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Infarct Size Measured by Single Photon Emission Computed Tomographic Imaging With 99mTc-Sestamibi

A Measure of the Efficacy of Therapy in Acute Myocardial Infarction
Originally publishedhttps://doi.org/10.1161/01.CIR.101.1.101Circulation. 2000;101:101–108

    Abstract

    Background—Use of mortality as an end point in randomized trials of reperfusion therapy requires increasingly large sample sizes to test advances compared with existing therapy, which is already highly effective. There has been a growing interest in infarct size measurements by 99mTc-sestamibi SPECT (single photon emission computed tomographic) imaging as a surrogate end point.

    Methods and Results—We reviewed the reports published in English regarding infarct size measurements by 99mTc-sestamibi. Four separate lines of published evidence support the validity of SPECT imaging with 99mTc-sestamibi for determination of infarct size. This end point has been used in a total of 7 randomized trials—1 single center and 6 multicenter. The end point compares favorably with left ventricular function and infarct size measurements with the use of other radiopharmaceuticals. The most important limitation of this approach is the absence thus far of a randomized trial that has shown a corresponding decrease in mortality in association with a therapy that reduces infarct size.

    Conclusions—SPECT imaging with 99mTc-sestamibi is the best available measurement tool for infarct size. It has already served as an end point in early pilot studies to evaluate potential efficacy and in dose-ranging studies. It has the potential to serve as a surrogate end point to uncover advantages of new therapies that may be equivalent to existing therapies with respect to early mortality.

    Multiple end points, including global left ventricular function,1 regional left ventricular function,2 early arterial patency,3 and clinical outcomes,4 have been used in various randomized trials as measures of the efficacy of reperfusion therapy in acute myocardial infarction. Clearly, the most important clinical outcome is that of patient mortality, which has formed the basis for multiple megatrials comparing thrombolytic agents with placebo and with each other. However, use of mortality as an end point requires increasingly large sample sizes (Figure 1) to test advances compared with existing therapy, which is already highly effective. Such very large sample sizes limit the number of new therapies that can be tested and impose prohibitive financial barriers on the early testing of potentially promising therapies. End points that are potential “surrogates” for both early and late patient mortality are therefore attractive for several purposes: (1) to conduct very early pilot studies to demonstrate potential efficacy of a new agent, (2) to serve as end points for dose-ranging studies to select the “best dose” of a new agent, and (3) to indicate a possible late mortality benefit for a new therapy that may be “equivalent” to existing therapy with respect to early mortality.

    As existing therapy improves, the third possibility may become more likely. It will be increasingly difficult to demonstrate an advantage in early mortality, even if one really exists, because of the decreasing mortality with existing therapy and the distinct possibility that the deaths that still occur in acute myocardial infarction may be related to phenomena that cannot be altered by reperfusion therapy. For example, some patients may die of embolic complications (cerebral or pulmonary) that are unrelated to therapy. Thus, at least a portion of the existing low mortality with reperfusion therapy may reflect an “irreducible foundation” of early mortality that is unlikely to be prevented with any new therapy.

    In contrast, a new therapy might still reduce left ventricular damage and infarct size. Such a reduction might have favorable consequences for mortality over a much longer term (perhaps 5 to 10 years) than the short term (30 days) that has been used to date for megatrials of acute reperfusion therapy. Maintenance of a scientifically meaningful protocol over the long term to assess 5-year mortality in a megatrial (of 30 000 patients) would be extremely difficult. However, early measurements showing a reduction in infarct size are much more feasible and may indicate a potential benefit in late mortality.

    There has been a growing interest in infarct size by 99mTc-sestamibi single photon emission computed tomographic (SPECT) imaging as a surrogate end point for all 3 purposes listed earlier. Multiple animal studies have supported the premise that measurement of the acute myocardial perfusion defect by injection of sestamibi during coronary occlusion provides an indication of myocardium at risk.5 Similarly, animal studies have consistently demonstrated that injection of sestamibi after coronary reperfusion permits measurement of infarct size.6 Treatment efficacy can be assessed either by measuring both the acute and final perfusion defect to estimate myocardial salvage or more simply by measuring the final perfusion defect to assess infarct size.7 The earliest clinical study using sequential imaging8 demonstrated a treatment effect from thrombolytic therapy in a very small, uncontrolled series of only 12 patients, demonstrating its potential statistical power. Sample size estimates are available7 with either myocardial salvage or infarct size used to assess treatment efficacy.

    This review is intended to summarize the evidence to date supporting the validity of sestamibi infarct size as a measure of the efficacy of reperfusion therapy in human myocardial infarction.

    Evidence Supporting the Validity of SPECT Infarct Sizing

    Multiple lines of evidence now support the validity of SPECT imaging with 99mTc sestamibi for determination of infarct size:

    1. There is close association between this measurement and other parameters that have traditionally been used clinically to estimate infarct size. Table 1 summarizes the published comparisons of SPECT sestamibi infarct size and multiple other parameters, including global left ventricular function (ejection fraction),8910 end systolic volume,11 regional left ventricular function (regional wall motion),89 creatine kinase release,12 and 201Tl infarct size.13 Figure 2 shows the relationship between sestamibi infarct size measured at discharge and end-systolic volume of the left ventricle measured 1 year later by electron-beam CT imaging.11 Despite the potential confounders of cardiomyopathic processes, ventricular loading conditions, and intervening silent reinfarction, the association between these 2 measures is quite strong.

