Effects of streptokinase during acute myocardial infarction on the signal-averaged electrocardiogram and on the frequency of late arrhythmias

Effects of Streptokinase During Acute Myocardial Infarction on the Signal-Averaged Electrocardiogram and on the Frequency of Late Arrhythmias Tom J. M. Tobe, MD, Cees D. J. de Langen, PhD, Harry J. G. M. Crijns, MD, Ans C. P. Wiesfeld, MD, Wiek H. van Gilst, PhD, Karin G. Faber, MD, Kong I. Lie, MD, and Harry Wesseling, MD Atthough a number of studies have shown that the htcidence of late potentials is lower after thrombolytic therapy, it is not known whether this is paralleled by fewer atrhythmic events during ion&term foiiow+rp. in patients with first acute myocardiai hrfarction, filtered QRS duration was sigdflcantiy shorter when treated with streptoW nase (95 + 11 ms, n = 53) than when treated with conventional therapy (66 f 12 ms, n = 77, p <0.05). The iowanpiitude si~i (D& was shorter after thrombolysis (26 f 11 vs 22 +- 12 ms, p ~0.02). Terminal rootmean-square voltage did not dir significantly (412 24 vs 35 f 23 pV). inespective of treatment, late potentials were predie tive in the complete group (n q 171) for arfhytk mic events during foliowup (13 -t 6 months, range 6 to 24) (hazard ratio 7.7, p ~0.02, Cox propodionachazards survival analysis), but treatment (streptokinase vs conventional) did not si@dficantiy affect outcome when added to the model. it is concluded that thrombolysis prevents the development of late potentials. However, this study does not confirm the hypothesis that prevention of late potentiiis leads to a decrease in anltytk mic events. (Am J Cardiol1663;72:647~51)

From the Departments of Pharmacology, Clinical Pharmacology and Cardiology, University of Groningen, Groningen, the Netherlands. This study was supported by Grant 86.061 from the Netherlands Heart Foundation, The Hague, the Netherlands. Manuscript received August 27, 1992; revised manuscript received May 13, 1993, and accepted May 20. Address for reprints: Tom J. M. Tobe, MD, Department of Internal Medicine, Sophia Hospital, Dokter van Heesweg 2, P.O. Box 10400. 8000 GK Zwolle. the Netherlands.

V

entricular late potentials are low-amplitude potentials that prolong the QRS complex on a signal-averaged surface electrocardiogram. They are the body surfacerepresentationof slow and inhomogeneous conduction within damaged myocardium,1,2 known to be part of the substratefor reentrant ventricular tachycardia. The presence of late potentials in patients with recent myocardial infarction is a marker for both spontaneous’%4 and inducible ventricular tachycardia5 and is, thus, a harbinger of suddendeath. This study assessesthe effect of thrombolytic therapy on the incidence of late potentials after acute myocardial infarction and their relation to outcome. METHODS Patie&

The study population consistedof 171patients (aged 63 + 11 years, range 36 to 92) who were admitted to our hospital with acute myocardial infarction, defmedby the presenceof 22 of the following: (1) characteristic precordiaf chest pain lasting for >30 minutes and not relieved by sublingual nitroglycerin; (2) typical ST-segmentdeviation with reciprocal changesor ST-segmentelevation in the absenceof a bundle branch block; and (3) an increase in both creatine kinase >lOO U/liter and creature kinase-MB cardiac isoenzyme >lO U/liter. These 171patients were part of a group of 206 consecutive patients. Eighteen of them were excluded becauseof bundle branch block, 17 becauseonly 1 of the 3 criteria for the diagnosis of acute myocardial infarction was met. Seventy-two patients without contraindications to thrombolytic therapy who were admitted within 6 hours after the onset of symptoms were treated with intravenous streptokinase(1.5 MU in 30 minutes, Kabikinase, KabiVitrum AB, Stockholm, Sweden). Ninety-nine patients, who could not be treated with streptokinase(becauseof admission >6 hours after the onset of symptoms, absence of typical electrocardiographic features, peptic ulcer disease,recent surgery or hemorrhage,age >75 years) were treated conventionally with nitroglycerin, heparin, aspirin and B blockers, and served as control subjects. One hundred thirty patients had a first myocardial infarction, and 41 patients had reinfarction (Table I). Patients gave informed consent for the study. Signakaveraged electrocardiiaphy: Signal-averaging was done 3 to 27 days after acute myocardial infarction with the subjects in a supine position. Seven LATE POTENTIALSAND THROMBOLYSIS 647

