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(Circulation. 1995;92:2050-2057.)
© 1995 American Heart Association, Inc.

Articles

Thrombolytic Therapy of Peripheral Arterial Occlusion With Recombinant Staphylokinase

Steven Vanderschueren, MD; Luc Stockx, MD; Guy Wilms, MD, PhD; Hendrik Lacroix, MD; Raymond Verhaeghe, MD, PhD; Jozef Vermylen, MD, PhD; Désiré Collen, MD, PhD

From the Center for Molecular and Vascular Biology (S.V., R.V., J.V., D.C.) and the Departments of Radiology (L.S., G.W.) and Vascular Surgery (H.L.), University of Leuven (Belgium).

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.

	Abstract

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Background Recombinant staphylokinase (STAR) induces fibrin-specific coronary artery recanalization in patients with evolving myocardial infarction. The present pilot study evaluates its thrombolytic efficacy, safety, fibrin specificity, and immunogenicity in patients with peripheral arterial occlusive disease.

Methods and Results Thirty patients (37 to 86 years of age) with angiographically documented thromboembolic peripheral arterial occlusion of recent origin (21±5.5 days, mean±SEM) were treated with heparin and intra-arterial STAR given as a 1-mg bolus followed by a 0.5-mg/h infusion in 20 patients or as a 2-mg bolus followed by a 1-mg/h infusion in 10 subsequent patients. With 7.0±0.7 mg STAR infused over 8.7±1.0 hours, recanalization was complete in 25 patients, partial in 2, and absent in 3. Two major hemorrhagic complications occurred: one fatal hemorrhagic stroke and one hypovolemic shock caused by bleeding at the angiographic puncture site. Administration of STAR did not induce fibrinogen breakdown or a significant prolongation of template bleeding time. STAR-neutralizing activity and anti-STAR IgG were low at baseline, increased markedly from the second week on, and remained elevated for several months.

Conclusions Intra-arterial administration of STAR restores vessel patency in patients with peripheral arterial occlusion in the absence of fibrinogen degradation.

Key Words: peripheral vascular disease • thrombolysis • plasminogen activators • staphylokinase

	Introduction

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Intra-arterial infusion of thrombolytic agents for peripheral arterial occlusion (PAO) has largely replaced systemic infusion for achieving optimal thrombolysis at the occlusion site while minimizing the bleeding risks associated with systemic fibrinolytic activation.^{1 2 3 4} In recent years, catheter-directed fibrinolytic therapy has become a treatment strategy for many patients who require revascularization for acute or chronic limb ischemia, complementing surgical and endovascular procedures. The development of newer and safer agents may expand the use of this therapeutic modality and further improve the outcome of patients with PAO.

The profibrinolytic agent staphylokinase, secreted by certain strains of Staphylococcus aureus and produced by recombinant DNA technology, has recently been reinvestigated in experimental animal studies and in pilot studies in patients with acute myocardial infarction (see Reference 5 for a review). One of the most promising characteristics of this bacterial protein is its remarkable fibrin specificity; pharmacological doses do not produce fibrinogen breakdown in humans.^{6 7}

Fibrin specificity offers several theoretical advantages. First, systemic plasminogen activation and the ensuing "plasminogen steal" phenomenon are avoided, which ensures ongoing fibrinolysis because the clot is not depleted in plasminogen.^{8 9} Second, the absence of systemic hemostatic breakdown (the so-called lytic state) may reduce the incidence of hemorrhagic complications. Third, systemic plasminemia is believed to account at least in part for the paradoxical procoagulant effects of the currently used plasminogen activators.¹⁰ Thus, avoiding conversion of circulating plasminogen to plasmin may reinforce the net thrombolytic effect, potentiate recanalization, and decrease the frequency of reocclusion. In summary, fibrin-specific plasminogen activation might produce more efficient thrombolysis while reducing the bleeding risk.

The present pilot study was undertaken to explore whether recombinant staphylokinase (STAR) can induce efficacious and safe recanalization in patients with PAO.

	Methods

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Patients
Patients were studied after giving informed consent, and the protocol was approved by the Human Studies Committee of the University of Leuven. The following criteria were applied for inclusion: angiographically documented and penetrable thrombotic or embolic occlusion of a peripheral artery or bypass graft of <120 days' duration as assessed by clinical history, physical examination, or previous angiography. Exclusion criteria included limb-threatening ischemia requiring immediate surgery; major internal bleeding or ischemic stroke within the previous 6 months; previous intracranial or intraspinal bleeding and/or surgery; major operation, organ biopsy, or trauma within the last 21 days; severe uncontrollable hypertension (ie, systolic pressure 180 mm Hg or diastolic pressure 100 mm Hg despite adequate treatment); severe concomitant illness, including advanced hepatic or renal insufficiency, malignancy, or hematologic disorders; pregnancy or menstruation; recent puncture of a noncompressible vessel; and previous therapy with STAR.

