Published online before print April 12, 2007, doi: 10.1161/STROKEAHA.106.480988
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(Stroke. 2007;38:1752.)
© 2007 American Heart Association, Inc.
Original Contributions |
Risk of Myocardial Infarction or Vascular Death After First Ischemic Stroke
The Northern Manhattan Study
From the Department of Neurology (M.S.D., B.B.-A., T.R., R.L.S., M.S.V.E.), College of Physicians and Surgeons, Columbia University, New York, NY; the Department of Biostatistics (W.T., M.C.P.), Joseph P. Mailman School of Public Health, Columbia University, New York, NY; the Department of Sociomedical Sciences (B.B.-A.), Joseph P. Mailman School of Public Health, Columbia University, New York, NY; the Gertrude H. Sergievsky Center (R.L.S., M.S.V.E.), College of Physicians and Surgeons, Columbia University, New York, NY; and the Division of Epidemiology (R.L.S.), Joseph P. Mailman School of Public Health, Columbia University, New York, NY.
Correspondence to Mitchell S.V. Elkind, MD, Neurological Institute, 710 West 168th St, Box 182, New York, NY 10032. E-mail mse13{at}columbia.edu
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Abstract |
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Background and Purpose— In national guidelines, absolute long-term risk of myocardial infarction (MI) or coronary death determines target low-density lipoprotein levels, but stroke patients are not explicitly addressed. We determined the absolute 5-year risk of cardiovascular outcomes and their predictors after first ischemic stroke in a multiethnic cohort.
Methods— A population-based cohort of first ischemic stroke patients 
40 years old was prospectively followed annually for recurrent stroke, MI and cause-specific mortality. Kaplan-Meier 5-year risks for MI or vascular death (primary outcome), and other cardiovascular events, were calculated. Univariate and multivariate Cox proportional hazards models were used to calculate hazard ratios and 95% CI for predictors of cardiovascular outcomes.
Results— Mean age (n=655) was 69.7±12.7 years; 55.4% of participants were women, and 51.3% Hispanic. The 5-year risk of MI or vascular death was 17.4% (95% CI, 14.2% to 20.6%). Independent historical predictors of MI or vascular death were age >70 years (hazard ratio 1.62, 1.07 to 2.44), history of coronary artery disease (hazard ratio 1.76, 1.13 to 2.74), and atrial fibrillation (hazard ratio 1.76, 1.05 to 2.94). In the lowest risk group, those 
70 years old without coronary artery disease, 5-year risk of MI or vascular death was 9.7%.
Conclusions— The absolute risk of MI or vascular death after ischemic stroke, even in those without high-risk features, approximates levels used by national organizations to designate groups of patients at high risk of vascular events. The comparability of levels of absolute risk among stroke and cardiac patients may have treatment implications.
Key Words: cerebrovascular disease • mortality • prognosis • risk factors • stroke
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Introduction |
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Recent guidelines regarding target cholesterol levels from the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III)1,2 emphasize that target low-density lipoprotein (LDL) level be based on projected absolute risk of future coronary events rather than on presence or absence of specific risk factors. These guidelines state that patients at high risk of myocardial infarction (MI) and coronary death, defined as an absolute 10-year risk of 20% or more, should have a target LDL level <100 mg/dL and should receive statin therapy if needed to achieve this goal. Included in the group of patients with elevated risk are those who already have ischemic heart disease, as well as patients deemed to be "coronary risk equivalents," indicating those at the same elevated risk as patients with ischemic heart disease. Coronary risk equivalents include patients with diabetes mellitus, those with multiple risk factors that put them at elevated risk based on calculation of their Framingham Score,1,3 and patients with "other forms of symptomatic atherosclerotic disease." The latter group is further defined to include those with abdominal aortic aneurysm and symptomatic carotid artery disease.
