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1
Department of Radiology, University of Utah School of Medicine, 1A-71 SOM, 50
N. Medical Dr., Salt Lake City, UT 84132.
2
Present address: Department of Diagnostic Imaging, Kaiser Moanalua Medical
Center, 3288 Moanalua Rd., Honolulu, HI 96819.
Received June 4, 2001;
accepted after revision August 30, 2001.
Address correspondence to H-C. Yoon.
Abstract
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MATERIALS AND METHODS. We retrospectively reviewed our experience with the use of a GP IIb/IIIa receptor inhibitor, eptifibatide, during thrombolysis in 17 patients with acute lower extremity arterial occlusions who also received intraarterial recombinant tissue plasminogen activator (rt-PA) and heparin. Four of the 17 patients received their loading dose of eptifibatide by direct intraarterial injection, whereas the remaining 13 received an IV loading dose. We compared their results with those of 11 other patients who received only rt-PA and heparin with respect to success and complication rates, duration of thrombolytic therapy, and total rt-PA dose.
RESULTS. We found no significant difference in successful outcome (p = 1.00), major complications (p = 1.00), duration of therapy (p = 0.21), or total rt-PA dose (p = 0.67) between those who received eptifibatide and those who did not during thrombolytic therapy. However, those patients who received an intraarterial loading dose of eptifibatide required substantially less rt-PA (9.0 ± 4.4 mg vs 38.9 ± 30.7 mg) to achieve successful thrombolysis.
CONCLUSION. The adjunctive use of a GP IIb/IIIa platelet receptor inhibitor during thrombolysis for arterial occlusions may decrease the total dose of rt-PA required for thrombolysis without compromising success or complication rates. A prospective randomized study is needed to confirm that inhibitors of the GP IIb/IIIa platelet receptor can facilitate thrombolytic therapy in patients with acute lower extremity arterial occlusions.
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The 1999 recall of urokinase by the United States Food and Drug Administration forced many interventional radiologists to begin the use of recombinant tissue plasminogen activator or rt-PA (Activase [alteplase]; Genentech, San Francisco, CA) or the recombinant deletion mutant tissue plasminogen activator (Retavase [reteplase]; Centocor). A prior prospective randomized trial comparing urokinase and alteplase showed that both are equally effective at thrombolysis with no significant difference in major complication rates [12]. However, when we began to use alteplase at our institution, we subjectively noticed an increase in minor hemorrhagic complications that was supported by anecdotal reports from other institutions. Because bleeding complications appeared to increase with longer infusion times, we hypothesized that the use of a GP IIb/IIIa inhibitor might reduce the total infusion time and decrease the incidence of bleeding complications. The recent availability of a much less expensive GP IIb/IIIa inhibitor, eptifibatide (Integrilin; Cor Therapeutics, San Francisco, CA), further spurred our interest in the adjunctive use of GP IIb/IIIa inhibitors during thrombolysis for acute peripheral arterial occlusions.
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Among the 17 patients who received eptifibatide, four received the recommended loading dose directly into the thrombus (intraarterial bolus injection), whereas the remaining 13 received the loading dose IV. All 17 patients received a continuous IV eptifibatide drip after the loading dose.
All patients who underwent thrombolysis had heparin administered through an arterial sheath. Among the patients who did not receive eptifibatide, seven patients received a titrated dose of heparin in which activated partial thromoplastin time was maintained at a level of 60-90 sec. The remaining four patients received a lower dose of heparin (300-500 U/hr). In the group who received eptifibatide, every patient received a low dose of heparin (300-500 U/hr).
Thrombolysis was considered successful if there was restoration of antegrade flow with complete or near complete lysis of thrombus as defined by the Working Party on Thrombolysis in the Management of Limb Ischemia [13]. Thrombolysis was considered unsuccessful if sufficient residual thrombus remained to preclude normal antegrade flow or if a complication required early cessation of therapy.
We compared the occurrence of only major complications in the two groups. A major complication was defined as any complication that required surgical intervention—such as a fasciotomy or hematoma evacuation—or a blood transfusion as a consequence of thrombolysis. Complications that occurred but were not believed to be directly associated with thrombolysis, such as a postoperative wound infection or pneumonia after a surgical revision performed during the same admission as that for thrombolysis, were not compared, nor were minor complications, such as an access site hematoma that did not require evacuation or blood transfusion.
