Bivalirudin has also been studied as a procedural anticoagulant for transcatheter valve procedures in the adult population where its favorable bleeding profile is theoretically advantageous given the larger vascular access sheaths required for such procedures. With the exception of 1 retrospective study of patients undergoing balloon aortic valvuloplasty in which less major bleeding was seen (4.9% vs 13.2%; P = .003), bivalirudin was found to be noninferior to heparin in terms of safety and efficacy when dosed at the FDA-approved PCI dosing regimen (0.75 mg/kg bolus and an 1.75 mg/kg/h infusion).55–57 The design and results of these studies are summarized in Table 2.
CARDIAC SURGERY WITH CPB
Case reports of successful anticoagulation with bivalirudin in patients with HIT undergoing CPB began to appear in the literature in the early 2000s. These early cases, in addition to favorable outcomes in studies applying bivalirudin to PCI, acute coronary syndrome, and off-pump coronary artery bypass grafting (CABG), led to interest in the expanded application of bivalirudin anticoagulation to the general population of patients undergoing CPB for cardiac surgery. Koster et al58 published the first 2 pilot studies investigating the safety and PK of bivalirudin for on-pump coronary artery bypass, establishing the dosing regimen that would then be used in the EVOLUTION-ON study.
In the first pilot study,58 20 patients with moderately depressed renal function scheduled for CABG with normothermic CPB were administered a 1.5 mg/kg bolus of bivalirudin followed by a 2.5 mg/kg/h infusion adjusted to maintain a target ECT of 400–500 seconds. A 50-mg bivalirudin bolus was added to the pump prime. Blood samples for ECT, ACTPlus, and serum bivalirudin concentration were measured at 5 minutes postbolus, every 15 minutes during bivalirudin infusion, and every 30 minutes for 2 hours after discontinuation of bivalirudin. The measured bivalirudin serum concentrations during CPB ranged from 10.5 to 20.2 µg/mL, meeting or exceeding the target concentration of 10–15 µg/mL in all patients. The initial bolus of bivalirudin achieved a median ECT of 540 seconds (range, 447–700 seconds; goal >400 seconds). Both ECT and ACTPlus were found to be significantly correlated to the serum bivalirudin concentration; however, the ECT response was found to be more sensitive (R2, 0.6 vs 0.36) than that of the ACTPlus. The primary end point of death, urgent repeat revascularization, Q-wave MI, or stroke during hospitalization occurred in 2 patients (10%), both of whom suffered a MI. Last, zero-balance–modified ultrafiltration (MUF) was shown to increase the clearance of bivalirudin, decreasing the elimination half-life to 23.6 ± 7 minutes from the 35.3 ± 9 minutes and 39 ± 7.2 minutes seen in the patients with no or moderate renal dysfunction, respectively.
The objective of the second, smaller pilot study was to investigate bivalirudin’s ability to attenuate hemostatic activation during CPB.59 Ten patients scheduled for CABG with normothermic CPB were enrolled and randomized to 2 groups: 1 with and 1 without cardiotomy suction (CS). Given the high postbolus ECT values seen in the first pilot study, the initial bolus dose of bivalirudin was reduced to 1 mg/kg. The dosing protocol was further modified so that the patients received fixed infusions rates of 2.5 mg/kg/h with additional boluses as needed to maintain an ECT >400 seconds. A 50-mg bolus of bivalirudin was again added to the pump prime. ECTs and bivalirudin concentrations were measured every 15 minutes. Markers of hemostatic activation (D-dimers, fibrinopeptide-A, prothrombin fragments 1 and 2, thrombin–AT, and factor XIIa) were measured 10 minutes after the bivalirudin bolus and then immediately after termination of CPB. Attenuation of hemostatic activation was demonstrated in the patients who underwent CPB without CS but not those with CS. Of the 85 serum bivalirudin concentrations obtained with the new dosing regimen, 82 were above the target concentration of 10 µg/mL with a mean concentration of 13.0 µg/mL (range, 9.5–18.5 µg/mL) in the CS group and 13.3 µg/mL (range, 8.0–17.4 µg/mL) in the non-CS group. ECT values were not specifically reported, but no patients required a bolus of bivalirudin, indicating that the ECTs were above 400 seconds throughout. The postoperative blood loss was comparable to that seen in the initial pilot study. With the exception of 1 patient requiring reoperation for hemorrhage secondary to sternal artery bleeding, no other perioperative complications were reported.
