Abstract
Patients with heart failure with preserved ejection fraction (HFpEF) are often elderly and likely to have cardiac comorbidities such as coronary artery disease (CAD) and atrial fibrillation (AF). The primary chronic symptom of HFpEF patients is severe exercise intolerance. The inability to adequately increase heart rate during exercise is commonly present in HFpEF patients and contributes to their exercise intolerance. Although beta-blockers are frequently used for the treatment of myocardial ischemia and tachycardia in HFpEF patients, there is a concern that slowing heart rate by beta-blockers may worsen chronotropic incompetence and further exacerbate their symptoms. Although the effect of beta-blockers on heart failure severity in HFpEF patients has been examined in randomized controlled trials (RCTs), results are inconsistent due partly to limited power. We aimed to conduct a meta-analysis of RCTs on the effect of beta-blockers on heart failure severity in HFpEF patients. The search of electronic databases identified 5 RCTs including 538 patients. In pooled analyses, beta-blockers did not significantly change the New York Heart Association (NYHA) class, exercise capacity expressed as metabolic equivalents, or plasma B-type natriuretic peptide (BNP) levels compared with control but with substantial heterogeneity across trials. In meta-regression analyses, the higher proportion of CAD or AF in the included trials was associated with a decrease in NYHA class and BNP levels and with an increase in exercise capacity. Thus, we found no clear beneficial effect of beta-blockers on heart failure severity in HFpEF patients. However, beta-blockers may be beneficial in HFpEF patients with CAD or AF.
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Vasan RS, Larson MG, Benjamin EJ, Evans JC, Reiss CK, Levy D (1999) Congestive heart failure in subjects with normal versus reduced left ventricular ejection fraction: prevalence and mortality in a population-based cohort. J Am Coll Cardiol 33:1948–1955
Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM (2006) Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 355:251–259
Tsuchihashi-Makaya M, Hamaguchi S, Kinugawa S, Yokota T, Goto D, Yokoshiki H, Kato N, Takeshita A, Tsutsui H (2009) Characteristics and outcomes of hospitalized patients with heart failure and reduced vs preserved ejection fraction. Report from the Japanese Cardiac Registry of Heart Failure in Cardiology (JCARE-CARD). Circ J 73:1893–1900
Kitzman DW, Little WC, Brubaker PH, Anderson RT, Hundley WG, Marburger CT, Brosnihan B, Morgan TM, Stewart KP (2002) Pathophysiological characterization of isolated diastolic heart failure in comparison to systolic heart failure. JAMA 288:2144–2150
Bhella PS, Prasad A, Heinicke K, Hastings JL, rbab-Zadeh A, ms-Huet B, Pacini EL, Shibata S, Palmer MD, Newcomer BR, Levine BD (2011) Abnormal haemodynamic response to exercise in heart failure with preserved ejection fraction. Eur J Heart Fail 13:1296–1304
Borlaug BA (2014) Mechanisms of exercise intolerance in heart failure with preserved ejection fraction. Circ J 78:20–32
Vaduganathan M, Michel A, Hall K, Mulligan C, Nodari S, Shah SJ, Senni M, Triggiani M, Butler J, Gheorghiade M (2016) Spectrum of epidemiological and clinical findings in patients with heart failure with preserved ejection fraction stratified by study design: a systematic review. Eur J Heart Fail 18:54–65
Santas E, Valero E, Mollar A, Garcia-Blas S, Palau P, Minana G, Nunez E, Sanchis J, Chorro FJ, Nunez J (2017) Burden of recurrent hospitalizations following an admission for acute heart failure: preserved versus reduced ejection fraction. Rev Esp Cardiol (Engl Ed) 70:239–246
Zafrir B, Lund LH, Laroche C, Ruschitzka F, Crespo-Leiro MG, Coats AJS, Anker SD, Filippatos G, Seferovic PM, Maggioni AP, De Mora MM, Polonski L, Silva-Cardoso J, Amir O (2018) Prognostic implications of atrial fibrillation in heart failure with reduced, mid-range, and preserved ejection fraction: a report from 14 964 patients in the European Society of Cardiology Heart Failure Long-Term Registry. Eur Heart J 39:4277–4284
Bergstrom A, Andersson B, Edner M, Nylander E, Persson H, Dahlstrom U (2004) Effect of carvedilol on diastolic function in patients with diastolic heart failure and preserved systolic function. Results of the Swedish Doppler-echocardiographic study (SWEDIC). Eur J Heart Fail 6:453–461
