MEDICINE

Original Article The Pharmacological Treatment of Arterial Hypertension in Frail, Older Patients A Systematic Review

Viktoria Mühlbauer*, Dhayana Dallmeier*, Simone Brefka, Claudia Bollig, Sebastian Voigt-Radloff, Michael Denkinger

he current recommendations for blood pressure tar- Summary get values and pharmacological treatment of arterial hypertension in older people are heterogeneous (1, Background: It is debated whether the treatment goals and decision-making T 2). The 2017 guideline of the American College of Car- algorithms for elderly patients with hypertension should be the same as those for diology recommends a new target value of systolic blood younger patients. The American and European guidelines leave decisions about pressure <130 mmHg for persons ≥ 65 years living at antihypertensive treatment in frail, institutionalized patients up to the treating home (3). For the same age group, the recently published physician. We therefore systematically searched the literature for publications on guidelines of the European Society of Cardiology (ESC), the phamacotherapy of arterial hypertension in frail patients. state a target range of 130 to 139 mmHg for systolic Methods: The MEDLINE, Embase, and Central databases were systematically pressure (level of evidence A) (4). The German Hyperten- searched for randomized, controlled trials (RCTs) and non-randomized studies, sion League and the German College of General including observational studies, on the pharmacotherapy of arterial hypertension in Practitioners and Family Physicians (DEGAM) also elderly patients since the introduction of the concept of frailty, published over the recommend that the blood pressure should be period 1992–2017. <140/90 mmHg in the elderly (5–7). However, the Results: Out of 19 282 citations for randomized, controlled trials and 5659 for DEGAM describes the research data on antihypertensive non-randomized trials and observational studies, four RCTs and three observational treatment in older patients as inadequate (6). Management studies were included in the further analysis. The included RCTs showed a trend to- of high blood pressure is particularly challenging in frail, wards a benefit from pharmacotherapy of hypertension in frail patients with respect elderly persons owing to the potential complications and to mortality, cardiovascular disease, functional status, and quality of life. On the the problem of tolerance. The above-mentioned American other hand, some of the observational studies indicated a lower rate of falls and guideline (3) differentiates older patients primarily by lower mortality among patients who received no antihypertensive treatment. morbidity, age, and institutionalization, but not by degree of frailty. In contrast, the current ESC guideline distin- Conclusion: In view of the conflicting findings of RCTs and non-randomized studies, guishes between fit, independent patients and frail pa- the lower representation of frail subjects in RCTs, and the high risk of bias in non- tients (4). While it can be assumed that older hypertensive randomized studies, the findings of the studies included in this review do not enable patients who are not frail can be treated analogously to the formulation of any strictly evidence-based treatment recommendations. As a rule younger age groups, one has to question whether frail of thumb, the authors propose that a target systolic blood pressure of <150 mmHg elderly patients benefit from such a therapy (8). should be aimed at in patients whose gait speed is less than 0.8 m/s, while a target But what is “frailty”? The term has never been clearly range of 130–139 mmHg can be set for patients over age 80 who are no more than defined since its introduction in 1992 and remains con- mildly frail. troversial. While the explanatory model proposed by Cite this as: Fried et al. (9) defines frailty mainly in physical terms Mühlbauer V, Dallmeier D, Brefka S, Bollig C, Voigt-Radloff S, Denkinger M: such as measurements of grip strength, undesired weight The pharmacological treatment of arterial hypertension in frail, older patients— loss, physical activity, and gait speed, the Frailty Index a systematic review. Dtsch Arztebl Int 2019; 116: 23–30. (FI) of Rockwood et al. (10) also embraces cognitive par- DOI: 10.3238/arztebl.2019.0023 ameters, comorbidity, and malnutrition. In order to achieve comparable characterization of older participants in randomized controlled trials (RCTs), in 2015 the Euro- pean Medicines Agency (EMA) suggested measuring * Joint first authors. walking speed and carrying out the Short Physical Department of Geriatrics, University of Ulm and Geriatric Center Ulm/Alb-Donau, Performance Battery (11). Agaplesion Bethesda Hospital: Viktoria Mühlbauer, PD Dr. Dhayana Dallmeier, Ph.D., At present, both the American and European guide- Simone Brefka, Prof. Dr. Michael Denkinger lines leave the decision on antihypertensive treatment 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. of frail, older adults to the treating physician (3, 4). Freiburg Center for Geriatrics and Gerontology, Faculty of Medicine, University Hospital Freiburg: Although frailty already plays a role in guideline Dr. Sebastian Voigt-Radloff, M.Sc. recommendations, the existing systematic reviews

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The clinical perspective ● Before the commencement of treatment, older patients should be screened for physical frailty in terms of gait speed or Short Physical Performance Battery (SPPB) score. ● The evidence is insufficient for patients with severe physical frailty. Based on current knowledge, for patients with a gait s peed of <0.8 m/s we recommend a target systolic blood pressure of <150 mmHg. Adverse effects, particularly orthostatic hypotension, should be avoided if at all possible. ● In patients >80 years of age who are not or only slightly frail, the target systolic blood pressure should be 130–139 mmHg. It goes without saying that the patient’s tolerance of the treatment should be taken into account in each individual case. ● The greater the frailty and functional limitations of the patients, the more closely they should be monitored after any change in treatment.

have only considered age. For this reason, we took Randomized controlled trials frailty into account in a systematic assessment of the Four RCTs were identified (Table 1, eTable 1): evidence regarding the pharmacological treatment of ● HYVET (HYpertension in the Very Elderly Trial) arterial hypertension. (16, 17) ● DANTE (Discontinuation of Antihypertensive Method Treatment in Elderly People) (18) The MEDLINE, Embase, and Central databases were ● SHEP (Systolic Hypertension in the Elderly searched for relevant records in the period 1 January P r o g r a m ) ( 1 9 ) 1992 to 31 December 2017 (PROSPERO ● SPRINT (Systolic Blood Pressure Intervention CRD42017067253) (12). Two reviewers (VM, SB) inde- Trial) (14, 15, 23) pendently carried out the following steps: HYVET investigated the interaction between drug ● Selection of studies treatment (a combination of slow-release indapamide ● Data extraction 1.5 mg ± perindopril 2–4 mg) and frailty in patients ● Assessment of the risk of bias in the primary 80 years of age or older with a systolic blood pressure studies >160 mmHg (16). In this context the available data Any disagreements between the reviewers were re- suggest that the protective effect of antihypertensive solved by discussion or by a third person (MD, DD). treatment—with regard to the incidence of strokes Included for analysis were RCTs that investigated the and of fatal or non-fatal cardiovascular events—could effects of pharmacological treatment of hypertension be greater with increasing frailty. Further analysis of on the endpoints functionality, mortality, morbidity, the HYVET data with the change in frailty during the or quality of life in relation to physical frailty. Non- first 24 months as endpoint showed no significant randomized controlled trials (non-RCTs) were also difference, but the outcome tended to be better in the included if they analyzed physical frailty as effect intervention group (17). The risk of bias for HYVET modifier of antihypertensive treatment for the above- was found to be predominantly low. However, the de- mentioned endpoints (for further details, please refer scription of random sequence generation was insuffi- to the eMethods supplement). Physical frailty was cient (eTable 2). evaluated systematically on the basis of the functional In DANTE, short-term discontinuation of antihy- assessments (e.g., of mobility or activities of daily pertensive treatment in patients ≥ 75 years of age with living [ADL]) that had been performed (13). mild cognitive deficits (Mini-Mental State Examin- ation [MMSE] score 21–27) did not improve Results cognition or functionality (ADL) after 16 weeks (18). The survey revealed 19 282 records for RCTs based The treatment for hypertension also showed no differ- on the titles and abstracts, of which 39 were identified ences in effect on cognition between groups with and as potentially relevant. For non-RCTs and observa- without restricted ADL. The risk of bias was predomi- tional studies, 41 of 5659 records were judged poten- nantly low, but there was no blinding of participants tially relevant. After full-text screening, four RCTs or study personnel (18) (eTable 2). (14–19) and three prospective longitudinal cohort SHEP, published in 1991, was the first American studies (20–22) were included for analysis. One re- RCT to show the protective effect of antihypertensive analysis of an RCT (23) was identified and included treatment (chlorthalidone ± atenolol) against fatal and after an additional search for the first and last authors nonfatal stroke compared with placebo (25). A of these seven studies. Details of the studies included post-hoc analysis 25 years after the end of the study and their results are presented in Table 1 and eTable 1, demonstrated no modification of the effect by and the risk of bias for the RCTs is shown in eTable 2. self-reported functional limitations (19). There were

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FIGURE 1

Randomized controlled trials (RCTs) Non-RCTs including longitudinal cohort studies

19 282 records 1 additional record identified 5659 records 1 additional record identified i d e n t i f i e d t h r o u g h through other sources (reference lists, i d e n t i f i e d t h r o u g h through other sources(reference lists, d a t a b a s e s e a r c h i n g guidelines, citation search*) d a t a b a s e s e a r c h i n g guidelines, citation search*) Identification 16 537 records remain after removal of duplicates 5311 records remain after removal of duplicates

16 537 records 5311 records screened screened 16 498 records excluded 5270 records excluded Preselection

32 full-text articles 38 full-text articles excluded excluded Other 3 study Other 1 study study design protocols study design protocol 39 full text articles 7 non-RCTs 41 full text articles Other 19 Eligibility assessed for eligibility assessed for eligibility study questions 13 reviews Functionality 2 Other 4 not analyzed study questions Functionality 13 Functionality 1 analyzed, not analyzed but no further stratification Functionality 2 analyzed, but no Other 3 further stratification study population 4 studies

Included (described in 7 publications) Other 1 3 studies included in study population i n c l u d e d i n qualitative qualitative synthesis Other endpoints 1 synthesis

PRISMA flow chart of the various phases of the literature survey * Citation search = search for citations of the first and last authors of the studies included Non-RCTs, non-randomized studies

signs that the treatment increased the risk of occur- effect did not attain significance in those with rence of the secondary endpoints overall mortality, restricted mobility. Patients who reported worse cardiovascular mortality, myocardial infarction, and physical quality of life at the beginning of the study stroke in functionally impaired patients. The risk of showed a more rapid decrease in gait speed than bias was predominantly low; however, the risk was those whose self-assessment was better (15). After unclear for random sequence generation and high for stratification by frailty, no significant difference in incomplete outcome data (eTable 2). subjective quality of life was observed between the SPRINT examined, in a subanalysis, the effects on two groups (23). The risk of bias was predominantly the primary endpoints mortality and cardiovascular unclear due to inadequacies in the description of ran- disease of intensive treatment for high blood pressure dom sequence generation and in blinding (eTable 2) (<120 mmHg) compared with standard treatment (26, 27). (<140 mmHg) in patients aged 75 years and over (14). Intense lowering of blood pressure protected against Non-randomized controlled trials cardiovascular events regardless of gait speed. The three non-RTCs included for analysis were the Further analyses of the SPRINT data showed no Health, Aging, and Body Composition Study (Health differences between the groups for decrease in gait ABC) (21), the Medicare Current Beneficiary Survey speed over the following 3 years (15). For intensive (20), and the Jerusalem Longitudinal Study (22) (Table treatment the risk of death was lower in patients 1, eTable 1). (For information on study quality, please without restricted mobility. However, the protective refer to the eMethods supplement.)

