Professional Documents
Culture Documents
10.1016@j.jamda.2018.12.006
10.1016@j.jamda.2018.12.006
JAMDA
journal homepage: www.jamda.com
Original Studies
a b s t r a c t
https://doi.org/10.1016/j.jamda.2018.12.006
1525-8610/Ó 2018 AMDA e The Society for Post-Acute and Long-Term Care Medicine.
2 J.W. van Dalen et al. / JAMDA xxx (2019) 1e7
autoregulation associated with aging may cause BP lowering in older Memory Complaints, Dementia, and Mortality
people and evoke hypoperfusion, resulting in cerebral damage and
cognitive dysfunction.5 Cognitive symptoms might be the direct SMCs were defined according to item 10 (“Do you feel you have
consequence of hypoperfusion or may develop over time with accu- more problems with your memory than most people?”) of the 15-item
mulating cerebrovascular damage resulting from hypoperfusion.3,5,6 Geriatric Depression Scale.16 Dementia was defined as a clinical
Next to cognitive decline, low BP and antihypertensive drug (AHD) diagnosis according to Diagnostic and Statistical Manual of Mental
in older people have been associated with adverse events, depression, Disorders, Fourth Edition, criteria,17 confirmed by 2 members of an
and activities of daily living impairment.7e10 Consequently, it has been independent outcome adjudication committee, blinded to treatment
hypothesized that BP lowering in older people may be detrimental allocation, based on all available clinical information. Diagnoses of
and withdrawal of AHD treatment is warranted.5,11,12 dementia were re-evaluated after 1 year of additional follow-up to
To address this hypothesis, a few relatively small RCTs have been avoid false-positive diagnoses. For participants who dropped out of
conducted in patients with stroke and mild cognitive impairment.5,13 the study, the dementia status was retrieved by a research nurse from
These did not show any beneficial effects on cognition. However, they electronic health records and/or contact with the GP at the end of the
assessed short-term effects and short withdrawal periods only. study and presented to the blinded outcome adjudication committee.
Consequently, a Cochrane meta-analysis concluded there was insuf- The dementia diagnostic process is described in more detail else-
ficient evidence regarding the effects of AHD withdrawal on cognitive where.15 Survival status and date of death were obtained directly from
functioning.12 Given the beneficial effects of AHD in older people on the GP records supplemented with data from the national municipal
incident cardiovascular disease (CVD),14 ethical objections hinder the health registry.
conduct of long-term RCTs with extended withdrawal periods.
Therefore, observational data may present the best opportunity Statistics
available to study this relation and provide guidance on this matter,
although observational biases will need to be extensively addressed. Analyses were performed using lme and coxme packages in R
For this purpose, well-delineated cohorts with complete outcome data studio with R version 3.5.1.18e21 Groups were compared using Fisher
over a long follow-up are required. exact tests for proportions, and Student t tests for normal and Mann-
In this study, we evaluate the relation between withdrawal of AHD Whitney U tests for nonparametric distributed variables.
in community-dwelling older people and subjective memory com- The relation between AHD withdrawal and incident dementia and/
plaints (SMCs), incident dementia and mortality, using the detailed or mortality was assessed using Cox regression. We assessed dementia
data from the Prevention of Dementia by Intensive Vascular care and mortality separately and combined as 1 outcome to evaluate the
(preDIVA) trial.15 competing risk of death and because both can be considered unfa-
vorable. Age was used as time-scale and baseline age included as co-
Methods variate. Model 2 was additionally adjusted for sex and baseline values
of systolic BP and total number of prescribed AHD as proxies for hy-
Population pertension severity, and total number of prescribed medications as
proxy for comorbidity and polypharmacy. Model 3 was additionally
The preDIVA cluster-RCT evaluated the efficacy of an cardiovas- adjusted for factors deemed likely to influence both the decision to
cular risk intervention compared to usual care in community-dwelling withdraw AHD treatment and the risk of adverse outcomes according
older people (aged 70-78 years at baseline).15 The intervention to treatment guidelines.22 Stroke, CVD, and diabetes were included as
comprised 4-monthly appointments with a practice nurse who comorbidities included in AHD treatment guidelines that increase the
addressed cardiovascular risk factors. Exclusion criteria at baseline risk of poor outcome and reduce the likelihood of AHD withdrawal.
were dementia and disorders likely to impede successful long-term Body mass index and smoking were included as lifestyle factors
follow-up according to the general practitioner (GP), for example, associated with high BP that may also reduce the chance of AHD
terminal illness or alcoholism. The trial ran from 2006 to 2015. Follow- withdrawal and increase the risk of poor outcome. SMC and MMSE
up ranged from 6 years for participants randomized in 2009 up to score were included as markers of cognitive complaints to account for
8 years for those randomized in 2006-2007. Participants were potential reverse causality by GPs withdrawing AHD in response to
assessed at baseline and during 2-yearly assessments. At these visits, cognitive symptoms. Interactions between AHD withdrawal and these
data were collected on medical history, medication use, cardiovascular confounders were assessed for all outcomes.
