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Kornder N, Donner-Banzhoff N, Staudt I, Grede N, Becker A, Viniol A. Trials evaluating drug discontinuation: a scoping review sub-analysis focusing on outcomes and research questions. BMC Med Res Methodol 2025; 25:146. [PMID: 40426033 PMCID: PMC12108048 DOI: 10.1186/s12874-025-02597-z] [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: 01/30/2025] [Accepted: 05/15/2025] [Indexed: 05/29/2025] Open
Abstract
BACKGROUND The widespread use of long-term pharmacological treatments for chronic conditions has led to polypharmacy, raising concerns about adverse effects and interactions. Deprescribing, the discontinuation of drugs with unfavorable benefit-risk ratios, is gaining attention. Studies evaluating the discontinuation of drugs have a broad methodological spectrum. The selection of outcomes poses a particular challenge. This scoping review addresses the methodological challenges of outcome selection in RCTs investigating drug discontinuation. METHODS The scoping review includes RCTs that investigated the discontinuation of drugs whose efficacy and/or safety was in doubt. Data on study characteristics, the motivation for evaluating drug discontinuation, the number and type of primary endpoints, and the stated hypotheses were extracted and analyzed. RESULTS We included 103 RCTs. Most studies were from Europe and the USA and mainly investigated antipsychotics/antidepressants, immunosuppressants, steroids and antiepileptics. The discontinuation studies were often conducted due to side effects of the treatment and doubts about the benefits of the drug. The primary endpoints reflected either the course of the disease ("justification of treatment") or the disadvantages of the drug ("justification of withdrawal"). Non-inferiority hypotheses were generally prevalent in justification of treatment studies, while superiority hypotheses were more commonly used in justification of withdrawal studies. However, due to methodological and practical challenges this was not always the case. CONCLUSION We present a framework to choose outcomes and specify hypotheses for discontinuation studies. With regard to this, both key challenges (justification of treatment and justification of withdrawal) must be met.
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Affiliation(s)
- Nele Kornder
- Department of Primary Care, University of Marburg, Karl-Von-Frisch-Straße 4, Marburg, 35043, Germany.
| | - Norbert Donner-Banzhoff
- Department of Primary Care, University of Marburg, Karl-Von-Frisch-Straße 4, Marburg, 35043, Germany
| | - Ina Staudt
- Department of Primary Care, University of Marburg, Karl-Von-Frisch-Straße 4, Marburg, 35043, Germany
| | - Nina Grede
- Department of Primary Care, Goethe University Frankfurt, Theodor-Stern-Kai 7, Frankfurt Am Main, 60590, Germany
| | - Annette Becker
- Department of Primary Care, University of Marburg, Karl-Von-Frisch-Straße 4, Marburg, 35043, Germany
| | - Annika Viniol
- Department of Primary Care, University of Marburg, Karl-Von-Frisch-Straße 4, Marburg, 35043, Germany
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Isath A, Panza JA. Contemporary management of ischemic cardiomyopathy: The synergy of medical, revascularization, and device therapies. Prog Cardiovasc Dis 2025:S0033-0620(25)00045-3. [PMID: 40187673 DOI: 10.1016/j.pcad.2025.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2025] [Accepted: 04/01/2025] [Indexed: 04/07/2025]
Abstract
Ischemic heart disease (IHD) is the leading global cause of death, affecting millions and leading to significant morbidity and mortality. Ischemic cardiomyopathy (ICM), a manifestation of IHD, results in severe left ventricular dysfunction due to coronary artery disease and poses a significant challenge due to the complex pathophysiology, variable clinical presentation, and overall poor prognosis. Recent advances in medical therapy, device interventions, and revascularization techniques offer newfound hope in improving ICM patient outcomes. This article reviews the state-of-the-art management approaches for ICM, emphasizing the importance of personalized treatment plans that integrate the various contemporary therapies to address the multiple mechanisms of disease development and progression. A meticulously tailored treatment approach for each individual patient offers the hope of prolonged survival through the synergy of therapies designed to address the different and complex mechanisms that contribute to their disease process.
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Affiliation(s)
- Ameesh Isath
- Department of Cardiology, Westchester Medical Center and the Department of Medicine, New York Medical College, Valhalla, NY, USA
| | - Julio A Panza
- Department of Cardiology, Westchester Medical Center and the Department of Medicine, New York Medical College, Valhalla, NY, USA.
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Lam PH, Liu K, Ahmed AA, Butler J, Heidenreich PA, Anker MS, Faselis C, Deedwania P, Aronow WS, Kanonidis I, Masson R, Gill GS, Morgan CJ, Arundel C, Allman RM, Wu WC, Fonarow GC, Ahmed A. Digoxin Discontinuation in Patients With HFrEF on Beta-Blockers: Implication for Future 'Knock-Out Trials' in Heart Failure. Am J Med 2025; 138:495-503.e1. [PMID: 39424217 DOI: 10.1016/j.amjmed.2024.10.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Revised: 10/04/2024] [Accepted: 10/06/2024] [Indexed: 10/21/2024]
Abstract
BACKGROUND National heart failure guidelines recommend quadruple therapy with renin-angiotensin system inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and sodium-glucose cotransporter 2 inhibitors for patients with heart failure with reduced ejection fraction (HFrEF), most of whom also receive loop diuretics. However, the guidelines are less clear about the safe approaches to discontinuing older drugs whose decreasing or residual benefit is less well understood. The objective of this study was to examine whether digoxin can be safely discontinued in patients with HFrEF receiving beta-blockers. METHODS In OPTIMIZE-HF, of 2477 patients with HFrEF (EF ≤45%) receiving beta-blockers and digoxin, digoxin was discontinued in 450 patients. We assembled a propensity score-matched cohort of 433 pairs of patients in which digoxin continuation vs. discontinuation groups were balanced on 51 baseline characteristics. Using the same approach, from 992 patients not on beta-blockers, we assembled a matched cohort of 198 pairs of patients also balanced on 51 baseline characteristics. Hazard ratios (HRs) and 95% CIs for 1-year outcomes were estimated. RESULTS Among patients receiving beta-blockers, digoxin discontinuation had no association with the combined endpoint of heart failure readmission or death (HR, 1.01; 95% CI, 0.85-1.19), heart failure readmission (HR, 1.03; 95% CI, 0.85-1.25) or death (HR, 0.91; 95% CI, 0.72-1.14). Respective HRs (95% CIs) among patients not receiving beta-blockers were 1.60 (1.25-2.04), 1.62 (1.18-2.22) and 1.43 (1.08-1.89). CONCLUSIONS Digoxin can be discontinued without increasing the risk of adverse outcomes in patients with HFrEF receiving beta-blockers. Future studies need to examine the residual benefit of older heart failure drugs to ensure their safe discontinuation in patients with HFrEF receiving newer guideline-directed medical therapy.
