Current value of thrombolytic therapy for acute peripheral arterial occlusion
(Portuguese PDF version)

Fabio H. Rossi1, Nilo M. Izukawa2, Lannes A. V. Oliveira1, Domingos G. Silva1

1. Assistant Surgeon, Division of Vascular Surgery, Instituto Dante Pazzanese de Cardiologia - São Paulo.
2. Chief Surgeon, Division of Vascular Surgery, Instituto Dante Pazzanese de Cardiologia - São Paulo.

Correspondence:
Fabio H. Rossi
Instituto Dante Pazzanese de Cardiologia - São Paulo
Alameda Jurupis, 900/103/IV
CEP 04088-002 - São Paulo - SP
E-mail: vascular369@hotmail.com


 

ABSTRACT

Acute arterial occlusion of the lower limbs can be defined as a sudden deficiency of tissue blood perfusion, which leads to the risk of loss of limb functional capacity. Early revascularization of the affected arterial territory is the most important therapeutic principle. Today, in addition to surgical revascularization, thrombolytic infusion has been used with good results in some studies. In this article, we attempt to demonstrate the main concepts and the current value of thrombolytic therapy through the review of the most important studies that employed thrombolytic agents to treat acute arterial occlusion of the lower limbs.

Key words: thrombolytic therapy, lower extremity, arteries.
Palavras-chave: terapia fibrinolítica, membros inferiores, artérias.

J Vasc Br 2003;2(2):129-40


 

Acute lower extremity arterial occlusion can be defined as a sudden deficiency of tissue blood perfusion leading to risk of loss of limb functional capacity. Thromboembolectomy remains the treatment of choice for this condition. Recently, however, thrombolysis has been proposed as a less invasive alternative that may even replace surgery in certain specific cases.

The conventional surgical approach is well defined, so this review focuses on thrombolytic therapy, which could be better known and applied in specific situations.

PATHOPHYSIOLOGY OF ACUTE ARTERIAL OCCLUSION

The symptoms of acute arterial occlusion depend on the location of the occlusion, the speed of onset of the primary and secondary (collateral network) thrombosis, the number and level of previous development of the collateral vessels, the degree of injury to the microcirculation and the etiology of the occlusion (thrombosis, embolism).1 The majority of patients affected suffer from comorbidities that may lead to serious local or systemic complications. Atherosclerotic coronary disease and cardiac or renal insufficiency are examples of conditions that may interfere in the clinical progress of these patients.

On rare occasions, severe ischemia may occur when there are gradual segmental occlusions of an arterial segment. In chronic occlusion of the superficial femoral artery, there is frequently only intermittent claudication due to arterial flow in the collateral network between the deep femoral artery and the popliteal artery (genicular arteries). In the case of associated occlusion of the popliteal artery, however, there may be rest pain and ischemic tissue injury.

In embolism of cardiac origin, the occlusion tends to occur at the bifurcation of the common femoral artery, abruptly interrupting the blood flow to the deep and superficial femoral arteries. In this case, the collateral system is practically absent and the limb becomes acutely ischemic, with pain, paleness, paresthesia, coolness and, finally, paralysis.

DIAGNOSIS

Arterial occlusion is traditionally classified as acute or subacute.2,3,4 Acute arterial occlusion is characterized by abrupt onset, well defined by the patient, with less than 14 days of clinical development. Subacute arterial occlusion is insidious, with onset of symptoms poorly defined by the patient, and frequently with more than 14 days of clinical development.

Therapeutic results and morbidity-mortality are related to the severity of the symptoms present at the moment of surgery.2,3 Taking this association into account, Rutherford et al. published a classification of ischemia severity with the aim of universalizing and comparing published results4 (Table 1).

click hereTable 1 - SVS/ISCVS Clinical categories of acute lower limb ischemia4

Findings Doppler Signal
Category Description Sensory Loss Muscle Weakness Arterial Venous
I. Viable Not immediately threatened None None Audible Audible
II. Threatened
a. Marginal Salvageable if promptly treated Minimal (toe) or none None Often inaudible Audible
b. Immediately Salvageable with immediate revascularization More than toes, associated with rest pain Mild, moderate Usually inaudible Audible
III. Irreversible Major tissue loss or permanent nerve damage inevitable Profound, anesthetic Profound, paralysis (rigor) Inaudible Inaudible

 

Most authors recommend early arteriography followed by surgery or thrombolysis for groups I and IIa, immediate surgery with intraoperative arteriography for group IIb and amputation for group III.

