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Meta-Analysis
. 2021 May 24;5(5):CD004034.
doi: 10.1002/14651858.CD004034.pub4.

Pharmacological treatment of hypertension in people without prior cerebrovascular disease for the prevention of cognitive impairment and dementia

Emma L Cunningham  1 , Stephen A Todd  2 , Peter Passmore  1 , Roger Bullock  3 , Bernadette McGuinness  1
Affiliations
Meta-Analysis

Pharmacological treatment of hypertension in people without prior cerebrovascular disease for the prevention of cognitive impairment and dementia

Emma L Cunningham et al. Cochrane Database Syst Rev. .

Abstract

Background: This is an update of a Cochrane Review first published in 2006 (McGuinness 2006), and previously updated in 2009 (McGuinness 2009). Hypertension is a risk factor for dementia. Observational studies suggest antihypertensive treatment is associated with lower incidences of cognitive impairment and dementia. There is already clear evidence to support the treatment of hypertension after stroke.

Objectives: To assess whether pharmacological treatment of hypertension can prevent cognitive impairment or dementia in people who have no history of cerebrovascular disease.

Search methods: We searched the Specialised Register of the Cochrane Dementia and Cognitive Improvement Group, CENTRAL, MEDLINE, Embase, three other databases, as well as many trials registries and grey literature sources, most recently on 7 July 2020.

Selection criteria: We included randomised controlled trials (RCTs) in which pharmacological interventions to treat hypertension were given for at least 12 months. We excluded trials of pharmacological interventions to lower blood pressure in non-hypertensive participants. We also excluded trials conducted solely in people with stroke.

Data collection and analysis: Two authors independently assessed trial quality and extracted data. We contacted study authors for additional information. We collected information regarding incidence of dementia, cognitive decline, change in blood pressure, adverse effects and quality of life. We assessed the certainty of evidence using GRADE.

Main results: We included 12 studies, totaling 30,412 participants, in this review. Eight studies compared active treatment with placebo. Of the four non-placebo-controlled studies, two compared intensive versus standard blood pressure reduction. The two final included studies compared different classes of antihypertensive drug. Study durations varied from one to five years. The combined result of four placebo-controlled trials that reported incident dementia indicated no evidence of a difference in the risk of dementia between the antihypertensive treatment group and the placebo group (236/7767 versus 259/7660, odds ratio (OR) 0.89, 95% confidence interval (CI) 0.72 to 1.09; very low certainty evidence, downgraded due to study limitations and indirectness). The combined results from five placebo-controlled trials that reported change in Mini-Mental State Examination (MMSE) may indicate a modest benefit from antihypertensive treatment (mean difference (MD) 0.20, 95% CI 0.10 to 0.29; very low certainty evidence, downgraded due to study limitations, indirectness and imprecision). The certainty of evidence for both cognitive outcomes was downgraded on the basis of study limitations and indirectness. Study durations were too short, overall, to expect a significant difference in dementia rates between groups. Dementia and cognitive decline were secondary outcomes for most studies. Additional sources of bias include: the use of antihypertensive medication by the placebo group in the placebo-controlled trials; failure to reach recruitment targets; and early termination of studies on safety grounds. Meta-analysis of the placebo-controlled trials reporting results found a mean change in systolic blood pressure of -9.25 mmHg (95% CI -9.73, -8.78) between treatment (n = 8973) and placebo (n = 8820) groups, and a mean change in diastolic blood pressure of -2.47 mmHg (95% CI -2.70, -2.24) between treatment (n = 7700) and placebo (n = 7509) groups (both low certainty evidence downgraded on the basis of study limitations and inconsistency). Three trials - SHEP 1991, LOMIR MCT IL 1996 and MRC 1996 - reported more withdrawals due to adverse events in active treatment groups than placebo groups. Participants on active treatment in Syst Eur 1998 were less likely to discontinue treatment due to side effects, and participants on active treatment in HYVET 2008 reported fewer 'serious adverse events' than in the placebo group. There was no evidence of a difference in withdrawals rates between groups in SCOPE 2003, and results were unclear for Perez Stable 2000 and Zhang 2018. Heterogeneity precluded meta-analysis. Five of the placebo-controlled trials provided quality of life (QOL) data. Heterogeneity again precluded meta-analysis. SHEP 1991, Syst Eur 1998 and HYVET 2008 reported no evidence of a difference in QOL measures between active treatment and placebo groups over time. The SCOPE 2003 sub-study (Degl'Innocenti 2004) showed a smaller drop in QOL measures in the active treatment compared to the placebo group. LOMIR MCT IL 1996 reported an improvement in a QOL measure at twelve months in one active treatment group and deterioration in another.

