Diuretics, Potassium Sparing explode all trees Or #3 MeSH descriptor. Sodium Chloride Symporter Inhibitors explode all trees Or #4 MeSH descriptor Carbonic ...
Supplementary File 1. Electronic search strategy and protocol website MEDLINE
EMBASE
PsycINFO
SCOPUS
Cochrane
(Diuretics [MeSH] OR Diuretics, Potassium Sparing [MeSH] OR Sodium Chloride Symporter Inhibitors [MeSH] OR Carbonic Anhydrase Inhibitors [MeSH] OR potassium sparing diuretic* [tiab] OR thiazide diuretic* [tiab] OR loop diuretic* [tiab] OR high ceiling diuretic* [tiab] OR Carbonic anhydrase inhibitor* [tiab] OR calcium sparing diuretic* [tiab] OR osmotic diuretic* [tiab] OR diuretic* [tiab]) AND (Dementia [MeSH] OR Alzheimer Disease [MeSH] OR Dementia, Vascular [MeSH] OR Alzheimer’s disease [tiab] OR dementia [tiab] OR vascular dementia [tiab] OR severity of dementia [tiab])
'diuretics'/exp/mj OR 'diuretics'/mj OR 'potassium sparing diuretics'/exp/mj OR 'potassium sparing diuretics'/mj OR 'sodium chloride symporter inhibitors'/exp/mj OR 'sodium chloride symporter inhibitors'/mj OR 'carbonic anhydrase inhibitors'/exp/mj OR 'carbonic anhydrase inhibitors'/mj OR 'diuretic'/exp/mj OR 'diuretic'/mj OR 'potassium sparing diuretic'/exp/mj OR 'potassium sparing diuretic'/mj OR 'thiazide diuretic'/exp/mj OR 'thiazide diuretic'/mj OR 'loop diuretic'/exp/mj OR 'loop diuretic'/mj OR 'high ceiling diuretic'/exp/mj OR 'high ceiling diuretic'/mj OR 'carbonic anhydrase inhibitor'/exp/mj OR 'carbonic anhydrase inhibitor'/mj OR 'calcium sparing diuretic' OR 'osmotic diuretic'/exp/mj OR 'osmotic diuretic'/mj AND ‘Alzheimer’s disease’ OR Alzheimer’s dementia’ OR ‘dementia’ OR 'vascular dementia' or 'severity of dementia'
Diuretic$ or 'potassium sparing diuretic$' or 'Sodium Chloride Symporter Inhibitor$' or 'Carbonic Anhydrase Inhibitor$' or 'thiazide diuretic$' or 'loop diuretic$' or 'high ceiling diuretic$' or 'calcium sparing diuretic$' or 'osmotic diuretic$' [mp=title, abstract, heading word, table of contents, key concepts, original title, tests & measures] AND dementia$ or 'Alzheimer$ disease' or 'vascular dementia$' or 'severity of dementia$' [mp=title, abstract, heading word, table of contents, key concepts, original title, tests & measures]
TITLE-ABS-KEY "Diuretics” OR "Potassium Sparing Diuretics” OR “Sodium Chloride Symporter Inhibitors” OR “Carbonic Anhydrase Inhibitors” OR “diuretic” OR “potassium sparing diuretic” OR “thiazide diuretic” OR “loop diuretic” OR “high ceiling diuretic” OR “Carbonic anhydrase inhibitor” OR “calcium sparing diuretic” OR “osmotic diuretic” AND TITLE-ABS-KEY dementia OR “Alzheimer disease” OR “Alzheimer’s disease” OR “Vascular Dementia” OR “severity of dementia”
#1 MeSH descriptor Diuretics explode all trees Or #2 MeSH descriptor Diuretics, Potassium Sparing explode all trees Or #3 MeSH descriptor Sodium Chloride Symporter Inhibitors explode all trees Or #4 MeSH descriptor Carbonic Anhydrase Inhibitors explode all trees Or #5 potassium sparing diuretics in key words Or #6 thiazide diuretics in key words Or #7 loop diuretics in key words Or #8 high ceiling diuretics in key words Or #9 Carbonic anhydrase inhibitors in key words Or #10 calcium sparing diuretics in key words Or #11 osmotic diuretics in key words Or #12 diuretics in key words AND #13 MeSH descriptor Dementia explode all trees Or #14 MeSH descriptor Alzheimer’s Disease explode all trees Or #15 MeSH descriptor Dementia, Vascular explode all trees Or #16 Alzheimer disease in key words Or #17 dementia in key words Or #18 vascular dementia in key words Or #19 severity of dementia in key words
