Thrombus is highly prevalent in patients with peripheral arterial disease, particularly those with recent symptoms and occluded or subtotally occluded vessels. In a prospective registry of 17 consecutive patients with recent (< 6 months) symptoms and lower-extremity occluded vessels, intravascular ultrasound (IVUS) revealed the presence of a definite thrombus in 16/17 patients (94%). Definite thrombus was present angiographically in only 2/17 patients (11.8%) and therefore was largely underestimated by the angiogram.1
Thrombotic lesions are more likely to embolize during peripheral percutaneous intervention (PPI) with subsequent slow-flow, platelet aggregation and thrombosis. Clinically distal embolization requiring further therapy is likely to result in amputation, longer procedural time, a higher amount of radiation exposure to patient and operator, higher contrast dye use, longer hospital stay, more blood loss and higher cost. Treatment of thrombotic lesions in the periphery is complex and the choice of the best anticoagulant has not been well defined. Unfractionated heparin, bivalirudin and low-molecular weight heparins have all been used alone or in combination with thrombolysis, glycoprotein (GP) IIb/IIIa inhibitors or mechanical thrombectomy in high-risk patients including those with limb ischemia and occluded vessels.2–7
The combination of unfractionated heparin with GP IIb/IIIa inhibitors has been well established in the coronary literature to be superior to heparin alone, resulting in less cardiac enzyme leak and better microperfusion post intervention, probably as a result of less platelet aggregation, slow-flow or distal embolization.8–12 Recent data from PPI also showed a trend toward lower embolization rates with the use of the GP IIb/IIIa inhibitors eptifibatide and tirofiban, and a trend toward less secondary reintervention and improved limb salvage at 6-month follow up.5,6 Although observational data showed that GP IIb//IIIa inhibitors are safe overall in the periphery, their effectiveness in lower-extremity arterial interventions has not always been consistent.13 Currently, there areno clear guidelines or FDA labeling for GP IIb/IIIa inhibitor use in the periphery, and the use of these drugs is inconsistent between operators and centers.
In this study, we sought to define the pattern of use of GP IIb/IIIa inhibitors in the periphery in our center and patient outcomes by retrospectively analyzing data on patients receiving these platelet inhibitors from a prospectively-collected peripheral vascular registry.
Demographic, clinical and procedural data on patients who received GP IIb/IIIa inhibitors during PPI were extracted from an in-hospital prospective registry collecting data from 2 medical centers by 2 operators. Data in the registry are entered by the operators and audited by a monitoring coordinator. Eptifibatide (two 180 micrograms/kg boluses, 10 minutes apart, with a continuous infusion of 2.0 micrograms/ kg per minute for 16–18 hours ) and abciximab (0.25 mg/kg bolus with a continuous infusion of 10 micrograms/ minute for 12 hours) were used. The primary endpoint of the study was procedural success defined as lesion residual less than 30% and TIMI 3 flow in vessels treated with GP IIb/III inhibitors. Safety endpoints included death, major unplanned amputation, major bleeding, thrombocytopenia and vascular complications (atrioventricular [AV] fistula and pseudoaneurysm). The following variables collected by the registry were analyzed:
a. Demographic and clinical variables including indications for the procedure, Rutherford-Baker Class, cardiovascular risk factors, age, gender and body mass index (BMI), ankle-brachial index (ABI), with and without exercise, and laboratory values (white blood cells, hemoglobin, platelets, blood urea nitrogen and creatinine) before the procedure and at the time of discharge.
b. Procedural data including use of closure devices, runoff vessels, the extent and location of significant (> 50%) peripheral disease, type of anticoagulants used, stenosis severity pre- and post intervention, TIMI flow pre- and post intervention, TASC classification, lesion length, vessel diameter, presence of calcium, total occlusion, presence of a angiographic thrombus, success in treating the lesion (< 30% residual), site complication including dissection, thrombosis, embolization, slow-flow and successful recanalization.
c. In-hospital outcomes including death, nonfatal myocardial infarction (MI), major bleeding (a drop in Hb by 3 or more units with a source of bleed, intracranial bleed or retroperitoneal bleed), minor bleeding, atheroembolization, planned and unplanned major and minor amputation, urgent unplanned revascularization, vascular complications including AV fistula or pseudoaneurysm, stroke and renal failure (defined as an increase of creatine by > 0.5 from baseline).
