Association of Prior Atherosclerotic Cardiovascular Disease with Dementia After Stroke: A Retrospective Cohort Study

Background: Prior atherosclerotic cardiovascular disease (ASCVD), including coronary heart disease (CHD) and peripheral artery disease (PAD), are common among patients with stroke, a known risk factor for dementia. However, whether these conditions further increase the risk of post-stroke dementia remains uncertain. Objective: To examine whether prior ASCVD is associated with increased risk of dementia among stroke patients. Methods: A retrospective cohort study was conducted using the Clinical Practice Research Datalink with linkage to hospital data. Patients with first-ever stroke between 2006 and 2017 were followed up to 10 years. We used multi-variable Cox regression models to examine the associations of prior ASCVD with dementia and the impact of prior ASCVD onset and duration. Results: Among 63,959 patients, 7,265 cases (11.4%) developed post-stroke dementia during a median of 3.6-year follow-up. The hazard ratio (HR) of dementia adjusted for demographics and lifestyle was 1.18 (95% CI: 1.12–1.25) for ASCVD, 1.16 (1.10–1.23) for CHD, and 1.25 (1.13–1.37) for PAD. The HRs additionally adjusted for multimorbidity and medications were 1.07 (1.00–1.13), 1.04 (0.98–1.11), and 1.11 (1.00–1.22), respectively. Based on the fully adjusted estimates, there was no linear relationship between the age of ASCVD onset and post-stroke dementia (all p-trend >0.05). The adjusted risk of dementia was not increased with the duration of pre-stroke ASCVD (all p-trend >0.05). Conclusion: Stroke patients with prior ASCVD are more likely to develop subsequent dementia. After full adjustment for confounding, however, the risk of post-stroke dementia is attenuated, with only a slight increase with prior ASCVD.


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Supplementary Table 1 Codes for stroke S1 Supplementary Table 2 Codes for dementia S3 Supplementary Table 3 Codes for coronary heart disease S7 Supplementary Table 4 Codes for peripheral artery disease S14 Supplementary Table 5 Criteria for quality control S15 Supplementary Table 6 Baseline characteristics by coronary heart disease or peripheral artery disease S16 Supplementary Table 7 Baseline characteristics of patients with complete and incomplete baseline data S17 Supplementary Table 8 Baseline characteristics stratified according to follow-up status S18 Supplementary Table 9 Association of prior atherosclerotic cardiovascular disease with dementia after stroke: stratified by age of stroke S19 Supplementary  The RECORD statement -checklist of items, extended from the STROBE statement 47642 G64z100 Wallenberg syndrome 50594 G654.00 Multiple and bilateral precerebral artery syndromes 51767 G666.00 Pure sensory lacunar syndrome 53745 Gyu6400 [X]Other cerebral infarction 55247 G65z000 Impending cerebral ischaemia 57315 G618.00 Intracerebral hemorrhage, multiple localized 62342 G615.00 Bulbar hemorrhage 90572 Gyu6500 [X]Occlusion and stenosis of other precerebral arteries 91627 Gyu6300 [X]Cerebrl infarctn due/unspcf occlusn or sten/cerebrl artrs 92036 Gyu6600 [X]Occlusion and stenosis of other cerebral arteries 94482 Gyu6G00 [X]Cereb infarct due unsp occlus/stenos precerebr arteries 96630 Gyu6F00 [X]Intracerebral hemorrhage in hemisphere, unspecified ICD-10 Codes used in HES and ONS

I63