Protocol registration: PROSPERO [CRD42015023428] http://www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42015023428
1
Identification
Supplementary File 2. PRISMA flow chart of article selection
Records identified through database searching (n = 2,528)
Additional records identified through other sources (n = 0)
Screening
Records after duplicates removed (n = 2,490)
Included
Eligibility
Records screened (n = 79)
Additional studies included from full-text review (n = 2)
Full-text articles assessed for eligibility (n = 79)
Articles included in qualitative synthesis (n = 15)
Records excluded by title/abstract (n = 2,411) Not dementia (1152) Case report/letter/review (633) Cross-sectional (262) Not BP/medication (240) Animal (43) Language (2)
Full-text articles excluded (n = 66) Not dementia (21) Duplicate (12) Case report/letter/review (9) Retrospective (8) Cross-sectional (6) Not diuretic (5) Language (1) Data not available (4)
Articles included in quantitative synthesis (meta-analysis) (n = 15)
2
Supplementary File 3. Table showing the characteristics of the included studies Study
Recruitment setting
Sampling and Design
Age cut off, yrs M (SD)
Male N (%)
Anti-HTN diuretic medications (% of HTN user)
Anti-HTN method
2001-2008, Western and Eastern Europe incl. UK and RUS, CHI, IND, MAL, PHI, AUS, NZ , CAN
Randomized placebo controlled trial (treatment = 1 687; placebo = 1 649) free from diagnosis of dementia at baseline
≥ 55 yrs, treatment = 58 (9); placebo = 58 (9)
6 405 (57)
By doubleblind randomizatio n (ITT)
treatment SBP = 145 (22); placebo SBP = 145 (21)
Local physician (local endpoint adjudication committee)
Any dementia = 79
4.3 (ITT)
Randomization arm ITT
Chronotherapy
2001 – 2007, Western and Eastern Europe, CHI, TUN, Asia, and AUS
Randomized placebo controlled trial (treatment = 1 687; placebo = 1 649)
≥ 80 yrs, treatment = 83.5 (3.1); placebo = 83.5 (3.1)
1 319 (39.5)
Perindopril and indapamide (ThiazDiur) combination, perindopril 4mg/d and indapamide 1.25 mg/d versus matching placebo Initial 1.5mg/d slow release indapamide (ThiazDiur) with the option of perindopril versus matching placebo
HYVET-Cog: Peters 2008 [2]
By doubleblind randomizatio n (ITT)
treatment SBP = 173.1 (8.5); placebo SBP = 172.9 (8.5)
MMSE, CT scan of the brain, full or modified HIS (DSM-IV, consensus of three panel experts either geriatric psychiatrist, gerontologist, neuroradiologist, clinical trial researcher and epidemiologist blinded to treatment arm)
Any dementia = 263; AD = 164, VaD = 84
2.2 (ITT)
Randomization arm ITT; age, education, region
Dementia subtype; chronotherapy
PROGRESS: Tzourio 2003 [3]
1995-1995, AUS, NZ, CHI, BEL, FRA, ITA, JAP, SWE, UK, IRE,
Randomized placebo controlled trial (treatment = 3 051; placebo = 3 054) with stroke < 5 years at baseline
Treatment = 64 (10); placebo = 64 (10)
4 274 (70)