TREATMENT METHODS

The main current therapeutic options to restore pulsatile arterial blood flow are the various forms of vascular restoration (thromboembolectomy, endarterectomy, autograft, allograft and angioplasty) and thrombolysis.

Thromboembolectomy

Balloon catheter thromboembolectomy was introduced by Fogarty et al.5 in 1963 and became the most widely used surgical technique in acute lower extremity ischemia. Its most precise and accepted usage is in cases of arterial embolism which does not occur in chronic and subacute arterial thrombosis, where many authors prefer to perform an arterial graft.6-9

Blaisdell et al. have shown that thromboembolectomy is not a totally innocuous method, even in cases of embolism. They found a high mortality rate (25%), but lower percentages (7.5%) when the initial treatment involved systemic heparinization and clinical stabilization, followed by revascularization surgery for viable limbs and amputation for those whose condition worsens.10 Even though this clinical-observational treatment has been associated with lower mortality rates, its high amputation rate (33%) has not been well accepted by the vascular community.

Other authors have also found high mortality rates associated with thromboembolectomy3,11 (Table 2).

click hereTable 2 - Morbidity-mortality in thromboembolectomy for acute lower extremity ischemia

Author Year Etiology Amputation Mortality
Blaisdell10 1978 Embolism
Thrombosis
30% 25%
Jivegard3 1986 Embolism
Thrombosis
16% 18%
Yeager11 1990 Graft thrombosis 6% 23%

Thrombolysis

The use of thrombolytic agents in acute lower extremity arterial occlusion (< 14 days) has shown good results even in those patients without complete revascularization, appearing to reduce the complexity of the surgery required for limb salvage.

Plasminogen activators such as streptokinase and recombinant tissue plasminogen activator (rt-PA) have been administered with promising results.12-79 They can be administered via catheter to lyse primary and secondary thrombi in arterial trunks and branches (thus lowering resistance to blood flow) and in the arterial territory to be revascularized, improving prognosis for subsequent revascularization in the case of angioplasty or surgical revascularization of the ischemic arterial territory.

At present, however, the time required for lysing and thrombosis recurrence are the main factors limiting the use of this technique. Depending on the occlusion site, the number of arterial segments involved and the thrombolytic agent infusion location, the therapeutic success rate may vary between 50 and 88%, and the reocclusion rate between 20 and 50%.60,69

Tissue plasminogen activators (t-PA) and related agents

The common outcome in thrombus formation is the enzymatic breaking of the fibrinogen molecule into fibrin and thrombin. The fibrin network traps platelets and hemocytes, causing the formation of the thrombus. Enzymatic lysing of the fibrin network within the thrombus occurs through the formation of plasmin by the tissue plasminogen activator (t-PA). Plasmin, a natural polypeptide chain secreted by the endothelium, is the main factor responsible for the endogenous fibrinolytic process. Besides being responsible for breaking the fibrin structure, plasmin can convert t-PA into a double molecule.40,41 The most widely used activator agent is currently alteplase/actilyse (Activase; Genentech, San Francisco, California, USA), a single chain protease obtained through recombinant genetic techniques.

Three other fibrinolytic agents are in use in the United States: streptokinase (Streptase; Astra Pharmaceuticals, Wayne, Philadelphia), anistreplase (Eminase; Roberts Pharmaceutical Corporation, Eatontown, New Jersey) and reteplase (Retavase; Centocor, Inc, Malvern, Philadelphia).

