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Previous studies have reported that some patients presenting with unstable angina am found at coronary angiography to have no critical coronary stenosis. This study evaluated the clinical presentation and arteriographic findings in patients enrolled in the Thrombolysis in Myocardial Ischemia (TIMI-IIIA) trial, which assessed the effect of tissue-type plasminogen activator added to conventional therapy on the coronary arteriographic findings in patients presenting with ischemic pain at rest. Three hundred ninety-one patients were enrolled in the TIMI-IIIA trial and underwent coronary arteriography within 12 hours of enrollment. Fifty-three patients (140A) had no luminal diameter stenosis of a major coronary artery of [greater than or equal to] 60% on the baseline arteriogram. Compared with patients with unstable angina with an identifiable culprit lesion, patients without critical coronary obstruction were more likely to be women and non-white and less likely to have ST-segment deviation on the presenting electrocardiogram. Arteriography in such patients revealed no visually detectable coronary stenosis in half of the group; the remaining patients had noncritical coronary narrowing (i.e.,

The purpose of this study was to analyze angiographic findings, clinical course, and follow-up data on 1,752 patients who underwent protocol cardiac catheterization 18 to 48 hours after enrollment in the Thrombolysis in Myocardial infarction (TIMI) II pilot and randomized trial: 244 patients (14.0%) had 60% in diameter with TIMI grade 2 or 3 flow, and 259 patients (15%) had TIMI grade 0 or 1 flow (total occlusion). Patients with 55% (p < 0.001) than were other patient groups. The 1-year mortality rate of patients with < 60% diameter stenosis in the infarct-related artery was 1.6% compared with 4.4% for patients with stenosis >60% and TIMI grade 2 or 3 flow (p 0.05) and 7.0% for patients with total occlusion (p = 0.004). Patients with stenosis

Although preventing early mortality following acute myocardial infarction (MI) is the most important goal of thrombolytic therapy, insistence on its use as the only or principal endpoint in trials of acute MI will limit the number of new thrombolytic--antithrombotic regimens that can be tested, and thus may inhibit future progress of this important area of cardiovascular therapeutics. Trials of thrombolytic therapy over the past decade, as discussed in this article, have demonstrated that: (1) thrombolytic therapy improves both mortality and intermediate endpoints, and (2) intermediate nonfatal endpoints are strongly linked to long-term mortality. Taken together, these facts provide strong evidence that intermediate nonfatal events can be used as valid endpoints in future trials of thrombolytic therapy. The unsatisfactory outcome composite endpoint, which incorporates mortality and important intermediate endpoints, will make it possible to compare innovative new regimens in much smaller trials. Ultimately, both of these approaches (i.e., megatrials using a mortality endpoint and smaller trials utilizing a composite unsatisfactory outcome endpoint) can be used in a complementary fashion. A new regimen could first be tested using the unsatisfactory outcome endpoint; if it showed particular promise, it could then become a candidate for testing in a megatrial. Conversely, if it did not prove better than standard regimens, futile research in tens of thousands of patients might be prevented. Thus, the use of composite endpoints will expand the number of new thrombolytic--antithrombotic regimens that can be tested and, it is hoped, accelerate progress in the treatment of acute MI.

The diagnosis of unstable angina encompasses a broad spectrum of patients with myocardial ischemia, varying widely in cause, prognosis and responsiveness to therapy. A new clinical classification of unstable angina is based on the following 2 components: severity, and the clinical setting in which unstable angina develops. The hypothesis that this clinical classification correlates with the underlying coronary artery anatomy was tested. In 238 consecutive patients, an unstable angina score ranging from 2 to 6 was determined by adding the scores for severity (1 = unstable angina without pain at rest; 2 = pain at rest >48 hours before angiography; and 3 = pain at rest [less than or equal to]48 hours before angiographic evaluation) and the clinical setting of unstable angina (1 = unstable angina secondary to a noncardiac condition; 2 = primary unstable angina; and 3 = early postinfarction unstable angina). Fifty concurrently studied consecutive patients with stable angina were assigned a score of 0. Patients with unstable angina averaged 63 [+ or -] 11 years of age, and 165 were men (69%). Pain at rest occurred in 202 of 238 patients (85%), and angiography was performed [less than or equal to]48 hours in 139 of these patients (69%). Among patients with unstable angina, S (2%) had secondary unstable angina, 143 (60%) had primary unstable angina, and 90 (38%) had postinfarction unstable angina. Multivariable regression analysis identified the unstable angina score as the most important predictor of intracoronary thrombus (p = 0.011) and lesion complexity (p = 0.004) in the ischemia-related artery. The new clinical classification of unstable angina correlates with the underlying angiographic anatomy, and may thus aid in decisions regarding diagnostic procedures and provide a useful basis for comparing the response to therapy among patients with unstable angina. (Am J Cardiol 1993;72:544-550) The diagnosis of unstable angina is applied to several different conditions, each producing severe myocardial ischemia but manifesting a broad spectrum of severity, clinical presentations, angiographic findings and prognoses. The severity ranges from the abrupt intensification of chronic stable angina, or the onset of severe or frequent exercise-induced angina without pain at rest, to frequent episodes of angina at rest. Angiographic findings in unstable angina vary from an absence of serious coronary arterial obstruction[1-4] to high-grade stenoses sometimes containing nonocclusive thrombi.