Info

. 87% TIMI 3 Flow

Rescue

/ 9.6% Mortality

PTCA for

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Failed

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Thrombolysis

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0 Min.

90 Min. 120 Min. 150 Min.

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> 2 hrs. of vessel occlusion ^^^^

Fig. 8. Data from the TIMI 4 rescue PTCA experience, which shows that TIMI grade 3 flow is not always associated with improved outcomes if it is achieved too late. In the TIMI 4 trial, although successful rescue angioplasty for an occluded artery at 90 min resulted in a much higher rate of TIMI 3 flow than successful thrombolysis (86.5 vs 64.8%, p = 0.002), this higher rate of grade 3 flow was achieved later, at over 120 min after thrombolysis, and this time delay may explain in part the higher rate of mortality (9.6%) for this strategy than successful thrombolysis (3.3%).

Fig. 8. Data from the TIMI 4 rescue PTCA experience, which shows that TIMI grade 3 flow is not always associated with improved outcomes if it is achieved too late. In the TIMI 4 trial, although successful rescue angioplasty for an occluded artery at 90 min resulted in a much higher rate of TIMI 3 flow than successful thrombolysis (86.5 vs 64.8%, p = 0.002), this higher rate of grade 3 flow was achieved later, at over 120 min after thrombolysis, and this time delay may explain in part the higher rate of mortality (9.6%) for this strategy than successful thrombolysis (3.3%).

for all trials of front-loaded tPA to date. It is also notable that the survival curves did not diverge early (i.e., within 24 h), but rather they began to diverge at 1 to 2 wk in this trial, indicating that the occurrence of reinfarction, rather than early flow, may be driving the force in the mortality differential between the strategies.

While individual trials, including the relatively large GUSTO IIb trial, were unable to show significant difference in mortality between the two strategies, a meta-analysis of all ten randomized trials of primary angioplasty to date, involving 2066 patients (large enough to detect clinically relevant differences), reveals lower rates of mortality at 30 d (4.4 vs 6.5%, p = 0.02), death/reinfarction (7.2 vs 11.9%, p < 0.001), and stroke (0.7 vs 2.0%, p = 0.007) when primary angioplasty is compared with thrombolysis (72).

While primary angioplasty may restore a high rate of TIMI 3 flow, stenting may further improve upon lumen dimensions and may relieve intraluminal obstruction due to dissection planes and thrombus. In a pooled analysis of 20 nonrandomized trials of primary stenting within 24 h of acute MI involving 1357 patients, the incidence of mortality was 2.4%, the incidence of stent thrombosis was 1.5%, and the incidence of emergency coronary artery bypass graft (CABG) was 1.3% (73). Even if stenting was the ideal treatment modality for acute MI, it is unclear how many patients would have vessels ideally suited in size for stent placement. In a pooled analysis of quantitative angiographic data from the TIMI 4, 10A and 10B trials, only 69% of patients had a proximal reference segment diameter (PRSD) > 2.75 mm, and only 56% of patients had a PRSD > 3.0 mm (73). Given these restraints regarding the adequacy of vessel size, randomized trials of intracoronary stenting may facilitate the enrollment of patients with right coronary artery lesions, and this may result in favorable clinical outcomes in these trials. Thus, adequate reporting of the outcomes in smaller vessels and the number of patients excluded on the basis of reference segment diameter is needed to further evaluate the generalizability of the primary stenting technique.

