Review
A systematic review of calcium channel blocker use and cognitive decline/dementia in the elderly Ruth Peters a, Andrew Booth b, and Jean Peters b
Objective: Treating hypertension in those aged at least 80 years is now recommended; however, the best antihypertensive to choose remains unexplored. Calcium channel blocker (CCB) use has been associated with a decreased risk of incident dementia in a younger hypertensive group but with an increased risk of cognitive decline in the very elderly. Either result could have a large impact on a vulnerable population. The aim of this review was to assess the evidence relating CCB use to later cognitive decline or dementia in the very elderly. Methods: A systematic review of the literature was carried out. The databases Medline, PubMed, Embase and Psychinfo were searched from 1980 to 22 August 2013. Abstracts were reviewed by two independent reviewers and papers meeting the inclusion criteria were extracted. Results: One thousand, nine hundred and sixty-eight records were reviewed and 10 articles reporting on nine studies retained and extracted. Data were primarily from cohort studies. Only one reported a randomized controlled trial comparing CCBs with placebo. Populations, comparator groups, follow-up times, outcomes and exposure varied and overall results were mixed. It was not possible to combine all studies, but those reporting Alzheimer’s disease outcomes were combined to produce an overall risk ratio of 0.79 (95% confidence interval 0.53–1.17). Conclusion: At present, there is no clear evidence to suggest that CCB use increases or decreases risk of cognitive decline or dementia in the very elderly. A robust clinical trial is now required to resolve this. Keywords: aged, Alzheimer’s disease, calcium channel blockers, cognitive disorders, dementia Abbreviations: ACE-I, angiotensin-converting enzyme Inhibitor; BP, blood pressure; CASI, cognitive abilities screening instrument; CASP, critical appraisal skills program; CCB, calcium channel blocker; CI, confidence interval; MMSE, Mini Mental State Exam; OR, odds ratio; SD, standard deviation
veys/health-survey-for-england/health-survey-for-england– 2009-trend-tables.). Despite epidemiology suggesting that higher blood pressure (BP) may be better at an extreme age [2,3], a placebo-controlled trial in hypertensive participants aged at least 80 years found benefit associated with antihypertensive treatment. The Hypertension in the Very Elderly Trial (HYVET) found 21% reduction in total mortality and 37% reduction in stroke with active treatment [thiazide-like diuretic with or without an angiotensin-converting enzyme inhibitor (ACE-I)], over a mean follow-up of 2.1 years [4,5]. Several other classes of antihypertensive drug available to those with hypertension have similarly been shown to lower BP and reduce risk of cardiovascular events in predominantly younger adults. The very elderly are also at a higher risk of dementia. There is growing awareness of vascular risk factors increasing the risk of dementia, with plentiful evidence linking hypertension to later risk of cognitive decline/dementia [6–10]. Placebo-controlled clinical trials of antihypertensives have, however, found little evidence to suggest that lowering BP reduces risk of cognitive decline/dementia [11–15]. The one exception, the Systolic hypertension in Europe trial (SYST-EUR) found a 50% reduction in incident dementia, both vascular and Alzheimer’s, over a median 2-year follow-up in participants aged at least 60 years [16,17]. To date, SYST-EUR is the only such trial to use a calcium channel blocker (CCB)-based regimen. It has been suggested that this class of antihypertensive may have neuroprotective effects in addition to BP lowering, for example protecting against calcium dysregulation, reducing neuronal calcium influx and consequent neuronal damage [16–19]. Epidemiological studies give conflicting results, some suggesting that CCBs are associated with lesser decline in cognitive function [20,21], some the opposite [22]. For example, the Canadian Study of Health and Aging (CSHA) found that those taking CCBs were more likely to decline cognitively over 10 years than those taking other antihypertensives [22]. At present, it is unclear Journal of Hypertension 2014, 32:1945–1958 a Imperial Clinical Trials Unit (ICTU), Imperial College London, London and bSchool of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK
INTRODUCTION
I
n general, SBP rises with age. The very elderly are a fastgrowing group and are at the highest risk of hypertension and vascular events [1] (http://www,ic,nhs,uk/statis tics-and-data-collections/health-and-lifestyles-related-sur Journal of Hypertension
Correspondence to Ruth Peters, Imperial Clinical Trials Unit, School of Public Health, Faculty of Medicine, St Mary’s Campus, Praed Street, Imperial College London W2 1PG, UK. Tel: +20 75948974; fax: +20 75940768; e-mail: [email protected] Received 3 January 2014 Revised 14 May 2014 Accepted 15 May 2014 J Hypertens 32:1945–1958 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000273
www.jhypertension.com
1945
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Peters et al.
