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Dhamoon MS, Longstreth WT, Bartz TM, Kaplan RC, Elkind MSV. Disability Trajectories Before and After Stroke and Myocardial Infarction: The Cardiovascular Health Study. JAMA Neurol. 2017;74(12):1439–1445. doi:10.1001/jamaneurol.2017.2802
Is the slope of disability different before stroke and after recovery from stroke?
In this population-based cohort study, the slope of increase in disability was 3-fold greater after recovery from stroke compared with before stroke. The slope before and after the comparison event—myocardial infarction—was not different.
Stroke may be associated with potentially treatable long-term adverse effects on the brain that lead to accelerated accumulation of disability.
Ischemic strokes may accelerate long-term functional decline apart from their acute effects on neurologic function.
To test whether the increase in long-term disability is steeper after than before the event for ischemic stroke but not myocardial infarction (MI).
Design, Settings, and Participants
In the population-based, prospective cohort Cardiovascular Health Study (1989-2013), longitudinal follow-up was conducted for a mean (SD) of 13 (6.2) years. Follow-up data were used until September 1, 2013; data analysis was performed from August 1, 2013, to June 1, 2016. Models based on generalized estimating equations adjusted for baseline covariates and included a test for different slopes of disability before and after the event. Participants included 5888 Medicare-eligible individuals 65 years or older who were not institutionalized, expected to reside in the area for 3 or more years, and able to provide informed consent. Exclusions were needing a wheelchair, receiving hospice care, and undergoing radiotherapy or chemotherapy.
Ischemic stroke and MI.
Main Outcomes and Measures
Annual assessments with a disability scale (measuring activities of daily living [ADLs] and instrumental ADLs). The number of ADLs and instrumental ADLs (range, 0-12) that the participant could not perform was analyzed continuously.
The mean (SD) age of the entire cohort (n = 5888) was 72.8 (5.6) years; 2495 (42.4%) were male. During follow-up, 382 (6.5%) participants had ischemic stroke and 395 (6.7%) had MI with 1 or more disability assessment after the event. There was a mean of 3.7 (2.4) visits before stroke and 3.7 (2.3) visits after stroke; there was a mean of 3.8 (2.5) visits before MI and 3.8 (2.4) visits after MI. The increase in disability near the time of the event was greater for stroke (0.88 points on the disability scale; 95% CI, 0.57 to 1.20; P < .001) than MI (0.20 points on the disability scale; 95% CI, 0.06 to 0.35; P = .006). The annual increase in disability before stroke (0.06 points per year; 95% CI, 0.002 to 0.12; P = .04) more than tripled after stroke (0.15 additional points per year; 95% CI, 0.004 to 0.30; P = .04). The annual increase in disability before MI (0.04 points per year; 95% CI, 0.004 to 0.08; P = .03) did not change significantly after MI (0.02 additional points per year; 95% CI, −0.07 to 0.11; P = .69).
Conclusions and Relevance
In this large, population-based study, a trajectory of increasing disability became significantly steeper after stroke but not after MI. Thus, in addition to the acute brain injury and consequent impairment, ischemic stroke may also be associated with potentially treatable long-term adverse effects on the brain that lead to accelerated functional decline.
According to the traditional view (Figure, A), stroke is thought to cause disability acutely, followed by a 3- to 6-month recovery period, after which disability stabilizes unless recurrent events occur.1-4 However, stroke may accelerate the accumulation of disability over time, beyond disability progression due to nonpathologic cognitive aging.5 According to this new paradigm of the effect of vascular brain injury on functional status (Figure, A), disability may accelerate over time after recovery from stroke, even without recurrent clinical events.
Several lines of evidence support this paradigm. Stroke risk factors of diabetes and hypertension have a cumulative effect on vessel dysfunction, leading to ongoing vascular brain injury. In addition, ischemic stroke may cause delayed neuronal death and neurodegeneration,6 changes in local inflammation and systemic inflammatory profiles,7-9 progressive cardiovascular impairment and reduced fitness,10 and covert brain infarcts in the absence of clinically recognized overt events.
To determine the unique effect of stroke on disability trajectories, the comparison group of myocardial infarction (MI) is ideal, because patients with MI have similar distributions of vascular risk factors and experience a sudden event, in contrast to a healthy, community-based control group with no anchor point from which to measure follow-up. Such an anchor is essential because previous research has demonstrated trajectories that vary based on time from the event.11 We hypothesized that the slope of increasing disability over the long term is steeper after recovery from stroke than before stroke but similar before and after MI.