Perindopril 4mg/d with option of indapamide (ThiazDiur) 2.5 mg/d unless contraindicated versus matching placebo
By doubleblind randomizatio n (ITT)
SBP 147 (19) DBP 86 (11)
Dementia = 410
3.9 (ITT)
Randomization arm ITT
Chronotherapy
SHEP [4]
1985-1988, USA
Randomized placebo controlled
71.6 (6.7)
2 046 (43.2)
Initial 12.5mg/d chlortalidone
By doubleblind
SBP 170.3 (9.4)
MMSE, positive screen underwent formal diagnostic clinical assessment with local specialist experienced in the diagnosis of dementia (DSM-IV, Dementia Adjudication Committee) SHEP dementia
Any dementia = 81
4.5 (ITT)
Randomization arm ITT
Polytherapy,
RCT ADVANCE [1]
Baseline mean BP mm Hg (SD)
Dementia Assessment
Incident Dementia Endpoint
Length of F/U yrs (% complete d F/U)
Covariate Adjustment
Data Used In Stratified Analyses
3
trial (treatment = 2 365); placebo = 2 371)
Observational 90+ Study (unpublished results; Corrada 2010) [5]
2003-2007, USA
(ThiazDiur) with a stepped approach adding atenolol (or reserpine) versus matching placebo
randomizatio n (ITT)
DBP 76.6 (9.7)
screening scale, neuropsychological testing (DSM-IIIR, panel of physicians and neurologists)
Prospective longitudinal study of 549 community dwelling and institutionalized persons Prospective longitudinal study of 3 297 community dwelling and institutionalized persons
≥ 90 yrs, 94.2
166 (30.3)
Diur (41.7)
Self-report at baseline interview
NR
MMSE, DQ, CASIShort, neurological exam (DSM-IV)
Any dementia = 219
CD
Unadjusted
-
≥ 65 yrs, anti-HTN med users 74.9 (6.5); nonusers 73.4 (6.3)
1 378 (41.8)
Diur (26.5), LDiur (26.8) ThiazDiur (37.8) K+Diur (35.4)
Medication container inspection, institution medication records
NR
MMSE, IQCDE, DQ, clinical assessment, neurological assessment, neuropsychological testing, neuroimaging, (DSM-III-R and NINCDS-ADRDA, NINDS-AIREN neurologists, geriatric psychiatrist, neuropsychologist, cognitive neuroscience)
AD = 104
3 (72)
Age, sex, education, APOE4 alleles, DM, cholesterol, MI, stroke, myocardial infarction
Short-term f/u only
Cache Country Study on Memory Health and Aging: Khatchaturian 2006 (short term f/u) [6]
1995 -1998, USA
Cache Country Study on Memory Health and Aging: Chuang 2014 (long term f/u) [7]
1995 -1997, USA
Prospective longitudinal study of 3 424 community dwelling and institutionalized persons
≥ 65 yrs, anti-HTN med users 74.9 (6.4); nonusers 74.2 (6.5)
Anti-HTN med users 768 (38.6) nonusers 662 (46.5)
Diur (62.9), LDiur (30.8) ThiazDiur (75) K+Diur (38)
Medication container inspection, institution medication records
NR
MMSE, IQCDE, DQ, clinical assessment, neurological assessment, neuropsychological testing (DSM-III-R and NINCDSADRDA, psychiatrist, neuropsychologists )
AD = 327
7.1 (63.7)
Age, sex, education, APOE4 alleles, smoking and drinking habits at baseline, cholesterol, DM, stroke, CABG, and MI
Monotherapy, chronotherapy, dementia subtype,
EPESE; Morris 2001 [8]
1982 – 1988, USA
Prospective longitudinal study of 642 community dwelling persons
≥ 65 and ≤ 80 yrs, NR
173 (27.3)
ThiazDiur (26.1), K+ Diur (8.3), LDiur (4.5)
Medication container and prescription
SBP 142 DBP 76
neurological and neuropsychological assessment, neuropsychological
AD = 99 (5 with comorbid dementia)
6 (67)
Age, sex, education, interval to disease and stratified sampling
