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(Circulation. 1995;91:298-303.)
© 1995 American Heart Association, Inc.

Articles

Effect of Cigarette Smoking on Outcome After Thrombolytic Therapy for Myocardial Infarction

Cindy L. Grines, MD; Eric J. Topol, MD; William W. O'Neill, MD; Barry S. George, MD; Dean Kereiakes, MD; Harry R. Phillips, MD; Jeffrey D. Leimberger, PhD; Lynn H. Woodlief, MS; Robert M. Califf, MD

From the Division of Cardiology, Department of Medicine, William Beaumont Hospital, Royal Oak, Mich.

Correspondence to Cindy L. Grines, MD, Division of Cardiology, William Beaumont Hospital, 3601 W Thirteen Mile Rd, Royal Oak, MI.

	Abstract

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Background Smoking is known to be a strong risk factor for premature atherosclerosis, myocardial infarction, and sudden cardiac death. Unexpectedly, in the reperfusion era, investigators have reported that patients who smoke have a more favorable prognosis after thrombolysis compared with nonsmokers. Since smoking is associated with a relatively hypercoagulable state, we hypothesized that the coronary occlusion responsible for infarction may be primarily thrombotic, with improved outcome relating to enhanced patency or the absence of a residual stenosis after thrombolytic therapy.

Methods and Results To examine this issue, we evaluated 1619 patients treated with TPA, urokinase, or both in six consecutive myocardial infarction trials, of whom 878 (54%) were currently smoking. Patients underwent 90-minute and predischarge catheterizations, which were quantified blinded to the patients' smoking status. As expected, baseline fibrinogen (2.8 [2.5, 3.6] versus 2.7 [2.4, 3.5] g/dL, P=.003) and hematocrit (44% [41%, 47%] versus 43% [40%, 45%], P=.0001) levels were greater in smokers. Although there were no differences between smokers and nonsmokers with regard to 90-minute patency (73% versus 74%), smokers were more likely to have TIMI-3 flow (41.1% versus 34.6%, P=.034), with a larger minimum lumen diameter of the infarct stenosis both acutely (0.82 [0.51, 1.11] versus 0.72 [0.43, 1.04] mm, P=.0432) and at follow-up (1.2 [0.8, 1.74] versus 1.0 [0.7, 1.5], P=.002). Although smokers tended to have reduced in-hospital mortality compared with nonsmokers in univariate analysis (4.0% versus 8.9%, P=.0001), after adjustment for baseline differences between smokers and nonsmokers in age (54 [47, 62] versus 60 [54, 68] years, P<.0001), inferior infarct location (60% versus 53%, P<.0001), three-vessel disease (16% versus 22%, P<.001), and baseline ejection fraction (53% [44%, 60%] versus 50% [42%, 58%], P=.0069), smoking history was of no independent prognostic significance.

Conclusions Therefore, smokers have a relatively hypercoagulable state, documented by increased hematocrit and fibrinogen levels. Quantitative coronary angiographic analysis suggests that the mechanism of infarction in smokers is more often thrombosis of a less critical atherosclerotic lesion compared with nonsmokers. Enhanced perfusion status, as well as favorable baseline clinical and angiographic characteristics, may be responsible for the more benign prognosis of current smokers.

Key Words: myocardial infarction • thrombolysis • smoking

	Introduction

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Cigarette smoking has a number of adverse effects on the cardiovascular system. Hydrocarbons in cigarette smoke can injure arterial endothelium, initiate the atherosclerotic process, decrease levels of high-density lipoproteins, and have a dose-dependent effect on plaque deposition.^{1 2} Studies in both humans and animals have demonstrated that exposure to tobacco smoke increases fibrinogen levels and aggregation of platelets.^{3 4} In addition to its effect on platelets, nicotine stimulates catecholamine release, increasing heart rate and blood pressure⁵ and causing coronary vasoconstriction.^{6 7 8} Increased levels of carbon monoxide further reduce myocardial oxygen delivery.⁹ Thus, a number of mechanisms may accelerate coronary artery disease and precipitate myocardial infarction (MI) in smokers.

