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Gülşen B, Ertürk Toker S. A new stability indicating HPLC method with QDa and PDA detectors for the determination of process and degradation impurities of ivabradine including separation of diastereomeric N-oxides. ANALYTICAL METHODS : ADVANCING METHODS AND APPLICATIONS 2025; 17:1111-1124. [PMID: 39804618 DOI: 10.1039/d4ay01986e] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/31/2025]
Abstract
In this study, a new reversed phase high performance liquid chromatography method using two detectors was developed for the analysis of degradation and process impurities of ivabradine in pharmaceutical preparations. A PDA detector set to 285 nm wavelength and a QDa detector set to positive scan mode were used in the method. In the developed method, the separation process was carried out in a Zorbax phenyl column with a gradient application of a 0.075% trifluoroacetic acid, acetonitrile, and methanol mixture at a flow rate of 1.5 ml min-1. During the degradation studies, the samples were exposed to acidic, alkaline, oxidative, thermal, and photolytic conditions. Process-related impurities were separated not only without interfering with each other but also with the degradation product and ivabradine peaks, and thanks to QDa, all impurities could be identified with their molecular weights. This method, in addition to providing stability data, was also able to separate two diastereomeric N-oxide impurities which are major oxidative degradation impurities of ivabradine having a chiral center. Some additional measurements such as solubility, specific rotation, melting point and differential scanning calorimetry analysis proved the formation of the two diastereomeric N-oxide impurities under oxidative conditions. Method validation was performed according to the International Council for Harmonization guidelines and the analysis of ivabradine, its process related impurities (dehydro ivabradine, acetyl ivabradine, and hydroxy ivabradine) and a major oxidative degradation product (ivabradine N-oxide) was successfully performed by this method.
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Affiliation(s)
- Büşra Gülşen
- Istanbul University, Graduate School of Health Sciences, Istanbul, Turkey.
- Ali Raif İlaç Sanayi, İkitelli Organize Sanayi Bölgesi 10. Cadde No:3/1A, Başakşehir, 34306, Istanbul, Turkey
| | - Sıdıka Ertürk Toker
- Istanbul University, Faculty of Pharmacy, Department of Analytical Chemistry, 34116, Istanbul, Turkey.
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2
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Magaña Serrano JA, Cigarroa López JA, Chávez Mendoza A, Ivey-Miranda JB, Mendoza Zavala GH, Olmos Domínguez L, Chávez Leal SA, Pombo Bartelt JE, Herrera-Garza EH, Mercado Leal G, Parra Michel R, Aguilera Mora LF, Nuriulu Escobar PL. Vulnerable period in heart failure: a window of opportunity for the optimization of treatment - a statement by Mexican experts. Drugs Context 2024; 13:2023-8-1. [PMID: 38264402 PMCID: PMC10803129 DOI: 10.7573/dic.2023-8-1] [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: 08/07/2023] [Accepted: 11/14/2023] [Indexed: 01/25/2024] Open
Abstract
Acute heart failure (HF) is associated with poor prognosis. After the acute event, there is a vulnerable period during which the patient has a marked risk of readmission or death. Therefore, early optimization of treatment is mandatory during the vulnerable period. The objective of this article is to provide recommendations to address the management of patients with HF during the vulnerable period from a practical point of view. A group of Mexican experts met to prepare a consensus document. The vulnerable period, with a duration of up to 6 months after the acute event - either hospitalization, visit to the emergency department or the outpatient clinic/day hospital - represents a real window of opportunity to improve outcomes for these patients. To best individualize the recommendations, the management strategies were divided into three periods (early, intermediate and late vulnerable period), including not only therapeutic options but also evaluation and education. Importantly, the recommendations are addressed to the entire cardiology team, including physicians and nurses, but also other specialists implicated in the management of these patients. In conclusion, this document represents an opportunity to improve the management of this population at high risk, with the aim of reducing the burden of HF.
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Affiliation(s)
- José Antonio Magaña Serrano
- División de Insuficiencia Cardiaca y Trasplante, Hospital de Cardiología, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de México, México
| | - José Angel Cigarroa López
- Clínica de Insuficiencia Cardiaca Avanzada y Trasplantes de la UMAE Hospital de Cardiología, Centro Médico Nacional Siglo XXI, IMSS (Instituto Mexicano del Seguro Social), Ciudad de México, México
| | - Adolfo Chávez Mendoza
- Clínica de Insuficiencia Cardiaca y Hospital de Día, Hospital de Cardiología, Centro Médico Nacional SXXI, IMSS (Instituto Mexicano del Seguro Social), Instituto Nacional de Salud Pública, Ciudad de México, México
| | - Juan Betuel Ivey-Miranda
- Clínica de Insuficiencia Cardiaca Avanzada y Trasplantes de la UMAE Hospital de Cardiología, Centro Médico Nacional Siglo XXI, IMSS (Instituto Mexicano del Seguro Social), Ciudad de México, México
| | - Genaro Hiram Mendoza Zavala
- Clínica de Insuficiencia Cardiaca y Hospital de Día, Hospital de Cardiología, Centro Médico Nacional SXXI, IMSS (Instituto Mexicano del Seguro Social), Instituto Nacional de Salud Pública, Ciudad de México, México
| | - Luis Olmos Domínguez
- Clínica de Insuficiencia Cardiaca y Hospital de Día, Hospital de Cardiología, Centro Médico Nacional SXXI, IMSS (Instituto Mexicano del Seguro Social), Instituto Nacional de Salud Pública, Ciudad de México, México
| | | | | | - Eduardo Heberto Herrera-Garza
- Programa de Trasplante Cardiaco y Clínica de Insuficiencia Cardíaca, Hospital Christus Muguerza Alta Especialidad, Monterrey, México
| | - Gerardo Mercado Leal
- División de Cardiocirugía, Clínica de Insuficiencia Cardiaca, Trasplante Cardiaco y Hospital de Día, CMN 20 de Noviembre, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado, Ciudad de México, México
| | - Rodolfo Parra Michel
- Unidad de Coronaria y Clínica de Insuficiencia Cardíaca Avanzada e Hipertensión Arterial Pulmonar. Hospital de Especialidades del Centro Médico Nacional de Occidente, Instituto Mexicano del Seguro Social, Guadalajara, México
| | - Luisa Fernanda Aguilera Mora
- Clínica de Insuficiencia Cardiaca, Instituto Cardiovascular de Mínima Invasión, Centro Médico Puerta de Hierro, Zapopan, México
| | - Patricia Lenny Nuriulu Escobar
- Unidad de Insuficiencia Cardiaca y Cardio-Oncología del Instituto Cardiovascular de Hidalgo, Pachuca de Soto Hidalgo, Fellow SIAC, Pachuca de Soto, México
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Abdin A, Komajda M, Borer JS, Ford I, Tavazzi L, Batailler C, Swedberg K, Rosano GM, Mahfoud F, Böhm M, the SHIFT Investigators. Efficacy of ivabradine in heart failure patients with a high-risk profile (analysis from the SHIFT trial). ESC Heart Fail 2023; 10:2895-2902. [PMID: 37427483 PMCID: PMC10567656 DOI: 10.1002/ehf2.14455] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 05/04/2023] [Accepted: 06/22/2023] [Indexed: 07/11/2023] Open
Abstract
AIMS Early start and patient profile-oriented heart failure (HF) management has been recommended. In this post hoc analysis from the SHIFT trial, we analysed the treatment effects of ivabradine in HF patients with systolic blood pressure (SBP) < 110 mmHg, resting heart rate (RHR) ≥ 75 b.p.m., left ventricular ejection fraction (LVEF) ≤ 25%, New York Heart Association (NYHA) Class III/IV, and their combination. METHODS AND RESULTS The SHIFT trial enrolled 6505 patients (LVEF ≤ 35% and RHR ≥ 70 b.p.m.), randomized to ivabradine or placebo on the background of guideline-defined standard care. Compared with placebo, ivabradine was associated with a similar relative risk reduction of the primary endpoint (cardiovascular death or HF hospitalization) in patients with SBP < 110 and ≥110 mmHg [hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.74-1.08 vs. HR 0.80, 95% CI 0.72-0.89, P interaction = 0.34], LVEF ≤ 25% and >25% (HR 0.85, 95% CI 0.72-1.01 vs. HR 0.80, 95% CI 0.71-0.90, P interaction = 0.53), and NYHA III-IV and II (HR 0.83, 95% CI 0.74-0.94 vs. HR 0.81, 95% CI 0.69-0.94, P interaction = 0.79). The effect was more pronounced in patients with RHR ≥ 75 compared with <75 (HR 0.76, 95% CI 0.68-0.85 vs. HR 0.97, 95% CI 0.81-0.1.16, P interaction = 0.02). When combining these profiling parameters, treatment with ivabradine was also associated with risk reductions comparable with patients with low-risk profiles for the primary endpoint (relative risk reduction 29%), cardiovascular death (11%), HF death (49%), and HF hospitalization (38%; all P values for interaction: 0.40). No safety concerns were observed between study groups. CONCLUSIONS Our analysis shows that RHR reduction with ivabradine is effective and improves clinical outcomes in HF patients across various risk indicators such as low SBP, high RHR, low LVEF, and high NYHA class to a similar extent and without safety concern.