Notably excluded from the list of "coronary risk equivalents" in the ATP III guidelines are the vast majority of ischemic stroke patients without symptomatic carotid artery disease as cause of their stroke. The etiologies of ischemic stroke are more heterogeneous than those of coronary artery disease, which is almost always attributable to large vessel atherosclerosis. Because large-vessel atherosclerosis accounts for only 10% to 20% of ischemic stroke,4 there is no consensus in the neurological community regarding target levels of LDL in stroke patients. Whether stroke patients without symptomatic carotid artery disease (ie, those with lacunar disease or cryptogenic infarcts, for example, who together account for as many as 60% of patients) should have similar target levels of LDL remains unsettled in these US guideline statements. Of note, however, European guidelines include both stroke and cardiac patients in total cardiovascular assessment, reflecting the lack of consensus in the medical community.5
Data on the absolute risk of experiencing myocardial infarction or vascular death after stroke may help determine how to treat stroke patients, just as designation of "coronary risk equivalents" has implications for therapy. Population-based data on the future risk of myocardial infarction or vascular death among stroke patients, however, is very limited. We sought to determine absolute 5-year risks of major cardiovascular outcomes after first ischemic stroke in a population-based cohort. We further sought to determine whether absolute risk depended on simple clinical features that allow discrimination of subgroups of stroke patients as high vascular risk equivalents. This information could be used to apply to stroke patients target LDL levels, and statin therapy when needed, in accordance with NCEP guidelines.
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Subjects and Methods |
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The Northern Manhattan Study (NOMAS) includes a population-based incident ischemic stroke follow-up study designed to determine predictors of stroke recurrence and prognosis in a multiethnic, urban population. The race-ethnic mixture of the community consists of 20% black, 63% Hispanic, and 15% white residents.6 The Hispanic population is representative of the underlying Caribbean Hispanic community in New York.7
Selection of NOMAS Cohort
Methods of patient identification and enrollment have been previously described.8,9 Briefly, stroke patients were enrolled if they: (1) were diagnosed with a first stroke, (2) were >40 years, and (3) resided in Northern Manhattan for 3 months in a household with a telephone. For this analysis, only ischemic stroke cases were included. Over 80% of patients with acute stroke in northern Manhattan are hospitalized at Columbia University Medical Center (CUMC). Subjects hospitalized at other local hospitals were identified through active surveillance of admissions and through local physicians. Approximately 5% of incident ischemic stroke patients in northern Manhattan are not hospitalized.9 A member of the research team monitored for nonhospitalized events. Evaluation of patients was performed at the hospital; those subjects either not hospitalized or hospitalized elsewhere were evaluated in the research clinic. The study was approved by the CUMC Institutional Review Board. All participants gave consent directly or through a surrogate when appropriate.
Index Evaluation
Data were collected through interviews by trained research assistants, and physical and neurological examinations were conducted by study neurologists. When possible, data were obtained directly from subjects. When subjects were unable to provide answers, proxies were interviewed (29.1% of subjects). Assessments were conducted in the participant’s primary language. Race-ethnicity was based on self-identification through a series of questions modeled after the US census and conforming to standard definitions outlined by Directive 15.10 All participants responding affirmatively to being of Spanish origin or identifying themselves as Hispanic were so classified. All participants classifying themselves as white without any Hispanic origin, or black without any Hispanic origin were classified as white, non-Hispanic, or black, non-Hispanic, respectively. All other participants were classified under the category of "other" race.
Standardized questions were adapted from the Behavioral Risk Factor Surveillance System.11 Standard techniques were used to measure blood pressure, height, weight, and fasting glucose as previously described.8,9 Hypertension was defined as in prior publications8,9 and diabetes mellitus was defined by a fasting blood glucose level 126 mg/dL, the subject’s self-report of such history, or insulin or oral hypoglycemic use.
Stroke diagnostic evaluation included CT in 96.7% of participants, MRI in 43.6%, and both in 41.3%. Fewer than 1% of patients had neither CT nor MRI. In addition, cerebrovascular ultrasound evaluation and transthoracic or transesophageal echocardiogram was performed as appropriate. Assessment of stroke subtype using modified Stroke Data Bank criteria12 was determined by consensus of stroke neurologists, using all available information, as previously described.13,14
Follow-Up and Outcomes Assessment
Follow-up was conducted at 6 months and annually for 5 years. The 6-month evaluation was conducted by telephone. Information on vital status, functional status, and intercurrent symptoms, illness, or hospitalization was collected. Annual in-person follow-up visits were conducted at the medical center and included interview, vital signs, physical and neurological examination. Patients unable to come in were visited by research staff. Ongoing surveillance of admissions to CUMC and local hospitals, described previously,15 was used to identify participants who experienced recurrent stroke, MI, hospitalization, or death. When available, medical records were reviewed for all outcome events including death. All outcome events were reviewed by a specially trained research assistant. MI was defined by criteria adapted from the Lipid Research Clinics Coronary Primary Prevention Trial16 and required at least 2 of the 3 following criteria: (1) ischemic cardiac pain; (2) cardiac enzyme abnormalities; and (3) ECG abnormalities. MI was validated by review by a study cardiologist, and strokes by a study neurologist. Deaths were also validated by a study physician. Deaths were classified as vascular or nonvascular. Vascular causes of death included stroke, MI, heart failure, pulmonary embolus, cardiac arrhythmia (eg, sudden death), and other vascular deaths. Nonvascular causes of death included accidents, cancer, pulmonary causes (such as pneumonia or chronic obstructive pulmonary disease), and other miscellaneous causes.
