Skip main navigation
Close Drawer MenuOpen Drawer Menu
×

Effect of Infarct Artery Patency on Prognosis After Acute Myocardial Infarction

Originally published1 Sep 1995https://doi.org/10.1161/01.CIR.92.5.1101Circulation. 1995;92:1101–1109

    Abstract

    Background In patients with acute myocardial infarction (MI), early restoration of patency of the infarct-related artery (IRA) leads to preservation of left ventricular function and improved clinical outcome. However, there is evidence that the benefits associated with a patent IRA are out of proportion to the observed improvement in ventricular function and may result not only from salvage of ischemic myocardium but also from the opening of the IRA beyond a narrow postinfarct time window. The objectives of this study were (1) to assess the effect of IRA patency on outcome of patients after acute MI with left ventricular dysfunction while controlling for differences in left ventricular ejection fraction and the extent of coronary disease and (2) to determine the effect of angiotensin-converting enzyme (ACE) inhibitor therapy on patients with patent as well as occluded infarct arteries.

    Methods and Results The Survival and Ventricular Enlargement (SAVE) study consisted of 2231 patients with a documented MI and a left ventricular ejection fraction ≤40%. They were randomized to the ACE inhibitor captopril (50 mg TID) or placebo 3 to 16 days after MI and were followed for an average of 3.5 years. Left ventricular ejection fraction, measured with radionuclide left ventriculography, was repeated at the end of the follow-up period. The 946 patients in whom the patency of the IRA was established before randomization form the basis of this study. At cardiac catheterization averaging 4.2 days after infarction, 30.7% of patients had an initially occluded IRA. After revascularization, 162 of the 946 patients (17.1%) were left with an occluded IRA at the time of randomization. The 162 patients with persistently occluded IRAs and 784 with patent IRAs had similar clinical baseline characteristics, but those with occluded arteries had a slightly lower ejection fraction than the 784 patients with patent infarct arteries (30% versus 32%, P=.01). Cox proportional-hazards analyses showed that the independent predictors of all-cause mortality were hypertension (relative risk [RR] 1.94, P<.001), number of diseased coronary arteries (RR 1.68, P<.001), occluded IRA (RR 1.49, P=.039), ejection fraction (RR 1.36, P<.001), age (RR 1.10, P=.030), and use of β-adrenergic receptor blocking agents (RR 0.60, P=.007). Independent predictors of a composite end point consisting of cardiovascular mortality, morbidity, or reduction of ejection fraction of ≥9 units were occluded IRA (odds ratio [OR] 1.73, P=.002), hypertension (OR 1.71, P<.001), number of diseased vessels (OR 1.38, P<.001), ejection fraction (OR 1.18, P=.003), use of β-adrenergic receptor blocking agents (OR 0.67, P=.007), and randomization to captopril (OR 0.70, P=.009).

    Conclusions IRA patency within 16 days after MI predicts a favorable clinical outcome, independent of the number of obstructed coronary arteries or of left ventricular function. The beneficial effect of ACE inhibition is independent of patency status of the IRA. These findings support the need for additional, prospective clinical trials of late reperfusion in MI patients.

    It is well established that early thrombolytic therapy leads to better left ventricular function and survival in patients with acute myocardial infarction (MI).1234 This beneficial effect occurs presumably through the prompt restoration of patency of the infarct-related artery (IRA) and the salvage of jeopardized, ischemic myocardium. Some experimental evidence567 and clinical observations89101112131415161718 also suggest that the benefits of establishing patency of the IRA are not restricted to a narrow postinfarction time window of myocardial salvage. However, there is no clear consensus that a patent IRA is beneficial in patients with completed MI independent of left ventricular function. Although it has been demonstrated that the administration of an angiotensin-converting enzyme (ACE) inhibitor improves the long-term outcome of patients with MI and left ventricular dysfunction1920 and that β-adrenergic receptor blocking agents also improve the outcome of post-MI patients,212223 it is not clear whether these beneficial effects are independent of IRA patency.24

    The objectives of the present prospectively designed study, carried out on patients with a completed MI and significant residual left ventricular dysfunction, were to (1) assess the effect of IRA patency on clinical outcome while controlling for differences in left ventricular ejection fraction, the extent of coronary artery disease, and other important baseline clinical characteristics; (2) to determine the effect of ACE inhibitor therapy on patients with patent as well as occluded infarct arteries; and (3) to determine whether the benefit of β-adrenergic receptor blocking agents was independent of IRA patency.

    Methods

    The Survival and Ventricular Enlargement (SAVE) trial was a double-blind, randomized multicenter trial that tested the hypothesis that chronic therapy with the ACE inhibitor captopril enhances survival and clinical outcome in survivors of acute MI (AMI) with left ventricular dysfunction. Patients were 21 to 80 years old and had a radionuclide left ventricular ejection fraction ≤40%. Potentially eligible patients underwent catheterization if they had recurrent ischemia or a positive exercise test. Randomization to placebo or captopril occurred 3 to 16 days after a documented AMI. After randomization to placebo or captopril (to a maximum dose of 50 mg TID), patients were followed for 2 to 5 years (mean, 3.5 years). All surviving patients underwent a repeat left ventricular ejection fraction measurement during the last months of follow-up. Complete aspects of protocol design as well as the final results of the SAVE study have been published.1925 The SAVE Cardiac Catheterization Core Laboratory was established before the beginning of SAVE, and an analysis of the importance of infarct artery patency was a prespecified ancillary study. The present study focuses on the effect of infarct artery patency on the following end points: (1) total or all-cause mortality, (2) cardiovascular mortality, and (3) cardiovascular mortality or morbidity.

    This combined end point is a prespecified SAVE study end point that includes the development of severe heart failure requiring hospitalization or the use of an open-label ACE inhibitor, recurrent MI, or a drop in LV ejection fraction of 9 points or greater at the end of the study compared with the measurement of ejection fraction taken at the beginning of SAVE.

