Ventricular Dysfunction and the Risk of Stroke after Myocardial Infarction
Evan Loh, M.D., Martin St. John Sutton, M.D., Chuan-Chuan C. Wun, Ph.D., Jean L. Rouleau, M.D., Greg C. Flaker, M.D., Stephen S. Gottlieb, M.D., Gervasio A. Lamas, M.D., Lemuel A. Moyé, Ph.D., Samuel Z. Goldhaber, M.D., and Marc A. Pfeffer, M.D., Ph.D.
Background In patients who have had a myocardial infarction,the long-term risk of stroke and its relation to the extentof left ventricular dysfunction have not been determined. Westudied whether a reduced left ventricular ejection fractionis associated with an increased risk of stroke after myocardialinfarction and whether other factors such as older age and therapywith anticoagulants, thrombolytic agents, or captopril affectlong-term rates of stroke.
Methods We performed an observational analysis of prospectivelycollected data on 2231 patients who had left ventricular dysfunctionafter acute myocardial infarction who were enrolled in the Survivaland Ventricular Enlargement trial. The mean follow-up was 42months. Risk factors for stroke were assessed by both univariateand multivariate Cox proportional-hazards analysis.
Results Among these patients, 103 (4.6 percent) had fatal ornonfatal strokes during the study (rate of stroke per year offollow-up, 1.5 percent). The estimated five-year rate of strokein all the patients was 8.1 percent. As compared with patientswithout stroke, patients with stroke were older (mean [±SD]age, 63±9 years vs. 59±11 years; P<0.001) andhad lower ejection fractions (29±7 percent vs. 31±7percent, P = 0.01). Independent risk factors for stroke includeda lower ejection fraction (for every decrease of 5 percentagepoints in the ejection fraction there was an 18 percent increasein the risk of stroke), older age, and the absence of aspirinor anticoagulant therapy. Patients with ejection fractions of<28 percent after myocardial infarction had a relative riskof stroke of 1.86, as compared with patients with ejection fractionsof >35 percent (P = 0.01). The use of thrombolytic agentsand captopril had no significant effect on the risk of stroke.
Conclusions During the five years after myocardial infarction,patients have a substantial risk of stroke. A decreased ejectionfraction and older age are both independent predictors of anincreased risk of stroke. Anticoagulant therapy appears to havea protective effect against stroke after myocardial infarction.
Current estimates of the incidence of stroke among patientswith coronary artery disease are as low as 3.4 percent per 1000patient-years of follow-up.1 Stroke is also a known but infrequentearly complication of myocardial infarction. In the two-weekperiod after myocardial infarction, the reported incidence ofstroke ranges between 0.7 percent and 4.7 percent.2,3,4,5,6,7,8After myocardial infarction, focal areas of akinesia or dyskinesia(or both) in the left ventricle appear to increase the riskof mural thrombi.9,10,11,12 Moreover, a greater extent of myocardialdamage and greater left ventricular dysfunction after anteriormyocardial infarction, as well as the detection of mural thrombiby echocardiography, have been shown to be risk factors forboth peripheral thromboembolism and stroke in the period soonafter the infarction.13,14,15,16 The rate of occurrence of muralthrombi and the early rate of stroke appear to be lower afterinferior-wall myocardial infarction than after anterior infarction.17,18
Although strokes are primarily an early complication of myocardialinfarction, impaired left ventricular function after myocardialinfarction may be an additional risk factor for subsequent stroke.Estimates of short-term rates of stroke after myocardial infarction(i.e., stroke within 30 days) range from 3.0 percent to 5.2percent.7,19 In one study, the principal mechanism of strokeduring this period was embolic cerebral infarction, as documentedby computed tomographic (CT) scanning.19
The long-term cumulative risk of stroke and its relation tothe extent of left ventricular dysfunction after myocardialinfarction have not been determined. We used data from the Survivaland Ventricular Enlargement (SAVE) trial20 to study the relationbetween the left ventricular ejection fraction (LVEF) and theincidence of stroke in patients with left ventricular dysfunctionbut without symptomatic heart failure after myocardial infarction.In addition, we examined the effects of therapy with captopril,an agent known to reduce ventricular remodeling and enlargementafter myocardial infarction, on the rate of stroke. The aimsof the study were to examine the LVEF as a risk factor for strokeand to determine the effect of other factors, such as age andthe use of anticoagulants, thrombolytic agents, or captopril,on long-term rates of stroke.