Statistical Analyses
Statistical analyses were conducted using SAS Version 8.2 (SAS Inst). Descriptive statistics were calculated for the population as a whole, and for those who had and did not have an outcome event. Comparisons between the 2 groups were made using t tests for continuous variables and 
2 tests for categorical variables. Cumulative 5-year risk of the primary outcome, first occurrence of MI or vascular death, was then calculated using Kaplan-Meier survival analysis. Risks of other individual and composite cardiovascular events (MI, nonfatal stroke, and vascular death) were also calculated for comparison.
In addition, univariate Cox proportional hazard models were constructed to estimate hazard ratios and 95% CI for predictors of MI and vascular death. Both historical risk factors (age, sex, race-ethnicity, education, history of MI, coronary artery disease [CAD], congestive heart failure [CHF], atrial fibrillation [AF], peripheral arterial disease, current and past smoking, diabetes mellitus, hypertension, hypercholesterolemia), physiological variables (LDL and HDL levels), and stroke etiological subtypes were included in models. Multivariable models were then constructed using those variables significant in univariate models at P<0.10. Models including historical variables were analyzed first, and then models incorporating stroke subtype as well. All models satisfied proportionality assumptions. Cumulative 5-year risk of cardiovascular events was then calculated for strata of stroke patients with and without major individual predictors of the primary outcome.
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Results |
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Table 1 lists the baseline demographic characteristics and vascular disease risk factor profile of the study population, and in those who had and did not have an outcome event. Mean age was 69.7±12.7 years, and 44.6% were male. Participants were 18.9% white, 27.6% black and 51.3% Hispanic. Prevalence of vascular risk factors was high. Previous history of cardiovascular disease was also prevalent: 16.2% had history of MI, 33.4% CAD, 13.8% CHF, 11.0% AF, and 21.6% peripheral arterial disease.
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Median follow-up in survivors was 4.0 years. Loss to follow-up was 16 patients (2.4%). There were 86 vascular deaths, including MI (n=17), CHF (n=8), sudden cardiac death (n=15), fatal strokes (n=39), and other (n=7). The 30-day mortality rate was 5.3%. There were 19 nonfatal MIs. The cumulative 1-, 3-, and 5-year risk of cardiovascular outcomes among all participants is shown in Table 2. The risk of MI or vascular death was relatively higher during the first year after stroke than for each of the subsequent 4 years (8.2% at year 1 and 17.4% at year 5). Table 2 also shows cumulative risk data for 30-day survivors. The lower limit of the confidence interval for the 5-year risk of MI or vascular death among 30-day survivors (11.9%) is still above 10% (2% annually).
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The risks of other events are also shown in Table 2. Five-year risk of MI for the entire population was 5.4% (95% CI, 3.3 to 7.4), and was essentially the same for 30-day survivors.
Univariate predictors of MI or vascular death were age >70 years, history of MI, CAD, CHF, AF, and embolic stroke subtype. The following variables did not predict MI or vascular death: male sex, high school education, race-ethnicity, history of peripheral arterial disease, current and past smoking, diabetes mellitus, hypertension, hypercholesterolemia, LDL level, HDL level, LDL >130 mg/dL, HDL <40 mg/dL, and atherosclerotic and cryptogenic ischemic stroke subtypes. In stepwise regression models, CAD and AF emerged as significant independent predictors of MI and vascular death. CHF was not predictive of outcome independently of CAD and AF. In a multivariate model excluding stroke subtype (Table 3, model 1), there were 3 significant predictors of MI or vascular death: age >70 years, history of CAD, and history of AF. Both CAD and AF were associated with approximately a 75% increase in risk of MI or vascular death. In a model incorporating stroke subtype (model 2), only age >70 years and embolic subtype were found to be significant predictors of MI or vascular death. Lacunar subtypes appeared to be protective, although this was not statistically significant.
