(Circulation. 1995;92:2044-2049.)
© 1995 American Heart Association, Inc.
Articles |
A Randomized Trial of Recombinant Staphylokinase Versus Alteplase for Coronary Artery Patency in Acute Myocardial Infarction
From the Center for Molecular and Vascular Biology, University of Leuven. Participating centers and core facilities are listed in the "Appendix."
Correspondence to D. Collen, MD, PhD, Center for Molecular and Vascular Biology, University of Leuven, Campus Gasthuisberg, O&N, Herestraat 49, B-3000 Leuven, Belgium.
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Abstract |
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 Top Abstract IntroductionMethods Results Discussion Appendix References |
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Background Recombinant staphylokinase (STAR) was shown recently to offer promise for coronary arterial thrombolysis in patients with evolving myocardial infarction. The present multicenter randomized open trial was designed to assess the thrombolytic efficacy, safety, and fibrin specificity of STAR relative to accelerated alteplase (recombinant tissue-type plasminogen activator [RTPA]).
Methods and Results One hundred patients with evolving myocardial infarction of <6 hours' duration and with ST-segment elevation were allocated to accelerated and weight-adjusted RTPA over 90 minutes (52 patients) or to STAR (the first 25 patients to 10 mg and the next 23 patients to 20 mg given intravenously over 30 minutes). All patients received aspirin and intravenous heparin. The main end points were coronary artery patency and plasma fibrinogen levels at 90 minutes. Thrombolysis in Myocardial Infarction (TIMI) perfusion grade 3 at 90 minutes was achieved in 62% of STAR patients versus 58% of RTPA patients (risk ratio, 1.1; 95% CI, 0.76 to 1.5). With 10 mg STAR, TIMI grade 3 patency was 50% (risk ratio, 0.86; 95% CI, 0.54 to 1.4 versus RTPA); with 20 mg STAR, it was 74% (risk ratio, 1.3; 95% CI, 0.90 to 1.8 versus RTPA). Residual fibrinogen levels at 90 minutes were 118±47% (mean±SD) of baseline with STAR and 68±42% with RTPA (P<.0005). STAR therapy was not associated with an excess mortality or electric, hemorrhagic, mechanical, or allergic complications. However, patients developed antibody-mediated STAR-neutralizing activity from the second week after STAR treatment. As an addendum to the randomized study, 5 patients were given 40 mg STAR over 30 minutes, resulting in TIMI perfusion grade 3 at 90 minutes in 4 patients without fibrinogen breakdown (residual levels at 90 minutes of 105±8% of baseline).
Conclusions STAR appears to be at least as effective for early coronary recanalization as and significantly more fibrin-specific than accelerated RTPA in patients with evolving myocardial infarction.
Key Words: thrombolysis • myocardial infarction • plasminogen activators
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Introduction |
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TopAbstractIntroductionMethods Results Discussion Appendix References |
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Staphylokinase is a 136-amino-acid single-chain protein without disulfide bridges, secreted by some strains of Staphylococcus aureus,1 that can be readily produced by rDNA technology.2 Although the (pro)fibrinolytic properties of staphylokinase were already recognized more than four decades ago,3 its thrombolytic potential and fibrin specificity were demonstrated only recently.1 2 Two small pilot studies in patients with evolving MI and angiographically proven total infarct-related coronary artery occlusion demonstrated that STAR, in a 10-mg dose infused intravenously over 30 minutes, recanalized 9 of 10 occluded arteries without major side effects or fibrinogen breakdown.2 4
The present multicenter, randomized open trial compared the early coronary artery patency status and fibrin selectivity of STAR and alteplase (RTPA) in 100 patients with evolving MI.