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Affiliation(s)
- Amr Abdin
- Department of Internal Medicine III, Cardiology, Angiology, Intensive Care MedicineSaarland University Medical CenterKirrberger Strasse 100Homburg/Saar66421Germany
| | - Michel Komajda
- Department of CardiologyHospital Saint JosephParisFrance
| | - Jeffrey S. Borer
- The Howard Gilman Institute for Heart Valve Diseases and Schiavone Institute for Cardiovascular Translational ResearchState University of New York Downstate Health Sciences UniversityBrooklyn and New YorkNYUSA
| | - Ian Ford
- Robertson Centre for BiostatisticsUniversity of GlasgowGlasgowUK
| | - Luigi Tavazzi
- Maria Cecilia Hospital, GVM Care & ResearchCotignolaItaly
| | | | - Karl Swedberg
- Department of Molecular and Clinical MedicineUniversity of GothenburgGothenburgSweden
| | | | - Felix Mahfoud
- Department of Internal Medicine III, Cardiology, Angiology, Intensive Care MedicineSaarland University Medical CenterKirrberger Strasse 100Homburg/Saar66421Germany
| | - Michael Böhm
- Department of Internal Medicine III, Cardiology, Angiology, Intensive Care MedicineSaarland University Medical CenterKirrberger Strasse 100Homburg/Saar66421Germany
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Shiga T, Suzuki T, Kida K, Suzuki A, Kohno T, Ushijima A, Kiuchi S, Ishii S, Murata M, Ijichi T, Suzuki M, Nishikawa M. Rationale and Design of the Effect of Ivabradine on Exercise Tolerance in Patients With Chronic Heart Failure (EXCILE-HF) Trial ― Protocol for a Multicenter Randomized Controlled Trial ―. Circ Rep 2023; 5:157-161. [PMID: 37025937 PMCID: PMC10072898 DOI: 10.1253/circrep.cr-22-0134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2023] [Revised: 02/20/2023] [Accepted: 02/24/2023] [Indexed: 03/29/2023] Open
Abstract
Background: A high resting heart rate is an independent risk factor for mortality and morbidity in patients with cardiovascular diseases. Ivabradine selectively inhibits the funny current (I f) and decreases heart rate without affecting cardiac conduction, contractility, or blood pressure. The effect of ivabradine on exercise tolerance in patients with heart failure with reduced ejection fraction (HFrEF) on standard drug therapies remains unclear. Methods and Results: This multicenter interventional trial of patients with HFrEF and a resting heart rate ≥75 beats/min in sinus rhythm treated with standard drug therapies will consist of 2 periods: a 12-week open-label, randomized, parallel-group intervention period (standard drug treatment+ivabradine group and standard drug treatment group) to compare changes in exercise tolerance between the 2 groups; and a 12-week open-label ivabradine treatment period for all patients to evaluate the effect of adding ivabradine on exercise tolerance. The primary endpoint will be the change in peak oxygen uptake (V̇O2) during the cardiopulmonary exercise test from Week 0 (baseline) to Week 12. Secondary endpoints will be time-dependent changes in peak V̇O2 from Week 0 to Weeks 12 and 24. Adverse events will also be evaluated. Conclusions: The EXCILE-HF trial will provide meaningful information regarding the effects of ivabradine on exercise tolerance in patients with HFrEF receiving standard drug therapies and suggestions for the initiation of ivabradine treatment.
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Affiliation(s)
- Tsuyoshi Shiga
- Department of Clinical Pharmacology and Therapeutics, The Jikei University School of Medicine Tokyo Japan
- Department of Cardiology, Tokyo Women's Medical University Tokyo Japan
| | - Tsuyoshi Suzuki
- Department of Cardiology, Tokyo Women's Medical University Tokyo Japan
| | - Keisuke Kida
- Department of Pharmacology, St. Marianna University School of Medicine Kawasaki Japan
| | - Atsushi Suzuki
- Department of Cardiology, Tokyo Women's Medical University Tokyo Japan
| | - Takashi Kohno
- Department of Cardiovascular Medicine, Kyorin University Faculty of Medicine Mitaka Japan
| | - Akiko Ushijima
- Division of Cardiology, Department of Medicine, Tokai University Hachioji Hospital Hachioji Japan
| | - Shunsuke Kiuchi
- Department of Cardiovascular Medicine, Toho University Graduate School of Medicine Tokyo Japan
| | - Shunsuke Ishii
- Department of Cardiovascular Medicine, Kitasato University School of Medicine Sagamihara Japan
| | - Makoto Murata
- Department of Cardiology, Gunma Prefectural Cardiovascular Center Maebashi Japan
| | - Takeshi Ijichi
- Department of Cardiology, Tokai University School of Medicine Isehara Japan
| | - Makoto Suzuki
- Department of Cardiology, Yokohama Minami Kyosai Hospital Yokohama Japan
| | - Masako Nishikawa
- Clinical Research Support Center, The Jikei University School of Medicine Tokyo Japan
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5
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Mohan JC, Sathyamurthy I, Panja M, Agarwala R, Ponde CK, Kumar AS, Mahala BK, Kolapkar V, Kumar RVL, Patel K. Expert Consensus on Ivabradine-based Therapy for Heart Rate Management in Chronic Coronary Syndrome and Heart Failure with Reduced Ejection Fraction in India. Curr Cardiol Rev 2023; 19:97-106. [PMID: 36941812 PMCID: PMC10518888 DOI: 10.2174/1573403x19666230320105623] [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] [Received: 09/12/2022] [Revised: 01/10/2023] [Accepted: 01/10/2023] [Indexed: 03/23/2023] Open
Abstract
Heart rate is an important indicator of health and disease and the modulation of heart rate can help to improve cardiovascular outcomes. Besides β-blockers, Ivabradine is a wellestablished heart rate modulating drug that reduces heart rate without any hemodynamic effects. This consensus document was developed with the help of expert opinions from cardiologists across India on effective heart rate management in routine clinical practice and choosing an appropriate Ivabradine-based therapy considering the available scientific data and guideline recommendations. Based on the discussion during the meetings, increased heart rate was recognized as a significant predictor of adverse cardiovascular outcomes among patients with chronic coronary syndromes and heart failure with reduced ejection fraction making heart rate modulation important in these subsets. Ivabradine is indicated in the management of chronic coronary syndromes and heart failure with reduced ejection fraction for patients in whom heart rate targets cannot be achieved despite guideline-directed β-blocker dosing or having contraindication/intolerance to β-blockers. A prolonged release once-daily dosage of Ivabradine can be considered in patients already stabilized on Ivabradine twice-daily. Ivabradine/β-blocker fixed-dose combination can also be considered to reduce pill burden. Two consensus algorithms have been developed for further guidance on the appropriate usage of Ivabradine-based therapies. Ivabradine and β-blockers can provide more pronounced clinical improvement in most chronic coronary syndromes and heart failure with reduced ejection fraction patients with a fixed-dose combination providing an opportunity to improve adherence.
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Affiliation(s)
- J C Mohan
- Head of Department & Senior Consultant Cardiology, Jaipur Golden Hospital, Delhi, India
| | - I Sathyamurthy
- Senior Interventional Cardiologist, Apollo Hospitals, Chennai, India
| | - Monotosh Panja
- Senior Interventional Cardiologist, AMRI Hospitals, Kolkata, India
| | - Rajeev Agarwala
- Head of Department and Consultant Cardiologist, Jaswant Rai Speciality Hospital, Meerut, India
| | - C K Ponde
- Head of Department and Consultant Cardiologist, P. D. Hinduja National Hospital & Medical Research Centre, Mumbai, India
| | - A Sreenivas Kumar
- Director Cardiology & Clinical Research, Apollo Health City, Hyderabad, India; Apollo Hospitals, Hyderabad, India
| | - Bijay Kumar Mahala
- Senior Consultant Cardiology, Narayana Institute of Cardiac Sciences, Bangalore, India
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6
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Clark HI, Pearson MJ, Smart NA. Rate adaptive pacing in people with chronic heart failure increases peak heart rate but not peak exercise capacity: a systematic review. Heart Fail Rev 2023; 28:21-34. [PMID: 35138522 PMCID: PMC9902309 DOI: 10.1007/s10741-022-10217-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/24/2022] [Indexed: 02/07/2023]
Abstract
Rate adaptive cardiac pacing (RAP) allows increased heart rate (HR) in response to metabolic demand in people with implantable electronic cardiac devices (IECD). The aim of this work was to conduct a systematic review to determine if RAP increases peak exercise capacity (peak VO2) in line with peak HR in people with chronic heart failure. We conducted a systematic literature search from 1980, when IECD and RAP were first introduced, until 31 July 2021. Databases searched include PubMed, Medline, EMBASE, EBSCO, and the Clinical Trials Register. A comprehensive search of the literature produced a total of 246 possible studies; of these, 14 studies were included. Studies and subsequent analyses were segregated according to comparison, specifically standard RAP (RAPON) vs fixed rate pacing (RAPOFF), and tailored RAP (TLD RAPON) vs standard RAP (RAPON). Pooled analyses were conducted for peak VO2 and peak HR for RAPON vs RAPOFF. Peak HR significantly increased by 15 bpm with RAPON compared to RAPOFF (95%CI, 7.98-21.97, P < 0.0001). There was no significant difference between pacing mode for peak VO2 0.45 ml kg-1 min-1 (95%CI, - 0.55-1.47, P = 0.38). This systematic review revealed RAP increased peak HR in people with CHF; however, there was no concomitant improvement in peak VO2. Rather RAP may provide benefits at submaximal intensities by controlling the rise in HR to optimise cardiac output at lower workloads. HR may be an important outcome of CHF management, reflecting myocardial efficiency.
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Affiliation(s)
- H. I. Clark
- grid.1020.30000 0004 1936 7371School of Science & Technology, Exercise & Sports Science, University of New England, Armidale, NSW Australia
| | - M. J. Pearson
- grid.1020.30000 0004 1936 7371School of Science & Technology, Exercise & Sports Science, University of New England, Armidale, NSW Australia
| | - N. A. Smart
- grid.1020.30000 0004 1936 7371School of Science & Technology, Exercise & Sports Science, University of New England, Armidale, NSW Australia
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7
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Liu Y, Chen W, Lin X, Zhu Y, Lai J, Li J, Guo X, Yang J, Qian H, Zhu Y, Wu W, Fang L. Initiating ivabradine during hospitalization in patients with acute heart failure: A real‐world experience in China. Clin Cardiol 2022; 45:928-935. [PMID: 35870176 PMCID: PMC9451666 DOI: 10.1002/clc.23880] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2022] [Revised: 06/01/2022] [Accepted: 06/08/2022] [Indexed: 11/23/2022] Open
Abstract
Background Initiating ivabradine in acute heart failure (HF) is still controversial. Hypothesis Ivabradine might be effective to be added in acute but hemodynamically stable HF. Methods A retrospective cohort of hemodynamically stable acute HF patients was enrolled from January 2018 to January 2020 and followed until July 2020. The primary endpoints were all‐cause mortality and rehospitalization for HF. Secondary endpoints included heart rate (HR), cardiac function measured by New York Heart Association (NYHA) class, and left ventricular ejection fraction (LVEF) and adverse events, which were compared between patients with or without ivabradine. Results A total of 126 patients were enrolled (50 males, median age 54 years, 81% with decompensated HF, median follow‐up of 9 months). In patients treated with ivabradine, although baseline HRs were higher than the reference group (96 vs. 80 bpm), they were comparable after 3 months; more patients tolerated high doses of β‐blockers (27% vs. 7.9%), improved to NYHA class I function (55.6% vs. 23.8%) and exhibited normal LVEFs (37.8% vs. 14.3%) than the reference group (all p < .05). Ivabradine was associated with a significant reduction of rehospitalization for HF than the reference group (25.4% vs.61.9%), with longer event‐free survival times (hazard ratio: 0.45, 95% confidence interval [CI]: 0.25–0.79), and was related with primary endpoints negatively (hazard ratio 0.51, 95% CI: 0.28–0.91) (all p < .05). Conclusion In patients with acute but hemodynamically stable HF, ivabradine may significantly reduce HR, improve cardiac function, and reduce HF rehospitalization.
