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

Lower blood pressure during antihypertensive treatment is associated with higher all-cause... Abstract Background the appropriateness of lowering systolic blood pressure remains controversial in the oldest-old. We tested whether systolic blood pressure is associated with all-cause mortality and change in cognitive function for patients prescribed antihypertensive treatment and those without treatment. Methods we studied participants in the population-based Leiden 85-plus cohort study. Baseline systolic blood pressure and use of antihypertensive treatment were predictors; all-cause mortality and change in cognitive function measured using the Mini-Mental State Examination were the outcomes. Grip strength was measured as a proxy for physical frailty. We used Cox proportional hazards and mixed-effects linear regression models to analyse the relationship between systolic blood pressure and both time to death and change in cognitive function. In sensitivity analyses, we excluded deaths within 1 year and restricted analyses to participants without a history of cardiovascular disease. Results of 570 participants, 249 (44%) were prescribed antihypertensive therapy. All-cause mortality was higher in participants with lower blood pressure prescribed antihypertensive treatment (HR 1.29 per 10 mmHg lower systolic blood pressure, 95% CI 1.15–1.46, P < 0.001). Participants taking antihypertensives showed an association between accelerated cognitive decline and lower blood pressure (annual mean change −0.35 points per 10 mmHg lower systolic blood pressure, 95% CI −0.60, −0.11, P = 0.004); decline in cognition was more rapid in those with lower hand grip strength. In participants not prescribed antihypertensive treatment, no significant associations were seen between blood pressure and either mortality or cognitive decline. Conclusions lower systolic blood pressure in the oldest-old taking antihypertensives was associated with higher mortality and faster decline in cognitive function. hypertension, oldest-old, cognitive function, antihypertensive treatment, frailty, older people Introduction Hypertension is the most important preventable cause of cardiovascular disease (CVD), including stroke and myocardial infarction [1]. The prevalence of hypertension increases sharply with age [2]. It has been clear for at least two decades that older patients (>60 years) also benefit from antihypertensive treatment [3, 4], but guidelines may not apply equally to everyone over 60 years. For example, we do not know if the effects of treating hypertension are similar among individuals aged over 80 years (the oldest-old)—a segment of the population that is expected to triple in the next two decades [5]. Hypertension studies have tended to exclude patients with multimorbidity and frailty. These criteria disproportionately exclude the oldest-old because this age group is much more likely to have multimorbidity or to be frail [6, 7]. At the same time, observational studies have raised concerns about associations between low systolic blood pressure (SBP), increased mortality and accelerated cognitive decline, especially in the oldest-old living with frailty [8]. Studying associations between SBP and cognitive decline are challenging [9]. There is evidence that high SBP in midlife damages cerebral vessels and impairs brain function [10], but low SBP in late life, particularly in frail subjects, is associated with higher risk for cognitive decline [11]. A study by Mosello et al. [12] found that lower SBP was associated with faster cognitive decline in individuals who were already cognitively impaired; several other studies had produced similar findings [13–19]. Mosello et al. were the first to describe that antihypertensive therapy modified these associations: low SBP was associated with cognitive decline only in patients under antihypertensive therapy, but not in those who were not prescribed antihypertensive therapy. Unfortunately, the follow-up time was too short to detect long-term protective effects of antihypertensive treatment, and the population was limited to patients attending a memory clinic. There is, therefore, a need for rigorous, population-based observational studies with adequate follow-up time to test the association between antihypertensive therapy, blood pressure, mortality and cognitive decline in the oldest-old. We analysed data from a population-based cohort study with a 5-year follow-up to test if the association between low SBP with all-cause mortality and cognitive function differs for oldest-old patients under antihypertensive treatment and those without treatment, and to test if frailty modifies these associations. Methods Study design and setting We analysed data from a prospective, population-based cohort study with a 5-year follow-up—the Leiden 85-plus Study [20, 21]. All inhabitants of the city of Leiden, the Netherlands, were invited to join this cohort study if they turned 85 years between 1997 and 1999. No exclusion criteria were applied. The target population was 705 inhabitants. Of these, 14 (2.0%) died before being enrolled in the study; 599 (85.0%) provided informed or proxy consent [22]. The Medical Ethical Committee of the Leiden University Medical Center approved the original study. Participants For this analysis, we applied two pre-specified exclusion criteria. To lower the risk of reverse causality between SBP and mortality risk, we excluded participants who died <3 months after they entered the cohort (n = 5). We also excluded participants who had no SBP measurements at baseline (n = 24). Procedures and measurements A history of CVD (i.e. previously recorded diagnoses of angina pectoris, myocardial infarction, heart failure, intermittent claudication, peripheral arterial surgery, transient ischaemic attack, and stroke) was available from general practitioners (GPs) or nursing home physicians. At baseline, research nurses visited all participants to administer the Mini-Mental State Examination (MMSE) [23]. At baseline, SBP was measured twice with a mean time range between measurements of 2 weeks. SBP was measured using a mercury sphygmomanometer, in the seated position after at least 5 min of rest and with no vigorous exercise in the preceding 30 min. For this analysis, we averaged the two measurements of SBP. The research nurses also recorded socio-demographic characteristics (level of education, income, living place); current smoking status (yes/no); depressive symptoms if MMSE was >18 points using the 15-point Geriatric Depression Scale [24]; and hand grip strength using a hand dynamometer. During annual follow-up visits, nurses repeated MMSE measurements. All participants were followed for all-cause mortality for 5 years using municipal records. Statistical analysis We assessed associations between exposure (baseline SBP and use of antihypertensive medication) and outcomes (all-cause mortality and annual change in cognitive function) over 5 years. At baseline, we compared characteristics of participants prescribed and not prescribed antihypertensive therapy. The crude and adjusted modelling approaches for all-cause mortality using Cox proportional hazard models and annual change in MMSE using mixed-effects linear regression models are described in detail in Appendix 1, available at Age and Ageing online. Subgroup analyses were performed for the second aim, to test if grip strength (as a proxy for frailty) modified the associations of SBP and treatment with the outcomes. We stratified both models for low/high hand grip strength to explore effect sizes and directions of effects. However, due to small sample sizes, this subgroup analysis was only exploratory. In sensitivity analyses, we firstly excluded deaths within 1 year after baseline; secondly restricted the models to participants without