Frequency of low-grade residual coronary stenosis after thrombolysis during acute myocardial infarction

y-p-------BRONARY

ARTERY

DlSEASE

requency of Low-Grade Residual Coronary Stenosis After Thrombolysis During Acute Myocardial Infarction James C. Marshall, DO, Harvey L. Waxman, MD, Anthony Sauerwein, MD, tan Gilchrist, MD, and Peter B. Kurnik, MD

The clinical, angiographic and demographic characteristics of 42 patients with low-grade (O.lO) but were significantly older (52 f 12 vs 56 f 10 years, p = 0.02). Prior acute Ml or angina was unusual in group I. Sixty percent had no significant (>SO%) residual coronary artery disease while 25% had residual single artery disease. Average significant (>50% diameter stenosis) residual vessel disease was 0.6 f X.0 for group I and 1.9 f 0.9 for group II (p
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From the Division of Cardiology, Cooper Hospital/University Medical Center, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Camden, New Jersey. Manuscript received January 3, 1990; revised manuscript received and accepted May 14,199O. Address for reprints: James C. Marshall, DO, Presbyterian Medical Center, Philadelphia Heart Institute, 39th and Market Streets, Philadelphia, Pennsylvania 19104.

clearly associated with the infarct narrowing occurred earlier (4 f 4 months) than events not related to (23 f 15 months, p
he natural history and responseto treatment of patients with infarct lesion residual diameter stenosis (50% after thrombolytic therapy for acute myocardial infarction (MI) are unknown. Most acute MIS are related to thrombotic occlusion at the site of an atherosclerotic plaque.’ Recent published reports on thrombolysis have suggested that while a critical (270%) diameter stenosisis usually present before occlusion, the incidence of noncritical stenosis is not uncommon and approximates 10 to 20% of all patients undergoing thrombolysis.2m5 Information concerning nonsignificant (<50%) “low grade” stenosesafter thrombolysis including follow-up and responseto treatment is unavailable.6 This study provides demographic and clinical data on a population of acute MI patients who received thrombolytic therapy and underwent early arteriography, and were found to have low-grade infarct lesion residual diameter stenosis.

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METHODS Patients: One hundred ninety-eight consecutive patients admitted with a diagnosisof acute MI and receiving conventional dosesof thrombolytic therapy over a 59-month period (February 1984 to January 1989) were identified. All patients had routine therapy (heparin) after acute MI and had coronary arteriography. Cineangiographic films were reviewed and all lesionsassessedby digital caliper measurement when the infarctrelated artery had greatest residual diameter stenosisof 570% by visual estimate. Acute MI was diagnosed by conventional criteria including prolonged chest pain and ST elevation 20.1 mV in 2 contiguous leads,or Q-wave evolution, or both. Diagnostic creatinine kinase-MB isoenzyme pattern was present in all patients. Demographic and angiographic information was obtained for all THE AMERICAN

