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. 2016 Nov 1;11(11):CD011971.
doi: 10.1002/14651858.CD011971.pub2.

Antihypertensive withdrawal for the prevention of cognitive decline

Susan Jongstra  1 , Jennifer K Harrison, Terry J Quinn, Edo Richard
Affiliations

Antihypertensive withdrawal for the prevention of cognitive decline

Susan Jongstra et al. Cochrane Database Syst Rev. .

Abstract

Background: Clinical trials and observational data have variously shown a protective, harmful or neutral effect of antihypertensives on cognitive function. In theory, withdrawal of antihypertensives could improve cerebral perfusion and reduce or delay cognitive decline. However, it is also plausible that withdrawal of antihypertensives may have a detrimental effect on cognition through increased incidence of stroke or other vascular events.

Objectives: To assess the effects of complete withdrawal of at least one antihypertensive medication on incidence of dementia, cognitive function, blood pressure and other safety outcomes in cognitively intact and cognitive impaired adults.

Search methods: We searched ALOIS, the specialised register of the Cochrane Dementia and Cognitive Improvement Group, with additional searches conducted in MEDLINE, Embase, PsycINFO, CINAHL, LILACS, Web of Science Core Collection, ClinicalTrials.gov and the World Health Organization Portal/ICTRP on 12 December 2015. There were no language or date restrictions applied to the electronic searches, and no methodological filters were used to restrict the search.

Selection criteria: We included randomised controlled trials (RCTs) and controlled clinical trials (CCTs) provided they compared withdrawal of antihypertensive medications with continuation of the medications and included an outcome measure assessing cognitive function or a clinical diagnosis of dementia. We included studies with healthy participants, but we also included studies with participants with all grades of severity of existing dementia or cognitive impairment.

Data collection and analysis: Two review authors examined titles and abstracts of citations identified by the search for eligibility, retrieving full texts where needed to identify studies for inclusion, with any disagreement resolved by involvement of a third author. Data were extracted independently on primary and secondary outcomes. We used standard methodological procedures expected by Cochrane.The primary outcome measures of interest were changes in global and specific cognitive function and incidence of dementia; secondary outcomes included change in systolic and diastolic blood pressure, mortality, adverse events (including cardiovascular events, hospitalisation and falls) and adherence to withdrawal. The quality of the evidence was evaluated using the GRADE approach.

Main results: We included two RCTs investigating withdrawal of antihypertensives in 2490 participants. There was substantial clinical heterogeneity between the included studies, therefore we did not combine data for our primary outcome. Overall, the quality of included studies was high and the risk of bias was low. Neither study investigated incident dementia.One study assessed withholding previously prescribed antihypertensive drugs for seven days following acute stroke. Cognition was assessed using telephone Mini-Mental State Examination (t-MMSE) and Telephone Interview for Cognitive Status (TICS-M) at 90 days as a secondary outcome. The t-MMSE score was a mean of 1.0 point higher in participants who withdrew antihypertensive medications compared to participants who continued them (95% confidence interval (CI) 0.35 to 1.65; 1784 participants) and the TICS-M was a mean of 2.10 points higher (95% CI 0.69 to 3.51; 1784 participants). However, in both cases the evidence was of very low quality downgraded due to risk of bias, indirectness and evidence from a single study. The other study was community based and included participants with mild cognitive impairment. Drug withdrawal was for 16 weeks. Cognitive performance was assessed using a composite of at least five out of six cognitive tests. There was no evidence of a difference comparing participants who withdrew antihypertensive medications and participants who continued (mean difference 0.02 points, 95% CI -0.19 to 0.21; 351 participants). This evidence was of low quality and was downgraded due to risk of bias and evidence from single study.In one study, the systolic blood pressure after seven days of withdrawal was 9.5 mmHg higher in the intervention compared to the control group (95% CI 7.43 to 11.57; 2095 participants) and diastolic blood pressure was 5.1 mmHg higher (95% CI 3.86 to 6.34; 2095 participants). This evidence was low quality, downgraded due to indirectness, because the data must be interpreted in the context of the wider study looking at glyceryl trinitrate administration or not, and evidence from a single study. In the other study, systolic blood pressure increased by 7.4 mmHg in the withdrawal group compared to the control group (95% CI 7.08 to 7.72; 356 participants) and diastolic blood pressure increased by 2.6 mmHg (95% CI 2.42 to 2.78; 356 participants). This was moderate quality evidence, downgraded as evidence was from a single study. We combined data for mortality and cardiovascular events. There was no clear evidence that antihypertensive medication withdrawal affected adverse events, although there was a possible trend to increased cardiovascular events in the large post-stroke study (pooled mortality risk ratio 0.88, 95% CI 0.72 to 1.08; 2485 participants; and cardiovascular events risk ratio 1.29, 95% CI 0.96 to 1.72). Certain prespecified outcomes of interest (falls, hospitalisation) were not reported.