    2. There is close association between SPECT sestamibi infarct size and actual fibrosis in human hearts. Medrano et al14 have reported a close correlation between the actual amount of pathological fibrosis in human hearts explanted at the time of cardiac transplantation from patients with ischemic heart disease and the perfusion defect measured by ex vivo SPECT imaging after intravenous in vivo injection of 99mTc sestamibi (Figure 3). They reported excellent correlation (r=0.94) between their polar map technique (used in Figure 3) and a fixed threshold of 60% of peak counts (used by our laboratory). The regression line in Figure 3 is shifted upward from the line of identity, indicating that sestamibi imaging slightly overestimated the amount of fibrosis, presumably because some hibernating myocardium was misclassified as infarcted. However, in this highly selected series of patients with severe left ventricular dysfunction, hibernating myocardium should be more prevalent than in less selected patients. Because the mean overestimate by sestamibi in these highly selected patients was only 8% of the left ventricle, the error in less selected patients should be even smaller. These published data on fibrosis have been confirmed by 2 studies that used myocardial biopsies at the time of CABG.1516

    The relationship between the sestamibi SPECT perfusion defect and fibrosis demonstrated in these studies is superior to that previously reported for regional wall motion (Table 2). The data in these 4 studies are voluminous and beyond the scope of this article. Contrast left ventriculography, radionuclide angiography, and 2-dimensional echocardiography have all been shown to have a significant major error rate; at least 15% of segments judged to be akinetic or dyskinetic have proved not to have major fibrosis on pathological examination. Two-dimensional echocardiography, which should be the optimal modality because of its tomographic properties, has a reported correlation coefficient of only 0.53 between regional wall motion assessment and fibrosis.20

    3. Sestamibi uptake predicts the response of myocardial regions with abnormal function to subsequent revascularization. 201Tl has commonly been used to assess myocardial viability. As shown by Medrano et al,1499mTc-sestamibi might be expected to misclassify viable myocardial segments with decreased resting blood flow as infarcted. In a series of 31 patients with left ventricular dysfunction, Udelson et al21 compared regional sestamibi activity (as a percent of peak counts) with 201Tl activity (as a percent of peak counts) determined on a redistribution image after a resting 201Tl injection (Figure 4). The overall correlation between the 2 radiopharmaceuticals with respect to regional activity was highly significant (r=0.78). More importantly, the regional ventricular function of these segments was assessed by 2-dimensional echocardiography both before and after subsequent coronary revascularization with either PTCA or CABG. Segments that were abnormal at baseline and improved after revascularization had higher initial values of both sestamibi and thallium. Segments that were abnormal at baseline and did not improve after revascularization had lower initial uptake of both radiopharmaceuticals. A value of 60% of peak counts on resting sestamibi imaging separated those segments with reversible dysfunction (which were presumably viable at baseline) from those segments with irreversible dysfunction (which were presumably fibrotic at baseline). This 60% threshold is the same threshold developed independently by our laboratory to separate infarct from viable tissue.

    These findings were confirmed by Maes et al.15 Although the optimal sestamibi threshold for predicting functional improvement was 50% in their study, a 60% threshold did nearly as well.

    4. Sestamibi infarct size is associated with subsequent patient mortality. Miller et al22 reported a 2-year follow-up of 274 patients at the Mayo Clinic (86% with reperfusion therapy) who underwent predischarge imaging with sestamibi to measure infarct size (Figure 5). The measured infarct size in this series was quite small, with a median of 12% of the left ventricle. Approximately 25% of the patients had no measurable infarct by this technique, which is valid down to about 3% to 4% of the left ventricle.23 Despite the low 2-year mortality rate of 3%, sestamibi infarct size was highly associated with both overall mortality (χ2=8.66, P=0.003) and cardiac mortality (χ2=11.89, P<0.001). Miller et al24 have also shown a significant association between sestamibi infarct size at discharge and 1-year mortality in a separate multicenter study of 249 patients. These published data from relatively small patient series have been confirmed by preliminary data from Burns et al,25 who have demonstrated a similar association between discharge sestamibi infarct size and 6-month mortality in a much larger series of 1184 patients.

    Experience With SPECT Sestamibi Imaging in Clinical Trials

    Measurement of myocardial salvage and infarct size by 99mTc-sestamibi has now been used as end points in several randomized trials, discussed below.

    1. A randomized trial comparing tissue plasminogen activator and PTCA.26 In this single-center trial, there was no detectable difference in myocardial salvage assessed by sestamibi between the 2 therapies. After adjustment for baseline inequalities, the difference in myocardial salvage was 0% of the left ventricle, with 95% confidence limits of ±6% of the left ventricle. There was also no difference between the 2 therapies with respect to ejection fraction at discharge or 6 weeks.

    2. A pilot study assessing the potential efficacy of poloxamer-188 as adjunctive therapy in patients receiving thrombolytic therapy.27 In this randomized, multicenter trial of 114 patients, poloxamer-188–treated patients demonstrated a 38% reduction in median myocardial infarct size compared with placebo (Figure 6) and a 13% improvement in median ejection fraction.

    3. A pilot study of poloxamer-188 used as adjunctive therapy with PTCA.28 In this randomized, multicenter trial of 150 patients, there was no significant difference in final infarct size or ejection fraction between the poloxamer-188– and placebo-treated groups.

