Clinical Outcomes of Intensive Inpatient Blood Pressure.pdf

Clinical Outcomes of Intensive Inpatient Blood Pressure
Management in Hospitalized Older Adults
Timothy S. Anderson, MD, MAS; Shoshana J. Herzig, MD, MPH; Bocheng Jing, MS; W. John Boscardin, PhD;
Kathy Fung, MS; Edward R. Marcantonio, MD, SM; Michael A. Steinman, MD
IMPORTANCE Asymptomatic blood pressure (BP) elevations are common in hospitalized
older adults, and widespread heterogeneity in the clinical management of elevated inpatient
BPs exists.
OBJECTIVE To examine the association of intensive treatment of elevated inpatient BPs
with in-hospital clinical outcomes of older adults hospitalized for noncardiac conditions.
DESIGN, SETTING, AND PARTICIPANTS This retrospective cohort study examined Veterans
Health Administration data between October 1, 2015, and December 31, 2017, for patients
aged 65 years or older hospitalized for noncardiovascular diagnoses and who experienced
elevated BPs in the first 48 hours of hospitalization.
INTERVENTIONS Intensive BP treatment following the first 48 hours of hospitalization,
defined as receipt of intravenous antihypertensives or oral classes not used prior to
admission.
MAIN OUTCOME AND MEASURES The primary outcome was a composite of inpatient mortality,
intensive care unit transfer, stroke, acute kidney injury, B-type natriuretic peptide elevation,
and troponin elevation. Data were analyzed between October 1, 2021, and January 10, 2023,
with propensity score overlap weighting used to adjust for confounding between those who
did and did not receive early intensive treatment.
RESULTS Among 66 140 included patients (mean [SD] age, 74.4 [8.1] years; 97.5% male
and 2.6% female; 17.4% Black, 1.7% Hispanic, and 75.9% White), 14 084 (21.3%) received
intensive BP treatment in the first 48 hours of hospitalization. Patients who received early
intensive treatment vs those who did not continued to receive a greater number of additional
antihypertensives during the remainder of their hospitalization (mean additional doses, 6.1
[95% CI, 5.8-6.4] vs 1.6 [95% CI, 1.5-1.8], respectively). Intensive treatment was associated
with a greater risk of the primary composite outcome (1220 [8.7%] vs 3570 [6.9%]; weighted
odds ratio [OR], 1.28; 95% CI, 1.18-1.39), with the highest risk among patients receiving
intravenous antihypertensives (weighted OR, 1.90; 95% CI, 1.65-2.19). Intensively treated
patients were more likely to experience each component of the composite outcome except
for stroke and mortality. Findings were consistent across subgroups stratified by age, frailty,
preadmission BP, early hospitalization BP, and cardiovascular disease history.
CONCLUSIONS AND RELEVANCE The study’s findings indicate that among hospitalized
older adults with elevated BPs, intensive pharmacologic antihypertensive treatment
was associated with a greater risk of adverse events. These findings do not support
the treatment of elevated inpatient BPs without evidence of end organ damage,
and they highlight the need for randomized clinical trials of inpatient BP treatment targets.
JAMA Intern Med. 2023;183(7):715-723. doi:10.1001/jamainternmed.2023.1667
Published online May 30, 2023.
Supplemental content
Author Affiliations: Division of
General Medicine, Beth Israel
Deaconess Medical Center, Boston,
Massachusetts (Anderson, Herzig,
Marcantonio); Harvard Medical
School, Boston, Massachusetts
(Anderson, Herzig, Marcantonio);
San Francisco Veterans Affairs
Medical Center, San Francisco,
California (Anderson, Jing, Boscardin,
Fung, Steinman); Division of
Geriatrics, University of California,
San Francisco (Jing, Boscardin, Fung,
Steinman); Department of
Epidemiology and Biostatistics,
University of California, San Francisco
(Boscardin).
Corresponding Author: Timothy S.
Anderson, MD, MAS, Division of
General Medicine, Beth Israel
Deaconess Medical Center,
1309 Beacon St, Brookline, MA
02246 (tsander1@bidmc.
harvard.edu).
