Treatment of cardiovascular risk factors to prevent cognitive decline and dementia: a systematic review

Figures & data

Table 1 Hypertension

Authors (study name), year of publication	Population characteristics	Intervention (number of participants)	Primary end points (% RRR for stroke)	Mean follow-up	Effect on cognitive function (test)
SHEP, SHEP study group,^Citation26,Citation27 1991	isolated systolic HTN (160–219 mmHg), age ≥60 y	chlorthalidone ± atenolol or reserpine versus placebo (n = 2365/2371)	fatal/nonfatal stroke (36%)	5.0 y	no significant difference in incidence of CD (shortCARE)
MRC trial, Prince et al^Citation28 1996	not on anti-hypertensive medication, age 65–74 y	hydrochlorothiazide/amiloride or atenolol versus placebo (n = 633/640/1311)	stroke/coronary events/mortality (31%)	4.5 y	no effect on cognitive performance (PALT, TMT A)
Syst-Eur, Forette et al^Citation29,Citation30 1998, 2002	systolic HTN (160–219 mmHg), age ≥60 y	nitrendipine ± enalapril ± hydrochlorothiazide versus placebo (n = 1238/1180)	stroke (42%)	3.9 y	55% decrease in incidence of dementia (MMSE)
SCOPE, Lithell et al^Citation32,Citation33 2003/2008	treated or untreated systolic HTN (160–179 mmHg), age 70–89 y	candesartan versus placebo (n = 2477/2460)	stroke, MI, cardiovascular mortality (24%)	3.7 y	no decrease in incidence of dementia slightly less cognitive decline in those with MMSE 24–28/stroke (MMSE)
PROGRESS Tzourio et al^Citation31 2003	previous stroke or TIA, mean age 64 y	perindopril versus placebo. Indapamide added in both groups when necessary (n = 3051/3054)	recurrent stroke (28%)	3.9 y	decrease in cognitive decline (3 or more on MMSE), non-significant decrease in dementia (MMSE)
HYVETCog, Peters et al^Citation34 2008	systolic HTN (160–200 mmHg), age ≥80 y	indapamide ± perindopril versus placebo (n = 1687/1649)	stroke (30%)	2.2 y	no decrease in incidence of dementia (MMSE)

Abbreviations: RRR, relative risk reduction; y, years; HTN, hypertension; CD, cognitive decline; PALT, paired-associate learning test; TMT, trail making test; MMSE, Mini-Mental State Examination; MI, myocardial infarction; TIA, transient ischemic attack.

Table 2 Dyslipidemia

Authors, year of publication	Population characteristics	Intervention (number of participants)	Primary end-points (outcome)	Follow-up	Effect on cognitive function (test)
HPS, HPS study group,^Citation37 2002	occlusive arterial disease or DM, age 40–80 y	simvastatin versus placebo (n = 10269/10267)	all cause mortality/coronary death (HR 0.87, P = 0.0003)	5 y	no effect on cognition (TICS)
PROSPER, Shepherd et al^Citation38,Citation39 2002	history of VAD or risk factors, age 70–82 y	pravastatin versus placebo (n = 2891/2913)	coronary death, nonfatal MI, stroke (HR 0.85, P = 0.014)	3.2 y	no effect on cognitive function or disability (MMSE, NP test battery)

Abbreviations: DM, diabetes mellitus; y, years; HR, hazard ratio; TICS, telephone interview for cognitive status; VAD, vascular disease; MMSE, mini mental state examination; NP, neuropsychological.

Table 3 Hyperhomocysteinemia

Authors, year of publication	Population characteristics	Intervention (number of participants)	Primary end-points (outcome)	Follow-up	Effect on cognitive function (test)
Stott et al^Citation42 2005	ischemic vascular disease, age ≥65 y	oral vit B6, B12, folic acid (7 groups versus placebo, n = 185, 23/group)	plasma homocysteine (tHcy: 33% decrease)	1 y	no effect on cognitive function (letter digit coding test, TICS)
McMahon et al^Citation47 2006	raised tHcy, (≥13 mmol/L), age >65 y	oral vit B6, B12, folic acid versus placebo (n = 138/138)	plasma homocysteine, cognition (no effect on tHcy)	2 y	no effect on cognition (extensive test battery: MMSE, RAVLT, WMS, CWF TMT)
Durga et al^Citation46 2007 (substudy FACIT)	tHcy ≥13 and <26 mmol/L. Vit B12 < 200 pmol/L, age 50–70 y (mean: 60 y)	oral folic acid or placebo (406/413)	cognitive function (tHcy 26% decrease)	3 y	improvements in 3/5 domains (memory, processing and sensorimotor speed) (word learning, concept shifting, stroop test, verbal fluency and letter-digit substitution test)
Kang et al^Citation43 2008	women with CVD or >2 cardiovascular risk factors, age >65 y	oral vit B6, B12, folic acid versus placebo (n = 1002/1007)	sec. prevention of cardiovascular disease (no effect)	5.4 y	no effect on cognition (5 telephone tests: TICS, word learning, immediate and delayed recall, naming animals)
Brady et al^Citation45 2009 (substudy VA HOST)	chronic kidney disease/end-stage renal disease, tHcy ≥ 15 mmol/L, age ≥21 y (mean 67 y)	high dose B vitamins versus placebo (320/339)	mortality, vascular outcomes (no effect, tHcy decrease: 26.7%)	1 y	no effect on cognition (TICS, neuropsychological test battery: backward/forward digit span, animal naming).
Viswanathan et al^Citation44 2009 (substudy VISP)	ischemic stroke, tHcy ≥ 15 mmol/L, age ≥35 y (mean 67 y)	high dose pyridoxine/vit B12/folic acid versus low dose (n = 157/143)	stroke, MI, death. (no effect)	2 y	no effect on cognition. (MMSE)

Abbreviations: Vit, vitamin; tHcy, serum total homocysteine; FU, follow-up; y, years; TICS, telephone interview for cognitive status; MMSE, Mini-Mental State Examination; RAVLT, Rey Auditory Verbal Learning Test, WMS, Wechsler Memory Scales; CWF, category word fluency test; TMT, trail making test; CVD, cardiovascular disease; MI, myocardial infarction.

Table 4 Main limitations in the reviewed studies

Limitation	Remarks
1. Age group relatively young to see any effect on dementia within follow-up	– Low number of cases: applies to most studies
2. High number of dropouts, potentially selective dropout due to cognitive decline	– Applies to most studies
3. Placebo group received additional treatment (contamination)	– Present in most studies on antihypertensive treatment and to a lesser extent in cholesterol lowering trials
4. Bias in outcome measurement (dementia or cognitive decline)	–All studies on hypertension and dyslipidemia assessed dementia or cognitive decline as a secondary outcome parameter, criteria not always clear
5. Competing risks not taken into account	– Correction for increased life expectancy was not applied
6. Sensitivity of measurement insufficient	– Optimal screening instrument (crude or sensitive) and clinical relevance are matter of debate
7. Short follow-up	– Optimal follow-up time is unclear
8. Small groups, insufficient power	– Applies to some studies on lowering homocysteine
9. Patient group not selected on risk factor (no clear hypertension, dyslipidemia, hyperhomocysteinemia)	– Insufficient window of opportunity to see any effect in some studies

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