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en as the normal vessel diameter. Segments having diffuse disease were excluded from analysis of the normal Group I Group II diameter. Percent diameter stenosis was calculated us(n = 42) (n = 156) p Value ing the difference of the normal diameter and the residDemographic ual lumen diameter divided by the normal diameter and Mean age (years) 52f12 56flO 0.02 the quotient multiplied by 100. A value 550% was re% Men 86 75 NS quired in 2 orthogonal views for group I inclusion. Thrombolytic treatment To measure intraobserver and interobserver variabillntracoronary streptokinase (%) 43(28) NS 9 (21) ity, a series of 3 caliper measurements were performed Intravenous streptokinase (%) 5 (12) 8(5) NS Intravenous tissue plasminogen 28 (67) 105(67) NS on the infarct lesion by 2 independent observers where activator (%) the lesion location was mutually agreed on (40 of 42 Infarct artery (%) patients). For interobserver variability, linear regression Right 19 (45) 65(42) NS demonstrated an r value of 0.9. For intraobserver variLeft anterior descending 16 (38) 64(41) NS Circumflex 23(15) NS ability, the standard deviations (in percent diameter ste7 (17) Saphenous vein graft 4(2) NS 0 (0) nosis) from each series of 3 measurements were averNumber of vessels narrowed >50% 0.6 f 1.0 1.9 f 0.9 0.001 aged and this value was 2.4 (range 0.5 to 5.7), providing Ejection fraction (%) 56*14 52f12 NS an acceptable level of variability.7-9 NS = not significant. Data collection: Group I clinical data were subject to the following definitions: Family history was defined as acute MI at age 155 years in a first-degree relative. patients undergoing thrombolysis from the angiographic Tobacco use required smoking >lO cigarettes per day. data registry. In patients found to have residual infarct Cocaine use implied utilization within 24 hours of acute narrowing (50% (group I), clinical data were obtained MI. Hypercholesterolemia was defined as acute MI adby chart review and by patient interview. Those with mission serum total cholesterol 1250 mg/dl. The medisignificant infarct narrowing (>50%) were designated cation usage must have been present within 1 month of acute MI. Data concerning patient age, gender, infarctgroup II. Identification of the infarct-related lesion: Coronary related artery, extent of coronary artery disease, type arteriography was performed using the standard Jud- and route of thrombolytic therapy and ejection fraction kins technique and catheters in all cases. Ventriculogwere obtained from the angiography registry for both raphy was performed using standard technique in right group I and II patients. and/or left oblique views. The infarct narrowing was Follow-up: Follow-up concerned only group I paidentified anatomically in patients undergoing acute ar- tients and was obtained by office visit or direct teleteriography by the presence of 100% thrombotic occlu- phone interview as well as referring physician contact sion that later reperfused, the most critical residual ste- for 100% of study patients. Clinical end points terminatnosis in the infarct-related artery after thrombolysis, or ing further follow-up included aortocoronary bypass, intraluminal thrombus in the region of the most severe percutaneous transluminal coronary angioplasty of the atherosclerotic narrowing in a known infarct artery. infarct narrowing, demonstration of total occlusion of The anatomic location of the infarct lesion was consis- the infarct narrowing and death. Information obtained tent with infarct location as determined by electrocardiin the follow-up period included: mortality, cardiac ography as well as by wall motion abnormalities on symptoms including typical or atypical angina and dysventriculography. In patients having nonacute arteripnea, activity level, current medical regimen, reassessography before discharge, the infarct lesion was then ment of risk factors for coronary artery disease, subseidentified as that having the greatest diameter stenosis quent hospitalizations and repeat coronary arteriin the infarct artery. Stenosis of >50% by visual esti- ography or exercise testing. Repeat angiography was reviewed in all cases and caliper measurements permate was considered significant in noninfarct arteries. Measurements of infarct narrowing were obtained formed. Hospitalization data were reviewed when reusing a digital caliper as previously described and vali- peat angiography or a question of recurrent ischemia dated.7-9 Measurements were obtained in 2 orthogonal existed. A repeat event was defined as chest pain reviews by 2 independent observers using a standard cine- quiring readmission, sudden death or congestive heart angiographic projector (Vanguard Inc.). A tine frame failure. in diastole was selected from each view to allow the Statistics: The chi-square, Student’s t, Fisher’s exact clearest delineation of the lesion edges and most severe and log-rank tests were used. Data are expressed as diameter stenosis for caliper measurement (Mitumoyo, mean f standard deviation. A p value <0.05 was conFowler Inc.) Lesion morphology was defined according sidered statistically significant. to the criteria of Ambrose et allo and coronary flow was assessed using the Thrombolysis in Myocardial InfarcRESULTS tion trial classification.’ l Demography: Forty-two of 198 (21%) patients were The normal vessel diameter was defined in an angio- identified as having an infarct narrowing 150% and graphically normal arterial segment both proximal and constitute group I. The remaining 156 patients had sigdistal to the infarct narrowing before any branching oc- nificant (>50%) residual diameter stenosis and consticurred. These measurements were made as close to the tute group II. Average age was 52 f 12 years in group I infarct lesion as possible and their average was then tak- and 56 f 10 (p = 0.02) in group II. Risk factors in TABLE

