Combined, Superselective Pharmacological Management of Large Coronary Thrombus Burden

From Interventional Cardiology, Cardiovascular Department, Misericordia Hospital, Grosseto, Italy. The authors report no conflicts of interest regarding the content herein. Manuscript submitted September 2, 2008, provisional acceptance given October 27, 2008, final version accepted December 16, 2008. Address for correspondence: Bernardo Cortese, MD, Interventional Cardiology, Cardiovascular Department, Misericordia Hospital, via Senese 48, 58100 Grosseto, Italy. E-mail: bcortese@gmail.com _________________________________ ABSTRACT: Background. Percutaneous coronary intervention (PCI) in patients with a high thrombus burden is a demanding clinical situation, associated with impaired clinical outcomes. Mechanical and pharmacological management of coronary thrombosis has been shown to effectively remove a variable fraction of intracoronary thrombus. A large inter-patient variability is often observed, and large randomized trials failed to demonstrate any clear benefit of such mechanical strategies on clinical outcome. Methods and Results. In 12 patients undergoing urgent PCI who had a large coronary thrombus burden, we administered intracoronary, super-selective infusion of urokinase (100.000 U) followed by abciximab (5 mg) via a 2.9 Fr microcatheter. We observed a significantly reduced final thrombus area, with acceptable tissue perfusion (Table). Moreover, this strategy allowed us to abstain from stent implantation in 7/12 patients. The procedures and subsequent hospital stays were uneventful. At 30-day clinical follow up, no cardiovascular adverse events or bleeding complications were observed. Conclusion. In our study, intra-clot administration of urokinase followed by abciximab significantly reduced the thrombotic burden with respect to baseline. Such conspicuous reduction allowed us to abstain from stent implantation or to perform it without inducing angiographically visible distal embolization or residual slow-flow. Moreover, this treatment strategy did not increase the risk of bleeding. J INVASIVE CARDIOL 2009;21:168–171 Percutaneous coronary intervention (PCI) in patients with a large thrombus burden is a demanding clinical situation associated with impaired clinical outcomes.1 – 4 Mechanical management of thrombus, as achieved with thrombectomy or embolic protection devices, has been shown to effectively remove a variable fraction of intracoronary (IC) clot, although a large inter-patient variability in their effectiveness is often observed, and large randomized trials have shown contradictory results in clinical outcomes.5–8 Pharmacological management of IC thrombus may be attempted through intravenous (IV) and/or IC administration of glycoprotein (GP) IIb/IIIa inhibitors, as well as through IC administration of fibrinolytic agents.9–11 The simultaneous use of both types of drugs given intravenously may lead to improved thrombus resolution, but is usually avoided due to the expected sharp increase in bleeding risk.12–14 Here we discuss 12 consecutive patients with angiographic evidence of a large thrombus-burden culprit lesion treated with IC, super-selective, prolonged infusion of abciximab and urokinase, followed by stent deployment in cases of suboptimal results. Methods This study includes 12 patients (Tables 1 and 2) undergoing coronary angiography via transradial access for acute coronary syndrome and showing angiographic signs of a large thrombus burden (presence of angiographic thrombus with the greatest linear dimension > 3 times the reference luminal diameter, as previously described35) at the level of the culprit lesion. Patients did not receive a GP IIb/IIIa inhibitor until the completion of coronary angiography in accordance with our center’s in-lab protocol. All patients had been treated with 300 mg IV aspirin, and 600 mg oral clopidogrel at admission; a 60 IU/Kg unfractionated heparin bolus was given at the beginning of the procedure, with additive boluses administered in order to maintain an activated clotting time between 200 and 250 seconds. Thrombus aspiration with an Export catheter (Medtronic, Minneapolis, Minnesota) was attempted in 7/12 patients and resulted in inadequate thrombus removal in all of these patients, defined as a reduction of > 50% of clot area (Table 2). Pharmacological treatment of the thrombus was performed by the insertion of a 2.9 Fr MicroMewi microcatheter with multiple sideholes (ev3 Inc., Plymouth, Minnesota) advanced over a 0.014 inch guidewire inside