Research
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D
uring acute hospitalization, blood pressure (BP) is rou-
tinely checked multiple times per day, and the major-
ity of hospitalized patients, including those with nor-
mal home BPs, will experience elevated BPs (>140/90 mm Hg)
withoutsignsofacuteendorgandamage,oftentermedasymp-
tomatic BP elevations.1-3
The primary goal of routine inpa-
tientBPmonitoringistheearlydetectionofhypotension,which
may portend sepsis, hypovolemia, or blood loss. However,
asymptomatic elevated BP readings may lead to the adminis-
tration of oral and intravenous antihypertensives. To our
knowledge, there are no clinical trials or professional society
recommendations to guide treatment decisions for asymp-
tomatic elevated BPs in the hospital, and as a result, clinical
practice varies widely.1-4
While the benefits of lowering chronically elevated BPs in
the outpatient setting are clearly defined and include reduc-
tions in mortality and cardiovascular events,5
these benefits
may not extend to inpatient treatment decisions for 4 key rea-
sons. First, the duration of treatment and time to benefit from
chronic BP reduction is measured over months to years, while
inpatient treatment timelines are focused on hours to days,6
and antihypertensives started during hospitalization are of-
ten discontinued shortly after discharge.7
Second, inpatient
BPs may be transiently elevated due to hospitalization fac-
tors, including pain, fever, delirium, anxiety, new medica-
tions, and imprecise measurement. Third, the use of antihy-
pertensives may result in overly rapid BP lowering, which has
been associated with increased risk of cerebral hypoperfu-
sion and death among patients treated for symptomatic hy-
pertensive emergencies.8,9
Fourth, clinical trials of inpatient
diabetes management have demonstrated that applying out-
patient treatment targets to inpatient settings may result in
overtreatment and harms.10
Better evidence to inform clinical decision-making is
needed to optimize inpatient BP management, particularly for
older adults who endure the highest burdens of hyperten-
sion, hospitalization, and frailty. Two recent observational
studies have investigated this issue. Rastogi et al3
examined
hospitalized patients with elevated BP in a regional health sys-
tem and compared those exposed vs not exposed to new an-
tihypertensives following their single highest BP, finding that
treated patients had higher rates of subsequent acute kidney
injury (AKI) and myocardial injury. The clinical applicability
of this finding is limited, as inpatient BPs are highly variable
andcliniciansarenotabletoprospectivelyidentifywhichmea-
surement will be a patient’s highest. In a single-center study,
Mohandas et al11
compared patients who were exposed to as-
needed antihypertensives during hospitalization and those
exposed to scheduled antihypertensives, finding that pa-
tients exposed to as-needed antihypertensives had a higher
risk of mortality, stroke, and AKI. Both studies lacked data on
prehospitalBPrecordings,didnotmatchpatientsbasedonrea-
son for hospitalization, and included patients hospitalized for
atrial fibrillation and heart failure, which could lead to con-
founding by indication.
To inform this evidence gap and overcome limitations of
prior studies, we adopted a target trial emulation design12,13
in which older adults hospitalized in the Veterans Health Ad-
ministration (VHA) health care system were categorized ac-
cording to receipt of intensified antihypertensives in the first
48 hours of hospitalization. We examined the association of
exposure to antihypertensives with subsequent inpatient
clinical outcomes.
Methods
Data Sources
We conducted this retrospective cohort study using inpatient
and outpatient clinical and pharmacy data from the VHA Cor-
porate Data Warehouse linked to VHA and Medicare admin-
istrative claims from 2013 through 2018. This research was ap-
proved by the institutional review boards of the San Francisco
Veterans Affairs (VA) Medical Center and the University of
California, San Francisco, with a waiver of informed consent
because of the use of deidentified administrative data. The
study followed the Strengthening the Reporting of Observa-
tional Studies in Epidemiology (STROBE) reporting guideline.
Study Population
We included patients aged 65 years or older who were hospi-
talized in a VHA hospital between October 1, 2015, and De-
cember 31, 2017. As evidence-based guidelines exist for BP
management for hypertensive emergencies, admitting diag-
noses were used to exclude patients hospitalized for cardio-
vascular disease and symptoms that may portend hyperten-
sive emergencies. eMethods 1 in Supplement 1 provides
additional details on study inclusion criteria.
Inpatient Antihypertensive Exposure: Target Trial Emulation
We designed this observational study to emulate a target trial
of intensive vs nonintensive inpatient antihypertensive
treatment.12,13
An ideal clinical trial would randomly assign pa-
tients at hospital admission to an intensive vs permissive in-
patient BP treatment goal. We leveraged the known heteroge-
neity in inpatient BP management to identify 2 cohorts of
patients experiencing elevated inpatient BPs: those who re-
ceived intensive treatment in the first 48 hours of hospitaliza-
tion and those who did not. We chose a 48-hour exposure
Key Points
Question What is the association between intensive treatment
of elevated inpatient blood pressures and clinical outcomes of
hospitalized older veterans?
Findings In this cohort study that used propensity score overlap
weighting in 66 140 older adults hospitalized for noncardiac
conditions, receipt of intensive inpatient antihypertensive
treatment was associated with a greater risk of adverse events,
with still greater risks for patients receiving intravenous
antihypertensives.
Meaning The findings do not support the treatment of elevated
inpatient blood pressures in hospitalized older adults without
evidence of end organ damage and highlight the need for
randomized clinical trials of inpatient blood pressure treatment
targets.
Research Original Investigation Intensive Blood Pressure Management in Hospitalized Older Adults
716 JAMA Internal Medicine July 2023 Volume 183, Number 7 (Reprinted) jamainternalmedicine.com

window to provide greater homogeneity between patients, to
allowadequatetimeformultipleBPrecordingstobemeasured,
and to account for the frequent practice of fluid resuscitation
for patients with volume depletion in the first 24 hours. The
exposure window began at the time of the first recorded vital
sign measurement, which could occur in the emergency de-
partment or hospital ward. We then made, and tested, the as-
sumption that patients receiving intensive BP treatment
early in their hospitalization would continue to receive more
intensive BP treatment throughout the remainder of the
hospitalization.