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Affiliation(s)
- Phillip H Lam
- Veterans Affairs Medical Center, Washington, DC; Georgetown University, Washington, DC; Medstar Washington Hospital Center, Washington, DC
| | - Kevin Liu
- Veterans Affairs Medical Center, Washington, DC; Georgetown University, Washington, DC
| | - Amiya A Ahmed
- Yale University, New Haven, Conn; Veterans Affairs Medical Center, West Haven, Conn
| | - Javed Butler
- Baylor Scott and White Research Institute, Dallas, Tex; University of Mississippi, Jackson, Ms
| | - Paul A Heidenreich
- Veterans Affairs Palo Alto Health Care System, Palo Alto, Calif; Stanford University School of Medicine, Stanford, Calif
| | | | - Charles Faselis
- Veterans Affairs Medical Center, Washington, DC; George Washington University, Washington, DC
| | | | - Wilbert S Aronow
- Westchester Medical Center, Valhalla, NY; New York Medical College, Valhalla, NY
| | | | | | | | | | - Cherinne Arundel
- Veterans Affairs Medical Center, Washington, DC; Georgetown University, Washington, DC; George Washington University, Washington, DC
| | - Richard M Allman
- George Washington University, Washington, DC; University of Alabama at Birmingham, Birmingham, Al; Wake Forest University, Winston-Salem, NC
| | - Wen-Chih Wu
- Veterans Affairs Medical Center, Providence, RI; Brown University, Providence, RI
| | | | - Ali Ahmed
- Veterans Affairs Medical Center, Washington, DC; Georgetown University, Washington, DC; George Washington University, Washington, DC.
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Talha KM, Butler J, Packer M. Consequences of Discontinuing Long-Term Drug Treatment in Patients With Heart Failure and Reduced Ejection Fraction. J Am Coll Cardiol 2024; 84:2215-2232. [PMID: 39453366 DOI: 10.1016/j.jacc.2024.09.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 08/26/2024] [Accepted: 09/06/2024] [Indexed: 10/26/2024]
Abstract
There is uncertainty regarding the clinical effects of discontinuation of drugs for heart failure after long-term use. The withdrawal of long-term treatment can follow 1 of 4 distinct patterns: 1) loss of on-treatment effect with no observed changes following discontinuation (eg, prazosin); 2) attenuation or loss of on-treatment effect with rebound clinical worsening following discontinuation (eg, nitroprusside); 3) persistence of deleterious on-treatment effect followed by clinical worsening after discontinuation (eg, milrinone and flosequinan); and 4) persistence of favorable on-treatment effect followed by clinical worsening after discontinuation (eg, digoxin and sodium-glucose cotransporter 2 inhibitors). Persuasive evidence for persistence of efficacy has been demonstrated for the use of digoxin, diuretic agents, sodium-glucose cotransporter 2 inhibitors, and (to a limited extent) for angiotensin-converting enzyme inhibitors. Available evidence for worsening of clinical status following the withdrawal of neurohormonal antagonists largely consists of observational studies. However, their findings are difficult to interpret because of considerable confounding related to the fact that drugs were withdrawn for clinical reasons, which represented a more important contributor to the poor outcome of these patients than the withdrawal of an effective drug. Nevertheless, the totality of available evidence points to a meaningful clinical deterioration within a few weeks following the withdrawal for most drugs that have been evaluated for the treatment of heart failure. These findings suggests that that our current emphasis on the implementation of foundational drugs needs to include an equally important emphasis to avoid even short-term gaps in treatment.
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Affiliation(s)
- Khawaja M Talha
- Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA
| | - Javed Butler
- Department of Medicine, University of Mississippi Medical Center, Jackson, Mississippi, USA; Baylor Scott and White Research Institute, Dallas, Texas, USA.
| | - Milton Packer
- Baylor Heart and Vascular Institute, Dallas, Texas, USA; Imperial College London, London, United Kingdom.
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Williams KB, Larsson AT, Keller BJ, Chaney KE, Williams RL, Bhunia MM, Draper GM, Jubenville TA, Hudson WA, Moertel CL, Ratner N, Largaespada DA. Pharmacogenomic synthetic lethal screens reveal hidden vulnerabilities and new therapeutic approaches for treatment of NF1-associated tumors. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.03.25.585959. [PMID: 38585724 PMCID: PMC10996510 DOI: 10.1101/2024.03.25.585959] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 04/09/2024]
Abstract
Neurofibromatosis Type 1 (NF1) is a common cancer predisposition syndrome, caused by heterozygous loss of function mutations in the tumor suppressor gene NF1. Individuals with NF1 develop benign tumors of the peripheral nervous system (neurofibromas), originating from the Schwann cell linage after somatic loss of the wild type NF1 allele, some of which progress further to malignant peripheral nerve sheath tumors (MPNST). There is only one FDA approved targeted therapy for symptomatic plexiform neurofibromas and none approved for MPNST. The genetic basis of NF1 syndrome makes associated tumors ideal for using synthetic drug sensitivity approaches to uncover therapeutic vulnerabilities. We developed a drug discovery pipeline to identify therapeutics for NF1-related tumors using isogeneic pairs of NF1-proficient and deficient immortalized human Schwann cells. We utilized these in a large-scale high throughput screen (HTS) for drugs that preferentially kill NF1-deficient cells, through which we identified 23 compounds capable of killing NF1-deficient Schwann cells with selectivity. Multiple hits from this screen clustered into classes defined by method of action. Four clinically interesting drugs from these classes were tested in vivo using both a genetically engineered mouse model of high-grade peripheral nerve sheath tumors and human MPNST xenografts. All drugs tested showed single agent efficacy in these models as well as significant synergy when used in combination with the MEK inhibitor Selumetinib. This HTS platform yielded novel therapeutically relevant compounds for the treatment of NF1-associated tumors and can serve as a tool to rapidly evaluate new compounds and combinations in the future.
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Affiliation(s)
- Kyle B Williams
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Alex T Larsson
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Bryant J Keller
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Katherine E Chaney
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45229-0713, USA
| | - Rory L Williams
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Minu M Bhunia
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
- Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA
| | - Garrett M Draper
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Tyler A Jubenville
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Wendy A Hudson
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Christopher L Moertel
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
| | - Nancy Ratner
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45229-0713, USA
| | - David A Largaespada
- Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
- Department of Genetics, Cell Biology and Development, University of Minnesota, Twin Cities, Minneapolis, Minnesota 55455, USA
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Hattori Y, Hattori K, Ishii K, Kobayashi M. Challenging and target-based shifting strategies for heart failure treatment: An update from the last decades. Biochem Pharmacol 2024; 224:116232. [PMID: 38648905 DOI: 10.1016/j.bcp.2024.116232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2024] [Revised: 03/31/2024] [Accepted: 04/19/2024] [Indexed: 04/25/2024]
Abstract
Heart failure (HF) is a major global health problem afflicting millions worldwide. Despite the significant advances in therapies and prevention, HF still carries very high morbidity and mortality, requiring enormous healthcare-related expenditure, and the search for new weapons goes on. Following initial treatment strategies targeting inotropism and congestion, attention has focused on offsetting the neurohormonal overactivation and three main therapies, including angiotensin-converting enzyme inhibitors or angiotensin II type 1 receptor antagonists, β-adrenoceptor antagonists, and mineralocorticoid receptor antagonists, have been the foundation of standard treatment for patients with HF. Recently, a paradigm shift, including angiotensin receptor-neprilysin inhibitor, sodium glucose co-transporter 2 inhibitor, and ivabradine, has been added. Moreover, soluble guanylate cyclase stimulator, elamipretide, and omecamtiv mecarbil have come out as a next-generation therapeutic agent for patients with HF. Although these pharmacologic therapies have been significantly successful in relieving symptoms, there is still no complete cure for HF. We may be currently entering a new era of treatment for HF with animal experiments and human clinical trials assessing the value of antibody-based immunotherapy and gene therapy as a novel therapeutic strategy. Such tempting therapies still have some challenges to be addressed but may become a weighty option for treatment of HF. This review article will compile the paradigm shifts in HF treatment over the past dozen years or so and illustrate current landscape of antibody-based immunotherapy and gene therapy as a new therapeutic algorithm for patients with HF.
