A.A.Jennifer Adgey

Abciximab Facilitates the Rate and Extent of Thrombolysis Results of the Thrombolysis In Myocardial Infarction (TIMI) 14 Trial

BACKGROUND The TIMI 14 trial tested the hypothesis that abciximab, the Fab fragment of a monoclonal antibody directed to the platelet glycoprotein (GP) IIb/IIIa receptor, is a potent and safe addition to reduced-dose thrombolytic regimens for ST-segment elevation MI. METHODS AND RESULTS Patients (n=888) with ST-elevation MI presenting <12 hours from onset of symptoms were treated with aspirin and randomized initially to either 100 mg of accelerated-dose alteplase (control) or abciximab (bolus 0.25 mg/kg and 12-hour infusion of 0.125 microg. kg-1. min-1) alone or in combination with reduced doses of alteplase (20 to 65 mg) or streptokinase (500 000 U to 1.5 MU). Control patients received standard weight-adjusted heparin (70-U/kg bolus; infusion of 15 U. kg-1. h-1), whereas those treated with a regimen including abciximab received low-dose heparin (60-U/kg bolus; infusion of 7 U. kg-1. h-1). The rate of TIMI 3 flow at 90 minutes for patients treated with accelerated alteplase alone was 57% compared with 32% for abciximab alone and 34% to 46% for doses of streptokinase between 500 000 U and 1.25 MU with abciximab. Higher rates of TIMI 3 flow at both 60 and 90 minutes were observed with increasing duration of administration of alteplase, progressing from a bolus alone to a bolus followed by either a 30- or 60-minute infusion (P<0.02). The most promising regimen was 50 mg of alteplase (15-mg bolus; infusion of 35 mg over 60 minutes), which produced a 76% rate of TIMI 3 flow at 90 minutes and was tested subsequently in conjunction with either low-dose or very-low-dose (30-U/kg bolus; infusion of 4 U. kg-1. h-1) heparin. TIMI 3 flow rates were significantly higher in the 50-mg alteplase plus abciximab group versus the alteplase-only group at both 60 minutes (72% versus 43%; P=0.0009) and 90 minutes (77% versus 62%; P=0.02). The rates of major hemorrhage were 6% in patients receiving alteplase alone (n=235), 3% with abciximab alone (n=32), 10% with streptokinase plus abciximab (n=143), 7% with 50 mg of alteplase plus abciximab and low-dose heparin (n=103), and 1% with 50 mg of alteplase plus abciximab with very-low-dose heparin (n=70). CONCLUSIONS Abciximab facilitates the rate and extent of thrombolysis, producing early, marked increases in TIMI 3 flow when combined with half the usual dose of alteplase. This improvement in reperfusion with alteplase occurred without an increase in the risk of major bleeding. Substantial reductions in heparin dosing may reduce the risk of bleeding even further. Modest improvements in TIMI 3 flow were seen when abciximab was combined with streptokinase, but there was an increased risk of bleeding.

TNK–Tissue Plasminogen Activator Compared With Front-Loaded Alteplase in Acute Myocardial Infarction Results of the TIMI 10B Trial

BACKGROUND Bolus thrombolytic therapy is a simplified means of administering thrombolysis that facilitates rapid time to treatment. TNK-tissue plasminogen activator (TNK-tPA) is a highly fibrin-specific single-bolus thrombolytic agent. METHODS AND RESULTS In TIMI 10B, 886 patients with acute ST-elevation myocardial infarction presenting within 12 hours were randomized to receive either a single bolus of 30 or 50 mg TNK-tPA or front-loaded tPA and underwent immediate coronary angiography. The 50-mg dose was discontinued early because of increased intracranial hemorrhage and was replaced by a 40-mg dose, and heparin doses were decreased. TNK-tPA 40 mg and tPA produced similar rates of TIMI grade 3 flow at 90 minutes (62.8% versus 62.7%, respectively, P=NS); the rate for the 30-mg dose was significantly lower (54.3%, P=0.035) and was 65. 8% for the 50-mg dose (P=NS). A prespecified analysis of weight-based TNK-tPA dosing using median TIMI frame count demonstrated a dose response (P=0.001). Similar dose responses were observed for serious bleeding and intracranial hemorrhage, but significantly lower rates were observed for both TNK-tPA and tPA after the heparin doses were lowered and titration of the heparin was started at 6 hours. CONCLUSIONS TNK-tPA, given as a single 40-mg bolus, achieved rates of TIMI grade 3 flow similar to those of the 90-minute bolus and infusion of tPA. Weight-adjusting TNK-tPA appears to be important in achieving optimal reperfusion; reduced heparin dosing appears to improve safety for both agents. Together with the safety results from the parallel Assessment of the Safety of a New Thrombolytic: TNK-tPA (ASSENT I) trial, an appropriate dose of this single-bolus thrombolytic agent has been identified for phase III testing.

