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.
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.
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 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).
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.
This author helped edit the manuscript.
1. Moffett BS, Teruya J. Trends in parenteral direct thrombin inhibitor use in pediatric patients: analysis of a large administrative database. Arch Pathol Lab Med. 2013;14:e182–e188.
2. Anderson BJ, Holford NH. Mechanism-based concepts of size and maturity in pharmacokinetics. Annu Rev Pharmacol Toxicol. 2008;48:303–332.
3. Baier K, Cvirn G, Fritsch P, et al. Higher concentrations of heparin and hirudin are required to inhibit thrombin generation in tissue factor-activated cord plasma than in adult plasma. Pediatr Res. 2005;57:685–689.
5. Young G, Tarantino MD, Wohrley J, Weber LC, Belvedere M, Nugent DJ. Pilot dose-finding and safety study of bivalirudin in infants <6 months of age with thrombosis. J Thromb Haemost. 2007;5:1654–1659.
6. Rayapudi S, Torres A Jr, Deshpande GG, et al. Bivalirudin for anticoagulation in children. Pediatr Blood Cancer. 2008;51:798–801.
7. O’Brien SH, Yee DL, Lira J, Goldenberg NA, Young G. UNBLOCK: an open-label, dose-finding, pharmacokinetic and safety study of bivalirudin in children with deep vein thrombosis. J Thromb Haemost. 2015;13:1615–1622.
8. Pollak U, Yacobobich J, Tamary H, Dagan O, Manor-Shulman O. Heparin-induced thrombocytopenia and extracorporeal membrane oxygenation: a case report and review of the literature. J Extra Corpor Technol. 2011;43:5–12.
9. Ranucci M, Ballotta A, Kandil H, et al; Surgical and Clinical Outcome Research Group. Bivalirudin-based versus conventional heparin anticoagulation for postcardiotomy extracorporeal membrane oxygenation. Crit Care. 2011;15:R275.
10. Nagle EL, Dager WE, Duby JJ, et al. Bivalirudin in pediatric patients maintained on extracorporeal life support. Pediatr Crit Care Med. 2013;14:e182–e188.
11. Rutledge JM, Chakravarti S, Massicotte MP, Buchholz H, Ross DB, Joashi U. Antithrombotic strategies in children receiving long-term Berlin Heart EXCOR ventricular assist device therapy. J Heart Lung Transplant. 2013;32:569–573.
12. Preston TJ, Dalton HJ, Nicol KK, Ferrall BR, Miller JC, Hayes D Jr.. Plasma exchange on venovenous extracorporeal membrane oxygenation with bivalirudin anticoagulation. World J Pediatr Congenit Heart Surg. 2015;6:119–122.
13. Chetan D, Buchholz H, Bauman M, et al. Successful treatment of pediatric ventricular assist device thrombosis. ASAIO J. 2017 June 7 [Epub ahead of print].
14. Zamora R. Successful anticoagulation with bivalirudin in antithrombin-deficient pediatric patient undergoing stent placement. Catheter Cardiovasc Interv. 2006;68:292–295.
15. Breinholt JP, Moffett BS, Texter KM, Ing FF. Successful use of bivalirudin for superior vena cava recanalization and stent placement in a child with heparin-induced thrombocytopenia. Pediatr Cardiol. 2008;29:804–807.
16. Forbes TJ, Hijazi ZM, Young G, et al. Pediatric catheterization laboratory anticoagulation with bivalirudin. Catheter Cardiovasc Interv. 2011;77:671–679.
17. Almond CS, Harrington J, Thiagarajan R, et al. Successful use of bivalirudin for cardiac transplantation in a child with heparin-induced thrombocytopenia. J Heart Lung Transplant. 2006;25:1376–1379.
18. Gates R, Yost P, Parker B. The use of bivalirudin for cardiopulmonary bypass anticoagulation in pediatric heparin-induced thrombocytopenia patients. Artif Organs. 2010;34:667–669.
19. Dragomer D, Chalfant A, Biniwale R, Reemtsen B, Federman M. Novel techniques in the use of bivalirudin for cardiopulmonary bypass anticoagulation in a child with heparin-induced thrombocytopenia. Perfusion. 2011;26:516–518.
20. Argueta-Morales IR, Olsen MC, DeCampli WM, Munro HM, Felix DE. Alternative anticoagulation during cardiovascular procedures in pediatric patients with heparin-induced thrombocytopenia. J Extra Corpor Technol. 2012;44:69–74.
21. Faella KH, Whiting D, Fynn-Thompson F, Matte GS. Bivalirudin anticoagulation for a pediatric patient with heparin-induced thrombocytopenia and thrombosis requiring cardiopulmonary bypass for ventricular assist device placement. J Extra Corpor Technol. 2016;48:39–42.
22. Kamata M, Sebastian R, McConnell PI, Gomez D, Naguib A, Tobias JD. Perioperative care in an adolescent patient with heparin-induced thrombocytopenia for placement of a cardiac assist device and heart transplantation: case report and literature review. Int Med Case Rep J. 2017;10:55–63.
