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Bulletin of Emergency & Trauma logoLink to Bulletin of Emergency & Trauma
. 2015 Jul;3(3):86–92.

Effects of Intravenous and Catheter Directed Thrombolytic Therapy with Recombinant Tissue Plasminogen Activator (Alteplase) in Non-Traumatic Acute Limb Ischemia; A Randomized Double-Blind Clinical Trial

Abbas Saroukhani 1, Hassan Ravari 1,*, Masoud Pezeshki Rad 1
PMCID: PMC4771247  PMID: 27162909

Abstract

Objective:

To evaluate the efficacy and safety of intravenous and catheter directed thrombolysis by recombinant tissue plasminogen activator (Alteplase) in the patients with non-traumatic acute limb ischemia (ALI).

Methods:

This was a randomized clinical trial being performed between 2009 and 2011 in Mashhad University of Medical Sciences. We included those patients who were<75 years, with symptoms of less than 14 days duration, ALI of grade IIa and IIb (according to Rutherford classification) and absence of distal run off. Baseline assessment of peripheral circulation performed in all the patients. Patients were randomly assigned to undergo intravenous (n=18) or catheter directed thrombolysis (n=20) with Alteplase. The primary endpoint of the study was improvement of clinical status measured by Rutherford classification, ankle brachial index (ABI), visual analogue scale (VAS) score measured at 1, 3 and 6 months. The secondary endpoint of the study was complete or near complete recanalization of the occluded artery.

Results:

A total number of 38 patients with mean age of 54.13±13.5 years were included in the study. There were 23 (60.5%) men and 15 (39.5%) women among the patients. Overall 3 (7.9%) patients had upper and 35 (92.1%) lower extremity ischemia. There was no significant difference between two study groups. None of the patients experienced major therapeutic side effects. Both ABI and VAS score improved in patients who have received first dose of t-PA within 24-hourof ALI. There was no significant difference between two study groups regarding the 6-month clinical grade (p=0.088), VAS score (p=0.316) and ABI (p=0.360). The angiographic improvement was significantly higher in CDT group (p<0.001).

Conclusion:

Intravenous and catheter directed thrombolysis with t-PA is a safe and effective method in treatment of acute arteriolar ischemia of extremities. However there both intravenous thrombolysis and CDT are comparable regarding the clinical outcome.

Key Words: EThrombolytic therapy, Tissue plasminogen activator (t-PA), Acute limb ischemia, Catheter-directed thrombolysis, Intravenous thrombolysis, Alteplase

Introduction

Acute limb ischemia (ALI) is a life-threatening condition, defined as sudden decrease in limb perfusion resulting in a potential threat to the viability of the limb. ALI is considered an event occurring less than 14 days from presentation [1-3]. The hospital admissions due to ALI has increased significantly from 60.3 to 94.3 per 100,000 of the population between 2000 and 2011, with an average annual increase of 6.2% since 2003 in England [4]. In United States, however, the incidence of hospitalization for ALI decreased from 45.7 per 100,000 to 26.0 per 100,000 population between 1998 and 2009 [5]. Symptoms progress over a period of hours to days, pain in the extremity at rest, paresthesia, muscle weakness, and paralysis [1]. The classical “6 Ps” are the typical presentation of the patients with ALI: paresthesia, pain, pallor, paralysis, poikilothermia, and pulselessness [6]. Non-traumatic causes of ALI include acute thrombotic occlusion of a pre-existing stenotic artery, and embolism from the heart or a diseased artery [7].

The clinical status of the patients and the physical findings of the affected limb are of great importance in planning the treatment. Rutherford et al., [6] proposed a classification which is the most commonly used method to describe ALI. According to the Rutherford classification, ALI is categorized into three major grades: Patients with viable limbs (grade I), do not require emergent intervention. It is reasonable to admit, start anticoagulation, continue clinical evaluation, and considering treatment urgently but not emergently [6]. Catheter-directed thrombolysis (CDT) is indicated urgently for patients with marginally threatened (grade IIa) limbs, if there is no contraindication. Patients with immediately threatened limbs (grade IIb) require emergent operation to salvage the limb [6]. However, improved endovascular techniques have made it possible to perform endovascular interventions in this group of patients [7-11]. Thrombolysis may be the best option when the risk of general anesthesia outweighs the risk of delay in reperfusion. Primary amputation is the only option for limb salvage in patients with irreversible ischemia (grade III) [6].