    4. CORE (Collaborative Organization for RheothRX Evaluation) trial. This was a large (n=2948) international, multicenter, dose-ranging study29 that tested the hypothesis that poloxamer-188 plus standard therapy would improve patient outcome. Infarct size was measured with 99mTc-sestamibi as part of a substudy (n=1184). The dose of poloxamer-188 was adjusted downward during the course of the trial because of unacceptable renal toxicity. The subsequent lower doses were not associated with any significant reduction in infarct size or improvement in ejection fraction, despite a persistent increase in measured renal toxicity. Thus, the drug unintentionally targeted the kidney.

    5. Pilot study comparing CY-1503 (P-selectin blocker) with placebo as an adjunct to PTCA. This multicenter, randomized trial (CALYPSO: Cylexin as an Adjunct to LYtic therapy to Prevent SuperOxide reflow injury) enrolled 150 patients with sestamibi imaging as a primary end point before termination by the data and safety monitoring committee because of lack of efficacy.

    6. Single-center pilot study of 45 patients examining the efficacy of adenosine used as ancillary therapy with PTCA.30 Early predischarge images in this study did not show an increase in myocardial salvage compared with historical controls, but later (6 weeks after discharge) images did demonstrate greater myocardial salvage. Ejection fraction data were not reported.

    7. Phase 2 study of the efficacy of adenosine used as ancillary therapy with thrombolysis.31 In this randomized, multicenter trial of 236 patients, the patients treated with adenosine demonstrated a significant reduction in infarct size. The benefit was striking in the prespecified subgroup of anterior infarcts; median infarct size was 45.5% of the left ventricle in the placebo group compared with 15% of the left ventricle in the adenosine group (P=0.014). Ejection fraction was not measured.

    Sestamibi infarct size measurements have therefore been used to assess potential efficacy in these randomized trials and to assess the potential “best dose” in a larger dose-ranging trial (the CORE trial). In all the multicenter studies, images were acquired by each individual center but processed by a single central laboratory (Mayo Clinic). The results have generally been confirmed by similar findings with respect to ejection fraction.

    Comparison With Left Ventricular Function

    Compared with left ventricular function measurements, perfusion imaging provides a number of advantages. Perfusion images are not influenced by the presence of arrhythmias, cardiomyopathies, valvular heart disease, or ventricular loading, which have a substantial effect on left ventricular function. Infarct sizing by perfusion imaging is less affected by the presence of myocardial stunning or hibernation.932 Finally, perfusion imaging permits detection of treatment benefit with much smaller sample sizes. Although a detailed discussion of this issue is beyond the scope of this article, the main advantage of infarct sizing by perfusion imaging is the absence of any variability when there is no measurable infarct, ie, when infarct size is 0%, which occurs in about 25% of the patients who have received reperfusion therapy.22 In contrast, ejection fraction measurements have a considerable variability in such patients, in whom the normal ejection fraction ranges from 50% to 75%.

    Comparison With Other Radiopharmaceuticals

    Infarct size has been measured in experimental models with a variety of other radiopharmaceuticals, including 201Tl, 99mTc-pyrophosphate, and indium-111 antimyosin antibody.33 Clinical studies have shown an association between these measurements and left ventricular function, cardiac enzymes, cardiac pathology, and subsequent outcome. The largest such clinical study demonstrated the prognostic value of infarct size assessed by SPECT 201Tl imaging. Cerqueira et al34 reported the 5-year survival of 618 patients enrolled in multiple studies performed by the Western Washington Trials Group. There was a highly significant association (P=0.002) between thallium infarct size and subsequent mortality.

    Several studies have demonstrated that 201Tl and 99mTc-sestamibi provide similar results for determination of infarct size.21 However, 99mTc-sestamibi provides higher count images that are more accurately quantified35 and the option to do short-term imaging to assess myocardium at risk. Compared with sestamibi, infarct-avid agents (pyrophosphate and antimyosin) have the potential advantage of distinguishing new from old infarction. However, their uptake depends more on the timing of administration after the acute event, they do not allow the option of assessing myocardium of risk, and there is less experience with their use in the setting of acute reperfusion therapy. There are relatively few clinical data regarding the use of 99mTc-tetrofosmin in acute infarction. It has not been studied in experimental models. Thus, compared with other radiopharmaceuticals, sestamibi has technical advantages and has been much more extensively studied.

    Limitations of This Approach

    This approach has 5 major limitations:

    1. SPECT imaging of a beating heart has definite technical limitations for the purposes of quantification. The 2 major limitations are degradation of image quality resulting from the effects of scatter and attenuation and the partial volume effect related to severely abnormal wall motion. The threshold of 60% of peak counts used by our laboratory to identify infarction was established on the basis of cardiac phantom studies.23 It provided the highest correlation coefficient (r=0.98) and the slope of the regression line between true and measured infarct size that was closest to unity (slope=1.01). Both the correlation coefficient and slope were better with a 60% than with a 50% threshold, which theoretically should be optimal if scatter and attenuation did not exist. In a later cardiac phantom study34 that used a newer-generation gamma camera with enhanced energy resolution and hardware software to perform scatter correction, the optimal threshold proved to be 55%, closer to the theoretical ideal. The normal limits of activity distribution in the basal inferior wall may extend below the 60% threshold in some patients whose body habitus leads to greater attenuation. In a consecutive series22 of 100 overweight (89±19 kg) patients with a normal resting ECG and no history of infarction who were referred for sestamibi imaging, 81 had no measurable defect and 8 had trivial defects measuring between 1% and 3% of the left ventricle. Although the remaining 11 patients had inferior wall defects that measured between 4% and 21% of the left ventricle, 7 of these, including all 4 patients with defects of >10% of the left ventricle, had further cardiac evaluation that suggested that the measured inferior defects were real. Thus, tissue attenuation can certainly lead to “false-positive” infarctions, although these should be quantitatively small. Both of the aforementioned effects of attenuation—the nonoptimal threshold and false-positive infarctions—could theoretically be removed with attenuation correction, but this has not yet been widely applied in clinical imaging.

