Today, I review, link to, and excerpt from Incidence of Transient Ischemic Attack and Association With Long-term Risk of Stroke [PubMed Abstract] [Full-Text HTML] [Full-Text PDF]. JAMA. 2021;325(4):373-381. doi:10.1001/jama.2020.25071
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- Key Points
- Abstract
- Introduction
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Key Points
Question What is the incidence of first transient ischemic attack (TIA) and how is TIA associated with subsequent stroke risk?
Findings In this population-based cohort study from 1948-2017, the estimated crude TIA incidence was 1.19/1000 person-years, the risk of stroke was significantly greater after TIA compared with matched control participants who did not have a TIA (adjusted hazard ratio, 4.37), and the risk of stroke within 90 days after TIA was significantly lower in the most recent epoch from 2000-2017 compared with an earlier period from 1948-1985 (hazard ratio, 0.32).
Meaning Among participants in the Framingham Heart Study from 1948-2017, TIA was associated with greater risk of subsequent stroke compared with matched control participants without TIA, and the risk of stroke after a TIA was lower in more recent periods.
AbstractImportance Accurate estimation of the association between transient ischemic attack (TIA) and risk of subsequent stroke can help to improve preventive efforts and limit the burden of stroke in the population.
Objective To determine population-based incidence of TIA and the timing and long-term trends of stroke risk after TIA.
Design, Setting, and Participants Retrospective cohort study (Framingham Heart Study) of prospectively collected data of 14 059 participants with no history of TIA or stroke at baseline, followed up from 1948-December 31, 2017. A sample of TIA-free participants was matched to participants with first incident TIA on age and sex (ratio, 5:1).
Exposures Calendar time (TIA incidence calculation, time-trends analyses), TIA (matched longitudinal cohort).
Main Outcomes and Measures The main outcomes were TIA incidence rates; proportion of stroke occurring after TIA in the short term (7, 30, and 90 days) vs the long term (>1-10 years); stroke after TIA vs stroke among matched control participants without TIA; and time trends of stroke risk at 90 days after TIA assessed in 3 epochs: 1954-1985, 1986-1999, and 2000-2017.
Results Among 14 059 participants during 66 years of follow-up (366 209 person-years), 435 experienced TIA (229 women; mean age, 73.47 [SD, 11.48] years and 206 men; mean age, 70.10 [SD, 10.64] years) and were matched to 2175 control participants without TIA. The estimated incidence rate of TIA was 1.19/1000 person-years. Over a median of 8.86 years of follow-up after TIA, 130 participants (29.5%) had a stroke; 28 strokes (21.5%) occurred within 7 days, 40 (30.8%) occurred within 30 days, 51 (39.2%) occurred within 90 days, and 63 (48.5%) occurred more than 1 year after the index TIA; median time to stroke was 1.64 (interquartile range, 0.07-6.6) years. The age- and sex-adjusted cumulative 10-year hazard of incident stroke for patients with TIA (130 strokes among 435 cases) was 0.46 (95% CI, 0.39-0.55) and for matched control participants without TIA (165 strokes among 2175) was 0.09 (95% CI, 0.08-0.11); fully adjusted hazard ratio [HR], 4.37 (95% CI, 3.30-5.71; P < .001). Compared with the 90-day stroke risk after TIA in 1948-1985 (16.7%; 26 strokes among 155 patients with TIA), the risk between 1986-1999 was 11.1% (18 strokes among 162 patients) and between 2000-2017 was 5.9% (7 strokes among 118 patients). Compared with the first epoch, the HR for 90-day risk of stroke in the second epoch was 0.60 (95% CI, 0.33-1.12) and in the third epoch was 0.32 (95% CI, 0.14-0.75) (P = .005 for trend).
Conclusions and Relevance In this population-based cohort study from 1948-2017, the estimated crude TIA incidence was 1.19/1000 person-years, the risk of stroke was significantly greater after TIA compared with matched control participants who did not have TIA, and the risk of stroke after TIA was significantly lower in the most recent epoch from 2000-2017 compared with an earlier period from 1948-1985.
