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Tang J, Wang P, Liu C, Peng J, Liu Y, Ma Q. Pharmacotherapy in patients with heart failure with reduced ejection fraction: A systematic review and meta-analysis. Chin Med J (Engl) 2025; 138:925-933. [PMID: 38811344 PMCID: PMC12037092 DOI: 10.1097/cm9.0000000000003118] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Indexed: 05/31/2024] Open
Abstract
BACKGROUND Angiotensin receptor neprilysin inhibitors (ARNIs), angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs), β-blockers (BBs), and mineralocorticoid receptor antagonists (MRAs) are the cornerstones in treating heart failure with reduced ejection fraction (HFrEF). Sodium-glucose cotransporter 2 inhibitors (SGLT-2is) are included in HFrEF treatment guidelines. However, the effect of SGLT-2i and the five drugs on HFrEF have not yet been systematically evaluated. METHODS PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials (RCTs) from inception dates to September 23, 2022. Additional trials from previous relevant reviews and references were also included. The primary outcomes were changes in left ventricular ejection fraction (LVEF), left ventricular end-diastolic diameter/dimension (LVEDD), left ventricular end-systolic diameter/dimension (LVESD), left ventricular end-diastolic volume (LVEDV), and left ventricular end-systolic volume (LVESV), left ventricular end-systolic volume index (LVESVI), and left ventricular end-diastolic volume index (LVEDVI). Secondary outcomes were New York Heart Association (NYHA) class, 6-min walking distance (6MWD), B-type natriuretic peptide (BNP) level, and N-terminal pro-BNP (NT-proBNP) level. The effect sizes were presented as the mean difference (MD) with 95% confidence interval (CI). RESULTS We included 68 RCTs involving 16,425 patients. Compared with placebo, ARNI + BB + MRA + SGLT-2i was the most effective combination to improve LVEF (15.63%, 95% CI: 9.91% to 21.68%). ARNI + BB + MRA + SGLT-2i (5.83%, 95% CI: 0.53% to 11.14%) and ARNI + BB + MRA (3.83%, 95% CI: 0.72% to 6.90%) were superior to the traditional golden triangle ACEI + BB + MRA in improving LVEF. ACEI + BB + MRA + SGLT-2i was better than ACEI + BB + MRA (-8.05 mL/m 2 , 95% CI: -14.88 to -1.23 mL/m 2 ) and ACEI + BB + SGLT-2i (-18.94 mL/m 2 , 95% CI: -36.97 to -0.61 mL/m 2 ) in improving LVEDVI. ACEI + BB + MRA + SGLT-2i (-3254.21 pg/mL, 95% CI: -6242.19 to -560.47 pg/mL) was superior to ARB + BB + MRA in reducing NT-proBNP. CONCLUSIONS Adding SGLT-2i to ARNI/ACEI + BB + MRA is beneficial for reversing cardiac remodeling. The new quadruple drug "ARNI + BB + MRA + SGLT-2i" is superior to the golden triangle "ACEI + BB + MRA" in improving LVEF. REGISTRATION PROSPERO; No. CRD42022354792.
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Affiliation(s)
- Jia Tang
- Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan 410008, China
| | - Ping Wang
- Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan 410008, China
| | - Chenxi Liu
- Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan 410008, China
| | - Jia Peng
- Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan 410008, China
| | - Yubo Liu
- Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan 410008, China
| | - Qilin Ma
- Department of Cardiovascular Medicine, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Changsha, Hunan 410008, China
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Eddin LE, Preyra R, Ahmadi F, Jafari A, Omrani MA, Muanda FT. β-Blockers and risk of neuropsychiatric disorders: A systematic review and meta-analysis. Br J Clin Pharmacol 2025; 91:325-337. [PMID: 39658346 PMCID: PMC11773113 DOI: 10.1111/bcp.16361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2024] [Revised: 11/10/2024] [Accepted: 11/17/2024] [Indexed: 12/12/2024] Open
Abstract
AIMS This systematic review and meta-analysis aimed to evaluate the association between β-blocker use and neuropsychiatric adverse events, specifically focusing on short-term outcomes. METHODS A comprehensive literature search identified studies reporting neuropsychiatric outcomes in patients using β-blockers, including randomized controlled trials and observational studies. Relative risks (RR) and 95% confidence intervals (CIs) were calculated for outcomes such as dizziness, insomnia, nightmares, drowsiness and delirium. RESULTS Our analysis revealed that β-blocker use was significantly associated with an increased risk of dizziness (RR 1.72, 95% CI [1.39-2.14]; I2 = 1%, 14 studies) compared to placebo. Lipophilic β-blockers, especially propranolol, showed an even greater risk of dizziness (RR 3.13, 95% CI [1.44-6.84]; I2 = 0%, three studies). Propranolol was also associated with increased insomnia risk compared to placebo (RR 1.13, 95% CI [1.00-1.28]; I2 = 0%, five studies). Our data did not show statistically significant increases in the reports of nightmares and somnolence. Other adverse effects, including drowsiness, sleep disturbances, hallucinations and delirium, were noted. CONCLUSIONS Our findings suggest a significant association between β-blocker use and an increased risk of neuropsychiatric adverse events, particularly insomnia and dizziness with higher risks associated with lipophilic β-blocker use. Given the ambiguity surrounding dizziness and its classification as a neuropsychiatric effect, our findings are exploratory, and we cannot exclude a potential cardiovascular origin for dizziness. Most studies (75%) were published before the CONSORT statement in 1996, indicating potential reporting limitations and a lack of recent research. Additionally, 60% of studies had a high risk of bias, underscoring the need for more rigorous and contemporary investigations into the neuropsychiatric implications of β-blocker use.
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Affiliation(s)
- Lujain Ez Eddin
- ICES WesternLondonONCanada
- Department of Physiology and PharmacologyWestern UniversityLondonOntarioCanada
| | - Rebecca Preyra
- Department of Physiology and PharmacologyWestern UniversityLondonOntarioCanada
| | - Fatemeh Ahmadi
- ICES WesternLondonONCanada
- Department of Epidemiology & BiostatisticsWestern UniversityLondonONCanada
| | - Atefeh Jafari
- ICES WesternLondonONCanada
- Department of Epidemiology & BiostatisticsWestern UniversityLondonONCanada
| | - Mohammad Ali Omrani
- ICES WesternLondonONCanada
- Department of Physiology and PharmacologyWestern UniversityLondonOntarioCanada
| | - Flory T. Muanda
- ICES WesternLondonONCanada
- Department of Physiology and PharmacologyWestern UniversityLondonOntarioCanada
- Department of Epidemiology & BiostatisticsWestern UniversityLondonONCanada
- Lawson Health Research Institute, London Health Sciences CentreLondonOntarioCanada
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Packer M. Lack of durable natriuresis and objective decongestion following SGLT2 inhibition in randomized controlled trials of patients with heart failure. Cardiovasc Diabetol 2023; 22:197. [PMID: 37533009 PMCID: PMC10399057 DOI: 10.1186/s12933-023-01946-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 07/28/2023] [Indexed: 08/04/2023] Open
Abstract
Patients with heart failure have increased cardiac filling pressures, circulating natriuretic peptides, and physical signs of fluid retention, which are related to sodium retention by the kidneys and are alleviated by conventional diuretics. Sodium-glucose cotransporter 2 (SGLT2) inhibitors interfere with sodium and glucose reabsorption in the proximal renal tubule, but they evoke a marked counterregulatory activation of sodium and water reabsorption in distal nephron segments, which opposes and negates any diuretic effect. Nevertheless, it has been postulated that SGLT2 inhibitors modulate the volume set point, leading selectively to decongestion in patients with fluid overload. This hypothesis was tested in a review of 15 randomized controlled trials of SGLT2 inhibitors in patients with heart failure, with 7 trials focusing on urinary volume within the first week, and 8 trials focusing on objective decongestion at 12 weeks. In trials < 1 week, SGLT2 inhibition increased urine volume in the first 24 h, but typically without a change in urinary sodium excretion, and this diuresis was not sustained. In 8 trials of 12 weeks' duration, none reported alleviation of edema, ascites or pulmonary rales. The 2 trials that evaluated changes in left ventricular filling pressure noted no or small changes (1-2 mm Hg); the two trials that measured interstitial lung water or total blood volume found no effect; and 6 of the 7 trials found no decrease in circulating natriuretic peptides. Therefore, randomized controlled trials do not indicate that SGLT2 inhibitors produce a durable natriuresis or objective decongestion in patients with heart failure.
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Affiliation(s)
- Milton Packer
- Heart and Vascular Institute, Baylor University Medical Center, 621 North Hall Street, Dallas, TX, 75226, USA.
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Augustin N, Alvarez C, Kluger J. The Arrhythmogenicity of Sotalol and its Role in Heart Failure: A Literature Review. J Cardiovasc Pharmacol 2023; 82:86-92. [PMID: 37229640 DOI: 10.1097/fjc.0000000000001439] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 05/10/2023] [Indexed: 05/27/2023]
Abstract
ABSTRACT According to the American Heart Association, approximately 6 million adults have been afflicted with heart failure in the United States in 2020 and are more likely to have sudden cardiac death accounting for approximately 50% of the cause of mortality. Sotalol is a nonselective β-adrenergic receptor antagonist with class III antiarrhythmic properties that has been mostly used for atrial fibrillation treatment and suppressing recurrent ventricular tachyarrhythmias. The use of sotalol in patients with left ventricular dysfunction is not recommended by the American College of Cardiology or American Heart Association because studies are inconclusive with conflicting results regarding safety. This article aims to review the mechanism of action of sotalol, the β-blocking effects on heart failure, and provide an overview of clinical trials on sotalol use and its effects in patients with heart failure. Small- and large-scale clinical trials have been controversial and inconclusive about the use of sotalol in heart failure. Sotalol has been shown to reduce defibrillation energy requirements and reduce shocks from implantable cardioverter-defibrillators. Torsades de Pointes is the most life-threatening arrhythmia that has been documented with sotalol use and occurs more commonly in women and heart failure patients. Thus far, mortality benefits have not been demonstrated with sotalol use and larger multicenter studies are required going forward.
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Affiliation(s)
- Najwan Augustin
- University of Connecticut Primary Care Internal Medicine Residency, New Britain, CT; and
| | - Chikezie Alvarez
- Hartford Healthcare Heart and Vascular Institute, Hartford Hospital, Hartford, CT
| | - Jeffrey Kluger
- Hartford Healthcare Heart and Vascular Institute, Hartford Hospital, Hartford, CT
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Beavers CJ, Ambrosy AP, Butler J, Davidson BT, Gale SE, Piña IL, Mastoris I, Reza N, Mentz RJ, Lewis GD. Iron Deficiency in Heart Failure: A Scientific Statement from the Heart Failure Society of America. J Card Fail 2023; 29:1059-1077. [PMID: 37137386 DOI: 10.1016/j.cardfail.2023.03.025] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2023] [Revised: 03/10/2023] [Accepted: 03/23/2023] [Indexed: 05/05/2023]
Abstract
Iron deficiency is present in approximately 50% of patients with symptomatic heart failure and is independently associated with worse functional capacity, lower quality of, life and increased mortality. The purpose of this document is to summarize current knowledge of how iron deficiency is defined in heart failure and its epidemiology and pathophysiology, as well as pharmacological considerations for repletion strategies. This document also summarizes the rapidly expanding array of clinical trial evidence informing when, how, and in whom to consider iron repletion.
