ST-segment myocardial infarction (STEMI) is the result of a total occlusion of an epicardial coronary artery from an acute coronary thrombus, which is composed of platelet aggregates and fibrin. Thrombin plays a central role in thrombogenesis by converting fibrinogen to fibrin, and by directly enhancing platelet activation and aggregation.^1,2 Primary percutaneous coronary intervention (PCI) is the standard of treatment in all patients presenting with STEMI with ischemic symptoms of less than 12 hours duration.³ Iatrogenic damage to the endothelium during PCI further activates the blood coagulation cascade system and generation of thrombin resulting in thrombus formation. Hence, pharmacological agents aimed at inhibition of both platelet aggregation and thrombin generation are crucial in the setting of acute coronary syndromes (ACS) and primary PCI.

The pharmacotherapy during primary PCI has undergone substantial evolution over the last decade. Pre-procedural antiplatelet and anticoagulant therapy has been the focus of numerous clinical trials and currently there are several options available. Parenteral anticoagulants include indirect thrombin inhibitors such as unfractionated heparin (UFH) and enoxaparin, and direct thrombin inhibitors such as bivalirudin. Antiplatelet agents include aspirin, glycoprotein IIb/IIIa (GP IIb/IIIa) inhibitors, oral thienopyridine agents (clopidogrel and prasugrel) and non-thienopyridine P2Y12 inhibitors (ticagrelor and cangrelor). The best combination of these agents that results in maximum reduction in thrombotic complications without increasing the risk of peri-procedural bleeding is currently unknown. This is a review of the available literature in choosing the best anticoagulation therapy during primary PCI, specifically focusing on use of UFH and bivalirudin.

There are very few studies comparing bivalirudin directly with UFH in ACS. In majority of the studies, the comparison was between bivalirudin and heparin plus GP IIb/IIIa inhibitors. This is because several studies in the 1990s already established that effectiveness of GP IIb/IIIa inhibitors when added to aspirin and heparin for patients presenting with ACS in terms of significant reduction in composite endpoint of death and myocardial infarction.⁴ However most of these trials involving GP IIb/IIIa inhibitors were done in the era prior to the routine use of oral antiplatelet agents. The current guidelines recommend the use of GP IIb/IIIa inhibitors only in high risk situations (e.g. in high risk ACS patients and large thrombus burden who are not at increased risk of bleeding).³ Thus, over the last decade, the use of GP IIb/IIIa inhibitors has decreased drastically.

The use of bivalirudin as the preferred antithrombotic agent in patients with STEMI is primarily from the multicenter randomized trial HORIZONS AMI (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction).⁵ In this study involving 3602 STEMI patients undergoing primary PCI, anticoagulation with bivalirudin alone as compared to heparin plus GP IIb/IIIa inhibitors was associated with significant reduction at 30 days in rates of major bleeding (4.9% vs. 8.3%, p<0.01), death from cardiac causes (1.8% vs. 2.9%, p=0.03) and death from all causes (2.1% vs. 3.1%, p=0.047).⁵ Interestingly, the reduction in cardiac mortality in bivalirudin group persisted up to three years (rate of cardiac mortality: 2.9% vs. 5.1%, p=0.001).⁶ The following are some important points to consider when interpreting the results of this trial:

• A loading dose of clopidogrel 600mg or 300mg was given in all patients. Newer antiplatelet agents were not used.
• 65% of the patients in the bivalirudin group received heparin pre-procedure. Bivalirudin was started 30 minutes after the heparin was stopped but in all cases before the PCI.
• Bivalirudin resulted in an increased risk of acute stent thrombosis in the first 24 hours compared to heparin + GP IIb/IIIa inhibitors (1.3% vs. 0.3%, p <0.001).

What is the mechanism of mortality benefit seen from bivalirudin that exists up to three years? The effect of bivalirudin in reducing cardiac mortality, even at three years, cannot be completely explained by reduction in early rates of major bleeding.6 There appears to be some other non-hemorrhagic effect of bivalirudin driving the mortality benefit seen in HORIZONS AMI. The proposed (but not yet proven) mechanisms for this benefit include amelioration of reperfusion injury, reduction of inflammation and apoptosis, improvement of post-ischemic myocardial function, and reduced infarct size.⁶

Clinical practice has substantially changed since the HORIZONS AMI trial was conducted in terms of using newer antiplatelet agents, expanded use of radial access site, and decreased use of GP IIb/IIIa inhibitors. Because of these changes in clinical practice, the EUROMAX (European Ambulance Acute Coronary Syndrome Angiography) trial was conducted comparing bivalirudin initiated in the ambulance during transport for primary PCI in patients with STEMI with heparin and optional use of GP IIb/IIIa inhibitors.⁷ A total of 2218 patients across nine European countries were enrolled in this trial. At 30 days, bivalirudin was associated with significant reduction in major bleeding (2.6% vs. 6.0%, p<0.001), without any significant difference in the rates of death (2.9% vs. 3.1%) or reinfarction (1.7% vs. 0.9%). The following are the important points of consideration regarding these results from the EUROMAX trial compared to the results from HORIZONS AMI.

• EUROMAX was more representative of the contemporary clinical practice in terms of radial access site and use of new antiplatelet agents. However, this was still not a head-on-head trial comparing bivalirudin to heparin as GP IIb/IIIa inhibitors were used in 69% of patients in the control group together with heparin compared to 11.5% in the bivalirudin group.
• The mortality benefit seen in HORIZONS AMI was not replicated in the EUROMAX trial. Bivalirudin was associated with reduced risk of major bleeding but not reduced rates of death or reinfarction.
• Acute stent thrombosis was noted to be higher in the bivalirudin group (1.1% vs. 0.2%; p=0.007), similar to HORIZONS AMI.

