Transcatheter aortic valve replacement (TAVR) has established itself as a game-changing treatment strategy for patients with severe aortic stenosis (AS), and high or prohibitive surgical risk. The balloon-expandable SAPIEN heart-valve system (Edwards Lifesciences Corp., Irvine, CA) has been shown to yield similar one- and two-year outcomes to surgical aortic valve replacement (SAVR), including rates of all-cause death, cardiovascular death, and stroke.¹ Furthermore, two-year outcomes from the CoreValve U.S. Pivotal trial using a self-expanding aortic prosthesis (Medtronic Inc., Minneapolis, Minnesota) have demonstrated lower rates of all-cause death, all strokes, and major adverse cardiovascular and cerebrovascular events (MACCE) compared to traditional SAVR in patients at increased surgical risk.² The transfemoral approach has become an established approach for TAVR. Although new iterations of valve systems now involve smaller sheath sizes, there are specific bleeding and vascular complications akin to the transfemoral approach.³ Procedural anticoagulation raises the risk of bleeding, yet it is a crucial component during TAVR in order to prevent thrombosis or embolization during the periprocedural period. Landmark trials and registries have largely utilized unfractionated heparin (UFH) for anticoagulation during TAVR, which lends itself well to reversal by protamine in case of catastrophic bleeding or major vascular injury. Alternatively, the anticoagulant bivalirudin (Angiomax; The Medicines Company, Parsipanny, NJ), a direct thrombin inhibitor, offers immediate action, a shorter half-life of 25 minutes compared to the 90-minute half-life of UFH, yet it cannot be pharmacologically reversed.⁴

Several trials focusing on procedural anticoagulation during percutaneous coronary intervention (PCI) have investigated the safety and efficacy of UFH versus bivalirudin. In patients presenting with acute ST-elevation myocardial infarction, when compared to UFH, bivalirudin has been shown to reduce 30-day net adverse clinical events (NACE) due to reduced major bleeding; however, stent thrombosis was increased.⁵ In patients presenting with moderate- or high-risk acute coronary syndromes (ACS), bivalirudin yielded similar rates of composite of death, myocardial infarction (MI), or unplanned revascularization for ischemia, as well as major bleeding in comparison to UFH.⁶ Additionally, due to differences in bivalirudin infusion protocols across catheterization laboratories, a recent randomized trial examined patients with ACS for whom an invasive strategy was planned. This trial showed similar rates of major adverse cardiovascular events (MACE) with bivalirudin and UFH, regardless of whether the bivalirudin infusion was continued post-PCI or discontinued at the end of the procedure.⁷ The results from the aforementioned coronary intervention trials, as well as other analyses, have led to an interest in investigating the safety and efficacy of bivalirudin as an alternative to UFH for anticoagulation during balloon aortic valvuloplasty (BAV) and TAVR.

BAV for severe AS has never been shown to improve survival,⁸ yet it does result in temporary improvement in valve obstruction and symptoms. The ascent of TAVR for patients with severe AS at high or prohibitive surgical risk has invigorated an interest in BAV as a bridging therapy for patients who may be acutely ill and in need of immediate relief of valvular obstruction. The clinical outcomes of using bivalirudin versus UFH in patients undergoing transfemoral BAV was evaluated in the Effect of Bivalirudin on Aortic Valve Intervention Outcomes (BRAVO) study.⁹ The investigators retrospectively analyzed independently-adjudicated in-hospital clinical outcomes in 427 consecutive patients from 2005-2010 who underwent elective or urgent BAV with use of bivalirudin or UFH as procedural anticoagulation at two high volume centers. Of the 427 patients, 223 received bivalirudin and 204 received UFH.⁹ The primary endpoint was in-hospital Bleeding Academic Research Consortium (BARC) ≥3 major bleeding. Additional endpoints included MACE, and the composite of all-cause mortality, MI, and stroke as defined by the Valve Academic Research Consortium (VARC) criteria.¹⁰ Net adverse clinical events (NACE) included MACE and BARC ≥3 major bleeding.⁹ Per the reported baseline characteristics, patients in the bivalirudin group were significantly older, received more femoral artery preclosure, and were more likely to be in a critical pre-BAV state with acute kidney injury or cardiopulmonary support. Additionally, there were non-significant trends towards high use of warfarin in patients treated with bivalirudin. Data from the BRAVO study demonstrated that patients who received bivalirudin had lower rates of in-hospital BARC ≥3 major bleeding (4.9% vs. 13.2%, p=0.003), as well as lower rates of NACE (11.2% vs. 20.1%, p=0.01).⁹ However, MACE and vascular complications were no different between those who received bivalirudin versus those treated with UFH. Major bleeding rates remained statistically significantly lower in the bivalirudin group irrespective of how major bleed thresholds were defined (i.e., Thrombolysis in Myocardial Infarction [TIMI], Global Use of Strategies to Open Occluded Coronary Arteries [GUSTO], VARC, BARC).