TABLE I Baseline Characteristics on Admission to the Coronary Care Unit and Clinical Variables During Hospital Stay Treatment Thrombolysis Number of patients 72 Age (years) 60~ 11 Men/women 57115 Site of infarction Anterior 28 Inferior 36 Other 8 HR (beatslmin) 72 5 18 Systolic BP (mm Hg) 134 & 26 Diastolic BP (mm Hg) 83 t- 15 HR*BP 9,694 2 3,167 (mm Hg beatslmin) Previous infarction 18 Peak CK (U/L) 982 -c 1042 Time to peak CK (hours) 15.5 2 7.2 Peak CK-MB W/L) 89 zk 89 Time to peak CK-MB 14.6 + 7.1 (hours) Type of infarction Q-wave 58 Non-Q-wave 14 Ventricular fibrillation 4 < 48 hours Ejection fraction f%)* 46 2 15

Conventional 99 64% 11 66133 32 43 24 82 2 146 + 86 2 12,211 f 23 571 r 24.6 f 51 f 23.8 it

25 27 18 4,887

525 7.8 41 8.0

P Value 0.04

0.005 0.01 0.001

0.005 0.001 0.001 0.001

66 33 14 48 r 15

‘Radionuclide ventriculography was performed in 70% of the patients. Heart rate and blood pressure were measured on admission. BP = blood pressure; CK = creatine kinase; HR = heart rate.

self-adhesive silver/silver chloride electrodes (Red Dot, 3M, St. Paul, Minnesota) were attached: the horizontal (X) electrodes in the right and left midaxillary lines at the fourth intercostal spaces,the vertical (Y) electrodes on the suprastemalnotch and Vs position, and the sagittal (Z) electrodesin the V2 position anteriorly and at the corresponding position posteriorly. The seventh indifferent electrode was placed on the eighth rib in the right midaxillary line. Approximately 150 QRS complexes from the X, Y and Z leads were recorded, averagedusing an iterative cross-correlationprocedureto optimize QRS alignment,6 vector-summed and then filtered bidirectionally (40 Hz)? The filtered signals for the 3 leads were combined into a vector magnitude, the square root of X2 + Y2 + Z2. The mean noise level witbin the ST segment was 0.6 f 0.2 pV The beginning and the end of the filtered QRS complex were detectedautomatically when the signal rose above the level of 2 times the SD of noise before and after the QRS complex. Root-mean-square voltage (V,) was measuredin pV for the terminal 40 ms of the QRS vector complex. Low-amplitude signals (Dm) were measured in milliseconds from the point where the voltage camebelow 40 pV to the end of QRS complex. Normal values are: QRS 414 ms, Va 220 pV, and Da 138 ms. When 3 of these variables were abnormal, the signal-averagedelectrocardiogramwas consideredabnormal (late potential).8 lwelvdead elecboca diagram: The 1Zlead electrocardiogram was recorded 7 to 23 days after acute myocardial infarction and was interpreted independently 646