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Methods |
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TopAbstractIntroductionMethods Results Discussion Appendix References |
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Patient Enrollment
Seven clinical centers participated in this multicenter, prospective, randomized open trial (see the Appendix). From October 15, 1993, until October 20, 1994, 100 patients
75 years of age who
presented within 6 hours of the onset of symptoms of acute MI
were enrolled, provided that coronary angiography was feasible
within 90 minutes from study entry. Inclusion criteria included 
1-mm
ST-segment elevation in two or more limb leads or 2-mm ST-segment
elevation in two or more contiguous precordial leads on a
12-lead ECG. Exclusion criteria were active bleeding, history of stroke
or central nervous system damage (including neoplasm, aneurysm,
or intracranial or intraspinal surgery), major surgery or significant
trauma in the past 6 months, uncontrolled hypertension (ie, systolic
pressure 180 mm Hg and/or diastolic pressure 110
mm Hg despite adequate treatment), concomitant anticoagulation,
significant disease of noncoronary origin, previous
participation in the trial, and acute MI within the past 2 weeks.
Randomization and Treatment Strategies
Enrolling physicians
called the permanently staffed coordinating
center in Leuven, Belgium, to review patient eligibility and to receive
treatment assignment to either RTPA or STAR. Both agents were given
intravenously. RTPA (Actilyse, Boehringer
Ingelheim) was administered according to an accelerated and
weight-adjusted scheme: 15-mg bolus, then 0.75 mg/kg body weight over a
30-minute period not to exceed 50 mg, and finally 0.5 mg/kg up to 35 mg
over the next 60 minutes.5 6 7
STAR was produced by transfected Escherichia coli and purified as described elsewhere.2 It was provided in 10-mL vials containing 1 mg STAR per milliliter, which could be diluted up to 10-fold with saline before administration. During the first half of the randomized study, 10 mg STAR was administered over 30 minutes, as in the pilot trials2 4 : 1-mg bolus over 2 minutes, followed by an infusion of the remaining 9 mg over 30 minutes. It was prospectively determined that the STAR dose could be increased or decreased by a factor of two in the second half of the study, depending on the efficacy-to-toxicity ratio of the 10-mg dose. In view of the excellent safety (absence of treatment-related adverse effects), complete fibrin specificity, and suboptimal TIMI grade 3 flows after 10 mg STAR, the dose was doubled to 20 mg for the remainder of the study: a 2-mg bolus followed by an infusion of the remaining 18 mg over 30 minutes.
Conjunctive antithrombotic therapy consisted of 160 mg oral or chewable aspirin at entry, followed by a daily oral dose of 160 or 325 mg aspirin and intravenous heparin. A 5000-U heparin bolus was given to the first 25 patients at entry. Because the APTT at 90 minutes was found not to be consistently prolonged to at least 1.5 times control in the first 25 patients treated with STAR, all subsequent patients in both treatment groups were given a 10 000-U heparin bolus. In all patients, the heparin bolus was followed promptly by a 1000-U/h infusion, adjusted at 6, 12, and 24 hours from the initiation of thrombolytic therapy, to keep the APTT within the therapeutic range (at least 1.5 times control). The heparin infusion was continued for at least 48 hours unless emergency surgery or major bleeding events required its cessation. Major bleeding was defined as intracerebral or internal bleeding or hemorrhage requiring transfusion or surgical control or causing hemodynamic compromise. Other medications (eg, ß-blockers, nitrates, calcium channel blockers, angiotensin-converting enzyme inhibitors, and antiarrythmics) were to be used at the discretion of the attending physician.
Because of the complete fibrin specificity of the 20-mg STAR dose, the study was extended with 5 nonrandomized patients, 59±10 years of age, given 40 mg STAR (4-mg bolus and 36-mg infusion over 30 minutes).
Technical Procedures
Angiography of the infarct-related
vessel in at least two
orthogonal views was performed at 90 minutes and at 24±4 hours after
the start of thrombolytic therapy. The 90-minute patency
rate of the infarct-related artery at the initial injection of
contrast material and graded as described in the TIMI
trial8 constituted the primary end point.
PTCA or additional thrombolysis with a commercially available agent at 90 minutes to 24 hours was allowed if TIMI grade 0 or 1 flow persisted or in case of clear clinical evidence of recurrent infarction. At 24 hours, PTCA could be performed at the operator's discretion. All images were stored on film or videotape and sent, together with the case report forms and ECGs at baseline, before discharge, and during reinfarction if applicable, to the angiography core laboratory where they were reviewed and scored by an investigator blinded to treatment allocation and clinical outcome.
