Pre-procedural Administration of Aminophylline Does
Not Prevent AngioJet Rheolytic Thrombectomy-induced Bradyarrhythmias

Percutaneous coronary intervention (PCI) on thrombus-containing lesions represents a clinical challenge to the interventional cardiologist, since thrombus has been identified as a predictor of adverse outcome.^1,2 While attempting to reestablish coronary perfusion, PCI of thrombus-laden native coronary arteries and bypass saphenous venous grafts can lead to distal embolization.3 Distal embolization of thrombus, fibrin content, and other atherosclerotic plaque particulate matter can lead to flow limiting microvascular obstruction, which may result in the no-reflow phenomenon, abrupt closure, periprocedural myocardial infarction, emergent coronary artery bypass graft surgery, and death.^2,4–6 The AngioJet (AJ) rheolytic thrombectomy system (Possis Medical, Minneapolis, Minnesota) implements high-velocity fluid jets to macerate and produce a vacuum for thrombus aspiration and extraction. AJ thrombectomy has been used safely and successfully to remove thrombus in native coronary arteries in patients with acute myocardial infarction.^7,8 AJ thrombectomy has also been used shown to decrease the thrombus burden in saphenous vein graft lesions.^9,10 Insertion of a temporary transvenous pacemaker is recommended prior to activation of AJ thrombectomy because transient bradyarrhythmias including sinus pause, asystole and heart block occurs in 20–26% of cases involving AJ thrombectomy.⁹ The AJ thrombectomy induces the release of adenosine from hemolyzed red blood cells, which is the presumed mechanism responsible for bradyarrhythmias. Previous studies have reported that aminophylline, an adenosine receptor antagonist, decreased the incidence of rheolytic thrombectomy-induced bradyarrhythmias and obviated the need for a transvenous pacemaker.^11,12 The need for a transvenous pacemaker, with the associated risk of bleeding from vascular access-site complications and increased procedural cost, is thought to be circumvented by pharmacologic prevention with the administration of aminophylline. We evaluated the effectiveness of aminophylline in preventing AJ rheolytic thrombectomy-induced bradyarrhythmias. Materials and Methods Study population. The study population included 44 consecutive patients admitted to a university-affiliated community teaching hospital between April 2002 and September 2003 with acute myocardial infarction who underwent AJ thrombectomy for thrombotic lesions. Patients were treated with aspirin, heparin (to maintain activated clotting time > 250 seconds), and glycoprotein IIb/IIIa receptor inhibitor. Clopidogrel was continued for at least 1 month after PCI. Patients who met the following criteria were treated with AJ thrombectomy: 1) evidence of large thrombus burden in the culprit lesion on angiography; 2) reference vessel diameter > 2.5 mm; 3) the absence of calcification in the culprit lesion and extreme tortuosity in the proximal portion of the vessel. Procedure. Under 1% lidocaine hydrochloride local anesthesia, a 6 Fr arterial sheath was placed into the femoral artery. A 5 Fr venous sheath was placed into the femoral vein and a transvenous pacemaker was placed in the apex of the right ventricle. The backup rate was set at 50 beats per second. Five minutes prior to the first pass with the AJ catheter, 250 mg of aminophylline was administered intravenously over 2 minutes. A nonionic contrast media was used for all patients. The infarct-related lesion was crossed with a 0.014-inch coronary guidewire. The AJ catheter was initially “primed” by submerging the catheter in a container with sterilized saline and activating it to purge the remaining air out of the system. The AJ catheter was activated starting either at the proximal or distal end of the thrombus. In the first method, the AJ catheter was advanced over a guidewire just until it was proximal to the thrombus. The AJ catheter was advanced at 1–2 mm/second to the distal end of the thrombus and then deactivated. The alternative technique was to advance the AJ catheter to the distal end of the thrombus and then pull back through the thrombus after activation until the proximal portion of the thrombus was reached. On average, 3–5 passes, each pass lasting about 5–10 seconds, were made on the thrombotic lesion until no improvement in angiographic appearance was noted. Subsequent angioplasty or stenting was performed for definitive treatment of the lesion for optimal results along with the administration of GP IIb/IIIa antagonists. Endpoint. Baseline clinical, angiographic, and procedural data were collected from each patient. The primary endpoint was AJ-induced bradyarrhythmia leading to demand pacing when the heart rate fell below 50 beats/second. Statistical analysis. Discrete data are reported as percentages. Continuous data were compared using Student’s t-test and are presented as mean ± SD. Categorical data variables were compared using the chi-square test. All statistical analyses were performed using SPSS