THE AMERICANJOURNALOF CARDIOLOGY VOLUME72

by 2 investigators who were unaware of all data except age, gender, medication and potassium level. The following criteria were used: pathologic Q wave (chest leads, leads I and aVL 140 ms); lead II, any Q in the setting of inferior wall infarction; lead III, 240 ms and 24 of the R wave; and aVF, 230 ms and >I/ of the R wave. Anterior wall infarction was delined as new pathologic Q waves or evolving ST-segmentabnormalities in lead Vt-6, I or aVL. Inferior wall infarction was defined as new pathologic Q waves or evolving ST-segment abnormalities in lead II, III or aVE Posterior infarction was delined as R > S in VI. Anterior, septal and purely lateral infarction were categorizedas anterior infarction. Inferolateral, posterolateral and inferoposterior infarction were categorized as inferior infarction; this was done becausethe incidence of late potentials is known to be higher in inferior than in anterior wall infarction4 probably becauseof the relatively late activation of the posterobasalarea of the left ventricle.9 Previous myocardial infarction was delined as either documented or preexisting (i.e., not evolving) electrocardiographic abnormalities suggestivefor old myocardial infarction. Follonrup and study end pdnts: All patients were followed as outpatients for a minimum of 6 months (mean 13 f 6, range 6 to 24). At discharge,64% of the patients were taking P-blocking agents.A complete follow-up was conducted in all patients. Detailed inquiries were made of the general physicians or relatives of nonattenders to determine whether these patients had died and, if so, the mode of death. At the end of the study, a written questionnaire was sent to the general physician, including questions regarding syncope, hospitalization, recurrent myocardial infarction, coronary artery bypass surgery, percutaneous transluminal coronary angioplasty and death. An arrhythmic event was defined as sudden death or occurrence of documented sustained ventricular tachycardia or ventricular fibrillation (not associatedwith recurrent myocardialinfarction). Sustainedventricular tachycardia was defined as spontaneousventricular tachycardia lasting >30 secondsor requiring intervention before that time. The secondaryreasonfor exclusion was recurrent myocardial infarction. This was not characterizedas an arrhythmic event. These patients were excluded from further follow-up, becauserecurrent myocardial infarction can modify the arrhythmic substrateas it had developed after the index infarction at entrance to the study. Coronary artery bypass surgery or percutaneoustransluminal angioplasty were no reasonsfor exclusion, unless theseprocedureswere complicated by recurrent myocardial infarction. Statistical analysis Student’s t test and MannWhitney U test were used for testing continuous variables. Discrete variables were analyzed by &i-square analysis and Fisher’s exact test. A Cox proportional-hazards survival analysis (using late potentials, treatment, site of infarction, previous infarction, Q-wave infarction, peak creatine kinase, age, RR interval, QTc) was performed to assessthe impact of the reduction of late potentials on arrhythmic events. Data are presented as mean f SD unless stated otherwise.

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TABLE II Signal-Averaged Electrocardiography Infarction

for First Myocardial Infarction and Previous

First Myocardial Infarction Thrombolysis (n = 54)

Conventional (n = 76)

Previous Infarction Thrombolysis (n = 18)

p Value

Conventional tn = 23)

p Value

a

4 6 6

NS NS NS

102 f 17 34k 14 33 t 25

102 k 17 35 2 20 37 k 31

NS NS NS

Qualitative Analysis QRS >114ms D40 > 38 ms

2 6

<20

9

v40

pv

9 20 26

NS 0.05 0.05

5 7

Quantitative Analysis QRS Ims) D40

95+ 11 285 11 41 224

(ms)

V40 (PV)

992 12 33 2 12 35 + 23

0.05 0.02 NS

Data are presentedas mean + SD. D - low-amplitude signal < 40 pV; QRS = filtered QRS complex: Ills. 4o -

TABLE III Signal-Averaged Electrocardiography Infarctions

V4o = root-mean-square

Conventronal (n = 24)

40

for First Anterior and Inferior Wall Inferior Infarction

Anterior Infarction Thrombolysis tn = 26)

voltage in the terminal

p Value

Thrombolysis (n = 24)

Conventional (n = 39)

p Value

1 3 4

4 12 16*

NS NS 0.05

982 10 30 + 8 352 16

992 11 33 + 12 32 + 22

NS NS

Qualitative Analysis QRS >114ms D4o > 38 ms v40

<20

pv

1 3 5

3 6 a

NS NS NS

Quantitative Analysis QRS tms) D40 (ms) V40 (l.lV)

