ABSTRACT
Importance: Increasing the patient's heart rate (HR) has emerged as a therapeutic option in patients with heart failure with preserved ejection fraction (HFpEF). However, the evidence is conflicting, and the profile of patients who benefit most from this strategy remains unclear. Objective: To assess the association of ß-blocker treatment withdrawal with changes in the percentage of predicted peak oxygen consumption (VO2) across indexed left ventricular diastolic (iLVEDV) and indexed left ventricular systolic volumes (iLVESV), and left ventricular ejection fraction (LVEF) in patients with HFpEF and chronotropic incompetence. Design, Setting, and Participants: This post hoc analysis was conducted using data from the investigator-blinded multicenter, randomized, and crossover clinical trial, PRESERVE-HR, that took place from October 1, 2018, through December 31, 2020, to investigate the short-term effects (2 weeks) of ß-blocker withdrawal on peak oxygen consumption (peak VO2). Patients with stable HFpEF (New York Heart Association functional class II to III) receiving treatment with ß-blocker and chronotropic incompetence were included. Intervention: Participants in the PRESERVE-HR trial were randomized to withdraw vs continue with ß-blocker treatment. After 2 weeks, they were crossed over to receive the opposite intervention. This crossover randomized clinical trial examined the short-term effect of ß-blocker withdrawal on peak VO2. Main Outcomes and Measures: The primary outcome was to evaluate the association between ß-blocker withdrawal and short-term changes in percentage of peak VO2 across iLVEDV, iLVESV, and LVEF in patients with HFpEF and chronotropic incompetence treated with ß-blocker. Results: A total of 52 patients (mean age, 73 [SD, 13] years; 60% female) were randomized. The mean resting HR, peak HR, peak VO2, and percentage of peak VO2 were 65 (SD, 9) beats per minute (bpm), 97 (SD, 15) bpm, 12.4 (SD, 2.9) mL/kg per minute, and 72.4% (SD, 17.7%), respectively. The medians (minimum-maximum) of iLVEDV, iLVESV, and LVEF were 44 mL/m2 (IQR, 19-82), 15 mL/m2 (IQR, 7-32), and 64% (IQR, 52%-78%), respectively. After stopping ß-blocker treatment, the median increase in peak HR was plus 30 bpm (95% CI, 25-35; P < .001). ß-Blocker cessation was differentially associated with change of percentage of peak VO2 across the continuum of iLVESV (P for interaction = .02), indicating a greater benefit in those with lower iLVESV. Conclusions and Relevance: In this study, results showed that in patients with HFpEF and chronotropic incompetence receiving treatment with ß-blocker, lower iLVESV may identify those with a greater short-term improvement in maximal functional capacity after stopping ß-blocker treatment. Further studies are warranted for further investigation. Trial Registration: ClinicalTrials.gov (NCT03871803).
Subject(s)
Heart Failure , Aged , Female , Humans , Male , Adrenergic beta-Antagonists/therapeutic use , Heart Failure/drug therapy , Heart Rate/physiology , Stroke Volume/physiology , Ventricular Function, Left , Middle Aged , Aged, 80 and overABSTRACT
Introducción y objetivos: Los inhibidores del cotransportador 2 de sodio-glucosa (iSGLT2) inducen cambios a corto plazo en la función renal y la hemoglobina y su fisiopatología se comprende de manera incompleta. Nuestro objetivo es evaluar la relación entre los cambios de la tasa de filtrago glomerular estimado (TFGre) y la hemoglobina tras el inicio de dapagliflozina en pacientes estables con insuficiencia cardiaca y fracción de eyección reducida (IC-FEr). Métodos: Este análisis post hoc de un ensayo clínico aleatorizado evaluó el efecto de la dapagliflozina sobre el consumo máximo de oxígeno a 1 y 3 meses en pacientes ambulatorios con IC-FEr estable (ensayo DAPA-VO2, NCT04197635). Se utilizó un análisis de regresión lineal mixta para evaluar la relación entre los cambios en la TFGe y la hemoglobina a 1 y 3 meses. Resultados: Se evaluó a 87 pacientes. La media de edad era 67,0±10,5 años, y 21 pacientes (24,1%) eran mujeres. Las medias basales de TFGe y hemoglobina fueron de 66,9±20,7ml/min/1,73 m2 y 14,3±1,7g/dl respectivamente. En comparación con el placebo, la TFGe no cambió significativamente en el grupo de dapagliflozina, pero la hemoglobina aumentó significativamente a 1 y 3 meses. A 1 mes, el aumento de la hemoglobina se relacionó con la disminución de la TFGe solo en el grupo de dapagliflozina (p <0,001). A los 3 meses no había asociación significativa (p=0,123). Los cambios de la TFGe a 1 y 3 meses no se asociaron con cambios en el consumo pico de oxígeno, la calidad de vida o los péptidos natriuréticos. Conclusiones: En pacientes con IC-FEr estable, los cambios en la TFGe a 1 mes inducidos por la dapagliflozina están en relación inversa con cambios en la hemoglobina. Esta asociación no se observa a los 3 meses. (AU)
