The Use of Bivalirudin to Prevent Subacute Thrombosis During
Drug-Eluting Stent Implantation

ABSTRACT: Subacute thrombosis is an infrequent but potentially life-threatening complication of percutaneous coronary intervention (PCI) that has received much attention in association with drug-eluting stent (DES) deployment. We performed a retrospective case record review of 186 patients receiving PCI with DES placement at our facility. Patients received either bivalirudin (n = 115) or heparin (n = 71) as the foundation anticoagulant, with additional antiplatelet therapy as warranted. Two subacute thrombosis complications occurred and are described in detail. There were no deaths, major bleeding episodes or other significant complications. We report our findings and conclude that the addition of a glycoprotein IIb/IIIa inhibitor does not eliminate the risk of subacute thrombosis and that bivalirudin appears to provide effective anticoagulation for patients undergoing PCI with placement of a DES. J INVAS CARDIOL 2004;16:236–239 Key words: antithrombotic treatment, percutaneous coronary intervention Subacute thrombosis is an infrequent but serious complication of intracoronary stent deployment during percutaneous coronary intervention (PCI).^1,2 The impact of subacute stent thrombosis can be dramatic, frequently leading to the total occlusion of the treated vessel and an acute myocardial infarction (MI) or sudden death. Bivalirudin (Angiomax®, The Medicines Company, Parsippany, New Jersey), a direct thrombin inhibitor, has demonstrated reductions in both ischemic and bleeding complications compared to anticoagulation with heparin in PCI. In a recent contemporary, double-blind, randomized PCI trial, bivalirudin plus provisional glycoprotein (GP) IIb/IIIa inhibition was shown to be as effective as heparin plus GP IIb/IIIa inhibition, with a lower incidence of major bleeding.3 However, there are no data on the use of bivalirudin with drug-eluting stents (DES). DESs have been recently approved in the United States for the treatment of de novo coronary stenosis, as they have been found to decrease in-stent restenosis by inhibiting the development of intimal hyperplasia.⁴ The effect of DESs on the incidence of subacute thrombosis is unknown. Though a significant increase in subacute thrombosis has not been reported in clinical trials, there have been isolated reports of its occurrence. The manufacturer of the Cypher™ DES (Cordis Corp., Miami Lakes, Florida) recently issued a letter strongly advising against the use of stents smaller than the vessel diameter and against poor or inadequate stent apposition to vessel walls, and recommending antiplatelet therapy before and for 3 months after stenting. Our laboratory has had extensive experience with the use of bivalirudin both as monotherapy and in combination with GP IIb/IIIa inhibitors prior to the approval of the Cypher DES, and we have maintained our interest in bivalirudin as the foundation anticoagulant during PCI procedures with DES deployment. This retrospective study reviews our experience with bivalirudin as antithrombotic therapy during DES implantation since the approval of the Cypher DES earlier this year. Methods We performed a retrospective review of 186 case records for patients receiving PCI with DES implantation. Our review included all procedures performed in our laboratory between April 28, 2003, when the Cypher stent became available, until the end of the study period on July 31, 2003. Demographic parameters, procedural parameters (including antithrombotic and antiplatelet therapy administered), and patient outcomes including death, MI, revascularization and major bleeding were evaluated. Results The study population consisted of 186 patients, of whom 68% (127/186) were male. The age range was 39–88 years (average, 63 years) for males, and 38–86 years (average, 66 years) for females. Procedural characteristics and anticoagulant regimens are presented in Table 1. All patients received various combinations of aspirin and clopidogrel before and after the procedure. Bivalirudin was administered as an intravenous (IV) bolus of 0.75 mg/kg followed by a 1.75 mg/kg/hour infusion for the duration of the procedure (or continuing for up to 4 hours if warranted). Bivalirudin was administered as the foundation anticoagulant in 62% (115/186) of patients, with GP IIb/IIIa inhibition used in 36% (41/115) of bivalirudin-treated patients. Heparin was used in 38% (71/186) of patients, with 93% (66/71) receiving GP IIb/IIIa inhibition. GP IIb/IIIa inhibitors were administered according to the manufacturers’ prescribing information. Complications. Three patients in this study experienced ischemic complications. There were no deaths, major bleeding episodes or other significant complications. There were three instances of acute or subacute ischemic complications in the patients studied during this period. One of them was clearly a mechanical complication of the intervention, namely a coronary dissection at the distal end of the stent implanted in the left anterior descending (LAD) coronary artery, occurring while the patient was still in the catheterization laboratory area. This patient had been treated with bivalirudin and eptifibatide during the procedure. The complication was successfully treated with additional stenting. The other two complications were thrombotic in nature, and are analyzed in some detail below. Patient #1. The first case concerned a 61-year-old diabetic, dyslipidemic and hypertensive male with a previous history of coronary artery bypass surgery and intracoronary intervention. He presented with chest pain and dyspnea, and a scintigram showed a reversible infero-basal defect. Cardiac catheterization revealed open grafts [left internal mammary artery (LIMA) to the LAD and saphenous