Kathleen Trollinger

Combining thrombolysis with the platelet glycoprotein IIb/IIIa inhibitor lamifiban: Results of the platelet aggregation receptor antagonist dose investigation and reperfusion gain in myocardial infarction (PARADIGM) trial

OBJECTIVES The trial was designed to assess the safety, pharmacodynamics and effects on reperfusion of the platelet glycoprotein (GP) IIb/IIIa inhibitor lamifiban when given with thrombolysis to patients with ST segment elevation acute myocardial infarction. BACKGROUND Studies of fibrinolytic agents in acute myocardial infarction have demonstrated a direct relationship between early complete reperfusion and survival. Blockade of the platelet GP IIb/IIIa receptor complex inhibits platelet aggregation and may speed reperfusion when given in conjunction with thrombolysis to patients with acute myocardial infarction. METHODS Patients with ST segment elevation presenting within 12 h of symptom onset who were treated with either tissue-plasminogen activator or streptokinase were enrolled in this three-part Phase II dose exploration study. In Part A, all patients received the GP IIb/IIIa inhibitor lamifiban in an open-label, dose escalation scheme. Parts B and C were a randomized, double-blind comparison of a bolus plus 24-h infusion of lamifiban versus placebo with patients randomized in a 2:1 ratio. The goal was to identify a dose(s) of lamifiban that provided >85% adenosine diphosphate (ADP)-induced platelet aggregation inhibition. A composite of angiographic, continuous electrocardiographic and clinical markers of reperfusion was the primary efficacy end point, and bleeding was the primary safety end point. RESULTS Platelet aggregation was inhibited by lamifiban in a dose-dependent manner with the highest doses exceeding 85% ADP-induced platelet aggregation inhibition. There was more bleeding associated with lamifiban (transfusions in 16.1% lamifiban-treated vs. 10.3% placebo-treated patients). Lamifiban induced more rapid reperfusion as measured by all continuous electrocardiographic (ECG) parameters. CONCLUSIONS Lamifiban given with thrombolytic therapy appears to be associated with more rapid and complete reperfusion than placebo. As expected in this small sample, there were no obvious clinical benefits to lamifiban over placebo. Reconciliation of ECG monitoring with clinical outcomes will require a larger, adequately powered clinical trial.

Comparative prognostic significance of simultaneous versus independent resolution of ST segment depression relative to ST segment elevation during acute myocardial infarction.

OBJECTIVES We sought to determine the prognostic significance of simultaneous versus independent resolution of ST segment depression that occurs concomitant with ST segment elevation during acute myocardial infarction (AMI). BACKGROUND ST segment depression in leads other than those showing ST segment elevation during AMI is a common phenomenon. Whether this indicates adverse outcomes remains controversial. We hypothesized that the timing of ST segment depression resolution relative to ST segment elevation resolution might differentiate between a high risk group and a low risk group of patients. METHODS Continuous 12-lead ST segment monitoring was performed after thrombolytic therapy for AMI in 413 patients, 261 of whom met technical criteria for analysis. Blinded analysis of ST segment depression resolution patterns was used to group patients as follows: 1) no ST segment depression at any time (control group); 2) ST segment depression resolving simultaneously with ST segment elevation (simultaneous group); and 3) ST segment depression persisting after ST segment elevation resolution (independent group). These patterns were correlated with the outcomes-recurrent angina, reinfarction, heart failure and death-using chi-square analysis and the Fisher exact test for categoric variables and the Wilcoxon rank-sum test for continuous variables. RESULTS The incidence of recurrent angina, reinfarction and heart failure was similar among the three groups. In-hospital mortality, however, was significantly higher in the independent group (13%) than either the simultaneous group (1%, p < 0.001) or the control group (0%, p = 0.002). CONCLUSIONS Continuous analysis of ST segment resolution identifies, among patients with AMI with concomitantly occurring ST segment elevation and depression, a subgroup with increased in-hospital mortality. The pathogenic mechanism of increased mortality is not currently known.

Pooled analysis of adverse event collection from 4 acute coronary syndrome trials

BACKGROUND Adverse event collection in randomized clinical trials establishes drug safety. Although costly and regulated, it is rarely studied. METHODS Adverse event data from 4 clinical trials (APPRAISE-2, PLATO, TRACER, TRILOGY ACS) comprising 48,118 participants with acute coronary syndromes were pooled to compare patterns and determinants of reporting. Events were classified as serious (SAE) or nonserious (AE) from hospital discharge to 1 year; study end points were excluded. RESULTS In total, 84,901 events were reported. Of those, 12,266 (14.4%) were SAEs and 72,635 (85.6%) were AEs. Of all participants, 7,823 (16.3%) had SAEs, 18,124 (37.7%) had only AEs, and 22,171 (46.1%) had neither. Nonserious adverse events were distributed across system organ classes: general disorders (11%), infection (10%), gastrointestinal (10%), respiratory (9%), cardiovascular (8.4%), and other (35%). Serious adverse events had a higher proportion of cardiovascular causes (14.0%). Event reporting was highest after hospital discharge, decreasing rapidly during the following 3 months. In a Cox proportional hazards model, chronic obstructive pulmonary disease (hazard ratio 1.58, 95% CI 1.44-1.74), heart failure (1.55, 1.40-1.70), older age, and female sex were independent predictors of more SAEs, whereas enrollment in Eastern Europe (0.63, 0.58-0.69) or Asia (0.84, 0.75-0.94) were independent predictors of fewer SAEs. CONCLUSIONS Half of all participants reported adverse events in the year after acute coronary syndrome; most were AEs and occurred within 3 months. The high volume of events, as well as the variation in SAE reporting by characteristics and enrollment region, indicates that efforts to refine event collection in large trials are warranted.