Structured abstract
Purpose of Review:
We sought to summarize recent evidence regarding optimal blood pressure (BP) treatment targets and antihypertensive regimen intensity for nursing home (NH) residents and similar older, complex patients with hypertension.
Recent Findings:
Recent trials have demonstrated cardiovascular benefits from more intensive BP targets among ambulatory, less complex older adults, but generalizability to NH residents is questionable. Other trials have demonstrated that de-intensifying antihypertensives in frail, older patients is feasible, with no or modest increases in BP, but most have not assessed effects on patient-centered outcomes. Observational studies with patients more representative of NH residents suggest harms associated with more intensive BP treatment and reduction in fall risk associated with de-intensification, but findings and potential for bias vary across studies.
Summary:
Randomized trials and rigorous observational studies examining effects of de-intensified BP management on patient-centered outcomes in complex, older populations are needed to inform improved guidelines and treatment for NH residents.
Keywords: nursing homes, hypertension, antihypertensives, deprescribing, older adults, frailty
Introduction
By the year 2050, the number of adults age 65 and older in the United States is projected to nearly double, and the number of adults 85 years or older is expected to triple [1]. With the growing number of older adults, an estimated 27 million adults will receive nursing home (NH) or home-based services by 2050 [2]. As a result, there is a critical need for guidance in managing chronic diseases, such as hypertension, in the NH population [1–3]. Hypertension is extremely common among NH residents, with prevalence ranging from 72% to 90% worldwide [1,4–6]. Further, the majority of all NH residents are treated with at least one antihypertensive agent, and a substantial proportion of NH residents diagnosed with hypertension concurrently use multiple agents [4,5,7–10].
NH residents with hypertension represent a complex population that may require blood pressure (BP) targets and medication regimens that are tailored to their unique needs. On one hand, they are likely to have multiple comorbidities, including conditions that increase cardiovascular (CV) risk (e.g., diabetes or renal disease) as well as other cardiovascular conditions that are treated with antihypertensives (e.g., heart failure, atrial fibrillation, angina, stroke) [11,12]. Due to these indications, this population may potentially benefit from more intensive BP control to reduce CV risk [13–18]. On the other hand, frailty, fall risk, cognitive impairment, and polypharmacy (i.e., high medication burden) are major concerns among NH residents [17,19]. Intensive treatment with antihypertensives can exacerbate risk of falls, orthostasis, and adverse drug reactions in these patients [17,19]. This may be especially true in NH residents approaching the end of life, in whom a palliative care approach to medication management has been recommended [20]. Such an approach recognizes that as remaining life expectancy and time available to experience long-term benefits of medications decrease, goals of treatment should shift from curative or preventive to palliative, with a greater emphasis on avoiding short-term problems, including medication adverse events. In turn, less aggressive BP treatment targets may be appropriate, requiring a reduction in the number and/or dose of antihypertensives used [11].
Optimal treatment targets and medication management of hypertension in NH residents have not been well addressed in clinical practice guidelines and research. In this narrative review, we aimed to summarize and critically evaluate the quality of recent evidence on optimal BP targets and antihypertensive treatment approaches in NH residents specifically, as well as populations commonly represented in the NH with hypertension, i.e., older adults who are frail, have cognitive and functional impairments, and/or are nearing the end of life. We limited our review to publications within the last five years, with the exception of landmark clinical trials. We ordered our review by evidence type, including clinical practice guidelines, randomized controlled trials (RCTs), and observational studies. We summarized findings from primary literature using the PICO framework: population, interventions, comparators, and outcomes [21]. Specifically, we described groups of older adults (60 years or older with special attention given to patients in the “oldest old” age groups), with frailty, high-fall risk, cognitive impairment, cardiovascular comorbidities, and/or limited life expectancy. We defined interventions as specific BP targets (e.g. more intensive vs. less intensive control) and/or antihypertensive medication regimens (e.g., number or type of agents used; intensification or deintensification of medications). Additionally, we examined both cardiovascular and non-cardiovascular outcomes and described both benefits and risks of these treatments for hypertension. In conducting this review, our goal is to identify key gaps in evidence and define research priorities to help improve guidelines and care for NH residents with hypertension.
Evidence review
Clinical Practice Guidelines
Since the publication of results of the SPRINT trial showing cardiovascular benefits of more intensive BP control in ambulatory older adults (Table 1, and discussed in more detail below), there has been a paradigm shift in hypertension management guidelines from less intensive [13] to more intensive BP targets for older adults. Specifically, the 2017 AHA/ACC guidelines support a target of <130/80 mmHg for ambulatory adults age 65 or older [22], a revision from their earlier 2013 guidelines recommending a BP target of <140/90 mmHg. These same guidelines avoid stating a specific target BP range for adults 65 years or older with multiple comorbidities and limited life expectancy, instead recommending that treatment decisions be based on patient risks/benefits as determined by expert consensus, clinical judgment, patient preferences, and a team-based approach [22]. In adults 65 to 80 years old, the 2018 European Society of Cardiology (ESC)/European Society for Hypertension (ESH) guidelines recommend a systolic blood pressure (SBP) of 130–139 mmHg (with a diastolic target of <80 mmHg) [15]. These guidelines emphasize that age alone is not a basis for less intensive targets and stress the importance of close monitoring for those who are very old, frail, or have multiple comorbidities. For frail adults, ESC/ESH guidelines recommend considering antihypertensive monotherapy over combination therapy. Recent Canadian guidelines published in 2017 advocate a SBP target of <120 mmHg for adults who are age 75+, have cardiovascular disease, and/or are at high risk for cardiovascular disease [16]. In this update, the guidelines removed frailty as a factor for target modification, based on the SPRINT trial [16,18]. However, they caution generalizing this target to NH residents, due to limited evidence, and do not recommend this target for patients with high medication burden.
Table 1.
Evidence from randomized controlled trials (RCTs) on blood pressure (BP) treatment targets and antihypertensive management.