TIA DefinitionTIA was defined as an episode of rapid-onset focal neurologic dysfunction attributed to focal cerebral ischemia, with resolution within 24 hours. Transient visual disturbances associated with retinal ischemia were defined as transient monocular blindness and considered TIAs. Isolated transient symptoms such as altered consciousness, syncope, dizziness, amnesia, confusion, vertigo, dysarthria, dysphagia, or diplopia were not considered TIAs unless associated with other symptoms of brainstem ischemia. Focal symptoms associated with migraines were also excluded. Participants with a clinical diagnosis of TIA who were later found to have evidence of cerebral infarct in appropriate vascular distribution on computed tomography or magnetic resonance imaging were considered to have had a TIA. We characterized the duration, symptoms (motor, sensory, speech, and visual), and probable location (ocular, hemispheric, or brainstem) of the TIA. Further details regarding TIA subtyping are provided in the eMethods in the Supplement.
Stroke DefinitionStroke was defined as an acute-onset focal neurologic deficit of vascular etiology, persisting for more than 24 hours. Events with global neurologic dysfunction such as stupor or coma in the case of brainstem ischemia or subarachnoid hemorrhage were also considered strokes after review of the ancillary data and adjudication in the review process. Both ischemic and hemorrhagic stroke subtypes were included. Stroke subtypes were categorized based on preestablished criteria that include clinical features, imaging studies, and other laboratory criteria; noninvasive vascular studies; cardiac evaluations for a source of embolus; and, when available, information from autopsy studies. Ischemic stroke was diagnosed if a focal neurologic deficit was documented and the imaging showed no hemorrhage, the imaging showed an ischemic infarct that correlated with the clinical deficit, or an ischemic infarct was documented at autopsy.
A stroke was classified as cardioembolic if a cardiac source of embolus was found. All other ischemic infarcts were historically classified as atherosclerotic brain infarctions. This broad category initially included large-artery infarcts, lacunar infarcts, and infarcts of unknown origin. With the evolution in stroke phenotyping, more subcategories have been added. For the purpose of this analysis we have made a further distinction between lacunar and nonlacunar atherosclerotic brain infarctions outlined in detail in the eMethods in the Supplement. Other defined etiologies (eg, fibromuscular dysplasia, arterial dissection) are classified separately.
Risk Factors DefinitionThe study spans 70 years, during which some of the cardiovascular risk factor definitions have changed; presence or absence of a cardiovascular risk factor is in accordance with the accepted definition at the time of data recording. Blood pressure was recorded in each visit and used as a continuous variable. Hypertension was defined as systolic blood pressure greater than 140 mm Hg or diastolic blood pressure greater than 90 mm Hg, or use of an antihypertensive medication.12 Age was used both as continuous variable and dichotomized as younger than 65 years and 65 years or older, and education status as with and without high school degree. We also recorded current smoking, diagnosis of diabetes, atrial fibrillation, and coronary heart disease as binary variables.
Baseline characteristics of participants with TIA and matched controls are reported in Table 1. Patients with TIA had significantly higher prevalence of hypertension, diabetes, atrial fibrillation, and coronary artery disease and smoking. With the exception of smoking, these differences remained statistically significant between participants with TIA and matched controls in the third epoch. Clinical characteristics of incident TIAs are summarized in eTable 1 in the Supplement. Weakness was the most frequent symptom, reported in 47% of participants, and 59% of participants reported 1 symptom. Eighty-one percent of TIAs were referable to the anterior circulation and 66% of participants had symptoms lasting less than 1 hour, with only 9% reporting symptoms lasting 12 or more hours.
The crude and age- and sex-specific incidence of TIA are reported in Table 2. Overall crude incidence rate was 1.19/1000 person-years and increased with age; incidence in the age group 85 to 94 years was 4.88/1000 person-years, while for participants in the age group 45 to 54 years it was 0.22/1000 person-years. In the most recent epoch (2000-2014), the incidence rate was 1.29/1000 person-years (Table 2).
