Percutaneous coronary intervention (PCI) improves outcomes in patients with acute myocardial infarction (MI) and is used to improve symptoms in patients with stable angina. Anticoagulants such as unfractionated heparin or bivalirudin are used at the time of PCI in order to reduce the risk of thrombotic complications.

Unfractionated heparin is the anticoagulant used most commonly in support of PCI.¹ Glycosaminoglycans contained in unfractionated heparin bind to antithrombin resulting in the activation of antithrombin and potentiation of its effects on the coagulation cascade.² Activated antithrombin inhibits several coagulation factors resulting in an anticoagulation effect. Unfractionated heparin has a long clinical history that supports its efficacy in PCI; however, the methods by which the drug is manufactured lead to inconsistency in dosing. As a result, frequent monitoring of the activated clotting time (ACT) must occur when using heparin during PCI.

Bivalirudin is an intravenous direct thrombin inhibitor that is approved by the FDA for use in patients undergoing PCI. It has been hypothesized that the targeted effects of bivalirudin may result in more consistent anticoagulation effect while reducing the risk of bleeding. The drug is given as a 0.75 mg/kg bolus followed by a 1.75 mg/kg/h infusion while the PCI is being performed. Patients treated with bivalirudin should have an ACT measured five minutes after the start of the infusion. If the ACT is <225 seconds, the patient should be given an additional 0.3 mg/kg bolus. The pharmacokinetics and pharmacodynamics of bivalirudin are such that there is no need to routinely monitor the degree of anticoagulantion following the initial ACT.

Multiple large, well-powered, cardiovascular outcomes trials have been performed that compared bivalirudin-based regimens to heparin-based regimens.^3-6 In many of these trials, the primary endpoint was a net clinical endpoint that was a composite of both ischemic (e.g., MI) and bleeding outcomes (e.g., major bleeding). The majority of these studies found that bivalirudin was superior to heparin plus a glycoprotein IIb/IIIa inhibitor (GPI) with regard to the net clinical endpoint of death, MI, unplanned revascularization for ischemia, or major bleeding. In one of the studies (Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction [HORIZONS-AMI]), treatment with bivalirudin in patients undergoing PCI for ST-elevation myocardial infarction (STEMI) reduced mortality;⁵ however, these results have not been replicated in other trials with a similar design and population.^6,7

In the majority of trials comparing heparin and bivalirudin in patients undergoing PCI, GPIs were used routinely in the patients treated with heparin. While GPIs were an effective antiplatelet therapy that reduced peri-procedural events, the role of GPIs in the current era is no longer as clear. The Early Glycoprotein IIb/IIIa Inhibition in Patients With Non–ST-segment Elevation Acute Coronary Syndrome (EARLY ACS) trial randomized patients with high-risk non–ST-elevation myocardial infarction (NSTEMI) to either a strategy of routine early (upstream) GPI use or a strategy of provisional GPI use just prior to PCI (downstream).⁸ In the EARLY ACS trial, there was no difference between the two strategies on the primary endpoint of death, MI, recurrent ischemia requiring urgent revascularization, or need for thrombotic bailout at 96 hours. However, there were higher rates of TIMI major bleeding and red-cell transfusions in the patients treated routinely with GPIs. As a result of these data and the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) Timing trial, which had similar results,⁹ the routine use of GPIs in patients undergoing PCI is no longer recommended.¹⁰

The How Effective Are Antithrombotic Therapies in Primary Percutaneous Coronary Intervention (HEAT-PPCI) trial was the first large-scale, clinical outcomes trial in which bivalirudin was compared to a heparin regimen in which GPIs were used only on a provisional basis.⁶ This trial randomized patients with STEMI undergoing primary PCI to either a bivalirudin- or heparin-based regimen. GPIs were not used routinely in either group but were available for use if needed. The HEAT-PPCI trial found that patients treated with bivalirudin had an increased risk of death, MI, or stroke (risk ratio [RR] 1.52, 95% confidence interval [CI] 1.09-2.13; p = 0.01) Acute stent thrombosis was also more common in the patients treated with bivalirudin (RR 3.91, 95% CI 1.61-9.52). In contrast to prior studies of bivalirudin in patients undergoing PCI, there was no difference in major bleeding between bivalirudin- and heparin-based regimens (p = 0.59).