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group I included tobacco in 34 (8 l%), family history in 19 (45%), hypercholesterolemia in 13 (31%), hypertension in IO (24%), diabetes in 5 (12%), migraines in 3 (7%), prior acute MI in 1 (2%), birth control pill use in 1 (2%) and cocaine use in 1 (2%). Comparative data for groups I and II are listed in Table I. Clinical characteristics: Prior to acute MI, antecedent angina occurred in 19 (45%) group I patients. The use of antiplatelet (4 patients, 10%) or antianginal (1 patient, 2%) agents was infrequent. Thrombolysis and postmyocardial infarction angiography: All group I patients had a clinical and angio-

graphic response to thrombolysis as defined by diminution in chest pain, improvement in electrocardiographic injury current and a patent infarct artery. The average time to thrombolysis was 2.1 f 1.1 hours and angiography 5.4 f 7.3 days. Infarct narrowing residual diameter stenosis (average of 3 measurements from 2 observers) was 36 f 7 and 34 f 8% in the right and left oblique views, respectively. No other significant coronary artery disease was found in 25 (60%). Residual single artery disease (>50% stenosis) was found in 11 (25%), double artery disease in 2 (5%) and 3-artery or left main disease, or both, in 4 (10%). Comparative data are listed in Table I. For group II, residual single artery disease was present in 63 (40%), double artery in 42 (27%) and 3artery or left main disease in 5 1 (33%). Twenty-two group I patients underwent acute angiography and all had definite identification of the infarct narrowing based on the aforementioned criteria. Eighteen group I patients with only nonacute coronary arteriography had a high probability of infarct narrowing identification. Two group I patients had minimal or no atherosclerosis and therefore the infarct narrowing remained uncertain, although the infarct-related artery was known with high probability in both cases.

Several patients with 150% diameter stenosis on acute angiography had <50% diameter stenosis on subsequent predischarge follow-up angiography. This is a well-documented phenomenon.2,4,‘2 Follow-up angiograms were used to determine infarct lesion diameter stenosis. Gross lesion morphology was evaluated for group I and consisted of type I narrowing (smooth eccentric) in 12 patients (29%), type II (irregular eccentric) in 17 (41%), concentric irregular narrowing in 8 (19%), concentric smooth narrowing in 1 (2%), minimal irregularities or normal coronary arteries in 2 (5%), minimal irregularity with thrombus in 1 (2%) and thrombus only in 1 (2%). Three patients (7%) had collaterals to the infarct artery during acute arteriography, with resolution on later arteriography (when infarct narrowing was 150%) in all but 1 who had distal embolization. Flow grade from the Thrombolysis in Myocardial Infarction study was normalized (III) in all patients as seen on the cineangiogram from which caliper measurements were derived. Mean time to angiography differed for those with complex (types I and II) versus those without (7 f 8 vs 4 f 6 days) complex lesions, but not significantly (p >O.lO). In testing for significant differences in the frequency of low-grade residual stenosis for anatomic site, type and route of thrombolysis, no statistically significant result was evident. Noninvasive data: Admission and discharge electrocardiograms were reviewed for all group I patients Thirty-four patients had Q-wave acute MI (81%) and 8 had non-Q-wave acute MI (19%). Fifteen patients had anterior (36%), 23 had inferior or inferoposterior (55%) and 4 had lateral or posterolateral acute MI (9%) by electrocardiogram. Twenty-eight of 33 patients (85%) had no reperfusion or electrocardiographic change (when no thallium

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IGURE 1. Flow chart demonstrating clinical and angiographie outcome of patients having repeat events after infarction. ACB = aortocoronary bypass; CA = coronary arteries; IL = infarct lesion; MI = myocardial infarction; PTCA = percutaneous transluminal coronary angioplasty; SCD = sudden cardiac death; 0 = proportion having event secondary to infarct lesion.