The duration of therapy was calculated by checking the medical record to determine the time (to the nearest half-hour) at which thrombolytic therapy was begun and the time at which thrombolysis was terminated. The doses of rt-PA, heparin, and eptifibatide used for each patient were recorded. All surgical procedures performed during the patients' admission for thrombolysis were also noted.
The SPSS statistical package (version 9.0; SPSS, Chicago IL) was used. Comparisons of continuous variables were performed using the Mann-Whitney test. Comparisons of nominal variables were performed using the chi-square or Fisher's exact test. A value of p less than 0.05 was considered significant.
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Eleven patients undergoing catheter-directed thrombolysis received only rt-PA and heparin, whereas 17 received eptifibatide in addition to rt-PA and heparin. Summary statistics are presented in Table 1. There was no significant difference between the patients who received eptifibatide and those who did not with respect to age, sex, total dose of rt-PA required for thrombolysis, duration of thrombolysis, success rate, or complication rate.
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The group who received eptifibatide was further separated into those who received intraarterial delivery of the eptifibatide loading dose and those who received an IV loading dose. Statistical data are presented in Table 2. No significant difference between those who received the loading dose of eptifibatide IV and those who received it intraarterially with respect to age, sex, duration of thrombolysis, success rate, or complication rate. However, those who received an intraarterial loading dose of eptifibatide required a substantially lower total dose of rt-PA.
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When we compared the four patients receiving an intraarterial loading dose of eptifibatide with those patients who did not receive eptifibatide, we found no significant difference between cohorts with respect to age (p = 1.00), sex (p = 0.57), duration of thrombolysis (p = 0.06), success rate (p = 0.95), or complication rate (p = 0.84). Again, those who received an intraarterial loading dose of eptifibatide required a substantially lower total dose of rt-PA than those who did not receive eptifibatide (p = 0.05).
Two patients among the 11 undergoing thrombolysis with rt-PA and heparin failed to achieve successful thrombolysis. One patient, an 84-year-old man who presented with occlusion of his right popliteal and trifurcation arteries, experienced a significant drop in hematocrit (from 32% to 26%) after 45 hr of thrombolysis. He was given 2 U of packed RBC; the increase in hematocrit was 28%, suggesting there was continued bleeding. Therefore, thrombolysis was discontinued before any clinically relevant thrombus in his trifurcation arteries occurred. This patient eventually required an above-the-knee amputation of the affected extremity. The second patient, a 62-year-old man with occlusion of his aortofemoral and left-to-right femorofemoral bypass grafts, required surgical evacuation of a hematoma in his arm after 6 hr of lytic therapy administered through a catheter placed via the left brachial artery. No major lysis had occurred in his occluded grafts at the time of surgical intervention. This patient underwent axillobifemoral bypass.
Two patients in the group treated with eptifibatide failed to achieve successful thrombolysis. The first patient, a 79-year-old man with occlusion of his left popliteal and trifurcation arteries, developed left leg compartmental syndrome 12 hr after the initiation of thrombolytic therapy; this complication required termination of thrombolysis and emergent four compartment fasciotomy. This patient eventually underwent an above-the-knee amputation of the left lower extremity. The second patient, a 76-year-old woman, presented with limb-threatening ischemia due to an occluded left femoropopliteal bypass graft. After 16 hr of thrombolytic therapy, the graft was clear of thrombus, but no patent outflow vessel was present, resulting in a standing column of contrast medium in the graft. Because the left calf and foot showed neuromuscular compromise with tissue necrosis, thrombolysis was terminated. She subsequently underwent a left knee disarticulation.