Inclusion criteria were the occurrence of 2 or more el-
evated BP measurements (systolic BP ≥140 mm Hg) in the first
48 hours of hospitalization. Patients were classified as ex-
posed to early intensive treatment if they received 1 or more in-
travenous antihypertensive doses of any class or oral doses of
antihypertensive classes not being filled prior to hospitaliza-
tion. Preadmission antihypertensive use was identified using
apreviouslyvalidatedalgorithmthatdefinedmedicationsinuse
if the most recent pharmacy fill provided a supply to last until
at least 60 days before admission.14,15
Time-stamped barcode–
administered medication data were used to identify inpatient
antihypertensive exposure (eTable 1 in Supplement 1).
Study Outcomes
Alloutcomeswereascertainedfollowingtheinitial48-hourex-
posure window and through hospital discharge. To further re-
duce confounding by indication, patients who experienced a
study outcome in the first 48 hours of hospitalization or were
discharged in the first 48 hours of hospitalization were ex-
cluded.
The primary outcome was a composite of inpatient mor-
tality, AKI, stroke, myocardial injury, B-type natriuretic pep-
tide(BNP)elevation,andintensivecareunit(ICU)transfer.Sec-
ondary outcomes included each component of the composite
outcome, as well as hypotensive episode (systolic BP <100 mm
Hg), length of stay, and discharge disposition. Acute kidney
injury was defined as a serum creatinine increase of greater
than or equal to 0.3 mg/dL or 1.5 times the maximum value
measuredduringthefirst48hoursofhospitalization.16,17
Stage
2 or greater AKI was examined as a secondary outcome and
defined as a serum creatinine increase of greater than or equal
to 0.5 mg/dL or 2 times the baseline value. Myocardial injury
was defined as an elevated troponin level (>0.029 ng/mL for
troponin T and >0.045 ng/mL for troponin I). B-type natri-
uretic peptide elevation was defined by an elevation greater
than 900 pg/mL, as the cohort consisted exclusively of older
adults.18
Stroke was identified by discharge diagnosis, using
present-on-admission indicators to exclude strokes that
occurred prior to hospitalization.19
Statistical Analysis
To account for confounding by indication, we used a propen-
sity score overlap weighting approach. First, a logistic regres-
sion model was developed to estimate the propensity of
receiving intensive treatment in the first 48 hours of hos-
pitalization. Covariates were derived from variables exam-
inedinpriorantihypertensivetrials20
andbyclinicalexpertise,21
including demographic characteristics, comorbidities, vital
signs, admission diagnosis, laboratory values, health care use,
and baseline medications (eTable 2 in Supplement 1). Race and
ethnicity were obtained from VA administrative records and
were ascertained through a 2-question self-identified method
included at the time of application for health benefits or clini-
cal visits to a VA facility. We examined race and ethnicity given
previously documented disparities in BP treatment patterns.
Missing data were imputed using the fully conditional speci-
fication method and 20 imputation sets.22
Overlap weights,
in which treated patients are weighted by the probability of not
receivingtreatmentanduntreatedpatientsareweightedbythe
probability of receiving treatment, were calculated.23,24
Sec-
ond, we assessed the association between receiving inten-
sive BP treatment and the primary composite outcome using
an overlap-weighted logistic regression model. Identical
models were constructed for each secondary outcome except
for length of stay, which was examined using an overlap-
weighted univariable negative binomial regression model.
Third, to evaluate the assumption that patients receiving more
intensive BP treatment early in hospitalization would con-
tinue to receive intensive treatment, we compared the num-
ber of antihypertensive doses administered and the change in
mean systolic BP following the first 48 hours of hospitaliza-
tion after overlap weighting. Fourth, to evaluate for effect
modification by route of antihypertensive administration, we
compared outcomes of patients who received intravenous an-
tihypertensives and those who received only new oral antihy-
pertensives in the first 48 hours of hospitalization by adding
an indicator variable to regression models denoting receipt of
any intravenous antihypertensives.
Subgroup and Sensitivity Analyses
We conducted 5 subgroup analyses to examine differential as-
sociations among the following groups hypothesized to be
more or less likely to benefit: patients older than 75 years, pa-
tients with frailty,25,26
patients with elevated outpatient BP
(>140/90 mm Hg), patients with cardiovascular disease,27
and
patients who experienced systolic BPs greater than 180 mm
Hg in the first 48 hours of hospitalization. eMethods 2 in
Supplement 1 contains additional detail on subgroup and sen-
sitivity analyses to assess the robustness of the findings with
different model specifications and to calculate E-values.28
Analyses were conducted between October 1, 2021, and Janu-
ary10,2023,usingSAS,version9.3(SASInstituteInc)andStata,
version 14.1 (StataCorp LLC) statistical software. Statistical
significance was determined using 95% CIs. A 2-sided P < .05
was considered significant.
