Contemporary Use and Implications of Beta-Blockers in Patients With HFmrEF or HFpEF

,

B eta-blockers are cornerstone thera- peutic agents for the management of heart failure with reduced ejection fraction (HFrEF).Conversely, high-quality randomized trial data on beta-blocker use among patients with heart failure with mildly reduced ejection fraction (HFmrEF) and heart failure with preserved ejection fraction (HFpEF) remain sparse.2][3] Given the limited evidence from randomized trials, the latest European Society of Cardiology and American Heart Association (AHA)/American College of Cardiology (ACC)/Heart Failure Society of America (HFSA) guidelines do not recommend the use of beta-blockers for the treatment of HFpEF.
5][6][7][8] Concurrently, data from TOPCAT (Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function) and a recent analysis of the U.S. National Cardiovascular Data Registry PINNACLE (Practice Innovation and Clinical Excellence) Registry suggested that betablocker use may be associated with a potentially increased risk of hospitalizations for heart failure (HF) in patients with HFpEF. 9,10Similarly, the

PRESERVE-HR (beta-blockers Withdrawal in Patients
With HFpEF and Chronotropic Incompetence: Effect on Functional Capacity) trial showed that the withdrawal of beta-blockers may improve functional capacity in patients with HFpEF and chronotropic incompetence. 11though sodium glucose co-transporter 2 inhibitors (SGLT2is) were demonstrated to reduce worsening HF events or cardiovascular death across the spectrum of HF, it is unknown whether combined therapy with beta-blockers may attenuate these benefits. 12The DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure; NCT03619213) trial is the largest randomized trial conducted to date in heart failure (HF) patients with LVEF >40%, with twothirds of participants having LVEF $50%, and a substantial proportion (>80%) taking a beta-blocker.In this prespecified analysis of the DELIVER trial, we examine the implications of beta-blocker use in patients with HFmrEF or HFpEF.

METHODS
TRIAL DESIGN AND PATIENTS.4][15] Briefly, DELIVER was an international, randomized, double-     Beta-Blockers in HFpEF  beta-blocker use and clinical outcomes were not modified by LVEF according to categorical (LVEF #49% vs $50%) (P interaction >0.47 for all) and continuous (P interaction >0.63 for all) assessments (Figure 3).

EFFECT OF DAPAGLIFLOZIN ON CLINICAL OUTCOMES
ACCORDING TO BETA-BLOCKER USE.The treatment effect of dapagliflozin on the primary composite was similar in patients taking beta-blockers (HR 0.82: 95% CI: 0.72-0.94)and those not taking beta-blockers (HR: 0.79; 95% CI: 0.61-1.03;P interaction ¼ 0.85) (Table 3, Central Illustration).Similarly, the benefits of dapagliflozin on worsening HF events, cardiovascular death, all-cause mortality, and total HF events and cardiovascular death did not differ by beta-blocker use (P interaction >0.20 for all) (Table 3, Figure 4).
Moreover, improvements in KCCQ-TSS, KCCQ-CSS, and KCCQ-OSS with dapagliflozin were consistent among those patients taking and not taking beta-blockers (P interaction >0.12 for all) (Table 3).
The achievement of $50% of the guidelinerecommended beta-blocker target dose did not influence the treatment effect of dapagliflozin on clinical outcomes and KCCQ scores (P interaction >0.13 for all) (Supplemental Table 5).
SAFETY OUTCOMES.Discontinuation of the study treatment for any reason or because of an AE did not occur more frequently with dapagliflozin regardless of beta-blocker use, with no differences in the frequency of serious AEs, diabetic ketoacidosis, hypoglycemic events, volume depletion, renal events, hypotension, dizziness, presyncope, and bradycardia (Table 4).

DISCUSSION
In this prespecified analysis of DELIVER trial of patients with HFmrEF and HFpEF, more than 4 out of 5 participants were treated with a beta-blocker, and beta-blocker use was associated with a lower risk of worsening HF or cardiovascular death.The benefits of dapagliflozin on symptoms and clinical events did not differ in patients who were or were not taking a betablocker at baseline, with a consistent safety profile in both groups.
Despite the lack of recommendation in recent guidelines for the specific use of beta-blockers for the treatment of HFpEF, the high prevalence of 83% taking a beta-blocker in DELIVER is consistent with observations from previous randomized trials in patients with HFpEF. 6,7,17Given the considerable variation in beta-blockers by country ranging from 60% in Mexico to 94% in Hungary, prescription patterns likely mirror heterogeneity in global comorbidity

