Journal of Human Hypertension (2014) 28, 283–287 & 2014 Macmillan Publishers Limited All rights reserved 0950-9240/14 www.nature.com/jhh
REVIEW
The evidence for treating hypertension in older people with dementia: a systematic review LC Beishon1, JK Harrison2, RH Harwood3, TG Robinson2, JRF Gladman3 and SP Conroy4 Hypertension and dementia commonly co-exist in older people, yet guidance is lacking on how to manage these co-existing conditions. The aim of this systematic review was to assess the evidence for the treatment of hypertension in older people with dementia. Medline, EMBASE, Cochrane Library and the national research register archives were searched. Inclusion criteria were: randomised controlled trial of hypertension treatment, included participants aged 65 þ years, participants had a diagnosis of dementia (global cognitive decline for at least 6 months affecting daily function), and the study assessed cognitive outcomes using validated tools. Dementia prevention studies and poor quality studies were excluded. The initial search revealed 1178 papers of potential interest, of which 24 were selected for review and six met the full inclusion criteria. Trials included people with mild-tomoderate but not severe dementia; exclusion criteria for the trials were extensive. Four trials were placebo-controlled RCTs; the remaining two compared different antihypertensives. All trials reported MMSE scores at baseline and follow-up; four reported blood pressure changes at follow-up; and only three reported cardiovascular morbidity or mortality at follow-up. Only one of four placebo-controlled studies showed evidence of blood pressure reduction, but no clear evidence for benefit (or harm) from antihypertensives on cognition, physical function or other cardiovascular outcomes. We found no evidence to confirm or refute the hypothesis that treatment of hypertension in people with dementia leads to overall health benefit. Journal of Human Hypertension (2014) 28, 283–287; doi:10.1038/jhh.2013.107; published online 7 November 2013 Keywords: dementia; outcomes; blood pressure
INTRODUCTION Hypertension is one of the most common long-term conditions, with a prevalence of 50% in community dwelling people aged 65 years or older.1 Studies have confirmed important reductions in cardiovascular morbidity and mortality with antihypertensive treatment in older people.2–4 Hypertension is associated with an increased risk of dementia.5 A reduction in incident dementia through treating hypertension has been shown in number of studies: Sys-Eur,6 PROGRESS7 and SCOPE.8 However, HYVET-COG9 and SHEP10 failed to show such an association; this may but be related to short follow-up periods9 and differential loss to follow-up,10 respectively. There is a lack of consensus as to whether the treatment of hypertension is beneficial in older patients with established cognitive impairment, with concerns that antihypertensive treatment may accelerate cognitive decline.11 Hypertensive patients who develop dementia have a paradoxical fall in blood pressure just before diagnosis, potentially as a result of autonomic dysregulation.11 This fall in blood pressure could induce cerebral hypoperfusion, worsening dementia. A cross sectional study demonstrated an association between low diastolic blood pressure and dementia, especially in patients receiving antihypertensive drugs.12 Patients with Alzheimer’s disease appear to have an increased vulnerability to alterations in cortical tissue perfusion.13 Hence, there is potential harm to cognition from antihypertensive treatment.
Although untreated hypertension is associated with increased cardiovascular, renal and cerebral morbidity and death,14 lowering blood pressure is not without risks.12 Orthostatic hypotension is a major factor contributing to falls in older people and can be exacerbated by antihypertensive drugs.15 Further, orthostatic hypotension has been shown to be associated with a history of myocardial infarction, transient ischaemic attack, frequent falls and difficulty walking.16 Significant diurnal variation in blood pressure,17 low resting diastolic blood pressure and postprandial hypotension,18 all potentially exacerbated by anti-hypertensive treatment, are associated with poorer cognitive outcomes and increased risk of mortality.19 There is no guidance on the management of hypertension in patients with dementia. A previous review of antihypertensive treatment in dementia20 combined findings from a combination of RCTs and cohort studies and concluded that antihypertensives appear to reduce the progression of dementia, but did not address the overall risk–benefit issue. The aim of this systematic review is to address this gap, by evaluating the RCT evidence for the treatment of older people with hypertension and concomitant dementia, and to examine a range of outcomes, including; blood pressure, cognition, activities of daily living and adverse outcomes (mortality, cardio and cerebrovascular events, side effects and institutionalisation). The primary outcome of interest for this review is the impact of blood pressure management on dementia progression, and thus studies excluding participants with cognitive impairment have been excluded from this review.
