European Journal of Vascular & Endovascular Surgery
Volume 31, Issue 6 , Pages 651-660, June 2006

Thrombolysis for Acute Lower Limb Ischaemia—A Prospective, Randomised, Multicentre Study Comparing Two Strategies

  • G. Plate

      Affiliations

    • Department of Surgery, Central Hospital, Helsingborg, Sweden
    • Corresponding Author InformationCorresponding author. Gunnar Plate, MD, PhD, Department of Surgery, Central Hospital, SE-251 87 Helsingborg, Sweden.
    • ,
  • I. Jansson

      Affiliations

    • Department of Surgery, Central Hospital, Eskilstuna, Sweden
    • ,
  • C. Forssell

      Affiliations

    • Department of Surgery, Central Hospital, Västerås, Sweden
    • ,
  • P. Weber

      Affiliations

    • Department of Surgery, Central Hospital, Växjö, Sweden
    • ,
  • S. Oredsson

      Affiliations

    • Department of Surgery, Central Hospital, Helsingborg, Sweden

Accepted 17 November 2005. published online 20 January 2006.

Article Outline

Abstract 

Objectives

To test if initial high-dose, pulse-spray thrombolysis improves the early and late outcome of lower limb ischaemia as compared with low-dose infusion alone.

Design

Prospective randomised multicentre study.

Material and methods

Patients with acute and sub-acute (<30 days) lower limb ischaemia were randomised following angiography. Group 1 (n=58) received pulse-spray infusion of recombinant plasminogen activator (rt-PA, 15mg/h) for 2h followed by low-dose infusion if needed. Group 2 (n=63) were only treated with low-dose infusion (0.5mg/h) of rt-PA for 48h. Underlying lesions were corrected if required.

Results

The study was stopped prematurely. Complications were equally frequent in both groups. More than 75% lysis was accomplished in 78 versus 67% of the patients (p=0.21). Primary endpoints (re-occlusion, incomplete lysis, life-threatening complication, amputation, or death) were reached in 24 versus 32% of the patients (p=0.35). Neither vascular patency nor clinical parameters differed during the first year, but re-interventions tended to be more frequent (p=0.040 at 1 month; p=0.090 at 1 year) and of a greater magnitude (p=0.028) in group 2.

Conclusions

There was no obvious advantage with initial high-dose thrombolysis, which may be a type-2 error. A reduction of major re-interventions was recorded.

Keywords: Arterial occlusive disease, Acute limb ischaemia, Thrombolytic therapy, Lower extremity, Fibrinolytic agents, Recombinant tissue plasminogen activator, Adverse effects

 

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1. Introduction 

Acute ischaemia of the lower extremity caused by arterial embolism or thrombosis of native vessels and grafts is a serious condition afflicted with substantial morbidity and mortality. Blaisdell et al.1 and others2, 3 have reported amputation and death in 15–30% of patients treated with anticoagulation therapy or surgery.

Thrombolysis with intravenous administration of streptokinase was first described by Tillett et al. in 1955,4 but was initially not very successful and compromised by considerable haemorrhagic complications.5, 6, 7 These problems have subsequently been ameliorated by refinements of techniques (intra-arterial, catheter-directed, and intra-thrombotic drug delivery) and drugs (urokinase and recombinant tissue plasminogen activator, rt-PA).3, 6, 7, 8 Three prospective, randomised trials thereafter compared low-dose intra-thrombotic thrombolysis of urokinase or rt-PA with initial surgical intervention.9, 10, 11, 12 The studies demonstrated a reduction in the magnitude of interventions required and a better early survival with thrombolysis, but severe haemorrhages were recorded and recurrent ischaemia hampered the late clinical outcome. Reviewers concluded that low-dose, intra-thrombotic thrombolysis was not conclusively better than surgical treatment.13

During the beginning of the 1990s, various techniques for initial high-dose delivery of the thrombolytic agent, including forced periodic (e.g. pulse-spray) infusion, to accelerate lysis of the thrombus were developed.14, 15, 16, 17 Two prospective, randomised studies comparing conventional low-dose infusion with different techniques of high-dose thrombolysis demonstrated contradictory results.18, 19

The primary aim of the study was to investigate if initial high-dose thrombolysis with the pulse-spray technique improves the outcome of acute and sub-acute lower limb ischaemia as compared with low-dose thrombolysis alone.

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2. Material and Methods 

2.1. Setting 

Four Swedish vascular surgical centres at the county hospitals in Eskilstuna, Helsingborg, Västerås, and Växjö participated. One vascular surgeon and one interventional radiologist in each centre were responsible for treatment consistency and reporting of data. Study coordinator was Sven Oredsson, Helsingborg, where the registry was located. The study was conducted according to the guidelines for good clinical practice for research and the declaration of Helsinki. The Ethical Committees of the universities in Lund, Göteborg, Linköping, and Örebro, Sweden approved the study.

2.2. Participants 

Patients with sudden onset of unilateral lower limb ischaemia within 30 days and angiographic evidence of thrombo-embolic occlusion distal to the aortic bifurcation in whom a guide-wire could be passed at least 5cm into the thrombus were evaluated for inclusion in the study. Occlusions of embolic origin and in situ thromboses of native vessels and vascular grafts were accepted. All patients that met the clinical inclusion criteria, but did not have any exclusion criteria (Table 1), were provided oral and written information of the study before angiography. In accordance with the recommendations of the ethical committees and the Swedish practice at that time, no written consent was obtained. All participants provided oral consent.