Epidemiological data have consistently shown that the risk of MI increases progressively with the number of cigarettes smoked per day.¹⁰ Studies have demonstrated that the risk of fatal and nonfatal MI is about two to three times higher in smokers than in nonsmokers, and the risk of sudden cardiac death may be 10 times higher.¹¹ Furthermore, continued smoking after MI may double the rate of reinfarction and subsequent death.¹²

Paradoxically, recent thrombolytic trials have reported that MI patients with a history of current smoking had a favorable prognosis compared with nonsmokers.^{13 14 15} Since smoking has been associated with a hypercoagulable state, we postulated that the coronary occlusion may be primarily thrombotic, with improved outcome relating to enhanced patency or the presence of a less severe residual stenosis after thrombolytic therapy. Therefore, this study was conducted to determine the effect of current cigarette smoking on outcome after thrombolytic therapy for acute MI in a large patient population in whom extensive clinical and angiographic data were prospectively collected.

	Methods

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Study Population
The study population consisted of 1619 patients enrolled in six consecutive MI trials.^{16 17 18 19 20 21} Enrollment criteria for these trials were similar and included patients between the ages of 18 and 75 years with chest discomfort less than 6 hours in duration whose ECGs demonstrated ST elevation of at least 1 mm in two contiguous leads. Patients were excluded if they developed cardiogenic shock before enrollment or if they had contraindications for thrombolytics.

Thrombolytic Therapy
All patients received intravenous thrombolytic therapy as soon as possible after informed consent was obtained. The first 386 patients were enrolled into the Thrombolysis and Angioplasty in Myocardial Infarction trial (TAMI-1), in which patients, after receiving tissue-type plasminogen activator (TPA), 150 mg over 6 to 8 hours, were randomized to either delayed or immediate percutaneous transluminal coronary angioplasty (PTCA).¹⁶ The next 147 patients were entered into a dose-ranging pilot study (TAMI-2) that examined the efficacy of combination thrombolytic therapy with TPA (25 mg to 1 mg/kg) and urokinase (0.5 to 2 million U).¹⁷ The next trial (TAMI-3) randomized patients to early (10 000 U bolus) or late intravenous heparin after TPA therapy (1.5 mg/kg over 4 hours).¹⁸ In the urokinase patency study, 102 patients received intravenous urokinase (3 million U over 45 to 60 minutes).¹⁹ The TAMI-5 study randomized 575 patients to TPA alone (100 mg over 3 hours), urokinase alone (3 million U over 60 minutes), or combination TPA (1 mg/kg) with urokinase (1.5 million U) over 60 minutes followed by a second randomization to immediate catheterization with rescue percutaneous transluminal coronary angioplasty (PTCA) or late catheterization just before hospital discharge.²⁰ Finally, the TAMI-7 trial was a dose-ranging study investigating various accelerated dosing regimens of TPA or combined TPA with urokinase.²¹

Cardiac Catheterization
With the exception of patients randomized to the deferred catheterization strategy in the TAMI-5 study (n=288), all patients were referred for coronary angiography 90 minutes after initiation of thrombolytic therapy. Patency of the infarct-related vessel was determined in accordance with the Thrombolysis in Myocardial Infarction (TIMI) study classification.²² PTCA of the infarct-related vessel was generally attempted in patients who failed thrombolysis (TIMI grade 0 to 1 flow) and/or in patients with ongoing ischemia with a high-grade coronary stenosis. An additional 99 patients with a patent vessel were randomized to immediate PTCA as part of the TAMI-1 study.¹⁶ Contrast left ventriculography was performed in the 30° right anterior oblique projection. Predischarge catheterization was performed in 1347 of 1518 survivors (89%).

In-Hospital Therapy
All patients were admitted to the coronary care unit and monitored for at least 24 hours. After the heparin bolus, intravenous heparin, adjusted to prolong the activated partial thromboplastin time 2 to 2.5 times control, was continued for at least 3 days. During the first 24 hours, the patients received intravenous nitroglycerin and lidocaine unless contraindicated. Patients also received one aspirin tablet (325 mg) per day and 30 to 60 mg QID diltiazem soon after hospitalization. ß-Blockers were not given unless clinically indicated, because left ventricular function was a key end point of these trials. If recurrent ischemia occurred, emergency catheterization was performed and revascularization with PTCA or coronary artery bypass grafting was considered. Repeat coronary arteriography and left ventriculography were obtained before hospital discharge. Infarct vessel reocclusion was defined as angiographically documented occlusion of a vessel (TIMI grade 0 to 1 flow) that was patent after the acute intervention. Multivessel coronary disease was defined as >50% stenosis in one or more vessels remote from the infarct artery. Left main coronary disease was considered to be at least two-vessel involvement.

