Randomized clinical trials performed during last 20 years have clearly shown that the benefit of antihypertensive treatments on cardiovascular events is not significantly different at ages above rather than below 65 years, with a greater absolute benefit in the elderly because of the higher cardiovascular risk characterizing old age [63]. These results have been extended to very old age with Hypertension in the Very Elderly Trial (HYVET), which was prematurely terminated after the demonstration of a clear benefit of antihypertensive treatment in reducing total mortality, heart failure, and stroke in subjects aged 80+ [64].

Yet some points have not been clarified yet, one of the first being the effect of age on the cutoff and the target for antihypertensive treatment. Since 2013, European [13] and US [65] guidelines have acknowledged different cutoffs and target values for antihypertensive drugs treatment in old age (Table 8.1). This was mainly based on the critical reappraisal of previous guidelines, which clearly indicated that the treatment of grade I AH and the previously indicated cutoff of 140/90 mmHg were not evidence-based in the elderly [66]. In fact all randomized clinical trials including only subjects 65+ had SBP ≥160 mmHg as inclusion criterion, enrolled subjects showed a mean baseline SBP included between 166 and 196 mmHg, and generally did not attained a mean SBP <140 mmHg in the actively treated group. This is particularly true for subjects enrolled in HYVET, who were over 80, with no severe comorbidity, had mean BP values 173/91 mmHg at baseline and attained BP values of 144 and 159 mmHg at follow-up in active treatment and placebo group, respectively [64].

Only few intervention studies have addressed the issue of different BP targets among older subjects, with somehow conflicting results. In a subgroup analysis of the FEVER study, 3179 older Chinese patients randomized to more intense treatment (low-dose hydrochlorothiazide plus felodipine, achieved SBP 138 mmHg) had a lower risk of stroke, cardiovascular events, and total mortality compared to the ones randomized to less intense treatment (low-dose hydrochlorothiazide plus placebo, achieved SBP 142 mmHg) [67]. Yet it has to be acknowledged that this was a subgroup analysis and that “older subjects” group was 65+, with a mean age 69.5. Two other Japanese studies have specifically focused on different treatment targets for older subjects [68, 69]. In the VALISH study, 3260 patients aged 70–84 (mean age 76) were randomized to strict BP control (target SBP < 140 mmHg, achieved SBP 137 mmHg) vs. moderate control (target SBP 140–150 mmHg, achieved SBP 142 mmHg). After 3 years the two groups did not differ for the primary composite end point neither for any of the secondary end points, including stroke, cardiac events, cardiovascular mortality, total mortality, and for incidence of adverse events [69]. Moreover, in the JATOS study, 4418 patients aged 65–85 (42 % over 75) were randomized to strict BP control (target SBP < 140 mmHg, achieved SBP 136 mmHg) vs. moderate control (target SBP 140–160 mmHg, achieved SBP 146 mmHg). After 2 years the two groups did not differ for the combined primary end point (stroke, cardiac events, renal failure) neither for total mortality nor for incidence of adverse events. Yet an interaction between age and treatment group was associated with primary end point, with the highest risk in the subgroup aged 75+ undergoing more strict control [68].

The abovementioned data are consistent with the results of a meta-analysis of data pertaining to subjects aged 80+ enrolled in different RCTs. In those subjects a significant effect of active treatment was confirmed for stroke, cardiovascular events, and heart failure, while no effect was observed for cardiovascular death and total mortality. In a meta-regression analysis, mortality risk was reduced in the treatment arm of trials that adopted a lower-intensity treatment and achieved the least BP reduction [70].

Moreover in observational studies of subjects aged 85+, SBP <140 mmHg has repeatedly been associated with higher mortality risk [8–10]. Yet this association might differ according to antihypertensive treatment status, as shown in an international study of home BP monitoring in older subjects aged 80+, aimed at identifying optimal BP targets in regard to mortality risk over a 5.5-year follow-up. In fact, cardiovascular mortality and morbidity showed a direct association with SBP among subjects non-treated with antihypertensives, with highest risk at values >152 mmHg, while it showed a curvilinear association with SBP in the subgroup receiving antihypertensive drugs, with an increased cardiovascular risk for SBP <127 mmHg [71]. Moreover the risk associated with low BP in old age appears to be greater among subjects with a history of AH at midlife, in regard both to survival [8] and to brain atrophy and cognitive decline [72].

On the whole the cited data raise a caveat for excessive SBP lowering among actively treated subjects in very old age, with a cutoff for increased risk around the age of 80, especially for those with a long-standing history of AH. On a pathophysiological ground, the observed epidemiological and clinical data might be explained by a small reduction of perfusion of vital organs coupled with an altered vascular autoregulation associated with chronic AH, possibly leading to critical hypoperfusion if associated with decreased BP [72]. This hypothesis has not been proven yet, as a recent study of the association between BP and cerebral blood flow of very old subjects with mild cognitive impairment was not able to show any correlation between lower BP values and cerebral hypoperfusion [73]. Moreover it should be remembered that low BP is often associated with more severe clinical, and especially cardiovascular, conditions and that at least part of the observed association might be confounded by comorbidities. For these and other reasons, the so-called J-curve phenomenon regarding the prognostic role of BP has been widely debated [74].

