Volume 20, Issue 1 , Pages 17-21, January 2009
Clinical Experience with the Use of Bivalirudin in a Large Population Undergoing Endovascular Abdominal Aortic Aneurysm Repair
Article Outline
Purpose
To retrospectively evaluate the safety and effectiveness of the use of bivalirudin, a direct thrombin antagonist, compared with unfractionated heparin in endovascular aneurysm repair (EVAR).
Materials and Methods
Between March 1994 and September 2007, 740 consecutive patients (mean age, 75.7 y ± 7.7; 69 women) underwent elective EVAR for infrarenal abdominal aortic aneurysm. Bivalirudin was used in 98 of these 740 (13.2%) and unfractioned heparin was used in the other 642 (86.8%). Complications were classified according to the Society of Vascular Surgery/International Society for Cardiovascular Surgery criteria. Major bleeding was defined as 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, transfusion of 2 U or more of red blood cells, or intracranial or retroperitoneal hemorrhage.
Results
Grade 1 major complications were observed in 161 of 642 patients (25.2%) in the heparin group and 12 of 98 patients (12.2%) in the bivalirudin group (P = .0046), whereas the incidences of grade 3 major complications were not significantly different between groups (P = .57). The rate of total complications was higher in the heparin group than in the bivalirudin group (247 of 642 [38.5%] vs 21 of 98 [21.4%]; P = .001). Major bleeding occurred in 10 of 98 patients (10.2%) receiving bivalirudin and in 91 of 642 patients (14.2%) receiving heparin (P = .34). One of 21 major complications (4.76%) in the bivalirudin group and 12 of 247 major complications (4.86%) in the heparin group were attributable to thrombosis (P = 1.0).
Conclusions
Bivalirudin is a safe and feasible alternative to unfractionated heparin in patients undergoing EVAR.
Abbreviations: AAA, abdominal aortic aneurysm, EVAR, endovascular aneurysm repair
UNFRACTIONATED heparin is the most widely used anticoagulant in peripheral endovascular revascularization and in open and endovascular abdominal aortic aneurysm (AAA) repair. It inhibits thrombin indirectly by binding to antithrombin and accelerating its ability to inactivate thrombin. However, unfractionated heparin also binds to various other coagulation factors, plasma proteins, endothelial cells, and macrophages, thereby leading to a highly variable anticoagulant effect between individuals, resulting in well understood bleeding complications (1). Other clinically relevant drawbacks of unfractionated heparin include its ability to bind and inhibit clot-bound thrombin and its propensity to promote heparin-induced thrombocytopenia (2, 3).
These limitations of heparin have fueled the increasing use of bivalirudin, a direct thrombin antagonist that has significant advantages over unfractionated heparin associated with its pharmacology (4, 5, 6): bivalirudin does not rely on antithrombin to achieve its effects, has a more predictable dose–response pattern and therefore does not require blood test monitoring, and has a short plasma half-life. However, a major disadvantage of bivalirudin is that the costs are much higher than for unfractionated heparin.
The use of bivalirudin has been shown to be feasible and safe in patients undergoing coronary (7) and peripheral (8, 9, 10, 11) procedures. To our knowledge, the use of bivalirudin during endovascular aneurysm repair (EVAR) has yet to be investigated. The purpose of this study was to compare the safety and clinical effectiveness of bivalirudin with that of unfractionated heparin in patients undergoing elective EVAR. Our hypothesis was that the clinical effectiveness and safety profile of bivalirudin is similar to that of unfractionated heparin.
Materials and Methods
Between March 1994 and November 2006, 740 consecutive patients (mean age, 75.7 y ± 7.7; 69 women) underwent elective EVAR for infrarenal AAA at a single center and were entered in a prospectively maintained database. Institutional review board approval for retrospective review of these imaging materials was obtained.
Patients with anatomically suitable AAAs were eligible for EVAR if they had an infrarenal aortic aneurysm that was 50 mm or larger in maximum transverse diameter or if they had documented imaging evidence of 1.5 times the reference aortic diameter and an expansion rate of more than 10% per year. Exclusion criteria for the present investigation included a life expectancy less than 1 year, pregnancy, systemic infection, inflammatory aneurysm, AAA associated with connective tissue disease or Marfan syndrome, untreatable bleeding diathesis, and hypercoagulable state.