Cardiovascular Health Study (CHS) participants (n = 5888) were recruited from 1989 to 1993 from a sex- and age-stratified random sample of Medicare-eligible individuals in 4 states,12 aged 65 years or older, not institutionalized, expected to reside in the area for 3 or more years, and able to provide informed consent. Individuals needing a wheelchair or receiving hospice care and undergoing radiotherapy or chemotherapy were excluded. Baseline sociodemographic, functional, and health data were obtained from interviews, clinical examinations, medical record abstraction, and publicly released Medicare claims data, as previously described.12,13 Longitudinal follow-up was conducted for a mean (SD) of 13 (6.2) years. Follow-up data were used until September 1, 2013; data analysis was performed from August 1, 2013, to June 1, 2016. The institutional review boards at University of California, Davis; The Johns Hopkins University; Wake Forest University School of Medicine; and University of Pittsburgh approved the study, and each participant gave written informed consent; there was no financial compensation.
Potential events were identified through regular contact with participants and proxies.14 Data on vascular events were collected at local sites and adjudicated by centralized end point committees for stroke and MI.15 Stroke was classified as ischemic (lacunar, cardioembolic, atherosclerotic, or indeterminate), hemorrhagic, or unknown.16 Potential incident MI cases were adjudicated based on a review of clinical history of cardiac symptoms, elevated cardiac enzyme levels, and serial electrocardiographic changes.
Disability was assessed annually by the activities of daily living (ADL) and instrumental ADL (IADL) scale, modified from the National Center for Health Statistics Supplement on Aging17 and the New Haven Established Populations for Epidemiologic Studies of the Elderly Study.18 The scale assesses the ability to carry out ADLs (walking around the home, getting out of bed, eating, dressing, bathing, and using the toilet) and IADLs (heavy housework, light housework, shopping, preparing meals, paying bills, and using the telephone). The scale is scored from 0 to 12 based on the number of ADLs and IADLs with which the participant reported having difficulty or could not perform, and was analyzed as a continuous variable as in previous research.13,19 In secondary analysis, the scale was dichotomized as nondisabled (score, 0) and disabled (score, ≥1). Disability assessments were missing in 14% of measurements among individuals with stroke (8% before and 18% after) and 9% with MI (5% before and 15% after).
Covariates were assessed at baseline and included demographic variables (self-reported age, sex, race/ethnicity, and level of education), lifestyle variables (self-reported smoking, alcohol consumption, and physical activity), and vascular risk factors (body mass index, hypertension, diabetes, cardiac disease, and hyperlipidemia, as previously defined16). The strength of participants’ social networks was assessed with the Lubben Social Network Scale,20 a validated, 10-item measure that includes assessments of 5 aspects of social networks. Depression was defined by a score higher than 9 on the Centers for Epidemiologic Studies–Depression scale.21 The Modified Mini-Mental State Examination score22 was assessed at 1 year of follow-up. Personal income was defined as total family income before taxes from all sources in the past 12 months and was categorized as less than $12 000, $12 000 to $34 999, and $35 000 or more, based on prior analyses.23 Due to associations in prior studies between vascular outcomes and levels of the inflammatory biomarker C-reactive protein and the atherothrombotic marker lipoprotein A, we adjusted for baseline C-reactive protein and lipoprotein A levels, log-transformed because of skewed distributions; measurement and sample processing have been previously described.24,25
Distributions of baseline characteristics and follow-up times, stroke and MI events during follow-up, and disability assessments before and after events were examined. With 2-tailed testing, the level of significance was 0.05. SAS, version 9.3, was used (SAS Institute Inc) for analysis.
We sought to determine whether the slope of disability differed before and after stroke. Participants without prevalent stroke who experienced ischemic stroke during follow-up and had 1 or more disability assessments after stroke were included. Due to correlations among repeated measures of outcomes in the same participant, regression models based on generalized estimating equations with an exchangeable correlation structure and robust SEs were used, with an identity link function for continuous disability and a logit link function for dichotomous disability.