Consistent Benefits With Dapagliflozin Irrespective of Beta-Blocker Use
In the DELIVER trial of 6,263 participants with HF with LVEF >40%: • 83% were treated with beta-blockers, with the vast majority having 1 or more potential indications such as hypertension, atrial fibrillation/flutter, previous LVEF ≤40%, and CAD.• Beta-blocker use was not associated with adverse HF outcomes and mortality.
• Dapagliflozin consistently reduced CV death or worsening HF events, regardless of baseline beta-blocker use.HF and LVEF of 50% or greater, whereas the associations between beta-blocker use and clinical events in DELIVER were not influenced by LVEF. 9,10It is possible that the broader international population, younger age, higher prevalence of comorbidities such as AFF, hypertension, diabetes, or previous MI, and the enrollment of patients with improved LVEF in DELIVER may have contributed to the discrepancies compared with previous studies. 24Indeed, because inhibition of adrenergic activity can alter multiple distinct pathways in addition to its direct influence on the myocardium, the role of beta-blockers in these patients may ultimately vary depending on cause, ventricular phenotype, and comorbidity burden. 25In addition, although natriuretic peptides are important prognostic markers in HF, the foregoing analyses in TOPCAT and PINNACLE were not adjusted for NT-proBNP. 26,27Moreover, despite apprehensions that negative chronotropic effects of beta-blockers may adversely affect outcomes and symptoms in HFpEF, we observed similar heart rates at baseline in patients who were or were not taking a beta-blocker, but we were not able to capture heart rate response at peak or submaximal exercise performance. 12,28,29We further found that baseline KCCQ scores did not differ regardless of beta-blocker use, with no increased risk of worsening at 8 months in patients taking a betablocker.These observations appear to diverge from those that resulted from a specific subset with coexisting chronotropic incompetence. 11otably, although the observed lower point estimates could Although the mechanisms of SGLT2is and betablockers are thought to be distinct, given the current concerns and sparse evidence regarding betablocker use in HFpEF, it remained uncertain whether combined therapy can alter the treatment benefits of SGLT2is. 30In DELIVER, the benefits of dapagliflozin on clinical events were consistent in patients who were and were not taking a betablocker, with no treatment effect modification by beta-blocker use for any outcome.Despite objections that beta-blockers may worsen functional capacity in HFpEF, dapagliflozin therapy similarly led to improved KCCQ scores, regardless of beta-blocker use. 11,31Although differences in background therapy dosing may affect clinical outcomes and healthrelated quality of life, the achievement of beta-blocker target dosing did not influence the treatment effect of dapagliflozin. 32Importantly, with the total of concomitant medications in DELIVER. 33,34The current analysis from DELIVER extends these findings to support consistency of treatment efficacy and safety, irrespective of betablocker use or dosing.
STUDY LIMITATIONS.Although the number of participants not taking a beta-blocker was relatively small, there was wide variation in its use by geographic region and country.Data on medication use were based on case report forms and were not cross-validated against additional sources such as pharmacy fill data.In addition, measures of

CONCLUSIONS
In DELIVER, most participants were treated with a beta-blocker, whereas most of these patients had at least 1 potential indication for use.Beta-blocker use was not associated with a higher risk of worsening HF events or cardiovascular death and deteriorations of health-related quality of life.The benefits of dapagliflozin on clinical events were consistent among patients taking or not taking a beta-blocker, with a similar safety profile.These data provide reassurance for background beta-blocker treatment in HFmrEF or HFpEF and complement previous evidence supporting SGLT2is as therapeutic options in these patients irrespective of background medical therapy.
blind trial comparing dapagliflozin, 10 mg once daily, with a matching placebo in patients with HFmrEF or HFpEF.The study enrolled ambulatory and hospitalized patients 40 years of age or older, with NYHA functional class II to IV, LVEF >40%, elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels ($300 pg/mL in sinus rhythm or $600 pg/mL in patients in atrial fibrillation or flutter [AFF]), and evidence of structural heart disease (left atrial enlargement or left ventricular hypertrophy).Patients with SGLT2i treatment within 4 weeks of randomization, intolerance to SGLT2is, type 1 diabetes mellitus, estimated glomerular filtration rate (eGFR) <25 mL/ min/1.73m 2 , systolic blood pressure $160 mm Hg if not using $3 antihypertensive medications or $180 mm Hg regardless of number of medications, or alternative diagnoses potentially accounting for the patients' HF symptoms were excluded.The study protocol was approved by the Institutional SEE PAGE 645 A B B R E V I A T I O N S A N D A C R O N Y M S AE = adverse event AFF = atrial fibrillation or flutter CAD = coronary artery disease eGFR = estimated glomerular filtration rate HF = heart failure HFmrEF = heart failure with mildly reduced ejection fraction HFpEF = heart failure with preserved ejection fraction LVEF = left ventricular ejection fraction NT-proBNP = N-terminal pro-B-type natriuretic peptide