Monotherapy, dementia subtype,
4
inspection (NR) GEMS: Yasar 2013 [9]
2000 – 2002, USA
Doublie blind RCT ginko biloba 240 mg/d vs placebo in 2 248 persons
≥ 75 and ≤ 95 yrs, 78.7
1189 (53)
Diur (15.6)
Medication container and prescription inspection
SBP 133.0 (18.3) ; DBP 68.9 (9.8)
Kungsholmen Project: Guo 1999 [10]
1987-1989, SWE
Prospective longitudinal study of 1 301 community dwelling persons
≥ 75 yrs, 82.5 (IQR 75 - 101)
433 (23.9)
Diuret (56.1)
Medication container and prescription inspection (ATC CO2, CO3, CO7)
SBP 154(22) DBP 81 (11)
Ohrui 2004 [11]
1993-2003, JAP
Prospective database study of 4 124 persons
≥ 65 yrs, 69 (NR)
2227 (54)
Diuret (9.3)
Diuret users SBP 138 (3)
The Rotterdam Study: in’t Veld 2001 (short term f/u) [12]
1990 – 1993, NL
Prospective longitudinal study of 6 416 community dwelling persons
≥ 55 yrs, HTN med users 71.4 (NR) Non-users 67.4 (NR)
2648 (41.3)
Diur (48.9)
Continuous use based upon electronic hospital records Medication container and prescription inspection (ATC)
HTN med users SBP 142.5 (NR) DSP 75.1 (NR) Non-users SBP 137.7 (NR) DSP 73.1 (NR)
The Rotterdam Study: Haag 2009 (long term f/u) [13]
1990 – 1993, NL
Prospective longitudinal study of 6 249 community dwelling persons
≥ 55 yrs, 68.2 (8.3)
2 500 (40.0)
ThiazDiur (NR), LDiur (NR)
Automated pharmacy records of filled prescriptions (ATC)
SBP 139.0 (21.6)
testing (NINCDSADRDA including probable AD) MMSE, CDR, ADAS-Cog, neuropsychological battery, MRI (DSM-IV and NINCDS-ADRDA, panel of neurologists, neuropsychologists , psychometrician blinded to treatment arm) MMSE, episodic and primary memory incl. free recall and recognition, digitspan, CDRS, (DSM-IIIR consensus by 3 physicians) NINCDS-ADRDA
AD = 290
6.1 (73.2)
age, sex, education, income, smoking, BMI, SBP, DBP, MCI, number of vascular diseases
Monotherapy, dementia subtype,
Any dementia = 224
3.1 (75.9)
Age, sex, education, SBP, HD, stroke
Monotherapy, chronotherapy,
AD = 90
8.1 (NR)
Unadjusted
Dementia subtype,
MMSE, GMS, Cambridge examination, neuropsychological testing, imaging (DSM-III-R and NINCDS-ADRDA, NINDS-AIREN, panel of experts)
Any dementia = 118 (AD = 82, VaD = 18)
2.2 (85)
Age, gender, DBP, SBP, stroke, DM
Short-term f/u only
MMSE, GMS, Cambridge examination, neuropsychological testing, imaging (DSM-III-R and NINCDSADRDA,
Any dement = 527 (AD = 432, VaD = 50, other = 45)
8.0 (88.7)
Age, sex, SBP, DBP, smoking, total serum cholesterol, education, BMI, DM, HD, CVD,
Dementia subtype
5
Three-Cities (unpublished) [14]
1999-2012, FRA
Prospective longitudinalpopulation study of 8239 community dwelling persons aged ≥ 65 yrs (Bordeaux, Dijon, Montpellier)
≥ 65 yrs, 71.6 (5.4)
3180 (38.6)
ThiazDiur (2.3), K+ Diur (9.3), LDiur (4.8)
Medication container and prescription inspection, pharmacy records (ATC)
SBP 146.4 (21.7) DBP 82.3 (11.3)
Vantaa 85+ Study 2010 [15]
1991-2000, FIN
Prospective longitudinalpopulation study of 339 persons aged ≥ 85 yrs in Vantaa (community dwelling and institutionalized)
≥ 85 yrs, dementia 87.9 (2.7); no dementia 88.0 (2.6)
73 (21.5)
Diuretic (42.8)
Self-report, relative, institution records or electronic primary care database
SBP 149 (27.7); DBP 82 (12.7)
1. 2. 3. 4.
5. 6.
7. 8.
