Evolution of Early TIMI 2 Flow After Thrombolysis for Acute Myocardial Infarction
Background Patients with early Thrombolysis in Myocardial Infarction (TIMI) grade 2 flow after thrombolysis appear to have outcomes similar to thrombolytic failures. To evaluate the origin and evolution of early TIMI 2 flow, we examined early and late angiographic and ventriculographic data from the Global Utilization of Streptokinase and TPA for Occluded Arteries (GUSTO-1) angiographic study.
Methods and Results Of the 914 patients with both 90-minute and 5- to 7-day catheterizations, 278 patients had TIMI grade 2 flow at 90 minutes. At follow-up, 188 (67%) had improved to TIMI grade 3 flow. At 90 minutes, patients with TIMI grade 2 flow had greater infarct vessel narrowing and a significantly greater incidence of thrombus than patients with TIMI grade 3 flow. At the 5- to 7-day follow-up, patients whose flow had improved from TIMI grade 2 at 90 minutes to grade 3 flow at follow-up had larger-caliber vessels (minimum luminal diameter, 0.99±0.47 versus 0.84±0.48 mm; P=.03) and a lower incidence of visible thrombus (26% versus 38%, P=.04) than those with persistent TIMI grade 2 flow. These patients also had a higher mean ejection fraction (57.5±14.1% versus 52.8±12.9%, P=.02) and better infarct zone wall motion (−2.1±1.5 versus −2.6±1.3 SD per chord, P=.01) at the 5- to 7-day follow-up. Patients in whom flow improved from TIMI grade 2 at 90 minutes to TIMI grade 3 by 5 to 7 days had significantly better left ventricular function than patients with persistent TIMI grade 0, 1, or 2 flow and constituted a group whose left ventricular function was intermediate between those who had no reperfusion (TIMI grades 0 and 1) and those whose reperfusion was complete (TIMI grade 3).
Conclusions These data suggest that incomplete clot lysis plays a significant role in the pathogenesis of TIMI grade 2 flow. Furthermore, early TIMI grade 2 flow may be sufficient to provide prolonged myocyte viability, which will further recover if flow normalizes.
The benefits of early restoration of infarct-related coronary artery patency in the setting of acute myocardial infarction have been demonstrated extensively.1 2 3 4 5 Recently, however, attention has shifted to the question of what degree of reperfusion constitutes a sufficiently “open” artery.6 7 To date, most angiographic trials have used a coronary flow grading system first introduced in the TIMI 1 study8 to describe the perfusion status of the infarct artery. With these criteria, vessels with TIMI grade 0 or 1 flow are considered functionally “closed,” and vessels with TIMI grade 2 (sluggish) or 3 (brisk) flow are considered functionally “open.” Successful angiographic reperfusion, however, may not closely correlate with successful myocardial reperfusion.9 Several trials,10 11 12 13 14 15 including the TEAM trials10 11 and the GUSTO-1 angiographic trial,12 have demonstrated that early, postthrombolysis TIMI grade 2 flow does not result in as great a benefit in terms of clinical outcome or left ventricular functional recovery as early TIMI grade 3 flow. Indeed, these trials have shown that patients with early “incomplete” reperfusion (TIMI grade 2 flow) have clinical outcomes closer to those of patients with closed arteries (TIMI grade 0 or 1 flow) than patients with complete reperfusion (TIMI grade 3 flow).
Whether the apparent suboptimal outcome in patients with early TIMI grade 2 flow is secondary to temporally delayed restoration of flow or whether the sluggish flow is a result of more downstream muscular and/or vascular damage (hence the impaired flow is merely a “marker” of a poor outcome) remains unresolved. To further evaluate the role of incomplete thrombolysis in the pathogenesis of early TIMI grade 2 flow, we examined angiographic and ventriculographic data, obtained by protocol, early (90 minutes) and late (5 to 7 days) after thrombolysis for acute myocardial infarction in the GUSTO-1 angiographic study. We were particularly interested in the evolution of flow grades in patients with initial TIMI grade 2 flow and in the relationships between the evolution of flow and ventricular functional recovery.
GUSTO-1 was conducted in 75 centers in North America, Europe, and Australia participating in the GUSTO-1 trial. Sites agreed to enroll all their GUSTO patients in the angiographic study. The entry criteria were described previously4 and, briefly, included patients with ST-segment elevation and symptom duration of <6 hours. The study was approved by the institutional review board at each site, and all patients gave informed consent.