whether CCB use in the very elderly is beneficial with respect to cognitive decline and/or incident dementia. To date, HYVET is the only trial to focus on those aged at least 80 years, finding no effect of active treatment on incident cognitive decline/dementia. Because active treatment in HYVET reduced cardiovascular events, guidelines now routinely recommend treatment in this age group [23–30]. It is therefore key to find out whether different classes of antihypertensives have differing impacts on cognitive function. This is particularly the case for CCBs given the conflicting evidence so far and recommendations that treatment is initiated with CCBs [31,32]. The aim of this systematic review is to assess the extant evidence relating to CCB use and later cognitive decline/ dementia in the very elderly.
MATERIALS AND METHODS Search strategy The search strategy was derived from search strategies used in two Cochrane reviews [33,34] adapted as necessary. Additional names of CCBs were collected from the British National Formulary and following discussion with international experts in hypertension. The databases Medline, Embase, PsychInfo and Pubmed were searched from 1980 (when CCBs became widely available) to 22 August 2013. Appendix A shows the full search strategy. Reference lists of all articles identified were screened to identify additional published studies. Lead authors who have previously published related to CCBs and cognitive function were also contacted. The following sources were also searched for any ongoing trials. 1. Cochrane Library (1980–22 August 2013). 2. International Standard Randomised Controlled Trial Number (ISRCTN) Register 3. ClinicalTrials.gov (http://www.ClinicalTrials.gov) All identified abstracts, or titles, where abstracts were unavailable, were independently read by two reviewers and a list of potentially relevant evidence compiled independently by each. These lists were then compared and any differences resolved by discussion. Full text copies of publications selected from abstract review were read by both reviewers and assessed for relevance independently by both. Any discrepancy was resolved by discussion. Articles were included if they reported longitudinal studies or trials of antihypertensives that included analysis of a CCB group, a comparator group and with at least 1 year of follow-up, presented some evidence, or clear implication, that participants were free of cognitive decline or dementia at baseline assessment (authors were contacted for clarification where this was unclear). Studies were also required to include evidence that at least some participants were aged at least 80 years at follow-up, reported use of formal assessment of cognitive function and reported on cognitive decline or dementia outcomes. Non-English publications were not included owing to constraints on translation costs. Each included article was assessed for validity. Formal scoring was not used, as existing instruments have poor 1946
www.jhypertension.com
discriminative ability when assessing quality. Instead, each article was assessed against key criteria given in Critical Appraisal Skills Programme (CASP) checklists [35] and, for those articles reporting trials, using the Cochrane Risk of Bias tool [36]. A summary table (Appendix B) was produced indicating the extent to which each article met key validity criteria. A review-specific data extraction form was designed and included details of the patients, interventions and outcomes [35,36]. Data extraction for each study was carried out independently by each reviewer and any discrepancies resolved by discussion. In order to be as conservative as possible, results following adjustment for confounding were preferred, for inclusion in the table. The principle summary measures were anticipated to include risk ratios and mean differences. Where possible, data reporting number of incident events were combined using meta-analysis. Summary statistics and heterogeneity were reported and assessment made as to potential publication bias using a funnel plot. The protocol for this review is registered with the International prospective register of systematic reviews CRD42013003580.