NINDS-AIREN, neurologist, neurophysiologist, and physician) MMSE, Isaac’s set test, neurologist examination with neuropsychological testing, imaging (DSM-IV and NINCDSADRDA, NINDS-AIREN, blinded panel of neurologists)
MMSE and neurologist assessment, relative, nurse and carer reports, (DSM-III-R, consensus by two neurologists)
Any dement = 830 (AD = 569, VaD/mixed = 159)
8.1 (NR)
Dementia = 100
9.0 (92)
Centre, sex, education, BMI, cardiovascular disease incl. stroke, hypercholesterole mia, DM, alcohol, smoking, depression, disability, concomitant use of other HTN medication classes Unadjusted
Dementia subtype, monoand chronotherapy
-
In ADVANCE we calculated the HR from the corresponding relative risk reduction and CI (-4%; -64 to 33) as ([1-hazard ratio]X100) reported pg 835. with Cochrane Review Manager. The calculated dementia event rates were 40/5569 in the active treatment and 39/5532 in the control group. In HYVET sitting SBP values are reported in the Table. The add-on therapy included the option of 2-4 mg/d perindopril (versus placebo). The authors performed analyses adjusted for age, education and location of recruitment with similar results to the unadjusted ITT model. In PROGRESS we calculated the diuretic/perindopril chronotherapy exposure (106/1770) versus combination-placebo (1774), perindopril (1281) or single-placebo (1280; 304/4355) with Cochrane Review Manager. In SHEP a stepped approach was applied to achieve SBP target 160 mm Hg or DBP > 95 mm Hg) was 0.7 (95% CI 0.4-1.2) in Cochrane Review Manager. 11. In Ohrui eligibility criteria were users of anti-hypertensive medication and stable SBP < 150 mmHg. 12. The findings of in’t Veld (2001) Rotterdam Study were only used in sub-group analyses for short term dementia. 13. In The Rotterdam Study (Haag et al. 2009) percent f/up NR but calculated as proportion of participants analyzed (6 249) from those free from dementia at baseline (7 046). HRs for incident AD are the same as that reported for total dementia by the authors. The authors excluded the first 4 years of f/u from analyses. 14. In Three-Cities study we used the method report (Neuroepidemiology, 2003; 22:316-325) to extract missing information. Diuretic use is reported as a percentage of the total sample. Calculation of HRs was performed with SPSS® Version 23. Other classes of medication included in analyses were adrenergic, beta-blockers, calcium channel blockers, angiotensin converting enzyme inhibitor, angiotensin receptor blockers 15. In the Vantaa 85+ study (Rastas et al.) diuretic use is reported as % of total sample. The sample N was reported as 239 in Table 1 and 229 in Table 2, we used 239 in the calculation of dementia risk (diuretic exposure 38/145 versus no exposure 62/184) with Cochrane Review Manager. List of acronyms: AD, Alzheimer’s disease; ADAS-Cog, Alzheimer Disease Assessment Scale; ATC, Anatomical Therapeutic Chemical classification system; AUS, Australia; BEL, Belgium; BP, blood pressure; BMI, body mass index; CASI-Short, Cognitive Abilities Screening Instrument-short form; CDR, Clinical Dementia Rating Scale; CHI, China; CRPD, Clinical Research Practice Datalink; DBP, diastolic blood pressure; Diur, diuretics; DM, diabetes mellitus; DPD, dementia in Parkinson’s disease; DQ Dementia Questionnaire; EPESE; East Boston Established Populations for Epidemiologic Studies of the Elderly; FI, Finland; FRA, France; GAT, Geriatric Assessment Tool ; GEMS, Ginkgo Evaluation of Memory Study; GPRD, General Practice Research Database; HF, heart failure; HIS, Hachinski ischaemic scores; HTN, hypertension; HYVET, Hypertension in the Very Elderly trial ; IQCDE, Informant Questionnaire for Cognitive Decline in the Elderly ; IQR, interquartile range; IRE, Ireland; ITA, Italy ; ITT, intention-to-treat; JAP, Japan; K+ Diur, potassium sparing diuretic; LDiur, loop diuretic; MMSE, Mini-Mental State Examination; NINCDSADRDA, National Institute of Neurological and Communicative Disorders and Stroke and Alzheimer’s Disease and Related Disorders Association; NINDS-AIREN, National Institute of Neurological Disorders and Stroke Association-Internationale pour la Recherche en l’Enseignement en Neurosciences; NZ, New Zealand; OXMIS, Oxford Medical Information System; PROGRESS, Perindopril Protection Against Recurrent Stroke Study; RCT, randomized control trial; SES, socio-economic status; SBP, systolic blood pressure; SWE, Sweden; ThiazDiur, thiazide and thiazide like diuretics; UK, United Kingdom; VaD, vascular dementia; VHA, Veterans Health Administration; WHO DDD, World Health Organization daily defined dose; Calculations for combining Hazard Ratios (Haag et al. 2009; Morris et al. 2001) vHR1 is the square of the SE. wHR1 = 1/vHR1 (and wHR2 = 1/vHR2) Combined HR (lHR) = (wHR1 * lnHR1 + wHR2 * lnHR2) / (wHR1 + wHR2) SE (vHR) = 1 / (wHR1 + wHR2). SE = √variance 95% CI = log (HR) +/- 1.96 SE
