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Use of Bivalirudin as the Foundation Anticoagulant during Percutaneous Peripheral Interventions
March 2006
Patients with peripheral artery disease (PAD) undergoing percutaneous peripheral interventions (PPI) are at high risk for thrombotic complications. Though not approved for use in PPI, heparin is the most commonly used anticoagulant, despite its well-known pharmacological and clinical limitations. Data in the literature regarding heparin use in PPI are limited; however, in-hospital complication rates have been reported as ranging from 3.5% to 32.7%.1
The direct thrombin inhibitor bivalirudin (Angiomax®, The Medicines Company, Parsippany, New Jersey) has been shown to be as effective as heparin, but with significantly fewer hemorrhagic complications in clinical PCI trials.2–4 Following preliminary coronary data from the REPLACE–1 Trial,3 the author and his colleagues implemented almost exclusive use of bivalirudin and provisional glycoprotein (GP) IIb/IIIa inhibitors during coronary interventions. This was followed by a dramatic reduction in procedure-related bleeding complications. This powerful (although limited) coronary experience prompted a liberal use of bivalirudin for almost all PPIs performed at our institution.
Given the unique mechanism of action and pharmacokinetic profile of bivalirudin, it may provide potential benefits over heparin in PPI as well. Preliminary data of bivalirudin use in PPI have been promising. This retrospective chart review evaluated the use of bivalirudin as the foundation anticoagulant during PPI. This paper reports the ischemic, hemorrhagic and procedural complication rates in 150 patients undergoing PPI of the renal, iliac, femoral and other peripheral arteries at our institution.
Methods
A retrospective chart review was performed of patients who underwent PPI at three institutions from January 2002 to February 2004, with bivalirudin as the procedural anticoagulant. Demographic and procedural characteristics were collected. The occurrence of any procedural complications was also noted.
Study endpoints included procedural success, defined as less than or equal to 20% residual stenosis, as well as ischemic and bleeding complications. Ischemic events included death, unplanned revascularization or surgical intervention for ischemia of the target vessel, myocardial infarction (MI) and amputation prior to discharge. All bleeding complications at discharge were classified as major or minor. Major hemorrhage was defined as intracranial or retroperitoneal hemorrhage, a fall in hemoglobin (Hgb) of > 3 g/dL (or 10% hematocrit [Hct]) with spontaneous or nonspontaneous bleeding, a fall in Hgb of > 4 g/dL (or 12% Hct) with no bleeding site identified, and transfusion of greater than or equal to 2 units of whole blood or packed red blood cells (PRBC). Any observed bleeding that did not meet the criteria for major hemorrhage was considered a minor hemorrhage. Closure device use and time-to-sheath removal, ambulation and discharge were also collected.
Simple descriptive statistics were used to assess most endpoints. Categorical variables were summarized by using frequencies, and percentages and continuous variables were summarized by using means, standard deviations, interquartile ranges, and max/min values. Logistic regression analyses were also performed to examine the relationship between GP IIb/IIIa inhibitor use, urokinase use and renal function with bleeding events. A p-value 65 years of age and 52.7% were female. Hypertension (92.6%) and hyperlipidemia (79.5%) were the most common comorbidities. Approximately 46% of the patient population had moderate or severe renal impairment as determined by creatinine clearance (CrCl) values measured at baseline.
All patients received bivalirudin; there were no patients who required bailout to unfractionated heparin (UFH), as no major thrombotic complications were encountered. Bivalirudin was administered as a 0.75 mg/kg bolus, followed by a 1.75 mg/kg/hour infusion. The median infusion time and duration of procedure was 30 and 27 minutes, respectively. The majority of patients received aspirin and clopidogrel, with only 5.4% of patients receiving GP IIb/IIIa inhibitors (Table 1). Over 90% of patients received at least one stent.