23. Weitz JI, Buller HR. Direct thrombin inhibitors in acute coronary syndromes: present and future. Circulation. 2002;105:1004–1011.
24. Buck ML. Bivalirudin as an alternative to heparin for anticoagulation in infants and children. J Pediatr Pharmacol Ther. 2015;20:408–417.
25. Fox I, Dawson A, Loynds P, et al. Anticoagulant activity of Hirulog, a direct thrombin inhibitor, in humans. Thromb Haemost. 1993;69:157–163.
26. Warkentin TE, Greinacher A, Craven S, Dewar L, Sheppard JA, Ofosu FA. Differences in the clinically effective molar concentrations of four direct thrombin inhibitors explain their variable prothrombin time prolongation. Thromb Haemost. 2005;94:958–964.
27. Casserly IP, Kereiakes DJ, Gray WA, et al. Point-of-care ecarin clotting time versus activated clotting time in correlation with bivalirudin concentration. Thromb Res. 2004;113:115–121.
28. Cheneau E, Canos D, Kuchulakanti PK, et al. Value of monitoring activated clotting time when bivalirudin is used as the sole anticoagulation agent for percutaneous coronary intervention. Am J Cardiol. 2004;94:789–792.
29. Stone GW, Witzenbichler B, Guagliumi G, et al; HORIZONS-AMI Trial Investigators. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med. 2008;358:2218–2230.
30. Zucker ML, Koster A, Prats J, Laduca FM. Sensitivity of a modified ACT test to levels of bivalirudin used during cardiac surgery. J Extra Corpor Technol. 2005;37:364–368.
31. Carroll RC, Chavez JJ, Simmons JW, et al. Measurement of patients’ bivalirudin plasma levels by a thrombelastograph ecarin clotting time assay: a comparison to a standard activated clotting time. Anesth Analg. 2006;102:1316–1319.
32. Koster A, Chew D, Gründel M, Bauer M, Kuppe H, Spiess BD. Bivalirudin monitored with the ecarin clotting time for anticoagulation during cardiopulmonary bypass. Anesth Analg. 2003;96:383–386.
33. Van Cott EM, Roberts AJ, Dager WE. Laboratory monitoring of parenteral direct thrombin inhibitors. Semin Thromb Hemost. 2017;43:270–276.
34. Topol EJ, Bonan R, Jewitt D, et al. Use of a direct antithrombin, Hirulog, in place of heparin during coronary angioplasty. Circulation. 1993;87:1622–1629.
35. Bittl JA, Strony J, Brinker JA, et al. Treatment with bivalirudin (Hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina. Hirulog Angioplasty Study Investigators. N Engl J Med. 1995;333:764–769.
36. Bittl JA, Chaitman BR, Feit F, Kimball W, Topol EJ. Bivalirudin versus heparin during coronary angioplasty for unstable or postinfarction angina: Final report reanalysis of the Bivalirudin Angioplasty Study. Am Heart J. 2001;142:952–959.
37. Lincoff AM, Kleiman NS, Kottke-Marchant K, et al. Bivalirudin with planned or provisional abciximab versus low-dose heparin and abciximab during percutaneous coronary revascularization: results of the Comparison of Abciximab Complications with Hirulog for Ischemic Events Trial (CACHET). Am Heart J. 2002;143:847–853.
38. Lincoff AM, Bittl JA, Kleiman NS, et al; REPLACE-1 Investigators. Comparison of bivalirudin versus heparin during percutaneous coronary intervention (the Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events [REPLACE]-1 trial). Am J Cardiol. 2004;93:1092–1096.
39. Lincoff AM, Bittl JA, Harrington RA, et al; REPLACE-2 Investigators. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA. 2003;289:853–863.
40. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patient with acute coronary syndromes. N Engl J Med. 2006;355:2203–2216.
41. Kastrati A, Neumann FJ, Mehilli J, et al; ISAR-REACT 3 Trial Investigators. Bivalirudin versus unfractionated heparin during percutaneous coronary intervention. N Engl J Med. 2008;359:688–696.
42. Kastrati A, Neumann FJ, Schulz S, et al; ISAR-REACT 4 Trial Investigators. Abciximab and heparin versus bivalirudin for non-ST-elevation myocardial infarction. N Engl J Med. 2011;365:1980–1989.
43. Steg PG, van ‘t Hof A, Hamm CW, et al; EUROMAX Investigators. Bivalirudin started during emergency transport for primary PCI. N Engl J Med. 2013;369:2207–2217.
44. Shahzad A, Kemp I, Mars C, et al; HEAT-PPCI Trial Investigators. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet. 2014;384:1849–1858.
45. Briguori C, Visconti G, Focaccio A, et al. Novel Approaches for Preventing or Limiting Events (NAPLES) III trial. J Am Coll Cardiol Intv. 2015;8:414–423.