7
Supplementary File 4. Adjudication of risk of bias and precision at main dementia outcome level according to RTI item bank Risk of bias item
ADVANC E
HYVETCog
PROGRES S
SHEP
90+ Study
Cache County
ESPESE
GEMS
Kungsholm en
Ohrui
Rotterdam
Vantaa 85 +
1. Retrospective/ prospective
Prosp
Prosp
Prosp
Prosp
Prosp
Prosp
Prosp
Prosp
Prosp
Prosp
Prosp
Prosp
2. Inclusion/ exclusion criteria stated
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
Yes
3. Inclusion/ exclusion criteria reliable
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
CD
Yes
Yes
4. Inclusion/ exclusion criteria uniform
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
CD
Yes
Yes
5. Recruitment across groups
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
6. Statistical power
No
Yes
Yes
No
Yes
Yes
No
Yes
Yes
No
Yes
Yes
7. Detail of exposure
High
High
High
High
Low
High
Low
High
High
Low
High
Low
8. Specification of outcomes
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
9. Appropriate comparison group
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
10. Attempt to Balance
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
No
Yes
No
11. Adjustment for unintended exposure
ITT
ITT
ITT
ITT
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
12. Variation in execution of protocol
No
Yes (trial stopped early due to favorable
No
No
Yes (variation in dementia adjudication due to health)
No
No
No
No
CD
No
No
8
mortality and stroke results) 13. Blind outcomes assessment
Yes
Yes
Yes
Yes
CD
Yes
CD
Yes
Yes
CD
Yes
CD
14. Exposures assessed using valid and reliable measures
Yes
Yes
Yes
Yes
CD
Yes
No
Yes
Yes
Yes
Yes
Yes
15. Outcomes assessed using valid and reliable measures
CD
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
16. Equality of length of f/u
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
CD
Yes
Yes
17. Length of f/u adequate (> 5 years)
No
No
No
Yes
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
18. High attrition
No
No (trial stopped early due to favorable mortality and stroke results)
No
No
CD
No
No
No
No
CD
No
No
19. Attrition difference
No
No
No
No
CD
No
No
No
No
No
No
No
20. Baseline differences controlled
No (ITT)
No (ITT)
No (ITT)
No (ITT)
No
Yes
Yes
Yes
Yes
No
Yes
No
21. Measurement of confounding variables reliable
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
CD
Yes
Yes
22. Confounding variables in design/
ITT
ITT
ITT
ITT
No
Yes
Yes
Yes
Yes
No
Yes
No
9
analysis 23. ITT or sensitivity analysis for loss to f/u
Yes
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
24. Primary outcomes missing
CD
No
No
No
No
No
No
No
No
No
No
No
27. Appropriate statistics for outcome
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
28. Appropriate interpretation
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
29. Funding
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
No
Yes
Yes
CD, cannot determine; ITT, intention-to-treat
List of RTI item bank items (Viswanathan & Berkman 2012) 1. Is the study design prospective, retrospective, or mixed? 2. Are critical inclusion/exclusion criteria clearly stated (does not require the reader to infer)? 3. Are the inclusion/exclusion criteria measured using valid and reliable measures? 4. Did the study apply inclusion/exclusion criteria uniformly to all comparison groups/arms of the study? 5. Was the strategy for recruiting participants into the study the same across study groups/arms of the study? 6. Was the sample size sufficiently large to detect a clinically significant difference of 5% or more between groups in at least one primary outcome measure? 7. What is the level of detail in describing the intervention or exposure? 8. Are the important outcomes pre-specified by the researchers? Do not consider harms in answering this question unless they should have been prespecified. 9. Is the selection of the comparison group appropriate, after taking into account feasibility and ethical considerations 10
10. Any attempt to balance the allocation between the groups (e.g., through stratification, matching, propensity scores). 11. Did researchers isolate the impact from a concurrent intervention or an unintended exposure that might bias results, e.g., through multivariate analysis, stratification, or subgroup analysis? 12. Did execution of the study vary from the intervention protocol proposed by the investigators and therefore compromise the conclusions of the study? 13. Were the outcome assessors blinded to the intervention or exposure status of participants? 14. Are interventions/exposures assessed using valid and reliable measures, implemented consistently across all study participants? 