Comparison in Acute Myocardial Infarction of Anisoylated Plasminogen Streptokinase

Activator Complex Versus Heparin Evaluated by Simultaneous Thallium=201/Technetium=99m

Pyrophosphate Tomography Thomas Krause, MD, Wolfgang Kasper, MD, Thomas Meinertz, MD, Markus Schnitzler, MD,

Hanjijrg Just, MD, Carl Schtimichen, MD, and Ernst Moser, MD

lnasubgroupof45patie&swithacutemy~ al infarction (AM) lbm the Oerman multicenW tlial of iwlisoylated plasnlinogm streptokinase 80 tivator complex (APSAC) (n = 20) versus heparin (n = 25), simultaneous thallium (Tl)201 S tium (lcm Wrophosphate (PW t-vitmhy wasiniWtedtoelud&teapossibiebenefitof AP5AC over mn. Findings in the 2 batmant #oups were similar with respect to TM01 defect score, relative sdntii iM%ct size, and in keeping with the main group coronmy =teyps tency,gkaalejectionfmctionandmaximal~ atinekinaseleveJ. Howevef,2dii lWOl/ Tc-99m PYP accumulation patterns within the M of infarction (v s, @-up 4 inhomoge neous,jjroupB)wereidantiGed.Both- gmups were similar with #ard to the frequency ofthe-zmdinhomogeneouspattem. lncomp&lgthe2accumulationpattemqcrea tinekinasepsakedWierin@oupAthanin ~w~a~~leffvW~eiection*

mlyhighsrin@wpAthanin groupB.InGrwpA,2Oof2lpatienbandin groupB7ofllpatienbhadapatentinfat&W& ed vessel (p <0.025). TWO1 defect score was lower in @oup A thzm in group B. likewise, rela tivesizeoftheinfarctionasdetemlinedlVom1~ 99m PYP images was significantly lower in &oup Athanin#oupB.Fiipatienbexp&enced cmdiogenic shodf or severe heart failure. Patients ingmupBMahigherinddsnceoftheseif&os- pital~thanpatientsin@wpA(92vs 12X, p *0.0005). 5cintimic infarct size and ll- 2Oldefectscoreweregrwterinpatienbwiththe aforementioned dinical events. In addiii to sciWgraphiiinfarctsizeandcomnaIypatency, the lMOl/Tc-99m PYP accumulation pattem was usefulin~ngpatienbwithfnrmthose witbut an adverse clinical course.

From Albert-Ludwigs-Universitlt, Radiologische Universitltsklinik, Abteilung Nuklearmedizin; and Medizinische UniversitStsklinik, Ab- teilung Kardiologie, Freiburg, Germany. Manuscript received February 18, 1992; revised manuscript received and accepted August 3, 1992.

Address for reprints: Thomas Krause, MD, Radiologische Klinik, Abteilung Nuklearmedizin, Hugstetter Strasse 55, 7800 Freiburg, Ger- many.

ltiscondudedthat~2ol/lc-s9m PYPW raphy is a promising tool for evaluating AMI and predMngthedinicalcourseofpatien&

(Am J Cardiol1993;71:94.2)

adionuclide R studies are frequently used to evalu- ate patients with acute myocardial infarction (AMI) undergoing thrombolytic therapy. Myo-

cardial salvage can be assessed using serial examinations after either intravenous or intracoronary thallium-201 (Tl-201) application.1,2 Some studies suggested early technetium pyrophosphate (Tc-99m PYP) uptake as a marker of reperfusion. 3,4 Only few investigators per- formed dual radioisotope studies using a marker for per- fusion and a marker for necrosis simultaneously.5-9 Ha- shimoto et al7 demonstrated that Tl-201/R-99m PYP overlap on dual emission computed tomography can dif- ferentiate early reperfttsion from slightly delayed re- canalization. With use of combined simultaneous Tl- 201/Tc-99m PYP tomography, the present randomized study was undertaken (1) to elucidate a possible benefit of anisoylated plasminogen streptokinase activator com- plex (APSAC) over heparin, (2) to relate different Tl- 201/R-99m accumulation patterns to clinical tindings, and (3) to test the feasibility of dual radioisotope to- mography for predicting the clinical course of patients after AMI.