Methods
The Save Trial
The SAVE trial was a prospective, randomized, placebo-controlledstudy of 2231 patients with myocardial infarction and left ventriculardysfunction (LVEF, <40 percent as measured by radionuclideventriculography). From 3 to 16 days after myocardial infarction(mean, 11 days), patients were randomly assigned to receivetherapy with the angiotensin-converting–enzyme inhibitorcaptopril or placebo. Patients with overt heart failure requiringvasodilator therapy were excluded. In patients with symptomsor signs of myocardial ischemia, cardiac catheterization wasused to guide treatment. If coronary revascularization (angioplastyor coronary-artery bypass grafting) was considered necessary,it was performed before randomization. Other criteria for exclusionwere contraindications to captopril therapy and coexisting medicaldisorders such as renal insufficiency (creatinine concentration,>2.5 mg per deciliter [220 µmol per liter]), severevalvular disease, refractory hypertension, cancer, or otherconditions considered likely to limit survival. The design andresults of the SAVE trial have been reported previously.20 Allthe patients provided informed consent.
Definitions
Stroke was a prospectively defined end point of this study.The definition included all strokes that occurred either asearly complications of acute myocardial infarction (i.e., betweenthe index myocardial infarction and randomization on day 3 throughday 16 after infarction) or after random assignment to therapywith captopril or placebo.
Statistical Analysis
Univariate comparisons of characteristics between patients whohad stroke and those who did not were performed with the chi-squaretest for categorical variables (sex, history of previous myocardialinfarction, history of diabetes, history of hypertension, currentsmoking status, and location of myocardial infarction) and withthe two-sample t-test for continuous variables (age and LVEF).The relation between LVEF and stroke was assessed by both univariateand multivariate Cox proportional-hazards analysis. The covariatesincluded in the multivariate Cox regression analysis were age,use or nonuse of an anticoagulant agent (heparin or warfarin)after myocardial infarction, use or nonuse of aspirin aftermyocardial infarction, smoking status before randomization,presence or absence of hypertension, presence or absence ofdiabetes, presence or absence of a previous myocardial infarction,random assignment to captopril or placebo, presence or absenceof atrial fibrillation or flutter as a complication of the indexmyocardial infarction, and use or nonuse of thrombolytic therapyat the time of the myocardial infarction.
The data on the use of anticoagulants (either warfarin or heparin)and aspirin that were included in the analyses were those obtainedat the study visit just before the index admission to the hospitalfor stroke or before death from stroke; these variables wereanalyzed as time-dependent covariates in the multivariate Cox-modelanalysis. For patients who did not have stroke, the use of ananticoagulant or aspirin was determined at the last follow-upvisit or at the final visit at the end of the SAVE study. Nodata on the intensity of anticoagulation (i.e., the internationalnormalized ratio) were prospectively collected in the SAVE database. Kaplan–Meier estimates of the distribution of timesfrom randomization to stroke were computed. Log-rank analysiswas performed to compare the event curves for different groups.In all analyses, a P value of 0.05 or less was considered toindicate statistical significance.
Results
Study Population
Patients enrolled in the SAVE trial were followed for an average(±SD) of 42±10 months (range, 24 to 60). The averageage was 59 years (range, 26 to 79); 82 percent of patients weremale; 36 percent had had a previous myocardial infarction; 38percent had a history of hypertension; and 22 percent had diabetesmellitus. Sixty percent of the patients were in Killip class1 and 40 percent were in Killip class 2 or higher during theacute infarction. The mean LVEF was 31.0±6.7 percent(measured 2 to 16 days after infarction by radionuclide ventriculography).Thirty-four percent of the patients received thrombolytic therapy.Two hundred twenty-seven (10 percent) of the patients had atrialfibrillation or atrial flutter for at least one hour as a complicationof the index myocardial infarction.
Adjuvant medications (i.e., medications other than captopril)at the time of randomization were given at the discretion ofthe treating physicians and recorded in the case-report forms.Medications used at the time of randomization included beta-blockers(received by 35 percent of the patients), nitrates (52 percent),calcium-channel blockers (42 percent), aspirin (59 percent),other antiplatelet agents (14 percent), and anticoagulant drugs(heparin or warfarin, received by 28 percent).