Introduction and objectives: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) induce short-term changes in renal function and hemoglobin. Their pathophysiology is incompletely understood. We aimed to evaluate the relationship between 1- and 3-month estimated glomerular filtration rate (eGFR) and hemoglobin changes following initiation of dapagliflozin in patients with stable heart failure with reduced ejection fraction (HFrEF). Methods: This is a post hoc analysis of a randomized clinical trial that evaluated the effect of dapagliflozin on 1- and 3-month peak oxygen consumption in outpatients with stable HFrEF (DAPA-VO2 trial, NCT04197635). We used linear mixed regression analysis to assess the relationship between eGFR and hemoglobin changes across treatment arms. Results: A total of 87 patients were evaluated in this substudy. The mean age was 67.0± 10.5 years, and 21 (24.1%) were women. The mean baseline eGFR and hemoglobin were 66.9±20.7mL/min/1.73m2 and 14.3±1.7g/dL, respectively. Compared with placebo, eGFR did not significantly change at either time points in the dapagliflozin group, but hemoglobin significantly increased at 1 and 3 months. At 1 month, the hemoglobin increase was related to decreases in eGFR only in the dapagliflozin arm (P <.001). At 3 months, there was no significant association in either treatment arms (P=.123). Changes in eGFR were not associated with changes in peak oxygen consumption, quality of life, or natriuretic peptides. Conclusions: In patients with stable HFrEF, 1-month changes in eGFR induced by dapagliflozin are inversely related to changes in hemoglobin. This association was no longer significant at 3 months. (AU)
Subject(s)
Humans , Male , Female , Aged , Aged, 80 and over , Sodium-Glucose Transporter 2 Inhibitors , Heart Failure/drug therapy , Hemoglobins/administration & dosage , Glomerular Filtration Rate , Sodium-Glucose Transporter 2 Inhibitors/pharmacology , Sodium-Glucose Transporter 2 Inhibitors/therapeutic useABSTRACT
BACKGROUND: Some studies have indicated that sodium-glucose cotransporter-2 (SGLT2) inhibitors promote an increase in cell iron use. OBJECTIVES: The aim of this study was to examine, in patients with stable heart failure with reduced left ventricular ejection fraction (HFrEF), the effect of dapagliflozin on ferrokinetic parameters and whether short-term changes in peak oxygen consumption (Vo2) after dapagliflozin treatment are influenced by baseline and serial ferrokinetic status. METHODS: This was an exploratory analysis of a randomized, double-blind clinical trial that evaluated the effect of dapagliflozin vs placebo on peak Vo2 in patients with HFrEF (NCT04197635) and included 76 of the 90 patients initially enrolled in the trial. Changes in peak Vo2 at 1 and 3 months were explored according to baseline and longitudinal ferrokinetic parameters (natural logarithm [ln] ferritin, transferrin saturation index [TSAT], soluble transferrin receptor, and hepcidin). Linear mixed-effect regression was used for the analyses. RESULTS: Compared with placebo, dapagliflozin led to a significant decrease in 3-month ln ferritin (P = 0.040) and an increase in 1-month ln soluble transferrin receptor (P = 0.023). Between-treatment comparisons revealed a stepwise increase in peak Vo2 in the dapagliflozin group at 1 and 3 months, which was especially apparent at lower baseline values of TSAT and ferritin (P < 0.05). Lower time-varying values of TSAT (1 and 3 months) also identified patients with greater improvements in peak Vo2. CONCLUSIONS: In patients with stable HFrEF, treatment with dapagliflozin resulted in short-term increases in peak Vo2, which were most marked in patients with surrogates of greater iron deficiency at baseline and during treatment. (Short-Term Effects of Dapagliflozin on Peak Vo2 in HFrEF [DAPA-VO2]; NCT04197635).
