DiR chemical

Hypotension in Nursing Home Residents on Antihypertensive Treatment: Is it Associated with Mortality?

Gulistan Bahat MD a,*, Birkan Ilhan MD a,b, Asli Tufan MD a,c, Sevilay Muratli MD a,d, Hilal Ozkaya MD e,f, Cihan Kilic PhD a, Meryem Merve Oren MD g, Hafize Dogan MD f, Esad Karisik MD f, Mehmet Akif Karan MD a, Athanase Benetos MD h

Abstract

Measurements: Demographic characteristics, mobility status, number of chronic diseases and drugs, nutritional status, and antihypertensive medications were noted. At the first visit, we recorded blood pressure (BP) measurements of last 1 year, which were measured regularly at 2-week intervals and considered their mean values. SBP and DBP thresholds were analyzed for mortality by ROC analysis. Multivariate Cox regression analyses were performed to determine factors related to mortality.
Results: The sample included 253 residents with a mean age of 75.7 8.7 years, and 66% were male. Residents were evaluated at a mean follow-up time of 14.3 5.2 months (median: 15) for short-term mortality and 31.6 14.3 months (median: 40) for long-term mortality. The prevalence of low SBP (110 mm Hg) and low DBP (65 mm Hg) was 34.8% and 15.8%, respectively. In follow-up, the shortterm mortality rate was 21.7% (n ¼ 55) and the long-term mortality rate was 42.2% (n ¼ 107). Low
SBP (110 mm Hg) was related to mortality in short- and long-term follow-ups [short-term follow-upfidence interval (CI) 1.5-8.6, P ¼ .01; long-term follow-up: HR 1.8, 95% CI: hazard ratio (HR) 3.7, 95% con1.1-3.0, P ¼ .02], adjusted for age, mobility status, nutritional state, and total number of diseases and drugs. Low DBP (65 mm Hg) was related to mortality in short- and long-term follow-ups [short-term follow-up: HR 3.0, 95% CI 1.2-7.8, P ¼ .02, long-term follow-up: HR 2.8, 95% CI 1.5-5.2, P ¼ .001], adjusted for age, mobility status, nutritional state, and total number of diseases and drugs.
Conclusions and Implications: Systolic hypotension was found in more than one-third of the NH residents receiving antihypertensive treatment. Low SBP and DBP were significant factors associated with mortality. Particular attention should be paid to prevent low SBP and DBP in NH residents on antihypertensive treatment.

Keywords: Hypertension mortality nursing home older adults treatment Objective: To assess whether low systolic blood pressure (SBP) or diastolic blood pressure (DBP) due to antihypertensive medications might be related to mortality among nursing home (NH) residents.

Introduction

Hypertension is a well-known risk factor related to atherosclerotic diseases, which are associated with significant morbidity and morstage 1 [systolic blood pressure (SBP),140-159 mm Hg; diastolic blood pressure (DBP), 90-99 mm Hg) and stage 2 hypertension (SBP 160 mm Hg; DBP 100 mm Hg) among normotensive individuals aged 55-65 years was 90% and 40%, respectively.2 Earlier, high blood pressure (BP) was regarded as a natural and necessary compensatory mechanism associated with aging.3 There was reluctance in the treatment of hypertension owing to possible negative consequences of treatment related to the hypoperfusion of vital organs.4 However, in recent years, studies on the treatment of hypertension were extrapolated to include older adults. They demonstrated the benefit of treatment of hypertension in this age group as well.5 The obvious consequence is the increasing trend in the use of antihypertensive medications in older adults. The use of antihypertensives is most common among those aged 80 years.6
Older adults constitute a heterogeneous group in terms of functionality, ranging between very fit, fully functional individuals to very frail, disabled, totally dependent ones. The frail older adults are more prone to treatment-related side effects of drugs.7 They generally have limited life expectancy, which may decrease the benefit gained from the hypertension treatment as well. Thus, it can be speculated that treatment of hypertension in frail older adults may not be of benefit or even be hazardous. Consequent recent trials studied this hypothesis, suggesting that frail older adults may not really benefit from hypertension treatment,8e10 and some trials suggested hazardous consequences of treatment of