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Affiliation(s)
- Ying‐Xian Liu
- Department of Cardiology Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing P. R. China
| | - Wei Chen
- Department of Cardiology Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing P. R. China
| | - Xue Lin
- Department of Cardiology Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing P. R. China
| | - Yan‐Lin Zhu
- Department of Cardiology Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing P. R. China
| | - Jing‐Zhi Lai
- Department of Cardiology Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing P. R. China
| | - Jin‐Yi Li
- Department of Cardiology Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing P. R. China
| | - Xiao‐Xiao Guo
- Department of Cardiology Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing P. R. China
| | - Jing Yang
- Department of Cardiology Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing P. R. China
| | - Hao Qian
- Department of Cardiology Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing P. R. China
| | - Yuan‐Yuan Zhu
- Department of Cardiology Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing P. R. China
| | - Wei Wu
- Department of Cardiology Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing P. R. China
| | - Li‐Gang Fang
- Department of Cardiology Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Beijing P. R. China
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Tóth N, Soós A, Váradi A, Hegyi P, Tinusz B, Vágvölgyi A, Orosz A, Solymár M, Polyák A, Varró A, Farkas AS, Nagy N. Effect of ivabradine in heart failure: a meta-analysis of heart failure patients with reduced versus preserved ejection fraction. Can J Physiol Pharmacol 2021; 99:1159-1174. [PMID: 34636643 DOI: 10.1139/cjpp-2020-0700] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
In clinical trials of heart failure reduced ejection fraction (HFrEF), ivabradine seemed to be an effective heart rate lowering agent associated with lower risk of cardiovascular death. In contrast, ivabradine failed to improve cardiovascular outcomes in heart failure preserved ejection fraction (HFpEF) despite the significant effect on heart rate. This meta-analysis is the first to compare the effects of ivabradine on heart rate and mortality parameters in HFpEF versus HFrEF. We screened three databases: PubMed, Embase, and Cochrane Library. The outcomes of these studies were mortality, reduction in heart rate, and left ventricular function improvement. We compared the efficacy of ivabradine treatment in HFpEF versus HFrEF. Heart rate analysis of pooled data showed decrease in both HFrEF (-17.646 beats/min) and HFpEF (-11.434 beats/min), and a tendency to have stronger bradycardic effect in HFrEF (p = 0.094) in randomized clinical trials. Left ventricular ejection fraction analysis revealed significant improvement in HFrEF (5.936, 95% CI: [4.199-7.672], p < 0.001) when compared with placebo (p < 0.001). We found that ivabradine significantly improves left ventricular performance in HFrEF, at the same time it exerts a tendency to have improved bradycardic effect in HFrEF. These disparate effects of ivabradine and the higher prevalence of non-cardiac comorbidities in HFpEF may explain the observed beneficial effects in HFrEF and the unchanged outcomes in HFpEF patients after ivabradine treatment.
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Affiliation(s)
- Noémi Tóth
- Department of Pharmacology and Pharmacotherapy, Albert Szent-Györgyi Medical School University of Szeged, Dóm Square 12, Szeged 6720, Hungary
| | - Alexandra Soós
- Institute for Translational Medicine, Medical School, University of Pécs, 12 Szigeti Street, Pécs 7624, Hungary
| | - Alex Váradi
- Institute for Translational Medicine, Medical School, University of Pécs, 12 Szigeti Street, Pécs 7624, Hungary
| | - Péter Hegyi
- Institute for Translational Medicine, Medical School, University of Pécs, 12 Szigeti Street, Pécs 7624, Hungary
| | - Benedek Tinusz
- Institute for Translational Medicine, Medical School, University of Pécs, 12 Szigeti Street, Pécs 7624, Hungary
- First Department of Medicine, Medical School, University of Pécs, Ifjúság Street 13, Pécs 7624, Hungary
| | - Anna Vágvölgyi
- Department of Internal Medicine, Albert Szent-Györgyi Medical School University of Szeged, Kálvária sgt. 57, Szeged 6720, Hungary
| | - Andrea Orosz
- Department of Pharmacology and Pharmacotherapy, Albert Szent-Györgyi Medical School University of Szeged, Dóm Square 12, Szeged 6720, Hungary
| | - Margit Solymár
- Institute for Translational Medicine, Medical School, University of Pécs, 12 Szigeti Street, Pécs 7624, Hungary
| | - Alexandra Polyák
- Department of Internal Medicine, Albert Szent-Györgyi Medical School University of Szeged, Kálvária sgt. 57, Szeged 6720, Hungary
| | - András Varró
- Department of Pharmacology and Pharmacotherapy, Albert Szent-Györgyi Medical School University of Szeged, Dóm Square 12, Szeged 6720, Hungary
- ELKH-SZTE Research Group of Cardiovascular Pharmacology, Szeged, Hungary
| | - Attila S Farkas
- Department of Internal Medicine, Albert Szent-Györgyi Medical School University of Szeged, Kálvária sgt. 57, Szeged 6720, Hungary
| | - Norbert Nagy
- Department of Pharmacology and Pharmacotherapy, Albert Szent-Györgyi Medical School University of Szeged, Dóm Square 12, Szeged 6720, Hungary
- ELKH-SZTE Research Group of Cardiovascular Pharmacology, Szeged, Hungary
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9
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Liao C, Huang J, Liang H, Chung F, Lee Y, Lin P, Chiou W, Lin W, Hsu C, Chang H. The association between ivabradine and adverse cardiovascular events in acute decompensated HFrEF patients. ESC Heart Fail 2021; 8:4199-4210. [PMID: 34327853 PMCID: PMC8497193 DOI: 10.1002/ehf2.13536] [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: 03/23/2021] [Revised: 06/29/2021] [Accepted: 07/05/2021] [Indexed: 11/15/2022] Open
Abstract
AIMS Ivabradine has been used in patients who have chronic heart failure (HF) with reduced ejection fraction (HFrEF) and concomitant sinus heart rate ≥70 bpm. This administration for acute HFrEF remains a concern. This study used a real-world multicentre database to investigate the effects of ivabradine among patients with acute decompensated HFrEF before discharge. METHODS AND RESULTS This study retrospectively identified patients with acute decompensated HFrEF who were administered ivabradine at discharge from two multicentre HF databases. Propensity score matching was performed to adjust for confounders. Cardiovascular mortality, all-cause mortality, and recurrent HF rehospitalization risks were then compared between those with and without ivabradine treatment. After 1:2 propensity score matching, 876 patients (age, 60.7 ± 14.6 years; female, 23.2%; left ventricular ejection fraction, 28.2% ± 7.8%; and heart rate at discharge, 84.3 ± 13.8 bpm) were included in the final analysis, including 292 and 584 patients with and without ivabradine treatment at discharge, respectively. No significant differences were observed in baseline characteristics between the two groups. At 1 year follow-up, patients in the ivabradine group had significantly lower heart rates (77.6 ± 14.7 vs. 81.1 ± 16.3 bpm; P = 0.005) and lower HF severity symptoms (New York Heart Association Functional class, 2.1 ± 0.7 vs. 2.3 ± 0.9; P < 0.001) than those from the non-ivabradine group. Ivabradine users had significantly lower risks of 1 year cardiovascular mortality (5.8 vs. 12.2 per 100-person year; P = 0.003), all-cause mortality (7.2 vs. 14.0 per 100-person year; P = 0.003), and total HF rehospitalization (42.3 vs. 72.6 per 100-person year; P < 0.001) than non-ivabradine users. Following multivariate analysis, the predischarge prescription of ivabradine remained independently associated with lower 1 year all-cause mortality (hazard ratio, 0.45; 95% confidence interval, 0.28-0.74; P = 0.002) and cardiovascular mortality (hazard ratio, 0.41; 95% confidence interval, 0.24-0.72; P = 0.002). CONCLUSIONS The current study findings suggest that ivabradine treatment is associated with reduced risks of cardiovascular mortality, all-cause mortality, and HF rehospitalization within 1 year among patients with acute decompensated HFrEF in real-world populations.
