Original Investigation | Cardiology

Association of β-Blocker Use With Heart Failure Hospitalizations

and Cardiovascular Disease Mortality Among Patients With Heart Failure
With a Preserved Ejection Fraction
A Secondary Analysis of the TOPCAT Trial
Daniel N. Silverman, MD; Timothy B. Plante, MD, MHS; Margaret Infeld, MD, MS; Peter W. Callas, PhD; Stephen P. Juraschek, MD, PhD;
Geoff B. Dougherty, PhD, MPH; Markus Meyer, MD

Abstract Key Points

Question Is there an association of
IMPORTANCE β-Blockers are prescribed to most patients with heart failure (HF) with a preserved
β-blocker use with heart failure
ejection fraction (HFpEF), but their effect on HFpEF remains unclear.
hospitalizations and cardiovascular
disease mortality among patients with
OBJECTIVE To determine the association of β-blocker use with HF hospitalizations and
heart failure with a preserved ejection
cardiovascular disease (CVD) mortality, overall and in strata of patients with an ejection fraction (EF)
fraction?
of 50% or greater or less than 50%.
Findings In this secondary analysis of
DESIGN, SETTING, AND PARTICIPANTS For 1761 participants from North and South America the Treatment of Preserved Cardiac
enrolled in the multicenter, double-blinded Treatment of Preserved Cardiac Function Heart Failure Function Heart Failure with an
with an Aldosterone Antagonist randomized clinical trial of spironolactone for patients with HFpEF Aldosterone Antagonist randomized
between August 10, 2006, and January 31, 2012, the association of baseline β-blocker use with HF clinical trial of spironolactone for
hospitalization and CVD mortality was analyzed using unadjusted and adjusted Cox proportional patients with heart failure with a
hazards regression models, overall and in strata of patients with an EF of 50% or greater or less than preserved ejection fraction of 50% or
50%. Participants had symptomatic HF with a left ventricular EF of 45% or greater, with enrollment greater, β-blocker use was associated
based on either hospitalization attributed to decompensated HF in the prior year or elevated with a higher risk of heart failure
natriuretic peptide levels. Statistical analysis was performed from January 31 to May 2, 2019. hospitalizations compared with patients
not taking β-blockers. This association
EXPOSURE Use of β-blockers. was not present among patients with an
ejection fraction between 45%
MAIN OUTCOMES AND MEASURES Incident HF hospitalization and CVD mortality. and 49%.

Meaning Prospective studies of the role

RESULTS Among 1761 participants included in the analysis (879 women and 882 men; mean [SD]
β-blockers play in heart failure among
age, 71.5 [9.6] years), 1394 (79.2%) reported β-blocker use and 1567 (89.0%) had an EF of 50% or
patients with a preserved ejection
greater. Hospitalizations for HF occurred for 399 participants (22.7%), and CVD mortality occurred
fraction appears to be warranted to
for 229 participants (13.0%). Use of β-blockers was associated with a higher risk of HF hospitalization
clarify the effectiveness of these drugs
among patients with HFpEF with an EF of 50% or greater (hazard ratio, 1.74 [95% CI, 1.28-2.37];
for patients with an ejection fraction of
P < .001) but not among patients with an EF between 45% and 49% (hazard ratio, 0.68 [95% CI,
50% or greater.
0.28-1.63]; P = .39). There was a significant interaction between β-blocker use and EF threshold for
incident HF hospitalizations (P = .03). Use of β-blockers was not associated with a change in CVD
mortality. + Supplemental content
Author affiliations and article information are
CONCLUSIONS AND RELEVANCE For patients with an EF of 50% or greater, β-blocker use was listed at the end of this article.

associated with an increased risk of HF hospitalizations but not CVD mortality. For patients with an
EF between 45% and 49%, there was no such association.

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Open Access. This is an open access article distributed under the terms of the CC-BY License.