    Although SAVE did not restrict or mandate specific aspects of management that occurred between the qualifying MI and randomization, if patients had unstable postinfarct angina or low-threshold ischemia, cardiac catheterization was required before randomization. These requirements, as well as clinical preferences across centers, led to a clinically directed cardiac catheterization being obtained between the qualifying MI and randomization in 1301 of the 2231 patients. Moreover, if catheterization identified a need for revascularization therapy, SAVE required that such revascularization be completed before randomization. Thus, this management strategy guaranteed that, at randomization, SAVE patients did not have active or easily provoked ischemia.

    Analysis of Coronary Arteriograms

    Participating SAVE Centers submitted 990 angiograms from these 1301 patients for inclusion in this analysis. Three cardiologists in the SAVE Cardiac Catheterization Core Laboratory who were experienced in invasive procedures (G.A.L., G.F., S.S.) analyzed these 990 angiograms. Coronary arteries were analyzed on the basis of standard, multiple-view angiograms. Multiple segments (proximal, mid, and distal) in each coronary artery and bypass graft were analyzed according to the angiographic analysis scheme published by the Coronary Artery Surgery Study.26 Each individual coronary artery segment was measured by digital electronic caliper and analyzed for percent reduction in luminal diameter and antegrade and collateral flow as described below.

    Definitions of IRA Occlusion

    Infarct location was defined electrocardiographically by the SAVE ECG Core Laboratory. In patients with anterior infarctions, the left anterior descending coronary artery was defined as the IRA. In patients with inferior or posterior infarctions, the IRA was defined as either the left circumflex or the right coronary artery, whichever was occluded or more severely narrowed on the angiogram. Occlusion of the IRA required the presence of grade 0 or 1 antegrade flow and grade 0 or 1 collateral flow as defined by the TIMI investigators.27 The patency status of the IRA was further modified by the results of revascularization performed between the SAVE MI and randomization. Patients who underwent percutaneous transluminal coronary angioplasty of the IRA before randomization had the patency status redefined on the basis of final results of the angioplasty. Patients with occluded IRAs who underwent successful surgical bypass of an occluded IRA before randomization were considered to have patent IRAs.

    Forty-nine patients with indeterminate MI locations and 3 patients with incomplete coronary angiograms were excluded from the analysis. This led to a cohort of 938 patients (990 minus 52 patients) with known IRA status before revascularization and 946 patients after coronary bypass surgery was performed on 8 patients with indeterminate infarct locations (938 plus 8). All subsequent analyses were carried out on these 946 patients.

    Analysis of Left Ventriculograms

    The decision to perform left ventriculography as part of the catheterization procedure was based on clinical indications and local practice in each catheterization laboratory and was not protocol-determined. Left ventriculography was performed and quantitatively analyzed in 674 of the 946 patients (71.2%). The presence and extent of mitral regurgitation were graded on a standard scale (0 to 4).28 The left ventriculograms at end diastole and at end systole were traced and digitized. When extrasystoles were present, care was taken to analyze a cardiac cycle at least two beats after the last extrasystole. Computer-assisted analysis of the traced left ventriculograms provided (1) left ventricular volumes calculated by the area-length method29 in the 411 patients in whom calibration for magnification correction was available; (2) determination of left ventricular shape by use of the sphericity index,30 an index of overall left ventricular shape based on calculating ventricular volume and dividing it by a hypothetical spherical volume generated by using the longest axis of the left ventricle as the diameter of a sphere (calculation of the sphericity index does not require correction for magnification); and (3) analysis of wall motion by the centerline method31 ; the percentages of the diastolic left ventricular circumference that were dyskinetic or akinetic, hypokinetic, and normal were calculated.

    Statistical Analyses

    The analysis of baseline characteristics in mutually exclusive categories was examined by χ2 statistics, and continuous variables were compared by one-way ANOVA. The univariate analysis of end points by infarct artery status was performed with the Cox proportional-hazards model.32 Multivariate analyses to determine whether infarct artery status, captopril therapy, and β-adrenergic receptor therapy were independent predictors of all-cause mortality and cardiovascular mortality were performed with this same method, controlling for important clinical covariates. A logistic regression analysis33 was used to analyze the composite end point. Survival curves were generated by the Kaplan-Meier method.34 Curves were generated by univariate as well as multivariate methods to correct for the effects of other covariates.35

    Results

    Baseline Characteristics

    The 946 patients in whom the IRA status was known and who form the basis for this analysis were compared with the other 1285 patients in the SAVE trial (Table 1). The former were in general at lower risk; they were younger, had a higher left ventricular ejection fraction, were less likely to be diabetic or to have experienced a previous MI, and were less likely to have pulmonary congestion during the index (SAVE) infarction than were the patients who were not catheterized. In addition, they were more likely to have received thrombolytic therapy and to have undergone mechanical revascularization.

    Initial Management of the IRA

    Cardiac catheterization was carried out between the day of infarction and 16 days after infarction (mean, 4.2 days; median, 3.0 days). At baseline, before myocardial revascularization, 288 of the 938 patients (30.7%) in whom the IRA had been identified had an occluded IRA. Patients who had not received thrombolytic therapy were more likely to demonstrate occluded IRAs at the baseline cardiac catheterization before surgical or transcatheter revascularization than were patients who had received thrombolysis (184 of 494 [37.2%] versus 104 of 444 [23.4%], P<.001). Of these 288 patients with an initially occluded IRA, 130 had revascularization leading to a patent IRA (coronary angioplasty, 101; coronary bypass, 25; and coronary bypass after unsuccessful angioplasty, 4), and an occluded IRA persisted in 158. An initially patent IRA was observed in 650 patients. Coronary angioplasty was performed in 165 patients. In 6 (3.6%), angioplasty of an initially patent IRA led to an occluded IRA. In 2 of these 6 patients, IRA patency was restored by coronary bypass operations. Thus, 4 patients with postangioplasty IRA occlusions were added to the 158 patients with nonrevascularized IRA occlusions. An additional 8 patients with indeterminate MI locations and indeterminate status of the IRA had multivessel coronary bypass graft surgery and were therefore reclassified as having a patent IRA. These procedures led to the final group of 946 patients for analysis; 162 (17.1%) had an occluded and 784 (82.9%) a patent IRA at the time of randomization into SAVE.