92 k 12 28k 12 45 k 29

100 + 14 34 + 13 37227

0.05 NS NS

NS

Data are presented as mea” k SD. Abbreviations as in Table II

RESULTS An abnormal D4a and VN were significantly more frequent after conventional treatment, but for QRS only a trend toward a higher incidence after conventional treatment was found (Table II). If analyzed as a continuous variable, QRS was significantly longer after conventional treatment. Previous myocardial infarction: Forty-one patients who had experiencedprevious myocardial infarction (36 of them experienced 1 previous infarction, 4 had 2 previous infarctions, and 1 had 3 previous infarctions) were studied. Table II shows that the incidence of late potentials was not lower in streptokinase-treatedpatients, in contrast to the effects after a lirst myocardial infarction. Even a trend toward a beneficial effect of thrombolysis was absent. Anterior versus inferior infarctiow A subgroup analysis in the patients with a tirst myocardial infarction was performed. The site of myocardial infarction was determined on the basis of the 1Zlead electrocardiogram. Fifty were characterizedas anterior wall myocardial infarction, 63 as inferior wall myocardial infarction. Treatment did not differ between subgroups. The electrocardiographic site of infarction could not be determined in 15 patients; they were excluded in this subgroup analysis. First myocadial

infardow

The effects of treatment according to the site of infarction are listed in Table III. The differencesbetween thrombolytic and conventional therapy showed the same trend in these subgroups,but becauseof the breakdown into smaller numbers, they were less frequently significant. Thrombolysis showed differential effects on the signal-averagedelectrocardiogramdepending on the site of myocardial infarction. Prolongation of the filtered QRS duration was apparently prevented by thrombolytic therapy in anterior wall myocardial infarction, whereas no such difference was observedin inferior wall myocardial infarction. However, in inferior wall myocardial infarction an abnormal Va was less frequent after thrombolytic therapy (4 of 24 [17%] vs 16 of 39 [41%] after conventional treatment, p <0.05), whereas no statistical difference was found in anterior wall infarction. Followup: During follow-up 10patients (6%) had an arrhythmic event. One patient had documented ventricular fibrillation that was not associated with acute myocardial infarction, and 2 patients presentedwith sustained monomorphic ventricular tachycardia. Seven patients died suddenly within 1 hour after the onset of symptoms. Total cardiac mortality was 15 of 171 (9%). The above-mentioned7 patients died suddenly: 4 died of recurrent myocardial infarction, and 4 died becauseof proLATE POTENTIALS AND THROMBOLYSIS