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Affiliation(s)
- Yuichi Hattori
- Advanced Research Promotion Center, Health Sciences University of Hokkaido, Tobetsu, Japan; Department of Molecular and Medical Pharmacology, Faculty of Medicine, University of Toyama, Toyama, Japan.
| | - Kohshi Hattori
- Department of Anesthesiology, Center Hospital of the National Center for Global Health and Medicine, Tokyo, Japan
| | - Kuniaki Ishii
- Department of Pharmacology, Yamagata University Faculty of Medicine, Yamagata, Japan
| | - Masanobu Kobayashi
- Advanced Research Promotion Center, Health Sciences University of Hokkaido, Tobetsu, Japan
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Çetin Güvenç R, Güvenç TS, Çağlar ME, Al Arfaj AA, Behrad A, Yılmaz MB. Digoxin is Not Related to Mortality in Patients with Heart Failure: Results from the SELFIE-TR Registry. Am J Cardiovasc Drugs 2024; 24:399-408. [PMID: 38573460 DOI: 10.1007/s40256-024-00639-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/10/2024] [Indexed: 04/05/2024]
Abstract
AIMS Digoxin has been used in the treatment for heart failure for centuries, but the role of this drug in the modern era is controversial. A particular concern is the recent observational findings suggesting an increase in all-cause mortality with digoxin, although such observations suffer from biased results since these studies usually do not provide adequate compensation for the severity of disease. Using a nationwide registry database, we aimed to investigate whether digoxin is associated with 1-year all-cause mortality in patients with heart failure irrespective of phenotype. METHODS A total of 1014 out of 1054 patients in the registry, of whom 110 patients were on digoxin, were included in the study. Multivariable adjustments were done and propensity scores were calculated for various prognostic indicators, including signs and symptoms of heart failure and functional capacity. Crude mortality, mortality adjusted for covariates, mortality in the propensity score-matched cohort, and Bayesian factors (BFs) were analyzed. RESULTS Crude 1-year mortality rate did not differ between patients on and off digoxin (17.3% vs 20.1%, log-rank p = 0.46), and digoxin was not related to mortality following multivariable adjustment (hazard ratio 0.87, 95% confidence interval 0.539-1.402, p = 0.57). Similarly, all-cause mortality was similar in 220 propensity-score adjusted patients (17.3% vs 20.0%, log-rank p = 0.55). On Bayesian analyses, there was moderate to strong evidence suggesting a lack of difference between in unmatched cohort (BF10 0.091) and weak-to-moderate evidence in the matched cohort (BF10 0.296). CONCLUSIONS In this nationwide cohort, we did not find any evidence for an increased 1-year mortality in heart failure patients on digoxin.
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Affiliation(s)
- Rengin Çetin Güvenç
- Division of Cardiology, Department of Internal Medical Sciences, Istanbul Okan University School of Medicine, Tepeören Mahallesi Tuzla Kampüsü, 34959, Istanbul, Turkey.
| | - Tolga Sinan Güvenç
- Division of Cardiology, Department of Internal Medical Sciences, Istinye University School of Medicine, Istanbul, Turkey
| | - Mert Efe Çağlar
- Division of Cardiology, Department of Internal Medical Sciences, Istanbul Okan University School of Medicine, Tepeören Mahallesi Tuzla Kampüsü, 34959, Istanbul, Turkey
| | - Abdullah Ayar Al Arfaj
- Division of Cardiology, Department of Internal Medical Sciences, Istanbul Okan University School of Medicine, Tepeören Mahallesi Tuzla Kampüsü, 34959, Istanbul, Turkey
| | - Ailin Behrad
- Division of Cardiology, Department of Internal Medical Sciences, Istanbul Okan University School of Medicine, Tepeören Mahallesi Tuzla Kampüsü, 34959, Istanbul, Turkey
| | - Mehmet Birhan Yılmaz
- Division of Cardiology, Department of Internal Medical Sciences, Dokuz Eylul University School of Medicine, Istanbul, Turkey
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8
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J J C, J G F C, A L C. Diuretic Treatment in Patients with Heart Failure: Current Evidence and Future Directions-Part II: Combination Therapy. Curr Heart Fail Rep 2024; 21:115-130. [PMID: 38300391 PMCID: PMC10923953 DOI: 10.1007/s11897-024-00644-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/03/2024] [Indexed: 02/02/2024]
Abstract
PURPOSE OF REVIEW Fluid retention or congestion is a major cause of symptoms, poor quality of life, and adverse outcome in patients with heart failure (HF). Despite advances in disease-modifying therapy, the mainstay of treatment for congestion-loop diuretics-has remained largely unchanged for 50 years. In these two articles (part I: loop diuretics and part II: combination therapy), we will review the history of diuretic treatment and current trial evidence for different diuretic strategies and explore potential future directions of research. RECENT FINDINGS We will assess recent trials, including DOSE, TRANSFORM, ADVOR, CLOROTIC, OSPREY-AHF, and PUSH-AHF, and assess how these may influence current practice and future research. There are few data on which to base diuretic therapy in clinical practice. The most robust evidence is for high-dose loop diuretic treatment over low-dose treatment for patients admitted to hospital with HF, yet this is not reflected in guidelines. There is an urgent need for more and better research on different diuretic strategies in patients with HF.
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Affiliation(s)
- Cuthbert J J
- Centre for Clinical Sciences, Hull York Medical School, University of Hull, Cottingham Road, Kingston-Upon-Hull, East Yorkshire, UK.
- Department of Cardiology, Castle Hill Hospital, Hull University Teaching Hospitals Trust, Castle Road, Cottingham, East Yorkshire, UK.
| | - Cleland J G F
- Robertson Centre for Biostatistics, Glasgow Clinical Trials Unit, University of Glasgow, Glasgow, UK
| | - Clark A L
- Department of Cardiology, Castle Hill Hospital, Hull University Teaching Hospitals Trust, Castle Road, Cottingham, East Yorkshire, UK
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9
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Blaustein MP, Hamlyn JM. Sensational site: the sodium pump ouabain-binding site and its ligands. Am J Physiol Cell Physiol 2024; 326:C1120-C1177. [PMID: 38223926 PMCID: PMC11193536 DOI: 10.1152/ajpcell.00273.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2023] [Revised: 12/22/2023] [Accepted: 01/10/2024] [Indexed: 01/16/2024]
Abstract
Cardiotonic steroids (CTS), used by certain insects, toads, and rats for protection from predators, became, thanks to Withering's trailblazing 1785 monograph, the mainstay of heart failure (HF) therapy. In the 1950s and 1960s, we learned that the CTS receptor was part of the sodium pump (NKA) and that the Na+/Ca2+ exchanger was critical for the acute cardiotonic effect of digoxin- and ouabain-related CTS. This "settled" view was upended by seven revolutionary observations. First, subnanomolar ouabain sometimes stimulates NKA while higher concentrations are invariably inhibitory. Second, endogenous ouabain (EO) was discovered in the human circulation. Third, in the DIG clinical trial, digoxin only marginally improved outcomes in patients with HF. Fourth, cloning of NKA in 1985 revealed multiple NKA α and β subunit isoforms that, in the rodent, differ in their sensitivities to CTS. Fifth, the NKA is a cation pump and a hormone receptor/signal transducer. EO binding to NKA activates, in a ligand- and cell-specific manner, several protein kinase and Ca2+-dependent signaling cascades that have widespread physiological effects and can contribute to hypertension and HF pathogenesis. Sixth, all CTS are not equivalent, e.g., ouabain induces hypertension in rodents while digoxin is antihypertensinogenic ("biased signaling"). Seventh, most common rodent hypertension models require a highly ouabain-sensitive α2 NKA and the elevated blood pressure is alleviated by EO immunoneutralization. These numerous phenomena are enabled by NKA's intricate structure. We have just begun to understand the endocrine role of the endogenous ligands and the broad impact of the ouabain-binding site on physiology and pathophysiology.
