Springer Nature is making SARS-CoV-2 and COVID-19 research free. View research | View latest news | Sign up for updates

Current periprocedural anticoagulation in transcatheter aortic valve replacement: could bivalirudin be an option? Rationale and design of the BRAVO 2/3 studies


Transcatheter aortic valve replacement (TAVR) is considered an important option in the management of patients with critical aortic valve stenosis that are either inoperable or have a high surgical risk. Despite continued advances in the procedural aspects of TAVR and decreasing complications rates, the risks of major vascular complications and stroke remain significant, which may in turn confer worse clinical outcomes and impact morbidity and mortality. In this review, we outline certain limitations of the currently recommended periprocedural anticoagulation in TAVR, namely unfractionated heparin that is guided by activated clotting times and protamine use if the bleeding risk is high. We will explore the potential for bivalirudin in this setting, which has become a frontrunner in acute coronary syndrome management because of favorable pharmacokinetics and lower bleeding complications. Finally, we will describe an ongoing large multicenter multinational trial that compares intravenous bivalirudin to unfractionated heparin during TAVR procedures using standardized clinical endpoints.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2



Antithrombotic regimens and outcome


Anti-thrombotic strategy for reduction of myocardial damage during angioplasty-bivalirudin versus heparin


Bleeding academic research consortium


Effect of bivalirudin on aortic valve intervention outcomes


Harmonizing outcomes with revascularization and stents in acute myocardial infarction


Intracoronary stenting and antithrombosis regimen, rapid early action for coronary treatment 3


Placement of aortic transcatheter valves


Transcatheter aortic valve replacement


Valve academic research consortium


  1. 1.

    Turina J, Hess O, Sepulcri F, Krayenbuehl HP (1987) Spontaneous course of aortic valve disease. Eur Heart J 8(5):471–483

  2. 2.

    Bach DS, Siao D, Girard SE, Duvernoy C, McCallister BD Jr, Gualano SK (2009) Evaluation of patients with severe symptomatic aortic stenosis who do not undergo aortic valve replacement: the potential role of subjectively overestimated operative risk. Circ Cardiovasc Qual Outcomes 2(6):533–539

  3. 3.

    Genereux P, Head SJ, Wood DA, Kodali SK, Williams, Paradis JM et al (2012) Transcatheter aortic valve implantation 10 year anniversary: review of current evidence and clinical implications. Eur Heart J 33(19):2388–2398

  4. 4.

    Rodes-Cabau J (2012) Transcatheter aortic valve implantation: current and future approaches. Nat Rev Cardiol 9(1):15–29

  5. 5.

    Makkar RR, Fontana GP, Jilaihawi H, Kapadia S, Pichard AD, Douglas PS et al (2012) Transcatheter aortic-valve replacement for inoperable severe aortic stenosis. N Engl J Med 366(18):1696–1704

  6. 6.

    Kodali SK, Williams MR, Smith CR, Svensson LG, Webb JG, Makkar RR et al (2012) Two-year outcomes after transcatheter or surgical aortic-valve replacement. N Engl J Med 366(18):1686–1695

  7. 7.

    Leon MB, Smith CR, Mack M, Miller DC, Moses JW, Svensson LG et al (2010) Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N Engl J Med 363(17):1597–1607

  8. 8.

    Smith CR, Leon MB, Mack MJ, Miller DC, Moses JW, Svensson LG et al (2011) Transcatheter versus surgical aortic-valve replacement in high-risk patients. N Engl J Med 364(23):2187–2198

  9. 9.

    Genereux P, Webb JG, Svensson LG, Kodali SK, Satler LF, Fearon WF et al (2012) Vascular complications after transcatheter aortic valve replacement: insights from the PARTNER (placement of AoRTic TraNscathetER valve) trial. J Am Coll Cardiol 59:235–243

  10. 10.