Patient Treatment
EVAR was carried out by a dedicated interdisciplinary team consisting of interventional radiologists, vascular surgeons, and anesthesiologists as described previously (12, 13). A total of 332 of the 740 patients (44.9%) were treated within five multicenter clinical trials of specific endografts. The results of several of these trials have recently been published (14, 15, 16, 17). The study protocols were in accordance with the Declaration of Helsinki and approved by the local ethics committee. Each patient gave written informed consent before participating in the trial.
Four hundred eight of 740 patients (55.1%) were treated with use of commercially available endografts. Ethics committee approval was not obtained for these patients, as they were treated on a regular clinical basis with United States Food and Drug Administration–approved devices.
The following endografts were used: Talent (Medtronic, Santa Rosa, California; n = 188), Excluder (W.L. Gore & Associates, Flagstaff, Arizona; n = 131), Ancure (Guidant, Menlo Park, California; n = 124), Aneurx (Medtronic; n = 106), Zenith (Cook, Bloomington, Illinois; n = 90), EVT (Endovascular Technologies, Menlo Park, California; n = 69), Vanguard (Boston Scientific, Natick, Massachusetts; n = 22), Trivascular (Boston Scientific; n = 6), and Powerlink (Endologix, Irvine, California; n = 4).
The anticoagulant agent to be used was left to the discretion of the interventionalist, and the choice of agent did not follow specific guidelines. Unfractionated heparin was administered intravenously as an initial bolus of 100 U/kg before placement of the arterial sheath, whereas bivalirudin (Angiomax R; The Medicines Company, Parsippany, New Jersey) was administered intravenously as a bolus of 0.75 mg/kg followed by continuous infusion of 1.75 mg/kg/h for the duration of the procedure.
Study Endpoints and Definitions
General definitions, reporting of complications (18), and classification of cardiovascular risk factors (19) followed the standards proposed by the Society of Vascular Surgery/International Society for Cardiovascular Surgery. Procedural data included fluoroscopy time, total dose of contrast material administered, arterial sheath size, type of anesthesia (ie, general, general and regional, regional and local), and type of arterial access (ie, percutaneous vs surgical cutdown). Periprocedural outcome parameters included deployment success, angiographic success, technical success, major complications, major and minor bleeding events, need for transfusion, and length of stay (ie, time from admission to discharge). Major bleeding was defined as clinically overt blood loss resulting in a decrease of hemoglobin level of more than 3 g/dL, any decrease in hemoglobin of more than 4 g/dL, transfusion of at least 2 U of whole blood or packed red blood cells, or intracranial or retroperitoneal hemorrhage (20). The definition of minor bleeding events included all hematomas that did not meet the criteria for major bleeding, transfusion of less than 2 U of packed red blood cells, or other nonintracranial or retroperitoneal bleeding (9).
Statistical Analysis
Continuous data are presented as means ± SD. Categorical data are given as absolute numbers and percentages. For univariable comparison of unpaired continuous data, the Student t test was used. For univariable comparison of paired continuous data, the paired t test was utilized. Categoric data were compared with use of the Fisher exact test. Logistic regression analysis (adjusted for all baseline variables with statistically significant difference in bivariable comparisons with an entry level of P < .05) was applied to assess the associations of heparin versus bivalirudin on the aforementioned specific endpoints. A P value less than .05 was considered to indicate a statistically significant difference. All calculations were performed with SPSS software (version 13.0; SPSS, Chicago, Illinois).
Results
Ninety-eight patients (13.2%) received bivalirudin and 642 (86.8%) received heparin. Clinical and baseline characteristics of patients from the present series are outlined in Table 1. Rates of arterial hypertension, hyperlipidemia, and use of β-blockers and statins were higher in the bivalirudin group, whereas the incidence of a history of peripheral arterial occlusive disease was higher in the heparin group. The groups differed slightly with regard to type of anesthesia and arterial access (Table 2).
