The Angiomax Peripheral Procedure Registry of Vascular Events Trial (APPROVE): In-Hospital and 30-Day Results

Peripheral arterial disease (PAD) affects 8–12 million Americans with an estimated 12–20% of the population > 65 years of age afflicted. Approximately 50% of patients are asymptomatic, which may explain why this disease is often under-diagnosed and thus under-treated.¹ As the population ages and awareness increases, the prevalence of PAD will increase. PAD is associated with significant mortality and morbidity, and patients with PAD undergoing procedures are at an increased risk for ischemic and hemorrhagic events.² Peripheral procedures are often technically more complex than percutaneous coronary interventions (PCI), requiring prolonged procedural times and using larger sheath sizes that increase the risk of vascular and bleeding complications.^3–5 The high-risk patient characteristics and complexity of percutaneous peripheral intervention (PPI) procedures suggest a need for predictable and reliable anticoagulation. Currently, there is no approved procedural anticoagulant for use during PPI. Generally, patients with PAD have been treated with long-term oral anticoagulants and/or antiplatelet drugs. Although they appear to offer some benefit, the risks of these drugs may outweigh the benefits.^6,7 Interventions or surgery are typically conducted with a regimen that includes unfractionated heparin (UFH). UFH has historically formed the basis of anticoagulation during PPI, but dosing is empiric and its anticoagulant effects are unpredictable.⁸ Bivalirudin has demonstrated clinical benefit over UFH as an anticoagulant in PCI.^9–11 We therefore undertook this study to assess the safety of bivalirudin as the procedural anticoagulant in patients undergoing PPI of the renal, iliac, or femoral artery. Methods Study Population. The Angiomax Peripheral Procedure Registry of Vascular Events (APPROVE) Trial was an open-label, multi-center, single-arm, clinical trial conducted at 26 centers in the U.S. Patients 18 years and older undergoing percutaneous vascular intervention of the renal, iliac, or femoral arteries were considered for inclusion. Exclusion criteria included, but were not limited to: patients with total occlusion > 15 cm in the superficial femoral artery (SFA), those with cardiogenic shock or bleeding diatheses, and those with platelet count Study Protocol. Patients were pre-treated with aspirin (300–325 mg) and clopidogrel (300 mg) up to 12 hours (h) prior to the intervention. Bivalirudin was administered intravenously at a dose of 0.75 mg/kg bolus followed by an infusion of 1.75 mg/kg/hr for the duration of the procedure. A post-procedural bivalirudin infusion of 0.25 mg/kg/hr and the use of glycoprotein (GP) IIb/IIIa inhibitors were permitted at the discretion of the treating physician. ACTs were collected immediately prior to the bivalirudin bolus, 5 minutes post-bolus, and at the end of the procedure (defined as the removal of the last catheter or guidewire). Sheaths were removed 2 hours after discontinuation of the bivalirudin infusion for all patients unless a closure device was used, in which case the sheath was removed immediately following the procedure. Study Endpoints. The primary endpoint of this trial was procedural success defined as residual stenosis 0.04 seconds duration in two or more contiguous leads or elevated CKMB (or CK in the absence of CKMB) > 3 times ULN in one sample. Major bleeding was defined as intracranial or retroperitoneal hemorrhage, clinically overt blood loss resulting in a decrease of hemoglobin of more than 3 g/dL, any decrease in hemoglobin of more than 4 g/dL, or transfusion of 2 or more units whole blood or packed red blood cells. Minor bleeding was defined as clinically overt bleeding that did not meet the criteria for major bleeding. Bleeding events were also classified as major or minor according to the criteria of the Thrombolysis in Myocardial Infarction (TIMI) Study Group.