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SUPPLEMENTAL MATERIAL

Blood pressure-lowering interventions to prevent dementia: a and meta- analysis

Tessa van Middelaar, Lonneke A. van Vught, Willem A. van Gool, Esther M.F. Simons, Bert-

Jan van den Born, Eric P. Moll van Charante, Edo Richard

Page

Appendix S1. Search strategy 2

Appendix S2. Potential influence of SPRINT-MIND 6

Table S1. Cochrane risk of bias assessment 7

Table S2. Dementia incidence rate 8

Table S3. Pairwise meta-analysis of specific classes of antihypertensive 10

Table S4. Funders of the included trials 11

Figure S1. Funnel plot to assess publication bias 12

Figure S2. Subgroup analyses on population characteristics 13

Figure S3. Subgroup analyses on type of intervention 14

Figure S4. Meta-regression assessing the influence of systolic on 15 the effect of blood pressure lowering treatment to prevent dementia

Figure S5. Forest plot on the effect of antihypertensive treatment on mortality 16

References 17

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Appendix S1. Search strategy

((((("Dementia"[Mesh] OR dement*[tiab] OR alzheimer*[tiab]))) AND (((((("Antihypertensive

Agents"[Mesh] OR "Antihypertensive Agents" [Pharmacological Action] OR

"/drug therapy"[Mesh] OR "Hypertension/prevention and control"[Mesh] OR

"Hypertension/therapeutic use"[Mesh] OR "Hypertension/therapy"[Mesh] OR

"Hypertension/diet therapy"[Mesh] OR "Hypertension/drug effects"[Mesh] OR "Nutrition

Therapy"[Mesh] OR "Diet, Food, and Nutrition"[Mesh] OR "Diet"[Mesh] OR "

Drinking"[Mesh] OR "Exercise"[Mesh] OR "Exercise Therapy"[Mesh] OR "Exercise

Movement Techniques"[Mesh] OR "Sports"[Mesh] OR "Physical Fitness"[Mesh] OR "Body

Weight"[MeSH] OR "Life Style"[Mesh] OR "Tobacco Use"[Mesh] OR "Tobacco Use

Cessation"[Mesh] OR "Smoking Cessation"[MeSH] OR exercis*[tiab] OR aerobic*[tiab] OR physical activit*[tiab] OR sport*[tiab] OR physical fitness*[tiab] OR diet*[tiab] OR nutrition*[tiab] OR nutrient*[tiab] OR food[tiab] OR feeding[tiab] OR weigh*[tiab] OR overweigh*[tiab] OR obes*[tiab] OR smok*[tiab] OR life style*[tiab] OR lifestyle*[tiab]))) OR

(((pharmacolog*[tiab] OR nonpharmacolog*[tiab] OR non-pharmacolog*[tiab]) AND

(intervention*[tiab] OR treatment*[tiab] OR therap*[tiab] OR management[tiab] OR strateg*[tiab])))) OR ((" Symporter Inhibitors"[Mesh] OR "Sodium

Potassium Chloride Symporter Inhibitors" [Pharmacological Action] OR ""[Mesh]

OR "Ethacrynic Acid"[Mesh] OR ""[Mesh] OR "torsemide" [Supplementary

Concept] OR " Symporter Inhibitors"[Mesh] OR "Sodium Chloride Symporter

Inhibitors" [Pharmacological Action] OR ""[Mesh] OR

""[Mesh] OR ""[Mesh] OR ""[Mesh] OR

""[Mesh] OR "Chlorthalidone"[Mesh] OR ""[Mesh] OR ",

Potassium Sparing"[Mesh] OR ""[Mesh] OR ""[Mesh] OR

"Dihydropyridines"[Mesh] OR ""[Mesh] OR "" [Supplementary Concept]

OR ""[Mesh] OR ""[Mesh] OR "" [Supplementary Concept]

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OR ""[Mesh] OR ""[Mesh] OR ""[Mesh] OR

""[Mesh] OR "mepirodipine" [Supplementary Concept] OR ""

[Supplementary Concept] OR "" [Supplementary Concept] OR ""

[Supplementary Concept] OR " hydrochloride" [Supplementary Concept] OR

"" [Supplementary Concept] OR "" [Supplementary Concept] OR

"" [Supplementary Concept] OR "" [Supplementary Concept] OR

"" [Supplementary Concept] OR "" [Supplementary Concept] OR

""[Mesh] OR "Nitrendipine"[Mesh] OR "" [Supplementary Concept] OR

"" [Supplementary Concept] OR ""[Mesh] OR ""[Mesh] OR

"-Converting Enzyme Inhibitors"[Mesh] OR ""[Mesh] OR

""[Mesh] OR ""[Mesh] OR ""[Mesh] OR ""[Mesh] OR

"" [Supplementary Concept] OR ""[Mesh] OR "" [Supplementary

Concept] OR "" [Supplementary Concept] OR "" [Supplementary

Concept] OR "" [Supplementary Concept] OR ""[Mesh] OR "Angiotensin

Receptor Antagonists"[Mesh] OR "" [Supplementary Concept] OR ""