Assessments of disability occurring within 6 months after stroke (n = 163) were ignored, since the course of recovery during this period is well documented and our interest was the long-term course of disability. Follow-up was censored at the time of recurrent stroke. The primary covariate was time of follow-up, and the parameter term associated with this signified the slope of increasing disability. The model included a product term (between poststroke status and time of follow-up) that allowed for a different slope before and after stroke, and allowed for a direct test of a difference in slope, as follows:
where FU indicates follow-up time and poststroke is 0 if the time of follow-up was before the stroke and 1 if after the stroke. β1 estimated the annual change in disability before the event (Figure, B[a]), β2 estimated the change in disability around the time of event (Figure, B[b]), and β3 estimated additional annual change in disability after the event (Figure, B[c]). This modeling strategy has been used in several previous studies.26-28
In model building, we sequentially added groups of variables, including demographics, vascular risk factors, social variables, and cognitive and mood factors. To maximize power to estimate the primary associations of interest, we removed variables not significant at a P value cutoff of .10, while retaining demographic variables. We tested nonlinearity of time trends with quadratic terms, and nonlinearity was lacking.
We conducted an analysis similar to that outlined above, except that the event of interest was MI instead of stroke and participants were free of prevalent MI at baseline. Hence, the models assessed the slope of increasing disability before and after MI in participants who had an MI during follow-up allowing for a drop in function after MI. Disability assessments within 6 months of MI were included, since the 3- to 6-month course of recovery documented with stroke does not exist in MI with the same biological implications as with stroke.29,30 Follow-up was censored at the time of recurrent MI.
To directly compare the change in disability around the time of event (Figure, B[b]) between stroke and MI, we performed another analysis in which the entire CHS cohort was included. We used generalized estimating equation models as described above. For the determination of events, we considered the first stroke or MI only.
First, different cutoffs of the disability scale were tested systematically, dichotomizing at each level of the scale in adjusted and unadjusted models to determine whether there was a threshold effect at a particular cutoff. To determine whether the trajectories of disability before stroke and MI were different between patients who had these events and those who did not experience stroke or MI, we compared these slopes with those in the whole cohort excluding those who experienced stroke, MI, or both, in unadjusted and fully adjusted models.
The effect of ischemic stroke subtype on disability trajectories was tested by stratifying models by stroke subtype and comparing trajectories of disability before and after stroke. To assess for bias due to differential mortality between MI and stroke, we performed an analysis in which the worst possible disability score was assigned at the time of death.
Among patients free of stroke at baseline (n = 5639), during follow-up, 415 incident strokes occurred with 1 or more disability assessment after stroke, of which 382 were ischemic; 305 participants had more than 1 poststroke disability assessment. Mean (SD) follow-up time was 11.1 (5.0) years in this group, with a mean of 3.7 (2.4) assessments before stroke and 3.7 (2.3) after stroke. Among participants free of MI at baseline (n = 4734), 395 incident MIs occurred with 1 or more disability assessment after MI; mean follow-up time was 12.4 (5.4) years, with a mean of 3.8 (2.5) assessments before MI and 3.8 (2.4) after MI. The mean baseline age was similar across the entire, stroke, and MI cohorts (Table 1). Men were more common than women in the MI cohort. The prevalence of vascular risk factors was higher in the stroke and MI cohorts than in the overall cohort. In the overall cohort, the mean baseline disability score was 0.59 (1.13).
In the fully adjusted model of the stroke cohort (Table 2), the mean change around the time of stroke was 0.45 points (95% CI, −0.05 to 0.95) (Figure, B[b]). The annual change in disability score before stroke was 0.06 points per year (95% CI, 0.002 to 0.12) (Figure, B[a]), with an additional 0.15 points per year after stroke (95% CI, 0.004 to 0.30) (Figure, B[c]). In these models, assessments of disability were censored after recurrent stroke. The pattern of associations was similar when a dichotomous definition of disability was used (0 vs ≥1). Different cutoffs of the disability scale were tested systematically in adjusted and unadjusted models, and no definite threshold effect was found for a particular cutoff of the disability score.
In the MI cohort (Table 3), the mean change around the time of MI was 0.34 points (95% CI, 0.07-0.61) in a fully adjusted model. Because the term for additional annual change after MI was nonsignificant in all models (Figure, B[c]), the slope of change was similar before and after MI in unadjusted and adjusted models with recurrent MI censored.