Authors' conclusions: The effects of withdrawing antihypertensive medications on cognition or prevention of dementia are uncertain. There was a signal of a positive effect in one study looking at withdrawal after acute stroke but these results are unlikely to be generalisable to non-stroke settings and were not a primary outcome of the study. Withdrawing antihypertensive drugs was associated with increased blood pressure. It is unlikely to increase mortality at three to four months' follow-up, although there was a signal from one large study looking at withdrawal after stroke that withdrawal was associated an increase in cardiovascular events.

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Conflict of interest statement

SJ has no known conflicts of interest.

JH was a named co‐applicant on a UK National Institute for Health Research (NIHR) grant conducting a feasibility study of antihypertensive withdrawal for people with dementia, jointly run by the University of Nottingham and the University of Leicester.

TQ has no known conflicts of interest.

ER has no known conflicts of interest.

Figures

1
1
PRISMA Study flow diagram.
2
2
Cochrane 'Risk of bias' summary: review authors' judgements about each risk of bias item for each included study.
3
3
Forest plot of comparison: 1 Cognitive function (at 90 days), outcome: 1.1 Telephone Mini‐Mental State Examination score.
4
4
Forest plot of comparison: 1 Cognitive function (at 90 days), outcome: 1.2 Modified Telephone Interview for Cognitive Status score.
5
5
Forest plot of comparison: 2 Change in cognitive function (over 16 weeks), outcome: 2.1 Composite score.
6
6
Forest plot of comparison: 4 Adverse events, outcome: 4.1 Mortality.
7
7
Forest plot of comparison: 4 Adverse events, outcome: 4.2 Cardiovascular events.
1.1
1.1. Analysis
Comparison 1 Cognitive function (at 90 days), Outcome 1 Telephone Mini‐Mental State Examination score.
1.2
1.2. Analysis
Comparison 1 Cognitive function (at 90 days), Outcome 2 Modified Telephone Interview for Cognitive Status score.
2.1
2.1. Analysis
Comparison 2 Change in cognitive function (over 16 weeks), Outcome 1 Composite score.
2.2
2.2. Analysis
Comparison 2 Change in cognitive function (over 16 weeks), Outcome 2 Mini‐Mental State Examination score.
2.3
2.3. Analysis
Comparison 2 Change in cognitive function (over 16 weeks), Outcome 3 Stroop Interference score.
2.4
2.4. Analysis
Comparison 2 Change in cognitive function (over 16 weeks), Outcome 4 Trail making test score.
2.5
2.5. Analysis
Comparison 2 Change in cognitive function (over 16 weeks), Outcome 5 15‐Word Verbal Learning Immediate Recall score.
2.6
2.6. Analysis
Comparison 2 Change in cognitive function (over 16 weeks), Outcome 6 15‐Word Verbal Learning Delayed Recall score.
2.7
2.7. Analysis
Comparison 2 Change in cognitive function (over 16 weeks), Outcome 7 Visual Association Test score.
3.1
3.1. Analysis
Comparison 3 Blood pressure (at 7 days), Outcome 1 Systolic blood pressure.
3.2
3.2. Analysis
Comparison 3 Blood pressure (at 7 days), Outcome 2 Diastolic blood pressure.
4.1
4.1. Analysis
Comparison 4 Change in blood pressure (at 16 weeks), Outcome 1 Systolic blood pressure.
4.2
4.2. Analysis
Comparison 4 Change in blood pressure (at 16 weeks), Outcome 2 Diastolic blood pressure.
5.1
5.1. Analysis
Comparison 5 Adverse events, Outcome 1 Mortality.
5.2
5.2. Analysis
Comparison 5 Adverse events, Outcome 2 Cardiovascular events.
5.3
5.3. Analysis
Comparison 5 Adverse events, Outcome 3 Hospitalisation within 16 weeks.
6.1
6.1. Analysis
Comparison 6 Adherence to withdrawal, Outcome 1 Adherence over all 7 days.
See this image and copyright information in PMC

Update of

References

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