Catheter-directed  thrombolysis (CDT) has been shown to be an effective armamentarium to salvage the ischemic limb resulting from acute embolism and acute thrombosis  of  native  artery.  However bleeding complication is a major problem of this treatment. Although CDT is usually applied for ALI patients with ischemic symptom onset less than 14 days, it also provides technical success for those with the symptom onset between the second and the sixth weeks [12-14]. CDT is reserved for patients with non- life-threatening ALI due to occlusion of less than 14 days duration, and patients with thrombosis of more than 30 days duration are unlikely to respond to local fibrinolysis [13,14]. Several pharmacologic regimens have been used. Each agent facilitates thrombolysis by converting plasminogen to plasmin, which then degrades fibrin and fibrinogen to their fragmented byproducts [1,11]. Streptokinase was once the most commonly used thrombolytic agent which has been replaced by urokinase, and recombinant t-PAs [15]. Direct delivery of a thrombolytic agent to the desired location has been associated with greater success than systemic lytic therapy [8,12-14]. As there is still controversy  on this issue, the current study was designed to evaluate the efficacy and safety of intravenous and catheter directed thrombolysis by recombinant tissue plasminogen activator (Alteplase) in the patients with non-traumatic ALI.

Materials and Methods

Study Population

This  was  a  randomized  single  blind  clinical trial being performed between October 2009 and December 2011 in emergency departments of Imam Reza and Ghaem hospitals, both tertiary healthcare centers affiliated with Mashhad University of Medical Sciences, Mashhad, Iran.We included consecutively presenting patients with initial diagnosis of acute limb ischemia.The  inclusion  criteria  was age of less than 75 years, symptoms of less than 14 days duration, ALI of grade IIa and IIb according to the Rutherford classification (Table 1) [6], and absence of distal run off in angiography before the intervention. The exclusion criteria were severe anemia (Hb<8gr/dl),  thrombocytopenia  (platelet<80000/ µl),  low  serum  fibrinogen  (fibrinogen<100mg/ dL), sever hypertension (systolic>160mmHg, diastolic>100mmHg),  trauma  or surgery  within the previous 14 days before intervention, history of subarachnoid  hemorrhage,  life expectancy  of less than 14 months, major internal bleeding less than 6 months before intervention, pregnancy, and lumbar puncture 2 weeks before intervention. The study protocol was approved by both institutional review boards (IRB) and medical ethics committee of Mashhad University of Medical Sciences. All the patients gave written informed consent before inclusion to the study. The study protocol was also registered with Iranian registry for clinical trials (IRCT2014100719427N1; ww.irct.ir).

Table 1.

Clinical grades of acute limb ischemia according to the Rutherford classification [6] .

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

Study Protocol

The baseline characteristics of the patients including demographic information, risk factors, clinical presentation, drug history, and imaging studies were recorded. Baseline assessment of peripheral circulation was performed in all the patients. The assessment included grading of acute limb ischemia according to the Rutherford classification, measurement of the ankle-brachial index (ABI), scoring the pain severity according to the visual analogue scale (VAS) and limb angiography.The patients were randomly assigned to two study groups using a computer-based random digit generator. The first group was treated with systemic intravenous alteplase (Activase®, Genentech, Inc., San Francisco, USA) and the other treated through CDT and with intra-arterial alteplase (Activase®, Genentech, Inc., San Francisco, USA) administration. The first group was treated intravenously with 0.6 mg/kg (with an upper limit of 50 mg) of alteplase. Of the total dose, 20% was administrated as a bolus, and the remainder was given through intravenous infusion over a period of 2 hours. A same administration was done a day after initial dose, if there was an improvement in peripheral circulation assessment parameters.  Post intervention angiography was not performed in this group. Patients in the CDT group were transferred to angiography room. First, a guide wire passed through the occlusion and then a side-hole catheter was imbedded into the occluded artery. The length of catheter which had side holes were fitted with the length of occlusion. CDT with Alteplase was done with infusion rate of 0.05mg/ kg/hr. First, 5 mg of alteplase was administrated as a bolus and the remainder was given in divided doses every 2 hours over a period of 24 hours. A similar dosage of alteplase was  given  a day after initial dose, if an improvement was seen in peripheral circulation assessment parameters. After completion of thrombolysis regimen, all the patients were transferred to surgical intensive care unit. The patients’ clinical status was closely monitored for the first 24 hours and daily prothrombin time (PT), prothromboplastin time (PTT), hemoglobin (Hb), and fibrinogen were measured. Patients were discharged from hospital after completing the thrombolysis treatment and the required care. They were followed for 6 months after the thrombolysis therapy. The interventionists and the patients were not blinded to the route of therapy. However those recording the outcome and measuring the indices were blinded to the study groups.