hypertension in this subgroup.11e13 Thus, both the 2014 Joint National Committee and the 2013 European Society of Cardiology/European Society of Hypertension reports on the treatment of hypertension suggested a higher BP level (ie, <150/90 mm Hg) target for the older adults compared with their corresponding previous editions.14,15 This debate flared up with a recent trial, the Systolic Blood Pressure Intervention Trial (SPRINT), which suggested even lower targets of SBP in older adults, including the frail ones with no significant side effect.16,17 Thus, currently, there is a suggestion and tendency to treat frail older adults to lower BP targets. In this study, we aimed to assess the prevalence of hypotension and its relationship to mortality in nursing home (NH) residents receiving antihypertensive medications. Methods Population and Setting This study was designed as a single-center, observational, longitudinal study and performed in 1 NH in the most densely populated city of the country. It was the largest NH in that city and was affiliated to Metropolitan Municipality. The acceptance depended solely on the lack of sufficient support of the older adult for remaining in their homes. All the maintenance and health expenses of the residents were met by the Metropolitan Municipality. Because the residents had no financial resource or family support during their stay in the institution, none of the residents left the institution in the study period. The NH included 592 residents aged 60 years. All the residents who were on antihypertensive medication were asked to be involved. First visits were completed between June 2014 and February 2015. Measurements At the first visit, the data on age (years), sex, mobility status (ambulatory, need assistance for ambulation, wheelchair bound, or bedridden), number of chronic diseases, number of drugs and antihypertensive drugs were noted. Information was obtained from NH physicians and nurses with face-to-face interviews, and by reviewing the patients’ medical files. The following conditions were mentioned as chronic diseases: asthma, atrial fibrillation, benign prostate hyperplasia, bipolar mood disorder, cancer, cerebrovascular disease, chronic obstructive pulmonary disease, chronic renal disease, coronary artery disease, dementia, depression, diabetes mellitus, epilepsy, glaucoma, heart failure, hyperlipidemia, hypertension, hypothyroidism, hyperthyroidism, liver cirrhosis, multiple sclerosis, osteoporosis, Parkinson’s disease, rheumatoid arthritis, and schizophrenia. In addition, any disease requiring chronic medication use was specifically included to the list of chronic diseases. In other words, if a resident was prescribed vitamin D or vitamin B12, we clinically expressed it as the presence of deficiency and it was added to the list of chronic diseases. The number of drugs used long-term including vitamin supplements and over-the-counter medications was recorded. For combination antihypertensives, each antihypertensive agent was counted as 1 prescription. Nutrition was assessed by the MiniNutritional Assessment-Short Form (MNA-SF). The MNA-SF is a validated instrument to evaluate nutritional status. An MNA-SF score <8 was evaluated as undernourished, with an MNA score of 8 to 11 as at risk of undernutrition and 12 as well-nourished.18 As a routine of NH care, BPs were measured and noted at 2-week intervals by skilled NH nurses in all NH residents. BPs were measured with manual aneroid sphygmomanometer (ERKA brand) in a sitting position for ambulatory residents and in a supine position for bedridden residents. At the first visit, we noted 26 consecutive BP measurements of each participant that were performed at 2-week intervals in the last 1 year. Thereby, we calculated the mean values of the past 1 year’s SBP and DBP measurements for each participant. There were no missing variables for BP data. The residents were followed for mortality. The data on short-term mortality was recorded in May 2016 and long-term mortality in June 2018. Ethical approval was obtained from the local ethics committee. This study was conducted according to the guidelines laid down in the Declaration of Helsinki. Informed consent was obtained from all patients and/or their related