RESULTS From 1968 records reviewed, 14 articles were identified in the initial search. A further three were located from examination of references and correspondence with key authors. See Fig. 1. After assessment against the inclusion criteria, 10 articles remained for data extraction (Table 1), representing nine studies [16,17,21,22,37–42]. However, SYST-EUR reported results of a double-blind placebo-controlled trial ([17] SYST-EUR-trial) and, extending this, an open-label follow-up cohort study ([17] SYST-EUR-extension). Given differences in study design and for ease of understanding, these two have been treated as separate studies. Seven studies were rejected, one did not use a formal assessment of cognitive function [43], four because prevalent cases were not excluded, or it was unclear whether this was the case [20,44–46], one because the analyses were crosssectional [47] and one where it was not clear whether the population in the longitudinal analyses met the age criteria [48]. Of the 10 studies meeting the inclusion criteria, seven reported data from longitudinal population-based observational studies. These were carried out in the United States (Cache County study [37], Baltimore Longitudinal Study of Aging [39], Indianapolis community study [40] and Honolulu Asia Aging Study, (HAAS) [42]), Canada (CSHA) [22], Israel [21] and Europe (Rotterdam study) [37]. Of the remaining three, one reported results from a double-blind placebocontrolled trial of antihypertensives (CCB-based regimen), which recruited from 19 European countries (SYST-EURtrial) [16]. Another reported results from the open-label extension of the same trial (SYST-EUR-extension) [17]. The third was a secondary analysis from the Ginkgo Evaluation of Memory (GEM) study, a randomized placebo-controlled trial of ginkgo biloba [41]. Only one study focused on a particular ethnic group, specifically recruiting residents with an African-American family member [40]. Volume 32 Number 10 October 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Calcium channel blockers and cognition
Number of records identified from searches:
Number of records identified from other sources:
Embase: 1748 Psychinfo: 131 Medline: 562 Pubmed 684 Cochrane: 2
From searching reference lists: 46 From contacting key authors: 2
Number of records after duplicates removed: 1968
Number of records screened (before duplicates removed): 3127
Number of records excluded including duplicates: 3110
Number of full text articles assessed: 17
Number of full text articles excluded: 7 Not clear whether prevalent cases excluded: 4 Cross sectional analyses only: 1 No clear assessment of cognitive function 1 Not clear whether age criteria met 1
Number of studies used in qualitative analyses: 10 papers reporting on 9 studies
Number of studies used in quantitative analyses: 10 papers reporting on 9 studies FIGURE 1 Flow chart.
Study and population characteristics Table 1 contains details of the study populations. Studies reported age and follow-up information differently. None of the studies were carried out solely in the very elderly nor were any entire study populations aged at least 80 years at the time of follow-up visits, although the GEM participants came close [41]. Although age at follow-up was not routinely reported, it was estimated using age at baseline and study duration. This estimated results in a range of approximately 72–101 years after a follow-up of approximately 2–11 years duration. Three studies did not report the percentage of men/women at baseline [17,21,40]. The SYSTEUR-extension [17] did not report participant characteristics upon initiation, although these were reported upon entry to the SYST-EUR-trial [16]. However, it was unclear whether differences existed between the two study populations. Paran et al. [21] reported 70.6% of the population as female at follow-up. Murray et al. [40] reported the percentage female at follow-up as 66% for those deemed cognitively intact and 63% for those with cognitive impairment; the Journal of Hypertension
overall percentage was not given. Of the remaining studies, one reported just 27.3% female at baseline [38], one 47% [41], HAAS included only men [42], whilst the remaining studies all report women as a majority [16,22,35,39].
Assessment of cognitive function Table 2 contains details of the assessments of cognitive function. Assessment of cognitive function and/or incident dementia was fairly robust with all studies using standard screening and diagnostic tools. Two studies added additional assessments, one resampled those in the full study population who had scored in medium or high cognitive function categories and carried out more detailed investigations [40]. The second applied additional criteria for those aged at least 80 years at follow-up [37]. All other studies essentially used the same testing procedures at baseline and follow-up. Five studies specified that they excluded prevalent dementia [16,17,22,41,42], although for the CSHA [22] it was not clear whether participants classed as ‘Cognitively-Impaired-No-Dementia’ at baseline www.jhypertension.com