Stroke Risk After TIAThe etiologic classification and timing of subsequent strokes are summarized in eTable 2 and the eFigure in the Supplement. No participant was lost to follow-up. Over a median of 8.86 (interquartile range [IQR], 3.98-10.00) years of follow-up, 130 participants (29.8%) experienced a stroke; of those strokes, 121 were ischemic. Eighty-nine (68.5% of all ischemic strokes) were classified as nonlacunar atherosclerotic infarctions and ischemic strokes of unknown etiology and 20 (15.4% of all ischemic strokes) as cardioembolic. Among the 130 participants who had a stroke, 28 strokes (21.5%) occurred within 7 days; 40 (30.8%) occurred within 30 days; 51 (39.2%) occurred within 90 days; and 63 (48.5%) occurred more than 1 year after the index TIA (eFigure in the Supplement). Median time to stroke was 601 (IQR, 24-2414) days (1.64 [IQR, 0.07-6.6] years).
Factors Associated With Subsequent Stroke Within TIA CasesComparisons of baseline demographics and clinical characteristics between patients with TIA and subsequent stroke vs patients with TIA but without a stroke on 7 and 90 days are presented in eTables 3A and 3B in the Supplement. Stroke risk was mainly associated with hypertension (odds ratio for 7-day stroke, 5.83 [95% CI, 1.35-25.11]). A statistically significant linear association between both systolic and diastolic blood pressure was noted for both early and late risk of stroke. With regard to TIA features, only presence of language symptoms was significantly associated with early stroke risk after TIA (odds ratio, 2.74 [95% CI, 1.21-6.21]).
Stroke Risk After TIAThere were 130 stroke events after TIA among 435 participants with TIA compared with 165 strokes among 2175 matched control participants without TIA (age- and sex-adjusted HR, 4.81 [95% CI, 3.82-6.06]; P < .001) (Table 3). The age- and sex-adjusted cumulative 10-year hazard was 0.46 (95% CI, 0.39-0.55) in cases and 0.09 (95% CI, 0.08-0.11) in controls. A significant association between TIA and subsequent stroke was observed in fully adjusted models taking into account common stroke risk factors, with an HR for up to 10 years of follow-up (median, 8.86 years) of 4.37 (95% CI, 3.31-5.78); P < .001) (Table 3). The adjusted 5-year HR was 6.24 (95% CI, 4.44-8.75) (eTable 4 in the Supplement). These associations were unaltered in analyses limited to the last epoch (2000-2017) (eTable 5 in the Supplement): the adjusted HR of stroke was 4.67 (95% CI, 2.49-8.76; P < .001). Iterations of the adjusted models without adjustments for the variables with high rates of data missingness yield similar results (Table 3; eTable 6 in the Supplement): the adjusted HR without adjustment for diabetes was 4.50 (95% CI, 3.52-5.75; P < .001). Stroke incidence in participants with TIA was higher over time, diverging from stroke risk in participants without TIA throughout the entire follow-up period (Figure).
Trend in Stroke Risk After TIATemporal trends in stroke risk after TIA are summarized in Table 4. There was a significant decrease in both short- and long-term stroke risk across the 3 epochs. Compared with the first epoch, the HR for 90-day risk of stroke in the second epoch was 0.60 (95% CI, 0.33-1.12) and in the third epoch was 0.32 (95% CI, 0.14-0.75) (P = .005 for trend). Similarly lower risk was observed for 1-, 5-, and 10-year risks of stroke (Table 4).
DiscussionIn this population-based cohort study from 1948-2017, the estimated crude TIA incidence was 1.19/1000 person-years and remained unchanged in the most recent epoch after 2000. The risk of stroke was significantly greater after TIA compared with risk among matched participants who did not have TIA, and this association did not change in contemporary analyses focused on the years after 2000 only. However, the short- and long-term risk of stroke after TIA was significantly lower in the most recent epoch from 2000-2017, compared with an earlier period from 1948-1985.
