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(Stroke. 1995;26:801-806.)
© 1995 American Heart Association, Inc.

Articles

Predictors of Major Vascular Events in Patients With a Transient Ischemic Attack or Minor Ischemic Stroke and With Nonrheumatic Atrial Fibrillation

J.C. van Latum, MD; P.J. Koudstaal, MD; G.S. Venables, DM; J. van Gijn, MD; L.J. Kappelle, MD; A. Algra, MD for the European Atrial Fibrillation Trial (EAFT) Study Group

From the University Hospital Rotterdam Dijkzigt (Netherlands) (J.C. van L., P.J.K.); Royal Hallamshire Hospital, Sheffield, United Kingdom (G.S.V.); and University Hospital Utrecht (Netherlands) (J. van G., L.J.K., A.A.). Participating clinics for the EAFT have been listed elsewhere (Lancet. 1993;342:1255-1262).

Correspondence to Dr Peter J. Koudstaal, MD, Department of Neurology, University Hospital Rotterdam Dijkzigt, 40 Dr Molewaterplein, 3015 GD Rotterdam, Netherlands.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose The risk of major vascular events after an initial episode of cerebral ischemia in patients with nonrheumatic atrial fibrillation (NRAF) varies from 2% to 15% in the first year and is approximately 5% yearly thereafter. Few studies have reported on risk factors that can be used to identify high-risk subgroups within this patient population.

Methods We studied the predictive value of several easily obtainable clinical characteristics in a group of 375 placebo-treated patients with NRAF and a recent episode of transient or nondisabling cerebral ischemia who were entered in a multicenter clinical trial. The mean follow-up was 1.6 years.

Results By means of multivariate modeling, six independent variables were identified: history of previous thromboembolism, ischemic heart disease, enlarged cardiothoracic ratio on chest roentgenogram, systolic blood pressure greater than 160 mm Hg at study entry, NRAF for more than 1 year, and presence of an ischemic lesion on CT scan. These variables could also be used to stratify patients in low-, medium-, and high-risk subgroups for the other two arms of the trial, those treated with anticoagulation and aspirin. Patients older than 75 years with three or more risk factors seemingly benefited less from both aspirin and anticoagulant treatment.

Conclusions Easily obtainable patient characteristics are helpful in estimating the potential effect of adequate secondary prevention in patients with NRAF who recently suffered a transient ischemic attack or minor ischemic stroke.

Key Words: atrial fibrillation • cerebral ischemia, transient • risk factors • stroke prevention

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In different studies the reported risk for recurrent arterial embolism and other major vascular events after an initial episode of embolism in patients with nonrheumatic atrial fibrillation (NRAF) varies from 2% to 15% in the first year and is approximately 5% yearly thereafter,^{1 2} depending on the type of underlying cardiac abnormality. The value of anticoagulant therapy in the prevention of secondary events in patients with NRAF has been demonstrated by the results from the European Atrial Fibrillation Trial (EAFT).³ However, an ingrained reluctance of physicians to prescribe oral anticoagulant therapy over any extended period of time,^{4 5} especially in older and less mobile patients, has prompted the question of whether certain risk factors for recurrent stroke and other vascular events can be used to identify high-risk subgroups within this patient population. Very few studies have addressed this specific question. Predictors of thromboembolic events have been identified in primary prevention studies^{6 7 8 9 10} and in retrospective studies,^{11 12 13} but since the most important determinant was that of previous thromboembolism, this is of little value in predicting who might be at high risk in the present setting. Other studies have identified risk factors for recurrent vascular events in patients with a transient ischemic attack (TIA) or minor ischemic stroke,^{14 15 16 17} but most of these studies included patients with or without atrial fibrillation,^{14 15 17} and little attention was given to predictors according to the presumed source of thromboembolism.