Trial name (Authors, year) | Sample description (N, age range, setting) | Intervention and Comparator(s) | Outcomes | Summary of Results |
---|---|---|---|---|
RCTs Comparing More Intensive vs. Less Intensive Control/BP Targets | ||||
Garrison et al., 2017 meta-analysis[25] | Meta-analysis included three RCTs, with a sample comprising N=8,221 adults age 65+ who are either: 1) already being treated for hypertension; or 2) have elevated BP (BP≥140/90 mmHg) documented in a standard way on at least two occasions | BP Target: More intensive (<140/90 mmHg) vs. less intensive BP target (two trials defined less intensive BP target as 150/90 mmHg and one trial defined it as 160/90 mmHg). |
|
Treating to a more intensive BP target did not result in a significant difference in all-cause mortality, stroke, or total CV serious adverse events over a mean follow-up of 2.6 years. There was no significant difference in withdrawal due to adverse effects over a mean follow-up of 2.4 years among the two RCTs that measured this outcome. |
SPRINT (ad hoc) (Williamson et al., 2016)[18] | N=2,636 adults age 75+ recruited from 100 clinics in the United States | SBP Target: More Intensive (<120 mmHg) vs. Less Intensive (<140 mmHg) Treatment |
|
More intensive treatment resulted in significantly lower rates of fatal and nonfatal major CV events (HR: 0.66, 95% CI 0.51–0.85) and death from any cause (HR: 0.67, 95% CI 0.49–0.91). There was no statistically significant differences in SAEs, although rates of hypotension, syncope, electrolyte abnormalities, and acute kidney injury were numerically higher in the more intensive treatment group. |
SPRINT (ad hoc) (Odden et al., 2017)[29] | N=2,636 adults age 75+ recruited from 100 clinics in the United States | SBP Target: More Intensive (<120 mmHg) vs. Less Intensive (<140 mmHg) Treatment |
|
More intensive treatment was not associated with changes in gait speed or changes in mobility limitation. |
SPRINT (ad hoc) Berlowitz et al. 2017)[30] | N=9,361 participants age 50+ with SBP 130–180 mmHg recruited from 102 clinics in the United States | SBP Target: More Intensive (<120 mmHg) vs. Less Intensive (<140 mmHg) Treatment | Patient-reported outcomes:
|
There were no significant differences in physical health, mental health, satisfaction with BP care and antihypertensives, or adherence to antihypertensives among participants who received more intensive vs. less intensive treatment, including among participants with decreased physical or cognitive function. |
HYVET (ad hoc) (Warwick et al., 2015)[31] | N=2,656 adults age 80+ recruited from 195 hospital and general practice centers in Europe, China, Australasia, and Tunisia | BP target and antihypertensive management: Receiving antihypertensives and BP <150/80 mmHg vs. Placebo group and BP ≥160 |
|
More intensive treatment resulted in significantly lower risk of stroke (HR: 0.64, 95% CO 0.42–0.96) and CV events (HR: 0.59, 95% CI 0.45–0.77), and no significant difference in total mortality. There was no evidence of an interaction between effect of treatment for hypertension and frailty in fully adjusted models. |
RESPECT (Kitagawa et al., 2019)[32] | N=1,280 adults age 50–85, with SBP 130–180 mmHg or DBP 80–110 mmHg, independent ambulation, on a regimen of 0–3 antihypertensive drugs, and a history of stroke within the previous 3 years were recruited from 140 hospitals in Japan Sample was divided into age <70 and ≥70 in subgroup analyses | BP target: More Intensive (<120/80 mmHg) vs. Less Intensive (<140/90 mmHg; or <130/80 mmHg for patients with diabetes, CKD, or a history of MI) |
|
Among participants age 70+, there was a non-significant trend toward reduction in likelihood of recurrent stroke in those receiving more intensive vs. less intensive treatment (HR 0.57, 95% CI 0.32–1.04). SAEs were similar between groups. |
PAST-BP (Mant et al, 2016)[33] | N=379 participants with a history of stroke or transient ischemic attack with a SBP of >125 mmHg Age was not included as inclusion criteria, but the sample was divided into age <80 and ≥ 80 in subgroup analyses | SBP target: More Intensive (<130 mmHg, or 10 mm Hg reduction if baseline SBP was <140 mmHg) vs. Less Intensive (<140 mmHg) |
|
Among participants age 80+, there was no difference in SBP or DBP levels achieved in the more intensive vs. less intensive treatment groups. The study was not adequately powered to detect differences in clinical events (e.g., cardiovascular events). Therefore, fidelity to randomized targets were reported. |
PODCAST (Bath et al, 2017)[34] | N=83 functionally independent adults with a stroke within the previous 3–7 months, who were over 70 with t-MMSE >16 or age 60–70 with t-MMSE 17–20, with a SBP 125–70 mmHg. who had an informant who could provide information on cognitive measures | SBP target: More Intensive (<125 mmHg and/or LDL-cholesterol <2.0mmol/l) vs. Less Intensive (<140 mmHg and/or LDL-cholesterol <3.0 mmol/l) |
|
Participants in the more intensive treatment group had significantly reduced mean BP (difference −10.6/−5.5 mmHg) relative to the less intensive treatment group. Cognitive scores, functional/dependency, mood, quality of life, CV events, resource use and safety outcomes were not significantly different between treatment groups over two-year follow-up. |
RCTs Comparing Deprescribing of Antihypertensives vs. No Deprescribing | ||||
COSMOS (ad hoc) (Gulla et al., 2018)[35] | N=295 adults age 65+ with antihypertensive treatment were recruited from 32 Norwegian nursing homes | Antihypertensive management: Systematic medication review where physician received support from peers vs.usual care |
|
A systematic medication review supported by collegial mentoring significantly decreased the number of antihypertensive drugs used (IRR vs.usual care: 0.8, 95% CI 0.7–0.9) in nursing home patients from baseline to four months, with no significant change between month four and month nine. Patients in the intervention group who had a reduction in antihypertensive drugs from baseline to month four had an increase in SBP (mean difference = 14 mmHg, 95% CI 7.7, 21.2) but no significant difference in SBP and pulse between baseline and month nine assessments. Hospitalization was significantly higher among the usual care group, and death rates did not differ. |
DANTE (Moonen et al., 2015)[36] | N=385 adults age 75+ with mild cognitive deficits recruited from 128 general practices in the Netherlands | Antihypertensive management: Discontinuation vs. continuation of antihypertensive drugs |
|
Discontinuation of antihypertensive treatment did not improve cognitive, psychological, or general daily functioning with no differences between groups in adverse events. |
OPTiMISE (protocol) (Sheppard et al., 2018)[37] | (Protocol) N=540 adults age 80+ with SBP<150 mmHg and receiving 2+ antihypertensive medications will be recruited from the United Kingdom Clinical Research Network. | Antihypertensive management: De-intensification vs.usual care |
|
Results not yet available. |
BP=blood pressure; SBP=systolic blood pressure; DBP=diastolic blood pressure; CV=cardiovascular; CI=confidence interval; NH=nursing home; ADL=activities of daily living; PCS=Physical Component Summary; MCS=Mental Component Summary; PHQ=Patient Health Questionnaire 9-item depression scale; IRR=incidence rate ratio; HR=hazard ratio; CKD=chronic kidney disease; MI=myocardial infarction; SAE = serious adverse event (life threatening, associated with death/disability, required hospitalization/emergency care/immediate medical attention); t-MMSE=telephone-Mini Mental State Examination
In contrast, the American College of Physicians (ACP) and the American Academy of Family Physicians (AAFP) hypertension guidelines for adults aged 60 years and older did not weigh the SPRINT trial as heavily in their review and focused on risks of hypotension and adverse drug reactions among older adults [23,24]. Their recommended treatment target for older adults is a SBP <150 mmHg, similar to the 2014 JNC-8 (8th Joint National Committee) guideline recommendation of <150/90 mmHg [13,23]. The ACP/AAFP Task Force concluded that treating hypertension in older adults to <140 mmHg (compared to <150 mmHg) did not have additional benefit and may increase risk of harm, although stated that this lower target may be considered for patients with history of stroke/transient ischemic attack or those at high cardiovascular risk [23].