1 University of Leicester, Leicester, UK; 2Cardiovascular Sciences, Clinical Sciences Building, Leicester Royal Infirmary, Leicester, UK; 3Division of Rehabilitation and Ageing, Medical School, Queen’s Medical Centre, Nottingham, UK and 4Department of Geriatric Medicine, University Hospitals of Leicester NHS Trust, Leicester royal Infirmary, Leicester, UK. Correspondence: Dr L Beishon, Department of Geriatric Medicine, University of Leicester, Room 034, Level 5, Windsor Building, Leicester LE1 5WW, UK. E-mail: [email protected] Received 27 March 2013; revised 22 August 2013; accepted 18 September 2013; published online 7 November 2013
Treatment of hypertension in people with dementia LC Beishon et al
284 MATERIALS AND METHODS The following databases were searched from inception until August 2011:
Ovid Medline(R) 1966–2012 EMBASE 1988–2012 Cochrane Library National research register archives
The following search terms were used: Population: Elderly/Aged/Older people/Geriatric Assessment/Elders/Ger-
iatrics/Frail/Frail Elderly/Age460 years/Age480 years/Aged, 80 and over Disease/disorder: Cognition disorders/Alzheimer Disease/Cognitive Impairment/Memory Disorders/Dementia/Delirium/Amnestic/Vascular Dementia/Multi infarct Dementia/Frontotemporal Dementia Intervention: Hypertension/Antihypertensives/Antihypertensive Agents/ Blood Pressure/(named classes of antihypertensives and individual antihypertensives) The search strategy was then tailored individually to each database and limits applied where appropriate. The abstracts were screened from each database and identified for further review if the following inclusion criteria were met: Randomised controlled trial Included participants aged 65 þ years Participants had a diagnosis of dementia (global cognitive decline for at
least six months affecting daily function) The study included cognitive outcomes using validated tools
Exclusion criteria: Clinical trials deemed not to be of high quality using the van Tulder
criteria (o9/19)21
Trials studying participants who were cognitively intact and in whom
prevention of cognitive impairment was being assessed
Ohrui et al.23 recruited participants in a care home setting; Kume et al.22 recruited from those attending a Memory Clinic;22 and Sze et al.26 recruited people from a stroke unit. Otherwise participants were community dwelling older people,7 or the source of participants was unclear.24 Two of the studies7,26 only included participants who had previously experienced a stroke, with Sze et al.26) being restricted to the acute period 7–14 days post-event. Pantoni et al.25 and Kume et al.22 were designed to assess potential neuroprotective effects from the interventions tested rather than the treatment of blood pressure per se. Blood pressure at entry was stated as X140/90 mm Hg in all trials apart from PROGRESS,7 in which hypertension was not an entry criterion although the mean blood pressure of participants was 144/83 mm Hg, and Sze et al.,26 in which the baseline blood pressure was not stated. The severity of cognitive impairment at entry is shown in Table 1; no trials included people with severe dementia. Exclusion criteria for the trials were extensive. Individuals with common comorbidities such as heart failure, myocardial infarction, stroke, diabetes, renal failure and cancer were ineligible for participation in three of the trials.22,23 One specifically excluded people with Parkinson’s disease.25 Co-morbid psychiatric conditions including depression were also common exclusions.22–26 PROGRESS was the least exclusive only requiring that participants have no definite indication or contraindication for ACE-inhibitor treatment and tolerated a 4-week run-in period.7 Most trials excluded people with moderate to advanced dementia by virtue of their consent processes, although Kume et al.22 made provision to obtain consent from legal representatives. Follow-up ranged from a minimum of 3 months to a maximum of 47 months; all trials reported MMSE scores at baseline and follow-up; five reported blood pressure changes at followup;7,22,24,25 and only three reported cardiovascular morbidity or mortality at follow-up.24–26
Trials in people with mild cognitive impairment (amnesic syndrome not
affecting daily function) Trials using non-antihypertensives as treatment for dementia (e.g.
cholinesterase inhibitors) which might have had an effect on blood pressure Insufficient English language content to permit meaningful information extraction The review was limited to randomised controlled trials to identify the evidence least likely to be affected by selection, ascertainment or recall bias. Studies were screened for eligibility by one reviewer using the above criteria based on the title and/or abstract. The studies for inclusion were then assessed by two reviewers independently and graded using the van Tulder criteria; trials with a mean score of o9 were rejected.21 Two reviewers extracted trial data, and any differences were resolved through discussion. The PRISMA checklist for this review can be seen in Supplementary Appendix 1.
RESULTS The initial search revealed 1178 papers of potential interest, of which 24 were selected for review and six met the full inclusion criteria (Figure 1). Overall trial quality was high with a mean van Tulder score of 11.4/19 (range 10–16). Detailed results for all the studies included in this review can be seen in Supplementary Appendix Table. Trial characteristics Table 1 summarises the characteristics of included trials. Disease type varied; three trials included people with Alzheimer’s dementia (Kume et al.,22 Ohrui et al.23 and Morich et al.24): one involving mixed dementia (Tzourio et al.,7 also known as PROGRESS) and two vascular dementia (Pantoni et al.25and Sze et al.26). Four trials were placebo-controlled RCTs,7,24–26 and the remaining two compared different antihypertensives.22,23 Journal of Human Hypertension (2014) 283 – 287
Placebo-controlled study outcomes Blood pressure. Pantoni et al.25 and Sze et al.26 found no difference in mean blood pressure with Nimodipine treatment compared with placebo. Tzourio et al.7 found a mean difference of 9 mm Hg in systolic blood pressure difference at follow-up following treatment with Indapamide and Perindopril. Morich et al.24 did not report blood pressure values at follow-up. Cognition. Pooled data from Morich et al.24 showed that Nimodipine treatment was associated with reduced level of decline in MMSE (scored between 0–30 points), 90 mg/day 1.68 points, 180 mg/day 1.37 points compared with 1.97 points for those treated with placebo (P ¼ 0.004). Pantoni et al.25 found that treatment with Nimodipine resulted in improved performance in Lexical Production (8.6–8.3 at 52 weeks) compared with those receiving placebo (10.5–8.1 at 52 weeks, Po0.01). Sze et al.26 used two measures to assess cognition: MMSE and Fuld Object Memory Evaluation (FOME), which is scored from 0 to 10 points. At 12 weeks, there was no clinically significant difference in FOME score (9.2±0.3 vs 8.5±0.5) or MMSE scores (Group A 29.86±0.07 vs 29.63±0.16; Group B 25.11±1.09 vs 19.00±2.43).26 PROGRESS7 is the only study to include cognitively intact, as well as cognitively impaired participants. They report a reduced risk of developing cognitive decline in those without cognitive impairment at study entry (relative risk reduction 19%; 95% CI: 4 to 32%). However, for those with baseline cognitive impairment, these results are not matched. There was no evidence of reduced cognitive decline with treatment (relative risk reduction (RRR) 5%; 95% CI: 42 to 22%). & 2014 Macmillan Publishers Limited
Treatment of hypertension in people with dementia LC Beishon et al
285 Medline 249 papers
EMBASE 730 papers
Cochrane 199 papers
National research register 0 papers
Total abstracts obtained - 1178
Duplicates: 134 Total papers screened - 1044
Rejected: Not relevant (title or abstract review) = 1020 Papers reviewed: 24
Papers retained: 6
Figure 1.