Total Incidence of Stroke
Twelve (0.5 percent) of the 2231 patients in the SAVE trialhad acute stroke as a complication of the index myocardial infarction,before randomization. After randomization, during the entirefollow-up period, 91 additional patients (4.1 percent) had afatal or nonfatal stroke. In 10 of these patients, the strokewas considered the proximate cause of death. The estimated five-yearcumulative rate of stroke in all the patients was 8.1 percent.The normalized rate of stroke was 1.5 percent per patient-yearof follow-up (Figure 1). In 50 patients with documentation ofstroke on CT scanning or magnetic resonance imaging (MRI), 48(96 percent) had a stroke of ischemic origin and 2 (4 percent)had cerebral hemorrhage.
Figure 1. Kaplan–Meier Estimate of the Cumulative Rate of Stroke among 2231 Patients in the SAVE Trial.
A total of 103 patients (4.6 percent) had strokes during follow-up. The estimated cumulative rate of stroke over a five-year period was 8.1 percent. The annualized incidence was 1.5 percent per patient-year of follow-up. The top and bottom curves show the 95 percent confidence interval for the rate of stroke.
Risk Factors for Stroke
Univariate characteristics of patients with and without strokeare shown in Table 1. Independent risk factors for stroke determinedby multivariate Cox proportional-hazards analysis (Table 2)included a reduced LVEF (there was an 18 percent increase inthe risk of stroke for every reduction of 5 percentage pointsin the LVEF at the time of randomization), older age, and nonuseof aspirin and anticoagulant agents at the clinic visit justbefore a clinically documented stroke (this was a time-dependentcovariate). Random assignment to therapy with captopril andthe use of thrombolytic agents to treat the index myocardialinfarction did not decrease the risk of stroke during follow-up.
Table 2. Risk Factors for Stroke in the Multivariate Analysis.
The presence of atrial fibrillation or flutter before randomizationwas not an independent long-term risk factor for stroke. Patientswith atrial fibrillation or flutter before randomization hadlower rates of use of aspirin (52 percent, vs. 59 percent inthose without atrial fibrillation or flutter; P = 0.04), beta-blockers(27 percent vs. 36 percent, P = 0.001), and thrombolytic therapy(29 percent vs. 35 percent, P = 0.05), but they had similarrates of use of anticoagulants.
LVEF as a Longitudinal Risk Factor for Stroke
To determine a threshold LVEF at which the rate of stroke wasincreased, the subjects were divided into three subgroups onthe basis of the LVEF (<28 percent [n = 724], 29 to 35 percent[n = 817], and >35 percent [n = 690]). The characteristicsof the patients in these subgroups are shown in Table 3. Thetotal cumulative rate of stroke in each subgroup was as follows:8.9 percent for patients with an LVEF of <28 percent; 7.8percent for those with an LVEF of 29 to 35 percent; and 4.1percent for those with an LVEF above 35 percent (Figure 2).Univariate analysis demonstrated that patients in whom the LVEFwas 28 percent or lower after myocardial infarction had a riskof stroke during the follow-up that was nearly twice as highas that among the other patients (relative risk, 1.86; 95 percentconfidence interval, 1.15 to 3.04; chi-square = 6.27; P = 0.01).
Figure 2. Cumulative Rate of Stroke in the SAVE Trial, According to the Left Ventricular Ejection Fraction (LVEF).
The patients were divided into three subgroups: those with an LVEF of 28 percent (n = 724), those with an LVEF of 29 to 35 percent (n = 817), and those with an LVEF >35 percent (n = 690). The cumulative rates of stroke in these subgroups were 8.9 percent, 7.8 percent, and 4.1 percent, respectively. When the group with LVEF values above 35 percent was used as the reference category, the relative risk of stroke was 1.15 (95 percent confidence interval, 0.69 to 1.91; P not significant) for patients with LVEF values of 29 to 35 percent and 1.86 (95 percent confidence interval, 1.15 to 3.04; P = 0.01) for patients with LVEF values of 28 percent.
In the multivariate analysis, the protective effects of anticoagulanttherapy in reducing the rate of stroke were evident in all threesubgroups defined by LVEF: for an LVEF of <28 percent, therelative risk was 0.17 (95 percent confidence interval, 0.09to 0.29; chi-square = 38.33; P<0.001); for an LVEF of 29to 35 percent, the relative risk was 0.14 (95 percent confidenceinterval, 0.06 to 0.28; chi-square = 29.38; P<0.001); foran LVEF above 35 percent, the relative risk was 0.23 (95 percentconfidence interval, 0.12 to 0.47; chi-square = 16.82; P<0.001).The beneficial effects of aspirin were observed both among thepatients with the lowest LVEF values (LVEF, <28 percent;reduction in risk, 66 percent; chi-square = 11.63; P<0.001)and those with intermediate values (LVEF, 29 to 35 percent;reduction in risk, 59 percent; chi-square = 5.03; P<0.03).The effect of age on the risk of stroke did not differ significantlyamong the three LVEF groups, although there was a suggestionof a stronger effect of age in the lowest-LVEF group. No otherrisk factors had a significant effect on the risk of stroke,after adjustment for the LVEF, in these multivariate analyses.