    Comparison Between Patients With Patent and Occluded IRAs

    Patients with occluded or patent IRAs were similar in age, sex distribution, and important clinical baseline variables to patients with patent IRAs (Tables 2 and 3). However, patients with occluded IRAs were significantly less likely to have sustained a Q-wave anterolateral MI and to have received thrombolytic therapy than patients with a patent IRA, and they had slightly lower baseline radionuclide left ventricular ejection fractions than did patients with a patent IRA. Coronary angiography revealed that patients with occluded IRAs were more likely to have three-vessel coronary disease (occluded versus patent: 46 of 162, 28.4%, versus 149 of 784, 19.0%; P=.027).

    Although there were no significant differences between the two groups with regard to left ventricular volumes (Table 3), patients with occluded IRAs had a more spherical systolic left ventricular shape. Patients with occluded IRAs also were more likely to have mitral regurgitation on left ventriculography.

    Patient Outcomes

    During the follow-up, which ranged from 2 to 5 years and averaged 3.5 years, patients with occluded IRAs demonstrated higher unadjusted all-cause mortality (occluded versus patent, 24% versus 14%; P<.001) and cardiovascular mortality (occluded versus patent, 23% versus 12%; P<.001) than did patients with patent IRAs (Table 4, Fig 1). The prespecified composite end point occurred more frequently in patients with occluded than patent IRAs (51% versus 37%, P<.001).

    Multivariate Analyses

    An occluded IRA was an independent predictor of all-cause mortality, cardiovascular mortality, and the composite “unfavorable cardiovascular outcome” end point. The components of the multivariate analyses are detailed in Table 5 and Fig 2.

    Effect of Captopril

    In the subset of 946 patients who form the basis of this analysis, randomization to captopril was not an independent predictor of survival as it was for the total SAVE cohort.14 However, randomization to captopril did show a significant, independent effect in reducing the incidence of the composite end point of cardiovascular mortality or morbidity. Patients with a patent IRA who were randomized to captopril had a composite end point incidence of 34.3%; the incidence of this end point was intermediate in patients with a patent IRA who were randomized to placebo and in patients with an occluded IRA who were randomized to captopril (38.8% and 40.2%, respectively); patients with an occluded IRA randomized to placebo had the highest event rate (62.7%) (Table 5 and Fig 3).

    Effect of β-Adrenergic Receptor Blockade

    Of 784 patients with patent IRAs, 299 (38.1%) were taking β-adrenergic receptor blocking agents before randomization. Of 162 patients with occluded IRAs, 64 (39.5%) were taking β-adrenergic receptor blocking agents before randomization. Multivariate analyses demonstrated that patients taking β-adrenergic receptor blocking agents were less likely than those not taking these agents to have clinical end points independent of IRA patency (Table 5).

    Analysis of Patients With Occluded IRAs Undergoing Revascularization

    The effect of revascularization on the outcome of patients with an initially occluded IRA was tested by comparing the baseline characteristics and eventual outcome of 130 patients who underwent successful revascularization (angioplasty, 101; unsuccessful angioplasty followed by coronary bypass, 4; and coronary bypass alone, 25) with those of 158 patients with persistent occlusion of the IRA. (This latter number excludes 4 patients with an initially patent IRA that was later occluded after unsuccessful angioplasty.) There were no significant differences in the patients’ age or sex, other risk factors, assignment to captopril therapy, and baseline coronary anatomy; however, patients with an initially occluded IRA that was opened did have a significantly higher ejection fraction but a lower overall use of β-adrenergic receptor blocking agents than did those patients whose IRAs were not successfully opened (Table 6). Although the difference in ejection fraction between groups was small, there were large differences favoring the revascularized group in the incidence of all-cause mortality, cardiovascular mortality, and the combined end point.

    Discussion

    The patency status of the IRA after coronary occlusion is a function of the balance between spontaneous and pharmacologically induced lysis of intracoronary thrombi and of mechanical revascularization on the one hand and of resistance to lysis and spontaneous reocclusion of patent arteries on the other. Therefore, depending on the nature of the patient population, the therapy given, and the timing of catheterization, different investigators have found widely varying patency rates of IRAs.83637 The present study, based on the subgroup of 946 of the 2231 SAVE patients in whom patency status at randomization was known, found 17.1% of patients with occluded IRAs. The principal objective of these analyses was to determine the long-term effects of the actual patency status of the IRA in patients who had recently sustained a documented MI resulting in significant left ventricular dysfunction and who did not have residual active or easily provokable ischemia.

    Recent studies have emphasized that in patients with acute MI, early attainment of a patent infarct artery is associated with improved left ventricular function,38 and they support the well-established concept that early myocardial reperfusion limits myocardial necrosis and thereby reduces mortality.39 However, the hypothesis tested by the present study, ie, that a patent IRA improves clinical outcome independent of left ventricular function, has not been tested prospectively. There are, however, retrospectively obtained clinical data that support this idea. Cigarroa et al10 reviewed 179 patients catheterized 1 month after MI and followed for an average of 47 months. Although the ejection fraction at 1 month did not appear to be influenced by the patency status of the IRA, patients with occluded infarct arteries experienced a total mortality of 18%, in sharp contrast to the 0% in patients with a patent infarct artery. Schroder et al12 addressed these questions in patients with AMI enrolled in a trial of thrombolytic therapy. Patients who had demonstrated no evidence of early reperfusion, based on the presence of late-peaking creatine kinase curves, were catheterized 1 month after AMI. The long-term survival of patients with patent infarct arteries was better than would have been expected on the basis of the difference in ejection fraction of the patent and occluded-artery groups. Similarly, Galvani et al18 retrospectively assessed patients with Q-wave infarctions and reported that infarct artery patency and end-systolic volume were independent predictors of survival. Other data reported by the Western Washington study8 and reviewed elsewhere91314 also support the concept that the improvement in survival after thrombolysis is greater than would be expected from the observed improvement in ejection fraction alone.

