Discussion
TopAbstractIntroductionMethods Results Discussion References Potential Pitfalls in the Conventional TIMI Flow-Grade System The conventional TIMI flow-grade system1 has been widely used to compare thrombolytic agent efficacy and to stratify patients according to risk, but it has limitations. Whereas previous studies2 3 4 5 6 7 associated TIMI grade 2 flow after thrombolysis with suboptimal clinical outcomes, the present study demonstrates that there is a poor rate of agreement between an angiographic core laboratory and clinical centers in the assessment of TIMI grade 2 flow, which may limit the broad clinical applicability of this measure. Although the rate of agreement in assessment of the CTFC between the angiographic core laboratory and clinical centers remains to be determined, the variability at the core laboratory between two consecutive injections appears low (<5 variation="9.0%)." href="http://circ.ahajournals.org/cgi/content/full/93/5/879#T2">). Despite all the potential factors that introduce variability into the CTFC (variability in the distance to the landmark between patients, variability in rate of injection, intraobserver variability in counting frames, variability in catheter size, variability in the degree of engagement, variability in heart rate, variability in the phase of the cardiac cycle injected, etc) the SD of the CTFC in 78 normal arteries remained very low, at only 3.1 frames. Flow also has been estimated angiographically in the past by use of the mean contrast-appearance time, which involved calculating the time between peaks in contrast intensity at two points separated by known distances along the length of the artery. Unfortunately, this radiographic technique was limited by technical factors that confounded the videodensitometric analysis of angiograms, such as adhesion of the dye to the wall of the artery, scatter, veiling glare, variability in mask-mode subtraction, and motion artifact from patient movement.14 15
Even if excellent concordance could be demonstrated within or between experienced angiographic core laboratories in the assessment of TIMI grade flow, several major limitations remain when this categorical method is used to assess angiographic success after thrombolysis. First, the present study shows that coronary flow after thrombolysis is unimodally distributed (Fig 6). Distinct subpopulations of patients with either slow (TIMI 2) or fast (TIMI 3) flow do not exist, and a categorical classification of coronary flow is, at best, arbitrary. Second, even if TIMI flow grading is proved to be reproducible, it may be inaccurate or may misclassify flow as a result of the use of a flawed gold standard to gauge "normal" flow. The original definition of TIMI grade 3 flow requires that flow into or clearance of contrast material from the involved bed be "as rapid as clearance from an uninvolved bed in the same vessel or the opposite artery."1 However, the present study demonstrates that the velocity of contrast in an uninvolved bed may not be normal and is actually 21% slower (ie, the frame count is higher, 25.5 versus 21.0 frames, P<.001). This observation of reduced basal flow in nonculprit vessels at 90 minutes after thrombolysis extends the findings of Uren et al,16 who showed that at 1 week after MI, the vasodilatory response of nonculprit arteries remains reduced, which has been attributed to an abnormality in resistance vessel function. The fact that by 1 day after thrombolysis, these uninvolved arteries do eventually achieve flow virtually identical to that of arteries in the absence of acute MI (21.7 versus 21.0 frames) indicates that the delayed flow at 90 minutes was not an artifact of selecting a subpopulation of vessels with slower flow for analysis. In contrast to nonculprit vessels, flow in culprit vessels remained persistently reduced by 32% at 1 day after thrombolysis, which approximates the 26% flow reduction documented at 1 week after MI by positron emission tomography scanning.16 This persistent reduction in flow (which, paradoxically, is frequently classified as normal TIMI grade 3 flow) may be due either to the residual stenosis or to reduced oxygen consumption secondary to diminished contractility in the infarct zone. Changes in epicardial vasomotor tone do not appear to be responsible for these changes in frame counts over time, as the diameters of the normal reference segments were identical at 90 minutes and 18 to 36 hours (3.37 mm for both, P=.97).