Takeda Y, Fukutomi T, Suzuki S, Yamamoto K, Ogata M, Kondo H, Sugiura M, Shigeyama J, Itoh M (2004) Effects of carvedilol on plasma B-type natriuretic peptide concentration and symptoms in patients with heart failure and preserved ejection fraction. Am J Cardiol 94:448–453
Conraads VM, Metra M, Kamp O, De Keulenaer GW, Pieske B, Zamorano J, Vardas PE, Bohm M, Dei CL (2012) Effects of the long-term administration of nebivolol on the clinical symptoms, exercise capacity, and left ventricular function of patients with diastolic dysfunction: results of the ELANDD study. Eur J Heart Fail 14:219–225
Yamamoto K, Origasa H, Hori M (2013) Effects of carvedilol on heart failure with preserved ejection fraction: the Japanese diastolic heart failure study (J-DHF). Eur J Heart Fail 15:110–118
Mittal N, Shafiq N, Reddy S, Malhotra S, Kumari S, Varma S (2017) Evaluation of efficacy of metoprolol in patients having heart failure with preserved ejection fraction: a randomized, double-blind, placebo-controlled pilot trial. Perspect Clin Res 8:124–131
Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151:264–269 W64
Follmann D, Elliott P, Suh I, Cutler J (1992) Variance imputation for overviews of clinical trials with continuous response. J Clin Epidemiol 45:769–773
Wan X, Wang W, Liu J, Tong T (2014) Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 14:135
Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327:557–560
Lebeau R, Di LM, Amyot R, Veilleux M, Lemieux R, Sauve C (2003) A new tool for estimating left ventricular ejection fraction derived from wall motion score index. Can J Cardiol 19:397–404
Zheng SL, Chan FT, Nabeebaccus AA, Shah AM, McDonagh T, Okonko DO, Ayis S (2018) Drug treatment effects on outcomes in heart failure with preserved ejection fraction: a systematic review and meta-analysis. Heart 104:407–415
Martin N, Manoharan K, Thomas J, Davies C, Lumbers RT (2018) Beta-blockers and inhibitors of the renin-angiotensin aldosterone system for chronic heart failure with preserved ejection fraction. Cochrane Database Syst Rev 6:CD012721
Cheng CP, Igarashi Y, Little WC (1992) Mechanism of augmented rate of left ventricular filling during exercise. Circ Res 70:9–19
Bonow RO, Udelson JE (1992) Left ventricular diastolic dysfunction as a cause of congestive heart failure. Mechanisms and management. Ann Intern Med 117:502–510
Zile MR, Brutsaert DL (2002) New concepts in diastolic dysfunction and diastolic heart failure: part I: diagnosis, prognosis, and measurements of diastolic function. Circulation 105:1387–1393
Zile MR, Brutsaert DL (2002) New concepts in diastolic dysfunction and diastolic heart failure: part II: causal mechanisms and treatment. Circulation 105:1503–1508
Chan PK, Heo JY, Garibian G, Askenase A, Segal BL, Iskandrian AS (1988) The role of nitrates, beta blockers, and calcium antagonists in stable angina pectoris. Am Heart J 116:838–848
Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJ, Mitchell JE, Peterson PN, Riegel B, Sam F, Stevenson LW, Tang WH, Tsai EJ, Wilkoff BL (2013) ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013(62):e147–e239
Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, Gonzalez-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P (2016) ESC guidelines for the diagnosis and treatment of acute and chronic heart failure: the task force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC)developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur Heart J 2016(37):2129–2200
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Dr. Ohte has received lecture fees from the Daiichi Sankyo Co. and grant support from the Takeda Pharmaceutical Co. Ltd., Daiichi Sankyo Co., Ltd., and Otsuka Pharmaceutical Co., Ltd. Dr. Kamiya has received lecture fees from the Astellas Pharma Inc. and Mochida Pharmaceutical Co., Ltd.
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Supplement Fig. 1
Forest plots showing the effects of beta-blockers (BBs) on heart rate (bpm; a), left ventricular (LV) mass (g; b), left atrial (LA) dimension (mm, c), ejection fraction (EF; %, d), the ratio of peak early to late diastolic mitral inflow velocities (E/A; e), and the ratio of early diastolic mitral inflow to annular velocities (E/e’; f). (PPTX 47 kb)
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Fukuta, H., Goto, T., Wakami, K. et al. Effect of beta-blockers on heart failure severity in patients with heart failure with preserved ejection fraction: a meta-analysis of randomized controlled trials. Heart Fail Rev 26, 165–171 (2021). https://doi.org/10.1007/s10741-020-10013-5
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DOI: https://doi.org/10.1007/s10741-020-10013-5