A Safety and Feasibility Report of Combined Direct Thrombin and GP IIb/IIIa Inhibition with Bivalirudin and Tirofiban in Periphe

It is estimated that as many as 20% of Americans ? 65 years old and 50% ? 75 years old have peripheral arterial disease (PAD), a total approaching 14–16 million Americans.^1-4 With our rapidly increasing elderly population, it is likely that the incidence of PAD and diabetes mellitus (DM) will continue to grow. Critical limb ischemia (CLI) is the end-stage of lower extremity PAD in which severe obstruction of blood flow results in ischemic rest pain, ulcers and a significant risk for limb loss. CLI is responsible for an estimated 220,000–240,000 amputations yearly in the United States and Europe, and is a source of significant mortality, morbidity, disability and social and economic costs.^4–9 The annual costs of CLI have recently been estimated to be > $10 billion for the United States alone.⁴Percutaneous peripheral interventions (PPI) are frequently performed as treatment for PAD and CLI. Although technically similar to percutaneous coronary interventions (PCI), PPI outcomes tend to be poorer and carry higher risk as a result of patient and procedural characteristics, with restenosis, bleeding, ischemic events and femoral access complications (FAC) remaining major sources of morbidity, mortality and economic costs.^10,11 Despite recently developed new PPI technology and techniques that have somewhat improved the clinical outcomes for PAD, few advancements have been made in the pharmacotherapy or “endopharmacotherapy” for treating PAD. Therefore, complication rates remain high and may be attributable to the use of unfractionated heparin (UFH) as the antithrombin agent.^10-11 These complications are exceedingly high in patients with PAD and CLI, and suggest the need for new anticoagulation regimens.¹² We believe the high-risk PPI patient population reasonably justifies the need for a novel anticoagulation and antiplatelet treatment strategy such as combined direct thrombin and glycoprotein (GP) IIb/IIIa inhibition, especially in higher-risk CLI patients. Both individually and in combination, GP IIb/IIIa and direct thrombin inhibition (DTI) have shown clinical outcome benefits in both ischemic and bleeding endpoints and in decreasing FACs in PCI.^13-16 Several recent reports have shown DTI to be safe and feasible in treating PAD and describe the potential clinical benefits.^17-18 Recently, Shammas has suggested that GP IIb/IIIa inhibitors may have beneficial effects in treating patients undergoing PPI that are secondary to the significant anti-inflammatory effects of GP IIb/IIIa inhibition¹⁸. However, sparse data exist on the potential synergistic effect of GP IIb/IIIa and DTI in PPI. We therefore performed this study to evaluate the safety and feasibility of utilizing a combination of DTI with bivalirudin (Angiomax,® The Medicines Company, Cambridge,Massachusetts) and GP IIb/IIIa inhibition with tirofiban (Aggrastat,® Merck & Company, Inc., Whitehouse Station, New Jersey) compared to a matched historical UFH group in treating CLI. According to the documented literature, this is the first report describing the use of bivalirudin and tirofiban in PPI to treat PAD and CLI. Methods A retrospective consecutive chart review by trained research staff was undertaken to identify patients presenting with Rutherford classifications 4, 5, and 6 CLI and severe infrainguinal PAD who underwent PPI between January 1, 2000 and January 31, 2003, and were treated with a combination of bivalirudin and tirofiban. Bivalirudin was administered at a 0.75 mg/kg bolus followed by a 1.75 mg/kg/hour infusion for the duration of the procedure, and tirofiban with 10 mcg/kg/minute 30-minute bolus with a peri- and post-PPI 0.1 mcg/kg/minute continuous drip for 12 hours. A historical matched UFH monotherapy control group was also identified. UFH was administered at a bolus dose of 50–100 U/kg, with a target activated clotting time (ACT) > 250 seconds. All patients in both groups required 6-month follow-up. Exclusion criteria included brachial artery access and serum creatinine ? 1.6 mg/dL. Since this was a safety and feasibility study, baseline data were sought in a patient population with relatively normal function to avoid any influence of renal impairment on patient outcomes. Cases were reviewed and matched for demographics, clinical characteristics, technique and operator. Procedural success as an efficacy endpoint was defined as successful PPI with re-institution of flow with 5.0 cm groin hematoma, any complication requiring surgery, any overt procedure-related bleeding with a hemoglobin drop ? 