Table 1. Exclusion criteria
Major surgery<10 days
Haematuria<10 days
Gastrointestinal bleeding<10 days
Stroke<3 months
Coagulopathy
Pregnancy
Brain tumour
Malignant hypertension
Dacron prosthesis implanted<3 months
Graft infection
Irreversible or profound ischaemia
Contrast allergy
Life-expectancy<30 days
Age<18 years
Non-cooperative patient

2.3. Objectives 

The main objective was to compare high-dose thrombolysis using pulse-spray technique with low-dose thrombolysis in terms of mortality, life-threatening complications, limb salvage, and requirement for re-intervention. The primary hypothesis was that initial high-dose thrombolysis improves the early results (numbers and scores of endpoints) as compared to the conventional low-dose technique. Secondary objectives were to study the angiographic degree of lysis, requirement for additional endovascular and surgical re-intervention as well as clinical and economic outcome. An analysis of subgroups was intended to find prognostic factors determining outcome and reported in a later communication.

2.4. Interventions 

2.4.1. Angiography 

Contra- or ipsi-lateral puncture of the femoral artery was performed dependent on the presumed thrombus location. The proximal and distal thrombus extension and the peripheral run-off were investigated and guide-wire passage through the thrombus was attempted. Introducers (5–6F) were left in place during the entire thrombolysis.

2.4.2. Study treatment 

Group 1: Pulse-spray, high-dose infusion: Recombinant tissue plasminogen activator (rt-PA, Actilyse®, Boehringer-Ingelheim GmbH, Ingelheim, Germany) was used as the thrombolytic agent. This was dissolved in sodium chloride into a solution of 0.33mg/ml. Forced periodic (pulse-spray) infusion was administered into the thrombus with a special infusion pump (Pulse Spray Injector® PSI-1, Angio Dynamics, Glen Falls IL, USA) in doses of about 0.13mg (0.4ml of the prepared solution) twice per minute (15mg/h) using catheters with 10–20cm long distal heads with multiple orifices and tip occluders (Pulse*Spray®, AngioDynamics Inc, Glen Falls IL, USA). Pulse-spray infusion was continued until the lysis was complete, severe complications occurred, or for the recommended 2h. Control angiograms were obtained every 30min and catheter repositioning was performed as required. The extent of remaining thrombus was assessed and complementary low-dose infusion (technique as described below) was instituted if the lysis was considered insufficient. Minor remaining thrombi were accepted if an adequate peripheral blood flow had been restored.

Group 2: End-hole, low-dose treatment: Rt-PA (Actilyse®) was administered into the thrombus using end-hole catheters. A bolus of 0.25mg (2.5ml) was followed by a continuous infusion of 0.5mg (5ml)/h until the lysis was complete, severe complications occurred, or for recommended 48h. Control angiograms were obtained every 12h and catheter repositioning was performed as required.

2.4.3. Patient monitoring 

The heart rate, blood pressure, puncture sites, and status of the ischaemic limb were checked at least twice every hour. Blood levels of haemoglobin, platelets, prothrombin time (PK), and activated partial thromboplastin time (APTT) were checked every 6h.

2.4.4. Adjunctive medical therapy 

Five thousand units of heparin were administered intravenously immediately before starting the thrombolysis. During low-dose thrombolysis, heparin (600U/h) was continuously infused via the introducer using a separate infusion pump adjusting the APTT to 60–120s. After completing thrombolysis, anticoagulation with low molecular weight heparin was administered subcutaneously twice daily for 3 days and the patients were given oral anticoagulants or antiplatelet drugs on the discretion of the treating physician.

2.4.5. Adjunctive interventions 

Underlying vascular lesions causing the acute thrombosis (mainly stenoses exceeding 50% luminal reduction) were treated with percutaneous transluminal angioplasty (PTA) with or without stenting immediately after termination of thrombolysis. If the responsible surgeon considered that surgical correction of the underlying lesion was necessary, these operations were performed within 1 week.

2.5. Outcomes 

Before the start of the study, primary endpoints were defined and each was given a specific value according to an ordinal scale: five points=death; four points=life-threatening complication; three points=amputation; two points=incomplete lysis requiring immediate surgical intervention; one point=re-occlusion requiring new thrombolysis or surgery. If several endpoints were reached, only the one with the highest value was used (endpoint-score).

According to the recommendations of ‘The Working Party on Thrombolysis in the Management of Limb Ischemia’ and ‘The Society of Interventional Radiology Technology Assessment Committee’ both published in 2003,20, 21 we also assessed (secondary analyses) separate endpoints: Degree of lysis, patency of the initially occluded vessel, and clinical outcome including amputation-free survival (major amputations). Comparisons of economic consequences as well as the number and magnitude of re-interventions performed are considered as ancillary analyses.

Case record forms were completed by the responsible surgeon and sent to the study centre in Helsingborg. In order to achieve as correct and uniform evaluation as possible, all data were validated and analysed by one single author (G.P.).

2.6. Sample size 

We assumed that 30% of the patients treated with low-dose infusion would reach a primary endpoint within 30 days and estimated that this would reduce to 20% using the high-dose technique. To demonstrate this difference 590 patients are required (power=0.80, p=0.05). At the time of initiation of the study, 10 centres were involved, each having the intention of enrolling 30 patients per year, with conclusive results expected to be available after 2 years.