Deutsches Ärzteblatt International | Dtsch Arztebl Int 2019; 116: 23–30 25 MEDICINE 0.10 0.08 0.08 0.04 0.48 0.84 0.91 interaction interaction P value for P value for P value for i n t e r a c t i o n Overall mortality 0.89 [0.63; 1.25] 0.84 [0.66; 1.07] 0.80 [0.61; 1.04] 0.76 [0.50; 1.14] 0.72 [0.40; 1.29] 0.68 [0.32; 1.48] 0.74 [0.54; 1.04] 0.56 [0.29; 1.07] Based on gait speed gait on Based MCS difference MCS 0.68 [0.45; 1.01] [0.45; 0.68 0.91] [0.43; 0.63 1.39] [0.13; 0.47 0.160; 0.156] 0.160; 0.279] 0.281; 0.122; 0.276] − − − 0.002 [ 0.002 [ 0.001 1.22 [0.79; 1.88] [0.79; 1.22 2.28] [0.71; 1.27 2.89] [0.54; 1.25 2.00] [0.87; 1.32 1.46] [0.44; 0.80 0.077 [ 0.077 − − Limited physical function 0.21) ≤ 0.10 0.09 [–0.21; 0.40] [–0.21; 0.09 ≤ (hazard[95%ratio CI]) –0.07 [–0.36; 0.22] [–0.36; –0.07

0.49 Fit: FI Frail: FI >0.21 i n t e r a c t i o n P value for 0.62 [0.42; 0.92] 0.60 [0.45; 0.78] 0.57 [0.42; 0.79] 0.55 [0.34; 0.89] 0.53 [0.26; 1.06] 0.50 [0.20; 1.27] 0.62 [0.43; 0.90] 0.82 [0.52; 1.28] No effect, regardless offunctionality regardless effect, No Cardiovascular events Cardiovascular Results Less fit: (0.1022 GARS-Score Fit (FI Frail (FI>0.21) Frail FI Myocardial infarction Myocardial Cardiovascular Cardiovascular death 0.1 0.2 0.3 0.4 0.5 0.6 0.8 m/s 0.8 Symptomatic hypotension Symptomatic <0.8 <0.8 m/s ≥ Less fit (0.10

→ → 1984–1996, USA 1984–1996, USA 2010–2016, USA 2010–2016, USA Parameters of functionality (Rockwood): FI Median Placebo group 0.17 0.24] [0.11; CI: 95% Intervention group 0.16 0.24] [0.11; CI: 95% FI (Rockwood) Activity Restriction Groningen Scale (GARS): intervention 18–28); (IQR 23 group: 19–29) (IQR 22 group control Self-reporting of limited physical function: 545 patients (11.9%) functionally limited Gaitspeed:<0.8m/s, (28.1%) patients 740 FI (Rockwood): >0.21,815 patients (30.9%) Gait speed self-reported and mobility:(18%) patients limitationsFI (Rockwood): characterized (27.3%) patients 2560 in frail 464as 2000–2008, Europe, China, Australasia, Tunisia Tunisia Australasia, China, Europe, 2000–2008, 80 years systolic blood pressure 75 years, mild cognitive deficit 75 years (n = 2636) (14) 75 years with data on mobility 50 years (n = 9361) (23) ≥ ≥ ≥ ≥ ≥ Study question/Population/Endpoints (HYVET), Trial Elderly the in Very HYpertension cardiovascular Endpoints: Stroke, total mortality, heart and infarction, myocardial (stroke, events failure) Patients: >160 (n=mmHg 2656)(16) Endpoints:Changes FIover months in 24 (n= 1665) (17) inElderly People (DANTE), AntihypertensiveTreatment Discontinuation of Endpoints: cognitive, psychological and general f u n c tPatients: i o n a (n= (18)385) l i t y Systolic Hypertension in the Elderly Program (SHEP), Endpoints: all-cause death, cardiovascular death, symptomatic falls, stroke, infarction, myocardial hypotension Patients: > 60 years (n = 4593) (19) Systolic (SPRINT), Blood Pressure Intervention Trial Endpoint: Myocardial infarction, coronary syndrome,events cardiovascular from death Patients: stroke,Endpoint:Gait speed and mobility decompensatedPatients: (n= 2629) (15) heart Endpoint: Physical (PCS) and mental (MCS) failure, the by measured as life of quality health-related Veterans RAND 12-Item HealthPatients: Survey TABLE1a analysis for ofCharacteristics included trials randomized the 95% CI, 95% confidence interval; FI, frailty index; IQR, interquartile range; MCS, Mental Component Summary Score; PCS, Physica PCS, Score; Summary Component Mental MCS, range; interquartile IQR, index; frailty FI, interval; confidence 95% CI, 95%

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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 1 ADL* 1

≥ adults (21). A sensitivity analysis showed no effect modification by gait speed. The risk of bias was

Reference assessed as moderate. 0.93 [0.35; 2.42] [0.35; 0.93 2.80] [0.67; 1.37 1.59] [0.76; 1.10 5.29] [1.01; 2.31

l o w e r i n g t r e a t m e n t One of the analyses in the Medicare Current Dependent in in Dependent Intensive blood pressure- Beneficiary Survey showed that administration of intensive drug treatment for high blood pressure was associated with an increased risk of serious fall in- 0.61 [0.35; 1.06] [0.35; 0.61 1.74] [0.56; 0.99 juries in 4961 Medicare patients ≥ 70 years of age. The risk was significantly higher in patients who were (hazard (hazard [95%CI]) ratio physically frail (as defined by falls in the foregoing

Risk of recurrent falls over 7-year period* over falls of recurrent Risk year); however, there was no essential difference in risk between the groups with moderate and high de- creases in blood pressure (20). The risk of bias was Results (hazard (hazard [95%CI]) ratio

Risk of severe injuries over 3-year period* over 3-year of injuries severe Risk assessed as serious. treatment Reference

0.90 [0.31; 2.67] [0.31; 0.90 3.92] [0.78; 1.75 1.73] [0.89; 1.24 4.80] [0.98; 2.17 The Jerusalem Longitudinal Study examined the Low grip strength* grip Low association between medicinal treatment of arterial hypertension and overall mortality in patients over 90 Moderate blood pressure-lowering pressure-lowering blood Moderate years of age depending on frailty, assessed in terms of ADL and grip strength (22). There were trends to- wards slightly lower mortality in untreated persons with hypertension and higher mortality in those who 1.17 m/s 1.17 <1.17 m/s ≥ Gaitspeed received treatment for hypertension compared with normotensive persons who did not receive treatment. The protective effect without treatment was greater CI, 95 % confidence interval confidence % 95 CI, among the participants with better physical Yes (n = 503) No (n =(n4621) No Normotensive functionality (22). The risk of bias was assessed as Fall in previous year Treated hypertension Untreated hypertension hypertension Untreated moderate

Discussion

association of consumption of antihypertensive medication with recurrent falls recurrent with medication antihypertensive of consumption of association 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 association of groups below with 5-year mortality independent of functionality we identified show that even patients with pronounced → physical frailty may benefit from treatment of hyper- tension in terms of mortality, cardiovascular disease, 1 ADL, 1 ≥ functionality, and quality of life. However, because the risk of bias was often unclear, the proportion of partici-

association of groups below with risk of severe injuries from falls (hazard ratio [95 % CI) pants with marked functional limitations mostly low,

→ and the heterogeneity of the studies analyzed high, the Parameters of functionality strength Reduced grip (men kg, <26 women<16 kg) n= (31.0%) 149 in Dependence Gait speed comparedwith medianat baseline, m/s 1.17 Falls in previous year: n = 503 (10.1%) n = 1919IADL one least at in (56.3%) 2791 = n (38.7%) restricted in at least one BADL, n = 194 (40.4%) 194 = n quality of the evidence does not permit derivation of treatment recommendations. The quality of the non- since 1997 (survey period 1997–2014), USA RCTs we identified is also too low to evaluate whether physical frailty can be considered an effect modifier. 2004–2009, USA 2004–2009, USA HYVET and SPRINT can be described as landmark RCTs for our study question, as they were the first to 70 years with since 1990 (survey period 2010–2011), Israel Israel 2010–2011), period (survey 1990 since ≥ characterize the participants precisely in terms of frail- ty (eTable 3). The results show that antihypertensive treatment has a protective effect even in physically frail older patients. However, the subgroup analyses ); ADL, activities of daily living; BADL, basic activities of daily living; IADL, instrumental activities of daily living; % 95 daily living; of activities IADL, instrumental dailyliving; of activities basic BADL, ADL,daily living; of activities ); lacked the necessary statistical power for robust conclusions. Furthermore, it is questionable to what : 5-year mortality : recurrent falls : severe fall injuries eTable 1b eTable extent the RCTs’ selected patient populations reflect the the reality of prescription practice. For instance,

Study question/Population/Endpoints Study, Longitudinal Jerusalem Endpoint Participants: 90 years old (n = 480) (22) BodyComposition Aging, Study, and Health, Endpoint Participants: no functional limitations (n = 2948) (21) Survey, Beneficiary Current Medicare Endpoint Participants:hypertension data and available medication on (n= 4961) (20) Medicare patients SPRINT excluded patients with diabetes, symp - TABLE1b analysis for ofCharacteristics included controlledtrials non-randomized the