risk factors, cognitive status [Mini Mental-State Examination To further examine reverse causality by AHD withdrawal in
(MMSE)], depression [Geriatric Depression Scale (GDS-15)], and response to memory complaints, we performed subgroup analyses
disability. In both treatment groups, BP levels were reported back to based on ever reporting SMCs during the study. To further address
both the participant and the GP; whether AHD treatment was initiated confounding by severe medical conditions leading to AHD withdrawal,
was left to the GP’s discretion. The trial found no difference between we performed subgroup analyses based on whether participants used
intervention and control groups in incident dementia or mortality.15 other medication when withdrawing from AHD. Finally, in a previous
For the current study, we evaluated the RCT population as 1 single qualitative study among GPs participating in preDIVA into motivations
cohort. A sensitivity analysis was conducted adjusting for the for deprescribing AHD, the reasons given were prolonged achieve-
intervention. ment of target blood pressure, side effects, patient preference (non-
adherence), terminal illness, and expected quality of life.23 Based on
Antihypertensive Withdrawal this, because withdrawing AHD in participants whose hypertension
was not under control (ie, >140 mmHg) is more likely to have occurred
At each assessment, AHD use was derived from the GP prescription in the context of potentially confounding reasons such as non-
list. To limit bias introduced by comparing participants with long- adherence, unacceptable side effects, or severe disease, we performed
standing hypertension to those who only developed hypertension analyses in subgroups of participants who did and did not attain a
during the course of the study, we only included participants using systolic BP 140 during the course of the study.
AHD at baseline. AHD withdrawal was defined as discontinuation of To evaluate whether SMCs were associated with concurrent AHD
AHD treatment and remaining without AHD prescription for the use and whether AHD withdrawal was associated with improvement
remainder of the study participation. of SMCs, we assessed SMCs and AHD use in the total preDIVA
J.W. van Dalen et al. / JAMDA xxx (2019) 1e7 3
population, regardless of AHD use at baseline. Mixed models were (mean standard deviation: 147.9 21.9 vs 156.1 20.9, P ¼ .001),
employed, including all available measurements during the study, lower mean body mass index (27.0 3.6 vs 28.5 4.3, P ¼ .001), and
with a random intercept per participant to adjust for multiple mea- less often a history of CVD (28.2% vs 43.0%, P ¼ .01). Compared with
surements per individual. The cross-sectional relation between SMCs AHD continuation, AHD withdrawal was more common in the lowest
and concurrent AHD was assessed with AHD use as predictor and (55.3% vs 33.5%, P ¼ .01) and less common in the highest tertile (17.6%
SMCs at the same visit as outcome. The relation between AHD with- vs 32.9%, P ¼ .03) of baseline systolic BP. During the course of the study,
drawal and improvement of SMC was assessed with SMC as outcome 67.1% in the AHD withdrawal group attained a systolic BP 140 mmHg
and AHD withdrawal compared to the preceding visit as predictor, compared to 55.6% in the nonwithdrawal group (P ¼ .04). Participants
only including measurements with SMC present at the preceding visit. discontinuing AHD more often reported SMC at least once during the
study (44.7% vs 33.7%, P ¼ .045), and 25.9% reported SMC at the visit
Ethical Approval and Registration preceding AHD withdrawal. At the time of discontinuing AHD, 65.9%
used other medication. Dementia occurred more often in participants
The preDIVA study was approved by the ethics committee of the discontinuing AHD treatment compared to those who did not (13.4%
Academic Medical Center Amsterdam, and all participants gave vs 6.2%, P ¼ .02); mortality was not significantly different (16.5% vs
written informed consent prior to the study. The preDIVA trial was 13.9%, P ¼ .52). Most incident cases of dementia (7/11, 63.6%) and
registered with ISRCTN, number ISRCTN29711771. mortality (11/14, 78.6%) occurred more than 2 years after AHD with-
drawal (Supplementary Figure 1). There were no significant differ-
Results ences in cause of death between participants with and without AHD
withdrawal, but subgroups were small (Supplementary Table 1).
In total, 1541 of 1934 participants (79.7%) on AHD at baseline Results of Cox regression of incident dementia and/or mortality are
attended at least 1 follow-up assessment (Figure 1). Of those, 85 listed in Table 2. Withdrawal of AHD treatment was associated with an
participants (5.5%) discontinued AHD during the study. Follow-up for approximately 2-fold higher hazard of dementia in model 1 [hazard
dementia was complete for 1512/1541 participants (98.1%) and for ratio (HR) (95% confidence interval [CI]) ¼ 2.15 (1.15-4.03)]. This was
mortality for 1537/1541 participants (99.7%). Characteristics of par- somewhat attenuated after adjustment for sex, systolic BP, total
ticipants who did and did not discontinue AHD during the study are number of prescribed medications, and antihypertensives in model 2
compared in Table 1. At baseline, participants who discontinued AHD [HR ¼ 1.92 (1.01-3.65)] and additional adjustment for history of stroke,
generally used less antihypertensive drugs [median (interquartile CVD, diabetes, smoking, SMC, and MMSE score in model 3 [HR ¼ 1.79
range): 1 (1-2) vs 2 (1-2), P < .001], had a lower systolic BP (0.93-3.44)]. AHD withdrawal was associated with an approximately
Fig. 1. Flow-chart of participants included in the study. “AHD stop” indicates cessation of AHD use for the remainder of the study with at least 1 additional subsequent visit
attended.