2.7. Randomisation 

The random allocation sequence was computer generated, separately for each centre. The sequence was concealed to all participants. The responsible vascular surgeon contacted Helsingborg Hospital switchboard by telephone from the angiography suite. After receiving patient identification, the operator immediately provided treatment group allocation using centre and risk index (low/high risk, Table 2) as stratification parameters. No blinding of assigned treatment was possible.

Table 2. Risk index used for stratification
Risk factorPoint
Myocardial infarction<6 months ago10
Myocardial infarction>6 months ago5
Frequent angina pectoris10
Heart failure10
Aortic valve stenosis10
Arrhythmia5
Stroke<6 months ago10
Stroke>6 months ago5
Age>70 years5

Risk index=sum of points; low risk=index<20; high risk=index≥20.

2.8. Statistical methods 

Statistical analysis was performed using SPSS 11.0 (Statistical Package for the Social Sciences, SPSS Inc, Chicago, IL, USA) and Stata 9.0 (Stata Statistical Software, StataCorp LP, College Station, TX, USA). Pearson chi-square test was used for 2×2 tables and the Wilcoxon–Mann–Whitney test (WMW) for ordinal data. The log rank test was used for life-table analysis of patency; since only grouped data on times to occlusion were available, Kaplan–Meier curves would not be very useful. p-Values<0.05 were considered statistically significant.

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3. Results 

3.1. Recruitment and patient flow 

For various reasons, only four centres went on to include patients starting in May 1997. The study was terminated after 3 years when 121 patients had been included. The study design and flow of patients is presented in Fig. 1. All patients received the intended treatment, but thrombolysis was in some cases extended beyond the recommended time due to clinical decisions made by the responsible surgeon and radiologist. All surviving patients were available for follow-up after 1 month (n=108) and 1 year (n=95).

3.2. Baseline data 

The patients' demographic and clinical data are presented in Table 3, Table 4. Thirty-four patients (26 versus 30%) were older than 80 years of age. Separation of occlusions with embolic origin from in situ thromboses was not possible, although most cases probably belonged to the latter group. Thirty-five patients had occluded grafts (30 with synthetic and five with autogenous graft material) in an aorto-iliac (8), femoro-popliteal (22), or tibial (5) position. The proximal level of occlusion and run-off was demonstrated by contrast angiography (Table 5). There were fewer proximal (iliac) occlusions in group 1 (7%, 95% CI=0–14%) than in group 2 (21%, 95% CI=10–31%). There were more distal (popliteal and crural) occlusions in group 1 (24%, 95% CI=13–35%) than in group 2 (11, 95% CI=3–19%). Guide-wire passage through the entire thrombus was possible in 42/57 patients (74%, 95% CI=62–85%) in group 1 and in 30/62 patients (48%, 95% CI=36–61%) in group 2. There were no other notable differences between the groups.

Table 3. Demographic data
VariableGroup 1 (n=58)Group 2 (n=63)All (n=121)
Age (mean; range)73; 52–8972; 47–9772; 47–97
Female sex24 (41%)34 (54%)58 (48%)
Smoking20 (35%)*23 (37%)*43 (36%)*
Diabetes9 (16%)11 (18%)20 (17%)
Heart disease36 (62%)40 (64%)76 (63%)
Hypertension15 (26%)28 (44%)43 (36%)
Cerebrovascular disease8 (14%)15 (24%)23 (19%)
Hyperlipidaemia6 (10%)*10 (16%)*16 (13%)*
Previous vascular intervention24 (41%)30 (48%)54 (45%)
Risk index (median; range)7.5; 0–355; 0–255; 0–35

Number of patients.

*Information missing in several patients.

Table 4. Clinical data
VariableGroup 1Group 2All
Severity of symptoms(n=58)(n=63)(n=121)
Claudication11 (19%)7 (11%)18 (15%)
Rest pain42 (72%)50 (79%)92 (76%)
Tissue loss5 (9%)6 (10%)11 (9%)
Duration of symptoms(n=58)(n=63)(n=121)
<1 day14 (24%)15 (24%)29 (24%)
1–3 days13 (22%)15 (24%)28 (23%)
4–7 days14 (24%)18 (29%)32 (26%)
8–30 days17 (29%)15 (24%)32 (26%)
Muscle weakness(n=57)(n=63)(n=120)
None34 (60%)42 (67%)76 (63%)
Mild21 (37%)17 (27%)38 (32%)
Severe2 (4%)4 (6%)6 (5%)
Ankle/brachial index(n=56)(n=62)(n=118)
Median (range)0.3 (0–0.8)0.0 (0–0.8)0.1 (0–0.8)

Number of patients.

Table 5. Angiographic findings
VariableGroup 1Group 2All
Proximal occlusion level(n=58)(n=63)(n=121)
Iliac4 (7%)13 (21%)17 (14%)
Femoral40 (69%)43 (68%)83 (69%)
Popliteal or crural14 (24%)7 (11%)21 (17%)
Run-off*(n=57)(n=62)(n=120)
Good21 (36%)22 (36%)43 (36%)
Bad24 (41%)20 (32%)44 (37%)
Very bad13 (22%)20 (32%)33 (28%)

Number of patients.

*Run-off was classified as: good=2–3 crural arteries, bad=1 crural artery, or very bad=fragments of crural arteries.

