Introduction
It has been suggested that treatment strategies for acute and chronic critical limb ischemia (CLI) can be tailored, analogous to treating chronic, and especially, acute coronary syndromes (ACS).^1,2 Mechanical thrombectomy devices, distal protection devices, excimer laser and drug-eluting stents are just a few examples of device technologies first applied in coronary artery disease and ACS that are now increasingly being utilized in the treatment of CLI. Substantial clinical evidence showing improved outcomes exists, supporting the use of novel antiplatelet and antithrombin strategies utilizing glycoprotein (GP) IIb/IIIa inhibition and direct thrombin inhibition (DTI) in treating ACS and during percutaneous coronary intervention (PCI).^3–6 These results prompted the ACC/AHA 2002 guidelines to recommend the use of GP IIb/IIIa inhibition in diabetes mellitus (DM) patients with ACS undergoing PCI.⁷ Unfortunately, sparse data exist detailing similar “endopharmacotherapies” in treating peripheral arterial disease (PAD) patients, especially in those requiring percutaneous peripheral interventional (PPI) treatment of CLI.

It is estimated that one out of every four patients with DM will face CLI in their lifetime, and that a diabetic patient is 7 to 40 times more likely to suffer an amputation than the nondiabetic patient.^8,9 Similarly, patients with chronic renal insufficiency (CRI) are at higher risk of CLI and amputations, and the incidence of both DM and CRI is significantly higher (2 to 3 times) in the CLI versus the PCI population.^{1,4,5,10–12} It is now known that PAD, DM and CRI are individually and cumulatively associated with hypercoagulability, inflammation, prothrombotic states, increased thrombin generation, platelet dysfunction, and even unfractionated heparin (UFH) and aspirin (ASA) resistance.^13–19 These factors are likely responsible for the higher level of ischemic and hemorrhagic complications during PPI versus PCI, underscoring the need for optimization of antiplatelet and antithrombin strategies in treating CLI.^13–15

GP IIb/IIIa and DTI agents, when used individually or in combination, have demonstrated ischemic and hemorrhagic outcomes benefits in PCI.^3–6,20 Multiple large PCI trials have shown GP IIb/IIIa inhibition to have improved outcomes in patients with ACS, DM, CRI, small vessels, complex anatomy, visible thrombus and acute and subacute stent outcomes, with the DM subsets deriving the greatest benefits.^20–24 The potential for GP IIb/IIIa inhibition to decrease platelet aggregation, therefore minimizing the impact and the role of distal microembolization in CLI patients, is particularly attractive in this clinical setting with already-established, severe, outflow infrapopliteal disease and critically low pedal blood flow.¹ Three recent reports describing macroembolization, retrieved by distal protection devices during lower extremity PPI, further suggest that an “upstream” GP IIb/IIIa platelet inhibition strategy has the potential to improve ischemic or thrombotic outcomes.^25–27 Similarly, DTI with bivalirudin (Angiomax, The Medicines Company, Parsippany, New Jersey) has shown hemorrhagic outcome benefit in PCI. The safety and feasibility in PPI was reported in the multicenter Angiomax Peripheral Procedure Registry of Vascular Events (APPROVE) trial, further strengthening the evidence that a simultaneous combination of DTI and GP IIb/IIIa inhibition may hold promise to improve overall outcomes in CLI patients undergoing PPI.²⁸

It is estimated that CLI is responsible for 220,000–240,000 amputations yearly in the United States and Europe, with an annual cost of $10–20 billion in the United States alone.^6,8,9 The 30-day periprocedural mortality and morbidity rates after an amputation are 4–30% and 20–37%, respectively, with less than 50% ever achieving full mobility.^29–39 The overall 1-year mortality rate after an amputation is 20–30%, with a 3-year mortality rate of >50–60%.^32–38 Any treatment strategy designed to improve the clinical outcomes of CLI would potentially offer significant clinical and economic benefits. It is estimated that just a 25% reduction of amputations could save $2.9–3.0 billion yearly in U.S. healthcare costs alone.^8,32 Therefore, the staggering clinical and economic impact of CLI must be taken into consideration when criticizing the incremental costs of adding new “endopharmaceutical” treatment strategies in managing the challenging clinical scenario of CLI.