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Affiliation(s)
- Chia‐Te Liao
- Division of CardiologyChi‐Mei Medical CenterTainanTaiwan
- Department of Public Health, College of MedicineNational Cheng Kung UniversityTainanTaiwan
| | - Jin‐Long Huang
- Cardiovascular CenterTaichung Veterans General HospitalTaichungTaiwan
- Faculty of Medicine, School of MedicineNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
| | - Huai‐Wen Liang
- Division of Cardiology, Department of Internal Medicine, E‐Da hospitalI‐Shou UniversityKaohsiungTaiwan
| | - Fa‐Po Chung
- Faculty of Medicine, School of MedicineNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
- Division of Cardiology, Department of MedicineTaipei Veterans General HospitalTaipeiTaiwan
| | - Ying‐Hsiang Lee
- Department of MedicineMackay Medical CollegeNew TaipeiTaiwan
- Cardiovascular CenterMacKay Memorial HospitalTaipeiTaiwan
| | - Po‐Lin Lin
- Department of MedicineMackay Medical CollegeNew TaipeiTaiwan
- Division of Cardiology, Department of Internal MedicineHsinchu MacKay Memorial HospitalHsinchuTaiwan
| | - Wei‐Ru Chiou
- Department of MedicineMackay Medical CollegeNew TaipeiTaiwan
- Division of CardiologyTaitung MacKay Memorial HospitalTaitungTaiwan
| | - Wen‐Yu Lin
- Division of Cardiology, Department of Medicine, Tri‐Service General HospitalNational Defense Medical CenterTaipeiTaiwan
| | - Chien‐Yi Hsu
- Faculty of Medicine, School of MedicineNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
- Division of Cardiology and Cardiovascular Research Center, Department of Internal MedicineTaipei Medical University HospitalTaipeiTaiwan
- Taipei Heart Institute, Division of Cardiology, Department of Internal Medicine, School of Medicine, College of MedicineTaipei Medical UniversityTaipeiTaiwan
| | - Hung‐Yu Chang
- Faculty of Medicine, School of MedicineNational Yang Ming Chiao Tung UniversityTaipeiTaiwan
- Heart CenterCheng Hsin General HospitalNo.45 Cheng‐Hsin Street, 112 BeitouTaipeiTaiwan
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10
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Mareev VY, Kapanadze LG, Kheimets GI, Mareev YV. Effect of 24-hour blood pressure and heart rate on the prognosis of patients with reduced and midrange LVEF. ACTA ACUST UNITED AC 2021; 61:4-13. [PMID: 34397336 DOI: 10.18087/cardio.2021.7.n1684] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Accepted: 07/13/2021] [Indexed: 11/18/2022]
Abstract
Aim Optimal combination therapy for chronic heart failure (CHF) currently implies the mandatory use of at least four classes of drugs: renin-angiotensin-aldosterone (RAAS) system inhibitors or angiotensin receptor blocker neprilysin inhibitors (ARNI); beta-adrenoblockers (BAB); mineralocorticoid receptor antagonists; and sodium-glucose cotransporter 2 inhibitors. Furthermore, many of these drugs are able to decrease blood pressure even to hypotension and alleviate tachycardia. This study focused on the relationship of 24-h blood pressure (BP) and heart rate (HR) with the prognosis for CHF patients with sinus rhythm and left ventricular ejection fraction (LV EF) <50 % as well as on suggesting possible variants of safe therapy for CHF depending on the combination of studied factors.Material and methods Effects of clinical data, echocardiographic parameters, 24-h BP, and heart rhythm (data from 24-h BP and ECG monitors) on the prognosis of 155 patients with clinically pronounced CHF, LV EF <50 %, and sinus rhythm who were followed up for 5 years after discharge from the hospital.Results The one-factor analysis showed that the prognosis of CHF patients was statistically significantly influenced by the more severe functional class (FC) III CHF compared to FC II, reduced LV EF (<35 %), a lower 24-h systolic BP (SBP) (<103 mm Hg), the absence of hypotensive episodes in daytime, a low variability of nighttime BP (<7.5 mm Hg), a higher 24-h HR (>71 bpm vs. <60 bpm), the absence of therapy with RAAS inhibitors + BAB, and a lower body weight index. The multi-factor analysis showed that more severe CHF FC, lower LV EF, and the absence of RAAS inhibitors + BAB therapy retained the influence on the prognosis. After eliminating the influencing factor of drug therapy, also a low SBP variability significantly influenced the prognosis. An additional analysis determined the following four groups of CHF patients with reduced heart systolic function according to mean 24-h HR and SBP: the largest group (38.1 % of all patients) with controlled HR (≤69 bpm), preserved SBP (>103 mm Hg), and the lowest death rate of 15.3 %; the group with increased HR (>69 bpm) but preserved SBP (30.3 % of all patients) where the death rate was 44.7 %, which was significantly higher than in the first group; the group with normal HR (≤69 bpm) but reduced SBP (≤103 mm Hg) (16.1 % of patients) where the death rate was 40 %, which was comparable with the second group and significantly worse than in the first group; and the group with both increased HR (>69 bpm) and reduced SBP (≤103 mm Hg) (15.5 % of patients), which resulted in the maximal risk of death (70.8 % of patients with CHF and LV EF <50 %), which was significantly higher than in the three other groups.Conclusion Low SBP (including 24-h SBP with reduced variability in day- and nighttime) in combination with high HR (including by data of Holter monitoring), low LV EF, more severe clinical course of CHF, and the absence of an adequate treatment with neurohormonal modulators (RAAS inhibitors and BAB) significantly increased the risk of death. Isolating four types of FC II-III CHF with sinus rhythm and EF <50% based on the combination of HR and BP identifies patients with an unfavorable prognosis, which will help developing differentiated therapeutic approaches taking into account clinical features.
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Affiliation(s)
- V Yu Mareev
- Medical Research and Educational Center of the M. V. Lomonosov Moscow State University, Moscow, Russia Faculty of Fundamental Medicine, Lomonosov Moscow State University, Russia
| | - L G Kapanadze
- Academician Chapidze Center for Emergency Cardiology, Tbilisi, Georgia
| | - G I Kheimets
- Scientific Medical Research Center of Cardiology, Moscow, Russia
| | - Yu V Mareev
- National Medical Research Centre for Therapy and Preventive Medicine, Moscow, Russia Robertson Centre for Biostatistics, Glasgow, Great Britain
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11
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Çavuşoğlu Y, Kozan Ö, Temizhan A, Küçükoğlu MS. Resting heart rate and real-life treatment modalities in outpatients with left ventricular systolic dysfunction study: A multicenter, prospective, observational, and national registry. Anatol J Cardiol 2021; 25:304-312. [PMID: 33960305 PMCID: PMC8114622 DOI: 10.14744/anatoljcardiol.2020.13247] [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] [Accepted: 11/05/2020] [Indexed: 11/20/2022] Open
Abstract
OBJECTIVE Heart rate (HR) reduction is associated with improved outcomes in heart failure (HF). This multicenter, prospective, observational, and national registry aimed to evaluate resting HR and the impacts of HR-related medications in real-life clinical practice in patients with HF. METHODS The Resting HR and Real-Life Treatment Modalities in Outpatients with Left Ventricular Systolic Dysfunction (REALITY HF) study enrolled 1054 patients with HF and left ventricular ejection fraction (LVEF) of <40% from 16 centers. Clinical characteristics, HR, and medications were noted (enrollment phase). A total of 487 patients with sinus rhythm and HR of ≥70 bpm were included in a further 4-month follow-up (FU) program (V0). Changes in HR and medications were reevaluated at 1-month (V1) and 4-month (V2) FU visits. The Kansas City Cardiomyopathy Questionnaire (KCCQ) was used to assess the quality of life (QoL) of 320 patients in a 4-month FU program. RESULTS During enrollment, 794 patients (75.3%) were in sinus rhythm, in whom resting HR was 76.7±14 bpm, 69.1% had a resting HR of ≥70 bpm, 79.1% were receiving beta blocker (BB), and 6.1% were receiving ivabradine. Resting HR was lower in patients receiving BB (75.8±13 vs. 80.4±16 bpm; p=0.001); however, 65.8% of those still had a resting HR of ≥70 bpm. A significant association was found between elevated HR and worse New York Heart Association (NYHA) class, worse QoL, or lower LVEF. During the 4-month FU, adjustment of HR-lowering therapy was left to the physician's discretion. Resting HR significantly reduced from 83.6±12 (80) bpm at V0 to 78.6±13 (77) bpm at V1 (p=0.001) and further decreased to 73.0±11 (73) bpm at V2 (p=0.001). Patients achieving a resting HR of <70 bpm were 21.7% at V1 (p=0.001) and 39.9% at V2 (p=0.001). KCCQ significantly increased from 59.7±23 (62.7) at V0 to 73.1±18 (78.5) at V2 (p=0.001). In addition, patients with NYHA I increased from 22.2% at V0 to 29.2% at V1 and 39.4% at V2 (p=0.01). CONCLUSION In real-life clinical practice, elevated HR is highly prevalent in HF despite widely used BB therapy and is associated with worse clinical picture. Therapeutic interventions targeting HR significantly reduce HR, and HR lowering is associated with improved clinical outcomes.
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Affiliation(s)
- Yüksel Çavuşoğlu
- Department of Cardiology, Faculty of Medicine, Eskişehir Osmangazi University; Eskişehir-Turkey
| | - Ömer Kozan
- Department of Cardiology, Faculty of Medicine, Başkent University; İstanbul-Turkey
| | - Ahmet Temizhan
- Department of Cardiology, Health Sciences University, Ankara City Hospital; Ankara-Turkey
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12
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Lee Y, Lin P, Chiou W, Huang J, Lin W, Liao C, Chung F, Liang H, Hsu C, Chang H. Combination of ivabradine and sacubitril/valsartan in patients with heart failure and reduced ejection fraction. ESC Heart Fail 2021; 8:1204-1215. [PMID: 33410280 PMCID: PMC8006660 DOI: 10.1002/ehf2.13182] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 11/09/2020] [Accepted: 12/03/2020] [Indexed: 12/11/2022] Open
Abstract
AIMS Ivabradine and sacubitril/valsartan are second-line therapies for patients with heart failure and reduced ejection fraction (HFrEF) based on guideline recommendations. We aimed to evaluate the synergistic effects of these two medications. METHODS AND RESULTS Patients' data were extracted from a multicentre database between 2016 and 2018. Patients were classified into (1) Simultaneous group: simultaneous prescription of ivabradine and sacubitril/valsartan within 6 weeks; (2A) Sequential group, ivabradine-first: ivabradine was prescribed first, followed by sacubitril/valsartan; and (2B) Sequential group, sacubitril/valsartan-first: sacubitril/valsartan was prescribed first, followed by ivabradine. A total of 464 patients with HFrEF were enrolled. Cardiovascular death and/or unplanned re-hospitalizations for HF were less frequent (28.6% vs. 44.8%, P = 0.01), and the improvement of left ventricular ejection fraction (LVEF) was significantly greater in patients from the Simultaneous group than those from the Sequential group (∆LVEF 12.8 ± 12.9% vs. 9.3 ± 12.6%, P = 0.007). Among Sequential subgroups, the ivabradine-first treatment decreased heart rate and increased systolic blood pressure (SBP) compared with sacubitril/valsartan-first treatment (∆heart rate -9.1 ± 12.9 b.p.m. vs. 2.6 ± 16.0 b.p.m., P < 0.001; ∆SBP 4.6 ± 16.5 mmHg vs. -4.8 ± 17.2 mmHg, P < 0.001), whereas sacubitril/valsartan-first treatment showed a higher degree of LVEF improvement (∆LVEF 3.6 ± 7.8% vs. 0.7 ± 7.7%, P = 0.002) than ivabradine-first treatment. At the end of follow-up, SBP, LVEF, and left ventricular volume were comparable between two Sequential subgroups. CONCLUSIONS Among patients with HFrEF, simultaneous rather than sequential treatment with sacubitril/valsartan and ivabradine was a better strategy to reduce adverse events and achieve left ventricular reverse remodelling. Ivabradine treatment had a more significant benefit on improving haemodynamic stability, whereas sacubitril/valsartan treatment showed a more significant effect on improving LVEF.