    Van Mieghem NM, Tchetche D, Chieffo A, Dumonteil N, Messika-Zeitoun D, van der Boon RM et al (2012) Incidence, predictors, and implications of access site complications with transfemoral transcatheter aortic valve implantation. Am J Cardiol 110(9):1361–1367

  11. 11.

    Leon MB, Piazza N, Nikolsky E, Blackstone EH, Cutlip DE, Kappetein AP et al (2011) Standardized endpoint definitions for transcatheter aortic valve implantation clinical trials: a consensus report from the valve academic research consortium. Eur Heart J 32(2):205–217

  12. 12.

    Genereux P, Head SJ, Van Mieghem NM, Kodali S, Kirtane AJ, Xu K et al (2012) Clinical outcomes after transcatheter aortic valve replacement using valve academic research consortium definitions: a weighted meta-analysis of 3,519 patients from 16 studies. J Am Coll Cardiol 59(25):2317–2326

  13. 13.

    Holmes DR Jr, Mack MJ, Kaul S, Agnihotri A, Alexander KP, Bailey SR et al (2012) ACCF/AATS/SCAI/STS expert consensus document on transcatheter aortic valve replacement. J Am Coll Cardiol 59(13):1200–1254

  14. 14.

    Sun JC, Davidson MJ, Lamy A, Eikelboom JW (2009) Antithrombotic management of patients with prosthetic heart valves: current evidence and future trends. Lancet 374(9689):565–576

  15. 15.

    Ussia GP, Scarabelli M, Mule M, Barbanti M, Sarkar K, Cammalleri V et al (2011) Dual antiplatelet therapy versus aspirin alone in patients undergoing transcatheter aortic valve implantation. Am J Cardiol 108(12):1772–1776

  16. 16.

    Kadakia MB, Desai NR, Alexander KP, Chen AY, Foody JM, Cannon CP et al (2010) Use of anticoagulant agents and risk of bleeding among patients admitted with myocardial infarction: a report from the NCDR ACTION Registry–GWTG (National Cardiovascular Data Registry Acute Coronary Treatment and Intervention Outcomes Network Registry–Get With the Guidelines). JACC Cardiovasc Interv 3(11):1166–1177

  17. 17.

    Hirsh J, Anand SS, Halperin JL, Fuster V (2001) American heart A. Guide to anticoagulant therapy: heparin : a statement for healthcare professionals from the American heart association. Circulation 103(24):2994–3018

  18. 18.

    Hillegass WB, Brott BC, Chapman GD, Phillips HR, Stack RS, Tcheng JE et al (2002) Relationship between activated clotting time during percutaneous intervention and subsequent bleeding complications. Am Heart J 144(3):501–507

  19. 19.

    Shimada YJ, Nakra NC, Fox JT, Kanei Y (2010) Relation of race (Asian, African-American, European-American, and Hispanic) to activated clotting time after weight-adjusted bolus of heparin during percutaneous coronary intervention. Am J Cardiol 105(5):629–632

  20. 20.

    Ferguson JJ, Fathy Waly HM, Le D, Thomakos N, Wilson JM (1998) The effect of body weight and body surface area correction on the distribution of the ACT response to bolus doses of heparin for PTCA. J Invasive Cardiol 10(6):318–322

  21. 21.

    Shantsila E, Lip GY, Chong BH (2009) Heparin-induced thrombocytopenia. a contemporary clinical approach to diagnosis and management. Chest 135(6):1651–1664

  22. 22.

    Hirsh J, Bauer KA, Donati MB, Gould M, Samama MM, Weitz JI et al (2008) Parenteral anticoagulants: American college of chest physicians evidence-based clinical practice guidelines (8th Edition). Chest 133(6 Suppl):141S–159S

  23. 23.

    Butterworth J, Lin YA, Prielipp RC, Bennett J, Hammon JW, James RL (2002) Rapid disappearance of protamine in adults undergoing cardiac operation with cardiopulmonary bypass. Ann Thorac Surg 74(5):1589–1595

  24. 24.