As stated previously, the rate of agreement between an angiographic core laboratory and clinical centers is only moderate in assessing TIMI grade 3 flow, and it is poor in the assessment of TIMI grade 2 flow (2). Indeed, while the PAMI investigators have reported a 96% rate of TIMI grade 3 flow following stent placement in acute MI (6), the TIMI study group has reported a much lower 83% rate of TIMI grade 3 flow following adjunctive stent placement following thrombolysis (35). As discussed previously, the 3 cardiac cycle definition used by the PAMI group may increase the rates of TIMI grade 3 flow by 10% (10). As suggested by Drs. Topol, Ellis and Califf, the disparity in the rate of TIMI grade 3 flow following primary angioplasty in the PAMI and GUSTO trials may be overstated, and a more objective method of assessing coronary blood flow such as the TIMI frame count may be the preferred method in the assessment of TIMI grade 3 flow in these interventional trials (69). As discussed previously, the TIMI frame count method indicates that stenting does not restore a CTFC of 21 to infarct arteries, highlighting the fact that downstream microvascular resistance remains elevated despite relief of the epicardial stenosis.

When comparing thrombolytic and interventional strategies, it must be kept in mind that a successful revascularization strategy is one that opens arteries both fully and quickly. Fig. 9 shows the relationship between vessel patency and the time after a patient comes to the emergency room. As shown in Fig. 9, the advantage of a throm-bolytic regimen is speed, and the advantage of an interventional strategy is a higher rate of full reperfusion. The data for thrombolytic agents is taken from Kawai et al. (74), in which they performed cardiac catheterization at 15, 30, 45, 60, 75, and 90 min after the administration of a thrombolytic agent that is a variant of tPA. By 15 min after thrombolytic administration, 37% of culprit arteries were patent, and by 45 min after thrombolytic administration, 74% were patent (74). This 74% rate of patency is 90% of the treatment effect that is achieved by 90 min (84% patency). If the patient undergoes primary PTCA with a door to balloon time of 120 min (shown by the light grey line in Fig. 9), the GUSTO IIb trial has shown that there will be a 25% spontaneous rate of vessel opening. As shown by the blocked area in Fig. 9, there will be a significant amount of time during which the patency rates for a thrombolytic will exceed that of primary angioplasty. This is what we have termed the early PTCA "flow debt". At 120 min, however, the patency for PTCA will exceed that of thrombolysis. If the primary PTCA is performed quicker, with a door to balloon time of 75 min as shown by the dark grey line in Fig. 9, then by 75 min, the patency rate for the inter-ventional strategy will exceed that for lysis. This is what we would term the late "flow debt" for thrombolysis. Despite the superior patency of the interventional strategy at 75 min, it appears that thrombolytics may open a substantial number of vessels more quickly prior to the performance of the intervention. Thus, while interventional strategies may achieve a higher rate of patency, it appears that thrombolytics have an advantage of opening arteries very quickly in a substantial number of patients. Thus, the challenge for interventional strategies is to achieve even earlier opening than is currently the case, and the challenge for thrombolytic agents remains to achieve higher rates of patency.

Fig. 9. This figure combines data pertaining to both speed and patency for a variety of strategies. If a patient enters the door at time 0, 30 min later they will be given a thrombolytic (as signified by "drug"). From the data of Kawai et al. (74) (shown by the dark black line), 15 min after lytic administration (45 min after presentation) there will be a 37% patency rate, at 30 min after lytic administration a patency rate of 62%, at 45 min a patency rate of 74%, and at 90 min a patency rate of 84%. Thus, speed of reperfusion is the advantage of a thrombolytic agent. If the patient undergoes primary PTCA with a door to balloon time of 120 min (shown by the light grey line), the GUSTO lib trial has shown that there will be a 25% spontaneous rate of vessel opening, however, as shown by the blocked area, there will be a significant amount of time during which the patency rates for a thrombolytic will exceed that of primary angioplasty. This is what we have termed the early PTCA "flow debt". At 120 min, however, the patency for PTCA will exceed that of thrombolysis. If the primary PTCA is performed more quickly, with a door to balloon time of 75 min as shown by the dark grey line, then by 75 min, the patency rate for the interventional strategy will exceed that for lysis. This is what we would term the late flow debt for thrombolysis. Despite the superior patency of the interventional strategy at 75 min, it appears that thrombolytics may open a substantial number of vessels more quickly prior to the performance of the intervention.

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