conservators. Statistical Analysis We investigated the variables for normality by using visual (histograms and probability plots) and analytical methods. Numerical variables were given as mean standard deviation for normally distributed variables and as median (minimum-maximum) for skewdistributed continuous variables. We showed categorical variables with numbers and frequencies. Two groups were compared with independent sample t test or Mann-Whitney U test when necessary. Chi-square test with Yates correction and Fisher exact test was used for 2 2 contingency tables when appropriate for non-numerical data. The cutoff values of SBP and DBP that predicted the short- and long-term mortality were determined by receiver operating characteristic (ROC) analysis. The area under the ROC curve (AUC) and 95% confidence interval (CI) were calculated. The sensitivity and specificity of the cutoff values of SBP and DBP were calculated for short- and long-term mortality. The Kaplan-Meier analysis was used to plot survival curves in groups with lower and higher BPs according to the cutoff points obtained from ROC analysis. We used the long rank test to compare survival between the groups with lower and higher BPs. Multivariate time-to-event analyses were performed using Cox proportional hazards regression with short- and long-term mortality as the outcome. Results were presented as hazard ratio (HR) and 95% CI. Statistical analyses were performed using SPSS, version 21.0 (IBM, Armonk, NY) and MedCalc Statistical Software, version 15.2 (MedCalc Software bvba, Ostend, Belgium). The alpha value was set to <0.05 to determine significance. Results A total of 253 residents with a mean age of 75.7 8.7 years were included. Sixty-six percent (n ¼ 167) were male and 34% were female (n ¼ 86). Four percent were bedridden, 15.8% were wheelchair bound, 14.5% were in need of assistance for ambulation, and 62.7% were ambulatory. The medians and ranges for number of chronic diseases were 7 (1-17), number of daily drugs 10 (2-19), number of antihypertensive drugs 2 (1-6), and MNA-SF score 13 (3-14) points. At follow-up, the short-term mortality rate was 21.7% (n ¼ 55) and longterm mortality rate was 42.2% (n ¼ 107). Residents were evaluated at a mean follow-up time of 14.3 5.2 months (median 15, interquartile range 1) for short-term mortality; and at a mean follow-up time of 31.6 þ 14.3 months (median 40, interquartile range 18) for long-term mortality. ROC Analyses to Determine SBP and DBP Thresholds for Short- and Long-Term Mortality The SBP cutoff was 110 mm Hg (sensitivity 52%, specificity 69.7%, AUC 0.634, 95% CI 0.572-0.694, P ¼ .002, for short-term mortality; sensitivity 43.6%, specificity 69.5%, AUC 0.566, 95% CI 0.499-0.630,P(sensitivity 32%, speci¼ .08 for long-term mortality). The DBP cutoff wasficity 88.6%, AUC 0.616, 95% CI 0.553-0.677,65 mm HgP ¼ .008 for short-term mortality; sensitivity 25.7% specificity 90.1%, AUC 0.573, 95% CI 0.507-0.638, P ¼ .04) (Supplementary Figures 1-4). Considering these cutoffs for low SBP and DBP, the prevalence of lowSBP (110 mm Hg) and low DBP (65 mm Hg) was 34.8% (n ¼ 88) and15.8% (n ¼ 40), respectively. Univariate Analyses Factors related to the presence of low SBP The residents with low SBP had lower MNA-SF scores compared with the high-SBP group (P ¼ .006). The male residents were more likely to have lower SBP levels than the female residents (P ¼ .006). However, there was no difference regarding age (years), mobility status, the total number of diseases, number of drugs, and number of antihypertensive drugs between the SBP groups (Table 1). Relationship between low SBP and mortality Kaplan-Meier log rank test revealed that the patients with high SBP (>110 mm Hg) survived significantly longer than the residents with low SBP (110 mm Hg) (mean survival time 21.4 months, 95% CI 20.4-22.4, vs 18.8 months, 95% CI 16.9-20.5, respectively; P ¼ .002) when analyzing short-term follow-up (Supplementary Figure 5). For the long-term follow-up, residents with high SBP (>110 mm Hg) had survived significantly longer than the residents with low SBP (110 mm Hg) (mean survival time 37.5 months, 95% CI 34.9-40.1, vs 31.5 months, 95% CI 27.5-35.4, respectively; P ¼ .02) (Supplementary Figure 6).