the thrombus. Thereafter, a sequential infusion of 100,000 U of urokinase (the fibrinolytic drug used at our institution), followed by 5 mg of abciximab, were given through the microcatheter over a 20-minute period. Contrast agent injections were avoided during urokinase infusion due to a previously described inhibitory effect of contrast media on this drug.15 PCI was finally performed in a case of an unsatisfactory resolution of the thrombus or evidence of a residual significant luminal stenosis. In 10 patients without evidence of hemorrhagic diathesis, 0.25 mg/Kg abciximab (reduced by 5 mg), followed by a 12-hour 0.125 µg/Kg/minute infusion, were also administered. Thrombus area in a reference angiographic view was measured at baseline, after urokinase administration and after abciximab infusion using Image Tool software (UTHSCSA Image Tool, University of Texas Health Science Center, San Antonio, Texas) and was expressed as percentage with respect to baseline. Final thrombolysis in myocardial infarction (TIMI) flow grade, myocardial perfusion blush grade (MBG), angiographically visible distal embolization and percent ST-segment shift resolution at 60 minutes, when appropriate, were also evaluated. A plan of 12-month, double anti-aggregation with aspirin and clopidogrel was made for all patients. Results The main results of the study are reported in Table 2. Thrombus area was significantly reduced by 37 ± 9% after urokinase administration (p 70%). In 7 patients, the procedure terminated without the need for stent implantation, whereas in the remaining 5 patients, a bare-metal stent was implanted due to significant residual stenosis caused by an underlying atherosclerotic plaque in 3 patients, or to unsatisfactory thrombus burden reduction in 2 patients. Final TIMI flow grade 3 without angiographic signs of distal embolization was observed in all patients but one. A 1.9 mean final MBG was observed in our population. No ischemic or major and minor bleeding complications occurred during the patients’ subsequent hospitalization, which lasted an average of 3.9 days. At 30-day follow up, none of the treated patients experienced major adverse cardiovascular events or bleeding complications. Discussion In the present study, we have shown that in patients with a large coronary thrombus burden, a super-selective, intra-clot, prolonged infusion of urokinase and abciximab may lead to complete or nearly-complete resolution of the thrombus in the majority of patients, with acceptable final tissue perfusion and no significant tradeoff in terms of bleeding complications. Management of a spontaneous or iatrogenic large coronary thrombus is a matter of concern in modern interventional cardiology. Its occurrence has been associated with impaired final TIMI flow grade and myocardial perfusion and worse clinical outcomes, even after successful PCI, most likely reflecting suboptimal thrombus management.16,17 Moreover, major concerns have recently been raised among interventional cardiologists due to the supposed higher risk of late and very late stent thrombosis after drug-eluting stent implantation.18–20 A recently presented registry, the OPTIMIST study (F. Burzotta et al, oral communication, European Congress of Cardiology 2007, Barcelona, Spain), showed a 6-month mortality rate of 16% in patients affected by stent thrombosis; in this registry, the use of mechanical thrombectomy did not affect clinical outcomes during emergency PCI, whereas re-stenting of the lesion was associated with worse outcomes. Mechanical management of coronary thrombus during ST-segment elevation myocardial infarction (STEMI), as achieved with different thrombectomy or embolic protection devices, has been tested in several randomized trials, with conflicting results.5–8,21,22 If their selective use in the face of evident coronary thrombosis has been advocated23 and was effective in a large randomized, controlled trial,36 they often fail in removing large coronary clots. In fact, mechanical thrombectomy achieved with various devices (ultrasound sonication, rheolytic thrombectomy, laser, aspiration catheters) is of limited efficacy for the treatment of organized thrombi, while distal filters have limited clot volume-loading ability and pores > 100 microns, too large to prevent microembolization.24 We attempted thrombus aspiration in 7/12 patients, and in 3/7 patients with STEMI. When we performed the procedures, the results of the TAPAS trial36 were not yet published, and this approach during primary PCI was not routine practice at