Procedural success, defined as less than or equal to 20% residual stenosis, was achieved in 98.5% (133/135) of the patients. Approximately 94% of the patients had 0% residual stenosis. The overall procedural complication rate was 0.7%, with 1 patient experiencing a spiral dissection from the origin of the superficial femoral artery (SFA) that was successfully stented during the procedure. There were 3 deaths, 1 revascularization and no MIs or amputations. Major and minor hemorrhage occurred in 4.7% and 2.0% of patients, respectively. Outcomes are presented in Table 2.
Closure devices were used in 56.1% of patients. Time-to-sheath removal, ambulation and discharge were short, with 57.1% of patients discharged the same day. Results are detailed in Table 3.
Additional analyses to examine the relationship between GP IIb/IIIa inhibitor use, urokinase use, or renal function and bleeding outcomes were also performed. Major hemorrhage was significantly higher in those patients who received a GP IIb/IIIa antagonist compared to those who did not (25.0% versus 3.6%; p = 0.047). Similarly, those patients who were treated with urokinase had significantly more major bleeding events than those who were not (75.0% versus 2.8%; p = 0.0003). However, these results should be interpreted with caution due to the small sample size and the fact that other variables were not controlled for. And while the sample size is too small to make a definitive assessment, the data suggest that patients with renal impairment are at increased risk of bleeding, with 8.5% of patients with moderate renal impairment experiencing a major hemorrhage compared with 0% of those with normal renal function.
Discussion
In this multicenter experience, bivalirudin with provisional GP IIb/IIIa inhibitors resulted in a high level of procedural success (98.5%) and a low incidence of ischemic and bleeding complications in patients undergoing PPI. Approximately 94% of patients had 0% residual stenosis. The findings of this study are consistent with data published from other trials using bivalirudin in PPI and compare favorably to event rates previously reported with heparin.
PPI patients at high risk. PPIs are technically complex, involving larger sheath sizes, multiple catheter and guidewire use, longer length diseased vessels and longer segments requiring angioplasty or stenting.5 Furthermore, known predictive variables of poorer outcomes in PCIs such as longer procedural times with prolonged sheath dwell times, diabetes, renal insufficiency and hypertension are more common in the PAD population than in patients with isolated CAD undergoing PCI.5–7
In this study, 38% of patients had diabetes, 93% had hypertension, 52% were female and 49% were > 65 years of age, making this population high-risk for poorer outcomes. Our institution’s experience was more favorable than expected, despite a fair number of complicated cases.
Perhaps of greatest concern is the hypercoaguable state of patients with PAD.8 Data have shown that PAD patients have increased platelet activity, heightened plasma levels of thrombotic mediators such as fibrinogen,9 and potentially larger acute and chronic thrombus burden,5 making thrombin inhibition a critical component during PPI. Thrombin plays a central role in regulating coagulation, converting fibrinogen to fibrin, amplifying its own production by activating coagulation factors V and VIII, and stabilizing a developing clot by activating factor XIII to crosslink the fibrin strands.10–12 Implementation of an effective anticoagulation strategy targeted at more complete thrombin inhibition appears to be an important factor in reducing ischemic and hemorrhagic complications during PPI. One may however argue that procedure only, i.e., short-term administration of the drug would not allow for sufficient long-term effect in these patients with a hypercoaguable state. Further studies may therefore be needed to evaluate the benefit of a longer infusion, either preceding or following PPI.