a history of CVD at baseline; and thirdly recoded participants who could not perform the hand grip strength test as missing. A two-sided P-value of 0.05 was taken as statistically significant for all analyses. We used STATA 15.0 (StataCorp, College Station, TX, USA) for all analyses. Results We analysed data from 570 individuals, of whom 249 (43.7%) were prescribed antihypertensive therapy at baseline (Table 1). Participants prescribed antihypertensive therapy and those not prescribed antihypertensives were similar in all aspects except for a higher prevalence of CVD in those prescribed antihypertensives (61.9% vs. 35.8%, P < 0.001). The other cardiovascular, socio-demographic, and functional characteristics at baseline were equally distributed among the two groups. Table 1. Baseline characteristics of participants at age 85 years by antihypertensive treatment (n = 570) Domains Overall (n = 570) Antihypertensive treatment (n = 249) No antihypertensive treatment (n = 321) P-valuea Socio-demographic characteristics  Women, n (%) 380 (66.7) 173 (69.5) 207 (64.5) 0.21  Low educationb, n (%) 358 (64.9) 163 (66.8) 195 (63.3) 0.39  Low incomec, n (%) 280 (50.9) 122 (50.8) 158 (51.0) 0.98  Institutionalised, (%) 102 (18.4) 45 (18.4) 57 (18.3) 0.97 Cardiovascular characteristics  SBP in mmHg, mean (SD)d 155.2 (18.7) 154.8 (16.8) 155.5 (20.0) 0.64  Current smoker, n (%) 89 (15.7) 33 (13.3) 56 (17.6) 0.16  Diabetes mellitus, n (%) 91 (16.3) 46 (18.9) 45 (14.2) 0.14  CVDe, n (%) 269 (47.2) 154 (61.9) 115 (35.8) <0.001 Functional characteristics  Cognition (MMSEf), median (IQR) 26 (22–28) 26 (21–28) 26 (23–28) 0.094  Depression (GDSg), median (IQR) 2 (1–3) 2 (1–3) 2 (1–3) 0.70  Low hand grip strengthh, n (%) 362 (63.5) 161 (64.7) 201 (62.6) 0.62 Domains Overall (n = 570) Antihypertensive treatment (n = 249) No antihypertensive treatment (n = 321) P-valuea Socio-demographic characteristics  Women, n (%) 380 (66.7) 173 (69.5) 207 (64.5) 0.21  Low educationb, n (%) 358 (64.9) 163 (66.8) 195 (63.3) 0.39  Low incomec, n (%) 280 (50.9) 122 (50.8) 158 (51.0) 0.98  Institutionalised, (%) 102 (18.4) 45 (18.4) 57 (18.3) 0.97 Cardiovascular characteristics  SBP in mmHg, mean (SD)d 155.2 (18.7) 154.8 (16.8) 155.5 (20.0) 0.64  Current smoker, n (%) 89 (15.7) 33 (13.3) 56 (17.6) 0.16  Diabetes mellitus, n (%) 91 (16.3) 46 (18.9) 45 (14.2) 0.14  CVDe, n (%) 269 (47.2) 154 (61.9) 115 (35.8) <0.001 Functional characteristics  Cognition (MMSEf), median (IQR) 26 (22–28) 26 (21–28) 26 (23–28) 0.094  Depression (GDSg), median (IQR) 2 (1–3) 2 (1–3) 2 (1–3) 0.70  Low hand grip strengthh, n (%) 362 (63.5) 161 (64.7) 201 (62.6) 0.62 aChi-square test for categorical variables, t-test for normally distributed continuous and Wilcoxon rank-sum test for non-normally distributed data was used. bDefined as primary school only. cDefined as state pension only (about EUR 750 monthly). dSBP was measured twice during home visit at baseline in a seated position, 2 weeks apart, and after at least 5 minutes of rest and no vigorous exercise in the preceding 30 minutes. Both measurements were averaged. eCVD included angina pectoris, myocardial infarction, heart failure, intermittent claudication, peripheral arterial surgery, TIA and stroke. fMMSE, possible scores range from 0 to 30 points (worst to best). Missing data in n = 7. gGDS-15, possible scores range from 0 to 15 (worst to best). Data not available for participants with Mini-Mental State Examination (MMSE) scores <18 (n = 97). hParticipants with hand grip strength below the sex-specific medians or unable to perform the test (n = 35). Table 1. Baseline characteristics of participants at age 85 years by antihypertensive treatment (n = 570) Domains Overall (n = 570) Antihypertensive treatment (n = 249) No antihypertensive treatment (n = 321) P-valuea Socio-demographic characteristics  Women, n (%) 380 (66.7) 173 (69.5) 207 (64.5) 0.21  Low educationb, n (%) 358 (64.9) 163 (66.8) 195 (63.3) 0.39  Low incomec, n (%) 280 (50.9) 122 (50.8) 158 (51.0) 0.98  Institutionalised, (%) 102 (18.4) 45 (18.4) 57 (18.3) 0.97 Cardiovascular characteristics  SBP in mmHg, mean (SD)d 155.2 (18.7) 154.8 (16.8) 155.5 (20.0) 0.64  Current smoker, n (%) 89 (15.7) 33 (13.3) 56 (17.6) 0.16  Diabetes mellitus, n (%) 91 (16.3) 46 (18.9) 45 (14.2) 0.14  CVDe, n (%) 269 (47.2) 154 (61.9) 115 (35.8) <0.001 Functional characteristics  Cognition (MMSEf), median (IQR) 26 (22–28) 26 (21–28) 26 (23–28) 0.094  Depression (GDSg), median (IQR) 2 (1–3) 2 (1–3) 2 (1–3) 0.70  Low hand grip strengthh, n (%) 362 (63.5) 161 (64.7) 201 (62.6) 0.62 Domains Overall (n = 570) Antihypertensive treatment (n = 249) No antihypertensive treatment (n = 321) P-valuea Socio-demographic characteristics  Women, n (%) 380 (66.7) 173 (69.5) 207 (64.5) 0.21  Low educationb, n (%) 358 (64.9) 163 (66.8) 195 (63.3) 0.39  Low incomec, n (%) 280 (50.9) 122 (50.8) 158 (51.0) 0.98  Institutionalised, (%) 102 (18.4) 45 (18.4) 57 (18.3) 0.97 Cardiovascular characteristics  SBP in mmHg, mean (SD)d 155.2 (18.7) 154.8 (16.8) 155.5 (20.0) 0.64  Current smoker, n (%) 89 (15.7) 33 (13.3) 56 (17.6) 0.16  Diabetes mellitus, n (%) 91 (16.3) 46 (18.9) 45 (14.2) 0.14  CVDe, n (%) 269 (47.2) 154 (61.9) 115 (35.8) <0.001 Functional characteristics  Cognition (MMSEf), median (IQR) 26 (22–28) 26 (21–28) 26 (23–28) 0.094  Depression (GDSg), median (IQR) 2 (1–3) 2 (1–3) 2 (1–3) 0.70  Low hand grip strengthh, n (%) 362 (63.5) 161 (64.7) 201 (62.6) 0.62 aChi-square test for categorical variables, t-test for normally distributed continuous and Wilcoxon rank-sum test for non-normally distributed data was used. bDefined as primary school only. cDefined as state pension only (about EUR 750 monthly). dSBP was measured twice during home visit at baseline in a seated position, 2 weeks apart, and after at least 5 minutes of rest and no vigorous exercise in the preceding 30 minutes. Both measurements were averaged. eCVD included angina pectoris, myocardial infarction, heart failure, intermittent claudication, peripheral arterial surgery, TIA and stroke. fMMSE, possible scores range from 0 to 30 points (worst to best). Missing data in n = 7. gGDS-15, possible scores range from 0 to 15 (worst to best). Data not available for participants with Mini-Mental State Examination (MMSE) scores <18 (n = 97). hParticipants with hand grip strength below the sex-specific medians or unable to perform the test (n = 35). Appendix 2, available at Age and Ageing online describes the sample of 214 participants grouped in lowest/highest SBP-quintile. In the group prescribed antihypertensive therapy, participants with SBP <140 mmHg were more often institutionalised than those with SBP >170 mmHg (33.3% vs. 4.7%, P = 0.001), and had slightly lower baseline MMSE (median 26 vs. median 27, P = 0.021). The same pattern was evident in participants not prescribed antihypertensive therapy. All-cause mortality over time Appendix 3, available at Age and Ageing online shows the Kaplan–Meier survival curves for participants in the highest and lowest quintiles of SBP. Those prescribed antihypertensive therapy with SBP > 170 mmHg had the lowest risk of all-cause mortality, and those with SBP <140 mmHg had the highest risk (log rank test P < 0.001). During the 5-year follow-up, 263 (46.1%) participants died. For those participants prescribed antihypertensive therapy, all-cause mortality was significantly higher with decreasing SBP (HR 1.29 per 10 mmHg lower SBP, 95%CI 1.15–1.46, P < 0.001) (Table 2). For those not prescribed antihypertensives, the effect was smaller and did not reach significance (HR 1.08 per 10 mmHg lower SBP, 95% 1.00–1.18, P = 0.057). The sensitivity analyses returned similar results in the model excluding deaths (n = 47) within 1-year after baseline (see Appendix 4, available at Age and Ageing online) and when the model was restricted to participants with no