*Adjusted (see (see *Adjusted tomatic heart failure, orthostatic hypotension, or

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dementia and nursing home residents (29, 30). De- problem: in the months before death, treatments may mentia and the need for 24-h care were also exclusion be no longer indicated or required but are nevertheless criteria in HYVET (16). continued (33). The risk of bias in SPRINT was predominantly un- The target systolic blood pressure of clear, with inadequacies in the description of random 130–139 mmHg in the new ESC guideline for sequence generation and in blinding of study persons over 80 years of age may need critical re- personnel (26, 27). Gait speed and mobility restriction evaluation for patients with severe or very severe were not considered endpoints at the beginning of the physical limitations (4). In HYVET, for instance, study according to the registered study protocol (Clini there was a reduction in mortality for target pressures calTrials.gov identifier: NCT01206062). Since all the <150 mmHg (16). More research is needed to ascer- study results display wide confidence intervals, the tain to what extent a further reduction of the target to precision of the estimate of effect is low. Both <140 mmHg would provide further protection. The HYVET and SPRINT were terminated prematurely, ongoing INFINITY study (“Intensive Versus Standard so the effect of the intervention may be overestimated Blood Pressure Lowering to Prevent Functional (31). Moreover, in HYVET the FI, used to classify Decline in Older People”; ClinicalTrials.gov functionality, was also calculated for participants in NCT01650402) will also achieve little with regard to whom not all, or not at least half, of the items were persons with severe to very severe limitations, present (16). Therefore, the classification of the because it excluded patients with signs of physical participants may be erroneous in this respect. frailty (Short Physical Performance Battery score <10 In addition, a higher risk of bias must be assumed points). for the non-RCTs. The results presented are of little assistance in deciding on differential treatment Strengths and limitations depending on physical frailty. Here too, many of the The strength of this systematic review is that for the study participants had only slight functional first time the available literature—both RCTs and non- limitations or none at all (21). While the known risk RCTs, including observational studies—on the of a higher rate of falls with more intensive treatment treatment of hypertension has been evaluated taking for high blood pressure was confirmed, functional into account physical frailty. We strove to ensure identi- limitation seems to increase the risk (20). Many non- fication of all relevant publications by hand-searching RCTs had to be excluded from our analysis either be- the reference lists of systematic reviews on antihyper- cause they merely used the measured blood pressure tensive treatment in older patients (35–37) and further as a surrogate for antihypertensive treatment or be- landmark studies (eTable 3). However a small risk cause they investigated neither greater functional remains that single subgroup-analyses were not con- limitation nor physical frailty as effect modifier. Only sidered. Another critical point is the method used to the PARTAGE study looked at the interaction be- identify physically frail, functionally impaired patients. tween systolic blood pressure and the number of The heterogeneity of the definitions of frailty high - antihypertensive medications in residents of nursing lighted the considerable differences between function- homes. The results showed that patients with systolic oriented assessments, cognition-oriented assessments, blood pressure <130 mmHg who were taking at least and deficit models such as Rockwood’s cumulative FI two antihypertensive medications had the highest risk (used in SPRINT and HYVET). For instance, the FI in of death (32). Unfortunately there was no stratifi- SPRINT features hardly any aspects of physical func- cation of participants according to physical frailty, so tion. Moreover, post-hoc subgroup analyses limit the this study had to be excluded. robustness of the results. In most non-RCTs not all con- The PARTAGE findings are in accordance with founding factors can be taken into account. Assessment those of other epidemiological studies that postulate a of publication bias was not feasible owing to the small J-shaped association between blood pressure and mor- number of studies identified. tality. However, there is a distinct danger of reverse causation. For example, persons over 80 years old in Summary Great Britain were found to be at greater risk of death Even after a systematic analysis of the published data with systolic blood pressure <120 mmHg (33). On with regard to physical frailty, questions remain open. examination of the blood pressure over time, however, The SPRINT and HYVET findings seem to show that a sharp drop in pressure was found particularly in the antihypertensive treatment as recommended in the pre- last 2 years of life, independent of antihypertensive vailing guidelines may also be indicated in this group treatment. The association may thus be explained by of patients. Whether patients with severe physical frail- an as yet pathophysiologically unexplained blood ty were included in these studies is uncertain because of pressure decrease up to 2 years before death, rather the deficit-oriented FI they used. Furthermore, these than by treatment for hypertension or by the blood two studies are not representative due to their exclusion pressure at the beginning of the study (33, 34). In the criteria. Among the non-RCTs only a small number of absence of sensitivity analyses to exclude reverse studies have analyzed both drug treatment and physical causation, results should therefore always be viewed function in detail. To ensure reliable characterization critically. However, these analyses point to a basic and facilitate comparability among studies, not only

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should older members of the population be included in future research, as stated so often before, but systemati- Key messages cally evaluated geriatric assessment instruments should be used. This is the only way in which modification of ● Although the term “frailty” was introduced as early as 1992, effects by physical frailty can be evaluated. Moreover, the physical function and/or frailty of older study participants in order to fill the gaps in evidence, not only classical is hardly ever documented in randomized controlled trials clinical studies but also deprescribing RCTs and new (RCTs) or non-RCTs. methodological approaches including prospective ● The lower target blood pressures in the current guidelines meta-analyses should be carried out in established must be critically reconsidered and, as the guidelines state, r e s e a r c h n e t w o r k s . the target must be decided on an individual basis for each patient. Acknowledgments The authors are grateful to their fellow members of the MedQol Group for ● When interpreting the results with regard to a possible fruitful discussions and excellent cooperation with regard to further questions of diabetes, dementia and depression. The membership is as J-shaped association between blood pressure and mortality follows: University of Heidelberg: Walter E. Haefeli, Hanna M. Seidling in observational studies, one should, even in the presence of (Department of Clinical Pharmacology and Pharmacoepidemiology), Jürgen M. Bauer, Annette Eidam (Agaplesion Bethanien Hospital Heidel- conceivable pathophysiology, take the methodological limi- berg); University of Freiburg: Claudia Bollig, Gabriel Torbahn, Sebastian tations (reverse causation) into account. Voigt-Radloff (Institute for Evidence in Medicine [for the Cochrane Germany Foundation], Faculty of Medicine, University Hospital Freiburg); ● To improve the characterization of older persons in clinical University of Ulm: Simone Brefka, Dhayana Dallmeier, Michael D. studies and observational studies with regard to their func- Denkinger, Viktoria Mühlbauer (Agaplesion Bethesda Hospital, Depart- ment of Geriatrics, University of Ulm and Geriatric Center Ulm/Alb-Donau), tionality, validated instruments for functional assessment Carlos Schönfeldt-Lecuona (Department of Psychiatry and Psychotherapy should be used. We agree with the European Medicines III, University Hospital Ulm), Christine von Arnim (Department of Neurol- ogy, University Hospital Ulm); University of Bern: Stefan Klöppel (Univer- Agency that at least gait speed and the Short Physical sity Psychiatric Service Bern [UPD], Department of Geriatric Psychiatry Performance Battery should be included. and Psychotherapy, University of Bern).

Funding This work was financed by the open funding line of the special line “Medicine,” an element of the University Funding Contract ( Hochschul - finanzierungsvertrag) Baden-Württemberg, as part of the joint project “Medication and Life Circumstances in Old Age” (“Medikation und Lebens- 10. Rockwood K, Song X, Mitnitski A: Changes in relative fitness and frailty situation im Alter”). across the adult lifespan: evidence from the Canadian National Popula - tion Health Survey. CMAJ 2011; 183: E487–94. Conflict of interest statement The authors declare that no conflict of interest exists. 11. European Medicines Agency (EMA): Reflection paper on physical frail- ty: instruments for baseline characterisation of older populations in clinical trials. Manuscript submitted on 13 September 2018, revised version accepted on EMA/CHMP/778709/2015. www.ema.europa.eu/documents/scientific- 4 December 2018 guideline/ reflection-paper-physical-frailty-instruments-baseline-characterisation- Translated from the original German by David Roseveare older- populations-clinical_en.pdf (last accessed 18. December 2018). References 12. Denkinger M, Dallmeier D, Brefka S, Mühlbauer V: Antihypertensive pharmacotherapy in frail older adults: a systematic review on efficacy 1. Conroy SP, Westendorp RGJ, Witham MD: Hypertension treatment for and safety. www.crd.york.ac.uk/PROSPERO/display_record. older people-navigating between Scylla and Charybdis. Age Ageing php?ID=CRD42017067253 (last accessed on 19 November 2018). 2018; 47: 505–8. 13. Brefka S, Dallmeier D, Mühlbauer V, et al.: A proposal for the retrospec- 2. Stott DJ, Applegate WB: Perspectives on hypertension treatment in tive identifi cation and categorization of older people with functional im- older persons. J Am Geriatr Soc 2018; 66: 1060–1. pairments in scientific studies—Recommendations of the Medication 3. Whelton PK, Carey RM, Aronow WS, et al.: 2017 ACC/AHA/AAPA/ABC/ and Quality of Life in frail older persons (MedQoL) Research Group. ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, JAMDA (in press). Detection, Evaluation, and Management of High Blood Pressure in 14. Williamson JD, Supiano MA, Applegate WB, et al.: Intensive vs standard Adults. A report of the American College of Cardiology/American Heart blood pressure control and cardiovascular disease outcomes in adults Association Task Force on Clinical Practice Guidelines. Circulation 2018; aged ≥ 75 years: a randomized clinical trial. JAMA 2016; 315: 2673–82. 138: e484–e594. 15. Odden MC, Peralta CA, Berlowitz DR, et al.: Effect of intensive blood 4. Williams B, Mancia G, Spiering W, et al.: 2018 ESC/ESH Guidelines for pressure control on gait speed and mobility limitation in adults 75 years the management of arterial hypertension. Eur Heart J 2018; 39: or older: a randomized clinical trial. JAMA Intern Med 2017; 177: 500–7. 3021–104. 16. Warwick J, Falaschetti E, Rockwood K, et al.: No evidence that frailty 5. Deutsche Hochdruckliga e.V. (DHL): Deutsche Hochdruckliga hält an modifies the positive impact of antihypertensive treatment in very elderly moderaten Zielwerten fest. www.hochdruckliga.de/pressemeldung/ people: an investigation of the impact of frailty upon treatment effect in items/deutsche-hochdruckliga-haelt-an-moderaten-zielwerten-fest.html the HYpertension in the Very Elderly Trial (HYVET) study, a double-blind, (last accessed on 19 November 2018). placebo-controlled study of antihypertensives in people with hyperten- sion aged 80 and over. BMC Med 2015; 13: 78. 6. Deutsche Gesellschaft für Allgemeinmedizin und Familienmedizin (DEGAM): DEGAM Statement zu Blutdruck-Zielwerten. 17. Beckett N, Warwick J, Rockwood K, et al.: Impact of blood pressure lowering treatment on frailty in the hypertension in the very elderly trial www.degam.de/ files/Inhalte/Degam-Inhalte/Sektionen_und_ Arbeits- (HYVET). Eur Geriatr Med.2015; 6: S6. gruppen/Sektion_ Versorgungsaufgaben/DEGAM%20Statement% 20zur%20Blutdruckabsenkung%202017_11_28_final.pdf 18. Moonen JEF, Foster-Dingley JC, de Ruijter W, et al.: Effect of discontinu- (last accessed on 19 November 2018). ation of antihypertensive treatment in elderly people on cognitive func- tioning—the DANTE Study Leiden: a randomized clinical trial. JAMA In- 7. Jordan J, Kurschat C, Reuter H: Arterial Hypertension. Dtsch Arztebl Int tern Med 2015; 175: 1622–30. 2018; 115: 557–68. 19. Charlesworth CJ, Peralta CA, Odden MC: Functional status and anti - 8. Odden MC, Peralta CA, Haan MN, Covinsky KE: Rethinking the associ- hypertensive therapy in older adults: a new perspective on old data. Am ation of high blood pressure with mortality in elderly adults: the impact of J Hypertens 2016; 29: 690–5. frailty. Arch Intern Med 2012; 172: 1162–8. 20. Tinetti ME, Han L, Lee DSH, et al.: Antihypertensive medications and 9. Fried LP, Tangen CM, Walston J, et al.: Frailty in older adults: evidence serious fall injuries in a nationally representative sample of older adults. for a phenotype. J Gerontol A Biol Sci Med Sci 2001; 56: M146–56. JAMA Intern Med 2014; 174: 588–95.