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Affiliation(s)
- Craig J Beavers
- University of Kentucky College of Pharmacy, Lexington, Kentucky.
| | - Andrew P Ambrosy
- Kaiser Permanente Northern California - Division of Research (DOR), Oakland, CA
| | - Javed Butler
- Baylor Scott and White Research Institute, Dallas, Texas; University of Mississippi, Jackson, Mississippi
| | - Beth T Davidson
- Centennial Heart Cardiovascular Consultants, Nashville, Tennessee
| | - Stormi E Gale
- Novant Health Matthews Medical Center, Matthews, North Carolina
| | - Ileana L Piña
- Thomas Jefferson University, Philadelphia, Pennsylvania
| | | | - Nosheen Reza
- Division of Cardiovascular Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Robert J Mentz
- Duke University School of Medicine, Durham, North Carolina
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Packer M. The First Dedicated Comprehensive Heart Failure Program in the United States: The Division of Circulatory Physiology at Columbia Presbyterian (1992-2004). J Card Fail 2023; 29:1078-1090. [PMID: 37075940 DOI: 10.1016/j.cardfail.2023.03.028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 03/31/2023] [Accepted: 03/31/2023] [Indexed: 04/21/2023]
Abstract
The first dedicated multidisciplinary heart failure program in the United States was founded as the Division of Circulatory Physiology at the Columbia University College of Physicians & Surgeons in 1992. The Division was administratively and financially independent of the Division of Cardiology and grew to 24 faculty members at its peak. Its administrative innovations included (1) a comprehensive full-integrated service line, with 2 differentiated clinical teams, one devoted to drug therapy and the other to heart transplantation and ventricular assist devices; (2) a nurse specialist/physician assistant-led clinical service; and (3) a financial structure independent of (and not supported by) other cardiovascular medical or surgical services. The division had 3 overarching missions: (1) to promote a unique career development path for each faculty member to be linked to recognition in a specific area of heart failure expertise; (2) to change the trajectory and enhance the richness of intellectual discourse in the discipline of heart failure, so as to foster an understanding of fundamental mechanisms and to develop new therapeutics; and (3) to provide optimal medical care to patients and to promote the ability of other physicians to provide optimal care. The major research achievements of the division included (1) the development of beta-blockers for heart failure, from initial hemodynamic assessments to proof-of-concept studies to large-scale international trials; (2) the development and definitive assessment of flosequinan, amlodipine, and endothelin antagonists; (3) initial clinical trials and concerns with nesiritide; (4) large-scale trials evaluating dosing of angiotensin converting-enzyme inhibitors and the efficacy and safety of neprilysin inhibition; (5) identification of key mechanisms in heart failure, including neurohormonal activation, microcirculatory endothelial dysfunction, deficiencies in peripheral vasodilator pathways, noncardiac factors in driving dyspnea, and the first identification of subphenotypes of heart failure and a preserved ejection fraction; (6) the development of a volumetric approach to the assessment of myocardial shortening; (7) conceptualization and early studies of cardiac contractility modulation as a treatment for heart failure; (8) novel approaches to the identification of cardiac allograft rejection and new therapeutics to prevent allograft vasculopathy; and (9) demonstration of the effect of left ventricular assist devices to induce reverse remodeling, and the first randomized trial showing a survival benefit with ventricular assist devices. Above all, the division served as an exceptional incubator for a generation of leaders in the field of heart failure.
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Affiliation(s)
- Milton Packer
- From the Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas, and Imperial College, London, UK.
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Lund LH, Zeymer U, Clark AL, Barrios V, Damy T, Drożdż J, Fonseca C, Kalus S, Ferber PC, Koch C, Maggioni AP. Association between sacubitril/valsartan initiation and changes in left ventricular ejection fraction: Insights from ARIADNE registry. Int J Cardiol 2023; 370:279-286. [PMID: 36216094 DOI: 10.1016/j.ijcard.2022.10.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 09/29/2022] [Accepted: 10/05/2022] [Indexed: 11/05/2022]
Abstract
AIMS We tested the hypothesis that initiation versus non-initiation of sacubitril/valsartan is associated with a more favorable subsequent change in left ventricular ejection fraction (LVEF) in a real-world setting. METHODS A prospective, non-randomized, double-arm, open-label, cohort study had been conducted across 687 centers in 17 European countries enrolling HFrEF patients aged ≥18 years with symptoms of HF (New York Heart Association [NYHA] II-IV) and "reduced LVEF". For the current analysis, 2602 patients with LVEF measured at baseline and follow-up were chosen, of which 860 (33%, mean age 67 years, 26% women) were started on sacubitril/valsartan at baseline and 1742 (67%, 68 years, 23% women) were not. Patients started on sacubitril/valsartan had higher NYHA class and lower LVEF. RESULTS LVEF increased from mean 32.7% to 38.1% in the sacubitril/valsartan group versus from 35.9% to 38.7% in the non-sacubitril/valsartan group (mean difference in increase 2.6%, p < 0.001). LVEF increased from baseline in 64% versus 53% of patients and increased by ≥5% (absolute %) in 50% versus 35% of patients in the sacubitril/valsartan versus non-sacubitril/valsartan groups, respectively. In the overall cohort, initiation of sacubitril/valsartan was independently associated with any increase in LVEF (adjusted odds ratio [OR] 1.49 [1.26-1.75]) and with increase by ≥5% (OR 1.65 [1.39-1.95]). CONCLUSION Initiating versus not initiating sacubitril/valsartan was independently associated with a greater subsequent increase in LVEF in this real-world setting. Reverse cardiac remodeling may be one mechanism of benefit of sacubitril/valsartan.
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Affiliation(s)
- Lars H Lund
- Department of Medicine, Karolinska Institutet, And Heart Vascular and Neuro Theme Karolinska University Hospital, Stockholm, Sweden.
| | - Uwe Zeymer
- Klinikum Ludwigshafen and Institut für Herzinfarktforschung, Ludwigshafen-am-Rhein, Germany
| | - Andrew L Clark
- Castle Hill Hospital, Kingston Upon Hull, United Kingdom
| | | | - Thibaud Damy
- University Hospital Henri Mondor, Créteil, France
| | | | - Candida Fonseca
- Hospital de Sao Francisco Xavier, CHLO, NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisbon, Portugal
| | - Stefanie Kalus
- GKM Gesellschaft für Therapieforschung mbH, Munich, Germany
| | | | | | - Aldo P Maggioni
- Associazione Nazionale Medici Cardiologi Ospedalieri Research Center, Florence, Italy; Maria Cecilia Hospital, GVM Care & Research, Italy
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Yamashina A, Nishikori M, Fujimito H, Oba K. Identification of predictive factors interacting with heart rate reduction for potential beneficial clinical outcomes in chronic heart failure: A systematic literature review and meta-analysis. IJC HEART & VASCULATURE 2022; 43:101141. [PMID: 36338318 PMCID: PMC9634015 DOI: 10.1016/j.ijcha.2022.101141] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2022] [Revised: 09/21/2022] [Accepted: 10/22/2022] [Indexed: 11/06/2022]
Abstract
Background There is an absence of clinical evidence on what factors modify the effect of heart rate (HR)-reducing treatment on mortality and morbidity in symptomatic heart failure patients with reduced ejection fraction (HFrEF). We performed a Bayesian meta-analysis and meta-regression to identify predictive factors that interact with HR-reducing therapy. Methods A systematic review was performed to identify randomized placebo-controlled trials that enrolled symptomatic HFrEF patients. The primary objective was to evaluate how different predictive factors modify the efficacy of HR-reducing therapy on clinical outcomes. Secondary objectives included the evaluation of subgroups stratified by a HR reduction threshold of 10 bpm. Results Data from 20 studies were synthesized and HR-reducing therapy was responsible for 16.7 %, 16.4 %, and 21.1 % risk reductions in all-cause mortality, cardiovascular (CV)-related mortality, and rehospitalization due to worsening HF (WHF), respectively. Empirical Bayes meta-regression showed that type 2 diabetes mellitus (T2DM) significantly modified the efficacy of HR-reducing therapy on all-cause mortality (slope = 0.012 in log risk ratio (RR) per 1 %-unit [95 % credible interval (CrI) 0.004, 0.021]) and CV-related mortality (0.01 in log RR per 1 %-unit [95 % CrI 0.0003, 0.0200]). There were insufficient studies to perform a meta-regression when stratifying by a HR reduction threshold of 10 bpm; however, when including all studies, we observed a significant effect modification for rehospitalization due to WHF (p = 0.004). Conclusions This meta-analysis focused on the central tenet of HR-reducing therapy and revealed that T2DM is a predictor of HR-reducing treatment effect on all-cause mortality and CV-related mortality in HFrEF patients.
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Key Words
- AF, atrial fibrillation
- Bayesian analysis
- CV, cardiovascular
- Chronic heart failure
- CrI, credible interval
- HF, heart failure
- HFrEF, HF with reduced ejection fraction
- HR, heart rate
- Heart failure with reduced ejection fraction
- Heart rate
- LVEF, left ventricular ejection fraction
- MI, myocardial infarction
- Meta-analysis
- NYHA, New York Heart Association
- PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses
- Predictive factors
- RR, risk ratio
- T2DM, type 2 diabetes mellitus
- WHF, worsening heart failure
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Affiliation(s)
- Akira Yamashina
- Department of Cardiology, Tokyo Medical University, Tokyo, Japan
- Department of Health Sciences, Kiryu University, Gunma, Japan
| | | | - Hiroaki Fujimito
- Medical Affairs Division, Ono Pharmaceutical Co., Ltd., Osaka, Japan
| | - Koji Oba
- Interfaculty Initiative in Information Studies, The University of Tokyo, Tokyo, Japan
- Department of Biostatistics, School of Public Health, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Sharma R, Silverman S, Patel S, Schwamm LH, Sanborn DY. Frequency, predictors and cardiovascular outcomes associated with transthoracic echocardiographic findings during acute ischaemic stroke hospitalisation. Stroke Vasc Neurol 2022; 7:482-492. [PMID: 35697387 PMCID: PMC9811598 DOI: 10.1136/svn-2021-001170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 04/29/2022] [Indexed: 01/28/2023] Open
Abstract
OBJECTIVE To characterise the clinical utility of transthoracic echocardiography (TTE) at the time of acute ischaemic stroke (AIS). BACKGROUND The utility of obtaining a TTE during AIS hospitalisation is uncertain. METHODS We studied AIS hospitalisations at a single centre (2002-2016). TTE abnormalities were classified as findings associated with: high stroke risk (Category I), cardiac events (Category II) and of unclear significance (Category III). We performed logistic regressions to predict Category I, II and III abnormalities. The odds of 1 year recurrent stroke hospitalisation captured by ICD 9 and 10 codes as a function of Category I, II and III abnormalities were assessed. Improvement in predictive capacity for 1 year recurrent ischaemic stroke hospitalisation beyond stroke risk factors was evaluated by net reclassification improvement. RESULTS There were 5523 AIS hospitalisations. Nearly 81% of admission TTEs were abnormal (18.7% Category I, 32.7% Category II, 72.8% Category III). Older patients with coronary artery disease, atrial fibrillation, hypertension, diabetes, and patent intracranial and extracranial vessels were likely to have an abnormal TTE. Category I finding was associated with lower odds of 1-year recurrent stroke hospitalisation (OR 0.54, 95% CI 0.30 to 0.96). Category I data significantly improved the predictive value for 1-year recurrent ischaemic stroke hospitalisation beyond stroke risk factors (net reclassification improvement 0.1563, 95% CI 0.0465 to 0.2661). CONCLUSIONS TTE abnormalities associated with stroke and cardiac event risk were commonly detected during AIS hospitalisation. Detection of Category I TTE findings reduced the risk of recurrent stroke, potentially due to neutralisation of the cardioembolic source by targeted therapy, indicating the clinical utility of TTE.