version 10.0 (SPSS Inc., Chicago, Illinois). Results Baseline characteristics and lesions are presented in Table 1. Except for the patients who received aminophylline being older than the patients who did not receive aminophylline (63 ± 12 years versus 57 ± 14 years, p = 0.05), baseline characteristics between the two groups were well matched. Fifteen patients with angiographic evidence of thrombus in native coronary arteries (10 left anterior descending arteries, 2 left circumflex arteries, 3 right coronary arteries) were given intravenous aminophylline prior to AJ thrombectomy. The mean age was 63 ± 12 years, and 8 (53%) were male. Twelve patients (80%) presented with ST-elevation myocardial infarction, and 3 patients (20%) presented with non-ST-elevation myocardial infarction. Twenty-nine patients with angiographic evidence of thrombus did not receive intravenous aminophylline prior to AJ thrombectomy (12 left anterior descending arteries, 7 left circumflex arteries, 9 right coronary arteries, 1 saphenous vein graft). The mean age was 57 ± 14 years, and 18 (62%) were male. Twenty-three patients (79%) presented with ST-elevation myocardial infarction, and 6 patients (21%) presented with non-ST-elevation myocardial infarction. One patient went into ventricular fibrillation and was promptly defibrillated into normal sinus rhythm. Transient bradyarrhythmias requiring temporary pacing occurred in 11 of the 15 patients (73%) who received aminophylline and in 23 of the 29 patients (79%) who did not receive aminophylline (p = 0.65). Of the 4 patients who received aminophylline and did not develop transient bradyarrhythmia requiring temporary pacing, 1 patient was on dopamine with a pre-procedural heart rate of 150 beats/minute. This patient’s heart rate dropped to 105 beats/minute during activation of AJ thrombectomy. Another patient was on dobutamine. Three patients who did not receive aminophylline received dopamine for inotropic support during AJ thrombectomy. Discussion AJ thrombectomy macerates and removes thrombus by generating a Bernoulli effect-induced vacuum at the tip. It potentially reduces embolization due to its ability to extract thrombotic debris that is not removed with conventional PCI techniques. Several studies have shown this technique to be effective in treating thrombotic lesions in both coronary and saphenous vein graft circulation. Temporary cardiac rhythm disturbances, bradyarrhythmia and heart block (high-grade atrioventricular block, complete heart block, asystole) requiring temporary pacing have been reported to occur in 20–26% of cases involving AJ thrombectomy.⁹ However, bradyarrhythmias were more commonly seen in our patient population treated with AJ thrombectomy, regardless whether aminophylline was administered or not. If a transvenous pacemaker is not prophylactically inserted, transient bradyarrhythmias may occur during AJ thrombectomy leading to potentially disastrous clinical events. Nakagawa et al¹³ reported one case of a patient who had asystole for 12 seconds followed by bradycardia for 20 seconds during AJ thrombectomy in the left anterior descending artery, leading to transient left hemiplegia lasting 2 hours. Bradyarrhythmias occurring during AJ thrombectomy may be related to the release of intracellular adenosine from hemolyzed red blood cells during AJ thrombectomy.¹² Adenosine is a coronary vasodilator (A2 receptor subtype mediated) with negative dromotropic and chronotropic and anti-beta-adrenergic effects (A1 receptor mediated). Stimulation of the A1 receptor in sinoatrial and atrioventricular nodal cells activates the outward K+ current via a cAMP-independent mechanism, inhibiting the “slow” Ca2+/Na+ mediated action potential of the atrioventricular node.^14,15 It is postulated that adenosine and other products released from hemolyzed red blood cells flow into the vascular bed supplying the sinoatrial and atrioventricular node and alter heart rate and conduction. Bradyarrhythmias occur more frequently in the right coronary artery, perhaps because the right coronary artery most commonly provides the arterial supply to the atrioventricular node.¹⁶ Concomitant abrupt and dramatic ST-segment elevation secondary to hemolysis (producing localized hyperkalemia) during activation of AJ thrombectomy and chest discomfort is not uncommon.¹⁷ This can be palliated by narcotics and limiting each thrombectomy pass to less than 30 seconds.¹⁸ The chest discomfort usually resolves after cessation of AJ thrombectomy. Sustained ventricular arrhythmias have been reported to occur in 1.1% of patients in the Vein Graft AngioJet Study (VeGAS) 2 trial,¹⁰ but all resolved and did not lead to significant clinical sequelae. It is believed that aminophylline, a methylxanthine and a competitive inhibitor of the adenosine receptor, may prevent AJ thrombectomy-associated bradyarrhythmias. Bertolet et al¹⁹ reported that the administration of another methylxanthine, theophylline, restored normal sinus rhythm after clinically significant atrioventricular block in the setting of an acute inferior myocardial infarction. Administration of aminophylline may potentially have unfavorable effects during acute myocardial infarction. Aminophylline has arrhythmogenic and chronotropic effects.20 Aminophylline is associated with atrial fibrillation, presumably from a shortened atrial refractory period and dispersed recovery of excitability induced by aminophylline, engendering to multiple reentrant circuits and leading to atrial fibrillation.