4 J.W. van Dalen et al. / JAMDA xxx (2019) 1e7
Table 1
Characteristics of Participants With Antihypertensive Drugs at the Start of the Study Who Did and Did Not Discontinue Treatment During the Study
Baseline
Age, y, mean (SD) 74.5 (2.5) 74.3 (2.5) .50
Women 50 (58.8) 778 (53.6) .37
Systolic BP, mmHg
Mean (SD) 147.9 (21.9) 156.1 (20.9) .001
99-146 47 (55.3) 486 (33.5) .01
146-164 23 (27.1) 487 (33.6) .42
164-232 15 (17.6) 478 (32.9) .03
Systolic BP preceding AHD stop, mmHg
Diastolic BP, mmHg .20
Mean (SD) 79.8 (11.5) 81.5 (10.8)
49e76.5 35 (41.2) 488 (33.6) .33
76.5e85.5 26 (30.6) 484 (33.4) .82
85.5e131 24 (28.2) 479 (33.0) .57
Diastolic BP preceding AHD stop, mmHg
Number of AHDs <.001
Median (IQR) 1 (1-2) 2 (1-2)
1 58 (68.2) 582 (40.1) .003
2 23 (27.1) 544 (37.5) .18
3 3 (3.5) 261 (18.0) .001
4 1 (1.2) 64 (4.4) .26
Number of prescriptions other than AHD, median (IQR) 4 (3-7) 5 (3-7) .06
BMI, mean (SD) 27.0 (3.6) 28.5 (4.3) .001
Diabetes 17 (2) 403 (27.8) .13
Smoking 14 (16.5) 161 (11.1) .16
History of CVD 24 (28.2) 620 (43.0) .01
History of stroke 12 (14.1) 184 (12.8) .74
MMSE score, median (IQR) 28 (27-29) 29 (27-29) .50
VAT score <6 390 (27.0) 387 (26.9) .01
During study
Systolic BP 140 mmHg achieved 57 (67.1) 809 (55.6) .04
Medication other than AHD during study 76 (89.4) 1313 (90.2) .85
Medication concurrent with AHD stop 56 (65.9)
Subjective memory complaints (GDS 10y) during study 38 (44.7) 488 (33.7) .045
Subjective memory complaints preceding AHD stop 22 (25.9)
Incident dementia during study 11 (13.4) 89 (6.2) .02
Incident mortality during study 14 (16.5) 201 (13.9) .52
Incident dementia or mortality during study 24 (29.3) 268 (18.8) .03
60% increased hazard for dementia and/or mortality combined in (1.04-1.59) per 10 mmHg increase, P ¼ .02], suggesting the HR for
model 1 [HR ¼ 1.58 (1.04-2.40)] and model 2 [HR ¼ 1.64 (1.07-2.51)], discontinuing AHD treatment increased by approximately 30% per
which was slightly attenuated in model 3 [HR ¼ 1.49 (0.96-2.30), 10 mmHg higher systolic BP. Other interactions between AHD with-
P ¼ .07]. The hazard for mortality for participants who discontinued drawal and confounders included in the models were not significant
AHD was 16% to 21% higher but not significantly in any of the models (all P > .13).
(all P .38). Sensitivity analyses excluding participants who did not attain a BP
HRs were not significantly different between subgroup pairs for 140 mmHg during the course of the study (Supplementary Table 1)
any of the outcomes. HRs for dementia in participants discontinuing gave largely similar results regarding dementia [model 3 overall
AHD appeared slightly lower in those with concurrent medication at HR ¼ 1.73 (0.79-3.83)]. HRs were generally lower for dementia/mor-
the time of AHD withdrawal compared to those without [model 3 tality combined [overall HR ¼ 1.16 (0.66-2.02)] and mortality [overall
HR ¼ 1.54 (0.69-3.45) vs 2.60 (0.93-7.24)] and for participants with HR ¼ 0.89 (0.66-2.02)]. Results of sensitivity analyses excluding par-
SMCs during the course of the study compared to those without ticipants in whom dementia/mortality occurred within 2 years of
[HR ¼ 1.57 (0.68-3.59) vs 2.17 (0.71-6.60)]. For dementia and/or follow-up (Supplementary Table 2) were also largely similar, with a
mortality combined, HRs appeared higher in subgroups of participants somewhat increased HR for dementia [2.08 (1.00-4.33), P ¼ .049], a
without other medication at the time of AHD withdrawal [HR ¼ 2.33 similar HR for dementia/mortality combined [HR ¼ 1.42 (0.86-2.36)],
(1.22-4.42) vs 1.18 (0.68-2.06)] and those not attaining a systolic BP of and a neutral HR for mortality [HR ¼ 1.00 (0.51-1.95)]. Subgroup pairs
140 mmHg during the study [HR ¼ 2.07 (1.02-4.21) vs 1.18 (0.68- showed corresponding trends, and none of the subgroup pairs were
2.05)]. HRs for mortality for AHD withdrawal appeared higher in significantly different. Sensitivity analysis adjusting for the interven-
participants without concurrent medication [2.30 (1.07-4.95) vs 0.80 tion gave results similar to the main analysis.