An additional problem with the conventional TIMI flow-grading system is that uninvolved arteries that are used as the gold standard to classify the TIMI flow grade in the culprit artery may not all be slowed to the same degree, depending on their location. Flow in nonculprit LAD arteries was disproportionately slowed by 36% compared with that in uninvolved circumflex arteries, which confounds the classification of conventional TIMI flow grades. Although the present study shows that the CTFC in LAD culprits is, on the whole, higher (reflecting slower flow) than that in other locations at 90 minutes after successful thrombolysis, the CTFC for TIMI grade 3 flow was actually 32% lower for LAD culprits compared with the circumflex artery (25.7 versus 34.0 frames). This paradox is explained by the fact that TIMI grade 3 flow in culprit LAD arteries was gauged against faster flow in nonculprit circumflex arteries (22.5 frames), and consequently, few LAD culprits (26.2%) achieved a velocity rapid enough to be classified as achieving TIMI grade 3 flow. In contrast, flow in circumflex culprits was graded against the 36% slower flow in nonculprit LADs (30.6 frames), and consequently, the vast majority of circumflex arteries (92%) were classified as achieving TIMI grade 3 flow. Thus, the conventional notion that flow in uninvolved arteries is normal may be erroneous and may lead to the misclassification of TIMI flow grades. In the RCA, no adjacent comparative normal artery is even present. The problem of visual flow-grade assessment is further compounded by the fact that international cinefilms are filmed at a wide variety of speeds (12.5, 15, 25, 30, 50, or 60 frames/s). Another limitation of the conventional TIMI flow-grading system is that observers who grade flow might be biased by their concurrent assessment of the ejection fraction of the patient (which has been linked to clinical outcomes), and an objective frame-counting method might reduce this potential for bias.
The CTFC could facilitate the standardization of TIMI flow grades and flow assessment. However, devising a valid definition of normal flow is complicated. The mean CTFC for culprit arteries with normal TIMI grade 3 flow (30.2 frames) was significantly higher than for nonculprit arteries (25.5 frames, P<.001) and was higher yet (43.8%) than for normal arteries in the absence of acute MI (21.0 frames, P<.001). Thus, TIMI grade 3 flow in culprit arteries is not truly representative of normal flow. In our view, a valid threshold for defining normal flow would be to use the upper bound of the 95% CI for arteries that have normal flow in the absence of acute MI (27 frames with predominantly 6F and 7F catheters). By this definition, only one third (32.6%) of patients with a patent artery in the TIMI 4 trial actually achieved flow within the range observed in normal arteries (Fig 7).
The use of either an objective classification system or the CTFC itself should facilitate the comparison of angiographic end points between trials. In addition, such an objective definition could improve on the large intraobserver variability experienced by submitting clinical centers, and such a comparison is currently under way. Use of the CTFC might permit meaningful analysis of the vast amount of angiographic data that are gathered by clinical centers and currently are not analyzed because a single core laboratory could not process tens of thousands of films from large clinical trials.1 2 This method is simple and should have broad applicability because it can be measured by any investigator with the frame counter that is present on most cineviewers. We have found that variability can be encountered in selecting the first frame for analysis, and care should be taken to ensure that all three criteria are fulfilled for the selection of the first frame as set forth in "Methods."
The use of a continuous variable such as the CTFC for comparison of angiographic outcomes might be superior to the use of a categorical variable such as TIMI flow grade in terms of statistical power and sensitivity. As newer thrombolytic agents reportedly achieve a higher incidence of TIMI grade 3 flow, a categorical scale may fail to distinguish their efficacies, because there is a range of dye velocities that constitute TIMI grade 3 flow. Even if two agents result in the same proportion of TIMI grade 3 flow, there may be a difference in dye velocity between the two agents when analyzed as a continuous variable with the CTFC. For instance, two future thrombolytic agents may both achieve TIMI grade 3 flow in 75% of patients, but one agent may achieve a mean CTFC of 30 frames and the other a mean CTFC of 40 frames.