Blood Samples
Plasma samples were collected immediately
before therapy and
were repeated at 25 and 90 minutes; at 6, 12, 24, and 48 hours; and at
4, 7, and 10 to 14 days after the start of thrombolytic
infusion. Analyses in the core laboratory included prothrombin
time, aPTT, fibrinogen, plasminogen,
2-antiplasmin, D-dimer, CK and its CK-MB
fraction, and STAR and TPA antigen (by ELISA); in patients treated with
STAR, STAR-neutralizing activity (measured as described
elsewhere9 ) and total anti-STAR antibody (by ELISA) were
analyzed.
Statistical Analysis
The data represent mean±SD unless
stated otherwise.
Statistical significance was determined by Student's t test
for paired or unpaired values or by 
2 or
Fisher's exact test, as applicable.
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Results |
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TopAbstractIntroductionMethods Results Discussion Appendix References |
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Patient Characteristics
Of the 100 patients enrolled, 52 were randomized to RTPA and 48 patients to STAR (25 patients to 10 mg and 23 patients to 20 mg STAR over 30 minutes). The RTPA and STAR treatment groups did not differ in relevant selected baseline variables (Table 1
).
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Complications and Adverse Clinical Outcome
Table
2 details the complications in both treatment
groups. The rates of hemorrhagic, mechanical, and electric
complications did not differ significantly between the treatment arms.
Cerebrovascular accidents or allergic reactions were not observed.
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More patients in the RTPA group experienced sustained hypotension, defined as systolic pressure <90 mm Hg for more than 1 hour despite fluid resuscitation (7 RTPA versus 1 STAR patient, P<.05). Borderline-significant excess mortality was noted in the RTPA treatment group (5 versus 0 patients in the RTPA and STAR treatment groups, respectively; .025<P<.05). All deaths occurred within 48 hours of admission and were due to cardiogenic shock.
Coronary Artery Patency
Table 3 summarizes the
coronary artery
patency rates at 90 minutes and 24 hours. The 90-minute angiography of
the infarct-related vessel could not be performed in 1 patient
treated with 10 mg STAR because of technical failure to catheterize the
target artery and in 4 patients treated with RTPA (because of
hemodynamic instability or premature death in 3
patients and erroneous overdosage of heparin in 1 patient). Reasons not
to perform the angiography at 24 hours included coronary stent
implantation at 8 hours in 1 patient treated with 20 mg STAR and
premature death in 4 patients and emergency CABG in 1 patient in the
RTPA treatment group. Of the patients who were catheterized, 62% in
the STAR group had TIMI perfusion grade 3 flow of the culprit vessel at
90 minutes versus 58% in the RTPA group (risk ratio, 1.1; 95% CI,
0.76 to 1.5). Corresponding figures in the two subgroups of STAR
treatment were 50% for the 10-mg dose (risk ratio versus RTPA, 0.86;
95% CI, 0.54 to 1.4) versus 74% for the 20-mg dose (risk ratio versus
RTPA, 1.3; 95% CI, 0.90 to 1.8). The risk ratio was 0.68 for the 10-mg
versus the 20-mg dose of STAR (95% CI, 0.42 to 1.1). Additional
emergency reperfusion strategies between the first and second
angiograms, performed because of TIMI grade 0 or 1 flow at 90 minutes
or because of reocclusion within the first 24 hours, included PTCA in 9
patients of the STAR treatment group (7 treated with 10 mg; and 2
treated with 20 mg) and in 4 RTPA-treated patients, rescue
thrombolysis in 2 patients in each treatment group, and
emergency CABG in 1 patient after RTPA therapy (Table 3). TIMI
perfusion grade 3 flow rates at 24 hours, reflecting the combined
angiographic outcome after thrombolysis and PTCA, were 79%
for the STAR treatment group (80% and 77% for the 10- and 20-mg
doses, respectively) and 68% for the RTPA treatment group (Table
3).
