Original Contribution

“Bail–Out” Bivalirudin Use in Patients with Thrombotic Complications

Luigi La Vecchia, MD, FESC, Ester Cabianca, MD, Leonardo Varotto, MD, Paolo Vincenzi, MD, Alessandro Fontanelli, MD, FESC Author Affiliations: From the Catheterization Laboratory, S. Bortolo Hospital, Vicenza, Italy. The authors report no conflicts of interest regarding the content herein. Manuscript submitted April 18, 2008, provisional acceptance given May 22, 2008, and final version accepted May 28, 2008. Address for correspondence: Ester Cabianca, MD, Catheterization Laboratory, Department of Cardiovascular Medicine, S. Bortolo Hospital, Viale Rodolfi 37, 36100 Vicenza, Italy. E-mail: cabi72@libero.it
Luigi La Vecchia, MD, FESC, Ester Cabianca, MD, Leonardo Varotto, MD, Paolo Vincenzi, MD, Alessandro Fontanelli, MD, FESC Author Affiliations: From the Catheterization Laboratory, S. Bortolo Hospital, Vicenza, Italy. The authors report no conflicts of interest regarding the content herein. Manuscript submitted April 18, 2008, provisional acceptance given May 22, 2008, and final version accepted May 28, 2008. Address for correspondence: Ester Cabianca, MD, Catheterization Laboratory, Department of Cardiovascular Medicine, S. Bortolo Hospital, Viale Rodolfi 37, 36100 Vicenza, Italy. E-mail: cabi72@libero.it

Unresponsive to Conventional Treatment during Percutaneous Coronary Intervention

ABSTRACT: Percutaneous coronary intervention (PCI) is routinely performed in patients with non-ST elevation acute coronary syndromes after pretreatment with clopidogrel and periprocedural administration of unfractionated heparin on a weight-adjusted basis. Although activated clotting time (ACT) monitoring is encouraged to verify the adequacy of anticoagulation during the procedures, this is not a common practice in many laboratories. The Authors describe 4 cases of patients with bifurcation lesions involving the left anterior descending coronary artery, who developed periprocedural thrombosis with acute transmural ischemia. All patients had inadequate ACT measurements, despite conventional heparin dosage and ongoing clopidogrel treatment. In order to achieve complete anticoagulation, patients were switched to bivalirudin, which determined a prompt effect on measured ACT. This therapeutic regimen, coupled with further intervention, allowed resolution of the thrombotic complication without bleeding. This report suggests the feasibility of a strategy of bivalirudin use in patients who have some degree of heparin “resistance” in the setting of complicated PCI. J INVASIVE CARDIOL 2008;20:E316–E319 Percutaneous coronary intervention (PCI) is routinely performed in interventional catheterization laboratories to revascularize patients with either unstable or stable coronary syndromes. In order to reduce the risk of thrombotic complications, periprocedural treatment includes aspirin, unfractionated heparin on a weight-adjusted basis, and clopidogrel, especially effective for patients undergoing stent implantation.1 Despite these measures, thrombotic complications during PCI do occur, particularly in patients with preexisting intracoronary thrombus during complex procedures or as a consequence of coronary dissection. These complications are most commonly seen in acute coronary syndromes, as a manifestation of systemic activation of the coagulation system,2 while they are less common in patients who have been successfully stabilized with medical therapy. We report 4 cases of patients with recent-onset angina who underwent PCI on a bifurcation lesion in the anterior territory after pretreatment with aspirin and clopidogrel and who developed intracoronary thrombosis refractory to conventional treatment. These patients were successfully managed with the use of “bail-out” bivalirudin. Case Reports Patient 1. A 69-year-old male underwent percutaneous coronary intervention (PCI) on the left anterior descending coronary artery (LAD) because of 2 episodes of chest pain at rest which occurred 1 week before admission. His baseline electrocardiogram was normal. Risk factors included only mild hypertension. Coronary angiography revealed a lesion located at the bifurcation of the LAD and first diagonal branch. After administration of 7,500 U of unfractionated heparin (UFH) (corresponding to approximately 100 U/kg) through the arterial sheath, two wires were advanced, one in the diagonal branch and one in the LAD, followed by sequential predilatation with a semicompliant balloon (2.0 x 10 mm and 2.5 x 15 mm, respectively). Subsequent dye injection revealed slow flow and extensive intraluminal thrombus, soon accompanied by chest pain and ST-segment elevation. Despite several attempts including clot removal with the Diver CE aspiration device (Invatec SRL, Roncadelle BS, Italy), abciximab administration and stenting of the LAD, the angiographic appearance of the vessel persistently showed mobile thrombus and slow flow. The activated clotting time (ACT) after heparin was 130 seconds (sec). We decided to remove the intracoronary wires, which appeared to be covered by thrombus, and bivalirudin was administered according to the REPLACE-2 dose schedule. The patient’s ACT was monitored and reached 345 sec after 10 minutes (min). The angiographic appearance of the treated vessel improved, with evidence of mild distal embolization and resolution of the intraluminal thrombus. The patient had no further intracoronary manipulation. The following day, the patient’s peak troponin I was 5.2 ng/ml (upper limit of normal 0.17 ng/ml), his electrocardiogram (ECG) was normal, and the angiographic control revealed normal Thrombolysis In Myocardial Infarction (TIMI) 3 flow, an absence of residual stenosis or intracoronary thrombus and a widely patent distal bed. The subsequent in-hospital course was uneventful and the patient was discharged on dual antiplatelet therapy, a statin and a beta-blocker. Patient 2. A 56-year-old male had undergone PCI on the mid-LAD with implantation of a 3.0 x 10 mm bare-metal stent (BMS) and balloon dilatation of the ostial diagonal branch in may 2007. After 3 months, the patient developed recurrent angina and thus underwent another coronary angiography that revealed critical diffuse in-stent restenosis and moderate restenosis of the ostial diagonal branch (Figure 1). UFH was administered through the arterial sheath (7,500 U) and both branches were easily wired. After balloon dilatation of the diagonal lesion and cutting-balloon dilatation of the stent lesion, intracoronary thrombosis became apparent with occlusion of the ostial LAD and marked ST-segment elevation in the anterior leads (Figure 2). The ACT was 232 sec; bivalirudin was started and the ACT rose to > 400 seconds after 5 min. In this case, abciximab administration was deferred due to the presence of Barrett’s esophagitis. Ten min later, the angiographic appearance of the LAD improved, with restored, albeit suboptimal, distal flow (Figure 3). A 3.5 x 8 mm BMS was implanted at the LAD ostium and the diagonal branch was further dilated through the stent struts. At the end of the procedure, TIMI 3 flow was achieved and the ST segment had normalized (Figure 4). An intra-aortic balloon pump (IABP) was started due to the extent of the myocardium at risk. The patient’s troponin I rose to a peak of 11.5 ng/ml at 24 hours and his subsequent clinical course was uneventful. Patient 3. A 53-year-old male was sent to our department because of two episodes of prolonged chest pain at rest in the previous 24 hours. His past medical history revealed a previous anteroseptal myocardial infarction in 2001. Upon admission, the patient was asymptomatic and his troponin I was slightly elevated (0.29 ng/ml); his total CK and myoglobin were also abnormal. The following morning, his troponin I reached a peak of 13 ng/ml. The patient underwent coronary angiography, which revealed a totally occluded LAD. The other vessels were not diseased. After administration of 7,500 U of UFH through the arterial sheath, a 0.014 inch floppy coronary guidewire was easily advanced through the occlusion and balloon inflations were performed on the LAD and on the first diagonal branch involved in the lesion. After retrieval of the balloon, a massive intracoronary thrombosis became evident, extending proximally up to the left main coronary artery with TIMI flow grade 2; abciximab was administered and mechanical thrombus aspiration was attempted, but was unsuccessful. The patient’s ACT was 132 sec despite full-dose heparin; thus, an intravenous bolus of bivalirudin was started; the resulting ACT was > 400 sec 5 min later. Approximately 30 min later, angiography showed a patent left coronary artery with slightly reduced flow and a residual mural thrombus in the proximal LAD. A 4.5 x 15 mm BMS was therefore implanted in the left main-LAD with subsequent kissing-balloon inflation at the bifurcation between the left main and the intermediate branch. After balloon inflation, minimal residual thrombus was still present at the distal stent edge on the LAD, and more so in the intermediate branch, with preserved flow. No further treatment was performed, and an IABP was started to improve distal coronary flow. Troponin I reached an early peak of 36 ng/ml 6 hours after the procedure. The following day, repeat angiography showed a completely resolved thrombus on the intermediate branch and a mild persistent mural thrombus at the distal edge of the LAD stent, which was left untreated. PCI on a distal LAD-diagonal bifurcation was deferred. Patient 4. A 45-year-old male was referred to our department 1 year after successful PCI of the right coronary artery (RCA) due to crescendo exertional angina with a positive exercise stress test. The patient’s troponin I was negative. Coronary angiography showed good result of the RCA PCI and a new critical lesion of the proximal LAD before the origin of a first diagonal branch. The LAD was wired and the lesion dilated with a 2.5 x 15 mm balloon. After removal of the balloon, angiography showed extensive thrombosis in the LAD and diagonal branch. Abciximab was started and a 3.0 x 24 mm paclitaxel-eluting stent was implanted. Subsequently, residual intracoronary thrombus was evident at the proximal edge of the stent, while the distal LAD appeared occluded. ST elevation became evident in the anterior leads. A Diver CE clot extraction catheter was advanced to the distal LAD and removed a small amount of particulate matter, partially restoring flow to TIMI grade 2. The measured ACT was 169 sec despite 7,000 U of UFH administered 30 min earlier through the arterial sheath. Due to the persistence of haziness proximal to the stent despite abciximab, suboptimal distal flow and an absence of stenosis, guidewires were removed and bivalirudin was started, raising the ACT to 327 sec after 10 min. The patient’s subsequent clinical course was uneventful. The peak troponin I was 1.86 ng/ml. Angiography performed 24 hours later showed an open LAD with TIMI flow grade 3 and a patent distal bed and no residual lesion. The patient was discharged 5 days later and is asymptomatic 8 months