[2,3,1-8] The results of treatment of unstable angina range from complete resolution to refractory ischemia, myocardial infarction or death.[9-12] To help the clinician in dealing with this complex syndrome, a clinical classification was developed that considers both the severity of the condition (specifically, the occurrence and timing of pain at rest) and the clinical circumstances in which the unstable angina occurs.[13] This classification is being used increasingly in clinical studies.[14-17] The present study tests the hypothesis that this classification correlates with the underlying coronary artery morphology. A secondary aim was to describe the differences in coronary artery morphology between stable and unstable angina. METHODS Unstable angina: From January 1 to July 31, 1990, 1,169 patients underwent diagnostic coronary arteriography at the Brigham and Women's Hospital. Of these patients, 277 (24%) had unstable angina. Thirty-nine of these patients were excluded from this analysis for the following reasons: 11 had angiograms that were not available or suitable for analysis, 8 had prior coronary artery bypass surgery, 4 had charts pertaining to the hospital admission for unstable angina that were not available, and 16 could not be accurately classified from the available hospital records. Complete hospital records and suitable coronary arteriograms were available for 238 of 277 patients (86%). In this classification, the severity of unstable angina is expressed as follows: class 1, no pain at rest; class II, pain at rest with last episode >48 hours; and class III, pain at rest with last episode [less than or equal to]48 hours. The clinical circumstances in which unstable angina develops is expressed as follows: type A, unstable angina secondary to a noncoronary condition such as anemia (secondary unstable angina); type B, primary unstable angina; and type C, early ( Stable angina: Fifty consecutive patients with chronic stable angina who underwent cardiac catheterization during the same time period were also studied. These patients were identified as having had no change in their anginal pattern for [greater than or equal to]3 months before catheterization and by not fulfilling the clinical definition of unstable angina, as defined previously.[13] Most of these patients were referred for angiography because of severe but stable symptoms or a markedly abnormal exercise treadmill test, or were considered for coronary revascularization, or a combination. Coronary angiography: Cardiac catheterization was performed from the brachial or femoral approach using standard catheters and techniques. Coronary arteriograms were reviewed by an experienced angiographer unaware of the patients' clinical classifications. Qualitative and quantitative analyses were performed in the ischemia-related artery. In patients with 1-vessel disease, the diseased artery was considered the ischemia-related vessel, whereas in those with multivessel disease, a correlation between electrocardiographic changes during angina and coronary anatomy was used to identify the ischemia-related artery.[18] If there were no electrocardiographic changes, the vessel with thrombus was identified as the ischemia-related vessel. If no thrombus was apparent, the ischemia-related artery was determined to be the one containing the most complex stenosis (see later). Quantitative measurements of minimal lesion diameter and percent diameter stenosis were obtained using electronic calipers (Mitutoyo, Tokyo) in magnified, end-diastolic frames. Repeated measurements with the caliper system showed no evidence of bias related to vessel size; intraobserver estimation of stenosis severity (n = 20) showed a coefficient of variation of 10%.[19] Coronary artery flow was classified according to the Thrombolysis in Myocardial Infarction (TIMI) criteria.[20] The extent of collateral formation was scored according to Rentrop as follows: grade 3, brisk flow that fills the target artery completely; 2, partial filling of the target artery; and 1, barely detectable filling of collateral channels without apparent spillover of contrast into the target artery.[21] Coronary morphology: The complexity of coronary lesions was scored according to a classification modified from that described by Ambrose et al[22]: (1) A simple stenosis was classified as any luminal narrowing with 50% reduction in vessel diameter, causing a symmetric or asymmetric stenosis with smooth or slightly irregular borders (1 point). (2) A complex stenosis was defined as an asymmetric luminal narrowing of 50% reduction in diameter with overhanging edges or irregular borders, including lesion ulceration or severe diffuse irregularities (2 points). (3) Intracoronary thrombus was detected angiographically by an intracoronary filling defect, usually globular in shape, surrounded by contrast on [greater than or equal to]3 sides, proximal or distal to a stenosis with or without contrast staining (3 points). (4) Total occlusion (4 points). Statistical analysis: The unstable angina score was based on the clinical classification previously presented,[13] and was calculated from the added scores for severity (unstable angina without pain at rest [class I] = 1; pain at rest >48 hours before angiography [class II] = 2; and pain at rest within 48 hours [class III] = 3) and clinical circumstances (unstable angina secondary to a medical condition such as anemia [type A] = 1; primary unstable angina [type B] = 2; and unstable angina within 2 weeks of myocardial infarction [type C] = 3). The score for patients with stable angina was by definition 0, whereas that for those with unstable angina ranged from 2 to 6 (Table I). [TABULAR DATA I OMITTED] Baseline comparisons among the groups of patients were obtained with 1-way analysis of variance for continuous variables and with chi-square analysis for categoric variables.