    Welsby IJ, Newman MF, Phillips-Bute B, Messier RH, Kakkis ED, Stafford-Smith M (2005) Hemodynamic changes after protamine administration: association with mortality after coronary artery bypass surgery. Anesthesiology 102(2):308–314

  25. 25.

    Abdel-Wahab M, Richardt G (2012) Safety of bivalirudin in patients with coronary artery disease. Expert Opin Drug Saf 11(1):141–150

  26. 26.

    Stone GW, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR, Dudek D et al (2011) Heparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction (HORIZONS-AMI): final 3 year results from a multicentre, randomised controlled trial. Lancet 377(9784):2193–2204

  27. 27.

    Verheugt FW, Steinhubl SR, Hamon M, Darius H, Steg PG, Valgimigli M et al (2011) Incidence, prognostic impact, and influence of antithrombotic therapy on access and nonaccess site bleeding in percutaneous coronary intervention. JACC Cardiovasc Interv 4(2):191–197

  28. 28.

    Kastrati A, Neumann FJ, Mehilli J, Byrne RA, Iijima R, Buttner HJ et al (2008) Bivalirudin versus unfractionated heparin during percutaneous coronary intervention. N Engl J Med 359(7):688–696

  29. 29.

    Parodi G, Migliorini A, Valenti R, Bellandi B, Signorini U, Moschi G et al (2010) Comparison of bivalirudin and unfractionated heparin plus protamine in patients with coronary heart disease undergoing percutaneous coronary intervention (from the antithrombotic regimens aNd outcome [ARNO] trial). Am J Cardiol 105(8):1053–1059

  30. 30.

    Patti G, Pasceri V, D’Antonio L, D’Ambrosio A, Macri M, Dicuonzo G et al (2012) Comparison of safety and efficacy of bivalirudin versus unfractionated heparin in high-risk patients undergoing percutaneous coronary intervention (from the anti-thrombotic strategy for reduction of myocardial damage during angioplasty-bivalirudin vs heparin study). Am J Cardiol 110(4):478–484

  31. 31.

    Bertrand OF, Jolly SS, Rao SV, Patel T, Belle L, Bernat I et al (2012) Meta-analysis comparing bivalirudin versus heparin monotherapy on ischemic and bleeding outcomes after percutaneous coronary intervention. Am J Cardiol 110(4):599–606

  32. 32.

    Drews T, Pasic M, Buz S, Unbehaun A, Dreysse S, Kukucka M et al (2011) Transcranial doppler sound detection of cerebral microembolism during transapical aortic valve implantation. Thorac Cardiovasc Surg 59(4):237–242

  33. 33.

    Hynes BG, Rodes-Cabau J (2012) Transcatheter aortic valve implantation and cerebrovascular events: the current state of the art. Ann N Y Acad Sci 1254:151–163

  34. 34.

    Nuis RJ, Van Mieghem NM, Schultz CJ, Moelker A, van der Boon RM, van Geuns RJ et al (2012) Frequency and causes of stroke during or after transcatheter aortic valve implantation. Am J Cardiol 109(11):1637–1643

  35. 35.

    Daneault B, Kirtane AJ, Kodali SK, Williams MR, Genereux P, Reiss GR et al (2011) Stroke associated with surgical and transcatheter treatment of aortic stenosis: a comprehensive review. J Am Coll Cardiol 58(21):2143–2150

  36. 36.

    Nietlispach F, Wijesinghe N, Gurvitch R, Tay E, Carpenter JP, Burns C et al (2010) An embolic deflection device for aortic valve interventions. JACC Cardiovasc Interv 3(11):1133–1138

  37. 37.

    Rodes-Cabau J, Dumont E, Boone RH, Larose E, Bagur R, Gurvitch R et al (2011) Cerebral embolism following transcatheter aortic valve implantation: comparison of transfemoral and transapical approaches. J Am Coll Cardiol 57(1):18–28

  38. 38.

