The Pharmacological Treatment of Arterial Hypertension in Frail, Older Patients
A systematic review
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Background: It is debated whether the treatment goals and decision-making algorithms for elderly patients with hypertension should be the same as those for younger patients. The American and European guidelines leave decisions about antihypertensive treatment in frail, institutionalized patients up to the treating physician. We therefore systematically searched the literature for publications on the phamacotherapy of arterial hypertension in frail patients.
Methods: The MEDLINE, Embase, and Central databases were systematically searched for randomized, controlled trials (RCTs) and non-randomized studies, including observational studies, on the pharmacotherapy of arterial hypertension in elderly patients since the introduction of the concept of frailty, published over the period 1992–2017.
Results: Out of 19 282 citations for randomized, controlled trials and 5659 for non-randomized trials and observational studies, four RCTs and three observational studies were included in the further analysis. The included RCTs showed a trend towards a benefit from pharmacotherapy of hypertension in frail patients with respect to mortality, cardiovascular disease, functional status, and quality of life. On the other hand, some of the observational studies indicated a lower rate of falls and lower mortality among patients who received no antihypertensive treatment.
Conclusion: In view of the conflicting findings of RCTs and non-randomized studies, the lower representation of frail subjects in RCTs, and the high risk of bias in non-randomized studies, the findings of the studies included in this review do not enable the formulation of any strictly evidence-based treatment recommendations. As a rule of thumb, the authors propose that a target systolic blood pressure of <150 mmHg should be aimed at in patients whose gait speed is less than 0.8 m/s, while a target range of 130–139 mmHg can be set for patients over age 80 who are no more than mildly frail.
The current recommendations for blood pressure target values and pharmacological treatment of arterial hypertension in older people are heterogeneous (1, 2). The 2017 guideline of the American College of Cardiology recommends a new target value of systolic blood pressure <130 mmHg for persons ≥ 65 years living at home (3). For the same age group, the recently published guidelines of the European Society of Cardiology (ESC), state a target range of 130 to 139 mmHg for systolic pressure (level of evidence A) (4). The German Hypertension League and the German College of General Practitioners and Family Physicians (DEGAM) also recommend that the blood pressure should be <140/90 mmHg in the elderly (5–7). However, the DEGAM describes the research data on antihypertensive treatment in older patients as inadequate (6). Management of high blood pressure is particularly challenging in frail, elderly persons owing to the potential complications and the problem of tolerance. The above-mentioned American guideline (3) differentiates older patients primarily by morbidity, age, and institutionalization, but not by degree of frailty. In contrast, the current ESC guideline distinguishes between fit, independent patients and frail patients (4). While it can be assumed that older hypertensive patients who are not frail can be treated analogously to younger age groups, one has to question whether frail elderly patients benefit from such a therapy (8).
But what is “frailty”? The term has never been clearly defined since its introduction in 1992 and remains controversial. While the explanatory model proposed by Fried et al. (9) defines frailty mainly in physical terms such as measurements of grip strength, undesired weight loss, physical activity, and gait speed, the Frailty Index (FI) of Rockwood et al. (10) also embraces cognitive parameters, comorbidity, and malnutrition. In order to achieve comparable characterization of older participants in randomized controlled trials (RCTs), in 2015 the European Medicines Agency (EMA) suggested measuring walking speed and carrying out the Short Physical Performance Battery (11).
At present, both the American and European guidelines leave the decision on antihypertensive treatment of frail, older adults to the treating physician (3, 4). Although frailty already plays a role in guideline recommendations, the existing systematic reviews have only considered age. For this reason, we took frailty into account in a systematic assessment of the evidence regarding the pharmacological treatment of arterial hypertension.
The MEDLINE, Embase, and Central databases were searched for relevant records in the period 1 January 1992 to 31 December 2017 (PROSPERO CRD42017067253) (12). Two reviewers (VM, SB) independently carried out the following steps:
- Selection of studies
- Data extraction
- Assessment of the risk of bias in the primary studies
Any disagreements between the reviewers were resolved by discussion or by a third person (MD, DD). Included for analysis were RCTs that investigated the effects of pharmacological treatment of hypertension on the endpoints functionality, mortality, morbidity, or quality of life in relation to physical frailty. Nonrandomized controlled trials (non-RCTs) were also included if they analyzed physical frailty as effect modifier of antihypertensive treatment for the above-mentioned endpoints (for further details, please refer to the eMethods supplement). Physical frailty was evaluated systematically on the basis of the functional assessments (e.g., of mobility or activities of daily living [ADL]) that had been performed (13).
