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Unfractionated heparin is a widely utilized anticoagulant during peripheral angioplasty procedures (PTA). In contrast to heparin, bivalirudin is a direct thrombin inhibitor with predictable anticoagulation, does not activate platelets, and inhibits both soluble and bound thrombin. The experience with bivalirudin during PTA remains limited. In this single-center prospective study, 48 consecutive patients (60.4% males, mean age 70.0 ± 12.1) received bivalirudin as the primary anticoagulant during PTA (0.75 mg/kg bolus, 1.75 mg/kg/h during the procedure). Thirty-four (70.8%) had claudication and 6 (12.5%) had ulceration. Thrombus was angiographically seen in 3 (6.3%) patients. In-hospital serious procedural complications were limited to 2 (4.2%) (exact 95% confidence interval: (0.5%,14.3%]) patients with major bleeding; none (0.0%) of the other following endpoints occurred: death, limb loss, emergent need for revascularization of the same vessel, embolic strokes, and vascular complications (exact 95% confidence intervals: [0.0%,6.1%]). This compared favorably to previously reported data using unfractionated heparin and the same serious procedural complications endpoints from our group at the same institution (9.2%). We conclude that the use of bivalirudin during PTA appears feasible and safe. Large prospective registries are needed to confirm these findings.
This article is reprinted with permission from the Journal of Invasive Cardiology 2003;15:401-404.
Unfractionated heparin (UFH) is the current antithrombotic agent utilized during peripheral angioplasty procedures (PTA). UFH has an unpredictable anticoagulation response, is an indirect thrombin inhibitor, does not inhibit bound thrombin and activates platelets.1 We have recently reported our procedural complications rate (9.2%) during PTA with the use of UFH as a primary anticoagulant.2 Our experience was in concordance with multiple published reports showing a complication rate of 3.5–32.7%.3-9
Bivalirudin, a direct thrombin inhibitor, has been recently shown to reduce both ischemic and bleeding complications during coronary interventions when compared to UFH.z10,11 In contrast to UFH, bivalirudin has a short half-life, provides predictable anticoagulation response, and inhibits free and bound thrombin. These properties provide potential benefits over UFH during PTA where thrombin activation is expected to be significant given the extent of atherosclerotic burden and large vessel size dilated with balloon angioplasty. The short half-life of bivalirudin might also allow early sheath removal, less bleeding complications than UFH, and a more reliable anticoagulation with no need for frequent activated clotting time (ACT) measurements during long procedures. Early experience with bivalirudin in the periphery has been recently presented at scientific meetings.12-14 The data appear favorable showing low major bleeding rate and adverse events compared to historic data with UFH. In this single-center experience, we report on our in-hospital complication rate during PTA in 48 consecutive patients who received bivalirudin as their primary anticoagulant, and compare this rate to a published historic control from the same institution using the same adverse events endpoints.
Methods
Forty-eight consecutive patients underwent PTA from February 5, 2002 through August 6, 2002 at our institution, using bivalirudin as a primary anticoagulant (0.75 mg/kg bolus, 1.75 mg/kg/hour during the procedure) and did not meet one of the following exclusion criteria: 1) planned staged two or more peripheral procedures during the same hospital stay; 2) acute myocardial infarction (MI) preceding the PTA; 3) the use of elective adjunctive intravenous glycoprotein (GP) IIb/IIIa inhibitors during the procedure; 4) concomitant coronary procedures; or 5) being on continuous intravenous heparin drip prior to the procedure. Clinical, angiographic, and serious event rates were collected prospectively. An interventional cardiologist not involved in the procedure adjudicated the in-hospital serious procedural complications (SPC). SPC were defined as follows:
• Major bleed: defined as requiring >= 2 units of PRBC transfusion, retroperitoneal bleed, or a drop of hemoglobin (Hb) after the procedure by more than 3 g/dL;
• Vascular complications: defined as an AV fistula or pseudoaneurysm after the procedure when suspected clinically and confirmed by duplex ultrasound;
• Death due to procedural complications;
• Limb loss;
• Need for in-hospital salvage revascularization (angioplasty or surgery) of the same treated vessel;
• Embolic stroke.
The following clinical variables were collected: age, gender, history of diabetes, MI, angina, hypertension, hyperlipidemia, smoking (never, prior to the past year and within the past year), prior cerebrovascular events, body mass index, blood pressure at onset of procedure, the presence of peripheral vascular disease with ulceration, recent onset of claudication (<= 1 month), claudication <= 200 feet of walking, and pre-procedure ankle-brachial indices (ABI). The following angiographic criteria were collected: presence or absence of visible thrombus during the intervention, ACT (10 minutes after bivalirudin bolus using the Hemochron machine), vessels treated and procedure time. The Institutional Review Board of the Genesis Health System approved the protocol.
Statistical analysis. Descriptive statistics on all variables are initially summarized as proportions or mean ± SD. The primary analysis of the study was to estimate the rate of SPCs.
Kruskal-Wallis tests were used to compare age and body mass indices across pre-existing conditions. Kaplan-Meier plots and exact log-rank tests were used to contrast procedure times and lengths of stay. Fisher’s exact tests were performed for comparisons of dichotomous and unordered categorical variables. SPC rates are estimated with exact 95% confidence intervals.
