio
State University Medical Center, Columbus: PI, R. Magorien; RCs, L.
McCloud-Clouse, A.M. Nordgren. Mount Sinai Medical Center, New York,
NY: PI, S. Duvvuri; RC, D. Ratner. UC Davis Medical Center, Sacramento,
Calif: PI, G. Gershony; RC, B. Atherton-Pierce. Brookdale University
Hospital and Medical Center, Brooklyn, NY: PI, H. Chadow; RC, L.
Giarraffa. Winona Memorial Hospital, Indianapolis, Ind: PI, J. Hall;
RCs, D. Fausset, P. Linden. Trinity Mother Frances Hospital, Tyler,
Tex: PI, R. Carney; RC, G. Murphy. Brigham and Women's Hospital,
Boston, Mass: PI, R.N. Piana; RC, S. Marble. Froedtert Memorial
Lutheran Hospital, Milwaukee, Wis: PI, M. Cinquegrani; co-PI, T.P.
Aufderheide; RC, S. Mauermann. Madigan Army Medical Center, Tacoma,
Wash: PI, A. Mascette; RC, K. Courtney. Saint Elizabeth's Medical
Center, Brighton, Mass: PI, D. Losordo; RCs, S. Farley, K. Osborne.
Carolinas Medical Center, Charlotte, NC; PI, R. Bersin; RCs, D.
Applegate, C. Dellinger. Lindner Center for Clinical
Cardiovascular Research, Cincinnati, Ohio: PI, J.
Runyon; RC, N. Higby. Ben Taub General Hospital, Houston, Tex:
PI, N.S. Kleiman; RC, K. Maresh. Proctor Hospital, Peoria, Ill: PI, P.
Schmidt; RC, C. Ness. Citrus Memorial Hospital, Ocala, Fla: PI, R.
Feldman; RC, Chris Hiller.
France (93 patients): CHU Côte de Nacre, Caen: PI, G. Grollier. Hôpital Tenon/Service de Cardiologie, Paris: PI, A. Vahanian. Service Hemodynamique. CHU Hotel Dieu, Rennes: PI, H. Le Breton. Service de Cardiologie Purpan, Toulouse: PI, D. Carrie. CHU Timone Marseilles, Marseille: PI, J.-L. Bonnet.
Belgium (84 patients): UZ Gasthuisberg, Leuven: PI, F.J.J. Van de Werf; co- PI, J. Dens; RC, A. Luyten. CHR La Citadelle, Liege: PI, J.L. Boland. Ziekenhuis Oost Limburg, Genk: PI, M. Vrolix; RC, J. Hollants. AZ St Jan/Dienst Cardiologie, Brugge: PI, E. Van der Stichele; RC, J. Voet. Cliniques Universitaires St-Luc, Brussels: PI, J. Col.
Canada (69 patients): Vancouver General Hospital, Vancouver, BC: PI, C. Buller; co- PI, A. Fung; RCs, H. Abbey, C. Davies. Health Sciences Center, Winnipeg, Manitoba: PI, J. Ducas; RC, U. Schick. St Paul's Hospital, Vancouver, BC: PI, C. Thompson; RCs, E. Buller, C. Li. Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, Quebec: PI, V. Dangoisse; RC, J. Dangoisse. Royal University Hospital, Saskatoon, Saskatchewan: PI, J. Lopez; RC, P. Kuny. University of Ottawa Heart Institute, Ottawa, Ontario: PI, M. Labinaz; RC, S.-A. Kearns.
United Kingdom (67 patients): Royal Victoria Mobile Unit and Royal Victoria Hospital, Belfast: PI, A.A. Jennifer Adgey; coinvestigator, I.B.A. Menown; RCs, B.A. Smith, Y.R. McKay. Department of Medicine/Gardiener Institute, Glasgow: PI, W.S. Hillis; coinvestigators, D. Muir, L. Swan, J. McCann.
Germany (37 patients): Universitäts Krankenhaus Eppendorf, Hamburg: PI, C.A. Nienaber. Johannes Gutenberg Universität, Mainz: PI, H.J. Rupprecht; RC, T. Cyrus. Medizinische Klinik 1 der Medizinische Hochschule, Aachen: PI, J. vom Dahl. Klinikum der Stadt Ludwigshafen: PI, J. Senges. Klinikum der Albert-Ludwigs-Universität, Freiburg: PI, M. Just; RC, Med Loo.
Netherlands (21 patients): Catharina Ziekenhuis/Afdeling Cardiologe, Eindhoven: PI, H.R. Michels.
Received May 15, 1998; revision received August 31, 1998; accepted September 16, 1998.