    Marechaux S, Corseaux D, Vincentelli A, Richardson M, Ung A, Susen S et al (2009) Identification of tissue factor in experimental aortic valve sclerosis. Cardiovasc Pathol 18(2):67–76

  39. 39.

    Breyne J, Juthier F, Corseaux D, Marechaux S, Zawadzki C, Jeanpierre E et al (2010) Atherosclerotic-like process in aortic stenosis: activation of the tissue factor-thrombin pathway and potential role through osteopontin alteration. Atherosclerosis 213(2):369–376

  40. 40.

    Kini A, Yu J, Cohen M et al (2013) Results of a Two Center Registry. EuroIntervention, Bivalirudin versus Unfractionated Heparin During Aortic Valvuloplasty (in press)

  41. 41.

    Stone GW, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR, Dudek D et al (2008) Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 358(21):2218–2230

  42. 42.

    Mehran R, Lansky AJ, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR et al (2009) Bivalirudin in patients undergoing primary angioplasty for acute myocardial infarction (HORIZONS-AMI): 1 year results of a randomised controlled trial. Lancet 374(9696):1149–1159

  43. 43.

    Stone GW, McLaurin BT, Cox DA, Bertrand ME, Lincoff AM, Moses JW et al (2006) Bivalirudin for patients with acute coronary syndromes. N Engl J Med 355(21):2203–2216

  44. 44.

    Cohen DJ, Lincoff AM, Lavelle TA, Chen HL, Bakhai A, Berezin RH et al (2004) Economic evaluation of bivalirudin with provisional glycoprotein IIB/IIIA inhibition versus heparin with routine glycoprotein IIB/IIIA inhibition for percutaneous coronary intervention: results from the REPLACE-2 trial. J Am Coll Cardiol 44(9):1792–1800

  45. 45.

    Lincoff AM, Bittl JA, Harrington RA, Feit F, Kleiman NS, Jackman JD et al (2003) 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 289(7):853–863

  46. 46.

    Ndrepepa G, Schulz S, Keta D, Mehilli J, Birkmeier A, Massberg S et al (2010) Bleeding after percutaneous coronary intervention with bivalirudin or unfractionated Heparin and 1 year mortality. Am J Cardiol 105(2):163–167

  47. 47.

    Doll JA, Nikolsky E, Stone GW, Mehran R, Lincoff AM, Caixeta A et al (2009) Outcomes of patients with coronary artery perforation complicating percutaneous coronary intervention and correlations with the type of adjunctive antithrombotic therapy: pooled analysis from REPLACE-2, ACUITY, and HORIZONS-AMI trials. J Interv Cardiol 22(5):453–459

  48. 48.

    Romaguera R, Sardi G, Laynez-Carnicero A, Ben-Dor I, Maluenda G, Wakabayashi K et al (2011) Outcomes of coronary arterial perforations during percutaneous coronary intervention with bivalirudin anticoagulation. Am J Cardiol 108(7):932–935

Download references

Confict of interest

Ziad Sergie, Socrates Kakoulides and Usman Baber have no conflict of interest. Jochen Reinöhl—research funding: the Medicines Company, Edwards Lifescience, consulting: Medtronic, the Medicines Company. Eric Van Belle—research funding: the Medicines Company, consulting: AstraZeneca, Bayer. Roxana Mehran—research funding: the Medicines Company, BMS/Sanofi; consulting: AstraZeneca, Janssen. George D. Dangas—research funding: the Medicines Company, BMS/Sanofi; consulting: AstraZeneca, Janssen.

Author information

Correspondence to George D. Dangas.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Sergie, Z., Lefèvre, T., Van Belle, E. et al. Current periprocedural anticoagulation in transcatheter aortic valve replacement: could bivalirudin be an option? Rationale and design of the BRAVO 2/3 studies. J Thromb Thrombolysis 35, 483–493 (2013).

Download citation


  • Unfractionated heparin
  • Protamine
  • Bivalirudin
  • Transcatheter aortic valve replacement