Despite conflicting recommendations for optimal BP targets, all guidelines express caution in extrapolating treatment targets to those who are very frail, have limited functional status, and have multiple comorbidities (i.e., NH populations), noting limited evidence. In general, guidelines support use of five antihypertensive classes generally in all patients: angiotensin II receptor blockers (ARB); angiotensin converting enzyme inhibitors (ACEi); beta blockers; calcium channel blockers (CCB); and thiazide diuretics.
Expert Consensus Recommendations
Expert consensus recommendations have expanded on hypertension management in NH populations, specifically in antihypertensive selection and intensity. An ESH-European Union Geriatric Medicine Society consensus statement asserted that, for adults 80 years or older, ACEi, thiazide diuretics, and CCB can be considered, and monotherapy with slow titration is recommended, especially for frail patients [14]. A 2014 consensus statement from the CRIME project (CRIteria to assess appropriate Medication use among Elderly complex patients) specifically recommended against more intensive control (BP target <140/90 mmHg) in adults with dementia, cognitive impairment, or limited functional status and against use of more than three antihypertensive agents due to reduced benefit and risk of adverse events [25]. More intensive control was also not recommended for those with limited life expectancy [25]. Finally, according to the Beer’s criteria, an expert consensus recommendation from the American Geriatrics Society, peripheral alpha-1 blockers should be avoided for treatment of hypertension due to higher risk of orthostatic hypotension compared to other antihypertensives [26]. Taken together, these expert consensus recommendations consistently suggest that less intensive BP control targets and de-intensified antihypertensive regimens are more appropriate for NH populations.
Randomized Controlled Trials (RCTs)
Table 1 provides a summary of recent RCTs testing hypertension management approaches in older patients, with varying generalizability to NH residents.
RCTs Comparing More Intensive vs. Less Intensive Control/BP Targets
A systematic review of past RCTs showed insufficient evidence to support more intensive control over higher BP targets among older adults [27]. Specifically, combining the results of three trials comparing BP targets of <160/90 mmHg or <150/90 mmHg versus a more intensive target of <140/90 mmHg showed no statistically significant difference in mortality, stroke, or combined cardiovascular events, although clinical extrapolation is limited due to high risk of bias and heterogeneity among these studies. However, the SPRINT trial was a pivotal study that shifted hypertension guidelines toward lower BP targets, specifically among ambulatory U.S. adults with increased CV risk, without diabetes, cognitive impairment, or history of stroke [18,28]. The sub-analysis of adults aged 75 years and older showed that more intensive control (SBP <120 mmHg compared to <140 mmHg) was associated with cardiovascular benefit and lower risk of all-cause mortality [18]. Follow-up studies of the SPRINT participants assessed other non-CV outcomes. Among SPRINT older adults, more intensive control was not associated with changes in gait speed or mobility, implying neither non-cardiovascular benefit nor harm [29]. Patient-reported outcomes (e.g. satisfaction with hypertension care, adherence to antihypertensives) were similar between BP target groups, both within those aged <75 years and 75 years and older [30]. In both SPRINT and HYVET participants, there was no evidence of effect modification by patient frailty, but the restrictive exclusion criteria used in these trials resulted in the exclusion of very frail older adults [18,31]. Therefore, the benefit of intensive control can only be inferred for populations reflecting fit, ambulatory older adults.
The SPRINT trial excluded adults with a history of stroke [28], and there is generally a lack of available evidence regarding risks and benefits of more intensive control in older adults with a stroke history. One exception is the RESPECT study, a large RCT among Japanese, ambulatory adults aged 50–85 years with a history of stroke-related hospitalization, which included a stratified analysis for those 70–85 years old [32]. Among this older group, there was a non-significant, protective effect of more intensive BP control (<120/80 mmHg vs. <140/90 mmHg) on risk of recurrent stroke (hazard ratio [HR]=0.57, 95% confidence interval [CI] of 0.32–1.04 for a composite outcome of ischemic stroke and intracerebral hemorrhage) [32]. Two other trials examined the impact of more intensive control (<130 or <125 mmHg) compared to less intensive control (SBP <140 mmHg) in older adults with stroke history, but assessed changes in BP as primary endpoint [33,34]. “PAST-BP” was a trial among older adults in primary care settings within the United Kingdom which found no difference in systolic BP at follow-up. However, this study suffered from low statistical power overall and the small number of safety events (e.g., cardiovascular events) overall prohibited conclusions about effects on patient-centered outcomes [33]. PODCAST was a smaller trial among older adults, including those with cognitive impairment, and described a non-significant benefit in cognition (secondary endpoint) with more intensive BP control [34]. Clearly, there is a lack of RCTs powered to detect patient-centered outcomes (i.e., recurrent stroke with sub-analyses of stroke type, cognitive function) and representative of older adults in NH with a history of stroke and stroke-related cognitive impairment.
RCTs Comparing Deprescribing of Antihypertensives vs. No Deprescribing
Other RCTs (bottom of Table 1) have focused on interventions to de-intensify antihypertensive medications (i.e., “deprescribing” interventions) in patients with characteristics reflective of typical NH populations, including both patients with diagnosis of hypertension as well as patients with other CV indications for antihypertensive treatment. These deprescribing RCTs mainly assessed the impact of interventions to de-intensify antihypertensive medications on process measures such as number of antihypertensives and changes in BP, and less often examined patient-centered outcomes (e.g., CV events, mortality, adverse drug events). COSMOS included NH residents in Norway aged ≥65 years [35]. Compared to usual care, deprescribing rates were higher in the deprescribing intervention group, with no significant differences in secondary outcomes of changes in pulse or SBP among those deprescribed. The DANTE trial included ambulatory older adults aged 75 years and older with hypertension and mild cognitive impairment, the majority of which used diuretics and combination treatment with >2 antihypertensives [36]. The study showed that compared to usual care, deintensification or discontinuation of antihypertensives was associated with an increase in BP, but no harm or benefit in cognition or functional and psychological assessments at 16-weeks [36]. An ongoing study among ambulatory adults aged ≥80 years, OPTiMISE, will describe the impact of deprescribing antihypertensives compared to usual care in primary care settings on BP control at 12 weeks [37]. Clearly, there is a dearth of trial data on patient-centered outcomes of deprescribing antihypertensives in this population.
Overall, most RCTs assessed CV endpoints and, with the exception of SPRINT [18], did not find a different in CV outcomes between more and less intensive control, among older ambulatory adults. In studies that showed a CV benefit, frailty did not modify effect, but very frail patients were not well-represented [18,31]. Most RCTs excluded NH residents as well as older adults who were very frail, cognitively impaired, or nearing the end-of-life, possibly due to ethical and feasibility challenges, thereby limiting their generalizability to NH residents [17]. Among deprescribing trials, there was notable effort to include NH populations, but greater emphasis on patient-centered outcomes (e.g., cognitive, functional, all-cause negative events) is needed to inform best practices for hypertension management.
