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1 Department of Radiology, Medical College of Wisconsin, 9200 W. Wisconsin Ave.,
Milwaukee, WI 53226.
2 Great Lakes Radiologists, 2560 Norman Ct., Brookfield, WI 53045.
3 Department of Radiologists, Our Lady of Lourdes Medical Center, 1600 Haddon
Ave., Camden, NJ 08103.
Received July 5, 2002;
accepted after revision October 1, 2002.
Address correspondence to P. Drescher.
Abstract
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SUBJECTS AND METHODS. Fifty patients with arterial occlusive disease (age range, 40–96 years; mean age, 69 years) were prospectively enrolled at two centers. Eighteen patients (36%) had native artery thromboses, and 32 patients (64%) had graft thromboses. Catheter-directed intraarterial thrombolytic infusion of reteplase (average dose, 0.51 U/hr; range, 0.25–1 U/hr) was combined with IV infusion of abciximab (bolus, 0.25 mg/kg of body weight; 12-hr infusion, 0.125 µg/kg of body weight per minute). Nontherapeutic heparin (100–400 U/hr) was given intraarterially during the thrombolytic infusion.
RESULTS. Complete thrombolysis was achieved in 89% of the patients with native artery occlusions and 94% of the patients with graft occlusions for an overall rate of 92%. The average thrombolysis time was 20.7 hr (range, 4–41 hr) with a mean reteplase dose of 12.1 U (range, 2–23 U). Major hematoma occurred in 12% of the patients, with an average blood transfusion of 3.1 U of packed RBC (range, 1–11 U), and correlated to increased thrombolysis time and dose. No intracranial hemorrhage occurred. The 30-day primary patency rate was 92%. Two patients (4%) underwent amputation, including one major amputation (2%), within 30 days of thrombolysis.
CONCLUSION. The combination of reteplase and abciximab in catheter-directed arterial thrombolysis is feasible and effective. Results of this combination therapy suggest acceptable thrombolysis times and doses with tolerable complication rates. Which patient group might benefit the most from combination therapy and the long-term results of combination therapy still need to be determined.
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The PROMPT (i.e., the Platelet Receptor Antibodies in Order to Manage Peripheral Artery Thrombosis) study [6], for which patients were randomly assigned to receive thrombolysis with or without the addition of a glycoproteins IIb and IIIa receptor inhibitor, showed faster thrombolysis and slightly higher rates of major bleeding in the combination therapy group. That study, however, enrolled only a limited number of patients and used urokinase, a first-generation thrombolytic agent that has been removed from the United States market by the United States Food and Drug Administration [7]. No large-scale study to date has reported the use of a third-generation thrombolytic agent in combination with glycoproteins IIb and IIIa inhibition.
The goal of this study is to report the joint experience of two centers with combination therapy using the third-generation thrombolytic agent reteplase and the glycoproteins IIb and IIIa inhibitor abciximab in catheter-directed thrombolysis. In particular, this article is intended to establish the thrombolytic efficacy, complication rate, and 30-day patency in patients undergoing combination therapy for thrombotic peripheral artery occlusions.
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Patient Selection
For the workup before each procedure, the patient's medical history was
obtained, a physical examination was performed, and the ankle–brachial
indexes were measured within 3 days before procedure. Patients with acute
(<14 days) and chronic (
14 days) peripheral artery thrombosis were
included. Exclusion criteria included acute irreversible limb ischemia;
pregnancy; acute gastrointestinal or genitourinary hemorrhage; recent (<1
month) surgery or major trauma; liver cirrhosis; unwillingness to sign the
consent form; noncorrectable coagulopathy (international normalized ratio >
1.7); thrombocytopenia; and allergy to reteplase, heparin, abciximab, or
contrast medium that could not be treated before the procedure.
Retrospectively, all patients were divided into groups and compared with
each other. Patients with chronic symptoms (14 days) were compared in
terms of thrombolytic infusion length, dose, and complication rate with
patients with acute symptoms (<14 days). The hemorrhagic complications were
correlated with the length and dose of thrombolytic infusion. The time to
complete thrombolysis and the complication rate of patients receiving an
initial bolus were compared with those who did not receive an initial bolus.
The paired Student's t test was used to compare the groups. A
p value of less than 0.05 was considered significant.