46. Schulz S, Richardt G, Laugwitz KL, et al; Bavarian Reperfusion Alternatives Evaluation (BRAVE) 4 Investigators. Prasugrel plus bivalirudin vs clopidogrel plus heparin in patients with ST-segment elevation myocardial infarction. Eur Heart J. 2014;35:2285–2294.
47. Han Y, Guo J, Zheng Y, et al; BRIGHT Investigators. Bivalirudin vs heparin with or without tirofiban during primary percutaneous coronary intervention in acute myocardial infarction: the BRIGHT randomized clinical trial. JAMA. 2015;313:1336–1346.
48. Valgimigli M, Frigoli E, Leonardi S, et al; MATRIX Investigators. Bivalirudin or unfractionated heparin in acute coronary syndromes. N Engl J Med. 2015;373:997–1009.
49. Fabris E, Kilic S, Van’t Hof AWJ, et al. One-year mortality for bivalirudin vs heparins plus optional glycoprotein IIb/IIIa inhibitor treatment started in the ambulance for ST-segment elevation myocardial infarction: a secondary analysis of the EUROMAX randomized clinical trial. JAMA Cardiol. 2017;2:791–796.
50. Erlinge D, Omerovic E, Fröbert O, et al. Bivalirudin versus heparin monotherapy in myocardial infarction. N Engl J Med. 2017;377:1132–1142.
51. Nairooz R, Sardar P, Amin H, et al. Meta-analysis of randomized clinical trials comparing bivalirudin versus heparin plus glycoprotein IIb/IIIa inhibitors in patients undergoing percutaneous coronary intervention and in patients with ST-segment elevation myocardial infarction. Am J Cardiol. 2014;114:250–259.
52. Shah R, Rogers KC, Matin K, Askari R, Rao SV. An updated meta-analysis of bivalirudin vs heparin use in primary percutaneous coronary intervention. Am Heart J. 2016;171:14–24.
53. Cavender MA, Sabatine MS. Bivalirudin versus heparin in patients planned for percutaneous coronary intervention: a meta-analysis of randomised controlled trials. Lancet. 2014;384:599–606.
54. Fahrni G, Wolfrum M, De Maria GL, Banning AP, Benedetto U, Kharbanda RK. Prolonged high-dose bivalirudin infusion reduces major bleeding without increasing stent thrombosis in patients undergoing primary percutaneous coronary intervention: novel insights from an updated meta-analysis. J Am Heart Assoc. 2016;5:e003515.
55. Kini A, Yu J, Cohen MG, et al. Effect of bivalirudin on aortic valve intervention outcomes study: a two-centre registry study comparing bivalirudin and unfractionated heparin in balloon aortic valvuloplasty. EuroIntervention. 2014;10:312–319.
56. Lange P, Greif M, Bongiovanni D, et al. Bivalirudin vs heparin in patients who undergo transcatheter aortic valve implantation. Can J Cardiol. 2015;31:998–1003.
57. Dangas GD, Lefèvre T, Kupatt C, et al; BRAVO-3 Investigators. Bivalirudin versus heparin anticoagulation in transcatheter aortic valve replacement: the randomized BRAVO-3 trial. J Am Coll Cardiol. 2015;66:2860–2868.
58. Koster A, Spiess B, Chew DP, et al. Effectiveness of bivalirudin as a replacement for heparin during cardiopulmonary bypass in patients undergoing coronary artery bypass grafting. Am J Cardiol. 2004;93:356–359.
59. Koster A, Yeter R, Buz S, et al. Assessment of hemostatic activation during cardiopulmonary bypass for coronary artery bypass grafting with bivalirudin: results of a pilot study. J Thorac Cardiovasc Surg. 2005;129:1391–1394.
60. Dyke CM, Smedira NG, Koster A, et al. A comparison of bivalirudin to heparin with protamine reversal in patients undergoing cardiac surgery with cardiopulmonary bypass: the EVOLUTION-ON study. J Thorac Cardiovasc Surg. 2006;131:533–539.
61. Koster A, Dyke CM, Aldea G, et al. Bivalirudin during cardiopulmonary bypass in patients with previous or acute heparin-induced thrombocytopenia and heparin antibodies: results of the CHOOSE-ON trial. Ann Thorac Surg. 2007;83:572–577.
63. Young G, Yonekawa KE, Nakagawa PA, Blain RC, Lovejoy AE, Nugent DJ. Recombinant activated factor VII effectively reverses the anticoagulant effects of heparin, enoxaparin, fondaparinux, argatroban, and bivalirudin ex vivo as measured using thromboelastography. Blood Coagul Fibrinolysis. 2007;18:547–553.
64. Downey L, Brown ML, Faraoni D, Zurakowski D, DiNardo JA. Recombinant factor VIIa is associated with increased thrombotic complications in pediatric cardiac surgery patients. Anesth Analg. 2017;124:1431–1436.
65. Malloy KM, McCabe TA, Kuhn RJ. Bivalirudin use in an infant with persistent clotting on unfractionated heparin. J Pediatr Pharmacol Ther. 2011;16:108–112.