Bivalirudin: Difference between revisions

{{Short description|Anticoagulant drug}}

{{Use dmy dates|date=March 2024}}

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| verifiedrevid = 459980478

| width =

| alt =

| tradename = Angiomax, Angiox, others

| licence_EU = yes

| ATC_prefix = B01

| ATC_suffix = AE06

| legal_CA = Rx-only

| legal_CA_comment = <ref>{{cite web | title=Regulatory Decision Summary - Bivalirudin Injection | website=Health Canada | date=23 October 2014 | url=https://hpr-rps.hres.ca/reg-content/regulatory-decision-summary-detail.php?linkID=RDS00817 | access-date=5 June 2022}}</ref>

| legal_US = Rx-only

| legal_US_comment = <ref name="Angiomax FDA label">{{cite web | title=Angiomax- bivalirudin injection | website=DailyMed | date=30 June 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=5f133813-f74e-4508-bc64-debbf104ff1e | access-date=31 March 2024}}</ref><ref>{{cite web | title=Angiomax RTU- bivalirudin injection, solution | website=DailyMed | date=5 November 2019 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=72c5413f-882a-4784-9be6-312c0a0a2a97 | access-date=31 March 2024}}</ref>

| legal_EU = Withdrawn

| legal_EU_comment = <ref>{{cite web | title=Angiox EPAR | website=[[European Medicines Agency]] (EMA) | date=2 September 2009 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/angiox | access-date=31 March 2024}}</ref>

| legal_status = Rx-only

| IUPHAR_ligand = 6470

| DrugBank_Ref = {{drugbankcite|correct|drugbank}}

| ChEBI_Ref = {{ebicite|correct|EBI}}

| ChEMBL = 1201455

<!--Chemical data-->

| C=98 | H=138 | N=24 | O=33

| smiles = CC[C@H](C)[C@@H](C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CCC(=O)O)C(=O)N[C@@H](CC2=CC=C(C=C2)O)C(=O)N[C@@H](CC(C)C)C(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CCC(=O)O)NC(=O)[C@H](CC3=CC=CC=C3)NC(=O)[C@H](CC(=O)O)NC(=O)CNC(=O)[C@H](CC(=O)N)NC(=O)CNC(=O)CNC(=O)CNC(=O)CNC(=O)[C@@H]4CCCN4C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H]5CCCN5C(=O)[C@@H](CC6=CC=CC=C6)N

| synonyms = d-Phenylalanyl-l-prolyl-l-arginyl<br />-l-prolylglycylglycylglycylglycyl-l-asparaginylglycyl<br />-l-alpha-aspartyl-l-phenylalanyl<br />-l-alpha-glutamyl-l-alpha-glutamyl-l-isoleucyl<br />-l-prolyl-l-alpha-glutamyl-l-alpha-glutamyl<br />-l-tyrosyl-l-leucine

'''Bivalirudin''', sold under the brand names '''Angiomax''' and '''Angiox''', among others, is a specific and reversible [[direct thrombin inhibitor]] (DTI).<ref name="Angiomax FDA label" /> Chemically, it is a synthetic [[Congener (chemistry)|congener]] of the naturally occurring drug [[hirudin]], found in the saliva of the medicinal leech ''[[Hirudo medicinalis]]''. It is manufactured by The Medicines Company.<ref>{{cite press release | title=The Medicines Company Reacquires Angiox Rights in Europe from Nycomed | website=Fierce Biotech | date=2 July 2007 | url=https://www.fiercebiotech.com/financials/press-release-medicines-company-reacquires-angiox-rights-europe-from-nycomed | access-date=31 March 2024}}</ref>