Observational Studies
In addition to RCTs, recent observational studies provid insight on hypertension management, specifically harm related to more intensive treatment within NH-representative populations. Such studies have important advantages with regard to external validity, in their purposeful inclusion of older patients that better represent typical characteristics of NH residents in terms of comorbidity burden, frailty, fall risk, cognitive impairment, and/or polypharmacy. However, because the “real-world” patients included in observational studies are not randomized to receive different BP targets or antihypertensive regimens of varying intensity, there is a greater potential for bias due to confounding. For example, providers may be inclined toward more intensive treatment and to avoid de-intensification in patients with the greatest CV risk, which could bias the relationship of more intensive treatment and CV risk upward. Or conversely, providers may be more likely to de-intensify antihypertensives in the frailest patients who are in the last months of life, which may bias the relationship of more intensive treatment and mortality downward. Ideally, such studies would follow best practices in employing strategies that reduce bias and emulate a randomized trial to the extent possible [38,39]. Here we review recent observational studies conducted with NH residents as well as non-NH residents with similar characteristics, as shown in Table 2, and briefly comment on potential for bias.
Table 2.
Evidence from observational studies on blood pressure treatment targets and antihypertensive management.
Study name (if available) Authors, year | Sample description (N, age range, setting) | Intervention and Comparator(s) | Design and Analysis | Outcomes | Summary of Results |
---|---|---|---|---|---|
Observational Studies Comparing Treatment Intensity | |||||
PARTAGE (Benetos et al., 2015)[6] | N=1,127 residents of three French and two Italian nursing homes age 80+ years without severe dementia or under guardianship or a ‘measure of legal protection’ | Both BP target and Antihypertensive Management: Patients receiving more intensive treatment (SBP < 130 mmHg who were receiving combination antihypertensive treatment) were compared with all other participants receiving less intensive treatment | Longitudinal cohort study, employing Cox proportional hazards, with potential confounders entered in an interactive backward selection model. Sensitivity analyses included: 1) propensity-score matched patients; 2) models adjusting for CV comorbidities; and 3) models excluding patients without hypertension but who were receiving BP-lowering drugs for other indications. |
|
In adjusted models, there was a higher risk of mortality in the more intensive treatment group, compared to all other patients (HR: 1.78, 95% CI 1.34–2.37). Sensitivity analyses confirmed the excess risk: 1) propensity score-matched subsets (HR: 2.05, 95% CI 1.37–3.06); 2) adjustment for CV comorbidities: (HR: 1.73, 95% CI 1.29–2.32); and 3) exclusion of patients without a history of hypertension (HR: 1.76, 95% CI 1.28–2.41). |
Boockvar et al., 2019[8] | N=255,670 long-term nursing home residents (residing in a NH for 100+ days by the second quarter of 2013) age 66+, who had hypertension, and were taking at least one first-line antihypertensive medication were identified from Minimum Data Set Nursing Home resident assessments in the second quarter of 2013. | Antihypertensive management: More intensive treatment vs. less intensive treatment, defined as the number of first-line hypertension medications (3+, 2, or 1) received on the index date. | Retrospective cohort study, employing multivariable logistic regression. In sensitivity analysis, models were applied to only residents who did not die during the 180-day follow-up pe11riod |
|
In adjusted models, higher intensity was significantly associated with small increases in hospitalization (Marginal difference (%): 0.24, 95% CI 0.03, 0.45) and CV-related hospitalizations (Marginal difference (%): 0.30, 95% CI 0.21, 0.39), and a small decrease in ADL (Marginal difference (%): −0.46, 95% CI −0.67, −0.25), all compared to lower antihypertensive treatment intensity. There was no significant difference in mortality between different antihypertensive treatment intensities. |
Tinetti et al., 2014[40] | N=4,961 community-dwelling adults age 70+ with hypertension who were participants in the Medicare Current Beneficiary Survey (US) enrolled from 2004–2007 | Antihypertensive management: Antihypertensive medication intensity based on the defined daily dose (DDD) for each antihypertensive medication class that participants used. Patients were categorized into antihypertensive intensity groups as: nonusers (0 to <0.2 DDD); moderate (0.2–2.5 DDD), or high (>2.5 DDD). |
Retrospective cohort study, employing Cox proportional hazards and competing risk analyses with propensity score matching. A competing risk model using subdistribution hazards regression to analyze serious fall injury events to account for potential bias due to high attrition from mortality. |
|
In adjusted models, there was a greater rate of serious fall injuries among participants in the moderate-intensity antihypertensive group (HR: 1.40, 95% CI 1.03–1.90), compared to nonusers. The rate of serious fall injuries among participants in the high-intensity antihypertensive group had an adjusted HR of 1.28 (95% CI 0.91–5.29) was not significantly different than that of nonusers. Among 503 participants with a previous fall injury, compared to nonusers in adjusted models, high-intensity antihypertensive patients had a greater rate of recurrent falls (HR: 2.31, 95% CI 1.01–5.29), and there was no significant difference in rates of recurrent falls among moderate-intensity patients. |
Health ABC (Marcum et al., 2015)[42] | N=2,948 adults age 70–79 who reported no difficulty walking ¼ mile or climbing 10 steps at baseline (1997) were followed to 2004 | Antihypertensive management: Antihypertensive medication use was examined in multiple ways, including:
|
Retrospective cohort design, employing regression models with a forward stepwise selection approach to select covariates, in addition to a priori covariates that may affect recurrent falls over time. Sensitivity analyses were also conducted by restricting the sample only those with hypertension at baseline and stratifying that analysis by any fall history and median gait speed at baseline. |
|
In adjusted models, there was no difference in risk of recurrent falls between patients with any antihypertensive use compared to those with no antihypertensive use, nor was there any difference when antihypertensive use was defined by duration of use or SDD category. Patients using a loop diuretic were found to have a modest increase in risk of recurrent falls (OR: 1.50, 95% CI 1.11–2.03). |
Jerusalem Longitudinal Study (Stessman et al., 2017)[43] | N=480 adults age 90+ and residents in Western Jerusalem in 2010–2011. | Both BP target and Antihypertensive Management: Participants were categorized as normotensive (no antihypertensive treatment medication and sitting SBP <140 mmHg and DBP <90 mmHg), untreated hypertension, or treated hypertension | Prospective observational longitudinal study, employing Cox proportional hazard models to determine mortality hazard ratios during follow-up from age 90 to 95 years. Two models were constructed: Medical Model, adjusting for gender, education, self-rated health, ischemic heart disease, diabetes, and CKD; and a Medical/Functional model which also included depression, ADL difficulty, and grip strength. Analyses were repeated among the total sample and 6 patient subgroups: dependent/independent in ADL; high/low grip strength, and high/low comorbidity. |