Given the uncertainty surrounding the effectiveness of bivalirudin in patients undergoing PCI, a meta-analysis of 16 trials was performed that compared bivalirudin-based regimens to heparin-based regimens. The risk of major adverse cardiovascular events (MACE; defined in most trials as death, MI +/- urgent revascularization) was increased with bivalirudin-based regimens (RR 1.09, 95% CI 1.01-1.17; p = 0.02). The increase in MACE was driven by an increase in MI (RR 1.12, 95% CI 1.03-1.23), and there was evidence of ischemia-driven revascularization possibly increased with bivalirudin (RR 1.16, 95% CI 0.997-1.34). In addition, the risk of stent thrombosis was significantly increased in patients treated with bivalirudin-based regimens (RR 1.38, 95% CI 1.09-1.74; p = 0.007). Patients with STEMI treated with bivalirudin appeared to be at particularly high risk of acute stent thrombosis (RR 4.27, 95% CI 2.28-8.00; p <0.0001). The increase in ischemic events with bivalirudin did not result in an increase in death (RR 0.99, 95% CI 0.82-1.18) (Table 1).

Table 1: Cardiovascular Events in Patients Undergoing PCI

	Risk Ratio (95% CI)	P-Value
MACE	1.09 (1.01-1.17)	0.02
Death	0.99 (0.82-1.18)	0.88
MI	1.12 (1.03-1.23)	0.001
Ischemic-Driven Revascularization	1.16 (0.997-1.34)	0.10
Stent Thrombosis	1.38 (1.09-1.74)	0.007
Acute	3.86 (2.11-7.07)	<0.0001
Subacute	0.89 (0.53-1.49)	0.66

Bivalirudin significantly reduced the risk of major bleeding (RR 0.62, 95% CI 0.49-0.78; p <0.0001). However, the reduction in bleeding seen with bivalirudin varied depending on how GPIs were used with heparin. Bivalirudin had the greatest relative reduction in bleeding when it was compared to patients who were routinely treated with both heparin and GPI (RR 0.53, 95% CI 0.47-0.61; p <0.0001). There was no difference in bleeding in those trials in which bivalirudin was compared to a heparin-based regimen that did not routinely use GPI (RR 0.78, 95% CI 0.51-1.19; p=0.25). There was no evidence that bivalirudin reduced bleeding when GPIs were routinely used in both bivalirudin and heparin arms (RR 1.07, 95% CI 0.87-1.31; p = 0.53).

This study raises questions regarding the efficacy and benefit of bivalirudin in the current era. In this meta-analysis, bivalirudin increases the risk of thrombotic complications, such as MI and stent thrombosis. While the data show that bivalirudin decreases bleeding when compared to heparin and routine GPI, the latter anticoagulation strategy is no longer utilized in most PCI cases. There was significant heterogeneity in the results based upon the concomitant use of GPI in the heparin arm. In the trials in which both the heparin and bivalirudin arms used GPI in a similar manner, bivalirudin did not reduce the risk of bleeding.

Thus, clinicians should consider the patient's individual risk of bleeding and his or her overall risk of thrombotic complications when choosing an anticoagulant. Further research is needed to understand how to utilize bivalirudin more effectively so as to reduce the risk of thrombotic events and to better define the preferred anticoagulants for different patient populations.

References

1. Marso SP, Amin AP, House JA, et al. Association between use of bleeding avoidance strategies and risk of periprocedural bleeding among patients undergoing percutaneous coronary intervention. JAMA 2010;303:2156-64.
2. Rao SV, Ohman EM. Anticoagulant therapy for percutaneous coronary intervention. Circ Cardiovasc Interv 2010;3:80-8.
3. Lincoff AM, Bittl JA, Harrington RA, et al. Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003;289:853-63.
4. Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med 2006;355:2203-16.
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. Shahzad A, Kemp I, Mars C, et al. Unfractionated heparin versus bivalirudin in primary percutaneous coronary intervention (HEAT-PPCI): an open-label, single centre, randomised controlled trial. Lancet 384:1849-58.
7. Steg PG, van 't Hof A, Hamm CW, et al. Bivalirudin started during emergency transport for primary PCI. N Engl J Med 2013;369:2207-17.
8. Giugliano RP, White JA, Bode C, et al. Early versus delayed, provisional eptifibatide in acute coronary syndromes. N Engl J Med 2009;360:2176-90.
9. Stone GW, Bertrand ME, Moses JW, et al. Routine upstream initiation vs deferred selective use of glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: the ACUITY Timing trial. JAMA 2007;297:591-602.
10. Windecker S, Kolh P, Alfonso F, et al. 2014 ESC/EACTS 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) Developed with the special contribution of the European Association of Percutaneous Cardiovascular Interventions (EAPCI). Eur Heart J 2014;35:2541-619.

Keywords: Acute Coronary Syndrome, Angina, Stable, Anticoagulants, Antithrombins, Blood Coagulation Factors, Catheterization, Glycosaminoglycans, Heparin, Hirudins, Myocardial Infarction, Odds Ratio, Peptide Fragments, Percutaneous Coronary Intervention, Recombinant Proteins, Stents, Stroke, Thrombosis, Triage, omega-Chloroacetophenone, Platelet Glycoprotein GPIIb-IIIa Complex

< Back to Listings