    Regions of severely abnormal wall motion could possibly lead to partial volume effects that result in overestimation of infarct size, particularly if the infarction is large and associated with an extensive area of dyskinesia. However, a previous study36 examined the influence of gating in 29 patients 5 to 8 days after myocardial infarction. Gated images provided significantly greater estimates of infarct size (mean difference of 4%), opposite in direction to the difference expected if partial volume effects significantly influence perfusion defect size. Partial volume effects therefore appear to have minimal clinical impact.

    2. Sestamibi infarct size measurements are less commonly available and more technically demanding than left ventricular function measurements. Although this is true, the availability of SPECT imaging is certainly improving. Medicare data from 1994 show that nearly 1 million SPECT myocardial perfusion imaging studies were performed nationally and that this procedure is increasing at a rate of >10%/y. Although the procedure is technically demanding, we have used a quality control study and a phantom experiment to assess the technical performance of laboratories.37 Most laboratories are capable of acquiring high-quality SPECT images of a phantom that when processed in a central laboratory, provide measured “infarct” sizes that are very closely correlated with the actual defect size, with an average absolute error of <3% of the left ventricle.37

    3. There may be late recovery of myocardium which will alter the measurement of infarct size over time. Galli et al38 carefully studied 71 patients with anterior myocardial infarction by sestamibi SPECT imaging at 5 weeks and 7 months after acute infarction. Using a polar map “normal limits” technique, they reported a late decline in measured infarct size. Their study design incorporated a number of features—use of a polar map technique, restriction to anterior infarcts, and inclusion of patients who did not receive reperfusion therapy and had occluded arteries by angiography—that would be expected to produce a larger perfusion defect at 5 weeks and therefore greater potential for a late decrease. Nevertheless, the change in extent of the defect was relatively modest (6% of the left ventricle). Given the difference in measurement technique and image timing used by Galli et al, applicability of their findings to the approach we have developed is questionable. Although this late change might argue for performing perfusion imaging after a longer delay following myocardial infarction, it would probably be much more difficult from the standpoint of patient compliance and patient dropout because of deaths, recurrent infarction, or other intervening clinical events. All the data validating infarct size measurements by SPECT sestamibi described previously were based on measurements performed at the time of hospital discharge. Clearly, further data are needed on serial determinations of defect size with the use of this technique in an unselected population of postinfarction patients to determine the overall magnitude of late change.

    4. No randomized trial has shown a corresponding decrease in mortality in association with a therapy that reduces infarct size. This requirement has assumed increasing importance because of the experiences with ventricular arrhythmias on ambulatory monitoring as a surrogate end point. Frequent premature ventricular contractions after myocardial infarction were known to be associated with increased subsequent mortality. Although it was hypothesized that their suppression with antiarrhythmic therapy could be used as a measure of efficacy, the CAST trial demonstrated that such therapy produced an increase rather than a decrease in mortality. The only published randomized trial to demonstrate a reduction in infarct size involved poloxamer-188, which was subsequently shown in the CORE trial29 to have unacceptable renal toxicity at the doses initially used in the pilot study.

    However, randomized trial data are available that compare therapies that did not have a demonstrable difference in infarct size (Table 3). The Mayo trial comparing tissue plasminogen activator and PTCA mentioned previously did not show a significant difference in infarct size between these 2 therapies. The difference reported was 0% of the left ventricle, with 95% confidence limits of ±6% of the left ventricle. Although the randomized PAMI (Primary Angioplasty in Myocardial Infarction) trial40 reported a significant, large difference in reinfarction or death between these 2 therapies, the larger GUSTO IIb trial (Global Use of Strategies To Open occluded coronary arteries in acute coronary syndromes)41 found that the differences in reinfarction and death between these 2 therapies were significant but more modest. The modest difference in clinical outcome data observed in GUSTO IIb could not be excluded by the results of the Mayo trial.

    A number of observational studies using sestamibi have reported treatment effects that are similar to those reported by a randomized trial using mortality as an end point (Table 3). Myocardial salvage by sestamibi is greater with tissue plasminogen activator than by conventional therapy without thrombolysis (13% versus 4% of the left ventricle, P<0.003).8 Randomized clinical trials have clearly shown a reduction in mortality with tissue plasminogen activator compared with placebo.4

    When patients with patent arteries after reperfusion therapy have been compared with patients with occluded arteries after reperfusion therapy, patients with patent arteries have greater myocardial salvage (17% versus 0% of the left ventricle, P<0.001) and smaller infarct size (9% versus 19% of the left ventricle, P<0.05).39 The angiographic substudy of the GUSTO trial demonstrated a reduction in mortality associated with arterial patency.42

    Myocardial salvage by sestamibi is clearly greater in anterior infarcts than in inferior infarcts (24% versus 10% of the left ventricle, P<0.01).39 A meta-analysis of randomized clinical trials showed that absolute mortality reduction was greater in anterior infarcts (3.7%) than in inferior infarcts (0.9%).43 Thus, the treatment effects on salvage and infarct size demonstrated by sestamibi have generally been consistent with the effects on mortality.