649

that is not related to the previous infarct cannot cause the late potential to disappear.Third, reinfarction in the same coronary artery may lead to disappearanceof a previously present late potential. It is known that removal of myocardium can make late potentials disappear2(jIn this way, late potentials may have disappeared in patients receiving conventional treatment, thereby confounding statistical analysis. Fourth, owing to the greater baseline heterogeneity, a larger group size is required to detect an effect of treatment (lack of power). Therefore, a definite negative conclusion regarding the effect of thrombolysis on late potentials in patients with reinfarction cannot be drawn on the basis of these negative results. Site of myocadial InfaMiow After thrombolysis, V4a was higher in patients with inferior wall myocardial DISCUSSION In this study, the incidence of late potentials was infarction. VM is low when low-amplitude signals are lower after thrombolytic therapy in patients with Iirst presentat the end of the QRS complex and beyond. This myocardial infarction, but it was not paralleled by a sig- situation is more likely to be presentwhen late potentials nilicant reduction in arrhythmic events. The latter lind- commenceat the end of the activation of the QRS coming is in agreementwith recent studies.10s1 ’ Like other plex, i.e., in the case of inferior wall myocardial infarcstudies, our study was nonrandomized,which may have tion. The anterior wall is activated early9 and the chance resulted in some differencesin baseline parameters.12-17 of low-amplitude signals to be present beyond the end The effect of these initial differences on the subsequent of the QRS complex is smaller than in inferior wall developmentof late potentials is unknown, but the over- myocardial infarction. Effects of treatment on V40 are all result is that thrombolytic therapy is effective in re- therefore to be expected more often in inferior wall ducing the incidence of late potentials after myocardial myocardial infarction. infarction. Evidence is growing that patency of the infarct-related coronary artery is the mechanism by which Acknowledgment: We wish to thank Dr. V Fidler, thrombolysis can prevent the development of late poten- Department of Medical Statistics, for performing statistials after myocardial infarction.12~13J6J*J9 tical analysis, Dr. A. Dijk, and Dr. W van der Velden Patency of the infarct-related coronary artery is an for their support in creating the database,and Dr. PH. independent predictor of survival after myocardial in- Mook for designing the software for signal-averaged farction.20Moreover, the improved l-year survival after electrocardiography. thrombolytic therapy was obtained despite a limited effect on left ventricular ejection fraction.21,22Furthermore, a considerable reduction in mortality was observed in patients who received thrombolytic therapy 12 1. Simson MB. Euler D. Michelson EL. Falcone RA. Suea JF. Moore EN. Detertion of delayed ventricular activation on the body surface in dogs. Am J Physiol to 24 hours after the onset of symptoms,23when myo- 1981;24l:H363-H369. cardial salvagedue to thrombolysis is no longer expect- 2. Gardner PI, Ursell PC, Fenoglio JJ, Wit AL. Electmphysiologic and anatomic for fractionated electrograms recorded from healed myocardial infarcts. Cired to occur. This indicates that factors other than myo- basis culation 1985;72:596-611. cardial salvagealso play an important role in improving 3. Kuchar D, Thorbum CW, Sammel NL. Late potentials detected after myocarthe long-term prognosis after thrombolytic therapy?4 dial infarction: natural history and prognostic significance. Circulation 1986;74: Improvement in electrical stability, prevention of re- 4.1280-1289. Games JA, Winters SL, Martinson M, Machac J, Stewart D, Targonski A. The modeling, and maintenance of collateral flow to other prognostic significance of quantitative signal-averaged variables relative to clinical variables, site of myocardial infarction, ejection fraction and ventricular premature stenotic vessels are proposed as potential mechanisms beats: a prospective study. J Am CON Cardio/ 1989;13:377-384. other than pure myocardial salvagethat can improve sur- 5. N&s PC, Gang ES, Mandel WJ, Ladenheim ML, Lass Y, Peter T. The signalaveraged electrocardiogram as a saeening test for inducibility of sustained venvival.24 tachycardia in high risk patients: a prospective study. J Am Coil Cardiol Previous myocadial infarction: Despite beneficial tricular 1987;9:539-548. effects in patients with a first myocardial infarction, 6. Den&s AR, Richards DA, Farrow RH, Davison A, Ross DL, Uther JB. Techthrombolysis was not able to reduce the incidence of late nique for maximizing the frequency response of the signal averaged Frank vectorJ Biomed Eng 1986;8:207-212. potentials after reinfarction. There are several reasons cmliogram. 7. Simson MB. Use of signals in the terminal QRS complex to identify patients for this apparent lack of effect. First, collateral cir- with ventricular tachycardia after mywardial infarction. Circulation 198 1;64: culation may have developed to a greater extent in pre- 235-242. B. Breithardt G, Cain ME, El-Sherif N, Flowers N, Hombach V, Jaw MJ, Simviously infarcted hearts than in hearts without myocar- son MB, Steinbeck G. Standards for analysis of ventricular late potentials using dial infarction. Late potentials are in part dependenton high resolution or signal-averaged electmcardiography. J Am CON Cardiol 1991; 17: the histologic shapeof the infarct border zone, and this 99!%1006. S. Dumx D, van Dam RTh, Freud GE, Janse MJ, Meijler FL, Arzbaecher RC. may have been influenced by the presenceof collateral Total excitation of the isolated human heart. Circularion 1970:41:89%912. circulation during the process of infarction and heal- 10. Pedretti R, Laporta A, Etm MD, Gementi A, Bonelli R, AI& C, Colombo E, F, Santoro F, Carh B. Influence of thrombolysis on signal-averaged ing.25 Second, if an old infarct causing a late potential Maslowsky electrocardiogram and late arrhythmic events after acute myocardial infarction. Am is present, effective thrombolysis in a coronary artery I Cardiol 1992;69:8%-872. gressive pump failure. Four patients had nonfatal recurrent myocardial infarction. Two patients died of cancer. Using Cox proportional-hazards survival analysis, late potentials appeared to predict at-rhythmic events @vard ratio 7.7,p 4.02, 95% confidencelimit 1.4-42.0). However, treatment (streptokinase or conventional) did not significantly affect outcome when this was added to the model. Although an abnormal signal-averagedelectrocardiogram was less frequent in the streptokinasetreated group and thrombolysis is known to have a beneficial effect on survival after myocardial infarction, improvement in survival through a streptokinase-related effect on late potentials could not be proved in this study.