MmHODS The study group comprised 45 of 55 consecutive pa-

tients with AMI admitted to the intensive care unit of the medical department, University of Freiburg. These patients were part of the German multicenter trial of APSAC versus heparin which was published recently.lO Ten patients could not be examined by scintigraphy for logistic reasons. Patients were included in the study when they had 230 minutes of chest pain and ST-seg- ment elevation of 20.1 mV in at least 1 standard elec- trocardiographic lead and 20.2 mV in at least 1 V lead persisting even after sublingual administration of either 0.8 mg nitroglycerin or 10 mg nifedipine. Patients with contraindications to fibrinolytic therapy, as well as pa- tients in cardiogenic shock, were excluded from the study. Additional exclusion criteria were chest pain last- ing for >4 hours before presentation and ST-segment

8 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 71 JANUARY 1,1993

elevation in the presence of Q waves, indicating previ- ous infarction.

Study protocol: Methylprednisolone (100 mg) was given to both groups intravenously before treatment. Immediately after randomization, either 30 U of APSAC as an intravenous injection over 5 minutes, or 5,000 U of heparin followed by an infusion of 17 U/kg/hour was given. In the APSAC group, heparin infusion was also begun 4 hours after the administration of APSAC. Hep- arin treatment was continued until cardiac catheteriza- tion was performed 14 to 21 days later. Care was taken to adjust the partial thromboplastin time to 1.5 to 2 times normal. Cardioactive drug treatment was given, if clini- cally indicated, at the discretion of the attending physi- cian.

Myocadial ima@ng Simultaneous Tl-201/Tc-99m PYP tomography was performed within 4 days after the onset of chest pain. All patients were examined during a stable phase of 212 hours after AMI. Tomography was obtained using the 7 pinhole technique in an approxi- mately 40” left anterior oblique, 10” cephalad tilt pro- jection. Scintigrams were recorded using a 38 cm large field-of-view camera (Dyna 4, Picker) with 2 impulse height analyzers. A commercial Fpinhole collimator fo- cused at 13.5 cm with seven 5.3 mm pinholes was fit- ted to the camera. Energy discrimination was provided by a 15% window centered on the 75 keV peak for Tl- 201 and a 5% window centered on 140 keV for Tc-99m. This adjustment yields optimal results, as shown in a previous study.‘l The imaging time ranged between 12 and 17 minutes.

Scatter come&ii The raw data were corrected for down-scattered Tc-99m counts and for radioactivity from Tl-201 gamma rays (135 and 167 keV) according to the following formulas, as reported12: a = A - Ba; b = B - AB (a = corrected Tl-201 counts; A = total sample counts at 75 keV; 01 = Tc-99m standard at 75 keV/Tc-99m standard at 140 keV; b = corrected Tc- 99m counts; B = total sample counts at 140 keV; B = Tl-201 standard at 140 keV/n-201 standard at 75 keV).

Data procesing and overlay technique: Tl-201 and Tc-99m PYP tomograms were separately recon- structed according to the method employed by Vogel et all3 Sixteen slices of nominal 0.8 cm intervals were generated. After reconstruction, images were viewed using a 15- step color scale. For dual isotope display, the Tc-99m PYP images were background-subtracted to ensure that residual blood pool activity of Tc-99m PYP could no longer be seen. Then the images were inverse- ly colored and overlaid on the normally-colored and background-subtracted Tl-201 images.

Image analysis: The lirst 6 short-axis slices follow- ing the apex were used for evaluation. Tl-201 defects or Tc-99m PYP accumulations had to be present on 22 contiguous slices. A Tl-201 defect was diagnosed if the regional viability index as delined by Stimer et all4 was below 75%. In the Tl-201/Tc-99m PYP tomograms, ev- ery accumulation with greater intensity than residual blood pool activity localized in the ventricular wall was judged pathologic, as previously described.15

From each Tl-201/Tc-99m PYP tomogram, the angle (Y under which the Tc-99m PYP accumulation appeared

was measured for each short-axis slice and expressed in degrees. Relative infarct size (in degrees) was defined as mean value of the 6 slices. Accordingly, a Tl-201 defect score (in arbitrary units) was calculated from areas of moderately reduced Tl-201 uptake (MRU: 45% I VI < 75%) or extensively reduced uptake (ERU: VI ~45%) using the following formula:

6 MRU + l/2. ERU Scorer, = C

n=l 6

Tl-20l/Tc-SSm pyrophosphat e accumulation pat- tems: Additional analyses were based on 2 different Tl- 201/Tc-99m PYP accumulation patterns that could be identified (Figure 1): (1) intense and homogeneous Tc- 99m PYP accumulation corresponding to a Tl-201 de- fect (group A); and (2) inhomogeneous Tc-99m PYP accumulation within the Tl-201 defect (group B). In group B, the maximal activity was predominantly local- ized in the infarct periphery with relatively less or no pathologic central uptake.