5g/dl, or a ? 2-unit procedure related blood transfusion. Minor complications included all other non-intracranial or retroperitoneal bleeding, a hemoglobin drop ? 5g/dl, and a small (Results Between January 1, 2000 and January 31, 2003, a total of 149 patients presented with CLI and underwent infrainguinal PPI treated with bivalirudin and tirofiban. Patients were available for at least 6-month follow-up. A historical matched UFH control group with equivalent follow-up was identified, treating 149 CLI patients between January 1, 1999 and May 31, 2003, without DTI or GP IIb/IIIa inhibition. Patient demographics and clinical characteristics were well-matched, with no significant differences between the bivalirudin/tirofiban-treated and the UFH control group (Table 1). Procedural characteristics were also matched for operator and vessels treated. Multiple arteries were treated in 45.6% of patients (68/149) in the bivalirudin/tirofiban group. The arteries treated included the superficial femoral (SFA) (98/149), popliteal (51/149), profunda (11/149), and infrapopliteal (110/149) arteries. Procedural and lesion characteristics are detailed in Table 2. The PPI revascularization techniques used included percutaneous transcatheter angioplasty (PTA) with or without stenting, excimer laser revascularization (ELR) (Spectranetics Corporation, Colorado Springs, Colorado), and plaque excision using the SilverHawk™ device (FoxHollow Technologies, Inc., 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 “endopharmacologic” 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 barotrauma, diminish postdilatation pressures (4–6 atmospheres), and a trend towards less stenting were noted in the last half of the bivalirudin/tirofiban group. The sheath sizes used were well-matched between groups, with 6 French (Fr) utiliaztion = 20/149 (13.4%), 7 Fr = 120/149 (80.5%), and 8 Fr = 9/149 (6.0%) in the bivalirudin/tirofiban group, and 6 Fr = 10/149 (6.7%), 7 Fr = 126/149 (83.8%), and 8 Fr = 14/149 (9.3%) in the UFH control group. The rates of procedural success were similar between groups (Table 3), with all failures related to uncrossable 100% occlusions. There were no vascular perforations or dissections requiring emergent surgical treatment. Although not statistically significant, patients treated with bivalirudin/tirofiban had less acute ( 5.0 cm non-surgical hematomas and 2 procedure-related > 2-unit transfusions in the bivalirudin/tirofiban group, and 3 > 5.0 cm hematomas and 3 > 2-unit procedure-related transfusions in the UFH control group. There were no incidents of intracranial bleeding in either group. At 6 months, there were 7 (4.6%) deaths in the bivalirudin/tirofiban group, and 9 (6.0%) deaths in the UFH control group. All deaths were cardiac-related. Statistically significant differences were observed for sheath removal time 50%) than the UFH control group, although this difference was not statistically significant. The decision to repeat angiography or repeat PPI was individualized and at the clinician’s discretion. Discussion Results of this study demonstrate that DTI with bivalirudin can be safely used in conjunction with GP IIb/IIIa platelet inhibition with tirofiban in CLI patients undergoing PPI. Procedural success was achieved in 97.3%, which compares favorably to a 95.9% success rate in a matched UFH control group. The overall mortality rates in these high-risk CLI groups were found to be lower than those reported in the literature in comparable CLI patients.^1,3,6,18 Ischemic and vascular access complications were low and suggest that a treatment strategy using DTI with bivalirudin in conjunction with tirofiban is a safe alternative to UFH during PPI. Endovascular interventions are helpful in reducing overall cardiovascular morbidity and mortality, however, immediate-and long-term clinical outcomes in PPI, especially in CLI, have consistently been reported inferior to similar outcomes in PCI.^16–17 Several distinctive characteristics of PAD and infrainguinal PPI have been identified and are likely responsible for poorer outcomes as compared to PCI.¹⁷ These include an increased incidence of diabetes and renal insufficiency, hypercoagulability, calcification, longer diseased vessels, therefore PTA/stented segments, longer procedural times, increased atherosclerotic and thrombus burden, and a “low-flow” state in the PPI versus PCI environment.