    Large multicenter trials such as the Second International Study of Infarct Survival,2 the LATE study,40 and the meta-analysis provided by the Fibrinolytic Therapy Trialists’ Collaborative Group4 have shown that patients receiving thrombolytic therapy beyond the usual time window in which salvage of myocardium might be expected to occur (>6 hours after the onset of symptoms) and who may be presumed to have a higher IRA patency rate than patients who did not receive a thrombolytic intervention experienced improved survival. However, these studies provided no direct information regarding IRA patency or left ventricular function, and we cannot infer from them that late IRA patency is an independent predictor of clinical outcome.

    The present study differs from prior studies in that (1) it was designed prospectively at the time the SAVE Catheterization Core Laboratory was conceived in 1988, and an analysis of the importance of infarct-artery patency was a prespecified ancillary study end point; (2) the analysis was restricted to patients with completed infarctions, documented left ventricular dysfunction, and no clinically overt ischemia or heart failure at randomization; (3) patients in whom a variety of different strategies led to the final patency status of the IRA were included, more accurately reflecting present clinical practice; (4) the coronary anatomy and baseline as well as follow-up ejection fractions were available in all patients; and (5) corrections for initial differences in left ventricular function and other baseline variables were made. We observed that patients with patent IRAs had a significantly better prognosis than did patients with occluded arteries. After adjustment for differences in baseline characteristics, including ejection fraction, the patency status of the IRA remained an independent predictor of all-cause mortality, cardiovascular mortality, and the composite end point consisting of cardiovascular mortality, morbidity, and serious reduction of left ventricular ejection fraction.

    There are several possible mechanisms by which the patency status of the IRA may affect postinfarct survival independently of myocardial salvage and postinfarction left ventricular function. Jeremy et al41 and Pfeffer et al42 demonstrated that an occluded IRA is associated with greater increases in left ventricular volume, known to be an important predictor of long-term mortality in postinfarction patients.43 Within 1 month of an anterior Q-wave acute MI, patients with occluded IRAs have been shown to have greater left ventricular volumes and more spherical left ventricles than do patients with a patent infarct artery, despite minor differences in ejection fraction.1644 Topol et al45 administered tissue plasminogen activator or placebo to 197 patients with 6 to 24 hours of symptoms and ST elevations. Left ventricular volumes were assessed by contrast left ventriculography. Placebo patients demonstrated a small but significant increase in left ventricular volume. Patients receiving thrombolysis did not have any change in left ventricular volumes. Nidorf et al17 used quantitative echocardiography to study patients who had undergone coronary reperfusion at different times after MI; those with occluded IRAs demonstrated progressive left ventricular dilatation. However, 13 patients with late coronary angioplasty of an occluded IRA an average of 5 days after infarction demonstrated early dilatation but a later trend toward normalization of left ventricular size. In the present study, the measurement of left ventricular volumes was limited to a single early point in time, and therefore, this study cannot determine whether the measurable clinical benefit of a patent infarct artery is due to prevention of left ventricular remodeling.

    The patency status of the IRA may also affect the incidence of postinfarct arrhythmia and thereby prognosis. Patients with occluded IRAs are more likely to demonstrate late potentials4647 as well as inducible ventricular tachycardia4849 and therefore to be at higher risk of sudden death. Patients with patent IRAs may also have hibernating myocardium5051 in proximity to the infarct, whose viability is maintained by the patent vessel. Although it does not contribute to left ventricular performance, hibernating myocardium might be less subject to dyskinesis and deformation than transmurally infarcted myocardium and thereby may reduce left ventricular remodeling and lead to a more favorable outcome.

    The presence of mitral regurgitation after acute MI has been reported to be a predictor of poor outcome.52 This study found that patients with occluded IRAs have more spherical left ventricles during end systole and are more likely to have mitral regurgitation. These associated findings suggest that IRA occlusion is associated with subtle geometric alterations in left ventricular shape, which may have functional consequences. In turn, the presence of mitral regurgitation in patients with occluded IRAs may contribute to their poorer prognosis.

    Effect of ACE Inhibition and β-Adrenergic Receptor Blockade

    Several investigators395354 have demonstrated that therapy with ACE inhibitors attenuates left ventricular volume enlargement after MI. The most prominent effect of captopril in attenuating left ventricular volume enlargement occurred in patients who had occluded IRAs.42 An important objective of the present study was to determine whether the clinical benefits of postinfarction captopril therapy are dependent on the patency status of the infarct artery.

    The SAVE trial demonstrated that the ACE inhibitor reduced all-cause mortality in postinfarct patients with impaired left ventricular function.19 The present analysis, based on a subset of the patients in SAVE, had limited statistical power and did not demonstrate the significant reduction in all-cause mortality that was observed in the overall SAVE trial. However, the event rate and statistical power were higher when the prospectively defined composite end point of cardiovascular mortality, morbidity, and a marked deterioration of left ventricular function was used. This composite end point provided sufficient statistical power to demonstrate that randomization to captopril was an independent predictor of improved overall clinical outcome (RR for the combined end point in patients randomized to captopril, 0.70; P<.001). The finding that ACE inhibitor therapy and IRA patency are independent predictors of clinical outcome suggests that the previously described benefits of ACE inhibition in the total SAVE population may be extended to the subgroups with patent as well as occluded IRAs.

    Glamann et al24 reported that patients with an occluded IRA who were taking β-adrenergic receptor blocking agents had a markedly better prognosis (2% cardiac mortality over 4 years) than did patients with an occluded IRA who were not taking β-adrenergic receptor blocking agents (30% cardiac mortality). Thus, the present study attempted to ascertain whether the benefit of postinfarct β-adrenergic receptor blockade was present in patients with a patent IRA. Although the use of β-blockade in the SAVE study was clinically determined and not randomized, multivariate analyses clearly demonstrated that β-blockade is beneficial independent of IRA patency and independent of captopril therapy.