history of CVD at baseline. Table 2. Subgroup analysis for hand grip strength and associations of SBP and all-cause mortality per 10 mmHg lower SBP (n = 570) Hazard ratio (95% CI) per 10 mmHg lower SBP P-value Treatment  Overalla (n = 249) 1.29 (1.15, 1.46) <0.001  By hand grip strengthb Low (n = 161) 1.24 (1.08, 1.42) 0.002 High (n = 88) 1.40 (1.09, 1.80) 0.009 No treatment  Overalla (n = 321) 1.08 (1.00, 1.18) 0.057  By hand grip strengthb Low (n = 201) 1.10 (1.00, 1.21) 0.060 High (n = 120) 0.99 (0.86, 1.15) 0.90 Hazard ratio (95% CI) per 10 mmHg lower SBP P-value Treatment  Overalla (n = 249) 1.29 (1.15, 1.46) <0.001  By hand grip strengthb Low (n = 161) 1.24 (1.08, 1.42) 0.002 High (n = 88) 1.40 (1.09, 1.80) 0.009 No treatment  Overalla (n = 321) 1.08 (1.00, 1.18) 0.057  By hand grip strengthb Low (n = 201) 1.10 (1.00, 1.21) 0.060 High (n = 120) 0.99 (0.86, 1.15) 0.90 aParticipants during and without antihypertensive treatment, adjusted for sex and CVD. bParticipants who were unable to perform the test (n = 35) were classified to be low in hand grip strength, adjusted for sex and CVD. Table 2. Subgroup analysis for hand grip strength and associations of SBP and all-cause mortality per 10 mmHg lower SBP (n = 570) Hazard ratio (95% CI) per 10 mmHg lower SBP P-value Treatment  Overalla (n = 249) 1.29 (1.15, 1.46) <0.001  By hand grip strengthb Low (n = 161) 1.24 (1.08, 1.42) 0.002 High (n = 88) 1.40 (1.09, 1.80) 0.009 No treatment  Overalla (n = 321) 1.08 (1.00, 1.18) 0.057  By hand grip strengthb Low (n = 201) 1.10 (1.00, 1.21) 0.060 High (n = 120) 0.99 (0.86, 1.15) 0.90 Hazard ratio (95% CI) per 10 mmHg lower SBP P-value Treatment  Overalla (n = 249) 1.29 (1.15, 1.46) <0.001  By hand grip strengthb Low (n = 161) 1.24 (1.08, 1.42) 0.002 High (n = 88) 1.40 (1.09, 1.80) 0.009 No treatment  Overalla (n = 321) 1.08 (1.00, 1.18) 0.057  By hand grip strengthb Low (n = 201) 1.10 (1.00, 1.21) 0.060 High (n = 120) 0.99 (0.86, 1.15) 0.90 aParticipants during and without antihypertensive treatment, adjusted for sex and CVD. bParticipants who were unable to perform the test (n = 35) were classified to be low in hand grip strength, adjusted for sex and CVD. Change in cognitive function over time Appendix 5, available at Age and Ageing online describes the median annual change in MMSE for those in the highest and lowest quintiles of SBP, both for those prescribed antihypertensives and those not prescribed antihypertensives. In the group prescribed antihypertensives, those with SBP in the lowest quintile showed faster cognitive decline compared to those in the highest SBP-quintile (−1.1 points per year [IQR1.4] vs −0.1 points per year [IQR 0.6]; P = 0.022). For those not prescribed antihypertensive therapy, no significant difference between the lowest and highest quintiles of blood pressure was evident (−0.7 points per year [IQR 2.2] vs. −0.5 points per year [IQR 1.4] P = 0.46). After accounting for baseline differences, those prescribed antihypertensives showed a faster rate of decline in MMSE with lower blood pressure (annual change in MMSE of −0.35 [95% −0.60 to −0.11] per 10 mmHg drop in SBP; P = 0.004). For those not prescribed antihypertensive therapy, the rate of decline was not significantly faster with lower baseline blood pressure (annual change in MMSE −0.14 [95% −0.39 to 0.11] per 10 mmHg drop in SBP; P = 0.28) (Table 3). The sensitivity analysis returned similar results when the model was restricted to participants with no history of CVD at baseline. Table 3. Subgroup analysis for hand grip strength and changes in cognitive function measured by the Mini-Mental State Examination (MMSE) according to SBP at age 85 (per 10 mmHg lower SBP) Baseline difference Annual change Accelerated change Estimate (95% CI) P-value Estimate (95% CI) P-value Estimate (95% CI) P-value Treatment  Overalla (n = 220) −0.33 (−0.63, −0.03) 0.032 +1.20 (−0.50, +2.91) 0.17 −0.35 (−0.60, −0.11) 0.004  By hand grip strengthb Low (n = 141) −0.38 (−0.78, +0.02) 0.061 +1.14 (−1.18, +3.45) 0.34 −0.37 (−0.70, −0.05) 0.023 High (n = 79) −0.04 (−0.47, +0.39) 0.84 +0.87 (−1.30, +3.05) 0.43 −0.24 (−0.57, +0.09) 0.15 No treatment  Overalla (n = 284) −0.72 (−1.00, −0.44) <0.001 −0.62 (−2.39, +1.16) 0.50 −0.14 (−0.39, +0.11) 0.28  By hand grip strengthb Low (n = 172) −0.80 (−1.20, −0.40) <0.001 −0.90 (−3.60, +1.79) 0.51 −0.13 (−0.49, +0.24) 0.50 High (n = 112) −0.18 (−0.49, +0.12) 0.23 −0.76 (−2.13, +0.61) 0.28 −0.04 (−0.24, +0.17) 0.74 Baseline difference Annual change Accelerated change Estimate (95% CI) P-value Estimate (95% CI) P-value Estimate (95% CI) P-value Treatment  Overalla (n = 220) −0.33 (−0.63, −0.03) 0.032 +1.20 (−0.50, +2.91) 0.17 −0.35 (−0.60, −0.11) 0.004  By hand grip strengthb Low (n = 141) −0.38 (−0.78, +0.02) 0.061 +1.14 (−1.18, +3.45) 0.34 −0.37 (−0.70, −0.05) 0.023 High (n = 79) −0.04 (−0.47, +0.39) 0.84 +0.87 (−1.30, +3.05) 0.43 −0.24 (−0.57, +0.09) 0.15 No treatment  Overalla (n = 284) −0.72 (−1.00, −0.44) <0.001 −0.62 (−2.39, +1.16) 0.50 −0.14 (−0.39, +0.11) 0.28  By hand grip strengthb Low (n = 172) −0.80 (−1.20, −0.40) <0.001 −0.90 (−3.60, +1.79) 0.51 −0.13 (−0.49, +0.24) 0.50 High (n = 112) −0.18 (−0.49, +0.12) 0.23 −0.76 (−2.13, +0.61) 0.28 −0.04 (−0.24, +0.17) 0.74 ‘Baseline difference’ means the association per 10 mmHg lower SBP and MMSE at baseline. ‘Annual change’ indicates the annual difference in MMSE over time until age 90. ‘Accelerated change’ is the additional change in MMSE over time associated per 10 mmHg lower SBP. aParticipants with and without antihypertensive treatment, adjusted for sex and CVD. bParticipants unable to perform the test (n = 35) were classified to have less hand grip strength, adjusted for sex and CVD. Table 3. Subgroup analysis for hand grip strength and changes in cognitive function measured by the Mini-Mental State Examination (MMSE) according to SBP at age 85 (per 10 mmHg lower SBP) Baseline difference Annual change Accelerated change Estimate (95% CI) P-value Estimate (95% CI) P-value Estimate (95% CI) P-value Treatment  Overalla (n = 220) −0.33 (−0.63, −0.03) 0.032 +1.20 (−0.50, +2.91) 0.17 −0.35 (−0.60, −0.11) 0.004  By hand grip strengthb Low (n = 141) −0.38 (−0.78, +0.02) 0.061 +1.14 (−1.18, +3.45) 0.34 −0.37 (−0.70, −0.05) 0.023 High (n = 79) −0.04 (−0.47, +0.39) 0.84 +0.87 (−1.30, +3.05) 0.43 −0.24 (−0.57, +0.09) 0.15 No treatment  Overalla (n = 284) −0.72 (−1.00, −0.44) <0.001 −0.62 (−2.39, +1.16) 0.50 −0.14 (−0.39, +0.11) 0.28  By hand grip strengthb Low (n = 172) −0.80 (−1.20, −0.40) <0.001 −0.90 (−3.60, +1.79) 0.51 −0.13 (−0.49, +0.24) 0.50 High (n = 112) −0.18 (−0.49, +0.12) 0.23 −0.76 (−2.13, +0.61) 0.28 −0.04 (−0.24, +0.17) 0.74 Baseline difference Annual change Accelerated change Estimate (95% CI) P-value Estimate (95% CI) P-value Estimate (95% CI) P-value Treatment  Overalla (n = 220) −0.33 (−0.63, −0.03) 0.032 +1.20 (−0.50, +2.91) 0.17 −0.35 (−0.60, −0.11) 0.004  By hand grip strengthb Low (n = 141) −0.38 (−0.78, +0.02) 0.061 +1.14 (−1.18, +3.45) 0.34 −0.37 (−0.70, −0.05) 0.023 High (n = 79) −0.04 (−0.47, +0.39) 0.84 +0.87 (−1.30, +3.05) 0.43 −0.24 (−0.57, +0.09) 0.15 No treatment  Overalla (n = 284) −0.72 (−1.00, −0.44) <0.001 −0.62 (−2.39, +1.16) 0.50 −0.14 (−0.39, +0.11) 0.28  By hand grip strengthb Low (n = 172) −0.80 (−1.20, −0.40) <0.001 −0.90 (−3.60, +1.79) 0.51 −0.13 (−0.49, +0.24) 0.50 High (n = 112) −0.18 (−0.49, +0.12) 0.23 −0.76 (−2.13, +0.61) 0.28 −0.04 (−0.24, +0.17) 0.74 ‘Baseline difference’ means the association per 10 mmHg lower SBP and MMSE at baseline. ‘Annual change’ indicates the annual difference in MMSE over time until age 90. ‘Accelerated change’ is the additional change in MMSE over time associated per 10 mmHg lower SBP. aParticipants with and without antihypertensive treatment, adjusted for sex and CVD. bParticipants unable to perform the test (n = 35) were classified to have less hand