Results
Characteristics of the Study Population
The study base consisted of 114 367 hospitalized patients, of
whom 66 140 (57.8%) had multiple elevated BPs in the first 48
hours of hospitalization and were included in the final cohort
(mean [SD] age, 74.4 [8.1] years; 97.5% male, 2.6% female; and
17.4% Black, 1.7% Hispanic, 75.9% White, 1.8% other race and
Intensive Blood Pressure Management in Hospitalized Older Adults Original Investigation Research
jamainternalmedicine.com (Reprinted) JAMA Internal Medicine July 2023 Volume 183, Number 7 717

ethnicity, and 3.3% unknown race and ethnicity) (eFigure 1 in
Supplement 1). In the first 48 hours, 14 084 patients (21.3%)
received intensive BP treatment, of whom 2504 (17.8%) re-
ceived intravenous antihypertensives. Patients receiving in-
tensive treatment had similar demographic characteristics to
those who did not receive intensive treatment, had higher sys-
tolic BPs prior to hospitalization (mean [SD], 140.4 [17.4] vs
135.2 [15.6] mm Hg), and were more likely to have a systolic
BP reading greater than 180 mm Hg in the first 48 hours (5326
of 14 064 [37.9%] vs 7913 of 52 076 [15.2%]). Following over-
lapweighting,allcovariateswereexactlybalancedonthemean
(Table 1; eTable 2 in Supplement 1).
Antihypertensive Treatments and Inpatient BP
Following First 48 Hours of Hospitalization
Patients who received intensive BP treatment in the first 48
hours received a greater number of additional antihyperten-
sivedosesduringtheremainderofhospitalization(meandoses
overall,6.1[95%CI,5.8-6.4]vs1.6[95%CI,1.5-1.8];meandoses
per day, 0.9 [95% CI, 0.9-1.0] vs 0.3 [95% CI, 0.3-0.3]) (eFig-
ure 2 in Supplement 1).
During the post–48-hour period, mean systolic BPs were
slightly lower for the intensively treated group (mean sys-
tolic BP, 138.0 mm Hg; 95% CI, 137.7-138.3 mm Hg) compared
with the untreated group (mean systolic BP, 139.4 mm Hg;
95% CI, 139.2-139.6 mm Hg) (Figure 1). Comparing the first 48
hours with the post–48-hour period, patients receiving inten-
sive BP treatment had a 5.5-mm Hg (95% CI, 5.8-5.3 mm Hg)
reduction in mean systolic BP; this change was modestly larger
than the observed reduction in the untreated group (mean, 4.1
mm Hg; 95% CI, 4.3-4.0 mm Hg).
Clinical Outcomes of Intensive Inpatient
Antihypertensive Treatment
Patients receiving intensive BP treatment were more likely to
experience the primary composite outcome (1220 [8.7%] vs
3570 [6.9%]; weighted odds ratio [OR], 1.28; 95% CI, 1.18-
1.39), corresponding to a number needed to harm of 56
(95% CI, 37-75). Intensively treated patients were also more
likely to experience each of the individual components of the
composite outcome except for stroke, which occurred infre-
quently, and mortality, which was not significant (Figure 2).
Intensively treated patients were also more likely to experi-
ence a hypotensive episode with systolic BP less than 100 mm
Hg (2078 [14.8%] vs 7283 [14.0%]; weighted OR, 1.22; 95% CI,
1.15-1.30). Intensively treated patients were less likely to be
discharged home (11 936 [84.9%] vs 45 372 [87.1%]; weighted
OR, 0.89; 95% CI, 0.83-0.94).
Receipt of Intravenous vs Oral Antihypertensives
Compared with patients who received only new oral antihy-
pertensives in the first 48 hours of hospitalization, patients
who received intravenous antihypertensives received a greater
meannumberofadditionalintravenousantihypertensivedoses
during the remainder of hospitalization (1.4 [95% CI, 1.2-1.6]
vs 0.1 [95% CI, 0.1-1.2]). Compared with patients who did not
receive intensive treatment, receipt of intravenous antihyper-
tensives was associated with greater odds of the primary out-
come(weightedOR,1.90;95%CI,1.65-2.19)thanreceiptofonly
oral antihypertensives (weighted OR, 1.15; 95% CI, 1.05-1.26;
P for interaction < .001) (Table 2). Patients who received in-
travenous antihypertensives also had an increased odds of in-
patient mortality (weighted OR, 1.79; 95% CI, 1.26-2.53), while
those receiving only oral antihypertensives did not (weighted
OR, 0.96; 95% CI, 0.76-1.21; P for interaction = .008).
Prespecified Subgroup Analyses by Age, Frailty, Outpatient
BP, History of Cardiovascular Disease, and Initial BP
Intensive inpatient BP treatment was associated with higher
rates of the primary outcome across each subgroup, except for
patients with a maximum systolic BP of greater than or equal
to 180 mm Hg in the first 48 hours, who had a weighted odds
of the primary outcome of 1.15 (CI, 0.997-1.33) (Figure 3). There
was little heterogeneity in primary and secondary outcomes
between subgroups defined by age, frailty, baseline BP, and
cardiovascular disease (eTables 3-7 in Supplement 1).