|
In the Medical/Functional model, participants with treated hypertension had a greater risk of mortality (HR: 1.39, 95% CI 0.83–2.33) and participants with untreated hypertension had a lower risk of mortality (HR: 0.67, 95% CI 0.31–1.45), both compared to normotensive participants. Findings were consistent in subsets according to ADL status, grip strength, and comorbidity. |
Observational Studies Comparing Treatment Intensification | |||||
Anderson et al., 2019[44] | N=4,056 adults age 65+, with hypertension, who were hospitalized in VA facilities from Jan. 1, 2011 to Dec. 31, 2013 for common noncardiac conditions (pneumonia, UTI, or venous thromboembolism) and discharged to the community setting. | Antihypertensive management: Patients were categorized as being discharged with intensified antihypertensive regimens (relative to their baseline regimen) versus being discharged without having their therapy intensified. | Retrospective cohort study, employing propensity score matched Cox proportional hazards regression models for mortality and the Fine and Gray proportional subdistribution hazards models for all other outcomes to account for the competing risk of death. Within propensity score-matched groups, change in SBP after hospital discharge was estimated using a difference-in-differences approaches. Exploratory a priori sensitivity analyses conducted to determine differential association of exposure with intensified antihypertensive medications by prehospitalization SBP (then conducted priority score matching on different baseline SBP groups). E-values were calculated for statistically significant primary outcomes to assess robustness of observed associations to potential unmeasured confounding. |
|
In adjusted models, compared to patients not receiving antihypertensive intensification, patients receiving intensifications had higher risk of readmission (HR: 1.23, 95% CI 1.07–1.42) and serious adverse events (HR: 1.41, 95% CI 1.06–1.88) within 30 days. At one year, no significant differences were found in cardiovascular events or change in SBP among those who did versus did not receive intensifications. |
Observational Studies Comparing Treatment Deintensification/Deprescribing | |||||
Song et al., 2018[41] | N=2,212 long-stay VA NH residents (stay of 91+ days from Oct. 2009 through Sep. 2015) age 65+, taking at least one first-line antihypertensive medication, with a diagnosis of hypertension, and at least 1 year of prior VA enrollment were identified in the VA NH resident assessments and other administrative data. Participants were included if they fulfilled criteria for an index clinical scenario in which antihypertensive deintensification might have been indicated, defined as having an SBP of 80–120 mmHg and a fall within 3 days of each other. | Antihypertensive management: Antihypertensive deintensification (defined as discontinuation of 1+ first-line hypertension medications without substitution) vs.no deintensification within 7 days of index date. | Retrospective cohort study, using propensity score with scaled Kernel weighting to balance deintensification and comparison groups in logistic regression models. |
|
In propensity weighted models, antihypertensive deintensification was associated with a lower risk of recurrent fall among residents with SBP 80–100 mmHg (marginal effect: −13.6%, SE 0.04%) but a higher risk of death among residents with SBP 101–120 mmHg (marginal effect: 4.3%, SE 0.02%). Hospitalization was not significantly different (though numerically higher) in both SBP 80–100 and 101–120 groups. |
Observational Studies Comparing Antihypertensive Classes | |||||
Hiremath et al., 2019[45] | N=14,106 women age 66+, with a previous diagnosis of hypertension and prescribed an antihypertensive medication | Antihypertensive management: Patients were categorized as receiving an alpha-blocker prescription (terazosin, prazosin, and doxazosin), with the prescription date serving as the study index date. Alpha-blocker users were matched to patients who received non-alpha-blocker antihypertensives. | Retrospective cohort study, employing high dimensional propensity score matched Cox proportional hazards regression models. Several sensitivity analyses were conducted: 1) patients with a previous history of adverse cardiac events (5-year look back window) at baseline were excluded; 2) patients were censored at medication discontinuation where individuals were considered to be continuously exposed during a series of prescriptions if the gap to the next prescription was not >50% of the length in days of the previous prescription; 3) alpha-blocker exposure was treated as a time-varying covariate; 4) follow-up time was limited to 90 days; and 5) the primary analysis and sensitivity analyses 1 to 3 were repeated using a stricter matching algorithm. |
|
In adjusted models, patients who had been prescribed alpha-blockers were at a greater risk of hypotension and related events (IRR: 1.20, 95% CI 1.10–1.30), hypotension (HR: 1.71, 95% CI 1.33–2.20), and syncope (HR: 1.44, 95% CI 1.18–1.75), compared to patients prescribed non-alpha-blocker antihypertensive medications. There was no statistically significant difference in falls, fractures, CV events, or all-cause mortality. |
BP=blood pressure; SBP=systolic blood pressure; DBP=diastolic blood pressure; CV=cardiovascular; CI=confidence interval; VA=Veterans Affairs; NH=nursing home; FFS=Fee for Service; SE=standard error; UTI=urinary tract infection; DDD/SDD=defined daily dose/standardized daily dose; ADL=activities of daily living; IRR=incidence rate ratio; HR=hazard ratio; CKD=chronic kidney disease; MI=myocardial infarction.
Observational Studies Comparing Treatment Intensity
Two studies assessed the impact of treatment intensity on outcomes in NH settings. PARTAGE was a large, retrospective cohort analysis of NH residents aged ≥80 years which showed an association between more intensive BP targets and CV and non-CV related death within 2 years of follow-up [6]. Specifically, mortality rates were higher among residents with SBP < 130 mmHg who took at least two antihypertensives, compared to all other patient groups with higher BP levels and/or taking fewer medications [6]. However, this study had a limitation of potential residual confounding by baseline risk. Notably, the most intensely treated group exhibited a much higher baseline prevalence of CV risk factors and heart failure. Although in sensitivity analyses the researchers attempted to balance patient subgroups using propensity score matching (PSM), they did not report the extent to which this matching achieved balance on these factors. Thus, the increased risk seen in the group with the lowest BP levels and most intense BP regimens may still reflect greater baseline risk for CV events rather than intense BP treatment itself. Another study included Medicare beneficiaries in NHs and assessed the association between number of antihypertensives and CV and non-CV outcomes, stratified by diagnosis of dementia [8]. Higher treatment intensity was associated with incremental CV and non-CV harm but with no significant differences in mortality, and cognitive performance did not significantly modify these effects. However, dementia and worse performance status were significantly associated with less intensive treatment; therefore, harm was potentially biased towards the null, given possible residual confounding from lack of PSM and use of prevalent rather than new users. Also, this study used separate models to individually estimate risk of death, CV, and non-CV outcomes, and did not account for competing risks or differential censoring across those with higher intensity versus not lower treatment intensity, which could bias results.