[23] Separate analyses were performed to determine whether the unstable angina score was predictive of intracoronary thrombus and lesion complexity. Logistic regression analysis was used to determine the correlation between the unstable angina score, age, sex, ST-segment change, diabetes, systemic hypertension, tobacco use or hypercholesterolemia and the presence of intracoronary thrombus. Variables associated with a p value RESULTS Clinical characteristics: Fifteen percent of patients had new onset of severe angina or accelerated angina without pain at rest (i.e., class I in the clinical classification).[13] Pain at rest was reported by 202 of 238 patients (85%) with unstable angina. More than 48 hours had elapsed between the most recent episode of pain at rest and coronary arteriography in 63 patients (class II, 26%) and Of 238 patients with unstable angina, only 5 (2%) had secondary unstable angina (type A). In these 5 patients, chronic stable angina had been intensified by anemia (n = 2), fever (n = 1), new-onset atrial fibrillation with a rapid ventricular response (n = 1), and acute anaphylactic reaction (n = 1). One hundred forty-three patients (60%) had primary unstable angina (type B), and 90 (38%) had early postmyocardial infarction unstable angina (type C). The average age of patients with unstable angina was 63 years; 69% were men. There were no significant differences among the 3 unstable angina classes and types with respect to coronary risk factors such as diabetes, hypertension, tobacco use and hypercholesterolemia (Table II). [TABULAR DATA II OMITTED] Of 238 patients with unstable angina, the ischemia-related artery was the left anterior descending coronary artery in 40%, the right in 36%, the circumflex in 17%, and the left main in 3%. This distribution did not differ in patients with stable versus unstable angina, nor was it affected by the class or type of unstable angina, or the unstable angina score (Table III). [TABULAR DATA III OMITTED] Angiographic morphology: Patients with unstable angina had a higher incidence of thrombus (p = 0.01) and complex lesions (p = 0.004) than did those with chronic stable angina. Minimal lesion diameter and percent stenosis showed no differences among patients with the 3 classes and types of unstable angina (Table III). The incidence of intracoronary thrombus varied widely (Figure 1), ranging from 0% in patients with secondary unstable angina (type A) to 20% in those with postinfarction unstable angina (type C). The incidence of intracoronary thrombus was 17% in patients with unstable angina without pain at rest (class I), 13% in those with pain at rest >48 hours before angiographic evaluation (class 11), and 17% in those with pain at rest A lesion with complex morphology, with either evidence of ulceration or an abrupt face to an eccentric lesion,[22] was observed in 12% of patients with stable angina, and in a higher proportion (32%) of all those with unstable angina (p = 0.004) (Table III). With use of the composite score for lesion complexity (Figure 2), we observed that patients with unstable angina had a higher lesion complexity score than did those with stable angina (average 2.1 [+ or -] 1.3 vs 1.8 [+ or -] 1.3; p = 0.011). The probability of discovering thrombus-containing plaques, complex stenoses or total occlusions was high (61 %) for patients with unstable angina scores >3. Left ventricular ejection fraction: Ejection fraction was measured by left ventriculography at the time of cardiac catheterization in 30 of 50 patients with stable angina and in 150 of 238 with unstable angina (Table III). The mean ejection fraction tended to be higher in patients with stable than with unstable angina (68 [+ or -] 11% vs 64 [+ or -] 16%; p = 0.097). The mean ejection fraction did not differ significantly among patients in the 3 classes of unstable angina; however, it was higher in those with unstable angina without recent infarction (type B, 66 [+ or -] 14%) than in those with postinfarction angina (type C, 59 [+ or -] 16%; p = 0.003). Logistic regression analysis for intracoronary thrombus: The unstable angina score was found to be a powerful predictor of intracoronary thrombus by both univariable and multivariable analysis (Figure 3). For each incremental increase in score, the odds of intracoronary thrombus increased by 1.37 (95% confidence interval 1.08, 1.75; p = 0.006). Patients with pain at rest (classes II and III) were more likely to have intracoronary thrombus than were those with no pain at rest (class 1, OR 1.49 [1.04, 2.13]; p = 0.031 by univariable analysis). Increasing age showed an increased odds of intracoronary thrombus (OR 1.05 [1.01, 1.09] per additional year; p = 0.019), but other risk factors were not significantly associated with an increased incidence of intracoronary thrombus by logistic regression analysis. Linear regression analysis for lesion complexity: Multiple linear regression analysis was performed to identify predictors of lesion complexity. The model included continuous variables such as age, percent stenosis, minimal lumen diameter and lesion length, as well as discrete quantitative variables such as TIMI flow grade, extent of collateral formation, and unstable angina score (Table IV). Angiographic variables including minimal lumen diameter and TIMI flow measurements were inversely related to lesion complexity (p DISCUSSION The diagnosis of unstable angina is made in a heterogeneous group of patients with widely varying severities, clinical presentations and angiographic findings. It was the principal objective of this study to determine whether the severity and