Anticoagulation with heparin in peripheral interventions has limitations. Although not approved for use in PPI, heparin is the anticoagulant agent most commonly used despite its well-documented limitations. Despite heparin’s wide use, published literature detailing outcomes with heparin in the PPI setting are sparse, with reported in-hospital complication rates ranging from 3.5% to 32.7%.1
Many of the well-known limitations of heparin use in PCI are also relevant to PPI. Heparin binds nonspecifically to plasma proteins, resulting in wide variability among patients and hence necessitates frequent monitoring.13 Heparin also activates platelets, further activating the coagulation process, heparin-mediated inflammation processes and the release of heparin-binding proteins.14 Perhaps the most severe limitation as well as the most relevant to PPI is heparin’s inability to inhibit clot-bound thrombin, leaving thrombin free to activate platelets, generate more thrombin and stabilize clots.15
Bivalirudin in PPI. Bivalirudin is a specific, direct and reversible inhibitor of thrombin. Bivalirudin is approved for use in PCI and is rapidly being adopted in this setting. Bivalirudin overcomes many of the limitations of heparin. Because bivalirudin does not bind to plasma proteins, it provides a predictable anticoagulant effect that does not require monitoring. Bivalirudin binds bivalently to thrombin and is slowly cleaved at the active site permitting a return to hemostasis, which may account for the improved bleeding profile observed in PCI trials.2,4,16 Bivalirudin is able to inhibit both fluid-phase and clot-bound thrombin, shutting down the generation of thrombin and providing more complete anticoagulation.10,17
The short, 25 minute half-life of bivalirudin contributes to a reduced bleeding risk, and permits for earlier sheath removal and potentially earlier ambulation and discharge.18 In this study, a relatively high usage of closure devices was noted. As opposed to UFH, there is no effective way for rapid reversal of bivalirudin. Yet, its short half-life permits relatively high safety with concomitant use of such devices. Despite initial hesitancy, our institution’s favorable experience allowed us to continue with this trend — now almost a routine practice for PPI.
Preliminary evidence supports the use of bivalirudin in PPI (Table 4). In a prospective study by Shammas et al., the in-hospital complication rate with bivalirudin (n = 48) was 4.2%. A complication rate of 9.2% with heparin (n = 131) was previously reported by the same group.19 Allie et al. reported 100% procedural success with no deaths, MIs, or thromboses in a series of 180 renal and 75 iliac procedures using bivalirudin.5 Further, times to sheath removal 20 Bivalirudin was used as the procedural anticoagulant in 505 patients undergoing PPI of the renal, iliac or femoral arteries. GP IIb/IIIa inhibitors were used in 4.4% of the patients at the operators’ discretion. Ischemic complications were low: no deaths, 1 MI and 4 revascularizations. Hemorrhagic events were also low, with major and minor bleeding rates of 2.2% and 8.5%, respectively.
The present study is similar to the APPROVE trial with regard to patient population, bivalirudin administration and clinical outcome definitions. Event rates were slightly higher in the present study, however that is likely attributable to the fact that APPROVE was a controlled clinical trial, while the data from the present study are based upon bivalirudin use in a “real world” setting. Our institution’s data confirm the results from APPROVE and provide further support for bivalirudin as a safe and feasible alternative to UFH in PPI.
Results from the present study compare favorably with other published reports of bivalirudin in PPI. The slightly higher bleeding rates, comparable to those reported by Shammas et al.20 are in part due to use of GP IIb/IIIa inhibitors and urokinase and a generally high-risk patient population prone to bleeding. As it has been well established that patients with moderate renal impairment have a higher risk of bleeding,21 the large percentage of patients in this study’d group with moderate-to-severe renal impairment (approximately 46%) may also have been a contributing factor. While there were more deaths reported in this study as compared to other PPI trials using bivalirudin, none were related to either sub- or supra-therapeutic effects of anticoagulation.
Study limitations. Not all PPI cases are suitable for the use of bivalirudin. Chronic total occlusions are worth mentioning, and should be approached with caution. These may require UFH, as the likelihood of perforation may be higher, and quick reversal of bivalirudin is not possible. If one chooses to use bivalirudin in such cases, stopping the infusion and applying low-pressure balloon inflation for several minutes may be sufficient to seal the perforation. Alternatively, a stent graft such as the Viabahn® Endoprosthesis (W.L. Gore & Associates, Inc., Flagstaff, Arizona) may be used.
Conclusion
Data support the safety and feasibility of bivalirudin as a procedural anticoagulant in patients undergoing PPI. The findings from the present study are consistent with those in the literature and compare favorably to reported event rates using heparin. The more complete thrombin inhibition and reduced bleeding complications associated with the use of bivalirudin may make it a particularly attractive anticoagulant in the PAD patient population. Further prospective, randomized trials are warranted in this setting.
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