Subject(s)
Heart Failure , Ventricular Function, Left , Humans , Stroke Volume , Heart Failure/drug therapy , Iron , Treatment Outcome , Ferritins , Receptors, Transferrin/therapeutic useABSTRACT
Introducción y objetivos: Poco se sabe sobre la utilidad de la respuesta de la frecuencia cardiaca (FC) al ejercicio para la estratificación del riesgo en la insuficiencia cardiaca con fracción de eyección conservada (ICFEc). El objetivo de este estudio fue evaluar la asociación entre la respuesta de la FC al ejercicio y el riesgo de episodios de descompensación por insuficiencia cardiaca (DIC) en pacientes sintomáticos estables con ICFEc. Métodos: Se trata de un estudio unicéntrico que incluyó a un total de 133 pacientes con ICFEc (NYHA II-III) tras la realización de una prueba de esfuerzo cardiopulmonar máxima. La respuesta de la FC al ejercicio se evaluó mediante la fórmula del índice cronotrópico (IxC). Para el análisis se utilizó un método de regresión binomial negativa. Resultados: La edad media fue de 73,2±10,5 años, el 56,4% eran mujeres y el 51,1% estaban en fibrilación auricular. La mediana de IxC fue de 0,4 (0,3-0,55). Tras una mediana de seguimiento de 2,4 (1,6-5,3) años, se registraron un total de 146 DIC en 58 pacientes y 41 (30,8%) muertes. El IxC no se asoció con eventos adversos (muerte, p=0,319, y DIC, p=0,573) cuando se analizó de forma conjunta toda la muestra. Sin embargo, se encontró un efecto diferencial en función del ritmo electrocardiográfico para DIC (p para interacción=0,002). El IxC se asoció inversa y linealmente con el riesgo de DIC en aquellos pacientes con ritmo sinusal y de forma lineal y positiva con aquellos en fibrilación auricular. Conclusiones: En pacientes con ICFEc, el IxC se asoció diferencialmente con el riesgo de DIC en función del ritmo electrocardiográfico. Un Ixc más bajo surgió como un factor de riesgo para predecir un mayor riesgo de DIC en pacientes en ritmo sinusal. Por el contrario, un IxC más alto identificó un mayor riesgo en aquellos pacientes en fibrilación auricular. (AU)
Introduction and objectives: Little is known about the usefulness of heart rate (HR) response to exercise for risk stratification in heart failure with preserved ejection fraction (HFpEF). Therefore, this study aimed to assess the association between HR response to exercise and the risk of total episodes of worsening heart failure (WHF) in symptomatic stable patients with HFpEF. Methods: This single-center study included 133 patients with HFpEF (NYHA II-III) who performed maximal cardiopulmonary exercise testing. HR response to exercise was evaluated using the chronotropic index (CIx) formula. A negative binomial regression method was used. Results: The mean age of the sample was 73.2± 10.5 years; 56.4% were female, and 51.1% were in atrial fibrillation. The median for CIx was 0.4 [0.3-0.55]. At a median follow-up of 2.4 [1.6-5.3] years, a total of 146 WHF events in 58 patients and 41 (30.8%) deaths were registered. In the whole sample, CIx was not associated with adverse outcomes (death, P=.319, and WHF events, P=.573). However, we found a differential effect across electrocardiographic rhythms for WHF events (P for interaction=.002). CIx was inversely and linearly associated with the risk of WHF events in patients with sinus rhythm and was positively and linearly associated with those with atrial fibrillation. Conclusions: In patients with HFpEF, CIx was differentially associated with the risk of total WHF events across rhythm status. Lower CIx emerged as a risk factor for predicting higher risk in patients with sinus rhythm. In contrast, higher CIx identified a higher risk in those with atrial fibrillation. (AU)