The patency and clinical outcome were measured according to the Rutherford classification, ABI and VAS scale. Adverse events related to the intervention including hemorrhage, hematoma, and hypersensitivity reaction were recorded. Adverse events were categorized as major and minor. Adverse events were considered major if the patient required infusion of pack cell or accompanied with a disability for the patient and the others were considered minor. The primary endpoint of the study was improvement of clinical status, defined as upward shift of at least one grade in Rutherford grading of the patient, improvement of ABI (≥0.1), and upward shift of at least 2 scores in VAS. The secondary endpoint of the study was complete or near complete recanalization of the occluded artery in angiography.

Statistical Analysis

All the statistical analysis was performed using statistical package for social sciences (SPSS Inc., Chicago, USA) version 16.0. All the data are presented as mean±SD or proportions as appropriate. The parametric data was compared between two study groups using independent t-test while paired t-test was used for comparing  the results within the groups. Proportions were compared using chi- square test. A two-sided p-value of less that 0.05 was considered statistically significant.

Results

Overall we included 40 patients with ALI, out of whom 2 were excluded from the study. Thus 38 patients were assigned to undergo intravenous (n=18) or CDT (n=20). All the patients finished the study and thus the number of the patients for final analysis was 38 (Figure 1).

Fig. 1.

Fig. 1

CONSORT flow diagram of the study

The mean age of the patients was 54.13±13.5 (ranging from 20 to 75) years. There were 23 (60.5%) men and 15 (39.5%) women among the patients. Only 3 (7.9%) patients had upper limb ischemia while 35 (92.1%) had lower extremity ischemia. The cause of ALI in 34 (89.4%) patients was found to be thrombosis while 4 (10.6%) patients were diagnosed to suffer from embolism from another source. The baseline characteristics of the patients are summarized in Table 2. There was no significant difference between two study groups regarding the baseline characteristics.

Table 2.

Baseline characteristics of 38 patients with acute limb ischemia undergoing intravenous (n=18) or catheter directed thrombolysis (n=20) with alteplase

  Catheter directed thrombolysis (n=40) Intravenous thrombolysis (n=38) p -value
Age (years) 55.52 ± 16.05 88.55 ± 9.98 0.442
Sex      
     Men (%) 14 (36.84%) 9(23.96%) 0.944
     Women (%) 11 (28.94%) 4 (10.52%) 0.932
Duration of symptoms (days) 5.45 ±3.95 6.38±2.99 0.419
Affected limb      
     Upper (%) 2 (5.26%) 1 (2.63%) 0.608
     Lower(%) 18 (47.36%) 17 (44.74%) 0.618
Cause
     Thrombosis(%) 17 (44.74%) 17 (44.74%) 0.332
      Emboli (%) 3 (7.89%) 1 (2.63%) 0.350
Risk factors  
     Hypertension (%) 10 (25%) 8 (22%) 0.998
      DMa (%) 13 (35%) 12 (33.6%) 0.914
      Smoking (%) 4 (20%) 4(22.2%) 0.867
      IHDb (%) 7(17%) 8 (22%) 0.934
      Anticoagulation (%) 5 (15%) 6 (16.7%) 0.993
Rutherford grade      
      I (n) 0 (0%) 0 (0%) 0.825
      IIa (n) 14 (36.84%) 12 (33.6%)
      IIb (n) 6 (16.7%) 6 (16.7%)
      III (n) 0 (0%) 0 (0%)
ABI c 0.0725 ± 0.13 0.0533 ± 0.08 0.360
a

DM: Diabetes Mellitus;

b

IHD: Ischemic heart disease;

c

ABI: Ankle-brachial index.

The patients’ outcome in two study groups is demonstrated in Table 3. Overall 10 (26.3%) patients underwent limb amputations due to severe ischemia. There was no significant difference between two study groups regarding the incidence of limb amputations (p=0.096). None of the patients experienced major therapeutic side effects including extensive  hematoma  or emergency  of pack  cell injection while 4 (10.5%) experienced minor side effects, all in CTD group. However there was no significant difference between two study groups regarding the frequency of side effects (p=0.017). Those who underwent CDT had significantly higher rate of angiographic improvement of thrombosis when compared to intravenous thrombolysis groups (p<0.001). Although the ABI increased in both study groups after 6 months, there was no significant difference between two study groups regarding the ABI (p=0.360). The VAS decreased significantly in both study groups after 6 months; however both study groups were comparable regarding the VAS score (p=0.316).

Table 3.

Outcome of 38 patients with acute limb ischemia undergoing intravenous (n=18) or catheter directed thrombolysis (n=20) with alteplase in 6-month follow-up.