    5. Sestamibi infarct size is a measure of efficacy, not safety. The demonstration of efficacy by this approach requires modest sample sizes, which are clearly not large enough to detect possible increases in adverse events that occur infrequently with existing therapy. The CORE trial29 demonstrated this principle.

    This limitation is most relevant to the third purpose described earlier. From a regulatory standpoint, demonstration that a new therapy is “equivalent” to existing therapy with respect to early mortality will require a reasonably sized trial of perhaps 5000 to 10 000 patients. Such a trial should have sufficient power to assess other important safety concerns (strokes, renal insufficiency) that cannot be addressed by infarct size measurements. The development of reteplase is a potential example of this approach; the RAPID (Recombinant plasminogen activator Angiographic Phase II International Dose finding study) trial3 demonstrated an advantage in patency compared with tissue plasminogen activator, and the INJECT (INternational Joint Efficacy Comparison of Thrombolytics) trial44 showed equivalence to streptokinase with respect to mortality.

    Conclusions

    On the basis of the available scientific evidence, SPECT imaging with 99mTc-sestamibi is the best available measurement tool for infarct size in clinical medicine. It has already served as an end point in early pilot studies to demonstrate potential efficacy of new therapies. It will likely be increasingly used in dose-ranging studies. Does the available evidence justify the use of this end point as a true “surrogate” to potentially uncover advantages of new therapies that may be “equivalent” to existing therapies with respect to early mortality? When this regulatory issue was last addressed by the Food and Drug Administration in 1992, the answer was clearly “no.”45 The large body of evidence that has emerged since would appear to justify a reexamination of this issue.

    
          Figure 1.

    Figure 1. Total patient (Pt) enrollment in selected major randomized therapeutic trials in acute myocardial infarction displayed by year of publication. GISSI, GISSI-2, and GISSI-3 indicate Gruppo Italiano per lo Studio della Streptochinasi nell’Infarto miocardico I, II, and III; ISAM, Intravenous Streptokinase in Acute Myocardial infarction; ISIS-2, ISIS-3, and ISIS-4, International Study of Infarct Survival 2, 3, and 4; ASSET, Anglo-Scandanavian Study of Early Thrombolysis; AIMS, APSAC Intervention Mortality Study; LATE, Late Assessment of Thrombolytic Efficacy; EMERAS, Estudio Multicéntrico Estreptoquinasa Repúblicas de Américas del Sur; and GUSTO, GUSTO-II, and GUSTO-III, Global Utilization of Streptokinase and Tissue plasminogen activator for Occluded coronary arteries, Global Use of Strategies To Open occluded arteries, and Global Use of Strategies To Open occluded coronary arteries.

    
          Figure 2.

    Figure 2. Correlation between tomographic 99mTc infarct size at hospital discharge and end-systolic volume (ESV) of left ventricle (LV) measured by electron-beam CT 1 year later (reprinted with permission from Reference 11).

    
          Figure 3.

    Figure 3. Correlation between perfusion defect measured by SPECT perfusion imaging with 99mTc-sestamibi and amount of fibrosis measured by histology in human hearts explanted at time of cardiac transplantation (reprinted with permission from Reference 14).

    
          Figure 4.

    Figure 4. Correlation between sestamibi activity on resting image and thallium activity on redistribution image after resting injection. Segmental values are expressed as percent of peak counts. There is reasonable correlation between the uptake of the 2 radiopharmaceuticals. Segments shown had abnormal regional function before revascularization. It is evident that a sestamibi threshold of 60% of peak counts separated segments with reversible from those with irreversible dysfunction (reprinted with permission from Reference 21).

    
          Figure 5.

    Figure 5. Two-year survival in 274 patients who had infarct size measured by 99mTc-sestamibi at discharge at Mayo Clinic. Mortality in entire group was 3% at 2 years. Patients with infarct size below median of 12% had no mortality over 2 years. Those with infarct size above median of 12% had 7% mortality over 2 years. Infarct size was significantly associated with mortality on linear proportional hazard analysis (reprinted with permission from Reference 22).

    
          Figure 6.

    Figure 6. Box plot (25th percentile/median/75th percentile) showing myocardial salvage (% of left ventricle) in patients treated with thrombolysis and placebo (left) vs patients treated with thrombolysis and poloxamer-188 (right) (reprinted with permission from Reference 27).

    Table 1. Clinical Validation of 99mTc-Sestamibi Infarct Size

    MeasurementrPReference
    Discharge EF−0.80<0.00018
    6-wk EF−0.81<0.00019
    1-y EF−0.76<0.000110
    ESV at 1 year (CT)0.80<0.000111
    Discharge RWM−0.75<0.00018
    RWM at 6 weeks−0.81<0.00019
    CPK release0.780.00212
    201T1 defect size0.87<0.000113

    EF indicates ejection fraction; ESV, end-systolic volume; RWM, regional wall motion; and CPK, creatine phosphokinase.

    Table 2. Assessment of Fibrosis in the Human Heart by Regional Left Ventricular Wall Motion

    Wall Motion TechniqueInstitutionReferencePercent of LV Segments With Akinesia/Dyskinesia Without Major Fibrosis
    Contrast ventriculographyDuke1732
    Radionuclide angiographyVermont18241
    Radionuclide angiographyYale1924
    EchocardiographyMayo20152

    LV indicates left ventricular.