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Affiliation(s)
- Ying‐Hsiang Lee
- Cardiovascular CenterMacKay Memorial HospitalTaipeiTaiwan
- Department of MedicineMackay Medical CollegeNew TaipeiTaiwan
| | - Po‐Lin Lin
- Department of MedicineMackay Medical CollegeNew TaipeiTaiwan
- Division of Cardiology, Department of Internal MedicineHsinchu MacKay Memorial HospitalHsinchuTaiwan
| | - Wei‐Ru Chiou
- Department of MedicineMackay Medical CollegeNew TaipeiTaiwan
- Division of CardiologyTaitung MacKay Memorial HospitalTaitungTaiwan
| | - Jin‐Long Huang
- Cardiovascular CenterTaichung Veterans General HospitalTaichungTaiwan
- Faculty of Medicine, School of MedicineNational Yang‐Ming UniversityTaipeiTaiwan
| | - Wen‐Yu Lin
- Division of Cardiology, Department of MedicineTri‐Service General Hospital, National Defense Medical CenterTaipeiTaiwan
| | - Chia‐Te Liao
- Division of CardiologyChi‐Mei Medical CenterTainanTaiwan
| | - Fa‐Po Chung
- Faculty of Medicine, School of MedicineNational Yang‐Ming UniversityTaipeiTaiwan
- Division of Cardiology, Department of MedicineTaipei Veterans General HospitalTaipeiTaiwan
| | - Huai‐Wen Liang
- Division of Cardiology, Department of Internal MedicineE‐Da Hospital; I‐Shou UniversityKaohsiungTaiwan
| | - Chien‐Yi Hsu
- Faculty of Medicine, School of MedicineNational Yang‐Ming UniversityTaipeiTaiwan
- Division of Cardiology and Cardiovascular Research Center, Department of Internal MedicineTaipei Medical University HospitalTaipeiTaiwan
- Taipei Heart Institute, Division of Cardiology, Department of Internal Medicine, School of Medicine, College of MedicineTaipei Medical UniversityTaipeiTaiwan
| | - Hung‐Yu Chang
- Faculty of Medicine, School of MedicineNational Yang‐Ming UniversityTaipeiTaiwan
- Heart CenterCheng Hsin General HospitalNo. 45 Cheng‐Hsin Street, 112 BeitouTaipeiTaiwan
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13
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McDonald M, Virani S, Chan M, Ducharme A, Ezekowitz JA, Giannetti N, Heckman GA, Howlett JG, Koshman SL, Lepage S, Mielniczuk L, Moe GW, O'Meara E, Swiggum E, Toma M, Zieroth S, Anderson K, Bray SA, Clarke B, Cohen-Solal A, D'Astous M, Davis M, De S, Grant ADM, Grzeslo A, Heshka J, Keen S, Kouz S, Lee D, Masoudi FA, McKelvie R, Parent MC, Poon S, Rajda M, Sharma A, Siatecki K, Storm K, Sussex B, Van Spall H, Yip AMC. CCS/CHFS Heart Failure Guidelines Update: Defining a New Pharmacologic Standard of Care for Heart Failure With Reduced Ejection Fraction. Can J Cardiol 2021; 37:531-546. [PMID: 33827756 DOI: 10.1016/j.cjca.2021.01.017] [Citation(s) in RCA: 173] [Impact Index Per Article: 43.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 01/15/2021] [Accepted: 01/16/2021] [Indexed: 12/14/2022] Open
Abstract
In this update of the Canadian Cardiovascular Society heart failure (HF) guidelines, we provide comprehensive recommendations and practical tips for the pharmacologic management of patients with HF with reduced ejection fraction (HFrEF). Since the 2017 comprehensive update of the Canadian Cardiovascular Society guidelines for the management of HF, substantial new evidence has emerged that has informed the care of these patients. In particular, we focus on the role of novel pharmacologic therapies for HFrEF including angiotensin receptor-neprilysin inhibitors, sinus node inhibitors, sodium glucose transport 2 inhibitors, and soluble guanylate cyclase stimulators in conjunction with other long established HFrEF therapies. Updated recommendations are also provided in the context of the clinical setting for which each of these agents might be prescribed; the potential value of each therapy is reviewed, where relevant, for chronic HF, new onset HF, and for HF hospitalization. We define a new standard of pharmacologic care for HFrEF that incorporates 4 key therapeutic drug classes as standard therapy for most patients: an angiotensin receptor-neprilysin inhibitor (as first-line therapy or after angiotensin converting enzyme inhibitor/angiotensin receptor blocker titration); a β-blocker; a mineralocorticoid receptor antagonist; and a sodium glucose transport 2 inhibitor. Additionally, many patients with HFrEF will have clinical characteristics for which we recommended other key therapies to improve HF outcomes, including sinus node inhibitors, soluble guanylate cyclase stimulators, hydralazine/nitrates in combination, and/or digoxin. Finally, an approach to management that integrates prioritized pharmacologic with nonpharmacologic and invasive therapies after a diagnosis of HFrEF is highlighted.
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Affiliation(s)
- Michael McDonald
- Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada.
| | - Sean Virani
- University of British Columbia, Vancouver, British Columbia, Canada
| | - Michael Chan
- University of Alberta, Royal Alexandra Hospital, Edmonton, Alberta, Canada
| | - Anique Ducharme
- Institut de Cardiologie de Montréal, Université de Montréal, Montréal, Québec, Canada
| | | | | | - George A Heckman
- Schlegel-University of Waterloo Research Institute for Aging, University of Waterloo, Waterloo, Ontario, Canada
| | - Jonathan G Howlett
- Cumming School of Medicine, University of Calgary, Libin Cardiovascular Institute, Calgary, Alberta, Canada
| | | | - Serge Lepage
- Université de Sherbrooke, Sherbrooke, Québec, Canada
| | - Lisa Mielniczuk
- University of Ottawa Heart Institute, Ottawa, Ontario, Canada
| | - Gordon W Moe
- St Michael's Hospital, University of Toronto, Toronto, Ontario, Canada
| | - Eileen O'Meara
- Institut de Cardiologie de Montréal, Université de Montréal, Montréal, Québec, Canada
| | - Elizabeth Swiggum
- Royal Jubilee Hospital, University of British Columbia, Victoria, British Columbia, Canada
| | - Mustafa Toma
- University of British Columbia, Vancouver, British Columbia, Canada
| | | | - Kim Anderson
- Dalhousie University QEII Health Sciences Centre, Halifax, Nova Scotia, Canada
| | - Sharon A Bray
- Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada
| | - Brian Clarke
- Cumming School of Medicine, University of Calgary, Libin Cardiovascular Institute, Calgary, Alberta, Canada
| | | | | | - Margot Davis
- University of British Columbia, Vancouver, British Columbia, Canada
| | - Sabe De
- London Health Sciences, Western University, London, Ontario, Canada
| | - Andrew D M Grant
- Cumming School of Medicine, University of Calgary, Libin Cardiovascular Institute, Calgary, Alberta, Canada
| | - Adam Grzeslo
- Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Jodi Heshka
- Ottawa Cardiovascular Centre, Ottawa, Ontario, Canada
| | - Sabina Keen
- Hamilton Health Sciences, McMaster University, Hamilton, Ontario, Canada
| | - Simon Kouz
- Centre Intégré de Santé et de Services Sociaux de Lanaudière - Centre Hospitalier de Lanaudière, Joliette, Québec, Canada
| | - Douglas Lee
- Peter Munk Cardiac Centre, University Health Network, Toronto, Ontario, Canada
| | | | - Robert McKelvie
- St Joseph's Health Care, Western University, London, Ontario, Canada
| | - Marie-Claude Parent
- Institut de Cardiologie de Montréal, Université de Montréal, Montréal, Québec, Canada
| | - Stephanie Poon
- Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada
| | - Miroslaw Rajda
- Dalhousie University QEII Health Sciences Centre, Halifax, Nova Scotia, Canada
| | | | | | - Kate Storm
- Dalhousie University QEII Health Sciences Centre, Halifax, Nova Scotia, Canada
| | - Bruce Sussex
- Memorial University, St John's, Newfoundland, Canada
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Wan H, Huang T, Zhang H, Wu Q. Effects of Ivabradine on Cardiac Remodeling in Patients With Stable Symptomatic Heart Failure: A Systematic Review and Meta-analysis. Clin Ther 2020; 42:2289-2297.e0. [PMID: 33160681 DOI: 10.1016/j.clinthera.2020.10.005] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2020] [Revised: 09/30/2020] [Accepted: 09/16/2020] [Indexed: 10/23/2022]
Abstract
PURPOSE Ivabradine reduces heart rate (HR) in patients with heart failure (HF). However, its effect on cardiac remodeling is not obvious. The goal of this study was to explore the extra effect of ivabradine on cardiac remodeling in patients with HF. METHODS We searched PubMed from database inception to January 31, 2020, Cochrane and Embase from database inception to February 2, 2020, and Web of Science and ClinicalTrials.gov from database inception to February 3, 2020, for randomized controlled trials on ivabradine treatments in patients with stable symptomatic HF, left ventricular ejection fraction (LVEF) < 45%, and resting HR ≥ 60 beats/min in sinus rhythm. We pooled the mean differences (MDs) or standardized mean differences and their 95% CIs. An inverse variance was used to combine data. Fixed- or random-effects models were used to outline the outcomes based on heterogeneity levels. We assessed the heterogeneity among studies according to the I2 statistic. A sensitivity analysis for select results was performed to assess the robustness of the outcomes. FINDINGS Of 2277 trials, 9 trials fulfilled the inclusion criteria. A total of 1523 patients were enrolled in 9 studies. There were 796 participants in the ivabradine group and 727 participants in the control group. The duration of follow-up ranged from 6 weeks to 19.6 months. The mean (SD) age of the participants was 59.7 (11.2) years, and 1187 participants (77.9%) were men. Therapy with ivabradine was related to reversing cardiac remodeling with a significant increase in LVEF (MD = 3.04%; 95% CI, 2.07%-4.00%; p < 0.001), decrease in the left ventricular end-systolic volume index (LVESVI) (MD = -7.30 mL/m2; 95% CI, -12.94 to -1.66 mL/m2; p = 0.01), and reduction in the left ventricular end-diastolic volume index (LVEDVI) (MD = -7.27 mL/m2; 95% CI, -14.04 to -0.50 mL/m2; p = 0.04). In the subgroup of enrolled patients with a resting HR of ≥70 beats/min, greater progress in LVEF was detected in the ivabradine group (MD = 3.60%; 95% CI, 2.40%-4.81%; p < 0.001), and a higher improvement in LVESVI was identified in the ivabradine group (MD = -11.06 mL/m2; 95% CI, -21.15 to -0.98 mL/m2; p = 0.03). IMPLICATIONS In patients with stable symptomatic HF, LVEF <45%, and resting HR ≥ 60 beats/min in sinus rhythm, ivabradine use was associated with reversing cardiac remodeling with a significant increase in LVEF, a decrease in LVESVI, and a reduction in LVEDVI.