1947
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1948
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Cohort study
Cohort study
Maxwell CSHA et al. [22]
Haag Rotterdam et al. [39] study
Forette SYST-EUR et al. [16]
Population
n ¼ 2418
Age follow-up
Not reported
68.2 (SD 8.3)
Age at end, for cognitively intact 77 (SD 6.2) for those with incident cognitive impairment 80.7 (SD 7.3) Not reported
Not reported
Not reported
3 years
Length of follow-up
Median 2.0 years
5 years
Average 8 years, maximum 13 years
5 years
Without incident Mean 11 years AD mean 78.1 (0.3–19.6) (range 61.1–104.2)
77.8 (SD5.7)
Not reported
74.9 (SD 6.5) Not reported treated 73.4 (SD 6.3) untreated
Age baseline
Placebo 69.9 n ¼ 1861 in (SD 6.2), double-blind active 69.9 at final visit (SD 6.5) and 303 in open follow-up
This study reports on AD alone and excludes others from analysis 3227 (104 with AD) analyses includes those with baseline and follow-up n ¼ 1092, analyses Volunteers from the include those with Baltimore Washington baseline and area, >60 years, follow-up predominantly white and of mid to high socioeconomic status, in this analysis >70% have a College degree or higher Population-based cohort of n ¼ 205 in these community and institution analyses (509 met dwelling participants inclusion criteria >65 years across 5 for analysis but regions of Canada not all were able to be included) n ¼ 6249, analyses Population-based cohort include those with recruited from all those baseline and aged 55 years living in follow-up a district of Rotterdam, 78% consented. n ¼ 1557 at Random sample of 60% of n ¼ 1617 with baseline 2 years the residents from 29 information, drug and n ¼ census tracts in use details 1151 at Indianapolis >65 at 5 years baseline with an African-American family member All elderly aged 65 years permanent residents of Cache County USA
Source of individuals
60 years primary and Randomized, secondary care centres double-blind in 19 European countries placebo-controlled trial (nitrendipine 10–40 mg/day combined with or replaced by enalapril 5–20 mg/day or hydrochlorothiazide 12.5–25 mg/day or both versus matching placebos)
Murray Community- Cohort study et al. [40] based sample of AfricanAmericans
Cohort study
Yasar BLSA et al. [38]
Design
Cohort study
Study name
Khactaturian Cache et al. [37] County study
Author
TABLE 1. Study populations
Placebo 767 (65%), active 822 (66.4%)
Placebo SBP 173.4 (SD 10.1)/DBP 86.0 (SD 5.7) Active SBP 173.5 (SD 10.1) /DBP 86.1 (SD 5.6)
Not reported
139 (SD 21.6) No diastolic
60%
Not reported
152.9 (SD 23.1)/ 81.2 (SD 11.7 )mmHg
70%
Fall in BP placebo 13.4 (SD 16.2)/2.6 (7.8), active 21.7 (SD 1 6.2)/6.4 (SD 8.3)
Not reported
Not reported
Not reported
Not reported
Not reported
27.30%
BP follow-up Not reported
SBP/DBP baseline
62.6% treated Not reported 54.5% untreated
% female baseline
Peters et al.
Volume 32 Number 10 October 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Journal of Hypertension
Cohort study
Gelber Honolulu et al. [42] Asia Aging Study
AD, Alzheimer’s disease.
Four United States communities across three States
Double-blind, randomized, placebocontrolled trial of ginkgo biloba supplementation.
Yasar GEM et al. [41]
Japanese American men residing in Oahu in 1965–1968 and participating in the Honolulu Heart Program and subsequently in the Honolulu Asia Aging Study
Uninstitutionalised elderly living in Israel
Open label extension Primary and secondary of SYST-EUR care centres in 19 European countries
Cohort study Paran A 6-year et al. [21] follow-up study
Forette SYST-EUR et al. [17]
n ¼ 3734, n ¼ 2197 available for analysis
n ¼ 318, n ¼ 6249, analyses includes those with baseline and follow-up n ¼ 2248 (1928 normal cognition and 320 with MCI)
77–92, mean 83.0 (þ/-6.41)
Not reported
71–93, mean 77
Not reported
75–96, mean Not reported 78.7
70-85
Median 68 n ¼ 2908 analysed. Number at (60–92) final visit 1417 originally not reported randomised to placebo
Mean 5.8 (SD 5.1)
Median 6.1, mean 5.6
N/A
47%
Not reported Median at start of (original open label trial and extension open label extension reported together) 3.9 years (interquartile range 2.8–5.6) 6 years Not reported
26.7% Not reported, normal or 45.1% normalised normal or BP normalised BP Treated: (SBP) 1 Not reported 30.9 (SD 17.6)/ (DBP) 69.6 (SD 9.8) Untreated: (SBP) 126.1 (SD 15.5)/ (DBP) 67.9 (SD 8.7) No hantihyper- Not reported tensive drug use SBP 159 (SD 16)/DBP 83 [9] CCB use alone 156 [22]/82 [12]
Former placebo Not reported group 156.1 (SD 12)/82.5 (SD 6) Former active group 149.1 (SD 9.7) /79.4 (SD 6.1) from final trial visit before extension
Calcium channel blockers and cognition
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1949
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Peters et al. TABLE 2. Assessment of cognitive function/dementia Author
Assessment of cognitive function at baseline
Khactaturian et al. [37] 3MS or IQCODE (Informant Questionnaire for Cognitive Disorders in the Elderly). If 3MS
A systematic review of calcium channel blocker use and cognitive decline/dementia in the elderly Ruth Peters a, Andrew Booth b, and Jean Peters b