    1Wall motion graded as “abnormal”; additional gradations not used.

    2Correlation of regional wall motion score to fibrosis (r=0.53).

    Table 3. Summary of Evidence Showing Similar Treatment Effects for Myocardial Salvage and Infarct Size by Sestamibi and Clinical End Points in Randomized Controlled Trials

    Study DesignPrimary End PointResultReference
    Comparison of TPA vs PTCARCTMyocardial salvageNo difference26
    RCT: GUSTO IIbDeath/MI/CVADecreased with PTCA41
    tPA vs conventional therapy without thrombolysisObservationalMyocardial salvageIncreased with tPA8
    RCTMortalityDecreased with tPA4
    Patent artery vs occluded artery after reperfusion therapyObservationalMyocardial salvageIncreased with patency39
    ObservationalInfarct sizeDecreased with patency39
    RCT: angiographic substudyMortalityDecreased with patency42
    Anterior vs inferior MIObservationalMyocardial salvageIncreased in anterior MI39
    Meta-analysis of RCTMortalityMortality reduction greater in anterior MI43

    RCT indicates randomized controlled trial; MI, myocardial infarction; CVA, cerebral vascular accident; and tPA, tissue plasminogen activator.

    This work was supported in part by the Dupont Merck Pharmaceutical Company, North Billerica, Mass.

    Footnotes

    Correspondence to Raymond J. Gibbons, MD, E16A, Mayo Clinic, 200 1st St SW, Rochester, MN 55905.