Differences in Flow Among the Three Coronary Arteries The unadjusted TIMI frame count for LAD culprits was corrected to account for its longer length by dividing by 1.7, the ratio of the LAD TIMI frame count to the mean of normal LCx and RCAs in the absence of acute MI. This ratio is consistent with the mean ratio of 1.55 predicted by use of three-dimensional vector algebra devised by Dodge et al11 to calculate the distance to the TIMI landmarks in the normal-sized human heart. In addition to controlling for differences in artery length and minimizing the effect of discrepancies in the proportion of LAD culprit arteries between agents and between trials, this correction improves the power of this end point by reducing the SD of the TIMI frame count among patients with culprit arteries in the LAD versus other locations.
TIMI grade 3 flow more frequently was achieved in patients with an infarct-related artery other than the LAD in the present trial (74% versus 26%, P<.001), a finding that was also observed in the TEAM-2 study (61% versus 37%, P=.06).6 Further objective documentation of this observation is the fact that the CTFC (ie, the frame count already corrected for the difference in artery length) was higher (reflecting slower flow) in LAD culprit arteries compared with the other two arteries. Furthermore, flow in nonculprit LADs was also delayed compared with the other two arteries. This apparent overrepresentation of LAD culprit arteries with TIMI grade 2 flow and the preponderance of RCA culprit arteries with TIMI grade 3 flow has major implications when the clinical outcomes of the various flow grades are compared. In several recent analyses of angiographic data, it was demonstrated that patients with TIMI grade 2 flow had poorer outcomes than patients with TIMI grade 3 flow. However, data pertaining to the location of the infarct artery were neither presented nor corrected for in these analyses of outcomes.2 17 18 Thus, it would be appropriate that any analysis comparing the clinical, enzymatic, ventriculographic, or electrocardiographic outcomes of the various TIMI flow grades should correct for the large potential imbalances in infarct-artery location.
Despite differences in the CTFC in the three coronary arteries, there were no differences in their lumen dimensions, and there was no correlation between the CTFC and hemodynamic variables. This discrepancy in flow was transient and resolved by 18 to 36 hours. A question that therefore arises is whether slowed flow causes larger infarcts in the LAD or, conversely, if larger infarctions in the LAD cause slower flow. Seiler et al19 showed that the length of an artery is proportional to the myocardial mass subtended by the artery, and Kloner et al20 21 showed in turn that the myocardial mass injured is proportional to the magnitude of no reflow. Thus, the higher CTFC of LADs and the preponderance of LAD culprits among patients with TIMI grade 2 flow may be related to more extensive necrosis (LAD CK leaks were larger) as a result of the large myocardial mass subtended by this 1.7-times-longer coronary artery.
Although both the epicardial lesion and the microvasculature are determinants of flow after thrombolysis, the role of the microvasculature is supported by the following observations: (1) flow is slowed in uninvolved nonculprit arteries at 90 minutes after thrombolysis but returns to normal by 1 day after thrombolysis; (2) in culprit arteries, there is no relationship between the improvement in the CTFC and the change in minimal lumen diameter over the first day after thrombolysis (with no documented change in vasomotor tone); and (3) the improvement in flow over the course of the first day after thrombolysis does not differ significantly between nonculprit and culprit arteries. These findings implicating the microvasculature are consistent with the myocardial contrast echocardiography studies of Ito et al,22 in which no relationship was observed between epicardial stenosis severity and the incidence of myocardial no reflow after successful thrombolysis. That group also demonstrated that intracoronary injections of verapamil in the setting of acute MI may improve microvascular perfusion and left ventricular function.23 We again emphasize that in the current study, TIMI grade 3 flow (30.2 frames) was slower than flow in the absence of acute MI (21.0 frames), and the relative contribution of microvascular and epicardial resistance as well as reduced oxygen consumption to this delay in TIMI grade 3 flow remains to be determined.