(0.37-1.73)] and higher in participants who did not attain a BP 140 Table 3 lists the results of mixed model analyses of the association
[1.86 (0.78-4.42) vs 0.89 (0.78-4.42)]. HRs in the other subgroup pairs between AHD use and SMCs at any time point during the study.
were similar. Combining 11,252 observations in 3518 individual participants, par-
There was a significant interaction between AHD withdrawal and ticipants with SMCs were more often concurrently on AHD compared
baseline systolic BP in the risk for mortality [HR interaction ¼ 1.29 to participants without memory complaints [64.2% vs 60.5%, odds
J.W. van Dalen et al. / JAMDA xxx (2019) 1e7 5
Table 2
Cox Regression of Dementia and/or Mortality on Discontinuation of AHD Treatment in Participants With AHD at Baseline
Outcome: dementia
AHD stop 100/1507 2.15 (1.15-4.03) .02 100/1507 1.92 (1.01-3.65) .047 98/1467 1.79 (0.93-3.44) .08
Concurrent medication
AHD stop without other medication 93/1453 2.70 (0.99-7.39) .053 93/1453 2.59 (0.94-7.11) .07 91/1415 2.60 (0.93-7.24) .07
AHD stop with other medication 96/1479 1.96 (0.91-4.25) .09 96/1479 1.70 (0.77-3.77) .19 94/1439 1.54 (0.69-3.45) .29
Memory complaints during study
AHD stop without complaints 34/985 3.04 (1.07-8.69) .04 34/985 2.33 (0.79-6.89) .13 33/961 2.17 (0.71-6.60) .17
AHD stop with complaints 66/521 1.50 (0.68-3.30) .31 66/521 1.39 (0.62-3.13) .42 65/509 1.57 (0.68-3.59) .29
Systolic BP on target during study
AHD stop systolic BP 140 mmHg 62/903 2.25 (1.07-4.73) .03 62/903 1.94 (0.90-4.18) .09 61/884 1.73 (0.79-3.83) .17
AHD stop systolic BP >140 mmHg 38/604 2.20 (0.67-7.18) .19 38/604 2.05 (0.61-6.89) .25 37/583 1.93 (0.56-6.65) .30
Outcome: dementia/mortality
AHD stop 292/1505 1.58 (1.04-2.40) .03 292/1505 1.64 (1.07-2.51) .02 287/1475 1.49 (0.96-2.30) .07
Concurrent medication
AHD stop without other medication 278/1451 2.24 (1.19-4.22) .01 278/1451 2.42 (1.28-4.57) .01 272/1413 2.36 (1.24-4.48) .01
AHD stop with other medication 282/1477 1.31 (0.76-2.24) .33 282/1477 1.32 (0.76-2.29) .32 276/1437 1.22 (0.70-2.12) .49
Memory complaints during study
AHD stop without complaints 157/984 1.36 (0.70-2.67) .37 157/984 1.43 (0.72-2.85) .30 153/960 1.34 (0.67-2.70) .40
AHD stop with complaints 135/520 1.55 (0.90-2.65) .11 135/520 1.60 (0.92-2.79) .10 133/505 1.60 (0.91-2.81) .11
Systolic BP on target during study
AHD stop systolic BP 140 mmHg 173/901 1.42 (0.83-2.41) .20 173/901 1.32 (0.77-2.27) .32 170/882 1.20 (0.69-2.09) .52
AHD stop systolic BP >140 mmHg 119/604 2.04 (1.03-4.05) .04 119/604 2.31 (1.15-4.64) .02 116/583 2.15 (1.06-4.39) .04
Outcome: mortality
AHD stop 215/1532 1.16 (0.68-2.00) .59 215/1532 1.28 (0.74-2.22) .38 210/1491 1.21 (0.69-2.11) .51
Concurrent medication
AHD stop without other medication 208/1476 2.00 (0.94-4.26) .07 208/1476 2.33 (1.09-4.97) .03 203/1437 2.30 (1.07-4.95) .03
AHD stop with other medication 208/1503 0.82 (0.38-1.73) .60 208/1503 0.86 (0.4-1.86) .70 203/1462 0.80 (0.37-1.73) .57
Memory complaints during study
AHD stop without complaints 133/1007 1.02 (0.45-2.31) .96 133/1007 1.18 (0.51-2.72) .69 129/982 1.24 (0.53-2.87) .62
AHD stop with complaints 82/524 1.25 (0.60-2.60) .55 82/524 1.38 (0.65-2.93) .40 81/509 1.22 (0.57-2.62) .61
Systolic BP on target during study
AHD stop systolic BP 140 mmHg 121/915 0.99 (0.48-2.03) .98 121/915 0.98 (0.47-2.04) .96 119/896 0.89 (0.42-1.86) .75
AHD stop systolic BP >140 mmHg 94/617 1.57 (0.68-3.62) .29 94/617 1.89 (0.81-4.42) .14 91/595 1.86 (0.78-4.42) .16
ratio (95% CI) ¼ 1.28 (1.06-1.55), P ¼ .01]. However, withdrawal of AHD Dementia risk was similar for participants who did and did not attain a
treatment was not associated with co-occurring improvement of systolic BP 140 mmHg during the study. Results were not markedly
memory complaints [odds ratio (95% CI) ¼ 0.96 (0.55-1.67), P ¼ .89]. different after adjustment for confounders relating to comorbidity,
polypharmacy, cardiovascular risk, or cognitive symptoms. Partici-
Discussion pants on AHD more often reported SMCs, but there was no association
between withdrawal of AHD treatment and change in memory
Our results suggest AHD withdrawal in community-dwelling older complaints.