    References

    • 1 Kennedy JW, Martin JC, David KB, Maynard C, Stadius M, Sheehan RH, Ritchie JL. The Western Washington Intravenous Streptokinase in Acute Myocardial Infarction randomized trial. Circulation.1988; 77:345–352.CrossrefMedlineGoogle Scholar
    • 2 Sheehan FH, Braunwald E, Canner P, Dodge HT, Gore J, Van Natta P, Passamani ER, Williams DO, Zaret B. The effect of intravenous thrombolytic therapy on left ventricular function: a report on tissue-type plasminogen activator and streptokinase from the Thrombolysis in Myocardial Infarction (TIMI phase I) trial. Circulation.1987; 75:817–829.CrossrefMedlineGoogle Scholar
    • 3 Smalling RW, Bode C, Kalbfleisch J, Sen S, Limbourg P, Forycki F, Habib G, Feldman R, Hohnloser S, Seals A, for the RAPID Investigators. More rapid, complete and stable coronary thrombolysis with bolus administration of reteplase compared with alteplase infusion in acute myocardial infarction. Circulation.1995; 91:2725–2732.CrossrefMedlineGoogle Scholar
    • 4 Anglo-Scandinavian Study of Early Thrombolysis Study Group. Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction: Anglo-Scandinavian Study of Early Thrombolysis (ASSET). Lancet.1988; 2:525–530.CrossrefMedlineGoogle Scholar
    • 5 DeCoster PM, Wijns W, Cauwe F, Robert A, Beckers C, Melin JA. Area-at-risk determination by technetium-99m-hexakis-2-methoxyisobutyl isonitrile in experimental reperfused myocardial infarction. Circulation.1990; 82:2152–2162.CrossrefMedlineGoogle Scholar
    • 6 Sinusas AJ, Trautman KA, Bergin JD, Watson DD, Ruiz M, Smith WH, Beller GA. Quantification of “area at risk” during coronary occlusion and degree of myocardial salvage after reperfusion with technetium-99m-methoxy isobutyl isonitrile. Circulation.1990; 82:1424–1437.LinkGoogle Scholar
    • 7 Gibbons RJ, Christian TF, Hopfenspirger M, Hodge DO, Bailey KR. Myocardium at risk and infarct size after thrombolytic therapy for acute myocardial infarction: implications for the design of randomized trials of acute intervention. J Am Coll Cardiol.1994; 24:616–623.CrossrefMedlineGoogle Scholar
    • 8 Gibbons RJ, Verani MS, Behrenbeck T, Pellikka PA, O’Connor MK, Mahmarian JJ, Chesebro JH, Wackers FJ. Feasibility of tomographic technetium-99m-hexakis-2-methoxy-2-methylpropyl-isonitrile imaging for the assessment of myocardial area at risk and the effect of acute treatment in myocardial infarction. Circulation.1989; 80:1277–1286.CrossrefMedlineGoogle Scholar
    • 9 Christian TF, Behrenbeck T, Pellikka PA, Huber KC, Chesebro JH, Gibbons RJ. Mismatch of left ventricular function and perfusion with Tc-99 m-isonitrile following reperfusion therapy for acute myocardial infractions: identification of myocardial stunning and hyperkinesia. J Am Coll Cardiol.1990; 16:1632–1638.CrossrefMedlineGoogle Scholar
    • 10 Christian TF, Behrenbeck T, Gersh BJ, Gibbons RJ. Relation of left ventricular volume and function over one year after acute myocardial infarction to infarct size determined by technetium-99m sestamibi. Am J Cardiol.1991; 68:21–26.CrossrefMedlineGoogle Scholar
    • 11 Chareonthaitawee P, Christian TF, Hirose K, Gibbons RJ, Rumberger JA. The relationship of infarct size with the extent of left ventricular remodeling following myocardial infarction. J Am Coll Cardiol.1995; 25:567–573.CrossrefMedlineGoogle Scholar
    • 12 Behrenbeck T, Pellikka PA, Huber KC, Bresnahan JF, Gersh BJ, Gibbons RJ. Primary angioplasty in myocardial infarction: assessment of improved myocardial perfusion with technetium-99m-isonitrile. J Am Coll Cardiol.1991; 17:365–372.CrossrefMedlineGoogle Scholar
    • 13 Christian TF, O’Connor MK, Hopfenspirger MR, Gibbons RJ. Comparison of reinjection thallium 201 and resting technetium 99m sestamibi tomographic images for the quantification of infarct size after acute myocardial infarction. J Nucl Cardiol.1994; 1:17–28.CrossrefMedlineGoogle Scholar
    • 14 Medrano R, Lowry RW, Young UB, Weibaecher DG, Michael LH, Afridi I, He ZX, Mahmarian JJ, Verani MS. Assessment of myocardial viability with 99mTc sestamibi in patients undergoing cardiac transplantation. Circulation.1996; 94:1010–1017.CrossrefMedlineGoogle Scholar
    • 15 Maes AF, Borgers M, Flameng W, Nuyts JL, Van de Werf F, Ausma JJ, Sergeant P, Mortelmans LA. Assessment of myocardial viability in chronic coronary artery disease using technetium-99m sestamibi SPECT. J Am Coll Cardiol.1997; 29:62–68.CrossrefMedlineGoogle Scholar
    • 16 Dakik HA, Howell JF, Lawrie GM, Espada R, Weilbaecher DG. Assessment of myocardial viability with 99mTc-sestamibi tomography before coronary bypass graft surgery: correlation with histopathology and postoperative improvement in cardiac function. Circulation.1997; 96:2892–2898.CrossrefMedlineGoogle Scholar
    • 17 Ideker RE, Behar VS, Wagner GS, Starr JW, Starmer F, Lee KL, Hackel DB. Evaluation of asynergy as an indicator of myocardial fibrosis. Circulation.1978; 57:715–725.CrossrefMedlineGoogle Scholar
    • 18 Sinusas AJ, Hardin NJ, Clements JP, Wackers FJ. Pathoanatomic correlates of regional left ventricular wall motion assessed by equilibrium radionuclide angiocardiography: a postmortem correlation. Am J Cardiol.1984; 54:975–981.CrossrefMedlineGoogle Scholar
    • 19 Cabin HS, Clubb KS, Vita N, Zaret BL. Regional dysfunction by equilibrium radionuclide angiocardiography: a clinicopathologic study evaluating the relation of degree of dysfunction to the presence and extent of myocardial infarction. J Am Coll Cardiol.1987; 10:743–747.CrossrefMedlineGoogle Scholar
    • 20 Shen WK, Khandheria BK, Edwards WD, Oh JK, Miller FA, Naessens JM, Tajik AJ. Value and limitations of two-dimensional echocardiography in predicting myocardial infarct size. Am J Cardiol.1991; 68:1143–1149.CrossrefMedlineGoogle Scholar
    • 21 Udelson JE, Coleman PS, Metherall J, Pandian NG, Gomez AR, Griffith GL, Oates E, Konstam MA. Predicting recovery of severe regional dysfunction: comparison of resting scintigraphy with 201-T1 and 99mTc-sestamibi. Circulation.1994; 89:2552–2561.CrossrefMedlineGoogle Scholar
    • 22 Miller TD, Christian TF, Hopfenspirger MR, Hodge DO, Gersh BJ, Gibbons RJ. Infarct size after acute myocardial infarction measured quantitative tomographic 99mTc sestamibi imaging predicts subsequent mortality. Circulation.1995; 92:334–341.MedlineGoogle Scholar