vein graft (SVG) to the left circumflex (LCX) coronary artery, with a 75% stenosis of the proximal right coronary artery (RCA) and a 99% stenosis of the distal RCA]. His left ventricular function was normal, with an ejection fraction of 59%. He was pre-treated with clopidogrel and aspirin, and brought to the cardiac catheterization laboratory for PCI. A 3.0 x 28 mm DES was implanted in the proximal RCA, and a second 2.5 x 13 mm DES was placed in the distal RCA, both with good results. Antithrombotic therapy consisted of heparin and eptifibatide. The patient recovered uneventfully, and was discharged to home. Four days after the procedure, he returned to our facility with an acute inferior wall MI. Upon emergency cardiac catheterization, he was found to have a complete occlusion of the proximal RCA. The patient was treated with abciximab and heparin, and was successfully treated for acute thrombotic occlusion with balloon angioplasty, using a 3.5 mm balloon. Subsequent to the second procedure, the patient developed thrombocytopenia with the platelet count dropping from 223,000 on admission to 31,000. The patient was treated with the direct thrombin inhibitor argatroban, recovered uneventfully and was discharged to home three days later. Patient #2. The second case of thrombotic complication was a 50-year-old hypertensive and dyslipidemic cigarette smoker with a previous history of PCI with stenting of the RCA in 1998. This patient presented with recurrent angina that was refractory and increasing in intensity. Cardiac catheterization was performed and the patient was found to have a 90% stenosis in the proximal to mid-LAD, and a 99% stenosis in the proximal to mid-LCX. There was non-obstructive disease within the previous stent in the RCA, which had remained patent. The patient’s left ventricular (LV) function was normal. He had been pre-treated with aspirin and clopidogrel, and was referred for intervention the same day. The procedure included the implantation of a 3.0 x 18 mm DES in the LAD and a 2.5 x 23 mm DES in the LCX, both with good results. Antithrombotic therapy in the catheterization laboratory was limited to bivalirudin bolus and infusion. The patient recovered uneventfully and was discharged to home the following day. After discharge, the patient did not comply with his prescribed regimen of clopidogrel (he did not fill his prescription) and, according to his family, he restarted his smoking habit. Five days after the procedure, he presented to his local hospital with an acute anterior wall MI. Despite prompt thrombolytic treatment with reteplase, the patient’s condition deteriorated and he developed cardiogenic shock and congestive heart failure. He was airlifted to our facility the same day, and taken immediately to the catheterization laboratory. Repeat cardiac catheterization showed occlusion of both of the previously treated vessels, i.e., the LAD and the LCX. The patient was treated with PCI using a 3.0 x 15 mm balloon in both vessels, and the LCX was further treated with a 3.0 x 23 mm stent proximal to the previous device. The patient arrived on a therapeutic heparin IV drip and was treated with abciximab in the catheterization laboratory. An intraaortic balloon was then inserted via the left femoral artery and the patient was treated with IV diuretics and a dopamine infusion. His hemodynamic status improved significantly and he did not require intubation. After a lengthy and complicated hospital stay, he was discharged to home. His left ventricular ejection fraction (LVEF) prior to discharge was approximately 30%. Discussion This single-center review of 186 case records over a 3-month period for patients undergoing PCI with DES deployment suggests that the addition of GP IIb/IIIa inhibitors to a heparin regimen does not eliminate the risk of subacute thrombosis; that oral antiplatelet therapy during and after the procedure is of paramount importance; and finally that bivalirudin appears to provide adequate anticoagulation in conjunction with DES. While no severe bleeding complications were reported in this study, in large PCI trials, bivalirudin demonstrated significantly fewer bleeding complications when compared to heparin.^3,5 Bleeding complications are associated with increased morbidity, prolonged hospitalization and economic cost, and thus should not be dismissed as insignificant.^6,7 Various antithrombotic strategies have been developed for the catheterization laboratory to prevent ischemic events, including subacute thrombosis. Such strategies have included heparin combined with a GP IIb/IIIa inhibitor and the addition of oral antiplatelet therapy with aspirin and clopidogrel. However, heparin is associated with numerous limitations, including the activation of platelets and its inability to inhibit fibrin-bound thrombin.^8–10 Thrombin itself is a potent activator of platelets.¹¹ Antiplatelet agents when combined with heparin reduce the risk of ischemic complications, but the efficacy benefits are at least partially offset by an increased risk of bleeding complications.¹² Direct thrombin inhibitors such as bivalirudin have been more recently added to the armamentarium of antithrombotic drugs for use during coronary interventions due, in part, to their more precise and predictable effect on coagulation, and their powerful effects not only as anticoagulants but also as a means of preventing thrombin-mediated platelet activation. Of the available direct thrombin inhibitors, bivalirudin has been the most extensively studied. Two large-scale, double-blind, randomized PCI trials^3,5 as well as numerous smaller studies^13–15 have demonstrated fewer ischemic and bleeding complications compared to heparin. In a large, contemporary PCI trial,³ bivalirudin and provisional GP IIb/IIIa inhibition (used in 7.2% of patients) were found to be as effective as heparin plus GP IIb/IIIa inhibition, with a significant reduction in the risk of major bleeding and thrombocytopenia at 30 days. Recently presented16 6-month data from the same trial have confirmed these conclusions. The non-significant mortality benefit observed at 30 days was maintained at 6 months (30% risk reduction) and 6-month data continued to demonstrate no other significant differences in MI or revascularization. DESs decrease the risk of in-stent restenosis by inhibiting the development of intimal hyperplasia.