Bivalirudin lacks many of the limitations seen with indirect thrombin inhibitors, such as [[heparin]]. A short, synthetic peptide, it is a potent and highly specific inhibitor of [[thrombin]]<ref name="Angiomax FDA label" /><ref name=Anand2007>{{cite journal | vauthors = Anand SX, Kim MC, Kamran M, Sharma SK, Kini AS, Fareed J, Hoppensteadt DA, Carbon F, Cavusoglu E, Varon D, Viles-Gonzalez JF, Badimon JJ, Marmur JD | title = Comparison of platelet function and morphology in patients undergoing percutaneous coronary intervention receiving bivalirudin versus unfractionated heparin versus clopidogrel pretreatment and bivalirudin | journal = The American Journal of Cardiology | volume = 100 | issue = 3 | pages = 417–24 | date = August 2007 | pmid = 17659921 | doi = 10.1016/j.amjcard.2007.02.106 }}</ref><ref name=Weitz1990>{{cite journal | vauthors = Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsh J | title = Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors | journal = The Journal of Clinical Investigation | volume = 86 | issue = 2 | pages = 385–91 | date = August 1990 | pmid = 2384594 | pmc = 296739 | doi = 10.1172/JCI114723 }}</ref> that inhibits both circulating and clot-bound thrombin,<ref name=Weitz1990 /> while also inhibiting thrombin-mediated platelet activation and aggregation.<ref name=Stone2006>{{cite journal | vauthors = Stone GW, McLaurin BT, Cox DA, Bertrand ME, Lincoff AM, Moses JW, White HD, Pocock SJ, Ware JH, Feit F, Colombo A, Aylward PE, Cequier AR, Darius H, Desmet W, Ebrahimi R, Hamon M, Rasmussen LH, Rupprecht HJ, Hoekstra J, Mehran R, Ohman EM | title = Bivalirudin for patients with acute coronary syndromes | journal = The New England Journal of Medicine | volume = 355 | issue = 21 | pages = 2203–16 | date = November 2006 | pmid = 17124018 | doi = 10.1056/NEJMoa062437 | url = http://diposit.ub.edu/dspace/bitstream/2445/49765/1/633096.pdf | hdl = 2445/49765 | s2cid = 12034067 | hdl-access = free }}</ref> Bivalirudin has a quick onset of action and a short half-life.<ref name="Angiomax FDA label" /> It does not bind to plasma proteins (other than thrombin) or to red blood cells. Therefore, it has a predictable antithrombotic response. There is no risk for [[heparin-induced thrombocytopenia]] or heparin-induced thrombosis-thrombocytopenia syndrome.<ref name="Angiomax FDA label" /> It does not require a binding cofactor such as antithrombin and does not activate platelets.<ref name=Anand2007 /><ref name=Weitz2002>{{cite journal | vauthors = Weitz JI, Bates SM | title = Acute coronary syndromes: a focus on thrombin | journal = The Journal of Invasive Cardiology | volume = 14 Suppl B | pages = 2B–7B | date = April 2002 | pmid = 11967385 }}</ref> These characteristics make bivalirudin an ideal alternative to heparin.

Bivalirudin clinical studies demonstrated consistent positive outcomes in patients with stable [[angina]], unstable angina (UA), [[NSTEMI|non–ST-segment elevation myocardial infarction]] (NSTEMI), and [[ST-segment elevation myocardial infarction]] (STEMI) undergoing [[Percutaneous coronary intervention|PCI]] in seven major randomized trials.<ref name="Angiomax FDA label" /><ref name=Weitz1990 /><ref name=Stone2006 /><ref name=Bittl2001>{{cite journal | vauthors = Bittl JA, Chaitman BR, Feit F, Kimball W, Topol EJ | title = Bivalirudin versus heparin during coronary angioplasty for unstable or postinfarction angina: Final report reanalysis of the Bivalirudin Angioplasty Study | journal = American Heart Journal | volume = 142 | issue = 6 | pages = 952–9 | date = December 2001 | pmid = 11717596 | doi = 10.1067/mhj.2001.119374 }}</ref><ref name=Lincoff2003>{{cite journal | vauthors = Lincoff AM, Bittl JA, Harrington RA, Feit F, Kleiman NS, Jackman JD, Sarembock IJ, Cohen DJ, Spriggs D, Ebrahimi R, Keren G, Carr J, Cohen EA, Betriu A, Desmet W, Kereiakes DJ, Rutsch W, Wilcox RG, de Feyter PJ, Vahanian A, Topol EJ | title = Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial | journal = JAMA | volume = 289 | issue = 7 | pages = 853–63 | date = February 2003 | pmid = 12588269 | doi = 10.1001/jama.289.7.853 | doi-access = free }}</ref> Patients receiving bivalirudin had fewer adverse events compared to patients that received heparin.<ref>{{cite news|last1=Brauser|first1=Deborah |title=BRIGHT in Print: Bivalirudin Bests Heparin for Fewer Bleeding Events During PCI, but Dose Matters|url=http://www.medscape.com/viewarticle/843024|access-date=14 April 2015|publisher=Medscape|date=13 April 2015}}</ref><ref>{{ClinicalTrialsGov|NCT01696110|BivaliRudin in Acute Myocardial Infarction vs Glycoprotein IIb/IIIa and Heparin :a Randomised Controlled Trial. (BRIGHT)}}</ref>