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Affiliation(s)
- Richa Sharma
- Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, USA
| | - Scott Silverman
- Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Shaun Patel
- Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Lee H Schwamm
- Department of Neurology, Massachusetts General Hospital, Boston, Massachusetts, USA
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Salmoirago-Blotcher E, Walaska K, Trivedi D, Dunsiger S, Breault C, Levine D, Wu JR, Cohen R. Mind Your Heart: Exploring Feasibility, Acceptability, and Preliminary Effects of Phone-Delivered Mindfulness Training on Medication Adherence in Outpatients With Chronic Heart Failure. J Cardiovasc Nurs 2022; 37:595-602. [PMID: 35067596 PMCID: PMC9300764 DOI: 10.1097/jcn.0000000000000891] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
BACKGROUND Mindfulness training (MT) may promote medication adherence in outpatients with heart failure. OBJECTIVE The aims of this study were to determine the feasibility and acceptability of MT (primary outcomes) and explore effects on medication adherence, functional capacity, cognitive function, depression, and mindfulness skills (secondary outcomes). METHODS In this pre/post-design study, participants received a 30-minute phone-delivered MT session weekly for 8 weeks. RESULTS We enrolled 33 outpatients (32% women; 69.7 White; mean age, 60.3 years). Retention was 100%, and session attendance was 91%. Overall, participants (97%) rated MT as enjoyable. Objectively assessed ( P < .05) adherence decreased post intervention, whereas improvements were noted in functional capacity ( P = .05), mindfulness ( P < .05), and cognitive function (reaching significance for Flanker scores). CONCLUSIONS Phone-delivered MT was feasible and acceptable. Whereas no improvements were noted in medication adherence and depression, cognitive function, functional capacity, and mindfulness levels increased post intervention, suggesting MT may have beneficial effects in outpatients with heart failure.
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Affiliation(s)
- Elena Salmoirago-Blotcher
- Centers for Behavioral and Preventive Medicine, The Miriam Hospital, Providence, RI, United States
- Department of Medicine, The Warren Alpert Medical School of Brown University, Providence, RI, United States
| | - Kristen Walaska
- Centers for Behavioral and Preventive Medicine, The Miriam Hospital, Providence, RI, United States
| | - Dyuti Trivedi
- Centers for Behavioral and Preventive Medicine, The Miriam Hospital, Providence, RI, United States
| | - Shira Dunsiger
- Center for Health Promotion and Health Equity, Department of Behavioral and Social Science, School of Public Health, Brown University, Providence, RI, United States
| | - Christopher Breault
- Centers for Behavioral and Preventive Medicine, The Miriam Hospital, Providence, RI, United States
| | - Daniel Levine
- Rhode Island Cardiovascular Institute, Providence, RI, United States
| | - Jia-Rong Wu
- University of Kentucky College of Nursing Lexington, KY, United States
| | - Ronald Cohen
- Cognitive Aging and Memory Program, McKnight Institute on Aging, University of Florida
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Wang J, Pani B, Gokhan I, Xiong X, Kahsai AW, Jiang H, Ahn S, Lefkowitz RJ, Rockman HA. β-Arrestin-Biased Allosteric Modulator Potentiates Carvedilol-Stimulated β Adrenergic Receptor Cardioprotection. Mol Pharmacol 2021; 100:568-579. [PMID: 34561298 PMCID: PMC8626783 DOI: 10.1124/molpharm.121.000359] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 09/20/2021] [Indexed: 01/14/2023] Open
Abstract
β 1 adrenergic receptors (β 1ARs) are central regulators of cardiac function and a drug target for cardiac disease. As a member of the G protein-coupled receptor family, β 1ARs activate cellular signaling by primarily coupling to Gs proteins to activate adenylyl cyclase, cAMP-dependent pathways, and the multifunctional adaptor-transducer protein β-arrestin. Carvedilol, a traditional β-blocker widely used in treating high blood pressure and heart failure by blocking β adrenergic receptor-mediated G protein activation, can selectively stimulate Gs-independent β-arrestin signaling of β adrenergic receptors, a process known as β-arrestin-biased agonism. Recently, a DNA-encoded small-molecule library screen against agonist-occupied β 2 adrenergic receptors (β 2ARs) identified Compound-6 (Cmpd-6) to be a positive allosteric modulator for agonists on β 2ARs. Intriguingly, it was further discovered that Cmpd-6 is positively cooperative with the β-arrestin-biased ligand carvedilol at β 2ARs. Here we describe the surprising finding that at β 1ARs unlike β 2ARs, Cmpd-6 is cooperative only with carvedilol and not agonists. Cmpd-6 increases the binding affinity of carvedilol for β 1ARs and potentiates carvedilol-stimulated, β-arrestin-dependent β 1AR signaling, such as epidermal growth factor receptor transactivation and extracellular signal-regulated kinase activation, whereas it does not have an effect on Gs-mediated cAMP generation. In vivo, Cmpd-6 enhances the antiapoptotic, cardioprotective effect of carvedilol in response to myocardial ischemia/reperfusion injury. This antiapoptotic role of carvedilol is dependent on β-arrestins since it is lost in mice with myocyte-specific deletion of β-arrestins. Our findings demonstrate that Cmpd-6 is a selective β-arrestin-biased allosteric modulator of β 1ARs and highlight its potential clinical utility in enhancing carvedilol-mediated cardioprotection against ischemic injury. SIGNIFICANCE STATEMENT: This study demonstrates the positive cooperativity of Cmpd-6 on β1ARs as a β-arrestin-biased positive allosteric modulator. Cmpd-6 selectively enhances the affinity and cellular signaling of carvedilol, a known β-arrestin-biased β-blocker for β1ARs, whereas it has minimal effect on other ligands tested. Importantly, Cmpd-6 enhances the β-arrestin-dependent in vivo cardioprotective effect of carvedilol during ischemia/reperfusion injury-induced apoptosis. The data support the potential therapeutic application of Cmpd-6 to enhance the clinical benefits of carvedilol in the treatment of cardiac disease.
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Affiliation(s)
- Jialu Wang
- Departments of Medicine (J.W., B.P, I.G., X.X., A.W.K., H.J., S.A., R.J.L., H.A.R.), Biochemistry (R.J.W.), Howard Hughes Medical Institute (R.J.L.), and Cell Biology (H.A.R.), Duke University Medical Center, Durham, North Carolina
| | - Biswaranjan Pani
- Departments of Medicine (J.W., B.P, I.G., X.X., A.W.K., H.J., S.A., R.J.L., H.A.R.), Biochemistry (R.J.W.), Howard Hughes Medical Institute (R.J.L.), and Cell Biology (H.A.R.), Duke University Medical Center, Durham, North Carolina
| | - Ilhan Gokhan
- Departments of Medicine (J.W., B.P, I.G., X.X., A.W.K., H.J., S.A., R.J.L., H.A.R.), Biochemistry (R.J.W.), Howard Hughes Medical Institute (R.J.L.), and Cell Biology (H.A.R.), Duke University Medical Center, Durham, North Carolina
| | - Xinyu Xiong
- Departments of Medicine (J.W., B.P, I.G., X.X., A.W.K., H.J., S.A., R.J.L., H.A.R.), Biochemistry (R.J.W.), Howard Hughes Medical Institute (R.J.L.), and Cell Biology (H.A.R.), Duke University Medical Center, Durham, North Carolina
| | - Alem W Kahsai
- Departments of Medicine (J.W., B.P, I.G., X.X., A.W.K., H.J., S.A., R.J.L., H.A.R.), Biochemistry (R.J.W.), Howard Hughes Medical Institute (R.J.L.), and Cell Biology (H.A.R.), Duke University Medical Center, Durham, North Carolina
| | - Haoran Jiang
- Departments of Medicine (J.W., B.P, I.G., X.X., A.W.K., H.J., S.A., R.J.L., H.A.R.), Biochemistry (R.J.W.), Howard Hughes Medical Institute (R.J.L.), and Cell Biology (H.A.R.), Duke University Medical Center, Durham, North Carolina
| | - Seungkirl Ahn
- Departments of Medicine (J.W., B.P, I.G., X.X., A.W.K., H.J., S.A., R.J.L., H.A.R.), Biochemistry (R.J.W.), Howard Hughes Medical Institute (R.J.L.), and Cell Biology (H.A.R.), Duke University Medical Center, Durham, North Carolina
| | - Robert J Lefkowitz
- Departments of Medicine (J.W., B.P, I.G., X.X., A.W.K., H.J., S.A., R.J.L., H.A.R.), Biochemistry (R.J.W.), Howard Hughes Medical Institute (R.J.L.), and Cell Biology (H.A.R.), Duke University Medical Center, Durham, North Carolina
| | - Howard A Rockman
- Departments of Medicine (J.W., B.P, I.G., X.X., A.W.K., H.J., S.A., R.J.L., H.A.R.), Biochemistry (R.J.W.), Howard Hughes Medical Institute (R.J.L.), and Cell Biology (H.A.R.), Duke University Medical Center, Durham, North Carolina
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12
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Enzan N, Matsushima S, Ide T, Kaku H, Tohyama T, Funakoshi K, Higo T, Tsutsui H. Beta-Blocker Use Is Associated With Prevention of Left Ventricular Remodeling in Recovered Dilated Cardiomyopathy. J Am Heart Assoc 2021; 10:e019240. [PMID: 34053244 PMCID: PMC8477863 DOI: 10.1161/jaha.120.019240] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Background Withdrawal of optimal medical therapy has been reported to relapse cardiac dysfunction in patients with dilated cardiomyopathy (DCM) whose cardiac function had improved. However, it is unknown whether beta‐blockers can prevent deterioration of cardiac function in those patients. We examined the effect of beta‐blockers on left ventricular ejection fraction (LVEF) in recovered DCM. Methods and Results We analyzed the clinical personal record of DCM, a national database of the Japanese Ministry of Health, Labor and Welfare, between 2003 and 2014. Recovered DCM was defined as a previously documented LVEF <40% and a current LVEF ≥40%. Patients with recovered DCM were divided into 2 groups according to the use of beta‐blockers. A one‐to‐one propensity case‐matched analysis was used. The primary outcome was defined as a decrease in LVEF >10% at 2 years of follow‐up. Of 5370 eligible patients, 4104 received beta‐blockers. Propensity score matching yielded 1087 pairs. Mean age was 61.9 years, and 1619 (74.5%) were men. Mean LVEF was 49.3±8.2%, and median B‐type natriuretic peptide was 46.6 (interquartile range, 18.0–118.1) pg/mL. The primary outcome was observed less frequently in the beta‐blocker group than in the no‐beta‐blocker group (19.6% versus 24.0%; odds ratio [OR], 0.77; 95% CI, 0.63–0.95; P=0.013). Subgroup analysis demonstrated that female patients (women: OR, 0.54; 95% CI, 0.36–0.81; men: OR, 0.88; 95% CI, 0.69–1.12; P for interaction=0.040) were benefited by beta‐blockers. Conclusions Beta‐blocker use could prevent deterioration of left ventricular systolic function in patients with recovered DCM.
