Effect of Discontinuation of Antihypertensive Treatment in Elderly People on Cognitive Functioning—the DANTE Study Leiden: A Randomized Clinical Trial | Cerebrovascular Disease | JAMA Internal Medicine | JAMA Network
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Strandgaard  S, Paulson  OB.  Cerebrovascular consequences of hypertension.  Lancet. 1994;344(8921):519-521.PubMedGoogle ScholarCrossref
Debette  S, Seshadri  S, Beiser  A,  et al.  Midlife vascular risk factor exposure accelerates structural brain aging and cognitive decline.  Neurology. 2011;77(5):461-468.PubMedGoogle ScholarCrossref
Kennelly  SP, Lawlor  BA, Kenny  RA.  Blood pressure and the risk for dementia: a double edged sword.  Ageing Res Rev. 2009;8(2):61-70.PubMedGoogle ScholarCrossref
Qiu  C, Winblad  B, Fratiglioni  L.  The age-dependent relation of blood pressure to cognitive function and dementia.  Lancet Neurol. 2005;4(8):487-499.PubMedGoogle ScholarCrossref
Peters  R, Beckett  N, Forette  F,  et al; HYVET investigators.  Incident dementia and blood pressure lowering in the Hypertension in the Very Elderly Trial cognitive function assessment (HYVET-COG): a double-blind, placebo controlled trial.  Lancet Neurol. 2008;7(8):683-689.PubMedGoogle ScholarCrossref
McGuinness  B, Todd  S, Passmore  P, Bullock  R.  Blood pressure lowering in patients without prior cerebrovascular disease for prevention of cognitive impairment and dementia.  Cochrane Database Syst Rev. 2009;(4):CD004034. PubMedGoogle Scholar
Staessen  JA, Thijs  L, Richart  T, Odili  AN, Birkenhäger  WH.  Placebo-controlled trials of blood pressure-lowering therapies for primary prevention of dementia.  Hypertension. 2011;57(2):e6-e7. doi:10.1161/HYPERTENSIONAHA.110.165142.PubMedGoogle ScholarCrossref
Euser  SM, van Bemmel  T, Schram  MT,  et al.  The effect of age on the association between blood pressure and cognitive function later in life.  J Am Geriatr Soc. 2009;57(7):1232-1237.PubMedGoogle ScholarCrossref
Birns  J, Markus  H, Kalra  L.  Blood pressure reduction for vascular risk: is there a price to be paid?  Stroke. 2005;36(6):1308-1313.PubMedGoogle ScholarCrossref
Kim  YS, Davis  SC, Truijen  J, Stok  WJ, Secher  NH, van Lieshout  JJ.  Intensive blood pressure control affects cerebral blood flow in type 2 diabetes mellitus patients.  Hypertension. 2011;57(4):738-745.PubMedGoogle ScholarCrossref
Mossello  E, Pieraccioli  M, Nesti  N,  et al.  Effects of low blood pressure in cognitively impaired elderly patients treated with antihypertensive drugs.  JAMA Intern Med. 2015;175(4):578-585.PubMedGoogle ScholarCrossref
Marshall  RS, Lazar  RM.  Pumps, aqueducts, and drought management: vascular physiology in vascular cognitive impairment.  Stroke. 2011;42(1):221-226.PubMedGoogle ScholarCrossref
Lenoir  H, Lacombe  JM, Dufouil  C,  et al.  Relationship between blood pressure and depression in the elderly: the Three-City Study.  J Hypertens. 2008;26(9):1765-1772.PubMedGoogle ScholarCrossref
Sabayan  B, Oleksik  AM, Maier  AB,  et al.  High blood pressure and resilience to physical and cognitive decline in the oldest old: the Leiden 85-Plus Study.  J Am Geriatr Soc. 2012;60(11):2014-2019.PubMedGoogle Scholar
Honda  H, Terada  S, Sato  S,  et al.  Subjective depressive mood and regional cerebral blood flow in mild Alzheimer’s disease.  Int Psychogeriatr. 2014;26(5):817-823.PubMedGoogle ScholarCrossref
Nadkarni  NK, Levy-Cooperman  N, Black  SE.  Functional correlates of instrumental activities of daily living in mild Alzheimer’s disease.  Neurobiol Aging. 2012;33(1):53-60.PubMedGoogle ScholarCrossref
Folstein  MF, Folstein  SE, McHugh  PR.  “Mini-Mental State”: a practical method for grading the cognitive state of patients for the clinician.  J Psychiatr Res. 1975;12(3):189-198.PubMedGoogle ScholarCrossref
