Primary percutaneous coronary intervention (PCI) is the standard of care for patients with ST-segment elevation myocardial infarction (STEMI).⁽¹⁾ Thrombin plays a central role in arterial thrombogenesis by converting fibrinogen to fibrin, activating platelets, and promoting a procoagulant and proinflammatory enviroment. Therefore, inhibiting either thrombin generation or activity is crucial in the context of acute coronary syndromes, as well as during primary PCI, due to the risk of thrombus formation related to arterial injury or esposure of thrombogenic material from disrupted plaques to intraluminal blood.

Current ACCF/AHA guidelines provide a Class I indication for the use of an anticoagulant as soon as the diagnosis of STEMI is made.⁽¹⁾ Parenteral anticoagulants include indirect thrombin inhibitors, such as unfractionated heparin (UFH) and enoxaparin, and direct thrombin inhibitors, such as bivalirudin. The early initiation of UFH is common practice in many emergency departments ambulances, hospital wards or clinics, due to its universal availability, low price and ease of use as a bolus. Intravenous enoxaparin may be a viable alternative to UFH in patients with STEMI undergoing primary PCI, and sheath removal considerations should account for its long half-life.⁽²⁾ Evidence supporting a prominent role of bivalirudin as the preferred anticoagulation strategy in the STEMI setting, stems from the large HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial. From 30-day, and up to 3-year follow-up, bivalirudin monotherapy (with 7% GPIIb/IIIa inhibitor infusion for thrombotic bailout) resulted in significantly lower of major bleeding, all-cause mortality and cardiac mortality compared with the combination of UFH plus routine GP IIb/IIIa blocker administration.⁽³⁾ The bivalirudin arm was also associated with a reduction in reinfarction and overall similar stent thrombosis at 3 years (despite a statistically significant ~1% increase within the first 24 hours).

But how to reconcile the established benefit of bivalirudin observed in the HORIZONS-AMI trial with the widespread use and availability of heparin in clinical practice? It is certainly reasonable and abides by all the treatment guidelines to administer the most available aspirin and UFH bolus at the time of first medical contact with a STEMI patient. Upon further evaluation and hospital admission with transfer to the interventional cardiology suite for primary PCI, further consideration can be given to optimal pharmacological therapy. In the HORIZONS-SWITCH substudy, patients treated with UFH before enrollment in the HORIZONS-AMI trial were analyzed according to their subsequent randomization to bivalirudin or UFH plus a GP IIb/IIIa inhibitor. Switching to bivalirudin before primary PCI resulted in significantly reduced 30-day and 2-year major bleeding (Figure 1).⁽⁴⁾ Consistent with the overall trial, the switching strategy also yielded significant reductions in cardiac mortality and reinfarction. These results were not related to the pre-procedure activated clotting time (ACT) value. These data support the study protocol for switching patients on UFH to bivalirudin, i.e., wait 30 minutes after discontinuing UFH, or begin bivalirudin administration in all cases before PCI, regardless of ACT. The early use of UFH before bivalirudin should not be discouraged, as pre-randomization UFH was found to be an independent predictor of reduced acute and subacute stent thrombosis.⁽⁵⁾ Bivalirudin can be discontinued at the completion of the index procedure, or continued for 2 to 6 hours after PCI at low dose if clinically indicated (ie. residual dissection, TIMI flow grade under 3, reduced blush grade, residual coronary microthrombi, ulcerated or aneurismal lesions). It is clinically reasonable to extend the infusion when the interventional result is somewhat imperfect, especially in the presence of a slowly absorbed oral thienopyridine agent (see below).

In addition, this optimal anticoagulant approach should be pursued on a background of optimal antiplatelet pharmacotherapy including aspirin and an adenosine diphosphate (ADP) receptor (P2Y12 receptor) antagonist. The finding of a significant greater incidence of acute stent thrombosis with bivalirudin in STEMI provides the opportunity for strategies that enhance periprocedural platelet inhibition. In the HORIZONS-AMI trial, a 600-mg loading dose of clopidogrel had no effect on acute stent thrombosis but was associated with a significant decrease in subacute stent thrombosis compared with a 300-mg loading dose.⁽⁵⁾ This finding is consistent with the fact that a 300-mg loading dose of clopidogrel leads to lower and slower platelet inhibition than 600 mg, perhaps even more so in the STEMI setting with reduced drug absorption and metabolism in relation to hemodynamic instability. In this regard, more rapidly acting and potent ADP receptor antagonists than clopidogrel, such as prasugrel or ticagrelor, have the potential to provide incremental benefits; e.g. full antiplatelet activity can be achieved within 30-60min and with less dependence on absorption and hepatic metabolism. Patients who received bivalirudin in the TRITON-TIMI 38 (Trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel—Thrombolysis in Myocardial Infarction 38) and PLATO (Platelet Inhibition and Patient Outcomes) trials, however, were substantially under-represented, hampering any attempt to draw meaningful considerations in the setting of STEMI (Figure 2).^(6,7) Given the lower stent thrombosis rates associated with use of these new potent agents compared to clopidogrel in STEMI, one may select them in anticipation of improved outcomes. Nonetheless, clinical trials with these new agents in combination with bivalirudin in STEMI are currently under way in order to investigate whether preloading with a potent ADP antagonist may further reduce early stent thrombosis and improve the prognosis in patients treated with bivalirudin.

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References

1. Kushner FG, Hand M, Smith SC Jr, et al. 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. J Am Coll Cardiol. 2009;54:2005-41.
2. Montalescot G, Cohen M, Goldstein P et al. ATOLL: an international randomized study comparing IV enoxaparin to IV UFH in primary PCI. Presented at European Society of Cardiology Congress, Stockholm, August 30, 2010.
3. Stone GW, Witzenbichler B, Guagliumi G, et al. 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, randomized controlled trial. Lancet. 2011;377:2193-204.
4. Dangas GD, Mehran R, Nikolsky E, et al. Effect of switching antithrombin agents for primary angioplasty in acute myocardial infarction. The HORIZONS-SWITCH analysis. J Am Coll Cardiol. 2011;57:2309-16.
5. Dangas GD, Caixeta A, Mehran R, et al. Frequency and predictors of stent thrombosis after percutaneous coronary intervention in acute myocardial infarction. Circulation. 2011;123:1745-56.
6. Montalescot G, Wiviott SD, Braunwald E. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double blind, randomized controlled trial. Lancet. 2009;373:723-31.
7. Steg PG, James S, harrington RA, et al. Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: A Platelet Inhibition and Patient Outcomes (PLATO) trial subgroup analysis. Circulation. 2010;122:2131-41.

Keywords: Acute Coronary Syndrome, Blood Platelets, Coagulants, Fibrin, Fibrinogen, Myocardial Infarction, Percutaneous Coronary Intervention, Thrombin, Thrombosis

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