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 JAMA Network Open | Cardiology Association of β-Blocker Use With HF Hospitalizations and CVD Mortality Among Patients With HF With a Preserved EF

Introduction
Heart failure (HF) is a leading cause of hospitalizations and is associated with increased health care
costs.1,2 More than half of the patients with HF have a preserved ejection fraction (HFpEF), defined as
an ejection fraction (EF) of 50% or greater. Heart failure with a preserved EF continues to increase
in prevalence and is associated with a high rate of hospitalization, yet, to our knowledge, evidenced-
based therapies are lacking.1-4
β-Adrenergic receptor blockers (β-blockers) provide an unequivocal benefit in the treatment of
chronic HF with a reduced EF (HFrEF), with a strong foundation of evidence to support their use.5-11
Most patients with HFpEF enrolled in contemporary clinical trials or in published cohorts also receive
β-blockers, despite an uncertain benefit.12-17 A recent patient-based meta-analysis of 11 randomized
β-blocker HF trials that enrolled patients with HFrEF also included a small number of patients with
HFpEF.18 This analysis reinforced the benefit of β-blockers for patients with a reduced EF but did not
demonstrate any benefit for patients with an EF greater than 50%.
To extend our understanding of the role β-blockers play in HFpEF, we performed an analysis of
data from participants randomized in the Treatment of Preserved Cardiac Function Heart Failure with
an Aldosterone Antagonist (TOPCAT) clinical trial. The primary focus of this analysis was to
investigate the association of β-blocker use with HF hospitalizations among patients at different EF
thresholds.11

Methods
TOPCAT Trial Design
The TOPCAT trial and its design have been previously described in detail, as have its main results.19,20
The trial was an international, multicenter, double-blinded, randomized clinical trial of the
aldosterone antagonist spironolactone for patients with HFpEF, defined as symptomatic HF at the
time of screening and within the preceding 12 months in patients with a left ventricular EF of 45% or
greater. Enrollment took place between August 10, 2006, and January 31, 2012, with mean follow-up
of 3.3 years, and was based on either a hospitalization attributed to decompensated HF in the
preceding year or elevated brain natriuretic peptide (BNP) or N-terminal pro BNP (NT-proBNP) levels
(BNP level ⱖ100 pg/mL [to convert to nanograms per liter, multiply by 1.0] or NT-proBNP level ⱖ360
pg/mL) within 60 days of screening.19,20 The initial comprehensive baseline visit included a detailed
medical history of comorbidities, social history, risk factor documentation, medication survey, quality
of life questionnaire, and assessment of physical activity and medications. Not all follow-up visits
included a medication inventory.20 The University of Vermont Institutional Review Board deemed
this research to be exempt from review as it was a retrospective analysis performed on a deidentified
data set. Enrolled patients provided written informed consent. This study followed the Consolidated
Standards of Reporting Trials (CONSORT) reporting guideline.

Analyzed Population
We used the deidentified TOPCAT database from the National Heart, Lung, and Blood Institute
Biologic Specimen and Data Repositories Information Coordinating Center. Because of reported trial
quality concerns in some regions, we analyzed the data only from South America and North
America.21-23 Patients without a baseline EF and those without a recorded baseline visit were also
excluded. We used baseline and follow-up medication logs to chart β-blocker use.

Statistical Analysis
Statistical analysis was performed from January 31 to May 2, 2019. Baseline characteristics were
tabulated by use of a β-blocker vs no use of a β-blocker. β-Blocker use itself was defined as the receipt
of any β-blocker at the baseline visit. To assess the association between β-blockers and incident HF
hospitalizations, hazard ratios were calculated comparing baseline β-blocker use vs no β-blocker use

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 JAMA Network Open | Cardiology Association of β-Blocker Use With HF Hospitalizations and CVD Mortality Among Patients With HF With a Preserved EF