We analyzed the clinical features of 375 patients assigned to placebo treatment in the EAFT to determine clinical predictors for recurrent stroke and other major vascular events in patients with NRAF and recent TIA or minor ischemic stroke. Subsequently, these factors were used to stratify all study patients in high- and low-risk subgroups and to assess the value of antithrombotic therapy for these different subgroups.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The EAFT included patients with one or more nondisabling episodes of cerebral ischemia and concomitant NRAF. These patients were randomized between treatment with oral anticoagulants (international normalized ratio, 2.5 to 4.0), aspirin (300 mg/d), or placebo. Patients with other cardiac sources of embolism and patients with specific causes for cerebral ischemia, such as hematologic disorders or vasculitis, were excluded, as were patients with contraindications for aspirin. Patients ineligible for anticoagulant treatment were randomized between aspirin or placebo only. After randomization, patients were followed up every 4 months to assess treatment compliance and the occurrence of outcome events or bleeding complications.

Clinical Predictors for Recurrent Vascular Events
Risk factors for vascular death, recurrent stroke, and other vascular events were identified in a subgroup of 378 patients randomized to placebo treatment. Two patients were excluded from this analysis because they had been inappropriately entered into the study (no atrial fibrillation ever); 1 patient was excluded because no adequate baseline information was available (these 3 patients suffered no outcome events during follow-up). The remaining 375 patients were followed up for a total of 818 patient-years. To correct for the effect of changes from placebo to active treatment, the following analyses include only the 116 events that occurred during the follow-up period on placebo treatment. The mean follow-up was 1.6 years (minimum, 1 day; maximum, 4.5 years).

A baseline data form was completed for each patient at study entry, on which nature, duration, and severity of the patient's qualifying event were recorded, along with demographic data, vascular risk factors, vascular and cardiac history, and duration and pattern of atrial fibrillation. Uniform working definitions for most of the requested data had been supplied in a user's manual. Hypertension was defined as a history of hypertension or current drug treatment for hypertension. Diabetes was defined as glucose intolerance controlled by either diet alone or medication. Congestive heart failure was judged present if the patient had clinically evident congestive heart failure at the time of study entry. Prior myocardial infarction (MI) was defined on the basis of history and medical records. Previously unrecognized MI detected only on the baseline electrocardiogram was not included. Previous thromboembolism was recorded in patients with clinically evident ischemic stroke, TIA, or systemic embolism other than pulmonary embolism preceding the qualifying event; it did not include evidence of silent cerebral infarction on baseline CT scan.

Patients were required to have a CT scan before randomization. These scans were reviewed by an independent committee of at least two neurologists who were not aware of the clinical data; this assessment took place as soon as possible after study entry.

Analyses were aimed primarily at identifying clinical factors that predict the occurrence of any important arterial occlusion, represented by the composite outcome event of stroke, MI, systemic embolism, or vascular death, whichever occurred first. Additional aims were to evaluate the relationship between these variables and the occurrence of stroke alone (both fatal and nonfatal). Suitable factors for analysis were identified in advance both on grounds of biological plausibility and on the basis of earlier reports on risk factors for vascular events in patients with NRAF and patients with TIA or minor ischemic stroke.^{6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22} Univariate hazard ratios and 95% confidence intervals for each characteristic were calculated by means of the Cox proportional hazards model. Variables selected from univariate analyses were sequentially entered in a multivariate model until no remaining candidate variable met a significance level of .10. Variables were removed from the model when the probability value for removal exceeded .15. Two multivariate models were assessed for each of the two composite outcome events. The first (model 1) included only those variables that are usually recorded during the first patient contact by means of clinical history taking. A second model (model 2) further included variables obtained by standard ancillary investigations such as chest roentgenogram and cerebral CT scan. Although M-mode and, if possible, two-dimensional echocardiography were mandatory in all patients to exclude the presence of rheumatic valve disease and to assess left atrial size, these investigations were not audited centrally, and no specific criteria were defined for the mode of measurement. Echocardiographic parameters therefore could not be included in this latter model, nor could results of carotid investigations (duplex or angiography), because they were not performed routinely. Only 40% of all centers performed routine carotid investigations in more than 75% of the patients they entered in the trial.