¹⁷ These anatomic and procedure-related differences in PPI versus PCI potentially make infrainguinal PPI a higher-risk procedure in terms of ischemic and hemorrhagic complications and potentially result in poor long-term patency outcomes as compared to PCI, realizing a need for a safer and more effective anticoagulation strategy for PPI.^17–19 UFH has been the most widely-used antithrombin; however, the limitations of this agent have been well-documented in PCI.^17–20 In particular, 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.^17–20 Furthermore, there are no known UFH dosing guidelines for PVD, especially for high-risk patients such as those with diabetes mellitus (DM) and chronic renal disease (CRD). Some of the limitations of UFH during PCI have been addressed by the use of GP IIb/IIIa inhibitors to decrease ischemic events; however, rates of bleeding are in turn increased.^{15,16,20–21} The impact of bleeding complications post-PPI is unknown, but recent reports have documented the high clinical and economic costs of bleeding complications post-PCI.^{12,18,21–24} 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 rate has been reported in post-PCI patients who experience a FAC versus patients without complications.²³ Unquestionably, the clinical and economic costs of hemorrhagic and ischemic complications after PCI, and likely PPI, are underestimated and very high. Many of the ischemic and hemorrhagic complications during both PCI and PPI are associated with UFH limitations.^10–11,17 The limitations may be amplified in the PAD and especially the CLI population where predictors of complications are more common, platelet activity is enhanced, and a prothrombotic state is often present^12,17,19 (Table 5). For example, DM and CRD are associated with platelet dysfunction and increased thrombin generation, resulting in a higher incidences of ischemic and bleeding complications post-PCI and an increased risk of amputation and mortality in CLI patients.^25–28 While the incidence of both DM and CRD are reported at approximately 20% in PCI trials,^{15–16,28–30} the incidence in CLI patients is reported at 60–70% and 30–40%, respectively.31–34 Additionally, recent data show that patients with PAD demonstrate hypercoagulability and dysfunctional platelet responses to UFH, potentially increasing complications and underscoring the need for optimization of anticoagulation in PPI.^35–38 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. The direct thrombin inhibitor bivalirudin has consistently demonstrated decreased hemorrhagic complications. Several large PCI trials using bivalirudin have shown a decrease in ischemic complication rates versus UFH, and have reported this agent to be a safer and potentially more efficient anticoagulant than UFH in PPI.^{12,17,36–40} In the REPLACE-2 trial, bivalirudin demonstrated a 68% risk reduction of FACs versus UFH with planned GP IIb/IIIa inhibition (0.8 versus 2.5%, p 13,40 Bivalirudin is removed by proteolytic cleavage (80%) and renal clearance (20%), and a glomerular filtration rate (GFR) weight-based bolus and continuous infusion have proven safe and effective in patients with CRD undergoing PCI and PPI.^{17,34,39–40} In a subset analysis of the Bivalirudin Angioplasty Trial (BAT), in which 75% of the patients experienced some degree of renal dysfunction, complications occurred less frequently regardless of the renal function in the bivalirudin versus UFH group.36 Notably, patients with pre-treatment risk factors of post-MI status and prior treatment with UFH were at increased risk of ischemic and hemorrhagic complications when given UFH; however, these same clinical risk factors did not increase the risk of ischemic and hemorrhagic complications among patients undergoing PTA with bivalirudin.^17,38–40 Several recent single-center reports have demonstrated safety and efficacy using bivalirudin in renal, iliac and femoral PPI.^17,38–40 A pooled meta-analysis of results from 439 PPIs reported by Knopf et al., Shammas et al., Grubbs et al., and Allie et al. demonstrate a procedure success rate > 99% (437/439; 99.5%), no major complications or FACs, and significantly less event rates when compared retrospectively to UFH control groups.^17,38–40 Allie et al. demonstrated significant improvements in sheath removal time and time-to-ambulation after renal and iliac PPI.