Streptokinase is a proteolytic enzyme produced by Β-hemolytic streptococcus and was the first fibrinolytic agent to be used, by Charles Dotter in 1974.26 Despite its effectiveness in thrombus lysing, it has the disadvantage of being antigenic: circulating antibodies after streptococcal infection or previous administration may cause allergic reactions or reduce the bioavailability of the drug. Comparative studies have shown that streptokinase is inferior in its lower extremity thrombosis lytic potential to urokinase (the sale of which has been suspended) and to recombinant activators. These studies have also shown that recombinant activators result in faster lysing than streptokinase or urokinase.43

Anistreplase is an inactive derivative composed of streptokinase and lys-plasminogen, approved for use in acute myocardial infarction. It has antigenic potential related to Β-hemolytic streptococcus and no studies have been published on its use in lower extremity arterial occlusion.

Reteplase is a deletion mutant variant of rt-PA produced using recombinant technology. It is currently approved for use in acute myocardial ischemia and is under clinical evaluation for acute lower extremity arterial occlusion. No results have yet been published.

Urokinase was widely used until 1999 when the US FDA suspended its sale.38,39 It is produced through the culture of neonatal human renal cells. Its principal advantages are low immunogenicity and reduced risk of bleeding compared to streptokinase. The drug has recently been genetically sequenced and its recombinant form is being researched in clinical studies. It will probably soon be approved for sale in North America.

Recombinant tissue plasminogen activator (rt-PA)

Recombinant tissue plasminogen activator (rt-PA) was initially approved by the FDA in 1987 for use in acute myocardial infarction, acute pulmonary embolism and acute stroke. Use of rt-PA for acute lower extremity occlusion is a technique still under study. The clinical criteria for indication, infusion concentrations, method of administration, management of complications and other factors related to thrombolytic treatment are not yet well defined (Table 3). Some studies have, nonetheless, shown the effectiveness and safety of the use of rt-PA in acute lower extremity occlusion.32,44

click hereTable 3 - Exclusion criteria for rt-PA treatment

Events
  • Recent bleeding

  • Proximal arterial embolization

  • Severe hypertension

  • Hemorrhagic diathesis or presence of risk factor for bleeding (e.g.
  • peptic ulcer)
  • Hemorrhagic stroke in previous two months

  • Recent major surgery (< 10 days)

  • Recent polytrauma (< 2 weeks)

  • Graft infection

  • Infectious endocarditis

  • Impossibility of passing guide wire through occlusion

  • Impossibility of continuing treatment for more than 24 hours (critical ischemia)

  • Irreversible ischemic lesion

  • Arterial thrombosis with severe ischemia and distal wall favorable for revascularization

  • Pregnancy

  • Absence of informed medical consent
  • Yusuf et al., 199544; Berridge et al., 199132

    Clinical experience with thrombolytic agents

    The introduction of new techniques should ideally be preceded by comparisons with those that have well-known long-term effectiveness and results. A number of studies have been performed on thrombolysis in acute lower extremity arterial occlusion in the attempt to demonstrate its benefits.

    The use of thrombolytic agents in acute arterial occlusion only began in the 1950s. Tillet and Garner discovered streptokinase in the 1930s,12 but its antigenicity and impurity limited its use to extravascular applications, such as the dissolution of thoracic hematomas.75 Despite Tillet's initial experiment, carried out on 11 volunteers,76 Cliffton and Grossi were the first to publish a study on the use of intravascular streptokinase for thrombolysis.77 Sherry et al. studied the clinical applicability of the drug,78 which was approved for use in 1977.13,79 Since then, a number of studies have been performed using different concentrations and infusion routes.14-24

    Intravenous administration of high streptokinase concentrations (100,000 U/h) is related to elevated bleeding risk (15 to 35%) and death (5 to 10%).17.Graor and Dotter were the first to use low doses administered via catheter.25,26 In 1983, Berni et al.17 published a prospective study showing their initial experience with use of low doses of streptokinase (5,000 U/h) in 16 patients with acute arterial thrombosis. Treatment was successful in 75% of cases and the authors observed no influence of etiology (thrombosis or embolism), ischemic time (maximum of 14 days; 75% < three days) or occlusion location (native artery, autograft, allograft) on the results. A major limitation of the technique was the time necessary for complete thrombolysis (37.5 ± 17.5 hours).