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21. Marcum ZA, Perera S, Newman AB, et al.: Antihypertensive use and nursing home residents: The PARTAGE Study. JAMA Intern Med 2015; recurrent falls in community-dwelling older adults: findings from the 175: 989–95. Health ABC Study. J Gerontol A Biol Sci Med Sci 2015; 70: 1562–8. 33. Ravindrarajah R, Dregan A, Hazra NC, Hamada S, Jackson SHD, Gulli- 22. Stessman J, Bursztyn M, Gershinsky Y, Hammerman-Rozenberg A, ford MC: Declining blood pressure and intensification of blood pressure Jacobs JM: Hypertension and Its Treatment at Age 90 Years: Is There an management among people over 80 years: cohort study using electronic Association with 5-Year Mortality? J Am Med Dir Assoc 2017; 18: health records. J Hypertens 2017; 35: 1276–82. 277.e13–277.e19. 34. Sattar N, Preiss D: Reverse causality in cardiovascular epidemiological 23. Berlowitz DR, Foy CG, Kazis LE, et al.: Effect of intensive blood- research: More Common Than Imagined? Circulation 2017; 135: pressure treatment on patient-reported outcomes. N Engl J Med 2017; 2369–72. 377: 733–44. 35. Weiss J, Freeman M, Low A, et al.: Benefits and harms of intensive 24. Beckett NS, Peters R, Fletcher AE, et al.: Treatment of hypertension in blood pressure treatment in adults aged 60 years or older: a systematic patients 80 review and meta-analysis. Ann Intern Med 2017; 166: 419–29. years of age or older. N Engl J Med 2008; 358: 1887–98. 25. SHEP Cooperative Research Group: Prevention of stroke by antihyper- 36. Moraes AAI, Baena CP, Muka T, et al.: Achieved systolic blood pressure tensive drug treatment in older persons with isolated systolic hyperten- in older people: a systematic review and meta-analysis. BMC Geriatr sion. Final results of the Systolic Hypertension in the Elderly Program 2017; 17: 279. (SHEP). JAMA 1991; 265: 3255–64. 37. Musini VM, Tejani AM, Bassett K, Wright JM: Pharmacotherapy for 26. Ambrosius WT, Sink KM, Foy CG, et al.: The design and rationale of a hypertension in the elderly. Cochrane Database Syst Rev 2009; 4: multicenter clinical trial comparing two strategies for control of systolic CD000028. blood pressure: the Systolic Blood Pressure Intervention Trial (SPRINT). Clin Trials 2014; 11: 532–46. Corresponding author 27. SPRINT Research Group, Wright JT, Williamson JD, et al.: A r andom - Prof. Dr. med. Michael Dieter Denkinger ized trial of intensive versus standard blood-pressure control. Geriatrie der Universität Ulm N Engl J Med 2015; 373: 2103–16. und Geriatrisches Zentrum Ulm/Alb-Donau 28. Buchner DM, Wagner EH: Preventing frail health. Clin Geriatr Med 1992; Agaplesion Bethesda Klinik 8: 1–17. Zollernring 26 29. Supiano MA, Williamson JD: Applying the systolic blood pressure inter- 8 9 0 7 3 U l m , G e r m a n y vention trial results to older adults. J Am Geriatr Soc 2017; 65: 16–21. [email protected] 30. Düsing R. [Treatment Targets in Hypertension]. Dtsch Med Wochenschr 2017; 142: 1420–9. ►Supplementary material 31. Kulig M, Perleth M, Langer G, et al.: [GRADE guidelines: 6. Rating the For eReferences please refer to: quality of evidence: imprecision]. Z Evid Fortbild Qual Gesundhwes www.aerzteblatt-international.de/ref0319 2012; 106: 677–88. 32. Benetos A, Labat C, Rossignol P, et al.: Treatment with multiple blood eMethods, eBoxes, eTables: pressure medications, achieved blood pressure, and mortality in older www.aerzteblatt-international.de/19m0023

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Supplementary material to: The Pharmacological Treatment of Arterial Hypertension in Frail, Older Patients A Systematic Review by Viktoria Mühlbauer, Dhayana Dallmeier, Simone Brefka, Claudia Bollig, Sebastian Voigt-Radloff, and Michael Denkinger

Dtsch Arztebl Int 2019; 116: 23–30. DOI: 10.3238/arztebl.2019.0023

eReferences e1. Ressing M, Blettner M, Klug SJ: Data analysis of epidemiological studies: part 11 of a series on evaluation of scientific publications. Dtsch Arztebl Int 2010; 107: 187–92. e2. van de Glind EMM, van Munster BC, Spijker R, Scholten RJPM, Hooft L. Search filters to identify geriatric medicine in Medline. J Am Med Inform Assoc JAMIA. 2012; 19: 468–72. e3. Higgins J, Green S, editors. Cochrane handbook for systematic reviews of interventions version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. http://handbook.cochrane.org. (last accessed on 6 Dez 2018) e4. BMJ Best Pracice: Study design search filters. http://bestpractice. bmj.com/info/toolkit/learn-ebm/study-design-search-filters/ (last accessed on 6 Dez 2018). e5. Sterne JA, Hernán MA, Reeves BC, Savovi J, Berkman ND, Viswanathan M, et al.: ROBINS-I: Atool for assessing risk of bias in non-randomised studies of interventions. BMJ 2016 ; 355: i4919. e6. Vandenbroucke JP, von Elm E, Altman DG, Gøtzsche PC, Mulrow CD, Pocock SJ, et al.: Strengthening the reporting of observational studies in epidemiology (STROBE): explanation and elaboration. PLoS Med 2007; 4(10): e297. e7. Jacobs JM, Cohen A, Bursztyn M, et al. Cohort profile: The Jerusa- lem Longitudinal Cohort Study. Int J Epidemiol 2009; 38:1464e1469. e8. Stessman J, Cohen A, Ginsberg GM et al. The Jerusalem 70-year- olds longitudinal study. I: Description of the initial cross sectional survey. European J Epidemiol 1995; 11: 675–84.

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he search strategy was based on a validated filter for geriatric patients (e2) and established search filters for ran - domized controlled trials (RCTs) (e3) and non-RCTs including observational studies (e4), supplemented with T further search terms related to functionality and hypertension (eBox 2). The search was carried out with no language restrictions of publication. In addition, the referen ce lists of national and international guidelines were hand- searched. Finally, a search was conducted for citations of the first and last author of all studies included for analysis over the whole period. The permitted comparisons were antihypertensive treatment versus placebo, no treatment, or other drug treatment. Comparisons of different target blood pressures were also included. Observational studies that exclu- sively investigated the measured blood pressure values as the exposure of interest were excluded. To optimize comparability of the estimation of functionality across various studies/indications, we analyzed all of the functionality scores (including a frailty index) used in studies and arranged them into a comparative system (13). The references were selected with the aid of Covidence, which is a screening software from the Cochrane Collaboration with various functions that accelerate the selection process. The studies chosen for full-text screening were those on pharmacological treatment of hypertension that referred to assessment of functionality in the abstract. The risk of bias was assessed by means of the Cochrane Risk of Bias Tool (e3) for RCTs. The non-RCTs were assessed for risk of bias according to ROBINS-I (e5) (eTable 4) and reported according to STROBE (e6) (eTable 5).

eBOX 1

Effect modification Effect modification is present when the influence of a factor (in our case the drug treatment of arterial hypertension) on an endpoint is modified by the presence of another factor, the so-called effect modifier (in our case physical frailty). One can also talk of an interaction between the exposure of interest and the effect modifier (e1). A question increasingly being asked in the field of clinical epidemiology is whether the effects of a treatment on various endpoints in elderly populations could be modified by frailty. There are several ways of investigating an interaction. First, one can test, in the statistical model, whether an interaction term, made up of the variable of interest and the possible effect modifier (interaction term = variable*effect modifier), is rel- evant. If the interaction is significant, the statistical model must contain the interaction term; this, however, complicates in- terpretation of the effects of the variable. Another way of investigating a possible interaction is to conduct stratified ana- lyses—stratified by the effect modifier (e.g., frail versus not frail). By this means the effects of the variable of interest on the various strata are calculated and contrasted. However, stratification reduces the number of observations per group (stra- tum), so the statistical power may be affected.