Table 1. Demographics, Risk Factors, and Comorbidities of 740 Consecutive Patients Undergoing Elective EVAR
| Baseline Factor | Bivalirudin (n = 98) | Heparin (n = 642) | P Value |
|---|---|---|---|
| Female sex | 12 (12.2) | 57(8.9) | .27 |
| Age (y) | 76.1±7.5 | 75.7±7.7 | .58 |
| Maximum AAA diameter (mm) | 58.2±10.3 | 58±10.6 | .91 |
| Height (inches) | 68.6±3.6 | 68.9±3.3 | .38 |
| Weight (lb) | 184.0±35.1 | 182.3±35.5 | .66 |
| Baseline hemoglobin (g/dL) | 13.6±1.5 | 13.5±1.7 | .55 |
| Baseline hematocrit (%) | 40.7±4.1 | 40.4±4.7 | .55 |
| White blood cell count (cells/μL) | 7.1±2.6 | 7.5±7.1 | .58 |
| Creatinine clearance (mL/min) | 52.9±19.2 | 53.3±19.2 | .86 |
| History of cancer | 28(28.6) | 167(26.0) | .62 |
| Arterial hypertension | 90(91.8) | 512(79.8) | .0032 |
| Hyperlipidemia | 71(72.1) | 334(52.0) | .0001 |
| Diabetes mellitus | 16(16.3) | 95(14.8) | .65 |
| Smoking | 73(74.5) | 507(79.0) | .36 |
| COPD | 27(27.6) | 210(32.7) | .35 |
| History of cerebrovascular disease | 11(11.2) | 84(13.1) | .75 |
| History of PAOD | 23(23.5) | 249(38.8) | .0033 |
| History of coronary artery disease | 4(4.1) | 10(1.6) | .10 |
| History of atrial fibrillation | 14(14.2) | 91(14.2) | 1.00 |
| Cardiac risk | |||
| 0 | 26(26.5) | 203(31.6) | .35 |
| 1 | 14(14.3) | 71(11.1) | .39 |
| 2 | 56(57.1) | 337(52.5) | .45 |
| 3 | 2(2.0) | 31(4.8) | .30 |
| Renal risk | |||
| 0 | 75(76.5) | 488(76.0) | 1.00 |
| 1 | 21(21.4) | 111(17.3) | .32 |
| 2 | 2(2.0) | 35(5.5) | .21 |
| 3 | 0 | 8(1.2) | .61 |
| Pulmonary risk | |||
| 0 | 49(50) | 329(51.2) | .83 |
| 1 | 27(27.6) | 187(29.1) | .81 |
| 2 | 18(18.4) | 86(13.4) | .21 |
| 3 | 4(4.1) | 40(6.2) | .50 |
| β-blocker | 61(62.2) | 268(41.7) | .0002 |
| Statin | 66(67.3) | 262(40.8) | .0001 |
| Antiplatelet therapy | 66(67.3) | 381(59.3) | .15 |
| ACE inhibitor | 24(24.5%) | 162(25.2%) | 1.00 |
Table 2. Procedural Characteristics of 740 Consecutive Patients Undergoing Elective EVAR
| Characteristic | Bivalirudin (n = 98) | Heparin (n = 642) | P Value |
|---|---|---|---|
| Fluoroscopy time (min) | 27.7 ± 17.1 | 27.8 ± 14.4 | .91 |
| Size of sheath (mm) | |||
| All patients | 27.7 ± 3.6 | 27.2 ± 3.7 | .24 |
| Cutdown | 27.9 ± 3.2 | 27.5 ± 3.4 | .35 |
| Percutaneous | 25.1 ± 3.1 | 24.9 ± 3.2 | .54 |
| Type of anesthesia | |||
| General | 39(39.8) | 129(20.1) | <.0001 |
| General and regional | 11(11.2) | 47(7.3) | .2226 |
| Regional | 48(49.0) | 462(72.0) | <.0001 |
| Local | 0 | 4(0.62) | 1.00 |
| Type of arterial access | |||
| Cutdown/cutdown | 79(80.6) | 399(62.2) | .0003 |
| Cutdown/percutaneous | 12(12.2) | 238(37.1) | <.0001 |
| Percutaneous/percutaneous | 7(7.1) | 5(0.78) | .0003 |
Acute and 30-day outcomes are detailed in Table 3. Deployment success, angiographic success, and technical success rates among all patients were 96.8%, 87.4%, and 87.4%, respectively, and did not differ between groups.