Table 1.
Rejected: MCI only = 1 No cognitive outcomes reported = 3 Not randomised study = 3 Duplicate publications = 3 Protocol only = 1 Unobtainable = 3 Language issues = 3 No difference in blood pressure management = 1
Flow diagram illustrating the selection of papers.
Summary characteristics of selected trials examining the effects of antihypertensives on cognitive outcomes
Author/year
22
Kumeet al. Pantoni et al.25 Ohrui et al.23 Tzourio et al.7
Intervention
Telmisartan 40 mg vs Amlodipine 5 mg Nimodipine 90 mg vs placebo Perindopril or Captopril vs Enalapril or Imidapril vs Nifedipine or Nivaldipine Perindopril 4 mg, Indapamide 2.5 mg vs placebo
Sze et al.26
Nimodipine 90 mg vs placebo
Morich et al.24
Nimodipine 90 mg/ 180 mg vs placebo
Participants’ cognition
MMSE at entry
Sample size
Followup (months)
Van Tulder scores
IV
DC
SC
Total
Mild (probable) Alzheimer’s Mild-tomoderate vascular dementia Mild to moderate Alzheimer’s Cognitive impairment
Cognitive diagnosis not determined by MMSE X12 and p24
20
6
6
4
0
10
230
12
8
6
1
15
13–23
162
12
6
5
1
12
6105
47
9
5
2
16
Mixed dementia Predominant vascular dementia, moderate severity Probable Alzheimer’s
p25 Mean MMSE 21.5 (intervention), 18.5 (control); (in ‘severe disability’ cohort only)
3
4
5
2
11
7
10
5
1
16
Unclear
Stratum 1: 12–18
964a 86
1605
Stratum 2: 19–23 Abbreviations: DC, descriptive criteria; IV, internal validity; SC, statistical criteria. aSubgroup with cognitive impairment at baseline.
& 2014 Macmillan Publishers Limited
Journal of Human Hypertension (2014) 283 – 287
Treatment of hypertension in people with dementia LC Beishon et al
286 Activities of daily living. Only Sze et al.26 assessed ADL performance as an outcome measure. They assessed Barthel index at baseline and at follow-up and found that treatment with Nimodipine did not result in any difference in mean score change (P ¼ 0.6), although the scores are not provided. Adverse outcomes. Pantoni et al.25 found that Nimodipine treatment reduced the risk of both cardiovascular (relative risk (RR) 2.3; 95% CI: 1.1–4.6) and cerebrovascular (RR 3.9; 95% CI: 1.5– 10.2) events at 1 year. Morich et al.24 report drop-out rates, primarily related to adverse drug side effects and that two of the six deaths within the treatment group were likely related to Nimodipine, presenting clinical descriptions of the cases. Comparative study outcomes Blood pressure. All three comparative studies demonstrated effects of treatment in lowering blood pressure. However, none of them demonstrated that a particular class or combination of drugs was superior in lowering blood pressure.22,23 Cognition. Kume et al.22 used three measures of cognitive performance: MMSE, Alzheimer’s Disease Assessment Scale Cognitive subscale, Japanese version (ADASJCOG scored from 0 to 70 points) and the Wechsler Memory Scale Revised (WMSR). There was a benefit from Telmisartan over Amlodipine in slowing the decline in cognition on one of these measures, the ADASJCOG (Telmisartan 18.1±4.5 vs 16.7±5.1 at 6 months; Amlodipine 15.0±5.6 vs 17.8±6.7). Ohrui et al.23 found that those treated with ‘brain-penetrating’ ACE-inhibitors, Perindopril or Captopril, showed a clinically important reduced rate of 1-year decline of MMSE score of 0.6±0.1 points, compared with Enalapril or Imidapril (non-brainpenetrating ACE-inhibitors) 4.6±0.3 points (P ¼ 0.0023), or Nifedipine or Nivaldipine (calcium-channel blockers) 4.9±0.3 points (Po0.001). Activities of daily living (ADL). Neither Kume et al.22 nor Ohrui et al.23 reported activities of daily living in their outcome measures. Adverse outcomes. Neither Kume et al.22 nor Ohrui et al.23 report rates of morbidity and mortality.