3.3. Treatment provided 

3.3.1. Group 1 

Pulse-spray, high-dose thrombolysis was continued for 120 (40–310) min, with a calculated dose of 30 (10–75) mg of rt-PA. Complementary low-dose infusion was given to 38/58 patients (66%) for 18 (1–50) h with a calculated dose of 9 (0.5–25) mg. The calculated total dose of rt-PA given was 36 (19–93) mg in group 1. All numbers are given as median (range).

3.3.2. Group 2 

Low-dose infusion was administered for 25 (2–60) h with a calculated dose of 13 (1–30) mg of rt-PA. All numbers are given as median (range).

3.3.3. Adjunctive treatment 

Adjunctive medical therapy and interventions performed are described in Table 6. The same principles were applied in both groups and there was no notable difference recorded. Underlying vascular lesions were detected and corrected in 81/121 patients (67% in both groups).

Table 6. Adjunctive treatment
VariableGroup 1Group 2All
Medical*
Antiplatelet drugs28 (56%)35 (65%)63 (61%)
Oral anticoagulation20 (40%)18 (33%)38 (37%)
None2 (4%)1 (2%)3 (3%)

Interventions

PTA†36 (62%)36 (57%)72 (60%)
Stenting2 (3%)4 (6%)6 (5%)
Aneurysm exclusion‡1 (2%)1 (2%)2 (2%)
Endarterectomy§01 (2%)1 (1%)

Number of patients.

*Information missing in 17 patients.

†Percutaneous transluminal angioplasty.

‡Popliteal aneurysms.

§Outflow in groin.

3.4. Early outcomes 

3.4.1. Primary analysis 

After 1 month, 14/58 (24%) of the patients in group 1 and 20/63 (32%) of the patients in group 2 had reached a primary endpoint (χ2=0.87, 1 d.f., p=0.35; 95% CI for difference: −24 to 8%). The endpoint scores (Table 7) did not differ between the groups (WMW, Z=−0.79, p=0.43).

Table 7. Endpoints (score), 1 month
VariableGroup 1 (n=58)Group 2 (n=63)
None (0)44 (76%)43 (68%)
Re-occlusion* (1)2 (3%)2 (3%)
Incomplete lysis* (2)2 (3%)8 (13%)
Amputation (3)3 (5%)2 (3%)
Life-threatening complication (4)1 (2%)1 (2%)
Death (5)6 (10%)7 (11%)

Number of patients. Endpoint with highest score recorded in each patient.

*Only if re-intervention (surgery or re-thrombolysis) was required. WMW, Z=−0.790, p=0.43.

3.4.2. Secondary analyses 

The outcome of each separate endpoint is presented in Fig. 2, in which incomplete lysis (aided by adjunctive procedures) and re-occlusion is recorded even if no additional intervention was performed. No endpoint was significantly different when comparing the groups, although incomplete lysis was recorded in 7/58 patients (12%) in group 1 and in 15/63 patients (24%) in group 2 (χ2=2.80, 1 d.f., p=0.094). The 30-day mortality was 6/58 (10%) and 7/63 (11%) and major amputations were performed in 4/58 patients (7%) and 3/63 patients (5%), respectively. The amputation-free survival was 49/58 patients (85%) and 54/63 patients (86%), respectively. The early clinical results, which are presented in Table 8, did not differ between the groups. Non-amputated surviving patients (n=48 and n=53) had a median (range) ankle/brachial index of 0.9 (0–1.4) and 0.9 (0–1.3), respectively. The degree of lysis, as assessed by angiograms obtained immediately after completed thrombolysis (unaided by adjunctive procedures) did not differ between the groups. More than 75% lysis was accomplished in 45/58 patients (78%) in group 1 and in 41/61 patients (67%) in group 2 (χ2=1.60, 1 d.f., p=0.21).

  • View full-size image.
  • Fig. 2. 

    Separate endpoints at 1 month. All endpoints recorded including incomplete lysis and re-occlusion without re-intervention. Lysis was considered incomplete if sufficient peripheral flow was not accomplished following thrombolysis aided by adjunctive procedures.

Table 8. Clinical results
VariableEarlyLate
Group 1 (n=57)*Group 2 (n=62)*All (n=119)Group 1 (n=57)*Group 2 (n=60)*All (n=117)
No symptoms35 (61%)39 (63%)74 (62%)34 (60%)31 (52%)65 (56%)
Claudication8 (14%)4 (7%)12 (10%)3 (5%)3 (5%)6 (5%)
Rest pain1 (2%)3 (5%)4 (3%)1 (2%)1 (2%)2 (2%)
Tissue loss4 (7%)7 (11%)11 (9%)2 (4%)4 (7%)6 (5%)

Number of patients.

*Symptoms not registered in 1–3 patients.

3.5. Late outcomes 

Endpoints were now evaluated separately, since some of these were not designed for late analysis. After 1 year, 12/58 patients (21%) in group 1 and 14/63 patients (22%) in group 2 had died. Seven (12%) and eight patients (13%), respectively, had been amputated. The amputation-free survival was 41/58 (71%) and 43/63 (68%), respectively. There was no difference in clinical results between the two groups (Table 8). The non-amputated patients (n=43 and n=45) had a median (range) ankle/brachial index of 0.8 (0–1.3) and 0.9 (0–1.3). Using information from 1 week, 1 month, and 1 year, with corrections made for the slight difference in survival, a life-table analysis (log‐rank test) did not show any significant difference in primary (p=0.19) or secondary (p=0.11) patency.

