Anticoagulation with Bivalirudin During Percutaneous Coronary
Intervention for ST-Segment Elevation Myocardial Infarction

The goal in treatment of ST-segment elevation myocardial infarction (STEMI) is rapid and complete reperfusion of the microvasculature. Optimal treatment strategies, however, are still being defined. Combined therapy (facilitated angioplasty) utilizing pharmacological agents for reperfusion followed by immediate percutaneous coronary intervention (PCI) has improved ischemic outcomes, but is associated with increased bleeding risk and no mortality benefit.1,2 Primary mechanical revascularization or primary PCI, when conducted in a timely fashion by experienced operators, is generally recognized as the reperfusion therapy of choice for STEMI resulting in 90% normal TIMI Grade 3 flow compared to approximately 60% with fibrinolytics.3–7 In patients with stable or unstable angina without ST-segment elevation undergoing urgent or elective PCI, the thrombin-specific anticoagulant bivalirudin (Angiomax®) with provisional glycoprotein (GP)IIb/IIIa receptor inhibitors (used 7.2% of the time) was at least as effective as unfractionated heparin plus GPIIb/IIIa receptor inhibitors in reducing ischemic events. In contrast to most PCI trials, this ischemic protection was coupled with a significant reduction in thrombocytopenia and bleeding complications.8 While bivalirudin has been used successfully in elective and urgent angioplasty in patients with non-STEMI, no studies have been published examining the use of bivalirudin in patients with STEMI. The purpose of this retrospective study was to assess the feasibility of using bivalirudin in patients with STEMI undergoing primary PCI. This report details outcomes from 91 consecutive patients with STEMI undergoing primary PCI with bivalirudin. Methods From September 2000 to May 2003, at the Heart Care Centers of Illinois, Blue Island, Illinois, 91 consecutive patients with STEMI = 24 hours. Bleeding outcomes were assessed according to TIMI major criteria.9 Statistical analysis. Data are reported as ranges and simple percentages. Results A retrospective evaluation was performed of 91 consecutive patients with STEMI and undergoing primary angioplasty. These patients, ranging in age from 38–92 years, possessed several high-risk characteristics (40% female, 30% diabetes mellitus, 21% previous MI, and 18% cardiogenic shock) (Table 1). PCI procedures utilized balloons (4.4% patients), stents (30%), balloons and stents (60%), cutting balloon (1.1%), or Angiojet® devices (4.4%). Counterpulsation with an intraaortic balloon pump was employed for 41% and closure devices employed for 24% of patients. No patients received a preload dose of clopidogrel, and two patients, in which TIMI 3 flow was not established, received abciximab. TIMI flow was assessed at completion of PCI. TIMI 3 flow was reestablished in 97.8% of patients. Three patients died (3.3%). There were no reports of recurrent ischemia, stroke, subacute thrombosis, bleeding, or transfusion. Other events are described in Table 2. Discussion This study demonstrates that treatment with bivalirudin in patients with STEMI undergoing PCI is a feasible alternative to current heparin-based strategies and warrants further investigation. In this analysis, bivalirudin was the anticoagulant utilized based upon our experience in using it for ST-segment myocardial infarctions in patient populations with a high risk of bleeding with conventional anticoagulants (i.e., recent abdominal, pelvic, and orthopedic surgeries), and its use as well in HIPA (HITS) patients who had acute coronary syndromes. In this study, a substantial number of patients had high-risk characteristics known to predict poorer outcomes, including being female or having prior MI, diabetes, or cardiogenic shock.10–13 Intraaortic balloon pumps were employed in all patients in shock and also in patients who had an anterior wall myocardial infarction with significant LV systolic dysfunction. In addition, the left anterior descending was the vessel treated in over 40% of patients. Although a valid comparison of event rates in this study to other similar trials cannot be made, such comparison provides a reasonable expectation that bivalirudin is a safe alternative to current combination therapies for patients with STEMI undergoing PCI. Despite the high-risk population in our study, establishment of TIMI Grade 3 flow rates (97.8%) post-PCI were comparable to rates reported at 30 days in lower-risk patients in ADMIRAL (95.1%) and CADILLAC (96.9%) (Table 3).14,15 In this analysis, two patients received abciximab because TIMI 3 flow was not attained. The addition of abciximab in these patients did not alter TIMI flow. Mortality rates at 30 days (3.3%) were also comparable to those reported in the abciximab arms of the ADMIRAL Trial (3.4%) and the CADILLAC Trial (2.7%). In our cohort, two patients died. These two deaths were attributable to pump failure in one patient and cardiac rupture in the other. One death occurred in a patient in which TIMI 3 flow was unable to be established. There were no reports of recurrent ischemia, subacute thrombosis, stroke, major bleeding, or transfusions. Early restoration of TIMI Grade 3 flow is key to reducing the risk of death in patients with STEMI. Reductions in thrombus formation can reduce the risk of thrombotic microvascular embolism and improve tissue level perfusion. To that end, fibrinolytic therapy, adjunctive antiplatelet and fibrinolytic therapy, facilitated PCI, and primary PCI are strategies employed in the treatment of patients with STEMI. Primary PCI is currently regarded as the treatment of choice when rapid access to cath lab facilities is possible. Outcomes for patients undergoing primary PCI are generally superior to outcomes for patients treated with fibrinolysis. Fibrinolytic studies demonstrate improvement in TIMI flow in about 50–60% of patients,6,7 whereas improvement in TIMI flow is about 90% for patients undergoing primary PCI when patients are readily (under 90 minutes) admitted to an experienced cardiac catheterization laboratory facility.3–5 The value of primary PCI treatment is limited if the patient is in an outlying community without a facility equipped to perform coronary intervention in near proximity. While facilitated PCI may be of value in these patients, studies of facilitated PCI to date have not been able to demonstrate a reduction in mortality, and decreased rates of reinfarction have been offset by increases in intracranial hemorrhage or other major bleeding risks.1,2 None of these current therapies, however, have been based on the effective inhibition of thrombin. ST-segment elevation MI is a step along the ACS continuum, which begins with endothelial erosion, followed by plaque rupture and subsequent thrombus formation. Consequently, the presence of thrombin is abundant in a patient with STEMI. Thrombin is a potent activator of platelets and plays a key role in converting fibrinogen to fibrin; causing vasoconstriction; augmenting the binding of fibrinogen, von Willebrand’s factor and collagen to platelets; and generating more active thrombin.16 Thrombin, then, should be a key target for inhibition. Current pharmacotherapies employed for treatment of STEMI, however, are not effective inhibitors of thrombin. Fibrinolytic agents act on the clot surface, cleaving plasminogen (already bound to fibrin) to plasmin and opening up more binding sites for continued and sustained fibrinolysis. Fibrinolysis also generates elevated concentrations of free thrombin and activates platelet aggregation.17,18 Heparin and low molecular weight heparin, both indirect thrombin inhibitors,16 effectively inhibit soluble thrombin but not bound thrombin, which remains active to generate more thrombin and activate more platelets. The heparins also activate platelets, contributing further to an already hostile environment.19 Consequently antiplatelet strategies — including aspirin, thienopyridines, and GPIIb/IIIa inhibitors aimed at blocking platelet aggregation — have been employed as part of a facilitated PCI strategy, but with limited success. In an effort to achieve more complete reperfusion, facilitated PCI combines antiplatelet agents with fibrinolytics. However, these trials have not provided overwhelming evidence of substantial benefit to date.1,2 Current trials demonstrate reductions in non-fatal endpoints that are offset by increased bleeding risks and no mortality benefit at 30 days.1,2,20 In GUSTO V, reductions in reinfarction, recurrent ischemia, and need for early urgent revascularization in the combination treatment group were offset by a near doubling of the bleeding risk.2 Similarly, 30-day mortality rates in ASSENT-3 were not improved between patients receiving full-dose tenecteplase vs. half-dose tenecteplase + abciximab. A similar pattern of modest reductions in reinfarction and refractory ischemia were offset by increased bleeding risks.1 These therapeutic strategies were all built on a foundation of indirect thrombin