Among the nine patients who underwent successful thrombolysis with rt-PA and heparin alone, three patients subsequently had vascular surgery. One 82-year-old man was found to have a superficial femoral artery aneurysm after thrombolysis. He underwent a femoral popliteal bypass procedure to exclude the aneurysmal segment of artery. The second patient, a 66-year-old man, underwent surgical revision of a stenosis at the proximal anastomosis of his existing right femoral-anterior tibial artery bypass graft. The third patient, a 61-year-old man, underwent a short-segment bypass for a right popliteal aneurysm that caused his extensive arterial occlusion. Two other patients in the group who did not receive eptifibatide underwent endovascular interventions after successful thrombolysis. Both of these men had successful placement of intravascular stents for underlying stenoses in their common iliac arteries (Fig. 1A,1B,1C). The remaining four patients in the group who did not receive eptifibatide were treated with anticoagulation without any other intervention. In one patient, a 26-year-old woman who initially presented with occlusion of her right popliteal and trifurcation arteries, the cause of thrombosis was believed to be her previously undiagnosed protein S deficiency. In the three other patients, no focal underlying lesion was identified.
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Among the 15 patients who underwent successful thrombolysis with rt-PA, heparin, and eptifibatide, six patients required vascular surgery. These included two patients who underwent revision of their existing bypass grafts because a culprit stenosis was identified after successful thrombolysis. Two other patients both underwent a revision of their existing grafts with placement of a graft extension (Fig. 2A,2B,2C). Another patient, an 82-year-old man, underwent right popliteal—peroneal bypass grafting because of underlying disease in the native popliteal artery. In the case of the sixth patient, who had residual thrombus in the left common iliac artery despite restoration of flow, the referring vascular surgeon requested that the patient undergo operative thrombectomy rather than angioplasty or a stent procedure. One additional patient underwent right anterior tibial artery angioplasty rather than a surgical bypass.
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Three patients who received only rt-PA and heparin suffered major complications. These included the two patients who had unsuccessful thrombolysis: one who suffered a major drop in hematocrit and required a blood transfusion, and the other who required surgical evacuation of a hematoma. The third patient, a 51-year-old man, underwent successful left common and external iliac artery thrombolyis with subsequent left common iliac artery stenting. However, during the immediate postprocedure period, the patient developed abdominal pain and became hypotensive. Emergent abdominopelvic CT revealed a large retroperitoneal hematoma. The patient received a blood transfusion, and no further interventions were required.
Five patients in the eptifibatide group experienced major complications, including one patient who had unsuccessful thrombolysis and developed compartmental syndrome. Another, a 33-year-old man, required surgical evacuation of a hematoma at the right groin access site after successful lysis of left popliteal and trifurcation vessel occlusions. At surgery, the major bleeding site proved to be the adjacent femoral vein that was presumed to have been injured during initial arterial entry. The third patient, an 82-year-old woman, became tachycardic and intermittently hypotensive shortly after successful thrombolysis of her left femorotibial bypass graft. She was found to have retroperitoneal hemorrhage and required resuscitation with fluid and blood transfusion. The fourth patient, a 27-year-old man, developed compartmental syndrome despite successful thrombolysis requiring only a 5-hr infusion. This patient required four compartmental fasciotomies. The fifth patient, an 81-year-old woman, underwent successful thrombolysis of an occluded right limb of an aortobifemoral graft over a period of 6 hr 30 min. However, she developed a large symptomatic access site hematoma in the left brachial artery that required surgical evacuation. No patient in either group died during hospitalization for thrombolysis.
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Tepe et al. [11] have shown that the use of the irreversible GP IIb/IIIa platelet receptor inhibitor abciximab was safe when used in combination with urokinase in the setting of acute peripheral arterial occlusions. However, the high cost of this monoclonal protein fragment limits its usefulness in today's cost-conscious environment. Furthermore, abciximab binds irreversibly to the platelet receptor and results in receptor blockage with the long biologic half-life of 24 hr [14]. Because the newer small-molecule inhibitors of the GP IIb/IIIa platelet receptor are peptide-based molecules, their cost of production is less than that of the recombinant protein abciximab. The two small-molecule inhibitors currently available in the United States: tirofiban (Aggrastat; Merck Pharmaceutics, Whitehouse Station, NJ) and eptifibatide are reversible inhibitors with a much shorter biologic half-life of 1-2 hr [15, 16]. The lower cost and shorter half-life of the small-molecule GP IIb/IIIa platelet receptor inhibitors make them attractive agents for adjunctive use in thrombolysis of acute peripheral arterial occlusions if they can be shown to have some beneficial effect on the efficacy, safety, or duration of thrombolytic therapy.