Value of signal-averaged electrocardiography, radionuclide ventriculography, holter monitoring and clinical variables for prediction of arrhythmic events in survivors of acute myocardial infarction in the thrombolytic era

OBJECTIVES This study assessed the ability of signal-averaged electrocardiography, radionuclide ventriculography and Holter electrocardiographic (ECG) monitoring and clinical variables to identify patients at risk of serious arrhythmic events after myocardial infarction in the thrombolytic era. BACKGROUND Most studies of signal-averaged electrocardiography, radionuclide ventriculography and Holter ECG monitoring in risk stratification after myocardial infarction preceded the introduction of thrombolytic therapy. METHODS A consecutive series of 301 survivors of myocardial infarction, 205 (68%) of whom received thrombolytic agents, underwent signal-averaged electrocardiography (1st 48 h, day 6 and discharge), Holter ECG monitoring (days 6 to 7) and radionuclide left ventriculography (days 7 to 14). Median follow-up time was 1.03 years. RESULTS Thirteen patients (4.3%) had an arrhythmic event (sudden death in 11, sustained ventricular tachyarrhythmia in 2). The 25-Hz high pass filtered signal-averaged ECG at discharge was 64% sensitive (95% confidence intervals [CI] 36% to 92%) and 81% specific (95% CI 76% to 86%). High grade ventricular ectopic activity on the Holter ECG was only 38% sensitive (95% CI 12% to 64%) and 74% specific (95% CI 71% to 77%). Left ventricular ejection fraction < 0.4 was the best test for prediction of arrhythmic events (sensitivity 75% [95% CI 50% to 100%] and specificity 81% [95% CI 76% to 85%]). In multivariate analysis, in rank order, digoxin therapy at discharge, an abnormal 25-Hz signal-averaged ECG before discharge, absence of angina before index infarction and previous infarction were predictive of arrhythmic events. With digoxin therapy excluded, ejection fraction was an independent predictor. Discriminant analysis identified a high risk group (12% of the study patients) with an event rate of 26%. CONCLUSIONS The signal-averaged ECG and left ventricular ejection fraction are each independently predictive of arrhythmic events after myocardial infarction, but the Holter ECG is not. A combination of clinical and investigative variables, including the signal-averaged ECG, best identifies patients at highest risk.

Pre-hospital coronary care: The mobile coronary care unit∗

Abstract The majority of deaths from myocardial infarction occur soon after the onset of symptoms and before the victims reach hospital coronary care units. The mobile scheme described allows intensive care to commence in the patients own home or at the site of infarction and thus reduces considerably the interval between the onset of symptoms and the initiation of intensive care. The prevention of fatal dysrhythmias by early pre-hospital care should have a significant effect on the early high mortality rates. Since the correction of ventricular fibrillation outside the hospital is a practical proposition, a further impact on the early high mortality will result when mobile units are supported by first aid training programs in methods of resuscitation.

Management of recurrent ventricular tachyarrhythmias associated with Q-T prolongation

Eleven patients with acquired prolongation of the Q-Tc interval and recurrent ventricular tachyarrhythmias were studied. Five patients required 5 to 44 direct current shocks to correct prolonged ventricular tachyarrhythmias, and five were given at least two antiarrhythmic agents in an attempt to control the arrhythmias. In 4 of the 11 patients, when thioridazine, diuretic drugs and antiarrhythmic agents were withdrawn and hypokalemia or hypocalcemia corrected, ventricular tachyarrhythmias did not recur. The Q-Tc interval normalized in 2 to 3 days. Ventricular tachyarrhythmias were recurrent in the remaining seven patients, despite withdrawal of the drugs that caused the Q-Tc prolongation, attempted correction of hypokalemia when present and the administration of antiarrhythmic agents to four of the seven. All antiarrhythmic agents were then withdrawn in this group. Immediately on the establishment of overdrive ventricular or atrioventricular sequential pacing in these patients, ventricular tachyarrhythmias were abolished. No breakthrough ventricular tachyarrhythmias occurred during temporary pacing. Temporary pacing was required for an average of 10 days and the Q-Tc interval normalized an average of 5 days from the onset of pacing. Three patients required a permanent pacemaker, one because of chronic complete heart block, one because of the sick sinus syndrome, and one because of frequent ventricular ectopic complexes complicating ischemic heart disease. All 11 patients survived their period of hospitalization.