van Rookhuijzen  AE, Touwen  DP, de Ruijter  W, Engberts  DP, van der Mast  RC.  Deliberating clinical research with cognitively impaired older people and their relatives: an ethical add-on study to the protocol “Effects of Temporary Discontinuation of Antihypertensive Treatment in the Elderly (DANTE) with Cognitive Impairment.”  Am J Geriatr Psychiatry. 2014;22(11):1233-1240.PubMedGoogle ScholarCrossref
Arbuthnott  K, Frank  J.  Trail Making Test, part B as a measure of executive control: validation using a set-switching paradigm.  J Clin Exp Neuropsychol. 2000;22(4):518-528.PubMedGoogle ScholarCrossref
Houx  PJ, Jolles  J, Vreeling  FW.  Stroop Interference: aging effects assessed with the Stroop Color-Word Test.  Exp Aging Res. 1993;19(3):209-224.PubMedGoogle ScholarCrossref
Lezak  MD, Howieson  DB, Loring  DW.  Neuropsychological Assessment.4th ed. New York, NY: Oxford University Press; 2004.
van der Elst  W, van Boxtel  MP, van Breukelen  GJ, Jolles  J.  The Letter Digit Substitution Test: normative data for 1,858 healthy participants aged 24-81 from the Maastricht Aging Study (MAAS): influence of age, education, and sex.  J Clin Exp Neuropsychol. 2006;28(6):998-1009.PubMedGoogle ScholarCrossref
Starkstein  SE, Mayberg  HS, Preziosi  TJ, Andrezejewski  P, Leiguarda  R, Robinson  RG.  Reliability, validity, and clinical correlates of apathy in Parkinson’s disease.  J Neuropsychiatry Clin Neurosci. 1992;4(2):134-139.PubMedGoogle ScholarCrossref
Sheikh  JI, Yesavage  JA.  Geriatric Depression Scale (GDS): recent evidence and development of a shorter version.  Clin Gerontol. 1986;5(1/2):165-173.Google Scholar
Kempen  GI, Miedema  I, Ormel  J, Molenaar  W.  The assessment of disability with the Groningen Activity Restriction Scale: conceptual framework and psychometric properties.  Soc Sci Med. 1996;43(11):1601-1610.PubMedGoogle ScholarCrossref
Cantril  H.  The Pattern of Human Concerns. New Brunswick, NJ: Rutgers University Press; 1965.
Matsushita  K, Kuriyama  Y, Nagatsuka  K, Nakamura  M, Sawada  T, Omae  T.  Periventricular white matter lucency and cerebral blood flow autoregulation in hypertensive patients.  Hypertension. 1994;23(5):565-568.PubMedGoogle ScholarCrossref
van Vliet  P, Westendorp  RG, van Heemst  D, de Craen  AJ, Oleksik  AM.  Cognitive decline precedes late-life longitudinal changes in vascular risk factors.  J Neurol Neurosurg Psychiatry. 2010;81(9):1028-1032.PubMedGoogle ScholarCrossref
Qiu  C, Winblad  B, Marengoni  A, Klarin  I, Fastbom  J, Fratiglioni  L.  Heart failure and risk of dementia and Alzheimer disease: a population-based cohort study.  Arch Intern Med. 2006;166(9):1003-1008.PubMedGoogle ScholarCrossref
Lewington  S, Clarke  R, Qizilbash  N, Peto  R, Collins  R; Prospective Studies Collaboration.  Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies.  Lancet. 2002;360(9349):1903-1913.PubMedGoogle ScholarCrossref
Bejan-Angoulvant  T, Saadatian-Elahi  M, Wright  JM,  et al.  Treatment of hypertension in patients 80 years and older: the lower the better? a meta-analysis of randomized controlled trials.  J Hypertens. 2010;28(7):1366-1372.PubMedGoogle ScholarCrossref
Muller  M, Smulders  YM, de Leeuw  PW, Stehouwer  CD.  Treatment of hypertension in the oldest old: a critical role for frailty?  Hypertension. 2014;63(3):433-441.PubMedGoogle ScholarCrossref
James  PA, Oparil  S, Carter  BL,  et al.  2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8).  JAMA. 2014;311(5):507-520.PubMedGoogle ScholarCrossref
Mallery  LH, Allen  M, Fleming  I,  et al.  Promoting higher blood pressure targets for frail older adults: a consensus guideline from Canada.  Cleve Clin J Med. 2014;81(7):427-437.PubMedGoogle ScholarCrossref
Original Investigation
October 2015