The Systolic Blood Pressure Intervention Trial (SPRINT) [75] has strengthened the position of those supporting the preventive efficacy of aggressive BP treatment also among older subjects. In patients at high cardiovascular risk and already using antihypertensive drugs, a treatment strategy targeting a systolic BP of 120 mmHg resulted in lower incidence of major cardiovascular events and death from any cause compared to a less strict approach targeting a systolic BP of 140 mmHg; this result was also statistically significant in the subgroup (28 % of the entire sample, n=2636) of patients more than 75 years old. Yet, it has to be pointed out that patients with severe disability, living in nursing, affected by dementia, decompensated heart failure, previous stroke, or diabetes were excluded from the study. Conversely included subjects had a mean 20 % 10-year Framingham cardiovascular risk score and a mean BMI of 30. On the whole SPRINT results add relevant information regarding antihypertensive treatment of a significant part of the older population but seem to apply to high vascular risk patients without disability and abovementioned diseases, and therefore may not be unconditionally applied to the oldest old.

Apart from chronological age, several studies in most recent years have pointed out at a role for “frailty” in increasing the risk associated with antihypertensive treatment among elderly subjects [11].

In geriatric research frailty is conceptualized as a physiological syndrome characterized by decreased functional reserve and diminished resistance to stressors, causing vulnerability to adverse health outcomes, including disability and death [76]. While frailty should be reliably identified with a comprehensive geriatric assessment, identifying multiple physical, mental, and social impairments whose accumulation may ultimately lead to the increased vulnerability status [77], rapid screener for this condition is often needed in clinical practice due to time and resource constraints. Therefore simple clinical tools have been operationalized to detect frailty with sufficient sensitivity and specificity [56], instruments based on lower extremity performance being among the most useful for this purpose [59].

An analysis from the National Health and Nutrition Examination Survey (NHANES) supports a role for motor performance as a powerful modulator of BP-associated risk. In fact, in a cohort of 2340 older subjects (mean age 74), the association between BP and a 7-year mortality varied markedly among subjects, according to their ability to walk 6 m as fast walkers (≥0.8 m/s), slow walkers (<0.8 m/s), or unable to complete the task. In fact, while high SBP was associated with increased mortality among fast walkers, the association disappeared among slow walkers and was reverted among subjects unable to walk, who had a greater risk associated with low values of SBP and DBP [78].

In keeping with these data, a condition of overt disability in activities of daily living associated with low BP has been identified as a condition with a negative prognostic outcome among oldest old (age 85+), in terms of both increased risk of cognitive decline [45] and increased risk for stroke [79]. Moreover, in the vast group of disabled nursing home subjects, BP was found as unrelated to a 1-year mortality risk in one study [32] and inversely associated with increased 2-year mortality risk in another one [80]. Of notice, in the latter study the increased risk for mortality was restricted to subjects with SBP < 130 mmHg in combination with 2+ antihypertensive drugs, thus supporting the need of less intensive treatment in this highly impaired population.

Finally, subjects with cognitive impairment might represent a subpopulation at high risk for brain hypoperfusion. Yet in this condition the data are not clear-cut. In fact, one study of 1385 subjects with mild cognitive impairment (mean age 73.6, baseline MMSE 28/30) has found a faster progression of cognitive decline over 2 years among subjects with repeated detection of high BP (≥140/90 mmHg) [81]. In keeping with these data, subjects with mild cognitive impairment (mean age 67.8, baseline MMSE 26/30) have been found to have an increased risk of conversion to Alzheimer’s disease after 5 years, while antihypertensive treatment reduced the risk [82]. Conversely a subsequent study conducted with ambulatory BP monitoring in a sample of 172 older subjects with dementia or mild cognitive impairment (mean age 79, MMSE 22/30) has observed an increased risk of cognitive decline after 9 months among subjects with lower mean daytime SBP (<129 mmHg) actively treated with antihypertensive drugs [83]. Another study of 141 subjects with mild cognitive impairment (mean age 74) has observed an independent association between orthostatic hypotension and increased risk for conversion to dementia after 2 years [84]. Therefore, the presence of mild cognitive impairment might be a caveat for possible detrimental effects of excessive BP lowering, at least among oldest old and for subjects with orthostatic hypotension and overt dementia. ABPM seems to be more useful than clinical measure in predicting the cognitive detrimental effects of low BP.

On the whole, the presence of functional disability, motor impairment, and cognitive impairment might be useful markers of increased vulnerability to antihypertensive treatment. These factors together with old age can suggest a more prudent approach to vascular risk factor prevention, including antihypertensive treatment [85]. A treatment discontinuation randomized trial of 385 older subjects 75+ with mild cognitive decline (mean age 81, MMSE 26/30) was recently published. Subjects were included if they took at least one antihypertensive drug, and SBP was ≤160 mmHg. After 16 weeks SBP went from 148.8 mmHg to 154.2 mmHg, but no positive effect was evident on cognitive function, psychological status, or daily functioning [86]. Further studies of treatment de-intensification are warranted, with the aim of identifying the role of different BP measures (clinical vs. ambulatory) and different BP targets for specific subgroups of frail older subjects.