Coronary Blood Flow In The Assessment Of Thrombolytic Agents

A variety of thrombolytic agents have been developed over the past two decades with the hope of improving coronary blood flow and, hence, mortality in acute MI. Initial efforts to restore antegrade flow to occluded vessels began with the administration of intracoronary thrombolytic agents in the late 1970s and the early 1980s (44-47). These recanalization trials and the intracoronary route of thrombolytic administration were logistically demanding, and they were soon replaced by trials involving the simpler and the more rapid intravenous route of thrombolytic administration in 90-min patency trials in the mid 1980s (47,48). The original open artery hypothesis, namely that early and full reperfusion would lead to improved clinical outcomes, was subsequently confirmed by large-scale megatrials with angiographic substudies that linked improved 90-min patency profiles of front-loaded recombinant tissue plasminogen activator (rtPA) to improved left ventricular function and, in turn, to improved mortality (49,50).

The interobserver variability inherent in the TFG classification scheme is reflected in the wide range of rates of TIMI grade 3 flow reported for a single drug, front-loaded tissue-type plasminogen activator (tPA). A pooled analysis involving 1492 patients from all large angiographic thrombolytic trials of front-loaded tPA to date, reveals a 90-min patency rate of 82% (60% rate of TIMI 3 flow and 22% rate of TIMI 2 flow) (50-57) (Fig. 7). As shown in Fig. 7, the rates of TIMI grade 3 flow vary tremendously from a high of 71% in the initial report of Neuhaus et al. (51) to a low of 45% in the RAPID 2 trial (57). The overall rate of TIMI grade 3 flow in the TIMI Angiographic Core Laboratory over the years has been 60%, which is the same as the rate reported across all

Fig. 7. The interobserver variability in the assessment of TIMI grade 3 flow for a single drug (tPA) is shown here. The rate of TIMI grade 3 flow following front-loaded tPA administration extends from a high value of 71% to a low value of 45%. Overall, the rate of TIMI grade 3 flow is 60%, the same as that reported over the years by the TIMI Angiographic Core Laboratory.

Fig. 7. The interobserver variability in the assessment of TIMI grade 3 flow for a single drug (tPA) is shown here. The rate of TIMI grade 3 flow following front-loaded tPA administration extends from a high value of 71% to a low value of 45%. Overall, the rate of TIMI grade 3 flow is 60%, the same as that reported over the years by the TIMI Angiographic Core Laboratory.

trials to date. Thus, the TIMI Angiographic Core Laboratory reflects the central tendency of how TIMI grade 3 flow is read in a variety of angiographic core laboratories from around the world.

In an effort to improve upon this 60% rate of TIMI grade 3 flow, variants of tPA have been developed such as recombinant plasminogen activator (rPA) (57), which is a nong-lycosylated deletion mutant of wild-type tPA, novel plasminogen activator (NPA), and a genetically engineered mutant of tPA (TNK) (54). The Reteplase vs Alteplase Patency Investigation during Myocardial Infarction (RAPID-2) trial was a small angiographic patency study which demonstrated a higher 90-min rate of TIMI grade 3 flow for rPA compared to tPA (60 vs 45%, p = 0.01). It should be noted that this 45% rate of TIMI grade 3 flow for front-loaded tPA was significantly lower than the rates reported in many of the trials in Fig. 7. Consistent with the 60% rate of TIMI grade 3 flow observed for rPA, the results of the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) III trial demonstrated no significant difference in mortality at 30 d (7.47% for rPA vs 7.24% for tPA, p = 0.54) or the combined endpoint of death/disabling stroke (7.89% for rPA vs 7.91% for tPA,p = 0.97) (58). Both TNK and NPA have also achieved approx 60% rates of TIMI grade 3 flow at the doses studied (54).

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