Discussion
This study confirms the results of earlier investigations thatsuggested that the size of a myocardial infarction8 is associatedwith the subsequent risk of stroke and establishes that theLVEF (especially in patients with an LVEF of <28 percent)is the most powerful independent predictor of stroke in patientsafter myocardial infarction. Furthermore, for every absolutedecrease of 5 percentage points in the LVEF, the risk of strokeincreases by 18 percent. Finally, our results suggest that ageand systemic anticoagulation or aspirin use are also independentfactors that affect the long-term risk of stroke after myocardialinfarction.
Many studies have examined heart size and decreased LVEF asrisk factors for systemic embolic events after myocardial infarction.Segal et al.21 stratified patients according to the size ofthe heart on a chest roentgenogram and noted a trend towardmore embolic events in the patients with the largest hearts.Tanne et al.22 also suggested that increased heart size on thechest roentgenogram was an independent risk factor for strokeafter myocardial infarction. Kyrle et al.23 used fractionalshortening, determined echocardiographically, as an index ofventricular dysfunction and noted a similar trend toward morevenous and arterial embolic events in patients with worse ventricularfunction. Finally, Dunkman et al.,24 over a period of follow-upsimilar to that in this study, noted a trend toward a higherrate of all thromboembolic events (stroke and pulmonary andsystemic embolism) among patients with reduced LVEF values.
During the early period after infarction, reported rates ofstroke range between 0.5 percent and 2.5 percent.2,3,5,6,7 Consistentwith these observations was the 0.5 percent rate of early stroke(before randomization — i.e., within 3 to 16 days aftermyocardial infarction) in the SAVE trial. Univariate analysisdemonstrated that atrial arrhythmia as a complication of theindex myocardial infarction increased the risk of stroke. However,multivariate analysis did not establish the importance of atrialdysrhythmia between myocardial infarction and the time of randomizationas a long-term risk factor for stroke. It also appears fromthe univariate data that the use of thrombolytic therapy decreasedthe risk of early stroke. Again, multivariate analysis did notdemonstrate the persistence of the early effects of thrombolytictherapy on the overall risk of stroke, suggesting that the beneficialeffect of thrombolytic therapy is limited to the early postinfarctionperiod. Therapy with captopril did not protect patients againststrokes, suggesting that the preservation of left ventricularsize alone25 may not reduce the relative risk of stroke aftermyocardial infarction.
On the basis of longitudinal data on cumulative rates of strokein the SAVE trial, in contrast to the previous reports, it appearsthat stroke rates continue to increase in a constant fashioneven beyond the first six months after myocardial infarction.This analysis further demonstrates that patients with LVEF valuesof <28 percent appear to have the highest risk of such events.Specifically, although the rate of events is low in patientswith left ventricular dysfunction (LVEF, <40 percent) andno symptoms of heart failure, especially as compared with therate in patients with reduced left ventricular function andsymptomatic heart failure, the risk over time is not negligible.
Given the persistent risk of stroke after myocardial infarction,the implications with respect to long-term anticoagulant therapyin these patients become more apparent. Anticoagulant therapywith either warfarin and heparin or aspirin appears to be associatedwith significant protection from stroke. These observationsconfirm the results of previous studies. In one study of 999patients after acute myocardial infarction, the value of short-termwarfarin therapy (in the first 28 days) in reducing the riskof stroke was clear (rate of stroke, 0.8 percent, vs. 3.8 percentin the control group; P<0.001).26 A similar but nonsignificantreduction in the rates of both stroke and thromboembolism inthe period immediately following myocardial infarction was alsoobserved in the Medical Research Council trial.27 In contrast,beneficial effects on the rate of stroke were not observed ina study of therapy with heparin and phenindione during hospitalizationafter myocardial infarction.28
The long-term benefit of anticoagulation after myocardial infarctionin reducing the risk of stroke has also been demonstrated inboth the Warfarin Re-Infarction Study (WARIS) (total strokerate, 6.7 percent; reduction in the rate of total stroke withwarfarin, 55 percent)29 and the Anticoagulants in the SecondaryPrevention of Events in Coronary Thrombosis (ASPECT) study (totalstroke rate, 3.6 percent; reduction in the rate of total strokewith warfarin, 39 percent).30 The reduction in risk with anticoagulationin our retrospective analysis of data from the SAVE trial (81percent) was even greater than the reductions in previous randomizedtrials. However, in neither the WARIS nor the ASPECT study wasinformation on the LVEF available, nor was the reduction inthe rate of stroke specifically analyzed in relation to theLVEF and other clinical variables. Our study suggests that thebeneficial effects of anticoagulation on the rate of strokeafter myocardial infarction is evident not only in patientswith moderate-to-severe decreases in the LVEF but also in patientswith relatively well preserved left ventricular function (LVEF,>35 percent).