Thrombolytic Therapy Protocol
Multi–side-hole infusion catheters were used in a single or coaxial
fashion bridging the thrombosed segment. Reteplase (Retavase; Centocor,
Malvern, PA) was infused at doses ranging from 0.25 to 1 U/hr (mean, 0.51
U/hr). The dosing regimen—including the use of bolus or pulse-spray
techniques at the initiation of thrombolysis—was left to the discretion
of the individual investigator. Eight patients (16%) at OLLMC received an
initial average bolus of 2.1 U reteplase (range, 1–5 U). No mechanical
thrombectomy was performed in any of the patients. Through a separate
peripheral IV line, abciximab (ReoPro; Eli Lilly, Indianapolis, IN) was
administered as an IV bolus at a dose of 0.25 mg/kg of body weight followed by
an IV infusion at a rate of 0.125 µg/kg per minute for 12 hr. The abciximab
infusion was continued for 12 hr regardless of the duration of thrombolytic
infusion. In only one patient, the abciximab infusion was stopped prematurely
because of a bleeding complication.
Through an arterial sheath, heparin was infused at a rate of 400 U/hr (OLLMC) or 100 U/hr (MCW). Thrombolytic therapy was continued until thrombolytic success or failure was documented on angiography. Angiographic follow-up was performed when clinical improvement or clinical deterioration became apparent and the angiographic schedule allowed. After thrombolytic therapy had been completed, the access sheaths were removed immediately and 70% of all access sites (n = 35) were closed with percutaneous closure devices (Perclose, Menlo Park, CA; or AngioSeal, St. Jude Medical, Minnetonka, MN).
Follow-Up
Patient follow-up included clinical evaluation immediately after the
procedure and 30 days after the termination of therapy. Clinical and
thrombolytic success was reported according to the reporting guidelines
established by the Society of Cardiovascular & Interventional Radiology
[8]. Complete lysis was defined
as restoration of antegrade blood flow and reestablishment of pulses with
angiographic evidence of greater than 90% thrombolysis. A major bleeding
complication was defined as an intracranial hemorrhage or bleeding that
necessitated a blood transfusion, surgical intervention, or prolonged hospital
stay.
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Eighteen native thromboses (36%) were treated, two of which were upper extremity thromboses (4%). Thirty-two patients (64%) had graft thromboses. Of these 32 patients, 11 (34%) had venous bypass grafts, and the remaining 21 patients (66%) had prosthetic grafts. Five (10%) of the 50 patients had documented embolic occlusions; in the remaining 45 patients (90%), thrombotic occlusion was the presumed diagnosis.
Of all the patients with a native artery occlusion, the mean duration of symptoms was 30 days (range, 2–180 days) because two patients with documented long-standing upper extremity ischemia (Figs. 1A, 1B) were included in the study group. Most of these patients (10/18 [56%]) had class IIa Rutherford limb ischemia [9], two patients (11%) had class IIb limb ischemia, and six patients (33%) had class I limb ischemia.
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The average duration of symptoms in the patients with a graft thrombosis was 10 days (range, 1–60 days). Most of these patients (18/32 [56%]) had class IIa limb ischemia, and four patients (13%) had class IIb limb ischemia. The remaining 10 patients (31%) had class I limb ischemia.
The length of the occlusions varied (Tables 2 and 3). In the patients with thrombotic graft occlusions, the average length of the occlusions was 45 cm (range, 20–90 cm). The longest occlusions were encountered in five patients with axillofemoral bypass grafts. In patients with native artery thrombotic occlusions, the mean occlusion length was 20 cm (range, 5–60 cm).
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Thrombolytic Success
All but four patients (92%) had complete thrombolytic success. One patient
with embolic occlusion of the femoral artery did not achieve clinical
improvement or angiographic thrombolysis. This patient ultimately underwent
surgical embolectomy and major amputation. A second patient who had chronic
radial artery thrombosis and symptoms of more than 3 months' duration achieved
only partial thrombolysis angiographically because of the lack of outflow into
the palmar arch. A third patient with a femoropopliteal synthetic graft did
not achieve complete thrombolysis because of high-grade stenosis in the tibial
peroneal trunk. Angioplasty was performed to improve the outflow; however,
angioplasty led to a dissection, and the patient underwent surgical revision
of the distal anastomosis and embolectomy of the femoropopliteal graft.
Finally, a patient who had experienced 2 months of increasing claudication and
who was experiencing rest pain had a femoral-to–posterior tibial vein
bypass graft that appeared chronically occluded on the initial angiogram and
did not improve angiographically or clinically after thrombolysis. This
patient was treated with anticoagulation, which led to stabilization of her
symptoms.
The remaining patients (n = 46) had complete thrombolysis with improvement in ischemia of at least one Rutherford class [9].