¹⁷ The recently-completed APPROVE (Angiomax Peripheral Procedure Registry of Vascular Events) trial was a 25-site U.S. multi-center 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/hour infusion until procedure termination).39 This registry confirmed the 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%).³⁹ The data have demonstrated bivalirudin to be a safe and predictable anticoagulant in PPI, with lower ischemic and bleeding complication rates than similar outcomes reported with UFH in PPI.^17,35 A randomized trial in PPI is needed. In general, comparisons of GP IIb/IIIa inhibition across all PCI trials have shown overall benefits. Multiple large PCI trials have shown GP IIb/IIIa utilization to have improved outcomes or benefits in acute coronary syndrome (ACS), DM, CRD, small vessels, complex anatomy, and acute and subacute stent outcomes.^14–16 Reduced mortality and morbidity rates in ACS patients treated with GP IIb/IIIa inhibition have been reported, with the DM subset deriving even greater benefits.^44-47 Potential beneficial GP IIb/IIIa effects in PCI that are likely applicable to infrainguinal PPI include: decreasing distal microembolization and platelet aggregation, decreasing vascular thrombus formation, thus potentially decreasing abrupt PPI closure, increased efficacy of thrombolytic therapy, and improved longer-term revascularization rates with a potential decreased need for secondary re-interventions, especially in the diabetic CLI population.^45–48 Furthermore, data suggest that GP IIb/IIIa inhibitors have significant anti-inflammatory properties, a condition highly prevalent in the peripheral vascular patients.^18,49 In a subgroup analysis of the PRISM-PLUS trial, tirofiban demonstrated superior benefits of GP IIb/IIIa blockage to be greater in the diabetic versus non-diabetic patients with regard to death and MI at 7 and 30 days, suggesting potential clinical differences in GP IIb/IIIa blocking agents.46 These reported positive benefits of GP IIb/IIIa inhibition have resulted in the ACC/AHA 2002 guidelines recommending the use of GP IIb/IIIa inhibition in DM patients with ACS undergoing PCI.⁵⁰ The beneficial PRISM-PLUS DM results, economic considerations, and a shorter half-life resulted in tirofiban becoming our GP IIb/IIIa agent of choice in treating patients with CLI. Tirofiban use in PAD has been reported previously in the literature.^51–53 Allie et al. reported 2 series of acute limb ischemia patients treated with the tirofiban TARGET trial bolus (10 mcg/kg/minute) and 12-hour infusion (0.1 mcg/kg/minute), combined with bivalirudin and continuous tenecteplase (TNK, Genentech, Inc., South San Francisco, California) infusion (0.25–0.50 mg/hour) thrombolysis and in combination with the AngioJet® thrombectomy system (Possis Medical, Inc., Minneapolis, Minnesota) with the novel Power Pulse™ (Possis Medical, Inc.) spray delivery system.^51,53 The combination of bivalirudin and tirofiban, in addition to the mechanical and chemical thrombolytic strategies, were reported to be safe and efficacious. These authors theorized that the addition of GP IIb/IIIa inhibition with tirofiban would lessen the risk and any clinical sequela of distal microembolization. Study limitations. Limitations inherent in this study include the lack of a randomized control arm, the use of a historical matched control for comparison, a single-center experience, the relatively small patient sample size, and the potential for observational and selection bias with the retrospective randomized study design. A detailed analysis of the role of ACTs and other anticoagulation and hemocoagulation parameters was not performed, as this analysis used primarily clinical endpoints. Changing practice patterns and the introduction of new devices and technologies over the study time period could also have introduced bias. Despite these study limitations, the combination of DTI and GP IIb/IIIa inhibition in treating CLI appears to be safe and feasible. Conclusion The combination of direct thrombin inhibition with bivalirudin and GP IIb/IIIa inhibition with tirofiban is safe, feasible, and potentially a more effective anticoagulation and antiplatelet strategy when compared to a matched historical UFH control group utilizing PPI in treating patients with CLI. Randomized data are warranted to validate this novel “endopharmacotherapy” strategy which has allowed us to successfully “treat CLI like ACS.” Email: david.allie@cardio.com

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