grip strength, adjusted for sex and CVD. Modification by frailty Our results did not change in our subgroup analyses for all-cause mortality (Table 2), when we stratified by low- or hih-hand grip strength in participants prescribed antihypertensive therapy (p for interaction = 0.28) or not prescribed antihypertensive therapy (p for interaction = 0.29). There was weak evidence for an association in those participants not prescribed antihypertensives who had low hand grip strength (HR 1.10, 95% CI 1.00, 1.21, P = 0.060). The subgroup analyses for annual change in cognitive function (Table 3) showed that accelerated change in MMSE with lower SBP was significant for those under antihypertensive therapy when they had low hand grip (annual change in MMSE −0.37, [95% CI −0.70, −0.05] per 10 mmHg drop in SBP; P = 0.023) but did not reach significance for those with high hand grip strength (annual change in MMSE −0.24, [95%CI −0.57, 0.09] per 10 mmHg drop in SBP; P = 0.15). There was no evidence of interaction of hand grip strength in those without therapy (p for interaction = 0.10). The sensitivity analysis returned similar results when participants who could not perform the hand grip strength test were classified as missing data instead of categorised as having low hand grip strength. Discussion In this population-based cohort of individuals aged 85 years with a 5-year follow-up, we found lower SBP was associated with higher all-cause mortality and faster annual cognitive decline in participants prescribed antihypertensive therapy. In participants without antihypertensive treatment, no relation was found between SBP and mortality or cognitive decline. Low grip strength did not modify the association of SBP and mortality, but did for cognitive decline. Our findings are in line with other cohort studies showing the same associations of low SBP and increased mortality although previous analyses did not stratify for antihypertensive treatment [25, 26]. For cognition, age seems to modify the associations; in studies with patients aged >60 there was either no association between SBP and cognitive decline [27] or an association of higher SBP with a lower risk of dementia [28]. At age 85 years and older, low SBP predicts the onset of dementia [15] and is associated with worse cognitive function [17]. Similarly, a cohort of male participants whose SBP trajectories were followed over 32 years showed that those who develop dementia had a greater increase in SBP followed by a decrease in SBP compared to those who did not develop dementia [29]. These findings could explain the accelerated cognitive decline we found in our patients with low SBP under antihypertensive treatment. Our results are also in line with Mosello et al.’s findings [12] where 172 patients with a mean age of 79 years, taking antihypertensive therapy, and with a diagnosis of dementia or mild cognitive impairment of outpatient memory clinics were followed-up for a median of 9 months. Our results confirm and extend these findings by showing similar associations in a population-based cohort over a longer observation period of 5 years. This cohort study has several strengths. The population-based sample included a large number of participants, extensive measurements and high follow-up rates with a low risk for selection bias. The inclusion of participants from nursing homes further enhances the generalisability of the findings. This is an observational study, with all the limitations that implies. However, it is useful to look at the associations we identified by situating them within the GRADE framework and apply the Bradford Hill’s criteria for causation because ‘observational studies may provide more relevant information than RCTs’ [30]. The strength of association we found, consistency with prior studies, and the dose–response relationship in our study are three of these criteria. In addition, this study established a temporal relationship between SBP values measured at baseline and outcome assessments over 5 years. Our sensitivity analysis showed robust results when we excluded deaths within 1 year after baseline, which reduces, but does not exclude, the risk that our findings are due to reverse causality. We acknowledge further limitations. First, there was no SBP measurement at baseline for about 5% of participants. Excluding these participants is unlikely to introduce bias as the numbers are small. Second, the risk for confounding by indication limits the causal interpretation of our associations. Interpretation of the results is helped by the findings of a large international study including >2,500 GPs [31], which may allow us to understand and adjust for factors (for example frailty) that influence GPs’ decision to start or not start antihypertensive therapy in the oldest-old. Third, if participants are prescribed with antihypertensive therapy but did not adhere to treatment, misclassification bias could be introduced. However, Dutch individuals seem to adhere best to therapy compared to seven other countries [32], and this high level of adherence reduces the risk of such bias in our sample. Despite these limitations, the finding that low SBP is associated with increased mortality and cognitive decline in oldest-old under antihypertensive therapy is concerning. For clinicians, this study raises the question of what the optimal target blood pressure level is for 85-year-old frail patients. We support the suggestions from Benetos et al.[33] to follow an individualised approach when treating hypertension in oldest-old >80 years with frailty, due to the lack of evidence [6, 34]. Observational studies remain at risk for bias (i.e. reverse causality, residual confounding), and the way to provide more evidence could be via deprescribing trials to test effectiveness and safety of lowering or removing antihypertensive therapy. The Dutch DANTE trial used this approach over a 16-week period in patients aged 75 and older with mild cognitive impairment [35]. In DANTE, deprescribing was not beneficial but was safe. Future studies should try to recruit patients that could benefit the most from deprescribing such as individuals with frailty and/or limited life expectancy. Key points We tested if the association of low systolic blood pressure with mortality/cognition is modified by antihypertensive therapy We followed-up 570 persons all 85-year-old for 5 years. Mortality was 29% higher per 10 mmHg lower blood pressure under therapy The same participants showed a cognitive decline of −0.35 in MMSE/year and even more rapid in those with lower hand grip strength In participants without therapy, there were no such associations Oldest-old with low systolic blood pressure during antihypertensive treatment are at risk for higher mortality and accelerated cognitive decline Supplementary Data Supplementary data mentioned in the text are available to subscribers in Age and Ageing online. Acknowledgements The authors wish to thank Kali Tal, PhD, for editorial assistance. Conflicts of interest None. Funding The Leiden 85-plus Study was funded in part by an unrestricted grant from the Dutch Ministry of Health, Welfare and Sports. Dr Streit’s research is supported by grants (P2BEP3_165353) from the Swiss National Science Foundation (SNF) and the Gottfried and Julia Bangerter-Rhyner Foundation, Switzerland. References (Appendix 6 provides the full list of references) 1 Wilson PW . Established risk factors and coronary artery disease: the Framingham Study . Am J Hypertens 1994 ; 7 : 7S – 12S . Google Scholar CrossRef Search ADS PubMed 2 Lacruz ME , Kluttig A , Hartwig S et al. . Prevalence and Incidence of Hypertension in the General Adult Population: Results of the CARLA-Cohort Study . Medicine (Baltimore) 2015 ; 94 : e952 . doi:10.1097/MD.0000000000000952 . Google Scholar CrossRef Search ADS PubMed 3 Staessen JA , Fagard R , Thijs L et al. . Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial Investigators . Lancet 1997 ; 350 : 757 – 64 . 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J Epidemiol Community Health 2011 ; 65 : 392 – 5 . doi:10.1136/jech.2010.119933 . Google Scholar CrossRef Search ADS PubMed © The Author(s) 2018. Published by Oxford University Press on behalf of the British Geriatrics Society. All rights reserved. For permissions, please email: journals.permissions@oup.com This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Age and Ageing Oxford University Press