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 T K Nordt and C Bode Thrombolysis: newer thrombolytic agents and their role in clinical medicine Heart, November 1, 2003; 89(11): 1358 - 1362. [Full Text] [PDF]
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C. L. Dubois, A. Belmans, C. B. Granger, P. W. Armstrong, L. Wallentin, P. M. Fioretti, J. L. Lopez-Sendon, F. W. Verheugt, J. Meyer, F. Van de Werf, et al. Outcome of urgent and elective percutaneous coronary interventions after pharmacologic reperfusion with tenecteplase combined with unfractionated heparin, enoxaparin, or abciximab J. Am. Coll. Cardiol., October 1, 2003; 42(7): 1178 - 1185. [Abstract] [Full Text] [PDF]
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C. M. Gibson, J. Karha, S. A. Murphy, D. James, D. A. Morrow, C. P. Cannon, R. P. Giugliano, E. M. Antman, E. Braunwald, and TIMI Study Group Early and long-term clinical outcomes associated with reinfarction following fibrinolytic administration in the thrombolysis in myocardial infarction trials J. Am. Coll. Cardiol., July 2, 2003; 42(1): 7 - 16. [Abstract] [Full Text] [PDF]
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R. P. Giugliano, M. T. Roe, R. A. Harrington, C. M. Gibson, U. Zeymer, F. Van de Werf, K. W. Baran, H.-P. Hobbach, L. H. Woodlief, K. L. Hannan, et al. Combination reperfusion therapy with eptifibatide and reduced-dose tenecteplase for ST-elevation myocardial infarction: Results of the integrilin and tenecteplase in acute myocardial infarction (INTEGRITI) Phase II Angiographic urial J. Am. Coll. Cardiol., April 16, 2003; 41(8): 1251 - 1260. [Abstract] [Full Text] [PDF]
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D. Stewart, M. Kong, V. Novokhatny, G. Jesmok, and V. J. Marder Distinct dose-dependent effects of plasmin and TPA on coagulation and hemorrhage Blood, April 15, 2003; 101(8): 3002 - 3007. [Abstract] [Full Text] [PDF]
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 W. F. Baker Jr Thrombolytic Therapy Clinical and Applied Thrombosis/Hemostasis, October 1, 2002; 8(4): 291 - 314. [PDF]
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 H. P. Selker, J. R. Beshansky, J. L. Griffith, and for the TPI Trial Investigators* Use of the Electrocardiograph-Based Thrombolytic Predictive Instrument To Assist Thrombolytic and Reperfusion Therapy for Acute Myocardial Infarction: A Multicenter, Randomized, Controlled, Clinical Effectiveness Trial Ann Intern Med, July 16, 2002; 137(2): 87 - 95. [Abstract] [Full Text] [PDF]
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 J. Llevadot, R. P. Giugliano, and E. M. Antman Bolus Fibrinolytic Therapy in Acute Myocardial Infarction JAMA, July 25, 2001; 286(4): 442 - 449. [Abstract] [Full Text] [PDF]
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P. W. Armstrong and D. Collen Fibrinolysis for Acute Myocardial Infarction : Current Status and New Horizons for Pharmacological Reperfusion, Part 1 Circulation, June 12, 2001; 103(23): 2862 - 2866. [Full Text] [PDF]
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C. M. Gibson, J. A. de Lemos, S. A. Murphy, S. J. Marble, C. H. McCabe, C. P. Cannon, E. M. Antman, and E. Braunwald Combination Therapy With Abciximab Reduces Angiographically Evident Thrombus in Acute Myocardial Infarction : A TIMI 14 Substudy Circulation, May 29, 2001; 103(21): 2550 - 2554. [Abstract] [Full Text] [PDF]
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D. F. Chapman, P. Lyden, P. A. Lapchak, S. Nunez, H. Thibodeaux, and J. Zivin Comparison of TNK With Wild-Type Tissue Plasminogen Activator in a Rabbit Embolic Stroke Model Stroke, March 1, 2001; 32(3): 748 - 752. [Abstract] [Full Text] [PDF]
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P. W. Armstrong, C. Granger, and F. Van de Werf Bolus Fibrinolysis : Risk, Benefit, and Opportunities Circulation, February 27, 2001; 103(8): 1171 - 1173. [Full Text] [PDF]
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J. W. Eikelboom, S. R. Mehta, J. Pogue, and S. Yusuf Safety Outcomes in Meta-analyses of Phase 2 vs Phase 3 Randomized Trials: Intracranial Hemorrhage in Trials of Bolus Thrombolytic Therapy JAMA, January 24, 2001; 285(4): 444 - 450. [Abstract] [Full Text] [PDF]
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E. M. Ohman, R. A. Harrington, C. P. Cannon, G. Agnelli, J. A. Cairns, and J.W. Kennedy Intravenous Thrombolysis in Acute Myocardial Infarction Chest, January 1, 2001; 119(1_suppl): 253S - 277S. [Full Text] [PDF]
