Cognitive Impairment and Risk of Cardiovascular Events
Cognitive Impairment and Risk of Cardiovascular Events
In total, 31 546 were enrolled into the ONTARGET and TRANSCEND trials. Of these, 30 959 participants (98.1%) completed a baseline MMSE and are included in the current analyses. Loss to follow-up was 0.2%. Participants with reduced MMSE scores were older, had fewer years of formal education, had lower intake of fruit and vegetables, were less likely to be current smokers or consume alcohol and more likely to be female, have a previous history of stroke, hypertension, diabetes mellitus, atrial fibrillation, and a sedentary lifestyle (Table 1).
Cardiovascular and Non-cardiovascular Mortality On follow-up, 12% of participants died, ranging from 9.3% in the group with baseline MMSE of 30–21.3% in the group with an MMSE of 24 or less (P < 0.0001) ( Table 2 ). Sixty per cent of deaths were attributed to a CV cause ( Table 2 ). Compared with an MMSE of 30, participants with a MMSE scores of 29–27 (HR: 1.08; 95% CI: 1.00–1.18), 26–24 (HR: 1.28; 95% CI: 1.15–1.42), and <24 (HR: 1.68; 95% CI: 1.49–1.90) were associated with a graded increase in risk of all-cause mortality on multivariable analyses. Baseline MMSE score was a significant predictor of both CV and non-CV mortality (Figure 2). Within the common causes of non-CV death, there was a significant association between MMSE and infectious and respiratory causes of death, but no association with cancer, injury, gastrointestinal, or neurological causes other than stroke ( Table 2 ).
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Figure 1.
Kaplan–Meier Curve for hazard of composite of cardiovascular death, stroke, myocardial infarction and hospitalization for congestive heart failure, categorizes by the baseline Mini-Mental State Examination score. Black line represents those with a baseline MMSE = 30; Green line represents those with a baseline Mini-Mental State Examination of 29–27, red line represents those with a baseline MMSE = 26–24, and blue line represents those with baseline MMSE <24.
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Figure 2.
Two Forest plots for unadjusted and adjusted Cox models (hazard ratios and 95% confidence intervals) for the association between baseline Mini-Mental State Examination (categorized into baseline scores of 30, 29–27, 26–24, and <24, where 30 is the reference category) and cardiovascular death, non-cardiovascular death, stroke, myocardial infarction, and hospitalization for congestive heart failure. Adjusted analyses includes the following variables in multivariate model: age, sex, education, English-speaking, region, prior history of stroke or myocardial infarction and creatinine clearance, co-morbid vascular risk factors (hypertension, diabetes mellitus, glucose, LDL, HDL, smoking, atrial fibrillation), cardiovascular medications (β-blockers, Ca antagonists, diuretics, statin, ACE-inhibitor, anticoagulant, and antiplatelet), fruit and vegetable consumption; exercise, alcohol intake pattern, baseline blood pressure and change in blood pressure from baseline to final follow-up, depression, and psychosocial stress.
Stroke On follow-up, 1374 (4.4%) of participants experienced a stroke, ranging from 3.3% in the group with baseline MMSE of 30 to7.0% in the group with an MMSE of 24 or less (P < 0.0001). Compared with an MMSE of 30, participants with a MMSE scores of 29–27 (HR: 1.19; 95% CI: 1.04–1.37), 26–24 (HR: 1.30; 95% CI: 1.09–1.55), and <24 (HR: 1.44; 95% CI: 1.17–1.77) were associated with a graded increase in risk of stroke on multivariable analyses. (Figure 2 and Table 3 ).
Myocardial Infarction, Hospitalization for Unstable or New Angina On follow-up, 1527 (4.9%) of participants experienced a myocardial infarction, ranging from 4.7% in the group with baseline MMSE of 30 to 5.0% in the group with an MMSE of 24 or less (P = 0.06). We did not find an association between MMSE score and risk of myocardial infarction [MMSE 26–24 (HR: 1.11; 95% CI: 0.94–1.30) and MMSE <24 (HR: 0.99; 95% CI: 0.79–1.22)] (Figure 2) or for admission for unstable angina or new angina [MMSE 26–24 (HR: 1.11; 95% CI: 0.95–1.29) and MMSE <24 (HR: 1.12; 95% CI: 0.91–1.37)].