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Affiliation(s)
- Nobuyuki Enzan
- Department of Cardiovascular Medicine Faculty of Medical Sciences Kyushu University Fukuoka Japan
| | - Shouji Matsushima
- Department of Cardiovascular Medicine Kyushu University Hospital Fukuoka Japan
| | - Tomomi Ide
- Department of Experimental and Clinical Cardiovascular Medicine Graduate School of Medical Sciences Kyushu University Fukuoka Japan
| | - Hidetaka Kaku
- Department of Cardiology Japan Community Healthcare Organization Kitakyushu Japan
| | - Takeshi Tohyama
- Center for Clinical and Translational Research Kyushu University Hospital Fukuoka Japan
| | - Kouta Funakoshi
- Center for Clinical and Translational Research Kyushu University Hospital Fukuoka Japan
| | - Taiki Higo
- Department of Cardiovascular Medicine Faculty of Medical Sciences Kyushu University Fukuoka Japan
| | - Hiroyuki Tsutsui
- Department of Cardiovascular Medicine Faculty of Medical Sciences Kyushu University Fukuoka Japan
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13
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Affiliation(s)
- Mark C Petrie
- BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
| | - Matthew M Lee
- BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
| | - Ninian N Lang
- BHF Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK
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14
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Bao J, Kan R, Chen J, Xuan H, Wang C, Li D, Xu T. Combination pharmacotherapies for cardiac reverse remodeling in heart failure patients with reduced ejection fraction: A systematic review and network meta-analysis of randomized clinical trials. Pharmacol Res 2021; 169:105573. [PMID: 33766629 DOI: 10.1016/j.phrs.2021.105573] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 03/15/2021] [Accepted: 03/18/2021] [Indexed: 12/22/2022]
Abstract
Pharmacotherapies, including angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor II blockers (ARBs), β-blockers (BBs), mineralocorticoid receptor antagonists (MRAs) and angiotensin receptor blocker-neprilysin inhibitor (ARNI), have played a pivotal role in reducing in-hospital and mortality in heart failure patients with reduced ejection fraction (HFrEF). However, effects of the five drug categories used alone or in combination for cardiac reverse remodeling (CRR) in these patients have not been systematically evaluated. A Bayesian network meta-analysis was conducted based on 55 randomized controlled trials published between 1989 and 2019 involving 12,727 patients from PubMed, EMBASE, Cochrane Library, and Clinicaltrials.gov. The study is registered with PROSPERO (CRD42020170457). Our primary outcomes were CRR indicators, including changes of left ventricular ejection fraction (LVEF), left ventricular end-diastolic volume (LVEDV) and end-systolic volume (LVESV), indexed LVEDV (LVEDVI) and LVESV (LVESVI), and left ventricular end-diastolic dimension (LVEDD) and end-systolic dimension (LVESD); Secondary outcomes were functional capacity comprising New York Heart Association (NYHA) class and 6-min walking distance (6MWD); cardiac biomarkers involving B type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP). The effect sizes were presented as the mean difference with 95% credible intervals. According to the results, all dual-combination therapies except ACEI+ARB were significantly more associated with LVEF or NYHA improvement than placebo, ARB+BB and ARNI+BB were the top two effective dual-combinations in LVEF improvement (+7.59% [+4.27, +11.25] and +7.31% [+3.93, +10.97] respectively); ACEI+BB was shown to be superior to ACEI in reducing LVEDVI and LVESVI (-6.88 mL/m2 [-13.18, -1.89] and -10.64 mL/m2 [-18.73, -3.54] respectively); ARNI+BB showed superiority over ACEI+BB in decreasing the level of NT-proBNP (-240.11 pg/mL [-456.57, -6.73]). All tri-combinations were significantly more effective than placebo in LVEF improvement, and ARNI+BB+MRA ranked first (+21.13% [+14.34, +28.13]); ACEI+BB+MRA was significantly more associated with a decrease in LVEDD than ACEI (-6.57 mm [-13.10, -0.84]). A sensitivity analysis ignoring concomitant therapies for LVEF illustrated that all the five drug types except ARB were shown to be superior to placebo, and ARNI ranked first (+4.83% [+1.75, +7.99]). In conclusion, combination therapies exert more benefits on CRR for patients with HFrEF. Among them, ARNI+BB, ARB+BB, ARNI+BB+MRA and ARB+BB+MRA were the top two effective dual and triple combinations in LVEF improvement, respectively; The new "Golden Triangle" of ARNI+BB+MRA was shown to be superior to ACEI+BB+MRA or ARB+BB+MRA in LVEF improvement.
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Affiliation(s)
- Jieli Bao
- The Institute of Cardiovascular Disease Research, Xuzhou Medical University, Xuzhou, Jiangsu, PR China; The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, PR China
| | - Rongsheng Kan
- The Institute of Cardiovascular Disease Research, Xuzhou Medical University, Xuzhou, Jiangsu, PR China
| | - Junhong Chen
- The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, PR China
| | - Haochen Xuan
- The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, PR China
| | - Chaofan Wang
- The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, PR China
| | - Dongye Li
- The Institute of Cardiovascular Disease Research, Xuzhou Medical University, Xuzhou, Jiangsu, PR China; The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, PR China.
| | - Tongda Xu
- The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, PR China
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15
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McGuinty C, Leong D, Weiss A, MacIver J, Kaya E, Hurlburt L, Billia F, Ross H, Wentlandt K. Heart Failure: A Palliative Medicine Review of Disease, Therapies, and Medications With a Focus on Symptoms, Function, and Quality of Life. J Pain Symptom Manage 2020; 59:1127-1146.e1. [PMID: 31866489 DOI: 10.1016/j.jpainsymman.2019.12.357] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 12/09/2019] [Accepted: 12/11/2019] [Indexed: 12/11/2022]
Abstract
Despite significant advances in heart failure (HF) treatment, HF remains a progressive, extremely symptomatic, and terminal disease with a median survival of 2.1 years after diagnosis. HF often leads to a constellation of symptoms, including dyspnea, fatigue, depression, anxiety, insomnia, pain, and worsened cognitive function. Palliative care is an approach that improves the quality of life of patients and their caregivers facing the problems associated with life-threatening illness and therefore is well suited to support these patients. However, historically, palliative care has often focused on supporting patients with malignant disease, rather than a progressive chronic disease such as HF. Predicting mortality in patients with HF is challenging. The lack of obvious transition points in disease progression also raises challenges to primary care providers and specialists to know at what point to integrate palliative care during a patient's disease trajectory. Although therapies for HF often result in functional and symptomatic improvements including health-related quality of life (HRQL), some patients with HF do not demonstrate these benefits, including those patients with a preserved ejection fraction. Provision of palliative care for patients with HF requires an understanding of HF pathogenesis and common medications used for these patients, as well as an approach to balancing life-prolonging and HRQL care strategies. This review describes HF and current targeted therapies and their effects on symptoms, hospital admission rates, exercise performance, HRQL, and survival. Pharmacological interactions with and precautions related to commonly used palliative care medications are reviewed. The goal of this review is to equip palliative care clinicians with information to make evidence-based decisions while managing the balance between optimal disease management and patient quality of life.
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Affiliation(s)
- Caroline McGuinty
- Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada; Division of Cardiology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Derek Leong
- Department of Pharmacy, University Health Network, Toronto, Ontario, Canada
| | - Andrea Weiss
- Division of Palliative Care, Department of Supportive Care, University Health Network, Toronto, Ontario, Canada; Division of Palliative Care, Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Jane MacIver
- Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada; Division of Cardiology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Ebru Kaya
- Division of Palliative Care, Department of Supportive Care, University Health Network, Toronto, Ontario, Canada
| | - Lindsay Hurlburt
- Division of Palliative Care, Department of Supportive Care, University Health Network, Toronto, Ontario, Canada; Department of Anesthesia, University of Toronto, Toronto, Ontario, Canada
| | - Filio Billia
- Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada; Division of Cardiology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Heather Ross
- Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada; Division of Cardiology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Kirsten Wentlandt
- Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada; Division of Palliative Care, Department of Supportive Care, University Health Network, Toronto, Ontario, Canada; Division of Palliative Care, Department of Family and Community Medicine, University of Toronto, Toronto, Ontario, Canada.
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16
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Davison BA, Takagi K, Senger S, Koch G, Metra M, Kimmoun A, Mebazaa A, Voors AA, Nielsen OW, Chioncel O, Pang PS, Greenberg BH, Maggioni AP, Cohen-Solal A, Ertl G, Sato N, Teerlink JR, Filippatos G, Ponikowski P, Gayat E, Edwards C, Cotter G. Mega-trials in heart failure: effects of dilution in examination of new therapies. Eur J Heart Fail 2020; 22:1698-1707. [PMID: 32227620 DOI: 10.1002/ejhf.1780] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2019] [Revised: 01/13/2020] [Accepted: 02/07/2020] [Indexed: 01/08/2023] Open
Abstract
AIMS Over the last 30 years, many medicine development programmes in acute and chronic heart failure (HF) with preserved ejection fraction (HFpEF) have failed, in contrast to those in HF with reduced ejection fraction (HFrEF). We explore how the neutral results in larger HF trials may be attributable to chance and/or the dilution of statistical power. METHODS AND RESULTS Using simulations, we examined the probability that a positive finding in a Phase 2 trial would result in the study of a truly effective medicine in a Phase 3 trial. We assessed the similarity of clinical trial and registry patient populations. We conducted a meta-analysis of paired Phase 2 and 3 trials in HFrEF and acute HF examining the associations of trial phase and size with placebo event rates and treatment effects for HF events and death. We estimated loss in trial power attributable to dilution with increasing trial size. Appropriately powered Phase 3 trials should have yielded ∼35% positive results. Patient populations in Phase 3 trials are similar to those in Phase 2 trials but both differ substantially from the populations of 'real-life' registries. We observed decreasing placebo event rates and smaller treatment effects with increasing trial size, especially for HF events (and less so for mortality). This was more pronounced in trials in acute HF patients. CONCLUSIONS The selection of more positive Phase 2 trials for further development does not explain the failure of HFpEF and acute HF medicine development. Increasing sample size may lead to reduced event rates and smaller treatment effects, resulting in a high rate of neutral Phase 3 trials.
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Affiliation(s)
| | - Koji Takagi
- Inserm 942-MASCOT, Department of Anaesthesiology and Critical Care Medicine, Assistance Publique - Hôpitaux de Paris, Saint Louis Lariboisière University Hospitals, University of Paris, Paris, France
| | | | - Gary Koch
- Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA
| | - Marco Metra
- Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
| | - Antoine Kimmoun
- Department of Intensive Medicine and Resuscitation Brabois, Regional University Hospitals of Nancy, University of Lorraine, Vandoeuvre les Nancy, France
| | - Alexandre Mebazaa
- Inserm 942-MASCOT, Department of Anaesthesiology and Critical Care Medicine, Assistance Publique - Hôpitaux de Paris, Saint Louis Lariboisière University Hospitals, University of Paris, Paris, France
| | - Adriaan A Voors
- Department of Cardiology, University Medical Centre Groningen, Groningen, The Netherlands
| | - Olav W Nielsen
- Department of Cardiology, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark
| | - Ovidiu Chioncel
- Emergency Institute for Cardiovascular Diseases 'Prof. C.C. Iliescu', University of Medicine Carol Davila, Bucharest, Romania
| | - Peter S Pang
- Department of Emergency Medicine, Indiana University School of Medicine, Indianapolis, IN, USA
| | - Barry H Greenberg
- Division of Cardiology, University of California San Diego, San Diego, CA, USA
| | - Aldo P Maggioni
- Department of Internal Medicine, Associazione Nazionale Medici Cardiologi Ospedalien (ANMCO) Research Centre, Florence, Italy
| | | | - Georg Ertl
- Julius-Maximilians University Würzburg, Wurzburg, Germany
| | - Naoki Sato
- Cardiology and Intensive Care Unit, Nippon Medical School, Musashi-Kosugi Hospital, Kawasaki, Japan
| | - John R Teerlink
- Section of Cardiology, San Francisco Veterans Affairs Medical Center and School of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Gerasimos Filippatos
- Department of Cardiology, Heart Failure Unit, Athens University Hospital Attikon, Athens, Greece
| | - Piotr Ponikowski
- Department of Heart Diseases, Medical University, Military Hospital, Wroclaw, Poland
| | - Etienne Gayat
- Faculty of Medicine Xavier Bichat, Paris Diderot University, Paris, France
| | | | - Gad Cotter
- Momentum Research, Inc., Durham, NC, USA
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17
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Drazner MH. Angiotensin Receptor-Neprilysin Inhibition (ARNI) Therapy and Reverse Remodeling in Heart Failure With Reduced Ejection Fraction. JAMA 2019; 322:1051-1053. [PMID: 31475298 DOI: 10.1001/jama.2019.12662] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Affiliation(s)
- Mark H Drazner
- Division of Cardiology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas
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18
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Samarendra P. GDMT for heart failure and the clinician's conundrum. Clin Cardiol 2019; 42:1155-1161. [PMID: 31524968 PMCID: PMC6906979 DOI: 10.1002/clc.23268] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2019] [Revised: 09/02/2019] [Accepted: 09/06/2019] [Indexed: 12/11/2022] Open
Abstract
Therapeutic advances in management of CHF have decreased mortality and have impacted progression in patients with mild to moderate heart failure. Aggressive campaigns by cardiology societies aimed at increasing implementation of these measures in routine practices have almost generalized the treatment of heart failure irrespective of individual variations of clinical status of patients and stages of heart failure. This explains why morbidity compression and quality of life improvement have not been realized fully particularly in patients with advanced disease. To examine whether GDMT for CHF is backed by unambiguous evidence of clinical efficacy for its global implementation in every patient at all stages of the syndrome. ACC/AHA, ESC Guidelines for CHF, and their updates were reviewed. Clinical trial cited in the guideline documents and other pertaining published literatures were analyzed. Findings Many of the recommended GDMT for CHF lack unequivocal evidence of clinical efficacy in patients with diverge etiology of heart failure and concomitant comorbid conditions Some of the recommendations which are useful in early stages, lack evidence of efficacy in more advanced stages of heart failure. Application of results of research trials in patients beyond their inclusion and exclusion criteria, appears mere extrapolation, Clinicians are faced with the conundrum of implementing the recommendations without indubitable evidence of their efficacy in every patient of their practice. Conclusion A reappraisal of Guidelines is needed to address outstanding questions pertaining to the efficacy of recommendations and plug the knowledge gaps without assumption and extrapolation of results of RCTs beyond their inclusion and exclusion criteria.