¹² Also assessed were ACT values, times to sheath removal, ambulation, and discharge, and the use of closure devices during hospitalization. Statistics. Simple descriptive statistics were used to assess the data. Continuous variables were summarized by using means, standard deviations, inter-quartile ranges, and max/min values. Categorical variables were summarized by using frequencies and percentages. A regression analysis to examine the relationship between renal function (creatinine clearance) at entry into the trial and clinical ischemic and bleeding outcomes during hospitalization through 30 days was performed. A p-value of 2 h being reached in each of the 3 vessel types. Median stenosis prior to intervention was 90.0%, with 40% of patients undergoing intervention in > 2 vessels. Procedural success, defined as 250 seconds was achieved in 95.8% (476/497) of patients 5 min after the first bolus. This level was maintained until the end of the procedure in 92.7% (460/496) of patients. Event rates at discharge and 30 days were low and comparable between groups. (Tables 2 and 3) There were no deaths and one MI (0.2%) to day 30. Unplanned revascularization was performed in 4 instances (0.8%) and amputation occurred in 2 patients (0.4%) by 30 days. Overall, protocol-defined major and minor hemorrhage occurred in 2.2% and 8.5% respectively. Rates of TIMI major and minor hemorrhage were 0.4% and 2.0%, respectively. A post hoc regression analysis found that GP IIb/IIIa inhibitor use (n = 22) was associated with increased major and minor bleeding at 30 days (p = 0.023). In contrast, hemorrhagic events were not correlated with ACT levels (p = 0.1411). An analysis of outcomes by renal function was also performed. Although there was no apparent correlation between ischemic or bleeding events and degree of renal impairment, the numbers are too small to say with any certainty that renal function has no impact on outcomes. Closure devices were used in 37.5% of the overall population. For those patients without closure devices, the median time to sheath removal was 2.67 h Median time to ambulation was 8.78 h time to discharge was 20.90 hours, and length of stay was 0.90 days (Table 4). Discussion Bivalirudin provided safe anticoagulation in patients undergoing renal, iliac, or femoral artery PPI. Procedural success was achieved in 95.0% of patients overall, comparable to rates reported in the current literature ranging from 91% to 100%.^13-17 ACT levels were similar among groups, and maintained through the end of the procedure, demonstrating reliable anticoagulation at the dose tested. Ischemic and bleeding events were low, comparable between groups, and compare favorably to reported data with UFH.^13,14,17,18 The data from the APPROVE study demonstrate that bivalirudin is a safe anticoagulant for use during PPI. With heightened awareness and diagnosis of PAD, the number of PPIs being performed has grown. PPIs are technically similar to PCI, however, patients with PAD requiring intervention are, in general, a higher risk population than those requiring coronary intervention. These interventions require prolonged procedure times and larger sheath sizes, factors that are associated with an increased risk of ischemic and bleeding complications post-PCI.^3-5 Furthermore, angiographic thrombus is more often present, and given longer lesion length in some circumstances, the actual thrombus burden is larger than typically found in the coronary vasculature necessitating reliable anticoagulation for PPI.²⁰ Because atherosclerosis is a systemic disease, the risk factors for developing PAD are very similar to those of atherosclerotic disease elsewhere, such as in the coronary arteries. Significant factors include hypertension, hyperlipidemia, and diabetes, all of which have been shown to increase the likelihood of complication during surgery or interventional procedures, including thromboembolic events.^2,21–24 Patients with peripheral atherosclerosis frequently have underlying coronary artery disease (CAD), and therefore those undergoing procedures are at increased risk for ischemic events.^2,25,26 The nature of the patient and the procedure suggests that reliable antithrombotic treatment is necessary to help prevent occlusion and ischemic complications during PPI. However, there is no currently approved anticoagulant for PPI, and a lack of standardization exists among those agents that are used. Although not an approved anticoagulant for PPI, UFH has historically been the procedural anticoagulant of choice based primarily on anecdotal experience and its extensive use for coronary interventions. Ischemic complication rates (death, MI, or revascularization) for UFH in PCI are reported at approximately 7.5% in low risk populations and can double in higher risk patients. Rates of hemorrhage vary widely, ranging between 0.4% and 17%. Studies supporting the use of UFH in PPI are sparse and event rates are not well characterized; however, the literature shows that in-hospital complication rates range from 2.5–32.7%.