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

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Abstract

Abstract Background the appropriateness of lowering systolic blood pressure remains controversial in the oldest-old. We tested whether systolic blood pressure is associated with all-cause mortality and change in cognitive function for patients prescribed antihypertensive treatment and those without treatment. Methods we studied participants in the population-based Leiden 85-plus cohort study. Baseline systolic blood pressure and use of antihypertensive treatment were predictors; all-cause mortality and change in cognitive function measured using the Mini-Mental State Examination were the outcomes. Grip strength was measured as a proxy for physical frailty. We used Cox proportional hazards and mixed-effects linear regression models to analyse the relationship between systolic blood pressure and both time to death and change in cognitive function. In sensitivity analyses, we excluded deaths within 1 year and restricted analyses to participants without a history of cardiovascular disease. Results of 570 participants, 249 (44%) were prescribed antihypertensive therapy. All-cause mortality was higher in participants with lower blood pressure prescribed antihypertensive treatment (HR 1.29 per 10 mmHg lower systolic blood pressure, 95% CI 1.15–1.46, P < 0.001). Participants taking antihypertensives showed an association between accelerated cognitive decline and lower blood pressure (annual mean change −0.35 points per 10 mmHg lower systolic blood pressure, 95% CI −0.60, −0.11, P = 0.004); decline in cognition was more rapid in those with lower hand grip strength. In participants not prescribed antihypertensive treatment, no significant associations were seen between blood pressure and either mortality or cognitive decline. Conclusions lower systolic blood pressure in the oldest-old taking antihypertensives was associated with higher mortality and faster decline in cognitive function. hypertension, oldest-old, cognitive function, antihypertensive treatment, frailty, older people Introduction Hypertension is the most important preventable cause of cardiovascular disease (CVD), including stroke and myocardial infarction [1]. The prevalence of hypertension increases sharply with age [2]. It has been clear for at least two decades that older patients (>60 years) also benefit from antihypertensive treatment [3, 4], but guidelines may not apply equally to everyone over 60 years. For example, we do not know if the effects of treating hypertension are similar among individuals aged over 80 years (the oldest-old)—a segment of the population that is expected to triple in the next two decades [5]. Hypertension studies have tended to exclude patients with multimorbidity and frailty. These criteria disproportionately exclude the oldest-old because this age group is much more likely to have multimorbidity or to be frail [6, 7]. At the same time, observational studies have raised concerns about associations between low systolic blood pressure (SBP), increased mortality and accelerated cognitive decline, especially in the oldest-old living with frailty [8]. Studying associations between SBP and cognitive decline are challenging [9]. There is evidence that high SBP in midlife damages cerebral vessels and impairs brain function [10], but low SBP in late life, particularly in frail subjects, is associated with higher risk for cognitive decline [11]. A study by Mosello et al. [12] found that lower SBP was associated with faster cognitive decline in individuals who were already cognitively impaired; several other studies had produced similar findings [13–19]. Mosello et al. were the first to describe that antihypertensive therapy modified these associations: low SBP was associated with cognitive decline only in patients under antihypertensive therapy, but not in those who were not prescribed antihypertensive therapy. Unfortunately, the follow-up time was too short to detect long-term protective effects of antihypertensive treatment, and the population was limited to patients attending a memory clinic. There is, therefore, a need for rigorous, population-based observational studies with adequate follow-up time to test the association between antihypertensive therapy, blood pressure, mortality and cognitive decline in the oldest-old. We analysed data from a population-based cohort study with a 5-year follow-up to test if the association between low SBP with all-cause mortality and cognitive function differs for oldest-old patients under antihypertensive treatment and those without treatment, and to test if frailty modifies these associations. Methods Study design and setting We analysed data from a prospective, population-based cohort study with a 5-year follow-up—the Leiden 85-plus Study [20, 21]. All inhabitants of the city of Leiden, the Netherlands, were invited to join this cohort study if they turned 85 years between 1997 and 1999. No exclusion criteria were applied. The target population was 705 inhabitants. Of these, 14 (2.0%) died before being enrolled in the study; 599 (85.0%) provided informed or proxy consent [22]. The Medical Ethical Committee of the Leiden University Medical Center approved the original study. Participants For this analysis, we applied two pre-specified exclusion criteria. To lower the risk of reverse causality between SBP and mortality risk, we excluded participants who died <3 months after they entered the cohort (n = 5). We also excluded participants who had no SBP measurements at baseline (n = 24). Procedures and measurements A history of CVD (i.e. previously recorded diagnoses of angina pectoris, myocardial infarction, heart failure, intermittent claudication, peripheral arterial surgery, transient ischaemic attack, and stroke) was available from general practitioners (GPs) or nursing home physicians. At baseline, research nurses visited all participants to administer the Mini-Mental State Examination (MMSE) [23]. At baseline, SBP was measured twice with a mean time range between measurements of 2 weeks. SBP was measured using a mercury sphygmomanometer, in the seated position after at least 5 min of rest and with no vigorous exercise in the preceding 30 min. For this analysis, we averaged the two measurements of SBP. The research nurses also recorded socio-demographic characteristics (level of education, income, living place); current smoking status (yes/no); depressive symptoms if MMSE was >18 points using the 15-point Geriatric Depression Scale [24]; and hand grip strength using a hand dynamometer. During annual follow-up visits, nurses repeated MMSE measurements. All participants were followed for all-cause mortality for 5 years using municipal records. Statistical analysis We assessed associations between exposure (baseline SBP and use of antihypertensive medication) and outcomes (all-cause mortality and annual change in cognitive function) over 5 years. At baseline, we compared characteristics of participants prescribed and not prescribed antihypertensive therapy. The crude and adjusted modelling approaches for all-cause mortality using Cox proportional hazard models and annual change in MMSE using mixed-effects linear regression models are described in detail in