    • 23 O’Connor MK, Hammell T, Gibbons RJ. In vitro validation of a simple tomographic technique for estimation of percent myocardium “at risk” using technetium-99m methoxy isobutyl isonitrile (sestamibi). Eur J Nucl Med.1990; 17:69–76.CrossrefMedlineGoogle Scholar
    • 24 Miller TD, Hodge DO, Sutton JM, Grines CL, O’Keefe JH, DeWood MA, Okada RD, Fletcher WO, Gibbons RJ. Technetium-99m sestamibi infarct size predicts mortality. Am J Cardiol.1998; 81:1491–1493.CrossrefMedlineGoogle Scholar
    • 25 Burns RJ, Gibbons RJ, Roberts RS, Tadros SS, Miller TD, Foster G, Yusuf S. LV function and infarct size predict six-month mortality post MI treated by thrombolysis. Circulation. 1996;94(suppl I):I-655. Abstract.Google Scholar
    • 26 Gibbons RJ, Holmes DR, Reeder GS, Bailey KK, Hopfenspirger MR, Gersh BJ. Immediate angioplasty compared with the administration of a thrombolytic agent followed by conservative treatment for myocardial infarction. N Engl J Med.1993; 328:685–691.CrossrefMedlineGoogle Scholar
    • 27 Schaer GL, Spaccarento LJ, Bronne KF, Kraeger KA, Krichbaum D, Phelan JM, Frehher WO, Grines LL, Edwards S, Jolly MK, Gibbons RJ. Beneficial effects of RheothRX injection in patients receiving thrombolytic therapy for acute myocardial infarction. Circulation.1996; 94:298–307.CrossrefMedlineGoogle Scholar
    • 28 O’Keefe JH Jr, Grines CL, DeWood MA, Schaar GL, Browne K. Majorien RD, Kalbfleisch JM, Fletcher WO Jr, Bakman TM, Gibbons RJ. Poloxamer-188 as an adjunct to primary percutaneous transluminal coronary angioplasty for acute myocardial infarction. Am J Cardiol.1996; 78:747–750.CrossrefMedlineGoogle Scholar
    • 29 Collaborative Organization for RheothRX Evaluation (CORE). Effects of RheothRX on mortality, morbidity, left ventricular function, and infarct size in patients with acute myocardial infarction. Circulation.1997; 96:192–201.MedlineGoogle Scholar
    • 30 Garratt KN, Holmes DR, Molina-Viamonte V, Reeder GS, Hodge D, Bailey KR, Lobl J, Laudon D, Gibbons RJ. Intravenous adenosine and lidocaine in patients with acute myocardial infarction. Am Heart J.1998; 136:196–204.CrossrefMedlineGoogle Scholar
    • 31 Mahaffey KW, Puma JA, Barbagelata NA, DiCarli MF, Leesar MA, Browne KF, Eisenberg PR, Casas AC, Molina-Viamonte V, Orlandi C, Blevins R, Gibbons RJ, Califf RM, Granger CB, for the AMISTAD Investigators. Adenosine as an adjunct to thrombolytic therapy for acute myocardial infarction: results of a multicenter, randomized, placebo-controlled trial. J Am Coll Cardiol. In press.Google Scholar
    • 32 Christian TF, Gitter MJ, Miller TD, Gibbons RJ. Prospective identification of myocardial stunning using technetium-99m sestamibi–based measurements of infarct size. J Am Coll Cardiol.1997; 30:1633–1640.CrossrefMedlineGoogle Scholar
    • 33 Johnson LL, Lerrick KS. Coromilas J, Seldin DW, Esser PD, Zimmerman JM, Keller AM, Alderson PO, Bigger JT, Cannon PJ. Measurement of infarct size and percentage myocardium infarcted in a dog preparation with single photon-emission computed tomography, thallium-201, and indium 111 monoclonal antimyosin Fab. Circulation.1987; 76:181–190.CrossrefMedlineGoogle Scholar
    • 34 Cerqueira MD, Maynard C, Ritchie JL, Davis KB, Kennedy JW. Long-term survival in 618 patients from the Western Washington Streptokinase in Myocardial Infarction trials. J Am Coll Cardiol.1992; 20:1452–1459.CrossrefMedlineGoogle Scholar
    • 35 O’Connor MK, Caiati C, Christian TF, Gibbons RJ. Effects of scatter correction on the measurement of infarct size from SPECT cardiac phantom studies. J Nucl Med.1995; 36:2080–2086.MedlineGoogle Scholar
    • 36 Christian TF, O’Connor MK, Glynn RB, Rogers PJ, Gibbons RJ. The influence of gating on measurements of myocardium at risk and infarct size during acute myocardial infarction by tomographic technetium-99m sestamibi imaging. J Nucl Cardiol.1995; 2:207–216.CrossrefMedlineGoogle Scholar
    • 37 O’Connor MK, Gibbons RJ, Juny JE, O’Keefe JH Jr, Ali A. Quantitative myocardial SPECT for infarct sizing: feasibility of a multicenter trial evaluated using a cardiac phantom. J Nucl Med.1995; 36:1130–1136.MedlineGoogle Scholar
    • 38 Galli M, Mariassa C, Bolli R, Grannuzzi P, Temporelli PL, Importo A, Silva Orrego PL, Giubbini R, Giordano A, Tavazzi L. Spontaneous delayed recovery of perfusion and contraction after the first five weeks after anterior infarction. Circulation.1994; 90:1386–1397.CrossrefMedlineGoogle Scholar
    • 39 Christian TF, Gibbons RJ, Gersh BJ. Effect of infarct location on myocardial salvage assessed by technetium-99m isonitrile. J Am Coll Cardiol.1991; 17:1303–1308.CrossrefMedlineGoogle Scholar
    • 40 Grines CL, Browne KF, Marco J, Rothbaum D, Stone GW, O’Keefe J, Overlie P, Donohue B, Chelliah N, Timmis GC, Vlietstra RE, Strzelecki M, Puchrowicz-Ochocki S, O’Neill WW. A comparison of immediate angioplasty with thrombolytic therapy for acute myocardial infarction. N Engl J Med.1993; 328:673–679.CrossrefMedlineGoogle Scholar
    • 41 Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO IIb) Angioplasty Substudy Investigators. A clinical trial comparing primary coronary angioplasty with tissue plasminogen activator for acute myocardial infarction. N Engl J Med.1997; 336:1621–1630.CrossrefMedlineGoogle Scholar
    • 42 The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med.1993; 329:1615–1622.CrossrefMedlineGoogle Scholar
    • 43 Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomized trials of more than 1000 patients. Lancet.1994; 343:311–322.CrossrefMedlineGoogle Scholar
    • 44 Randomized, double-blind comparison of reteplase double-bolus administration with streptokinase in acute myocardial infarction (INJECT) trial to investigate equivalence. Lancet.1995; 346:329–336.CrossrefMedlineGoogle Scholar
    • 45 Transcript of proceedings. Department of Health and Human Services, Public Health Service, Food and Drug Administration, Cardiovascular and Renal Drugs Advisory Committee. 67th meeting, December 16, 1992. Washington, DC: Miller Reporting Co Inc.Google Scholar

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