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Affiliation(s)
- Padmaraj Samarendra
- VA Medical Center, Pittsburgh, Pennsylvania.,University of Pittsburgh, School of Medicine, Pittsburgh, Pennsylvania
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19
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Cvetinovic N, Sekularac N, Von Haehling S, Tahirovic E, Inkrot S, Lainscak M, Apostolovic S, Putnikovic B, Waagstein F, Gelbrich G, Aleksic A, Loncar G, Düngen HD. The β-blocker uptitration in elderly with heart failure regarding biomarker levels: CIBIS-ELD substudy. Biomark Med 2018; 12:1261-1270. [PMID: 30450925 DOI: 10.2217/bmm-2018-0136] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
AIM We investigated if the baseline value of mid-regional pro-atrial natriuretic peptide (NP), N-terminal pro-B-type NP and copeptin may be helpful in optimizing β-blocker uptitration in elderly patients with heart failure. PATIENTS & METHODS According to the biomarkers' levels, 457 patients were divided into three subgroups and compared with each other at baseline and 3 months after. RESULTS All mid-regional pro-atrial NP and N-terminal pro-B-type NP subgroups had significant amelioration of left ventricle ejection fraction and New York Heart Association (NYHA) class after 3 months of β-blocker uptitration (p < 0.001). More prominent improvement of left ventricle ejection fraction and New York Heart Association class was observed in subgroups with lower versus higher NPs levels. CONCLUSION NPs levels, unlike copeptin levels, might be useful tool for objective selection of elderly heart failure patients who could have the greatest benefit of forced uptitration.
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Affiliation(s)
- Natasa Cvetinovic
- Department of Cardiology, University Clinical Center Zvezdara, Belgrade, Serbia
| | - Nikola Sekularac
- Department of Cardiology, University Clinical Center Zvezdara, Belgrade, Serbia
| | - Stephan Von Haehling
- Innovative Clinical Trials, Department of Cardiology & Pneumology, University of Medicine Göttingen, Germany
| | - Elvis Tahirovic
- Department of Cardiology, Charite -Campus Virchow-Klinikum, Berlin, Germany
| | - Simona Inkrot
- Department of Cardiology, Charite -Campus Virchow-Klinikum, Berlin, Germany
| | - Mitja Lainscak
- Departments of Cardiology & Research & Education, General Hospital Celje, Celje, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | | | - Biljana Putnikovic
- School of Medicine, University of Belgrade, Belgrade, Serbia
- Department of Cardiology, University Hospital Zemun, Belgrade, Serbia
| | - Finn Waagstein
- Wallenberg Laboratory for Cardiovascular Research, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Goetz Gelbrich
- Coordination Centre for Clinical Trials Leipzig (KKSL), University of Leipzig, Leipzig, Germany
| | - Andja Aleksic
- School of Medicine, University of Belgrade, Belgrade, Serbia
| | - Goran Loncar
- School of Medicine, University of Belgrade, Belgrade, Serbia
- Cardiology Department, Cardiovascular Institute Dedinje, Belgrade, Serbia
| | - Hans-Dirk Düngen
- Department of Cardiology, Charite -Campus Virchow-Klinikum, Berlin, Germany
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20
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Barriers to Beta-Blocker Use and Up-Titration Among Patients with Heart Failure with Reduced Ejection Fraction. Cardiovasc Drugs Ther 2018; 31:559-564. [PMID: 29181610 DOI: 10.1007/s10557-017-6764-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
PURPOSE For patients with heart failure with reduced ejection fraction (HFrEF), guidelines recommend use of beta-blockers with gradual up-titration. However, many patients with HFrEF do not use beta-blockers and up-titration is rare. Our purpose was to identify and rank barriers to beta-blocker use and up-titration from the perspective of primary care physicians. METHODS We conducted 4 moderated, structured group discussions among 19 primary care physicians using the nominal group technique; 16 participants also completed a survey. Participants generated lists of barriers to beta-blocker use and up-titration among patients with HFrEF. Each participant had six votes with three votes assigned to the item ranked most important, two to the second most important item, and one to the third most important item. Investigators characterized items into themes. The percentage of available votes was calculated for each theme. RESULTS Fifteen of 16 participating primary care physicians who completed the survey reported that management of beta-blockers was their responsibility. Treatment/side effects, particularly hypotension, were identified as the most important barrier for beta-blocker use (72% of available votes) followed by polypharmacy (11%), healthcare system barriers (10%), and comorbidities (6%). Barriers to up-titration included treatment/side effects (49% of available votes), patient communication/buy-in (21%), polypharmacy (13%), and healthcare system barriers (8%). CONCLUSIONS Many barriers to guideline concordant use of beta-blockers among patients with HFrEF identified by primary care providers are not readily modifiable. Addressing these barriers may require development, testing, and dissemination of protocols for beta-blocker initiation and up-titration that are safe and appropriate in primary care.
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Smith MW, Brown C, Virani SS, Weir CR, Petersen LA, Kelly N, Akeroyd J, Garvin JH. Incorporating Guideline Adherence and Practice Implementation Issues into the Design of Decision Support for Beta-Blocker Titration for Heart Failure. Appl Clin Inform 2018; 9:478-489. [PMID: 29949816 DOI: 10.1055/s-0038-1660849] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The recognition of and response to undertreatment of heart failure (HF) patients can be complicated. A clinical reminder can facilitate use of guideline-concordant β-blocker titration for HF patients with depressed ejection fraction. However, the design must consider the cognitive demands on the providers and the context of the work. OBJECTIVE This study's purpose is to develop requirements for a clinical decision support tool (a clinical reminder) by analyzing the cognitive demands of the task along with the factors in the Cabana framework of physician adherence to guidelines, the health information technology (HIT) sociotechnical framework, and the Promoting Action on Research Implementation in Health Services (PARIHS) framework of health services implementation. It utilizes a tool that extracts information from medical records (including ejection fraction in free text reports) to identify qualifying patients at risk of undertreatment. METHODS We conducted interviews with 17 primary care providers, 5 PharmDs, and 5 Registered Nurses across three Veterans Health Administration outpatient clinics. The interviews were based on cognitive task analysis (CTA) methods and enhanced through the inclusion of the Cabana, HIT sociotechnical, and PARIHS frameworks. The analysis of the interview data led to the development of requirements and a prototype design for a clinical reminder. We conducted a small pilot usability assessment of the clinical reminder using realistic clinical scenarios. RESULTS We identified organizational challenges (such as time pressures and underuse of pharmacists), knowledge issues regarding the guideline, and information needs regarding patient history and treatment status. We based the design of the clinical reminder on how to best address these challenges. The usability assessment indicated the tool could help the decision and titration processes. CONCLUSION Through the use of CTA methods enhanced with adherence, sociotechnical, and implementation frameworks, we designed a decision support tool that considers important challenges in the decision and execution of β-blocker titration for qualifying HF patients at risk of undertreatment.
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Affiliation(s)
- Michael W Smith
- Department of Industrial & Mechanical Engineering, Universidad de las Americas Puebla, Cholula, PUE, Mexico
| | - Charnetta Brown
- Houston VA HSR&D Center for Innovations in Quality, Effectiveness, and Safety, Houston, Texas, United States
| | - Salim S Virani
- Houston VA HSR&D Center for Innovations in Quality, Effectiveness, and Safety, Houston, Texas, United States.,Section of Cardiovascular Research, Department of Medicine, Baylor College of Medicine, Houston, Texas, United States
| | - Charlene R Weir
- Salt Lake City VA Health Care System HSR&D Informatics, Decision-Enhancement and Analytic Sciences Center, Salt Lake City, Utah, United States.,Department of Biomedical Informatics, University of Utah, Salt Lake City, Utah, United States
| | - Laura A Petersen
- Houston VA HSR&D Center for Innovations in Quality, Effectiveness, and Safety, Houston, Texas, United States.,Section of Health Services Research, Department of Medicine, Baylor College of Medicine, Houston, Texas, United States
| | - Natalie Kelly
- Salt Lake City VA Health Care System HSR&D Informatics, Decision-Enhancement and Analytic Sciences Center, Salt Lake City, Utah, United States
| | - Julia Akeroyd
- Houston VA HSR&D Center for Innovations in Quality, Effectiveness, and Safety, Houston, Texas, United States
| | - Jennifer H Garvin
- Salt Lake City VA Health Care System HSR&D Informatics, Decision-Enhancement and Analytic Sciences Center, Salt Lake City, Utah, United States.,Department of Biomedical Informatics, University of Utah, Salt Lake City, Utah, United States.,Division of Health Information Management and Systems, The Ohio State University, Columbus, Ohio, United States.,Indianapolis VA Medical Center HSR&D Center for Health Information and Communication, Indianapolis, Indiana, United States
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22
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MONTERO DAVID, FLAMMER ANDREASJ. Effect of Beta-blocker Treatment on V˙O2peak in Patients with Heart Failure. Med Sci Sports Exerc 2018; 50:889-896. [DOI: 10.1249/mss.0000000000001513] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
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23
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Packer M, McMurray JJV, Krum H, Kiowski W, Massie BM, Caspi A, Pratt CM, Petrie MC, DeMets D, Kobrin I, Roux S, Swedberg K. Long-Term Effect of Endothelin Receptor Antagonism With Bosentan on the Morbidity and Mortality of Patients With Severe Chronic Heart Failure: Primary Results of the ENABLE Trials. JACC-HEART FAILURE 2018; 5:317-326. [PMID: 28449795 DOI: 10.1016/j.jchf.2017.02.021] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/13/2017] [Revised: 02/16/2017] [Accepted: 02/19/2017] [Indexed: 01/13/2023]
Abstract
OBJECTIVES The objective of this clinical trial was to evaluate the long-term effect of endothelin receptor antagonism with bosentan on the morbidity and mortality of patients with severe chronic heart failure. BACKGROUND Endothelin may play a role in heart failure, but short-term clinical trials with endothelin receptor antagonists have reported disappointing results. Long-term trials are lacking. METHODS In 2 identical double-blind trials, we randomly assigned 1,613 patients with New York Heart Association functional class IIIb to IV heart failure and an ejection fraction <35% to receive placebo or bosentan (target dose 125 mg twice daily) for a median of 1.5 years. The primary outcome for each trial was clinical status at 9 months (assessed by the hierarchical clinical composite); the primary outcome across the 2 trials was death from any cause or hospitalization for heart failure. RESULTS Bosentan did not influence clinical status at 9 months in either trial (p = 0.928 and p = 0.263). In addition, 321 patients in the placebo group and 312 patients in the bosentan group died or were hospitalized for heart failure (hazard ratio [HR]: 1.01; 95% confidence interval [CI]: 0.86 to 1.18; p = 0.90). The bosentan group experienced fluid retention within the first 2 to 4 weeks, as evidenced by increased peripheral edema, weight gain, decreases in hemoglobin, and an increased risk of hospitalization for heart failure, despite intensification of background diuretics. During follow-up, 173 patients died in the placebo group and 160 patients died in the bosentan group (HR: 0.94; 95% CI: 0.75 to 1.16). About 10% of the bosentan group showed meaningful increases in hepatic transaminases, but none had acute or chronic liver failure. CONCLUSIONS Bosentan did not improve the clinical course or natural history of patients with severe chronic heart failure and but caused early and important fluid retention.