and stratified by an EF of 50% or greater or less than 50%. This threshold was chosen because it
allows for a clinically meaningful separation between HF phenotypes as recommended by current
guidelines.5,6 In a minimally adjusted covariate model, we corrected for age, sex, race/ethnicity, and
treatment assignment (spironolactone or placebo). In the fully adjusted model, baseline myocardial
infarction, atrial fibrillation, chronic obstructive pulmonary disease, asthma, and hypertension were
added to the minimally adjusted model. This analysis was repeated for cardiovascular disease (CVD)
mortality. Schoenfeld residuals were examined to confirm no violation of the assumptions of the Cox
proportional hazards regression model.
The association between level of baseline EF and relative hazard of HF hospitalization for those
receiving β-blockers or not in the fully adjusted model was presented using restricted cubic spline
models with 95% CIs relative to the median. Knots were not prespecified and were chosen using the
Harrell method.24 The distribution of the baseline EF in both groups by HF hospitalizations was
visualized using kernel density plots.
We performed a sensitivity analysis among the participants whose β-blocker status was
constant from baseline through each follow-up visit, censoring at the end of follow-up or at the first
HF hospitalization. In this population with consistent documentation of β-blocker or no β-blocker
use, we calculated relative hazards using the unadjusted, minimally adjusted, and fully adjusted
models for HF hospitalizations overall and in the prespecified EF strata. In a second sensitivity
analysis among the participants whose β-blocker status was constant, propensity scores were
created using 30 baseline demographic, anthropometric, medication, and medical history patient
characteristics. Up to 3 patients receiving β-blockers were matched to each patient not receiving a
β-blocker. Heart failure hospitalization was analyzed for the propensity score–matched data using
stratified Cox proportional hazards regression, with the matched sets as the stratifying variable.
To provide some pathomechanistical insights, we compared BNP and NT-proBNP levels at
baseline by β-blocker status overall and stratified by an EF of 50%. We compared log-transformed
baseline levels of BNP and NT-proBNP using unadjusted 2-tailed t tests. We visualized distributions of
the quartiles of the BNPs and NT-proBNPs and the midrange of each quartile among those with an
EF of 50% or greater using stacked bar graphs.
The analyses were performed with Stata MP, version 15.1 (StataCorp) and the SAS, version 9.4
procedure PSMATCH (SAS Institute Inc) for the propensity score matching. We considered a 2-tailed
P < .05 to be statistically significant.

Results
Study Population
Among the 1767 TOPCAT participants from North America and South America, the mean (SD) age
was 71.5 (9.6) years; 879 participants were women and 882 were men, and 1378 participants were
white. Six participants were excluded because of missing EF data or missing baseline visit data
(Figure 1). The final analytic population was 1761. Median follow-up was 2.4 years (interquartile
range, 1.4-3.9 years).
A total of 1394 participants (79.2%) were receiving β-blockers at baseline and 1567 (89.0%) had
an EF of 50% or greater (Table 1). Irrespective of β-blocker use, most patients had preexisting
hypertension. The prevalence of atrial fibrillation was 42.6% (594 of 1393) among those receiving a
β-blocker and 40.7% (149 of 366) among those not receiving a β-blocker, and the prevalence of prior
myocardial infarction was 22.1% (308 of 1395) among those receiving a β-blocker and 13.7% (46 of
336) among those not receiving a β-blocker. The proportion of patients with an advanced functional
impairment (New York Heart Association class ⱖ3) was almost identical between groups.

HF Hospitalizations and CVD Mortality

Overall, 399 patients (22.7%) underwent hospitalization for HF (β-blocker group, 344 of 1394
[cumulative incidence, 24.7%; unadjusted incidence rate, 96 per 1000 person-years; 95% CI,

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 JAMA Network Open | Cardiology Association of β-Blocker Use With HF Hospitalizations and CVD Mortality Among Patients With HF With a Preserved EF

86-106]; no β-blocker group, 55 of 367 [cumulative incidence, 15.0%; unadjusted incidence rate, 56
per 1000 person-years; 95% CI, 43-73]). In the fully adjusted model, there was a higher incidence
of HF hospitalizations among patients with an EF of 50% or greater who were receiving β-blockers
(Table 2) compared with those not receiving β-blockers (hazard ratio, 1.74 [95% CI, 1.28-2.37];
P < .001) (Figure 2). There was a significant interaction between an EF threshold, β-blocker use, and
incident HF hospitalization (P = .03); higher EFs were associated with an increased risk for HF
hospitalizations among patients receiving β-blockers (Figure 3).24 Patients with the highest EFs who

Figure 1. Flow Diagram of Trial Participants

3445 Participants in the TOPCAT trial

1678 Excluded from Russia and Georgia

1767 Participants from the Americas

6 Excluded
1 Missing data on ejection fraction Flow diagram of patient inclusions and exclusions
5 Missing data on baseline visit
leading to the analyzed population. TOPCAT indicates
Treatment of Preserved Cardiac Function Heart Failure
1761 Included TOPCAT trial participants
with an Aldosterone Antagonist.