    Despite positioning of the catheter immediately proximal to the occlusion, five patients experienced hypofibrinogenemia (100 mg/dl), with fewer bleeding complications in four of these. The concomitant use of heparin (300 to 500 U/h) increased risk of bleeding with no increase of thrombolytic effect. No case of streptokinase intolerance or allergic reaction was found in this study. The authors conclude that streptokinase treatment should be used selectively, depending on the degree of ischemia, occlusion etiology and clinical status of the patient. They also suggested that an initial bolus infusion of 50,000 U followed by a maintenance dose of 5,000 U/h may reduce the time required to lyse the thrombus without increasing the bleeding risk, but this has not been confirmed by posterior studies.

    Kakkasseril et al.18 later used a dose of 5,000 to 10,000 U/h without heparin, obtaining therapeutic success in 43% of 35 patients with acute lower extremity ischemia (embolism/thrombosis: 14 patients; graft thrombosis: 21 patients). Streptokinase gave better results in native arteries (50%), in high-flow proximal arterial segments and in venous autografts. The success rate was 19% in grafts with prosthesis. Distal embolization was observed in four patients and limb loss in two patients. Bleeding complications were common (13 patients), indicating the need for rigorous monitoring of blood coagulation factors. The authors concluded that thrombolysis was not a good therapeutic alternative when the option of surgical reconstruction was not contraindicated by poor clinical conditions.

    Studies began in 1990 to compare intravenous and arterial thrombolysis and surgery. The first randomized studies involving use of fibrinolytic agents were published in 1991. The first study compared surgery and rt-PA thrombolysis in a small group of patients with acute ischemia (< 14 days). The limb salvage rate was 87% for surgery and 90% for thrombolysis.31 Berridge et al. studied the effectiveness of arterial infusion of streptokinase or rt-PA compared to intravenous infusion of rt-PA.32 In this prospective study, 66 patients were randomized in three groups. All presented with critical ischemia of less than 30 days. The three groups were treated according to the following regimes: 1) intra-arterial streptokinase: 5,000 U/h; 2) intra-arterial rt-PA: 0.5 mg/h; 3) intravenous rt-PA: 1 to 10 mg/h to a maximum of 100 mg. Success as determined by arteriography, clinical improvement and ankle brachial pressure index (ABPI) were better in the groups receiving intra-arterial streptokinase and rt-PA (Table 4). The number of patients experiencing bleeding was non-significantly higher in the group receiving intravenous infusion.

    click hereTable 4 - Results of intra-arterial versus intravenous thrombolysis32

    streptokinase IA rt-PA IA rt-PA IV
    Arteriographic success 80% 100% 45%
    Clinical improvement 80% 100%* 55%
    Increase in ABPI 0.24 0.57* 0.18
    Asymptomatic at 30 days post-op. 60% 80% 45%
    IA: intra-arterial, IV: intravenous
    rt-PA: recombinant tissue plasminogen activator, *P < 0.01


    This study thus showed that intra-arterial rt-PA was more effective and safer than intravenous administration and suggested that rt-PA was more effective than streptokinase.

    The second study to be published compared the speed of fibrinolysis with urokinase and rt-PA in patients with lower extremity ischemia of less than 90 days.33 In this prospective study, 32 patients were randomized in two groups. One received rt-PA in an initial dose of 10 mg, followed by 5 mg/h for 24 hours; the second received urokinase in an initial dose of 60,000 U, followed by 240,000 U/h for two hours, 120,000 U/h for two hours and 60,000 U/h for up to 20 hours. The outcome evaluated was 95% dissolution of the thrombus, as determined by arteriography (Table 5).

    click hereTable 5 - Speed of thrombolysis: rt-PA versus urokinase33

    Time (hours) 95% fibrinolysis
    rt-PA (n = 16) urokinase (n = 16) P
    4 25% 0% 0.10
    8 44% 6% 0.04
    16 44% 19% 0.25
    24 50% 38% 0.72

    The best result was found in the rt-PA group at eight hours of infusion (P = 0.04). There was no significant difference between the two groups at 24 hours. At these dosages, the most rapid lysing occurred in the rt-PA group. This group also experienced greater fibrinogen reduction at 24 hours of infusion.