An overview of the results of clinical trials with glycoprotein IIb/IIIa inhibitors

The era of platelet glycoprotein (GP) IIb/IIIa receptor inhibition in cardiology was inaugurated in 1994 with the publication of the Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC) trial results. EPIC demonstrated that the GP IIb/IIIa blocker abciximab, administered as a bolus and 12-hour infusion, afforded protection against ischemic complications in high-risk patients undergoing angioplasty and atherectomy, including those with unstable angina or evolving myocardial infarction (MI). A significant reduction in the incidence of death, acute MI, or revascularization was apparent at 30 days and also sustained at 6-month and 3-year follow-up. The subsequent Evaluation in PTCA to Improve Long-Term Outcome with Abciximab GP IIb/IIIa Blockade (EPILOG) study extended these findings to the full spectrum of coronary intervention patients, confirming that abciximab provided similar benefits in low-risk patients as well. The EPILOG trial also proved that any excess bleeding risk associated with potent antiplatelet therapy could be brought down to placebo levels through the use of a low-dose, weight-adjusted heparin regimen, early vascular sheath removal, and elimination of routine postprocedural heparinization. The potential for an advantage of GP IIb/IIIa blockade in patients with refractory unstable angina/non-Q-wave MI was demonstrated in the c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) trial, which showed that a 24-hour preprocedural abciximab infusion effectively stabilized these patients, thereby enhancing the safety of intervention and reducing the 30-day incidence of ischemic events. A similar pattern of benefit has emerged from clinical trials of such other GP IIb/IIIa inhibitors as eptifibatide, lamifiban, and tirofiban. Trials are currently underway to clarify the benefits of GP IIb/IIIa blockers in patients undergoing stenting and as an adjunct to thrombolytic therapy or primary angioplasty in patients with acute MI (ST-segment elevation).

High levels of platelet inhibition with abciximab despite heightened platelet activation and aggregation during thrombolysis for acute myocardial infarction: results from TIMI (thrombolysis in myocardial infarction) 14.

BACKGROUND We evaluated platelet activation and aggregation in patients with acute myocardial infarction (AMI) treated with thrombolytic therapy alone or with reduced-dose thrombolysis and concomitant abciximab. METHODS AND RESULTS The study was performed in 20 control subjects and 51 patients with AMI before and after reperfusion with either alteplase or reteplase or reduced doses of these agents with concomitant abciximab. Platelet activation was assayed by platelet surface expression of P-selectin. Turbidometric platelet aggregation in response to ADP was measured in patients before thrombolytic therapy and 90 minutes and 24 hours after the beginning of thrombolytic therapy. P-selectin expression was greater at baseline in patients than normal control subjects (30.4% versus 9. 8%, P<0.0001) but was identical between the 2 groups after stimulation with ADP (64.4% versus 69.3%, P=0.37). However, at 24 hours, basal P-selectin expression declined in patients (P=0.0025 versus baseline), whereas ADP-stimulated P-selectin expression was lower in patients than in control subjects (48% versus 69%, P=0. 0004). When combined with reduced doses of either alteplase or reteplase, abciximab achieved 91% and 83% inhibition of 5 and 20 micromol/L ADP-induced platelet aggregation, which decreased to 46% and 40%, respectively, at 24 hours. No appreciable difference in the platelet inhibition profile of abciximab was observed between the 2 thrombolytics. CONCLUSIONS Platelet activation and aggregation are heightened in the setting of thrombolysis for AMI. Despite this enhanced level of platelet activation, abciximab, combined with a reduced-dose thrombolytic, inhibited platelet aggregation similarly to the level reported in elective settings.

Efficacy of 100 mg of double-bolus alteplase in achieving complete perfusion in the treatment of acute myocardial infarction

OBJECTIVES The purpose of this study was to assess the efficacy of 150 mg of aspirin plus 100 mg of alteplase, administered as two intravenous bolus injections of 50 mg each given 30 min apart, and followed by intravenous heparin, on infarct-related coronary artery patency (Thrombolysis in Myocardial Infarction [TIMI] flow grade 3). BACKGROUND Previous workers have shown in animals that reducing the duration of an infusion of recombinant tissue-type plasminogen activator increases the initial rate of thrombolysis, resulting in high early infarct-related coronary artery patency rates. The logical progression of this idea is bolus administration. METHODS Consecutive patients presenting up to 6 h from the onset of symptoms were recruited for the study. Angiography was performed at 60 and 90 min after the first bolus and between 19 to 48 h after study entry. Patients were followed up for 1 month. RESULTS At 60 min, angiography revealed infarct-related coronary artery patency of TIMI flow grade 3 in 55 (86%) of 64 patients (95% confidence interval [CI] 75% to 93%) and TIMI flow grade 2 or 3 in 58 (91%) of 64 patients (95% CI 81% to 97%). At 90 min, infarct-related artery patency of TIMI flow grade 3 was achieved in 74 (88%) of 84 patients (95% CI 79% to 94%) and TIMI flow grade 2 or 3 in 78 (93%) of 84 patients (95% CI 85% to 97%). Two patients (2.4%) had early angiographic reocclusion whereas 10 (11.9%) had late reinfarction. Bleeding episodes were mostly minor, and there was no cerebrovascular bleeding. Five patients (6.0%) died within 1 month of the acute myocardial infarction. CONCLUSIONS In 84 patients with acute myocardial infarction, administration of 100 mg of double-bolus (2 x 50 mg) alteplase, aspirin and heparin is associated with remarkably high early infarct-related coronary artery patency rates (TIMI flow grade 3) of 86% and 88%, respectively, at 60 and 90 min.