    Effect of Revascularization of an Initially Occluded IRA

    Although the use of revascularization therapies in patients whose baseline angiograms demonstrated an initially occluded IRA was clinically determined and not randomized, striking differences in clinical outcomes were demonstrated between the revascularized and nonrevascularized groups. Indeed, these differences, which included a halving of long-term mortality, occurred in the setting of a minor, two-point difference in ejection fraction between groups. Thus, this subgroup analysis underscores the importance of IRA patency, even when patency has not been spontaneously achieved but rather is the result of revascularization therapies.

    Limitations of the Present Study and Conclusions

    The effects of the patency status of the IRA in post-MI patients would optimally be studied by determining coronary arterial patency early after infarction, excluding patients who required revascularization on clinical grounds, randomizing the remaining patients with occluded arteries to mechanical revascularization or no revascularization, and restudying patients weeks or months later to reassess coronary arterial patency. The present analyses of nonrandomized patients fall short of this idealized study, since the 946 patients in whom the patency status of the IRA was established and on whom this analysis is based were not selected at random. Furthermore, a single coronary angiogram between the day of infarction and up to 16 days later may misclassify the ultimate chronic patency status of the infarct artery, since it cannot take into account either spontaneous late reperfusion or spontaneous asymptomatic late reocclusion. Nevertheless, despite this imperfect methodology, the baseline features of these 946 patients, including left ventricular function, were well characterized, and the results observed are relevant to this population, which is representative of a large fraction of patients with acute MI and moderately depressed left ventricular function (Table 1). From the analysis of these patients, we may conclude that both patency of the IRA and treatment with the ACE inhibitor captopril are independent predictors of favorable clinical outcome in patients with MI and left ventricular dysfunction.

    Reprint requests to Gervasio A. Lamas, MD, Division of Cardiology, Mount Sinai Medical Center, 4300 Alton Rd, Miami Beach, FL 33140.

    Figure 1.
    Figure 1.

    Figure 1. Univariate survival curves for (top) total mortality by infarct artery patency and (bottom) cardiovascular mortality by infarct artery patency.

    Figure 2.
    Figure 2.

    Figure 2. Multivariate-adjusted survival curves for (top) total mortality by infarct patency and (bottom) cardiovascular mortality by infarct patency after adjustment for other covariates.

    Figure 3.

    Figure 3. Effect of captopril and infarct artery patency on the univariate unadjusted occurrence of the combined end point. The multivariate adjusted values are P=.003 for the effect of the occluded IRA and P=.01 for the effect of captopril.

    Table 1. Comparison of Baseline Characteristics in Patient Subgroups

    CharacteristicsTotal Patients (n=2231)Patients in Cath Core (n=946)Patients Not in Cath Core (n=1285)P,1 Cath Core vs Non–Cath Core Patients
    Mean age, y59.456.961.2<.001
    Male sex, %828483NS
    Clinical history at presentation with MI, %
    Prior MI353238<.001
    Diabetes mellitus221924<.003
    Hypertension373638NS
    Ever smoked222022NS
    Mean days to randomization111111NS
    Events between MI and randomization
    Highest serum creatine kinase213.714.812.9NS
    Killip class >1, %403444<.001
    Thrombolytic therapy, %334424<.001
    PTCA, %18328<.001
    Coronary artery bypass, %9126<.001
    Infarct type and location, %3
    Anterolateral Q wave556151<.001
    Inferoposterior Q wave181718
    Both121112
    Non–Q wave10109
    Other6110
    Mean radionuclide ejection fraction, %313231<.001
    Blood pressure, mm Hg
    Systolic113111114<.001
    Diastolic706970.012
    Heart rate, bpm777977.017

    Cath Core indicates patients analyzed by the SAVE Cardiac Catheterization Core Laboratory; MI, myocardial infarction; PTCA, percutaneous transluminal coronary angioplasty; and bpm, beats per minute.

    1P values were calculated by two-sample Student’s t test for continous variables and by Pearson χ2 test for categorical variables. Significance was taken at P<.05.

    2Expressed as a multiple of the upper limit of normal.

    3As assessed by electrocardiography.

    Table 2. Comparison of Baseline Characteristics of Patients With Patent Versus Occluded Infarct Arteries

    CharacteristicsPatent Artery (n=784)Occluded Artery (n=162)P1
    Mean age, y56.857.7NS
    Male sex, %8283NS
    Clinical history at presentation with MI, %
    Prior MI3136NS
    Diabetes mellitus1917NS
    Hypertension3635NS
    Ever smoked2019NS
    Mean days to randomization1111NS
    Events between MI and randomization
    Highest serum creatine kinase215.411.8<.001
    Killip class >1, %3530NS
    Thrombolytic therapy, %4636.016
    PTCA, %3611<.001
    Coronary artery bypass surgery, %150<.001
    Infarct type and location, %3
    Anterolateral Q wave6256.007
    Inferoposterior Q wave1626
    Both1012
    Non–Q wave116
    Other10
    Mean radionuclide ejection fraction, %3230.010
    Blood pressure, mm Hg
    Systolic111111NS
    Diastolic6969NS
    Heart rate, bpm7877NS

    MI indicates myocardial infarction; PTCA, percutaneous transluminal coronary angioplasty; and bpm, beats per minute.

    1P values were calculated by two-sample Student’s t test for continous variables and by Pearson χ2 test for categorical variables.

    2Expressed as a multiple of the upper limit of normal.

    3As assessed by electrocardiography.