Effect of Discontinuation of Antihypertensive Treatment in Elderly People on Cognitive Functioning—the DANTE Study Leiden: A Randomized Clinical Trial

Author Affiliations
  • 1Department of Psychiatry, Leiden University Medical Center, Leiden, the Netherlands
  • 2Department of Public Health and Primary Care, Leiden University Medical Center, Leiden, the Netherlands
  • 3Department of Radiology, Leiden University Medical Center, Leiden, the Netherlands
  • 4Department of Gerontology and Geriatrics, Leiden University Medical Center, Leiden, the Netherlands
  • 5Department of Neurology, Leiden University Medical Center, Leiden, the Netherlands
  • 6Section of Health, Medical and Neuropsychology, Department of Psychology, Leiden University, Leiden, the Netherlands
  • 7Leyden Academy on Vitality and Aging, Leiden University Medical Center, Leiden, the Netherlands
  • 8Center for Healthy Aging, Department of Public Health, University of Copenhagen, Cophenhagen, Denmark
  • 9Department of Psychiatry, Collaborative Antwerp Psychiatric Research Institute (CAPRI), University of Antwerp, Antwerp, Belgium
JAMA Intern Med. 2015;175(10):1622-1630. doi:10.1001/jamainternmed.2015.4103

Importance  Observational studies indicate that lower blood pressure (BP) increases risk for cognitive decline in elderly individuals. Older persons are at risk for impaired cerebral autoregulation; lowering their BP may compromise cerebral blood flow and cognitive function.

Objective  To assess whether discontinuation of antihypertensive treatment in older persons with mild cognitive deficits improves cognitive, psychological, and general daily functioning.

Design, Setting, and Participants  A community-based randomized clinical trial with a blinded outcome assessment at the 16-week follow-up was performed at 128 general practices in the Netherlands. A total of 385 participants 75 years or older with mild cognitive deficits (Mini-Mental State Examination score, 21-27) without serious cardiovascular disease who received antihypertensive treatment were enrolled in the Discontinuation of Antihypertensive Treatment in Elderly People (DANTE) Study Leiden from June 26, 2011, through August 23, 2013 (follow-up, December 16, 2013). Intention-to-treat analyses were performed from January 20 through April 11, 2014.

Interventions  Discontinuation (n = 199) vs continuation (n = 186) of antihypertensive treatment (allocation ratio, 1:1).

Main Outcomes and Measures  Change in the overall cognition compound score. Secondary outcomes included changes in scores on cognitive domains, the Geriatric Depression Scale–15, Apathy Scale, Groningen Activity Restriction Scale (functional status), and Cantril Ladder (quality of life).

Results  Compared with 176 participants undergoing analysis in the control (continuation) group, 180 in the intervention (discontinuation) group had a greater increase (95% CI) in systolic BP (difference, 7.36 [3.02 to 11.69] mm Hg; P = .001) and diastolic BP (difference, 2.63 [0.34 to 4.93] mm Hg; P = .03). The intervention group did not differ from the control group in change (95% CI) in overall cognition compound score (0.01 [−0.14 to 0.16] vs −0.01 [−0.16 to 0.14]; difference, 0.02 [−0.19 to 0.23]; P = .84). The intervention and control groups did not differ significantly in secondary outcomes, including differences (95% CIs) in change in compound scores of the 3 cognitive domains (executive function, −0.07 [−0.29 to 0.15; P = .52], memory, 0.08 [−0.12 to 0.29; P = .43], and psychomotor speed, −0.85 [−1.72 to 0.02; P = .06]), symptoms of apathy (0.17 [−0.65 to 0.99; P = .68]) and depression (0.14 [−0.20 to 0.48; P = .41]), functional status (−0.72 [−1.52 to 0.09; P = .08]), and quality-of-life score (−0.09 [−0.34 to 0.16; P = .46]). Adverse events were equally distributed.

Conclusions and Relevance  In older persons with mild cognitive deficits, discontinuation of antihypertensive treatment did not improve cognitive, psychological, or general daily functioning at the 16-week follow-up.

Trial Registration  trialregister.nl Identifier: NTR2829