The EVOLUTION-ON trial (2006)60 was a prospective, open-label, multicenter trial with 2:1 randomization to anticoagulation with bivalirudin or with UFH and protamine reversal in patients undergoing cardiac surgery with planned CPB. In total, 150 patients were enrolled with 101 randomized to the bivalirudin arm and 49 to the heparin/protamine arm; 3 patients were reassigned to the heparin/protamine after randomization. The bivalirudin dosing regimen was the same as that tested in the second pilot study by Koster et al58, while the heparin and protamine dosing was left to the discretion of each involved institution. Anticoagulation monitoring beyond baseline and 5 minutes postdrug administration measurements was also left to the discretion of each institution, with an ACT >2.5 times baseline used as a guideline in the bivalirudin group. There was no statistically significant difference in the primary end point of in-hospital procedural success defined as the absence of death, Q-wave MI, stroke, or revascularization at 7 days, 30 days, or 12 weeks. There was also no significant difference in the secondary outcomes of mortality, 24-hour blood loss, and duration of surgery between the 2 groups. The mean chest tube output at 2 hours was greater in the bivalirudin group (376.8 vs 190.2 mL; P = .0009), but this did not translate into a significant difference in the rate of overall transfusion despite a trend toward an increased incidence of platelet transfusion in the bivalirudin group. Additional bivalirudin boluses were given to 9.2% of patients after the initial loading doses and 8.2% of patients during CPB; 7.1% of infusions were rate adjusted (details not reported). Although no thrombosis was seen within the oxygenators, arterial, or cardioplegia lines, clot formation was seen in the venous reservoir (2 patients) and the cell salvage devices (6 patients) in the patients treated with bivalirudin.
The CHOOSE-ON trial (2007)61 was a single-arm, multicenter prospective trial investigating the safety and efficacy of bivalirudin for CPB in patients with antiplatelet factor 4 antibodies or either confirmed or suspected HIT. The anticoagulation protocol and definition of procedural success were the same as those in the EVOLUTION-ON trial. Procedural success was achieved in 85% and 82% of the patients at 30 days and 12 weeks, respectively, compared to the 94.9% and 94.8% rates of success demonstrated in the EVOLUTION-ON trial. The mean blood loss at 24 hours was 998 ± 595 mL; 84% of the patients in this study received transfusion versus 58.2% of those in the bivalirudin arm of the EVOLUTION-ON trial. The authors did not comment on the rate of thrombosis or on whether dosing changes were needed to attain the goal level of anticoagulation.
PEDIATRIC STUDIES AND CASE REPORTS
The reported experience with bivalirudin utilization during pediatric cardiac catheterization is currently limited to 2 case reports and a single small FDA-solicited, industry-sponsored study. Zamora14 was the first to describe a case of successful bivalirudin anticoagulation for right ventricle to pulmonary artery conduit stenting in a 3-month-old infant with AT deficiency. The patient was administered a bolus dose of 0.5 mg/kg and maintained on an infusion of 0.25 mg/kg/h throughout the entirety of the procedure. Despite the dosing regimen being lower than that tested in adults, the patient’s ACT increased to 353 seconds after the initial bolus and remained >200 seconds for the duration of the procedure without any thrombotic or bleeding complications. Groin hemostasis was attained after 15 minutes of digital compression 30 minutes after cessation of the infusion (ACT 180 seconds). Breinholt et al15 reported the use of bivalirudin during superior vena cava recanalization and stent placement in a 2-year-old boy with a history of HIT and partially palliated complex congenital heart disease. The authors used the Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Event-2 (REPLACE) trial dosing regimen of a 0.75 mg/kg bolus and a 1.75 mg/kg/h infusion and reported higher ACTs throughout the infusion (522–632 seconds) with no thrombotic or bleeding complications. Groin hemostasis was attained after 30 minutes of digital compression 30 minutes after cessation of the infusion (ACT 307 seconds).