Cerebral infarction I63.0 Cerebral infarction due to thrombosis of precerebral arteries I63.1 Cerebral infarction due to embolism of precerebral arteries I63.2 Cerebral infarction due to unspecified occlusion or stenosis of precerebral arteries I63.3 Cerebral infarction due to thrombosis of cerebral arteries I63.4 Cerebral infarction due to embolism of cerebral arteries I63.5 Cerebral infarction due to unspecified occlusion or stenosis of cerebral arteries I63.6 Cerebral infarction due to cerebral venous thrombosis, nonpyogenic I63.8 Other cerebral infarction (37.8) a A total of 397 (0.62%) patients had missing value of smoking status: 42 (0.28%), 355 (0.72%), 9 (0.23%), and 388 (0.65%) for CHD, no CHD, PAD, and no PAD, respectively. b A total of 5,924 (9.26%) patients had missing value of BMI: 656 (4.41%), 5,221 (10.64%), 222 (5.71%), and 5,655 (9.41%) for CHD, no CHD, PAD, and no PAD, respectively. c A total of 28,000 (43.78%) patients had an unspecified stroke subtype: 6,179 (41.53%), 21,821 (44.46%), 1,657 (42.64%), and 26,343 (43.85%) in CHD, no CHD, PAD, and no PAD group, respectively. BMI, body mass index; CHD, coronary heart disease; COPD, chronic obstructive pulmonary disease; IMD, Index of Multiple Deprivation; IQR, interquartile range; PAD, peripheral artery disease. S17  (14,182,14,540,18,407, and 10,773 for each age group, respectively) with complete baseline data were included in all the models (6057 were excluded due to missing value in smoking or BMI). a Event rates reported in 1000 person-years. b Model 1: adjusted for age (cubic spline variables), gender, IMD, smoking, and BMI (cubic spline variables). c Model 2: adjusted for the variables in model 1 plus comorbidities (stroke subtype, atrial fibrillation, alcohol problem, anxiety, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, depression, diabetes, epilepsy, hearing loss, heart failure, hyperlipidemia, hypertension, Parkinson's disease, and transient ischemic attack. The CHD and PAD models additionally adjusted for PAD and CHD, respectively. d Model 3: adjusted for the variables in model 2 plus consultation (cubic spline variables) and medications (statins, other lipid-lowering drugs, anticoagulant, antiplatelet, antihypertensive drugs, and antidiabetic drugs). BMI, body mass index; CHD, coronary heart disease; IMD, Index of Multiple Deprivation; PAD, peripheral artery disease. male, respectively) with complete baseline data were included in all the models (6,057 were excluded due to missing value in smoking or BMI). a Event rates reported in 1000 person-years. b Model 1: adjusted for age (cubic spline variables), gender, IMD, smoking, and BMI (cubic spline variables). c Model 2: adjusted for the variables in model 1 plus comorbidities (stroke subtype, atrial fibrillation, alcohol problem, anxiety, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, depression, diabetes, epilepsy, hearing loss, heart failure, hyperlipidemia, hypertension, Parkinson's disease, and transient ischemic attack. The CHD and PAD models additionally adjusted for PAD and CHD, respectively. d Model 3: adjusted for the variables in model 2 plus consultation (cubic spline variables) and medications (statins, other lipid-lowering drugs, anticoagulant, antiplatelet, antihypertensive drugs, and antidiabetic drugs). BMI, body mass index; CHD, coronary heart disease; IMD, Index of Multiple Deprivation; PAD, peripheral artery disease. with complete baseline data were included in all the models (6057 were excluded due to missing value in smoking or BMI). ** Tests for linear trend were conducted in patients with ASCVD/CHD/PAD only, by assigning the medians (ASCVD: 41,58,and 74;CHD: 41,58,and 74;PAD: 42,59,and 75) to the age levels of onset from the lowest to the highest and treating the variable as a numerical v ariable in the Cox models. a No confounding variables were adjusted for. b Model 1: adjusted for age (cubic spline variables), gender, IMD, smoking, and BMI (cubic spline variables). c Model 2: adjusted for the variables in model 1 plus comorbidities (stroke subtype, atrial fibrillation, alcohol problem, anxiety, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, depression, diabetes, epilepsy, hearing loss, heart failure, hyperlipidemia, hypertension, Parkinson's disease, and transient ischemic attack. The CHD and PAD models additionally adjusted for PAD and CHD, respectively. ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index; CHD, coronary heart disease; HR: hazard ratio; IMD, Index of Multiple Deprivation; PAD, peripheral artery disease.