⁴ While a significant increase in subacute thrombosis has not been reported in clinical trials, there have been isolated reports of its occurrence since approval of the Cypher stent earlier this year, and suggestions have arisen that bivalirudin may not provide optimal ischemic protection when used in conjunction with DESs. Interim results from 215 patients administered bivalirudin and provisional GP IIb/IIIa inhibition (7%) with Cypher stent deployment, compared to 215 historical controls for patients receiving bivalirudin (with 12% use of GP IIb/IIIa inhibition) and bare metal stents, demonstrated no significant differences in outcomes between the two groups and offered preliminary evidence that bivalirudin provides effective anticoagulation with minimal GP IIb/IIIa inhibition.¹⁷ Our review of 186 case records supports these interim findings and illustrates several important points. First, although the occurrence of subacute thrombosis does not seem to have markedly increased with the introduction of DESs in patients presenting at our center, there remains a risk of subacute thrombosis after DES deployment. Effective antithrombotic agents are clearly indicated during and after PCI with DES. In case #2 described above, the development of subacute thrombosis was almost certainly related to the patient’s noncompliance with the prescribed antiplatelet regimen, as well as his exposure to cigarette smoke. Second, there are distinct disadvantages with respect to the selection of heparin as foundation anticoagulation therapy in combination with the antiplatelet GP IIb/IIIa inhibitors, including the risk of thrombocytopenia. This is illustrated by case #1, in which heparin and GP IIb/IIIa inhibitors were administered during both interventions. In this patient, thrombocytopenia developed after the second intervention. In contrast to heparin, bivalirudin has the distinct advantage of not being associated with heparin-induced thrombocytopenia. Given that bivalirudin is an effective foundation anticoagulant in PCI and significantly reduces the risk of bleeding and thrombocytopenia compared to heparin, the question remains as to the role of the antiplatelet GP IIb/IIIa inhibitors in preventing subacute thrombosis. The answer is not yet clear, as illustrated in our case review. GP IIb/IIIa inhibitors were used in only 36% of patients treated with bivalirudin and 93% of patients treated with heparin. However, the patient in case #1 developed subacute thrombosis despite the addition of a GP IIb/IIIa inhibitor to heparin therapy during PCI and compliance with the oral antiplatelet regimen. This patient had received eptifibatide during the index PCI procedure, which obviously did not prevent the development of this serious complication. In fact, the use of a regimen that relied on the combination of GP IIb/IIIa inhibitors with heparin to prevent complications instead precipitated the development of potentially serious thrombocytopenia after the second successful intervention. In summary, the advent of DESs has been heralded as a major improvement in the treatment of coronary artery disease, significantly decreasing the incidence of in-stent restenosis; however, there remains a continued risk of subacute thrombosis. Our experience shows that the effectiveness of bivalirudin supports its use as foundation anticoagulation therapy during PCI with DES deployment. There is no clinical evidence that the incidence of subacute thrombosis has increased with DESs, but anecdotal reports have heightened the need for preventive measures during PCI procedures deploying these devices. Our experience confirms that subacute thrombosis continues to be a potentially life-threatening complication in the era of DESs. At the same time, the clinical course and outcomes from the cases we reported serve to make some important points. Specifically, our experience shows that: 1) the addition of GP IIb/IIIa inhibitors to a heparin regimen does not eliminate the occurrence of subacute thrombosis; 2) oral antiplatelet therapy during and after the procedure is of paramount importance; 3) fastidious risk factor management including smoking cessation is important; and finally 4) the direct thrombin inhibitor bivalirudin appears to show great promise in this area, as the use of bivalirudin during PCI with stent deployment reduces the risk of complications such as bleeding or thrombocytopenia while providing excellent antithrombotic coverage. Study limitations. This study is limited with respect to its design as a retrospective case review, the number of patients evaluated and the lack of more detailed information on patient demographics. However, given that the only significant complications we encountered in this case series were the two occurrences of subacute thrombosis, these data contribute to a growing body of evidence that bivalirudin provides effective anticoagulation in patients undergoing PCI with DES placement. Conclusion. Effective antithrombotic and antiplatelet therapy during and after procedures involving DESs is critically important in preventing subacute thrombosis. Bivalirudin with provisional GP IIb/IIIa inhibition appears to represent an effective option for procedures involving the Cypher stent and other DESs.