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eBOX 2a

Search strategies

MEDLINE search strategy RCTs 54. exp diabetes mellitus/ 1. elder*.ti,ab,kf. 55. or/45–54 2. (community adj1 dwelling).ti,ab,kf. 56. 44 not 55 3. geriatric.ti,ab,kf. 57. drug therapy/ or drug administration routes/ or drug adminis- 4. „mini-mental state“.ti,ab,kf. tration schedule/ or drug delivery systems/ or drug dosage cal- 5. alzheimer*.ti,ab,kf. culations/ or drug prescriptions/ or drug therapy, combination/ 6. mmse.ti,ab,kf. or drug therapy, computer-assisted/ or inappropriate prescrib - 7. caregiver*.ti,ab,kf. ing/ or medication errors/ or polypharmacy/ or self adminis- 8. falls.ti,ab,kf. tration/ or self medication/ 9. adl.ti,ab,kf. 58. „drug therap*“.ti,ab,kf,fs. 10. frail*.ti,ab,kf. 59. (pharmacotherap* or pharmaco-therap*).ti,ab,kf. 11. Gds.ti,ab,kf. 60. exp „antihypertensive agents“/ 12. Ag?ing.ti,ab,kf. 61. („antihypertensive agent*“ or „anti-hypertensive 13. Mci.ti,ab,kf. agent*“).ti,ab,kf. 14. dement*.ti,ab,kf. 62. drugs.ti,ab,kf. 15. (psycho-geriatric* or psychogeriatric*).ti,ab,kf. 63. medication.ti,ab,kf. 16. „cognitive impairment“.ti,ab,kf. 64. 57 or 58 or 59 or 60 or 61 or 62 or 63 17. „postmenopausal women“.ti,ab,kf. 65. 56 and 64 18. comorbid*.ti,ab,kf. 66. exp thiazides/ 19. exp Nursing Homes/ 67. exp sodium chloride symporter inhibitors/ 20. exp Geriatric Assessment/ 68. exp sodium potassium chloride symporter inhibitors/ 21. exp Frail Elderly/ 69. ((ceiling or loop) adj diuretic?).ti,ab,kf,nm. 22. Alzheimer Disease/ep 70. (amiloride or benzothiadiazine or bendroflumethiazide or 23. Cognition Disorders/di bumetanide or chlorothiazide or cyclopenthiazide or furo- 24. Cognition disorders/ep semide or hydrochlorothiazide or hydroflumethiazide or 25. exp Homes for the Aged/ methyclothi azide or metolazone or polythiazide or trichlor - 26. disability.ti,ab,kf. methiazide or veratide or quinethazone or clopamide or 27. „functional decline“.ti,ab,kf. mefruside or meticrane or clorexolon or fenquizone or 28. (gerontopsychiatry or geronto-psychiatry).ti,ab,kf. thiazide?).ti,ab,kf,nm. 29. „activities of daily living“.ti,ab,kf. 71. (chlorthalidone or chlortalidone or phthalamudine or chlorph- 30. immobility.ti,ab,kf. thalidolone or oxodoline or thalitone or hygroton or indapa - 31. „Activities of daily living“/ mide or metindamide or azosemide ortriamterene or 32. exp dementia/ torasemide or xipamide or piretanide).ti,ab,kf,nm. 33. immobilization.ti,ab,kf. 72. or/66–71 [THZ] 34. disabled persons/ or persons with hearing impairments/ or 73. exp angiotensin-converting enzyme inhibitors/ visually impaired persons/ 74. angiotensin converting enzyme inhibit$.ti,ab,kf,nm. 35. or/1–34 75. (ace adj3 inhibit$).ti,ab,kf,nm. 36. exp Hypertension/ 76. acei.ti,ab,kf,nm. 37. hypertens*.ti,ab,kf. 77. (alacepril or altiopril or ancovenin or benazepril or captopril 38. (essential adj3 hypertension).ti,ab,kf. or ceranapril or ceronapril or cilazapril or deacetylalacepril 39. (isolat* adj3 hypertension).ti,ab,kf. or delapril or derapril or enalapril or epicaptopril or fasidotril 40. (elevat* adj3 blood adj pressur*).ti,ab,kf. or fosinopril or foroxymithine or gemopatrilat or idapril or 41. (high adj3 blood adj pressur*).ti,ab,kf. imidapril or indolapril or libenzapril or lisinopril or moexipril 42. (increase* adj3 blood pressur*).ti,ab,kf. or moveltipril or omapatrilat or pentopril$ or perindopril$ 43. ((systolic or diastolic or arterial) adj3 pressur*).ti,ab,kf. or pivopril or quinapril$ or ramipril$ or rentiapril or saralasin 44. or/36–43 or s nitrosocaptopril or spirapril$ or temocapril$ or teprotide 45. exp pregnancy/ or trandolapril$ or utibapril$ or zabicipril$ or zofenopril$ 46. exp Hypertension, Pregnancy-Induced/ or Aceon or Accupril or Altace or Capoten or Lotensin 47. (pre-eclampsia or preeclampsia).ti,ab,kf. or Mavik or Monopril or Prinivil or Univas or Vasotec 48. exp Hypertension, Malignant/ or Zestril).ti,ab,kf,nm. 49. exp Hypertension, Portal/ 78. or/73–77 [ACEI] 50. exp Hypertension, Pulmonary/ 79. exp Angiotensin Receptor Antagonists/ 51. exp Hypertension, Renal/ 80. (angiotensin adj3 (receptor antagon$ or receptor 52. exp Intracranial Hypertension/ block$)).ti,ab,kf,nm. 53. exp Ocular Hypertension/ 81. arb?.ti,ab,kf,nm.

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82. (abitesartan or azilsartan or candesartan or elisartan or 95. (acebutolol or adimolol or afurolol or alprenolol or amosulalol embusartan or eprosartan or forasartan or irbesartan or losar- or arotinolol or atenolol or befunolol or betaxolol or bevantolol tan or milfasartan or olmesartan or saprisartan or tasosartan or bisoprolol or bopindolol or bornaprolol or brefonalol or or telmisartan or valsartan or zolasartan or aliskiren or Atac- bucindolol or bucumolol or bufetolol or bufuralol or bunitrolol and or Avapro or Benicar or Cozaar or Diovan or Micardis or or bunolol or bupranolol or butofilolol or butoxamine or Teveten).ti,ab,kf,nm. carazolol or carteolol or carvedilol or celiprolol or cetamolol or 83. or/79–82 [ARB] chlortalidone cloranolol or cyanoiodopindolol or cyanopindolol 84. exp calcium channel blockers/ or deacetylmetipranolol or diacetolol or dihydroalprenolol or 85. (amlodipine or aranidipine or barnidipine or bencyclane or dilevalol or epanolol or esmolol or exaprolol or falintolol or benidipine or bepridil or cilnidipine or cinnarizine or clentiazem flestolol or flusoxolol or hydroxybenzylpinodolol or or clevidipine or darodipine or diltiazem or efonidipine or el- hydroxycarteolol or hydroxymetoprolol or indenolol or godipine or etafenone or fantofarone or felodipine or fendiline iodocyanopindolol or iodopindolol or iprocrolol or isoxaprolol or flunarizine or gallopamil or isradipine or lacidipine or ler - or labetalol or landiolol or levobunolol or levomoprolol or canidipine or lidoflazine or lomerizine or manidipine or mibe- medroxalol or mepindolol or methylthiopropranolol or fradil or nicardipine or nifedipine or niguldipine or nilvadipine metipranolol or metoprolol or moprolol or nadolol or nebivolol or nimodipine or nisoldipine or nitrendipine or perhexiline or or oxprenolol or penbutolol or pindolol or nadolol or nebivolol prenyl amine or semotiadil or terodiline or tiapamil or verapamil or nifenalol or nipradilol or oxprenolol or pafenolol or pamatolol or Cardizem CD or Dilacor XR or Tiazac or Cardizem Calan or or penbutolol or pindolol or practolol or primidolol or prizidilol Isoptin or Calan SR or Isoptin SR Coer or Covera HS or or procinolol or pronetalol or propranolol or proxodolol or Verelan PM).ti,ab,kf,nm. ridazolol or salcardolol or soquinolol or sotalol or spirendolol 86. (calcium adj2 (antagonist? or block$ or inhibit$)).ti,ab,kf,nm. or talinolol or tertatolol or tienoxolol or tilisolol or timolol or 87. or/84–86 [CCB] tolamolol or toliprolol or tribendilol or xibenolol).ti,ab,kf,nm. 88. (methyldopa or alphamethyldopa or amodopa or dopamet or 96. (beta adj2 (adrenergic? or antagonist? or block$ or recep- dopegyt or dopegit or dopegite or emdopa or hyperpax or tor?)).ti,ab,kf,nm. hyperpaxa or methylpropionic acid or dopergit or meldopa or 97. or/94–96 [BB] methyldopate or medopa or medomet or sembrina or aldomet 98. exp adrenergic alpha antagonists/ or aldometil or aldomin or hydopa or methyldihydroxyphenylal - 99. (alfuzosin or bunazosin or doxazosin or metazosin or neldazo- anine or methyl dopa or mulfasin or presinol or presolisin or sin or prazosin or silodosin or tamsulosin or terazosin or tio- sedometil or sembrina or taquinil or dihydroxyphenylalanine or dazosin or trimazosin).ti,ab,kf,nm. methylphenylalanine or methylalanine or alpha methyl 100. (adrenergic adj2 (alpha or antagonist?)).ti,ab,kf,nm. d o p a ) . t i , a b , k f , n m . 101. ((adrenergic or alpha or receptor?) adj2 block$).ti,ab,kf,nm. 89. sympatholytics/ or bethanidine/ or butoxamine/ or clonidine/ or 102. or/98–101 [AB] debrisoquin/ or dibenzylchlorethamine/ or guanethidine/ or 103. 72 or 78 or 83 or 87 or 93 or 97 or 102 methyldopa/ or moxisylyte/ or oxidopamine/ 104. 65 or 103 90. (reserpine or serpentina or rauwolfia or serpasil).ti,ab,kf,nm. 105. randomized controlled trial.pt. 91. (clonidine or adesipress or arkamin or caprysin or catapres$ 106. controlled clinical trial.pt. or catasan or chlofazolin or chlophazolin or clinidine or 107. randomi#ed.ab. clofelin$ or clofenil or clomidine or clondine or clonistada or 108. placebo.ab. clonnirit or clophelin$ or dichlorophenylaminoimidazoline or 109. drug therapy.fs. dixarit or duraclon or gemiton or haemiton or hemiton or 110. randomly.ab. imidazoline or isoglaucon or klofelin or klofenil or m-5041t or 111. groups.ab. normopresan or paracefan or st-155 or st 155 or tesno 112. trial.ab. timelets).ti,ab,kf,nm. 113. exp animals/ not humans.sh. 92. exp hydralazine/ 114. 105 or 106 or 107 or 108 or 109 or 110 or 111 or 112 93. or/88–92 [CNS] 115. 114 not 113 94. exp adrenergic beta-antagonists/ 116. 35 and 104 and 115