In 2011, Forbes et al16 published a small, prospective, multicenter trial evaluating the PK/PD profile of bivalirudin as a procedural anticoagulant for pediatric patients undergoing catheterization for the management of congenital heart disease. One hundred ten patients age birth to 16 years (11 neonates, 33 infants/toddlers, 32 young children, and 34 older children) were enrolled, with 106 patients ultimately receiving bivalirudin per the previously established FDA-approved dosing regimen of a 0.75 mg/kg bolus followed by a 1.75 mg/kg/h infusion for the duration of the procedure. Seventy percent of the patients underwent an interventional procedure with the remainder undergoing hemodynamic assessment or device-less interventions. Serum bivalirudin concentration and ACT (Hemochron Jr. Signature Plus device with ACT Plus cassettes; ITC, Bedford, MA) were measured immediately postbolus, at 30-minute intervals throughout the procedure, and then at 10 and 30 minutes after cessation of the infusion. The authors found the PK/PD response to be different across the studied age groups with clearance inversely related to age so that the half-life, steady-state concentration (cavg), and maximum serum concentration (cmax) were all lowest in the neonatal group (t1/2, 15 minutes; cavg, 3235 ng/mL; cmax, 4876 ng/mL) with values approaching those seen in adults with increasing age. The mean steady-state concentration was found to be 38%–62% lower than that seen in adults with the same weight-based dosing regimen.62 ACTs were found to correlate positively with serum concentration and remained in the target range of 200–400 seconds throughout with the highest values seen in the neonatal population. Pediatric patients <6 months of age were found to have a steeper ACT–serum bivalirudin concentration relationship with delayed attainment of a steady-state ACT. In addition, ACT normalization was delayed.62 This is in contrast to adults, where attainment of a steady-state ACT is believed to be almost immediate. The thrombosis rate was 7.5%. The majority of these thrombotic events occurred in younger patients (<2 years of age) within the vascular access sheaths themselves and did not require treatment beyond sheath removal, leading the authors to conclude that leaving the sheaths in place for postinfusion PK sampling may have artificially increased the complication rate. Minor bleeding was seen in 10.9% of the patients and major bleeding (both hematomas >2.5 cm) in 1.8%. The major limitations of this study were its size and the discrepancy between the intended and actual doses received by the patients due to the intermittent and irregular administration of bivalirudin line flushes. This discrepancy disproportionately affected smaller weight patients with a potential doubling of the intended weight-based dose as was demonstrated in 3 of the neonatal patients.
Pediatric Cardiac Surgery With CPB
The published experience describing the utilization of bivalirudin for pediatric CPB is limited to a number of case reports. The first case report, published by Almond et al17 in 2006, described the use of bivalirudin during cardiac transplantation in a 5-year-old with complex congenital heart disease who developed heparin induced thrombocytopenia and thrombosis (HITT) while on extracorporeal membrane oxygenation after an attempted biventricular repair. Bivalirudin was initially administered at approximately 10% (0.15 mg/kg bolus, 0.25 mg/kg/h infusion) of the EVOLUTION-ON study protocol dosing with a 50-mg bolus administered to the circuit prime; however, multiple boluses and rapid up-titration of the infusion were required to attain therapeutic ACT values. The authors reported acceptable postoperative bleeding with no significant thrombotic complications. Increases in serum bivalirudin concentration were found to correlate with increases in ACT, but rapid decreases in serum concentration were accompanied by slow normalization of the ACT. Gates et al18 next reported the case of a 5-month-old with HITT undergoing a stage 2 Norwood for hypoplastic left heart syndrome. The patient was managed according to the EVOLUTION-ON dosing regimen with a 1 mg/kg bolus, a 2.5 mg/kg/h infusion, and a 50 mg/400 mL bolus added to the CPB circuit prime. The patient required 1 additional 0.5 mg/kg bolus for a subtherapeutic ACT (286 seconds) before the initiation of bypass, but the ACTs were otherwise (461–597 seconds) acceptable. ACTs were noted to normalize quickly with MUF; bleeding was minimal, and there was no transfusion requirement beyond cell saver. Subsequent case reports by Dragomer et al,19 Argueta-Morales et al,20 Faella et al,21 and Kamata et al22 all reported similar experiences (Table 3) utilizing dosing regimens based on the EVOLUTION-ON protocol in the pediatric population undergoing CPB. Additional bolus dosing, delays reaching therapeutic ACT values before establishing CPB, and increased infusion rates were typical with total bolus dosing requirements of up to 4.35 mg/kg and infusion rates of up to 5mg/kg/h. Although ACTs were generally acceptable throughout CPB in all of these cases, maximal values approaching 1000 seconds were recorded at higher infusion rates. Only Kamata et al22 reported a thrombotic event (clot in the CPB reservoir with at an ACT of 514 seconds), while only Argueta-Morales et al20 reported greater-than-expected transfusion requirements that may have been partially attributable to their having continued the bivalirudin infusion up to the point of separation from CPB.