Cineventriculogrcrphy: Of the 45 patients, 42 had high-quality simultaneous biplane coronary angiography and underwent left-sided cardiac catheterization within 2 to 3 weeks after AMI.

Ctwatine kinase: Blood samples for determination of creatine kinase level were collected every 3 hours for up to 24 hours after the start of treatment and every 6 hours for the next 48 hours as a noninvasive measure to judge early reperfusion. Patients with a creatine kinase peak I 15 hours were regarded as having early reperfu- sion.16

Statistical analysis Values reported are mean value f 1 SD. Comparisons between groups were obtained with the Wilcoxon test. The &i-square test or Fisher’s exact test was used in the clinical course comparison.

RESULTS Of the 45 patients, 20 received APSAC and 25 hep-

at-in. Every patient showed a Tl-201 defect and a corre- sponding Tc-99m PYP accumulation. Thirty-three pa- tients (73%) had a homogeneous (group A) and 12 patients (27%) an inhomogeneous (group B) Tc-99m PYP accumulation pattern in the area of a Tl-201 defect.

APSAC versus heparin: Analysis of ‘the clinical data revealed no significant difference between the APSAC and the heparin groups with respect to sex, mean age, infarct location, time from AMI to treatment and time to scintigraphy (Table I). With regard to the Tl-201/Tc-99m PYP pattern, no significant difference was seen between the APSAC group (group A: n = 15; group B: n = 5) and the heparin group (group A: n = 18; group B: n = 7) (Table II). Moreover, scintigraphic infarct size, Tl-201 defect score, global ejection fraction, late patency of the infarct-related vessel, and maximal creatine kinase level were comparable in both groups, whereas creatine kinase in the APSAC group peaked after 11 * 6 hours and thus was seen significantly (p <O.OOl) earlier than in the heparin group with a creatine kinase peak after 19 & 7 hours (Table II).

we99n m uptalcs pdtem Base- line characteristics in patients with a homogeneous Tl-

TECHNETIUM-99M PYROPHOSPHATE IN AMI 9

201/k- 99m PYP pattern (group A) were not different from those with an inhomogeneous pattern (group B) (Table III). Additionally, maximal increase in creatine kinase was similar in both groups. However, creature kinase peaked earlier in group A than in group B (Table IV). Moreover, global left ventricular ejection fraction was significantly higher in group A than in group B (Table IV).

In Group A, 30 of 31 patients had a patent infarct- related coronary artery. One patient with occlusion of the left anterior descending coronary artery showed complete filling of the infarct vessel by collaterals. In group B, 7 of 11 patients had a patent infarct-related ves- sel (Table IV). Filling over collaterals was not seen in group B patients with persistently occluded infarct ves- sels.

FIRURE 1. vs (A and C) versus i nhom@mws (E and D) techneiium99m Wrophorphate (W99m PYP) acounn~latioa in acute myoaudid infarction indicating low or W@ risk of developing severe heart failure: sh0rhxiS cuts of thallium (ll~Ol/Y&Sm PYP tm in 4 dWfemnt patients. Normal lb2OZ accumulatii is shown in red, Tb201 dsfect in blue, and Tc-SSm PYP uptdce in yellow aml m. 4 homo%eneous m49m PYP accumulation wwespoMngtoall-201 defect is seen in anWosepM i-ion; S, inhomogeneous Tc-SBm PYP accumulation i-s) is located at the edge of thsconerpondingTl-2Oldefe4ctinanterosepMinfarction;C,homogeneous Te99m PYP accumulation colrerponding to R 201 defect is seen in postedateml intarction; D, Homogeneous Tc-SSm PYP accumulation (mws) is located at the edge of ths comspodng lb201 &fed in infe&u infarction.