TIMI perfusion grade 3 flow was obtained at 90 minutes in 4 of the 5
patients given 40 mg STAR initiated 100±45 minutes from the onset of
symptoms.
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Laboratory Measurements
Relevant laboratory data are shown in
Table 4 and
the Figure. Systemic fibrinogen degradation,
2-antiplasmin consumption, and plasminogen
activation were absent in the STAR treatment group but substantial in
the RTPA treatment group. Prothrombin time was prolonged in the RTPA
treatment group compared with the STAR group at 25 minutes and up to 12
hours (Fig 1); APTT was longer in the RTPA treatment group than
in the
STAR group at 90 minutes (Table 4), but not at the other time
points.
APTT levels at 12 and 24 hours were 120±55 and 100±53 seconds
for the
STAR treatment group and 100±56 and 100±52 seconds for the RTPA
treatment group, respectively. The evolution of D-dimer
and CK/CK-MB did not differ significantly between treatment groups
(Table 4). STAR-neutralizing activity (Table 4)
and total anti-STAR
antibody (data not shown) were low at baseline and during the first
week after STAR administration but increased substantially from the
second week on in the majority of patients treated with STAR. Table
4
summarizes the STAR and RTPA antigen levels in plasma.
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) and RTPA (
).
*P<.000001.
In the 5
patients given 40 mg STAR, residual fibrinogen levels at 90
minutes were 105±8% of baseline (P=.2), whereas
plasminogen and 2-antiplasmin levels were
slightly decreased to 80±15% and 86±9% of baseline
(P=.04 and P=.07), respectively. One patient
suffered gastric bleeding at 6 hours that required transfusion of 4 U
of packed red blood cells.
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Discussion |
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TopAbstractIntroductionMethods Results Discussion Appendix References |
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Restoration of coronary artery flow by thrombolytic agents administered early in the course of an evolving MI salvages jeopardized myocardium, preserves left ventricular function, and reduces mortality.10 11 "Accelerated" RTPA, administered with intravenous heparin, offers a recanalization and survival advantage over standard streptokinase infusion.6 7 An important difference between these fibrinolytic agents is that RTPA is fibrinogen-sparing.12 At pharmacological dosages, however, the fibrin specificity of RTPA is only relative, and some systemic plasminogen activation, with the ensuing lytic state and plasminogen steal, occurs.13 14 Theoretically, "clot-targeted" fibrinolysis by plasminogen activators with more pronounced fibrin specificity might improve the benefit-to-risk ratio of thrombolytic therapy.
Preclinical and early uncontrolled clinical studies suggested that the
fibrin specificity of STAR is higher than that of RTPA and other
plasminogen activators currently in use or
under clinical evaluation.1 2 4 The
present study was
therefore designed to compare the potency and fibrin specificity of
STAR with that of RTPA in a randomized, controlled trial, using 10 mg
STAR over 30 minutes in the first half of the study and 20 mg
thereafter. Neither dosage of intravenous STAR induced an
overt systemic lytic state, as shown by the unchanged levels of
circulating fibrinogen, plasminogen, and
2-antiplasmin, although these hemostatic markers were
significantly decreased during and after RTPA therapy. Even with 40 mg
STAR, administered to 5 subsequent nonrandomized patients, fibrin
specificity was still maintained.
STAR proved to be at least as effective as accelerated RTPA in inducing early coronary artery patency (TIMI perfusion grade 3 flow at 90 minutes in 62% versus 58% of catheterized patients). A trend toward a higher thrombolytic potency of 20 compared with 10 mg STAR was observed: TIMI perfusion grade 3 flow at 90 minutes occurred in 74% and 50% of patients, respectively, but this difference was not statistically significant.