The principal cause of stroke in the SAVE trial (responsiblefor 96 percent of the strokes) was ischemic infarction, documentedby CT scanning or MRI. The higher rate of use of anticoagulantagents at the time of randomization among patients who subsequentlyhad strokes did not appear to result in an increased incidenceof hemorrhagic stroke. These observations underscore the importantrole of anticoagulant therapy in protecting patients from thiscomplication of myocardial infarction. Because therapy withaspirin also reduced the risk of stroke (by 56 percent), itappears that therapy with one or both of these agents shouldbe considered for patients with left ventricular dysfunctionafter myocardial infarction, especially for those with LVEFvalues of <28 percent.
The limitations of this study include the small number of eventsand the fact that therapy with aspirin and anticoagulant agentswas not randomly assigned. Moreover, no data on the intensityof anticoagulation for patients receiving such therapy wereprospectively collected. Therefore, it remains unclear whatspecific range of values for the international normalized ratioshould be used to guide therapy in asymptomatic patients withreduced LVEF after myocardial infarction. Also, because of thenature of the data base, we were unable to differentiate retrospectivelybetween the use of aspirin alone and the use of warfarin alone.Finally, the lack of follow-up data on the presence or absenceof chronic atrial dysrhythmia did not permit us to evaluatethe role of this known risk factor for stroke.
Our results establish the importance of a reduced LVEF as anindependent risk factor for stroke after myocardial infarction.The relation between the magnitude of the reduction in the LVEFafter myocardial infarction and the subsequent risk of strokesuggests yet another context in which to understand the potentialrole of long-term anticoagulation.31,32 Studies designed todetermine whether aspirin alone offers as much protection aswarfarin and to establish the optimal intensity of anticoagulationwith warfarin are needed. Given the inclusion criteria withrespect to LVEF in the SAVE trial, our observations cannot beextrapolated to patients with an LVEF greater than 40 percentafter myocardial infarction or to patients with LVEF valuesof <40 percent and with other causes of heart failure, suchas idiopathic dilated cardiomyopathy,33,34 myocarditis, or valvularheart disease. These groups of patients also merit further study.
Supported in part by a National Heart, Lung, and Blood InstitutePhysician-Scientist Award (HL-02514, to Dr. Loh).
Source Information
From the Hospital of the University of Pennsylvania, Philadelphia (E.L., M.S.S.); the University of Texas Health Science Center, Houston (C.-C.C.W., L.A.M.); Montreal Heart Institute, Montreal (J.L.R.); the University of Missouri Hospital and Clinics, Columbia (G.C.F.); the University of Maryland Hospital, Baltimore (S.S.G.); Mt. Sinai Medical Center, Miami Beach, Fla. (G.A.L.); and Brigham and Women's Hospital, Boston (S.Z.G., M.A.P.).
Address reprint requests to Dr. Loh at the Hospital of the University of Pennsylvania, 9 Founders Pavilion, 3400 Spruce St., Philadelphia, PA 19104.
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Previous
28 percent (n = 724), those with an LVEF of 29 to 35 percent (n = 817), and those with an LVEF >35 percent (n = 690). The cumulative rates of stroke in these subgroups were 8.9 percent, 7.8 percent, and 4.1 percent, respectively. When the group with LVEF values above 35 percent was used as the reference category, the relative risk of stroke was 1.15 (95 percent confidence interval, 0.69 to 1.91; P not significant) for patients with LVEF values of 29 to 35 percent and 1.86 (95 percent confidence interval, 1.15 to 3.04; P = 0.01) for patients with LVEF values of