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Affiliation(s)
- Mordecai P Blaustein
- Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland, United States
- Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States
| | - John M Hamlyn
- Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland, United States
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10
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Lu JJ, Liu TT. Serum Cystatin C as a Risk Factor for Supratherapeutic Digoxin Concentration in Elderly Patients with Heart Failure and Chronic Kidney Disease. Am J Cardiovasc Drugs 2024; 24:303-311. [PMID: 38300453 DOI: 10.1007/s40256-024-00629-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 01/14/2024] [Indexed: 02/02/2024]
Abstract
BACKGROUND Digoxin is primarily metabolized by the kidney, and its toxicity is strongly associated with high concentrations, particularly in elderly patients. The purpose of this study was to evaluate the predictive performance of renal function biomarkers for supratherapeutic digoxin concentrations in elderly patients with heart failure (HF) and chronic kidney disease (CKD). METHODS Data were retrospectively obtained from elderly patient with HF and CKD who received digoxin treatment from January 2022 and December 2022. Logistic regression was used to assess independent risk factors for supratherapeutic concentrations. The predictive performance of serum creatinine, serum cystatin C, and blood urea nitrogen on supratherapeutic concentrations was compared by receiver operating characteristic analysis. RESULTS A total of 115 elderly patients with HF and CKD were enrolled in our study. Supratherapeutic concentrations were detected in 49 patients. Logistic regression analysis showed that estimated glomerular filtration rate calculated by serum cystatin C [eGFRCysC, odds ratio (OR): 0.962, P = 0.006], heart rate (OR: 1.024, P = 0.040), and NYHA class (OR: 3.099, P = 0.010) were independent risk factors for supratherapeutic concentration. Cutoff value for eGFRCysC between the two groups was 41 ml/min/1.73m2. Predictive performance of serum cystatin C was further improved in patients with obesity, CKD stage 4-5, and older than 75 years compared with normal weight, CKD stage 3, and aged 60-75-year-old patients. CONCLUSIONS Serum cystatin C is a sensitive renal function biomarker to predict supratherapeutic digoxin concentration in elderly patients with HF and CKD.
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Affiliation(s)
- Jie-Jiu Lu
- Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, 530021, Guangxi, People's Republic of China
| | - Tao-Tao Liu
- Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, No. 6 Shuangyong Road, Nanning, 530021, Guangxi, People's Republic of China.
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11
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See C, Wheelock KM, Caraballo C, Khera R, Annapureddy A, Mahajan S, Lu Y, Krumholz HM, Murugiah K. Patterns of Digoxin Prescribing for Medicare Beneficiaries in the United States 2013-2019. AMERICAN JOURNAL OF MEDICINE OPEN 2023; 10:100048. [PMID: 38213879 PMCID: PMC10783702 DOI: 10.1016/j.ajmo.2023.100048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/13/2024]
Abstract
Background Studies show that digoxin use is declining but is still prevalent. Recent data on digoxin prescription and characteristics of digoxin prescribers are unknown, which can help understand its contemporary use. Methods Using Medicare Part D data from 2013 to 2019, we studied the change in number and proportion of digoxin prescriptions and digoxin prescribers, overall and by specialty. Using logistic regression, we identified prescriber characteristics associated with digoxin prescription. Results From 2013 to 2019, total digoxin prescriptions (4.6 to 1.8 million) and proportion of digoxin prescribers decreased (9.1% to 4.3% overall; 26.6% to 11.8% among General Medicine prescribers and 65.4% to 48.9% among Cardiology). Of digoxin prescribers from 2013 practicing in 2019 (91.2% remained active), 59.1% did not prescribe digoxin at all, 31.7% reduced, and 9.2% maintained or increased prescriptions. The proportion of all digoxin prescriptions that were prescribed by General Medicine prescribers declined from 59.7% to 48.2% and increased for Cardiology (29% to 38.5%). Among new prescribers in 2019 (N = 85,508), only 1.9% prescribed digoxin. Digoxin prescribers when compared to non-digoxin prescribers were more likely male, graduated from medical school earlier, were located in the Midwest or South, and belonged to Cardiology (all P < .001). Conclusions Digoxin prescriptions continue to decline with over half of 2013 prescribers no longer prescribing digoxin in 2019. This may be a result of the increasing availability of newer heart failure therapies. The decline in digoxin prescription was greater among general medicine physicians than cardiologists, suggesting a change in digoxin use to a medication prescribed increasingly by specialists.
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Affiliation(s)
- Claudia See
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Conn
| | - Kevin M. Wheelock
- Department of Internal Medicine, Yale School of Medicine, New Haven, Conn
| | - César Caraballo
- Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Conn
| | - Rohan Khera
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Conn
- Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Conn
| | - Amarnath Annapureddy
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Conn
| | - Shiwani Mahajan
- Department of Internal Medicine, Yale School of Medicine, New Haven, Conn
- Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Conn
| | - Yuan Lu
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Conn
- Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Conn
| | - Harlan M. Krumholz
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Conn
- Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Conn
- Department of Health Policy and Management, Yale School of Public Health, New Haven, Conn
| | - Karthik Murugiah
- Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Conn
- Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Conn
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12
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Triska J, Uretsky BF, Pitt B, Birnbaum Y. Closing the Digitalis Divide: Back to the Basics of Randomized Controlled Trials. Cardiovasc Drugs Ther 2023; 37:807-813. [PMID: 34748147 DOI: 10.1007/s10557-021-07287-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/01/2021] [Indexed: 10/19/2022]
Abstract
PURPOSE Publishe d decades after several randomized controlled trials (RCT) demonstrating decreased hospitalizations and no effect on all-cause mortality with digoxin use, a series of meta-analyses linking digoxin treatment and mortality have contributed to a narrower application of this medication for the management of heart failure (HF) and atrial fibrillation (AF). Given the conflicting data from the earlier RCTs and more recent meta-analyses, there is a growing polarization among providers for and against the use of digoxin in managing these conditions. METHODS To help close this divide, we provide a perspective on the literature with special attention to the quality of both older and more recent studies on this subject. RESULTS The data from the highest quality studies we have, RCTs, suggest that digoxin use in patients with HF and/or AF is associated with improvement in several areas of outcomes including functional capacity, symptom management, reduced hospitalizations, fewer deaths due to HF, and treatment of refractory chronic heart failure with rEF, and may even have overall mortality benefit when serum digoxin concentrations are within therapeutic range. These effects are more pronounced in patients with EF < 25% and NYHA Class II-IV and at highest risk for hospitalization. CONCLUSION As the risk of confounding factors was minimized by the study design, the likelihood that positive outcomes were identified with digoxin use increased. Clinicians and researchers need further adequately designed and powered RCTs exploring the connection between digoxin therapy and mortality, hospitalizations, and symptom management.