A procedure was considered emergent if it needed to be performed within hours of presentation, urgent if needed to be performed during the same hospital stay and elective when scheduled on a routine basis, typically within a day to a few weeks of an office visit. Also, we defined acute presentation as the presence of symptom onset < 24 hours, subacute < 1 month but > 24 hours, and chronic > 1 month. Furthermore, intravascular flow was documented by the operators immediately after the procedure and was considered “slow” if a TIMI 2 or 1 flow were described. Finally, patients with rest limb pain (Rutherford Class IV) and those with ulcerations (Rutherford Classes V and VI) were labeled as “limb ischemia” patients in this study, in contrast to claudicants (Rutherford Classes I–III).
Patients were also divided into two groups, those who received planned GP IIb/IIIa inhibitors (prior to balloon inflation) and those who received bailout treatment (after angioplasty was initiated). Descriptive analysis was done on all variables on the entire cohort and on the bailout versus planned groups. Continuous variables were expressed as mean ± standard deviation (SD) and dichotomous variables as percentages.
A total of 46 patients (128 vessels) were included in this study (Table 1). These were distributed as iliacs (11.7%), femoral (53.9%) and infrapopliteal (34.4%). The procedure was performed emergently, urgently and electively in 13%, 26.1% and 60.9% of patients, respectively. The mean age was 70.9 ± 11.2 years, and 52.2% of patients were males. The patients’ Rutherford-Baker Classes III, IV and V–VI were observed in 32.6%, 32.6% and 34.8%, respectively. A runoff was considered present if the tibial vessel was patent irrespective of disease severity. The mean runoff was 1.6 ± 1.1 on the right and 1.5 ± 1.0 on the left. Superficial femoral arteries were classified as TASC B 7.4%, TASC C 14.8% and TASC D 77.8%.
Patients had the following comorbidities: current smokers 37%, diabetics 35.8%, dyslipidemics 71.7%, hypertensives 78.3%. Angiographic thrombus was suspected in 45.7% of patients prior and during the procedure. Percutaneous treatment was performed on all vessels using the following techniques: percutaneous transluminal angioplasty (PTA) alone in 27.8%, PTA with stenting in 49.2%, SilverHawk atherectomy (ev3, Inc., Plymouth, Minnesota) with other adjunctive therapies in 10.7% and laser atherectomy (Spectranetics) with other adjunctive treatment in 12.3%.
The primary success endpoint was met in 66.4% of vessels and 69.6% of patients. If success was defined as achieving < 50% residual narrowing and without considering TIMI flow as part of the definition, 94.5% of vessels would have been considered successful. Primary safety endpoints were as follows: death 2.2%, vascular access complication 2.2%, major unplanned amputation 0%, major bleeding 0% and thrombocytopenia 2.2%. One patient underwent minor planned amputation and another experienced minor bleeding.
Treatment with GP IIb/IIIa inhibitors was planned in 13 (28.3%) patients and bailout in 33 patients (71.7%). Reasons for planned GP IIb/IIIa were the presence of angiographic thrombus in 7 (53.8%) patients, advanced limb ischemia (Rutherford-Baker IV–VI) with total occlusions in 5 (38.5%) patients and acute presentation with total occlusion in 1 (7.7%) patient. Among the 13 patients who received planned GP IIb/IIIa inhibitors there were 7 patients treated electively, 3 emergently and 3 urgently. Of the 7 electively treated patients, 5 had advanced limb ischemia (Rutherford-Baker of IV or higher) and 2 were severe claudicants, 1 with an acute presentation and occluded vessel and 1 with an angiographically visible thrombus.
Reasons for bailout GP IIb/IIIa were slow-flow in 16 (48.5%) patients, nonobstructive thrombus with preserved normal flow in 12 (36.4%) patients, poor runoff in 1 (3%) patient and, during the procedure, in 4 (12%) patients for the following stated reasons: total occlusion (2), hazy lesion (1) and no pre-clopidogrel administration.1 In patients who received planned GP IIb/IIIa treatment slow-flow occurred in 1/13 (7.7%) and embolization in 0/13 (0%) patients.