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eBOX 2b

Search strategies

MEDLINE search strategy non-RCTs 54. exp diabetes mellitus/ 1. elder*.ti,ab,kf. 55. or/45–54 2. (community adj1 dwelling).ti,ab,kf. 56. 44 not 55 3. geriatric.ti,ab,kf. 57. drug therapy/ or drug administration routes/ or drug adminis- 4. „mini-mental state“.ti,ab,kf. tration schedule/ or drug delivery systems/ or drug dosage cal- 5. alzheimer*.ti,ab,kf. culations/ or drug prescriptions/ or drug therapy, combination/ 6. mmse.ti,ab,kf. or drug therapy, computer-assisted/ or inappropriate prescrib - 7. caregiver*.ti,ab,kf. ing/ or medication errors/ or polypharmacy/ or self adminis- 8. falls.ti,ab,kf. tration/ or self medication/ 9. adl.ti,ab,kf. 58. „drug therap*“.ti,ab,kf,fs. 10. frail*.ti,ab,kf. 59. (pharmacotherap* or pharmaco-therap*).ti,ab,kf. 11. Gds.ti,ab,kf. 60. exp „antihypertensive agents“/ 12. Ag?ing.ti,ab,kf. 61. („antihypertensive agent*“ or „anti-hypertensive 13. Mci.ti,ab,kf. agent*“).ti,ab,kf. 14. dement*.ti,ab,kf. 62. drugs.ti,ab,kf. 15. (psycho-geriatric* or psychogeriatric*).ti,ab,kf. 63. medication.ti,ab,kf. 16. „cognitive impairment“.ti,ab,kf. 64. 57 or 58 or 59 or 60 or 61 or 62 or 63 17. „postmenopausal women“.ti,ab,kf. 65. 56 and 64 18. comorbid*.ti,ab,kf. 66. exp thiazides/ 19. exp Nursing Homes/ 67. exp sodium chloride symporter inhibitors/ 20. exp Geriatric Assessment/ 68. exp sodium potassium chloride symporter inhibitors/ 21. exp Frail Elderly/ 69. ((ceiling or loop) adj diuretic?).ti,ab,kf,nm. 22. Alzheimer Disease/ep 70. (amiloride or benzothiadiazine or bendroflumethiazide or 23. Cognition Disorders/di bumetanide or chlorothiazide or cyclopenthiazide or furo- 24. Cognition disorders/ep semide or hydrochlorothiazide or hydroflumethiazide or 25. exp Homes for the Aged/ methyclothiazide or metolazone or polythiazide or 26. disability.ti,ab,kf. trichlormeth iazide or veratide or quinethazone or clopamide or 27. „functional decline“.ti,ab,kf. mefruside or meticrane or clorexolon or fenquizone or thia - 28. (gerontopsychiatry or geronto-psychiatry).ti,ab,kf. zide?).ti,ab,kf,nm. 29. „activities of daily living“.ti,ab,kf. 71. (chlorthalidone or chlortalidone or phthalamudine or chlorph- 30. immobility.ti,ab,kf. thalidolone or oxodoline or thalitone or hygroton or indapa - 31. „Activities of daily living“/ mide or metindamide or azosemide ortriamterene or 32. exp dementia/ tora semide or xipamide or piretanide).ti,ab,kf,nm. 33. immobilization.ti,ab,kf. 72. or/66–71 [THZ] 34. disabled persons/ or persons with hearing impairments/ or 73. exp angiotensin-converting enzyme inhibitors/ visually impaired persons/ 74. angiotensin converting enzyme inhibit$.ti,ab,kf,nm. 35. or/1–34 75. (ace adj3 inhibit$).ti,ab,kf,nm. 36. exp Hypertension/ 76. acei.ti,ab,kf,nm. 37. hypertens*.ti,ab,kf. 77. (alacepril or altiopril or ancovenin or benazepril or captopril or 38. (essential adj3 hypertension).ti,ab,kf. ceranapril or ceronapril or cilazapril or deacetylalacepril or 39. (isolat* adj3 hypertension).ti,ab,kf. delapril or derapril or enalapril or epicaptopril or fasidotril or 40. (elevat* adj3 blood adj pressur*).ti,ab,kf. fosinopril or foroxymithine or gemopatrilat or idapril or imidapril 41. (high adj3 blood adj pressur*).ti,ab,kf. or indolapril or libenzapril or lisinopril or moexipril or moveltipril 42. (increase* adj3 blood pressur*).ti,ab,kf. or omapatrilat or pentopril$ or perindopril$ or pivopril or quina- 43. ((systolic or diastolic or arterial) adj3 pressur*).ti,ab,kf. pril$ or ramipril$ or rentiapril or saralasin or s nitrosocaptopril 44. or/36–43 or spirapril$ or temocapril$ or teprotide or trandolapril$ or 45. exp pregnancy/ utibapril$ or zabicipril$ or zofenopril$ or Aceon or Accupril or 46. exp Hypertension, Pregnancy-Induced/ Altace or Capoten or Lotensin or Mavik or Monopril or Prinivil 47. (pre-eclampsia or preeclampsia).ti,ab,kf. or Univas or Vasotec or Zestril).ti,ab,kf,nm. 48. exp Hypertension, Malignant/ 78. or/73–77 [ACEI] 49. exp Hypertension, Portal/ 79. exp Angiotensin Receptor Antagonists/ 50. exp Hypertension, Pulmonary/ 80. (angiotensin adj3 (receptor antagon$ or receptor 51. exp Hypertension, Renal/ block$)).ti,ab,kf,nm. 52. exp Intracranial Hypertension/ 81. arb?.ti,ab,kf,nm. 53. exp Ocular Hypertension/ 82. (abitesartan or azilsartan or candesartan or elisartan or

Deutsches Ärzteblatt International | Dtsch Arztebl Int 2019; 116: 23–30 | Supplementary material V MEDICINE

embusartan or eprosartan or forasartan or irbesartan or 93. or/88–92 [CNS] losartan or milfasartan or olmesartan or saprisartan or taso- 94. exp adrenergic beta-antagonists/ sartan or telmisartan or valsartan or zolasartan or aliskiren or 95. (acebutolol or adimolol or afurolol or alprenolol or amosulalol Atacand or Avapro or Benicar or Cozaar or Diovan or Micardis or arotinolol or atenolol or befunolol or betaxolol or bevantolol or Teveten).ti,ab,kf,nm. or bisoprolol or bopindolol or bornaprolol or brefonalol or bu- 83. or/79–82 [ARB] cindolol or bucumolol or bufetolol or bufuralol or bunitrolol or 84. exp calcium channel blockers/ bunolol or bupranolol or butofilolol or butoxamine or carazolol 85. (amlodipine or aranidipine or barnidipine or bencyclane or or carteolol or carvedilol or celiprolol or cetamolol or chlortali- benidipine or bepridil or cilnidipine or cinnarizine or clentiazem done cloranolol or cyanoiodopindolol or cyanopindolol or or clevidipine or darodipine or diltiazem or efonidipine or deacetylmetipranolol or diacetolol or dihydroalprenolol or elgodipine or etafenone or fantofarone or felodipine or dilevalol or epanolol or esmolol or exaprolol or falintolol or fendiline or flunarizine or gallopamil or isradipine or lacidipine flestolol or flusoxolol or hydroxybenzylpinodolol or hydroxy - or lercani dipine or lidoflazine or lomerizine or manidipine or carteolol or hydroxymetoprolol or indenolol or iodocyanopindo- mibefradil or nicardipine or nifedipine or niguldipine or nilvadi- lol or iodopindolol or iprocrolol or isoxaprolol or labetalol or pine or nimodipine or nisoldipine or nitrendipine or perhexiline landiolol or levobunolol or levomoprolol or medroxalol or me- or prenylamine or semotiadil or terodiline or tiapamil or ver- pindolol or methylthiopropranolol or metipranolol or metoprolol apamil or Cardizem CD or Dilacor XR or Tiazac or Cardizem or moprolol or nadolol or nebivolol or oxprenolol or penbutolol Calan or Isoptin or Calan SR or Isoptin SR Coer or Covera HS or pindolol or nadolol or nebivolol or nifenalol or nipradilol or or Verelan PM).ti,ab,kf,nm. oxprenolol or pafenolol or pamatolol or penbutolol or pindolol 86. (calcium adj2 (antagonist? or block$ or inhibit$)).ti,ab,kf,nm. or practolol or primidolol or prizidilol or procinolol or pronetalol 87. or/84–86 [CCB] or propranolol or proxodolol or ridazolol or salcardolol or 88. (methyldopa or alphamethyldopa or amodopa or dopamet or soquinolol or sotalol or spirendolol or talinolol or tertatolol or dopegyt or dopegit or dopegite or emdopa or hyperpax or tienoxolol or tilisolol or timolol or tolamolol or toliprolol or hyperpaxa or methylpropionic acid or dopergit or meldopa or tribendilol or xibenolol).ti,ab,kf,nm. methyldopate or medopa or medomet or sembrina or aldomet 96. (beta adj2 (adrenergic? or antagonist? or block$ or recep- or aldometil or aldomin or hydopa or methyldihydroxyphenylal- tor?)).ti,ab,kf,nm. anine or methyl dopa or mulfasin or presinol or presolisin or 97. or/94–96 [BB] sedometil or sembrina or taquinil or dihydroxyphenylalanine or 98. exp adrenergic alpha antagonists/ methylphenylalanine or methylalanine or alpha methyl 99. (alfuzosin or bunazosin or doxazosin or metazosin or neldazo- d o p a ) . t i , a b , k f , n m . sin or prazosin or silodosin or tamsulosin or terazosin or tio- 89. sympatholytics/ or bethanidine/ or butoxamine/ or clonidine/ or dazosin or trimazosin).ti,ab,kf,nm. debrisoquin/ or dibenzylchlorethamine/ or guanethidine/ or 100. (adrenergic adj2 (alpha or antagonist?)).ti,ab,kf,nm. methyldopa/ or moxisylyte/ or oxidopamine/ 101. ((adrenergic or alpha or receptor?) adj2 block$).ti,ab,kf,nm. 90. (reserpine or serpentina or rauwolfia or serpasil).ti,ab,kf,nm. 102. or/98–101 [AB] 91. (clonidine or adesipress or arkamin or caprysin or catapres$ 103. 72 or 78 or 83 or 87 or 93 or 97 or 102 or catasan or chlofazolin or chlophazolin or clinidine or 104. 65 or 103 clofelin$ or clofenil or clomidine or clondine or clonistada or 105. exp cohort studies/ clonnirit or clophelin$ or dichlorophenylaminoimidazoline or 106. cohort$.tw. dixarit or duraclon or gemiton or haemiton or hemiton or 107. controlled clinical trial.pt. imidazoline or isoglaucon or klofelin or klofenil or m-5041t or 108. epidemiologic methods/ normopresan or paracefan or st-155 or st 155 or tesno 109. limit 108 to yr=1971–1988 timelets).ti,ab,kf,nm. 110. or/105–107,109 92. exp hydralazine/ 111. 35 and 104 and 110