==Medical uses==

=== United States ===

*Bivalirudin is indicated for use as an anticoagulant in patients with unstable angina undergoing percutaneous transluminal coronary angioplasty (PTCA).<ref name="Angiomax FDA label" />

=== European Union ===

*Percutaneous Coronary Intervention (PCI), including patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary PCI.<ref name=Angiox>{{cite web|url= http://www.themedicinescompany.com/new-images/Angiox-PIs/emea-combined-h562en.pdf|title= Annex 1 - Summary of Product Characteristics|date= March 2010|work= www.themedicinescompany.com|publisher= The Medicines Company UK Ltd|access-date= 2 December 2011|url-status= dead|archive-url= https://web.archive.org/web/20120426012235/http://www.themedicinescompany.com/new-images/Angiox-PIs/emea-combined-h562en.pdf|archive-date= 26 April 2012}}</ref>

== Pharmacology ==

=== Mechanism of action ===

Bivalirudin directly inhibits thrombin by specifically binding both to the catalytic site and to the anion-binding exosite of circulating and clot-bound thrombin.<ref name="Angiomax FDA label" /> Thrombin is a serine proteinase that plays a central role in the thrombotic process. It cleaves fibrinogen into fibrin monomers, activates Factor V, VIII, and XIII, allowing fibrin to develop a covalently cross-linked framework that stabilizes the thrombus. Thrombin also promotes further thrombin generation, and activates platelets, stimulating aggregation and granule release. The binding of bivalirudin to thrombin is reversible as thrombin slowly cleaves the bivalirudin-Arg₃-Pro₄ bond, resulting in recovery of thrombin active site functions.<ref name="Angiomax FDA label" />

=== Pharmacokinetics ===

*Following an IV bolus of bivalirudin of 1&nbsp;mg/kg and a 4-hour 2.5&nbsp;mg/kg/h IV infusion a mean steady state concentration of 12.3 ± 1.7&nbsp;μg/mL is achieved<ref name="Angiomax FDA label" />

-Normal renal function (≥&nbsp;90&nbsp;mL/min) = 25 minutes

-Mild renal dysfunction (60–89&nbsp;mL/min) = 22 minutes

-Moderate renal dysfunction (30-59&nbsp;mL/min) = 34 minutes

-Severe renal dysfunction (≤&nbsp;29&nbsp;mL/min) = 57 minutes

-Dialysis-dependent = 3.5 hours

'''Pharmacodynamics'''<ref name="Angiomax FDA label" />

== Chemistry ==

Bivalirudin is a 20 amino acid long peptide with the sequence D-Phe-Pro-Arg-Pro-Gly-Gly-Gly-Gly-Asn-Gly-Asp-Phe-Glu-Glu-Ile-Pro-Glu-Glu-Tyr-Leu (FPRPGGGGNGDFEEIPEEYL), where the first residue is D-phenylalanine instead of the natural L-phenylalanine.