3.6. Ancillary analyses 

3.6.1. Economic analysis (prescribed) 

In group 1: Pulse-spray thrombolysis was performed in the radiology suite in all patients, whereas the complementary low-dose regimen was given in the intensive care unit (ICU) in 9/38 patients (24%), in a recovery room in 27/38 patients (71%), and in an ordinary ward room in 2/38 patients (5%). In group 2 (information missing in one patient): the ICU was used in 21/62 (33%), recovery room in 37/62 (59%), and a ward room in 4/62 (6%). The median number of hours spent in the ICU and recovery were 2.8 and 8.4, respectively, in group 1, and to 8.2 and 14.7, respectively in group 2. Since these figures are based on calculations and not precise no statistical comparison was performed. The mean hospital stay was 5.1 days in group 1 and 6.6 days in group 2 (WMW, Z=−1.91, p=0.056). No other economic comparisons were performed.

3.6.2. Analysis of re-interventions (prescribed) 

Re-interventions due to incomplete lysis, re-stenosis, or re-occlusion were performed within 1 month in 7/58 patients (10 procedures) in group 1 and in 17/63 patients (20 procedures) in group 2 (Table 9). Additional re-interventions were performed from 1 month to 1 year in 7/52 patients (seven procedures) in group 1 and in 8/56 patients (13 procedures) in group 2. Statistical analysis demonstrated that the number of patients subjected to re-intervention was lower in group 1 at 1 month (χ2=4.23, 1 d.f., p=0.040) but not at 1 year (χ2=2.87, 1 d.f., p=0.090). The number of procedures performed was also lower in group 1 at 1 month (WMW, Z=−1.97, p=0.049) but not at 1 year (Z=−1.74, p=0.082). The differences at 1 month could not be caused by a difference in observation time (survival), since the non-surviving patients in group 2 (n=7) died somewhat earlier than those in group 1 (n=6).

Table 9. Re-interventions
Variable1 Month1 Month to 1 year
ProceduresGroup 1 (n=58)Group 2 (n=63)All (n=121)Group 1 (n=52)Group 2 (n=56)All (n=108)
Thrombolysis202224
Percutaneous angioplasty224235
Thrombo-embolectomy6410000
Aorto-iliofemoral bypass011011
Iliac or femoral TEA*033011
Femoropopliteal bypass044145
Femorotibial bypass066224
Total10203071320

Number of procedures.

*Thrombendarterectomy.

3.6.3. Exploratory analysis 

The types of each additional vascular re-intervention performed are presented in Table 9. Of the 50 procedures performed, 25 were classified as minor (re-thrombolysis, percutaneous transluminal angioplasty, or thrombo-embolectomy) and 25 were classified as major (by-pass or thrombendarterectomy). Three patients (5%) were subjected to major and 10 (17%) to minor re-interventions in group 1, whereas 18 patients (27%) were subjected to major and five patients (8%) to minor re-interventions in group 2 (WMW, Z=−2.19, p=0.028).

3.7. Adverse events 

All in all 68 adverse events (35 and 33, respectively) were registered in 55 patients (47 versus 44%) and presented in Table 10. Most complications consisted of minor bleeding and peripheral embolisation. Thirteen events were fatal (10 versus 11%), all occurring in patients aged above 73 years of age. Thrombolysis was terminated due to complications in 14 patients (6 and 8, respectively). Bleeding from the puncture site was quite common (minor oozing was not even recorded as an adverse event). Three patients in each group developed gastrointestinal bleeding or haematuria, but these events were not considered life-threatening. Fourteen bleeding events required blood transfusion or surgery and were considered as major. Five of these major bleedings (3 and 2, respectively) were associated with the patient's death. Five of eight cardiac events (2 and 6%, respectively) were fatal. Four of these cardiac events were associated with bleeding complications.

Table 10. Adverse events
VariableGroup 1 (n=58)Group 2 (n=63)All (n=121)
Death (<30 days)6713
Bleeding
Minor12719
Major4814
Cardiac3*5†8
Haemorrhagic stroke2‡02
Ischaemic stroke11*2
Peripheral embolisation10818
Contra-lateral occlusion112
Compartmental syndrome112
Other§123

Number of events.

*One fatal.

†Four fatal.

‡Two fatal.

§Renal failure; septicaemia, allergy.

One ischaemic stroke was recorded in each group, but only that in group 2 was fatal. Both patients had chronic atrial fibrillation. In addition, two fatal cerebral haemorrhages occurred, both in group 1 (4%), creating a total incidence of stroke of 3/58 (5%) and 1/63 (2%), respectively.

Peripheral embolism regularly occurs during thrombolysis and was registered as an adverse event in 17 patients. Embolectomy was required in three of these (1 and 2, respectively) and two led to a major leg amputation within a month. Two patients (one in each group) required surgery for thrombotic occlusion at the puncture site in the contra-lateral groin. One of these subsequently had a major leg amputation. Fasciotomy was required in two patients due to development of a compartmental syndrome following restitution of peripheral blood flow. Both these limbs were saved.