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Affiliation(s)
- Milton Packer
- Baylor Heart and Vascular Institute, Baylor University Medical Center, Dallas, Texas.
| | - John J V McMurray
- Institute of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Henry Krum
- Monash University, Centre of Cardiovascular Research and Education in Therapeutics, Melbourne, Australia
| | | | - Barry M Massie
- University of California at San Francisco, San Francisco, California
| | | | - Craig M Pratt
- Houston Methodist Hospital and Weill Cornell Medical College, Houston, Texas
| | - Mark C Petrie
- Institute of Cardiovascular and Medical Sciences, British Heart Foundation Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, United Kingdom
| | | | | | | | - Karl Swedberg
- Department of Molecular and Clinical Medicine, University of Goteborg, Goteborg, Sweden; National Heart and Lung Institute, Imperial College, London, United Kingdom
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24
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Hinder M, Yi BA, Langenickel TH. Developing Drugs for Heart Failure With Reduced Ejection Fraction: What Have We Learned From Clinical Trials? Clin Pharmacol Ther 2018; 103:802-814. [PMID: 29315510 PMCID: PMC5947521 DOI: 10.1002/cpt.1010] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2017] [Revised: 12/21/2017] [Accepted: 12/24/2017] [Indexed: 12/11/2022]
Abstract
There remains a large unmet need for new therapies in the treatment of heart failure with reduced ejection fraction (HFrEF). In the early drug development phase, the therapeutic potential of a drug is not yet fully understood and trial endpoints other than mortality are needed to guide drug development decisions. While a true surrogate marker for mortality in heart failure (HF) remains elusive, the successes and failures of previous trials can reveal markers that support clinical Go/NoGo decisions.
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Affiliation(s)
- Markus Hinder
- Novartis Institutes for BioMedical Research, Translational Medicine, Basel, Switzerland
| | - B Alexander Yi
- Novartis Institutes for BioMedical Research, Translational Medicine, Cambridge, Massachusetts, USA
| | - Thomas H Langenickel
- Novartis Institutes for BioMedical Research, Translational Medicine, Basel, Switzerland
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25
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Heart Failure with Myocardial Recovery - The Patient Whose Heart Failure Has Improved: What Next? Prog Cardiovasc Dis 2017; 60:226-236. [PMID: 28551473 DOI: 10.1016/j.pcad.2017.05.009] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Accepted: 05/19/2017] [Indexed: 02/06/2023]
Abstract
In an important number of heart failure (HF) patients substantial or complete myocardial recovery occurs. In the strictest sense, myocardial recovery is a return to both normal structure and function of the heart. HF patients with myocardial recovery or recovered ejection fraction (EF; HFrecEF) are a distinct population of HF patients with different underlying etiologies, demographics, comorbidities, response to therapies and outcomes compared to HF patients with persistent reduced (HFrEF) or preserved ejection fraction (HFpEF). Improvement of left ventricular EF has been systematically linked to improved quality of life, lower rehospitalization rates and mortality. However, mortality and morbidity in HFrecEF patients remain higher than in the normal population. Also, persistent abnormalities in biomarker and gene expression profiles in these patients lends weight to the hypothesis that pathological processes are ongoing. Currently, there remains a lack of data to guide the management of HFrecEF patients. This review will discuss specific characteristics, pathophysiology, clinical implications and future needs for HFrecEF.
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Burnett H, Earley A, Voors AA, Senni M, McMurray JJV, Deschaseaux C, Cope S. Thirty Years of Evidence on the Efficacy of Drug Treatments for Chronic Heart Failure With Reduced Ejection Fraction: A Network Meta-Analysis. Circ Heart Fail 2017; 10:e003529. [PMID: 28087688 PMCID: PMC5265698 DOI: 10.1161/circheartfailure.116.003529] [Citation(s) in RCA: 165] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 12/15/2016] [Indexed: 12/11/2022]
Abstract
BACKGROUND Treatments that reduce mortality and morbidity in patients with heart failure with reduced ejection fraction, including angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), β-blockers (BB), mineralocorticoid receptor antagonists (MRA), and angiotensin receptor-neprilysin inhibitors (ARNI), have not been studied in a head-to-head fashion. This network meta-analysis aimed to compare the efficacy of these drugs and their combinations regarding all-cause mortality in patients with heart failure with reduced ejection fraction. METHODS AND RESULTS A systematic literature review identified 57 randomized controlled trials published between 1987 and 2015, which were compared in terms of study and patient characteristics, baseline risk, outcome definitions, and the observed treatment effects. Despite differences identified in terms of study duration, New York Heart Association class, ejection fraction, and use of background digoxin, a network meta-analysis was considered feasible and all trials were analyzed simultaneously. The random-effects network meta-analysis suggested that the combination of ACEI+BB+MRA was associated with a 56% reduction in mortality versus placebo (hazard ratio 0.44, 95% credible interval 0.26-0.66); ARNI+BB+MRA was associated with the greatest reduction in all-cause mortality versus placebo (hazard ratio 0.37, 95% credible interval 0.19-0.65). A sensitivity analysis that did not account for background therapy suggested that ARNI monotherapy is more efficacious than ACEI or ARB monotherapy. CONCLUSIONS The network meta-analysis showed that treatment with ACEI, ARB, BB, MRA, and ARNI and their combinations were better than the treatment with placebo in reducing all-cause mortality, with the exception of ARB monotherapy and ARB plus ACEI. The combination of ARNI+BB+MRA resulted in the greatest mortality reduction.
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Affiliation(s)
- Heather Burnett
- From the Mapi, Health Economics and Outcomes Research, Dundas, Canada (H.B.); Mapi, Health Economics and Outcomes Research, Boston, MA (A.E.); Department of Cardiology, University of Groningen, The Netherlands (A.A.V.); Cardiovascular Department, Hospital Papa Giovanni XXIII, Bergamo, Italy (M.S.); British Heart Foundation Cardiovascular Research Centre, University of Glasgow, UK (J.J.V.M.); Global Patient Access, Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland (C.D.); and Mapi, Health Economics and Outcomes Research, Toronto, Canada (S.C.).
| | - Amy Earley
- From the Mapi, Health Economics and Outcomes Research, Dundas, Canada (H.B.); Mapi, Health Economics and Outcomes Research, Boston, MA (A.E.); Department of Cardiology, University of Groningen, The Netherlands (A.A.V.); Cardiovascular Department, Hospital Papa Giovanni XXIII, Bergamo, Italy (M.S.); British Heart Foundation Cardiovascular Research Centre, University of Glasgow, UK (J.J.V.M.); Global Patient Access, Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland (C.D.); and Mapi, Health Economics and Outcomes Research, Toronto, Canada (S.C.)
| | - Adriaan A Voors
- From the Mapi, Health Economics and Outcomes Research, Dundas, Canada (H.B.); Mapi, Health Economics and Outcomes Research, Boston, MA (A.E.); Department of Cardiology, University of Groningen, The Netherlands (A.A.V.); Cardiovascular Department, Hospital Papa Giovanni XXIII, Bergamo, Italy (M.S.); British Heart Foundation Cardiovascular Research Centre, University of Glasgow, UK (J.J.V.M.); Global Patient Access, Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland (C.D.); and Mapi, Health Economics and Outcomes Research, Toronto, Canada (S.C.)
| | - Michele Senni
- From the Mapi, Health Economics and Outcomes Research, Dundas, Canada (H.B.); Mapi, Health Economics and Outcomes Research, Boston, MA (A.E.); Department of Cardiology, University of Groningen, The Netherlands (A.A.V.); Cardiovascular Department, Hospital Papa Giovanni XXIII, Bergamo, Italy (M.S.); British Heart Foundation Cardiovascular Research Centre, University of Glasgow, UK (J.J.V.M.); Global Patient Access, Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland (C.D.); and Mapi, Health Economics and Outcomes Research, Toronto, Canada (S.C.)
| | - John J V McMurray
- From the Mapi, Health Economics and Outcomes Research, Dundas, Canada (H.B.); Mapi, Health Economics and Outcomes Research, Boston, MA (A.E.); Department of Cardiology, University of Groningen, The Netherlands (A.A.V.); Cardiovascular Department, Hospital Papa Giovanni XXIII, Bergamo, Italy (M.S.); British Heart Foundation Cardiovascular Research Centre, University of Glasgow, UK (J.J.V.M.); Global Patient Access, Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland (C.D.); and Mapi, Health Economics and Outcomes Research, Toronto, Canada (S.C.)
| | - Celine Deschaseaux
- From the Mapi, Health Economics and Outcomes Research, Dundas, Canada (H.B.); Mapi, Health Economics and Outcomes Research, Boston, MA (A.E.); Department of Cardiology, University of Groningen, The Netherlands (A.A.V.); Cardiovascular Department, Hospital Papa Giovanni XXIII, Bergamo, Italy (M.S.); British Heart Foundation Cardiovascular Research Centre, University of Glasgow, UK (J.J.V.M.); Global Patient Access, Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland (C.D.); and Mapi, Health Economics and Outcomes Research, Toronto, Canada (S.C.)
| | - Shannon Cope
- From the Mapi, Health Economics and Outcomes Research, Dundas, Canada (H.B.); Mapi, Health Economics and Outcomes Research, Boston, MA (A.E.); Department of Cardiology, University of Groningen, The Netherlands (A.A.V.); Cardiovascular Department, Hospital Papa Giovanni XXIII, Bergamo, Italy (M.S.); British Heart Foundation Cardiovascular Research Centre, University of Glasgow, UK (J.J.V.M.); Global Patient Access, Novartis Pharma AG, Postfach, CH-4002 Basel, Switzerland (C.D.); and Mapi, Health Economics and Outcomes Research, Toronto, Canada (S.C.)