    In 1994 Ouriel et al. performed a classic study on 114 patients with severe acute lower extremity ischemia. Patients with arterial thrombosis and embolism and occlusion of previous grafts were included. They were randomized for surgical revascularization or thrombolytic treatment with urokinase.34 All patients received aspirin; heparin was not used in this study. The urokinase dosage used was 4,000 U/min for two hours, 2,000 U/min for two hours and 1,000 U/min for up to 44 hours. Lower rates of cardiopulmonary complications were found with urokinase treatment. In one year of follow-up, mortality was significantly lower in the thrombolysis group (16% versus 42%). There was no difference in the rate of limb salvage, which was 82% in both groups (Table 6).

    click hereTable 6 - Effectiveness and safety of urokinase thrombolysis versus surgery in lower extremity ischemia34

    Thrombolysis Surgery P
    Limb salvage 82% 82% ns
    Hemorrhage 11%* 2% 0.06
    Cardiopulmonary complications 16% 49% 0.01
    Mortality (1 year) 16% 42% 0.01
    Cost $15,672 $12,253 0.02
    *2% intracranial hemorrhage

    The results were criticized because of the inclusion of patients with severe ischemia (average ABPI of 0.4) of less than seven days. In addition, the majority of patients receiving thrombolytic treatment also received complementary surgery. The difference in mortality at one year was probably due to the larger number of cardiopulmonary complications in the surgery group.

    The randomized, prospective, multicenter Surgery or Thrombolysis for Ischemia of the Lower Extremity study (STILE)35 compared surgery with intra-arterial infusion of rt-PA and urokinase in patients with non-embolic lower extremity ischemia of less than three months or occlusion of previous graft. The hypothesis was that thrombolysis offered advantages over isolated surgery in these patients. The outcome studied was a composite of mortality, amputation, recurrent ischemia and morbidity (hemorrhage, serious postoperative complications, renal failure, anesthetic complications, vascular complications and surgical wound complications).

    The thrombolytic agent doses were as follows: urokinase: initial dose of 250,000 U followed by 4,000 U/h for four hours and 2,000 U/h up to 32 hours; rt-PA: 0.05 mg/kg/h. The method was considered to have failed when the catheter could not be introduced into the thrombus. This study, designed to include 1,000 patients, was interrupted when 393 patients had been evaluated, as the statistical analysis indicated a significant difference between the two groups in relation to the composition of clinical events, strongly in favor of the surgery group.

    The average ischemic time was 50.3 days and 43% of patients were over 70 years of age. Catheter positioning failed in 28% of patients. This fact later generated much criticism of the study, as these attempts were considered as treatment failure.

    No difference was observed in terms of effectiveness and safety of urokinase and rt-PA, but rt-PA was found to promote faster lysing (P < 0.001). Patients randomized for surgery experienced lower rates of adverse clinical events and maintenance of ischemia (Table 7).

    click hereTable 7 - Comparison of surgery and thrombolysis (urokinase and rt-PA) in lower extremity ischemia: adverse clinical effects and their components35

    Surgery Thrombolysis P
    Adverse clinical events 36.1% 61.7% < 0.001
    Mortality 4.9% 4.0% 0.693
    Amputation 6.3% 5.2% 0.685
    Ischemia at 30 days 25.7% 54% < 0.001
    Major morbidity 16% 20.6% 0.266
    Hemorrhage 0.7% 5.6% * 0.014
    *1.2% intracranial hemorrhage

    The authors established a surgical strategy for each patient after analysis of clinical status and complementary exams and before randomization of the patients in surgery and thrombolysis groups. Of the patients randomized for surgery, 94% received the surgical treatment initially proposed. Of the patients randomized for thrombolysis, 44% did not receive the planned complementary surgery (P < 0.001). This means a reduction of 56% in the magnitude of the treatment proposed for patients receiving thrombolytic treatment. Therapeutic results at 30 days and at six months of follow-up were grouped according to time in ischemia (Table 8).

    click hereTable 8 - STILE study: Mortality and amputation according to time in ischemia35

    0-14 days > 14 days

    Surgery Thrombolysis P Surgery Thrombolysis P
    30 days

    Death 5.1% 4.3% 0.810 4.2% 2.9% 0.617
    Amputation 17.9% 5.7% 0.061 2.1% 5.3% 0.218
    Ischemia 38.5% 48.6% 0.328 20.8% 58.2% < 0.001
    6 months