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4. Discussion 

Since this study was started, several publications have reviewed the role of thrombolytic therapy in the management of acute arterial ischaemia.21, 22, 23, 24 Most of these conclude that thrombolysis has no obvious benefit over surgical management. Several reports of recurrent ischaemia, haemorrhagic complications and stroke have hampered the enthusiasm with this treatment.22, 23, 24, 25, 26 The use of thrombolysis has decreased in favour of anticoagulation treatment or surgery and is nowadays mainly recommended for graft thromboses or in situ thromboses of native vessels of short duration.22, 27

According to most reviewers, no technique or drug has proven superior to any other as long as the thrombolytic agent is delivered into the thrombus.21, 28, 29, 30 The use of high doses of thrombolytic agents has been discouraged, mainly referring to an increased risk for bleeding complications and stroke.21, 29 In our study, the morbidity with high-dose thrombolysis was not discouraging and not worse than with the low-dose treatment (Table 10). Four major bleeding events occurred in patients with the high-dose (7%) versus eight events (13%) with the low-dose regimen. The mortality at 1 month was 10 and 11%, respectively. Our incidence of complications corresponded well with the findings of a UK audit.30

The major disadvantage with high-dose thrombolysis seems to be an increased risk for cerebral haemorrhage. This may be compensated for by a lower incidence of cardiac events than with low-dose thrombolysis. Stroke (haemorrhagic or ischaemic) occurred in 5% with high-dose versus 2% with low-dose thrombolysis, whereas fatal cardiac events were recorded in 2 and 6%, respectively (non-significant differences). Prolonged thrombolysis is often cumbersome and stressful for elderly patients. The time required for restoration of blood flow was in this study shorter with the high-dose regimen. Two hours of treatment was sufficient to restore blood flow in 34% of the patients and the complementary low-dose infusion performed in the remaining patients was shorter (18h) than the infusion time in the patients only treated with low-dose thrombolysis (25h). In addition, more frequent and extensive re-interventions were required following low-dose thrombolysis (Table 9). The extra stress provoked by prolonged thrombolysis and additional interventions may be responsible for the somewhat greater incidence of cardiac events with low-dose thrombolysis noted in the present study and suggested in other publications.14, 15, 31

Acute lower limb ischaemia is a dangerous condition and adverse events must be expected in this elderly population, regardless of what treatment is employed.24, 32 Thus, the risk of adverse events per se does neither justify avoidance of low- nor high-dose thrombolytic therapy. This concept is supported by some communications17, 19, 30, 33 and contradicts the bad reputation of high-dose thrombolysis promoted by other reviewers.21, 29

The fact that most of our fatal complications occurred in patients over the age of 75, supports the present concept that thrombolysis should be avoided in very old patients.24, 27, 30 Another relative contra-indication to thrombolytic treatment is chronic atrial fibrillation due to the risk of creating cardiac embolisation. Both ischaemic strokes reported in this study developed in patients with atrial fibrillation. Minimal interventions (e.g. PTA or embolectomy), lower doses of thrombolytic agents, or conservative management may be preferential in elderly patients and in patients with atrial fibrillation, especially in the presence of less severe ischaemia.21, 27, 34 The recent UK audit has demonstrated that good clinical results with low complication rates can be achieved with a better patient selection.30

The results of the present study indicate that initial high-dose thrombolysis may provide a reduction in the numbers and especially the magnitude of surgical interventions required (Table 9). This contradicts the conclusions of the Cochrane-analysis by Kessel et al.29 They did not find any reduction in adjunctive procedures. The reason for this discrepancy is uncertain, but could be related to variations in drugs, doses, and techniques utilised. We used rather high doses of thrombolytic agents and continued with a low-dose regimen in two thirds of the patients providing optimal clearance of thrombotic material. All patients received adjunctive anticoagulation or antiplatelet medication, as advocated in a consensus document,21 and underlying lesions were corrected, mostly with endovascular procedures, as suggested by Ouriel.35 It is likely that residual thrombi may cause recurrent thrombosis and ischaemia, which has afflicted some previous studies.26 The more thorough arterial clearance achieved with high-dose thrombolysis in combination with adjunctive medication and endovascular intervention may thus have been of importance in reducing the need for subsequent interventions.

We failed to demonstrate any significant difference in primary endpoints. Our study was closed prematurely, mainly due to a dropout of randomising centres and a subsequent declining enthusiasm among the remaining centres. This may have caused a type-2 error. After 1 month, 24% of the high-dose patients and 32% of those with low-dose thrombolysis had at least one endpoint. This is slightly less than our initial presumption. It cannot be excluded that a larger study would have provided a significant difference in primary endpoints.

The two treatment groups differed somewhat in baseline characteristics. The number of proximal (iliac) occlusions was lower, the number of distal (popliteal and crural) was higher, and guide-wire passage through the entire thrombus was more often accomplished in the patients randomised to high-dose thrombolysis. According to Ouriel et al.,36 thrombus location should not affect outcome whereas guide-wire passage through the thrombus is predictive of success. On the other hand, positioning of the infusion catheter within the thrombus, which was possible in all our patients, is also very predictive of successful thrombolysis.36 Therefore, we do not believe that the differences in baseline characteristics were responsible for our recorded differences in outcome.

The clinical results did not differ between the two regimens. The long-term results were satisfactory in both groups with an amputation-free survival of around 85% at 1 month and 70% at 1 year. Clinical outcome may be dependent not only on the technique of thrombolysis but also on the effect of additional interventions. The more frequently performed major surgical interventions after low-dose thrombolysis may therefore explain the lack of difference in clinical results despite a tendency towards better patency following high-dose thrombolysis. In other words, the good clinical results with both regimens reflect not only the influence of thrombolytic technique but also the quality of overall patient care at our hospitals.