Significant data exist that implicate a major role for inflammation in cardiovascular diseases and now PAD.^16,39–41 Recent data suggest that GP IIb/IIIa inhibitors also possess significant anti-inflammatory properties and may have potential clinical benefits during PPI.^42,43 Shammas et al recently published similar results, investigating the role of GP IIb/IIIa inhibition and inflammation in decreasing the vascular inflammation response during PPI in the Integrilin (Schering-Plough Corporation, Kenilworth, New Jersey) reduces inflammatory responses in patients undergoing peripheral vascular interventions (INFLAME) trial.¹⁶ This small, randomized trial (total N = 42) concluded that at low-dose, the UFH inflammatory response was equivalent, as compared with high-dose UFH alone in PPI.¹⁶ There is a paucity of data on the use of combination eptifibatide and bivalirudin in the treatment of CLI. Therefore, this retrospective analysis was performed to assess the safety and feasibility of utilizing a combination of eptifibatide and bivalirudin, compared to a matched historical UFH control group in treating CLI with PPI.

Methods
A retrospective chart review was undertaken by trained research staff to identify CLI patients presenting with Rutherford classifications 4, 5 and 6 who underwent PPI between July 1, 2001 and August 1, 2004, and who were treated with a combination of bivalirudin and eptifibatide. Bivalirudin was administered at a 0.75 mg/kg bolus followed by a 1.75 mg/kg/hr infusion for the duration of the procedure, and eptifibatide was administered with a dose of 180 mcg/kg intravenous bolus, followed by a 2 mcg/kg/min post-PPI continuous infusion for 12 hours. A historical UFH control group (UHG) from our institute was also identified. UFH was administered at a bolus dose of 50–100 units/kg, with a target activated clotting time (ACT) > 250 seconds. All patients in both groups required a 6-month follow up.

Exclusion criteria included brachial artery access and serum creatinine >/- 1.6 mg/dL. Baseline data were sought in a patient population with relatively normal function to avoid any influence of CRI on patient outcomes, considering this was a safety and feasibility study. Cases were reviewed and matched for demographics, clinical characteristics and technique.

Procedural success (PS) as a feasibility and efficacy endpoint was defined as successful PPI with reinstitution of flow with < 30% residual stenosis by visual angiographic evaluation. Other equivalent endpoints included acute (<48-hour) and subacute (< 30-day) vessel thrombosis, 6-month mortality, target lesion revascularization (TLR) and limb salvage (LS) rates. The composite safety endpoint of a major complication included: stroke, intracranial bleeding, retroperitoneal hematoma, pseudoaneurysm, > 5.0 cm groin hematoma, any complication requiring surgery and any overt procedure-related bleeding with a hemoglobin drop of >/-5 g/dl, or >/-2-unit procedure-related blood transfusion. Minor complications included all other nonintracranial or nonretroperitoneal bleeding, a hemoglobin drop of >/-5 g/dl and small (< 5.0 cm) groin hematoma.

Angiographically-relevant distal embolization was defined as any distal emboli (DE) identified periprocedurally, as compared with the initial angiogram. Clinical relevancy of embolization was determined by correlating the pre- and postprocedure symptoms and clinical exam with the angiographic sequence. Distal protection devices were not utilized during this analysis.