    Table 3. Results of Left Ventriculography in Patients With Patent or Occluded Infarct Arteries

    CharacteristicsPatent ArteryOccluded ArteryP
    EDV, mL196±67201 ±78.600
    ESV, mL114±44120 ±49.375
    DSI, %38±839±8.151
    SSI, %29 ±831±9.016
    MR, %16.926.5.015

    EDV indicates end-diastolic volume; ESV, end-systolic volume; DSI, diastolic sphericity index; SSI, systolic sphericity index; and MR, mitral regurgitation.

    Table 4. Relation Between Infarct Artery Patency and End Points: Univariate Analysis

    End PointPatent ArteryOccluded ArteryRelative Risk (95% CI)Wald χ2P
    n%n%
    Total mortality1109/7841439/162241.89 (1.31-2.72)11.5<.001
    CV mortality195/7841237/162232.04 (1.40-2.98)13.5<.001
    CV morbidity/ mortality2286/7843682/162511.79 (1.27-2.51)11.1<.001

    CI indicates confidence interval; CV, cardiovascular.

    1P was calculated by univariate Cox regression analysis.

    2P was calculated by univariate logistic regression analysis.

    Table 5. Relation Between Infarct Artery Status and End Points by Multivariate Analysis

    VariableTotal MortalityCV MortalityCV Morbidity or Mortality
    Relative Risk (95% CI)Wald χ2P1Relative Risk (95% CI)Wald χ2P1Odds Ratio (95% CI)Wald χ2P1
    Occluded infarct artery1.49 (1.02-2.17)4.25.0391.57 (1.06-2.33)5.03.0251.73 (1.22-2.47)9.21.002
    Number of diseased vessels (1-3)1.68 (1.37-2.05)25.53<.0011.80 (1.46-2.23)29.27<.0011.38 (1.16-1.64)13.25<.001
    Treatment (captopril vs placebo)0.96 (0.69-1.32)0.08NS0.96 (0.68-1.35)0.07NS0.70 (0.53-0.91)6.76.009
    Ejection fraction21.36 (1.21-1.52)28.36<.0011.40 (1.24-1.58)30.81<.0011.18 (1.06-1.31)8.66.003
    Age21.10 (1.01-1.19)4.70.0301.07 (0.98-1.17)2.32NS1.04 (0.97-1.11)1.24NS
    Hypertension1.94 (1.40-2.70)15.60<.0011.98 (1.40-2.81)14.79<.0011.71 (1.28-2.28)13.08<.001
    Diabetes0.81 (0.54-1.23)0.96NS0.81 (0.52-1.26)0.86NS1.21 (0.85-1.71)1.14NS
    β-Blockers at baseline0.60 (0.41-0.87)7.30.0070.49 (0.32-0.74)11.34<.0010.67 (0.50-0.89)7.38.007

    CV indicates cardiovascular; CI, confidence interval.

    1P was calculated by Cox regression analysis for total mortality. For the combined end point of CV morbidity/mortality plus deterioration of ejection fraction by 9 or more, P was calculated by logistic regression. Significance was taken at P<.05.

    2Relative risks and odds ratio were calculated for a decrease of 5% units for ejection fraction and an increase of 5 years for age.

    Table 6. Comparison of Baseline Characteristics and Outcomes of Patients With Initially Occluded Infarct Arteries

    Infarct Artery StatusP
    Occluded, Then Opened (n=130)Occluded (n=158)
    Age, y57±1158±11.481
    Male sex, %8284.655
    Prior MI, %3137.290
    Captopril, %4954.440
    β-Blocker, %2839.040
    MI location, %
    Anterior Q wave6556
    Inferoposterior Q wave1626
    Anterior+inferior Q wave1212
    Non–Q wave76.244
    Ejection fraction, %32±630±7.023
    Coronary disease, %
    1 Vessel5646
    2 Vessels2625
    3 Vessels1829.064
    PTCA or CABG, %1004<.001
    Outcome events, %
    Mortality1124.004
    Cardiovascular mortality923.001
    Combined end point3251.002

    MI indicates myocardial infarction; PTCA, percutaneous transluminal coronary angioplasty; and CABG, coronary artery bypass graft surgery after the presenting MI, before randomization.

    The SAVE study was funded by a grant from the Bristol Myers Squibb Institute for Pharmaceutical Research. The authors gratefully acknowledge the expert secretarial assistance provided by Lori Martens.