The economic relations between the two regimens have not been thoroughly investigated in this or in any other known study. The use of ICU- or recovery beds was somewhat lower and the hospital stay was 1 1/2 days shorter in the high-dose group. On the other hand, the radiology suite was occupied for about 2h more during the pulse-spray infusion and drug expenses were probably greater. Additional interventions were less frequent at 1 month, which was not sustained after 1 year. Although no detailed economic analysis has been performed, it is likely that the lower utilisation of hospital resources entails a reduction in total cost with the high-dose regimen.

In summary, this study does not support a superiority of initial high-dose, pulse-spray thrombolysis over low-dose infusion alone in the treatment of acute and sub-acute ischaemia in the lower extremities. On the other hand, this regimen does not seem to be afflicted with more complications and may provide a faster and more reliable restoration of limb perfusion as well as a reduction in required re-interventions and other utilisation of hospital resources. A larger study would probably provide more conclusive evidence.

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Acknowledgements 

The authors would like to thank Margit Svahn, Eskilstuna; Bengt Arvidsson,Västerås; Bengt Sjöberg, Växjö and Leif Stigsson, Helsingborg for radiological assistance as well as Åsa Persson and Peder Rogmark for data collection and processing. We also acknowledge Professor Jan Lanke, Department of Statistics, Lund University, Sweden for excellent statistical assistance.

The study was supported by a generous grant from Stig and Ragna Gorthon's Foundation. The pulse-spray infusion pumps were bought at a greatly reduced price from Gothia Medical AB®. There are no conflicts of interest reported.