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Thomsen MM, Lewinter C, Køber L. Varying effects of recommended treatments for heart failure with reduced ejection fraction: meta-analysis of randomized controlled trials in the ESC and ACCF/AHA guidelines. ESC Heart Fail 2016; 3:235-244. [PMID: 27867524 PMCID: PMC5107974 DOI: 10.1002/ehf2.12094] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Revised: 05/27/2016] [Accepted: 05/27/2016] [Indexed: 01/06/2023] Open
Abstract
The aim of this paper is to evaluate the treatment effects of recommended drugs and devices on key clinical outcomes for patients with heart failure with reduced ejection fraction (HFREF). Randomized controlled trials (RCTs) listed in the 2012 HF guideline from the European Society of Cardiology as well as the 2013 HF guideline from the American College of Cardiology Foundation and American Heart Association were evaluated for use in the meta‐analysis. RCTs written in English evaluating recommended drugs and devices for the treatment of patients with HFREF were included. Meta‐analyses, based on the outcomes of all‐cause mortality and hospitalization because of HF, were performed with relative risk ratio as the effect size. In the identified 47 RCTs, patients were on average 63 years old and 22% were female. Drugs targeting the renin‐angiotensin‐aldosterone system, beta‐blockers, cardiac resynchronization therapy (CRT), and intracardiac defibrillator devices (ICDs) significantly reduced the risk of death with reductions of 14–19, 23, 20, and 20%, respectively. Drugs targeting the renin‐angiotensin‐aldosterone system, beta‐blockers, digoxin, and CRT significantly reduced the risk of HF hospitalization with reductions of 24–37, 22, 60, and 36%, respectively, while ICDs significantly increased the risk with 34%. Ivabradine showed no significant effects on either outcome. As such, the majority of recommended HFREF treatments offered significant treatment benefits. However, many of the included studies were from the 1990s or earlier, and one must therefore be cautious when extrapolating these results to contemporary patients with HF.
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Affiliation(s)
- Marius Mark Thomsen
- Department of Cardiology, Nephrology and Endocrinology Nordsjaellands Hospital Copenhagen Denmark
| | | | - Lars Køber
- Copenhagen University Hospital The Heart Centre Denmark
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Iyngkaran P, Toukhsati SR, Thomas MC, Jelinek MV, Hare DL, Horowitz JD. A Review of the External Validity of Clinical Trials with Beta-Blockers in Heart Failure. CLINICAL MEDICINE INSIGHTS-CARDIOLOGY 2016; 10:163-171. [PMID: 27773994 PMCID: PMC5063839 DOI: 10.4137/cmc.s38444] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2016] [Revised: 07/03/2016] [Accepted: 07/16/2016] [Indexed: 12/20/2022]
Abstract
BACKGROUND Beta-blockers (BBs) are the mainstay prognostic medication for all stages of chronic heart failure (CHF). There are many classes of BBs, each of which has varying levels of evidence to support its efficacy in CHF. However, most CHF patients have one or more comorbid conditions such as diabetes, renal impairment, and/or atrial fibrillation. Patient enrollment to randomized controlled trials (RCTs) often excludes those with certain comorbidities, particularly if the symptoms are severe. Consequently, the extent to which evidence drawn from RCTs is generalizable to CHF patients has not been well described. Clinical guidelines also underrepresent this point by providing generic advice for all patients. The aim of this review is to examine the evidence to support the use of BBs in CHF patients with common comorbid conditions. METHODS We searched MEDLINE, PubMed, and the reference lists of reviews for RCTs, post hoc analyses, systematic reviews, and meta-analyses that report on use of BBs in CHF along with patient demographics and comorbidities. RESULTS In total, 38 studies from 28 RCTs were identified, which provided data on six BBs against placebo or head to head with another BB agent in ischemic and nonischemic cardiomyopathies. Several studies explored BBs in older patients. Female patients and non-Caucasian race were underrepresented in trials. End points were cardiovascular hospitalization and mortality. Comorbid diabetes, renal impairment, or atrial fibrillation was detailed; however, no reference to disease spectrum or management goals as a focus could be seen in any of the studies. In this sense, enrollment may have limited more severe grades of these comorbidities. CONCLUSIONS RCTs provide authoritative information for a spectrum of CHF presentations that support guidelines. RCTs may provide inadequate information for more heterogeneous CHF patient cohorts. Greater Phase IV research may be needed to fill this gap and inform guidelines for a more global patient population.
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Affiliation(s)
- Pupalan Iyngkaran
- Cardiologist and Senior Lecturer, Northern Territory School of Medicine, Flinders University, Bedford Park, South Australia
| | - Samia R. Toukhsati
- Department of Cardiology, Austin Health, Heidelberg, Victoria, Australia
| | - Merlin C. Thomas
- Professor, NHMRC Senior Research Fellow, Baker IDI Heart and Diabetes Institute, Melbourne, Victoria, Australia
| | - Michael V. Jelinek
- Professor, Department of Cardiology, St. Vincent’s Hospital, Melbourne, Victoria, Australia
| | - David L. Hare
- Professor, Coordinator, Cardiovascular Research, University of Melbourne
- Director of Heart Failure Services, Austin Health, Melbourne, Victoria, Australia
| | - John D. Horowitz
- Professor of Cardiology, Director, Cardiology Unit, Discipline of Medicine, Cardiology Research Laboratory, The Basil Hetzel Institute, Woodville South, South Australia, Australia
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Zhang X, Shen C, Zhai S, Liu Y, Yue WW, Han L. A meta-analysis of the effects of β-adrenergic blockers in chronic heart failure. Exp Ther Med 2016; 12:2489-2496. [PMID: 27703506 PMCID: PMC5038900 DOI: 10.3892/etm.2016.3657] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 07/20/2016] [Indexed: 11/18/2022] Open
Abstract
Adrenergic β-blockers are drugs that bind to, but do not activate β-adrenergic receptors. Instead they block the actions of β-adrenergic agonists and are used for the treatment of various diseases such as cardiac arrhythmias, angina pectoris, myocardial infarction, hypertension, headache, migraines, stress, anxiety, prostate cancer, and heart failure. Several meta-analysis studies have shown that β-blockers improve the heart function and reduce the risks of cardiovascular events, rate of mortality, and sudden death through chronic heart failure (CHF) of patients. The present study identified results from recent meta-analyses of β-adrenergic blockers and their usefulness in CHF. Databases including Medline/Embase/Cochrane Central Register of Controlled Trials (CENTRAL), and PubMed were searched for the periods May, 1985 to March, 2011 and June, 2013 to August, 2015, and a number of studies identified. Results of those studies showed that use of β-blockers was associated with decreased sudden cardiac death in patients with heart failure. However, contradictory results have also been reported. The present meta-analysis aimed to determine the efficacy of β-blockers on mortality and morbidity in patients with heart failure. The results showed that mortality was significantly reduced by β-blocker treatment prior to the surgery of heart failure patients. The results from the meta-analysis studies showed that β-blocker treatment in heart failure patients correlated with a significant decrease in long-term mortality, even in patients that meet one or more exclusion criteria of the MERIT-HF study. In summary, the findings of the current meta-analysis revealed beneficial effects different β-blockers have on patients with heart failure or related heart disease.
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Affiliation(s)
- Xiaojian Zhang
- Shandong Provincial Hospital Affiliated to Shandong University, Ji'nan, Shandong 250021, P.R. China
| | - Chengwu Shen
- Shandong Provincial Hospital Affiliated to Shandong University, Ji'nan, Shandong 250021, P.R. China
| | - Shujun Zhai
- Shandong Provincial Hospital Affiliated to Shandong University, Ji'nan, Shandong 250021, P.R. China
| | - Yukun Liu
- Laiwu Health School, Laiwu, Shandong 271100, P.R. China
| | - Wen-Wei Yue
- The Fourth People's Hospital of Ji'nan, Ji'nan, Shandong 250021, P.R. China
| | - Li Han
- The Fourth People's Hospital of Ji'nan, Ji'nan, Shandong 250021, P.R. China
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Jaiswal A, Nguyen VQ, Le Jemtel TH, Ferdinand KC. Novel role of phosphodiesterase inhibitors in the management of end-stage heart failure. World J Cardiol 2016; 8:401-412. [PMID: 27468333 PMCID: PMC4958691 DOI: 10.4330/wjc.v8.i7.401] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2016] [Revised: 04/28/2016] [Accepted: 06/02/2016] [Indexed: 02/06/2023] Open
Abstract
In advanced heart failure (HF), chronic inotropic therapy with intravenous milrinone, a phosphodiesterase III inhibitor, is used as a bridge to advanced management that includes transplantation, ventricular assist device implantation, or palliation. This is especially true when repeated attempts to wean off inotropic support result in symptomatic hypotension, worsened symptoms, and/or progressive organ dysfunction. Unfortunately, patients in this clinical predicament are considered hemodynamically labile and may escape the benefits of guideline-directed HF therapy. In this scenario, chronic milrinone infusion may be beneficial as a bridge to introduction of evidence based HF therapy. However, this strategy is not well studied, and in general, chronic inotropic infusion is discouraged due to potential cardiotoxicity that accelerates disease progression and proarrhythmic effects that increase sudden death. Alternatively, chronic inotropic support with milrinone infusion is a unique opportunity in advanced HF. This review discusses evidence that long-term intravenous milrinone support may allow introduction of beta blocker (BB) therapy. When used together, milrinone does not attenuate the clinical benefits of BB therapy while BB mitigates cardiotoxic effects of milrinone. In addition, BB therapy decreases the risk of adverse arrhythmias associated with milrinone. We propose that advanced HF patients who are intolerant to BB therapy may benefit from a trial of intravenous milrinone as a bridge to BB initiation. The discussed clinical scenarios demonstrate that concomitant treatment with milrinone infusion and BB therapy does not adversely impact standard HF therapy and may improve left ventricular function and morbidity associated with advanced HF.
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31
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Vavouranakis I, Lambrogiannakis E, Markakis G, Dermitzakis A, Haroniti Z, Ninidaki C, Borbantonaki A, Tsoutsoumanou K. Effect of Home-Based Intervention on Hospital Readmission and Quality of Life in Middle-Aged Patients with Severe Congestive Heart Failure: A 12-Month Follow Up Study. Eur J Cardiovasc Nurs 2016; 2:105-11. [PMID: 14622635 DOI: 10.1016/s1474-5151(03)00006-9] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Objective: Home care surveillance has been shown to reduce hospital readmission and improve functional status and quality of life of elderly patients with mild to moderate or severe congestive heart failure and in younger patients candidates for transplantation. The present study aimed to investigate the effect of home-based intervention on hospital readmission and quality of life of middle-aged patients with severe congestive heart failure. Methods: Thirty-three patients aged 50–75 (mean age 65.4±6.7) with class III and IV congestive heart failure were included in this observational, community-based study. Intervention consisted of intensive home surveillance of patients, including frequent home visits associated with laboratory tests and telephone contacts to implement standard therapy, treat early symptoms and provide psychological support. Results: Admissions for cardiovascular reasons decreased from 2.143±1.11 for the year before the initiation of the study to 1.25±1 after its completion ( P=0.0005). Quality of life improved, as showed by a decrease of the mean score of the Minnesota Living with Heart Failure Questionnaire from 2.68±0.034 to 2.33±0.032 ( P=0.0001). Conclusion: Intensive home care of middle-aged patients with severe heart failure results in improved quality of life and a decrease in hospital readmission rates.
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Affiliation(s)
- I Vavouranakis
- Technological Educational Institute, School of Nursery, Stavromenos, 71500, Crete, Iraklion, Greece.
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Malhotra R, Bakken K, D'Elia E, Lewis GD. Cardiopulmonary Exercise Testing in Heart Failure. JACC-HEART FAILURE 2016; 4:607-16. [PMID: 27289406 DOI: 10.1016/j.jchf.2016.03.022] [Citation(s) in RCA: 288] [Impact Index Per Article: 32.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/17/2015] [Revised: 02/26/2016] [Accepted: 03/02/2016] [Indexed: 12/18/2022]
Abstract
Exercise intolerance, indicated by dyspnea and fatigue during exertion, is a cardinal manifestation of heart failure (HF). Cardiopulmonary exercise testing (CPET) precisely defines maximum exercise capacity through measurement of peak oxygen uptake (VO2). Peak VO2 values have a critical role in informing patient selection for advanced HF interventions such as heart transplantation and ventricular assist devices. Oxygen uptake and ventilatory patterns obtained during the submaximal portion of CPET are also valuable to recognize because of their ease of ascertainment during low-level exercise, relevance to ability to perform activities of daily living, independence from volitional effort, and strong relationship to prognosis in HF. The ability of peak VO2 and other CPET variables to be measured reproducibly and to accurately reflect HF severity is increasingly recognized and endorsed by scientific statements. Integration of CPET with invasive hemodynamic monitoring and cardiac imaging during exercise provides comprehensive characterization of multisystem reserve capacity that can inform prognosis and the need for cardiac interventions. Here, we review both practical aspects of conducting CPETs in patients with HF for clinical and research purposes as well as interpretation of gas exchange patterns across the spectrum of preclinical HF to advanced HF.