Authors' conclusions: High certainty randomised controlled trial evidence regarding the effect of hypertension treatment on dementia and cognitive decline does not yet exist. The studies included in this review provide low certainty evidence (downgraded primarily due to study limitations and indirectness) that pharmacological treatment of hypertension, in people without prior cerebrovascular disease, leads to less cognitive decline compared to controls. This difference is below the level considered clinically significant. The studies included in this review also provide very low certainty evidence that pharmacological treatment of hypertension, in people without prior cerebrovascular disease, prevents dementia.

Trial registration: ClinicalTrials.gov NCT00122811.

PubMed Disclaimer

Conflict of interest statement

None known.

Figures

1
1
Study flow diagram for searches December 2014 (212), November 2015 (309), October 2016 (145), August 2017 (220), June 2018 (279), June 2019 (177), July 2020 (259)
1.1
1.1. Analysis
Comparison 1: Incidence of dementia, Outcome 1: Number of cases of dementia placebo studies
2.1
2.1. Analysis
Comparison 2: Cognitive change from baseline, Outcome 1: Change in MMSE placebo studies
3.1
3.1. Analysis
Comparison 3: Change in blood pressure from baseline, Outcome 1: Change in systolic blood pressure level (mmHg) placebo studies
3.2
3.2. Analysis
Comparison 3: Change in blood pressure from baseline, Outcome 2: Change in diastolic blood pressure level (mmHg) placebo studies
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rrAD 2019 {published data only}
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TRANSCEND 2008 {published data only}
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References to studies awaiting assessment

CHIEF 2012 {published data only (unpublished sought but not used)}
    1. Ma L, Lu P, Zhang Y, Meng X, Fan P, Ma L, et al. Effects of antihypertensive therapy on cognitive function and health-related quality of life in high-risk hypertensive patients. Journal of Hypertension. Conference: 27th Scientific Meeting of the International Society of Hypertension, ISH 2018;36(Suppl 3):e334-5.
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    1. Wang W, Ma LY, Liu MB, Deng Q, Zhang YQ, Li W, et al, CHIEF Cooperative Group. Effects of amlodipine plus telmisartan or amlodipine plus amiloride regimen on blood pressure control in hypertensive patients: preliminary report of Chinese Hypertension Intervention Efficacy (CHIEF) trial. Zhonghua Xin Xue Guan Bing Za Zhi 2009;37(8):701-7. - PubMed

References to ongoing studies

CEREBRAL {published data only}
    1. Yamano S, Horii M, Takami T, Sakuma M, Morimoto T, Okada S, et al. Comparison between angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on the risk of stroke recurrence and longitudinal progression of white matter lesions and silent brain infarcts on MRI (CEREBRAL study): rationale, design, and methodology. International Journal of Stroke 2015;10(3):452-6. - PubMed
ESPRIT {published data only}
    1. Effects of Intensive Systolic Blood Pressure Lowering Treatment in Reducing RIsk of Vascular evenTs (ESPRIT) Study (ESPRIT). Ongoing study. Starting date of trial not provided. Contact author for more information.
OPTIMAL DIABETES {published data only}
    1. Optimal Blood Pressure for the prevenTIon of Major vAscuLar Events in Patients With DIABETES Mellitus (OPTIMAL-DIABETES). Ongoing study. Starting date of trial not provided. Contact author for more information.

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References to other published versions of this review

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