STAR administration was not associated with excess mortality nor electric, mechanical, hemorrhagic, or allergic complications. Five patients assigned to RTPA developed fatal cardiogenic shock, while no in-hospital mortality occurred in the patients randomized to STAR therapy (.025<P<.05). This borderline statistically significant difference in in-hospital mortality was unexpected and may have been coincidental, resulting from a somewhat preferential allocation (by chance) of sicker patients to RTPA. Indeed, because cardiogenic shock was not an exclusion criterion, 4 patients with Killip class III (2 patients) or IV (2 patients) were randomized to RTPA, whereas 3 patients with Killip class III and none with Killip class IV were randomized to STAR. Bleeding was slightly but not significantly more frequent in the RTPA compared with the STAR treatment arm (31% versus 21% of patients). All bleeding complications occurred at the angiographic puncture site, except for one gingival and one gastric bleeding incident after STAR therapy and one retroperitoneal and two urinary hemorrhages after RTPA therapy. Larger comparative studies are needed to determine whether thrombolytic agents with improved fibrin specificity, by avoiding a (partial) systemic fibrinolytic state, will reduce the risk of intracranial or other hemorrhages.
Optimal conjunctive anticoagulation is believed to be a prerequiste for successful thrombolytic therapy with relatively fibrin-specific plasminogen activators such as RTPA.12 15 The need may be even more pronounced for a more fibrinogen sparing agent such as STAR. Indeed, the APTT at 90 minutes was significantly shorter for patients treated with STAR compared with those treated with RTPA. Suboptimal heparinization was believed to play a role in the persistent coronary artery occlusion in some patients treated with STAR in the beginning of the present study. This inspired a protocol amendment, the doubling of the heparin bolus (from 5000 to 10 000 U) in all subsequent patients.
As noted earlier in the pilot studies with STAR,2 4 antibody-related STAR-neutralizing activity was low at baseline and during the first week after treatment but increased significantly from the second week on in the majority of patients. Although no allergic reactions occurred, possibly reflecting the low baseline level of anti-STAR antibodies, the confirmation of the immunogenicity of this bacterial protein in the present trial and the demonstrated persistence of the neutralizing antibodies during several months in previous studies suggest that repeated use of STAR from the second week after initial therapy on, as with streptokinase, should be avoided.9 16
In summary, this randomized trial suggests that STAR may compare favorably with accelerated RTPA in achieving early coronary artery recanalization in patients with evolving MI at dosages that preserve circulating fibrinogen. Larger clinical studies are warranted to establish the efficacy and safety of this promising thrombolytic agent relative to other plasminogen activators currently in use.
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Appendix |
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TopAbstractIntroductionMethods Results Discussion Appendix References |
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Steering Committee
F. Van de Werf, MD, PhD (study chairman); S. Vanderschueren, MD (study coordinator); and D. Collen, MD, PhD (scientific adviser).
Angiographic Core Laboratory
L. Barrios, MD; P. Kerdsinchai,
MD; W. Desmet, MD, PhD; and F.
Van de Werf, MD, PhD.
Hemostasis Core Laboratory
D. Collen, MD, PhD.
Participating Belgian Centers
UZ Gasthuisberg, University of
Leuven: F. Van de Werf,
MD, PhD; I. De Scheerder, MD, PhD; W. Desmet, MD, PhD; S. Janssens, MD,
PhD; J. Van Cleemput, MD; and J. Vanhaecke, MD, PhD.
AZ Middelheim, Antwerpen: F. Van den Branden, MD; P. Van den Heuvel, MD; P. Vermeersch, MD; E. Vanagt, MD; P. Rogiers, MD; and R. Ranquin, MD.
AZ Imelda Ziekenhuis, Bonheiden: L. Janssens, MD; L. Hermans, MD; and G. Verstreken, MD.
AZ St-Jan, Genk: J. Eerdekens, MD; P. Noyens, MD; J. Van Lierde, MD; P. De Vusser, MD; W. Van Mieghem, MD, PhD; and M. Vrolix, MD.
AZ St Elisabeth, Ukkel: M. Beyloos, MD; F. De Man, MD; E. Haine, MD; and J.P. Melchior, MD.
AZ St-Jan Brugge: E. Van der Stichele, MD; J. Vincke, MD; L. Muyldermans, MD; and Y. Vandekerckhove, MD.