Antithrombotic Therapy for High- and Low-Risk Subgroups
The identified clinical predictors were used to define high-, moderate-, and low-risk subgroups. Within each treatment group of the EAFT cohort (oral anticoagulation and aspirin, in addition to the placebo group from which these predictors were derived), event rates, confidence intervals, and rate ratios were calculated for all risk subgroups, assuming a Poisson distribution and on an intention-to-treat basis.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Univariate Analyses
Table 1 summarizes the results of the univariate analyses of the baseline characteristics. Of all potential risk factors evaluated, evidence of ischemic heart disease (angina pectoris, prior MI) and prior vascular surgery were associated with a significantly increased risk of recurrent vascular events. This association was less pronounced for the risk of recurrent stroke. Other probable risk factors were female sex, history of previous thromboembolic events, long-standing chronic atrial fibrillation, and systolic blood pressure greater than 160 mm Hg at study entry. Table 1 also summarizes the univariate analyses of risk factors obtained through ancillary investigations. An enlarged cardiothoracic ratio on chest roentgenogram was found to be associated with both a higher risk of recurrent vascular events and a higher risk of recurrent stroke. The presence of any ischemic lesion on CT scan also indicated a higher risk of recurrent stroke as well as recurrent vascular events in general. This association was more marked if (one of) the ischemic lesions involved the posterior fossa or if lesions were found in more than one vascular territory.

View this table: [in this window] [in a new window]   Table 1. Results of Univariate Analysis of Risk Factors for the Combined Event of Vascular Death, Stroke, Systemic Embolism, or Myocardial Infarction and for Stroke Alone (Fatal or Nonfatal) in Placebo-Treated Patients

Multivariate Analyses
Nine clinical variables were selected for multivariate analyses: sex, ischemic heart disease (previous MI, angina, or coronary bypass surgery), peripheral vascular disease (intermittent claudication and/or previous vascular surgery), history of thromboembolism, history of hypertension, diabetes, congestive heart failure, duration of atrial fibrillation more than 1 year, and systolic blood pressure greater than 160 mm Hg at entry; age was forced into the model because an association between age and recurrent vascular events seemed highly probable even though not statistically proven. Only ischemic heart disease, history of thromboembolism, duration of atrial fibrillation, and systolic blood pressure remained independent factors (Table 2). In the second multivariate model, radiological indexes (chest roentgenogram and CT scan) were added. The same baseline characteristics (ischemic heart disease, prior thromboembolism, duration of atrial fibrillation more than 1 year, and systolic blood pressure greater than 160 mm Hg) from model 1 remained in model 2, but the presence of one or more ischemic lesions on CT scan as well as an enlarged cardiothoracic ratio on chest roentgenogram were additionally identified as independent risk factors for recurrent vascular events. The presence of ischemic heart disease and cardiomegaly on chest roentgenogram did not contribute to the risk of stroke alone (Table 2).

View this table: [in this window] [in a new window]   Table 2. Results of Multivariate Analysis of Risk Factors for the Combined Event of Vascular Death, Stroke, Systemic Embolism, or Myocardial Infarction and Stroke Alone (Fatal and Nonfatal) in Placebo-Treated Patients