Table 3. Acute and 30-day Outcomes of 740 Consecutive Patients Undergoing Elective EVAR
| Outcome | Bivalirudin (n = 98) | Heparin (n = 642) | P Value |
|---|---|---|---|
| Deployment success | 95(96.9) | 621(96.7) | 1.00 |
| Angiographic success | 83(84.7) | 564(87.9) | .41 |
| Technical success | 82(83.7) | 565(88.0) | .25 |
| Major complications | |||
| 0 | 77(78.6) | 395(61.5) | .0010 |
| 1 | 12(12.2) | 161(25.2) | .0046 |
| 2 | 7(7.1) | 60(9.3) | .57 |
| 3 | 2(2.0) | 26(4.0) | .57 |
| Total complications | 21(21.4) | 247(38.5) | .0010 |
| Major bleeding | 10(10.2) | 91(14.2) | .34 |
| Intracranial bleeding | 0 | 0 | NA |
| Retroperitoneal bleeding/hematoma | 1(1.02) | 2(0.3) | .35 |
| Minor bleeding | 12(12.2) | 90(14.0) | .75 |
| Any transfusion | 16(16.3) | 79(12.3) | .26 |
| Transfusion ≥2 U | 6(6.1) | 50(7.8) | .68 |
| PRBC | 13(13.3) | 68(10.6) | .49 |
| Platelets | 3(3.1) | 12(1.9) | .43 |
| FFP | 3(3.1) | 7(1.1) | .14 |
| Albumin | 0 | 2(0.3) | 1.00 |
| Length of stay (d) | 4.5 ± 10.7 | 4.2 ± 5.2 | .58 |
Major grade 1 complications were observed in 161 of 642 patients (25.2%) in the heparin group and 12 of 98 patients (12.2%) in the bivalirudin group (P = .0.0046), whereas grade 3 complications were not significantly different between groups (P = .57). Moreover, the rate of total complications was significantly higher in the heparin group than in the bivalirudin group (247 of 642 [38.5%] vs 21 of 98 [21.4%]; P = .001). One of 21 major complications (4.76%) in the bivalirudin group and 12 of 247 major complications (4.86%) in the heparin group were attributable to thrombosis (P = 1.0). Five of 642 patients (0.78%) who received heparin developed heparin-induced thrombocytopenia after EVAR.
Rates of major and minor bleeding and need for transfusion, as well as length of stay, were not significantly different between heparin and bivalirudin groups on univariate analysis. Four of 12 grade 1 complications (33.3%) in the bivalirudin group and 55 of 161 grade 1 complications (34.2%) in the heparin group were attributable to bleeding (P = 1.0).
The aforementioned significant differences in baseline and procedural characteristics of patients with AAA treated with heparin or bivalirudin (Table 1, Table 2) were included into a multivariable regression model. After adjustment for arterial hypertension, hyperlipidemia, peripheral arterial disease, β-blocker and statin use, as well as type of anesthesia and type of arterial access, the use of heparin or bivalirudin did not independently predict rates of major complications, major and minor bleeding, and need for transfusion (P > .05 for all).
Discussion
The present study compared the safety and effectiveness of bivalirudin with that of unfractionated heparin as antithrombotic agents in EVAR. We found no difference between bivalirudin and unfractionated heparin with regard to major and minor bleeding, as well as with regard to thrombotic complications.
Various limitations of heparin have fueled the increasing use of bivalirudin in endovascular arterial procedures (21). Besides an unpredictable dose response leading to well understood bleeding complications (1), the rate of heparin-induced thrombocytopenia is not insignificant; it varies from 7.5% to 50% as diagnosed by antigen assay, depending on the type of operative procedure (3). In addition, in contrast to unfractionated heparin, bivalirudin is capable of neutralizing clot-bound heparin (22).
Bivalirudin is a direct reversible thrombin inhibitor with a half-life of 25 minutes, and only 20% is excreted through the kidney (5). Bivalirudin leads to prolonged thrombin time, activated partial thromboplastin time, and prothrombin time, and increased International Normalized Ratio (6). Its effect is linear with respect to dose and plasma concentration, it has a low propensity for immune and inflammatory response, and it is unlikely to induce immune-mediated thrombocytopenia (4). Therefore, bivalirudin is particularly suitable for patients who are at high risk for bleeding, including those with impaired renal function (4).