Objective: Treating hypertension in those aged at least 80 years is now recommended; however, the best antihypertensive to choose remains unexplored. Calcium channel blocker (CCB) use has been associated with a decreased risk of incident dementia in a younger hypertensive group but with an increased risk of cognitive decline in the very elderly. Either result could have a large impact on a vulnerable population. The aim of this review was to assess the evidence relating CCB use to later cognitive decline or dementia in the very elderly. Methods: A systematic review of the literature was carried out. The databases Medline, PubMed, Embase and Psychinfo were searched from 1980 to 22 August 2013. Abstracts were reviewed by two independent reviewers and papers meeting the inclusion criteria were extracted. Results: One thousand, nine hundred and sixty-eight records were reviewed and 10 articles reporting on nine studies retained and extracted. Data were primarily from cohort studies. Only one reported a randomized controlled trial comparing CCBs with placebo. Populations, comparator groups, follow-up times, outcomes and exposure varied and overall results were mixed. It was not possible to combine all studies, but those reporting Alzheimer’s disease outcomes were combined to produce an overall risk ratio of 0.79 (95% confidence interval 0.53–1.17). Conclusion: At present, there is no clear evidence to suggest that CCB use increases or decreases risk of cognitive decline or dementia in the very elderly. A robust clinical trial is now required to resolve this. Keywords: aged, Alzheimer’s disease, calcium channel blockers, cognitive disorders, dementia Abbreviations: ACE-I, angiotensin-converting enzyme Inhibitor; BP, blood pressure; CASI, cognitive abilities screening instrument; CASP, critical appraisal skills program; CCB, calcium channel blocker; CI, confidence interval; MMSE, Mini Mental State Exam; OR, odds ratio; SD, standard deviation
veys/health-survey-for-england/health-survey-for-england– 2009-trend-tables.). Despite epidemiology suggesting that higher blood pressure (BP) may be better at an extreme age [2,3], a placebo-controlled trial in hypertensive participants aged at least 80 years found benefit associated with antihypertensive treatment. The Hypertension in the Very Elderly Trial (HYVET) found 21% reduction in total mortality and 37% reduction in stroke with active treatment [thiazide-like diuretic with or without an angiotensin-converting enzyme inhibitor (ACE-I)], over a mean follow-up of 2.1 years [4,5]. Several other classes of antihypertensive drug available to those with hypertension have similarly been shown to lower BP and reduce risk of cardiovascular events in predominantly younger adults. The very elderly are also at a higher risk of dementia. There is growing awareness of vascular risk factors increasing the risk of dementia, with plentiful evidence linking hypertension to later risk of cognitive decline/dementia [6–10]. Placebo-controlled clinical trials of antihypertensives have, however, found little evidence to suggest that lowering BP reduces risk of cognitive decline/dementia [11–15]. The one exception, the Systolic hypertension in Europe trial (SYST-EUR) found a 50% reduction in incident dementia, both vascular and Alzheimer’s, over a median 2-year follow-up in participants aged at least 60 years [16,17]. To date, SYST-EUR is the only such trial to use a calcium channel blocker (CCB)-based regimen. It has been suggested that this class of antihypertensive may have neuroprotective effects in addition to BP lowering, for example protecting against calcium dysregulation, reducing neuronal calcium influx and consequent neuronal damage [16–19]. Epidemiological studies give conflicting results, some suggesting that CCBs are associated with lesser decline in cognitive function [20,21], some the opposite [22]. For example, the Canadian Study of Health and Aging (CSHA) found that those taking CCBs were more likely to decline cognitively over 10 years than those taking other antihypertensives [22]. At present, it is unclear Journal of Hypertension 2014, 32:1945–1958 a Imperial Clinical Trials Unit (ICTU), Imperial College London, London and bSchool of Health and Related Research (ScHARR), University of Sheffield, Sheffield, UK
INTRODUCTION
I
n general, SBP rises with age. The very elderly are a fastgrowing group and are at the highest risk of hypertension and vascular events [1] (http://www,ic,nhs,uk/statis tics-and-data-collections/health-and-lifestyles-related-sur Journal of Hypertension
Correspondence to Ruth Peters, Imperial Clinical Trials Unit, School of Public Health, Faculty of Medicine, St Mary’s Campus, Praed Street, Imperial College London W2 1PG, UK. Tel: +20 75948974; fax: +20 75940768; e-mail: [email protected] Received 3 January 2014 Revised 14 May 2014 Accepted 15 May 2014 J Hypertens 32:1945–1958 ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins. DOI:10.1097/HJH.0000000000000273
www.jhypertension.com
1945
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Peters et al.