Effect of Antithrombotic Therapy in High- and Low-Risk Patients
Of the independent clinical predictors identified in the placebo group, history of previous thromboembolism, ischemic heart disease, enlarged cardiothoracic ratio on chest roentgenogram, systolic blood pressure greater than 160 mm Hg at study entry, presence of any form of atrial fibrillation for more than 1 year, and a visible ischemic lesion on CT scan were thought to be the most readily available indicators for risk stratification. Nine percent of the complete EAFT cohort (n=1001) had no risk factors at all, 61% had 1 or 2 risk factors, and 30% had 3 or more risk factors. Multivariate Poisson regression showed that the proposed risk stratification adequately identified high-, moderate-, and low-risk subgroups for recurrent vascular events in general and for recurrent stroke alone, independent of allocated treatment and age differences (Table 3). Contrary to the previous findings in placebo-treated patients only, age was now shown to be a risk factor for the occurrence of recurrent vascular events, irrespective of treatment and the existence of other risk factors. Incidence rates of recurrent vascular events were calculated for differing risk strata within each treatment group (Table 4), showing that the largest therapeutic effect of oral anticoagulation was obtained in patients aged 75 years or younger with 1 or more risk factors. Strikingly, the event rate on oral anticoagulation in patients older than 75 years with 3 or more risk factors was 30/100 patient-years compared with 30/100 patient-years on aspirin and 37/100 patient-years on placebo. When only on-treatment events were considered, the difference in event rates between the treatment groups for this subset of patients was somewhat larger (24/100 patient-years on anticoagulants, 31/100 patient-years on aspirin, and 37/100 patient-years on placebo), indicating that in part the reduced efficacy of anticoagulants in high-risk older patients may be attributed to decreased compliance, with more patients stopping treatment because of side effects, comorbid diseases, or difficulty in maintaining proper anticoagulant control. Still, a significant interaction between anticoagulant therapy and age (younger or older than 75 years) was found in multivariate analyses (P=.001 for all vascular events and P=.017 for recurrent stroke only), not only on an intention-to-treat basis but also for on-treatment data, which implies that factors other than compliance also played a role in reducing the overall benefit of anticoagulants in older patients. The treatment effect of aspirin for the prevention of vascular events in general, although not significant, was most pronounced in high-risk patients (event rate, 23/100 patient-years on aspirin and 33/100 patient-years on placebo) in both patients older than 75 years and patients younger than 75 years. Aspirin also seemed slightly less effective in patients older than 75 years in preventing recurrent vascular events, but no significant interaction term with age was found in multivariate analyses.

View this table: [in this window] [in a new window]   Table 3. Results of Multivariate Poisson Regression, Including Treatment, Risk Factors, and Age Categories, Showing Adjusted Treatment and Risk-Set–Specific Rate Ratios for Recurrent Vascular Events and Recurrent Strokes

View this table: [in this window] [in a new window]   Table 4. Annual Event Rates per Treatment Group According to Age and Number of Risk Factors

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
In this study six independent predictors for recurrent vascular events were identified in 375 patients with NRAF who had recently suffered a TIA or minor ischemic stroke and who were receiving placebo treatment in the context of a randomized clinical trial involving a total of 1001 patients. These variables were history of previous thromboembolism, ischemic heart disease, enlarged cardiothoracic ratio on chest roentgenogram, systolic blood pressure greater than 160 mm Hg at study entry, atrial fibrillation existing for more than 1 year, and evidence of an ischemic lesion on CT scan. Thirty-one percent of the placebo-treated patients had three or more risk factors, and their event rate for recurrent vascular complications (vascular death, MI, stroke, and systemic embolism) was 33/100 patient-years, almost 10 times the rate in placebo-treated patients with no risk factors (4/100 patient-years). This method of risk stratification also adequately distinguished high- and low-risk patients in the two active treatment arms of the trial, with aspirin and oral anticoagulation.

The practical application of this profile of risk factors for the clinical decision-making process in the initiation and choice of antithrombotic prophylaxis is not straightforward. The ability to identify patients at moderate or high risk of recurrent vascular events may support clinicians in their choice of a more aggressive approach with anticoagulant treatment in patients for whom they would otherwise have preferred to prescribe aspirin. On the other hand, our data also suggest that older patients in the high-risk group benefited relatively little from oral anticoagulant treatment compared with treatment with aspirin. To some extent such a finding is to be expected when one considers the fact that as patients get older, their death becomes a more or less inevitable event on which any form of treatment is bound to have less effect. Also, results of these post hoc analyses should be considered with appropriate care, partly because insufficient data were available to allow for definite conclusions.