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Because age and CAD were important easily identifiable clinical factors predicting risk of MI or vascular death, we calculated the Kaplan-Meier risks of these events for 4 subgroups stratified by age (70 and >70 years) and presence of CAD (Figure 1). For those at lowest risk based on the multivariate models (ie, age 70 years without CAD), the 5-year risk of MI or vascular death was 9.7% (95% CI, 5.5 to 13.4). Similarly, because lacunar stroke patients comprise an important independent subgroup of stroke patients and seemed to be at lowest risk, we calculated the risks of MI or vascular death for groups stratified by age (70 and >70 years) and type of cerebral infarct (lacunar versus nonlacunar; Figure 2). For those >70 years with lacunar infarcts, the risk of MI or vascular death at 5 years was 11.5%, whereas for those 70 years, the risk was 6.0%.
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Discussion |
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Our study provides population-based estimates of risk of MI and vascular death after a first ischemic stroke. Among all ischemic stroke patients, actual 5-year risk of MI or vascular death was 17.4%, or a risk of MI or vascular death of over 3% per year for 5 years. Therefore, according to our data, ischemic stroke patients have long-term risk of vascular events comparable to that of coronary risk equivalents (
2% per year).3 Considering ischemic stroke patients as a category of vascular risk equivalents has potential implications for the treatment of these patients because national guidelines (NCEP ATP III) recommend lowering LDL levels <100 mg/dL for patients at these high levels of risk. Current stroke prevention guidelines, however, do not recommend treatment based on levels of overall vascular risk, nor do they recommend statin treatment for unselected stroke patients.17,18
Because etiology of ischemic stroke is more heterogeneous than that of coronary artery disease, it remains likely that there are groups of stroke patients in whom the risks are lower than for stroke patients overall. We thus further attempted to define subgroups of ischemic stroke patients with higher or lower risk. We found that age >70, a history of CAD, and a history of AF all independently predicted an increased risk of MI or vascular death. Both CAD and AF increased by about 75% the risk of MI or vascular death over 5 years. Among those without predictors of increased cardiac risk, such as those 70 years without CAD, the risk is lower, although even in this group the actual 5-year risk of MI or vascular death (9.7%, or 1.9% per year) approaches 2% annually. Longer follow-up periods would provide more precise estimates of 10-year cumulative risk, but our 5-year risk data provide evidence that the long-term risk of MI and vascular death is as high after ischemic stroke as the risk of coronary risk equivalents. Because survivors of ischemic stroke may be more likely to die of cardiac causes than of recurrent stroke,19,20,21 our data reinforces the urgency of focusing on cardioprotective, as well as cerebroprotective, therapies in this patient population.
Lacunar stroke patients had a lower risk of subsequent MI and vascular death in our population, although even in this lower risk group, risk approached the level of a coronary risk equivalent. This lower risk of lacunar stroke patients is consistent with other studies. Among 145 patients with incident lacunar stroke in Portugal, only 3% (95% CI, 1% to 7%) had an MI after a median follow-up of 39 months,22 probably attributable to the young age of the sample (mean age 65 years), the low prevalence of MI in Portugal, and the differing pathophysiologies likely to be involved in MI and lacunar stroke. In a large randomized secondary prevention trial among blacks, moreover, in which two-thirds of patients enrolled had lacunar stroke at baseline, risk of MI and fatal vascular events was low (
3% over 2 years).23 Further studies may be needed before concluding that lacunar stroke patients are at the same absolute level of risk as coronary risk equivalents.
Because the NCEP ATP III guidelines do not include stroke as an outcome, we focused primarily on the risk of MI and vascular death. We also calculated, however, cumulative risk of events including stroke as an outcome (ie, MI, ischemic stroke, or vascular death). With ischemic stroke included, 5-year risk clearly exceeds the 10% absolute risk of the NCEP high-risk group. Based on growing evidence regarding the efficacy of statin therapy in reducing the risk of stroke as well as cardiac disease,24–28 moreover, we suggest that the coronary risk equivalent category may need to be expanded to include stroke (ie, "coronary and stroke risk equivalent").