after the procedure. Discussion. The use of bivalirudin in PCI has gained a level of recommendation 1-B in the recently published guidelines of the European Society of Cardiology concerning acute coronary syndromes.3 Evidence from randomized, controlled trials suggests equal efficacy and possibly less bleeding complications, especially in elderly patients.4 In the 4 cases presented here, patients pretreated with aspirin and clopidogrel underwent PCI that was complicated by extensive intracoronary thrombosis and were switched from UFH to bivalirudin while on abciximab. The treatment with both drugs was completed without bleeding complications and with a favorable angiographic and clinical outcome. To our knowledge, these are the first reported cases of “bail-out” administration of bivalirudin in complicated PCI. The association of bivalirudin and abciximab was tested in the REPLACE-2 trial as a bail-out strategy4 and in the the ACUITY trial as a routine strategy.5 In both studies, this association demonstrated efficacy and safety in as many as 9,000 patients. Contrary to the situation tested in these trials, in our cases, the sequence of administration of the two antithrombotic drugs was reversed. During the procedure, antithrombotic treatment was switched from UFH to bivalirudin in the setting of ongoing coronary thrombosis and inadequate anticoagulation, as demonstrated by a low ACT after UFH administration. The angiographic and clinical outcomes of all 4 cases was favorable, but clearly no conclusion can be drawn with regard to efficacy of bivalirudin per se, since combined pharmacologic treatment, further percutaneous intervention, time and chance could all be credited for the success. Table 1 summarizes the time sequence of antithrombotic treatment administration in the 4 patients described. Whether our cases represent a condition of heparin resistance, is very hard to say. This uncertainty is further increased by the unresolved debate as to the real existence of such clinical syndrome.6 In the setting of cardiac surgery, heparin resistance is operatively defined as the inability to obtain an ACT > 480 sec with a standard dose of 300–400 U/kg.7 In acute coronary syndromes, the definition is less stringent. In the GUSTO IIb experience, heparin resistance was defined as a “low” aPTT after a “high” UFH dosage.7 The hypothesis that UFH did not reach the patient at all seems highly unlikely, since it was administered by the operator through the arterial sheath and was then flushed, according to usual practice. On the other hand, the possibility that we were using a suboptimal UFH preparation cannot be completely ruled out, since no pharmacologic assay on that particular stock of heparin was performed. However, these 4 cases occurred over a timespan of almost 8 months, during which more than 500 PCI procedures were performed, without an excess of thrombotic complications as a whole. This finding makes unlikely that these complications were drug-related. Different conditions have been identified where heparin efficacy may be suboptimal, among which an increased thrombus burden, as in high-risk acute coronary syndrome patients, and a low antithrombin III level, as demonstrated in some cardiac surgery patients.8,9 To further complicate this issue, it is known that elevated factor VIII levels can interfere with the activated partial thromboplastin time (aPTT) measurement, such that the aPTT fails to reflect heparin concentration;3,10,11 It is also known that a high preoperative platelet count can inhibit heparin through the release of platelet factor 4 by activated platelets.12 Administration of higher doses of UFH is one of the therapeutic options offered to overcome resistance13 in surgical patients. Similarly, guidelines recommend the administration of additional UFH if a suboptimal ACT is measured after the initial bolus.3 Although this option was considered in our cases, we must recognize that systematic assessment of the ACT after an initial weight-adjusted bolus of UFH as a routine measure during uncomplicated PCI is seldom performed in many laboratories, including ours. Indeed, the relationship between ACT levels and the occurrence of complications remains controversial.14 In this particular series, a major complication had already occurred and we felt that UFH supplementation alone was an insufficient answer to a life-threatening problem. Moreover, it is known that increasing the dose of UFH is associated with an enhanced risk of bleeding.13 Again, experience in studies performed in cardiopulmonary bypass patients provides evidence that heparin supplementation is not effective in overcoming true resistance, while a direct thrombin inhibitor, r-hirudin, proved to be effective.13 Pharmacodynamic advantages of bivalirudin over UFH are manifold. First, bivalirudin neutralizes clot-bound thrombin, while UFH does not;15 second, bivalirudin may limit thrombin-mediated platelet activation.16 In a recent study, Rich et al demonstrated that the aPTT obtained in response to UFH was lower in acute coronary syndromes compared to normal controls or patients with stable angina, while this was not the case for bivalirudin; also, within each group of patients (stable, unstable and controls), the variability in achieved aPTT was much higher with UFH (± 30%) than with bivalirudin (± 12%).17 In conclusion, our observations suggest that bivalirudin treatment may represent a reasonable option for patients developing thrombotic complications during PCI when UFH fails to achieve adequate anticoagulation.