Clinical Events
The following in-hospital clinical events were obtained from the clinical case report form: (1) death; (2) reinfarction diagnosed by a second elevation of cardiac enzymes; (3) reocclusion, defined angiographically; (4) recurrent ischemia, defined by >20 minutes of symptoms compatible with myocardial ischemia associated with new ST- or T-wave changes; (5) the need for coronary angioplasty or coronary bypass surgery before the planned 7-day catheterization; and (6) congestive heart failure, diagnosed by radiographic pulmonary edema, rales more than bibasilar, or requirement for inotropic support.

Angiographic Analysis
All coronary angiograms and ventriculograms were analyzed at the University of Michigan core laboratory. The perfusion status was determined visually,²² and residual coronary stenosis was quantified with a computer-assisted edge detection algorithm by a technician with no knowledge of the smoking history. End-diastolic cine frames demonstrating the infarct-related artery stenosis in its more severe projection were digitized with a cine-video converter. An automated edge detection algorithm was applied to the digitized image, and the arterial contour was determined.²³ With the diagnostic coronary catheter as the reference diameter, the absolute minimal lumen diameter of a user-defined normal and a stenotic segment were determined.

The 30° right anterior oblique end-diastolic and end-systolic left ventricular endocardial contours from a normal sinus beat were traced by a single observer blinded to patient identity, time of study, therapy, and smoking status. Technically inadequate ventriculograms (ventricular tachycardia or substandard opacification) were excluded from analysis. Global ejection fraction was determined by the area-length method.²⁴ Regional wall motion for the infarct and noninfarct zones was determined by the centerline chord method.²⁵ Within each territory, regional wall motion was calculated as the mean motion of one half of the most abnormally contracting contiguous chords and expressed in SD per chord. Hypokinesis is indicated by negative values, and hyperkinesis by positive values.

Coagulation Variables
Blood samples were collected on 1.10 mol/L citrate and 200 kallicrein inhibitory units/mL aprotinin and immediately processed and kept frozen at -20°C until assayed in the core laboratory. Fibrinogen was determined by the coagulation rate assay described by Clauss.²⁶

Statistical Analysis
The Wilcoxon rank-sum test was used to examine differences between smokers and nonsmokers for continuous variables, which are expressed as medians with 25th and 75th percentiles. The likelihood ratio ² statistic was used to test the significance of differences between the groups for discrete variables. Since baseline demographic and angiographic variables differed between smokers and nonsmokers, we adjusted for other factors known to be related to risk of mortality in this population.²⁷ These factors included age, infarct location, systolic blood pressure, ejection fraction, number of diseased vessels, and TIMI flow grade at 90 minutes after presentation. Current smoking history was added to these variables in a logistic regression model to determine whether it independently contributed to the prediction of in-hospital mortality.

	Results

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Baseline Characteristics
Over a 6-year period (1986 to 1991), 1619 patients were enrolled in six thrombolytic protocols,^{16 17 18 19 20 21} with prospective collection of clinical and angiographic data. Of these patients, 878 (54%) were current smokers at the time of infarction. Smokers consumed a median of 1.5 (1, 2) packs per day over 30 (25, 40) years. As demonstrated in Table 1, smokers were more likely to be male (80% versus 76%, P=.043) and younger (54 [47, 62] versus 62 [54, 68] years, P<.0001) and less likely to have other cardiac risk factors of hypertension, diabetes, or elevated cholesterol. Inferior infarction occurred more commonly in smokers than nonsmokers (60% versus 53%, P<.0001).