The survey revealed 19 282 records for RCTs based on the titles and abstracts, of which 39 were identified as potentially relevant. For non-RCTs and observational studies, 41 of 5659 records were judged potentially relevant. After full-text screening, four RCTs (14–19) and three prospective longitudinal cohort studies (20–22) were included for analysis. One reanalysis of an RCT (23) was identified and included after an additional search for the first and last authors of these seven studies. Details of the studies included and their results are presented in Table 1 and eTable 1, and the risk of bias for the RCTs is shown in eTable 2.
Randomized controlled trials
Four RCTs were identified (Table 1, eTable 1):
- HYVET (HYpertension in the Very Elderly Trial) (16, 17)
- DANTE (Discontinuation of Antihypertensive Treatment in Elderly People) (18)
- SHEP (Systolic Hypertension in the Elderly Program) (19)
- SPRINT (Systolic Blood Pressure Intervention Trial) (14, 15, 23)
HYVET investigated the interaction between drug treatment (a combination of slow-release indapamide 1.5 mg ± perindopril 2–4 mg) and frailty in patients 80 years of age or older with a systolic blood pressure >160 mmHg (16). In this context the available data suggest that the protective effect of antihypertensive treatment—with regard to the incidence of strokes and of fatal or non-fatal cardiovascular events—could be greater with increasing frailty. Further analysis of the HYVET data with the change in frailty during the first 24 months as endpoint showed no significant difference, but the outcome tended to be better in the intervention group (17). The risk of bias for HYVET was found to be predominantly low. However, the description of random sequence generation was insufficient (eTable 2).
In DANTE, short-term discontinuation of antihypertensive treatment in patients ≥ 75 years of age with mild cognitive deficits (Mini-Mental State Examination [MMSE] score 21–27) did not improve cognition or functionality (ADL) after 16 weeks (18). The treatment for hypertension also showed no differences in effect on cognition between groups with and without restricted ADL. The risk of bias was predominantly low, but there was no blinding of participants or study personnel (18) (eTable 2).
SHEP, published in 1991, was the first American RCT to show the protective effect of antihypertensive treatment (chlorthalidone ± atenolol) against fatal and nonfatal stroke compared with placebo (25). A post-hoc analysis 25 years after the end of the study demonstrated no modification of the effect by self-reported functional limitations (19). There were signs that the treatment increased the risk of occurrence of the secondary endpoints overall mortality, cardiovascular mortality, myocardial infarction, and stroke in functionally impaired patients. The risk of bias was predominantly low; however, the risk was unclear for random sequence generation and high for incomplete outcome data (eTable 2).
SPRINT examined, in a subanalysis, the effects on the primary endpoints mortality and cardiovascular disease of intensive treatment for high blood pressure (<120 mmHg) compared with standard treatment (<140 mmHg) in patients aged 75 years and over (14). Intense lowering of blood pressure protected against cardiovascular events regardless of gait speed. Further analyses of the SPRINT data showed no differences between the groups for decrease in gait speed over the following 3 years (15). For intensive treatment the risk of death was lower in patients without restricted mobility. However, the protective effect did not attain significance in those with restricted mobility. Patients who reported worse physical quality of life at the beginning of the study showed a more rapid decrease in gait speed than those whose self-assessment was better (15). After stratification by frailty, no significant difference in subjective quality of life was observed between the two groups (23). The risk of bias was predominantly unclear due to inadequacies in the description of random sequence generation and in blinding (eTable 2) (26, 27).
Non-randomized controlled trials
The three non-RTCs included for analysis were the Health, Aging, and Body Composition Study (Health ABC) (21), the Medicare Current Beneficiary Survey (20), and the Jerusalem Longitudinal Study (22) (Table 1, eTable 1). (For information on study quality, please refer to the eMethods supplement.)
Health ABC investigated the association between consumption of antihypertensive medications and recurrent falls over a period of 7 years in 2948 community-dwelling, initially well-functioning older adults (21). A sensitivity analysis showed no effect modification by gait speed. The risk of bias was assessed as moderate.
One of the analyses in the Medicare Current Beneficiary Survey showed that administration of intensive drug treatment for high blood pressure was associated with an increased risk of serious fall injuries in 4961 Medicare patients ≥ 70 years of age. The risk was significantly higher in patients who were physically frail (as defined by falls in the foregoing year); however, there was no essential difference in risk between the groups with moderate and high decreases in blood pressure (20). The risk of bias was assessed as serious.