A P R I L 2 0 2 4 : 6 3 1 -6 4 4 Review
Board or ethics committee at each participating site, and each patient provided written informed consent.BETA-BLOCKER USE AND INDICATIONS.Data on medication at enrollment were collected by case report forms, with beta-blocker use categorized using Anatomical Therapeutic Chemical classification codes.Potential non-HF indications for beta-blocker treatment (defined as either hypertension, AFF, coronary artery disease [CAD], or previous LVEF #40%) were assessed on the basis of the participant's medical history examined through case report forms.Beta-blocker doses were standardized according to carvedilol equivalents (Supplemental Methods).Target doses for evidence-based beta-blockers for the treatment of HFrEF or HFmrEF (carvedilol, metoprolol succinate, and bisoprolol) were defined according to the latest AHA/ACC/HFSA guidelines.STUDY OUTCOMES.The primary outcome of DELIVER was the composite of worsening HF events (unplanned hospitalization for HF or urgent HF visit requiring intravenous therapy) or cardiovascular death.Secondary outcomes included the total number of HF events and cardiovascular death, cardiovascular death, death from any cause, and change in the Kansas City Cardiomyopathy Questionnaire (KCCQ)-Total Symptom Score (TSS) between baseline and 8 months.Additional analyses examined change from baseline to 8 months in KCCQ-Clinical Summary Score (CSS) and KCCQ-Overall Summary Score (OSS).Safety outcomes included serious adverse events (AEs), AEs leading to study treatment discontinuation, and selected AEs, including amputation, major hypoglycemic events, diabetic ketoacidosis, volume depletion, renal events, hypotension, dizziness, presyncope, and bradycardia.STATISTICAL ANALYSIS.Baseline characteristics were summarized as mean AE SD, median (Q1-Q3), or frequencies (%).Differences in baseline characteristics between patients who were and those who were not taking a beta-blocker were compared by Student's t-test for continuous variables and by the chi-square test or Fisher exact test for categorical variables.Associations between beta-blocker use and clinical events were examined using Cox proportional hazards models with and without stratification by site and adjustment for age, sex, race, AFF, type 2 diabetes mellitus, any CAD, hypertension, previous HF hospitalization, improved LVEF (previous LVEF #40%) status, baseline body mass index, baseline NYHA functional class, baseline LVEF, logtransformed baseline NT-proBNP levels, baseline heart rate, baseline systolic blood pressure, and baseline eGFR.For sensitivity, additional models were stratified by deciles of a propensity score on the basis of a multivariate logistic regression model including all baseline covariates.Additional sensitivity analyses were based on competing risk models accounting for all-cause mortality.Moreover, models with interaction terms analyzed the modification of the association between beta-blocker use and clinical events by baseline LVEF group (LVEF #49% vs $50%).The modification of the association between beta-blocker use and clinical events as a continuous function of LVEF was further examined by crude and adjusted Poisson regression models, with baseline LVEF expressed by restricted cubic splines with 3 knots.The effects of dapagliflozin compared with placebo were assessed by Cox proportional hazards models stratified by type 2 diabetes status at baseline with interaction terms for effect modification by beta-blocker use.Changes in KCCQ scores between baseline and 8 months according to beta-blocker use were examined by linear regression models adjusted for each score's respective baseline value.Differences in change in KCCQ scores from baseline to 8 months by randomized treatment were assessed by linear regression models adjusted for each score's respective baseline value and interaction terms for randomized treatment and beta-blocker use.Responder analyses examined the proportions of patients with clinically meaningful improvement

FIGURE 1
FIGURE 1 Potential Indications for Concomitant Beta-Blocker Use Peikert A, et al.J Am Coll Cardiol HF. 2024;12(4):631-644.Cumulative incidence of the primary composite outcome and treatment effect of dapagliflozin compared with placebo on the primary composite outcome and key secondary outcomes according to beta-blocker use, on the basis of Cox proportional hazards models.CAD ¼ coronary artery disease; CV ¼ cardiovascular; DELIVER ¼ Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure; HF ¼ heart failure; LVEF ¼ left ventricular ejection fraction.JACC: HEART FAILURE VOL. 12, NO.Beta-Blockers in HFpEF National Cardiovascular Data Registry PINNACLE registry, beta-blocker use was associated with an increased risk of HF hospitalizations in patients with

FIGURE 2
FIGURE 2 Cumulative Incidence of Key Outcomes by Beta-Blocker Use

FIGURE 3
FIGURE 3 Association Between Beta-Blocker Use and Key Outcomes by LVEF as a Continuous Measure

FIGURE 4
FIGURE 4 Effect of Dapagliflozin According to Beta-Blocker Use Beta-Blockers in HFpEF adherence were not collected in DELIVER, with potential differences in adherence rates between this trial and routine clinical practice, which could in turn affect the generalizability of our results.Despite accounting for confounding by a covariate-adjusted and propensity score-based models, imbalances in patient characteristics stemming from the nonrandomized use of beta-blockers may have influenced the results of this study.Finally, although conditions potentially recommending beta-blocker use were assessed on the basis of the patient's medical history, DELIVER did not capture specific clinical indications for background therapies.