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Affiliation(s)
- J Triska
- Internal Medicine Residency, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA.
| | - B F Uretsky
- University of Arkansas for Medical Sciences, Central Arkansas Veterans Health System, Little Rock, AR, 72205, USA
| | - B Pitt
- University of Michigan School of Medicine, Ann Arbor, MI, 48109, USA
| | - Y Birnbaum
- John S. Dunn Chair in Cardiology Research and Education, The Department of Medicine, Section of Cardiology, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA
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13
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Park SM, Lee SY, Jung MH, Youn JC, Kim D, Cho JY, Cho DH, Hyun J, Cho HJ, Park SM, Choi JO, Chung WJ, Kang SM, Yoo BS, on behalf of Committee of Clinical Practice Guidelines, Korean Society of Heart Failure. Korean Society of Heart Failure Guidelines for the Management of Heart Failure: Management of the Underlying Etiologies and Comorbidities of Heart Failure. INTERNATIONAL JOURNAL OF HEART FAILURE 2023; 5:127-145. [PMID: 37554691 PMCID: PMC10406556 DOI: 10.36628/ijhf.2023.0016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 07/01/2023] [Accepted: 07/11/2023] [Indexed: 08/10/2023]
Abstract
Most patients with heart failure (HF) have multiple comorbidities, which impact their quality of life, aggravate HF, and increase mortality. Cardiovascular comorbidities include systemic and pulmonary hypertension, ischemic and valvular heart diseases, and atrial fibrillation. Non-cardiovascular comorbidities include diabetes mellitus (DM), chronic kidney and pulmonary diseases, iron deficiency and anemia, and sleep apnea. In patients with HF with hypertension and left ventricular hypertrophy, renin-angiotensin system inhibitors combined with calcium channel blockers and/or diuretics is an effective treatment regimen. Measurement of pulmonary vascular resistance via right heart catheterization is recommended for patients with HF considered suitable for implantation of mechanical circulatory support devices or as heart transplantation candidates. Coronary angiography remains the gold standard for the diagnosis and reperfusion in patients with HF and angina pectoris refractory to antianginal medications. In patients with HF and atrial fibrillation, long-term anticoagulants are recommended according to the CHA2DS2-VASc scores. Valvular heart diseases should be treated medically and/or surgically. In patients with HF and DM, metformin is relatively safer; thiazolidinediones cause fluid retention and should be avoided in patients with HF and dyspnea. In renal insufficiency, both volume status and cardiac performance are important for therapy guidance. In patients with HF and pulmonary disease, beta-blockers are underused, which may be related to increased mortality. In patients with HF and anemia, iron supplementation can help improve symptoms. In obstructive sleep apnea, continuous positive airway pressure therapy helps avoid severe nocturnal hypoxia. Appropriate management of comorbidities is important for improving clinical outcomes in patients with HF.
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Affiliation(s)
- Sang Min Park
- Division of Cardiology, Nowon Eulji Medical Center, Eulji University School of Medicine, Seoul, Korea
| | - Soo Youn Lee
- Department of Cardiology, Cardiovascular Center, Incheon Sejong Hospital, Incheon, Korea
| | - Mi-Hyang Jung
- Division of Cardiology, Department of Internal Medicine, Seoul St. Mary’s Hospital, Catholic Research Institute for Intractable Cardiovascular Disease, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jong-Chan Youn
- Division of Cardiology, Department of Internal Medicine, Seoul St. Mary’s Hospital, Catholic Research Institute for Intractable Cardiovascular Disease, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Darae Kim
- Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae Yeong Cho
- Department of Cardiovascular Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Dong-Hyuk Cho
- Division of Cardiology, Department of Internal Medicine, Korea University Anam Hospital, Korea University Medicine, Seoul, Korea
| | - Junho Hyun
- Division of Cardiology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyun-Jai Cho
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Seong-Mi Park
- Division of Cardiology, Department of Internal Medicine, Korea University Anam Hospital, Korea University Medicine, Seoul, Korea
| | - Jin-Oh Choi
- Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Wook-Jin Chung
- Division of Cardiology, Department of Internal Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| | - Seok-Min Kang
- Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Byung-Su Yoo
- Division of Cardiology, Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
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14
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Park SM, Lee SY, Jung MH, Youn JC, Kim D, Cho JY, Cho DH, Hyun J, Cho HJ, Park SM, Choi JO, Chung WJ, Kang SM, Yoo BS. Korean Society of Heart Failure Guidelines for the Management of Heart Failure: Management of the Underlying Etiologies and Comorbidities of Heart Failure. Korean Circ J 2023; 53:425-451. [PMID: 37525389 PMCID: PMC10406530 DOI: 10.4070/kcj.2023.0114] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 07/01/2023] [Accepted: 07/11/2023] [Indexed: 08/02/2023] Open
Abstract
Most patients with heart failure (HF) have multiple comorbidities, which impact their quality of life, aggravate HF, and increase mortality. Cardiovascular comorbidities include systemic and pulmonary hypertension, ischemic and valvular heart diseases, and atrial fibrillation. Non-cardiovascular comorbidities include diabetes mellitus (DM), chronic kidney and pulmonary diseases, iron deficiency and anemia, and sleep apnea. In patients with HF with hypertension and left ventricular hypertrophy, renin-angiotensin system inhibitors combined with calcium channel blockers and/or diuretics is an effective treatment regimen. Measurement of pulmonary vascular resistance via right heart catheterization is recommended for patients with HF considered suitable for implantation of mechanical circulatory support devices or as heart transplantation candidates. Coronary angiography remains the gold standard for the diagnosis and reperfusion in patients with HF and angina pectoris refractory to antianginal medications. In patients with HF and atrial fibrillation, long-term anticoagulants are recommended according to the CHA2DS2-VASc scores. Valvular heart diseases should be treated medically and/or surgically. In patients with HF and DM, metformin is relatively safer; thiazolidinediones cause fluid retention and should be avoided in patients with HF and dyspnea. In renal insufficiency, both volume status and cardiac performance are important for therapy guidance. In patients with HF and pulmonary disease, beta-blockers are underused, which may be related to increased mortality. In patients with HF and anemia, iron supplementation can help improve symptoms. In obstructive sleep apnea, continuous positive airway pressure therapy helps avoid severe nocturnal hypoxia. Appropriate management of comorbidities is important for improving clinical outcomes in patients with HF.