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data were available) consistent with &hernia on their postinfarction treadmill study, whereas 5 patients had a scan suggesting ischemia. Postinfarction clinical events: During acute MI, 5 group I patients (12%) had primary ventricular fibrillation before the administration of thrombolytic therapy and were successfully resuscitated. Three patients underwent early bypass surgery and were excluded from follow-up. One patient had in-hospital angina after acute MI. There were no in-hospital deaths or episodes of congestive heart failure. Thirty-nine patients were discharged from the hospital on medical therapy. The mean followup period was 18 f 17 months. No patient had followup of <6 months. Medical therapy included antiplatelet or anticoagulant therapy in 38 of 39 (95%), nitrates in 28 of 40 (70%), calcium channel blocking therapy in 31 of 40 (78%) and p blockers in 13 of 40 (33%) patients. Twelve patients were discharged on warfarin with 4 taking dipyridamole or aspirin concomitantly. Mortality over the follow-up period was low, with 1 of 39 patients (3%) dying from apparent cardiovascular cause (sudden death). Over the course of follow-up, 16 of 39 patients (41%) had events, with 15 experiencing chest pain (Figure 1). Among the 15 patients with chest pain, 16 discrete events necessitated readmission and coronary angiography, whereas 1 patient had angina after catheterization. The 17 events were classified clinically as unstable angina in 8, atypical angina in 5 and acute MI in 4. Twenty-three patients (59%) had a benign course over the follow-up period as defined by the absence of reported symptoms. Repeat coronary angiography: All 14 patients readmitted for chest pain underwent coronary angiography. With use of the information obtained from angiography in addition to clinical and electrocardiographic data, an assessment was made regarding the involvement of the prior infarct narrowing in the new clinical syndrome.

FIGURE 2. Life table plot comparing freedom from ac events to events secondary to the infarct lesion. tivity attributable to the infarct lesion occurs early. faret lesion.

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This was based on the presence of progression in infarct narrowing diameter stenosis to critical range (>-70%), new ST changes in the leads denoting prior infarction due to the original infarct narrowing and the presence of a clinical syndrome compatible with angina pectoris or acute MI. Four of 8 patients with unstable angina were found to have progression of their prior nonsignificant infarct narrowing to the critical range, and that combined with electrocardiographic and clinical data suggested a relation to the new clinical syndrome in 3 of the 4 patients. These 3 patients had subsequent percutaneous transluminal coronary ‘angioplasty (see Figure 1) and clinical improvement. The fourth patient with unstable angina and infarct-narrowing progression had new critical stenosis in a region remote from the infarct artery as suggested by new electrocardiographic changes. Three patients had no progression and were given medical therapy. Three patients with unstable angina (1 with progression, 2 without) had a syndrome consistent with active coronary vasospasm at or near the previous infarct narrowing as documented by angina with ST elevation, response to nitroglycerin or nifedipine, and absence of thrombosis or occlusion on the coronary arteriogram. Five patients with atypical chest pain underwent repeat coronary angiography. All received medical therapy after no progression was found. The subsequent follow-up course remained benign for 4 of the 5 patients over a mean interval of 18 f 17 months, although 1 patient had acute MI secondary to infarct narrowing occlusion 8 months after the index acute MI. Four patients had acute MI and the data permitted clear identification of a former nonsignificant infarct narrowing