people does not convey clinical benefits regarding incident dementia Our data are observational, precluding firm conclusions regarding
or mortality. Conversely, participants discontinuing AHD treatment causality. We tried to address bias and confounding through extensive
seemed to be at higher risk of adverse outcome, particularly dementia. adjustment and subgroup analyses. Adjustment for SMC and MMSE
This increased risk appeared greater in participants without other scores together with SMC subgroup analyses suggest little risk of
medication at the time of AHD withdrawal and in those without SMCs. reverse causality caused by clinicians withdrawing AHD treatment in
Table 3
Repeated Measurements Analyses of the Association Between AHD Use and Co-occurring SMCs
Concurrent AHD use 11,252/3518 1354 (64.2) 5528 (60.5) 1.28 (1.06-1.55) .01
3. Iadecola C, Yaffe K, Biller J, et al. Impact of hypertension on cognitive function: prevention of dementia by intensive vascular care trial. J Am Geriatr Soc 2017;
A scientific statement from the American Heart Association. Hypertension 65:1505e1513.
2016;68:e67ee94. 26. Benetos A, Bulpitt CJ, Petrovic M, et al. An expert opinion from the European
4. Tadic M, Cuspidi C, Hering D. Hypertension and cognitive dysfunction in Society of Hypertension-European Union Geriatric Medicine Society Working
elderly: Blood pressure management for this global burden. BMC Cardiovasc Group on the management of hypertension in very old, frail subjects. Hyper-
Disord 2016;16:208. tension 2016;67:820e825.
5. Moonen JEF, Foster-Dingley JC, de Ruijter W, et al. Effect of discontinuation of 27. Benetos A, Rossignol P, Cherubini A, et al. Polypharmacy in the aging patient:
antihypertensive treatment in elderly people on cognitive functioningdThe Management of hypertension in octogenarians. JAMA 2015;314:170e180.
DANTE Study Leiden. JAMA Intern Med 2015;175:1622. 28. Odden MC, Beilby PR, Peralta CA. Blood pressure in older adults: The impor-
6. Yang T, Sun Y, Lu Z, et al. The impact of cerebrovascular aging on vascular tance of frailty. Curr Hypertens Rep 2015;17:55.
cognitive impairment and dementia. Ageing Res Rev 2017;34:15e29. 29. Tzourio C, Levy C, Dufouil C, et al. Low cerebral blood flow velocity and risk of
7. Lenoir H, Lacombe J-M, Dufouil C, et al. Relationship between blood pressure white matter hyperintensities. Ann Neurol 2001;49:411e414.
and depression in the elderly. The Three-City Study. J Hypertens 2008;26: 30. Skoog I, Lithell H, Hansson L, et al. Effect of baseline cognitive function and
1765e1772. antihypertensive treatment on cognitive and cardiovascular outcomes: Study
8. Sabayan B, Oleksik AM, Maier AB, et al. High blood pressure and resilience to on COgnition and Prognosis in the Elderly (SCOPE). Am J Hypertens 2005;18:
physical and cognitive decline in the oldest old: The Leiden 85-Plus study. J Am 1052e1059.
Geriatr Soc 2012;60:2014e2019. 31. Di Bari M, Pahor M, Franse LV, et al. Dementia and disability outcomes in large
9. Bangalore S, Toklu B, Gianos E, et al. Optimal systolic blood pressure target after hypertension trials: Lessons learned from the Systolic Hypertension in the
SPRINT: Insights from a network meta-analysis of randomized trials. Am J Med Elderly Program (SHEP) trial. Am J Epidemiol 2001;153:72e78.
2017;130:707e719.e8. 32. Peters R, Beckett N, Forette F, et al. Incident dementia and blood pressure
10. Tinetti ME, Han L, Lee DSH, et al. Antihypertensive medications and serious fall lowering in the Hypertension in the Very Elderly Trial cognitive function
injuries in a nationally representative sample of older adults. JAMA Intern Med assessment (HYVET-COG): A double-blind, placebo controlled trial. Lancet
2014;174:588e595. Neurol 2008;7:683e689.
11. van der Wardt V, Harrison JK, Welsh T, et al. Withdrawal of antihypertensive 33. Williamson JD, Supiano MA, Applegate WB, et al. Intensive vs standard blood
medication. J Hypertens 2017;35:1742e1749. pressure control and cardiovascular disease outcomes in adults aged 75
12. Jongstra S, Harrison JK, Quinn TJ, Richard E. Antihypertensive withdrawal for years: A randomized clinical trial. JAMA 2016;315:2673e2682.
the prevention of cognitive decline. Cochrane Database Syst Rev 2016;11: 34. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/
CD011971. AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection,
13. Bath PMW, Woodhouse L, Scutt P, et al. Efficacy of nitric oxide, with or without evaluation, and management of high blood pressure in adults. J Am Coll Cardiol
continuing antihypertensive treatment, for management of high blood pres- 2018;71:2199e2269.
sure in acute stroke (ENOS): A partial-factorial randomised controlled trial. 35. Khera R, Lu Y, Lu J, et al. Impact of 2017 ACC/AHA guidelines on prevalence of
Lancet 2015;385:617e628. hypertension and eligibility for antihypertensive treatment in United States and
14. Musini VM, Tejani AM, Bassett K, Wright JM. Pharmacotherapy for hyperten- China: Nationally representative cross sectional study. BMJ 2018;362:k2357.