    Death 10.0% 5.6% 0.45 7.9% 6.9% 0.81
    Amputation 30.0% 11.1% 0.02 3.0% 12.1% 0.01

    A larger number of bleeding complications were found in thrombolysis patients, who also experienced lower fibrinogen levels (P < 0.01). This study was designed to include the largest possible number of patients with non-embolic lower extremity ischemia. Most of the investigators, who were not surgeons, proposed that initial thrombolytic treatment would benefit all of the patients; with the results obtained, the authors concluded that surgery continued to be the treatment of choice for chronic ischemia patients. Acute ischemia patients (< 14 days) receiving thrombolytic treatment presented lower amputation rates and shorter hospitalization times. No difference in effectiveness was found between urokinase and rt-PA. According to this study, the best treatment plan is surgical revascularization for chronic ischemia and thrombolytic treatment with complementary surgery, where necessary, for acute ischemia.

    In response to the criticisms cited above and after retrospective analysis of the results, the authors later published a summary of their principal findings (Table 9).

    click hereTable 9 - Summary of STILE study results34,35

    Group Time Result Surgery
    %
    Thrombolysis
    %
    P
    All patients 1 month Clinical
    composition*
    36.1 61.7 < 0.001
    All patients 1 month Maintenance
    of ischemia
    25.7 54.0 < 0.001
    Any occlusion
    < 14 days
    6 months Mortality
    Amputation
    37.5 15.3 0.01
    Any occlusion
    > 14 days
    6 months Mortality
    Amputation
    9.9 17.8 0.08
    Arterial occlusion
    < 14 days
    12 months Mortality 18.8 6.3 ns
    Arterial occlusion
    < 14 days
    12 months Major
    amputation
    0 6.3 ns
    Arterial occlusion
    < or > 14 days
    1 month Maintenance
    of ischemia
    23.5 54.7 < 0.001
    Arterial occlusion
    < or > 14 days
    1 month Major
    amputation
    2.0 4.1 0.364
    *morbidity, maintenance of ischemia, complications

    A further randomized multicenter study was performed at the same time, with the aim of observing the treatment of acute lower extremity ischemia (thrombosis, embolism, graft occlusion). The Thrombolysis or Peripheral Artery Surgery study (TOPAS) compared urokinase thrombolysis and revascularization surgery.37

    The study was carried out in two phases: the first sought to compare surgery and three dosages of urokinase (2,000 U/h, 4,000 U/h or 6,000 U/h for four hours, followed in all cases by 2,000 U/h for a maximum of 48 hours) in patients with ischemia of less than 14 days. Factors studied were degree of recanalization and thrombus lysing, as verified by arteriography after four hours of fibrinolytic infusion. In the second phase, the object of study was the best thrombolytic dosage compared to surgical treatment in the same patient sample. Mortality and amputation rates were studied in the thrombolysis and surgery groups.

    No difference was observed in arterial recanalization between the three dosages used. A small difference was found in the hospitalization time and mortality at 30 days, favoring the 4,000 U/h dosage (Table 10).

    click hereTable 10 - TOPAS: Survival in lower extremity ischemia - urokinase versus surgery

    Treatment Group

    2,000 U 4,000 U 6,000 U Surgery
    In-hospital mortality 7% 0% 7% 7%
    Survival at 30 days 96% 100% 96% 95%
    Survival at 1 year 83% 86% 91% 84%

    The multivariate analysis between the various dosages favored the group receiving 4,000 U of urokinase. In 46% of this group, there was major reduction in the magnitude of the surgery programmed prior to thrombolysis. As in the STILE study, there was a reduction in the number of operations and in their complexity in acute ischemia patients randomized for thrombolysis.

    With these results it may be possible to define which patients will benefit most from initial thrombolytic treatment. The best form of administration is probably intra-arterial at the thrombus location. This treatment appears to be associated with lower mortality and with higher limb salvage rates. It appears that rt-PA promotes faster lysing than urokinase, although the results are similar at 24 hours of infusion (65% versus 84%). Bleeding risk is associated with falls in fibrinogen levels (1 to 2% - intracerebral hemorrhage). Surgical revascularization is still the best treatment in patients with chronic arterial insufficiency.