Sensitivity Analyses
SensitivityanalysesshowedthatORsacrosseachanalyticstruc-
ture were qualitatively consistent with the primary analysis,
with intensive inpatient BP treatment associated with higher
rates of the primary outcome across each model specification
(eTable 8 in Supplement 1), with similar patterns seen for each
individual secondary outcome (eTable 9 in Supplement 1).
The E-value for nonnull associations was 1.88 for the primary
composite outcome.
Discussion
In this retrospective cohort study of hospitalized older adults
who experienced elevated inpatient BPs, we found that 1 in 5
patients received intensive treatment in the first 48 hours of
hospitalization, and receipt of intensive treatment was asso-
ciated with a greater odds of adverse clinical outcomes, in-
cluding cardiac injury, AKI, and ICU transfer. Receipt of intra-
venous antihypertensives was associated with an even greater
risk of adverse clinical outcomes compared with receipt of oral
antihypertensives. Results were consistent across subgroups
defined by age, frailty, outpatient BP control, and history of
cardiovascular disease. These findings suggest that the com-
mon practice of acutely treating asymptomatic inpatient BPs
could be harmful.
Our findings build on prior observational studies.3,11
Con-
sistent with Rastogi et al,3
we found higher rates of AKI and
myocardial injury. We did not observe differences in stroke or
mortality as observed by Mohandas et al,11
except in the sub-
group of patients receiving intravenous antihypertensives,
which may reflect the exclusion in our study of patients ad-
mitted with potential hypertensive emergencies. Prior litera-
tureexaminingtheimmediateeffectofBPtreatmenthasdocu-
mented a potential pathway for the observed harms in which
BP immediately declines by greater than 25% over the course
of hours, leading to a risk for tissue hypoperfusion.8,29-31
Intravenous antihypertensives have a greater immediate
BP-lowering effect than oral medications,30
and while both

Table 1. Cohort Characteristics, Before and After Propensity Score Overlap Weightinga
Unadjusted After overlap weighting
Not intensively
treated (n = 52 076)
Intensively treated
(n = 14 064) SMD
Not intensively treated
(n = 52 076)
Intensively treated
(n = 14 064) SMD
Demographic characteristics
Age, mean (SD), y 74.5 (8.1) 74.1 (7.9) 0.05 74.3 (10.3) 74.3 (5.4) <0.001
Sex, %
Male 97.4 97.6
0.01
97.4 97.4
<0.001
Female 2.6 2.4 2.6 2.6
Race and ethnicity, %
0.09 <0.001
Black 16.7 (19.9 18.1 18.1
Hispanic 1.7 1.4 1.5 1.5
White 76.6 73.4 75.1 75.1
Otherb
1.8 1.6 1.7 1.7
Unknown 3.2 3.7 3.6 3.6
Preadmission health
Systolic BP, mean (SD), mm Hg 135.2 (15.6) 140.4 (17.4) −0.31 138.3 (20.6) 138.3 (10.9) <0.001
Diastolic BP, mean (SD), mm Hg 73.8 (9.3) 75.9 (10.1) −0.21 75.1 (12.0) 75.1 (6.4) <0.001
Creatinine, mean (SD), mg/dL 1.1 (0.6) 1.1 (0.7) 0.03 1.1 (0.9) 1.1 (0.4) <0.001
Frailty index, mean (SD) 0.2 (0.1) 0.2 (0.1) 0.02 0.2 (0.2) 0.2 (0.1) <0.001
Charlson Comorbidity Index, mean (SD) 4.5 (3.3) 4.3 (3.3) 0.08 4.3 (4.1) 4.3 (2.2) <0.001
Comorbidities, %
Atrial fibrillation 21.2 21.8 0.01 21.5 21.5 <0.001
Alzheimer disease 20.4 20.7 0.01 20.4 20.4 <0.001
Acute myocardial infarction 4.4 4.7 0.01 4.4 4.4 <0.001
Chronic kidney disease 47.4 47.2 <0.01 46.1 46.1 <0.001
COPD 43.9 38.6 0.11 40.3 40.3 <0.001
Diabetes 49.8 50.1 0.01 48.6 48.6 <0.001
Heart failure 24.3 23.7 0.01 23.2 23.2 <0.001
Hypertension 87.0 89.0 0.06 87.5 87.5 <0.001
Ischemic heart disease 40.0 39.8 0.01 38.6 38.6 <0.001
Stroke or TIA 13.7 13.9 <0.01 13.4 13.4 <0.001
Malignant neoplasm 30.8 25.9 0.11 27.8 27.8 <0.001
Metastatic malignant neoplasm 7.5 5.7 0.07 6.4 6.4 <0.001
Admission medications, %
Angiotensin-converting enzyme inhibitors 35.7 21.9 0.31 25.6 25.6 <0.001
α-Blockers 35.9 24.2 0.26 28.1 28.1 <0.001
Angiotensin II receptor blockers 12.1 7.6 0.15 8.9 8.9 <0.001
β-Blockers 47.8 26.9 0.44 33.0 33.0 <0.001
Calcium channel blockers 33.9 19.6 0.33 23.9 23.9 <0.001
Clonidine 1.6 1.6 <0.01 1.6 1.6 <0.001
Hydralazine 4.1 3.0 0.06 3.4 3.4 <0.001
Potassium-sparing diuretics 5.7 3.1 0.12 3.8 3.8 <0.001
Thiazide-type diuretics 16.1 10.4 0.17 12.1 12.1 <0.001