Peripheral arterial disease (PAD) is very thrombogenic and consists of a large percentage of diabetics, hyperlipidemics and smokers,14 conditions all associated with endothelial dysfunction and a hypercoagulable state. Patients with PAD have a heightened inflammatory state similar to patients with unstable angina15 and have a high incidence of coexisting arrhythmias, congestive heart failure and coronary artery disease, conditions associated with thromboembolism. In addition, PAD disease, particularly in limb ischemia patients, has a high prevalence of chronic occlusions,16 which predictably contain atherothrombus usually dynamic and multilayered with coexisting acute, subacute and organized thrombus. Furthermore, PPI itself is very thrombogenic and induces a heightened inflammatory reaction.17 Platelet activation is also a significant problem during PPI and allows the formation of micro and macro platelet aggregates, contributing to thrombosis and distal embolization.18 Finally, the length of the lesion, slow-flow and poor runoff in the lower extremity make the peripheral vascular bed very thrombogenic during PPI because of the extent of iatrogenic injury to the vessel wall and exposure of a larger amount of the subendothelial layers to circulating inflammatory and thrombotic cells and coagulation factors that activate the coagulation pathways.
The effectiveness of GP IIb/IIIa inhibitors in high-risk percutaneous coronary interventions is well established.9–12 Both abciximab and the small molecules eptifibatide and tirofiban were shown to be effective in reducing the combined endpoint of cardiovascular death, nonfatal MI and urgent revascularization. Data also support that these drugs lead to better microperfusion when compared to controls, probably as a result of less downstream microembolization and platelet aggregation.8
The role of these drugs is unclear in high-risk PPI. GP IIb/IIIa inhibitors were used in the setting of acute limb ischemia (ALI),2 , 3 subacute limb ischemia and high-risk lesions.4–6 In one randomized trial of patients with ALI,2 abciximab combined with urokinase showed a lower combined endpoint of surgical revascularization and limb amputation compared to urokinase alone. Also, the RELAX trial3 showed that distal embolization was reduced significantly with the addition of abciximab to reteplase compared to reteplase alone (5% vs. 31%) in patients with ALI. Furthermore, in the Circulate Pilot trial,4 85 patients with severe claudication or CLI were treated with eptifibatide in addition to conventional unfractionated heparin (UFH). The procedure was technically successful in 98.8% of these patients. Of these patients, 1.2% required target vessel revascularization within 30 days. A low rate of major bleeding and thrombocytopenia were reported. In a recent study by Allie et al,5 149 patients with chronic limb ischemia received tirofiban and bivalirudin and were matched to 149 patients who received UFH with no GP IIb/IIIa inhibitors. There was a trend toward less embolization, lower reintervention and higher limb salvage at 6 months in the bivalirudin-tirofiban group. Furthermore, the same group recently published their experience with eptifibatide- bivalirudin combination (n = 162) in treating critical limb ischemia matched to a historic control of patients with CLI treated with UFH without a GP IIb/IIIa inhibitor.6 In this study, the eptifibatide-bivalirudin group showed a trend toward less major access-site complications, secondary reinterventions, and 6-month limb salvage.
Our data indicates that patients who were treated with upfront GP IIb/IIIa inhibitors had a low rate of embolization and adverse events. However, bailout utilization of these drugs appears to be the dominant strategy, possibly because of a lack of large randomized trials supporting a routine upfront use of these drugs in the high-risk PPI patients. In general, these drugs were safe when combined with the various anticoagulants including UFH or bivalirudin, and had a low rate of major adverse events.
Data at this time support a large, multicenter randomized trial of GP IIb/IIIa inhibitors as an adjunctive therapy in high-risk PPI. The primary endpoint of this study needs to be target vessel failure defined as the combined endpoint of embolization rate, amputation, death and reintervention. Currently, we reserve GP IIb/IIIa inhibitor use for patients with angiographically observed intravascular thrombus, acute and subacute presentations and in patients with critical limb ischemia (Rutherford-Baker Classes IV–VI).
Study limitations. This study is limited by its small number of patients and observational nature. Data however have all been collected prospectively at the time of the procedure by the endovascular specialist and closely monitored for accuracy. Also, the study describes a pattern of use of GP IIb/IIIa inhibitors at 2 medical centers and may not reflect a wide pattern of practice. Furthermore, the presence of intravascular thrombus or flow characteristics in the vessels was determined by the operators based on their experience and was not validated prospectively by specific core lab criteria.
1. Shammas NW, Dippel EJ, Gayton L, et al. Prevalence of thrombus in patients with a recent history of claudication or rest limb pain: An intravascular ultrasound assessment. Presented at New Cardiovascular Horizons, New Orleans, September 5–7, 2007.