DISCUSSION AND CLINICAL IMPLICATIONS Given the importance of hypertension and dementia, the paucity of research addressing management of these commonly co-existing conditions is disappointing. The available evidence points towards antihypertensives being effective in lowering blood pressure in people with mild-moderate dementia, but with no consistent evidence of benefit in cognitive outcomes.7,22,25 Although Ohrui et al.23 noted some evidence of a slowing in cognitive outcomes in those people treated with brainpenetrating ACE-inhibitors, this was a small trial and the trial quality was modest. Sze et al.26 found some benefit from Nimodipine, but only in a small subgroup with severe disability following stroke, and the possibility of a type 1 error cannot be excluded.26 Morich et al.24 found that higher doses of Nimodipine were resulted in lower rates of cognitive decline in one subgroup but also directly attributed deaths during the study to treatment with this drug. The quality of data in some studies is weakened by the extensive use of post hoc analysis25 and multiple testing,24,25 which increase the risk of bias.27,28 Lack of clear reporting was common, for example, the values of MMSE and FOME scores in the study of Sze et al.26 Journal of Human Hypertension (2014) 283 – 287
Notably, most trial participants were relatively ‘well’, with only one trial recruiting participants from a care home23 and most excluding participants with more substantial physical or mental health problems.22,24–26 There was no evidence of any benefit (or harm) from the treatment of hypertension in the presence of severe dementia. Reporting of other important outcomes such as activities of daily living, side effects, quality of life and resource use was weak or absent. In the studies reporting cardiovascular morbidity or mortality, there was no overwhelming evidence of benefit or harm. The review also provides evidence that a cognitively intact population may respond differently to treatment than those with existing cognitive impairment. Tzourio et al.’s results of beneficial reduction in cognitive decline seen only in those without baseline impairment are thought to be mediated by the effects of reducing recurrent stroke events.7 This difference between the behaviour of those with dementia and those without is consistent with recent research that showed that, although hypertension has been demonstrated as a predictor of mortality in physically active older adults, this relationship is reversed in those who are frail and hypertensive and who have a reduced risk of mortality.29 It is also in-keeping with the findings of the Leiden-85 Plus Study, which reported that higher systolic blood pressure was associated with resilience to cognitive decline in the oldest old population.30 There was significant heterogeneity seen between the studies, particularly in terms of dementia type (vascular, Alzheimer’s etc.), and the type of antihypertensive therapy used, with a predominance of use of Nimodipine, not a typical antihypertensive drug. Different types of dementia are likely to respond differently to various treatments, for example, vascular dementia may show clinically significant benefit to antihypertensive medications as a result of reduced vascular damage from hypertension, which may be less important in the pathogenesis of Alzheimer’s disease. Strengths of this review include the focus on older people with dementia, hitherto relatively excluded from hypertension studies, the systematic approach and high quality of retained papers. Potential weaknesses include the lack of inclusion of nonrandomised studies, the marked heterogeneity in study design and trial outcome measures, which precluded a meta-analysis. The present data indicate that treating hypertension in older people with dementia is likely to confer benefits in terms of reducing blood pressure, which should lead to cardiovascular benefits.1 However, the evidence reviewed does not help answer other important questions relevant to an older population with dementia, especially for those people with concomitant physical health issues and disability, such as the impact on cognition and the relative benefits in cardiovascular outcomes contrasted with potential harms of treatment. Older people with dementia and physical disability with a limited life expectancy31,32 may have differing treatment priorities from the general population of community dwelling older people. Avoiding falls, fractures, hospitalisation and institutionalisation may be seen as more important than preventing cardiovascular events. This work highlights the need for additional studies in older people with hypertension and dementia, which can inform the delicate balance of risk and benefits of treatment, and will need to incorporate a variety of outcomes that are relevant to older people not just with early-stage dementia but also with more severe disease. Such studies will need to pay careful attention to recruitment and consent issues, ensure that older people with concomitant comorbidities or disability are represented and assess outcomes that reflect broader issues than traditional cardiovascular outcomes. CONFLICT OF INTEREST The authors declare no conflict of interest.
& 2014 Macmillan Publishers Limited
Treatment of hypertension in people with dementia LC Beishon et al
287 AUTHORSHIP All authors conform that they are entitled to be considered as authors according to the universal requirements set out at: http://mts-jhh.nature.com/ cgi-bin/main.plex?form_type=display_auth_instructions.
AUTHOR CONTRIBUTIONS SC had the original idea, which was moulded by LB, JKH, RHH, TGR and JRFG. SC, LB, JKH undertook the literature search, analysed the papers and abstracted data; all authors contributed to writing the paper.
14
15 16
17
18