In a recently published metaanalysis (7), the use of bivalirudin was noninferior with regard to rates of thrombotic complications and was associated with lower rates of major bleeding in patients with acute coronary syndromes and percutaneous coronary interventions. Moreover, the use of bivalirudin was shown to be safe and efficient in peripheral interventions (8, 9, 10, 11). Bivalirudin appears to be superior to heparin in reducing the risk of major bleeding events that may occur as a result of coronary intervention (4). Thus far, experiences with bivalirudin in surgical interventions has been limited to cardiac applications demonstrated in two studies (23, 24). Dyke et al (23) performed a safety study comparing systemic anticoagulation with bivalirudin versus unfractionated heparin with protamine reversal in patients undergoing cardiac surgery with cardiopulmonary bypass. Procedural success defined as freedom from death, Q-wave myocardial infarction, stroke, or repeat revascularization was not significantly different between the two groups at 7 days, 30 days, or 12 weeks. In addition, major bleeding events occurred in 6% of patients who received bivalirudin and 2% of patients who received heparin and protamine sulfate (P = .67). However, the rate of postoperative repeat exploration was higher in the bivalirudin group (6.1%) than in the heparin/protamine sulphate group (1.9%). The purpose of the study by Smedira et al (24) was to evaluate the safety and efficacy of bivalirudin in off-pump coronary artery bypass grafting. Procedural success defined as a composite of freedom from of death, myocardial infarction, stroke, and repeat revascularization at 7 days, 30 days, and 12 weeks was similar in both groups; however, three strokes (5.5%) occurred in the heparin group, whereas none occurred in the bivalirudin group (P = .05). Major bleeding events occurred at similar rates between the bivalirudin and heparin groups.
The present study exhibits a complication profile of bivalirudin that is comparable to those in other bivalirudin studies. A recent metaanalysis of five prospective randomized trials (7) compared the safety and efficacy of bivalirudin to that of heparin in percutaneous coronary intervention in acute coronary syndrome. This metaanalysis (7), which summarized experiences in 25,457 patients, demonstrated that bivalirudin is as effective as heparin for protection against cardiovascular events. In addition, patients receiving bivalirudin were found to have significantly reduced major bleeding complications.
The present study also shows that bivalirudin's complication profile is similar to those shown in peripheral revascularization studies. Shammas and coworkers (25) analyzed data from the Angiomax Peripheral Procedure Registry of Vascular Events to explore the predictors of complications with bivalirudin in renal, iliac, and femoral interventions. In this series, exchanges to larger arterial sheaths during percutaneous intervention were identified as a strong predictor of bleeding events.
In a further study investigating bivalirudin in peripheral interventions, Allie et al (26) concluded that the combination of bivalirudin and tirofiban is a safe alternative to unfractionated heparin and may offer improved clinical and hemostasis outcomes in the treatment of patients with critical limb ischemia. In that series, use of bivalirudin/tirofiban was associated with fewer overall major (4.0% vs 5.3%) and minor (9.4% vs 15.4%) femoral access complications compared with unfractionated heparin.
One limitation of the present study has to be addressed: the study is of an observational character and patients were not randomized to receive bivalirudin or unfractionated heparin, thereby limiting its level of evidence. However, significant differences in clinical baseline characteristics between patients who received bivalirudin and unfractionated heparin were adjusted for in multivariable analysis, thereby minimizing potential selection bias.
In conclusion, although it does not appear to provide the same reduction in bleeding complications as in percutaneous procedures, bivalirudin was shown to be a safe alternative to unfractionated heparin as the anticoagulation agent during EVAR in the present observational study. Given the aforementioned shortcomings associated with the retrospective nature of the present investigation, we believe the noninferiority of bivalirudin in patients undergoing elective EVAR should be validated in a prospective, randomized trial.
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None of the authors have identified a conflict of interest.
PII: S1051-0443(08)00889-0
doi:10.1016/j.jvir.2008.09.031
© 2009 SIR. Published by Elsevier Inc. All rights reserved.
Volume 20, Issue 1 , Pages 17-21, January 2009