Supplementary Table 12. Crude and partially adjusted association between length of time with prior atherosclerotic cardiovascular disease and dementia after stroke
* Of 63,959 patients in total, 57,902 patients with complete baseline data were included in all the models (6,057 were excluded due to missing value in smoking or BMI). ** Tests for linear trend were conducted in patients with ASCVD/CHD/PAD only, by assigning the medians (ASCVD: 3,11,and 20;CHD: 3,11,and 21;PAD: 3,8,and 15) to the length tertile levels from the lowest to the highest and treating the variable as a numerical variable in the Cox models. a No confounding variables were adjusted for. b Model 1: adjusted for age (cubic spline variables), gender, IMD, smoking, and BMI (cubic spline variables). c Model 2: adjusted for the variables in model 1 plus comorbidities (stroke subtype, atrial fibrillation, alcohol problem, anxiety, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, depression, diabetes, epilepsy, hearing loss, heart failure, hyperlipidemia, hypertension, Parkinson's disease, and transient ischemic attack. The CHD and PAD models additionally adjusted for PAD and CHD, respectively. ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index; CHD, coronary heart disease; HR: hazard ratio; IMD, Index of Multiple Deprivation; PAD, peripheral artery disease. 0.85 *1,518 patients with occurrence of dementia during the first 6 months of stroke were excluded. Of the remaining 62,441 patients in total, 56,533 patients with complete baseline data were included in all the models (5,908 were excluded due to missing value in smoking or BMI). For the adjusted estimates, 15,553 and 40,980 patients were in the ASCVD and no ASCVD group; 13,732 and 42,801 patients were in the CHD and no CHD group; 3,538 and 52,995 patients in the PAD and no PAD group, respectively. **Tests for linear trend were conducted in patients with ASCVD/CHD/PAD only, by assigning the medians (ASCVD: 41,58,and 74;CHD: 41,58,and 74;PAD: 42,59,and 75) to the age levels of onset from the lowest to the highest and treating the variable as a numerical v ariable in the Cox models. ***Tests for linear trend were conducted in patients with ASCVD/CHD/PAD only, by assigning the medians (ASCVD: 3,11,and 20;CHD: 3,11,and 21;PAD: 3,8,and 15) to the length tertile levels from the lowest to the highest and treating the variable as a continuous variable in the Cox models. a Model 1: adjusted for age (cubic spline variables), gender, IMD, smoking, and BMI (cubic spline variables). b Model 2: adjusted for the variables in model 1 plus comorbidities (stroke subtype, atrial fibrillation, alcohol problem, anxiety, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, depression, diabetes, epilepsy, hearing loss, heart failure, hyperlipidemia, hypertension, Parkinson's disease, and transient ischemic attack. The CHD and PAD models additionally adjusted for PAD and CHD, respectively. c Model 3: adjusted for the variables in model 2 plus consultation (cubic spline variables) and medications (statins, other lipid-lowering drugs, anticoagulant, antiplatelet, antihypertensive drugs, and antidiabetic drugs). ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index; CHD, coronary heart disease; HR, hazard ratio; IMD, Index of Multiple Deprivation; PAD, peripheral artery disease S26 Supplementary 0.95 *Of 63,959 patients in total, 57,902 patients with complete baseline data were included in all the models (6,057 were excluded due to missing value in smoking or BMI). For the adjusted estimates, 16,046 and 41,856 patients were in the ASCVD and no ASCVD group; 14,177 and 43,725 patients were in the CHD and no CHD group; 3651 and 54,251 patients in the PAD and no PAD group, respectively. **Tests for linear trend were conducted in patients with ASCVD/CHD/PAD only, by assigning the medians (ASCVD: 41, 58, and 74; CHD: 41, 58, and 74; PAD: 42, 59, and 75) to the age levels of onset from the lowest to the highest and treating the variable as a continuous variable in the Cox models. ***Tests for linear trend were conducted in patients with ASCVD/CHD/PAD only, by assigning the medians (ASCVD: 3, 11, and 20; CHD: 3, 11, and 21; PAD: 3, 8, and 15) to the length tertile levels from the lowest to the highest and treating the variable as a numerical variable in the Cox models. a Model 1: adjusted for age (cubic spline variables), gender, IMD, smoking, and BMI (cubic spline variables). b Model 2: adjusted for the variables in model 1 plus comorbidities (stroke subtype, atrial fibrillation, alcohol problem, anxiety, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, depression, diabetes, epilepsy, hearing loss, heart failure, hyperlipidemia, hypertension, Parkinson's disease, and transient ischemic attack. The CHD and PAD models additionally adjusted for PAD and CHD, respectively. c Model 3: adjusted for the variables in model 2 plus consultation (cubic spline variables) and medications (statins, other lipid-lowering drugs, anticoagulant, antiplatelet, antihypertensive drugs, and antidiabetic drugs). ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index; CHD, coronary heart disease; HR, hazard ratio; IMD, Index of Multiple Deprivation; PAD, peripheral artery disease. 0.60 *28,891 patients with no linkage to HES were excluded. Of the remaining 35,068 patients in total, 31,623 patients with complete baseline data were included in all the adjustment models (3,445 were excluded due to missing value in smoking or BMI). For the adjusted estimates, 9,534 and 22,089 patients were in the ASCVD and no ASCVD group; 8,490 and 23,133 patients were in the CHD and no CHD group; 2,156 and 29,467 patients in the PAD and no PAD group, respectively. **Tests for linear trend were conducted in patients with ASCVD/CHD/PAD only, by assigning the medians (ASCVD: 41, 58, and 75; CHD: 41, 58, and 75; PAD: 43, 59, and 75) to the age levels of onset from the lowest to the highest and treating the variable as a numerical v ariable in the Cox models. ***Tests for linear trend were conducted in patients with ASCVD/CHD/PAD only, by assigning the medians (ASCVD: 3, 10, and 19; CHD: 3, 10, and 20; PAD: 2, 7, and 14) to the length tertile levels from the lowest to the highest and treating the variable as a continuous variable in the Cox models. a Model 1: adjusted for age (cubic spline variables), gender, IMD, smoking, and BMI (cubic spline variables). b Model 2: adjusted for the variables in model 1 plus comorbidities (stroke subtype, atrial fibrillation, alcohol problem, anxiety, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, depression, diabetes, epilepsy, hearing loss, heart failure, hyperlipidemia, hypertension, Parkinson's disease, and transient ischemic attack. The CHD and PAD models additionally adjusted for PAD and CHD, respectively. c Model 3: adjusted for the variables in model 2 plus consultation (cubic spline variables) and medications (statins, other lipid-lowering drugs, anticoagulant, antiplatelet, antihypertensive drugs, and antidiabetic drugs). ASCVD, atherosclerotic cardiovascular disease; BMI, body mass index; CHD, coronary heart disease; IMD, Index of Multiple Deprivation; HES, Hospital Episode Statistics; HR: hazard ratio; PAD, peripheral artery disease.  (n=63,959) were included in all the models: 16,900 and 47,059 patients were in the ASCVD and no ASCVD group; 14,880 and 49,079 patients were in the CHD and no CHD group; 3,886 and 60,073 patients in the PAD and no PAD group, respectively. **Tests for linear trend were conducted in patients with ASCVD/CHD/PAD only, by assigning the medians (ASCVD: 41,58,and 74;CHD: 41,58,and 74;PAD: 42,59 and 75) to the age levels of onset from the lowest to the highest and treating the variable as a numerical v ariable in the Cox models. ***Tests for linear trend were conducted in patients with ASCVD/CHD/PAD only, by assigning the medians (ASCVD: 3,10,and 20;CHD: 3,11,and 21;PAD: 3,8,and 15) to the length tertile levels from the lowest to the highest and treating the variable as a continuous variable in the Cox models. a Model 1: adjusted for age (cubic spline variables), gender, IMD, smoking, and BMI (cubic spline variables). b Model 2: adjusted for the variables in model 1 plus comorbidities (stroke subtype, atrial fibrillation, alcohol problem, anxiety, rheumatoid arthritis, asthma, chronic obstructive pulmonary disease, depression, diabetes, epilepsy, hearing loss, heart failure, hyperlipidemia, hypertension, Parkinson's disease, and transient ischemic attack. The CHD and PAD models additionally adjusted for PAD and CHD, respectively. A product term for CHD and PAD was included in all the models.

Supplementary
*p-value for testing multiplicative interaction between CHD and PAD. **p-value for testing additive interaction between CHD and PAD.

Results
Participants 13 (a) Report the numbers of individuals at each stage of the study (e.g., numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analysed) (b) Give reasons for non-participation at each stage.