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but unrelated to cholinesterase-inhibitor use. J Alzheimers Dis 2010; 21(2): 519–526. Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008; 358(18): 1887–1898. Tinetti ME. Preventing falls in elderly persons. New Engl J Med 2003; 348(1): 42–49. Rutan GH, Hermanson B, Bild DE, Kittner SJ, LaBaw F, Tell GS. Orthostatic hypotension in older adults. The Cardiovascular Health Study. CHS Collaborative Research Group. Hypertension 1992; 19(6 Pt 1): 508–519. Kanemaru A, Kanemaru K, Kuwajima I. The effects of short-term blood pressure variability and nighttime blood pressure levels on cognitive function. Hypertens Res 2001; 24(1): 19–24. Fisher AA, Davis MW, Srikusalanukul W, Budge MM. Postprandial hypotension predicts all-cause mortality in older, low-level care residents. J Am Geriatr Soc 2005; 53(8): 1313–1320. Moretti R, Torre P, Antonello RM, Manganaro D, Vilotti C, Pizzolato G. Risk factors for vascular dementia: hypotension as a key point. Vasc Health Risk Manag 2008; 4(2): 395–402. Shah K, Qureshi SU, Johnson M, Parikh N, Schulz PE, Kunik ME. Does use of antihypertensive drugs affect the incidence or progression of dementia? A systematic review. Am J Geriatric Pharmacother 2009; 7(5): 250–261. vanTulder MW, Assendelft WJJ, Koes BW, Bouter LM. Method guidelines for systematic reviews in the Cochrane Collaboration back review group for spinal disorders. Spine 1997; 22(20): 2323–2330. Kume K, Hanyu H, Sakurai H, Takada Y, Onuma T, Iwamoto T. Effects of telmisartan on cognition and regional cerebral blood flow in hypertensive patients with Alzheimer’s disease. Geriatrics Gerontol Int 2012; 12: 207–214. Ohrui T, Tomita N, Sato-Nakagawa T, Matsui T, Maruyama M, Niwa K et al. Effects of brain-penetrating ACE inhibitors on Alzheimer disease progression. Neurology 2004; 63: 1324–1325. Morich FJ, Bieber F, Lewis JM, Kaiser L, Cutler NR, Escobar JI et al. Nimodipine in the Treatment of Probable Alzheimer’s Disease. Clin Drug Invest 1996; 11(4): 185–195. Pantoni L, del Ser T, Soglian AG, Amigoni S, Spadari G, Binelli D et al. Efficacy and safety of nimodipine in subcortical vascular dementia: a randomized placebocontrolled trial. Stroke 2005; 36: 619–624. Sze KH, Sim TC, Wong E, Cheng S, Woo J. Effect of nimodipine on memory after cerebral infarction. Acta Neurologica Scandinavica 1998; 97: 386–392. Wang R, Lagakos S, Ware J, Hunter D, Drazen J. Statistics in Medicine — Reporting of Subgroup Analyses in Clinical Trials. New Engl J Med 2007; 357(21): 2189–2194. Feise R. Do multiple outcome measures require P-value adjustment? BMC Med Res Methodol 2002; 2(1): 8. Odden MC, Peralta CA, Haan MN, Covinsky KE. Rethinking the association of high blood pressure with mortality in elderly adults: the impact of frailty. Arch Intern Med 2012; 172(15): 1162–1168. Sabayan B, Oleksik A, Maier A, van Buchem M, Poortvliet R, de Ruijter W et al. High blood pressure and resilience to physical and cognitive decline in the oldest old: The Leiden 85-Plus Study. J Am Geriatrics Soc 2012; 60: 2014–2019. Xie J, Brayne C, Matthews FE. Survival times in people with dementia: analysis from population based cohort study with 14 year follow-up. BMJ 2008; 336: 258–262. Gill TM, Gahbauer EA, Han L, Allore HG. Trajectories of Disability in the Last Year of Life. New Engl J Med 2010; 362(13): 1173–1180.
Supplementary Information accompanies this paper on the Journal of Human Hypertension website (http://www.nature.com/jhh)
& 2014 Macmillan Publishers Limited
Journal of Human Hypertension (2014) 283 – 287
REVIEW
The evidence for treating hypertension in older people with dementia: a systematic review LC Beishon1, JK Harrison2, RH Harwood3, TG Robinson2, JRF Gladman3 and SP Conroy4 Hypertension and dementia commonly co-exist in older people, yet guidance is lacking on how to manage these co-existing conditions. The aim of this systematic review was to assess the evidence for the treatment of hypertension in older people with dementia. Medline, EMBASE, Cochrane Library and the national research register archives were searched. Inclusion criteria were: randomised controlled trial of hypertension treatment, included participants aged 65 þ years, participants had a diagnosis of dementia (global cognitive decline for at least 6 months affecting daily function), and the study assessed cognitive outcomes using validated tools. Dementia prevention studies and poor quality studies were excluded. The initial search revealed 1178 papers of potential interest, of which 24 were selected for review and six met the full inclusion criteria. Trials included people with mild-tomoderate but not severe dementia; exclusion criteria for the trials were extensive. Four trials were placebo-controlled RCTs; the remaining two compared different antihypertensives. All trials reported MMSE scores at baseline and follow-up; four reported blood pressure changes at follow-up; and only three reported cardiovascular morbidity or mortality at follow-up. Only one of four placebo-controlled studies showed evidence of blood pressure reduction, but no clear evidence for benefit (or harm) from antihypertensives on cognition, physical function or other cardiovascular outcomes. We found no evidence to confirm or refute the hypothesis that treatment of hypertension in people with dementia leads to overall health benefit. Journal of Human Hypertension (2014) 28, 283–287; doi:10.1038/jhh.2013.107; published online 7 November 2013 Keywords: dementia; outcomes; blood pressure
INTRODUCTION Hypertension is one of the most common long-term conditions, with a prevalence of 50% in community dwelling people aged 65 years or older.1 Studies have confirmed important reductions in cardiovascular morbidity and mortality with antihypertensive treatment in older people.2–4 Hypertension is associated with an increased risk of dementia.5 A reduction in incident dementia through treating hypertension has been shown in number of studies: Sys-Eur,6 PROGRESS7 and SCOPE.8 However, HYVET-COG9 and SHEP10 failed to show such an association; this may but be related to short follow-up periods9 and differential loss to follow-up,10 respectively. There is a lack of consensus as to whether the treatment of hypertension is beneficial in older patients with established cognitive impairment, with concerns that antihypertensive treatment may accelerate cognitive decline.11 Hypertensive patients who develop dementia have a paradoxical fall in blood pressure just before diagnosis, potentially as a result of autonomic dysregulation.11 This fall in blood pressure could induce cerebral hypoperfusion, worsening dementia. A cross sectional study demonstrated an association between low diastolic blood pressure and dementia, especially in patients receiving antihypertensive drugs.12 Patients with Alzheimer’s disease appear to have an increased vulnerability to alterations in cortical tissue perfusion.13 Hence, there is potential harm to cognition from antihypertensive treatment.