Data on vascular access management, times to sheath removal, hemostasis and discharge were also collected. Sheath removal time (SRT) <2 hours was defined as the number (%) of cases in which the sheath was pulled within 2 hours of completion of the PPI. Sheath removal for the bivalirudin/eptifibatide group (BEG) was time-based (60–90 minutes after infusion discontinuation). Vascular closure devices (VCD) were not used in this CLI population. An ACT assessment was not required for the BEG. The sheath removal protocol in the UFH group (UHG) cases required an ACT of 180 sec followed by 30 minutes of manual compression and 4–6 hours of bedrest. Time to hemostasis was defined as the time between sheath removal and when the access site was dry, without oozing. The length of stay (LOS) included time from admission to discharge from the hospital.
Objective follow-up parameters included ankle-brachial index (ABI) at baseline, 1 month and 6 months, and a 6-month duplex ultrasound (DU). Simple descriptive statistics were employed and Chi-square tests were performed on the frequencies to compare treatment groups. All patients were treated with ASA 325 mg and clopidogrel (Plavix, Sanofi-Synthelabo, Inc., New York, New York) 75 mg po for at least 3 days preprocedure and at least 30 days postprocedure.

Results
Between July 1, 2001 and August 1, 2004, a group of 162 patients presented with CLI and underwent infrainguinal PPI treated with BEG. A historical, matched UHG with equivalent follow up was identified, treating 162 CLI patients between July 1, 1999 and May 31, 2004, without DTI or GP IIb/IIIa inhibition.

Patient demographics and clinical characteristics were matched, with no significant differences between the BEG and the UHG (Table 1). Procedural characteristics were also matched for vessels treated. Multiple arteries were treated in 45.1% of patients (73/162) in the BEG. The arteries treated included the superficial femoral (SFA) (101/162), popliteal (53/162), profunda (12/162) and infrapopliteal (116/162). Procedural characteristics are detailed in Table 2.

The PPI revascularization techniques used included percutaneous transcatheter angioplasty (PTA) with or without stenting, excimer laser revascularization (ELR) using the CVX 300^® system (Spectranetics Corporation, Colorado Springs, Colorado) and plaque excision using the SilverHawk™ device (FoxHollow Technologies, Redwood City, California). The PPI groups were matched for PTA/stent and ELR but were unmatched for plaque excision, as this technology was not available prior to 2003. ELR, plaque excision and PTA/stenting were considered technique-equivalent PPIs for the purposes of this analysis.

Self-expanding nitinol stents were used in all vessels stented, and the type and length of stents varied over time, as newer designs became available. A policy to avoid PTA barotraumas and diminish postdilation pressures (4–6 atmospheres), and a trend toward less stenting were noted in the last half of the BEG.
The sheath sizes used were well matched between groups, with the BEG utilizing 6 Fr = 26/162 (16.0%), 7 Fr = 125/162 (77.1%) and 8 Fr = 11/162 (6.7%), and the UHG using 6 Fr = 22/162 (13.5%), 7 Fr = 128/162 (79.0%) and 8 Fr = 12/162 (7.4%).

The rates of PS were similar between groups (Table 3), with all failures related to impenetrable 100% occlusions. There were no vascular perforations or dissections requiring emergent surgical treatment. Although not statistically significant, the BEG had less acute (< 48 hours) thrombosis (1.2% versus 2.5%) and subacute (30-day) thrombosis (1.8% versus 4.3%) compared to the UHG. Three of 4 (75.0%) BEG and 4/7 (57.1%) of the UHG subacute (30-day) PPI thrombosis patients underwent successful repeat PPI. Of the patients with subacute thrombosis not receiving repeat PPI or successful revascularization, 1/4 (25%) and 2/3 (66.6%) of the patients in the BEG and UHG, respectively, required major amputations.

Although not statistically different, PPIs performed in the BEG were associated with fewer overall major (3.7% versus 5.5%) and minor (8.6% versus 12.3%) FAC than in the UHG. Both groups experienced one major FAC requiring surgical repair for excessive bleeding and one nonsurgical retroperitoneal hematoma. The remaining major FAC included three > 5.0-cm nonsurgical hematomas and two procedure-related > 2-unit transfusions in the BEG and four > 5.0-cm hematomas and three > 2-unit procedure-related transfusions in the UHG. There was no intracranial bleeding in either group. At 6 months, there were 5 (3.1%) deaths in the BEG and 7 (4.3%) deaths in the UHG control group. All deaths were cardiac-related.