Treatment and Angiographic Randomization
The therapeutic and angiographic randomization strategies were described previously.4 5 Patients were randomized to one of four treatment regimens consisting of streptokinase (Kabbekinase, Kabi Vitrum) with intravenous heparin (sodium heparin, Sanofi) adjusted to maintain an activated partial thromboplastin time between 60 and 80 seconds; streptokinase with subcutaneous heparin 12 500 U twice daily beginning 4 hours after thrombolytic initiation; TPA (alteplase, Genentech) given in an accelerated dosing regimen with intravenous heparin; and a combination arm consisting of streptokinase and conventionally dosed TPA with intravenous heparin. At the time of treatment randomization, patients also were randomized to one of four times for initial angiography after thrombolytic initiation. The times were 90 minutes (n=1200), 180 minutes (n=400), 24 hours (n=400), and 5 to 7 days (n=400). All patients enrolled in the 90-minute group were also scheduled for follow-up angiography 5 to 7 days later. This report pertains to patients assigned to 90-minute and 5- to 7-day follow-up angiograms.
Coronary Angiography and Core Angiographic Laboratory Procedures
Infarct-related artery patency was determined from the first injection of contrast. Intracoronary nitroglycerin (100 to 200 μg) was then administered, and the infarct-related artery was filmed in at least two orthogonal projections for quantitative analysis. By protocol, patients with patent (TIMI grade 2 or 3 flow) infarct-related arteries were not to undergo angioplasty during the initial procedure unless clinical circumstances mandated. After angiography, a ventriculogram was filmed in the 30° right anterior oblique position. For calibration purposes, a 1×1-cm calibration grid (Namic) was filmed at magnification settings and distances identical to the ventriculogram. For each patient enrolled, angiographic case report forms, catheterization laboratory logs documenting the angulation of all filmed sequences, catheter tips used to inject the infarct-related artery (for calibration purposes), cinefilms, and qualifying ECGs were forwarded to the core angiographic laboratory (George Washington University, Washington, DC).
Films were interpreted by an experienced angiographer who was blinded to treatment, angiographic randomization, and clinical outcome. Films were read in sequence, but the angiographer was blinded to the specific timing of each film. The first injection of the infarct-related artery was used to determine the TIMI flow grade.8 TIMI grade 0 flow denoted absent antegrade flow beyond the point of obstruction; TIMI grade 1 flow denoted flow beyond the point of obstruction but incomplete filling of the distal vessel; TIMI grade 2 flow represented a patent vessel with slow filling and/or slow emptying; and TIMI grade 3 flow represented normally brisk flow. Core laboratory angiographers scored “visible thrombus” for a discrete intraluminal filling defect or contrast staining in the area of the infarct-related stenosis that was visible in multiple projections.
Quantitative Coronary Analysis
Two orthogonal views of the infarct-related artery were acquired digitally and analyzed quantitatively with a Tagarno 35AX cinevideo projector (Tagarno A/S) linked through an ITC RC Vision Plus frame grabber to an ImageComm StatVIEW workstation. Quantitative coronary analysis was performed, after manual centerline placement, by use of a first- and second-derivative edge-detection algorithm (ARTREK, University of Michigan). Lesion parameters obtained included percent diameter stenosis, and minimum lesion diameter. For determination of percent diameter stenosis, a “normal” reference segment was identified proximal to the stenosis. When two views were technically adequate, the more severe measured stenosis of the two views was used for this analysis.
Quantitative Ventriculographic Analysis
End-systolic and end-diastolic ventriculographic silhouettes, defined by the core laboratory angiographer, were digitized and stored. The analysis was limited to images derived from a 30° right anterior oblique ventriculogram. Ejection fraction was calculated with software (VENTREK, University of Michigan) that used the area-length method.16 Regional wall motion, defined as the mean excursion of the most abnormal 50% of chords, was calculated by use of the method of Bolson et al.17 Additional characterization of wall motion included determination of the number of consecutive chords in the infarct zone more than 2 SD below the norm.
For quantitative coronary angiography, interobserver variability was 0.01±0.03 mm (mean±SE) for minimum lesion diameter, 0.01±0.05 mm for normal segment diameter, and 1.0±1.1% for percent diameter stenosis. Intraobserver variability was 0.03±0.06 mm for minimum lesion diameter, 0.01±0.1 mm for normal segment diameter, and 1.6±1.6% for percent diameter stenosis. Combined interobserver and intraobserver agreement for closed versus open arteries was 96% for TIMI grade 0 and 1 versus grade 2 and 3 flow and 81% for TIMI grade 2 versus grade 3 flow. In this report, when variability testing produced a discrepancy between assigning grade 2 or 3 to a reperfused artery, the initial reader's grade assignment was used.