Subject(s)
Humans , Male , Female , Middle Aged , Aged , Aged, 80 and over , Heart Failure , Heart Rate , Spain , Prospective Studies , Heart Function Tests , Exercise TestABSTRACT
Circulating antigen carbohydrate 125 (CA125) has emerged as a proxy of fluid overload in heart failure. This study aimed to evaluate the effect of dapagliflozin on short-term CA125 levels in patients with stable heart failure with reduced ejection fraction (HFrEF) and whether these changes mediated the effects on peak oxygen consumption (peakVO2). This study is a post-hoc sub-analysis of a randomized, double-blinded clinical trial in which 90 stable patients with HFrEF were randomly assigned to receive either dapagliflozin or placebo to evaluate change in peakVO2 (NCT04197635). We used linear mixed regression analysis to compare changes in the natural logarithm of CA125 (logCA125) and percent changes from baseline (Δ%CA125). We used the "rwrmed" package to perform mediation analyses. CA125 was available in 87 patients (96.7%). LogCA125 significantly decreased in patients on treatment with dapagliflozin [1-month: Δ - 0.18, (CI 95% = - 0.33 to - 0.22) and 3-month: Δ - 0.23, (CI 95% = - 0.38 to - 0.07); omnibus p-value = 0.012]. Δ%CA125 decreased by 18.4% and 31.4% at 1 and 3-month, respectively (omnibus p-value = 0.026). Changes in logCA125 mediated the effect on peakVO2 by 20.4% at 1 month (p < 0.001). We did not find significant changes for natural logarithm of NTproBNP (logNT-proBNP) [1-month: Δ - 0.03, (CI 95% = - 0.23 to 0.17; p = 0.794), and 3-month: Δ 0.73, (CI 95% = - 0.13 to 0.28; p-value 0.489), omnibus p-value = 0.567]. In conclusion, in patients with stable HFrEF, dapagliflozin resulted in a significant reduction in CA125. Dapagliflozin was not associated with short-term changes in natriuretic peptides. These changes mediated the effects on peakVO2.
Subject(s)
Heart Failure , Humans , Heart Failure/drug therapy , Stroke Volume , CA-125 Antigen , Benzhydryl Compounds/pharmacology , Benzhydryl Compounds/therapeutic useABSTRACT
BACKGROUND: We aimed to evaluate the effect of dapagliflozin on short-term changes in hemoglobin in patients with stable heart failure with reduced ejection fraction (HFrEF) and whether these changes mediated the effect of dapagliflozin on functional capacity, quality of life and NT-proBNP levels. METHODS: This is an exploratory analysis of a randomized, double-blinded clinical trial in which 90 stable patients with HFrEF were randomly allocated to dapagliflozin or placebo to evaluate short-term changes in peak oxygen consumption (peak VO2) (NCT04197635). This substudy evaluated 1- and 3-month changes in hemoglobin levels and whether these changes mediated the effects of dapagliflozin on peak VO2, Minnesota Living-With-Heart-Failure test (MLHFQ) and NT-proBNP levels. RESULTS: At baseline, mean hemoglobin levels were 14.3 ± 1.7 g/dL. Hemoglobin levels significantly increased in those taking dapagliflozin (1 month:â¯+â¯0.45 g/dL (Pâ¯=â¯0.037) and 3 months:+ 0.55 g/dL (Pâ¯=â¯0.012)]. Changes in hemoglobin levels positively mediated the changes in peak VO2 at 3 months (59.5%; P < 0.001). Changes in hemoglobin levels significantly mediated the effect of dapagliflozin in the MLHFQ at 3 months (-53.2% and -48.7%; Pâ¯=â¯0.017) and NT-proBNP levels at 1 and 3 months (-68.0%; Pâ¯=â¯0.048 and -62.7%; Pâ¯=â¯0.029, respectively). CONCLUSIONS: In patients with stable HFrEF, dapagliflozin caused a short-term increase in hemoglobin levels, identifying patients with greater improvements in maximal functional capacity, quality of life and reduction of NT-proBNP levels.