Bivalirudin’s safety and efficacy as a procedural anticoagulant for both catheter-based and surgical interventions in the adult population are supported by a robust, growing body of literature. Although bivalirudin utilization has increased in the pediatric population, there are at present no FDA-approved indications or established dosing guidelines in this age group. The published experience of bivalirudin’s application as a procedural anticoagulant in the pediatric population is limited to the series of case reports and the single small PK/PD study described above. Until such time as further studies can be conducted to better elucidate bivalirudin’s seemingly age-dependent PK/PD profile for this application, it is imperative that the care teams managing these patients avail themselves of the collective experience of others and exercise vigilance with regard to potential safety issues.
Bivalirudin’s unique PK/PD profile necessitates procedural modifications that impact all members of the care team. At our institution, it was recognized that bivalirudin was increasingly being considered for use in patients at risk for, or with a confirmed diagnosis of, HIT. Consequently, after an extensive literature review as summarized in this article, a multidisciplinary group (cardiac surgery, cardiac anesthesiology, perfusion, cardiac intensive care unit) was convened to develop institutional protocols for the administration of bivalirudin. The protocol for the use of bivalirudin during CPB (Figure 2) serves as a safety tool and clinical aid during these rare cases. Until further experience dictates otherwise, we recommend the application of the adult weight-based dosing regimen studied in the EVOLUTION-ON and CHOOSE-ON trials (1 mg/kg bolus immediately followed by a 2.5 mg/kg/h infusion with 50 mg administered to the pump prime) for pediatric CPB cases. Although this dosing has been shown to be safe and effective in patients 5 months of age to 15 years of age, multiple boluses and higher infusion rates were almost always necessary to maintain target ACTs in this population. Providers should not be surprised by this and should be prepared to administer multiple additional boluses (0.5–1 mg/kg increments) and higher infusion rates (0.5 mg/kg/h incremental increases) to achieve and maintain a target ACT. Consideration should also be given to an empiric increase of the infusion rate should large volumes of blood products need to be added to the pump throughout the case.
Modifications to the bypass circuit and the timing of cannula insertion and removal are described in Figure 2. The anesthesiologist must be aware that the bypass cannulas and pump suckers will be removed within a set timeframe after the discontinuation of bivalirudin. This is done to minimize the chance of blood stagnation that would lead to bivalirudin proteolysis and result in thrombosis. Because of this, blood products (cell salvage or otherwise) must be readily available for transfusion in the period immediately after separation from bypass. MUF has been safely used in several of the reported cases and should be considered when clinically appropriate; care must be taken to prevent blood stasis in the hemoconcentrator once incorporated. Although recombinant activated factor VII has been shown to effectively reverse the anticoagulant effect of bivalirudin ex vivo, and its successful use for postbypass hemostasis after bivalirudin anticoagulation has been reported for pediatric CPB, we do not recommend its routine application given the increased risks (thrombosis, lengthened intensive care unit, and hospital stays) associated with its use.17,63,64
When bivalirudin anticoagulation is used for procedural anticoagulation during catheter-based cardiac procedures in the pediatric population, a similar approach to dosing should be used. Given the increased rate of thrombotic complications seen in the study by Forbes et al16 as well as the increased rate of acute in-stent thrombosis seen in the adult PCI population, we recommend that the adult bivalirudin dosing regimen of 0.75 mg/kg bolus followed by a 1.75mg/kg/h infusion for the duration of the procedure should be the minimum dosing regimen considered for use in the pediatric population despite the successful use of a lower dosing regimen by Zamora14. Providers should be prepared to administer additional boluses and a higher infusion rate just as for CPB cases. Furthermore, in smaller patients undergoing interventional catheterization procedures with a high risk of periprocedural thrombosis, it would not be inappropriate to consider a limited duration (≤4 hours) postprocedural bivalirudin infusion at 1.75 mg/kg/h based on the adult experience. In most cases, when bivalirudin will be continued only until the end of the procedure, vascular access sheaths should be removed expeditiously following the conclusion of the procedure and the discontinuation of bivalirudin.