Congestive Heart Failure On follow-up, 1314 (4.2%) of participants were hospitalized for congestive heart failure, ranging from 3.2% in the group with baseline MMSE of 30 to 6.8% in the group with an MMSE of 24 or less (P < 0.0001). Compared with an MMSE of 30, participants with a MMSE scores of 29–27 (HR: 1.16; 95% CI: 1.00–1.34), 26–24 (HR: 1.24; 95% CI: 1.04–1.49), and <24 (HR: 1.38; 95% CI: 1.12–1.71) were associated with a graded increase in risk of hospitalization for congestive heart failure on multivariable analyses (Figure 2 and Table 3 ).
On multivariable analyses, a previous history of stroke and myocardial infarction was associated with an HR of 1.40 (95% CI: 1.31–1.50) and 1.43 (95% CI: 1.34–1.53), respectively, for the composite of all CV outcomes.
The increased risk of CV events associated with reduced baseline MMSE score was similar in those younger or older than 75 years, participants from English- and non-English-speaking regions, men and women, different levels of formal education, and those with and without a previous history of stroke and hypertension (Figure 3). Among patients with diabetes mellitus without a history of CVD, the association between MMSE score and the composite outcome was consistent with the overall results [MMSE score of 29–27 (HR: 1.28; 95% CI: 0.98–1.68), 26–24 (HR: 1.50; 95% CI: 1.09–2.08), and <24 (HR: 1.74; 95% CI: 1.21–2.48) vs. MMSE 30]. In the multivariable model, adjustment for depression, psychosocial stress, fruit and vegetable intake, pattern of alcohol intake and level of physical activity did not materially influence the magnitude of risk associated with the baseline MMSE score ( Table 3 ). In addition, we did not find a significant interaction between MMSE and any of the following variables for any of the outcome measures: age, previous history of hypertension and baseline blood pressure, formal education level, previous history of stroke, alcohol intake pattern, depression, psychosocial stress, fruit and vegetable intake, and level of physical activity.
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Figure 3.
Univariate subgroup analyses by age (dichotomized into >75 and ≥75 years), previous history of hypertension, English-speaking and non-English speaking, and years of formal education (categorized into <9, 9–12 years, trade/university). Outcome measure is composite of cardiovascular mortality, stroke, myocardial infarction, and hospitalization for congestive heart failure.
For the composite outcome of all-cause death, stroke, myocardial infarction and hospitalization for congestive heart failure, orientation to place (HR: 1.52; 95% CI: 1.25–1.85), attention and calculation (HR: 1.10; 1.02–1.18), recall (HR: 1.10; 1.04–1.16), and design copy (HR: 1.15; 1.06–1.24) were significant predictors. Table 4 details the association between MMSE domains and CV mortality, non-CV mortality, stroke, myocardial infarction, and hospitalization for heart failure.
Between baseline and follow-up MMSE, 4559 participants had a decline of 2 points or more in the MMSE score. In the period after follow-up MMSE testing, the composite outcome was reported in 552/4559 (12.1%) 1936/22 007 (8.8%) of those without a decline in MMSE. On multivariable analyses, we found an association between decline in MMSE score (2 points) and risk of composite outcome (HR: 1.30; 1.18–1.44), CV death (HR: 1.47; 1.29–1.69), non-CV death (HR: 1.53; 1.30–1.80) and stroke (HR: 1.34; 1.11–1.61) and strong trend for increased risk of myocardial infarction (HR: 1.19; 0.99–1.43), and hospitalization for CHF (HR: 1.20; 0.99–1.46).