Subject(s)
Heart Failure , Ventricular Dysfunction, Left , Humans , Heart Failure/drug therapy , Stroke Volume , Quality of Life , Functional Status , Natriuretic Peptides , Natriuretic Peptide, Brain/therapeutic use , Ventricular Dysfunction, Left/drug therapy , Hemoglobins , Peptide FragmentsABSTRACT
INTRODUCTION AND OBJECTIVES: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) induce short-term changes in renal function and hemoglobin. Their pathophysiology is incompletely understood. We aimed to evaluate the relationship between 1- and 3-month estimated glomerular filtration rate (eGFR) and hemoglobin changes following initiation of dapagliflozin in patients with stable heart failure with reduced ejection fraction (HFrEF). METHODS: This is a post hoc analysis of a randomized clinical trial that evaluated the effect of dapagliflozin on 1- and 3-month peak oxygen consumption in outpatients with stable HFrEF (DAPA-VO2 trial, NCT04197635). We used linear mixed regression analysis to assess the relationship between eGFR and hemoglobin changes across treatment arms. RESULTS: A total of 87 patients were evaluated in this substudy. The mean age was 67.0± 10.5 years, and 21 (24.1%) were women. The mean baseline eGFR and hemoglobin were 66.9±20.7mL/min/1.73m2 and 14.3±1.7g/dL, respectively. Compared with placebo, eGFR did not significantly change at either time points in the dapagliflozin group, but hemoglobin significantly increased at 1 and 3 months. At 1 month, the hemoglobin increase was related to decreases in eGFR only in the dapagliflozin arm (P <.001). At 3 months, there was no significant association in either treatment arms (P=.123). Changes in eGFR were not associated with changes in peak oxygen consumption, quality of life, or natriuretic peptides. CONCLUSIONS: In patients with stable HFrEF, 1-month changes in eGFR induced by dapagliflozin are inversely related to changes in hemoglobin. This association was no longer significant at 3 months.
Subject(s)
Heart Failure , Sodium-Glucose Transporter 2 Inhibitors , Ventricular Dysfunction, Left , Humans , Female , Middle Aged , Aged , Male , Heart Failure/drug therapy , Glomerular Filtration Rate , Sodium-Glucose Transporter 2 Inhibitors/therapeutic use , Stroke Volume , Quality of Life , Benzhydryl Compounds/therapeutic use , Hemoglobins/therapeutic useABSTRACT
INTRODUCTION AND OBJECTIVES: Little is known about the usefulness of heart rate (HR) response to exercise for risk stratification in heart failure with preserved ejection fraction (HFpEF). Therefore, this study aimed to assess the association between HR response to exercise and the risk of total episodes of worsening heart failure (WHF) in symptomatic stable patients with HFpEF. METHODS: This single-center study included 133 patients with HFpEF (NYHA II-III) who performed maximal cardiopulmonary exercise testing. HR response to exercise was evaluated using the chronotropic index (CIx) formula. A negative binomial regression method was used. RESULTS: The mean age of the sample was 73.2± 10.5 years; 56.4% were female, and 51.1% were in atrial fibrillation. The median for CIx was 0.4 [0.3-0.55]. At a median follow-up of 2.4 [1.6-5.3] years, a total of 146 WHF events in 58 patients and 41 (30.8%) deaths were registered. In the whole sample, CIx was not associated with adverse outcomes (death, P=.319, and WHF events, P=.573). However, we found a differential effect across electrocardiographic rhythms for WHF events (P for interaction=.002). CIx was inversely and linearly associated with the risk of WHF events in patients with sinus rhythm and was positively and linearly associated with those with atrial fibrillation. CONCLUSIONS: In patients with HFpEF, CIx was differentially associated with the risk of total WHF events across rhythm status. Lower CIx emerged as a risk factor for predicting higher risk in patients with sinus rhythm. In contrast, higher CIx identified a higher risk in those with atrial fibrillation.