VI Deutsches Ärzteblatt International | Dtsch Arztebl Int 2019; 116: 23–30 | Supplementary material MEDICINE 0.10 0.08 0.08 0.04 0.48 interaction P value for Overall mortality 0.89 [0.63; 1.25] 0.84 [0.66; 1.07] 0.80 [0.61; 1.04] 0.76 [0.50; 1.14] 0.72 [0.40; 1.29] 0.68 [0.32; 1.48] 1.22 [0.79; 1.88] [0.79; 1.22 2.28] [0.71; 1.27 2.89] [0.54; 1.25 2.00] [0.87; 1.32 1.46] [0.44; 0.80 Limited physical function* physical Limited 0.09 [–0.21; 0.40] [–0.21; 0.09 –0.07 [–0.36; 0.22] [–0.36; –0.07 0.62 [0.42; 0.92] 0.60 [0.45; 0.78] 0.57 [0.42; 0.79] 0.55 [0.34; 0.89] 0.50 [0.20; 1.27] 0.53I [0.26; 1.06] [0.26; 0.53I No effect, regardless offunctionality regardless effect, No Cardiovascular events Cardiovascular Results Change in overall cognitive compound score cognitive in Changeoverall 0.82 [0.66; 1.00] [0.66; 0.82 0.98] [0.51; 0.71 0.81] [0.40; 0.57 0.99] [0.66; 0.81 0.85] [0.49; 0.64 No limited physical function* physical limited No Stroke No significant difference in average increase of FI over 24 months (p = 0.06): 0.06): months = (p over FI24 of average increase in difference significant No 0.75 [0.40; 1.38] [0.40; 0.75 0 . 6 6 [ 00.96] .[0.36; 0.59 4 3 ; 1 .1.09] 0[0.25; 0.52 1 ] 1.33] [0.16; 0.47 1.65] [0.10; 0.41 22 ≤ intervention group HR 0.79; 95% CI [0.26; 1.32] versus placebo group HR 1.53; 95% CI [0.97; 2.10] Falls Stroke Mortality Endpoint GARSscore>22 GARSscore FI Myocardial infarction Myocardial Cardiovascular Cardiovascular death 0.1 0.2 0.3 0.4 0.5 0.6 Symptomatic hypotension Symptomatic Effect of treatmentEffect with perindopril compared with placebo DBP and baselineSBP *Adjustedage,for sex, ethnicity, 2011–2013, Netherlands (hazard ratio 2011–2013, [95% CI]) 1984–1996, USA (hazard ratio 1984–1996, [95% CI]) USA Parameters of functionality (Rockwood): FI Median Placebo group 0.17 0.24] [0.11; Intervention group 0.16 0.24] [0.11; FI (Rockwood) Activity RestrictionScale Groningen (GARS): group (IQRintervention 23 (IQR 22 group control ; 18–28) 19–29) Self-reporting of limited physical function (response “no” to at least without you, ”Can question: one assistance: two up walk [b] house? the around flights of stairs? [c] walk half a [a] mile?”). do 545 in function physical Limited heavy p a twork i e n t s ( 1 1 . 9 % ) 2000–2008, Europa, China, Australasia, Tunisia (hazard ratio [95% CI]) [95% ratio (hazard Tunisia Australasia, China, Europa, 2000–2008, 75 years ≥ 60 years on the endpoints endpoints the on years 60 ≥ 80 years with systolic blood pressure ≥ Study question/Population/Endpoints (HYVET), Trial Elderly the in Very HYpertension of the Effect combination of slow-release indapa- in placebo or mg 2–4 perindopril ± mg 1.5 mide patients of the Effect above treatment on “frailty” (change in FI over period of 24 months) (n = 1665) (17) inElderly People (DANTE), AntihypertensiveTreatment Discontinuation of of short-termEffect discontinuation of antihyper- tensive treatment on cognitive, psychological and participants in functionality general with cognitive mild deficits (n= (18)385) Systolic Hypertension in the Elderly Program (SHEP), Influence of functional status on theof efficacy ± (chlorthalidone treatment antihypertensive atenolol)- myo death, cardiovascular mortality, all-cause symptomatic and falls, stroke, infarction, cardial in patients(19) 4593) = (n hypotension of 160of ormmHg onmore theendpoints stroke, and cardiovascular events (stroke,total mortality, myocardialinfarction, heartand failure) (n= 2656) (16) eTABLE 1a analysis for ofCharacteristics included trials randomized the

Deutsches Ärzteblatt International | Dtsch Arztebl Int 2019; 116: 23–30 | Supplementary material VII MEDICINE 0.84 0.91 interaction P value for P value for i n t e r a c t i o n 0.74 [0.54; 1.04] 0.56 [0.29; 1.07] Based on gait speed gait on Based 0.68 0.63 0.47 [0.45; 1.01] [0.43; 0.91] [ 0.13; 1.39] 0.002 0.001 0.077 0.077 − − MCS score MCS [–0.122; 0.276] –[0.160; –[0.160; 0.156] [–0.281; 0.279] 0.21) ≤ 0.10 Fit: ≤ Frail: Less fit: fit: Less FI >0.21 0.49 FI i n t e r a c t i o n P value for 0.62 [0.43; 0.90] 0.82 [0.52; 1.28] (0.100.21) Frail 0.8 m/s 0.8 <0.8 <0.8 m/s ≥ Intensive treatment versus standard treatment for primary endpoint Intensive treatment versus standard treatment Intensive treatment versus standard treatment (difference) Less fit (0.10< FI (0.10< fit Less SBP, systolic blood pressure; DBP, diastolic blood pressure; RAND, Research and Development systolicblood pressure; DBP, SBP,

2010–2016, USA (hazard ratio 2010–2016,[95% CI]) USA Parameters of functionality Gaitspeed:<0.8m/s, (28.1%) patients 740 FI (Rockwood): >0.21,815 patients (30.9%) Gait speed self-reported and mobility:(18%) patients limitations inFI (Rockwood): 464 2560 frail as patients (27.3%) characterized 50 ≥ 75 years ≥ 75 years with data on mobility mobility on data with years 75 ≥ Study question/Population/Endpoints Systolic (SPRINT), Blood Pressure Intervention Trial intensive blood pressure-lowering treat- of Effect standard with compared mmHg) (<120 ment treatment (<140 mmHg) on the primary endpoint (myocardialinfarction, coronary syndrome, from death failure, heart decompensated stroke, patients in events) cardiovascular (n= 2636) (14) (see blood pressure-lowering treatment of Effect mobility and speed gait on above) in patients (n= 2629) (15) (see blood pressure-lowering treatment of Effect health-rel- mental and (PCS) physical on above) Veterans the by measured as life of quality evant in patients Survey Health RAND 12-Item (23) 9361) = (n years FI, Frailty index; HR, hazard ratio; 95% CI, 95% confidence interval; IQR, interquartile range; interquartile IQR, interval; confidence 95% CI, 95% ratio; hazard HR, index; Frailty FI,

VIII Deutsches Ärzteblatt International | Dtsch Arztebl Int 2019; 116: 23–30 | Supplementary material MEDICINE 2 1 ADL* 1 ≥ 1 Reference 1 l o w e r i n g t r e a t m e n t Dependence in Dependence Intensive blood pressure- HR 0.93; 95% CI [0.35; 2.42] [0.35; CI 95% 0.93; HR 2.80] [0.67; CI 95% 1.37; HR 1.59] [0.76; CI 95% 1.10; HR 5.29] [1.01; CI 95% 2.31; HR Risk of repeated falls* repeated of Risk HR 0.61; 95% CI [0.35; 1.06] [0.35; CI 95% 0.61; HR 1.74] 0.56; CI[ 95% 0.99; HR 1 Results Risk of severe injuries over period* over 3-year of injuries severe Risk Reference Lowgripstrength* HR 1.75; 95% CI [0.78; 3.92] [0.78; CI 95% 1.75; HR 1.73] [0.89; CI 95% 1.2;4 HR 4.80] [0.98; CI 95% 2.17; HR HR 0.90; 95 % CI [0.31; 2.67] [0.31; CI 95 % HR 0.90; Moderate blood pressure-lowering treatment pressure-lowering blood Moderate 1.17 m/s 1.17 < 1.17 m/s 1.17 < ≥ Gaitspeed Yes (n = 503) No(n= 4621) Normotensive Fall previous in yearFall depression, ADL difficulty - cerebro use, alcohol status, marital age, education, falls, of risk increase that drugs hypertension, self-reported vascular disease,diabetes, disease,pulmonary arthritis,urinary problems,vision problems, total number pre-of syncope. medications, scription vision severe impairment, cognitive depression, disease, Parkinson osteoporosis, obesity, walking, difficulty impairment, measured pressure blood and health, self-perceived medications, non-antihypertensive of number use, statin past6months. the within physical function score, prior myocardial infarction, prior stroke, heart failure, diabetes, psychosis, Treated hypertension Adjusted for sex, education, self-rated health, ischemic heart disease, diabetes, chronic kidney disease, depression, ADL difficulty, grip strength. Adjusted for sex, education, self-rated health, ischemic heart disease, diabetes, chronic kidney disease, Adjusted for study site, heart failure, benign prostatic hyperplasia, cognitive impairment, depressive symptoms, Adjusted for year of study entry, propensity score, age, sex, fall injury in past year, use of an assistive device, Untreated hypertension hypertension Untreated 1 2 1 1 * * * * io 95% CI, 95% confidence interval 95% CI,95% confidence io 1 ADL in 194 participantsADL 1 ≥ Parameters of functionality (menkg, <26 strength Reduced grip (31.0%). 149participants kg)in <16 women in Dependence Gait speed comparedwith medianat baseline m/s 1.17 previousFalls in 503 in year participants (10.1%). ADLs: Basic and instrumental 1919(38.7%) restrictedat in BADL,one least2791 (56.3%) least at in IADL one (40.4%) since 1997 (survey (hazard period ratio 1997–2014),[95% CI]) USA 70 ≥ 2004–2009, USA (hazard ratio 2004–2009,[95% CI]) USA since 1990 (survey period 2010–2011), Israel (hazard ratio [95% CI]) [95% ratio (hazard Israel 2010–2011), period (survey 1990 since 90 years (n = 480) (22) in patients >70 years who had

≥ Study question/Population/Endpoints Study, Longitudinal Jerusalem and participants normotensive of Correlation treated or untreated hypertension with activities of mortal- 5-year and strength, grip (ADL), living daily ity in participants BodyComposition Aging, Study, and Health, Association of antihypertensive medication use falls with recurrent (21) 2948) = (n baseline at limitations functional no Survey, Beneficiary Current Medicare antihypertensive medication with Association of severe injury from falls in Medicare patients years with hypertension and data available on on available data and hypertension with years (20) 4961) = (n years 3 previous in medication eTABLE 1b analysis for ofCharacteristics included controlledtrials non-randomized the DL, Activities ofdaily life;BADL,basic activities of dailylife; instrumentalIADL, activities of daily DL, life;HR, hazard rat A

Deutsches Ärzteblatt International | Dtsch Arztebl Int 2019; 116: 23–30 | Supplementary material IX MEDICINE r e p o r t s Selective outcome outcome Selective Incomplete outcome data outcome Incomplete assessment Blinding of outcome Blinding of p e r s o n n e l Blinding of participantsand Blinding of Allocation Allocation concealment Random sequence generation sequence Random High risk of bias. of risk High

Unclearrisk ofbias.