Factors related to the presence of low DBP

The residents with low DBP had a higher number of drugs (P ¼.04) when compared to the higher-DBP group. The male residents were more likely to have low DBP compared to the female residents (P ¼.006). However, there was no difference regarding age (years), the total number of diseases, number of antihypertensive drugs, and the MNA-SF score between the DBP groups. In the follow-up, the mortality rate was higher in the low DBP group (P ¼ .007 and P ¼ .001, respectively) (Table 2).
Kaplan-Meier log rank test revealed that the patients with high DBP (>65 mm Hg) survived significantly longer than the residents with low DBP (65 mm Hg) (mean survival time 21.1 months, 95% CI 20.2-22, vs 17.1 months, 95% CI 14.3-19.9, P < .001) (Supplementary Figure 7). For the long-term follow-up, residents with high DBP (>65 mm Hg) survived significantly longer than the residents with low DBP (65 mm Hg) (mean survival time 37.1 months, 95% CI 34.8-39.5, vs 26.7 months, 95% CI 21.1-33.1, respectively, P < .001) (Supplementary Figure 8). Association of low SBP with mortality Low SBP was related to the mortality in the short- and long-term follow-ups. The results were as follows for the short-term followup: low SBP (HR 3.7, 95% CI 1.5-8.6, P ¼ .01), adjusted for age (years), mobility status, the total number of diseases, number of drugs, and MNA-SF score. Mortality was also higher in those using a higher number of drugs (HR 1.3, 95% CI 1.1-1.6, P ¼ .01) (Table 3). The results were as follows for the long-term follow-up: low SBP (HR 1.8, 95% CI 1.1-3.0, P ¼ .02), adjusted for age (years), mobility status, the total number of diseases, number of drugs, and MNA-SF score. Mortality was higher also in those using a higher number of drugs (HR 1.2, 95% CI 1.1-1.3, P ¼.002) and in those with older age (HR 1, 95% CI 1.01-1.08, P ¼.01), and it was lower in those with higher MNA-SF scores (HR 0.9, 95% CI 0.8-0.9, P ¼ .03) (Table 4). Association of low DBP with mortality Low DBP was related to the mortality in the short- and long-term follow-ups. The results were as follows for the short-term follow-up: low DBP (HR 3.0, 95% CI 1.2-7.8, P ¼ .02), adjusted for age (years), mobility status, the total number of diseases, number of drugs, and MNA-SF score. Mortality was also higher in those using a higher number of drugs (HR 1.3, 95% CI 1.1-1.5, P ¼ .03) (Table 5). The results were as follows for the long-term follow-up: low DBP (HR 2.8, 95% CI 1.5-5.2, P ¼ .001), adjusted for age (years), mobility status, the total number of diseases, number of drugs, and MNA-SF score. Mortality was higher also in those using a higher number of drugs (HR 1.1, 95% CI 1.03-1.2, P ¼.01) and in those with older age (HR 1.04, 95% CI 1.01-1.07, P ¼.02), and it was lower in those with higher MNA-SF scores (HR 0.9, 95% CI 0.8-0.98, P ¼ .02) (Supplementary Table 1). Discussion In this study, including 253 NH residents on antihypertensive treatment at a mean age of 75.7 years, we found that the SBP cutoff 110 mm Hg and DBP cutoff 65 mm Hg were independently associated with both short- and long-term mortality. The short-term mortality rate in a median follow-up period of 15 months was 21.7%, and the long-term mortality rate in a median follow-up period of 40 months was 42.2%. The survival time at a median follow-up of 3.5 years (range, 31.5-37.5 months) was 6 months shorter in patients with low SBP than in those with higher SBP. In addition, low DBP was found to be another independent factor associated with mortality because the survival time at a median follow-up of 3.5 years was about 9 months shorter in residents with low DBP. It is noteworthy that more than one-third of residents had low SBP, and about 15% had low DBP under antihypertensive treatment, which has been shown to be an unfavorable factor for survival. The approach to older-age hypertension has changed significantly in medical practice. As late as the 1950s, elevated BP was considered necessary for the adequate perfusion of vital organs,4 but this suggestion was not supported by any research owing to the exclusion of older adults from the clinical trials. Thankfully, in recent decades, hypertension treatment studies were enlarged to include older adults. The benefit of treatment of hypertension was demonstrated in the older adults in meta-analyses, including the very old, as well.5,19 Thus, clinicians prescribed more antihypertensive medications in older adults.5 The use of antihypertensives is most common among those aged 80 years and older.6 However, until recently, frailty was not considered as a possible