Subject(s)
Atrial Fibrillation , Heart Failure , Humans , Female , Middle Aged , Aged , Aged, 80 and over , Male , Atrial Fibrillation/complications , Stroke Volume/physiology , Electrocardiography , Exercise Test , PrognosisABSTRACT
AIMS: This study aimed to evaluate the effect of dapagliflozin on 1 and 3-month maximal functional capacity in patients with stable heart failure with reduced ejection fraction (HFrEF). METHODS AND RESULTS: In this multicentre, randomized, double-blind clinical trial, 90 stable patients with HFrEF were randomly assigned to receive either dapagliflozin (n = 45) or placebo (n = 45). The primary outcome was a change in peak oxygen consumption (peakVO2 ) at 1 and 3 months. Secondary endpoints were changes at 1 and 3 months in 6-min walk test (6MWT) distance, quality of life (Minnesota Living with Heart Failure Questionnaire [MLHFQ]), and echocardiographic parameters (diastolic function, left chamber volumes, and left ventricular ejection fraction). We used linear mixed regression analysis to compare endpoint changes. Estimates were adjusted for multiple comparisons. The mean age was 67.1 ± 10.7 years, 69 (76.7%) were men, 29 (32.2%) had type 2 diabetes, and 80 (88.9%) were in New York Heart Association class II. Baseline means of peakVO2 , 6MWT and MLHFQ were 13.2 ± 3.5 ml/kg/min, 363 ± 110 m, and 23.1 ± 16.2, respectively. The median (25th-75th percentile) of N-terminal pro-brain natriuretic peptide was 1221 pg/ml (889-2100). Most patients were on treatment with sacubitril/valsartan (88.9%), beta-blockers (91.1%), and mineralocorticoid receptor antagonists (74.4%). PeakVO2 significantly increased in patients on treatment with dapagliflozin (1 month: +Δ 1.09 ml/kg/min, 95% confidence interval [CI] 0.14-2.04; p = 0.021, and 3 months: +Δ 1.06 ml/kg/min, 95% CI 0.07-2.04; p = 0.032). Similar positive findings were found when evaluating changes from baseline. No significant differences were observed in secondary endpoints. CONCLUSIONS: Among patients with stable HFrEF, dapagliflozin resulted in a significant improvement in peakVO2 at 1 and 3 months. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04197635.
Subject(s)
Diabetes Mellitus, Type 2 , Heart Failure , Ventricular Dysfunction, Left , Male , Humans , Middle Aged , Aged , Female , Stroke Volume , Ventricular Function, Left , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/complications , Quality of Life , Ventricular Dysfunction, Left/complicationsABSTRACT
Sodium-glucose co-transporter 2 (SGLT2) inhibitors were initially conceived as glucose-lowering agents. However, striking renal and cardiovascular benefits were observed in type 2 diabetes trials. This led to evaluate it in dedicated studies in chronic heart failure (HF) and chronic kidney disease, which also showed remarkable clinical results. Given this findings, and taking into account the multiple mechanisms of action, the use of SGLT2 inhibitors in acute heart failure seemed promising. Sotagliflozin was the first SGLT2 inhibitor to reduce heart failure hospitalizations within the acute setting in the SOLOIST-WHF trial. Only type 2 diabetes patients were included, with a preserved and reduced ejection fraction. In slightly less than half of the cohort, this medication was started when the diuretic therapy was transitioned from intravenous to oral, during the hospital admission. In the rest of the patients, sotagliflozin was started early after discharge. Empagliflozin proved to be safe, well-tolerated, increased diuresis, and reduced a combined clinical endpoint (worsening HF, rehospitalization for HF, or death at 60 days) when administered within the first 24 hours of an acute heart failure hospitalization in the EMPA-RESPONSE-AHF trial. More recently, empagliflozin showed a reduction in a composite primary endpoint of death, heart failure events, and quality of life compared to placebo in the EMPULSE trial. Empagliflozin was started after the initial stabilization phase, but while patients were still admitted and receiving intravenous loop diuretics. Less than half of the patients were diabetic and two-thirds had a left ventricular ejection fraction below 40%. Dapagliflozin is currently being tested in the DAPA ACT HF-TIMI 68 trial, which plans to enroll 2400 patients admitted with acute heart failure and reduced ejection fraction. We envision SGLT2 inhibitors as a useful tool in acute heart failure syndrome given the additive diuretic effect, and minimal impact on blood pressure, kidney function, and electrolytes. Its dosage schedule is simple and can help initiation and tolerance of other medical therapy. However, there is an increased risk of genital infections and euglycaemic ketoacidosis. Notwithstanding, once critically ill and fasting patients are excluded, early administration of SGLT2 inhibitors is safe. This review summarizes the development of SGLT2 inhibitors and the available evidence supporting their use during an acute heart failure admission. We also propose a practical guideline for in-hospital initiation and monitoring.