clinical presentation, as reflected in a recently developed classification[13] and a score derived therefrom, could be used to predict angiographic findings. Most patients referred to our cardiac catheterization laboratory with unstable angina had pain at rest. In particular, patients with pain at rest in the 48 hours before angiography (class III) predominated over those with new onset of severe or accelerated angina on effort without pain at rest (class I), with an intermediate number with pain at rest, but no episode within 48 hours. In regard to presentation, most patients had experienced severe myocardial ischemia in the absence of a noncardiac precipitating event such as fever or anemia (i.e., they had primary unstable angina [type B] or developed unstable angina within 2 weeks of the onset of acute myocardial infarction [type C]). The relatively small proportion of patients with unstable angina precipitated by a noncardiac condition (2%) (i.e., with secondary unstable angina [type A]) should not be interpreted to reflect the infrequency of this type of unstable angina; it probably reflects referral patterns to the cardiac catheterization laboratory. To assess the complexity of the angiographic lesions, we used a modification of the classification by Ambrose et al[22] in which simple stenosis, complex morphology without and with thrombus, and total occlusion are considered as progressively more complex in the spectrum of severity of atherosclerotic plaques. This classification enables standardization and comparison with other studies. However, 1 potential limitation of the present study was the use of angiography to determine the presence of intracoronary thrombus. Although angiographic assessment of thrombus is less sensitive than is angioscopic assessment,[2] the 2 techniques have not been compared in a broad range of patients with unstable angina, such as those in this study. Angioscopic observations in unstable angina have focused on a highly selected group of patients, such as those referred for bypass surgery,[7] and have excluded [greater than or equal to]20% of patients, because of technical difficulties.[8] The reported incidence of intracoronary thrombus varied widely in previous angiographic studies of unstable angina. This variability may be secondary to differences in: (1) the selection of patients, (2) the timing of angiography in regard to the occurrence of pain at rest,[26] and (3) the angiographic criteria for thrombus. In most patients in the present study, angiography was performed within 48 hours of the most recent episode of pain at rest, and a relation between acuity and the incidence of intracoronary thrombus was observed. Various angiographic definitions have been proposed for intracoronary thrombus.[5,22] We used the presence of filling defects that are surrounded by contrast medium on [greater than or equal to]3 sides in nonoccluded vessels. With the use of this rigorous definition, we observed that the probability of intracoronary thrombus ranged from 0 to 22%, depending on the unstable angina score. Previous studies that reported a higher incidence of intracoronary thrombi included some totally occluded vessels as containing thrombi,[2,5,6] whereas others have excluded totally occluded vessels.[4] We included totally occluded vessels in the assessment of lesion complexity, but did not consider such vessels to be thrombus-containing, thereby probably underestimating the incidence of the latter. In this series, the combination of intracoronary thrombus in nonoccluded vessels and total occlusion was found to occur in 32 and 44% of primary (type B) and postinfarction (type C) unstable angina, respectively. These percentages are in good agreement with the range of values reported in recent angiographic studies.[2,3,5,6] We observed that in comparison with a reference group of patients with chronic stable angina, those with unstable angina had a higher frequency of complex lesions and angiographically apparent thrombus. However, the principal finding of this study is that among patients with unstable angina, there was a significant correlation between the clinical findings, as reflected in the clinical classification (and the unstable angina score derived therefrom), and the angiographic findings. Patients with unstable angina considered as a group were more likely than those with chronic, stable angina to have complex, thrombus-associated lesions. The model accounts for only 31% of variability in the lesion complexity, and this suggests that other mechanisms, such as the severity of the underlying stenosis, and the progressive impairment endothelial vasoactive function that occurs with atherosclerosis, may also have a role.[27,28] The probability of discovering thrombus-containing plaques, complex stenoses or total occlusions was low in patients with stable angina or in those with unstable angina whose scores were 2 or 3. Since complications of unstable angina, such as progression to myocardial infarction, and the need for urgent revascularization because of ischemia refractory to medical therapy, are related to the underlying angiographic anatomy,[2] it can be deduced that patients with scores [less than or equal to]3 are less likely to have a complication of unstable angina than are those with higher scores. It would be desirable to evaluate this finding in a prospective study based on a broad cross section of patients with unstable angina rather than limit it to a group referred to a cardiac catheterization laboratory, such as that in the present study. The finding of reduced ejection fractions in patients with higher unstable angina scores is probably due to prior myocardial infarction, and this finding has potentially important prognostic information additive to underlying coronary morphology. Acknowledgment: We are grateful to Elliott Antman, MD, John D. Rutherford, MD, and Thomas