Results are expressed as mean±SD unless otherwise noted. We used χ2 tests to compare categorical variables. Continuous end points were compared by use of unpaired Student's t test, and all probability values are two-tailed. Multiple comparisons were evaluated by ANOVA with Fisher's protected least significant difference test. A value of P≤.05 was considered significant. Statistical analysis was performed by use of SAS software (SAS Institute, Inc). Additional analysis was performed with StatView software (Abacus Concepts, Inc).
There were 2431 patients enrolled in the study. Of the 1210 patients randomized to initial angiography at 90 minutes, 1180 (98%) underwent at least one angiogram. Of this group, 12 patients were excluded because the TIMI grade flow of the infarct vessel could not be evaluated from either the initial or the follow-up angiogram, and 254 (22%) were excluded because no follow-up catheterization was performed. The reasons that patients did not undergo a follow-up angiogram included 72 physician or patient refusals, 49 patient deaths, 40 patients considered too unstable, 39 patients referred for early coronary bypass surgery, and 54 miscellaneous reasons. Compared with the group that underwent initial and follow-up angiographies, the group that did not undergo follow-up angiography (and were excluded) had more female patients (35% versus 19%, P<.001) and more previous myocardial infarctions (20% versus 11%, P<.001) and were older (63.9±12.1 versus 59.1±11.6 years, P<.0001).
Therefore, there were 914 patients who had both a 90-minute and 5-to 7-day follow-up catheterization and were included in this analysis. The median time to initial angiography was 1.6 hours (range, 1.5 to 1.7). For all thrombolytic treatment groups combined, at 90 minutes 349 (38%) patients had TIMI grade 3 perfusion in the infarct-related artery, 278 (30%) had TIMI grade 2 flow, and 287 (32%) had TIMI grade 0 or 1 flow. Fig 1⇓ depicts a flow diagram for the angiographic outcome of patients undergoing catheterization at 90 minutes and 5 to 7 days. Of the patients undergoing 90-minute catheterization who had early TIMI grade 2 flow, 188 (67%) improved to TIMI grade 3 flow at follow-up, whereas 73 (26%) continued to have TIMI grade 2 flow. Seventeen patients (6%) patients with early TIMI grade 2 flow had occluded (TIMI grade 0 or 1) arteries at follow-up. Patients whose infarct-related vessel was the right coronary artery improved from early TIMI grade 2 to grade 3 flow at follow-up more frequently than those whose infarct-related vessel was the left anterior descending coronary artery (34% versus 23%, P=.07). By protocol, patients with early TIMI grade 2 flow at 90 minutes were precluded from immediate angioplasty, and only 16 patients with early TIMI grade 2 flow (5.8% of the total 90-minute TIMI 2 population) underwent angioplasty at 90 minutes. These patients are included in the analysis. Fourteen patients with early TIMI grade 2 flow (5%) underwent repeated catheterization earlier than 5 days because of recurrent ischemia. Although there was a trend toward more previous infarctions for the group of patients with early TIMI grade 2 flow that subsequently improved to grade 3 flow compared with the group with TIMI grade 2 flow at both early and follow-up angiographies, there were no significant differences in any of the baseline clinical variables (Table 1⇓).
Fig 2⇓ demonstrates the percentages of patients with TIMI grade 0 or 1, 2, and 3 flow for each of the protocol catheterization time points. After 24 hours, the relative number of patients with TIMI grade 3 flow increased, whereas the proportion of patients with TIMI grade 2 flow decreased.
Infarct-Related Artery Flow and Left Ventricular Function
Table 2⇓ shows indexes of global and regional left ventricular function at 90 minutes and at the 5- to 7-day follow-up for patients with TIMI grade 2 flow at 90 minutes stratified by TIMI flow grade at 5 to 7 days. At 90-minute catheterization, there were no significant differences in ejection fraction, infarct zone wall motion, or number of ventriculographic chords with shortening <2 SD below the norm between the group with persistent TIMI grade 2 flow and the group that improved from TIMI grade 2 to grade 3 flow by 5 to 7 days. At 5- to 7-day catheterization, the group of patients whose infarct-related artery flow had improved to TIMI grade 3 flow had a significantly better mean ejection fraction and infarct zone wall motion and significantly fewer infarct zone chords with motion worse than 2 SD below the norm than the group of patients with persistent TIMI grade 2 infarct-related artery flow.