Our data are consistent with the few other previously published population-based studies that reported risk of cardiac events after stroke. In Rochester, MN from 1960 to 1979,29 the cumulative incidence of MI or "sudden unexpected death" after first cerebral infarction was 1.4% at 1 year, 10.6% at 5 years, and 16.6% at 10 years. A more recent study30 from Rochester, MN found that the probability of survival free of recurrent stroke after a first cerebral infarction was 70.8% at 5 years and 60.7% at 10 years. In that study both MI and stroke were significant causes of vascular deaths. Finally, among 409 Swedish patients31 (mean follow-up 5 years), the cumulative risk of MI (fatal and nonfatal) was 19±8% at 5 years.
Some clinical trials have also reported risks of MI or vascular death after stroke ranging from 1.8% to 4.6% per year,32–37 suggesting that this risk is substantial even among closely monitored and treated trial patients. There are limitations to using clinical trial data for risk estimates, but these data also suggest that cardiovascular risk approximates the 2% per year risk of "coronary risk equivalents."
There are several limitations to our study. First, we have only 5-year follow-up of patients in our study, whereas 10-year follow-up would have been more consistent with estimates from the NCEP recommendations. Nonetheless, our data provide evidence of a high cardiovascular event risk over the first 5 years. Second, we did not include patients <40 years, in whom the risk of cardiac events may be lower. Because the majority of ischemic strokes occur in patients over age 40, it is unlikely that including younger patients would change the results substantially. Generalizing results to those <40 years may be less reliable. Third, the high prevalence of risk factors such as diabetes, hypertension, and previous heart disease in our population may increase risk estimates. These risk factors are typical of urban, multiethnic populations that have a high burden of stroke. In addition, we did not analyze data on medication use or compliance, which may influence event rates. Fourth, we excluded patients without a telephone. It is likely that exclusion of these patients would lead to an underestimation of the risk of MI and cardiovascular events because these patients are likely to be of lower socioeconomic status and to have higher event rates than those with telephones. Fifth, ECGs were not undertaken at regular intervals in all subjects, and silent MIs were not included. Inclusion of these would also increase the absolute risks of cardiovascular events.
It is notable that lipid levels measured at the time of stroke were not predictive of cardiac outcomes in our population. It is possible that our numbers were too small to demonstrate this effect, but it also possible that lipid levels measured at the time of stroke do not provide an accurate measure of long-term lipid parameters. We did not assess lipid levels at regular intervals after stroke. Data from the Heart Protection Study (HPS),27 moreover, provide evidence that simvastatin therapy can reduce the risk of a composite end point of stroke, MI and vascular death among stroke patients, independently of the baseline cholesterol level. This may reflect the nonlipid-lowering effects of statins.38 Clinical trials of statin therapy in stroke patients have also recently suggested a modest benefit in reducing risk of recurrent stroke and major cardiovascular events.39 Although guidelines do not yet endorse the use of statin therapy for all stroke patients, these trials provide a rationale for statin therapy independently of considerations of the absolute cardiac risk of stroke patients. It is likely, however, that other treatments that are effective at reducing cardiac risk will be developed in the future. Thus, more precise estimates of the increased cardiovascular risks of stroke patients are likely to be helpful in determining the applicability of cardioprotective treatments to stroke patients.
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Acknowledgments |
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Sources of Funding
This work was supported by the Kathleen Scott Research Fellowship of the American Heart Association/American Stroke Association (to M.S.V.E.) and NIH/NINDS R01 48134 (to M.S.V.E.), K23 42912 (to M.S.V.E.), and R01 NS 29993 (to R.L.S.).
Disclosures
Dr Elkind discloses receiving personal compensation from Boehringer-Ingelheim, Inc (significant) and BMS-Sanofi Pharmaceutical Partnership (modest) for lecturing, personal compensation from Merck (significant) as an expert witness, and research grant support from BMS-Sanofi Pharmaceutical Partnership (significant) and diaDexus, Inc (significant). Dr Rundek discloses receiving personal compensation from BMS-Sanofi Pharmaceutical Partnership (modest) for lecturing and consulting, personal compensation from Pfizer (modest) for consulting, and research grant support from BMS-Sanofi Pharmaceutical Partnership (modest) and Pfizer (modest). Dr Sacco discloses receiving personal compensation from Boehringer-Ingelheim, Inc (modest) and BMS-Sanofi Pharmaceutical Partnership (modest) for lecturing, and personal compensation from Boehringer-Ingelheim, Inc (significant), Merck (modest), Wyeth (modest), and GlaxoSmithKline (modest) for consulting.
Received December 20, 2006; revision received January 17, 2007; accepted January 19, 2007.
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[Abstract/Free Full Text]
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