Statistically significant differences were observed for sheath removal time < 2 hours in the BEG compared to the UHG (74.1% versus 19.1%; p = < 0.0001). Length of stay < 72 hours occurred less frequently in the UHG than in the BEG (69.1% versus 43.8%; p = < 0.0001) and reached statistical significance (Table 3).

At 6 months, the overall secondary reintervention rate approached significance in the BEG compared to the UHG (11.7% versus 16.0%; p = 0.05), with mean times to reintervention being equivalent (24 hours–270 days; mean = 74 days, and 24 hours–259 days; mean = 73 days). A trend toward a statistically significant difference was also found in the 6-month limb salvage rate in the BEG versus the UHG (92.6% versus 87.6).

An analysis of DE revealed angiographically relevant DE in 2.4% (5/169) and 5.5% (9/162) in the BEG and UHG, respectively (Table 4). All DE in the BEG were treated with continuous 18- to 24-hour GP IIb/IIIa infusion, and in 2 of 3 clinically relevant DE, a low-dose continuous bivalirudin infusion of 0.25 mg/kg/hr was started after safe sheath removal and continued for 8 hours. All DE in the UHG were treated with continuous UFH infusion for at least 8–12 hours. Overall, a high percentage of both the BEG and UHG DE had minimal clinical sequelae. Two limited amputations occurred in the UHG. Clinical outcomes of DE are analyzed in Table 4.

The ABI improvements were equivalent for both groups as follows: BEG ABI at 1 month (0.16–0.38; mean 0.24 ± 0.19) and at 6 months (0.17–0.39; mean 0.23 ± 0.17), and UHG ABI at 1 month (0.18–0.31; mean 0.20 ± 0.18) and at 6 months (0.16–0.32; mean 0.24 ± 0.18). At 6-month SFA and popliteal artery duplex ultrasound follow up, the BEG experienced a lower restenosis rate (>50%) than those in the UHG, although this difference was not statistically significant (17.3% versus 24.7%; p = 1.016). The decision to repeat angiography or repeat PPI was individualized and at the clinicians’ discretion.

Discussion
This study demonstrates that the combination DTI with bivalirudin and GP IIb/IIIa platelet inhibition with eptifibatide is both safe and feasible in CLI patients undergoing PPI. PS was achieved in 96.2% of the BEG patients versus 93.8% of the patients in the matched UFH control group. The overall ischemic and VACs were low and suggest that a combination of bivalirudin and eptifibatide is a safe and feasible alternative to UFH during PPI. The low rate of clinically and angiographically evident DE in the BEG group may become clinically relevant, especially with several recent articles published describing a high rate of DE in PPI.^22–24 The potential clinical benefits of this anticoagulation and antiplatelet combination will be discussed.

The clinical, anatomic and procedure-related differences in PPI versus PCI potentially make infrainguinal PPI higher risk for ischemic and hemorrhagic complications and poor long-term PPI patency outcomes as compared to PCI.^1,13,15 UFH has been the most widely used anticoagulant in PPI, however the limitations of this agent have been well documented.^14,44 UFH is unable to inhibit clot-bound thrombin, thus leaving thrombin free to generate even more thrombin. UFH also stimulates platelet activation and aggregation, which increases the likelihood of a thrombotic event, and the unpredictable anticoagulant effect increases the risk of bleeding, which has been well-described in PCI.^1,28,45,46

The clinical impact of bleeding and thrombotic complications post-PPI is poorly known, but recent reports have documented the high clinical and economic costs of bleeding complications post-PCI.^30,45–48 In patients experiencing major or minor bleeding post-PCI, significant increases in in-hospital, 30-day, and 1-year adverse events have been reported. A 7.5% versus 1.8% 1-year mortality has been reported in post-PCI patients who experience a FAC versus patients without FAC complications.⁴⁶ In a prospective PPI study by Shammas et al using bivalirudin (N = 48), a 4.2% overall complication rate was reported compared to an overall PPI rate of 9.2% in a retrospective comparison with UFH (N = 131).^13,49 Unquestionably, the clinical and economic costs of hemorrhagic and ischemic complications after PCI, and likely PPI, are underestimated and high.