[Supplementary Concept] OR "" [Supplementary Concept] OR ""[Mesh]

OR "" [Supplementary Concept] OR "" [Supplementary Concept] OR

""[Mesh] OR "" [Supplementary Concept] OR "fimasartan"

[Supplementary Concept] OR ""[Mesh] OR "Metoprolol"[Mesh] OR "Nadolol"[Mesh]

OR ""[Mesh] OR "Oxprenolol"[Mesh] OR "Pindolol"[Mesh] OR ""[Mesh]

OR "Timolol"[Mesh] OR "Bisoprolol"[Mesh] OR "Acebutolol"[Mesh] OR "Celiprolol"[Mesh] OR

"esmolol" [Supplementary Concept] OR ""[Mesh] OR ""[Mesh] OR

""[Mesh] OR ""[Mesh] OR "Phenoxybenzamine"[Mesh] OR

""[Mesh] OR "Terazosin" [Supplementary Concept] OR ""[Mesh] OR

"" [Supplementary Concept] OR "Phentolamine"[Mesh] OR "carvedilol"

[Supplementary Concept] OR "Labetalol"[Mesh] OR "Hydralazine"[Mesh] OR

""[Mesh] OR "" [Supplementary Concept] OR "Mineralocorticoid Receptor

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Antagonists"[Mesh] OR "" [Supplementary Concept] OR ""[Mesh]

OR ""[Mesh] OR ""[Mesh] OR ""[Mesh] OR

""[Mesh] OR "" [Supplementary Concept] OR ""[Mesh]

OR ""[Mesh] OR " Sulfate"[Mesh] OR antihypertensive[tiab] OR anti-hypertensive[tiab] OR beta-blocker*[tiab] OR betablocker*[tiab] OR angiotensin*[tiab] OR loop *[tiab] OR bumetanide[tiab] ethacrynic acid[tiab] OR furosemide[tiab] OR torsemide[tiab] OR diuretic*[tiab] OR epitizide[tiab] OR hydrochlorothiazide[tiab] OR chlorothiazide[tiab] OR bendroflumethiazide[tiab] OR xipamide[tiab] OR indapamide[tiab] OR chlorthalidone[tiab] OR metolazone[tiab] OR amiloride[tiab] OR triamterene[tiab] OR amlodipine[tiab] OR cilnidipine[tiab] OR felodipine[tiab] OR isradipine[tiab] OR lercanidipine[tiab] OR [tiab] OR nicardipine[tiab] OR nifedipine[tiab] OR nimodipine[tiab] OR nitrendipine[tiab] OR [tiab] OR lacidipine[tiab] OR aranidipine[tiab] OR azelnidipine[tiab] OR benidipine[tiab] OR clevidipine[tiab] OR darodipine[tiab] OR efonidipine[tiab] OR manidipine[tiab] OR niguldipine[tiab] OR nilvadipine[tiab] OR nisoldipine[tiab] OR nitrendipine[tiab] OR oxodipine[tiab] OR pranidipine[tiab] OR diltiazem[tiab] OR verapamil[tiab] OR ACE-inhibitor*[tiab] OR captopril[tiab] OR enalapril[tiab] OR fosinopril[tiab] OR lisinopril[tiab] OR perindopril[tiab] OR quinapril[tiab] OR ramipril[tiab] OR trandolapril[tiab] OR benazepril[tiab] OR zofenopril[tiab]

OR imidapril[tiab] OR cilazapril[tiab] OR candesartan[tiab] OR eprosartan[tiab] OR irbesartan[tiab] OR losartan[tiab] OR olmesartan[tiab] OR telmisartan[tiab] OR valsartan[tiab]

OR azilsartan[tiab] OR fimasartan[tiab] OR atenolol[tiab] OR metoprolol[tiab] OR nadolol[tiab]

OR nebivolol[tiab] OR oxprenolol[tiab] OR pindolol[tiab] OR propranolol[tiab] OR timolol[tiab]

OR bisoprolol[tiab] OR acebutolol[tiab] OR celiprolol[tiab] OR esmolol[tiab] OR sotalol[tiab]

OR doxazosin[tiab] OR phentolamine[tiab] OR indoramin[tiab] OR phenoxybenzamine[tiab]

OR prazosin[tiab] OR terazosin[tiab] OR tolazolin[tiab] OR ketanserin[tiab] OR urapidil[tiab]