whether CCB use in the very elderly is beneficial with respect to cognitive decline and/or incident dementia. To date, HYVET is the only trial to focus on those aged at least 80 years, finding no effect of active treatment on incident cognitive decline/dementia. Because active treatment in HYVET reduced cardiovascular events, guidelines now routinely recommend treatment in this age group [23–30]. It is therefore key to find out whether different classes of antihypertensives have differing impacts on cognitive function. This is particularly the case for CCBs given the conflicting evidence so far and recommendations that treatment is initiated with CCBs [31,32]. The aim of this systematic review is to assess the extant evidence relating to CCB use and later cognitive decline/ dementia in the very elderly.
MATERIALS AND METHODS Search strategy The search strategy was derived from search strategies used in two Cochrane reviews [33,34] adapted as necessary. Additional names of CCBs were collected from the British National Formulary and following discussion with international experts in hypertension. The databases Medline, Embase, PsychInfo and Pubmed were searched from 1980 (when CCBs became widely available) to 22 August 2013. Appendix A shows the full search strategy. Reference lists of all articles identified were screened to identify additional published studies. Lead authors who have previously published related to CCBs and cognitive function were also contacted. The following sources were also searched for any ongoing trials. 1. Cochrane Library (1980–22 August 2013). 2. International Standard Randomised Controlled Trial Number (ISRCTN) Register 3. ClinicalTrials.gov (http://www.ClinicalTrials.gov) All identified abstracts, or titles, where abstracts were unavailable, were independently read by two reviewers and a list of potentially relevant evidence compiled independently by each. These lists were then compared and any differences resolved by discussion. Full text copies of publications selected from abstract review were read by both reviewers and assessed for relevance independently by both. Any discrepancy was resolved by discussion. Articles were included if they reported longitudinal studies or trials of antihypertensives that included analysis of a CCB group, a comparator group and with at least 1 year of follow-up, presented some evidence, or clear implication, that participants were free of cognitive decline or dementia at baseline assessment (authors were contacted for clarification where this was unclear). Studies were also required to include evidence that at least some participants were aged at least 80 years at follow-up, reported use of formal assessment of cognitive function and reported on cognitive decline or dementia outcomes. Non-English publications were not included owing to constraints on translation costs. Each included article was assessed for validity. Formal scoring was not used, as existing instruments have poor 1946
www.jhypertension.com
discriminative ability when assessing quality. Instead, each article was assessed against key criteria given in Critical Appraisal Skills Programme (CASP) checklists [35] and, for those articles reporting trials, using the Cochrane Risk of Bias tool [36]. A summary table (Appendix B) was produced indicating the extent to which each article met key validity criteria. A review-specific data extraction form was designed and included details of the patients, interventions and outcomes [35,36]. Data extraction for each study was carried out independently by each reviewer and any discrepancies resolved by discussion. In order to be as conservative as possible, results following adjustment for confounding were preferred, for inclusion in the table. The principle summary measures were anticipated to include risk ratios and mean differences. Where possible, data reporting number of incident events were combined using meta-analysis. Summary statistics and heterogeneity were reported and assessment made as to potential publication bias using a funnel plot. The protocol for this review is registered with the International prospective register of systematic reviews CRD42013003580.
