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Transitioning from Heparin to Bivalirudin in Patients undergoing Ad Hoc Transradial Interventional Procedures: A Pilot Study
March 2006
The benefits of transradial access for percutaneous coronary intervention have been clearly documented in the past several years.1–10 However, postprocedure radial artery occlusion is a potential complication, and adequate anticoagulation is an absolute prerequisite, even for diagnostic procedures.11–13
As a result of its proven efficacy in several recent clinical trials, the direct thrombin inhibitor bivalirudin (Angiomax®, The Medicines Company, Parsippany, New Jersey) is now increasingly utilized as the anticoagulant of choice for coronary interventions.14–19 However, it is currently not packaged for diagnostic procedures. Thus, patients undergoing ad hoc transradial interventions need unfractionated heparin (UFH) during the diagnostic catheterization, but it is unclear how the transition to bivalirudin should be undertaken if a subsequent intervention were performed.
The purpose of the present pilot study was to evaluate two concerns inherently involved in changing from heparin to bivalirudin anticoagulation during ad hoc transradial interventions. First, divided dosing with UFH should provide the same protection against postprocedure radial occlusion during the diagnostic catheterization as the standard 5,000 units (U) single dose.11,12 Second, the safety profile of bivalirudin during the coronary intervention should not be altered if it is given after an initial reduced heparin dose.
Methods
Study population. The study population included all patients undergoing ad hoc transradial coronary interventional procedures at our institution from May 2004 to July 2004. Exclusion criteria included confirmed pregnancy, active bleeding, known allergy to bivalirudin or any of its components, administration of a thrombolytic agent within 6 hours of the scheduled procedure, heparin or pork allergy, or previous history of heparin-induced thrombocytopenia. Informed consent was obtained from each patient.
Study protocol. The study was a prospective, open-label evaluation involving 4 groups of patients. A schematic of the protocol is illustrated in Figure 1.
Radial access was obtained using standard procedure, and 6 Fr catheters were utilized. All patients received aspirin 325 mg p.o. prior to the procedure and daily thereafter. Clopidogrel 300–600 mg orally was administered before or immediately after the procedure, followed by 75 mg a day for 6 months. Standing medications were continued as previously ordered.
Patients in Group 1H received 2,500 U of UFH after sheath insertion followed by an additional 2,500 U at the conclusion of the diagnostic procedure if an intervention was not performed. Patients in Group 2H received 1,000 U of intravenous UFH after sheath insertion followed by 4,000 U of UFH at the conclusion of the diagnostic procedure if an intervention was not performed.
All patients who subsequently underwent an ad hoc coronary intervention received standard bivalirudin dosing in addition to the initial UFH dose. Consequently, Group 1B received 2,500 U of UFH plus bivalirudin, and Group 2B received 1,000 U of UFH plus bivalirudin. A 0.75 mg/kg bolus of bivalirudin, followed by a 1.75 mg/kg/hour infusion for the duration of the procedure, were administered. The infusion was discontinued at the conclusion of the procedure.
The Group 1 dosage schedule was utilized in the initial 66 patients recruited in the study (26 in 1H; 40 in 1B). The Group 2 protocol was subsequently performed in 51 patients (25 in 2H; 26 in 2B).
Study endpoints. The primary endpoints of the study were the incidence of radial occlusion at hospital discharge as determined by arterial plethysmography and major or minor bleeding. The secondary endpoints of the study were a composite clinical endpoint of procedure MACE (death, postprocedural myocardial infarction, or unplanned repeat target lesion revascularization), and vascular access-related complications other than radial artery occlusion.
Clinical data and definitions. The activated clotting time (ACT) was measured using a Hemochron® machine (International Technidyne Corp., Edison, New Jersey). In patients undergoing diagnostic catheterization, ACT values were obtained 5 minutes after the initial administration of heparin, and at the conclusion of the procedure after the administration of the second heparin dose. In those transitioning to intervention, ACT values were obtained 5 minutes after the initial administration of heparin, and 5 minutes after the administration of bivalirudin. Hematocrit, hemoglobin and platelet count were obtained prior to the procedure and 24 hours thereafter. Creatine kinase MB (CK-MB) isoenzyme levels were measured at baseline and every 8 hours x 3 after the procedure.
Myocardial infarction was defined as a CK-MB elevation of 3 times the upper limit of normal. Major hemorrhage included intracranial, intraocular, or retroperitoneal hemorrhage or overt blood loss resulting in a decrease in hemoglobin of more than 3 g/dL, or transfusion. Minor bleeding was an access site hematoma that prolonged hospital stay.
Statistical analysis. Continuous variables were expressed as mean and standard error of the mean. Discrete variables were expressed as counts and percentages of the total population. Study endpoints among the groups were compared using a paired Student’s t-test. Differences were considered statistically significant if the p-value was Demographics. Baseline patient demographics are shown in Table 1. Sex, age and weight are similar in the study groups. There was no significant difference in the incidence of diabetes mellitus, previous radial catheterization or myocardial infarction within the 48 hours prior to the interventional procedure.
The incidence of patients presenting with an acute coronary syndrome (ACS) and the frequency of prior anticoagulation in the 2 interventional groups are shown in Table 2. Six (15%) of patients in Group 1B were receiving warfarin prior to the procedure, as opposed to none in Group 2B; this difference was statistically significant (p Activated clotting times. Activated clotting times are shown in Table 3 and Figure 2. Fifty-one patients (26 in Group 1H and 25 in Group 2H) underwent diagnostic catheterization only. In Group 1H, the baseline ACT was 126 ± 3, increasing to 172 ± 6 after 2,500 U of heparin. In Group 2H, the baseline ACT was 130 ± 4, increasing to 151 ± 5 after 1,000 U of heparin.