The 18 patients with native artery thromboses had a mean time of complete thrombolysis of 19.6 hr (range, 4–41 hr). Thrombolytic catheters had to be repositioned in two patients (11%) with popliteal artery aneurysms and one patient (6%) with an iliac artery occlusion. Both patients with popliteal artery aneurysms required prolonged thrombolytic infusion (36 and 41 hr). Two patients (11%) with occluded iliac arteries had a short infusion time (4 hr) and were discharged from the hospital the same day as the percutaneous intervention. The average dose of reteplase administered to patients with native artery occlusions was 12.1 U (range, 2–23 U). In the patients with graft thromboses, the mean time to achieve complete reperfusion was 21.3 hr (range, 4–41 hr). One patient who required 41 hr of thrombolysis had a femoropopliteal graft with no outflow into the distal popliteal artery. After successful thrombolysis of this patient's graft, elective distal popliteoperoneal bypass grafting to reestablish outflow was performed. Another patient who had a prolonged thrombolysis time (36 hr) compared with the rest of this group had a chronic occlusion of the femorofemoral graft that would not allow placement of the thrombolysis catheter initially. In addition, outflow obstruction at the distal anastomosis of the graft was present with lack of runoff. The stenosis at the distal anastomosis was relieved by balloon angioplasty and subsequent operative revision.
Four patients (12%) had a short-term infusion that lasted less than 8 hr. Three patients with occluded femoropopliteal grafts achieved complete thrombolysis in 4–7 hr. One of these patients underwent angioplasty of the distal anastomosis and was discharged from the hospital the same day. The other patients received anticoagulation only. Another patient with an occluded aortofemoral graft limb that was patent angiographically after 7 hr received a stent at the proximal anastomosis and was discharged from the hospital the same day. One patient with femoropopliteal thrombosis developed distal embolization to the previously patent tibioperoneal trunk, necessitating repositioning of catheters.
No correlation was identified between the duration of thrombotic occlusion and the time and dose of thrombolytic infusion. The thrombolysis times for patients with chronic symptoms (mean, 23.5 hr; range, 10–38 hr) were comparable to the thrombolysis times for those with acute symptoms (mean, 21.3 hr; range, 4–41 hr). Patients receiving an initial bolus did not achieve faster thrombolysis than those who did not.
Most patients (30/50 [60%]) underwent angioplasty or stent placement for underlying correctable lesions after thrombolysis. The percentage of patients who underwent an endovascular intervention differed between the two institutions: at OLLMC, a percutaneous intervention was performed in 81% (17/21) of the patients, whereas a percutaneous intervention was performed in 45% (13/29) of the patients at MCW. Seven (14%) of the 50 patients were treated with scheduled surgical intervention, including bypass graft placement or revision and atherectomy. Eight patients (16%) were exclusively treated with anticoagulation.
Complications
The number of periprocedural complications was low, with no deaths or
intracranial hemorrhages. A few patients (6/50 [12%]) had a major hematoma
that necessitated a blood transfusion. The transfusions required an average of
3.1 U of packed RBC (range, 1–11 U).
The patient who needed 11 U of blood products had a remote history of partial colectomy for colon cancer and had repeated retroperitoneal hematomas in the past while undergoing anticoagulation. This patient required surgery to evacuate the hematoma. Another patient developed a spontaneous retroperitoneal hematoma that was remote in relation to the access site and required transfusion of 3 U of packed RBC. No surgical intervention was necessary.
Four additional patients (8%) had major hematomas that necessitated transfusion at the access site. In two of these patients, surgical exploration of the access site and surgical correction of the puncture site were required. In another patient, the access sheath was left in place and was removed during elective surgery. Two (4%) of these 50 patients developed gross hematuria. One patient had intermittent hemoptysis. All these episodes were self-limiting and required neither therapy nor transfusion. Two patients (4%) developed thrombocytopenia with a greater than 50% decrease in the platelet count after the procedure compared with the platelet count before the procedure. One patient developed severe thrombocytopenia with zero platelets 4 days after termination of thrombolytic therapy. This patient developed generalized dermal petechial hemorrhage and antibodies to abciximab. The patient did not need any surgical intervention.
Four patients (8%) developed distal embolization after the initiation of thrombolysis. All patients with distal embolization had lysis times in excess of 24 hr. In one of these patients, toe amputation was needed 5 weeks after successful thrombolysis. One patient (2%) had an occlusion of the access site contralateral to the thrombosed segment due to a malfunctioning closure device. The occlusion had to be repaired surgically. Another patient (2%) had a stroke 32 days after thrombolysis.
A correlation was found between the duration of infusion and hemorrhagic complication. Patients with a major bleeding complication had an average infusion time of 24.6 hr, whereas those without hemorrhagic complications had an average infusion time of 21.7 hr. The mean thrombolytic dose in patients with major hemorrhage (15.7 U) was also higher than that in patients without a hemorrhagic complication (12.1 U). One patient who received an initial bolus experienced an increase in major bleeding complications; however, this increase was not statistically significant.