The known limitations of UFH are likely associated with the ischemic and hemorrhagic complications during PCI and PPI. These limitations are potentially even more problematic in the CLI patient population where the known risks for complications are higher, a proinflammatory state already exists and the incidence of DM and CRI are significantly higher than in the PCI population. It has now been shown that patients with PAD demonstrate inflammation, hypercoagulability and dysfunctional platelet responses to UFH, potentially increasing complications and underscoring the need for optimization of anticoagulation in PPI.^40,50,51

The combined use of direct thrombin and GP IIb/IIIa inhibition in PPI may have significant advantages in reducing ischemic, thrombotic, and hemorrhagic complications in high-risk CLI patients.^1,44,49 The direct thrombin inhibitor, bivalirudin, has consistently demonstrated decreased hemorrhagic complications in large PCI trials.^2,6 In the REPLACE-2 trial, bivalirudin demonstrated a 68% risk reduction of FAC versus UFH with planned GP IIb/IIIa inhibition (0.8 versus 2.5%; p < 0.001), and a significantly lower overall bleeding rate (2.4 versus 4.1%; p < 0.001) in the bivalirudin plus provisional GP IIb/IIIa arm.⁶ The recently completed APPROVE (Angiomax Peripheral Procedure Registry of Vascular Events) trial was a 25-site U.S. multicenter registry of 505 patients undergoing renal, iliac and femoral PPI utilizing bivalirudin as the sole anticoagulant with the REPLACE-2 dose (0.75 mg/kg IV bolus followed by a 1.75 mg/kg/hr infusion until procedure termination).²⁸ This registry confirmed several favorable single-center reports, with >95% overall procedural success, no deaths at 30 days, low rates of TIMI major and minor hemorrhage (0.4% and 0.2%, respectively) and a low secondary re-intervention rate (0.8%).²⁸ Several advantages of replacing UFH with DTI as the anticoagulation foundation in our experience in treating CLI include: avoidance of UFH and its limitations, the known lower bleeding complication rates of DTI, optimal and more predictable anticoagulation, the ability to effect clot-bound thrombin and the known outcomes advantages of DTI in DM and CRI patients.

GP IIb/IIIa use in PAD has been reported previously in the literature.^1,16,52–56 Allie et al reported 2 series of acute limb ischemia patients treated with the tirofiban (Aggrastat^®, Guilford Pharmaceuticals, Inc., Baltimore, Maryland) TARGET trial bolus (10 mcg/kg/min) and 12-hour infusion (0.1 mcg/kg/min) combined with bivalirudin and continuous tenecteplase (TNK, Genentech, South San Francisco, California) infusion (0.25–0.50mg/hr) thrombolysis.^1,53 The combination of DTI and GP IIb/IIIa inhibition was also reported in combination with the AngioJet^® (Possis Medical, Inc., Minneapolis, Minnesota) in the novel Power-Pulse^® (Possis Medical, Inc.) spray delivery system.² The combination of bivalirudin and tirofiban in addition to the mechanical and chemical thrombolytic strategies were reported to be safe and feasible. The authors theorized that the addition of GP IIb/IIIa inhibition to DTI would lessen the risk and any clinical sequela of distal microembolization.

In the multicenter BLASTER trial, Ansel et al reported the clinical outcomes of SFA stenting with and without abciximab (ReoPro^®, Eli Lilly & Company, Indianapolis, Indiana).⁵⁴ Adjunctive GP IIb/IIIa inhibition was found to be safe, but did not demonstrate an identifiable effect. This trial was not designed to evaluate CLI or microembolization, and was limited by its small sample size and midway point discontinuation.