Results
In total, 31 546 were enrolled into the ONTARGET and TRANSCEND trials. Of these, 30 959 participants (98.1%) completed a baseline MMSE and are included in the current analyses. Loss to follow-up was 0.2%. Participants with reduced MMSE scores were older, had fewer years of formal education, had lower intake of fruit and vegetables, were less likely to be current smokers or consume alcohol and more likely to be female, have a previous history of stroke, hypertension, diabetes mellitus, atrial fibrillation, and a sedentary lifestyle (Table 1).
Mini-mental State Examination and Risk of Cardiovascular Events and Mortality
Cardiovascular and Non-cardiovascular Mortality On follow-up, 12% of participants died, ranging from 9.3% in the group with baseline MMSE of 30–21.3% in the group with an MMSE of 24 or less (P < 0.0001) ( Table 2 ). Sixty per cent of deaths were attributed to a CV cause ( Table 2 ). Compared with an MMSE of 30, participants with a MMSE scores of 29–27 (HR: 1.08; 95% CI: 1.00–1.18), 26–24 (HR: 1.28; 95% CI: 1.15–1.42), and <24 (HR: 1.68; 95% CI: 1.49–1.90) were associated with a graded increase in risk of all-cause mortality on multivariable analyses. Baseline MMSE score was a significant predictor of both CV and non-CV mortality (Figure 2). Within the common causes of non-CV death, there was a significant association between MMSE and infectious and respiratory causes of death, but no association with cancer, injury, gastrointestinal, or neurological causes other than stroke ( Table 2 ).
(Enlarge Image)
Figure 1.
Kaplan–Meier Curve for hazard of composite of cardiovascular death, stroke, myocardial infarction and hospitalization for congestive heart failure, categorizes by the baseline Mini-Mental State Examination score. Black line represents those with a baseline MMSE = 30; Green line represents those with a baseline Mini-Mental State Examination of 29–27, red line represents those with a baseline MMSE = 26–24, and blue line represents those with baseline MMSE <24.
(Enlarge Image)
Figure 2.
Two Forest plots for unadjusted and adjusted Cox models (hazard ratios and 95% confidence intervals) for the association between baseline Mini-Mental State Examination (categorized into baseline scores of 30, 29–27, 26–24, and <24, where 30 is the reference category) and cardiovascular death, non-cardiovascular death, stroke, myocardial infarction, and hospitalization for congestive heart failure. Adjusted analyses includes the following variables in multivariate model: age, sex, education, English-speaking, region, prior history of stroke or myocardial infarction and creatinine clearance, co-morbid vascular risk factors (hypertension, diabetes mellitus, glucose, LDL, HDL, smoking, atrial fibrillation), cardiovascular medications (β-blockers, Ca antagonists, diuretics, statin, ACE-inhibitor, anticoagulant, and antiplatelet), fruit and vegetable consumption; exercise, alcohol intake pattern, baseline blood pressure and change in blood pressure from baseline to final follow-up, depression, and psychosocial stress.
Stroke On follow-up, 1374 (4.4%) of participants experienced a stroke, ranging from 3.3% in the group with baseline MMSE of 30 to7.0% in the group with an MMSE of 24 or less (P < 0.0001). Compared with an MMSE of 30, participants with a MMSE scores of 29–27 (HR: 1.19; 95% CI: 1.04–1.37), 26–24 (HR: 1.30; 95% CI: 1.09–1.55), and <24 (HR: 1.44; 95% CI: 1.17–1.77) were associated with a graded increase in risk of stroke on multivariable analyses. (Figure 2 and Table 3 ).
Myocardial Infarction, Hospitalization for Unstable or New Angina On follow-up, 1527 (4.9%) of participants experienced a myocardial infarction, ranging from 4.7% in the group with baseline MMSE of 30 to 5.0% in the group with an MMSE of 24 or less (P = 0.06). We did not find an association between MMSE score and risk of myocardial infarction [MMSE 26–24 (HR: 1.11; 95% CI: 0.94–1.30) and MMSE <24 (HR: 0.99; 95% CI: 0.79–1.22)] (Figure 2) or for admission for unstable angina or new angina [MMSE 26–24 (HR: 1.11; 95% CI: 0.95–1.29) and MMSE <24 (HR: 1.12; 95% CI: 0.91–1.37)].