our institution. Moreover, all attempts were unsuccessful. Although IV administration of a GP IIb/IIIa inhibitor has been proven to be beneficial in patients with acute coronary syndromes,25–27 the clinical indication for its use has not been specifically related to the presence of a high thrombus burden. Moreover, IV pretreatment with GP IIb/IIIa inhibitors does not seem to abolish the negative impact of a high thrombus burden on clinical outcomes after PCI.28 IV or IC administration of fibrinolytic agents has also been performed in the setting of facilitated primary PCI, but with unsatisfactory results.29,30 Theoretical advantages may be derived from the combined use of GP IIb/IIIa inhibitors and fibrinolytic agents in patients with a large thrombus burden, since both components of the thrombus, the fibrin network and platelet aggregates are pharmacologically counteracted. Abciximab at high concentration (50 µg/ml) has been shown to disaggregate platelet aggregates, as well as to inhibit platelet-monocyte aggregate production of tissue factor, a potent procoagulant agent.31,32 Unfortunately, IV administration of abciximab fails to reach such a high concentration, and the combined IV use of abciximab and fibrinolytics has been clearly demonstrated to induce a sharp increase in bleeding events.12,13,33 Moreover, systemic infusion of these drugs may fail to obtain adequate drug concentration within the clot due to the absence or extreme reduction of flow at this level. Even IC infusion via the guiding catheter may fail to obtain adequate intra-clot drug concentration due to preferential flow in the spared branches of the same coronary artery. Mitchel et al,34 in a porcine model, demonstrated how intra-clot administration of urokinase resulted in a three-fold time increase in thrombolysis as compared to the same dose administered through the guiding catheter. The decision to intervene locally and not to provide a systemic prolonged infusion of thrombolytics or GP IIb/IIIa inhibitors was mainly due to the following reasons: the impaired initial TIMI flow in the majority of the population (only 2 patients had TIMI 3 flow); the risk of distal embolization of large clots that could be managed instantly in the catheterization laboratory; the increased bleeding risk with such a strategy. In our opinion, a strategy of combined pharmacological management of a large thrombotic burden, consisting of low-dose, intra-clot administration of urokinase and abciximab might offer some theoretical advantages: • Intra-clot administration induces high drug concentration levels in the local environment, compatible with a “disaggregating” rather than just an “anti-aggregant” effect of abciximab together with maximal fibrinolytic urokinase action. • Intra-clot administration may induce the generation of an intramural reservoir of drug, determining prolonged local pharmacological activity. • The drug doses tested in the present work (about 30% of the systemic bolus dose of abciximab and about 10% of the systemic dose of urokinase) are not likely to significantly impact the systemic hemocoagulative balance. Therefore, this treatment could even be safely performed on patients with hemorrhagic diathesis, with the adjunctive systemic dose of abciximab (remaining bolus + 12-hour infusion) reserved only for patients who do not have a high risk of bleeding complications. In this small series of patients, we did not register bleeding complications; this finding is probably also related to the transradial approach used during these interventions. Conclusion In our study, intra-clot administration of urokinase significantly reduced the thrombotic burden with respect to baseline. Abciximab, on top of urokinase, induced a significant additive effect, leading to a final mean reduction in thrombotic burden > 65%. Such a conspicuous reduction allowed us to abstain from stent implantation or to perform it without inducing angiographically visible distal embolization or residual slow-flow. Interestingly, these favorable results were obtained without the expected tradeoff in terms of bleeding events. Based on current evidence, mechanical thrombectomy should be the firstline treatment for high thrombus-burden coronary arteries. These promising preliminary results warrant a larger prospective, randomized study comparing the safety and efficacy of this pharmacological strategy with standard IV GP IIb/IIIa inhibitor treatment plus adjunctive use of mechanical thrombectomy devices.

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