10 THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 71 JANUARY I,1993

TABLE I Baseline Characteristics of Treatment Groups TABLE Ill Baseline Characteristics of Groups A and B

Patient APSAC Heparin Characteristics (n = 20) (n = 25)

Age (years) 57 + a 56 + 9 Men/women 15/5 20/5 Infarct location

Anterior 11 11 lnfenor 9 14

Time to treatment (mm) 175 + 38 161 + 56 Time to scintigraphy (hours) 28 + 12 33 k 19

APSAC = anisoylated plasmlnogen streptokinase actlvtorcomplex.

TI-201/Tc-99m PYP Pattern

Homogeneous Inhomogeneous Patient (group A) (group B)

Characteristics (n = 33) n = 12)

Age (years) 57 + a 56 2 9 Men/women 2716 814 Infarct location

Anterior 15 7 Inferior ia 5

Time to treatment (min) 162 + 39 165 r 64 Time to scintigraphy (hours) 31+20 27 + 12

Abbreviations as in Table II.

TABLE II Comparison of 20 APSAC Patients and 25 Heparin Patients

APSAC (n = 20)

Heparin in = 251

P Value

TI-201/Tc-99m PYP pattern

Homogeneous (group A)

lnhomogeneous (group B)

TI-201 defect score Tc-99m PYP infarct

size Global LVEF Patency of the

culprit vessel (n = 42)

Max CK Time to CK peak

15

5

137 + 88 u 135 + 78”

57 -t 17 17119 (89%)

925 + 507 U/L 11 +6hours

la

7 NS

la3 + 106 u 143 r 45”

NS

NS

55 + 15 20123 (87%)

NS NS

1,025 -t 659 U/L NS

19 + 7 hours <O.OOl

APSAC = anlsoylated plasminogen streptokinase activator complex; CK = creatine klnase; LVEF = left ventricular ejection fraction,; Max. = maximal: PYP = pyrophos- phate; Tc = technetium; TI = thallium; U = arbitrary units.

With regard to Tl-201/R-99m PYP accumulation pattern, the Tl-201 defect score was lower in group A than in group B. Likewise, relative size of the infarction as determined from Tc-99m PYP images was signifi- cantly lower in group A than in group B (Table IV).

Clinical course: A total of 15 patients experienced cardiogenic shock or severe heart failure. Patients in group B had a higher incidence of these in-hospital complications compared with patients in group A (92 vs 12%, p <0.0005) (Figure 2). Two patients in group B died of cardiogenic shock.

Tl-201 defect score and scintigraphic infarct sizes were greater in patients with the above-mentioned clini- cal events (Tl-201: 229 + 87 vs 128 + 97 U, p <O.Ol; Tc-99m PYP: 193 f 65” vs 112 + 79”; p <0.0.5).

Other complications included arrhythmia in 18 pa- tients, infarct extension by routine clinical criteria in 4 patients, and atrioventricular block in 3 patients. How- ever, no correlation with the Tl-201nc-99m accumula- tion pattern was seen in these patients.

DISCUSSION APSAC versus heparin: The fist purpose of this

study was to assess noninvasively a possible benefit of APSAC over heparin by Tl-201/‘Tc-99m PYP tomog- raphy. The recently published German multicenter trial

TABLE IV Comparison of Homogeneous (group A) and Inhomogeneous {group B) TI-201/Tc-99m PYP Accumulation Patterns

Group A Group B (n = 33) (n = 12) p Value

TI-201 defect score 132 ? 89 U 242 +- 98 U < 0.005 Tc-99m PYP infarct 121 i 72” 188 2 740 <0.05

size Global LVEF 60 + 13% 46 + 14% < 0.005 Max CK 941 + 617 U/L 1,097 r 523 U/L NS Time to CK peak 15 -c 8 hours la + 7 hours < 0.05 Patency of the 30131 7/11 <0.025

culprit vessel 97% 64% (n = 42)

Abbreviations as in Table II.