RESULTS From 1968 records reviewed, 14 articles were identified in the initial search. A further three were located from examination of references and correspondence with key authors. See Fig. 1. After assessment against the inclusion criteria, 10 articles remained for data extraction (Table 1), representing nine studies [16,17,21,22,37–42]. However, SYST-EUR reported results of a double-blind placebo-controlled trial ([17] SYST-EUR-trial) and, extending this, an open-label follow-up cohort study ([17] SYST-EUR-extension). Given differences in study design and for ease of understanding, these two have been treated as separate studies. Seven studies were rejected, one did not use a formal assessment of cognitive function [43], four because prevalent cases were not excluded, or it was unclear whether this was the case [20,44–46], one because the analyses were crosssectional [47] and one where it was not clear whether the population in the longitudinal analyses met the age criteria [48]. Of the 10 studies meeting the inclusion criteria, seven reported data from longitudinal population-based observational studies. These were carried out in the United States (Cache County study [37], Baltimore Longitudinal Study of Aging [39], Indianapolis community study [40] and Honolulu Asia Aging Study, (HAAS) [42]), Canada (CSHA) [22], Israel [21] and Europe (Rotterdam study) [37]. Of the remaining three, one reported results from a double-blind placebocontrolled trial of antihypertensives (CCB-based regimen), which recruited from 19 European countries (SYST-EURtrial) [16]. Another reported results from the open-label extension of the same trial (SYST-EUR-extension) [17]. The third was a secondary analysis from the Ginkgo Evaluation of Memory (GEM) study, a randomized placebo-controlled trial of ginkgo biloba [41]. Only one study focused on a particular ethnic group, specifically recruiting residents with an African-American family member [40]. Volume 32 Number 10 October 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Calcium channel blockers and cognition
Number of records identified from searches:
Number of records identified from other sources:
Embase: 1748 Psychinfo: 131 Medline: 562 Pubmed 684 Cochrane: 2
From searching reference lists: 46 From contacting key authors: 2
Number of records after duplicates removed: 1968
Number of records screened (before duplicates removed): 3127
Number of records excluded including duplicates: 3110
Number of full text articles assessed: 17
Number of full text articles excluded: 7 Not clear whether prevalent cases excluded: 4 Cross sectional analyses only: 1 No clear assessment of cognitive function 1 Not clear whether age criteria met 1
Number of studies used in qualitative analyses: 10 papers reporting on 9 studies
Number of studies used in quantitative analyses: 10 papers reporting on 9 studies FIGURE 1 Flow chart.
Study and population characteristics Table 1 contains details of the study populations. Studies reported age and follow-up information differently. None of the studies were carried out solely in the very elderly nor were any entire study populations aged at least 80 years at the time of follow-up visits, although the GEM participants came close [41]. Although age at follow-up was not routinely reported, it was estimated using age at baseline and study duration. This estimated results in a range of approximately 72–101 years after a follow-up of approximately 2–11 years duration. Three studies did not report the percentage of men/women at baseline [17,21,40]. The SYSTEUR-extension [17] did not report participant characteristics upon initiation, although these were reported upon entry to the SYST-EUR-trial [16]. However, it was unclear whether differences existed between the two study populations. Paran et al. [21] reported 70.6% of the population as female at follow-up. Murray et al. [40] reported the percentage female at follow-up as 66% for those deemed cognitively intact and 63% for those with cognitive impairment; the Journal of Hypertension
overall percentage was not given. Of the remaining studies, one reported just 27.3% female at baseline [38], one 47% [41], HAAS included only men [42], whilst the remaining studies all report women as a majority [16,22,35,39].
Assessment of cognitive function Table 2 contains details of the assessments of cognitive function. Assessment of cognitive function and/or incident dementia was fairly robust with all studies using standard screening and diagnostic tools. Two studies added additional assessments, one resampled those in the full study population who had scored in medium or high cognitive function categories and carried out more detailed investigations [40]. The second applied additional criteria for those aged at least 80 years at follow-up [37]. All other studies essentially used the same testing procedures at baseline and follow-up. Five studies specified that they excluded prevalent dementia [16,17,22,41,42], although for the CSHA [22] it was not clear whether participants classed as ‘Cognitively-Impaired-No-Dementia’ at baseline www.jhypertension.com