Recently, a German multicenter retrospective analysis was reported, in which 461 patients undergoing transfemoral TAVR between 2007 and 2012 were treated with bivalirudin or UFH for procedural anticoagulation.¹¹ Of the 461 patients, 339 received bivalirudin and 122 received UFH. The SAPIEN XT valve was used in 47% of those who received bivalirudin, while 53% received the Medtronic CoreValve.¹¹ Notably, only the CoreValve system was used in the UFH group. The primary outcome focus was the incidence of any bleeding. Secondary outcomes included all-cause mortality and cardiovascular mortality at 72 hours post-procedure, and at 30-day follow-up. The investigators reported no significant difference between the bivalirudin and UFH groups for life-threatening bleeding (2.4% and 3.3%, respectively; p=0.59), or major bleeding (8.3% and 8.2%, respectively; p=0.98).¹¹ At 72 hours, there was no difference in all-cause mortality or cardiovascular mortality between the two groups. At 30 days, all-cause mortality was 5.3% in bivalirudin patients vs. 4.1% in the UFH patients (p=0.57).¹¹ The 30-day cardiovascular mortality was 4.4% vs. 2.5%, respectively (p=0.33).¹¹ Additionally, this analysis showed a non-significant signal towards increased stroke rate in the bivalirudin group (1.8% vs. 0.0%, p=0.139), a trend that was not seen in the retrospective BRAVO study.¹¹ Both bivalirudin- and UFH-treated patients enjoyed similar device implantation success rates greater than 90% without any significant difference between the groups, irrespective of the anticoagulant used. It is noteworthy that the low event rate limited the power to detect small differences between treatments in the efficacy and safety comparisons.

In order to better understand the safety and efficacy of bivalirudin as an alternative procedural anticoagulant during transfemoral TAVR, Dangas and colleagues recently reported results from the randomized open-label trial, Bivalirudin Versus Heparin Anticoagulation in Transcatheter Aortic Valve Replacement. A Randomized Phase 3 Trial (BRAVO 3) in The Journal. BRAVO 3 investigators hypothesized that bivalirudin would reduce major bleeding compared with UFH in transfemoral TAVR patients to a similar extent as that observed in several of the aforementioned PCI trials. The trial design randomized 802 patients at high surgical risk across 31 sites in seven countries with a European System for Cardiac Operative Risk Evaluation (EUROSCORE) ≥18 with AS who were scheduled for transfemoral TAVR to receive either bivalirudin (n=404) or UFH (n=398).¹² The bivalirudin administration protocol was standardized across all participating centers and consisted of an initial bolus of 0.75 mg/kg followed by a continuous infusion at 1.75mg/kg per hour in patients with estimated glomerular filtration rate (GFR) greater than or equal to 60 mL/min, 1.4 mg/kg per hour in patients with GFR 30-59 mL/min, and 1.0 mg/kg per hour in patents with a GFR <30.¹² UFH dosing was in accordance with weight-based dosing to achieve a target activated clotting time greater than 250 seconds. The decision to administer protamine reversal at the end of the procedure was left to the discretion of the institution's standard practice. Patients with planned surgical cutdown access, presence of a previous valve replacement, severe left ventricular dysfunction defined as ejection fraction less than 15%, common femoral artery diameter <6.5 mm, severe aortic or mitral valve regurgitation, concurrent PCI, recent bleeding or neurologic event, and dialysis-dependent patients were excluded from study.¹² At its inception, the trial targeted to enroll 522 patients (261 in each group), assuming an estimated rate of major bleeding of 19% in the control group and 47% in the experimental group, in order to reach 80% power to detect a significant bleeding reduction at an alpha level less than 0.05.¹² However, with its adaptive sample size design, analysis of interim bleeding rates led to a recommendation by the trial's data safety monitoring board to continue the study until the predefined maximum of 800 patients was enrolled. Additionally, BRAVO 3 was powered to show non-inferiority for 30-day NACE with a margin of 8.0% difference in event rates.¹² The trial's primary co-endpoints were BARC ≥3b major bleeding within 48 hours or before hospital discharge, whichever occurred first, and 30-day NACE (MACE plus major bleeding).¹² Several secondary endpoints were also analyzed including other major bleeding definitions, composite of MACE and its individual components, acute kidney injury, transient ischemic attacks, major vascular complications, acquired thrombocytopenia and new post-procedural atrial fibrillation or flutter. Patients were clinically followed on post-procedure day one, day two, on hospital discharge, and at 30-day follow-up; follow-up rates in each group were 97.5%.

The BRAVO 3 trial reported that the use of bivalirudin for procedural anticoagulation did not significantly reduce the primary outcomes of BARC ≥3b major bleeding at 48 hours or 30-day NACE when compared with UFH. Major bleeding occurred in 6.9% of bivalirudin-treated patients and 9.0% of UFH-treated patients (p=0.27).¹² At 30 days, NACE rates were 14.4% in the bivalirudin group and 16.1% in the UFH group (p=0.50), and the pre-specified non-inferiority hypothesis was met with a p_{non-inferioritiy}<0.01.¹² There was no difference in the rates of MACE at 48 hours between bivalirudin and UFH groups, and no difference in rates of stroke or death. At 48 hours there was a significantly higher rate of MI with UFH compared to bivalirudin (1.3% vs 0%, p=0.03), while bivalirudin-treated patients had higher rates of stage 1 acute kidney injury compared to UFH (10.9% vs 6.5%, p=0.03)¹². At 30-day follow-up; however, there were no significant differences in the rates of MI or stroke. Furthermore, in subgroup analyses, there was no difference in the rates of major bleeding based on sheath size (>18 French vs. <18 French) or valve type: self-expanding TAVR (5.7% with bivalirudin vs. 10.6% with UFH, p=0.14), balloon-expandable TAVR (7.6% with bivalirudin vs. 8.0% with UFH, p=0.85).¹² Subgroup analysis on whether heparin reversal with protamine affected outcomes was not possible due to lack of data on protamine use at each participating center.