Given that bivalirudin accumulation in the setting of renal dysfunction has been reported in the pediatric population,65 reduction of bivalirudin infusion rates should be considered in children with renal dysfunction undergoing procedures of extended duration. Although the Angiomax prescribing information calls for the consideration of infusion dose reductions to 1 mg/kg/h in patients with severe renal dysfunction (creatinine clearance <30 mL/min) and to 0.25 mg/kg/h in patients on hemodialysis, these recommendations are for the FDA-approved adult PCI indications only.4 It is unclear if the percent reductions called for can be extrapolated to other procedural applications or patient subgroups since the EVOLUTION-ON, CHOOSE-ON, and Forbes et al16 studies all excluded patients with severe renal dysfunction. Renal function–based infusion dose reductions have been reported in the pediatric population for nonprocedural indications, but the proposed reductions are inconsistent across indications and institutions.11,65 Until bivalirudin’s PK/PD profile is better elucidated in the pediatric population, we cannot make specific recommendations regarding empiric infusion dose reductions during pediatric cardiac procedures.
It is important to appreciate that as in adults, the ACT is a limited test for evaluating the coagulation status of pediatric patients being treated with bivalirudin. In both children and adults, serum bivalirudin concentration and ACT values have been shown to be positively correlated, but ultimately not predictive of bleeding or clotting complications. The degree of correlation has also been shown to be inconsistent across ACT management systems/cuvette types, age groups, and ACT ranges with the poorest correlation seen in younger patients and at high ACT values. Younger patients have been shown to have both a steeper ACT response curve and a slower rate of ACT normalization despite greater weight-based clearance. Other factors that have been shown to influence ACT values such as hemodilution, hypothermia, and inadequate platelet count/function are clinically relevant in pediatric, and especially neonatal, cardiac patients. Therefore, ACT values may have even less value as a measure of adequate anticoagulation in this population. Although we recommend up-titration of bivalirudin dosing from the established adult dosing regimens to maintain a minimum target ACT, we cannot recommend routine down-titration based on elevated ACTs alone. Sensitivity-improving modifications to available point-of-care tests (eg, ACTT, ECT–thromboelastography) and quantitative, drug-calibrated assays (eg, ECT, dilute thrombin time, and chromogenic anti-IIa assays) have not been validated in the pediatric population for this application and thus should be used with caution, if at all.
In conclusion, we present recommendations, based on the best available evidence, for the use of bivalirudin as a procedural anticoagulant in pediatric patients for both catheter-based cardiac interventions and cardiac surgery requiring CPB. Going forward, we intend to prospectively study the plasma concentration of bivalirudin attained during pediatric CPB utilizing our current bivalirudin protocol. Until more experience with the use of bivalirudin in pediatric patients is gained and reported, extreme vigilance during the use of this medication in children is warranted.
We would like to acknowledge Gregory Matte CCP, LP, FPP, Chief Perfusionist/Clinical Coordinator for Perfusion Services at Boston Children's Hospital as well as the members of the perfusion team for their contributions to the Bivalirudin for Cardiopulmonary Bypass Protocol.
Name: Katherine L. Zaleski, MD.
Contribution: This author helped edit the manuscript.
Name: James A. DiNardo, MD.
Contribution: This author helped edit the manuscript.
Name: Viviane G. Nasr, MD.
This author helped edit the manuscript.
This manuscript was handled by: Roman M. Sniecinski, MD.
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