Appendix 1, available at Age and Ageing online. Subgroup analyses were performed for the second aim, to test if grip strength (as a proxy for frailty) modified the associations of SBP and treatment with the outcomes. We stratified both models for low/high hand grip strength to explore effect sizes and directions of effects. However, due to small sample sizes, this subgroup analysis was only exploratory. In sensitivity analyses, we firstly excluded deaths within 1 year after baseline; secondly restricted the models to participants without a history of CVD at baseline; and thirdly recoded participants who could not perform the hand grip strength test as missing. A two-sided P-value of 0.05 was taken as statistically significant for all analyses. We used STATA 15.0 (StataCorp, College Station, TX, USA) for all analyses. Results We analysed data from 570 individuals, of whom 249 (43.7%) were prescribed antihypertensive therapy at baseline (Table 1). Participants prescribed antihypertensive therapy and those not prescribed antihypertensives were similar in all aspects except for a higher prevalence of CVD in those prescribed antihypertensives (61.9% vs. 35.8%, P < 0.001). The other cardiovascular, socio-demographic, and functional characteristics at baseline were equally distributed among the two groups. Table 1. Baseline characteristics of participants at age 85 years by antihypertensive treatment (n = 570) Domains Overall (n = 570) Antihypertensive treatment (n = 249) No antihypertensive treatment (n = 321) P-valuea Socio-demographic characteristics  Women, n (%) 380 (66.7) 173 (69.5) 207 (64.5) 0.21  Low educationb, n (%) 358 (64.9) 163 (66.8) 195 (63.3) 0.39  Low incomec, n (%) 280 (50.9) 122 (50.8) 158 (51.0) 0.98  Institutionalised, (%) 102 (18.4) 45 (18.4) 57 (18.3) 0.97 Cardiovascular characteristics  SBP in mmHg, mean (SD)d 155.2 (18.7) 154.8 (16.8) 155.5 (20.0) 0.64  Current smoker, n (%) 89 (15.7) 33 (13.3) 56 (17.6) 0.16  Diabetes mellitus, n (%) 91 (16.3) 46 (18.9) 45 (14.2) 0.14  CVDe, n (%) 269 (47.2) 154 (61.9) 115 (35.8) <0.001 Functional characteristics  Cognition (MMSEf), median (IQR) 26 (22–28) 26 (21–28) 26 (23–28) 0.094  Depression (GDSg), median (IQR) 2 (1–3) 2 (1–3) 2 (1–3) 0.70  Low hand grip strengthh, n (%) 362 (63.5) 161 (64.7) 201 (62.6) 0.62 Domains Overall (n = 570) Antihypertensive treatment (n = 249) No antihypertensive treatment (n = 321) P-valuea Socio-demographic characteristics  Women, n (%) 380 (66.7) 173 (69.5) 207 (64.5) 0.21  Low educationb, n (%) 358 (64.9) 163 (66.8) 195 (63.3) 0.39  Low incomec, n (%) 280 (50.9) 122 (50.8) 158 (51.0) 0.98  Institutionalised, (%) 102 (18.4) 45 (18.4) 57 (18.3) 0.97 Cardiovascular characteristics  SBP in mmHg, mean (SD)d 155.2 (18.7) 154.8 (16.8) 155.5 (20.0) 0.64  Current smoker, n (%) 89 (15.7) 33 (13.3) 56 (17.6) 0.16  Diabetes mellitus, n (%) 91 (16.3) 46 (18.9) 45 (14.2) 0.14  CVDe, n (%) 269 (47.2) 154 (61.9) 115 (35.8) <0.001 Functional characteristics  Cognition (MMSEf), median (IQR) 26 (22–28) 26 (21–28) 26 (23–28) 0.094  Depression (GDSg), median (IQR) 2 (1–3) 2 (1–3) 2 (1–3) 0.70  Low hand grip strengthh, n (%) 362 (63.5) 161 (64.7) 201 (62.6) 0.62 aChi-square test for categorical variables, t-test for normally distributed continuous and Wilcoxon rank-sum test for non-normally distributed data was used. bDefined as primary school only. cDefined as state pension only (about EUR 750 monthly). dSBP was measured twice during home visit at baseline in a seated position, 2 weeks apart, and after at least 5 minutes of rest and no vigorous exercise in the preceding 30 minutes. Both measurements were averaged. eCVD included angina pectoris, myocardial infarction, heart failure, intermittent claudication, peripheral arterial surgery, TIA and stroke. fMMSE, possible scores range from 0 to 30 points (worst to best). Missing data in n = 7. gGDS-15, possible scores range from 0 to 15 (worst to best). Data not available for participants with Mini-Mental State Examination (MMSE) scores <18 (n = 97). hParticipants with hand grip strength below the sex-specific medians or unable to perform the test (n = 35). Table 1. Baseline characteristics of participants at age 85 years by antihypertensive treatment (n = 570) Domains Overall (n = 570) Antihypertensive treatment (n = 249) No antihypertensive treatment (n = 321) P-valuea Socio-demographic characteristics  Women, n (%) 380 (66.7) 173 (69.5) 207 (64.5) 0.21  Low educationb, n (%) 358 (64.9) 163 (66.8) 195 (63.3) 0.39  Low incomec, n (%) 280 (50.9) 122 (50.8) 158 (51.0) 0.98  Institutionalised, (%) 102 (18.4) 45 (18.4) 57 (18.3) 0.97 Cardiovascular characteristics  SBP in mmHg, mean (SD)d 155.2 (18.7) 154.8 (16.8) 155.5 (20.0) 0.64  Current smoker, n (%) 89 (15.7) 33 (13.3) 56 (17.6) 0.16  Diabetes mellitus, n (%) 91 (16.3) 46 (18.9) 45 (14.2) 0.14  CVDe, n (%) 269 (47.2) 154 (61.9) 115 (35.8) <0.001 Functional characteristics  Cognition (MMSEf), median (IQR) 26 (22–28) 26 (21–28) 26 (23–28) 0.094  Depression (GDSg), median (IQR) 2 (1–3) 2 (1–3) 2 (1–3) 0.70  Low hand grip strengthh, n (%) 362 (63.5) 161 (64.7) 201 (62.6) 0.62 Domains Overall (n = 570) Antihypertensive treatment (n = 249) No antihypertensive treatment (n = 321) P-valuea Socio-demographic characteristics  Women, n (%) 380 (66.7) 173 (69.5) 207 (64.5) 0.21  Low educationb, n (%) 358 (64.9) 163 (66.8) 195 (63.3) 0.39  Low incomec, n (%) 280 (50.9) 122 (50.8) 158 (51.0) 0.98  Institutionalised, (%) 102 (18.4) 45 (18.4) 57 (18.3) 0.97 Cardiovascular characteristics  SBP in mmHg, mean (SD)d 155.2 (18.7) 154.8 (16.8) 155.5 (20.0) 0.64  Current smoker, n (%) 89 (15.7) 33 (13.3) 56 (17.6) 0.16  Diabetes mellitus, n (%) 91 (16.3) 46 (18.9) 45 (14.2) 0.14  CVDe, n (%) 269 (47.2) 154 (61.9) 115 (35.8) <0.001 Functional characteristics  Cognition (MMSEf), median (IQR) 26 (22–28) 26 (21–28) 26 (23–28) 0.094  Depression (GDSg), median (IQR) 2 (1–3) 2 (1–3) 2 (1–3) 0.70  Low hand grip strengthh, n (%) 362 (63.5) 161 (64.7) 201 (62.6) 0.62 aChi-square test for categorical variables, t-test for normally distributed continuous and Wilcoxon rank-sum test for non-normally distributed data was used. bDefined as primary school only. cDefined as state pension only (about EUR 750 monthly). dSBP was measured twice during home visit at baseline in a seated position, 2 weeks apart, and after at least 5 minutes of rest and no vigorous exercise in the preceding 30 minutes. Both measurements were averaged. eCVD included angina pectoris, myocardial infarction, heart failure, intermittent claudication, peripheral arterial surgery, TIA and stroke. fMMSE, possible scores range from 0 to 30 points (worst to best). Missing data in n = 7. gGDS-15, possible scores range from 0 to 15 (worst to best). Data not available for participants with Mini-Mental State Examination (MMSE) scores <18 (n = 97). hParticipants with hand grip strength below the sex-specific medians or unable to perform the test (n = 35). Appendix 2, available at Age and Ageing online describes the sample of 214 participants grouped in lowest/highest SBP-quintile. In the group prescribed antihypertensive therapy, participants with SBP <140 mmHg were more often institutionalised than those with SBP >170 mmHg (33.3% vs. 4.7%, P = 0.001), and had slightly lower baseline MMSE (median 26 vs. median 27, P = 0.021). The same pattern was evident in participants not prescribed antihypertensive therapy. All-cause mortality over time Appendix 3, available at Age and Ageing online shows the Kaplan–Meier survival curves for participants in the highest and lowest quintiles of SBP. Those prescribed antihypertensive therapy with SBP > 170 mmHg had the lowest risk of all-cause mortality, and those with SBP <140 mmHg had the highest risk (log rank test P < 0.001). During the 5-year follow-up, 263 (46.1%) participants died. For those participants prescribed