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Affiliation(s)
- Sang Min Park
- Division of Cardiology, Nowon Eulji Medical Center, Eulji University School of Medicine, Seoul, Korea
| | - Soo Youn Lee
- Department of Cardiology, Cardiovascular Center, Incheon Sejong Hospital, Incheon, Korea
| | - Mi-Hyang Jung
- Division of Cardiology, Department of Internal Medicine, Seoul St. Mary's Hospital, Catholic Research Institute for Intractable Cardiovascular Disease, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Jong-Chan Youn
- Division of Cardiology, Department of Internal Medicine, Seoul St. Mary's Hospital, Catholic Research Institute for Intractable Cardiovascular Disease, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Darae Kim
- Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jae Yeong Cho
- Department of Cardiovascular Medicine, Chonnam National University Medical School, Gwangju, Korea
| | - Dong-Hyuk Cho
- Division of Cardiology, Department of Internal Medicine, Korea University Anam Hospital, Korea University Medicine, Seoul, Korea
| | - Junho Hyun
- Division of Cardiology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyun-Jai Cho
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
| | - Seong-Mi Park
- Division of Cardiology, Department of Internal Medicine, Korea University Anam Hospital, Korea University Medicine, Seoul, Korea
| | - Jin-Oh Choi
- Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Wook-Jin Chung
- Division of Cardiology, Department of Internal Medicine, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea
| | - Seok-Min Kang
- Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
| | - Byung-Su Yoo
- Division of Cardiology, Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea.
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15
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Grede N, Kuss K, Staudt I, Donner-Banzhoff N, Viniol A. Mapping the methodological diversity of published drug discontinuation studies-a scoping review of study topics, objectives, and designs. Trials 2023; 24:58. [PMID: 36703178 PMCID: PMC9878942 DOI: 10.1186/s13063-023-07105-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Accepted: 01/18/2023] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Trials evaluating drug discontinuation (drug discontinuation trials, DDTs) show a broad methodological spectrum. There are several specific methodological aspects in drug discontinuation trials (e.g., determination of research question; configuration of intervention; definition of outcomes). To verify this specifies, we did a scoping review about the study designs of drug discontinuation trials. METHODS A systematic literature search in Medline (PubMed), The Cochrane Library, EMBASE, CINAHL, Web of Science, and PsycINFO was performed. In a two-step selection process, we identified DDTs, which evaluate the discontinuation of one or more long-term medication as the investigated intervention, by two independent reviewers. Besides bibliographic data, we extracted several parameters to describe the used study design of the included DDTs: motivation for DDT, initially treatment aim of the discontinued medication, study design, methods of discontinuation, follow-up times, number of study participants, and outcome parameter. RESULTS Out of 12,132 records, we included 581 DDTs. The most common motivation for doing a DDT were expected side effects (48.8%), the motivation of proving the efficacy of medication (21.6%), or doubts on the expected benefit of the used medication (13.8%). The majority of the discontinued medication was initially prescribed to improve the prognosis of a chronic disease (60.4%) or to relieve symptoms (31%). The study designs of the trials showed a broad methodological spectrum. The minority of the drug discontinuation trials were randomized controlled trials (34%). CONCLUSION The results of this scoping review illustrates the need for an evidence-based methodological standard for planning and conducting drug discontinuation trials.
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Affiliation(s)
- Nina Grede
- Department of General Medicine, Preventive and Rehabilitation Medicine, University of Marburg, Karl-Von-Frisch Str. 4, 35043, Marburg, Germany.
| | - Katrin Kuss
- Department of General Medicine, Preventive and Rehabilitation Medicine, University of Marburg, Karl-Von-Frisch Str. 4, 35043, Marburg, Germany
| | - Ina Staudt
- Department of General Medicine, Preventive and Rehabilitation Medicine, University of Marburg, Karl-Von-Frisch Str. 4, 35043, Marburg, Germany
| | - Norbert Donner-Banzhoff
- Department of General Medicine, Preventive and Rehabilitation Medicine, University of Marburg, Karl-Von-Frisch Str. 4, 35043, Marburg, Germany
| | - Annika Viniol
- Department of General Medicine, Preventive and Rehabilitation Medicine, University of Marburg, Karl-Von-Frisch Str. 4, 35043, Marburg, Germany
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16
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Mauro C, Chianese S, Cocchia R, Arcopinto M, Auciello S, Capone V, Carafa M, Carbone A, Caruso G, Castaldo R, Citro R, Crisci G, D’Andrea A, D’Assante R, D’Avino M, Ferrara F, Frangiosa A, Galzerano D, Maffei V, Marra AM, Mehta RM, Mehta RH, Paladino F, Ranieri B, Franzese M, Limongelli G, Rega S, Romano L, Salzano A, Sepe C, Vriz O, Izzo R, Cademartiri F, Cittadini A, Bossone E. Acute Heart Failure: Diagnostic-Therapeutic Pathways and Preventive Strategies-A Real-World Clinician's Guide. J Clin Med 2023; 12:846. [PMID: 36769495 PMCID: PMC9917599 DOI: 10.3390/jcm12030846] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 01/01/2023] [Accepted: 01/16/2023] [Indexed: 01/25/2023] Open
Abstract
Acute heart failure (AHF) is the most frequent cause of unplanned hospital admission in patients of >65 years of age and it is associated with significantly increased morbidity, mortality, and healthcare costs. Different AHF classification criteria have been proposed, mainly reflecting the clinical heterogeneity of the syndrome. Regardless of the underlying mechanism, peripheral and/or pulmonary congestion is present in the vast majority of cases. Furthermore, a marked reduction in cardiac output with peripheral hypoperfusion may occur in most severe cases. Diagnosis is made on the basis of signs and symptoms, laboratory, and non-invasive tests. After exclusion of reversible causes, AHF therapeutic interventions mainly consist of intravenous (IV) diuretics and/or vasodilators, tailored according to the initial hemodynamic status with the addition of inotropes/vasopressors and mechanical circulatory support if needed. The aim of this review is to discuss current concepts on the diagnosis and management of AHF in order to guide daily clinical practice and to underline the unmet needs. Preventive strategies are also discussed.