J. Ryan, Jr., MD, for critical review of the manuscript. [1.] Bosch X, Theroux P, Waters D, Pelletier GB, Roy D. Early postinfarction ischemia: clinical, angiographic, and prognostic significance. Circulation 1987;75: 988-995. [2.] Williams AE, Freeman MR, Chisholm RJ, Patt NL, Armstrong PW. Angiographic morphology in unstable angina pectoris. Am J Cardiol 1988;62:1024-1027. [3.] Freeman MR, Williams AE, Chisholm RJ, Armstrong PW. Intracoronary thrombus and complex morphology in unstable angina. Relation of timing of angiography arid in-hospital cardiac events. Circulation 1989;80:17-23. [4.] Bugiardini R, Pozzati A, Borghi A, Morgagni GL, Ottani F, Muzi A, Puddu P. Angiographic morphology in unstable angina and its relation to transient myocardial ischemia and hospital outcome. Am J Cardiol 1901;67: [5.] Gotoh K, Mihamino T, Katoh O, Hamano Y, Fukui S, Hori M, Kusuoka H, Mishima M, Inoue M, Kamada T. The role of intracoronary thrombus in unstable angina: angiographic assessment and thrombolytic therapy during ongoing anginal attacks. Circulation 1988;77:526-534. [6.] Rehr R, DiSciascio G, Vetrovec F, Cowley M. Angiographic morphology of coronary artery stenoses in prolonged rest angina: evidence of intracoronary thrombus. J Am Coll Cardiol 1989; 14:1429-1437. [7.] Sherman CT, Litvack F, Grundfest W, Lee M, Hickey A, Chaux A, Kass R, Blanche C, Matloff J, Morgenstern L, Ganz W, Swan HJC, Forrester J. Coronary angioscopy in patients with unstable angina pectoris. N Engl J Med 1986;315: 913-919. [8.] Mizuno K, Satomura K, Miyamoto A, Arakawa K, Shibuya T, Arai T, Kurita A, Nakamura H, Ambrose JA. Angioscopic evaluation of coronary-artery thrombi in acute coronary syndromes. N Engl J Med 1992;326:287-291. [9.] Gold HK, Johns JA, Leinbach RC, Yasuda T, Grossbard E, Zusman R, Collen D. A randomized, blinded, placebo-controlled trial of recombinant tissue-type plasminogen activator in patients with unstable angina pectoris. Circulation 1987;75: 1192-1199. [10.] de Zwaan C, Bar FW, Janssen JHA, de Swart HB, Vermeer F, Wellens HJJ. Effects of thrombolytic therapy on unstable angina: clinical and angiographic results. J Am Coll Cardiol 1988; 12:301-309. [11.] Topol EJ, Nicklas JM, Kander NH, Walton JA, Ellis SG, Gorman L, Pitt B. Coronary revascularization after intravenous tissue plasminogen activator for unstable angina pectoris: results of a randomized, double-blind, placebo-controlled trial. Am J Cardiol 1988;62:368-371. [12.] Theroux P, Ouimet H, McCans J, Latour JG, Joly P, Levy G, Pelletier E, Juneau M, Stasiak J, deGuise P, Pelletier G, Rinzler D, Waters D. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med 1988;319:1105-1111. [13.] Braunwald E. Unstable angina. A classification. Circulation 1989;80:410,AI4. [14.] Seggeweiss H, Fassbender D, Gleichmann U, Mannebach H, Vogt J, Minami K. Perkutane transluminale Koronarangioplastie (PTCA) bei instabiler Angina pectoris: Ergebnisse und Komplikationen unter Beruecksichtigung einer neuen Klassifikation. Z Kardiol 1991;80:423-430. [15.] de Feyter P, Serruys P, Brand M, Hugenholtz P. Percutaneous transluminal angioplasty for unstable angina. Am J Cardiol 1991;68:125B-135B. [16.] Renkin J, Wijns W, Ladha Z, Col J. Reversal of segmental hypokinesis by coronary angioplasty in patients with unstable angina, persistent T wave inversion, and left anterior descending artery stenosis. Additional evidence for myocardial stunning in humans. Circulation 1990;82:913-921. [17.] Hamm CW, Ravkilde J, Gerhardt W, Jorgensen P, Peheim E, Ljungdahl L, Goldmann B, Katus HA. The prognostic value of serum troponin T in unstable angina. N Engl J Med 1992;327:146-150. [18.] Fuchs RM, Achuff SC, Grunwald L, Yin FC, Griffith LS. Electrocardiographic localization of coronary artery narrowings: studies during myocardial ischemia and infarction in patients with one-vessel disease. Circulation 1982;66:1168-1176. [19.] Bland JM, Altman DG. Statistical methods for assessing agreement between two methods of clinical measurement. Lancet 1986; 1:307-310. [20.] TIMI Study Group. The Thrombolysis in Myocardial Infarction (TIMI) trial. Phase I findings. TIMI Study Group. N Engl J Med 1985;312:932-936. [21.] Rentrop KP, Cohen M, Blanke H, Phillips RA. Changes in collateral channel filling immediately after controlled coronary artery occlusion by an angioplasty balloon in human subjects. Circulation 1989;80:1166-1175. [22.] Ambrose JA, Winters SL, Stern A, Eng A, Teichholz LE, Gorlin R, Fuster V. Angiographic morphology and the pathogenesis of unstable angina pectoris. J Am Coll Cardiol 1985;5:609-616. [23.] Zar JH. Analysis of Variance. In: Zar JH, ed. Biostatistical Analysis. Englewood Cliffs, NJ: Prentice-Hall, 1984:162-252. [24.] Glantz SA, Slinker BK. Regression with a qualitative dependent variable. In: Glantz SA, Slinker BK, eds. Primer of Applied Regression and Analysis of Variance. New York: McGraw-Hill, 1990:512-568. [25.] Zar JH. Multiple regression and correlation. In: Zar JH, ed. Biostatistical Analysis. Englewood Cliffs, NJ: Prentice-Hall, 1984:328-360. [26.] Capone G, Wolf NM, Meyer B, Meister SG. Frequency of intracoronary filling defects by angiography in angina pectoris at rest. Am J Cardiol 1985;56:403-406. [27.] Lassila R, Badimon JJ, Vallabhajosula S, Badimon L. Dynamic monitoring of platelet deposition on severely damaged vessel wall in flowing blood: effects of different stenosis on thrombus growth. Atherosclerosis 1990;10:306-315. [28.] Zeiher AM, Drexler H, Wollschlager H, Just H. Modulation of coronary vasomotor tone in humans: progressive endothelial dysfunction with different early stages of coronary atherosclerosis. Circulation 1991;83:391-401. From the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts. Manuscript received November 30, 1992; revised manuscript received and accepted May 10, 1993. Address for reprints: John A. Bittl, MD, Brigham and Woman's Hospital, Boston, Massachusetts 02115.