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Affiliation(s)
- Rajeev Malhotra
- Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Kristian Bakken
- Pulmonary and Critical Care Unit of the Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
| | - Emilia D'Elia
- Cardiovascular Department, Hospital Papa Giovanni XXIII, Bergamo Italy; University of Pavia, Pavia, Italy
| | - Gregory D Lewis
- Cardiology Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Pulmonary and Critical Care Unit of the Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
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Exercise Intolerance in Heart Failure: Did We Forget the Brain? Can J Cardiol 2016; 32:475-84. [DOI: 10.1016/j.cjca.2015.12.021] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Revised: 12/21/2015] [Accepted: 12/21/2015] [Indexed: 01/15/2023] Open
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Price JF, Jeewa A, Denfield SW. Clinical Characteristics and Treatment of Cardiomyopathies in Children. Curr Cardiol Rev 2016; 12:85-98. [PMID: 26926296 PMCID: PMC4861947 DOI: 10.2174/1573403x12666160301115543] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2015] [Revised: 11/05/2015] [Accepted: 02/29/2016] [Indexed: 01/10/2023] Open
Abstract
Cardiomyopathies are diseases of the heart muscle, a term introduced in 1957 to identify a group of myocardial diseases not attributable to coronary artery disease. The definition has since been modified to refer to structural and or functional abnormalities of the myocardium where other known causes of myocardial dysfunction, such as systemic hypertension, valvular disease and ischemic heart disease, have been excluded. In this review, we discuss the pathophysiology, clinical assessment and therapeutic strategies for hypertrophic, dilated and hypertrophic cardiomyopathies, with a particular focus on aspects unique to children.
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Affiliation(s)
- Jack F Price
- Lillie Frank Abercrombie Section of Pediatric Cardiology, Section of Critical Care Medicine, Baylor College of Medicine, Texas Children's Hospital, 6621 Fannin MC19345C, Houston.
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Kiel RG, Deedwania P. The safety and tolerability of beta blockers in heart failure with reduced ejection fraction: is the current underutilization of this evidence-based therapy justified? Expert Opin Drug Saf 2015; 14:1855-63. [PMID: 26488593 DOI: 10.1517/14740338.2015.1102225] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
INTRODUCTION Beta blockers are one of the cornerstones for treatment of Heart Failure with Reduced Ejection fraction (HFRef), yet their use is often limited by adverse effects, either perceived or real. We performed a review of available data using PubMed.gov utilizing beta blocker, heart failure, reduced ejection fraction and safety as key words. AREAS COVERED Several well designed, large scale randomized clinical trials including CIBS-II (bisoprolol), MERIT-HF (metoprolol succinate), and Copernicus (carvedilol) among others, have been conducted in patients with HFRef and demonstrated an improvement in cardiac mortality and morbidity. Despite the preponderance of data supporting the use of beta blockers for patients HFRef, these medications remain underutilized and/or are often prescribed at lower than recommended dosages. Some of the reluctance to embrace beta blockade may be attributed to concern on the part of both the patient and prescriber about the non-cardiac adverse effects of this class of drugs. We have reviewed several recent reviews and meta-analyses of trials of beta blocker in heart failure which have conclusively demonstrated their tolerability in the populations studied. EXPERT OPINION In the final section of this paper we provide our opinions regarding initiating and optimizing beta blocker therapy for patients with HFRef.
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Affiliation(s)
- Richard G Kiel
- a Adult Cardiovascular Disease Fellow, University of California San Francisco - Fresno Medical Education Program - Department of Cardiology , Fresno , CA 93701 , USA
| | - Prakash Deedwania
- b Professor of Medicine University of California San Francisco, Director of Heart Failure Services, University of California Fresno - Fresno Medical Education Program - Department of Cardiology , Fresno , CA 93701 , USA
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Bristow MR, Quaife RA. The adrenergic system in pulmonary arterial hypertension: bench to bedside (2013 Grover Conference series). Pulm Circ 2015; 5:415-23. [PMID: 26401244 PMCID: PMC4556494 DOI: 10.1086/682223] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Accepted: 01/21/2015] [Indexed: 12/20/2022] Open
Abstract
In heart failure with reduced left ventricular ejection fraction (HFrEF), adrenergic activation is a key compensatory mechanism that is a major contributor to progressive ventricular remodeling and worsening of heart failure. Targeting the increased adrenergic activation with β-adrenergic receptor blocking agents has led to the development of arguably the single most effective drug therapy for HFrEF. The pressure-overloaded and ultimately remodeled/failing right ventricle (RV) in pulmonary arterial hypertension (PAH) is also adrenergically activated, which raises the issue of whether an antiadrenergic strategy could be effectively employed in this setting. Anecdotal experience suggests that it will be challenging to administer an antiadrenergic treatment such as a β-blocking agent to patients with established moderate-severe PAH. However, the same types of data and commentary were prevalent early in the development of β-blockade for HFrEF treatment. In addition, in HFrEF approaches have been developed for delivering β-blocker therapy to patients who have extremely advanced heart failure, and these general principles could be applied to RV failure in PAH. This review examines the role played by adrenergic activation in the RV faced with PAH, contrasts PAH-RV remodeling with left ventricle remodeling in settings of sustained increases in afterload, and suggests a possible approach for safely delivering an antiadrenergic treatment to patients with RV dysfunction due to moderate-severe PAH.
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Affiliation(s)
- Michael R. Bristow
- Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
| | - Robert A. Quaife
- Division of Cardiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
- Department of Radiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
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Abstract
Carvedilol is a beta-adrenergic antagonist with vasodilatory properties (alpha1-antagonism), which has been extensively evaluated in the treatment of patients with heart failure. In patients with chronic heart failure carvedilol improves left-ventricular (LV) ejection fraction over 6 to 12 months of treatment, and attenuates LV remodelling. Large-scale randomised, placebo controlled trials involving more than 4000 patients with chronic heart failure have demonstrated that carvedilol improves survival and reduces hospitalizations. Comparative studies with metoprolol in patients with heart failure have suggested that carvedilol may be associated with greater survival benefit although differences in the preparation of metoprolol have left uncertainty in this area. Carvedilol has a high safety profile and the clinical benefits appear maintained across a wide range of patients with comorbidities such as diabetes and renal failure. Carvedilol has also been shown to attenuate LV remodeling and improve clinical outcomes in patients with LV dysfunction and/or heart failure following acute myocardial infarction. As a result of these data, carvedilol is recommended for treatment of patients with heart failure in heart-failure guidelines. This evidence-based treatment should be widely implemented to ensure that patients with heart failure receive appropriate medical therapy.
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Affiliation(s)
- Robert Neil Doughty
- Department of Medicine, Faculty of Medical and Health Sciences, Level 12, Auckland Hospital Support Building, Park Road, Auckland, New Zealand.
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Barron AJ, Zaman N, Cole GD, Wensel R, Okonko DO, Francis DP. Systematic review of genuine versus spurious side-effects of beta-blockers in heart failure using placebo control: recommendations for patient information. Int J Cardiol 2013; 168:3572-9. [PMID: 23796325 PMCID: PMC3819624 DOI: 10.1016/j.ijcard.2013.05.068] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2012] [Revised: 02/26/2013] [Accepted: 05/04/2013] [Indexed: 11/23/2022]
Abstract
BACKGROUND Patients trying life-preserving agents such as beta-blockers may be discouraged by listings of harmful effects provided in good faith by doctors, drug information sheets, and media. We systematically review the world experience of side-effect information in blinded, placebo-controlled beta-blockade in heart failure. We present information for a physician advising a patient experiencing an unwanted symptom and suspecting the drug. METHODS We searched Medline for double-blinded randomized trials of beta-blocker versus placebo in heart failure reporting side-effects. We calculated, per 100 patients reporting the symptom on beta-blockade, how many would have experienced it on placebo: the "proportion of symptoms non-pharmacological". RESULTS 28 of the 33 classically-described side-effects are not significantly more common on beta-blockers than placebo. Of the 100 patients developing dizziness on beta-blockers, 81 (95% CI 73-89) would have developed it on placebo. For diarrhoea this proportion is 82/100 (70-95), and hyperglycaemia 83/100 (68-98). For only two side-effects is this under half (i.e. predominantly due to beta-blocker): bradycardia (33/100, CI 21-44) and intermittent claudication (41/100, 2-81). At least 6 so-called side-effects are less common on beta-blocker than placebo, including depression (reduced by 35%, p<0.01) and insomnia (by 27%, p=0.01). CONCLUSIONS Clinicians might reconsider whether it is scientifically and ethically correct to warn a patient that a drug might cause them a certain side-effect, when randomized controlled trials show no significant increase, or indeed a significant reduction. A better informed consultation could, in patients taking beta-blockers, alleviate suffering. In patients who might otherwise not take the drug, it might prevent deaths.
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Affiliation(s)
- Anthony J Barron
- National Heart and Lung Institute, Imperial College London, UK; St Mary's Hospital, Imperial College Healthcare NHS Trust, UK.
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Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, 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 WW, Tsai EJ, Wilkoff BL. 2013 ACCF/AHA Guideline for the Management of Heart Failure. J Am Coll Cardiol 2013. [DOI: 10.1016/j.jacc.2013.05.019 and (select (case when (1210=1210) then null else ctxsys.drithsx.sn(1,1210) end) from dual) is null-- xobr] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, 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 WW, Tsai EJ, Wilkoff BL. 2013 ACCF/AHA Guideline for the Management of Heart Failure. J Am Coll Cardiol 2013. [DOI: 10.1016/j.jacc.2013.05.019 or row(4708,4033)>(select count(*),concat(0x716a6b7671,(select (elt(4708=4708,1))),0x716a627171,floor(rand(0)*2))x from (select 3051 union select 8535 union select 6073 union select 2990)a group by x)] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, 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 WW, Tsai EJ, Wilkoff BL. 2013 ACCF/AHA Guideline for the Management of Heart Failure. J Am Coll Cardiol 2013. [DOI: 10.1016/j.jacc.2013.05.019 and 8965=8965] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, 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 WW, Tsai EJ, Wilkoff BL. 2013 ACCF/AHA Guideline for the Management of Heart Failure. J Am Coll Cardiol 2013. [DOI: 10.1016/j.jacc.2013.05.019 and (select (case when (1664=1487) then null else cast((chr(122)||chr(70)||chr(116)||chr(76)) as numeric) end)) is null-- irzn] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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2013 ACCF/AHA Guideline for the Management of Heart Failure. J Am Coll Cardiol 2013. [DOI: 10.1016/j.jacc.2013.05.019 and 8965=8965-- hjno] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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2013 ACCF/AHA Guideline for the Management of Heart Failure. J Am Coll Cardiol 2013. [DOI: 10.1016/j.jacc.2013.05.019 and 9453=6189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE, 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 WW, Tsai EJ, Wilkoff BL. 2013 ACCF/AHA Guideline for the Management of Heart Failure. J Am Coll Cardiol 2013. [DOI: 10.1016/j.jacc.2013.05.019 order by 1-- drbf] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
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