In the entire CHS cohort (Table 4), the change near the time of stroke (0.88 points; 95% CI, 0.57 to 1.20) was greater than around the time of MI (0.20 points; 95% CI, 0.09 to 0.20; P = .04 for difference). Also, the slope of increasing disability was steeper after stroke compared with before stroke (0.14 additional points per year; 95% CI, 0.09 to 0.20), but not after MI (0.01 points per year; 95% CI, −0.02 to 0.04).
In unadjusted and fully adjusted models, the disability trajectory before stroke was similar to the trajectory in the whole cohort excluding stroke, MI, or both. When the worst possible disability score was assigned at the time of death, results were similar to those in the primary analysis: in a fully adjusted model, the mean increase in the disability score around the time of the event was significant for stroke (0.68 points; 95% CI, 0.41 to 0.96) but not for MI. Increasing disability after the event was present for stroke (0.05 points per year additional increasing disability score after event; 95% CI, −0.001 to 0.10) but not for MI. Trajectories of disability before and after stroke were examined in ischemic stroke subtypes. Among patients with lacunar stroke (n = 75), change in the disability score around the time of stroke was not significant and the magnitude was small, and an increasing disability score after stroke did not reach significance (0.33 additional points per year; 95% CI, −0.06 to 0.72). For cardioembolic stroke (n = 107), the change in the disability score around the time of stroke was significant (1.52 points; 95% CI, 0.67 to 2.37), and an increasing disability score after stroke did not reach significance (0.25 additional points per year; 95% CI, −0.02 to 0.53). For other ischemic strokes (n = 211), the change in the disability score around the time of stroke was significant (1.37 points around the time of stroke; 95% CI, 0.85 to 1.90), but a trend was lacking for increasing disability score after stroke.
In this large, population-based study, the slope of increasing disability after recovery from stroke was higher compared with before stroke; such a pattern was not evident before and after MI. A significant increase in disability around the time of the event was evident for stroke and less so for MI. Among the cohort of those who had a stroke during follow-up, the slope of increasing disability after stroke was more than 2 times the slope before stroke. In all of these models, disability measurements after recurrent stroke were censored; therefore, the estimated disability trajectories were independent of recurrent clinically overt stroke. This study is novel for at least 2 reasons. First, we examined disability not at a single follow-up time but estimated trajectories over time, including the extent to which stroke and MI altered these trajectories around the time of the event (Figure, B[b]) and over time after the event (Figure, B[c]). Second, instead of comparing trajectories after stroke with a stroke-free population with fewer vascular risk factors and without an acute event to anchor the estimation of trajectories, we compared with disability trajectories in patients with MI, who have similar vascular risk profiles as patients with stroke and experience an acute vascular event requiring hospitalization. This study provides unique and valuable information about the effect of stroke on disability trajectories in the elderly.
Stroke is the leading cause of serious disability in the United States.31 Stroke is traditionally seen as a discrete, monophasic event, and functional status has been assumed to stabilize following the 3- to 6-month recovery period after stroke, unless recurrent events occur. However, we present evidence that a single ischemic stroke continues to be associated with a gradual increase in disability over the long-term after stroke. The discrete stroke event may have long-term and ongoing effects on disability. We showed that participants who eventually have a stroke do not have a higher slope of increasing disability before stroke than do those who do not eventually have a stroke.
Although the power to test subtypes of ischemic stroke was limited, slopes of disability among different ischemic stroke subtypes were similar. Further study would clarify whether a trajectory of increasing disability is steepest for the lacunar subtype, which could reflect underlying covert but progressive small-vessel disease. Cardioembolic and other subtypes were associated with an increase in disability around the time of stroke, whereas this association was not found for lacunar strokes, reflecting a relatively milder phenotype with lacunar strokes.
This study is one of the few that provides data on disability trajectories related to stroke. Among initially stroke-free participants in the Northern Manhattan Study,26 210 participants experienced an ischemic stroke during follow-up and lived more than 6 months after stroke. When stratified by insurance status, among those with Medicaid or no insurance, in a fully adjusted model, slope of change in functional status before and after stroke differed significantly (P = .04), with a decline in the 100-point Barthel Index of 0.58 Barthel Index points per year before stroke (P = .02) and 1.94 points after stroke (P = .001). In the Health and Retirement Survey, the course of functional and cognitive impairment was compared before and after 232 hospitalizations for stroke and 450 hospitalizations for MI.32 Using a combined measure of ADLs and IADLs, disability increased more around the time of stroke than MI; these findings are similar to ours in CHS.