15. Are outcomes assessed using valid and reliable measures, implemented consistently across all study participants? 16. Is the length of follow-up the same for all groups? 17. Is the length of time following the intervention/exposure sufficient to support the evaluation of primary outcomes and harms? 18. Did attrition from any group exceed 20 percent for 1 year follow-up? 19. Did attrition from any group exceed [x] percent? 20. Does the analysis control for baseline differences between groups? 21. Are confounding and/or effect modifying variables assessed using valid and reliable measures across all study participants? 22. Were the important confounding and effect modifying variables taken into account in the design and/or analysis (e.g., through matching, stratification, interaction terms, multivariate analysis, or other statistical adjustment)? 23. In cases of high loss to follow-up (or differential loss to follow-up), is the impact assessed (e.g., through sensitivity analysis or other adjustment method)? 24. Are any important primary outcomes missing from the results? 25. Are the statistical methods used to assess the primary benefit outcomes appropriate to the data? 26. Are any important harms or adverse events that may be a consequence of the intervention/exposure missing from the results? (dropped) 27. Are the statistical methods used to assess the main harm or adverse event outcomes appropriate to the data? 28. Are results believable taking study limitations into consideration? 29. Is the source of funding identified?
11
Included Study Citations: 1. ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. The Lancet. 2007; 370 (9590):829-40. 2. Peters R, Beckett N, Forette F, Tuomilehto J, Clarke R, Ritchie C, et al. Incident dementia and blood pressure lowering in the Hypertension in the Very Elderly Trial cognitive function assessment (HYVET-COG): a double-blind, placebo controlled trial. Lancet neurology. 2008; 7 (8):683-9. 3. Tzourio C, Anderson C, Chapman N, Woodward M, Neal B, MacMahon S, et al. Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med. 2003; 163 (9):1069-75. 4. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: Final results of the systolic hypertension in the elderly program (SHEP). JAMA. 1991; 265 (24):3255-64. 5. Corrada MM, Brookmeyer R, Paganini-Hill A, Berlau D, Kawas CH. Dementia Incidence Continues to Increase with Age in the Oldest Old The 90+ Study. Annals of Neurology. 2010; 67 (1):114-21. 6. Khachaturian AS, Zandi PP, Lyketsos CG, Hayden KM, Skoog I, Norton MC, et al. Antihypertensive medication use and incident Alzheimer disease: the Cache County Study. Arch Neurol. 2006; 63 (5):686-92. 7. Chuang Y-F, Breitner JCS, Chiu Y-L, Khachaturian A, Hayden K, Corcoran C, et al. Use of diuretics is associated with reduced risk of Alzheimer's disease: the Cache County Study. Neurobiology of Aging. 2014; 35 (11):2429-35. 8. Morris M, Scherr PA, Hebert LE, Glynn RJ, Bennett DA, Evans DA. Association of incident alzheimer disease and blood pressure measured from 13 years before to 2 years after diagnosis in a large community study. Archives of Neurology. 2001; 58 (10):1640-6. 9. Yasar S, Xia J, Yao W, Furberg CD, Xue Q-L, Mercado CI, et al. Antihypertensive drugs decrease risk of Alzheimer disease: Ginkgo Evaluation of Memory Study. Neurology. 2013; 81 (10):896-903. 10. Guo Z, Fratiglioni L, Zhu L, Fastbom J, Winblad B, Viitanen M. Occurrence and progression of dementia in a community population aged 75 years and older: Relationship of antihypertensive medication use. Archives of Neurology. 1999; 56 (8):991-6. 11. Ohrui T, Matsui T, Yamaya M, Arai H, Ebihara S, Maruyama M, et al. Angiotensin-converting enzyme inhibitors and incidence of Alzheimer's disease in Japan. Journal of the American Geriatrics Society. 2004; 52 (4):649-50. 12. in’t Veld BA, Ruitenberg A, Hofman A, Stricker BHC, Breteler MMB. Antihypertensive drugs and incidence of dementia: the Rotterdam Study. Neurobiology of Aging. 2001; 22 (3):407-12. 13. Haag MDM, Hofman A, Koudstaal PJ, Breteler MMB, Stricker BHC. Duration of antihypertensive drug use and risk of dementia: A prospective cohort study. Neurology. 2009; 72 (20):1727-34. 14. The 3C Study Group. Vascular factors and risk of dementia: design of the Three-City Study and baseline characteristics of the study population. Neuroepidemiol. 2003; 22 (6):316-25. 15. Rastas S, Pirttilä T, Mattila K, Verkkoniemi A, Juva K, Niinistö L, et al. Vascular risk factors and dementia in the general population aged >85 years. Prospective population-based study. Neurobiology of Aging. 2010; 31 (1):1-7. 16. The GRADE Working Group. GRADE handbook for grading quality of evidence and strength of recommendations. Updated October 2013. . In: Schünemann H, Brożek J, Guyatt G, Oxman AD, editors.; 2013.