    No consensus has been reached regarding the best rt-PA dosage. Doses vary from 0.02 to 0.1 mg/kg/h45-47 and from 0.23 to 10 mg/h.48,49 Only one randomized study has compared the effectiveness of two doses of rt-PA: 0.05 and 0.025 mg/kg/h using multi sidehole catheter.50 Both provided effective revascularization, although the lower dose required 12 hours of infusion for complete lysing, compared to 3.1 hours for the higher dose. The maximum dose should not exceed 100 mg.42 In summary, rt-PA has been shown to be effective in a range of doses. The ideal dose should be based on the clinical characteristics of each patient and the bleeding risk present. Until future studies show the best risk-benefit relationship, low doses (0.25 to 1 mg/h) should be used.

    The intravenous route has been found effective in coronary, pulmonary and cerebral thrombosis, but the thrombus volume in acute myocardial ischemia and stroke is very small in relation to that in acute lower extremity thrombosis. The intravenous route is also associated with higher rates of complication due to the larger volume of thrombolytic agent required for the treatment.51

    The most widely used administration method continues to be that of the single distal opening catheter. It is positioned immediately above the thrombus and gradually repositioned distally using arteriographic monitoring of treatment effectiveness. Current best practice consists of passing a guide wire through the thrombus, over which a multi sidehole catheter is passed, through which the thrombolytic agent is administered continuously.52

    Systemic anticoagulation with heparin is commonly used only after completion of thrombolytic treatment. Concomitant administration of heparin increases risk of bleeding complications and does not appear to increase effectiveness.52

    In studies that used a thrombolytic agent in association with heparin, therapy was successful in 91% of patients, with complication rates between 0 and 17.4%. The dosage and administration to these patients varied widely, from 250 IU/h by intravenous route to 10,000 IU in subcutaneous bolus. Success rate in those patients treated without heparin was 85%, with morbidity between 0 and 14%.53 Only one randomized prospective study has been performed to compare use of rt-PA associated or not with heparin, concluding that there is no benefit from the association.54

    The administration of a continuous dosage of rt-PA (0.5 to 1.0 mg/h) has been found effective in acute peripheral arterial insufficiency. At advanced levels of ischemia (IIa, IIIb), however, in which early revascularization is critical, the administration of a loading dose appears beneficial. Bleeding risk has been associated with reduced fibrinogen levels and increased fibrin degradation products. Infusion of higher concentrations for a shorter period would theoretically lead to fewer bleeding complications.55

    Braithwaite et al. have compared continuous rt-PA infusion (0.5 to 1.0 mg/h) to that preceded by a loading dose (3 x 5 mg for 30 minutes; 3.5 mg for four hours; 0.5 to 1.0 mg/h). The results showed that the loading dose provides important reductions in thrombus lysing time without increasing rates of bleeding complications (P < 0.0001). Average infusion time was reduced by 80%, from 20 to four hours, with 50% of patients presenting complete thrombolysis at four hours of infusion (P < 0.0001). Bleeding rate was comparable between the two groups. 56 Other studies, however, have shown higher bleeding rates and fatal bleeding with administration of loading dose.57-59

    Another form of administration is infusion under pressure, known as the pulse-spray technique.60-64 This approach appears to be associated with reduced infusion time, but is not used routinely because of the risk of thrombus rupture and migration, the need for special infusion pumps and the similarity of results to those under more conventional techniques.65

    Thrombolytic agents in association with platelet glycoprotein IIb/IIIa receptor antagonists

    Thrombus components include platelets and fibrin, with the platelets tending to accumulate especially at the atherosclerotic plaque rupture site. Platelets frequently resist dissociation after lysing of fibrin and are often reactivated by the rupture of the thrombosis-causing adhesion plaque. Platelet aggregation inhibition thus appears to favor definitive lysing of the thrombus.