^20,27 The shortcomings of UFH in association with PCI are well documented,⁸ and it is expected that these same limitations would also apply to PPI. UFH ineffectively inhibits clot-bound thrombin, activates platelets, has unpredictable pharmacokinetics which require frequent monitoring, and possesses immunogenic properties that can lead to heparin-induced thrombocytopenia (HIT).⁸ Its use in patients with PAD may carry more risk than in other patient populations, in that these patients have often had multiple prior interventions and therefore are at greater risk for developing heparin antibodies. Furthermore, studies have found that this patient group demonstrates a hypersensitive platelet response to UFH, which has been associated with thrombocytopenia and may be thrombogenic.^28,29 Aside from the pharmacokinetic limitations of UFH, there is no consensus with regard to heparin dose, method, and length of administration,³⁰ A review of the literature shows heparin doses ranging from 5000 U to 15,000 U^3,13,30,31 and a study conducted by Zaman, et al.³² found that apart from the variety of individual protocol differences between institutions, 75% of physicians surveyed were administering heparin as a bolus only and that none were monitoring clotting times, even in prolonged and complicated procedures. Despite technological advances which have served to decrease ischemic event rates, bleeding still appears to be the most common complication in the realm of percutaneous interventions.³³ Clinical characteristics prevalent in patients with PAD such as renal disease, hypertension, and multi-vessel disease have all been identified as factors predictive of hemorrhagic complications in PCI.^33–35 Kinnaird et al.⁵ found that patients undergoing PCI with longer procedural times and a greater number of guiding catheters experience an increased incidence of major bleeding and transfusions. Almost half of all bleeding events are due to hemorrhage at the vascular access site (VAS).33 Clinical predictors of VAS complications post-PCI include female gender, older age, hypertension, and the presence of PAD, and procedure-related predictors include prolonged procedure time, prolonged sheath dwell time, and the use of UFH.^4,33 The implications of bleeding are quite significant. Major and minor bleeding, as well as transfusion, is associated with a significant increase in adverse events as well as in-hospital and 1-year mortality.⁵ A retrospective analysis of over 10,000 patients who underwent PCI found that those who experienced a complication at the access site had a higher rate of in-hospital ischemic events (including death, MI and CABG), and multivariate analysis demonstrated that peripheral vascular complication was a significant predictor of 1-year mortality.⁴ Kinnaird et al. reported that patients who experienced peripheral vascular complications had a 1-year mortality rate of 7.5% compared to 1.1% of patients without these complications.⁵ Due to the similar clinical and procedural characteristics of PCI and PPI, it can be theorized that patients undergoing PPI would be at similar risk for ischemic and hemorrhagic complications. Bivalirudin, an anticoagulant approved for use in percutaneous transluminal coronary angioplasty (PTCA), has demonstrated significant reductions in bleeding events as well as simultaneous reductions in ischemic events compared to UFH. Because of the benefits observed in PCI, bivalirudin may also provide benefits in PPI. Bivalirudin is a bivalent, thrombin-specific compound. Unlike UFH, bivalirudin: 1) inhibits both clot-bound and circulating thrombin thereby providing more effective inhibition of thrombin and thrombin generation; 2) has a shorter half-life than UFH, which may contribute to reduced bleeding risk; 3) binds specifically to thrombin resulting in a linear and predictable dose-proportional anticoagulant response throughout the procedure, and 4) inhibits thrombin-mediated platelet activation.³⁶ Bivalirudin also eliminates the risk for the development of HIT. In controlled clinical PCI trials, bivalirudin has consistently shown reductions of ischemic and bleeding complications compared to UFH.^9-11 In the Bivalirudin Angioplasty Trial (BAT), bivalirudin reduced the risk of ischemic and bleeding events by 22% and 62%, respectively, when compared to UFH.⁹ In the REPLACE-1 Trial, there was a 19% risk reduction in the composite endpoint of death, MI, and repeat revascularization and a 22% reduction in bleeding events seen with the use of bivalirudin versus UFH with ~ 70% GP IIb/IIIa use in both treatment groups.