antihypertensive therapy, all-cause mortality was significantly higher with decreasing SBP (HR 1.29 per 10 mmHg lower SBP, 95%CI 1.15–1.46, P < 0.001) (Table 2). For those not prescribed antihypertensives, the effect was smaller and did not reach significance (HR 1.08 per 10 mmHg lower SBP, 95% 1.00–1.18, P = 0.057). The sensitivity analyses returned similar results in the model excluding deaths (n = 47) within 1-year after baseline (see Appendix 4, available at Age and Ageing online) and when the model was restricted to participants with no history of CVD at baseline. Table 2. Subgroup analysis for hand grip strength and associations of SBP and all-cause mortality per 10 mmHg lower SBP (n = 570) Hazard ratio (95% CI) per 10 mmHg lower SBP P-value Treatment  Overalla (n = 249) 1.29 (1.15, 1.46) <0.001  By hand grip strengthb Low (n = 161) 1.24 (1.08, 1.42) 0.002 High (n = 88) 1.40 (1.09, 1.80) 0.009 No treatment  Overalla (n = 321) 1.08 (1.00, 1.18) 0.057  By hand grip strengthb Low (n = 201) 1.10 (1.00, 1.21) 0.060 High (n = 120) 0.99 (0.86, 1.15) 0.90 Hazard ratio (95% CI) per 10 mmHg lower SBP P-value Treatment  Overalla (n = 249) 1.29 (1.15, 1.46) <0.001  By hand grip strengthb Low (n = 161) 1.24 (1.08, 1.42) 0.002 High (n = 88) 1.40 (1.09, 1.80) 0.009 No treatment  Overalla (n = 321) 1.08 (1.00, 1.18) 0.057  By hand grip strengthb Low (n = 201) 1.10 (1.00, 1.21) 0.060 High (n = 120) 0.99 (0.86, 1.15) 0.90 aParticipants during and without antihypertensive treatment, adjusted for sex and CVD. bParticipants who were unable to perform the test (n = 35) were classified to be low in hand grip strength, adjusted for sex and CVD. Table 2. Subgroup analysis for hand grip strength and associations of SBP and all-cause mortality per 10 mmHg lower SBP (n = 570) Hazard ratio (95% CI) per 10 mmHg lower SBP P-value Treatment  Overalla (n = 249) 1.29 (1.15, 1.46) <0.001  By hand grip strengthb Low (n = 161) 1.24 (1.08, 1.42) 0.002 High (n = 88) 1.40 (1.09, 1.80) 0.009 No treatment  Overalla (n = 321) 1.08 (1.00, 1.18) 0.057  By hand grip strengthb Low (n = 201) 1.10 (1.00, 1.21) 0.060 High (n = 120) 0.99 (0.86, 1.15) 0.90 Hazard ratio (95% CI) per 10 mmHg lower SBP P-value Treatment  Overalla (n = 249) 1.29 (1.15, 1.46) <0.001  By hand grip strengthb Low (n = 161) 1.24 (1.08, 1.42) 0.002 High (n = 88) 1.40 (1.09, 1.80) 0.009 No treatment  Overalla (n = 321) 1.08 (1.00, 1.18) 0.057  By hand grip strengthb Low (n = 201) 1.10 (1.00, 1.21) 0.060 High (n = 120) 0.99 (0.86, 1.15) 0.90 aParticipants during and without antihypertensive treatment, adjusted for sex and CVD. bParticipants who were unable to perform the test (n = 35) were classified to be low in hand grip strength, adjusted for sex and CVD. Change in cognitive function over time Appendix 5, available at Age and Ageing online describes the median annual change in MMSE for those in the highest and lowest quintiles of SBP, both for those prescribed antihypertensives and those not prescribed antihypertensives. In the group prescribed antihypertensives, those with SBP in the lowest quintile showed faster cognitive decline compared to those in the highest SBP-quintile (−1.1 points per year [IQR1.4] vs −0.1 points per year [IQR 0.6]; P = 0.022). For those not prescribed antihypertensive therapy, no significant difference between the lowest and highest quintiles of blood pressure was evident (−0.7 points per year [IQR 2.2] vs. −0.5 points per year [IQR 1.4] P = 0.46). After accounting for baseline differences, those prescribed antihypertensives showed a faster rate of decline in MMSE with lower blood pressure (annual change in MMSE of −0.35 [95% −0.60 to −0.11] per 10 mmHg drop in SBP; P = 0.004). For those not prescribed antihypertensive therapy, the rate of decline was not significantly faster with lower baseline blood pressure (annual change in MMSE −0.14 [95% −0.39 to 0.11] per 10 mmHg drop in SBP; P = 0.28) (Table 3). The sensitivity analysis returned similar results when the model was restricted to participants with no history of CVD at baseline. Table 3. Subgroup analysis for hand grip strength and changes in cognitive function measured by the Mini-Mental State Examination (MMSE) according to SBP at age 85 (per 10 mmHg lower SBP) Baseline difference Annual change Accelerated change Estimate (95% CI) P-value Estimate (95% CI) P-value Estimate (95% CI) P-value Treatment  Overalla (n = 220) −0.33 (−0.63, −0.03) 0.032 +1.20 (−0.50, +2.91) 0.17 −0.35 (−0.60, −0.11) 0.004  By hand grip strengthb Low (n = 141) −0.38 (−0.78, +0.02) 0.061 +1.14 (−1.18, +3.45) 0.34 −0.37 (−0.70, −0.05) 0.023 High (n = 79) −0.04 (−0.47, +0.39) 0.84 +0.87 (−1.30, +3.05) 0.43 −0.24 (−0.57, +0.09) 0.15 No treatment  Overalla (n = 284) −0.72 (−1.00, −0.44) <0.001 −0.62 (−2.39, +1.16) 0.50 −0.14 (−0.39, +0.11) 0.28  By hand grip strengthb Low (n = 172) −0.80 (−1.20, −0.40) <0.001 −0.90 (−3.60, +1.79) 0.51 −0.13 (−0.49, +0.24) 0.50 High (n = 112) −0.18 (−0.49, +0.12) 0.23 −0.76 (−2.13, +0.61) 0.28 −0.04 (−0.24, +0.17) 0.74 Baseline difference Annual change Accelerated change Estimate (95% CI) P-value Estimate (95% CI) P-value Estimate (95% CI) P-value Treatment  Overalla (n = 220) −0.33 (−0.63, −0.03) 0.032 +1.20 (−0.50, +2.91) 0.17 −0.35 (−0.60, −0.11) 0.004  By hand grip strengthb Low (n = 141) −0.38 (−0.78, +0.02) 0.061 +1.14 (−1.18, +3.45) 0.34 −0.37 (−0.70, −0.05) 0.023 High (n = 79) −0.04 (−0.47, +0.39) 0.84 +0.87 (−1.30, +3.05) 0.43 −0.24 (−0.57, +0.09) 0.15 No treatment  Overalla (n = 284) −0.72 (−1.00, −0.44) <0.001 −0.62 (−2.39, +1.16) 0.50 −0.14 (−0.39, +0.11) 0.28  By hand grip strengthb Low (n = 172) −0.80 (−1.20, −0.40) <0.001 −0.90 (−3.60, +1.79) 0.51 −0.13 (−0.49, +0.24) 0.50 High (n = 112) −0.18 (−0.49, +0.12) 0.23 −0.76 (−2.13, +0.61) 0.28 −0.04 (−0.24, +0.17) 0.74 ‘Baseline difference’ means the association per 10 mmHg lower SBP and MMSE at baseline. ‘Annual change’ indicates the annual difference in MMSE over time until age 90. ‘Accelerated change’ is the additional change in MMSE over time associated per 10 mmHg lower SBP. aParticipants with and without antihypertensive treatment, adjusted for sex and CVD. bParticipants unable to perform the test (n = 35) were classified to have less hand grip strength, adjusted for sex and CVD. Table 3. Subgroup analysis for hand grip strength and changes in cognitive function measured by the Mini-Mental State Examination (MMSE) according to SBP at age 85 (per 10 mmHg lower SBP) Baseline difference Annual change Accelerated change Estimate (95% CI) P-value Estimate (95% CI) P-value Estimate (95% CI) P-value Treatment  Overalla (n = 220) −0.33 (−0.63, −0.03) 0.032 +1.20 (−0.50, +2.91) 0.17 −0.35 (−0.60, −0.11) 0.004  By hand grip strengthb Low (n = 141) −0.38 (−0.78, +0.02) 0.061 +1.14 (−1.18, +3.45) 0.34 −0.37 (−0.70, −0.05) 0.023 High (n = 79) −0.04 (−0.47, +0.39) 0.84 +0.87 (−1.30, +3.05) 0.43 −0.24 (−0.57, +0.09) 0.15 No treatment  Overalla (n = 284) −0.72 (−1.00, −0.44) <0.001 −0.62 (−2.39, +1.16) 0.50 −0.14 (−0.39, +0.11) 0.28  By hand grip strengthb Low (n = 172) −0.80 (−1.20, −0.40) <0.001 −0.90 (−3.60, +1.79) 0.51 −0.13 (−0.49, +0.24) 0.50 High (n = 112) −0.18 (−0.49, +0.12) 0.23 −0.76 (−2.13, +0.61) 0.28 −0.04 (−0.24, +0.17) 0.74 Baseline difference Annual change Accelerated change Estimate (95% CI) P-value Estimate (95% CI) P-value Estimate (95% CI) P-value Treatment  Overalla (n = 220) −0.33 (−0.63, −0.03) 0.032 +1.20 (−0.50, +2.91) 0.17 −0.35 (−0.60, −0.11) 0.004  By hand grip strengthb Low (n = 141) −0.38 (−0.78, +0.02) 0.061 +1.14 (−1.18, +3.45) 0.34 −0.37 (−0.70, −0.05) 0.023 High (n = 79) −0.04 (−0.47, +0.39) 0.84 +0.87 (−1.30, +3.05) 0.43 −0.24 (−0.57, +0.09) 0.15 No treatment  Overalla (n = 284) −0.72 (−1.00, −0.44) <0.001 −0.62 (−2.39, +1.16) 0.50 −0.14 (−0.39, +0.11) 0.28  By hand grip strengthb Low (n = 172) −0.80 (−1.20, −0.40) <0.001 −0.90 (−3.60, +1.79) 0.51 −0.13 (−0.49, +0.24) 0.50 High (n = 112) −0.18 (−0.49, +0.12) 0.23 −0.76 (−2.13, +0.61) 0.28 −0.04 (−0.24, +0.17) 0.74 ‘Baseline difference’ means the association per 10 mmHg lower SBP and MMSE at baseline. ‘Annual change’ indicates the annual difference in MMSE over time until age 90. ‘Accelerated change’ is the additional change in MMSE over time associated per 10 mmHg lower SBP. aParticipants with and without antihypertensive treatment, adjusted for sex and CVD. bParticipants unable to perform the test (n = 35) were classified to have less hand grip strength, adjusted for sex and CVD. Modification by frailty Our results did not change in our subgroup analyses for all-cause mortality (Table 2), when we stratified by low- or hih-hand grip strength in participants prescribed antihypertensive therapy (p for interaction = 0.28) or not prescribed antihypertensive therapy (p for interaction = 0.29). There was weak evidence for an association in those participants not prescribed antihypertensives who had low hand grip strength (HR 1.10, 95% CI 1.00, 1.21, P = 0.060). The subgroup analyses for annual change in cognitive function (Table 3) showed that accelerated change in MMSE with lower SBP was significant for those under antihypertensive therapy when they had low hand grip (annual change in MMSE −0.37, [95% CI −0.70, −0.05] per 10 mmHg drop in SBP; P = 0.023) but did not reach significance for those with high hand grip strength (annual change in MMSE −0.24, [95%CI −0.57, 0.09] per 10 mmHg drop in SBP; P = 0.15). There was no evidence of interaction of hand grip strength in those without therapy (p for interaction = 0.10). The sensitivity analysis returned similar results when participants who could not perform the hand grip strength test were classified as missing data instead of categorised as having low hand grip strength. Discussion In this population-based cohort of individuals aged 85 years with a 5-year follow-up, we found lower SBP was associated with higher all-cause mortality and faster annual cognitive decline in participants prescribed antihypertensive therapy. In participants without antihypertensive treatment, no relation was found between SBP and mortality or cognitive decline. Low grip strength did not modify the association of SBP and mortality, but did for cognitive decline. Our findings are in line with other cohort studies showing the same associations of low SBP and increased mortality although previous analyses did not stratify for antihypertensive treatment [25, 26]. For cognition, age seems to modify the associations; in studies with patients aged >60 there was either no association between SBP and cognitive decline [27] or an association of higher SBP with a lower risk of dementia [28]. At age 85 years and older, low SBP predicts the onset of dementia [15] and is associated with worse cognitive function [17]. Similarly, a cohort of male participants whose SBP trajectories were followed over 32 years showed that those who develop dementia had a greater increase in SBP followed by a decrease in SBP compared to those who did not develop dementia [29]. These findings could explain the accelerated cognitive decline we found in our patients with low SBP under antihypertensive treatment. Our results are also in line with Mosello et al.’s findings [12] where 172 patients with a mean age of 79 years, taking antihypertensive therapy, and with a diagnosis of dementia or mild cognitive impairment of outpatient memory clinics were followed-up for a median of 9 months. Our results confirm and extend these findings by showing similar associations in a population-based cohort over a longer observation period of 5 years. This cohort study has several strengths. The population-based sample included a large number of participants, extensive measurements and high follow-up rates with a low risk for selection bias. The inclusion of participants from nursing homes further enhances the generalisability of the findings. This is an observational study, with all the limitations that implies. However, it is useful to look at the associations we identified by situating them within the GRADE framework and apply the Bradford Hill’s criteria for causation because ‘observational studies may provide more relevant information than RCTs’ [30]. The strength of association we found, consistency with prior studies, and the dose–response relationship in our study are three of these criteria. In addition, this study established a temporal relationship between SBP values measured at baseline and outcome assessments over 5 years. Our sensitivity analysis showed robust results when we excluded deaths within 1 year after baseline, which reduces, but does not exclude, the risk that our findings are due to reverse causality. We acknowledge further limitations. First, there was no SBP measurement at baseline for about 5% of participants. Excluding these participants is unlikely to introduce bias as the numbers are small. Second, the risk for confounding by indication limits the causal interpretation of our associations. Interpretation of the results is helped by the findings of a large international study including >2,500 GPs [31], which may allow us to understand and adjust for factors (for example frailty) that influence GPs’ decision to start or not start antihypertensive therapy in the oldest-old. Third, if participants are prescribed with antihypertensive therapy but did not adhere to treatment, misclassification bias could be introduced. However, Dutch individuals seem to adhere best to therapy compared to seven other countries [32], and this high level of adherence reduces the risk of such bias in our sample. Despite these limitations, the finding that low SBP is associated with increased mortality and cognitive decline in oldest-old under antihypertensive therapy is concerning. For clinicians, this study raises the question of what the optimal target blood pressure level is for 85-year-old frail patients. We support the suggestions from Benetos et al.[33] to follow an individualised approach when treating hypertension in oldest-old >80 years with frailty, due to the lack of evidence [6, 34]. Observational studies remain at risk for bias (i.e. reverse causality, residual confounding), and the way to provide more evidence could be via deprescribing trials to test effectiveness and safety of lowering or removing antihypertensive therapy. The Dutch DANTE trial used this approach over a 16-week period in patients aged 75 and older with mild cognitive impairment [35]. In DANTE, deprescribing was not beneficial but was safe. Future studies should try to recruit patients that could benefit the most from deprescribing such as individuals with frailty and/or limited life expectancy. Key points We tested if the association of low systolic blood pressure with mortality/cognition is modified by antihypertensive therapy We followed-up 570 persons all 85-year-old for 5 years. Mortality was 29% higher per 10 mmHg lower blood pressure under therapy The same participants showed a cognitive decline of −0.35 in MMSE/year and even more rapid in those with lower hand grip strength In participants without therapy, there were no such associations Oldest-old with low systolic blood pressure during antihypertensive treatment are at risk for higher mortality and accelerated cognitive decline Supplementary Data Supplementary data mentioned in the text are available to subscribers in Age and Ageing online. Acknowledgements The authors wish to thank Kali Tal, PhD, for editorial assistance. Conflicts of interest None. Funding The Leiden 85-plus Study was funded in part by an unrestricted grant from the Dutch Ministry of Health, Welfare and Sports. 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Age and AgeingOxford University Press

Published: May 8, 2018

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