Bivalirudin is contraindicated in patients with active major bleeding and hypersensitivity to bivalirudin or its components. (In the EU bivalirudin is also contraindicated in patients with an increased risk of bleeding due to hemostasis disorders and/or irreversible coagulation disorders, severe uncontrolled hypertension, subacute bacterial endocarditis, and severe renal impairment [GFR<30 ml/min] and in dialysis-dependent patients).<ref name="Angiomax FDA label" /><ref name=Angiox />

Bivalirudin is an anticoagulant. Therefore, bleeding is an expected adverse event. In clinical trials, bivalirudin treated patients exhibited statistically significantly lower rates of bleeding than patients treated with heparin plus a GP IIb/IIIa inhibitor. The most common (≥10%) adverse events of bivalirudin are back pain, pain, nausea, headache, and hypotension.<ref name="Angiomax FDA label" /><ref name=Angiox />

The submission was based on a prospective, open-label, multi-center, single arm study evaluating bivalirudin as a procedural anticoagulant in the pediatric population undergoing intravascular procedures for congenital heart disease.

Study outcomes suggest that the pharmacokinetic (PK) and pharmacodynamic (PD) response of bivalirudin in the pediatric population is predictable and behaves in a manner similar to that in adults.<ref name=Zamora2009>{{cite journal | vauthors = Zamora R, Forbes T, Hijazi Z, Qureshi A, Ringewald J, Rome J, Vincent R |year= 2009|title= Bivalirudin (Angiomax) As a Procedural Anticoagulant in the Pediatric Population Undergoing Intravascular Procedures for Congenital Heart Disease|journal= Catheterization and Cardiovascular Interventions|volume= 73|issue= S1|pages= S8}}</ref>

Bivalirudin is supported by several major randomized trials. These trials include REPLACE-2 (Randomized Evaluation of PCI Linking Angiomax to Reduced Clinical Events-2), BAT (Bivalirudin Angioplasty Trial), ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy Trial), and HORIZONS AMI (Harmonizing Outcomes With Revascularization and Stents in AMI). A total of 25,000 patients with a low to high risk for ischemic complications undergoing PCI were evaluated. Bivalirudin with or without provisional GPIIb/IIIa demonstrated similar angiographic and procedural outcomes and improved clinical outcomes when compared with heparin plus GPIIb/IIIa.<ref name="Angiomax FDA label" /><ref name=Stone2006 /><ref name=Bittl2001 /><ref name=Lincoff2003 /><ref name=Stone2008>{{cite journal | vauthors = Stone GW, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR, Dudek D, Kornowski R, Hartmann F, Gersh BJ, Pocock SJ, Dangas G, Wong SC, Kirtane AJ, Parise H, Mehran R | title = Bivalirudin during primary PCI in acute myocardial infarction | journal = The New England Journal of Medicine | volume = 358 | issue = 21 | pages = 2218–30 | date = May 2008 | pmid = 18499566 | doi = 10.1056/NEJMoa0708191 | url = http://researchonline.lshtm.ac.uk/7561/1/nejmoa0708191.pdf }}</ref>

'''HORIZONS-AMI'''<ref name=Stone2008 /><ref name=Mehran2009>{{cite journal | vauthors = Mehran R, Lansky AJ, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR, Dudek D, Kornowski R, Hartmann F, Gersh BJ, Pocock SJ, Wong SC, Nikolsky E, Gambone L, Vandertie L, Parise H, Dangas GD, Stone GW | title = Bivalirudin in patients undergoing primary angioplasty for acute myocardial infarction (HORIZONS-AMI): 1-year results of a randomised controlled trial | journal = Lancet | volume = 374 | issue = 9696 | pages = 1149–59 | date = October 2009 | pmid = 19717185 | doi = 10.1016/S0140-6736(09)61484-7 | s2cid = 205955934 }}</ref><ref name=Stone2009>{{cite conference |title= HORIZONS- AMI: Two-Year Follow-up from a Prospective, Randomized Trial of Heparin Plus Glycoprotein IIb/IIIa Inhibitors vs. Bivalirudin and Paclitaxel-Eluting vs. Bare-Metal Stents in STEMI|author= Gregg W. Stone|date= 25 September 2009|conference= TCT2009 Conference, San Francisco}}</ref>

HORIZONS AMI was a prospective, randomized, open-label, double-arm multicenter trial in STEMI patients undergoing primary PCI.