The clinical course of 363 patients with acute myocardial infarction who did not complete high school education was compared with that of 453 who completed at least high school. Both the in-hospital and 4-year mortality rates were markedly greater for the less educated than for the more educated patients (13 vs 5% [p

Selective thrombin inhibitors are a new class of antithrombotic drugs that, unlike heparin, can effectively inhibit clot-bound thrombin and escape neutralization by activated platelets. Hirulog is a 20 amino acid hirudin-based synthetic peptide that has shown promise in experimental models of thrombosis. Little information is available about the effects of hirulog in patients with coronary artery disease. Forty-five patients undergoing cardiac cathaterization, who were taking aspirin, were randomized to receive either (1) hirulog, 0.05 mg/kg intrevenous bolus followed by 0.2 mg/kg/hour intrevenous infusion until the end of the catheterization; (2) hirulog, 0.15 mg/kg intravenous bolus followed by 0.6 mg/kg/hour intravenous infusion; or (3) heparin; 5,000 U intravenous bolus. Seril activated partial thromboplastin time (APTT), prothrombin time, activated clotting time and fibrinopeptide A were measured. Hirulog produced a dose-dependent prolongation of all coagulation paramaters; the 0.6 mg/kg/hour dose pre longed the APTT to 218 [+ or -] 50% of baseline after 2 minutes and 248 [+ or -] 50% of baseline after 15 minates. The half-life of the effect on APTT was 40 minutes. The hirulog blood level correlated well with the APTT, prothrombin time and activated clotting time (r = 0.77, 0.73, and 0.82 respectively, all p (Am J Cardiol 1993;71:778-782)

Global and regional left ventricular performances were evaluated with equilibrium radionuclide angiocardiography in patients in the Thrombolysis in Myocardial Infarction (TIMI) II trial at the time of hospital discharge. Studies at rest were available in 1,162 (69%) of the invasive and 1,150 (69%) of the conservative strategy patients, and exercise studies in 1,133 (67%) of the invasive and 1,145 (69%) of the conservative patients. Repeat studies were performed at the time of 6-week follow-up. Global and regional ejection fraction at rest were both comparable in patients assigned to each of the treatment strategies. However, at the time of hospital discharge patients in the invasive strategy had normal exercise responses more frequently (29.7 vs 25.8% p = 0.01), greater peak exercise LV ejection fraction (54.8 [+ or -] 13.8% vs 53.1 [+ or -] 14.1%, p = 0.004), greater exercise - rest change in LV ejection fraction (3.7 [+ or -] 6.7% vs 2.7 [+ or -] 7.2%, p

The effect of simultaneous infusions of low-dose recombinant tissue-type plasminogen activator (t-PA) and single-chain urokinase-type plasminogen activator (scu-PA, pro-urokinase) on coronary arterial thrombolysis was investigated in 23 patients treated within 6 hours (mean 2.6 [+ or -] 1.1, range 1.2 to 5.9) of symptoms of an acute myocardial infarction. Infarct artery patency at 90 minutes was achieved in 16 (70%, 95% confidence limits of 0.47 to 0.87) of 23 patients after a 1-hour intravenous infusion of 20 and 16.3 mg of t-PA and scu-PA, respectively. At 90 minutes, the fibrinogen concentration decreased from 369 [+ or -] 207 to 316 [+ or -] 199 mg/dl (p = not significant), while plasminogen decreased to 69 [+ or -] 24% (p = 0.001) and [Alpha]-2-antiplasmin to 77 [plus or minus] 24% (p = 0.001) of pretreatment values. Although no bleeding requiring termination of drug infusion or transfusion occurred, 1 patient with cerebrovascular amyloidosis had a fatal intracerebral hemorrhage. These findings suggest that combination therapy may allow substantial reductions in total thrombolytic doses while still achieving effective fibrin-specific coronary thrombolysis. (Am J Cardiol 1991;68:1564-1569)

Heart failure, often associated with ventricular enlargement and recurrent myocardial infarction, is one of the major causes of postinfarction mortality. This observation suggests that measures used to prevent ventricular enlargement may improve postinfarction survival. The Survival and Ventricular Enlargement (SAVE) trial is a randomized, double-blind, placebo-controlled clinical trial with the purpose of evaluating the effect of angiotensin-converting enzyme (ACE) inhibition on postinfarction death and ventricular dilation. This multicenter trial had a sample size goal of 2,220 patients between 21 and 79 years of age who had recently sustained a myocardial infarction and who have an ejection fraction determined by radionuclide ventriculogram (RVG-EF) of [is less than or equal to] 40%. In addition to conventional therapy, patients were randomly assigned to captopril or placebo therapy commencing within 3--16 days following their myocardial infarction. A second RVG-EF is performed on all surviving participants at the end of the average 3.5-year treatment and follow-up period. The study has 90% power to detect a 25% improvement in postinfarction mortality or prevention of [is greater than or equal to] 9 unit absolute reduction in radionuclide ejection fraction. Additional end points, design features, and the administrative organization of the trial are described. (Am J Cardiol 1991;68:70D--79D)