factor that modifies the association of antihypertensive treatment with a mortality benefit in older adults. It should be stressed that older adults be regarded as a very heterogeneous group regarding functionality. They range from very fit, independent individuals to very frail, disabled, totally dependent ones. It is well documented that frail older adults are more prone to treatmentrelated side effects for drugs.7 Frailty is linked to limited life expectancy, which may possibly decrease the benefit of antihypertensive treatment.20 These factors open an area of suspicion that treatment of hypertension in frail older adults may not be beneficial, if not hazardous. This hypothesis has been tested in recent trials putting forward that frail older adults may not do well with antihypertensive treatment.8e10 Moreover, some trials put forward the hazardous consequences of treatment of hypertension in frail subjects.11e13 Accordingly, an expert opinion from the European Society of Hypertension and European Union Geriatric Medicine Society suggested some statements to consider in the treatment of hypertension signifying a fast and practical evaluation of frailty status while treating older adults for hypertension.21 However, the recent large-scaled SPRINT trial results suggested that lower targets of SBP are beneficial in the older adults.16 The SPRINT researchers published the results of older adults 75 years in detail, and here, they analyzed the possible modifier effect of frailty.17 They suggested that frailty did not affect the beneficial effect of antihypertensive treatment aimed at an SBP <120 mm Hg in their study population. These findings caused a modification of antihypertensive targets by the committees to a lower goal threshold in older adults.22,23 The current practice commonly tends to treat even frail older adults to lower BP targets. However, of note, the SPRINT trial has been criticized from the geriatrics perspective because of their inclusion of ambulatory, communitybased persons.24 The other exclusion criteria included unintentional weight loss, expected survival <3 years, significant heart or renal failure, or use of too many medications among many others, which would increase frailty risk. These exclusion criteria clearly result in the exclusion of more frail subjects. Moreover, in subjects with slow gait speed, none of the studied outcomes (ie, composite outcome of nonfatal myocardial infarction, acute coronary syndrome not resulting in a myocardial infarction, nonfatal stroke, nonfatal acute decompensated heart failure and death from cardiovascular causes, and allcause mortality) proved better in the intensive treatment group (P ¼.05 and .3, respectively). In the frail group, the composite outcome and all-cause mortality, again, was not better in the intensivetreatment group (P ¼ .06 and .05, respectively).17 The HYpertension in the Very Elderly Trial (HYVET) also investigated the possible interaction between the effects of hypertension treatment and frailty in older adults in its subsequent study.25 They reported no evidence of an interaction between the impact of antihypertensive treatment and frailty. They assessed frailty using the Frailty Index (FI). Of note, the important point is that the relationship between SBP and mortality was reported to vary by frailty designated by, specifically, “walking speed,”9,13 not by the FI. Recently, a reanalysis of the Systolic Hypertension in the Elderly Program (SHEP) data revealed that it is specifically the “functional status” that modify the outcomes related to antihypertensive treatment in older patients.12 FI is composed of a long checklist of clinical conditions and diseases, representing comorbidities rather than the patient’s functionality.26 There are some studies that invite the clinicians to be more careful while treating frail older adults with antihypertensive medication, supporting the results of this study. In their 2015 study, Benetos et al27 assessed all-cause mortality in institutionalized individuals older than 80 years according to SBP levels and the number of antihypertensive drugs in the PARTAGE study among 1127 residents. In this longitudinal study from NHs, they looked for the interaction between low SBP, defined as <130 mm Hg, and the presence of combination antihypertensive treatment on 2-year all-cause mortality. BP was measured with assisted self-measurements in the NH during 3 consecutive days. They reported a significant interaction between low SBP and treatment with 2 or more BP-lowering agents, resulting in a higher risk of mortality (adjusted HR 1.78, 