OR fentolamin[tiab] OR carvedilol[tiab] OR labetalol[tiab] OR hydralazine[tiab] OR minoxidil[tiab] OR aliskiren[tiab] OR eplerenone[tiab] OR spironolactone[tiab] OR

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clonidine[tiab] OR guanabenz[tiab] OR guanfacine[tiab] OR methyldopa[tiab] OR moxonidine[tiab] OR guanethidine[tiab] OR mecamylamine[tiab] OR magnesium sulfate[tiab])))) AND (("Blood Pressure"[Mesh] OR "Blood Pressure Determination"[Mesh] OR

"Blood Flow Velocity"[Mesh] OR "Hypertension"[Mesh] OR "Cardiovascular Diseases"[Mesh]

OR "Cardiovascular Physiological Processes"[Mesh] OR antihypertens*[tiab] OR anti- hypertens*[tiab] OR blood pressur*[tiab] OR systolic[tiab] OR diastolic[tiab] OR blood flow[tiab] OR (blood[tiab] AND lower*[tiab]) OR hypertens*[tiab] OR vascular[tiab] OR cardiovascular[tiab]))) AND ((("Randomized Controlled Trial" [Publication Type] OR "Random

Allocation"[Mesh] OR "Double-Blind Method"[Mesh] OR "Single-Blind Method"[Mesh] OR

"Placebos"[Mesh] OR "Meta-Analysis" [Publication Type] OR "Clinical Trials as Topic"[MeSH

Terms] OR "Randomized Controlled Trials as Topic"[Mesh] OR "Controlled "

[Publication Type] OR random*[tiab] OR trial*[tiab] OR RCT[tiab] OR RCTs[tiab] OR systematic review[tiab] OR meta-anal*[tiab] OR metaanal*[tiab]))) NOT (("Animals"[Mesh] OR animal*[tiab] OR rat[tiab] OR rats[tiab] OR mouse[tiab] OR mice[tiab] OR dog[tiab] OR dogs[tiab]) NOT "Humans"[Mesh])

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Appendix S2. Potential influence of SPRINT-MIND

Systolic Blood Pressure Intervention Trial memory and cognition in decreased hypertension

(SPRINT-MIND) will study if intensive blood pressure lowering leads to a lower risk of dementia over five years follow-up [1]. As this is an important and influential trial, we wanted to assess its potential influence on our meta-analysis.

In the SPRINT trial 4678 participants were included in the control group and 4683 participants in the intervention group, with a mean age at baseline of 68 years. For this analysis we estimated an incidence rate of 10.3 cases per 1000 person years in the control group, which was found in the Medical Research Council Cognitive Function and Ageing

Study (MRC CFAS) cohort aged 70-74 years [2]. This would result to an estimated 241 dementia cases in the control group. In this meta-analysis we included the nine studies included in our original meta-analysis and additionally included three hypothetical results of

SPRINT-MIND trial. To assess the potential range in pooled estimates we used the following two hypothetical results: 50% and 0% risk reduction. This led to a range in pooled estimates from 0.84 (95% confidence interval [95% CI] 0.70-1.00, I2 77%) with 50% risk reduction to

0.94 (95% CI 0.87-1.03, I2 9%) with 0% risk reduction.

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Table S1. Cochrane risk of bias assessment Blinding of outcome assessment Random sequence generation personnel (performance bias) Selective reporting (reporting Blinding of participants and Incomplete outcome data Allocation concealment (detection bias) (selection bias) (selection bias) (attrition bias) Other bias bias)

SHEP[3] + + + + ? + ? Syst-Eur[4] + + + + + + + SCOPE[5] + + + + + + ? PROGRESS[6] + + + + + + + ADVANCE[7] + + + ? + + + HYVET-COG[8] + + + + + + + PROFESS[9] + + + ? ? + - PreDIVA[10] + + - + + + + Look AHEAD[11] + + - + + + +

The green plus-signs indicate a low risk of bias, the jelow question mark-signs indicate an unclear risk of bias, and the red minus-sign indicates a high risk of bias.