The Jerusalem Longitudinal Study examined the association between medicinal treatment of arterial hypertension and overall mortality in patients over 90 years of age depending on frailty, assessed in terms of ADL and grip strength (22). There were trends towards slightly lower mortality in untreated persons with hypertension and higher mortality in those who received treatment for hypertension compared with normotensive persons who did not receive treatment. The protective effect without treatment was greater among the participants with better physical functionality (22). The risk of bias was assessed as moderate
Although the term “frailty” was introduced as long ago as 1992 (28), our literature search for this review found only a small number of studies that characterized their participants in this respect. The findings of the RCTs we identified show that even patients with pronounced physical frailty may benefit from treatment of hypertension in terms of mortality, cardiovascular disease, functionality, and quality of life. However, because the risk of bias was often unclear, the proportion of participants with marked functional limitations mostly low, and the heterogeneity of the studies analyzed high, the quality of the evidence does not permit derivation of treatment recommendations. The quality of the non-RCTs we identified is also too low to evaluate whether physical frailty can be considered an effect modifier.
HYVET and SPRINT can be described as landmark RCTs for our study question, as they were the first to characterize the participants precisely in terms of frailty (eTable 3). The results show that antihypertensive treatment has a protective effect even in physically frail older patients. However, the subgroup analyses lacked the necessary statistical power for robust conclusions. Furthermore, it is questionable to what extent the RCTs’ selected patient populations reflect the the reality of prescription practice. For instance, SPRINT excluded patients with diabetes, symptomatic heart failure, orthostatic hypotension, or dementia and nursing home residents (29, 30). Dementia and the need for 24-h care were also exclusion criteria in HYVET (16).
The risk of bias in SPRINT was predominantly unclear, with inadequacies in the description of random sequence generation and in blinding of study personnel (26, 27). Gait speed and mobility restriction were not considered endpoints at the beginning of the study according to the registered study protocol (ClinicalTrials.gov identifier: NCT01206062). Since all the study results display wide confidence intervals, the precision of the estimate of effect is low. Both HYVET and SPRINT were terminated prematurely, so the effect of the intervention may be overestimated (31). Moreover, in HYVET the FI, used to classify functionality, was also calculated for participants in whom not all, or not at least half, of the items were present (16). Therefore, the classification of the participants may be erroneous in this respect.
In addition, a higher risk of bias must be assumed for the non-RCTs. The results presented are of little assistance in deciding on differential treatment depending on physical frailty. Here too, many of the study participants had only slight functional limitations or none at all (21). While the known risk of a higher rate of falls with more intensive treatment for high blood pressure was confirmed, functional limitation seems to increase the risk (20). Many non-RCTs had to be excluded from our analysis either because they merely used the measured blood pressure as a surrogate for antihypertensive treatment or because they investigated neither greater functional limitation nor physical frailty as effect modifier. Only the PARTAGE study looked at the interaction between systolic blood pressure and the number of antihypertensive medications in residents of nursing homes. The results showed that patients with systolic blood pressure <130 mmHg who were taking at least two antihypertensive medications had the highest risk of death (32). Unfortunately there was no stratification of participants according to physical frailty, so this study had to be excluded.
The PARTAGE findings are in accordance with those of other epidemiological studies that postulate a J-shaped association between blood pressure and mortality. However, there is a distinct danger of reverse causation. For example, persons over 80 years old in Great Britain were found to be at greater risk of death with systolic blood pressure <120 mmHg (33). On examination of the blood pressure over time, however, a sharp drop in pressure was found particularly in the last 2 years of life, independent of antihypertensive treatment. The association may thus be explained by an as yet pathophysiologically unexplained blood pressure decrease up to 2 years before death, rather than by treatment for hypertension or by the blood pressure at the beginning of the study (33, 34). In the absence of sensitivity analyses to exclude reverse causation, results should therefore always be viewed critically. However, these analyses point to a basic problem: in the months before death, treatments may be no longer indicated or required but are nevertheless continued (33).
The target systolic blood pressure of 130–139 mmHg in the new ESC guideline for persons over 80 years of age may need critical re-evaluation for patients with severe or very severe physical limitations (4). In HYVET, for instance, there was a reduction in mortality for target pressures <150 mmHg (16). More research is needed to ascertain to what extent a further reduction of the target to <140 mmHg would provide further protection. The ongoing INFINITY study (“Intensive Versus Standard Blood Pressure Lowering to Prevent Functional Decline in Older People”; ClinicalTrials.gov NCT01650402) will also achieve little with regard to persons with severe to very severe limitations, because it excluded patients with signs of physical frailty (Short Physical Performance Battery score <10 points).