95% CI 1.34-2.37, P <.001) in patients with low SBP who were receiving multiple BP medicines compared with the other participants. Consequently, they raised a cautionary note regarding the safety of using combination antihypertensive therapy in frail older patients with low SBP.27 More recently, Streit et al28 showed that among 244 patients who were prescribed antihypertensive medication and recruited from the population-based Leiden 85-plus cohort study, all-cause mortality was higher in participants with lower BP during antihypertensive treatment. This study has some limitations and strengths. It is a single-center and single-county study. Although it included NH residents who were expected to represent a frail population, there was not a formal assessment of frailty status. However, instead, there was an assessment of dependency for ambulation. We suggest that this assessment provides some means for frailty assessment, and about 40% were suffering from some forms of dependency for ambulation. The number of participants was not quite high, reflecting the design as a singlecenter study. However, it was comparable to the reports studying similar associations.28 BP measurements were performed with a manual device that is prone to measurement error and interindividual variances. However, measurements were performed by skilled NH nurses. Another point is we recorded the SBP and DBP values of the past 1 year at the first visit and we did not consider follow-up data on BP measurements during the study period. We were not allowed to make any change in the treatment of the study participants because the institutional physicians were responsible from the pharmacologic management of the residents. In the study period, the institutional physicians remained constant. Therefore, it is unlikely that the BP management differed during the follow-up time. However, as we did not have absolute data on this issue, this should be noted as another limitation of the study. On the other hand, we noted the mean of BP measurements from the records of 26 consecutive measurements of the past 1 year measured regularly at 2-week intervals. In studies that examine associations between low BP and mortality, the BP measurements were recorded also at the beginning of the study but at a lower frequency and for a shorter time period, such as 18 times in 3 consecutive days or 2 times recorded 2 weeks apart.27,28 The higher frequency and longer time period of BP measurements may represent a strength of this study. Conclusions and Implications We have shown SBP and DBP cutoffs of 100 and 65 mm Hg for increased mortality among NH residents who were on antihypertensive treatment. Systolic hypotension was found in more than onethird and low DBP in about 15% of the residents. Low SBP and DBP were significantly associated with mortality both at about 15 and 40 months. Our results suggest that particular attention should be paid to prevent low SBP and DBP in NH residents on antihypertensive treatment. References 1. Burt VL, Whelton P, Roccella EJ, et al. Prevalence of hypertension in the US adult population. Results from the Third National Health and Nutrition Examination Survey, 1988-1991. Hypertension 1995;25:305e313. 2. Vasan RS, Beiser A, Seshadri S, et al. Residual lifetime risk for developing hypertension in middle-aged women and men: The Framingham Heart Study. JAMA 2002;287:1003e1010. 3. Pinto E. Blood pressure and ageing. Postgrad Med J 2007;83:109e114. 4. Moser M. Historical perspectives on the management of hypertension. J Clin Hypertens (Greenwich) 2006;8:15e20. quiz 39. 5. Briasoulis A, Agarwal V, Tousoulis D, Stefanadis C. Effects of antihypertensive treatment in patients over 65 years of age: A meta-analysis of randomised controlled studies. Heart 2014;100:317e323. 6. Charlesworth CJ, Smit E, Lee DS, et al. Polypharmacy among adults aged 65 years and older in the United States: 1988-2010. J Gerontol A Biol Sci Med Sci 2015;70:989e995. 7. Mallet L, Spinewine A, Huang A. The challenge of managing drug interactions in elderly people. Lancet 2007;370:185e191. 8. Peralta CA, Katz R, Newman AB, et al. Systolic and diastolic blood pressure, incident cardiovascular events, and death in elderly persons: The role of functional limitation in the Cardiovascular Health Study. Hypertension 2014; 64:472e480. 9. 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;172:1162e1168. 10. Odden MC, Covinsky KE, Neuhaus JM, et al. The association of blood DiR chemical pressure and mortality differs by self-reported walking speed in older Latinos. J Gerontol A Biol Sci Med Sci 2012;67:977e983.