Although untreated hypertension is associated with increased cardiovascular, renal and cerebral morbidity and death,14 lowering blood pressure is not without risks.12 Orthostatic hypotension is a major factor contributing to falls in older people and can be exacerbated by antihypertensive drugs.15 Further, orthostatic hypotension has been shown to be associated with a history of myocardial infarction, transient ischaemic attack, frequent falls and difficulty walking.16 Significant diurnal variation in blood pressure,17 low resting diastolic blood pressure and postprandial hypotension,18 all potentially exacerbated by anti-hypertensive treatment, are associated with poorer cognitive outcomes and increased risk of mortality.19 There is no guidance on the management of hypertension in patients with dementia. A previous review of antihypertensive treatment in dementia20 combined findings from a combination of RCTs and cohort studies and concluded that antihypertensives appear to reduce the progression of dementia, but did not address the overall risk–benefit issue. The aim of this systematic review is to address this gap, by evaluating the RCT evidence for the treatment of older people with hypertension and concomitant dementia, and to examine a range of outcomes, including; blood pressure, cognition, activities of daily living and adverse outcomes (mortality, cardio and cerebrovascular events, side effects and institutionalisation). The primary outcome of interest for this review is the impact of blood pressure management on dementia progression, and thus studies excluding participants with cognitive impairment have been excluded from this review.
1 University of Leicester, Leicester, UK; 2Cardiovascular Sciences, Clinical Sciences Building, Leicester Royal Infirmary, Leicester, UK; 3Division of Rehabilitation and Ageing, Medical School, Queen’s Medical Centre, Nottingham, UK and 4Department of Geriatric Medicine, University Hospitals of Leicester NHS Trust, Leicester royal Infirmary, Leicester, UK. Correspondence: Dr L Beishon, Department of Geriatric Medicine, University of Leicester, Room 034, Level 5, Windsor Building, Leicester LE1 5WW, UK. E-mail: [email protected] Received 27 March 2013; revised 22 August 2013; accepted 18 September 2013; published online 7 November 2013
Treatment of hypertension in people with dementia LC Beishon et al
284 MATERIALS AND METHODS The following databases were searched from inception until August 2011:
Ovid Medline(R) 1966–2012 EMBASE 1988–2012 Cochrane Library National research register archives
The following search terms were used: Population: Elderly/Aged/Older people/Geriatric Assessment/Elders/Ger-
iatrics/Frail/Frail Elderly/Age460 years/Age480 years/Aged, 80 and over Disease/disorder: Cognition disorders/Alzheimer Disease/Cognitive Impairment/Memory Disorders/Dementia/Delirium/Amnestic/Vascular Dementia/Multi infarct Dementia/Frontotemporal Dementia Intervention: Hypertension/Antihypertensives/Antihypertensive Agents/ Blood Pressure/(named classes of antihypertensives and individual antihypertensives) The search strategy was then tailored individually to each database and limits applied where appropriate. The abstracts were screened from each database and identified for further review if the following inclusion criteria were met: Randomised controlled trial Included participants aged 65 þ years Participants had a diagnosis of dementia (global cognitive decline for at
least six months affecting daily function) The study included cognitive outcomes using validated tools
Exclusion criteria: Clinical trials deemed not to be of high quality using the van Tulder
criteria (o9/19)21
Trials studying participants who were cognitively intact and in whom
prevention of cognitive impairment was being assessed
Ohrui et al.23 recruited participants in a care home setting; Kume et al.22 recruited from those attending a Memory Clinic;22 and Sze et al.26 recruited people from a stroke unit. Otherwise participants were community dwelling older people,7 or the source of participants was unclear.24 Two of the studies7,26 only included participants who had previously experienced a stroke, with Sze et al.26) being restricted to the acute period 7–14 days post-event. Pantoni et al.25 and Kume et al.22 were designed to assess potential neuroprotective effects from the interventions tested rather than the treatment of blood pressure per se. Blood pressure at entry was stated as X140/90 mm Hg in all trials apart from PROGRESS,7 in which hypertension was not an entry criterion although the mean blood pressure of participants was 144/83 mm Hg, and Sze et al.,26 in which the baseline blood pressure was not stated. The severity of cognitive impairment at entry is shown in Table 1; no trials included people with severe dementia. Exclusion criteria for the trials were extensive. Individuals with common comorbidities such as heart failure, myocardial infarction, stroke, diabetes, renal failure and cancer were ineligible for participation in three of the trials.22,23 One specifically excluded people with Parkinson’s disease.25 Co-morbid psychiatric conditions including depression were also common exclusions.22–26 PROGRESS was the least exclusive only requiring that participants have no definite indication or contraindication for ACE-inhibitor treatment and tolerated a 4-week run-in period.7 Most trials excluded people with moderate to advanced dementia by virtue of their consent processes, although Kume et al.22 made provision to obtain consent from legal representatives. Follow-up ranged from a minimum of 3 months to a maximum of 47 months; all trials reported MMSE scores at baseline and follow-up; five reported blood pressure changes at followup;7,22,24,25 and only three reported cardiovascular morbidity or mortality at follow-up.24–26
Trials in people with mild cognitive impairment (amnesic syndrome not
affecting daily function) Trials using non-antihypertensives as treatment for dementia (e.g.
cholinesterase inhibitors) which might have had an effect on blood pressure Insufficient English language content to permit meaningful information extraction The review was limited to randomised controlled trials to identify the evidence least likely to be affected by selection, ascertainment or recall bias. Studies were screened for eligibility by one reviewer using the above criteria based on the title and/or abstract. The studies for inclusion were then assessed by two reviewers independently and graded using the van Tulder criteria; trials with a mean score of o9 were rejected.21 Two reviewers extracted trial data, and any differences were resolved through discussion. The PRISMA checklist for this review can be seen in Supplementary Appendix 1.