Products
STAR, produced and purified as described elsewhere,⁷ was administered intra-arterially through an angiographic catheter positioned in the proximal end of the thrombus as a 1-mg bolus followed by a continuous infusion of 0.5 mg/h in the first 20 patients (patients 1 through 20; group 1) or as a 2-mg bolus followed by an infusion of 1 mg/h in 10 subsequent patients (patients 21 through 30; group 2).

Conjunctive intra-arterial heparin (Novo Nordisk) was routinely given at a rate of 1000 U/h. At the end of the angiographic procedure, an intravenous heparin infusion was started for at least 24 hours at an initial rate of 1000 U/h, which was subsequently adjusted to keep the activated partial thromboplastin time (aPTT) within therapeutic range (at least 1.5 times control). Maintenance therapy consisted of aspirin or oral anticoagulation at the discretion of the attending physician.

Procedure
The patency status of the occluded peripheral artery or bypass graft was serially evaluated before, at least every 4 hours during, and at the end of the STAR infusion. The angiographic patency status of the target vessel at the end of the STAR infusion constituted the main study end point. STAR administration was terminated under the following conditions: when adequate vessel patency was achieved, when complications required its cessation, or when two consecutive angiograms failed to demonstrate progression of clot lysis. Recanalization was defined as clot lysis sufficient to restore brisk anterograde flow throughout the previously occluded segment.

Complementary intravascular procedures, such as percutaneous transluminal angioplasty (PTA), were allowed once the investigators judged that the thrombus was sufficiently lysed or that no further thrombolysis was to be expected.

Blood pressure and heart rate were monitored before, during, and after STAR infusion. Blood samples were collected before, at the end of, and 6 hours after the angiographic procedure. Measurements included peripheral blood count, prothrombin time (PT), aPTT, fibrinogen, ₂-antiplasmin, plasminogen, and biochemical hepatic and renal function tests. Anti-STAR IgG and STAR-neutralizing activity were serially determined as described elsewhere¹¹ on blood samples drawn during hospitalization and after discharge. Template (Simplate II, Organon Teknika) bleeding time was measured before and after the angiographic procedure by the same investigator.

Clinical follow-up focused on recurrence and on such adverse events as allergic reactions and major bleeding (ie, need for blood transfusion or surgical control, drop of hematocrit of >10%, or intracranial bleeding).

Statistical Analysis
Values are expressed as mean±SEM if distributed normally in the population or as median and range. One-way ANOVA was used to compare data before and after STAR therapy and to contrast both dosages (groups 1 and 2).

	Results

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Patient Characteristics
Thirty patients (22 men and 8 women, 64±2.3 years of age) with angiographically documented PAO with a mean estimated duration of 21±5.5 days and a length of 8.1±1.1 cm were studied. Table 1 lists the relevant baseline characteristics of the individual patients, which were comparable for groups 1 and 2. The majority of PAO were at the femoropopliteal level. Eight patients presented with incapacitating claudication, 7 with chronic ischemic rest pain or gangrene, and 8 with subacute and 7 with acute ischemia. Two graft and 2 stent occlusions were included.

View this table: [in this window] [in a new window]   Table 1. Patient Characteristics

Treatment and Outcome
Tables 2 and 3 summarize the individual results of treatment and outcome. Intra-arterial STAR infusion at a mean dose of 7.0±0.7 mg and a duration of 8.7±1.0 hours induced complete recanalization in 25 patients, partial recanalization in 2 patients (reduction of the length of the occluded segment from 10 to 1 cm [patient 14] and from 12 to 6 cm [patient 17]), and no visible clot lysis in 3 patients with very poor distal runoff (patients 3, 19, and 22). Patient 3 presented with a chronic obstruction of a superficial femoral artery, and patients 19 and 22 presented with an obstruction of all infrapopliteal arteries. Poor distal runoff and long duration and distal localization of obstruction are known to predict a poor response to thrombolytic therapy.²

View this table: [in this window] [in a new window]   Table 2. Group 1 Treatment and Outcome

View this table: [in this window] [in a new window]   Table 3. Group 2 Treatment and Outcome