TABLE 1
Baseline Characteristics According to Beta-Blocker Use Baseline eGFR, mL/min/1.73m 2 61.0 AE 19.1 59.6 AE 18.9 61.3 AE 19.2 0.008 HbA 1c , % 6.6 AE 1.4 6.5 AE 1.4 6.6 AE 1.4 0.14 Continued on the next page Peikert et al JACC: HEART FAILURE VOL. 12, NO. 4, 2024 Beta-Blockers in HFpEF A P R I L 2 0 2 4 : 6 3 1 -6 4 4 ($5-point increase) and deterioration ($5-point decrease) in KCCQ scores by logistic regression models.Total events were analyzed on the basis of the semiparametric method of Lin et al. 16 Safety outcomes by beta-blocker use were examined using logistic regression models with interaction terms.Statistical analyses were performed using Stata software version 16.1 (StataCorp).Values of P < 0.05 were considered statistically significant.higher body mass index, had lower systolic blood pressure, had higher diastolic blood pressure, presented more frequently in AFF at enrollment, had higher eGFR, lower LVEF, worse NYHA functional class, and higher NT-proBNP levels when in AFF (Table 1).A history of AFF, diabetes, hypertension, previous HF hospitalization, previous LVEF #40%, CAD, and myocardial infarction were more common in patients taking beta-blockers.Patients taking betablockers were more frequently treated with loop diuretic agents, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and mineralocorticoid receptor antagonists, were less likely to have pacemakers, but were more likely to have received implantable cardioverter-defibrillator therapy.Randomized treatment, sex, heart rate, duration of HF, glycated hemoglobin levels, NT-proBNP levels in patients without AFF, baseline KCCQ scores, history of stroke, and sacubitril/valsartan use were similar in patients with and without beta-blocker use.
use are shown in Supplemental Table 4. Deteriorations in KCCQ-TSS, KCCQ-CSS, and KCCQ-OSS were similar between those patients taking vs not taking beta-blockers, and these findings remained consistent following covariate adjustment and in propensity score-based models (

TABLE 2
Primary Composite Outcome and Key Secondary Outcomes by Beta-Blocker Use Beta-Blocker Use, Clinical Outcomes, and Treatment Response to Dapagliflozin 1,9,22,23e n (%) or mean AE SD, unless otherwise indicated.Multivariable models were stratified by site and adjusted for age, sex, race, atrial fibrillation/flutter, type 2 diabetes mellitus, any coronary artery disease, hypertension, prior heart failure hospitalization, improved ejection (previous ejection #40%) status, baseline body mass index, baseline NYHA functional class, baseline left ventricular ejection fraction, log-transformed baseline N-terminal pro-B-type natriuretic peptide levels, baseline heart rate, baseline systolic blood pressure, and baseline estimated glomerular filtration rate.P values are reported for differences between participants withand without background beta-blocker therapy.CV ¼ cardiovascular; pt-y ¼ patient-years; Ref. ¼ reference; RR ¼ rate ratio; other abbreviations as in Table1.lowerrisk of clinical events in DELIVER, which comprised patients with HFmrEF and HFpEF, previous studies supported potential benefits of betablockers in patients with HFmrEF or HF with improved ejection fraction, and effects among those patients with HFpEF remain inconsistent.1,9,22,23Forinstance, in the TOPCAT trial and the U.S.-based CENTRAL ILLUSTRATION

TABLE 3
Treatment Effect According to Beta-Blocker UseValues are n (%) or mean AE SD, unless otherwise indicated.aPinteractionvaluesare reported for interaction between treatment effect and beta-blocker use.Abbreviations as in Tables1 and 2.

TABLE 4
Occurrence of Adverse Events According to Beta-Blocker Use Values are n (%). a Pinteraction values are reported for interaction between treatment effect and beta-blocker use.Safety analyses were performed in randomized participants who received at least 1 dose of study medication, with a total of 10 participants excluded.AE ¼ adverse event; DAE ¼ adverse events leading to treatment discontinuation; NA ¼ not applicable.