sion in the elderly. Cochrane Database Syst Rev 2009;4:CD000028. 36. Lamprea-Montealegre JA, Zelnick LR, Hall YN, et al. Prevalence of hypertension
15. Moll van Charante EP, Richard E, Eurelings LS, et al. Effectiveness of a 6-year and cardiovascular risk according to blood pressure thresholds used for diag-
multidomain vascular care intervention to prevent dementia (preDIVA): A nosis. Hypertension 2018;72:602e609.
cluster-randomised controlled trial. Lancet 2016;388:797e805. 37. Qaseem A, Wilt TJ, Rich R, et al. Pharmacologic treatment of hypertension in
16. Sheikh JI, Yesavage JA. Geriatric Depression Scale (GDS): Recent evidence and adults aged 60 years or older to higher versus lower blood pressure targets: A
development of a shorter version. Clin Gerontol 1986;5:165e173. clinical practice guideline from the american college of physicians and the
17. American Psychiatric Association. Diagnostic and Statistical Manual of Mental american academy of family physicians. Ann Intern Med 2017;166:430e437.
Disorders. 4th ed. Washington, DC: American Psychiatric Association; 2000. 38. Nerenberg KA, Zarnke KB, Leung AA, et al. Hypertension Canada’s 2018
18. Therneau TM. coxme: Mixed effects Cox models. R Packag version 22-10. guidelines for diagnosis, risk assessment, prevention, and treatment of hy-
Available at: 2018. https://cran.r-project.org/package¼coxme; 2018. pertension in adults and children. Can J Cardiol 2018;34:506e525.
19. Bates D, Maechler M, Bolder B, Walker S. Fitting linear mixed-effects models 39. Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH guidelines for the
using lme4. J Stat Softw 2015;67. management of arterial hypertension. Eur Heart J 2018;39:3021e3104.
20. RStudio Team. RStudio: Integrated Development for R. Boston, MA: RStudio, 40. Phillips RA, Arnold RM, Peterson LE. Hypertension guidelines: The threads that
Inc. Available at:http://www.rstudio.com; 2015. bind them. J Am Coll Cardiol 2018;72:1246e1251.
21. R Core Team. R: A language and environment for statistical computing. Vienna, 41. Cushman WC, Johnson KC. The 2017 U.S. hypertension guidelines: What is
Austria: R Foundation for Statistical Computinghttps://www.R-project.org/; important for older adults? J Am Geriatr Soc 2018;66:1062e1067.
2018. 42. Stessman J, Bursztyn M, Gershinsky Y, et al. Hypertension and its treatment at
22. Wiersma TJ, Walma EP, Thomas S, Assendelft WJJ. Summary of the practice age 90 years: Is there an association with 5-year mortality? J Am Med Dir Assoc
guideline “Hypertension” (third revision) from the Dutch College of General 2017;18:277.e13e277.e19.
Practitioners. [Dutch]yrSamenvatting van de standaard “Hypertensie” (derde 43. van Middelaar T, van Vught LA, van Gool WA, et al. Blood pressure-lowering
herziening) van het Nederlands Huisartsen Genootschap. Ned Tijdschr Gen- interventions to prevent dementia. J Hypertens 2018;36:1780e1787.
eeskd 2004;148:923e931. 44. Press release, AAIC conference. Study shows intensive blood pressure control
23. van Middelaar T, Ivens SD, van Peet PG, et al. Prescribing and deprescribing reduces risk of mild cognitive impairment (MCI) and the combined risk of MCI
antihypertensive medication in older people by Dutch general practitioners: A and dementia. Available at: 2018. https://www.alz.org/aaic/releases_2018/
qualitative study. BMJ Open 2018;8:e020871. AAIC18-Wed-developing-topics.asp. Accessed October 17, 2018.
24. Höfler M. The effect of misclassification on the estimation of association: A 45. Yuan JQ, Lv YB, Chen HS, et al. Association between late-life blood pressure and
review. Int J Methods Psychiatr Res 2005;14:92e101. the incidence of cognitive impairment: A community-based prospective cohort
25. Beishuizen CRL, Coley N, Moll van Charante EP, et al. Determinants of dropout study. J Am Med Dir Assoc; 2018. https://doi.org/10.1016/j.jamda.2018.05.029
and nonadherence in a dementia prevention randomized controlled trial: The [Epub ahead of print].