2. Duda SH, Tepe G, Luz O, et al. Peripheral artery occlusion: Treatment with abciximab plus urokinase versus with urokinase alone — A randomized pilot trial (the PROMPT Study). Platelet receptor antibodies in order to manage peripheral artery thrombosis. Radiology 2001;221:689–696.
3. Ouriel K, Castaneda F, McNamara T, et al. Reteplase monotherapy and reteplase/abciximab combination therapy in peripheral arterial occlusive disease: Results from the RELAX trial. J Vasc Interv Radiol 2004;15:229–238.
4. Rocha-Singh KJ, Rutherford J. Glycoprotein IIb-IIIa receptor inhibition with eptifibatide in percutaneous intervention for symptomatic peripheral vascular disease: The Circulate pilot trial. Catheter Cardiovasc Interv 2005;66:470–473.
5. Allie DE, Hebert CJ, Lirtzman MD, et al. A safety and feasibility report of combined direct thrombin and GP IIb/IIIa inhibition with bivalirudin and tirofiban in peripheral vascular disease intervention: Treating critical limb ischemia like acute coronary syndrome. J Invasive Cardiol 2005;17:427–432.
6. Allie DE, Hebert CJ, Lirtzman MD, et al. Combined glycoprotein IIb/IIIa and direct thrombin inhibition with eptifibatide and bivalirudin in the interventional treatment of critical limb ischemia: A safety and feasibility report. Vascular Disease Management 2006;3:368–375.
7. Shammas NW, Lemke JH, Dippel EJ, et al. In-hospital complications of peripheral vascular interventions using unfractionated heparin as the primary anticoagulant. J Invasive Cardiol 2003;15:242–246.
8. Gibson CM, Kirtane AJ, Murphy SA, et al; TIMI Study Group. Early initiation of eptifibatide in the emergency department before primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: Results of the Time to Integrilin Therapy in Acute Myocardial Infarction (TITAN)-TIMI 34 trial. Am Heart J 2006;152:668–675.
9. Zeymer U, Wienbergen H. A review of clinical trials with eptifibatide in cardiology. Cardiovasc Drug Rev 2007;25:301–315.
10. Islam MA, Blankenship JC, Balog C, et al; EPISTENT Investigators. Effect of abciximab on angiographic complications during percutaneous coronary stenting in the Evaluation of Platelet IIb/IIIa Inhibition in Stenting Trial (EPISTENT). Am J Cardiol 2002;90:916–921.
11. Topol EJ, Lincoff AM, Kereiakes DJ, et al. Multi-year follow-up of abciximab therapy in three randomized, placebo-controlled trials of percutaneous coronary revascularization. Am J Med 2002;113:1–6.
12. Chen SM, Hsieh YK, Guo GB, et al. Angiographic and clinical outcome in STsegment elevation myocardial infarction patients receiving an adjunctive double bolus regimen of tirofiban for primary percutaneous coronary intervention. Circ J 2006;70:536–541.
13. Ansel GM, Silver MJ, Botti CF Jr, et al. Functional and clinical outcomes of nitinol stenting with and without abciximab for complex superficial femoral artery disease: A randomized trial. Catheter Cardiovasc Interv 2006;67:288–297.
14. Shammas NW, Dippel EJ. Evidence-based management of peripheral vascular disease. Curr Atheroscler Rep 2005;7:358–363.
15. Rossi E, Biasucci LM, Citterio F, et al. Risk of myocardial infarction and angina in patients with severe peripheral vascular disease: Predictive role of C-reactive protein. Circulation 2002;105:800–803.
16. Laird JR, Zeller T, Gray BH, et al; LACI Investigators. Limb salvage following laser-assisted angioplasty for critical limb ischemia: Results of the LACI multicenter trial. J Endovasc Ther 2006;13:1–11.
17. Shammas NW, Dippel EJ, Lemke JH, et al. Eptifibatide does not reduce inflammatory markers in patients undergoing peripheral vascular interventions: Results of the INFLAME trial. J Invasive Cardiol 2006;18:6–12.
18. Shlansky-Goldberg R. Platelet aggregation inhibitors for use in peripheral vascular interventions: What can we learn from the experience in the coronary arteries? J Vasc Interv Radiol 2002;13:229–246.