Other cohort studies among ambulatory older adults showed mixed results with regard to harms of more intensive hypertension management. These studies share a limitation that antihypertensive treatment intensity was measured as a time-invariant (stable) exposure; however, the intensity of antihypertensives likely varies over time. In addition, they did not employ new user designs, which may have the effect of underestimating harms associated with more intensive treatment that may be more likely soon after intensification. One Medicare claims study found increased fall risk with antihypertensive intensity [40]. Strengths of the study include PSM that balanced patients with different levels of antihypertensive intensity on measured demographic and clinical variables, as well as using survival analysis accounting for competing risks [40]. On the other hand, details on BP control levels were not available; thus the potential for differential effects of antihypertensive medication intensity by BP level (suggested by the Song et al. deintensification study discussed below [41]) was not examined. The Health ABC cohort study did not find an association between use of antihypertensives (measured by participant interview) with recurrent falls in the following year [42]. A strength was that this studied used varying definitions to categorize antihypertensive intensity. In a prospective cohort study patients aged 90 years and older in Jerusalem with hypertension, using (versus not using) antihypertensives was not associated with differences in mortality, functional decline, loss of muscle strength [43]. For both studies, a strength was that several patient-relevant demographics and outcomes were captured by patient interview and assessment, which helped to accurately capture baseline confounders.
Observational Studies Comparing Treatment Intensification
One national cohort study among older U.S. Veterans receiving care at the Veterans Health Administration (VA) also demonstrated that antihypertensive intensification at hospital discharge was associated with increased all-cause re-hospitalization rates and serious adverse events at 30-day follow-up, compared to no intensification [44]. At one year, there were no significant differences were found in cardiovascular events or change in SBP among those who did versus did not receive intensifications.. This study had several methodological strengths, including use of a new-user design and excellent balance on a large number of measured potential confounders after PSM. However, the relatively small effect sizes observed meant that the researchers could not rule out the possibility for confounding by an unmeasured variable.
Observational Studies Comparing Treatment Deintensification/Deprescribing
We identified only one recent study, conducted in VA nursing homes, that directly examines the effect of deprescribing antihypertensives among those with a hypertension diagnosis in nursing home residents. After an index fall associated with low BP, deintensification was associated with a benefit of decreased likelihood of recurrent falls among those with the lowest BP ranges (80–100 mmHg), but also an increased risk of death in patients with SBP >100 mmHg to 120 mmHg, compared to those not deintensified [41]. Strengths of this study include a new-user design (i.e., deprescribing after incident falls), use of PSM to achieve covariate balance across treatment groups, and stratification by baseline SBP level. However, this study did not account for competing risks, which could bias the risk of recurrent falls associated with deintensification.
Observational Studies Comparing Antihypertensive Classes
Two recent observational studies assessed the effects of individual antihypertensive classes on harm. A population-based cohort study assessed the use of alpha-blockers (compared to other antihypertensives) and likelihood of severe hypotension and hypotension-related harm among older women with hypertension [45]. There was evidence of greater harm of alpha-blocker use within this population [45], which supports the Beer’s criteria statement against their use [26]. Possible sources of bias include lack of a new user design, lack of BP data, and confounding from changes in antihypertensive prescribing over time. In the previously mentioned Health ABC cohort study, ambulatory, older adults using a loop diuretic were found to have a modest increase in risk of recurrent falls (OR: 1.50, 95% CI 1.11–2.03) [42]. It is important to note that indications for and frequency of loop diuretic use are much different in NH populations (e.g., symptomatic treatment of heart failure, incontinence care and closer observation for falls) compared to ambulatory settings.
Despite variations in methodological quality and results, these studies are suggestive of a trend of potential harms related to more intensive treatment of hypertension, especially among studies that follow best practices to minimize bias. Future studies employing observational designs should utilize new-user designs, well-described PSM, survival analyses accounting for competing risks, sensitivity analyses for different definitions of antihypertensive use and intensive BP treatment targets, and analyses to account for potential interactions between antihypertensive use and BP treatment targets.
Discussion
Recent studies have provided some insights in tailoring HTN management for NH residents, but substantial gaps remain in evidence. Overall, RCTs support more intensive BP control to achieve CV and non-CV benefits in ambulatory, healthier older adults, but these trials do not represent the NH population, especially those with history of stroke. The limited life expectancy of many in this population may translate into insufficient time available to experience CV benefits, but direct evidence to support or refute this possibility is unavailable. On the other hand, multiple observational studies suggest increased potential for serious adverse effects (e.g. falls) associated with more intensive antihypertensive treatment, but these studies vary in terms of their results as well as methodological quality. Therefore, the risk/benefits of more intensive management, including more aggressive BP targets and greater antihypertensive regimen intensity, among NH populations remain unclear and for the time being, should be considered on a patient-level basis with shared decision-making, as described in clinical guidelines.
Many RCTs directly testing the effects of de-intensifying antihypertensive regimens have focused primarily on BP changes as the primary outcome. This measure provides minimal value, as we expect discontinuation of antihypertensives to result in BP elevations. Instead, the clinically relevant question is whether these BP changes translate into increased CV, hospitalization or mortality risk, and whether reduced antihypertensive drug burden results in reduced adverse events such as falls. Therefore, we see the greatest value in the assessment of the patient-centered outcomes associated with antihypertensive deprescribing. The outcomes of cognitive, functional, and psychological changes within the DANTE trial are examples of relevant outcomes [36], but additional RCTs examining a wider range of patient-centered outcomes are needed.
Overall, the observational studies in this review have included relevant outcomes but are subject to biases from residual confounding and measurement error (e.g. hypertension diagnoses, comorbidities, concomitant medications, measures of antihypertensive burden, lack of time-varying exposures and covariates). Also, many of these studies assume that outcomes are consistent regardless of the type of antihypertensive deprescribed, which is unlikely given that antihypertensives are used for various other CV and renal indications. Notably, no antihypertensive deprescribing studies used an active comparator (i.e., deprescribing of another class of drugs not expected to affect the outcome of interest) and negative outcome control to help reduce bias, such as increased surveillance for medication-related problems or confounding by indication [38,39]. Investigators can consider incorporating active comparators (e.g. deprescribing of other drug classes), negative outcome control, and describing the antihypertensives that are de-intensified or discontinued. We also recommend sensitivity analyses addressing alternative definitions of antihypertensive medication intensity and BP treatment targets, given the lack of consensus in this area. Lastly, NH populations are heterogenous, and we believe it is beneficial to stratify by subpopulations of interest, where possible (e.g., very frail, high-fall risk, cognitively impaired, CV comorbidities, and/or limited life expectancy).
Conclusion
In summary, the evidence regarding optimal BP treatment targets and antihypertensive regimen intensity in NH residents is still emerging. Additional RCTs and rigorous observational studies examining effects of de-intensified BP management on patient-centered outcomes in complex, older populations that address the limitations described in this article are needed to inform improved guidelines and treatment for NH residents.
Funding Sources and Acknowledgements:
The authors’ work on this paper was supported by the U.S. Department of Veterans Affairs (IIR 14-306, PI C. Thorpe; Office of Academic Affairs Fellowship in Medication Safety & Pharmacy Outcomes, Michelle Vu). The views expressed are those of the authors and do not represent the views of the Department of Veterans Affairs.
Footnotes
Human and Animal Rights: This article does not contain any studies with human or animal subjects performed by any of the authors.