ABSTRACT
BACKGROUND: Chronotropic incompetence has shown to be associated with a decrease in exercise capacity in heart failure with preserved ejection fraction (HFpEF), yet ß-blockers are commonly used in HFpEF despite the lack of robust evidence. OBJECTIVES: This study aimed to evaluate the effect of ß-blocker withdrawal on peak oxygen consumption (peak Vo2) in patients with HFpEF and chronotropic incompetence. METHODS: This is a multicenter, randomized, investigator-blinded, crossover clinical trial consisting of 2 treatment periods of 2 weeks separated by a washout period of 2 weeks. Patients with stable HFpEF, New York Heart Association functional classes II and III, previous treatment with ß-blockers, and chronotropic incompetence were first randomized to withdrawing from (arm A: n = 26) versus continuing (arm B: n = 26) ß-blocker treatment and were then crossed over to receive the opposite intervention. Changes in peak Vo2 and percentage of predicted peak Vo2 (peak Vo2%) measured at the end of the trial were the primary outcome measures. To account for the paired-data nature of this crossover trial, linear mixed regression analysis was used. RESULTS: The mean age was 72.6 ± 13.1 years, and most of the patients were women (59.6%) in New York Heart Association functional class II (66.7%). The mean peakVo2 and peak Vo2% were 12.4 ± 2.9 mL/kg/min, and 72.4 ± 17.8%, respectively. No significant baseline differences were found across treatment arms. Peak Vo2 and peak Vo2% increased significantly after ß-blocker withdrawal (14.3 vs 12.2 mL/kg/min [Δ +2.1 mL/kg/min]; P < 0.001 and 81.1 vs 69.4% [Δ +11.7%]; P < 0.001, respectively). CONCLUSIONS: ß-blocker withdrawal improved maximal functional capacity in patients with HFpEF and chronotropic incompetence. ß-blocker use in HFpEF deserves profound re-evaluation. (ß-blockers Withdrawal in Patients With HFpEF and Chronotropic Incompetence: Effect on Functional Capacity [PRESERVE-HR]; NCT03871803; 2017-005077-39).
Subject(s)
Adrenergic beta-Antagonists/administration & dosage , Heart Failure/drug therapy , Stroke Volume/physiology , Ventricular Function, Left/physiology , Withholding Treatment , Aged , Aged, 80 and over , Cross-Over Studies , Female , Heart Failure/diagnosis , Heart Failure/physiopathology , Heart Rate/drug effects , Heart Rate/physiology , Humans , Male , Single-Blind Method , Stroke Volume/drug effects , Ventricular Function, Left/drug effects , Withholding Treatment/trendsSubject(s)
Heart Failure , Exercise Test , Exercise Tolerance , Heart Failure/diagnosis , Heart Rate , Humans , Stroke Volume , Walk Test , WalkingABSTRACT
BACKGROUND: The pathophysiology of heart failure with preserved ejection fraction (HFpEF) is complex and multifactorial. Chronotropic incompetence (ChI) has emerged as a crucial pathophysiological mechanism. Beta-blockers, drugs with negative chronotropic effects, are commonly used in HFpEF, although current evidence does not support its routine use in these patients. HYPOTHESIS: We postulate beta-blockers may have deleterious effects in HFpEF and ChI. This work aims to evaluate the short-term effect of beta-blockers withdrawal on functional capacity assessed by the maximal oxygen uptake (peakVO2) in patients with HFpEF and ChI. METHODS: This is a prospective, crossover, randomized (1:1) and multicenter study. After randomization, the clinical and cardiac rhythm will be continuously registered for 30 days. PeakVO2 is assessed by cardiopulmonary exercise testing (CPET) at 15 and 30 days in both groups. Secondary endpoints include quality of life, cognitive, and safety assessment. Patients with stable HFpEF, functional class New York Heart Association (NYHA) II-III, chronic treatment with beta-blockers, and ChI will be enrolled. A sample size estimation [alfa: 0.05, power: 90%, a 20% loss rate, and delta change of mean peakVO2: +1.2 mL/kg/min (SD ± 2.0)] of 52 patients is necessary to test our hypothesis. RESULTS: Patients started enrolling in October 2018. As January 14th, 2020, 28 patients have been enrolled. It is projected to enroll the last patient at the end of July 2020. CONCLUSIONS: Optimizing therapy that improves functional capacity remains an unmeet priority in HFpEF. Deprescribing beta-blockers in patients with HFpEF and ChI seems a plausible intervention to improve functional capacity. This trial is an attempt towards precision medicine in this complex syndrome. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03871803.