Early diagnosis of right ventricular or posterior infarction associated with inferior wall left ventricular acute myocardial infarction.

Right ventricular (RV) or posterior infarction associated with inferior wall left ventricular acute myocardial infarction (AMI) has important therapeutic and prognostic implications. However, RV and posterior chest leads in addition to the 12-lead electrocardiogram are required for accurate detection. Body surface mapping (BSM) has greater spatial sampling and may further improve inferior wall AMI classification. Consecutive patients with chest pain lasting <12 hours were assessed to identify those with AMI and > or =0.1 mV ST elevation in > or =2 contiguous inferior leads of the 12-lead electrocardiogram (bundle branch block or left ventricular hypertrophy excluded). A 12-lead electrocardiogram, RV leads (V(2)R, V(4)R), posterior chest leads (V(7), V(9)), and a BSM were recorded. From each BSM, the 12 electrodes overlying the RV region (regional RV map) and 10 electrodes overlying the posterior wall (regional posterior map) were assessed for ST elevation. Infarct size was estimated by serial cardiac enzymes. AMI occurred in 173 of 479 patients. Of the 62 patients with inferior wall AMI, ST elevation > or =0.1 mV occurred in 26 patients (42 in V(2)R or V(4)R compared with 36 patients (58%) in > or =1 electrode on the regional RV map (p = 0.0019). ST elevation > or =0.1 mV occurred in 1 patient (2%) in V(7) or V(9) compared with 17 patients (27%) in > or =1 electrode on the regional posterior map (p = 0.00003). ST elevation > or =0.05 mV occurred in 6 patients (10%) in V(7) or V(9) compared with 22 patients (36%) in > or =1 electrode on the regional posterior map (p = 0.00003). Patients with ST elevation on regional RV and/or posterior maps had a trend toward larger infarct size (mean peak creatine kinase 1,789+/-226 vs. 1,546+/-392 mmol/L; p = NS). Thus, BSM, when compared with RV or posterior chest leads, provides improved classification of patients with inferior wall AMI and RV or posterior wall involvement.

Comparison of the 80-lead body surface map to physician and to 12-lead electrocardiogram in detection of acute myocardial infarction☆

Diagnosis of non-ST-elevation acute myocardial infarction (AMI) by a 12-lead electrocardiogram has poor sensitivity and specificity and, therefore, relies on biochemical markers of myocardial necrosis, which can only be reliably detected within 14 to 16 hours from symptom onset. The body surface map (BSM) improves AMI detection but is limited by its interpretation by inexperienced medical staff. To facilitate interpretation, an automated BSM algorithm was developed and is evaluated in this study. One hundred three patients with ischemic-type chest pain were recruited for this study from December 2001 to April 2002. A 12-lead electrocardiogram (Marquette Mac 5K) and BSM (PRIME-ECG) were recorded at initial presentation, and cardiac troponin I and/or creatine kinase-MB levels measured at 12 hours after symptom onset. The admitting physicians 12-lead electrocardiographic (ECG) interpretation, 12-lead ECG algorithm (Marquette 12 SL V233) diagnosis, and BSM algorithm diagnosis were documented for each patient. AMI, defined by elevation of troponin I to >1 microg/L and/or creatine kinase-MB to >25U/L, occurred in 53 patients. The admitting physician diagnosed 24 patients with AMI (sensitivity 45%, specificity 94%), the 12-lead ECG algorithm diagnosed 17 patients with AMI (sensitivity 32%, specificity 98%), and the BSM algorithm diagnosed 34 patients with AMI (sensitivity 64%, specificity 94%). The BSM algorithm improved the diagnostic sensitivity by 2.0 (p <0.001) and 1.4 (p = 0.002) compared with the 12-lead ECG algorithm or the admitting physician, respectively. There was no significant difference in specificity. Thus, the BSM algorithm improves detection of AMI compared with the 12-lead ECG algorithm or physicians 12-lead ECG interpretation.