Table 1. Baseline Characteristics of Participantsa

Characteristic No β-Blocker (n = 367 [20.8%]) β-Blocker (n = 1394 [79.2%])

Spironolactone 187 (51.0) 696 (49.9)
Age, mean (SD), y 72.4 (10.2) 71.3 (9.5)
Female sex 207 (56.4) 672 (48.2)
Race/ethnicity
White 291 (79.3) 1087 (78.0)
Black 59 (16.1) 243 (17.4)
Asian 7 (1.9) 12 (0.9)
Other 11 (3.0) 59 (4.2)
Hispanic 100 (27.2) 213 (15.3)
Anthropometric data, mean (SD)
Heart rate, beats per min 71 (13) 69 (11)
BP, mm Hg
Systolic 129 (16) 127 (16)
Diastolic 73 (12) 71 (11)
BMI 34 (9) 34 (8)
EF or heart failure
EF, mean (SD) 59.2 (7.7) 57.9 (7.8)
EF ≥50% 337 (91.8) 1229 (88.2)
EF ≥60% 201 (54.8) 654 (46.9)
NYHA class ≥3 124/364 (34.1) 494/1393 (35.5)
Medical history
Myocardial infarction 50 (13.6) 308/1393 (22.1)
Hypertension 312 (85.0) 1273/1393 (91.4)
Atrial fibrillation 149 (40.6) 594/1393 (42.6)
Abbreviations: ACEI, angiotensin converting enzyme
Medications inhibitor; ARB, angiotensin receptor blocker; BMI,
ACEI, ARB, aliskiren 296 (80.7) 1099 (78.8) body mass index (calculated as weight in kilograms
Diuretic 315 (85.8) 1258 (90.2) divided by height in meters squared); BP, blood
pressure; EF, ejection fraction; NYHA, New York Heart
Thiazide 106 (28.9) 341 (24.5)
Association.
Loop diuretic 257 (70.0) 1128 (80.9)
a
Data are presented as number (percentage) of
Calcium channel blocker 166 (45.2) 516 (37.0)
patients unless otherwise indicated.

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 JAMA Network Open | Cardiology Association of β-Blocker Use With HF Hospitalizations and CVD Mortality Among Patients With HF With a Preserved EF

did not receive β-blockers were least likely to be admitted for HF. There was a nonsignificant trend
toward a lower incidence of HF hospitalizations among patients with an EF between 45% and 49%
who were receiving β-blockers (hazard ratio, 0.68 [95% CI, 0.28-1.63]; P = .39). Cardiovascular
disease mortality occurred among 229 participants (13.0%); β-blockers were not significantly
associated with a change in CVD mortality (eTable 6 and eFigure 1 in the Supplement).
The sensitivity analysis that considered HF hospitalizations among patients who either
continued receiving a β-blocker or who never received a β-blocker through the end of follow-up or
first HF hospitalization confirmed the principal findings (eTable 1 in the Supplement). In the fully
adjusted model, patients with an EF of 50% or greater receiving β-blockers had a higher relative
hazard of HF hospitalization compared with those not receiving β-blockers (hazard ratio, 1.76 [95%
CI, 1.22-2.53]; P = .007). In a second sensitivity analysis of propensity score–matched cohorts,
β-blocker use was also associated with more HF hospitalizations among patients with EFs of 50% or
greater (eTable 2 and eTable 3 in the Supplement). This analysis also confirmed that patients
receiving β-blockers who had higher EFs had an associated risk of being hospitalized for HF.

BNP and NT-proBNP Levels

β-Blocker use was associated with higher NT-proBNP and BNP levels in patients with an EF of 50%
or greater (eTable 5 and eFigure 2 in the Supplement). This was not the case for patients with an EF
between 45% and 49%.