7.e1 J.W. van Dalen et al. / JAMDA xxx (2019) 1e7
Appendix
Supplementary Table 1
Causes of Death in Participants Discontinuing and Not Discontinuing Antihyper-
tensive Drug (AHD) Treatment
Event/n % Event/n %
Supplementary Table 2
Sensitivity Analysis Excluding Participants With AHD at Baseline Who Did Not Attain a Systolic BP 140 mmHg During the Course of the Study
Outcome: dementia
AHD stop 62/903 2.25 (1.07-4.73) .03 62/903 1.94 (0.90-4.18) .09 61/884 1.73 (0.79-3.83) .17
Concurrent medication
AHD stop without other medication 56/862 2.48 (0.6-10.28) .21 56/862 2.39 (0.57-9.99) .23 55/844 2.47 (0.58-10.57) .22
AHD stop with other medication 60/888 2.20 (0.95-5.13) .07 60/888 1.86 (0.77-4.48) .17 59/869 1.60 (0.64-3.96) .31
Memory complaints during study
AHD stop without complaints 22/569 4.25 (1.41-12.75) .01 22/569 3.61 (1.14-11.37) .03 22/558 2.54 (0.75-8.62) .14
AHD stop with complaints 40/333 1.33 (0.47-3.75) .59 40/333 1.18 (0.40-3.42) .77 39/328 1.25 (0.41-3.79) .69
Outcome: dementia/mortality
AHD stop 173/901 1.42 (0.83-2.41) .20 173/901 1.32 (0.77-2.27) .32 171/888 1.16 (0.66-2.02) .61
Concurrent medication
AHD stop without other medication 162/860 1.63 (0.60-4.42) .34 162/860 1.86 (0.68-5.07) .22 159/842 1.77 (0.65-4.85) .27
AHD stop with other medication 169/886 1.36 (0.74-2.51) .32 169/886 1.19 (0.64-2.23) .59 166/867 1.08 (0.57-2.04) .82
Memory complaints during study
AHD stop without complaints 93/568 1.47 (0.68-3.18) .33 93/568 1.46 (0.66-3.21) .35 91/557 1.22 (0.54-2.73) .63
AHD stop with complaints 80/332 1.27 (0.61-2.63) .53 80/332 1.08 (0.51-2.31) .83 79/325 1.21 (0.56-2.59) .63
Outcome: mortality
AHD stop 121/915 0.99 (0.48-2.03) .98 121/915 0.98 (0.47-2.04) .96 119/896 0.89 (0.42-1.86) .75
Concurrent medication
AHD stop without other medication 116/873 1.65 (0.52-5.21) .40 116/873 2.07 (0.65-6.60) .22 114/855 1.99 (0.62-6.38) .25
AHD stop with other medication 118/899 0.80 (0.33-1.97) .63 118/899 0.73 (0.29-1.82) .50 116/880 0.65 (0.26-1.64) .36
Memory complaints during study
AHD stop without complaints 75/579 0.97 (0.35-2.65) .95 75/579 1.05 (0.37-2.93) .93 73/568 0.96 (0.34-2.73) .94
AHD stop with complaints 46/335 1.03 (0.37-2.88) .95 46/335 0.88 (0.30-2.52) .81 46/328 0.89 (0.30-2.63) .84
Supplementary Table 3
Cox Regression of Dementia and/or Mortality on Discontinuation of AHD Treatment in Participants With AHD at Baseline Who Attended Visit 2, Excluding Events <2 Years of
Follow-up or <2 Years After AHD Withdrawal
Outcome: dementia
AHD stop 83/1286 2.08 (1.00-4.33) .049 83/1286 1.86 (0.88-3.92) .10 82/1253 2.08 (1.00-4.33) .049
Concurrent medication
AHD stop without other medication 79/1247 3.30 (1.20-9.07) .02 79/1247 3.16 (1.15-8.72) .03 78/1216 3.30 (1.20-9.07) .02
AHD stop with other medication 79/1266 1.55 (0.57-4.25) .39 79/1266 1.33 (0.48-3.72) .59 78/1233 1.55 (0.57-4.25) .39
Memory complaints during study
AHD stop without complaints 28/839 3.88 (1.15-13.05) .03 28/839 3.09 (0.9-10.65) .07 27/819 3.88 (1.15-13.05) .03
AHD stop with complaints 55/446 1.20 (0.48-3.01) .70 55/446 1.08 (0.42-2.76) .88 55/436 1.20 (0.48-3.01) .70
Systolic BP on target during study
AHD stop systolic BP 140 mmHg 49/774 2.00 (0.79-5.06) .14 49/774 1.76 (0.68-4.53) .25 49/758 2.00 (0.79-5.06) .14
AHD stop systolic BP >140 mmHg 34/512 2.65 (0.80-8.81) .11 34/512 2.37 (0.68-8.20) .17 33/495 2.65 (0.80-8.81) .11
Outcome: dementia/mortality
AHD stop 240/1284 1.42 (0.86-2.36) .18 240/1284 1.47 (0.88-2.47) .14 236/1258 1.42 (0.86-2.36) .18
Concurrent medication
AHD stop without other medication 231/1245 2.06 (0.97-4.38) .06 231/1245 2.26 (1.06-4.81) .04 226/1214 2.06 (0.97-4.38) .06
AHD stop with other medication 233/1264 1.15 (0.59-2.25) .68 233/1264 1.15 (0.59-2.28) .68 228/1231 1.15 (0.59-2.25) .68
Memory complaints during study
AHD stop without complaints 127/838 1.53 (0.67-3.49) .31 127/838 1.63 (0.71-3.77) .25 123/818 1.53 (0.67-3.49) .31
AHD stop with complaints 113/445 1.13 (0.59-2.17) .71 113/445 1.15 (0.59-2.24) .67 112/433 1.13 (0.59-2.17) .71
Systolic BP on target during study