Thirty-Day Patency and Clinical Outcome
Patients were followed up clinically, including color Doppler sonography
and segmental limb pressures, for 30 days after thrombolytic therapy was
terminated. Only two patients underwent repeated angiography during this time.
Forty-six (92%) of the 50 patients had clinically successful thrombolysis and
experienced persistent clinical improvement in ischemia of at least one
Rutherford class 30 days after termination of thrombolysis.
One patient with thrombolysis failure of a native iliofemoral segment underwent major amputation. In another patient with a chronic radial artery occlusion for which partial thrombolysis had been achieved, the same segment became occluded again 1 week later, and the patient underwent minor amputations. One patient achieved patency of a synthetic femoropopliteal graft initially, but 24 days after successful thrombolysis this patient was admitted to the hospital because the femoropopliteal graft had become occluded again; the patient underwent surgical thrombectomy and revision of the graft and distal anastomosis. In another patient, the femoralto–posterior tibial bypass graft did not achieve angiographic patency, but the patient improved clinically with anticoagulation.
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Additional confounding factors are the recent advent of new second- and third-generation recombinant plasminogen activators and the removal of urokinase, the thrombolytic agent of choice for the last decade [7]. We used reteplase in this study. This agent has a half-life that is similar to that of urokinase but has the advantage of higher fibrin specificity [13, 14, 15]. The initial clinical studies with reteplase showed a high efficacy with an acceptable safety profile at a dose of 0.5–1 U/hr for peripheral artery thrombolysis [16, 17].
The purpose of this prospective study was to assess the safety and efficacy of combining reteplase with a glycoproteins IIb and IIIa receptor blocker. This combination therapy has been studied mainly in patients with acute coronary syndromes, and the results indicate improved efficacy and durability of coronary reperfusion with the combination therapy compared with monotherapy [1, 2]. The combination of full-dose abciximab and half-dose thrombolytic agents resulted in thrombolysis in myocardial infarction grade III flows of 80% (at 90 min) without the addition of substantial hemorrhagic side effects. These initial superior results, however, did not translate into a decrease in 30-day mortality using a combination of half-dose reteplase and full-dose abciximab [18].
The role of a combination of platelet inhibitors and thrombolytic agents at a decreased dose compared with monotherapy of thrombolytic agents in the management of peripheral artery occlusive disease remains unknown. Our pilot study [5] of combination therapy revealed 93% complete thrombolysis with no major hemorrhagic complication, thus suggesting the feasibility and safety of this therapy in the management of acute peripheral artery occlusive disease. Others have investigated various combination therapies for peripheral artery occlusive disease but have taken a different approach. In one study [3], patients were randomized to receive abciximab or acetylsalicylic acid as adjunctive therapy to tissue plasminogen activators as the thrombolytic agent. The patients also received full heparinization and lacing with large doses (5 mg) of tissue plasminogen activators in addition to suction thrombectomy. This aggressive therapy was continued until complete thrombolysis or failure occurred, and the procedure was terminated the same day.
A randomized study comparing patients who received combination therapy (urokinase and abciximab) with those who received urokinase alone with a pulse-spray infusion pump followed by 4000 U/min in addition to thrombus aspiration also used large doses of a thrombolytic agent (25,000 U of urokinase per centimeter of thrombus) [6]. That study revealed faster thrombolysis and a higher amputation-free survival rate in the combination therapy group. Schweitzer et al. [3] documented a lysis time of 75 min, whereas in the PROMPT trial, the reported mean lysis time was 2 hr [6]. In that study, only 12% of all patients achieved complete thrombolysis, termination of therapy, and discharge the same day with a less aggressive approach using uniform catheter-directed thrombolytic infusions excluding mechanical therapy. Furthermore, angiographic follow-up was performed on a nonscheduled basis. This factor might have influenced the mean lysis time, which was significantly higher (20.7 hr) compared with the two trials. The true thrombolysis time for the 50 patients in our study is not clear because patients were not followed up angiographically after achieving Doppler signals or clinical improvement. Not knowing the true thrombolysis time is a clear limitation of our study. Our pilot study showed an indication of significant faster thrombolysis as indicated by patency on Doppler sonography [5]; this finding, however, needs to be proven angiographically.