Several lines of evidence support the paradigm proposed here of progressive brain dysfunction caused by cerebrovascular injury (Figure, A). First, stroke is caused by conditions, including vascular risk factors and inflammation, that may have an ongoing and cumulative effect on vessel and neuronal function, including small vessels in the case of lacunar stroke and carotid arteries in the case of large-artery strokes.33,34 In addition to causing recurrent strokes, vascular risk factors cause subclinical or covert brain injury manifest as infarcts and leukoaraiosis that may reduce functional status over the long term.35,36
Alternatively, an individual stroke may cause brain injury that leads to a chronic and degenerative process with progressive damage, dysfunction, and functional decline. Neuronal death through apoptosis and necrosis in the ischemic penumbra may be delayed.6 Furthermore, a single ischemic stroke may cause local changes in inflammation and an increase in systemic inflammatory profiles7 resulting in ongoing deleterious effects on brain structure and function8 that may persist years after stroke.9 Recent animal work and human pathologic studies, for example, demonstrate that B-lymphocyte–mediated autoimmunity after stroke due to exposure to neuronal antigens is associated with delayed cognitive decline.37 These data suggest that some patients who experience stroke may develop a B-lymphocyte response to stroke that contributes to cognitive and functional decline.38
Another possible mechanism of delayed poststroke decline involves progressive cardiovascular impairment and reduced fitness due to static functional impairment that disproportionately affects patients who experience stroke compared with those with MI. This cardiovascular, nonneurologic impairment adversely effects performance in ADLs.10 Although we adjusted for baseline depression, poststroke depression may also be responsible for a proportion of the decline that we observed. Finally, the concept of cognitive reserve explains differing susceptibility to cognitive impairment based on variables such as education, literacy, intelligence quotient, and engagement in leisure activities.39 An analogous concept, functional reserve, may explain how a deficit caused by stroke may result in a depleted functional reserve and a consequent failure to compensate for brain aging. This deficit would appear as an accelerated increase in disability after recovery from stroke, as we found in the present study.
This study has several strengths. The CHS is a large, nationally representative cohort of elderly community-dwelling participants with long-term follow-up. A sensitive measure of disability, including both ADL and IADL items, was measured regularly. Surveillance and adjudication of vascular events resulted in a substantial amount of data surrounding vascular events to estimate trajectories, with a mean of 4 annual measurements of disability before and after both stroke and MI.
The study also has limitations. Because we required disability measurements before and after the event to estimate trajectories reliably, sample sizes were not large. Also, detailed information about the stroke, such as location, size, and severity, were lacking, as was neuroimaging data through follow-up to determine the influence of recurrent covert infarcts and progressing leukoaraiosis on accumulating disability.
Several implications follow from our findings. First, stroke intervention trials that measure recurrent events or disability at a single follow-up time as outcomes may miss the progressive disability that we observed. Second, some therapies may be effective in altering the adverse functional trajectories that we found, even if they do not prevent strokes. For example, psychoactive or immunotherapies may influence the trajectories of decline. Third, recognition of the role of stroke in exacerbating neurodegeneration could have implications for development of therapies for neurodegeneration.
Accepted for Publication: July 27, 2017.
Corresponding Author: Mandip S. Dhamoon, MD, DrPH, Department of Neurology, Icahn School of Medicine at Mount Sinai, 1 Gustave Levy Place, New York, NY 10029 (email@example.com).
Published Online: October 23, 2017. doi:10.1001/jamaneurol.2017.2802
Author Contributions: Drs Dhamoon and Longstreth had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Dhamoon, Longstreth, Elkind.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Dhamoon.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Dhamoon.
Obtained funding: Dhamoon.
Administrative, technical, or material support: Bartz.
Study supervision: Longstreth, Elkind.
Conflict of Interest Disclosures: None reported.
Funding/Support: This Cardiovascular Health Study (CHS) was supported by contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086, and grants U01HL080295 and U01HL130114 from the National Heart, Lung, and Blood Institute (NHLBI),with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH). Additional support was provided by grant R01AG023629 from the National Institute on Aging. Dr Dhamoon was supported by grant K23NS079422 provided by the NINDS, NHS.
Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Additional Information: A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org.
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