    References

    • 1 ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet.1988; 2:349-360. MedlineGoogle Scholar
    • 2 GISSI (Gruppo Italiano per lo Studio della Streptochinasi Nell’Infarto Miocardico). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet.1986; 1:397-402. MedlineGoogle Scholar
    • 3 GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med.1993; 329:673-682. CrossrefMedlineGoogle Scholar
    • 4 Fibrinolytic Therapy Trialists’ (FTT) Collaborative Group. Indications for fibrinolytic therapy in suspected acute myocardial infarction: collaborative overview of early mortality and major morbidity results from all randomised trials of more than 1000 patients. Lancet.1994; 343:311-322. CrossrefMedlineGoogle Scholar
    • 5 Hochman JS, Choo H. Limitation of myocardial infarct expansion by reperfusion independent of myocardial salvage. Circulation.1987; 75:299-306. CrossrefMedlineGoogle Scholar
    • 6 Hale SL, Kloner RA. Left ventricular topographic alterations in the completely healed rat infarct caused by early and late coronary artery reperfusion. Am Heart J.1988; 116:1508-1513. CrossrefMedlineGoogle Scholar
    • 7 Force T, Kemper A, Leavitt M, Parisi AF. Acute reduction in functional infarct expansion with late coronary reperfusion: assessment with quantitative two-dimensional echocardiography. J Am Coll Cardiol.1988; 11:192-200. CrossrefMedlineGoogle Scholar
    • 8 Kennedy JW, Ritchie JL, Davis KB, Fritz JK. Western Washington randomized trial of intracoronary streptokinase in acute myocardial infarction. N Engl J Med.1983; 309:1477-1482. CrossrefMedlineGoogle Scholar
    • 9 Braunwald E. Myocardial reperfusion, limitation of infarct size, reduction of left ventricular dysfunction, and improved survival: should the paradigm be expanded? Circulation.1989; 79:441-444. CrossrefMedlineGoogle Scholar
    • 10 Cigarroa RG, Lange RA, Hillis LD. Prognosis after acute myocardial infarction in patients with and without residual anterograde coronary blood flow. Am J Cardiol.1989; 64:155-160. CrossrefMedlineGoogle Scholar
    • 11 Califf RM, Topol EJ, Gersh BJ. From myocardial salvage to patient salvage in acute myocardial infarction: the role of reperfusion therapy. J Am Coll Cardiol.1989; 14:1382-1388. CrossrefMedlineGoogle Scholar
    • 12 Schroder R, Neuhaus K-L, Linderer T, Bruggemann T, Tebbe U, Wegscheider K. Impact of late coronary artery reperfusion on left ventricular function one month after acute myocardial infarction (results from the ISAM Study). Am J Cardiol.1989; 64:878-884. CrossrefMedlineGoogle Scholar
    • 13 Fortin DF, Califf RM. Long-term survival from acute myocardial infarction: salutary effect of an open coronary vessel. Am J Med.1990; 88:9N-15N. CrossrefMedlineGoogle Scholar
    • 14 Gersh BJ. Benefits of the open artery: beyond myocardial salvage. J Myocard Ischemia.1990; 2:15-37. Google Scholar
    • 15 Kim CB, Braunwald E. Potential benefits of late reperfusion of infarcted myocardium: the open artery hypothesis. Circulation.1993; 88:2426-2436. CrossrefMedlineGoogle Scholar
    • 16 Lamas GA, Pfeffer MA, Braunwald E. Patency of the infarct-related coronary artery and ventricular geometry. Am J Cardiol.1991; 68:41D-51D. MedlineGoogle Scholar
    • 17 Nidorf SM, Siu SC, Galambos G, Weyman AE, Picard MH. Benefit of late coronary reperfusion on ventricular morphology and function after myocardial infarction. J Am Coll Cardiol.1993; 21:683-691. CrossrefMedlineGoogle Scholar
    • 18 Galvani M, Ottani F, Ferrini D, Sorbello F, Rusticali F. Patency of the infarct-related artery and left ventricular function as the major determinants of survival after Q-wave acute myocardial infarction. Am J Cardiol.1993; 71:1-7. CrossrefMedlineGoogle Scholar
    • 19 Pfeffer MA, Braunwald E, Moye L, Basta L, Brown EJ, Cuddy TE, Davis BR, Geltman EM, Goldman S, Flaker GC, Klein M, Lamas GA, Packer M, Rouleau J, Rouleau JL, Rutherford J, Wertheimer JH, Hawkins CM, on behalf of the SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med.1992; 327:669-677. CrossrefMedlineGoogle Scholar
    • 20 AIRE (The Acute Infarction Ramipril Efficacy) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet.1993; 342:821-826. MedlineGoogle Scholar
    • 21 Green KG, Chamberlain DA, Fulton RM, Hamer NAJ, Oliver MF, Pentecost BL. Reduction in mortality after myocardial infarction with long-term B-adrenoceptor blockade: multicenter international study: supplementary report. Br Med J.1977; 2:419-421. CrossrefMedlineGoogle Scholar
    • 22 Norwegian Multicenter Study Group. Timolol-induced reduction in mortality and reinfarction in patients surviving acute myocardial infarction. N Engl J Med.1981; 304:801-807. CrossrefMedlineGoogle Scholar
    • 23 B-Blocker Heart Attack Trial Research Group. A randomized trial of propranolol in patients with acute myocardial infarction, 1: mortality results. JAMA.1981; 247:1707-1714. Google Scholar
    • 24 Glamann DB, Lange RA, Hillis LD. Beneficial effect of long-term beta blockade after myocardial infarction in patients without anterograde flow in the infarct artery. Am J Cardiol.1991; 68:150-154. CrossrefMedlineGoogle Scholar
    • 25 Moye LA, Pfeffer MA, Braunwald E. Rationale, design and baseline characteristics of the Survival and Ventricular Enlargement Trial. Am J Cardiol.1991; 68:70D-79D. CrossrefMedlineGoogle Scholar
    • 26 CASS Investigators. Chest x-ray and coronary arteriography. Circulation.1981; 63:58-68. Google Scholar
    • 27 Chesebro JH, Knatterud G, Roberts R, Borer J, Cohen LS, Dalen J, Dodge HT, Francis CK, Hillis D, Ludbrook P, Markis JE, Mueller H, Passamani ER, Powers ER, Rao AK, Robertson T, Ross A, Ryan TJ, Sobel BE, Willerson J, Williams DO, Zaret L, Braunwald E. Thrombolysis in Myocardial Infarction (TIMI) trial, phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Circulation.1987; 76:142-154. CrossrefMedlineGoogle Scholar