²¹ Aminophylline also increases myocardial oxygen consumption, an effect that is undesirable in acute myocardial infarction.²² Aminophylline increased mean arterial pressure by 12 ± 2%, left ventricular systolic pressure by 8 ± 1%, left ventricular dP/dt by 20 ± 2%, systemic vascular resistance by 13 ± 5%, coronary vascular resistance by 26 ± 3%, and heart rate by 5 ± 2%.23 Distal embolization is one potential mechanism of the no reflow phenomenon and other adverse clinical events associated with PCI in thrombus-laden native coronary arteries and bypass saphenous venous grafts. Distal protection devices have been developed to recover plaque constituents (cholesterol crystals, foam cells, fibrous plaque) and thrombus liberated from PCI that might otherwise embolize into the myocardial bed.²⁴ The Enhanced Myocardial Efficacy and Removal by Aspiration of Liberated Debris (EMERALD) trial²⁵ assessed the safety and efficacy of the GuardWire distal protection device (Medtronic, Inc., Minneapolis, Minnesota) in acute myocardial infarction undergoing primary or rescue PCI. The use of the GuardWire distal embolic protection device in acute myocardial infarction patients did not improve microvascular blood flow or function, and was not associated with a reduction in infarct size or clinical events when compared with acute myocardial infarction patients treated with a conventional wire. The AngioJet Rheolytic Thrombectomy in Patients Undergoing Primary Angioplasty for Acute Myocardial Infarction (AiMI) trial will compare the final infarct size and clinical and angiographic outcomes in acute myocardial infarction patients treated with AJ thrombectomy followed by PCI versus direct PCI. Glycoprotein IIb/IIIa receptor inhibitors are clinically efficacious in the management of patients with acute coronary syndromes. Glycoprotein IIb/IIIa receptor inhibitors prevent the binding of fibrinogen, and thus platelet aggregation.²⁶ However, the different glycoprotein IIb/IIIa receptor inhibitors have different de-thrombotic effects acutely. Abciximab is a chimeric Fab human-mouse antibody fragment with a short plasma half-life but a long biologic half-life because of its strong affinity for the glycoprotein receptor.²⁷ It provides robust, consistent, and significant clinical efficacy in patients undergoing PCI. When patients were treated with abciximab, the proportion of patients with platelet aggregation inhibition below the target level of 80% steadily increased over time, from 20% at 40 minutes to 30% at 2 hours, 40% at 6 hours, and 50% at 12 hours (end of infusion).²⁸ However, eptifibatide, a cyclic heptapeptide that is specific for glycoprotein IIb/IIIa receptor, provided consistent platelet aggregation inhibition (> 80%), with virtually all patients achieving the targeted platelet aggregation inhibition at 40 minutes, 2 hours, 6 hours, and at the end of the infusion (18 hours). Despite previous reports demonstrating that pretreatment with aminophylline decreased the incidence of bradyarrhythmias associated with AJ thrombectomy, our single-center experience suggests that preprocedural treatment with aminophylline did not decrease the incidence of bradyarrhythmias associated with AJ thrombectomy. This study is limited because aminophylline was administered in a non-randomized manner. Because of the small number of patients, the overall efficacy of aminophylline to suppress AJ thrombectomy-induced bradyarrhythmias cannot be clearly defined. It is possible that passes with the AJ catheter of shorter duration, perhaps limiting each pass to 5 seconds, along with aminophylline might decrease the incidence of bradyarrhythmias and obviate the need for a transvenous pacemaker. A larger-scale prospective study of the use of aminophylline to suppress AJ thrombectomy-induced bradyarrhythmias and its safety profile in the setting of acute myocardial infarction would provide us with a more definitive role of aminophylline. Conclusions Administration of aminophylline does not prevent transient bradyarrhythmias and does not obviate the need for temporary pacing. Insertion of a transvenous pacemaker is highly recommended during AJ thrombectomy. There is currently no data on the safety of the administration of aminophylline in the setting of acute myocardial infarction. Intravenous aminophylline is not beneficial in suppressing bradyarrhythmias and is discouraged as it may potentially have deleterious effects because of its proarrhythmic properties as well as its effect on heart rate, vasomotor tone, and myocardial oxygen consumption.

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