The results of this preliminary investigation suggest that there may be a role for GP IIb/IIIa platelet receptor inhibitors during thrombolytic therapy. The small number of patients in our study made detection of small differences in end points difficult. The small subject pool likely explains the lack of significant difference found in the shorter duration of thrombolytic therapy when we used a GP IIb/IIIa platelet receptor inhibitor. There was a significant difference in the total dose of thrombolytic agent and a trend toward a shorter duration of therapy found in the results for those patients who received the loading dose of eptifibatide directly into the thrombus. The adjunctive use of eptifibatide did not produce the hoped-for reduction in major complication rates or an improvement in success rates.
As with all retrospective studies, it was not possible to control for all of the variables associated with thrombolytic therapy. Hence, there was a range of rt-PA and heparin doses used in these patients. Ideally, all patients who did not receive eptifibatide should have received rt-PA at 0.05 mg/kg per hour and should have received heparin at a dose that maintained the activated partial thromoplastin time at 60-90 sec, which were the levels found to be efficacious in the STILE study [12]. However, several authors have suggested that lower infusion rates for rt-PA, on the order of 1.0 mg/hr, may be acceptable for patients with acute arterial occlusions [13, 17, 18]. All of the patients in this study received rt-PA at an infusion dose between 0.5-2.0 mg/hr. There is also no consensus on the concomitant use of heparin to facilitate thrombolysis [17, 18]. Most patients whose records were reviewed for this study received low-dose heparin infusions (300-500 U/hr) to reduce the risk of thrombus forming at the arterial sheath rather than titrating heparin to keep the activated partial thromboplastin time at 60-90 sec. However, the first seven patients who received only rt-PA received a titrated heparin dose.
The time has arrived to critically reevaluate thrombolytic therapy for the treatment of peripheral arterial occlusions. Recent reviews have found considerable variation in the drugs and dosages used for thrombolysis and in reported results [17, 18]. For example, of the 20 clinical studies of rt-PA for peripheral arterial occlusions cited by Valji [18] in a review article, no two used the same infusion protocol. Reported success rates for the use of rt-PA ranged from as low as 50% to as high as 100% [19, 20]. Mean duration of therapy ranged from 90 min to 27 hr [21, 22]. Major bleeding complications alone ranged from no complications to a rate of 35% [22, 23]. Much of this variability likely arises from differences in patient selection, infusion protocols, and specific definitions for success or complications. However, these differences make it extremely difficult to compare results from one study with those from other studies.
In a recent study, Swischuk et al. [24] reported on 70 patients with acute peripheral arterial occlusions, 60 of whom were treated with rt-PA at a constant dose of 1.5 mg/hr and a titrated regimen of heparin. Successful thrombolysis was achieved in 60 patients (86%) with a mean thrombolysis duration of approximately 28 hr. Major bleeding complications—defined as any hemorrhagic event leading to surgery, transfusion, extended hospitalization, or decrease in hematocrit of 15% or hemoglobin of 5 g/dL—occurred in 33 patients (47%). The numbers from our study are comparable: We found thrombolysis was successful in seven (78%) of nine patients, the mean duration of thrombolysis was greater than 25 hr 36 min, and major bleeding complications occurred in three (33%) of nine patients in the group who received only rt-PA and heparin. These similarities confirm that thrombolysis for acute peripheral arterial occlusions remains an effective treatment requiring considerable time and risk. These results also reaffirm the need to carefully assess the most appropriate method to perform thrombolysis, including the possible use of GP IIb/IIIa inhibitors to reduce lysis times and rt-PA doses, without impairing efficacy or safety.
The adjunctive use of a GP IIb/IIIa platelet receptor inhibitor during thrombolysis for acute lower extremity arterial occlusion may decrease the total dose of rt-PA required for thrombolysis but does not significantly improve rates of success or major complications. Prospective randomized comparison studies are needed to determine if the adjunctive use of a GP IIb/IIIa platelet receptor inhibitor is of clinical benefit in the treatment of acute peripheral arterial thrombolysis.
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