of APSAC versus hepatin for AMI’O as well as other reports17-l9 demonstrated the favorable influence of APSAC on clinical course in the hospital. However, in contrast to other published reports,19,20 no differences were found in the German multicenter trial between the 2 treatment groups regarding coronary artery patency assessed by late angiography and left ventricular ejec- tion fraction. The subgroup of the present study exam- ined by scintigraphy showed similar results. In agree- ment with the clinical and angiographic data, scintigraphic iinamgs corresponded in both treatment groups. Other reports have described a significant reduc- tion in infarct size (up to 31%) in the APSAC group.‘9320 However, these studies also showed sign&ant differ- ences with respect to frequency of reperfusion. whether coronary patency is or is not achieved will probably determine the size of infarction.2o In contrast, Castaigne et a121 found that ejection fractions were not significant- ly higher in patients who received APSAC at home, with a gain of approximately 60 minutes compared with pa- tients who received APSAC after admission. Disparity of time of reperfusion in the 2 treatment groups of our study population, as indicated by mean time to creatine kinase peak, may be of minor importance for infarct size as assessed by scintigraphic parameters and global ejec- tion fraction. Further studies will have to clarify this point.

lb201/Tc-aam pyrophosphat e uptake pattern: The second question of the present study was to eluci- date the interrelation between Tl-201Rc-99m PYP ac-

TECHNETIUW99M PYROPHOSPHATE IN AMI 11

FIGURE 2. Diagmn of cawelation between scinti#aphic patterns and clinical course in all patients idepedat of therapy.

cumulation pattern and clinical findings, which has not been described until now. In this study, creatine kinase maximal peak was not different in both group A with a homogeneous pattern and group B with an .inhomoge- neous pattern. However, global left ventricular ejection fraction was higher and scintigraphic infarct size was lower in group A. These results strongly suggest that an inhomogeneous pattern is associated with a larger Ah4I size than is usually seen in patients with a homogeneous accumulation pattern. Furthermore, the significantly shorter time to creature kinase peak in group A suggests a relation between scintigraphic pattern and time to cor- onary perfusion. The inhomogeneous pattern was gener- ally associated with increased activity accumulation of Tc-99m PYP in the border infarct periphery, as indicat- ed by Tl-201 defect and decreased Tc-99m PYP uptake at the center. Prior studies described partial flow depen- dency of Tc-99m PYP uptake within necrosis.22,23 Tc- 99m PYP accumulation was found to achieve a maxi- mum in the range between 31 and 50% of control flow.24,25 Only moderate or extremely reduced Tc-99m PYP uptake was seen at low flow. Thus, it is likely that residual perfusion is required for homogeneous Tc-99m PYP uptake to the infarct area. Actually, 97% of the patients in group A had a patent infarct-related vessel, whereas 36% of the patients in group B showed an oc- clusion. However, the fact that coronary angiography was performed 2 to 3 weeks after AMI makes this tind- ing less convincing than it might possibly have been oth- erwise. Nevertheless, the hypothesis of Rude et a12’j con- cerning the development of the doughnut pattern as found with planar imaging technique is supported. From our results drawn by tomographic imaging, it is likely that an inhomogeneous accumulation corresponds to the doughnut pattern and is due to occlusion of the infarct- related vessel, as suggested by Rude et a1,26 or due to lack of capillary reperfusion (no reflow).27 In contrast to planar imaging, 26 the tomographic technique enables identification of a inhomogeneous pattern even of the inferior wall.

Clinical course: Patients with an inhomogeneous accumulation pattern (group B) had a higher risk of se- vere heart failure or cardiogenic shock. Other complica-

tions such as angina pectoris, arrhythmia, reinfarction or atrioventricular block were not related to a particular accumulation pattern. These furdings were in agreement with the data reported for the doughnut pattern in ante- rior infarction by Rude and co-workers.26 However, the results of the present study were more obvious. A pri- mary reason for the higher morbidity in group B patients was that they may have had progressive infarct expan- sion. In animals, even late reperfusion resulted in much less infarct expansion compared with permanent occlu- sion.28 Finally, infarct expansion, persistently occluded infarct-related coronary arteries and large infarcts appear to be risk factors for progressive left ventricular dilata- tion.29

In contrast, Botvinick et a130 found a larger extent of Tc-99m PYP accumulation and Tl-201 defect in symp- tomatic patients and in decreased patients than in asymptomatic patients. However, their data enabled identification of only 5 of 8 symptomatic patients. The Tl-201Ec-99m PYP pattern described in this present study provides more accurate prognosis regarding an adverse clinical course than conventional scintigraphic parameters.

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TECHNETIUM99M PYROPHOSPHATE IN AMI 13