Other reasons for the increased thrombolysis time in our study might be that the thrombus burden was larger in our study group than in study group for the PROMPT trial (mean length of occlusion, 34 vs 15 cm, respectively) and that our study included patients who had been experiencing symptoms longer than had the patients in the PROMPT trial (mean duration of symptoms, 17.4 vs 14 days, respectively). The average time to angiographically documented complete thrombolysis for our study does not differ significantly from the average time using reteplase alone: 20.7 hr reported by Davidian et al. [16] and 19.3 hr reported by Ouriel et al. [17]. These data dispute the need for combination therapy in light of potent second- and third-generation thrombolytic agents. The mean thrombolytic dose, however, was less in our study (12 U) than that used in both of the other studies (17.7 U [16] and 20.5 U [17]), indicating a potential benefit of adding a platelet inhibitor to the thrombolytic agent.
The decrease of thrombolytic dose influenced the incidence of hemorrhagic complications only minimally. Despite our initial experience without major hemorrhagic complications [5], in this larger study, major hematoma occurred in 12% of the patients. This rate compares favorably with our experience with urokinase (major hemorrhage rate, 33%) and tissue plasminogen activators (major hemorrhage rate, 27%) [19] and is comparable to major complication rates of 5–22% reported in a meta-analysis and two registries using second-generation thrombolytics [20, 21, 22].
The complication rate for our study is lower than that reported by Ouriel et al. [17]. Those researchers found major hemorrhagic complications in 19.2% of the patients when using reteplase monotherapy. In our study, a clear correlation was found between an increased dose of thrombolytic agent and the use of an initial bolus. We found that longer thrombolysis times and higher thrombolytic doses are associated with a higher rate of hemorrhagic complications, although our numbers are too small to make a final conclusion. Davidian et al. [16] report a 6% rate of major hemorrhagic complications that led to a fatal outcome. The bleeding complication rate conceivably is also influenced by the use of heparin as reported by others [12, 23]. This association was not confirmed by Ouriel et al. [17], who did not find an increased incidence of bleeding complication in patients who underwent full heparinization and reteplase infusion.
Finally, the high number of patients treated with arteriotomy closure devices likely contributed to the low incidence of major hemorrhage. Another safety concern is the incidence of severe thrombocytopenia, which led to self-limiting dermal petechial hemorrhage in one patient. This complication is known to occur with abciximab and has been reported in 1% of the patients in large coronary trials [1, 2, 18]. Therefore, routine monitoring of platelet counts is advised; in case of thrombocytopenia, the infusion should be stopped and platelet transfusion initiated if bleeding occurs [24].
The question remains as to which patient group will benefit from combination therapy versus monotherapy. We did not find any apparent differences in time to complete lysis or failure, dose of thrombolytic agent or complication rate in graft occlusions versus native occlusions, vascular territory, or chronicity of symptoms. The rationale for using antiplatelet therapy in combination with thrombolytic infusion is that fibrin degradation in thrombi by plasminogen activators leads to platelet activation, which in turn can lead to thrombolysis resistance and rethrombosis [25, 26]. Abciximab seems to be a suitable choice because it has been shown to have a dethrombotic effect that can lead to thrombolysis and prevent platelet-rich thrombolysis-resistant clots from forming [27]. All of these factors theoretically affect the overall outcome.
The 30-day survival rate of 92% without surgical intervention compares favorably with other studies. In Diffen and Kandarpa's review [28], the 30-day limb salvage rate was 93% in patients who underwent thrombolysis monotherapy. The PROMPT trial [6] reported a similar 30-day limb patency of 92% in the combination group compared with 75% for the monotherapy group. This amputation-free survival benefit continued to be present for several months, which might offset the initial added expense of combination therapy. The long-term benefit of the combination approach in our study still needs to be determined.
In summary, this report on our study of a large series of patients shows the safety and feasibility of a combination therapy of glycoproteins IIb and IIIa inhibitors and thrombolytic agents. The major hematoma rate of 12% compares favorably with those reported for larger studies using those for monotherapy and seems to correlate to infusion times and doses. Initial hopes of a significantly lower hematoma rate with the use of combination therapy did not materialize. Mean thrombolysis times were comparable to those for monotherapy, and the evaluation of this determinant is crucial to find a role for combination therapy in peripheral artery occlusive disease. The clear limitation of this study is the lack of a stringent angiographic follow-up to accurately assess thrombolysis times. However, this strategy seems comparable to the frequent practice in which thrombolytic infusion is performed overnight.
The limited number of patients enrolled in the study did not enable us to identify a subgroup who would benefit from combination therapy. Finding which group of patients would benefit the most from combination therapy appears to be crucial to define the role of this new therapeutic approach in the treatment of patients with acute and chronic peripheral artery occlusions. Lastly, long-term results and cost-effectiveness studies are needed to assess the effects of combination therapy in this patient group.
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