Discussion
To date, the efficacy of β-blockers for patients with HFpEF is unknown. This post hoc analysis of the
TOPCAT trial of spironolactone for patients with HFpEF suggests an association between β-blocker

Table 2. Hazard Ratios for Heart Failure Hospitalizations of Patients Receiving β-Blockers, by Ejection Fraction

Adjusted Hazard Ratio

Ejection Fraction Unadjusted Hazard Ratio Minimallya Fullyb
All 1.71 (1.28-2.27) 1.61 (1.21-2.14) 1.61 (1.20-2.15)
<50% 0.73 (0.32-1.65) 0.69 (0.29-1.64) 0.68 (0.28-1.63)
a
≥50% 1.86 (1.37-2.52) 1.74 (1.28-2.36) 1.74 (1.28-2.37) Adjusted for age, sex, race/ethnicity, and treatment
assignment.
≥55% 2.06 (1.45-2.92) 1.90 (1.33-2.70) 1.90 (1.33-2.71)
b
≥60% 2.03 (1.34-3.08) 1.84 (1.21-2.81) 1.80 (1.18-2.75) Minimally adjusted model plus prior myocardial
infarction, atrial fibrillation, chronic obstructive
≥65% 2.92 (1.46-5.82) 2.72 (1.35-5.47) 2.65 (1.31-5.36)
pulmonary disease, asthma, and hypertension.

Figure 2. Cumulative Incidence for Heart Failure Hospitalizations by β-Blocker Use Among Patients
With an Ejection Fraction of 50% or Greater

100
Log-rank P =.01
80
Cumulative Incidence, %

60

β-blocker
40

20
No β-blocker

0
0 1 2 3 4 5 6
Year of Follow-up
Kaplan-Meier plots for heart failure hospitalizations by
No. at risk
No β-blocker 240 205 138 79 51 16 4 β-blocker use at baseline stratified by an ejection
β-blocker 1324 1075 781 509 310 115 16 fraction of 50% or greater.

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 JAMA Network Open | Cardiology Association of β-Blocker Use With HF Hospitalizations and CVD Mortality Among Patients With HF With a Preserved EF

use and incident HF hospitalizations for patients with an EF of 50% or greater and an incremental
positive association between β-blocker use and the risk for HF hospitalization at higher EF
thresholds. There was no significant association between β-blocker use and CVD mortality.

β-Blocker Use for Patients With HFpEF

The TOPCAT trial corroborates the finding that most patients in contemporary HFpEF cohorts are
treated with β-blockers. A total of 79.2% of the patients in the North American and South America
cohort of this trial received β-blockers at baseline. This high prevalence of β-blocker use is similar to
other HFpEF studies, as shown in eTable 4 in the Supplement .12-16 Although evidence for the benefits
of β-blocker use for patients with HFpEF is lacking, this high rate of use is most likely explained by an
assumption that β-blockers are efficacious for treating common comorbidities such as hypertension,
coronary artery disease, and atrial fibrillation.

Benefits of β-Blockers for HF

Extensive, high-quality evidence supports the use of β-blockers for patients with HFrEF.5,6,9-11,25,26 In
addition, several recent analyses have investigated whether guideline-directed HF therapies have a
utility for patients with EFs between 40% and 49%, an entity termed HF with midrange EF.27-29 A
recent individual patient-level meta-analysis of 11 major HFrEF trials investigating the effects of
β-blockers at different ranges of EF identified a reduction in CVD mortality among patients with an EF
between 40% and 49%.18 Analogous to our findings, the same meta-analysis suggested that
patients with an EF of 50% or greater did not see any benefits from being randomized to receive
β-blockers. However, only 244 patients fell into this category.

Figure 3. Restricted Cubic Splines and Kernel Density Plot Relating Hazard Ratios for Heart Failure (HF)
Hospitalization and Ejection Fraction (EF)

A HF hospitalizations for follow-up period

5.000

2.500

1.000
Log Hazard Ratio (95% CI)

0.500

0.250

0.100

0.050
No β-blocker
0.025 β-blocker A, Hazard ratios for incident HF hospitalizations for the
follow-up period, according to baseline EF using
restricted cubic spline models, adjusted for age, sex,
45 50 55 60 65 70 75 80
race/ethnicity, treatment assignment, prior myocardial
Baseline EF, %
infarction, atrial fibrillation, chronic obstructive
pulmonary disease, asthma, and hypertension. The
Probability density
No β-blocker, no HF hospitalization No β-blocker, HF hospitalization
shaded areas represent the 95% CIs. The logarithmic
β-blocker, no HF hospitalization β-blocker, HF hospitalization scale on the y-axis indicates hazard ratios for HF
hospitalization, where values greater than 1 indicate
B Kernel density plots greater rate of HF hospitalizations and values less than
1 indicate fewer HF hospitalizations are related to an
0.075
EF on the x-axis. The models were expressed relative
Probability Density