inhibition with either heparin or low molecular weight heparin. The question is whether or not bivalirudin, as a foundation anticoagulant, can improve on current treatment strategies. Bivalirudin directly binds to both fibrin-bound and soluble thrombin.16 Further, bivalirudin has been shown to inhibit thrombin-mediated platelet activation at concentrations well below therapeutic levels for PCI.21 This direct mechanism of thrombin inhibition and reduction in thrombin-mediated platelet activation may partially explain how bivalirudin can provide clinical outcomes as effective as the combination of heparin plus GPIIb/IIIa inhibitor. In our study, only two patients (2.2%) who did not achieve TIMI 3 flow were given a GPIIb/IIIa inhibitor, suggesting that perhaps bivalirudin’s direct binding to soluble and bound thrombin results in a more potent antithrombin agent and better ischemic protection. A large meta-analysis of 11 randomized clinical trials comparing direct thrombin inhibitors (DTIs) to heparin in 35,970 patients demonstrated that DTIs are superior to heparin for the prevention of the composite death/MI in patients with ACS. Bivalent DTIs (bivalirudin and hirudin) demonstrated a significant reduction in the composite of death/MI at 30 days (7.4% versus 8.2%) compared to heparin.22 The results from the HERO-2 Trial in patients with acute myocardial infarction are consistent with these findings. Patients treated with bivalirudin and streptokinase had a 30% reduction in the rate of reinfarction compared to patients treated with heparin and streptokinase.23 Mortality rates were identical between the two treatment groups. Newer fibrinolytic agents (e.g., alteplase, reteplase, and tenecteplase) have shown restoration of epicardial flow in a greater proportion of patients compared to streptokinase,24 but these agents have not been tested with bivalirudin as a base anticoagulant. Newer fibrinolytics in conjunction with bivalirudin might result in event greater absolute reductions in reinfarction. The results of HERO-2 coupled with 1) a substantial efficacy benefit observed in post-MI patients undergoing PCI25 compared to heparin, 2) recent trial results demonstrating that bivalirudin with provisional GPIIb/IIIa inhibitor provides efficacy as good as heparin plus planned GPIIb/IIIa inhibitor in patients undergoing urgent and elective PCI,8 and 3) the results from our study support the concept that bivalirudin may have a role in the setting of primary PCI, possibly even facilitated PCI. The mechanism in which bivalirudin distinguishes itself from heparin in the treatment of acute ST-segment elevation MI may be the agent’s direct inhibition of soluble and fibrin-bound thrombin and its inhibition of thrombin-mediated platelet activation at low concentrations along with its reduction in bleeding. This suggests that bivalirudin may be an attractive alternative to the use of heparin during PCI in acute ST-segment elevation MI. Study Limitations. This is a retrospective evaluation of 91 patients without a control group. Critical assessment of the outcomes compared to current therapy is not possible, however, event rates appear to be comparable to those observed in randomized controlled trials. Such comparisons cannot correct for biases or differences in demographics and patient characteristics and therefore need to be substantiated by controlled clinical trials. Evaluation of bivalirudin in primary or facilitated PCI warrants critical evaluation in controlled trials before wide adoption in these settings. Conclusion The use of bivalirudin as an antithrombin strategy for patients with STEMI is a feasible alternative to heparin and worthy of further evaluation in controlled trials. The mode by which bivalirudin works is probably attributable to it being a potent platelet antagonist via its direct inhibition of thrombin. In addition, research relating to possible inhibition of leukocyte-platelet aggregates is ongoing. Bivalirudin therapy has the potential to be at least as effective as current combination therapies in the majority of patients with STEMI and undergoing PCI, is likely to be associated with fewer bleeding complications, and, as seen in REPLACE-2, potentially may be more cost effective than current combination therapies. Further data regarding the use of bivalirudin in acute coronary syndromes will be forthcoming upon completion of ACUITY (non-ST-segment elevation) and BIAMI (ST-segment elevation) acute coronary trials.

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