The high-dosage scheme (group 2, Table 3) resulted in a borderline statistically significant higher mean total dose of STAR administered in comparison with the low-dosage scheme (group 1, Table 2), 9.0±1.5 and 6.0±0.6 mg of STAR, respectively (P=.03), without significant shortening of the mean duration of STAR infusion, 7.0±1.5 hours and 9.6±1.4 hours for groups 2 and 1, respectively (P=.26). This may be due in part to continuation of STAR infusion because of distal embolization after endovascular procedures in two patients (patients 28 and 29) in the high-dosage group; in the low-dosage group, this complication was treated by either percutaneous aspiration (patient 10) or surgical embolectomy (patient 18). In the high-dosage group, only 1 of the 10 patients required STAR administration for more than 12 hours compared with 7 of the 20 patients in the low -dosage group.

Continuation of STAR administration successfully resolved distal embolization that occurred during thrombolytic infusion. Complementary endovascular procedures (mainly PTA) were performed in 22 and complementary surgery in 6 patients. Ultimately, after these combined procedures, limb viability was restored in all but 2 patients (patients 19 and 22) without clot lysis; these 2 patients underwent major amputation. Thrombosis reoccurred after the end of the angiographic procedure in 3 patients (patient 10 at 1 and 2 months, patient 26 at day 2, and patient 30 at days 1 and 3). These reocclusions were resistant to standard intra-arterial alteplase treatment (3 mg/h) in 2 patients and were treated surgically.

In most instances, bleeding complications were absent or limited to mild to moderate hematoma formation at the angiographic puncture site. However, two major hemorrhages occurred, one in each dosage group. An 86-year-old woman (patient 14) with arterial hypertension, moderate chronic renal failure, and severe ischemic rest pain that was unresponsive to standard analgetics and not amenable to vascular reconstructive surgery developed a hemorrhagic stroke within minutes after cessation of intra-arterial infusion of STAR and heparin, despite antihypertensive therapy before treatment, and died 2 days later. An 81-year-old woman (patient 24) needed intravenous fluid resuscitation and blood and plasma transfusion to counteract hypovolemic shock caused by a large hematoma at the angiographic puncture site.

A 79-year-old man (patient 26) who suffered an ischemic stroke 9 years before study entry experienced a transient worsening of neurological impairment on an ischemic basis. This patient also developed hemoculture-negative pyrexia 24 hours after STAR administration and was treated with antibiotics. With the possible exception of this event, no allergic reactions were noted.

Hematologic and Coagulation Parameters
A borderline statistically significant decline of mean hemoglobin concentration (from 14.4±0.3 to 13.4±0.3 g/dL, P=.03) occurred during the angiographic procedure. White blood cell and platelet count, renal, and hepatic function tests were not influenced by STARtherapy (data not shown). Circulating fibrinogen, plasminogen, and ₂-antiplasmin levels remained unchanged during STAR therapy; residual levels were 100%, 102%, and 99%, respectively (Table 4), reflecting absolute fibrin specificity of this agent at the dosages used. Substantial in vivo fibrin digestion occurred as evidenced by marked elevation of D-dimer after STAR therapy (from 440±84 to 10 000±1600 ng/mL, P<.0005; Table 4). The prolongation of the template bleeding time (from 360±28 seconds before to 410±27 seconds after the angiographic procedure) was not significant (P=.2). Intra-arterial STAR and heparin therapy significantly prolonged PT and aPTT (Table 4).

View this table: [in this window] [in a new window]   Table 4. Hematologic and Coagulation Parameters Before and After STAR Administration

Immunogenicity of STAR
Antibody-related STAR-neutralizing activity (Table 5) and anti-STAR IgG (Table 6) were low at baseline and during the first week after STAR treatment but increased markedly from the second week on and remained elevated for at least several months.

View this table: [in this window] [in a new window]   Table 5. STAR Neutralizing Activity

View this table: [in this window] [in a new window]   Table 6. Anti-STAR IgG

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
Catheter-directed intra-arterial infusion of STAR induced complete recanalization of an occluded peripheral artery or bypass graft in 25 of 30 patients (83%) within a mean of 8.7 hours (range, 2 to 22 hours). The dosage scheme used in the first 20 patients (1-mg bolus followed by a continuous intra-arterial infusion of 0.5 mg/h STAR) was estimated from previous experience with STAR in animal models and in patients with evolving myocardial infarction. Doubling the dose in the next 10 patients (to a 2-mg bolus followed by an infusion of 1 mg/h STAR) did not reduce the mean infusion time but eliminated lengthy (>12 hour) STAR administration in all but 1 patient. The overall mean duration of the continuous intra-arterial STAR infusion compares favorably with pooled data from reported studies on conventional plasminogen activators^{4 11} : 40 hours with streptokinase, 30 hours with urokinase, and 22 and 4.7 hours with low (0.5 to 1.0 mg/h) and high (0.1 mg · kg^-1 · h^-1) doses of recombinant tissue-type plasminogen activator (rTPA), respectively.