    • 28 Grossman W. Profiles in valvular heart disease. In: Grossman W, Baim DS, eds. Cardiac Catheterization, Angiography and Intervention. 4th ed. Philadelphia, Pa: Lea & Febiger; 1991:557-581. Google Scholar
    • 29 Wynne J, Green L, Mann T, Levin D, Grossman W. Estimation of left ventricular volumes in man from biplane cineangiograms filmed in oblique projections. Am J Cardiol.1978; 41:726-732. CrossrefMedlineGoogle Scholar
    • 30 Lamas GA, Vaughan DE, Parisi AF, Pfeffer MA. Effects of left ventricular shape and captopril therapy on exercise capacity after anterior wall acute myocardial infarction. Am J Cardiol.1989; 63:1167-1172. CrossrefMedlineGoogle Scholar
    • 31 Sheehan FH, Bolson EL, Dodge HT, Mathey DG, Schofer J, Woo HW. Advantages and applications of the centerline method for characterizing regional ventricular function. Circulation.1986; 74:293-305. CrossrefMedlineGoogle Scholar
    • 32 Cox DR. Regression models and life-tables. J R Stat Soc (B).1972; 34:187-220. Google Scholar
    • 33 Hosmer DW, Lemeshow SL. Applied Logistic Regression. New York, NY: John Wiley & Sons; 1989. Google Scholar
    • 34 Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc.1958; 53:457-481. CrossrefGoogle Scholar
    • 35 Lee ET. Statistical Methods for Survival Data Analysis. New York, NY: John Wiley & Sons; 1992. Google Scholar
    • 36 DeWood MA, Spores J, Notske R, Mouser LT, Burroughs R, Golden MS, Lang HT. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med.1980; 303:897-902. CrossrefMedlineGoogle Scholar
    • 37 Morgan CD, Roberts RS, Hag A, Baigrie RS, Daly PA, Gent M, Armstrong PW (for the TPA Study Group). Coronary patency, infarct size and left ventricular function after thrombolytic therapy for acute myocardial infarction: results from the tissue plasminogen activator: Toronto (TPAT) placebo-controlled trial. TPAT Study Group. J Am Coll Cardiol.1991; 17:1451-1457. CrossrefMedlineGoogle Scholar
    • 38 GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med.1993; 329:1615-1622. CrossrefMedlineGoogle Scholar
    • 39 Braunwald E. The open-artery theory is alive and well–again. N Engl J Med.1993; 329:1650-1652. CrossrefMedlineGoogle Scholar
    • 40 LATE Study Group. Late assessment of thrombolytic efficacy (LATE) study with alteplase 6-24 hours after onset of acute myocardial infarction. Lancet.1993; 342:759-766. CrossrefMedlineGoogle Scholar
    • 41 Jeremy RW, Hackworthy RA, Bautovich G, Hutton BF, Harris PJ. Infarct artery perfusion and changes in left ventricular volume in the month after acute myocardial infarction. J Am Coll Cardiol.1987; 9:989-995. CrossrefMedlineGoogle Scholar
    • 42 Pfeffer MA, Lamas GA, Vaughan DE, Parisi AF, Braunwald E. Effect of captopril on progressive ventricular dilatation after anterior myocardial infarction. N Engl J Med.1988; 319:80-86. CrossrefMedlineGoogle Scholar
    • 43 White HD, Norris RM, Brown MA, Brandt PWT, Whitlock RML, Wild CJ. Left ventricular end-systolic volume as the major determinant of survival after recovery from myocardial infarction. Circulation.1987; 76:44-51. CrossrefMedlineGoogle Scholar
    • 44 Mitchell GF, Lamas GA, Vaughan DE, Pfeffer MA. Left ventricular remodeling in the year after first anterior myocardial infarction: a quantitative analysis of contractile segment lengths and ventricular shape. J Am Coll Cardiol.1992; 19:1136-1144. CrossrefMedlineGoogle Scholar
    • 45 Topol EJ, Califf RM, Vandormael M, Grines CL, George BS, Sanz ML, Wall T, O’Brien M, Schwaiger M, Aguirre FV, Young S, Popma JJ, Sigmon KN, Lee KL, Ellis SG, and the Thrombolysis and Angioplasty in Myocardial Infarction-6 Study Group. A randomized trial of late reperfusion therapy for acute myocardial infarction. Circulation.1992; 85:2090-2099. CrossrefMedlineGoogle Scholar
    • 46 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. CrossrefMedlineGoogle Scholar
    • 47 Vatterott PJ, Hammill SC, Bailey KR, Wiltgen CM, Bailey KR, Gersh BJ. Late potential on signal-average electrocardiograms and patency of the infarct-related artery in survivors of acute myocardial infarction. J Am Coll Cardiol.1991; 17:330-337. CrossrefMedlineGoogle Scholar
    • 48 Sager PT, Perlmutter RA, Rosenfeld LE, McPherson CA, Wackers FJT, Batsford WP. Electrophysiologic effects of thrombolytic therapy in patients with a transmural anterior myocardial infarction complicated by left ventricular aneurysm formation. J Am Coll Cardiol.1988; 12:19-24. CrossrefMedlineGoogle Scholar
    • 49 Kersschot IE, Brugada P, Ramentol M, Zehender M, Waldecker B, Stevenson WG, Geibel A, De Zwaan C, Hein J, Wellens J. Effects of early reperfusion in acute myocardial infarction on arrhythmias induced by programmed stimulation: a prospective, randomized study. J Am Coll Cardiol.1986; 7:1234-1242. CrossrefMedlineGoogle Scholar
    • 50 Montalescot G, Faraggi M, Drobinski G, Messian O, Evans J, Grosgogeat Y, Thomas D. Myocardial viability in patients with Q wave myocardial infarction and no residual ischemia. Circulation.1992; 86:47-55. CrossrefMedlineGoogle Scholar
    • 51 Sabia P, Powers ER, Ragosta M, Sarembock IJ, Burwell LR, Kaul S. An association between collateral blood flow and myocardial viability in patients with recent myocardial infarction. N Engl J Med.1992; 327:1825-1831. CrossrefMedlineGoogle Scholar
    • 52 Lehmann KG, Francis CK, Dodge HT, and the TIMI Study Group. Mitral regurgitation in early myocardial infarction: incidence, clinical detection, and prognostic implications. Ann Intern Med.1992; 117:10-17. CrossrefMedlineGoogle Scholar
    • 53 Sharpe DN, Murphy J, Smith H, Hannan S. Treatment of patients with symptomless left ventricular dysfunction after myocardial infarction. Lancet.1988; 1:255-259. CrossrefMedlineGoogle Scholar
    • 54 Bonaduce D, Petretta M, Arrichiello P, Conforti G, Montemurro MV, Attisano T, Bianchi V, Morgano G. Effects of captopril treatment on left ventricular remodeling and function after anterior myocardial infarction: comparison with digitalis. J Am Coll Cardiol.1992; 19:858-863.CrossrefMedlineGoogle Scholar
    Back to top