Clinical Efficacy Of Thrombolytic Agents Coronary Recanalization and Patency Profiles

Based on theoretic considerations and clinical observations, it is believed that the establishment and maintenance of coronary perfusion is the major mechanism of thrombolytic benefit in AMI ("open artery hypothesis"). Given the difficulty in performing adequately sized mortality trials, angiographic studies have first been undertaken during development of thrombolytic regimens. These have assessed the recanalization (reperfusion) and patency profiles of the infarct-related coronary artery in response to thrombolytic therapy.

Recanalization (Reperfusion) Vs Patency

The earliest series of studies assessed coronary patency at baseline and, for those initially showing total coronary occlusion, the ability of thrombolytic regimens to recanal-ize ("reperfuse") through the site of obstruction on subsequent angiography (generally at 60-90 min). Larger and more recent studies have omitted the baseline angiogram in favor of rapid administration of iv therapy and have compared coronary patency between regimens at 60-90 min and later. Because spontaneous (re)perfusion (grade 2 or 3 flow) has occurred in approx 15-20% of patients studied angiographically in the early (<4-6) h of AMI, coronary patency rates are generally higher than recanalization rates (93,94). Although recanalization rates may be a better indicator of pharmacologic activity, patency rates may correlate better with patient outcome, are easier to obtain, and form the basis of the present discussion.

Base 60 min 90 min 2-3 24 3-21 hours hours days

Fig. 3. Pooled angiographic patency rates (TIMI 2 + 3 flow) over time with no thrombolytic agent, SK, APSAC, tPA, rPA, TNK, and combination therapy of half-dose tPA and abciximab.

Base 60 min 90 min 2-3 24 3-21 hours hours days

Fig. 3. Pooled angiographic patency rates (TIMI 2 + 3 flow) over time with no thrombolytic agent, SK, APSAC, tPA, rPA, TNK, and combination therapy of half-dose tPA and abciximab.

Coronary Perfusion (Patency) Profiles

A pooled analysis of 58 studies (n = 14,124 angiographic observations) formed the basis for an overall profile of patency rates of several commonly used reperfUsion regimens (Fig. 3) (94). In the absence of thrombolytic therapy, spontaneous perfusion was observed early after STE-AMI in only 15-21% of patients at 60-90 min after study entry. No further increases were observed within the first day, but subsequent follow-up demonstrated gradually increasing patency rates (to about 60% by 3 wk) associated with spontaneous, aspirin, or heparin-facilitated intrinsic thrombolysis.

All thrombolytic regimens improved early patency rates although the speed of thrombolysis varied. SK (generally, 1.5 MU over 1 h) achieved the lowest patency rates at 60 and 90 min (48 and 51%, respectively). Intermediate and roughly similar rates of patency were achieved by APSAC and 3-h tPA infusions (about 60% at 60 min and 70% at 90 min). Accelerated (90 min) tPA bolus-infusion regimens achieved higher patency rates (74 and 84%, respectively). Patency profiles of newer tPA variants given by bolus injection have been similar to tPA. Combination therapy with reduced dose accelerated tPA (or bolus tPA variants) and abciximab (or another platelet glycoprotein IIb/IIIa inhibitor) has improved patency rates further, up to 91 and 94%, respectively (79).

In contrast to the differing early patency profiles observed among various regimens, patency rates at 3-24 h and beyond have been found to be generally similar among standard thrombolytics, averaging 80-85% (94). Reocclusion rates have been generally higher after fibrin-specific therapy (e.g., tPA) than after nonfibrin-specific (systemically active) agents (13 vs 8%, p = 0.002), especially in the absence of optimal concurrent IV heparin with fibrin-specific therapies.

The validity of these composite patency rates, generated from many studies of varying design and size, was confirmed by the single large GUSTO angiographic substudy (95). This substudy, embedded within the much larger (41,021 patients) GUSTO mortality trial (96), also enabled clear demonstration of the importance of early (90 min) TIMI grade 3 (complete) perfusion compared with TIMI grade 2 (incomplete) and lower grades (TIMI 0,1) as an accurate predictor of mortality outcomes. Specifically, the GUSTO Angiographic Study (n = 2431 patients) demonstrated a 90-min patency rate (TIMI grades 2/3) of 81% for accelerated-dose tPA and heparin, compared with 54% for SK and subcutaneous (sc) heparin (p < 0.001 vs tPA) and 60% for SK with iv heparin (p < 0.001 vs tPA). At 180 min, patency rates were the same in the four treatment groups and remained constant over 7 d of observation (range, 72-86%). Reocclusion rates in the study were similar among regimens (about 6%).

Patency/Mortality Correlations

The achievement of early complete TIMI grade 3 perfusion, recognized recently to be a better predictor of outcome, was specifically evaluated in GUSTO (96). Rates of complete (grade 3) perfusion at 90 min were 54% with accelerated tPA, 29% with SK plus SC heparin, and 32% with SK plus iv heparin (p < 0.001 for comparison of SK groups with tPA). Differences in measures of left ventricular function and mortality paralleled differences in rates of patency at 90 min: ventricular function was best in those with normal (grade 3) flow irrespective of treatment. Likewise, mortality at 30 d was lowest among those with normal (TIMI 3) flow at 90 min (4.4%), highest (8.9%) among those with absent flow (p = 0.009), and intermediate in those with partial (TIMI 2) flow (7.4%). In a formal predictive model that was based on patency differences, the correlation between predicted and observed mortality rates was 0.97, providing strong evidence for the importance of early and complete infarct artery patency in determining mortality outcomes (97).

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