0.050 to the median EF. Four knots were specified using the
Harrell method and were not prespecified.24 Knots
0.025 were 43.0%, 53.0%, 59.0%, and 71.7% for β-blocker
and 47.0%, 57.0%, 62.0%, and 72.0% for no
0
β-blocker. The plots were truncated at 0.5% and
45 50 55 60 65 70 75 80 99.5% of baseline EF. B, Kernel density plots
Baseline EF, % demonstrating the distribution of baseline EFs.

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 JAMA Network Open | Cardiology Association of β-Blocker Use With HF Hospitalizations and CVD Mortality Among Patients With HF With a Preserved EF

HFpEF Trials of β-Blockers

Our observations contrast with prior randomized β-blocker trials, which did not report increased HF
hospitalizations among patients with HFpEF. However, there are several points to consider. First, to
our knowledge, only 2 randomized clinical outcome trials have been performed that studied
β-blockers in patients with HFpEF. The larger SENIORS trial (Randomized Trial to Determine the
Effect of Nebivolol on Mortality and Cardiovascular Hospital Admission in Elderly Patients With Heart
Failure) considered an EF greater than 35% to define HFpEF and analyzed 752 participants with an
EF in this range, among whom approximately half had an EF between 35% and 50%.30 In addition,
HF hospitalizations were not specifically recorded. The open-label Japanese Diastolic Heart Failure
(J-DHF) trial of carvedilol (mean dose, 8.5 mg/d) randomized 245 patients with an EF greater than
40%.31 It appears possible that assessing HF hospitalizations in mixed populations with a reduced
and normal EF may result in an overall neutral or even beneficial effect associated with
β-blockers.28,29 Furthermore, patients with a history of HF and a recovered EF have recently been
shown to gain sustained benefits from guideline-directed HFrEF therapies, which include
β-blockers.32 Their inclusion in HFpEF cohorts—although likely small in numbers—could also be
associated with beneficial HF outcomes.

Possible Pathophysiological Mechanisms

Evidence that may help explain these findings comes from related patient populations with
preserved EFs. Specifically, the LIFE (Losartan Intervention For Endpoint Reduction in Hypertension)
trial33 and contemporary randomized myocardial infarction trials34-36 have raised concerns that
β-blocker use is associated with adverse cardiovascular outcomes, including an increased risk of
developing HF. Mechanistically, this risk was explained by an increase in central blood pressure by
reflected pressure waves.35 In addition, prolonged diastolic filling increases ventricular volumes and
pressures, increasing the ventricular load.37,38 These mechanisms combine to increase myocardial
wall stress, which may explain why, in historical hypertension trials, BNP and NT-proBNP levels were
found to be elevated in patients receiving β-blockers.39
Similarly, in the TOPCAT trial, β-blocker use was associated with higher levels of circulating BNPs
and NT-proBNPs in patients with a normal EF. The same was seen in the ELANDD (Effects of the
Long-term Administration of Nebivolol on the Clinical Symptoms, Exercise Capacity, and Left
Ventricular Function of Patients With Diastolic Dysfunction) study, which assessed the effect of
nebivolol on clinical symptoms and exercise capacity in patients with diastolic dysfunction, and in the
CIBIS-ELD (Titration to Target Dose of Bisoprolol vs Carvedilol in Elderly Patients With Heart Failure)
study, which evaluated the tolerability of β-blocker up-titration in patients with HFpEF.40,41 In the
SWEDIC (Swedish Doppler-Echocardiographic) study of patients with HFpEF randomized to receive
carvedilol or placebo, BNP levels also increased, and the authors noted an unexpected worsening in
HF in the patients treated with carvedilol.42 As has been recently demonstrated, β-blocker cessation
for patients with stable HFpEF is safe and leads to marked reductions in NTpro-BNP levels.43
Although incremental increases in BNP and NT-proBNP levels have been associated with worse
outcomes for patients with HFpEF—including in another secondary analysis of the TOPCAT trial44—it
is not clear whether this predictive capacity is preserved if indeed modified by β-blockers. However,
in contrast with the observations of patients with HFpEF, BNP and NT-proBNP levels are markedly
lowered by sustained β-blocker use among patients with HFrEF.5,45

Limitations
Our examination has several limitations. Participants in the TOPCAT trial were randomized to receive
spironolactone and not β-blockers. Our adjustments may not sufficiently correct for all confounding
variables, and some confounders may be unidentified. We also cannot account for both duration and
intensity of β-blocker exposure. This secondary analysis can be viewed only as explorative and
hypothesis generating because it does not establish cause and effect.