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References 

  1. Blaisdell FW, Steele M, Allen RE. Management of acute lower extremity arterial ischemia due to embolism and thrombosis. Surgery. 1978;84(6):822–834
  2. Yeager RA, Moneta GL, Taylor LM, Hamre DW, McConnell DB, Porter JM. Surgical management of severe acute lower extremity ischemia. J Vasc Surg. 1992;15(2):385–391[discussion 392–393]
  3. Diffin DC, Kandarpa K. Assessment of peripheral intraarterial thrombolysis versus surgical revascularization in acute lower-limb ischemia: a review of limb-salvage and mortality statistics. J Vasc Interv Radiol. 1996;7(1):57–63
  4. Tillett WS, Johnson AJ, Mc CW. The intravenous infusion of the streptococcal fibrinolytic principle (streptokinase) into patients. J Clin Invest. 1955;34(2):169–185
  5. Boyles PW, Meyer WH, Graff J, Ashley CC, Ripic RG. Comparative effectiveness of intravenous and intra-arterial fibrinolysin therapy. Am J Cardiol. 1960;6:439–446
  6. Earnshaw JJ, Hopkinson BR, Makin GS. Acute critical ischaemia of the limb: a prospective evaluation. Eur J Vasc Surg. 1990;4(4):365–368
  7. Berridge DC, Gregson RH, Hopkinson BR, Makin GS. Randomized trial of intra-arterial recombinant tissue plasminogen activator, intravenous recombinant tissue plasminogen activator and intra-arterial streptokinase in peripheral arterial thrombolysis. Br J Surg. 1991;78(8):988–995
  8. DeMaioribus CA, Mills JL, Fujitani RM, Taylor SM, Joseph AE. A reevaluation of intraarterial thrombolytic therapy for acute lower extremity ischemia. J Vasc Surg. 1993;17(5):888–895
  9. Comerota AJ, Weaver FA, Hosking JD, Froehlich J, Folander H, Sussman B, et al. Results of a prospective, randomized trial of surgery versus thrombolysis for occluded lower extremity bypass grafts. Am J Surg. 1996;172(2):105–112
  10. Weaver FA, Comerota AJ, Youngblood M, Froehlich J, Hosking JD, Papanicolaou G. Surgical revascularization versus thrombolysis for nonembolic lower extremity native artery occlusions: results of a prospective randomized trial. The STILE investigators. Surgery versus thrombolysis for ischemia of the lower extremity. J Vasc Surg. 1996;24(4):513–521[discussion 521–523]
  11. Results of a prospective randomized trial evaluating surgery versus thrombolysis for ischemia of the lower extremity. The STILE trial. Ann Surg 1994;220(3):251–266 [discussion 266–268].
  12. Ouriel K, Veith FJ, Sasahara AA. Thrombolysis or peripheral arterial surgery: phase I results. TOPAS Investigators. J Vasc Surg. 1996;23(1):64–73[discussion 74–75]
  13. Weaver FA, Toms C. The practical implications of recent trials comparing thrombolytic therapy with surgery for lower extremity ischemia. Semin Vasc Surg. 1997;10(1):49–54
  14. McNamara TO, Fischer JR. Thrombolysis of peripheral arterial and graft occlusions: improved results using high-dose urokinase. AJR Am J Roentgenol. 1985;144(4):769–775
  15. Sullivan KL, Gardiner GA, Shapiro MJ, Bonn J, Levin DC. Acceleration of thrombolysis with a high-dose transthrombus bolus technique. Radiology. 1989;173(3):805–808
  16. Valji K, Bookstein JJ, Roberts AC, Oglevie SB, Pittman C, O'Neill MP. Pulse-spray pharmacomechanical thrombolysis of thrombosed hemodialysis access grafts: long-term experience and comparison of original and current techniques. AJR Am J Roentgenol. 1995;164(6):1495–1500[discussion 1501–1503]
  17. Armon MP, Yusuf SW, Whitaker SC, Gregson RH, Wenham PW, Hopkinson BR. Results of 100 cases of pulse-spray thrombolysis for acute and subacute leg ischaemia. Br J Surg. 1997;84(1):47–50
  18. Kandarpa K, Chopra PS, Aruny JE, Polak JF, Donaldson MC, Whittemore AD, et al. Intraarterial thrombolysis of lower extremity occlusions: prospective, randomized comparison of forced periodic infusion and conventional slow continuous infusion. Radiology. 1993;188(3):861–867
  19. Braithwaite BD, Buckenham TM, Galland RB, Heather BP, Earnshaw JJ. Prospective randomized trial of high-dose bolus versus low-dose tissue plasminogen activator infusion in the management of acute limb ischaemia. Thrombolysis Study Group. Br J Surg. 1997;84(5):646–650
  20. Patel N, Sacks D, Patel RI, Moresco KP, Ouriel K, Gray R, et al. SIR reporting standards for the treatment of acute limb ischemia with use of transluminal removal of arterial thrombus. J Vasc Interv Radiol. 2003;14(9 Pt 2):S453–S465
  21. Working Party on Thrombolysis in the management of limb ischemia. Thrombolysis in the management of lower limb peripheral arterial occlusion—a consensus document. J Vasc Interv Radiol 2003;14(9 Pt 2):S337–S349.
  22. Palfreyman SJ, Booth A, Michaels JA. A systematic review of intra-arterial thrombolytic therapy for lower-limb ischaemia. Eur J Vasc Endovasc Surg. 2000;19(2):143–157
  23. Kandarpa K, Becker GJ, Hunink MG, McNamara TO, Rundback JH, Trost DW, et al. Transcatheter interventions for the treatment of peripheral atherosclerotic lesions. Part I. J Vasc Interv Radiol. 2001;12(6):683–695
  24. Berridge DC, Kessel D, Robertson I. Surgery versus thrombolysis for acute limb ischaemia: initial management. Cochrane Database Syst Rev. 2002;3:CD002784
  25. Swischuk JL, Fox PF, Young K, Hussain S, Smouse B, Castaneda F, et al. Transcatheter intraarterial infusion of rt-PA for acute lower limb ischemia: results and complications. J Vasc Interv Radiol. 2001;12(4):423–430
  26. Nehler MR, Mueller RJ, McLafferty RB, Johnson SP, Nussbaum JD, Mattos MA, et al. Outcome of catheter-directed thrombolysis for lower extremity arterial bypass occlusion. J Vasc Surg. 2003;37(1):72–78
  27. Eliason JL, Wainess RM, Proctor MC, Dimick JB, Cowan JA, Upchurch GR, et al. A national and single institutional experience in the contemporary treatment of acute lower extremity ischemia. Ann Surg. 2003;238(3):382–389[discussion 389–390]
  28. Mahler F, Schneider E, Hess H. Recombinant tissue plasminogen activator versus urokinase for local thrombolysis of femoropopliteal occlusions: a prospective, randomized multicenter trial. J Endovasc Ther. 2001;8(6):638–647
  29. Kessel DO, Berridge DC, Robertson I. Infusion techniques for peripheral arterial thrombolysis. Cochrane Database Syst Rev. 2004;1:CD000985
  30. Earnshaw JJ, Whitman B, Foy C. National Audit of Thrombolysis for Acute Leg Ischemia (NATALI): clinical factors associated with early outcome. J Vasc Surg. 2004;39(5):1018–1025
  31. Braithwaite BD, Tomlinson MA, Walker SR, Davies B, Buckenham TM, Earnshaw JJ. Peripheral thrombolysis for acute-onset claudication. Thrombolysis Study Group. Br J Surg. 1999;86(6):800–804
  32. Ouriel K. Comparison of surgical and thrombolytic treatment of peripheral arterial disease. Rev Cardiovasc Med. 2002;3(Suppl 2):S7–S16
  33. Ouriel K, Kandarpa K. Safety of thrombolytic therapy with urokinase or recombinant tissue plasminogen activator for peripheral arterial occlusion: a comprehensive compilation of published work. J Endovasc Ther. 2004;11(4):436–446
  34. Castaneda F, Swischuk JL, Li R, Young K, Smouse B, Brady T. Declining-dose study of reteplase treatment for lower extremity arterial occlusions. J Vasc Interv Radiol. 2002;13(11):1093–1098
  35. Ouriel K. Endovascular techniques in the treatment of acute limb ischemia: thrombolytic agents, trials, and percutaneous mechanical thrombectomy techniques. Semin Vasc Surg. 2003;16(4):270–279
  36. Ouriel K, Shortell CK, Azodo MV, Guiterrez OH, Marder VJ. Acute peripheral arterial occlusion: predictors of success in catheter-directed thrombolytic therapy. Radiology. 1994;193(2):561–566

PII: S1078-5884(05)00720-3

doi:10.1016/j.ejvs.2005.11.017

European Journal of Vascular & Endovascular Surgery
Volume 31, Issue 6 , Pages 651-660, June 2006

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