Fig 3⇓ shows the association between patency grade at 5 to 7 days and left ventricular functions at 5 to 7 days. Compared with patients with persistently closed vessels (TIMI grade 0 or 1 flow at 90 minutes and grade 0 or 1 flow at 5 to 7 days), patients with persistent TIMI grade 2 flow had similar left ventricular functions. However, patients in whom flow improved from TIMI grade 2 flow at 90 minutes to grade 3 by 5 to 7 days had significantly better function than patients with persistently closed arteries (TIMI grade 0, 1 flow) or persistent TIMI grade 2 flow and overall constituted a group whose left ventricular function was intermediate between those who had no reperfusion (TIMI grade 0, 1 flow) and those whose reperfusion was complete (TIMI grade 3 flow; Fig 3⇓).
Patients with TIMI grade 2 flow at 90 minutes had greater narrowing in the infarct-related artery than patients with TIMI grade 3 flow (Table 3⇓). Furthermore, at 90 minutes, patients with TIMI grade 2 flow had a significantly greater incidence of angiographically visible thrombus than patients with TIMI grade 3 flow.
At the 90-minute angiography, there were no differences in infarct-related artery minimum luminal diameter, percent diameter stenosis, or presence of visible thrombus between the group of patients with early TIMI grade 2 flow that would ultimately improve to grade 3 flow at follow-up and those with persistent TIMI grade 2 flow (Table 4⇓). At the 5- to 7-day follow-up, however, patients whose flow had improved from TIMI grade 2 at 90 minutes to grade 3 flow at follow-up had larger-caliber vessels, as evidenced by a greater mean minimum luminal diameter (0.99±0.47 versus 0.84±0.48 mm, P=.03). The incidence of visible thrombus was identical at 90 minutes for the two groups; however, at the 5- to 7-day follow-up, the group with improved flow (TIMI grade 3) had a significantly lower incidence of visible thrombus (26% versus 38%, P=.04) than the group with persistent TIMI grade 2 flow.
Although confirming previous reports that described the suboptimal outcome of patients who achieve only partial early reperfusion (TIMI 2 flow), this study is the first to document the 1-week angiographic evolution of vessels with early TIMI grade 2 flow and to demonstrate the functional superiority when TIMI grade 2 flow improves to grade 3 flow by the 5- to 7-day follow-up. Furthermore, this study offers evidence for the hypothesis that early TIMI grade 2 flow most often represents incomplete clot lysis and may be sufficient to provide prolonged myocyte viability.
Evidence for Incomplete Clot Lysis in the Pathogenesis of TIMI Grade 2 Flow
Our observation that the infarct-related arteries in patients with TIMI grade 2 flow have smaller lumens and more frequently have visible thrombus compared with those with TIMI grade 3 flow at 90 minutes suggests that as-yet-incomplete clot lysis plays a significant role in the pathogenesis of incomplete (TIMI grade 2) reperfusion. Other studies18 19 have also documented more severe stenoses in patients with early TIMI grade 2 compared with grade 3 flow; however, this is the largest trial to document the qualitative and quantitative evolution of these infarct vessels over the first week. If epicardial stenosis severity has a role in early TIMI flow, then patients with early TIMI grade 2 flow who subsequently improve to TIMI grade 3 flow by follow-up might be expected to have more thrombus resolution and larger lumens than those who continue to demonstrate TIMI grade 2 flow at follow-up. This is, in fact, what we observed. At follow-up, the group of patients whose infarct-related arterial flow improved from TIMI grade 2 to 3 had a 32% increase in minimum luminal diameter and a 56% decrease in the incidence of visible thrombus compared with a 6% increase in minimum luminal diameter and a 36% decrease in the incidence of visible thrombus for the group with persistent TIMI grade 2 flow.
Early TIMI Grade 2 Flow and Outcome
Prior reports have described the suboptimal clinical outcome of patients with early partial reperfusion (TIMI grade 2 flow) after thrombolytic therapy for acute myocardial infarction. In a report by Karagounis et al11 of patients enrolled in the second multicenter TEAM-2, patients with early TIMI grade 2 flow did not differ significantly from those with early TIMI grade 0 or 1 flow with regard to various clinical and enzymatic indexes of myocardial infarction. In contrast, those with early TIMI grade 3 flow had significantly better enzymatic and ECG indexes of infarction than those with TIMI grade 0 through 2 flow. In a report from the TEAM-3 trial in 1993, Anderson and colleagues10 analyzed the association between infarct artery perfusion status 18 to 48 hours after treatment with either anisoylated plasminogen activator complex or TPA and various outcome measurements, including enzymatic activity, ECG score, radionuclide ventriculography, and clinical morbidity in 298 acute myocardial infarction patients. The outcome of patients with TIMI grade 2 flow did not differ from that of patients with TIMI grade 0 or 1 flow in terms of ejection fraction at 1 week and 1 month, enzyme peaks, ECG markers, or morbidity index. Consistent with the TEAM-2 results, compared with patients with TIMI grade 0 through 2 flow, patients with TIMI grade 3 flow had larger ejection fractions, lower and shorter times to enzyme peaks, smaller ECG scores, and a trend toward a lower morbidity index. In an analysis of results from four TAMI trials, Lincoff et al15 found a gradient of increasing mortality in patients with less than TIMI grade 3 flow at 90 minutes and lower acute left ventricular ejection fractions and infarct zone wall motion in the group with early TIMI grade 2 flow compared with those with TIMI grade 3 flow.