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 JAMA Network Open | Cardiology Association of β-Blocker Use With HF Hospitalizations and CVD Mortality Among Patients With HF With a Preserved EF

Conclusions
These results demonstrate that β-blocker use in the TOPCAT trial cohort was associated with a higher
risk for incident HF hospitalization among patients with an EF of 50% or greater, without an
associated change in CVD mortality. Future studies are needed to prospectively assess the effects of
β-blockers in HF populations with a normal EF.

ARTICLE INFORMATION
Accepted for Publication: October 7, 2019.
Published: December 4, 2019. doi:10.1001/jamanetworkopen.2019.16598
Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Silverman
DN et al. JAMA Network Open.
Corresponding Author: Markus Meyer, MD, Department of Medicine and Biostatistics Unit, Larner College of
Medicine, University of Vermont, UVMMC, McClure 1, Cardiology, 111 Colchester Ave, Burlington, VT 05401 (markus.
meyer@uvmhealth.org).
Author Affiliations: Department of Medicine and Biostatistics Unit, Larner College of Medicine, University of
Vermont, Burlington (Silverman, Plante, Infeld, Callas, Meyer); Department of Medicine, Beth Israel Deaconess
Medical Center, Harvard Medical School, Boston, Massachusetts (Juraschek); Department of Epidemiology, Johns
Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland (Dougherty).
Author Contributions: Drs Silverman and Plante had full access to all the data in the study and take responsibility
for the integrity of the data and the accuracy of the data analysis. Drs Silverman and Plante are co–first authors.
Concept and design: Silverman, Plante, Infeld, Dougherty, Meyer.
Acquisition, analysis, or interpretation of data: Silverman, Plante, Callas, Juraschek, Meyer.
Drafting of the manuscript: Silverman, Infeld, Meyer.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Plante, Callas, Juraschek, Dougherty, Meyer.
Obtained funding: Meyer.
Administrative, technical, or material support: Plante, Infeld.
Supervision: Plante, Meyer.
Conflict of Interest Disclosures: Dr Meyer reported having licensed patents on the use of pacemakers to prevent
and treat heart failure with preserved ejection fraction; the relationship is modest. No other disclosures were
reported.
Funding/Support: This research was supported by grant R01 HL-122744 from the National Institutes of Health (Dr
Meyer) and grant K23 HL135273 from the National Institutes of Health (Dr Juraschek).
Role of the Funder/Sponsor: The funding source 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.
Additional Contributions: We would like to acknowledge the investigators and patients that made the TOPCAT
trial possible. We also thank the National Institutes of Health–National Heart, Lung, and Blood Institute for making
the database available.

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SUPPLEMENT.
eTable 1. Sensitivity Analysis, Hazard Ratios for Heart Failure Hospitalizations by Ejection Fraction Among Those
Not Changing Baseline Beta-Blocker Status During Follow-up
eTable 2. Sensitivity Analysis, Hazard Ratios for Heart Failure Hospitalizations by Ejection Fraction Among Those
Not Changing Baseline Beta-Blocker Status During Follow-up Using the Propensity Score Matched Cohort
eTable 3. Baseline Characteristics of Propensity Score Matched Patients That Did Not Change Baseline Beta-
Blocker Status During Follow-up
eTable 4. Beta-blocker Utilization in Contemporary HFpEF Cohorts
eTable 5. Median and Interquartile Ranges for BNP and NT-proBNP Levels
eTable 6. Hazard Ratios for Cardiovascular Disease Mortality by Ejection Fraction
eFigure 1. Cumulative Incidence Plot for Cardiovascular Disease Mortality by Beta-Blocker Use in Patients With an
EFⱖ50%
eFigure 2. Quartile Ranges of BNP and NT-proBNP Levels by Beta-Blocker Use

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