The pathogenesis of acute myocardial infarction (AMI) involves a sudden thrombotic occlusion of a coronary artery. Spontaneous or pharmacologic thrombolysis may lead to myocardial salvage if patency is achieved within a narrow time window. However, patients in whom thrombolysis occurs late seem to demonstrate improved left ventricular (LV) function and prognosis, which may be independent of myocardial salvage. Preservation of normal LV geometry by reducing expansion of the infarcted segment is a likely mechanism for this benefit. Infarct expansion is most pronounced in patients with anterior wall AMI who have a persistently occluded infarct-related vessel. This process of expansion leads to early increases in LV volume and distortions of LV contour (abnormal LV geometry). Patients whose infarct segment is largest, patients who have manifested infarct expansion, and patients with a persistently occluded infarct-related artery are at highest risk for progressive LV dilation. Experimental data support the concept that reperfusion of occluded vessels that occurs too late for myocardial salvage will preserve LV geometry by limiting infarct expansion. Prospective clinical trials should address whether there is a late, 'second time window' during which infarct expansion and distortions of LV geometry may be reduced by (1) therapy with thrombolytic agents applied late after infarction, (2) late mechanical reperfusion with percutaneous transluminal coronary angioplasty (PTCA) or related methods, and (3) load-reducing agents to decrease remodelling, such as angiotensin-converting enzyme inhibitors or nitroglycerin. (Am J Cardiol 1991;68:41D-51D)

Severe myocardial ischemia, when sustained, leads to a predictable sequence of events, including myocardial necrosis, expansion of the infarct, and later its replacement by scar tissue. The nonischemic tissue sustains ventricular function, but it frequently adapts to the extra load placed on it by dilating. The enlargement and remodeling of the left ventricle may lead to ventricular failure and arrhythmias. Rational management to prevent these complications includes restoration of the patency of the occluded vessel and ventricular unloading. These two interventions may be useful both early and late in the course of infarction. (Am J Cardiol 1991;68:1D-6D)

The dilation and distortion of the left ventricle that may occur as a consequence of myocardial infarction are associated with heightened risk for adverse cardiovascular events. Infarcts that are extensive, transmural, and involve the apex as well as persistently occluded, infarct-related coronary arteries are predisposing factors for ventricular enlargement. Infarct expansion is an early component of the overall process of volume enlargement, which later continues as a volume overload hypertrophy of the remaining myocardium. Therapy to limit myocardial necrosis has been associated with the preservation of a more normal ventricular architecture. The late phase of ventricular remodeling has also been shown to be amenable to therapy, as chronic administration of angiotensin-converting anzyme (ACE) inhibitors has been associated with a reduction in the extent of ventricular dilation. There is currently a great deal of clinical investigate interest not only in whether ACE inhibition therapy following acute myocardial infarction will result in preservation of ventricular volume and topography, but, more importantly, whether it will lead to an improvement in clinical outcome. (Am J Cardiol 1991;68:127D-131D)

The coronary arteries supply blood to the heart, and any narrowing or occlusion of these arteries has a detrimental effect on cardiac function. When there is an acute blockage of a coronary artery (acute myocardial infarction or heart attack) by a dislodged blood clot or arterial plaque, the blood supply to the heart muscle is severely diminished. This may cause permanent heart damage and, in severe cases, death. One accepted treatment for acute myocardial infarction (AMI) is administration of thrombolytic (clot-dissolving) drugs, such as streptokinase or tissue plasminogen activator (tPA), which reduce or abolish the arterial blockage, restoring cardiac blood flow. To evaluate the effect of tPA administration on AMI-related anatomical changes in the heart, postmortem microscopic analysis was conducted on heart tissue removed from 61 patients who died as a result of their first heart attack. Twenty-three of the patients had received tPA following the onset of symptoms; 38 patients had not. The two groups were similar with respect to age, gender, history of hypertension, location of the infarct (damaged heart muscle), heart weight, type of arterial blockage precipitating the AMI, number of coronary arteries affected, and the severity of arterial disease. The group who had received tPA exhibited a greater frequency of fibrin-poor thrombi (the clot blocking the artery contained lower levels of blood clotting elements), a lower incidence of completely blocked arteries, and a lower incidence of myocardial rupture (physical damage to the walls of the heart). (Consumer Summary produced by Reliance Medical Information, Inc.)