View this table: [in this window] [in a new window]   Table 1. Baseline Data

As expected, smokers had a relatively hypercoagulable state, as assessed by increased hematocrit (44% [41%, 47%]; range, 30% to 78% versus 43% [40%, 45%]; range, 30% to 54%; P=.0001), fibrinogen levels (2.8 [2.5, 3.6] versus 2.7 [2.4, 3.5] g/dl, P=.0029), and platelet counts (277 [230, 323] versus 266 [222, 312]), compared with nonsmokers (Table 1).

Angiographic Findings
Acute patency after thrombolytics did not differ between smokers and nonsmokers (73.0% versus 73.9%) (Table 2). However, smokers appeared to have more complete reperfusion, as assessed by a greater proportion of vessels with TIMI-3 flow (41.1% versus 34.6%, P=.034). A larger minimum luminal diameter of the stenosis was observed (0.82 [0.51, 1.11] versus 0.72 [0.43, 1.04] mm), P=.0432) during the acute catheterization; however, because of differences in the reference segment, percent diameter stenosis was similar in the two groups (76% [66%, 84%] versus 74% [65%, 84%]). Acute PTCA of the infarct vessel was performed in 29% of smokers and 27% of nonsmokers (P=.333). Reocclusion rates were similar between smokers and nonsmokers in the overall series (10.3% versus 11.0%, P=.729) as well as in the subgroup of patients in whom acute PTCA was not performed (7.3% versus 9.3%, P=.32). However, predischarge catheterization continued to show less residual stenosis in smokers, as assessed by minimal lumen diameter (1.2 [0.8, 1.74] versus 1.0 [0.7, 1.5] mm, P=.0013) and percent residual stenosis (62% [44%, 74%] versus 66% [49%, 77%]), P=.04). Moreover, smokers had less extensive coronary disease, as assessed by the larger diameter of the "normal reference segment" of the infarct vessel at 3.08 (2.7, 3.61) versus 3.01 (2.6, 3.5) mm, P=.02, and the reduced incidence of three-vessel disease (16.0% versus 21.6%, P=.0001).

View this table: [in this window] [in a new window]   Table 2. Angiographic Data

Left Ventricular Function
Technically adequate contrast ventriculograms were available from the acute study in 1074 patients and follow-up in 1176 patients. As demonstrated in Table 3, at acute catheterization, smokers had better infarct zone function (-2.72 versus -2.87 SD/chord, P=.0205) and non–infarct zone function (0.37 versus 0.11 SD/chord, P=.0232), which contributed to a slightly higher ejection fraction (53% versus 50%, P=.0069). However, by the time of hospital discharge, there were no differences in regional or global ventricular function between the two groups.

View this table: [in this window] [in a new window]   Table 3. Left Ventricular Function

Clinical Outcome
In-hospital clinical events are outlined in Table 4. Recurrent unstable ischemia occurred less frequently in smokers compared with nonsmokers (17.6% versus 23%, P=.007), as did in-hospital death (4% versus 8.8%, P=.0001) and stroke (1.5% versus 3.2%, P=.18). Urgent revascularization procedures were performed slightly less frequently in smokers (emergency angioplasty, 8.0% versus 10.4%; emergency bypass surgery, 3.7% versus 4.9%; and urgent bypass surgery, 4.7% versus 5.5%), but these differences were not statistically significant. However, when taken together, urgent revascularization was required in 15.0% of smokers compared with 19.8% of nonsmokers, P=.011. The less complicated course resulted in a shorter length of hospital stay in smokers compared with nonsmokers (9 versus 10 days, P=.0018).

View this table: [in this window] [in a new window]   Table 4. Clinical Outcome

A previously established multiple logistic regression model predicting in-hospital mortality in MI patients was used to determine whether current smoking was related to a favorable prognosis. After adjustment for clinical variables of age, systolic blood pressure, and infarct location, current smokers appeared to have a prognostic advantage (²=3.8, P=.05). However, when acute catheterization variables were added to the model (number of diseased vessels, ejection fraction, and TIMI flow grade), a history of current smoking did not significantly add to or decrease the odds of death (²=0.97, P=.3247).