References
Papers of particular interest, published recently, have been highlighted as:
•• Of major importance
- 1.Harris-Kojetin L, Sengupta M, Lendon J, Rome V. Long-Term Care Providers and services users in the United States: data from the National Study of Long-Term Care Providers, 2015–2016. Vital Health Stat 3. 2019;3. [PubMed] [Google Scholar]
- 2.Department of Health and Human Services. The Future Supply of Long-Term Care Workers in Relation to the Aging Baby Boom Generation [Internet]. 2015. November. Available from: https://aspe.hhs.gov/pdf-report/future-supply-long-term-care-workers-relation-aging-baby-boom-generation [Google Scholar]
- 3.U.S. Census Bureau. Population projections. 2014 National population projections: Summary tables. Table 3. Projections of the population by sex and selected age groups for the United States: 2015 to 2060 (NP2014–T3); and Table 6. Percent distribution of the projected population by sex and selected age groups for the United States: 2015 to 2060 (NP2014–T6). 2014. Available from: https://www.census.gov/data/tables/2014/demo/popproj/2014-summary-tables.html. [Google Scholar]
- 4.Simonson W, Han LF, Davidson HE. Hypertension treatment and outcomes in US nursing homes: results from the US National Nursing Home Survey. J Am Med Dir Assoc. 2011;12:44–9. [DOI] [PubMed] [Google Scholar]
- 5.Könner F, Kuhnert R, Budnick A, Kolloch R, Scholze J, Dräger D, et al. Arterial hypertension, antihypertensive therapy, and visit-to-visit blood pressure variability of elderly nursing home residents. Dtsch Med Wochenschr 1946. 2014;139:2441–7. [DOI] [PubMed] [Google Scholar]
- 6.Benetos A, Labat C, Rossignol P, Fay R, Rolland Y, Valbusa F, et al. Treatment With Multiple Blood Pressure Medications, Achieved Blood Pressure, and Mortality in Older Nursing Home Residents: The PARTAGE Study. JAMA Intern Med. 2015;175:989–95. [DOI] [PubMed] [Google Scholar]
- 7.McCracken R, McCormack J, McGregor MJ, Wong ST, Garrison S. Associations between polypharmacy and treatment intensity for hypertension and diabetes: a cross-sectional study of nursing home patients in British Columbia, Canada. BMJ Open [Internet]. 2017. [cited 2019 Sep 7];7. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5724061/ [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Boockvar KS, Song W, Lee S, Intrator O Hypertension Treatment in US Long-Term Nursing Home Residents With and Without Dementia. J Am Geriatr Soc. 2019; [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Koka M, Joseph J, Aronow WS Adequacy of control of hypertension in an academic nursing home. J Am Med Dir Assoc. 2007;8:538–40. [DOI] [PubMed] [Google Scholar]
- 10.Drawz PE, Bocirnea C, Greer KB, Kim J, Rader F, Murray P Hypertension guideline adherence among nursing home patients. J Gen Intern Med. 2009;24:499–503. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Krishnaswami A, Steinman MA, Goyal P, Zullo AR, Anderson TS, Birtcher KK, et al. Deprescribing in Older Adults With Cardiovascular Disease. J Am Coll Cardiol. 2019;73:2584–95. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Mutasingwa DR, Ge H, Upshur RE How applicable are clinical practice guidelines to elderly patients with comorbidities? Can Fam Physician Med Fam Can. 2011;57:e253–62. [PMC free article] [PubMed] [Google Scholar]
- 13.James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, et al. 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults: Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8). JAMA. 2014;311:507–20. [DOI] [PubMed] [Google Scholar]
- 14.Benetos Athanase, Bulpitt Christopher J., Petrovic Mirko, Ungar Andrea, Agabiti Rosei Enrico, Cherubini Antonio, et al. An Expert Opinion From the European Society of Hypertension–European Union Geriatric Medicine Society Working Group on the Management of Hypertension in Very Old, Frail Subjects. Hypertension. 2016;67:820–5. [DOI] [PubMed] [Google Scholar]
- 15.Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018;39:3021–104. [DOI] [PubMed] [Google Scholar]
- 16.Leung AA, Daskalopoulou SS, Dasgupta K, McBrien K, Butalia S, Zarnke KB, et al. Hypertension Canada’s 2017 Guidelines for Diagnosis, Risk Assessment, Prevention, and Treatment of Hypertension in Adults. Can J Cardiol. 2017;33:557–76. [DOI] [PubMed] [Google Scholar]
- 17.Benetos A, Petrovic M, Strandberg T Hypertension Management in Older and Frail Older Patients. Circ Res. 2019;124:1045–60. [DOI] [PubMed] [Google Scholar]
- 18.Williamson JD, Supiano MA, Applegate WB, Berlowitz DR, Campbell RC, Chertow GM, et al. Intensive vs Standard Blood Pressure Control and Cardiovascular Disease Outcomes in Adults Aged ≥75 Years: A Randomized Clinical Trial. JAMA. 2016;315:2673–82. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Onder G, Vetrano DL, Villani ER, Carfì A, Lo Monaco MR, Cipriani MC, et al. Deprescribing in Nursing Home Residents on Polypharmacy: Incidence and Associated Factors. J Am Med Dir Assoc [Internet]. 2019. [cited 2019 Jun 5]; Available from: http://www.sciencedirect.com/science/article/pii/S1525861019301574 [DOI] [PubMed] [Google Scholar]
- 20.Holmes HM, Hayley DC, Alexander GC, Sachs GA Reconsidering medication appropriateness for patients late in life. Arch Intern Med. 2006;166:605–9. [DOI] [PubMed] [Google Scholar]
- 21.Huang X, Lin J, Demner-Fushman D. Evaluation of PICO as a Knowledge Representation for Clinical Questions. AMIA Annu Symp Proc. 2006;2006:359–63. [PMC free article] [PubMed] [Google Scholar]
- 22.Whelton Paul K, Carey Robert M, Aronow Wilbert S, Casey Donald E, Collins Karen J, Dennison Himmelfarb Cheryl, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71:e13–115. [DOI] [PubMed] [Google Scholar]
- 23.Qaseem A, Wilt TJ, Rich R, Humphrey LL, Frost J, Forciea MA, et al. Pharmacologic Treatment of Hypertension in Adults Aged 60 Years or Older to Higher Versus Lower Blood Pressure Targets: A Clinical Practice Guideline From the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. 2017;166:430–7. [DOI] [PubMed] [Google Scholar]
- 24.Wilt TJ, Kansagara D, Qaseem A, . Hypertension Limbo: Balancing Benefits, Harms, and Patient Preferences Before We Lower the Bar on Blood Pressure. Ann Intern Med. 2018;168:369–70. [DOI] [PubMed] [Google Scholar]
- 25.Onder G, Landi F, Fusco D, Corsonello A, Tosato M, Battaglia M, et al. Recommendations to Prescribe in Complex Older Adults: Results of the CRIteria to Assess Appropriate Medication Use Among Elderly Complex Patients (CRIME) Project. Drugs Aging Auckl. 2014;31:33–45. [DOI] [PubMed] [Google Scholar]
- 26.American Geriatrics Society 2019 Updated AGS Beers Criteria® for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2019;67:674–94. [DOI] [PubMed] [Google Scholar]