  Catheter directed thrombolysis (n=20) Intravenous thrombolysis (n=18) p -value
Amputation      
     Forefoot (%) 0 (0%) 1 (2.6%) 0.096
      Below knee (%) 0 (0%) 3 (16.66%)
      Ankle (%) 4 (20%) 2 (11.11%)
Rutherford grade      
      I (n) 10 (50%) 5 (27.7%) 0.088
      IIa (n) 3 (15%) 7 (38.8%)
      IIb (n) 3 (15%) 0 (0%)
      III (n) 4 (20%) 6 (33.5%)
Side effects (%) 4 (20%) 0 (0%) 0.107
ABI changes 0.0725 ±0.13 0.0533 ±0.08 0.360
Angiographic changes (%) 11 (55%) 1(5.55%) <0.001
VAS a score 0.8 ± 2.23 1.33 ± 1.41 0.392
a

VAS: Visual analogue scale

Discussion

Acute ischemia of lower extremities is among the causes of disability and in some circumstances mortality in developing and developed countries [7]. There are several guidelines for management of ALI such as the 2005 ACC/AHA guidelines on peripheral artery disease [16] and the 2012 American College of Chest Physician guidelines on antithrombotic therapy for peripheral artery disease [17]. These guidelines conclude that that CDT is effective and beneficial and is indicated in a subgroup of patients with ALI--patients in whom the signs do not dictate urgent time-critical intervention to avert immediate limb death. These recommendations were based on two randomized trials, the STILE [18] and TOPAS [19] trials, which compared thrombolysis and surgery.The application of endovascular method in treatment of the ALI has recently driven more attraction [20-23].

Tissue plasminogen activator (t-PA) is a drug with epithelial cell origin, so associated with less antigenicity. ABI and toe-pressure test have been both valuable and trusty in evaluation of extremity ischemia. In a study by Brothwayte and co-workers, bolus dose injection of t-PA has been reported as greatly valuable in acute arteriolar ischemia of extremities [24]. In a study by Nilson in Sweden, t-PA therapy has been reported as successful with 40% cases of acute arteriolar ischemia [25]. Pulse spry thrombolysis therapy in acute arteriolar ischemia has been introduced and reported as safe and effective [8]. Positive effects of high dose bolus therapy on obstructive ischemia of femoral artery, has been shown to be effective [26]. In the current study we compared that clinical and angiographic outcome of patients with ALI undergoing thrombolysis via intravenous route or CDT. We found that the clinical outcome as well as complication rate was comparable between two routs of t-PA administration. Most of the studies being performed till now have compared the outcome between surgery and CDT and data comparing the outcome between intravenous thrombolysis and CTD is scarce. Thus we performed that current study demonstrating that there is no difference between intravenous thrombolysis and CDT in ALI.

Thrombolysis has the benefit of being less invasive than surgery. The STILE [18] and TOPAS [19] trials reported that in patients who had received thrombolysis and later required surgical intervention, the magnitude and complexity of the procedure was often less than in those who had not received prior thrombolytic therapy. Thrombolysis is also a potentially attractive alternative to surgery because the culprit lesion can be identified and treated during the procedure with balloon angioplasty or stent placement.

A concern with thrombolysis is the risk of major hemorrhage [27]. Surgery has its own potential serious complications and therefore the specific risks for each patient need to be assessed [27]. In our audit, there was no major complication and adverse event recorded. In the Cochrane review, the stroke/ intracerebral hemorrhage rate was 1.3%, while the major hemorrhage rate of was 8.8 [27]. None of patients in intravenous thrombolysis group in the current study experiences major or minor complications. Given the complication rate, many patients requiring thrombolysis could be appropriately managed on general wards (bed cost approximately AUD $350 per day) if there were suitably trained staff. This would substantially reduce costs to approximately AUD $2,600 and AUD $3,000, respectively.

In conclusion, intravenous and catheter directed thrombolysis with t-PA is a safe and effective method in treatment of acute arteriolar ischemia of extremities. However there both intravenous thrombolysis and CDT are comparable regarding the clinical outcome.

Acknowledgments

We would like to acknowledge the cooperation and patience of all the patients and their families who participated in the study. This study is the result of a fellowship thesis in vascular surgery that is conducted and done in vascular surgery research center (grant number: 89489)

Conflict of interest: None declared.

Note

Clinical Trial Registry: The current study is registered with Iranian Registry for Clinical Trials (www.irct.ir ; IRCT2014100719427N1)

Funding/Support

This study was supported by Deputy Research of Mashhad University of Medical Sciences.

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