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Affiliation(s)
- Hongbing Wan
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
| | - Tieqiu Huang
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Hongzhou Zhang
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China
| | - Qinghua Wu
- Department of Cardiology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, China.
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15
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Cautela J, Tartiere J, Cohen-Solal A, Bellemain‐Appaix A, Theron A, Tibi T, Januzzi JL, Roubille F, Girerd N. Management of low blood pressure in ambulatory heart failure with reduced ejection fraction patients. Eur J Heart Fail 2020; 22:1357-1365. [PMID: 32353213 PMCID: PMC7540603 DOI: 10.1002/ejhf.1835] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 04/06/2020] [Accepted: 04/08/2020] [Indexed: 12/11/2022] Open
Abstract
Low blood pressure is common in patients with heart failure and reduced ejection fraction (HFrEF). While spontaneous hypotension predicts risk in HFrEF, there is only limited evidence regarding the relationship between hypotension observed during heart failure (HF) drug titration and outcome. Nevertheless, hypotension (especially orthostatic hypotension) is an important factor limiting the titration of HFrEF treatments in routine practice. In patients with signs of shock and/or severe congestion, hospitalization is advised. However, in the very frequent cases of non-severe and asymptomatic hypotension observed while taking drugs with a class I indication in HFrEF, European and US guidelines recommend maintaining the same drug dosage. In instances of symptomatic or severe persistent hypotension (systolic blood pressure < 90 mmHg), it is recommended to first decrease blood pressure reducing drugs not indicated in HFrEF as well as the loop diuretic dose in the absence of associated signs of congestion. Unless the management of hypotension appears urgent, a HF specialist should then be sought rather than stopping or decreasing drugs with a class I indication in HFrEF. If symptoms or severe hypotension persist, no recommendations exist. Our HF group reviewed available evidence and proposes certain steps to follow in such situations in order to improve the pharmacological management of these patients.
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Affiliation(s)
- Jennifer Cautela
- Heart Failure and Valvular Heart Diseases Unit, Department of CardiologyMediterranean University Cardio‐Oncology Center (MEDI‐CO Center), Hôpital Nord, Aix‐Marseille I UniversityMarseilleFrance
| | | | - Alain Cohen-Solal
- CUMR‐S 942 MASCOTParis University, Cardiology Department, Hôpital Lariboisière, Assistance Publique Hôpitaux de ParisParisFrance
| | | | - Alexis Theron
- Cardio‐Thoracic Surgery DepartmentHôpital de la TimoneMarseilleFrance
| | - Thierry Tibi
- Cardiology DepartmentCentre Hospitalier de CannesCannesFrance
| | - James L. Januzzi
- Cardiology DivisionMassachusetts General Hospital, Baim Institute for Clinical Research, Harvard Medical SchoolBostonMAUSA
| | - François Roubille
- PhyMedExp, Université de Montpellier, INSERM, CNRS, Cardiology Department, CHU de MontpellierFrance
| | - Nicolas Girerd
- Faculté de MédecineUniversité de Lorraine, Centre d'Investigations Cliniques Plurithématique 1433, Institut Lorrain du Cœur et des Vaisseaux, Vandoeuvre les Nancy France Groupe choc, INSERM U1116Vandoeuvre les NancyFrance
- F‐CRIN INI‐CRCT (Cardiovascular and Renal Clinical Trialists)NancyFrance
- Cardiology DepartmentInstitut Lorrain du Cœur et des Vaisseaux, CHRU NancyNancyFrance
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Liang B, Zhao YX, Zhang XX, Liao HL, Gu N. Reappraisal on pharmacological and mechanical treatments of heart failure. Cardiovasc Diabetol 2020; 19:55. [PMID: 32375806 PMCID: PMC7202267 DOI: 10.1186/s12933-020-01024-5] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Accepted: 04/25/2020] [Indexed: 02/07/2023] Open
Abstract
Heart failure (HF) is a highly frequent disorder with considerable morbidity, hospitalization, and mortality; thus, it invariably places pressure on clinical and public health systems in the modern world. There have been notable advances in the definition, diagnosis, and treatment of HF, and newly developed agents and devices have been widely adopted in clinical practice. Here, this review first summarizes the current emerging therapeutic agents, including pharmacotherapy, device-based therapy, and the treatment of some common comorbidities, to improve the prognosis of HF patients. Then, we discuss and point out the commonalities and areas for improvement in current clinical studies of HF. Finally, we highlight the gaps in HF research. We are looking forward to a bright future with reduced morbidity and mortality from HF.
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Affiliation(s)
- Bo Liang
- Nanjing University of Chinese Medicine, Nanjing, China
| | - Yu-Xiu Zhao
- Hospital (T.C.M.) Affiliated to Southwest Medical University, Luzhou, China
| | | | - Hui-Ling Liao
- Hospital (T.C.M.) Affiliated to Southwest Medical University, Luzhou, China
- College of Integrated Traditional Chinese and Western Medicine, Southwest Medical University, Luzhou, China
| | - Ning Gu
- Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing, China.
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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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18
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Optimization of Heart Failure Treatment by Heart Rate Reduction. INTERNATIONAL JOURNAL OF HEART FAILURE 2020; 2:1-11. [PMID: 36263079 PMCID: PMC9536732 DOI: 10.36628/ijhf.2019.0009] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 11/12/2019] [Indexed: 11/18/2022]
Abstract
Heart failure (HF) treatment should be optimized in addition to guideline-directed and recommended drugs to achieve an appropriate heart rate (i.e. 50−60 bpm) by ivabradine in patients with a heart rate >70 bpm in sinus rhythm and with an ejection fraction ≤35%. Heart rate reduction was to reduce cardiovascular death and HF hospitalization dependent on baseline resting heart rate. In particular in patients at a heart rate >75 bpm, a reduction in cardiovascular death, all-cause death, HF death, HF hospitalization and all-cause hospitalization has been observed. The optimal heart rate achieved appears to be between 50−60 bpm, if well tolerated as in these patients the lowest event rate is observed on treatment. Heart rate reduction is, therefore, a treatable risk factor in chronic HF. Observational studies support the concept that it is a risk indicator in other cardiovascular and non-cardiovascular conditions. Whether heart rate reduction is also modifying risk in other conditions than chronic HF should be explored in prospective clinical trials.
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Affiliation(s)
- Edimar Alcides Bocchi
- Heart Failure Team, Heart Institute (Incor) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | - Vera Maria Cury Salemi
- Heart Failure Team, Heart Institute (Incor) do Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
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20
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Lopatin YM, Cowie MR, Grebennikova AA, Sisakian HS, Pagava ZM, Hayrapetyan HG, Abdullaev TA, Voronkov LG, Chesnikova AI, Tseluyko VI, Tarlovskaya EI, Dadashova GM, Berkinbaev SF, Glezer MG, Koziolova NA, Rakisheva AG, Kipiani ZV, Kurlyanskaya AK. Optimization of heart rate lowering therapy in hospitalized patients with heart failure: Insights from the Optimize Heart Failure Care Program. Int J Cardiol 2018; 260:113-117. [PMID: 29622423 DOI: 10.1016/j.ijcard.2017.12.093] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/11/2017] [Revised: 12/18/2017] [Accepted: 12/22/2017] [Indexed: 12/28/2022]
Abstract
BACKGROUND Hospitalization is an opportunity to optimize heart failure (HF) therapy. As optimal treatment for hospitalized HF patients in sinus rhythm with heart rate≥70bpm is unclear, we investigated the impact of combined beta-blocker (BB) and ivabradine versus BBs alone on short and longer term mortality and rehospitalization. METHODS AND RESULTS A retrospective analysis was performed on 370 hospitalized HF patients with heart rate≥70bpm (150 BB+ivabradine, 220 BB alone) in the Optimize Heart Failure Care Program in Armenia, Azerbaijan, Belarus, Georgia, Kazakhstan, Russia, Ukraine, and Uzbekistan, from October 2015 to April 2016. RESULTS At 1month, 3months, 6months and 12months, there were fewer deaths, HF hospitalizations and overall hospitalizations in patients on BB+ivabradine vs BBs alone. At 12months, all-cause mortality or HF hospitalization was significantly lower with BB+ivabradine than BBs (adjusted hazard ratio [HR] 0.45 (95% confidence interval [CI] 0.32-0.64, P<0.0001). Significantly greater improvement was seen in quality of life (QOL) from admission to 12months with BB+ivabradine vs BBs alone (P=0.0001). With BB+ivabradine, significantly more patients achieved ≥50% target doses of BBs at 12months than on admission (82.0% vs 66.6%, P=0.0001), but the effect was non-significant with BBs alone. CONCLUSIONS Heart rate lowering therapy with BB+ivabradine started in hospitalized HF patients (heart rate≥70bpm) is associated with reduced overall mortality and re-hospitalization over the subsequent 12months. A prospective randomized trial is needed to confirm the advantages of this strategy.