Sixty-six patients (40 in Group 1B and 26 in Group 2B) transitioned to percutaneous intervention after the diagnostic catheterization. In Group 1B, the ACT increased from 128 ± 3 to 205 ± 11 after 2,500 U of heparin; the ACT after bivalirudin was 457 ± 19. In Group 2B, the ACT increased from 127 ± 2 to 160 ± 7 after 1,000 U of heparin; the ACT after bivalirudin was 405 ± 16.
In-hospital events. A summary of clinical endpoints for the study population is shown in Tables 4a and 4b. One patient in Group 2H had postprocedure radial occlusion, but this recanalized in 1 month. Radial occlusion did not occur in the other groups. No major or minor bleeding complications occurred.
There were no deaths and no patient underwent urgent target vessel revascularization. The incidence of myocardial infarction in the total study population undergoing intervention was 7.5%. Five patients (13%) in Group 1B experienced a postprocedure myocardial infarction. All of these patients had a CPK elevation only; no evolved Q-waves and no clinical sequelae of the infarction were observed. Myocardial infarction did not occur in Group 2B; this difference was not statistically significant.
The mean procedure time in those patients undergoing diagnostic catheterization was 14 ± 6 minutes in Group 1H, and 15 ± 2 minutes in Group 2H. The procedure time in those patients undergoing an interventional procedure was 39 ± 4 minutes in Group 1B, and 30 ± 3 minutes in Group 2B.
Discussion
In this small pilot study, bivalirudin was safely administered after UFH in patients undergoing ad hoc transradial procedures. Divided-dose UFH provided adequate anticoagulation to prevent radial occlusion during the diagnostic catheterization. No major or minor bleeding occurred when bivalirudin was administered for the interventional procedure after the initial reduced heparin dose.
UFH remains the most commonly used anticoagulant during coronary interventions, and its pharmacokinetic limitations can be attenuated by the addition of a glycoprotein (GP) IIb/IIIa inhibitor. While this combination decreases ischemic events, the risk of bleeding and vascular complications are significantly increased, particularly in patients with acute myocardial infarction, renal dysfunction, diabetes and the elderly.20,21
The REPLACE-2 trial demonstrated that bivalirudin monotherapy with provisional GP IIb/IIIa inhibition resulted in comparable ischemic complications to those obtained with UFH and routine adjunctive platelet GP IIb/IIIa inhibition with significantly less bleeding.18 The reduction in both major and minor bleeding complications as compared to UFH is the result of bivalirudin’s linear pharmacokinetics, predictable dose response, reversible mechanism of action and short half-life.14–19,22 Thus, bivalirudin is being increasingly utilized as the anticoagulation agent of choice for interventional procedures.
The transradial approach has been adopted worldwide due to a significant reduction in access site bleeding complications when compared to the femoral approach.1–9 Reduced patient morbidity due to immediate ambulation following interventional procedures is another benefit.3,6,9,10 Radial artery occlusion is a potential complication that can largely be prevented with adequate anticoagulation, and 5,000 U of UFH are mandatory for transradial diagnostic procedures.11,12
Currently, bivalirudin is packaged only for interventional procedures, and the protocol for its use during ad hoc transradial interventions is uncertain. The present study evaluated two divided dosing schedules of heparin for anticoagulation during the diagnostic procedure followed by a standard bivalirudin dose for the interventional procedure. The balance of the 5,000 U heparin dose was given at the conclusion of the diagnostic procedure if an intervention was not performed. Postprocedure radial occlusion occurred in only 1 patient with the divided heparin dosing. This incidence of postprocedure radial occlusion in the present study is similar to that reported in larger studies using an undivided heparin dosing.4,11–13 It should be emphasized that the authors have extensive experience with transradial catheterization, as reflected by the relatively short diagnostic procedure time.
There were no deaths in the present study and no patient required urgent target vessel revascularization. The incidence of postprocedure non-Q wave myocardial infarction in the present study was 7.5% (5 of 66 patients), and no patient required provisional administration of a platelet GP IIb/IIIa inhibitor. Group 1B contained a slightly higher percentage of patients with acute coronary syndromes, and all postprocedure myocardial infarctions occurred in this group.
Major or minor postprocedure bleeding complications did not occur. However, activated clotting times were higher than those customarily obtained in interventional procedures performed with either standard UFH or bivalirudin dosing. Although these relatively high ACT levels are a result of the combination of heparin and bivalirudin dosing, previous studies have documented a lack of correlation between the ACT level and bleeding risk after bivalirudin administration for percutaneous intervention.23 On the other hand, there is a strong correlation between ACT level and bleeding risk with UFH anticoagulation, particularly when heparin is administered in conjunction with a platelet GP IIb/IIIa inhibitor.24,25
The most important limitation of the present study is the small sample size. A larger study will be needed to validate that the safety profile of bivalirudin is not altered by a prior heparin dose and that the risk of radial occlusion after a divided heparin dose is not increased. ACT values may not be the ideal test for measuring the clinical effect of anticoagulation due to the inherent imprecision of the test. In addition, not all anticoagulants are equally sensitive to the ACT.26 Therefore, evaluating the effect of a combination of anticoagulants is not straightforward. However, in the present study, all ACTs were performed on the same Hemochron machine in an effort to minimize variability.
In conclusion, this pilot study suggests the administration of bivalirudin after a dose of UFH was safe in patients undergoing ad hoc transradial interventional procedures. The incidence of radial occlusion was not increased when the UFH dose was divided for diagnostic procedures, and no bleeding complications occurred when standard bivalirudin dosing was added for the intervention. While these results are encouraging, they need to be confirmed in a larger study.
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