1947
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
1948
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Cohort study
Cohort study
Maxwell CSHA et al. [22]
Haag Rotterdam et al. [39] study
Forette SYST-EUR et al. [16]
Population
n ¼ 2418
Age follow-up
Not reported
68.2 (SD 8.3)
Age at end, for cognitively intact 77 (SD 6.2) for those with incident cognitive impairment 80.7 (SD 7.3) Not reported
Not reported
Not reported
3 years
Length of follow-up
Median 2.0 years
5 years
Average 8 years, maximum 13 years
5 years
Without incident Mean 11 years AD mean 78.1 (0.3–19.6) (range 61.1–104.2)
77.8 (SD5.7)
Not reported
74.9 (SD 6.5) Not reported treated 73.4 (SD 6.3) untreated
Age baseline
Placebo 69.9 n ¼ 1861 in (SD 6.2), double-blind active 69.9 at final visit (SD 6.5) and 303 in open follow-up
This study reports on AD alone and excludes others from analysis 3227 (104 with AD) analyses includes those with baseline and follow-up n ¼ 1092, analyses Volunteers from the include those with Baltimore Washington baseline and area, >60 years, follow-up predominantly white and of mid to high socioeconomic status, in this analysis >70% have a College degree or higher Population-based cohort of n ¼ 205 in these community and institution analyses (509 met dwelling participants inclusion criteria >65 years across 5 for analysis but regions of Canada not all were able to be included) n ¼ 6249, analyses Population-based cohort include those with recruited from all those baseline and aged 55 years living in follow-up a district of Rotterdam, 78% consented. n ¼ 1557 at Random sample of 60% of n ¼ 1617 with baseline 2 years the residents from 29 information, drug and n ¼ census tracts in use details 1151 at Indianapolis >65 at 5 years baseline with an African-American family member All elderly aged 65 years permanent residents of Cache County USA
Source of individuals
60 years primary and Randomized, secondary care centres double-blind in 19 European countries placebo-controlled trial (nitrendipine 10–40 mg/day combined with or replaced by enalapril 5–20 mg/day or hydrochlorothiazide 12.5–25 mg/day or both versus matching placebos)
Murray Community- Cohort study et al. [40] based sample of AfricanAmericans
Cohort study
Yasar BLSA et al. [38]
Design
Cohort study
Study name
Khactaturian Cache et al. [37] County study
Author
TABLE 1. Study populations
Placebo 767 (65%), active 822 (66.4%)
Placebo SBP 173.4 (SD 10.1)/DBP 86.0 (SD 5.7) Active SBP 173.5 (SD 10.1) /DBP 86.1 (SD 5.6)
Not reported
139 (SD 21.6) No diastolic
60%
Not reported
152.9 (SD 23.1)/ 81.2 (SD 11.7 )mmHg
70%
Fall in BP placebo 13.4 (SD 16.2)/2.6 (7.8), active 21.7 (SD 1 6.2)/6.4 (SD 8.3)
Not reported
Not reported
Not reported
Not reported
Not reported
27.30%
BP follow-up Not reported
SBP/DBP baseline
62.6% treated Not reported 54.5% untreated
% female baseline
Peters et al.
Volume 32 Number 10 October 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Journal of Hypertension
Cohort study
Gelber Honolulu et al. [42] Asia Aging Study
AD, Alzheimer’s disease.
Four United States communities across three States
Double-blind, randomized, placebocontrolled trial of ginkgo biloba supplementation.
Yasar GEM et al. [41]
Japanese American men residing in Oahu in 1965–1968 and participating in the Honolulu Heart Program and subsequently in the Honolulu Asia Aging Study
Uninstitutionalised elderly living in Israel
Open label extension Primary and secondary of SYST-EUR care centres in 19 European countries
Cohort study Paran A 6-year et al. [21] follow-up study
Forette SYST-EUR et al. [17]
n ¼ 3734, n ¼ 2197 available for analysis
n ¼ 318, n ¼ 6249, analyses includes those with baseline and follow-up n ¼ 2248 (1928 normal cognition and 320 with MCI)
77–92, mean 83.0 (þ/-6.41)
Not reported
71–93, mean 77
Not reported
75–96, mean Not reported 78.7
70-85
Median 68 n ¼ 2908 analysed. Number at (60–92) final visit 1417 originally not reported randomised to placebo
Mean 5.8 (SD 5.1)
Median 6.1, mean 5.6
N/A
47%
Not reported Median at start of (original open label trial and extension open label extension reported together) 3.9 years (interquartile range 2.8–5.6) 6 years Not reported
26.7% Not reported, normal or 45.1% normalised normal or BP normalised BP Treated: (SBP) 1 Not reported 30.9 (SD 17.6)/ (DBP) 69.6 (SD 9.8) Untreated: (SBP) 126.1 (SD 15.5)/ (DBP) 67.9 (SD 8.7) No hantihyper- Not reported tensive drug use SBP 159 (SD 16)/DBP 83 [9] CCB use alone 156 [22]/82 [12]
Former placebo Not reported group 156.1 (SD 12)/82.5 (SD 6) Former active group 149.1 (SD 9.7) /79.4 (SD 6.1) from final trial visit before extension
Calcium channel blockers and cognition
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Peters et al. TABLE 2. Assessment of cognitive function/dementia Author
Assessment of cognitive function at baseline
Khactaturian et al. [37] 3MS or IQCODE (Informant Questionnaire for Cognitive Disorders in the Elderly). If 3MS