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H. V. Barron, C. P. Cannon, S. A. Murphy, E. Braunwald, and C. M. Gibson Association Between White Blood Cell Count, Epicardial Blood Flow, Myocardial Perfusion, and Clinical Outcomes in the Setting of Acute Myocardial Infarction : A Thrombolysis In Myocardial Infarction 10 Substudy Circulation, November 7, 2000; 102(19): 2329 - 2334. [Abstract] [Full Text] [PDF]
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 R. J. Stewart, J. C. Fredenburgh, B. A. Leslie, B. A. Keyt, J. A. Rischke, and J. I. Weitz Identification of the Mechanism Responsible for the Increased Fibrin Specificity of TNK-Tissue Plasminogen Activator Relative to Tissue Plasminogen Activator J. Biol. Chem., March 31, 2000; 275(14): 10112 - 10120. [Abstract] [Full Text] [PDF]
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 I.B.A Menown, G Mackenzie, and A.A.J Adgey Optimizing the initial 12-lead electrocardiographic diagnosis of acute myocardial infarction Eur. Heart J., February 2, 2000; 21(4): 275 - 283. [Abstract] [PDF]
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C. M. Gibson, C. P. Cannon, S. A. Murphy, K. A. Ryan, R. Mesley, S. J. Marble, C. H. McCabe, F. Van de Werf, and E. Braunwald Relationship of TIMI Myocardial Perfusion Grade to Mortality After Administration of Thrombolytic Drugs Circulation, January 18, 2000; 101(2): 125 - 130. [Abstract] [Full Text] [PDF]
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C. P. Cannon Overcoming thrombolytic resistance: Rationale and initial clinical experience combining thrombolytic therapy and glycoprotein IIb/IIIa receptor inhibition for acute myocardial infarction J. Am. Coll. Cardiol., November 1, 1999; 34(5): 1395 - 1402. [Abstract] [Full Text] [PDF]
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C. M. Gibson, S. Murphy, I. B. A. Menown, R. F. Sequeira, R. Greene, F. Van de Werf, M. J. Schweiger, M. Ghali, M. J. Frey, K. A. Ryan, et al. Determinants of coronary blood flow after thrombolytic administration J. Am. Coll. Cardiol., November 1, 1999; 34(5): 1403 - 1412. [Abstract] [Full Text] [PDF]
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F.J. Van de Werf The ideal fibrinolytic: can drug design improve clinical results? Eur. Heart J., October 2, 1999; 20(20): 1452 - 1458. [PDF]
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M. J. Tanasijevic, C. P. Cannon, E. M. Antman, D. R. Wybenga, G. A. Fischer, C. Grudzien, C. M. Gibson, J. W. Winkelman, E. Braunwald, and for the TIMI 10B Investigators Myoglobin, creatine-kinase-MB and cardiac troponin-I 60-minute ratios predict infarct-related artery patency after thrombolysis for acute myocardial infarction: Results from the thrombolysis in myocardial infarction study (TIMI) 10B J. Am. Coll. Cardiol., September 1, 1999; 34(3): 739 - 747. [Abstract] [Full Text] [PDF]
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T. J. Ryan, E. M. Antman, N. H. Brooks, R. M. Califf, L. D. Hillis, L. F. Hiratzka, E. Rapaport, B. Riegel, R. O. Russell, E. E. Smith III, et al. 1999 update: ACC/AHA guidelines for the management of patients with acute myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction) J. Am. Coll. Cardiol., September 1, 1999; 34(3): 890 - 911. [Full Text] [PDF]
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C. M. Gibson Primary Angioplasty Compared with Thrombolysis: New Issues in the Era of Glycoprotein IIb/IIIa Inhibition and Intracoronary Stenting Ann Intern Med, May 18, 1999; 130(10): 841 - 847. [Abstract] [Full Text] [PDF]
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C. M. Gibson, S. A. Murphy, M. J. Rizzo, K. A. Ryan, S. J. Marble, C. H. McCabe, C. P. Cannon, F. Van de Werf, and E. Braunwald Relationship Between TIMI Frame Count and Clinical Outcomes After Thrombolytic Administration Circulation, April 20, 1999; 99(15): 1945 - 1950. [Abstract] [Full Text] [PDF]
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C. M. Gibson, C. P. Cannon, S. A. Murphy, S. J. Marble, H. V. Barron, E. Braunwald, and for the TIMI Study Group Relationship of the TIMI Myocardial Perfusion Grades, Flow Grades, Frame Count, and Percutaneous Coronary Intervention to Long-Term Outcomes After Thrombolytic Administration in Acute Myocardial Infarction Circulation, April 23, 2002; 105(16): 1909 - 1913. [Abstract] [Full Text] [PDF]
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