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Thrombin inhibitors and acute coronary syndromes

An article from the E-Journal of the ESC Council for Cardiology Practice

Bivalirudin, a direct thrombin (IIa factor) inhibitor, has demonstrated significant benefit for patients with ACS (both NSTEACS and STEAMI) in short and long-term mortality due to a significant reduction in major bleeding and similar antithrombotic protection.

Acute Coronary Syndromes (ACS)


Acute coronary syndromes (ACS) are frequent and life-threatening episodes of acute myocardial ischemia increasing in our days. The majority are caused by a sudden rupture of a coronary artery plaque generating a downstream activation of platelets, coagulation cascade and thrombus formation (1).

After this initial event, activated platelets adhere to the endothelium and start to aggregate with each other, creating an expanded response (2). Both platelet aggregation and coagulation activation create a severe impairment of the coronary blood flow, resulting in the clinical manifestations of both acute myocardial infarction (AMI) and non-ST segment elevation acute coronary syndrome (NSTEACS).

Coronary catheterisation and stent implantation are the state-of-the-art treatment for patients with ACS of moderate to high risk. The aim of this procedure is to restore coronary blood flow to the myocardial ischemic heart. Ischemic and hemorrhagic complications are life-threatening and limit high mortality (3,4).

I - Thrombin inhibitors: Bivalirudin

Activated thrombin is one of the key steps causing ACS due to its potent effect over platelet activation. Aspirin plus clopidogrel/prasugrel are mandatory in the treatment of patients with ACS in order to avoid platelet aggregation and thrombus formation (1,2). Anticoagulant treatment for ACS has recently changed since bivalirudin emerged and has demonstrated clinical benefit over classic non-fractioned heparin/enoxaparin treatment.

In the recent history, several studies have achieved improved results combining many of these agents. Enoxaparin showed better outcomes in ACS than heparin (Sinergy Trial) (5). Abciximab gain a lot of interest due to its effect reducing ischemic events after ACS (6). Nevertheless, major bleeding became an increasing concern for cardiologists and interventional cardiologists, especially after Eikelboom et al (7) demonstrated an increased mortality for patients with haemorrhagic complications.

Bivalirudin is a hirudin analogue with a potent and reversible inhibition of thrombin (IIa factor) also inhibiting thrombin in developed clots. Moreover, its action starts 2 minutes after the bolus injection and lasts only 25 minutes after withdrawal (if normal creatinine clearance).

II - Clinical applications

Current treatment of ACS includes several antiplatelet agents (ASA, clopidogrel, prasugrel), potent antithrombotic agents inhibiting GP IIb/IIIa receptor (abciximab, tirofiban, eptifibatide) and anticoagulant therapy (non-fractioned heparin, enoxaparin and bivalirudin) (see Figure 1).

A) Non-ST elevation acute coronary syndromes (NSTEACS)

ACUITY trial8 enrolling 13819 patients from 17 different countries compared bivalirudin vs NFH + GPIIbIIIa inhibitors 1 month after ACS, showing a similar antithrombotic effect (ischemic composite of death, MI or unexpected revascularisation: 7,8% vs 7,3%, respectively, RR 1,08 [CI 95%: 0,93-1,24]) and markedly less major bleeding (see Figure 2) (3% vs 5,7%, respectively, RR 0,53 [CI 95%: 0,43-0,65]), resulting in a net clinical benefit (10,1% vs 11,7%, respectively, RR 0,86 [CI 95%: 0,77-0,97]).

At 1 year, mortality rates were higher in patients with myocardial infarction and bleeding complications (mean: 28%), followed by patients with bleeding complications (12,5%) and by those with myocardial infarction with no bleeding complications (8,6%). Moreover, lowest mortality was observed in patients without evidence of myocardial infarction and no bleeding complications (3,4%).

B) Acute myocardial infarction (AMI)

HORIZONS-AMI Trial conducted by Stone GW et al (9) enrolled 3602 patients with STEAMI undergoing a primary PCI strategy and were randomised to receive heparin + GPIIbIIIa inhibitors or bivalirudin alone. Patients receiving bivalirudin alone experienced less bleeding complications (8,4% vs 5% p< 0,0001) and similar major adverse cardiovascular events (5,4% vs 5,5%, p= 0,99) resulting in less mortality from cardiac and non-cardiac causes (1,8% vs 2,9%, p= 0,029) and a significant net clinical benefit (9,3% vs 12,2%, p= 0,006). In addition, patients treated with bivalirudin alone developed significantly less thrombocytopenia.