Congestive Heart Failure On follow-up, 1314 (4.2%) of participants were hospitalized for congestive heart failure, ranging from 3.2% in the group with baseline MMSE of 30 to 6.8% in the group with an MMSE of 24 or less (P < 0.0001). Compared with an MMSE of 30, participants with a MMSE scores of 29–27 (HR: 1.16; 95% CI: 1.00–1.34), 26–24 (HR: 1.24; 95% CI: 1.04–1.49), and <24 (HR: 1.38; 95% CI: 1.12–1.71) were associated with a graded increase in risk of hospitalization for congestive heart failure on multivariable analyses (Figure 2 and Table 3 ).
Prior Stroke or Myocardial Infarction
On multivariable analyses, a previous history of stroke and myocardial infarction was associated with an HR of 1.40 (95% CI: 1.31–1.50) and 1.43 (95% CI: 1.34–1.53), respectively, for the composite of all CV outcomes.
Subgroup Analyses and Interaction Between Mini-Mental State Examination and confounders
The increased risk of CV events associated with reduced baseline MMSE score was similar in those younger or older than 75 years, participants from English- and non-English-speaking regions, men and women, different levels of formal education, and those with and without a previous history of stroke and hypertension (Figure 3). Among patients with diabetes mellitus without a history of CVD, the association between MMSE score and the composite outcome was consistent with the overall results [MMSE score of 29–27 (HR: 1.28; 95% CI: 0.98–1.68), 26–24 (HR: 1.50; 95% CI: 1.09–2.08), and <24 (HR: 1.74; 95% CI: 1.21–2.48) vs. MMSE 30]. In the multivariable model, adjustment for depression, psychosocial stress, fruit and vegetable intake, pattern of alcohol intake and level of physical activity did not materially influence the magnitude of risk associated with the baseline MMSE score ( Table 3 ). In addition, we did not find a significant interaction between MMSE and any of the following variables for any of the outcome measures: age, previous history of hypertension and baseline blood pressure, formal education level, previous history of stroke, alcohol intake pattern, depression, psychosocial stress, fruit and vegetable intake, and level of physical activity.
(Enlarge Image)
Figure 3.
Univariate subgroup analyses by age (dichotomized into >75 and ≥75 years), previous history of hypertension, English-speaking and non-English speaking, and years of formal education (categorized into <9, 9–12 years, trade/university). Outcome measure is composite of cardiovascular mortality, stroke, myocardial infarction, and hospitalization for congestive heart failure.
Mini-Mental State Examination Domains and Risk of Cardiovascular Events
For the composite outcome of all-cause death, stroke, myocardial infarction and hospitalization for congestive heart failure, orientation to place (HR: 1.52; 95% CI: 1.25–1.85), attention and calculation (HR: 1.10; 1.02–1.18), recall (HR: 1.10; 1.04–1.16), and design copy (HR: 1.15; 1.06–1.24) were significant predictors. Table 4 details the association between MMSE domains and CV mortality, non-CV mortality, stroke, myocardial infarction, and hospitalization for heart failure.
Change in Mini-Mental State Examination Score and Risk of Cardiovascular Events
Between baseline and follow-up MMSE, 4559 participants had a decline of 2 points or more in the MMSE score. In the period after follow-up MMSE testing, the composite outcome was reported in 552/4559 (12.1%) 1936/22 007 (8.8%) of those without a decline in MMSE. On multivariable analyses, we found an association between decline in MMSE score (2 points) and risk of composite outcome (HR: 1.30; 1.18–1.44), CV death (HR: 1.47; 1.29–1.69), non-CV death (HR: 1.53; 1.30–1.80) and stroke (HR: 1.34; 1.11–1.61) and strong trend for increased risk of myocardial infarction (HR: 1.19; 0.99–1.43), and hospitalization for CHF (HR: 1.20; 0.99–1.46).
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