	Discussion

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The purpose of this study was to determine the relation of current smoking to angiographic variables and clinical outcome after MI in a large population in whom data were prospectively collected. Current smokers were found to be younger, to have fewer cardiac risk factors, to be more likely to sustain an inferior MI, and to have less extensive coronary disease and better perfusion status after thrombolysis and improved clinical outcome compared with nonsmokers. All of these differences may have contributed to lower in-hospital mortality.

Mechanisms
A lower frequency of multivessel disease and a larger lumen diameter of "normal" and stenotic segments suggest that smokers with acute MI have less extensive atherosclerotic disease. Initially, this observation may seem to contradict the well-known data that smoking promotes atherosclerosis. The lack of extensive coronary disease may be explained by the younger age of this population, as well as a lower prevalence of diabetes, hypertension, and hyperlipidemia. Elevated hematocrit, fibrinogen, and platelet levels suggest that smokers may have a hypercoagulable state promoting coronary thrombosis. Thus, these findings demonstrate that in patients who smoke, thrombosis occurs at an earlier stage of the atherosclerotic process, with a lesser influence of other risk factors. After medical therapies, including thrombolysis, heparin, and nitrates, smokers had enhanced perfusion of the infarct vessel and better acute infarct zone function, despite similar delays in initiation of therapy. This suggests that smokers may have spontaneously reperfused (endogenous thrombolysis) or experienced a more efficient response to exogenous thrombolytic drugs. Alternatively, acute coronary vasospasm may be important in the pathogenesis of MI. Clinical studies have demonstrated that cigarette smoking constricts both epicardial coronary arteries and myocardial resistance vessels^{28 29} and thus may contribute to infarction. In fact, independent of the severity of residual stenosis and exercise test results, continued smoking has been shown to be predictive of reinfarction.^{30 31}

Clinical Outcomes
Current smokers had fewer episodes of recurrent ischemia and better in-hospital survival compared with nonsmokers. However, the more benign prognosis of smokers was easily explained by favorable baseline demographic and angiographic variables. Numerous studies^{32 33 34 35 36 37 38 39} have demonstrated that prognosis after MI is directly related to age, factors reflecting infarct size (infarct location, ejection fraction), extent of coronary disease, infarct artery perfusion (TIMI flow grade), and propensity for diffuse atherosclerosis (diabetes), all of which favored smokers in this study. In short, smoking appears to contribute to earlier infarctions in otherwise healthier patients who are likely to survive.

The lower rates of recurrent ischemia may be related to less residual stenosis of the infarct vessel or less ischemia from multivessel disease. However, despite less residual stenosis and enhanced perfusion of the infarct vessel, smokers had reocclusion rates similar to those of nonsmokers. This may be explained by the increased frequency of inferior infarction with an increased risk of reocclusion of the right coronary artery.⁴⁰ Alternatively, if smokers have a greater component of coronary vasospasm, recurrent ischemia may have been more effectively controlled by the protocol administration of nitrates and calcium channel blockers.

Lack of association of current smoking with prognosis in the present study is somewhat discrepant with the TIMI-2B trial. This may relate to the use of acute catheterization variables in our statistical model that were not available in the TIMI-2B trial. A larger sample of patients may have further advanced our understanding of the independent risk (or decrease of risk) attributed to smoking.

Limitations
This study used pooled data from six thrombolytic trials. In general, acute catheterization was performed, with rescue PTCA reserved for patients who failed thrombolysis. However, two of the trials used slightly different invasive stratifiers. Thus, 99 patients from the TAMI-1 trial underwent acute catheterization with immediate PTCA of a patent vessel, and 288 patients from the TAMI-5 study were randomized to late catheterization with acute interventions performed only for clinical indications. Although these patients were excluded from acute patency and reocclusion analyses, it is possible that different treatment strategies may have affected the results.

Conclusions
These data demonstrate that smokers have a relatively hypercoagulable state and that the mechanism of infarction may be spasm or thrombosis of a less critical atherosclerotic lesion compared with nonsmokers. The more benign prognosis in smokers is a result of favorable baseline clinical and angiographic characteristics and younger age. After adjustment for these differences, a history of current smoking did not significantly add to or decrease the risk of death.

	Acknowledgments

 
The authors wish to thank Judy Snyder Wettstein and Phyllis McKinney for manuscript preparation.

Received April 28, 1994; accepted August 7, 1994.

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