11. Tinetti ME, Han L, Lee DS, et al. Antihypertensive medications and serious fall injuries in a nationally representative sample of older adults. JAMA Intern Med 2014;174:588e595.
12. Charlesworth CJ, Peralta CA, Odden MC. Functional status and antihypertensive therapy in older adults: A new perspective on old data. Am J Hypertens 2016; 29:690e695.
13. Gutierrez-Misis A, Sanchez-Santos MT, Banegas JR, et al. Walking speed and high blood pressure mortality risk in a Spanish elderly population. J Hum Hypertens 2015;29:566e572.
14. 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: 507e520.
15. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC practice guidelines for the management of arterial hypertension. Blood Press 2014;23:3e16.
16. Wright JT Jr, Williamson JD, Whelton PK, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103e 2116.
17. Williamson JD, Supiano MA, Applegate WB, et al. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged 75 years: A randomized clinical trial. JAMA 2016;315:2673e2682.
18. Vellas B, Guigoz Y, Garry PJ, et al. The Mini Nutritional Assessment (MNA) and its use in grading the nutritional state of elderly patients. Nutrition 1999;15: 116e122.
19. Bulpitt CJ, Fletcher AE, Amery A, et al. The Hypertension in the Very Elderly Trial (HYVET). Rationale, methodology and comparison with previous trials. Drugs Aging 1994;5:171e183.
20. Kojima G, Liljas AEM, Iliffe S. Frailty syndrome: Implications and challenges for health care policy. Risk Manag Healthc Policy 2019;12:23e30.
21. Benetos A, Bulpitt CJ, Petrovic M, et al. An expert opinion from the European Society of Hypertension-European Union Geriatric Medicine Society Working Group on the Management of Hypertension in Very Old, Frail Subjects. Hypertension 2016;67:820e825.
22. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/ AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: Executive summary: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2018;138: e426ee483.
23. Williams B, Mancia G, Spiering W, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J 2018;39:3021e3104.
24. Bahat G, I_lhan B, Tufan A, Karan MA. Blood pressure goals in functionally limited elderly patients. Am J Med 2017;130:e319ee320.
25. Warwick J, Falaschetti E, Rockwood K, et al. No evidence that frailty modifies the positive impact of antihypertensive treatment in very elderly people: An investigation of the impact of frailty upon treatment effect in the HYpertension in the Very Elderly Trial (HYVET) study, a double-blind, placebo-controlled study of antihypertensives in people with hypertension aged 80 and over. BMC Med 2015;13:78.
26. Cesari M, Gambassi G, Abellan van Kan G, Vellas B. The frailty phenotype and the frailty index: Different instruments for different purposes. Age Ageing 2013;43:10e12.
27. Benetos A, Labat C, Rossignol P, et al. Treatment with multiple blood pressure medications, achieved blood pressure, and mortality in older nursing home residents: The PARTAGE Study. JAMA Intern Med 2015;175:989e995.
28. Streit S, Poortvliet RKE, Gussekloo J. Lower blood pressure during antihypertensive treatment is associated with higher all-cause mortality and accelerated cognitive decline in the oldest-old. Data from the Leiden 85-Plus Study. Age Ageing 2018;47:545e550.