as the culprit lesion in the new acute MI in 2. The other 2 events were related to previously documented noncritical stenoses in arteries differing from the original infarct vessel. Therefore, 6 of 15 patients (40%) with cardiac events had progression of their prior nonsignificant infarct lesion. Vasospasm and progression at the infarct narrowing accounted for 7 of 17 total events (41%) and 7 of 12 documented ischemic events (58%). One patient who died suddenly did not have postmortem examination. Regarding the time course of events, the mean time to event in the 16 patients was 9 f 11 months. Mean time to the repeat cardiac event was 4 f 4 months in 7 patients with symptomatic progression or active spasm at the infarct narrowing. Mean time to event was 23 f 15 months (p
cigarettes per day (chi-square = 3.64, p = 0.06). There was no statistically significant difference in the frequency of use of antiplatelet agents, warfarin, nitrates, and calcium channel or p blockers in patients with and without repeat events. Non-Q-wave acute MI or reversible thallium defect, the latter finding not unexpected,13 did not correlate with events after acute MI. Lesion morphology was not useful in predicting future ischemic events, most likely because of the high prevalence of types I and II eccentric lesions in this relatively small group. This lack of predictive power, however, has recently been described in a larger group with more severe residual diameter stenosis after thrombolysis.i4 DISCUSSION Recent reports have suggested that the lesion responsible for acute MI has <50% diameter stenosis in 10 to 20% of patients.2m5 This is consistent with the data regarding the limitations of coronary angiography in correlating lesion severity with potential to produce acute MI.i5 This study expands on these observations by providing baseline and follow-up data on a group of patients with low-grade stenoses demonstrating a tendency to thrombose. This subgroup of patients with acute MI appears to have a high prevalence of young men. Recent studies have characterized such a population in a nonthrombolytic setting.i6,” Group I is demographically similar to those referenced groups with respect to age, gender and prevalence of tobacco use, and differed significantly in age from the remainder (group II) of this thrombolytic population. The lack of antecedent angina and prior acute MI may also be unique. Although postdischarge mortality appears low (3%), the follow-up data presented suggest a significant potential for subsequent cardiac events. The role of the original infarct lesion in these clinical events cannot be known with certainty, because ischemia was not documented in all patients with chest pain after acute MI, and silent ischemia was not assessed. The infarct lesion, either by progression to critical stenosis or coronary vasospasm, accounted for 41% of events after acute MI and 58% of documented ischemic episodes. When these lesions are responsible for significant angina or acute MI, they appear to manifest clinically within the first 6 months after acute MI. Reversible coronary vasospasm with ST elevation, as documented in 3 patients during early follow-up, has been reported in the early follow-up of patients who underwent percutaneous transluminal coronary angioplasty, a group that may have a similar pathophysiologic substrate. I8 Recurrent thrombosis at the infarct narrowing is suggested by recurrent total occlusion or relatively rapid “progression” of stenosis over a time course that would be consistent with thrombus formation and inconsistent with atherosclerotic progression. A recent report has suggested a role for thrombus layering at the site of the underlying complex, clinically active lesions,12 and such a process could have accounted for rapid progression in this group as well as in others noted in published reports.r4,19 In contrast, those clinical events that were probably related to atheroscle-