Strengths and limitations
The strength of this systematic review is that for the first time the available literature—both RCTs and non-RCTs, including observational studies—on the treatment of hypertension has been evaluated taking into account physical frailty. We strove to ensure identification of all relevant publications by hand-searching the reference lists of systematic reviews on antihypertensive treatment in older patients (35–37) and further landmark studies (eTable 3). However a small risk remains that single subgroup-analyses were not considered. Another critical point is the method used to identify physically frail, functionally impaired patients. The heterogeneity of the definitions of frailty highlighted the considerable differences between function-oriented assessments, cognition-oriented assessments, and deficit models such as Rockwood’s cumulative FI (used in SPRINT and HYVET). For instance, the FI in SPRINT features hardly any aspects of physical function. Moreover, post-hoc subgroup analyses limit the robustness of the results. In most non-RCTs not all confounding factors can be taken into account. Assessment of publication bias was not feasible owing to the small number of studies identified.
Even after a systematic analysis of the published data with regard to physical frailty, questions remain open. The SPRINT and HYVET findings seem to show that antihypertensive treatment as recommended in the prevailing guidelines may also be indicated in this group of patients. Whether patients with severe physical frailty were included in these studies is uncertain because of the deficit-oriented FI they used. Furthermore, these two studies are not representative due to their exclusion criteria. Among the non-RCTs only a small number of studies have analyzed both drug treatment and physical function in detail. To ensure reliable characterization and facilitate comparability among studies, not only should older members of the population be included in future research, as stated so often before, but systematically evaluated geriatric assessment instruments should be used. This is the only way in which modification of effects by physical frailty can be evaluated. Moreover, in order to fill the gaps in evidence, not only classical clinical studies but also deprescribing RCTs and new methodological approaches including prospective meta-analyses should be carried out in established research networks.
The authors are grateful to their fellow members of the MedQol Group for fruitful discussions and excellent cooperation with regard to further questions of diabetes, dementia and depression. The membership is as follows: University of Heidelberg: Walter E. Haefeli, Hanna M. Seidling (Department of Clinical Pharmacology and Pharmacoepidemiology), Jürgen M. Bauer, Annette Eidam (Agaplesion Bethanien Hospital Heidelberg); University of Freiburg: Claudia Bollig, Gabriel Torbahn, Sebastian Voigt-Radloff (Institute for Evidence in Medicine [for the Cochrane Germany Foundation], Faculty of Medicine, University Hospital Freiburg); University of Ulm: Simone Brefka, Dhayana Dallmeier, Michael D. Denkinger, Viktoria Mühlbauer (Agaplesion Bethesda Hospital, Department of Geriatrics, University of Ulm and Geriatric Center Ulm/Alb-Donau), Carlos Schönfeldt-Lecuona (Department of Psychiatry and Psychotherapy III, University Hospital Ulm), Christine von Arnim (Department of Neurology, University Hospital Ulm); University of Bern: Stefan Klöppel (University Psychiatric Service Bern [UPD], Department of Geriatric Psychiatry and Psychotherapy, University of Bern).
This work was financed by the open funding line of the special line “Medicine,” an element of the University Funding Contract (Hochschulfinanzierungsvertrag) Baden-Württemberg, as part of the joint project “Medication and Life Circumstances in Old Age” (“Medikation und Lebenssituation im Alter”).
Conflict of interest statement
The authors declare that no conflict of interest exists.
Manuscript submitted on 13 September 2018, revised version accepted on 4 December 2018
Translated from the original German by David Roseveare
For eReferences please refer to:
eMethods, eBoxes, eTables:
Department of Geriatrics, University of Ulm and Geriatric Center Ulm/Alb-Donau,
Agaplesion Bethesda Hospital: Viktoria Mühlbauer, PD Dr. Dhayana Dallmeier, Ph.D.,
Simone Brefka, Prof. Dr. Michael Denkinger
Institute for Evidence in Medicine (for the Cochrane Germany Foundation), Faculty of Medicine, University Hospital Freiburg: Claudia Bollig, M.Sc., Dr. Sebastian Voigt-Radloff, M.Sc.
Freiburg Center for Geriatrics and Gerontology, Faculty of Medicine, University Hospital Freiburg:
Dr. Sebastian Voigt-Radloff, M.Sc.
Prof. Dr. med. Michael Dieter Denkinger
Geriatrie der Universität Ulm
und Geriatrisches Zentrum Ulm/Alb-Donau
Agaplesion Bethesda Klinik
89073 Ulm, Germany
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