1. Silber S, Albertsson P, Fernandez-Avilès F, et al. Guidelines for percutaneous coronary interventions. Eur Heart J 2005;26:804–847.
2. Selwyn AP. Prothrombotic and antithrombotic pathways in acute coronary syndromes. Am J Cardiol 2003;91:3H–11H.
3. Bassand JL, Maarten L, Simoons, Keith A, et al. Guidelines for diagnosis and treatment of non-ST elevation acute coronary syndrome. Eur Heart J 2007;28:1598–1660.
4. Gibson CM, Ten Y Murphy SA, et al. Association of pre-randomization anticoagulants switching with bleeding in the setting of percutaneous coronary intervention (A REPLACE-2 analysis). Am J Cardiol 2007;99:1687–1690.
5. Stone GW, White AD, Moses JW, et al. Bivalirudin in patient with acute coronary syndrome undergoing percutaneous coronary intervention: A subgroup analysis from the acute catheterization and urgent intervention triage strategy (ACUITY) trial. Lancet 2007;369:907–919.
6. Metz BK, White HD, Granger CB, et al. Randomized comparison of direct thrombin inhibition versus heparin in conjunction with fibrinolytic therapy for acute myocardial infarction: Results from the GUSTO-IIb Trial. Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO-IIb) Investigators. J Am Coll Cardiol 1998;31:1493–1498.
7. Despotis GJ, Gravlee G, Filos K, et al. Anticoagulation monitoring during cardiac surgery: A review of current and emerging techniques. Anesthesiology 1999;91:1122–1151.
8. Dietrich W, Braun S, Spannagl M, et al. Low preoperative antithrombin activity causes reduced response to heparin in adult but not in infant cardiac-surgical patients. Anesth Analg 2001; 92:66–71.
9. Avidan MS, Levy JH, Sholz J, et al. A phase III, double-blind, placebo-controlled, multicenter study on the efficacy or recombinant human antithrombin in heparin-resistant patients scheduled to undergo cardiac surgery necessitating cardiolpulmonary bypass. Anesthesiology 2005;102:276–284.
10. Denson KE. Ratio of Factor VIII-related antigen and Factor VIII biological activity a san index of hypercoagulability and intravascular clotting. Thromb Res 1997;10:107–119.
11. Mehmedagic A, Skrbo S, Softic D, et al. In vitro modelling of the influence of Factor VIII activity and heparin-induced prolongation of APTT. Bosn J Basic Med Sci 2005;5:26–29.
12. Michalski R, Lane DA, Pepper DS, et al. Neutralization of heparin in plasma by planted factor 4 and protamine. Br J Haematol 1978;38:561–571.
13. Koster A, Fisher T, Guendel M, et al. Management of heparin resistance during cardiopulmonary bypass: The effect of five different anticoaugulant strategies on hemostatic activation. J Cardiothorac Vasc Anesth 2003;17:171–175.
14. ACC/AHA Task Force on Practice Guidelines. ACC/AHA/SCAI Guideline update for percutaneous coronary intervention. e62 www.acc.org.
15. Carswell CI, Plosker GL. Bivalirudin: A review of its potential place in the management of acute coronary syndromes. Drugs 2002;62:841–870.
16. Shojania AM, Tetreault J, Turnbull G. The variations between heparin sensivity of different lots of activated partial thromboplastin time reagent produced by the same manufacturer. Am J Clin Pathol 1988;89:19–23.
17. Rich JD, Maraganore JM, Young E, et al. Heparin resistance in acute coronary syndrome. J Thromb Thrombolysis 2007;23:93–100.