Limitations Further studies are required to prospectively validate this new angiographic end point. The relationship of the CTFC to major clinical end points, such as mortality, remains to be determined. The correlation between angiographic core laboratories in the assessment of this end point will also need to be determined. Circumflex and saphenous vein graft lesions are underrepresented in thrombolytic trials, and additional data are required to characterize and fully evaluate the CTFC of these arteries. Currently, we use the same distal native landmarks to characterize flow in bypass grafts. Culprit lesions in the distal posterolateral branch or the distal posterior descending artery may occasionally lie distal to the TIMI landmark. Infrequently, there may only be a short distance of delayed flow beyond a distal lesion located before the TIMI landmark. Further prospective studies are needed to confirm that flow in LAD culprit arteries is slower than in other locations as well as to confirm the observation that flow in nonculprit arteries improves slightly over time.
Usually, the rate at which images are captured to cinefilm is the same rate at which images are captured into the video format in the cardiac catheterization laboratory. This rate is generally 30 frames/s (SONY, Phillips, and General Electric Inc). The number of frames can be counted on line in the cardiac catheterization laboratory or on a VCR by simply advancing the video one frame at a time. The frame acquisition and display rate should be confirmed with the manufacturer of the laboratory equipment. Alternatively, for videotapes, a studio production recorder can be used to record the length of time in fractions of a second to the landmark. It should be confirmed that 30 single frames elapse per second. The time (in seconds) can then be multiplied by 30 frames/s to convert to frames. In some centers, cinefilming may instead be performed at 12.5, 15, 25, 50, or 60 frames/s. Therefore, a correction must be made for this difference by multiplying the TIMI frame count observed in these films by a factor of 30 divided by the actual number of frames filmed per second. The rate of frame acquisition must be communicated to the angiographic core laboratory.
The CTFC will vary depending on the length of the artery. Fortunately, this variability appears to be fairly low, as the SD of the CTFC among normal arteries was only 3.1 frames. Furthermore, if comparisons of the CTFC are made over time, then length is controlled for within the same artery. It must be emphasized that larger numbers of patients need to be studied to fully ascertain the influence of catheter size on the CTFC, the effects of which may have been overshadowed by a variety of confounding variables in acute MI. Predominantly 6F and 7F catheters were used in the present study, and more comparative data in the absence of acute MI are needed for the use of 8F and 9F catheters in restenosis trials, for instance. The mean catheter size or the distribution of catheter sizes should be confirmed to be the same among treatment groups and should be reported so that comparisons across trials can be evaluated for their applicability. Although the rate of entry of dye into the coronary tree may be affected by the force of the injection, the rate of egress or washout of dye may be more independent of the rate of injection and warrants further investigation. The view that is optimal for frame counting may not be the view that is optimal for quantitative angiography.
The TIMI frame count could not be measured in 9% of consecutive acute MI patients, and a technique of more rapid panning may be required for interventional trials in which the flow is more brisk and the magnification is often higher in the 5-in mode. If panning is insufficient, we advocate that an injection be obtained of the culprit vessel on 9-in mode so that the frame count can be ascertained in the vast majority of patients.
Conclusions In contrast to the conventional TIMI flow-grade system, the CTFC is quantitative rather than qualitative, is a continuous rather than a categorical variable, and is objective, reproducible, and sensitive to flow changes. This simple index of coronary flow allows calibration or standardization of flow grading and should facilitate comparisons of flow data between angiographic trials. Flow in nonculprit arteries routinely used to grade TIMI flow cannot be presumed to be normal, as demonstrated by the 21% reduction in flow in these arteries at 90 minutes after thrombolysis. Despite high rates of TIMI grade 3 flow reported in the literature, only a third of patients with an open artery actually achieve flow that is truly within the normal range (CTFC 27). Outcome analyses of TIMI flow grades should correct for imbalances in lesion location. The current study supports the idea that the disordered microvasculature tone plays a role in flow delays immediately after thrombolysis.