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Table S2. Dementia incidence rate

Definition of dementia Total no. Total study Age Mean duration No. dementia cases

dementia population (n=) (years)a of follow-up per 1000 participants,

cases (years) per yearb

SHEP[3] American Psychiatric 81 4736 72 4.5 3.8 Association criteria

Syst-Eur[4] DSM-lll-R 64 2902 70 3.9 5.7

SCOPE[5] Modified ICD-10 research 119 4937 76 3.7 6.5 criteria

PROGRESS[6] DSM IV 410 6105 64 3.9 17.2

ADVANCE[7] DSM IV 76 11140 66 4.3 1.6

HYVET-COG[8] DSM IV 263 3336 84 2.2 36.4

PROFESS[9] Based on clinical impression 817 17270 66 2.4 19.4 (not further specified)

PreDIVA[10] DSM IV 233 3454 75 6.7 10.1

Look Based on cognitive, functional 68 3802 70 11.4 1.6 and depression test scores and AHEAD[11] medical information

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a Mean age of intervention group. b The number of dementia cases per 1000 participants/year is calculated based on total dementia cases, study population and mean duration of follow-up when not reported. c Assessment based on cognitive, functional and depression test scores in combination with medical and health information.

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Table S3. Pairwise meta-analysis of specific classes of antihypertensive medication

No. of No. cases/ RR (95% CI) p- I2

trials participants * value

Diuretics 2 163 / 4052 0.89 (0.72-1.09) 0.25 0%

Calcium 1 21 / 1485 0.47 (0.28-0.78) <0.01 N.A.**

Angiotensin receptor 2 470 / 11101 1.01 (0.89-1.14) 0.88 0% blocker

Ace-inhibitor and diuretic 2 232 / 8620 0.91 (0.77-1.09) 0.30 0%

* Number of cases represent the number of dementia cases and total number of participants in the intervention group. **Statistical heterogeneity could not be assessed on the analysis on blockers as this was based on one trial. N.A. indicates not applicable.

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Table S4. Funders of the included trials

Trial Funder

SHEP[3] The National Heart, Lung, and Blood Institute; the National Institute on

Aging

Syst-Eur[4] Bayer AG; Merck Sharpe; Dohme

SCOPE[5] AstraZeneca

PROGRESS[6] Servier; the Health Research Council of New Zealand; the National Health

and Medical Research Council of Australia

ADVANCE[7] Servier; National Health and Medical Research Council of Australia

HYVET-COG[8] The British Heart Foundation; Servier; imperial college

PROFESS[9] Boehringer Ingelheim; Bayer-Schering Pharma; GlaxoSmithKline

PreDIVA[10] Dutch Ministry of Health, Welfare and Sport; Dutch Innovation Fund;

Netherlands Organisation for Health Research and Development

Look National Institutes of Health (and additional non-commercial funding)

AHEAD[11]

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Figure S1. Funnel plot to assess publication bias

Risk of publication bias is higher if the funnel plot is assymetrical. When for example smaller studies with non-significant effects are not published this will cause a gap in the bottom righ corner of the graph. Overall, we do not see a assymetrical funnel plot, however the outlying result from the Syst-Eur trial is notable.

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Figure S2. Subgroup analyses on population characteristics

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Figure S3. Subgroup analyses on type of intervention

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Figure S4. Meta-regression assessing the influence of systolic blood pressure on the effect of blood pressure lowering treatment to prevent dementia

Data on SBP was gathered from the primary publication in the PRoFESS and PROGRESS trial.[12, 13] SBP indicates systolic blood pressure; FU, follow-up.

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Figure S5. Forest plot on the effect of antihypertensive treatment on mortality

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References

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and cognitive function after recurrent in patients with ischaemic stroke in the Prevention Regimen for Effectively Avoiding Second (PRoFESS) trial: a double- blind, active and placebo-controlled study. Lancet Neurol. 2008;7(10):875-84. doi: 10.1016/S1474-4422(08)70198-4. PubMed PMID: 18757238; PubMed Central PMCID: PMCPMC2772657. 10. Moll van Charante EP, Richard E, Eurelings LS, van Dalen JW, Ligthart SA, van Bussel EF, et al. Effectiveness of a 6-year multidomain vascular care intervention to prevent dementia (preDIVA): a cluster-randomised controlled trial. Lancet. 2016. doi: 10.1016/S0140- 6736(16)30950-3. PubMed PMID: 27474376. 11. Espeland MA, Luchsinger JA, Baker LD, Neiberg R, Kahn SE, Arnold SE, et al. Effect of a long-term intensive lifestyle intervention on prevalence of cognitive impairment. Neurology. 2017;88(21):2026-35. doi: 10.1212/WNL.0000000000003955. PubMed PMID: 28446656; PubMed Central PMCID: PMCPMC5440245. 12. Yusuf S, Diener HC, Sacco RL, Cotton D, Ounpuu S, Lawton WA, et al. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med. 2008;359(12):1225-37. Epub 2008/08/30. doi: 10.1056/NEJMoa0804593. PubMed PMID: 18753639; PubMed Central PMCID: PMCPMC2714258. 13. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001;358(9287):1033-41. Epub 2001/10/09. doi: 10.1016/s0140-6736(01)06178-5. PubMed PMID: 11589932.

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