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Affiliation(s)
- Yuri M Lopatin
- Volgograd State Medical University, Volgograd Regional Cardiology Centre, 106, Universitetsky Prospect, Volgograd 400008, Russian Federation.
| | - Martin R Cowie
- Imperial College London (Royal Brompton Hospital), Sydney Street, London SW3 6HP, United Kingdom.
| | - Anna A Grebennikova
- Volgograd State Medical University, Volgograd Regional Cardiology Centre, 106, Universitetsky Prospect, Volgograd 400008, Russian Federation
| | - Hamayak S Sisakian
- University State Hospital 1, Yerevan State Medical University, 2, Koryun Street, Yerevan 375025, Armenia
| | - Zurab M Pagava
- Centre of Vascular and Heart Diseases, 5, Lubliana Street, Tbilisi, Georgia
| | | | | | - Leonid G Voronkov
- National Scientific Center Strazhesko Institute of Cardiology, National Academy of Medical Sciences, 5, Narodnogo Opolchenia Street, Kyiv 03680, Ukraine
| | - Anna I Chesnikova
- Rostov State Medical University, 29, Nahichevansky Avenue, Rostov-on-Don 344022, Russian Federation
| | - Vira I Tseluyko
- Kharkiv Medical Academy of Postgraduate Education, 58, Korchahintsiv Street, Kharkiv 61176, Ukraine
| | - Ekaterina I Tarlovskaya
- Nizhny Novgorod State Medical Academy, 10/1, Minin & Pozharsky Square, Nizhny Novgorod 603950, Russian Federation
| | - Gülnaz M Dadashova
- Scientific Research Institute of Cardiology, 316, Tbilisi Avenue, Baku, AZ1012, Azerbaijan
| | - Salim F Berkinbaev
- Scientific Research Institute of Cardiology and Internal Diseases, 120, Aiteke Bi Street, Almaty 050000, Kazakhstan
| | - Maria G Glezer
- I.M. Sechenov First Moscow State Medical University, 2, Bolshaya Pirogovskaya Street, Moscow 119991, Russian Federation
| | - Natalia A Koziolova
- Perm State Medical Academy, 39, Petropavlovskaya v Street, Perm 614000, Russian Federation
| | - Amina G Rakisheva
- Scientific Research Institute of Cardiology and Internal Diseases, 120, Aiteke Bi Street, Almaty 050000, Kazakhstan
| | | | - Alena K Kurlyanskaya
- Republican Scientific and Practical Centre of Cardiology, 110B, R. Luxemburg Street, Minsk 220036, Belarus
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21
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Vitale C, Ilaria S, Rosano GM. Pharmacological Interventions Effective in Improving Exercise Capacity in Heart Failure. Card Fail Rev 2018; 4:25-27. [PMID: 29892472 DOI: 10.15420/cfr.2018:8:2] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
Abstract
Heart failure (HF) is characterised by exercise intolerance, which substantially impairs quality of life (QOL) and prognosis. The aim of this review is to summarise the state of the art on pharmacological interventions that are able to improve exercise capacity in HF. Ivabradine, trimetazidine and intravenous iron are the only drugs included in the European Society of Cardiology HF guidelines that have consistently been shown to positively affect functional capacity in HF. The beneficial effects on HF symptoms, physical performance and QOL using these pharmacological approaches are described.
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Affiliation(s)
- Cristiana Vitale
- Centre for Clinical and Basic Research, Department of Medical Sciences, IRCCS San Raffaele Pisana Rome, Italy
| | - Spoletini Ilaria
- Centre for Clinical and Basic Research, Department of Medical Sciences, IRCCS San Raffaele Pisana Rome, Italy
| | - Giuseppe Mc Rosano
- Centre for Clinical and Basic Research, Department of Medical Sciences, IRCCS San Raffaele Pisana Rome, Italy
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22
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Heart rate manipulation in dilated cardiomyopathy: Assessing the role of Ivabradine. Indian Heart J 2017; 70:246-251. [PMID: 29716702 PMCID: PMC5993928 DOI: 10.1016/j.ihj.2017.08.009] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2017] [Revised: 07/27/2017] [Accepted: 08/10/2017] [Indexed: 01/06/2023] Open
Abstract
Background Heart rate (HR) reduction is of benefit in chronic heart failure (HF). The effect of heart rate reduction using Ivabradine on various echocardiographic parameters in dilated cardiomyopathy has been less investigated. Methods Of 187 patients with HF (DCM, NYHA II–IV, baseline HR > 70/min), 125 patients were randomized to standard therapy (beta blockers, ACEI, diuretics, n = 62) or add-on Ivabradine (titrated to maximum 7.5 mg BD, n = 63). Beta-blockers were titrated in both the groups. Results At 3 months both groups had improvement in NYHA class, 6 min walk test, Minnesota Living With Heart Failure (MLWHF) scores and fall in BNP, however the magnitude of change was greater in Ivabradine group. Those on Ivabradine also had lower LV volumes, higher LVEF (28.8 ± 3.6 vs 27.2 ± 0.5, p = 0.01) and more favorable LV global strain (11 ± 1.7vs 12.2 ± 1.1, p = <0.001), MPI (0.72 ± 0.1 vs 0.6 ± 0.1, p = <0.001), LV mass (115.2 ± 30 vs 131.4 ± 35, p = 0.007), LV wall stress (219.8 ± 46 vs 238 ± 54) and calculated LV work (366 ± 101 vs 401 ± 102, p = 0.05). The benefit of Ivabradine was sustained at 6 months follow up. The % change in HR was significantly higher in Ivabradine group (−32.2% vs −19.3%, p = 0.001) with no difference in blood pressure. Resting HR < 70/min was achieved in 96.8% vs 27.9%, respectively in the two groups. Conclusion Addition of Ivabradine to standard therapy in patients with DCM and symptomatic HF and targeting a heart rate < 70/min improves symptoms, quality of life and various echocardiographic parameters.
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23
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Anantha Narayanan M, Reddy YNV, Baskaran J, Deshmukh A, Benditt DG, Raveendran G. Ivabradine in the treatment of systolic heart failure - A systematic review and meta-analysis. World J Cardiol 2017; 9:182-190. [PMID: 28289533 PMCID: PMC5329746 DOI: 10.4330/wjc.v9.i2.182] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2016] [Revised: 01/07/2017] [Accepted: 01/16/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To perform a systematic-review and meta-analysis to compare outcomes of ivabradine combined with beta-blocker to beta-blocker alone in heart failure with reduced ejection fraction (HFrEF). METHODS We searched PubMed, Cochrane, EMBASE, CINAHL and Web of Science for trials comparing ivabradine + beta-blocker to beta-blocker alone in HFrEF. We performed a systematic-review and meta-analysis of published literature. Primary end-point was combined end point of cardiac death and hospitalization for heart failure. RESULTS Six studies with 17671 patients were included. Mean follow-up was 8.7 ± 7.9 mo. Combined end-point of heart failure readmission and cardiovascular death was better in ivabradine + beta-blocker group compared to beta-blocker alone (RR: 0.93, 95%CI: 0.79-1.09, P = 0.354). Mean difference (MD) in heart rate was higher in the ivabradine + beta-blocker group (MD: 6.14, 95%CI: 3.80-8.48, P < 0.001). There was no difference in all cause mortality (RR: 0.98, 95%CI: 0.89-1.07, P = 0.609), cardiovascular mortality (RR: 0.99, 95%CI: 0.86-1.15, P = 0.908) or heart failure hospitalization (RR: 0.87, 95%CI: 0.68-1.11, P = 0.271). CONCLUSION From the available clinical trials, ivabradine + beta-blocker resulted in a significantly greater reduction in HR coupled with improvement in combined end-point of heart failure readmission and cardiovascular death but with no improvement in all cause or cardiovascular mortality. Given the limited evidence, further randomized controlled trials are essential before widespread clinical application of ivabradine + beta-blocker is advocated for HFrEF.
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Affiliation(s)
- Mahesh Anantha Narayanan
- Mahesh Anantha Narayanan, Janani Baskaran, David G Benditt, Ganesh Raveendran, Division of Cardiovascular Diseases, University of Minnesota Medical Center, Minneapolis, MN 55455, United States
| | - Yogesh N V Reddy
- Mahesh Anantha Narayanan, Janani Baskaran, David G Benditt, Ganesh Raveendran, Division of Cardiovascular Diseases, University of Minnesota Medical Center, Minneapolis, MN 55455, United States
| | - Janani Baskaran
- Mahesh Anantha Narayanan, Janani Baskaran, David G Benditt, Ganesh Raveendran, Division of Cardiovascular Diseases, University of Minnesota Medical Center, Minneapolis, MN 55455, United States
| | - Abhishek Deshmukh
- Mahesh Anantha Narayanan, Janani Baskaran, David G Benditt, Ganesh Raveendran, Division of Cardiovascular Diseases, University of Minnesota Medical Center, Minneapolis, MN 55455, United States
| | - David G Benditt
- Mahesh Anantha Narayanan, Janani Baskaran, David G Benditt, Ganesh Raveendran, Division of Cardiovascular Diseases, University of Minnesota Medical Center, Minneapolis, MN 55455, United States
| | - Ganesh Raveendran
- Mahesh Anantha Narayanan, Janani Baskaran, David G Benditt, Ganesh Raveendran, Division of Cardiovascular Diseases, University of Minnesota Medical Center, Minneapolis, MN 55455, United States
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24
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Iellamo F, Werdan K, Narkiewicz K, Rosano G, Volterrani M. Practical Applications for Single Pill Combinations in the Cardiovascular Continuum. Card Fail Rev 2017; 3:40-45. [PMID: 28785474 DOI: 10.15420/cfr.2017:5:1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Despite the availability of new drugs and devices, the treatment of cardiovascular disease remains suboptimal. Single-pill combination therapy offers a number of potential advantages. It can combine different classes of drugs to increase efficacy while mitigating the risks of treatment-related adverse events, reduce pill burden, lower medical cost, and improve patient adherence. Furthermore, in hypertension, single pill combinations include standard to lower doses of each drug than would be necessary to achieve goals with monotherapy, which may explain their better tolerability compared with higher dose monotherapy. Combination therapy is now established in the treatment of hypertension. In ischaemic heart disease, the concept of a preventative polypill has been studied, but its benefits have not been established conclusively. However, the combination of ivabradine and beta-blockers has proven efficacy in patients with stable angina pectoris. This combination has also demonstrated benefits in patients with chronic heart failure.