Allie et al first reported safety and feasibility in “treating CLI like ACS” in 149 CLI patients treated with PPI, DTI and tirofiban.¹ In a retrospective comparison with a matched UFH control group, Allie et al reported no increase in bleeding with less angiographically relevant DE (4/49 [1.3%]; 9/149 [5.4%]).¹ A trend towards statistical significance was found in the 6-month secondary re-intervention and limb salvage rates of 10.7% versus 18.8% (p = 0.0501) and 93.9% versus 88.5% (p = 0.053), respectively in the DTI/GP IIb/IIIa group versus the UFH group.¹

Rocha-Singh reported safety in combining abciximab with reteplase (Retavase^®, Centocor, Inc., Malvern, Pennsylvania) in 13 patients.⁵⁵ Rocha-Singh also reported the CIRCULATE pilot trial utilizing eptifibatide and UFH in 85 patients undergoing PPI for severe claudication and CLI.56 A low rate of major bleeding (3.5%) and thrombocytopenia (1.2%) was again reported, demonstrating safety with eptifibatide in PPI. Additionally, high levels of platelet inhibition (> 92%) were determined by the Ultegra Rapid Platelet Function Assay (RPFA) (Accumetrics, Inc., San Diego, California). No patient required repeat PPI during hospitalization, and 1/85 (1.2%) required repeat PPI within 30 days. Distal embolization rates were not provided, but this trial lends further evidence of the safety and feasibility of combining novel antiplatelet and anticoagulation strategies in treating patients with complex PPI. The high platelet inhibition rate measured and reported by Rocha-Singh, in combination with the known, more optimal anticoagulation provided by DTI with bivalirudin, at least in theory, may be responsible for the low complication rates and potentially improved clinical outcomes reported in both the CIRCULATE pilot trial and this report. There were no statistical differences in clinical outcomes or complications between the BEG and UFH group, but statistical differences were achieved in LOS and SRT. It is likely that the larger LOS in the UFG is directly related to the longer SRT and a tendency to slowly ambulate CLI patients and keep them in the hospital overnight for groin observation the longer the sheath is in place. A shorter SRT would allow potentially earlier ambulation, therefore shorter LOS, but also potentially decrease ischemic time and a source for thrombotic complications with an obstructive sheath in a CLI patient with a high incidence of bilateral iliofemoral arterial disease.

Study Limitations
Multiple limitations inherent in this report include the following: lack of a randomized control arm and the use of a historical matched control group; a single-center, relatively small size experience; the potential for observational and selection bias with the retrospective nonrandomized study design; lack of a detailed analysis of ACTs and other anticoagulation parameters; and the reporting of primarily clinical endpoints with few “hard” objective measurable endpoints, which has been an “Achilles’ heel” of many PVD trials. Economic variables were not analyzed, therefore no definitive conclusions regarding the costs or cost saving with a shorter SRT or LOS can be concluded. Additionally, the rapid evolution of device technology over the timeframe of this analysis and changing practice patterns could also result in the introduction of bias into this analysis.

Conclusion
With the advent of novel lower-profile device technologies to treat complex CLI and infrapopliteal disease treated more often and more successfully, comes the realization that the potential for distal emboli and distal microembolization are likely “the rule,” not the exception. This realization is becoming undeniable as distal protection devices and novel mechanical thrombectomy devices show us the evidence, and we now embark regularly to cross and treat CTOs of all infrainguinal vessels. Lessons learned from “upstream” antiplatelet and direct thrombin inhibition in the high-risk PCI patients are likely applicable to the CLI patient population. The combination of GP IIb/IIIa inhibition with eptifibatide and direct thrombin inhibition with bivalirudin potentially provided an optimal PPI anticoagulation and antiplatelet strategy in treating our CLI patient population when considering the known limitations of UFH and the complexity of achieving successful, long-term interventional revascularization outcomes in this patient population. A randomized multicenter trial is warranted to properly validate these theoretical and clinical issues.