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Affiliation(s)
- Ciro Mauro
- Cardiology Division, A. Cardarelli Hospital, Via Cardarelli, 9, 80131 Naples, Italy
| | - Salvatore Chianese
- Cardiology Division, A. Cardarelli Hospital, Via Cardarelli, 9, 80131 Naples, Italy
- Department of Advanced Biomedical Sciences, University of Naples Federico II, Via Sergio Pansini, 5, 80131 Naples, Italy
| | - Rosangela Cocchia
- Cardiology Division, A. Cardarelli Hospital, Via Cardarelli, 9, 80131 Naples, Italy
| | - Michele Arcopinto
- Department of Translational Medical Sciences, Federico II University, 80131 Naples, Italy
| | - Stefania Auciello
- First Aid—Short Intensive Observation Division, A. Cardarelli Hospital, Via Cardarelli, 9, 80131 Naples, Italy
| | - Valentina Capone
- Cardiology Division, A. Cardarelli Hospital, Via Cardarelli, 9, 80131 Naples, Italy
- Department of Advanced Biomedical Sciences, University of Naples Federico II, Via Sergio Pansini, 5, 80131 Naples, Italy
| | - Mariano Carafa
- Emergency Medicine Division, A. Cardarelli Hospital, Via Cardarelli, 9, 80131 Naples, Italy
| | - Andreina Carbone
- Unit of Cardiology, Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Monaldi Hospital, 80131 Naples, Italy
| | - Giuseppe Caruso
- Long-Term Care Division, Cardarelli Hospital, Via Cardarelli, 9, 80131 Naples, Italy
| | - Rossana Castaldo
- Istituto di Ricovero e Cura a Carattere Scientifico SYNLAB SDN, Via Emanuele Gianturco, 113, 80143 Naples, Italy
| | - Rodolfo Citro
- Heart Department, University Hospital of Salerno, 84131 Salerno, Italy
| | - Giulia Crisci
- Department of Translational Medical Sciences, Federico II University, 80131 Naples, Italy
| | - Antonello D’Andrea
- Department of Cardiology, Umberto I Hospital Nocera Inferiore, 84014 Nocera, Italy
| | - Roberta D’Assante
- Department of Translational Medical Sciences, Federico II University, 80131 Naples, Italy
| | - Maria D’Avino
- Long-Term Care Division, Cardarelli Hospital, Via Cardarelli, 9, 80131 Naples, Italy
| | - Francesco Ferrara
- Heart Department, University Hospital of Salerno, 84131 Salerno, Italy
| | - Antonio Frangiosa
- Post Operative Intensive Care Division, A. Cardarelli Hospital, 80131 Naples, Italy
| | - Domenico Galzerano
- Heart Centre, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Vincenzo Maffei
- Post Operative Intensive Care Division, A. Cardarelli Hospital, 80131 Naples, Italy
| | - Alberto Maria Marra
- Department of Translational Medical Sciences, Federico II University, 80131 Naples, Italy
| | - Rahul M. Mehta
- ProMedica Monroe Regional Hospital, Monroe, MI 48162, USA
| | - Rajendra H. Mehta
- Duke Clinical Research Institute, 300 W Morgan St., Durham, NC 27701, USA
| | - Fiorella Paladino
- First Aid—Short Intensive Observation Division, A. Cardarelli Hospital, Via Cardarelli, 9, 80131 Naples, Italy
| | - Brigida Ranieri
- Istituto di Ricovero e Cura a Carattere Scientifico SYNLAB SDN, Via Emanuele Gianturco, 113, 80143 Naples, Italy
| | - Monica Franzese
- Istituto di Ricovero e Cura a Carattere Scientifico SYNLAB SDN, Via Emanuele Gianturco, 113, 80143 Naples, Italy
| | - Giuseppe Limongelli
- Unit of Cardiology, Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, Monaldi Hospital, 80131 Naples, Italy
| | - Salvatore Rega
- Department of Public Health University “Federico II” of Naples, Via Sergio Pansini, 5, 80131 Naples, Italy
| | - Luigia Romano
- Department of General and Emergency Radiology, Antonio Cardarelli Hospital, Via Cardarelli, 9, 80131 Naples, Italy
| | - Andrea Salzano
- Istituto di Ricovero e Cura a Carattere Scientifico SYNLAB SDN, Via Emanuele Gianturco, 113, 80143 Naples, Italy
| | - Chiara Sepe
- Technical Nursing and Rehabilitation Service (SITR) Department, Cardarelli Hospital, 80131 Naples, Italy
| | - Olga Vriz
- Heart Centre, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia
| | - Raffaele Izzo
- Department of Advanced Biomedical Sciences, University of Naples Federico II, Via Sergio Pansini, 5, 80131 Naples, Italy
| | - Filippo Cademartiri
- Department of Radiology, Fondazione G. Monasterio CNR-Regione Toscana, Via Moruzzi, 1, 56124 Pisa, Italy
| | - Antonio Cittadini
- Department of Translational Medical Sciences, Federico II University, 80131 Naples, Italy
| | - Eduardo Bossone
- Department of Public Health University “Federico II” of Naples, Via Sergio Pansini, 5, 80131 Naples, Italy
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Blaustein MP, Gottlieb SS, Hamlyn JM, Leenen FHH. Whither digitalis? What we can still learn from cardiotonic steroids about heart failure and hypertension. Am J Physiol Heart Circ Physiol 2022; 323:H1281-H1295. [PMID: 36367691 DOI: 10.1152/ajpheart.00362.2022] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Cloning of the "Na+ pump" (Na+,K+-ATPase or NKA) and identification of a circulating ligand, endogenous ouabain (EO), a cardiotonic steroid (CTS), triggered seminal discoveries regarding EO and its NKA receptor in cardiovascular function and the pathophysiology of heart failure (HF) and hypertension. Cardiotonic digitalis preparations were a preferred treatment for HF for two centuries, but digoxin was only marginally effective in a large clinical trial (1997). This led to diminished digoxin use. Missing from the trial, however, was any consideration that endogenous CTS might influence digitalis' efficacy. Digoxin, at therapeutic concentrations, acutely inhibits NKA but, remarkably, antagonizes ouabain's action. Prolonged treatment with ouabain, but not digoxin, causes hypertension in rodents; in this model, digoxin lowers blood pressure (BP). Furthermore, NKA-bound ouabain and digoxin modulate different protein kinase signaling pathways and have disparate long-term cardiovascular effects. Reports of "brain ouabain" led to the elucidation of a new, slow neuromodulatory pathway in the brain; locally generated EO and the α2 NKA isoform help regulate sympathetic drive to the heart and vasculature. The roles of EO and α2 NKA have been studied by EO assay, ouabain-resistant mutation of α2 NKA, and immunoneutralization of EO with ouabain-binding Fab fragments. The NKA α2 CTS binding site and its endogenous ligand are required for BP elevation in many common hypertension models and full expression of cardiac remodeling and dysfunction following pressure overload or myocardial infarction. Understanding how endogenous CTS impact hypertension and HF pathophysiology and therapy should foster reconsideration of digoxin's therapeutic utility.
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Affiliation(s)
- Mordecai P Blaustein
- Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland.,Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - Stephen S Gottlieb
- Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland
| | - John M Hamlyn
- Department of Physiology, University of Maryland School of Medicine, Baltimore, Maryland
| | - Frans H H Leenen
- Brain and Heart Research Group, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
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18
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Hafkamp FJ, Tio RA, Otterspoor LC, de Greef T, van Steenbergen GJ, van de Ven ART, Smits G, Post H, van Veghel D. Optimal effectiveness of heart failure management - an umbrella review of meta-analyses examining the effectiveness of interventions to reduce (re)hospitalizations in heart failure. Heart Fail Rev 2022; 27:1683-1748. [PMID: 35239106 PMCID: PMC8892116 DOI: 10.1007/s10741-021-10212-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/15/2021] [Indexed: 12/11/2022]
Abstract
Heart failure (HF) is a major health concern, which accounts for 1-2% of all hospital admissions. Nevertheless, there remains a knowledge gap concerning which interventions contribute to effective prevention of HF (re)hospitalization. Therefore, this umbrella review aims to systematically review meta-analyses that examined the effectiveness of interventions in reducing HF-related (re)hospitalization in HFrEF patients. An electronic literature search was performed in PubMed, Web of Science, PsycInfo, Cochrane Reviews, CINAHL, and Medline to identify eligible studies published in the English language in the past 10 years. Primarily, to synthesize the meta-analyzed data, a best-evidence synthesis was used in which meta-analyses were classified based on level of validity. Secondarily, all unique RCTS were extracted from the meta-analyses and examined. A total of 44 meta-analyses were included which encompassed 186 unique RCTs. Strong or moderate evidence suggested that catheter ablation, cardiac resynchronization therapy, cardiac rehabilitation, telemonitoring, and RAAS inhibitors could reduce (re)hospitalization. Additionally, limited evidence suggested that multidisciplinary clinic or self-management promotion programs, beta-blockers, statins, and mitral valve therapy could reduce HF hospitalization. No, or conflicting evidence was found for the effects of cell therapy or anticoagulation. This umbrella review highlights different levels of evidence regarding the effectiveness of several interventions in reducing HF-related (re)hospitalization in HFrEF patients. It could guide future guideline development in optimizing care pathways for heart failure patients.