RESULTS The initial search revealed 1178 papers of potential interest, of which 24 were selected for review and six met the full inclusion criteria (Figure 1). Overall trial quality was high with a mean van Tulder score of 11.4/19 (range 10–16). Detailed results for all the studies included in this review can be seen in Supplementary Appendix Table. Trial characteristics Table 1 summarises the characteristics of included trials. Disease type varied; three trials included people with Alzheimer’s dementia (Kume et al.,22 Ohrui et al.23 and Morich et al.24): one involving mixed dementia (Tzourio et al.,7 also known as PROGRESS) and two vascular dementia (Pantoni et al.25and Sze et al.26). Four trials were placebo-controlled RCTs,7,24–26 and the remaining two compared different antihypertensives.22,23 Journal of Human Hypertension (2014) 283 – 287
Placebo-controlled study outcomes Blood pressure. Pantoni et al.25 and Sze et al.26 found no difference in mean blood pressure with Nimodipine treatment compared with placebo. Tzourio et al.7 found a mean difference of 9 mm Hg in systolic blood pressure difference at follow-up following treatment with Indapamide and Perindopril. Morich et al.24 did not report blood pressure values at follow-up. Cognition. Pooled data from Morich et al.24 showed that Nimodipine treatment was associated with reduced level of decline in MMSE (scored between 0–30 points), 90 mg/day 1.68 points, 180 mg/day 1.37 points compared with 1.97 points for those treated with placebo (P ¼ 0.004). Pantoni et al.25 found that treatment with Nimodipine resulted in improved performance in Lexical Production (8.6–8.3 at 52 weeks) compared with those receiving placebo (10.5–8.1 at 52 weeks, Po0.01). Sze et al.26 used two measures to assess cognition: MMSE and Fuld Object Memory Evaluation (FOME), which is scored from 0 to 10 points. At 12 weeks, there was no clinically significant difference in FOME score (9.2±0.3 vs 8.5±0.5) or MMSE scores (Group A 29.86±0.07 vs 29.63±0.16; Group B 25.11±1.09 vs 19.00±2.43).26 PROGRESS7 is the only study to include cognitively intact, as well as cognitively impaired participants. They report a reduced risk of developing cognitive decline in those without cognitive impairment at study entry (relative risk reduction 19%; 95% CI: 4 to 32%). However, for those with baseline cognitive impairment, these results are not matched. There was no evidence of reduced cognitive decline with treatment (relative risk reduction (RRR) 5%; 95% CI: 42 to 22%). & 2014 Macmillan Publishers Limited
Treatment of hypertension in people with dementia LC Beishon et al
285 Medline 249 papers
EMBASE 730 papers
Cochrane 199 papers
National research register 0 papers
Total abstracts obtained - 1178
Duplicates: 134 Total papers screened - 1044
Rejected: Not relevant (title or abstract review) = 1020 Papers reviewed: 24
Papers retained: 6
Figure 1.
Table 1.
Rejected: MCI only = 1 No cognitive outcomes reported = 3 Not randomised study = 3 Duplicate publications = 3 Protocol only = 1 Unobtainable = 3 Language issues = 3 No difference in blood pressure management = 1
Flow diagram illustrating the selection of papers.
Summary characteristics of selected trials examining the effects of antihypertensives on cognitive outcomes
Author/year
22
Kumeet al. Pantoni et al.25 Ohrui et al.23 Tzourio et al.7
Intervention
Telmisartan 40 mg vs Amlodipine 5 mg Nimodipine 90 mg vs placebo Perindopril or Captopril vs Enalapril or Imidapril vs Nifedipine or Nivaldipine Perindopril 4 mg, Indapamide 2.5 mg vs placebo
Sze et al.26
Nimodipine 90 mg vs placebo
Morich et al.24
Nimodipine 90 mg/ 180 mg vs placebo
Participants’ cognition
MMSE at entry
Sample size
Followup (months)
Van Tulder scores
IV
DC
SC
Total
Mild (probable) Alzheimer’s Mild-tomoderate vascular dementia Mild to moderate Alzheimer’s Cognitive impairment
Cognitive diagnosis not determined by MMSE X12 and p24
20
6
6
4
0
10
230
12
8
6
1
15
13–23
162
12
6
5
1
12
6105
47
9
5
2
16
Mixed dementia Predominant vascular dementia, moderate severity Probable Alzheimer’s
p25 Mean MMSE 21.5 (intervention), 18.5 (control); (in ‘severe disability’ cohort only)
3
4
5
2
11
7
10
5
1
16
Unclear
Stratum 1: 12–18
964a 86
1605
Stratum 2: 19–23 Abbreviations: DC, descriptive criteria; IV, internal validity; SC, statistical criteria. aSubgroup with cognitive impairment at baseline.
& 2014 Macmillan Publishers Limited
Journal of Human Hypertension (2014) 283 – 287
Treatment of hypertension in people with dementia LC Beishon et al
286 Activities of daily living. Only Sze et al.26 assessed ADL performance as an outcome measure. They assessed Barthel index at baseline and at follow-up and found that treatment with Nimodipine did not result in any difference in mean score change (P ¼ 0.6), although the scores are not provided. Adverse outcomes. Pantoni et al.25 found that Nimodipine treatment reduced the risk of both cardiovascular (relative risk (RR) 2.3; 95% CI: 1.1–4.6) and cerebrovascular (RR 3.9; 95% CI: 1.5– 10.2) events at 1 year. Morich et al.24 report drop-out rates, primarily related to adverse drug side effects and that two of the six deaths within the treatment group were likely related to Nimodipine, presenting clinical descriptions of the cases. Comparative study outcomes Blood pressure. All three comparative studies demonstrated effects of treatment in lowering blood pressure. However, none of them demonstrated that a particular class or combination of drugs was superior in lowering blood pressure.22,23 Cognition. Kume et al.22 used three measures of cognitive performance: MMSE, Alzheimer’s Disease Assessment Scale Cognitive subscale, Japanese version (ADASJCOG scored from 0 to 70 points) and the Wechsler Memory Scale Revised (WMSR). There was a benefit from Telmisartan over Amlodipine in slowing the decline in cognition on one of these measures, the ADASJCOG (Telmisartan 18.1±4.5 vs 16.7±5.1 at 6 months; Amlodipine 15.0±5.6 vs 17.8±6.7). Ohrui et al.23 found that those treated with ‘brain-penetrating’ ACE-inhibitors, Perindopril or Captopril, showed a clinically important reduced rate of 1-year decline of MMSE score of 0.6±0.1 points, compared with Enalapril or Imidapril (non-brainpenetrating ACE-inhibitors) 4.6±0.3 points (P ¼ 0.0023), or Nifedipine or Nivaldipine (calcium-channel blockers) 4.9±0.3 points (Po0.001). Activities of daily living (ADL). Neither Kume et al.22 nor Ohrui et al.23 reported activities of daily living in their outcome measures. Adverse outcomes. Neither Kume et al.22 nor Ohrui et al.23 report rates of morbidity and mortality.