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Supplementary File 5. Dementia risk in studies stratified by baseline hypertension
CI, confidence interval; IV, inverse-variance; SE, standard error; Blood pressure difference achieved, systolic / diastolic mmHg SHEP, -11.1/-3.4
13
Supplementary File 6. Results of meta-regression for primary dementia endpoint Meta-Regression Variable
Point Estimate
SE (95% CI)
Q
P
Mean age, years
0.002
0.004 (-0.007 to 0.011)
0.160
0.690
Male sex %
-0.001
0.003 (-0.006 to 0.006)
0.014
0.906
Systolic blood pressure mm Hg
0.004
0.003 (-0.003 to 0.010)
1.105
0.293
Mean follow-up, years
-0.015
0.020 (-0.055 to 0.025)
0.569
0.451
Attrition/Follow-up completion, %
0.006
0.003 (-0.001 to 0.012)
2.936
0.087
Mortality rate, %
0.001
0.001 (-0.002 to 0.003)
0.096
0.757
Mean education, years 1
-0.018
0.022 (-0.061 to 0.025)
0.642
0.423
Low education, < 8 years 2
-0.005
0.006 (-0.016 to 0.007)
0.688
0.407
Stroke 3
0.0001
0.001 (-0.003 to 0.003)
0.001
0.989
Apolipoprotein E allele 4
-0.013
0.011 (-0.035 to 0.009)
1.388
0.239
MMSE, mean 5
0.003
0.043 (-0.0780 to 0.087)
0.006
0.937
Heart failure 6
-0.075
0.063 (-0.200 to 0.049)
1.413
0.235
Diabetes
0.002
0.004 (-0.006 to 0.010)
.198
0.657
Meta-regression uses the unrestricted maximum likelihood assumption; 1 Calculated from 5 studies (CACHE, EPESE, GEMS, SHEP, Vantaa 85+) 2 Calculated from 6 studies (90+ Study, HYVET-COG, Kungsholmen, PROGRESS, Rotterdam, Three Cities) 3 Calculated from all studies excluding Ohrui 2004 (data not available) 4 Calculated from 6 studies (90+ Study, Cache-County, EPESE, PROGRESS, Three Cities, Vantaa 85+ Study) 14
5 6
Calculated from 6 studies (90+ Study, HYVET-COG, Kungsholmen, PROGRESS, Rotterdam, Three Cities) Calculated from 5 studies (GEMS, HYVET-COG, PROGRESS, SHEP, Thee-Cities)
CI, confidence interval; MMSE, Mini-Mental State Examination SE; standard error
15
Supplementary File 7. A Funnel plot of publication bias calculated with the trim and fill method
Funnel Plot of Standard Error by Log hazard ratio 0.0
Standard Error
0.1
0.2
0.3
0.4
0.5 -2.0
-1.5
-1.0
-0.5
0.0
0.5
1.0
1.5
2.0
Log hazard ratio
Funnel plot depicting publication bias ascertained by log standard error graphed by log hazard ratio. Bolded circles denote imputed study effect sizes
16
Supplementary File 8. Assessment of strength of recommendations using the GRADE criteria
GRADE Item
Dementia (n = 12)
AD (n = 7)
VaD (n = 2)
Risk of bias
No
No
-
Inconsistency
No
No
-
Indirectness
No
No
-
Imprecision
No
No
-
Publication bias
Undetected
Undetected
-
Large effect
No
No
-
Plausible confounding would change
Reduced it for RR