rotic progression of stenosis at sites of previously nonsignificant disease occurred over a longer duration after acute MI and accounted for 25% of documented clinical ischemia in this group. A slight degree of underestimation of diameter stenosis can occur for stenoses in this range.20 However, the lesser likelihood of diffuse disease in patients with no residual or single artery coronary disease should have minimized this. The retrospective design of this study is also a limitation, because type, dosage and route of thrombolysis, duration and intensity of heparinization, and time to angiography may influence the angiographic frequency of these lesions.2~4~12~17 Although the data presented here are relatively small and therefore susceptible to statistical error, there was no clear advantage afforded by any particular combination of medical therapies. Smoking may be related to recurrent events, but the data are inconclusive. The relative efficacy of antiplatelet versus anticoagulant therapy versus a combination of therapies (including coronary vasodilators) warrants more detailed investigation. Acknowledgment: We wish to thank Lois Murray for her expert secretarial assistance.

REFERENCES 1. DeWood MA. Soores J. Notske IZ. Mouser LT. Burroueha Y K. Golden MS. Lang HT. Prevalence of total coronary occlusion d&g the early hours of transmural myocardial infarction. N Engr J Med 1980;303:897m901. 2. Topol EJ, Califf RM, George BS, Kereiakes DJ, Abbottsmith CW, Candela RJ, Lee KL, Pitt B, Stack RS; O’Ncill WW. A randomized trial of immediate versus delayed elective angioplasty after intravenous tissue plasminogcn activator in acute mvocardial infarction. N Em1 J Med /987:317:581~588. 3. Serruys bW, Wijns W, Van Den Brand M, Rib&o V, Fioretti P, Simoons ML, Kooijman CJ, Reiber JHC, Hugenholtz PG. Is transluminal angioplasty mandatory after successful thrombolysis? Br Heart J /983;50:257-265. 4. Harrison DG, Ferguson DW, Collins SM, Skorton DJ, Ericksen EE, Kioschos JM, Marcus ML, White CW. Rethrombosis after reperfusion with strcptokinase: imoortance of aeometrv of residual lesions. Circulation 1984:69:99/b999. B.^Brown BG,%allcry-CA, Badger RS, Kennedy JW, Mathey D, Bolson EL, Dodge HT. Incomplctc lysis of thrombus in the moderate underlying atherosclerotic lesion during intracoronary infusion of streptokinase for acute myocardial infarction: quantilative angiographic observations. Circulation 1986;73:653-66/. 6. The Thrombolysis and Angioplasty in Acute Myocardial Infarction (TIMI) Trial. In: Top01 E, ed. Acute Coronary Intervention. Nrw York: Allan R. I,is.\, 1987:153-174. 7. Scoblionko DP, Brown BG, Mitten S, Caldwcll JH, Kennedy JW, B&on El., Dodge HT. A new digital electronic caliper for measurement of coronary artery stenosis: comparison with visual estimates of computer assisted measurements. Am .I Cardiol 1984;S3:689m693. 3. Harrison D, White C, Hiratzka I., Duty D, Burncs D, Eastharn C, Marcus M. The value of lesion cross sectional area determined by quantitative coronary angiography in assessing the physiologic significance of proximal left anterior descending coronary arterial stcnoses. Circulation 1984;69:11 Ii- 1119. 9. Wilson JR, Martin JL, Untereker WJ, Hirshfeld JW. Regional coronary anatomy in rest angina. Chest 1982;4:416-421. 10. Ambrose JA, Hjemdahl-Monsen C, Borrico S, Sherman W, Cohen M, Gorlin R, Faster V. Quantitative and qualitative effects of intracoronary streptokinase in unstable angina and non-Q wax infarction. J Am Co11 Cardiol /987;9:11561165. 11. TIM1 Study Group. The Thrombolysis in Myocardial Infarction (TIMI) trial: phase I findings. N Engl J Mrd 1985;312:932-936. 12. Nakagawa S, Hanada Y, Joiwaya Y, Tanaka K. Angiographic features in the infarct related artcry after intracoronary urokinase followed by prolonged anticoagulation. Circulation 1988;78:133Sm1344. 13. Brown KA, Osbakken M, Boucher C, Strauss HW, Pohost GM, Okada RD. Positive exercise thallium test responses in patients with less than 50% maximal coronary stenosis: angiagraphic and clinical predictors. Am J Cardjo/ 1985: D-:54-57.

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14. Ellis SG, Top01 EJ, George BS, Kereiakes DJ, Debowey D, Sigmon KN, Pickel A, Lee KL, Califf RM. Recurrent ischemia without warning: analysis of risk factors for in-hospital ischemic events following successful thormbolysis with intravenous tissue plasminogen activator. Circulation 1989;80:1159-1165. IS. Little WC, Constantinescu M, Applegate RJ, Kutcher MA, Burrows MT, Kahl FR, Santamore WP. Can coronary angiography predict the site of subsequent myocardial infarction in patients with mild to moderate coronary artery disease? Circulation 1988;78:1157-1166. 16. Hoit BD, Gilpin EA, Henning H, Maisal AA, Dittrich H, Carlisle J, Ross J. Myocardial infarction in young patients, an analysis by age subsets. Circulation 1986;74:712-721. 17. Pecora MJ, Roubin GS, Cobbs W, Ellis SG, Weintraub WS, King SB.

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Presentation and late outcome of myocardial infarction in the absence of angiographically significant coronary artery disease. Am J CardioI 1988;62:363-367. 18. Hollman J, Austin GE, Gruentzig AR, Douglas JS, King SB. Coronary artery spasm at the site of angioplasty in the first 2 months after successful percutaneous transluminal coronary angioplasty. J Am Coil Cardiol 1983;2: 1039-1045. 19. Moise A, Theroux P, Taeymans Y, Descoings B, Lesperance J, Waters D, Pelletier G, Bourassa M. Unstable angina and progression of coronary atherosclerosis. N Engl J Med 1983:309:685-689. 20. Arnett EN, Isner JM, Redwood DR, Kent KM, Baker WP, Ackerstien H, Roberts WC. Coronary artery narrowing in coronary heart disease: comparison of cineangiographic and necropsy findings. Ann Intern Med 1979;91:350-356.