There were no large scale randomized trials comparing bivalirudin directly to heparin alone without GP IIb/IIIa inhibitors, until the availability of the results of HEAT PPCI (How Effective are Antithrombotic Therapies in Primary Percutaneous Coronary Intervention) trial presented at the recent American College of Cardiology (ACC) 2014 Scientific Sessions.⁸ This moderate-sized, open-label, randomized trial involved all patients with STEMI presenting to a single center and compared bivalirudin with UFH. GP IIb/IIIa inhibitors were used only in bail-out situations in both groups. A total of 1829 STEMI patients were recruited over a span of 22 months. Interestingly, at four weeks, the use of heparin was associated with a significant reduction in the major cardiovascular endpoints of all-cause mortality, cerebrovascular accidents, reinfarction, and target vessel revascularization compared to bivalirudin (5.7% vs. 8.7%, p=0.01) with no significant difference in the rate of major bleeding in both the groups (3.5% vs. 3.1%, p= 0.59). The following are the most notable key points of this study:

• It is a single-center, randomized trial that was open-label. The trial data has not yet been published in a peer-reviewed journal.
• The trial population is representative of patients seen in clinical practice as all patients with STEMI at the center were asked to participate.
• GP IIb/IIIa inhibitors were used only in bail-out situations, similar to the current clinical practice in both bivalirudin and heparin groups (13.5% in bivalirudin group; 15.5% in heparin group).
• The use of new antiplatelet agents and radial access site (about 60% of the patients in both groups were given ticagrelor, and radial access was used in 80% of patients in both groups) reflects the current clinical practice.
• Definite or probable stent thrombosis was higher with bivalirudin use compared to heparin (3.4% vs. 0.9%, p=0.001). Target vessel revascularization and reinfarction probably related to stent thrombosis was driving the increased major adverse cardiovascular events (MACE) in the bivalirudin group.

Two other trials also presented at the ACC 2014 – NAPLES III (Novel Approaches in Preventing and Limiting Events trial)⁹ and BRAVE 4 (Efficacy study of combined prasugrel and bivalirudin versus clopidogrel and heparin in myocardial infarction)¹⁰ – support the controversial results of the HEAT PPCI trial. In both these studies, no differences in the rates of bleeding with bivalirudin were observed compared to heparin without the use of GP IIb/IIIa inhibitors.

In summary, the available literature comparing bivalirudin with heparin provides conflicting results. The current clinical practice is changing rapidly with increasing use of newer, more potent oral antiplatelet drugs and restricting the use of GP IIb/IIIa inhibitors to patients at high thrombotic risk or in a bail-out situation during a complicated PCI. Hence, the results of the HORIZONS AMI trial and EUROMAX showing reduced bleeding rates with bivalirudin may not be applicable to the current era. The mortality benefit seen in HORIZONS AMI was not replicated in EUROMAX. Given the results of the HEAT PPCI trial, in which the population and practice was more representative of the current trends, it is probably time to rethink the use of bivalirudin as the preferred antithrombotic drug in primary PCI. Also, bivalirudin has been consistently associated with increased risk of acute stent thrombosis in all the studies. Hence, in the current era of using new antiplatelet agents, extensive use of radial access, and decreased GP IIb/IIIa inhibitors, clinical equipoise should be maintained in choosing bivalirudin or heparin as the antithrombotic agent until further evidence is available.

References

1. Davie EW, Kulman JD. An overview of the structure and function of thrombin. Semin Thromb Hemost 2006;32(suppl 1):3–15.
2. Coughlin SR. Thrombin signalling and protease-activated receptors. Nature 2000;407:258 –264
3. American College of Emergency Physicians, Society for Cardiovascular Angiography and Interventions, O'Gara PT, Kushner FG, Ascheim DD, Casey DE, Jr, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013;61:e78-140.
4. Labinaz M, Ho C, Banerjee S, Martin J, Chen S, Mensinkai S. Meta-analysis of clinical efficacy and bleeding risk with intravenous glycoprotein IIb/IIIa antagonists for percutaneous coronary intervention. Can J Cardiol 2007;23:963-970.
5. 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;358:2218-2230.
6. Stone GW, Clayton T, Deliargyris EN, Prats J, Mehran R, Pocock SJ. Reduction in cardiac mortality with bivalirudin in patients with and without major bleeding: The HORIZONS-AMI trial (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction). J Am Coll Cardiol 2014;63:15-20.
7. Steg PG, van 't Hof A, Hamm CW, Clemmensen P, Lapostolle F, Coste P, et al. Bivalirudin started during emergency transport for primary PCI. N Engl J Med 2013;369:2207-2217.
8. Shahzad A. How Effective are Antithrombotic Therapies in Primary Percutaneous Coronary Intervention (HEAT PPCI). Presented at the American College of Cardiology Annual Scientific Sessions. March 31st, 2014, Washington DC.
9. Briguori C. Novel Approaches in Preventing or Limiting Event III trial (NAPLES III). Presented at the American College of Cardiology Annual Scientific Sessions, March 29th, 2014, Washington DC.
10. Richardt G. Bavarian Reperfusion Alternatives Evaluation (BRAVE 4). Presented at the American College of Cardiology Annual Scientific Sessions, March 29th, 2014, Washington DC.

Keywords: Acute Coronary Syndrome, Blood Coagulation, Blood Platelets, Coronary Vessels, Endothelium, Fibrin, Fibrinogen, Iatrogenic Disease, Myocardial Infarction, Percutaneous Coronary Intervention, Platelet Activation, Platelet Aggregation, Thrombin, Thrombosis

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