In the present study, when all patients with TIMI grade 2 flow at 90 minutes were combined, quantitative ventriculographic measures of global and regional infarct zone function at 5 to 7 days were indistinguishable from those observed in patients with closed vessels at 90 minutes. Likewise, patients with TIMI grade 2 flow at the 5- to 7-day follow-up had ventricular function at 5 to 7 days that was nearly identical to that seen in patients with closed infarct-related arteries at follow-up. By contrast, patients with TIMI grade 2 flow at 90 minutes that subsequently improved to normal flow (TIMI grade 3) by 5 to 7 days demonstrated a measurable improvement in left ventricular function and had significantly better left ventricular function at 5 to 7 days than those with persistent TIMI grade 2 flow. The patients with early TIMI grade 2 flow but improved (TIMI grade 3) flow at follow-up constituted a group whose ventricular function at 5 to 7 days was intermediate between that of patients with vessels that were persistently closed and those who had persistent TIMI grade 3 flow (Fig 3⇑). Although in this study it was not possible to determine the precise time when infarct vessel flow improved, it appears that flow may improve as early as 3 hours and possibly as late as 24 hours after thrombolytic initiation (Fig 2⇑). The proposition that ventricular function can recover after a late improvement in infarct vessel flow is supported by studies from the prethrombolytic era of initially closed but later spontaneously opened infarct arteries.20 21 In the absence of thrombolytic therapy, Jeremy et al21 showed that a patent infarct vessel at discharge was associated with less ventricular dilatation and better regional wall motion at 1 month than occluded vessels at hospital discharge. Verheugt et al22 demonstrated improved ejection fractions 2 weeks after myocardial infarction in patients with spontaneously open coronary arteries. In a report from GUSTO-1, we described a measurable ventricular functional advantage for patients who had arteries with TIMI grade 0 or 1 flow at 90 minutes but spontaneously patent (TIMI grade 2 or 3) vessels at a 5- to 7-day follow-up catheterization.23 Our data suggest that early TIMI grade 2 flow may be sufficient to provide prolonged myocyte viability, which will further recover if flow normalizes, a phenomenon akin to myocardial stunning.24
While it has been shown that patients with early TIMI grade 0 or 1 flow after thrombolysis derive a benefit from “rescue” angioplasty,25 few studies have evaluated a strategy of angioplasty for early TIMI grade 2 flow. A small, post hoc analysis of patients with TIMI grade 2 flow enrolled in the TAMI-1 trial reported a modest but statistically significant advantage in ejection fraction for patients undergoing early angioplasty compared with medical therapy.26 In a small study of 30 infarct patients with early TIMI grade 2 flow, both immediate and delayed angioplasty procedures were associated with significant improvement in infarct zone wall motion when assessed by ventriculography at 3 hours, 10 days, and 4 months.27 Because at early angiography (eg, 90 minutes) one cannot predict the natural evolution of a given infarct-related artery with TIMI grade 2 flow (progression to grade 3 or arrest at grade 2) and because improvement in infarct arterial flow from TIMI grade 2 to 3 is associated with a significant improvement in left ventricular function, our observations suggest that perhaps a strategy of rescue angioplasty for vessels demonstrating early, sluggish flow warrants consideration.
Selected Abbreviations and Acronyms
|GUSTO-1||=||Global Utilization of Streptokinase and TPA for Occluded Arteries|
|TAMI||=||Thrombolysis and Angioplasty in Myocardial Infarction|
|TEAM||=||Thrombolysis Trial of Eminase in Acute Myocardial Infarction|
|TIMI||=||Thrombolysis in Myocardial Infarction|
|TPA||=||tissue plasminogen activator|
This work was funded by a combined grant from Bayer (New York, NY), CIBA-Corning (Medfield, Mass), Genentech (South San Francisco, Calif), ICI Pharmaceuticals (Wilmington, Del), and Sanofi Pharmaceuticals (Paris, France). We gratefully acknowledge the statistical assistance of Deneane Boyle and the editorial assistance of Patricia A. Williams.
- Received December 7, 1995.
- Revision received June 11, 1996.
- Accepted June 17, 1996.
- Copyright © 1996 by American Heart Association
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