Comparison of the results of the present pilot trial, which focused on angiographic recanalization, with historical data, however, is hampered by the lack of uniformity in the reported series and by the paucity of large randomized studies. Moreover, our study population was deliberately heterogeneous, encompassing occlusion of grafts and native arteries—of thrombotic and of embolic origins, upper and lower extremities, and up to 120 days of duration—representing the vast spectrum of clinical and anatomic presentation of PAO. Therapeutic success rates with conventional thrombolytic agents range between 25% and 85% for acute limb ischemia and between 60% and 90% for chronic arterial occlusions, with a major complication rate (mainly bleeding) of 7% to 19% and an early recurrence rate of 10%.^{1 2 3 4 12} Three patients in the present series suffered from recurrence of thrombosis in the first month after STAR therapy.

Hemorrhage remains the most troublesome complication of thrombolytic therapy. In a recent trial evaluating surgery versus thrombolysis with urokinase or rTPA for ischemia of the lower extremity (the STILE Trial),¹³ fibrinogen depletion emerged as the strongest predictor of bleeding complications in the thrombolysis group. The absence of systemic fibrinogen breakdown and ₂-antiplasmin depletion in the present trial, as in studies with STAR in acute myocardial infarction,^{6 7} underscores the fibrin specificity of STAR in the dosages used as opposed to currently used thrombolytic agents.^{14 15} Nevertheless, two major bleeding complications occurred in this study: one hemorrhagic shock necessitating blood and plasma transfusions and one fatal hemorrhagic stroke.

Hemorrhagic side effects may constitute an inherent risk of thrombolytic therapy. Most likely, plasminogen activators, whether fibrin-specific or not, cannot discriminate between hemostatic plugs and occlusive thrombi. In addition, conjunctive heparin treatment and circulating fibrin degradation products may promote bleeding. Further studies are needed to clarify whether fibrin-specific fibrinolytic agents attenuate the bleeding risk compared with agents with relative or absent fibrin specificity. Meanwhile, and in the absence of controlled studies in patients with PAO, the experience gathered from treatment of patients with myocardial infarction, suggesting that systemic hypertension, old age, and female sex constitute risk factors for intracerebral bleeding during thrombolysis,¹⁶ may guide patient selection. These factors were all present in the 1 patient with hemorrhagic stroke in the present study.

STAR, although of bacterial origin, did not produce hypotensive episodes or allergic reactions (with the possible exception of pyrexia at 24 hours in 1 patient). However, most patients, like those treated with STAR for myocardial infarction,^{6 7 17} produced neutralizing antibodies against STAR after a lag phase of more than 1 week that remained elevated for several months. This demonstration of immunogenicity argues against repeated therapy, primarily in view of the anticipated risk of partial or complete therapeutic refractoriness. With STAR, the mean baseline neutralizing activity in plasma was significantly lower and the lag phase of antibody induction was longer than observed with streptokinase,^{17 18} suggesting that, in contrast to streptokinase, STAR elicits a primary immune response, which makes allergic reactions during the first treatment unlikely. Engineering variants with reduced antigenic but retained thrombolytic potential and clot selectivity may be clinically useful.

In summary, the present study reports the first experience with catheter-directed infusion of STAR in patients with PAO. Although the efficacy and speed of recanalization are encouraging, the limited size and the nonrandomized design of the present study preclude definitive conclusions. STAR is remarkably fibrin-specific, but life-threatening hemorrhage may still occur, underscoring the importance of careful patient selection. Additional studies are needed to define the optimal dose and mode of administration (continuous versus pulsed dose) and the efficacy and safety of STAR relative to other thrombolytic agents in the treatment of patients with PAO.

	Acknowledgments

 
Dr Vanderschueren is a research assistant of the National Fund for Scientific Research (Belgium). Dr Vermylen holds the Dr Jean Choay Chair in Haemostasis Research at the University of Leuven, Belgium.

Received February 9, 1995; revision received March 27, 1995; accepted April 1, 1995.

	References

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