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11. Malik M, Kulakowski P, Odemuyiwa 0, Poloniecki I, Staunton A, Millane T, Farrell T, Camm AJ. Effect of thrombolytic therapy on the predictive value of signal-averaged electrocardiography after acute myocardial infarction. Am J Cardiol 1992;70:21-25. 12. Gang ES, Lew AS, Hong M, Wang FZ, Siebert CA, Peter T. Decreased incidence of ventricular late potentials after successful thrombolytic therapy for acute myocardial infarction. N Engl J Med 1989;321:712-716. 13. Chew EW, Motton P, Mmtagh JG, Scott ME, O’Keeffe DB. Intravenous streptokinase for acute myocardial infarction reduces the incidence of ventricular late potentials. Br Heart J 1990$4%8. 14. Vatterott PJ, Hammill SC, Bailey KR, Wiltgen CM, Gush BJ. Late potentials on signal-averaged electrocardiograms and patency of the infarct-related a&ry in survivors of acute myocardial infarction. J Am CoN Cardiol 1991;17:330-337. 11. Breithardt G, Borggrefe M, Karbenn U. Late potentials as predictors of risk after thrombolytic treatment? Br Heorr J 1990;64:17C176. 16. Eldar M, Lear J, Hod H, Rotstein Z, Truman S, Kaplinsky E, Abboud S. Effect of thmmbolysis on the evolution of late potentials withm 10 days of infarction. Er Heart J 1990:63x273-276. 17. Winters SL, Games IA. Editorial comment. Thrombolytic therapy, infarct vessel patency and late potentials: can the arrhythmic substrate be altered? J Am Co/l Cardiol 1990,15:1277-1278. 18. Lange RA, Cigarma RG, Wells PJ, Kremen MS, Hillis LD. Influence of anterograde flow in the infarct artery on the incidence of late potentials after acute myocxdial infarction. Am J Cardiol 1990,65:554-558. 19. de Chillou C, Sadoul N, Briancon S, Aliot E. Factors determining the occur-

rence of late potentials on the signal-averaged electrocardiogram after a first myocardial infarction: a multivariate analysis. J Am Co// Cardiol 1991; 18:163X-1642. 20. Stadius ML, Davis K, Maynard C, Ritchie JL, Kennedy JW Risk stratification for 1 year survival based on characteristics identified in the early hours of acute myocardial infarction. The Western Washington Irmacoronary Streptokinase Trial. Circulation 1986;74:703-7 11. 21. Kennedy JW, Ritchie JL, Davis KB, Stadius ML, Maynard C, Fritz JK. The Western Washington randomized trial of intracoronary streptokinase in acute myocardial infarction: a 12 month follow-up report. N En,q/ J Med 1985:312: 1073-1078. 22. Sheehan FH, Braunwaid E, Canner P, Dodge HT. Gore J, Van Netta P, Passamani ER, Williams DO, Zaret B, and co-investigators. The effect of intravenous thrombolytic therapy on left ventricular dysfunction: a report on tissue-type plasminogen activator and streptokinase from the Thrombolysis in Myocardial Infarction (TIM1 Phase I) trial. Cirrukmon 1987:75:817-829. 23. ISIS-2 Collaborative Group. Random&d toal of intravenous strcptokinase, oral aspirin, both, or neither among 17.187 cases of suspected acute myocardial infaw tion: ISIS-2. Lanret 1988;2:349-360 24. Braunwald E. Myxardial reperfusion, IimitatIon of infarct sue, reduction of left ventricular dysfunction, and improved survival. Should the paradigm be expanded? Circularion 1989;79:441-444. 25. Factor SM. Okun EM, Kirk ES. The histological lateral border of acute canine myocardial infarction. A function of microcirculation. Cwc Res 198 1;48:64CG~49. 26. Marcus NH, Fakone RA, Harken AH, Josephson ME, Simson MB. Body barface late potentials: effects of endccardial resection in patients with ventricular tachycardia. Cwrulan’on 1984:70:632-637.

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