The observed TIA incidence rate was higher than rates in previously reported population-based cohorts, ranging from 0.42/100 person-years to 0.83/1000 person-years2,15,16; there was no significant difference in a focused analysis of the most recent epoch after 2000. A more recent population study in Sweden also provided a lower estimate,17 although the estimated incidence rate in a recent population-based study in the US was comparable to that observed in the current study.18 Given the rigorous diagnostic approach for TIA in the study, it is unlikely that TIA mimics accounted for this observation. TIAs tend to be poorly recognized19 and prone to underreporting by patients20 and are often diagnosed in retrospect only if followed by a stroke. A National Stroke Association–sponsored survey conducted in 2000 estimated that about 1.2 million US residents older than 45 years experienced 1 or more symptoms of TIA, and most likely experienced a TIA without realizing it.21 Therefore, this study’s mode of active surveillance is advantageous, ensuring capture of more TIAs than a passive surveillance mode. This study spanned more than 6 decades of follow-up, during which advances in cardiovascular risk prevention have decreased the risk of cerebrovascular disease, likely including TIAs, and it is possible that the calculation including participants from past decades is mildly inflated. However, analysis of the most contemporary era after the year 2000 did not show a notable difference in the incidence rate. Taking all of the above competing factors into account, it is likely that this study’s estimation is a relatively accurate representation of contemporary TIA incidence in the general population.
The rate of subsequent stroke in the studied cohort was high; 30% of participants with TIA experienced a stroke over a median of 8.9 years of follow-up. This rate is higher than those from previously reported TIA cohorts with long-term follow-up, ranging from 6% after 1 year of follow-up22 to 9% in 5 years of follow-up.7 Active surveillance monitoring methods used in this study may account for this difference to some extent. However, access to specialized care and advances in secondary preventive practices are more likely contributors. The present cohort is community-based, and it cannot be ensured that all participants had access to specialists and received optimal secondary preventive care. In contrast, a recent large longitudinal TIA registry recruited patients from specialized centers and clinics with access to vascular neurologists and generally receiving a comprehensive stroke workup and preventive care.7,22 In addition, this very high risk does not reflect the substantial decreases in both short- and long-term stroke risk after TIA over time, despite the overall population aging: 1- and 5-year risks of post TIA stroke in the 2000-2017 era are 7.6% and 16.1%, respectively, considerably lower than the respective cumulative risks over the entire observation period and closer to modern era estimates. These decreases most likely reflect the effectiveness of secondary prevention interventions such as stricter blood pressure control and administration of antithrombotic medications; a recent study in Australia23 documented a similar trend in the first decade of 2000.
Despite advances in secondary prevention, stroke risk after TIA remains higher compared with risk among TIA-free participants, even after accounting for confounding cardiovascular risk factors; the risk remained generally unchanged across most subgroups. Although early stroke risk is often highlighted,4,6 the subsequent stroke incidence continued to increase and diverge from that of TIA-free participants over the entire follow-up period in this study; 49% of strokes occurred more than 12 months from the index TIA, a finding in line with recent large longitudinal studies with similarly long follow-up periods, despite general adherence to prescribed preventive practices.7 With the exception of higher blood pressure and language symptoms on presentation, none of the traditionally recognized prognostic factors of higher early stroke risk6,24 were associated with subsequent early or delayed stroke. Taken together, these findings suggest that patients with TIA represent a particularly high-risk group in need of vigorous surveillance beyond the early, high-risk period and with special attention to hypertension monitoring and treatment.
ConclusionsIn this population-based cohort study from 1948-2017, the estimated crude TIA incidence was 1.19/1000 person-years, the risk of stroke was significantly greater after TIA compared with matched control participants who did not have TIA, and the risk of stroke after TIA was significantly lower in the most recent epoch from 2000-2017 compared with an earlier period from 1948-1985.