AHD stop systolic BP 140 mmHg 145/772 1.27 (0.67-2.42) .46 145/772 1.16 (0.60-2.24) .65 143/756 1.27 (0.67-2.42) .46
AHD stop systolic BP >140 mmHg 95/512 1.88 (0.82-4.35) .14 95/512 2.23 (0.95-5.25) .07 92/495 1.88 (0.82-4.35) .14
Outcome: mortality
AHD stop 180/1310 1.00 (0.51-1.95) .99 180/1310 1.08 (0.55-2.13) .83 175/1276 1.00 (0.51-1.95) .99
Concurrent medication
AHD stop without other medication 175/1269 1.47 (0.54-3.95) .45 175/1269 1.72 (0.64-4.66) .29 170/1237 1.47 (0.54-3.95) .45
AHD stop with other medication 176/1289 0.79 (0.32-1.92) .60 176/1289 0.82 (0.33-2.02) .66 171/1255 0.79 (0.32-1.92) .60
Memory complaints during study
AHD stop without complaints 109/860 1.10 (0.41-2.99) .85 109/860 1.30 (0.47-3.58) .61 105/839 1.10 (0.41-2.99) .85
AHD stop with complaints 71/449 0.86 (0.35-2.13) .74 71/449 0.93 (0.37-2.36) .88 70/437 0.86 (0.35-2.13) .74
Systolic BP on target during study
AHD stop systolic BP 140 mmHg 106/785 0.99 (0.43-2.25) .98 106/785 0.93 (0.40-2.16) .87 104/769 0.99 (0.43-2.25) .98
AHD stop systolic BP >140 mmHg 74/525 1.07 (0.33-3.45) .91 74/525 1.38 (0.42-4.51) .60 71/507 1.07 (0.33-3.45) .91
Supplementary Table 4
Cox Regression of Dementia and/or Mortality on Discontinuation of AHD Treatment in Participants With AHD at Baseline Adjusting for the preDIVA Intervention
Outcome: dementia
AHD stop 100/1507 2.15 (1.15-4.02) .02 100/1507 1.90 (1.00-3.62) .05 98/1467 1.75 (0.90-3.37) .10
Concurrent medication
AHD stop without other medication 93/1453 2.70 (0.99-7.40) .05 93/1453 2.61 (0.95-7.15) .06 91/1415 2.71 (0.97-7.57) .06
AHD stop with other medication 96/1479 1.96 (0.90-4.24) .09 96/1479 1.68 (0.76-3.73) .20 94/1439 1.48 (0.66-3.33) .35
Memory complaints during study
AHD stop without complaints 34/985 3.15 (1.10-9.02) .03 34/985 2.44 (0.83-7.20) .11 33/961 2.21 (0.73-6.72) .16
AHD stop with complaints 66/521 1.50 (0.68-3.29) .31 66/521 1.39 (0.62-3.12) .43 65/509 1.57 (0.68-3.59) .29
Systolic BP on target during study
AHD stop systolic BP 140 mmHg 62/903 2.23 (1.06-4.68) .04 62/903 1.91 (0.89-4.11) .10 61/884 1.63 (0.73-3.63) .23
AHD stop systolic BP >140 mmHg 38/604 2.23 (0.68-7.32) .19 38/604 2.08 (0.62-7.00) .24 37/583 1.93 (0.56-6.65) .30
Outcome: dementia/mortality
AHD stop 292/1505 1.58 (1.04-2.39) .03 292/1505 1.63 (1.06-2.50) .03 287/1475 1.48 (0.96-2.28) .08
Concurrent medication
AHD stop without other medication 278/1451 2.24 (1.19-4.22) .01 278/1451 2.42 (1.28-4.56) .01 272/1413 2.35 (1.23-4.46) .01
AHD stop with other medication 282/1477 1.31 (0.76-2.24) .33 282/1477 1.31 (0.75-2.27) .34 276/1437 1.20 (0.69-2.10) .52
Memory complaints during study
AHD stop without complaints 157/984 1.37 (0.70-2.68) .36 157/984 1.42 (0.71-2.82) .32 153/960 1.33 (0.66-2.67) .42
AHD stop with complaints 135/520 1.55 (0.90-2.65) .11 135/520 1.61 (0.92-2.80) .10 133/505 1.59 (0.90-2.81) .11
Systolic BP on target during study
AHD stop systolic BP 140 mmHg 173/901 1.41 (0.83-2.39) .21 173/901 1.30 (0.76-2.24) .34 170/882 1.17 (0.67-2.04) .58
AHD stop systolic BP >140 mmHg 119/604 2.04 (1.03-4.04) .04 119/604 2.32 (1.16-4.66) .02 116/583 2.16 (1.06-4.41) .03
Outcome: mortality
AHD stop 215/1532 1.16 (0.68-2.00) .59 215/1532 1.28 (0.74-2.23) .38 210/1491 1.21 (0.69-2.11) .51
Concurrent medication
AHD stop without other medication 208/1476 2.00 (0.94-4.26) .07 208/1476 2.33 (1.09-4.97) .03 203/1437 2.30 (1.07-4.95) .03
AHD stop with other medication 208/1503 0.82 (0.38-1.73) .60 208/1503 0.86 (0.40-1.86) .70 203/1462 0.79 (0.37-1.72) .56
Memory complaints during study
AHD stop without complaints 133/1007 1.02 (0.45-2.32) .96 133/1007 1.18 (0.51-2.73) .69 129/982 1.24 (0.53-2.87) .62
AHD stop with complaints 82/524 1.25 (0.60-2.60) .55 82/524 1.39 (0.65-2.94) .40 81/509 1.21 (0.56-2.60) .63
Systolic BP on target during study
AHD stop systolic BP 140 mmHg 121/915 0.99 (0.48-2.02) .97 121/915 0.97 (0.47-2.03) .94 119/896 0.88 (0.42-1.85) .73
AHD stop systolic BP >140 mmHg 94/617 1.56 (0.68-3.59) .30 94/617 1.90 (0.81-4.45) .14 91/595 1.86 (0.78-4.43) .16