Loop diuretics 22.5 13.7 0.23 16.3 16.3 <0.001
Statins 56.9 36.6 0.41 42.8 42.8 <0.001
Reason for hospital admission, %
Respiratory 21.9 19.6
0.17
20.9 20.9
<0.001
Digestive 14.5 13.7 14.1 14.1
Neoplasms 7.6 6.6 7.0 7.0
Injury or poisoning 6.9 6.9 7.0 7.0
Genitourinary 6.6 6.3 6.2 6.2
Endocrine, nutrition, metabolic 6.5 7.5 6.9 6.9
Infectious diseases 6.2 5.2 5.5 5.5
Mental illness 6.1 5.8 5.7 5.7
Skin or soft tissue 5.6 6.0 5.7 5.7
Musculoskeletal 5.5 9.3 7.8 7.8
Neurologic 5.0 5.3 5.3 5.3
Symptoms/signs 4.0 4.1 4.1 4.1
Hematologic 2.5 2.2 2.2 2.2
Other 1.1 1.4 1.4 1.4
(continued)

formulations have been associated with immediate BP lower-
ing of greater than 25%,8
this is more common with intrave-
nousmedications,occurringasoftenasone-thirdofthetime.31
This association between immediate BP lowering and risk for
harms is consistent with our findings of greater risks of ad-
verse outcomes among patients receiving intravenous antihy-
pertensives and an additional observational study of intrave-
nous antihypertensives for severely elevated BPs that found
an association with increased risk for myocardial injury.32
It remains possible that unmeasured confounders, such as re-
quirements for nothing by mouth, could be associated with re-
ceipt of intravenous treatment and adverse outcomes.
None of these studies found signals of benefit from more
intensive treatment of elevated inpatient BPs; however, pro-
spective randomized clinical trials are necessary to overcome
the risk of unmeasured confounding inherent in each study.
The design of such trials may be difficult given the heteroge-
neity of reasons for hospitalization. One path forward may be
for trials designed to assess treatment thresholds across inpa-
tient settings (medical, surgical, ICU) and levels of cardiovas-
cular risk.
In the absence of randomized trial data, our findings sug-
gest that the safest path forward may be to rethink the under-
lying reason for inpatient BP measurement and reorient clini-
cal practice. Distinguishing symptomatic and asymptomatic
inpatienthypertensionremainsthekeydecisionpoint,aspath-
ways for treatment of specific symptomatic syndromes are
more clearly defined and evidence based.21
For patients with
asymptomatic elevated BP recordings, increased emphasis on
correct measurement, confirmation of elevated BP, and evalu-
ation for reversible factors of transient elevations may re-
duce the risk of overtreatment.32
Use of intravenous antihy-
pertensives should be discouraged. Management of elevated
inpatient BP might be reenvisioned as similar to the manage-
Table 1. Cohort Characteristics, Before and After Propensity Score Overlap Weightinga
(continued)
Unadjusted After overlap weighting
Not intensively
treated (n = 52 076)
Intensively treated
(n = 14 064) SMD
Not intensively treated
(n = 52 076)
Intensively treated
(n = 14 064) SMD
First 48 h of hospitalization
≥1 Systolic BP reading ≥180 mm Hg, % 15.2 37.9 0.53 29.5 29.5 0.03
Systolic BP categories, %
≥2 Readings 140-159/90-99 mm Hg 63.8 39.6
0.61
47.6 47.6
<0.001
≥2 Readings 160-179 mm Hg 30.6 37.0 37.4 37.4
≥2 Readings ≥180 mm Hg 5.6 23.4 15.0 15.0
BP measurements
Systolic BP, mean (SD), mm Hg 138.9 (12.0) 146.8 (15.6) −0.57 143.7 (16.5) 143.7 (9.6) <0.001
Maximum systolic BP, mean (SD), mm Hg 164.2 (14.8) 174.6 (19.8) −0.59 170.5 (21.4) 170.5 (11.8) <0.001
Minimum systolic BP, mean (SD), mm Hg 114.4 (15.0) 119.1 (17.2) −0.29 117.4 (20.1) 117.4 (10.9) <0.001
Count BPs >140/90 mm Hg, mean (SD) 5.4 (3.3) 7.5 (4.6) −0.51 6.7 (4.9) 6.7 (2.7) <0.001
Kidney function
Maximum creatinine, mean (SD), mg/dL 1.3 (0.5) 1.3 (0.6) −0.04 1.3 (0.7) 1.3 (0.4) <0.001
Abbreviations: BP, blood pressure; COPD, chronic obstructive pulmonary
disease; SMD, standardized mean difference; TIA, transient ischemic attack.
a
Missing data, prior to imputation, were as follows: prehospitalization
creatinine (n = 2167), outpatient systolic BP (n = 11), and outpatient diastolic
BP (n = 11). Overlap weighting leads to an exact balance on the mean for all
covariates included in the propensity score model.
b
Other race and ethnicity included American Indian or Alaska Native, Asian,
and Native Hawaiian or other Pacific Islander.