Authors Warwick et al. 2015 (16) Beckett et al. 2015 (17) (18) 2015 al. et Moonen (19) et 2016 al. Charlesworth Williamson et al. 2016 (14) Oddenet 2017 al. (15) Berlowitz et al. 2017 (23) Trial HYVET DANTE SHEP SPRINT Low risk of bias. bias. of risk Low eTABLE 2 analysisof for Assessment included controlled trials randomized the in bias

X Deutsches Ärzteblatt International | Dtsch Arztebl Int 2019; 116: 23–30 | Supplementary material MEDICINE Functionality docu- mented/addressed? No No No Yes No No No No No No No No No No No Yes No No No No Yes th lic lic or - th th

80 mmHg) and cardio - 80 mmHg) and cardio ≤ 85, 85, ≤ 90, ≤ vascular morbidity and mortality as well as the effect of low-dose ASS (75 mg/d) on morbidity and mortality. and morbidity on mg/d) (75 ASS low-dose of effect the as well as mortality and morbidity vascular Study question What isof the antihypertensive effect treatment in older persons aged 60 years and over? and disease, coronaryheart stroke, of rates the influence 79 years 60 to aged in patients treatment Does antihypertensive m o r t a l iwi patients older death in disease, and heart coronary of stroke, risk the reduce beta-blocker or diuretic a with Can treatment t y ? hypertension? systolic hypertension? isolated with in patients stroke and non-fatal fatal the of lower risk treatment Does antihypertensive Are beta-blockers and diuretics better than placebo for decreasing the rates of stroke, myocardial infarction, and other cardio years? 70–84 aged patients in endpoints vascular This trial investigated the relationships between three diastolic blood pressure levels ( Are drugs such as amlodipine, lisinopril, and doxazosine better than chlorthalidone for reducing the rate and speed of progressionsysto isolated with patients in cardiovascular complications other strokeand the of lower risk treatment Does antihypertensive hypertension? of coronarysysto isolated with patients in cardiovascular complications other strokeand the of lower risk treatment Does antihypertensive hypertension? heartACE Whatinhibitor isof the long-termon effect the rate treatment of stroke with in patientsan who have already had a stroke disease?TIA? a The influence of treatment myocardial with infarction, verapamil or and strokeatenolol in patientson mortality, with coronary hypertension and disease heart wi patients in older dementia or deficit, cognitive cardiovascularevents, of rate decrease the candesartan with Does treatment hypertension? moderate or mild What isof the atenolol effect + thiazide compared with amlodipine + perindopril on the rates von myocardial infarction and coronaryWhat isof the a combination effect of a low-dose diuretic and a low-dose calcium antagonist compared with monotherapy with a heartpatients? Chinese in events cardiovascular other and stroke of rates the on diuretic low-dose a disease?diabetics mmHg) in (<140 treatment and standard (<120 mmHg) treatment blood pressure-lowering intensive of Comparison of treatmentEffect with indapamide ± perindopril or placebo on the endpoints stroke, cardiovascular events, and mortality in patients pressure 140 (systolic blood treatment moderate mmHg) and blood pressure <140 (systolic treatment intensive of Comparison agedrenal failure to 160 mmHg) on the endpoints stroke, cardiovascular events, and 80 years and safetyEfficacy of a fixed combination of perindopril and indapamide for lowering the blood pressure of patients with diabetesand overIs intensive treatment (systolic blood pressure <140 mmHg) superior to moderate treatment (systolic blood pressure 140–<150 mellituswith hypertension? systolic isolated with patients older in mortality cardiovascular reducing for mmHg) systolic<140 blood pressure (systolic treatment mmHg)andstandard blood pressure <130 (systolic treatment intensive of Comparison typenon-diabetics in hypertrophy ventricular left on mmHg) 2blood in in of intensiveEffect blood pressure-lowering treatment (<120 mmHg) compared with standard treatment (<140 mmHg) on the pressure the mortality and events, cardiovascular infarction, myocardial endpoints age ofgroups 160 mmHgbelow or 65, higher 65 to 74, and 75 years or older Name of RCT, beginning of study RCT, Name of EWPHE (European Party onWorking High Blood Pressure in the Elderly) 1972 HEP Hypertensionof in PatientsElderly Primary in Care) 1978 (Trial Hyperten- of Treatment of Trial Council Research (Medical MRC 1981 Adults) Older in sion (SystolicSHEP Hypertension in the Elderly Program) 1984 in Old Patients with Hypertension)Trial (Swedish 1985 STOP 1992 Treatment) Optimal (Hypertension HOT (Antihypertensive to and Treatment Lipid Lowering ALLHAT PreventSyst-China (Systolic Hypertension in China) 1988 Heart AttackSyst-Eur (Systolic Hypertension in Europe) 1989 Trial) 1993Against RecurrentPROGRESS Stroke (Perindopril Protection Study) 1995 Study)Trandolapril 1997 (InternationalINVEST Verapamil/ SCOPE (Study on Cognition and Prognosis in the Elderly) 1997 (Anglo-Scandinavian Cardiac OutcomesASCOT–BPLA Trial–Blood Pressure LoweringArm) 1998 FEVER (Felodipine Event Reduction Study) 1998 ACCORD (Action to Control Cardiovascular Risk in Diabetes Blood Pressure) 1999 2000 Trial) Elderly (Hypertension theVery in HYVET - Pres Blood Systolic Optimal Assess to Trial (Japanese JATOS sure theElderly) in 2001 Disease: preterAx (Action in Diabetes and Vascular ADVANCE DiamicroN-MRand Controlled Evaluation) 2001 VALISH (Valsartan in2003 Elderly Isolated SystolicSystolic of Effects Cardiovascular the Study on (Italian Cardio-Sis Hypertension)Blood Pressure Control) 2005 2010 Trial) (Systolic Blood PressureIntervention SPRINT eTABLE 3 Overview of ofavailability parameters functional in large controlledarterial on randomized trials hypertension age old in

Deutsches Ärzteblatt International | Dtsch Arztebl Int 2019; 116: 23–30 | Supplementary material XI MEDICINE

eTABLE 4a

Risk of bias assessment (systematic errors) by ROBINS-I

Stessman et al. 2017, Jerusalem Longitudinal Study (22) Bias due to confounding Moderate Bias in selection of participants into the study Low Bias due to the classification of interventions Low Bias due to deviations from intended interventions Low Bias due to missing data Moderate Bias in measurement of outcomes Low Bias due selection in reporting of the result Low Overall bias Moderate

eTABLE 4b

Risk of bias assessment (systematic errors) by ROBINS-I

Marcum et al. 2015, Health, Aging and Body Composition Study (Health ABC) (21) Bias due to confounding Moderate Bias in selection of participants into the study Low Bias due to the classification of interventions Low Bias due to deviations from intended interventions Moderate Bias due to missing data Moderate Bias in measurement of outcomes Low Bias due selection in reporting of the result Low Overall bias Moderate

eTABLE 4c

Risk of bias assessment (systematic errors) by ROBINS-I

Tinetti et al. 2014, Medicare Current Beneficiary Survey (20) Bias due to confounding High Bias in selection of participants into the study Low Bias due to the classification of interventions Low Bias due to deviations from intended interventions Not specified Bias due to missing data Low Bias in measurement of outcomes Low Bias due selection in reporting of the result Low Overall bias High

XII Deutsches Ärzteblatt International | Dtsch Arztebl Int 2019; 116: 23–30 | Supplementary material MEDICINE

eTABLE 5a

STROBE Statement—checklist of items for reports of observational studies

Stessman et al. 2017, Jerusalem Longitudinal Study (22) STROBE checklist Page (p.) in Stessman et al. 2017 (22) Title and abstract Title and abstract p. 277.e13 Abstract Introduction Background/rationale p. 277.e14 Objectives p. 277.e14 Methods Study design p. 277.e14 Study population Setting p. 277.e14 Study population Participants p. 277.e14 Study population Variables p. 277.e14 Measurements Data sources/measurement p. 277.e14 Blood pressure measurement and hypertension diagnosis Bias p. 277.e14 Study population Study size Stessman 1995: The Jerusalem seventy year olds longitudinal study; p. 677 Quantitative variables p. 277.e14 Measurements p. 277.e14 Blood pressure measurement and hypertension diagnosis Statistical methods p. 277.e14–p. 277.e15 Statistical analyses Results Participants Phase I-III: Jacobs et al. 2009 (e7), p. 1464 Phase IV: p. 277 e15 Study population Descriptive data p. 277.e15 Table 1 p. 277.e18 Table 3 Outcome data p. 277.e16 Figure 1 Main results p. 277.e16 Table 2 Other analyses p. 277.e16 Table 2 Discussion Key results p. 277.e15–p. 277.e16 Limitations p. 277.e16 Strengths and weaknesses of this study Interpretation p. 277.e18 Comparison with other studies Generalizability p. 277.e19 Conclusions and implications Other information Funding Jacobs 2009 (e7), p. 1468 Stessman 1995 (e8), p. 683

The references in bold type can be found in the reference lists of this article; the remaining citations refer to page numbers in the article by Stessman, where e14 is the first page and e19 the last page of the article.

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eTABLE 5b

STROBE Statement—checklist of items for reports of observational studies

Marcum et al. 2015, Health, Aging and Body Composition Study (Health ABC) (21) STROBE checklist Page (p.) in Marcum et al. 2015 (21) Title and abstract Title and abstract p.1562 Abstract Introduction Background/rationale p.1563 Objectives p.1563 Methods Study design p.1563 Study design, data source, and sample Setting p.1563 Study design, data source, and sample Participants p.1563 Study design, data source, and sample, p.1565 Table 1 Variables p.1563 Methods Data sources/measurement p.1563 Methods Bias p.1563 Control variables, p.1564 Statistical analysis Study size p.1563 Study design, data source, and sample Quantitative variables p.1563 Primary independent variables, Control variables Statistical methods p.1563 Statistical analysis Results Participants p.1564 Results, p.1565 Table 1 Descriptive data p.1565 Table 1 Outcome data p.1566 Tables 2–4 Main results p.1566 Table 4 Other analyses p.1564 Results Discussion Key results p.1564–1565 Discussion Limitations p.1567 Interpretation p.1564–1567 Generalizability p.1566–1567 Other information Funding National Institute on Aging, Intramural Research Program of the National Institutes of Health, National Institute of Nursing

The references in bold type can be found in the reference lists of this article; the remaining citations refer to page numbers in the article by Marcum et al.

XIV Deutsches Ärzteblatt International | Dtsch Arztebl Int 2019; 116: 23–30 | Supplementary material MEDICINE

eTABLE 5c

STROBE Statement—checklist of items for reports of observational studies

Tinetti et al. 2014, Medicare Current Beneficiary Survey (20) STROBE checklist Page (p.) in Tinetti et al. 2014 (20) Title and abstract Title and abstract p. 588 Abstract Introduction Background/rationale p. 589 Objectives p. 589 Methods Study design p. 588 Design, participants, and setting Setting p. 589 Study design and sample Participants p. 589 Study design and sample, p. 591 Variables p. 590 Statistical analysis Data sources/measurement p. 589 Methods Bias p. 590 Statistical analysis Study size p. 589 Study design and sample Quantitative variables p. 589 Medication data Statistical methods p. 590 Statistical analysis Results Participants p. 590 Results Descriptive data p. 591 Table 1 Outcome data p. 592, Table 2, p. 593 Figure Main results p. 592 Table 2 Other analyses p. 593 Figure Discussion Key results p. 592 Table 2 Limitations p. 593–594 Interpretation p. 592–594 Generalizability p. 594 Other information Funding Unclear

The references in bold type can be found in the reference lists of this article; the remaining citations refer to page numbers in the article by Tinetti et al.

Deutsches Ärzteblatt International | Dtsch Arztebl Int 2019; 116: 23–30 | Supplementary material XV