*Patients receiving Angiomax monotherapy had similar rates of overall stent thrombosis (Academic Research Consortium (ARC) definition) at 30 days versus UFH plus a GP IIb/IIIa inhibitor (2.5% vs. 1.9%), with the exception of acute stent thrombosis (<24 hours), which was higher for the bivalirudin-treated patients at 1.3% vs 0.3% for the UFH-GP IIb/IIIa-inhibitor-treated patients.

*At 1-year follow-up, a reduction in the incidence of net adverse clinical events (15.7% vs. 18.3%) and major bleeding (5.8% vs. 4.9%) was maintained in the bivalirudin monotherapy group versus UFH plus a GP IIb/IIIa inhibitor group, with no difference in the rate of [[major adverse cardiovascular events]] (11.9% vs. 11.9%)

*A significant reduction in the rate of cardiac mortality in patients treated with bivalirudin monotherapy versus UFH plus a GP IIb/IIIa inhibitor was maintained at 1 year in the HORIZONS AMI trial (2.1% vs. 3.8%)The incidence of stent thrombosis at 1 year was also similar between the 2 treatment groups (3.5% in the Angiomax group vs. 3.2% in the UFH plus GP IIb/IIIa inhibitor group).

*At 2-year follow-up, a reduction in the incidence of net adverse clinical events (22.3% vs. 24.8%) and major bleeding (6.4% vs. 9.6%) was maintained in the bivalirudin monotherapy group versus UFH plus a GP IIb/IIIa inhibitor group, with no difference in the rate of major adverse cardiovascular events (18.7% vs. 18.8%)

*At 2-year follow-up, treatment with bivalirudin monotherapy resulted in a 25% reduction in all-cause mortality, representing 15 lives saved per 1000 patients treated (number needed to treat [NNT] = 67 to save 1 life).

'''ACUITY'''<ref name=Stone2006 />

'''REPLACE-2'''<ref name=Lincoff2003 />

REPLACE-2 was a multicenter, double-blind, triple-dummy randomized clinical trial in patients with low to moderate risk for ischemic complications undergoing PCI.

''30 Days''

'''BAT'''<ref name=Bittl2001 />

The Phase III Bivalirudin Angioplasty Trial (BAT) was a randomized, prospective, double blind, multicenter study in patients with unstable angina undergoing PTCA.