Figure 1. Change in Mean Systolic Blood Pressure (BP) by Treatment Group
180
200
160
140
120
100
–120
Mean
systolic
BP,
mm
Hg
Mean systolic BP in first 48 h and subsequent hospital stay
A
Post 48 h
First 48 h
Treatment intensity
Not intensively treated Intensively treated
40
20
0
–20
–40
Change
in
mean
systolic
BP,
mm
Hg
Change in mean systolic BP following first 48 h
B
Treatment intensity
Not intensively treated Intensively treated
Boxes represent median and IQR, with whiskers representing the upper and lower adjacent values. Results reflect overlap-weighted cohorts.

ment of inpatient sinus tachycardia, for which the focus is on
treating the underlying disorder rather than routinely pre-
scribing antiarrhythmics.
Thus, for patients with persistently elevated inpatient
BPs, should initiation of a daily oral antihypertensive be con-
sidered? Our findings should be considered in conjunction
with studies indicating that intensification of outpatient
antihypertensive therapy at hospital discharge may be asso-
ciated with both adverse posthospital outcomes and low
persistence to discharge medications,3,4,7
as well as studies
indicating that the time to benefit from BP lowering accrues
over years.6,33,34
In combination, these findings suggest that
pharmacologic treatment of asymptomatic elevated inpa-
tient BP should be the exception rather than the rule.
Instead, concerns of persistently elevated inpatient BPs
should be communicated to patients and their outpatient cli-
nicians for close follow-up, and if uncontrolled hypertension
is confirmed in the outpatient setting, a decision to intensify
antihypertensive treatment can be made after recovery
from acute illness.
Limitations
Our study has several limitations. First, the VHA is a large, na-
tional, integrated health system, but it serves a predomi-
Figure 2. Clinical Outcomes of Intensive Inpatient Antihypertensive Treatment
Intensively
treated, No. (%)
(n=14064)
Not intensively
treated, No. (%)
(n=52076) OR (95% CI)
Primary outcome
1220 (8.7) 3570 (6.9)
Composite 1.28 (1.18-1.39)
Clinical outcome
156 (1.1) 573 (1.1)
Death 1.11 (0.91-1.37)
21 (0.2) 43 (0.1)
Stroke 1.46 (0.77-2.78)
38 (0.3) 95 (0.2)
BNP elevation 1.81 (1.16-2.82)
227 (1.6) 710 (1.4)
Troponin elevation 1.20 (1.00-1.43)
2078 (14.5) 7283 (14.0)
Hypotension 1.22 (1.15-1.30)
408 (2.9) 1322 (2.5)
ICU transfer 1.20 (1.05-1.37)
Disposition
1714 (12.2) 5239 (10.1)
SNF discharge 1.12 (1.04-1.20)
11936 (84.9) 45372 (87.1)
Home 0.89 (0.83-0.94)
AKI
769 (5.5) 2031 (3.9)
Any stage 1.43 (1.29-1.58)
165 (1.2) 440 (0.8)
Stage 2 or 3 1.34 (1.08-1.66)
0.5 3
2
1
OR (95% CI)
Event rates presented for each
treatment group are unadjusted,
while odds ratios (ORs) are following
overlap weighting. Composite
outcome includes mortality, intensive
care unit (ICU) transfer, any-stage
acute kidney injury (AKI), stroke,
troponin elevation, or B-natriuretic
peptide (BNP) elevation.
Hypotension defined as any systolic
blood pressure less than 100 mm Hg
in the post–48-hour hospitalization
period. SNF indicates skilled nursing
facility.