The hearts of 52 patients (aged 61 +/- 1 1 years, 34 men) who participated in the Thrombolysis in Myocardial infarction (TIMI) Study and died from 5 hours to 260 days (median 2.7 days) after onset of chest pain were studied. One heart became available at cardiac transplantation. Of the S2 patients, 38 received recombinant tissue plasminogen activator (rt-PA) not followed by percutaneous transluminal coronary angloplasty (PTCA) or coronary artery bypass grafting (CABG). Eight had PTCA, and 6 had CABG. The infarcts were hemorrhagic by gross inspection with histologic confirmation) in 23 patients, nonhemorrhagic in 20, not visible grossly in 2 and, in 7, there was no myocardial necrosis by either gross or histologic examination. Comparisons between the 23 patients with hemorrhagic infarcts and the 20 patients with nonhemorrhagic infarcts showed: (1) similar frequencies of myocardial rupture (left ventricular free wall or ventricular septum) [6 26%) of 23 vs S (25%) of 20], cardiogenic shock [10 (43%) of 23 vs 9 (47%) of 19], and fatal hemorrhage [2 (9%) of 23 vs 2 (10%) of 20]; (2) similar percents of necrotic portions of left ventricular wall among patients surviving >18 hours from onset of chest pain (26 +/- 11 vs 23 +/- 11%) with the hemorrhage confined to areas of necrotic myocardium in all cases; (3) similar frequencies of thrombi in the infarct-related arteries [7 (32%) vs 7 37%)], but all thrombi in patients with hemorrhagic infarcts were nonocclusive, and all thrombi in those with nonhemorrhagic infarcts were occlusive (p = 0.0002); (4) similar degrees of luminal cross-sectional area narrowing over all 5-mm segments of the 4 major (left main, left anterior descending, left cimumflex and right) epicardial coronary arteries in 27 patients receiving rt-PA alone between patients with hemorrhagic and nonhemorrhagic infarcts; (5) similar numbers of patients in whom the infarct-related artery was narrowed >7S% in cross-sectional area at some point by plaque [21 (9S%) of 22 vs 16 84%) of 19], and similar mean percent reduction in cross sectional area by plaque of the infarct-related arteries calculated by planimetry (67 +/- 10 vs 68 9%); (6) similar frequencies of plaque rupture [11 (55%) of 20 vs 12 (75%) of 161 and similar frequencies of hemorrhage into a plaque [13 (65%) of 20 vs 13 (81%) of 16] in patients without PTCA; (7) fewer right ventricular infarcts in patients with hemorrhagic infarcts (2 of 10 posterior hemorrhagic infarcts vs 6 of 9 posterior nonhemorrhagic infarcts); (8) similar percents of plaque with pultaceous debris (13 +/- 11 vs 18 +/- 9%), calcific deposits (14 12 vs 20 +/- 14%) and acellular fibrous tissue (49 +/- 14 vs 53 +/- 11 ). Thus, hemorrhage occurs frequently in the infarcts of patients who receive rt-PA. Hemorrhage into an infarct does not appear to extend the infarct, and patients with hemorrhagic vs nonhemorrhagic) infarcts have no greater frequency of myocardial rupture or cardiogenic shock, and no significant differences in coronary luminal narrowing, plaque rupture or plaque composition. However, those with hemorrhagic infarcts had only nonocclusive thrombi and fewer right ventricular infarcts. (Am J Cardiol 1990;65:9S3-961), A heart attack, also called an acute myocardial infarction (AMI), is an often fatal event that arises due to an decrease in the blood supply to the heart. This often occurs when a blood clot (thrombus) becomes lodged in one of the coronary arteries, which supply blood to the heart. Therapies used to treat this condition include genetically produced proteins, such as recombinant tissue plasminogen activator (rt-PA), which dissolve blood clots and restore blood flow. A procedure called percutaneous transluminal coronary angioplasty (PTCA) involves the placement of a small inflatable balloon into a clogged vessel; when inflated, blood flow is restored. Coronary artery bypass grafting (CABG) is a procedure in which a portion of a healthy vein is grafted onto a coronary vessel to bypass a clogged artery and restore blood flow to the heart. The first two therapies, rt-PA and PTCA, can be used to treat an active AMI; CABG is used to prevent further AMIs. Prior to the development of these therapies, heart tissue that died during an AMI did not show evidence of bleeding (hemorrhage), but since the advent of these therapies, an increase in the frequency of hemorrhage has been observed, especially with rt-PA. To see if rt-PA increases the risk of hemorrhage and the development of complications, the hearts of 52 patients who received rt-PA, PTCA and CABG were examined at the time of their deaths for evidence of hemorrhage. Twenty-three of the 52 patients had evidence of hemorrhage, 20 did not, and the status of the remainder could not be determined. Patients having evidence of hemorrhage and patients not having signs of hemorrhage had similar complication rates, similar rates of thrombi formation, and similar narrowing of the coronary arteries. The coronary arteries of patients with non-hemorrhagic AMI were blocked by thrombi. In contrast, the coronary arteries of patients with hemorrhagic AMI were not blocked by thrombi. In conclusion, hemorrhage occurred more frequently in patients who received rt-PA, but, compared with PTCA and CABG, this did not affect the progression of the AMI. (Consumer Summary produced by Reliance Medical Information, Inc.)