Retrospective analyses and the randomized open-label BRAVO 3 trial all suggest that the degree of reduction in major bleeding seen in coronary intervention trials does not translate to TAVR patients who receive bivalirudin for procedural anticoagulation. These findings may underline the point that TAVR patients are fundamentally different from the vast majority of ACS patients enrolled in PCI trials. Alternatively, the data also highlight the fact that the published experience with bivalirudin in TAVR has been limited to small numbers of patients in comparison to larger coronary intervention trials, thus leaving the possibility that a beneficial effect of bivalirudin may be present but not adequately detectable, thus larger trials may be warranted. Although the totality of current data do not support the superiority of bivalirudin over UFH during transfemoral TAVR, they do demonstrate the comparable safety and efficacy of bivalirudin and UFH. Perhaps the most impactful contribution of the retrospective and randomized data is that bivalirudin can be safely used for procedural anticoagulation in patients undergoing transfemoral TAVR with a history of heparin-induced thrombocytopenia or ideological convictions against receiving the porcine elements used in UFH formulations. While further randomized trials may help to elucidate the interplay between bivalirudin and UFH use in TAVR, UFH remains the standard of care due to its lower cost and equivalent safety and efficacy.

References

1. Kodali SK, Williams MR, Smith CR, et al. Two-year outcomes after transcatheter or surgical aortic-valve replacement. N Engl J Med 2012;366:1686-95.
2. Reardon MJ, Adams DH, Kleiman NS, et al. 2-Year Outcomes in Patients Undergoing Surgical or Self-Expanding Transcatheter Aortic Valve Replacement. J Am Coll Cardiol 2015;66:113-121.
3. Genereux P, Cohen DJ, Williams MR, et al. Bleeding complications after surgical aortic valve replacement compared with transcatheter aortic valve replacement: insights from the PARTNER 1 trial. J Am Coll Cardiol 2014;63:1100-9.
4. Weitz JI. Chapter 30. Blood Coagulation and Anticoagulant, Fibrinolytic, and Antiplatelet Drugs. In: Brunton LL, Chabner BA, Knollmann BC. eds. Goodman & Gilman's The Pharmacological Basis of Therapeutics, 12e. New York, NY: McGraw-Hill; 2011.
5. Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008;358:2218-30.
6. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006;355:2203-16.
7. Valgimigli M, Frigoli E, Leonardi M, et al. Bivalirudin or Unfractionated Heparin in Acute Coronary Syndromes. N Engl J Med 2015;373:997-1009.
8. O'Keefe JH Jr, Vlietstra RE, Bailey KR, Holmes DR Jr. Natural history of candidates for balloon aortic valvuloplasty. Mayo Clin Proc. 1987;62:986-91.
9. Kini A, Yu J, Cohen MG, et al. Effect of bivalirudin on aortic valve intervention outcomes study: a two-center registry study comparing bivalirudin and unfractionated heparin in balloon aortic valvuloplasty. Eurointervention 2014;10:312-9.
10. Leon MG, Piazza N, Nikolsky E, et al. Standardized endpoint definitions for Transcatheter Aortic Valve Implantation clinical trials: a consensus report from the Valve Academic Research Consortium. J Am Coll Cardiol. 2011;57:253-69.
11. 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.
12. Dangas GD, Lefevre T, Kupatt C, et al. Bivalirudin Versus Heparin Anticoagulation in Transcatheter Aortic Valve Replacement: The Randomized BRAVO-3 Trial. J Am Coll Cardiol 2015;66:2860-8.

Keywords: Acute Coronary Syndrome, Acute Kidney Injury, Anticoagulants, Antithrombins, Aortic Valve, Aortic Valve Stenosis, Atrial Fibrillation, Catheterization, Clinical Trials Data Monitoring Committees, Control Groups, Coronary Vessels, Femoral Artery, Follow-Up Studies, Glomerular Filtration Rate, Glomerular Filtration Rate, Half-Life, Heparin, Hirudins, Ischemic Attack, Transient, Mitral Valve Insufficiency, Myocardial Infarction, Peptide Fragments, Percutaneous Coronary Intervention, Prostheses and Implants, Protamines, Randomized Controlled Trials as Topic, Registries, Renal Dialysis, Research Personnel, Research Personnel, Retrospective Studies, Standard of Care, Stents, Thrombocytopenia, Thrombosis, Transcatheter Aortic Valve Replacement, Vascular System Injuries, Ventricular Dysfunction, Left, Warfarin

< Back to Listings