Results at 3 years have been recently presented in TCT 2010 Congress (Washington DC, USA, September 2010) showing global mortality benefit in patients receiving bivalirudin alone vs patients receiving heparin + GPIIbIIIa inhibitors (5,9% vs 7,7%, p= 0,03). Furthermore, cardiac mortality significantly decreased (2,9% vs 5,1%, p< 0,001), re-infarction rates decreased (6,2% vs 8,2%, p= 0,04) in patients with STEAMI receiving bivalirudin. Indeed, major bleeding rates decreased dramatically in those receiving bivalirudin (6,9% vs 10,5%, p< 0,001) resulting in mortality benefit previously described. Besides, best survival rates were obtained in patients receiving bivalirudin and with Taxus® (paclitaxel) stents vs bare metal stents.

An increasing concern has been raised due to the high rates of definite and/or probable stent thrombosis observed. Investigators from HORIZONS-AMI have presented data at 3 years confirming results from other drug eluting stents (DES) implantation groups. Bivalirudin patients experimented 1,5% stent thrombosis in the first 24 hours after stent implantation vs 0,3% stent thrombosis in patients receiving heparin + GPIIbIIIa inhibitors, raising serious concern in both interventional and clinical cardiologists. Nevertheless, stent thrombosis rates tend to equalise (bivalirudin 3% vs 2,2%, p> 0,05 at 1 year; 4,5% vs 5,1%, p> 0,05 at 3 years) but are the target of further investigation nowadays.

Figure 1. Practical guidelines: antithrombotic treatment options in myocardial revascularisation (10).

Figure 2. Major bleeding definition (ACUITY8 scale).

  • Intracranial
  • Intraocular
  • Retroperitoneal
  • Access site - requiring intervention/surgery
                         - hematoma =5 cm
  • Hgb ß =3 g/dL with overt source
  • Hgb ß =4 g/dL w/o overt source
  • Blood transfusion
  • Reoperation for bleed


  • Bivalirudin is a potent thrombin inhibitor with rapid and reversible action that has shown decreased mortality in patients with ACS undergoing PCI or moderate to high-risk NSTEACS due to reduce bleeding rates
  • ACUITY and HORIZONS-AMI studies demonstrated net clinical benefit for patients receiving bivalirudin compared with those receiving heparin + GPIIbIIIa inhibitors (less bleeding complications). Both studies emphasized the importance of an appropriate antiplatelet treatment (aspirin + clopidogrel/prasugrel with loading doses) for ACS patients receiving bivalirudin.
  • Bivalirudin treatment should be considered in those with moderate/high risk bleeding complications: age > 65 years, diabetes mellitus, renal function impairment, women, hypertension, previous CVA, intra-aortic counterpulsation balloon.


1. Mackman N. Triggers, targets and treatments for thrombosis. Nature 2008; 451: 914-918.
2. Pérez-Gómez F, Bover R. The new coagulation cascade and its possible influence on the delicate balance between thrombosis and haemorrhage. Rev Esp Cardiol 2007; 60: 1217-1219.
3. Cook S, Windecker S. Early stent thrombosis: past, present and future. Circulation 2009; 119: 657-659.
4. Prasad A, Singh M, Lerman A, Lennon RJ, Holmes DR Jr, Rihal CS. Isolated elevation in troponin T after percutaneous coronary intervention is associated with higher long-term mortality. J Am Coll Cardiol 2006; 48(9): 1756-1770.

5. Ferguson JJ, Califf RM, Antman EM, Cohen M, Grines CL, Goodman S, et al. Enoxaparin vs unfractioned heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA 2004; 292(1): 45-54.

6. Topol EJ, Byzova TV, Plow EF. Platelet GPIIb-IIIa blockers. Lancet 1999; 353 (9148): 227-231.

7. Eikelboom JW, Mehta SR, Anand SS, Xie C, Fox KA, Yusuf S. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation 2006; 114(8): 774-782.

8. Stone GW, McLaurin BT, Cox DA, Bertrand ME, Lincoff AM, Moses JW, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006; 355(21): 2203-2216.
9. Stone GW, Witzenbichler B, Guagliumi G, Peruga JZ, Brodie BR, Dudek D, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med 2008; 358(21): 2218-2230.

10. Wijns W, Kolh P, Danchin N, DiMario C, Falk V, Folliguet T, et al. Guidelines on myocardial revascularization. The Task Force on Myocardial Revascularization of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur J Cardiothorac Surg 2010;38S1: S1-S52.*


Vol9 N°5

Notes to editor

Alegría Barrero E 1, Alegría Barrero A2
1 Cardiology and Cardiovascular Surgery. Rotger Clinic. Palma de Mallorca, Spain. Member of the Cardiovascular Thrombosis Group of the Spanish Society of Cardiology.
2 Cardiology and Cardiovascular Surgery. University of Navarre Clinic. Pamplona, Spain.

Eduardo Alegría Barrero
Instituto de Cardiología (Hemodinámica), Clínica Rotger
c/ Santiago Russiñol, 9  
07012 - Palma de Mallorca, Spain
Tel. +34 971 44 85 02    Fax +34 971 72 90 66

The content of this article reflects the personal opinion of the author/s and is not necessarily the official position of the European Society of Cardiology.