DISCUSSION AND CLINICAL IMPLICATIONS Given the importance of hypertension and dementia, the paucity of research addressing management of these commonly co-existing conditions is disappointing. The available evidence points towards antihypertensives being effective in lowering blood pressure in people with mild-moderate dementia, but with no consistent evidence of benefit in cognitive outcomes.7,22,25 Although Ohrui et al.23 noted some evidence of a slowing in cognitive outcomes in those people treated with brainpenetrating ACE-inhibitors, this was a small trial and the trial quality was modest. Sze et al.26 found some benefit from Nimodipine, but only in a small subgroup with severe disability following stroke, and the possibility of a type 1 error cannot be excluded.26 Morich et al.24 found that higher doses of Nimodipine were resulted in lower rates of cognitive decline in one subgroup but also directly attributed deaths during the study to treatment with this drug. The quality of data in some studies is weakened by the extensive use of post hoc analysis25 and multiple testing,24,25 which increase the risk of bias.27,28 Lack of clear reporting was common, for example, the values of MMSE and FOME scores in the study of Sze et al.26 Journal of Human Hypertension (2014) 283 – 287
Notably, most trial participants were relatively ‘well’, with only one trial recruiting participants from a care home23 and most excluding participants with more substantial physical or mental health problems.22,24–26 There was no evidence of any benefit (or harm) from the treatment of hypertension in the presence of severe dementia. Reporting of other important outcomes such as activities of daily living, side effects, quality of life and resource use was weak or absent. In the studies reporting cardiovascular morbidity or mortality, there was no overwhelming evidence of benefit or harm. The review also provides evidence that a cognitively intact population may respond differently to treatment than those with existing cognitive impairment. Tzourio et al.’s results of beneficial reduction in cognitive decline seen only in those without baseline impairment are thought to be mediated by the effects of reducing recurrent stroke events.7 This difference between the behaviour of those with dementia and those without is consistent with recent research that showed that, although hypertension has been demonstrated as a predictor of mortality in physically active older adults, this relationship is reversed in those who are frail and hypertensive and who have a reduced risk of mortality.29 It is also in-keeping with the findings of the Leiden-85 Plus Study, which reported that higher systolic blood pressure was associated with resilience to cognitive decline in the oldest old population.30 There was significant heterogeneity seen between the studies, particularly in terms of dementia type (vascular, Alzheimer’s etc.), and the type of antihypertensive therapy used, with a predominance of use of Nimodipine, not a typical antihypertensive drug. Different types of dementia are likely to respond differently to various treatments, for example, vascular dementia may show clinically significant benefit to antihypertensive medications as a result of reduced vascular damage from hypertension, which may be less important in the pathogenesis of Alzheimer’s disease. Strengths of this review include the focus on older people with dementia, hitherto relatively excluded from hypertension studies, the systematic approach and high quality of retained papers. Potential weaknesses include the lack of inclusion of nonrandomised studies, the marked heterogeneity in study design and trial outcome measures, which precluded a meta-analysis. The present data indicate that treating hypertension in older people with dementia is likely to confer benefits in terms of reducing blood pressure, which should lead to cardiovascular benefits.1 However, the evidence reviewed does not help answer other important questions relevant to an older population with dementia, especially for those people with concomitant physical health issues and disability, such as the impact on cognition and the relative benefits in cardiovascular outcomes contrasted with potential harms of treatment. Older people with dementia and physical disability with a limited life expectancy31,32 may have differing treatment priorities from the general population of community dwelling older people. Avoiding falls, fractures, hospitalisation and institutionalisation may be seen as more important than preventing cardiovascular events. This work highlights the need for additional studies in older people with hypertension and dementia, which can inform the delicate balance of risk and benefits of treatment, and will need to incorporate a variety of outcomes that are relevant to older people not just with early-stage dementia but also with more severe disease. Such studies will need to pay careful attention to recruitment and consent issues, ensure that older people with concomitant comorbidities or disability are represented and assess outcomes that reflect broader issues than traditional cardiovascular outcomes. CONFLICT OF INTEREST The authors declare no conflict of interest.
& 2014 Macmillan Publishers Limited
Treatment of hypertension in people with dementia LC Beishon et al
287 AUTHORSHIP All authors conform that they are entitled to be considered as authors according to the universal requirements set out at: http://mts-jhh.nature.com/ cgi-bin/main.plex?form_type=display_auth_instructions.
AUTHOR CONTRIBUTIONS SC had the original idea, which was moulded by LB, JKH, RHH, TGR and JRFG. SC, LB, JKH undertook the literature search, analysed the papers and abstracted data; all authors contributed to writing the paper.
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Supplementary Information accompanies this paper on the Journal of Human Hypertension website (http://www.nature.com/jhh)
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Journal of Human Hypertension (2014) 283 – 287