- 27.Garrison SR, Kolber MR, Korownyk CS, McCracken RK, Heran BS, Allan GM Blood pressure targets for hypertension in older adults. Cochrane Database Syst Rev. 2017;8:CD011575. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Wright JT, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, et al. A Randomized Trial of Intensive versus Standard Blood-Pressure Control. N Engl J Med. 2015;373:2103–16. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Odden MC, Peralta CA, Berlowitz DR, Johnson KC, Whittle J, Kitzman DW, et al. Effect of Intensive Blood Pressure Control on Gait Speed and Mobility Limitation in Adults 75 Years or Older: A Randomized Clinical Trial. JAMA Intern Med. 2017;177:500–7. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Berlowitz DR, Foy CG, Kazis LE, Bolin LP, Conroy MB, Fitzpatrick P, et al. Effect of Intensive Blood-Pressure Treatment on Patient-Reported Outcomes. N Engl J Med. 2017;377:733–44. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Warwick J, Falaschetti E, Rockwood K, Mitnitski A, Thijs L, Beckett N, et al. No evidence that frailty modifies the positive impact of antihypertensive treatment in very elderly people: an investigation of the impact of frailty upon treatment effect in the HYpertension in the Very Elderly Trial (HYVET) study, a double-blind, placeb. BMC Med. 2015;13:78. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Kitagawa K, Yamamoto Y, Arima H, Maeda T, Sunami N, Kanzawa T, et al. Effect of Standard vs Intensive Blood Pressure Control on the Risk of Recurrent Stroke: A Randomized Clinical Trial and Meta-analysis. JAMA Neurol. 2019; [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Mant J, McManus RJ, Roalfe A, Fletcher K, Taylor CJ, Martin U, et al. Different systolic blood pressure targets for people with history of stroke or transient ischaemic attack: PAST-BP (Prevention After Stroke—Blood Pressure) randomised controlled trial. BMJ. 2016;352:i708. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34.Bath PM, Scutt P, Blackburn DJ, Ankolekar S, Krishnan K, Ballard C, et al. Intensive versus Guideline Blood Pressure and Lipid Lowering in Patients with Previous Stroke: Main Results from the Pilot ‘Prevention of Decline in Cognition after Stroke Trial’ (PODCAST) Randomised Controlled Trial. PLOS ONE. 2017;12:e0164608. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Gulla C, Flo E, Kjome RL, Husebo BS Deprescribing antihypertensive treatment in nursing home patients and the effect on blood pressure. J Geriatr Cardiol JGC. 2018;15:275–83. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.••.Moonen JE, Foster-Dingley JC, de Ruijter W, van der Grond J, Bertens AS, van Buchem MA, et al. Effect of Discontinuation of Antihypertensive Treatment in Elderly People on Cognitive Functioning--the DANTE Study Leiden: A Randomized Clinical Trial. JAMA Intern Med. 2015;175:1622–30. [DOI] [PubMed] [Google Scholar]; This RCT included a relevant population of ambulatory, older adults with mild cognitive impairment and was the only recent RCT to include patient-centered, non-CV outcomes, specifically those associated with cognitive, psychological, and general daily functioning. Compared to usual care, deintensification or discontinuation of antihypertensives was associated with an increase in BP, but no harm or benefit in cognition or in secondary outcomes of functional and psychological assessments at 16-weeks.
- 37.Sheppard JP, Burt J, Lown M, Temple E, Benson J, Ford GA, et al. OPtimising Treatment for MIld Systolic hypertension in the Elderly (OPTiMISE): protocol for a randomised controlled non-inferiority trial. BMJ Open. 2018;8:e022930. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38.Hernán MA, Robins JM. Using Big Data to Emulate a Target Trial When a Randomized Trial Is Not Available. Am J Epidemiol. 2016;183:758–64. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 39.Huitfeldt A, Hernan MA, Kalager M, Robins JM. Comparative Effectiveness Research Using Observational Data: Active Comparators to Emulate Target Trials with Inactive Comparators. EGEMS Wash DC. 2016;4:1234. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Tinetti ME, Han L, Lee DS, McAvay GJ, Peduzzi P, Gross CP, et al. Antihypertensive medications and serious fall injuries in a nationally representative sample of older adults. JAMA Intern Med. 2014;174:588–95. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.••.Song W, Intrator O, Lee S, Boockvar K. Antihypertensive Drug Deintensification and Recurrent Falls in Long-Term Care. Health Serv Res. 2018;53:4066–86. [DOI] [PMC free article] [PubMed] [Google Scholar]; This observational study included a representative population of nursing home residents diagnosed with hypertension and assessed the effect of antihypertensive deintensification on risk of recurrent falls, additionally identifying that this effect varies by baseline BP range. Deintensification was associated with a benefit of decreased likelihood of recurrent falls among those with the lowest BP ranges (80–100 mmHg), but also an increased risk of death in patients with SBP >100 mmHg to 120 mmHg, compared to those not deintensified.
- 42.Marcum ZA, Perera S, Newman AB, Thorpe JM, Switzer GE, Gray SL, et al. Antihypertensive Use and Recurrent Falls in Community-Dwelling Older Adults: Findings From the Health ABC Study. J Gerontol A Biol Sci Med Sci. 2015;70:1562–8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Stessman J, Bursztyn M, Gershinsky Y, Hammerman-Rozenberg A, Jacobs JM Hypertension and Its Treatment at Age 90 Years: Is There an Association with 5-Year Mortality? J Am Med Dir Assoc. 2017;18:277.e13–277.e19. [DOI] [PubMed] [Google Scholar]
- 44.••.Anderson TS, Jing B, Auerbach A, Wray CM, Lee S, Boscardin WJ, et al. Clinical Outcomes After Intensifying Antihypertensive Medication Regimens Among Older Adults at Hospital Discharge. JAMA Intern Med. 2019. [DOI] [PMC free article] [PubMed] [Google Scholar]; This observational study was the only study in older adults to assess intensification of antihypertensive therapy and its association with CV and non-CV harm. The study minimized potential bias through a strong methodological design. Antihypertensive intensification at hospital discharge was associated with increased all-cause re-hospitalization rates and serious adverse events at 30-day follow-up, but there was no difference in CV events at one-year follow-up, compared to no intensification. There was an increased risk of CV events at 30-day follow-up in patients receiving antihypertensive intensification at discharge.
- 45.Hiremath S, Ruzicka M, Petrcich W, McCallum MK, Hundemer GL, Tanuseputro P, et al. Alpha-Blocker Use and the Risk of Hypotension and Hypotension-Related Clinical Events in Women of Advanced Age. Hypertens Dallas Tex 1979. 2019;74:645–51. [DOI] [PubMed] [Google Scholar]