AZ Virga Jesse Hasselt: E. Benit, MD; R. Geukens, MD; and Ph. Timmermans, MD.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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Dr Vanderschueren is a research assistant for the National Fund for Scientific Research in Belgium.
Received February 9, 1995; revision received April 24, 1995; accepted May 22, 1995.
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S. Jenne, K. Brepoels, D. Collen, and L. Jespers High Resolution Mapping of the B Cell Epitopes of Staphylokinase in Humans Using Negative Selection of a Phage-Displayed Antigen Library J. Immunol., September 15, 1998; 161(6): 3161 - 3168. [Abstract] [Full Text] [PDF]
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B. Schlott, K.-H. Guhrs, M. Hartmann, A. Rocker, and D. Collen NH2-terminal Structural Motifs in Staphylokinase Required for Plasminogen Activation J. Biol. Chem., August 28, 1998; 273(35): 22346 - 22350. [Abstract] [Full Text] [PDF]
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H. D. White and F. J. J. Van de Werf Thrombolysis for Acute Myocardial Infarction Circulation, April 28, 1998; 97(16): 1632 - 1646. [Abstract] [Full Text] [PDF]
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 S. Vanderschueren, I. Van Vlaenderen, and D. Collen Intravenous Thrombolysis With Recombinant Staphylokinase Versus Tissue-Type Plasminogen Activator in a Rabbit Embolic Stroke Model Stroke, September 1, 1997; 28(9): 1783 - 1788. [Abstract] [Full Text]
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B. Schlott, K.-H. Guhrs, M. Hartmann, A. Rocker, and D. Collen Staphylokinase Requires NH2-terminal Proteolysis for Plasminogen Activation J. Biol. Chem., February 28, 1997; 272(9): 6067 - 6072. [Abstract] [Full Text] [PDF]
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C. P. Cannon, C. H. McCabe, C. M. Gibson, M. Ghali, R. F. Sequeira, G. R. McKendall, J. Breed, N. B. Modi, N. L. Fox, R. P. Tracy, et al. TNK-Tissue Plasminogen Activator in Acute Myocardial Infarction: Results of the Thrombolysis in Myocardial Infarction (TIMI) 10A Dose-Ranging Trial Circulation, January 21, 1997; 95(2): 351 - 356. [Abstract] [Full Text]
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D. Collen, F. De Cock, E. Demarsin, S. Jenne, I. Lasters, Y. Laroche, P. Warmerdam, and L. Jespers Recombinant Staphylokinase Variants With Altered Immunoreactivity: III: Species Variability of Antibody Binding Patterns Circulation, January 21, 1997; 95(2): 455 - 462. [Abstract] [Full Text]
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D. V. Sakharov, H. R. Lijnen, and D. C. Rijken Interactions between Staphylokinase, Plasmin(ogen), and Fibrin. STAPHYLOKINASE DISCRIMINATES BETWEEN FREE PLASMINOGEN AND PLASMINOGEN BOUND TO PARTIALLY DEGRADED FIBRIN J. Biol. Chem., November 1, 1996; 271(44): 27912 - 27918. [Abstract] [Full Text] [PDF]
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D. Collen, R. Bernaerts, P. Declerck, F. De Cock, E. Demarsin, S. Jenne, Y. Laroche, H. R. Lijnen, K. Silence, and M. Verstreken Recombinant Staphylokinase Variants With Altered Immunoreactivity: I: Construction and Characterization Circulation, July 15, 1996; 94(2): 197 - 206. [Abstract] [Full Text]
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D. Collen, H. Moreau, L. Stockx, and S. Vanderschueren Recombinant Staphylokinase Variants With Altered Immunoreactivity: II: Thrombolytic Properties and Antibody Induction Circulation, July 15, 1996; 94(2): 207 - 216. [Abstract] [Full Text]
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D. Collen Fibrin-Selective Thrombolytic Therapy for Acute Myocardial Infarction Circulation, March 1, 1996; 93(5): 857 - 865. [Full Text]
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 A BETTER THROMBOLYTIC AGENT IN THE WINGS? Journal Watch (General), October 31, 1995; 1995(1031): 5 - 5. [Full Text]
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