    Most studies using fibrinolytic agents in acute lower extremity arterial occlusion have used aspirin as the platelet antiaggregant, although the pharmaceutical industry has begun studying the glycoprotein IIb/IIIa receptor activation mechanism for platelet aggregation. The glycoprotein IIb/IIIa receptor antagonist - abciximab (c7E3 Fab: Centocor, Malvern, Philadelphia; Lilly, Indianapolis, Indiana) - has recently been used in patients with acute coronary ischemia undergoing angioplasty.71,72 Two studies are underway (Timi, Gusto) to observe the effectiveness of fibrinolytic agent use in association with abciximab in coronary arteries.

    Gunnar et al.73 have published initial results regarding use of abciximab and urokinase in acute lower extremity arterial occlusion. They used this association in 14 patients and observed good results in 100% of cases, with treatment time varying between 50 minutes and eight hours. The only complication was one distal embolization episode, with no cases of bleeding. Schweizer et al.74 have recently studied the use of abciximab and aspirin in association with rt-PA in patients with acute arterial occlusion. Eighty-four patients were randomized to receive 5 mg/h of intravenous rt-PA and 500 U/h of heparin with acetyl-salicylic acid (500 mg) or with abciximab (loading dose of 0.25 mg/kg of followed by 10 µg/min for 12 hours, heparin reduced to 250 U/h). The authors observed number of post-treatment hospitalizations, reinterventions, amputations up to six months, changes to degree of ischemia, ABPI, claudication at six months and total treatment duration. Concomitant use of abciximab reduced the number of new hospitalizations, reinterventions and amputations in comparison with use of aspirin. Degree of ischemia, ABPI and claudication distance were quite favorable to the abciximab group (P < 0.001).

    Platelet aggregation is involved in arterial thrombosis and its recurrence after thrombolytic treatment. Studies have demonstrated that thrombolytic treatment is associated with platelet activation via the activation of glycoprotein IIb/IIIa surface receptors.80 The association of abciximab with fibrinolytic agents in acute arterial occlusion may lead to improved results. Its use is currently approved in the United States only for patients undergoing coronary angioplasty.

    FINAL COMMENTS

    The results of clinical studies comparing thrombolysis with surgery must be analyzed critically, as they depend on the technical capabilities of those performing the two procedures and on the inclusion and exclusion criteria established for the study. The STILE study has been criticized for its high failure rate in placement of the catheter within the thrombus. The main probable source of bias, however, remains the definition of inclusion and exclusion criteria. The subgroup of clinically unstable patients with acute ischemia (< 14 days) would most benefit from thrombolytic treatment, and their exclusion, as in the case of the TOPAS study, may have resulted in bias against thrombolysis. The inclusion of patients with chronic ischemia, as in the case of the STILE study, may have had the same effect.

    A number of randomized, prospective, multicenter studies have shown that patients with lower extremity ischemia of up to 14 days benefit from thrombolytic treatment in terms of survival, limb salvage, later patency and magnitude of complementary surgery.34,35-37,52,69

    Most studies have not distinguished between ischemic etiologies (thrombosis of native arterial wall or acute arterial embolism). Only one study has examined this difference, comparing therapeutic response to infusion of rt-PA (10 mg) and heparin (3,000 IU) for a period of six hours, to a maximum of four cycles. The results showed better response in arterial embolism than in arterial thrombosis (88% versus 49%; P < 0.001), even after two years of follow-up (82% versus 29%; P < 0.001). Clinical improvement at hospital discharge was also greater for patients with arterial embolism (92% versus 67%).70 Thrombolysis with rt-PA seems to be equally effective in native arterial wall and in arterial, venous and prosthetic grafts.35,66-68 No differences have been found in terms of thrombolytic effectiveness related to occlusion extension or time required for complete lysing.60,68

    At present, the main limiting factors for thrombolytic treatment are the time required for complete lysing of the thrombus and high rethrombosis rates.52 The association of thrombolytic agents with glycoprotein IIb/IIIa receptor antagonists appears to improve the results obtained in this patient group. On the basis of the results obtained in the principal studies performed up to the present, it can be affirmed that future research should concentrate on the use of new thrombolytic agents and treatment strategies, rather than on comparisons between thrombolysis and surgery.

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