Table 2. Clinical Outcomes of Intensive Inpatient Antihypertensive Treatment by Use
of Intravenous vs Oral Antihypertensives
OR (95% CI)
P value for
interaction
Overall
Route of antihypertensive administration
Oral only Any intravenous
No. of patients exposed to
intensive BP treatment
14 064 11 560 2504 NA
Primary outcome
Compositea
1.28 (1.18-1.39) 1.15 (1.05-1.26) 1.90 (1.65-2.19) <.001
Clinical outcome
Death 1.11 (0.91-1.37) 0.96 (0.76-1.21) 1.79 (1.26-2.53) .008
ICU transfer 1.23 (1.09-1.39) 0.92 (0.79-1.07) 2.54 (2.08-3.11) <.001
AKI, any stage 1.43 (1.29-1.58) 1.38 (1.23-1.54) 1.63 (1.34-1.97) .14
AKI, stage 2 or 3 1.34 (1.08-1.66) 1.30 (1.03-1.64) 1.53 (1.02-2.28) .47
Stroke 1.46 (0.77-2.78) 1.19 (0.58-2.44) 2.67 (1.02-7.04) .23
BNP elevation 1.81 (1.16-2.82) 1.88 (1.18-2.99) 1.47 (0.54-4.10) .62
Troponin elevation 1.20 (1.00-1.43) 1.09 (0.90-1.33) 1.67 (1.22-2.31) .03
Hypotension (systolic BP
<100 mm Hg)
1.22 (1.15-1.30) 1.21 (1.13-1.29) 1.27 (1.12-1.44) .48
Disposition
SNF discharge 1.12 (1.04-1.20) 1.13 (1.05-1.21) 1.06 (0.92-1.22) .40
Home 0.89 (0.83-0.94) 0.90 (0.84-0.96) 0.83 (0.73-0.94) .25
Abbreviations: AKI, acute kidney
injury; BNP, B-type natriuretic
peptide; BP, blood pressure;
ICU, intensive care unit; NA, not
applicable; OR, odds ratio;
SNF, skilled nursing facility.
a
Composite outcome includes
mortality, ICU transfer, any-stage
AKI, stroke, troponin elevation,
or BNP elevation. Odds ratios
presented are following overlap
weighting.

nately male population with greater multimorbidity that may
not be generalizable to the entire US. Second, because we fo-
cused on older adults who may be at higher risk of in-hospital
adverse outcomes, our findings are not generalizable to
younger populations. Third, although we used validated phar-
macy database methods to identify baseline and inpatient an-
tihypertensive exposure, these methods could misclassify pa-
tients who stopped home antihypertensives in the immediate
prehospitalizationperiod,14,15
biasingresultstothenull.Fourth,
we used biomarkers to identify cardiac injury rather than ad-
judicated clinical events, and these tests were not performed
for all patients. Fifth, although we sought to exclude patients
admittedforahypertensiveemergency,moresubjectivesymp-
toms may not have been identified (eg, hypertensive encepha-
lopathy). Sixth, because of the observational study design, we
cannot exclude the possibility of unmeasured confounding;
E-value analysis indicates that a confounder associated with
treatment and the primary outcome by an OR of 1.88 would
be necessary to fully account for the observed findings.
Conclusions
In this cohort study using VHA data of a predominately male
population with multiple morbidities, we found that 21% of
older adults with elevated inpatient BP recordings received
intensive antihypertensive treatment in the first 48 hours of
hospitalization and that receipt of intensive treatment was
associated with a greater odds of adverse events, including
cardiac injury, AKI, and ICU transfer. Our findings do not
support the pharmacologic treatment of elevated BPs with-
out evidence of acute end organ damage in hospitalized
older adults and highlight the need for adequately powered
randomized clinical trials of BP treatment thresholds in the
inpatient setting.
ARTICLE INFORMATION
Accepted for Publication: March 24, 2023.
Published Online: May 30, 2023.
doi:10.1001/jamainternmed.2023.1667
Author Contributions: Dr Anderson had full access
to all of the data in the study and takes
responsibility for the integrity of the data and the
accuracy of the data analysis.
Concept and design: Anderson, Jing, Steinman.
Acquisition, analysis, or interpretation of data:
All authors.
Drafting of the manuscript: Anderson.
Critical revision of the manuscript for important
intellectual content: All authors.
Statisticalanalysis:Anderson,Jing,Boscardin,Fung.
Obtained funding: Anderson.
Administrative, technical, or material support:
Steinman.
Supervision: Herzig, Marcantonio, Steinman.
Conflict of Interest Disclosures: Dr Anderson
reported receiving grants from the American Heart
Association and Boston Pepper Center outside the
submitted work. Dr Steinman reported receiving
honoraria from UpToDate for chapter authorship
and the American Geriatrics Society for guideline
development outside the submitted work. No other
disclosures were reported.
Funding/Support: This study was supported by
grants R03 AG064373 and K76 AG074878
(Dr Anderson); K24 AG049057, P30 AG044281,
and R24 AG064025 (Dr Steinman); and K24
AG0350750 (Dr Marcantonio) from the National
Institute on Aging and a Bellows Geriatric
Cardiology Career Development Award from the
American College of Cardiology (Dr Anderson).
Role of the Funder/Sponsor: The funders had no
role in the design and conduct of the study;
collection, management, analysis, and
interpretation of the data; preparation, review, or
approval of the manuscript; and decision to submit
the manuscript for publication.
Disclaimer: The views expressed herein are those
of the authors and do not necessarily represent the
views of the National Institute on Aging, American
College of Cardiology, US Department of Veterans
Affairs, the University of California, San Francisco,
Harvard University, or Beth Israel Deaconess
Medical Center.
Data Sharing Statement: See Supplement 2.
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