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Affiliation(s)
- Ferdinando Iellamo
- Dipartimento di Scienze Mediche, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Pisana, Rome, Italy.,Department of Clinical Science and Translational Medicine, University Tor Vergata, Rome, Italy
| | - Karl Werdan
- Department of Medicine III, University Hospital Halle (Saale), Martin Luther University Halle-Wittenberg, Halle, Germany
| | - Krzysztof Narkiewicz
- Department of Hypertension and Diabetology Medical University of Gdansk, Gdansk, Poland
| | - Giuseppe Rosano
- Dipartimento di Scienze Mediche, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Pisana, Rome, Italy.,St George's University of London, London, UK
| | - Maurizio Volterrani
- Dipartimento di Scienze Mediche, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Pisana, Rome, Italy
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Abstract
There has been much research linking elevated resting heart rate to cardiovascular morbidity and mortality. Based on these findings, a lower resting heart rate would be of theoretical benefit in patients with cardiovascular disease. From a pathophysiologic perspective, a lower resting heart rate would be of particular benefit in patients with ischemic heart disease and/or heart failure. Although β-blockers and nondihydropyridine calcium channel blockers are effective at lowering heart rate, they have many other pharmacologic effects that may not be desirable in some patients, such as negative inotropy. Ivabradine is a drug designed to lower heart rate without any other demonstrable pharmacologic effects; in other words, a pure heart rate-lowering drug. It functions by blocking the hyperpolarization-activated cyclic nucleotide gated channels (f-channels) specific for the sinoatrial node and disrupting If ion current flow. This effectively prolongs diastolic depolarization and slows firing in the sinoatrial node, which lowers heart rate. The effects of ivabradine are most pronounced at higher heart rates (use-dependence), which is important in minimizing the development of symptomatic bradycardia. Clinical trials have demonstrated ivabradine to be an effective antianginal drug both alone and in combination with β-blocker therapy, although it has not been shown to produce a demonstrable effect on reducing major adverse cardiovascular events. In patients with heart failure, ivabradine has demonstrated many hemodynamic benefits, but its effect on clinical outcomes have been mixed and dependent on baseline heart rate, ie, the drug may be of benefit with higher baseline heart rates, but detrimental with low baseline heart rates. The adverse effects of ivabradine are not uncommon, but are rarely severe and include visual disturbances, bradycardia, and atrial fibrillation. Although ivabradine is a very interesting new agent, its variable benefits in large-scale clinical trials leave its exact place in therapy still somewhat nebulous. Unanswered questions include which patient populations would benefit most from this drug, and which concomitant medications would produce the best clinical outcomes when used with ivabradine.
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26
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Tsutsui H, Momomura S, Yamashina A, Ogawa H, Shimokawa H, Kihara Y, Saito Y, Hagiwara N, Ito H, Ako J, Inomata T, Tanaka T, Kawasaki Y. Heart Rate Control With If Inhibitor, Ivabradine, in Japanese Patients With Chronic Heart Failure - A Randomized, Double-Blind, Placebo-Controlled Phase II Study. Circ J 2016; 80:668-76. [PMID: 26763489 DOI: 10.1253/circj.cj-15-1112] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Elevated heart rate (HR) is an independent risk factor for cardiovascular outcomes in various cardiac diseases, including heart failure (HF). METHODS AND RESULTS Randomized placebo-controlled study was conducted to evaluate the effects of ivabradine, an Ifinhibitor, on the resting HR in 126 Japanese symptomatic HF patients with left ventricular ejection fraction ≤35%, resting HR ≥75 beats/min in sinus rhythm, and stable, optimal background treatment. Patients were randomly allocated into 3 groups: placebo; starting dose of ivabradine 2.5 mg twice daily (BID; 2.5 mg group); 5 mg BID group. The dose was increased up to 7.5 mg BID according to dose-adjustment criteria. After the 6-week treatment, the reductions in resting HR were significant in both the 2.5-mg (16.6±8.1 beats/min) and 5-mg (16.4±9.6 beats/min) groups (P<0.0001 for both groups) compared with placebo (1.7±8.7 beats/min). The most frequent side effect of ivabradine was phosphenes, but all were mild. Treatment was discontinued in 1 patient due to HF in the 5 mg group. CONCLUSIONS Ivabradine starting at 2.5 or 5 mg BID effectively reduced resting HR in Japanese HF patients. Ivabradine at the starting dose of 2.5 mg BID could be safer than 5 mg BID. (Circ J 2016; 80: 668-676).
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Affiliation(s)
- Hiroyuki Tsutsui
- Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine
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27
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Milinković I, Rosano G, Lopatin Y, Seferović PM. The Role of Ivabradine and Trimetazidine in the New ESC HF Guidelines. Card Fail Rev 2016; 2:123-129. [PMID: 28785466 DOI: 10.15420/cfr.2016:13:1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
The prevalence of heart failure (HF) is increasing, representing a major cause of death and disability, and a growing financial burden on healthcare systems. Despite the use of effective treatments with both drugs and devices, mortality remains high. There is therefore a need for new and effective therapeutic agents. Ivabradine is a specific sinus node inhibiting agent that was approved in 2005 by the European Medicines Agency, alone or in combination with a beta-blocker. Trimetazidine is a cytoprotective, anti-ischaemic agent established in the treatment of angina pectoris. In the 2012 European Society of Cardiology (ESC) guidelines for diagnosis and treatment of HF, ivabradine was recommended in symptomatic HF patients who are in sinus rhythm with left ventricular ejection fraction ≤35 % and heart rate higher than 70 beats per minute, despite optimal medical therapy, including maximally tolerated dose of beta-blocker. The role of trimetazidine in this setting was not mentioned. In the 2016 ESC guidelines, recommendations for ivabradine are unchanged but trimetazidine is included for the treatment of angina pectoris with HF. This article discusses the need for new therapeutic options in HF and reviews clinical evidence in support of these two therapeutic options.
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Affiliation(s)
- Ivan Milinković
- Department of Cardiology,Clinical Centre of Serbia, Belgrade, Serbia
| | - Giuseppe Rosano
- IRCCS San Raffaele,Rome, Italy.,Cardiovascular and Cell Sciences Institute,St George's University of London, London, UK
| | - Yuri Lopatin
- Volgograd Medical University,Cardiology Centre, Volgograd, Russia
| | - Petar M Seferović
- Department of Cardiology,Clinical Centre of Serbia, Belgrade, Serbia
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28
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Cada DJ, Bindler R, Baker DE. Ivadradine. Hosp Pharm 2015; 50:806-17. [PMID: 26912922 PMCID: PMC4750831 DOI: 10.1310/hpj5009-806] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/26/2024]
Abstract
Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are sent in print and are also available on-line. Monographs can be customized to meet the needs of a facility. A drug class review is now published monthly with The Formulary Monograph Service. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service, call The Formulary at 800-322-4349. The October 2015 monograph topics are sacubitril/valsartan, daclatasvir, sonidegib, alirocumab, and sodium zirconium cyclosilicate. The Safety MUE is on sacubitril/valsartan.
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Affiliation(s)
| | - Ross Bindler
- Drug Information Resident, College of Pharmacy, Washington State University Spokane
| | - Danial E Baker
- Director, Drug Information Center, and Professor of Pharmacy Practice, College of Pharmacy, Washington State University Spokane. The authors indicate no relationships that could be perceived as a conflict of interest
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Pereira-Barretto AC. Cardiac and Hemodynamic Benefits: Mode of Action of Ivabradine in Heart Failure. Adv Ther 2015; 32:906-19. [PMID: 26521191 DOI: 10.1007/s12325-015-0257-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2015] [Indexed: 01/19/2023]
Abstract
Heart failure has seen a number of therapeutic advances in recent years. Despite this, heart failure is still related to increasing rates of morbidity, repeated hospitalizations, and mortality. Ivabradine is a recent treatment option for heart failure. It has a mode of action that includes reduction in heart rate, and leads to improvement in outcomes related to heart failure mortality and morbidity, as demonstrated by the results of the SHIFT trial in patients with systolic heart failure, functional classes II and III on the New York Heart Association classification, and left ventricular ejection fraction ≤ 35%. These results are intriguing since many heart failure drugs reduce heart rate without such benefits, or with quite different effects, making it more difficult to understand the novelty of ivabradine in this setting. Many of the drugs used in heart failure modify heart rate, but most have other pathophysiological effects beyond their chronotropic action, which affect their efficacy in preventing morbidity and mortality outcomes. For instance, heart rate reduction at rest or exercise with ivabradine prolongs diastolic perfusion time, improves coronary blood flow, and increases exercise capacity. Another major difference is the increase in stroke volume observed with ivabradine, which may underlie its beneficial cardiac effects. Finally, there is mounting evidence from both preclinical and clinical studies that ivabradine has an anti-remodeling effect, improving left ventricular structures and functions. All together, these mechanisms have a positive impact on the prognosis of ivabradine-treated patients with heart failure, making a compelling argument for use of ivabradine in combination with other treatments.
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