'''US guidelines'''<ref name=Kushner2009>{{cite journal | vauthors = Kushner FG, Hand M, Smith SC, King SB, Anderson JL, Antman EM, Bailey SR, Bates ER, Blankenship JC, Casey DE, Green LA, Hochman JS, Jacobs AK, Krumholz HM, Morrison DA, Ornato JP, Pearle DL, Peterson ED, Sloan MA, Whitlow PL, Williams DO | title = 2009 focused updates: ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction (updating the 2004 guideline and 2007 focused update) and ACC/AHA/SCAI guidelines on percutaneous coronary intervention (updating the 2005 guideline and 2007 focused update) a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines | journal = Journal of the American College of Cardiology | volume = 54 | issue = 23 | pages = 2205–41 | date = December 2009 | pmid = 19942100 | doi = 10.1016/j.jacc.2009.10.015 | doi-access = free }}</ref><ref name=Anderson2007>{{cite journal | vauthors = Anderson JL, Adams CD, Antman EM, Bridges CR, Califf RM, Casey DE, Chavey WE, Fesmire FM, Hochman JS, Levin TN, Lincoff AM, Peterson ED, Theroux P, Wenger NK, Wright RS, Smith SC, Jacobs AK, Adams CD, Anderson JL, Antman EM, Halperin JL, Hunt SA, Krumholz HM, Kushner FG, Lytle BW, Nishimura R, Ornato JP, Page RL, Riegel B | title = ACC/AHA 2007 guidelines for the management of patients with unstable angina/non-ST-Elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 2002 Guidelines for the Management of Patients With Unstable Angina/Non-ST-Elevation Myocardial Infarction) developed in collaboration with the American College of Emergency Physicians, the Society for Cardiovascular Angiography and Interventions, and the Society of Thoracic Surgeons endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation and the Society for Academic Emergency Medicine | journal = Journal of the American College of Cardiology | volume = 50 | issue = 7 | pages = e1–e157 | date = August 2007 | pmid = 17692738 | doi = 10.1016/j.jacc.2007.02.013 | doi-access = free }}</ref><ref name=Harrington2008>{{cite journal | vauthors = Harrington RA, Becker RC, Cannon CP, Gutterman D, Lincoff AM, Popma JJ, Steg G, Guyatt GH, Goodman SG | title = Antithrombotic therapy for non-ST-segment elevation acute coronary syndromes: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) | journal = Chest | volume = 133 | issue = 6 Suppl | pages = 670S–707S | date = June 2008 | pmid = 18574276 | doi = 10.1378/chest.08-0691 | author10 = American College of Chest Physicians }}</ref>

'''EU guidelines'''<ref name=Silber2005>{{cite journal | vauthors = Silber S, Albertsson P, Avilés FF, Camici PG, Colombo A, Hamm C, Jørgensen E, Marco J, Nordrehaug JE, Ruzyllo W, Urban P, Stone GW, Wijns W | title = Guidelines for percutaneous coronary interventions. The Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology | journal = European Heart Journal | volume = 26 | issue = 8 | pages = 804–47 | date = April 2005 | pmid = 15769784 | doi = 10.1093/eurheartj/ehi138 | author14 = Task Force for Percutaneous Coronary Interventions of the European Society of Cardiology | doi-access = free }}</ref><ref name=Bassand2008>{{cite journal | vauthors = Bassand JP, Hamm CW, Ardissino D, Boersma E, Budaj A, Fernández-Avilés F, Fox KA, Hasdai D, Ohman EM, Wallentin L, Wijns W | title = Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes | journal = European Heart Journal | volume = 28 | issue = 13 | pages = 1598–660 | date = July 2007 | pmid = 17569677 | doi = 10.1093/eurheartj/ehm161 | doi-access = free }}</ref><ref name=VandeWerf2008>{{cite journal | vauthors = Van de Werf F, Bax J, Betriu A, Blomstrom-Lundqvist C, Crea F, Falk V, Filippatos G, Fox K, Huber K, Kastrati A, Rosengren A, Steg PG, Tubaro M, Verheugt F, Weidinger F, Weis M | title = Management of acute myocardial infarction in patients presenting with persistent ST-segment elevation: the Task Force on the Management of ST-Segment Elevation Acute Myocardial Infarction of the European Society of Cardiology | journal = European Heart Journal | volume = 29 | issue = 23 | pages = 2909–45 | date = December 2008 | pmid = 19004841 | doi = 10.1093/eurheartj/ehn416 | last20 = De Caterina | last21 = Dean | last22 = Dickstein | last23 = Filippatos | last24 = Funck-Brentano | last25 = Hellemans | last26 = Kristensen | last27 = McGregor | last28 = Sechtem | author17 = ESC Committee for Practice Guidelines (CPG) | first23 = G. | first22 = K. | first21 = V. | first20 = R. | first27 = K. | first26 = S. D. | first25 = I. | first24 = C. | first29 = S. | first28 = U. | last29 = Silber | last19 = Camm | last18 = Vahanian | last31 = Widimsky | last30 = Tendera | first19 = J. | first30 = M. | first31 = P. | first18 = A. | doi-access = free }}</ref>

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