Results
Demographic and health history characteristics of the population studied are shown in Table 1. Twenty nine (60.4%) patients were males. The mean age was 70.0 ± 12.1 years; however, the age distribution is skewed with ages ranging from 41-89 and a median age of 73 (Figure 1). There were 32 (66.7%) patients with a documented history of smoking (17 [35.4%]) current smokers, that is, smoked within the past year). Embedded in the histogram is the age distribution of recent smokers. All patients below the age of 59 are current smokers. In Figure 2, the boxplots demonstrate how the age distribution for previous smokers is the same as the never smokers and significantly different from the current smokers.
Of these 48 patients, 35.4% (17) had a history of heart disease (either MI, angina, or previous percutaneous coronary intervention) and 43.8% (21) had diabetes. There were 12.5% (6) of patients with lower leg ulceration, 4.2% (2) of patients with a recent onset of claudication (<= 1 month), and 70.8% (34) of patients with symptomatic claudication. Baseline pre-procedure creatinine was 1.2 ± 0.6.
Intraprocedural thrombus occurred in 6.3% of patients. Even though the previous smokers were older than current smokers, their durations of surgery were similar. Any smoking (past and current) had longer procedure times (Figure 3). The difference in median procedure times was only 8 minutes, but the difference is over an hour in the last quartiles of completed procedures for the “never” versus “ever” smokers. The mean time of the procedure was 82.4 minutes for “never” smokers, but 108.1 minutes for the “ever” smokers.
A total of 80 vessels were treated in 48 patients (mean of 1.7 vessels per patient). The 80 primary vessels treated were categorized as follows: suprainguinal (n = 33), superficial femoral arteries and popliteal (n = 36), and tibials (n = 11). The mean Ankle-Brachial index was 0.7 ± 0.2. Closure devices were used in 41 patients (85.4%). There were 90.2% of them who received the Perclose suturing device and 9.8% who received Angio-Seal. Forty-seven patients had an ACT measured 10 minutes after the bivalirudin bolus. The ACTs were distributed as follows: 38 (80.8%) > 400 seconds and 9 (19.2%) between 300-399 seconds.
Overall, there were 2 (4.2% with a 95% confidence interval of (0.5%,16.4%) of the patients with at least one SPCs, both of which were major bleeding (Table 2). There were no deaths, amputations, urgent limb salvage revascularization, vascular complications or embolic strokes. With bivalirudin, we are 95% confident that the true underlying SPC rate for each of these none-occurring events and these two physicians is less than 6.1%.
Discussion
In this single-center experience from February 5, 2002 through August 6, 2002, we had two experienced peripheral interventionalists (each of the 2 experienced operators has performed a minimum of 200 peripheral procedures) who used bivalirudin exclusively during PTA. The overall complication rate with bivalirudin in this series was 4.2% (2 patients out of 48 met at least one of the endpoints). Previously, we have reported that peripheral vascular complications are not trivial with unfractionated heparin as the base anticoagulant (SPCs were 9.2% using the same definitions as in this study).2 Our in-hospital outcomes with bivalirudin during PTA compare favorably with UFH. The complication rate appeared doubled with UFH when compared to bivalirudin. This is also in concordance with data recently reported in scientific meetings.12-14 Grubbs and colleagues12 reported their experience with 69 PTA patients receiving bivalirudin as a primary anticoagulant. In their series, there were no adverse events reported, including no major bleeding, acute thrombosis, or death. Knopf et al.13 also reported on 72 patients receiving bivalirudin during PTA. There were no deaths, major bleeding, strokes, or distal embolization in their series. Furthermore, Allie et al.14 have used bivalirudin in 180 renals and 75 iliac interventions with no major complications reported. In contrast, complication rates with UFH have ranged from 3.5-32.7% in several published series.3-9
The differences between smoking history cohorts make it difficult to make global claims across all patients, as well as difficult to simply estimate the effect of accepted risk factors on SPCs. It is likely that the much older previous smokers quit a long time ago. This is one of many survivorship effects; older patients continue to have fewer co-morbid conditions, especially histories of cardiovascular diseases.
The safer profile of bivalirudin over heparin during percutaneous procedures has been shown in several studies. In the Bivalirudin Angioplasty Trial (BAT),10 bivalirudin reduced the risk of bleeding by 62% when compared to UFH (p < 0.001). The recently published Replace-2 trial11 also showed a major bleeding rate of 2.4% in the bivalirudin arm versus 4.1% in the heparin plus GP IIb/IIIa arm (p < 0.001). A recent meta-analysis by Yusuf et al.15 has shown that bivalirudin has a significant advantage over UFH in reducing major bleeding during percutaneous procedures. Our preliminary experience and others seem to support the safety of bivalirudin during PTA procedures. A large registry or a randomized trial against UFH during PTA is now needed to confirm these small observations.
Limitations of this study. This is a single center experience and might not be shared by other operators. The data is preliminary and needs to be validated in a large, multi-center prospective study. Nevertheless, this study was prospective and data collection was timely and accurate. Although the sample size is small, this manuscript adds to the current limited experience with bivalirudin during PTA.
Acknowledgment. The authors wish to thank Peter Teuber, PhD, for his valuable input in this study and the manuscript.
Reprinted with permission from the Journal of Invasive Cardiology 2003;15:401-404.
Authors’ affiliation: Genesis Heart Institute, Cardiovascular Medicine, P.C., and the *Genesis Health System, Davenport, Iowa. Dr. Shammas can be contacted at shammas@mchsi.com
** Supported in part by a grant from the Genesis Foundation
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