¹⁰ The REPLACE-2 trial demonstrated that bivalirudin with provisional GP IIb/IIIa inhibition was as effective as UFH and planned GP IIb/IIIa inhibition but with a significantly lower major bleeding rate in the bivalirudin arm (2.4% versus 4.1%, p 11 Limited data regarding hemorrhagic and ischemic complications and the predictors of these events in PPI exist in the literature. Ischemic endpoints are less well defined and bleeding complications rates in elective PPI patients are virtually nonexistent. However, it can be postulated that due to the systemic nature of atherosclerosis, the predictors for events in PCI would be applicable to the PPI population. In general, data suggest that patients undergoing PPI have worse outcomes compared to those undergoing PCI, potentially due to the high comorbidity in PAD. It has been estimated that 20% of PCI patients have diabetes and chronic renal disease (exclusive), and the incidence of these risk factors are higher in patients with PAD. The fact that this population is more prone to hemorrhagic, ischemic, and thrombotic complications underscores the need for optimal anticoagulation during treatment.²⁷ Analysis of the APPROVE data did not demonstrate higher rates of bleeding in patients with increasing severity of renal impairment. Patients with impaired kidney function are at higher risk for poor outcomes in PCI.^35,37 Chew et al.³⁵ conducted a meta-analysis of 3 randomized trials (n = 5,035) comparing heparin and bivalirudin use in PCI, stratified by estimated creatinine clearance. Within the overall population, greater renal impairment was associated with a concomitant increase in ischemic and bleeding events. Bivalirudin was associated with lower rates of death, MI, urgent revascularization, and major hemorrhage. Furthermore, when considering the combined ischemic and bleeding complications associated with PCI, a greater absolute benefit with bivalirudin was seen in patients with increased renal impairment (normal 2.2%, mild 5.8%, moderate 7.7%, severe 14.4%; p trend 27 A prospective study by Shammas et al. resulted in an overall complication rate of 4.2% with bivalirudin (n = 48), compared to a reported event rate of 9.2% in a retrospective study of patients treated with UFH (n = 131) during PPI.^18,20 Another study of 69 interventions demonstrated adequate anticoagulation with bivalirudin, with no adverse events such as bleeding, acute thrombosis, death, or development of HIT.³⁸ Knopf et al. administered bivalirudin to 72 patients undergoing peripheral interventions; there were no reports of major bleeding, death, or stroke, and procedural success was achieved in 100% of cases.³⁹ In addition to reducing ischemic and hemorrhagic events, several PCI and PPI trials have consistently shown reductions in time to sheath removal, ambulation, and discharge post-intervention in patients treated with bivalirudin.^40–44 Allie et al.²⁷ evaluated the use of bivalirudin as the procedural anticoagulant during PPI of the renal and iliac arteries (n = 255). Significant differences were observed for sheath removal time Limitations. Limitations inherent in this study include the lack of a control or comparator arm, a relatively low risk patient population than one might expect in PPI, with low rates of diabetes, smoking, and old age compared to rates reported in the literature, and no codified measure of the degree of need for PPI. Given the potential for ischemic complications in this population, it would be unethical to conduct this study with a placebo arm and illogical to incorporate a UFH control group because there is no standardized dosing. Since bivalirudin is an approved anticoagulant, this trial was designed to assess the safety of bivalirudin in PPI. The lower-risk patient population was unplanned and unexpected. The benefits of bivalirudin in high risk patients undergoing PCI has been demonstrated^9,35,45 but studies among higher risk patients in PPI are needed. Conclusion Bivalirudin provided consistent anticoagulation and similar outcomes in all vessel-types treated at the dose tested. Ischemic and bleeding event rates were low and comparable between treatment groups, making bivalirudin an attractive alternative to UFH during PPI. Data from this study demonstrate that bivalirudin may be a safe and predictable procedural anticoagulant for use in PPIs of the renal, iliac or femoral arteries.

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