Meta-analysis of the pooled data of all primary prevention trials in patients with NRAF showed increasing age, previous stroke or TIA, history of hypertension, and diabetes to be independent risk factors for stroke.⁶ Our results do not directly conflict with these findings. It is conceivable that, because of the higher average age of our placebo-treated patients, age was no longer found to be an independent risk factor within this subgroup. Age was indeed identified as an independent risk factor for recurrent vascular events when the analysis involved the entire EAFT population, including patients randomized to aspirin or to oral anticoagulation. As for hypertension, the distinction "history of hypertension" was not identified as an independent risk factor in our secondary prevention study group, but the closely related variable of high systolic blood pressure at study entry was. Other studies of risk factors for recurrent stroke in patients with TIA or minor ischemic stroke, as well as studies assessing risk profiles for first-ever stroke, have on one or more occasions identified the following factors as conferring a higher risk for recurrent stroke as well as for recurrent vascular events in general: evidence of ischemic heart disease (angina pectoris, prior MI), peripheral vascular disease (intermittent claudication, prior vascular surgery), history of previous thromboembolic events, diabetes, enlarged cardiothoracic ratio on chest roentgenogram, systolic blood pressure greater than 160 mm Hg at study entry, and presence of any ischemic lesion on CT scan.^{14 15 16 23 24 25 26 27} Probably one of the most striking findings was that any ischemic lesion on CT scan and particularly multiple ischemic lesions were predictive for both cardiac events and recurrent stroke. Despite marked differences in CT scan findings after episodes of transient or nondisabling cerebral ischemia between patients with atrial fibrillation on the one hand and those in sinus rhythm on the other,²⁸ the presence of typically "embolic" infarcts (large end-zone infarctions) was no stronger predictor of recurrent events than that of typically "nonembolic" lesions (small deep infarcts). Whereas border-zone infarcts were found to be strongly associated with recurrent vascular events in sinus rhythm patients,¹⁶ an association that could be explained by assuming severe carotid stenosis in these patients, no such relation was found in patients with atrial fibrillation, possibly because of the differences in underlying pathogenesis. We did find an unexpectedly high recurrence rate of ischemic stroke in patients with lesions in the cerebellum or brain stem at study entry, but this may well have been a chance effect.

Risk factors associated with recurrence of vascular events (including strokes) have in common that they are either manifestations of atherosclerosis or contribute to the certainty with which the initial diagnosis of cerebral events (in the case of CT scan indexes) or atrial fibrillation (long-standing history of arrhythmia) could be made. The individual merits of each separate risk factor should be viewed in this context, and the fact that different studies report slightly different predictors should therefore not be considered as evidence of poor validity of the conclusions. Because of the multicenter (108 centers) and multinational (13 different countries) character of the EAFT group, the results of our secondary analyses can be applied to a broad spectrum of patients with NRAF who have experienced a recent TIA or minor ischemic stroke. The clinical definitions of the various predictors used in this evaluation may well have been interpreted differently in the many collaborating centers. This may have caused an underestimation of most of the reported associations, but on the other hand the biologically plausible associations that we did find are therefore likely to hold in general hospital practice. Because the predictions were derived from hospital-referred patients, they might well overestimate the actual risk in the general population.²⁹

In conclusion, easily obtainable patient characteristics (history of previous thromboembolism, ischemic heart disease, enlarged cardiothoracic ratio on chest roentgenogram, systolic blood pressure greater than 160 mm Hg at study entry, atrial fibrillation existing for more than 1 year, and evidence of an ischemic lesion on CT scan) are helpful in estimating the potential effect of adequate secondary prevention in patients with NRAF who recently suffered a TIA or minor ischemic stroke.

	Acknowledgments

 
This study was supported by grants from the Netherlands Heart Foundation (No. 87.048); Bayer Wuppertal, Germany; the UK Stroke Association; and University Hospital Utrecht and University Hospital Rotterdam, Netherlands.

Received November 7, 1994; revision received January 20, 1995; accepted January 21, 1995.

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