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Affiliation(s)
| | - Rene A. Tio
- Netherlands Heart Network, Veldhoven, The Netherlands
- Catharina Hospital, Eindhoven, The Netherlands
| | - Luuk C. Otterspoor
- Netherlands Heart Network, Veldhoven, The Netherlands
- Catharina Hospital, Eindhoven, The Netherlands
| | - Tineke de Greef
- Netherlands Heart Network, Veldhoven, The Netherlands
- Catharina Hospital, Eindhoven, The Netherlands
| | | | - Arjen R. T. van de Ven
- Netherlands Heart Network, Veldhoven, The Netherlands
- St. Anna Hospital, Geldrop, The Netherlands
| | - Geert Smits
- Netherlands Heart Network, Veldhoven, The Netherlands
- Primary care group Pozob, Veldhoven, The Netherlands
| | - Hans Post
- Netherlands Heart Network, Veldhoven, The Netherlands
- Catharina Hospital, Eindhoven, The Netherlands
| | - Dennis van Veghel
- Netherlands Heart Network, Veldhoven, The Netherlands
- Catharina Hospital, Eindhoven, The Netherlands
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19
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Broberg MCG, Cheifetz IM, Plummer ST. Current evidence for pharmacologic therapy following stage 1 palliation for single ventricle congenital heart disease. Expert Rev Cardiovasc Ther 2022; 20:627-636. [PMID: 35848073 DOI: 10.1080/14779072.2022.2103542] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
Abstract
INTRODUCTION Infants with single ventricle congenital heart disease are vulnerable to complications between stage 1 and stage 2 of palliation. Pharmaceutical treatment during this period is varied and often dependent on institutional practices as there is little evidence supporting a particular treatment path. AREAS COVERED This review focuses on medical management of patients following stage I palliation. We performed a scoping review of the current literature regarding angiotensin converting enzyme inhibitors and digoxin treatment in the interstage period. In addition, we discuss other medication classes frequently used in these patients. EXPERT OPINION Due to significant heterogeneity of anatomy, rarity of disease, and other confounding factors, there is limited evidence to support most commonly used medications within the interstage period. Digoxin is associated with improved mortality within the interstage period and should be considered; however, no large randomized controlled trial exists supporting its use. Prevention of thrombotic complication with aspirin is also associated with improved outcomes and should be considered unless a contraindication exists. The addition of other prescriptions in this patient population should be considered only after an evaluation of the risks and benefits of each medication, recognizing the burden and risk of polypharmacy in this fragile patient population.
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Affiliation(s)
- Meredith C G Broberg
- Department of Pediatrics, Division of Pediatric Cardiac Critical Care, University Hospitals Rainbow Babies and Children's Hospital, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Ira M Cheifetz
- Department of Pediatrics, Division of Pediatric Cardiac Critical Care, University Hospitals Rainbow Babies and Children's Hospital, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA.,Department of Pediatrics, Division of Pediatric Cardiology, University Hospitals Rainbow Babies and Children's Hospital, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
| | - Sarah T Plummer
- Department of Pediatrics, Division of Pediatric Cardiology, University Hospitals Rainbow Babies and Children's Hospital, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA
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20
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Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, Deswal A, Drazner MH, Dunlay SM, Evers LR, Fang JC, Fedson SE, Fonarow GC, Hayek SS, Hernandez AF, Khazanie P, Kittleson MM, Lee CS, Link MS, Milano CA, Nnacheta LC, Sandhu AT, Stevenson LW, Vardeny O, Vest AR, Yancy CW. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2022; 145:e895-e1032. [PMID: 35363499 DOI: 10.1161/cir.0000000000001063] [Citation(s) in RCA: 1099] [Impact Index Per Article: 366.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
AIM The "2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure" replaces the "2013 ACCF/AHA Guideline for the Management of Heart Failure" and the "2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure." The 2022 guideline is intended to provide patient-centric recommendations for clinicians to prevent, diagnose, and manage patients with heart failure. METHODS A comprehensive literature search was conducted from May 2020 to December 2020, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from MEDLINE (PubMed), EMBASE, the Cochrane Collaboration, the Agency for Healthcare Research and Quality, and other relevant databases. Additional relevant clinical trials and research studies, published through September 2021, were also considered. This guideline was harmonized with other American Heart Association/American College of Cardiology guidelines published through December 2021. Structure: Heart failure remains a leading cause of morbidity and mortality globally. The 2022 heart failure guideline provides recommendations based on contemporary evidence for the treatment of these patients. The recommendations present an evidence-based approach to managing patients with heart failure, with the intent to improve quality of care and align with patients' interests. Many recommendations from the earlier heart failure guidelines have been updated with new evidence, and new recommendations have been created when supported by published data. Value statements are provided for certain treatments with high-quality published economic analyses.
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Affiliation(s)
| | | | | | | | | | | | - Anita Deswal
- ACC/AHA Joint Committee on Clinical Practice Guidelines Liaison
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21
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Digoxin Use in Atrial Fibrillation; Insights from National Ambulatory Medical Care Survey. Curr Probl Cardiol 2022:101209. [PMID: 35460684 DOI: 10.1016/j.cpcardiol.2022.101209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Accepted: 04/13/2022] [Indexed: 11/22/2022]
Abstract
OBJECTIVE To evaluate the characteristics and trends of digoxin use during outpatient visits with atrial fibrillation in the US from 2006 to 2015. METHODS We conducted a retrospective analysis of adult (age ≥18) patient visits to office-based physicians from National Ambulatory Medical Care Survey (NAMCS) database between 2006-2015. The International Classification of Diseases, Ninth Revision, Clinical Modification codes were used to identify patients with atrial fibrillation. Visits in which digoxin was listed as a medication were analyzed with descriptive statistics. Multivariable logistic regression analysis was used to identify the predictors of digoxin usage. RESULTS Of a weighted sample of 108,113,894 patient visits, 17,617,853 (16.3%) visits included use of digoxin. Patients who used digoxin had a mean age of 75 ± 0.7 years and were predominantly Caucasian (92.56%). Among the patients who used digoxin, 24% had a diagnosis of heart failure. Multivariate analysis showed that the increased likelihood of digoxin utilization was associated with female sex (adjusted odds ratio [aOR] 1.34, 95% CI 1.05-1.71, p = .019), heart failure (aOR 1.51, 95% CI 1.05-1.17, p = .025), and usage of ³5 medications (aOR 5.32, 95% CI 3.67-7.71, p = <0.001). Among the visits with atrial fibrillation, the percentage of visits with digoxin usage decreased from 23% in 2006 to 9% in 2013 and then again increased to 14% in 2015(P-trend <0.001). CONCLUSION This is the first study to examine the use of digoxin in atrial fibrillation patients in a large outpatient setting. During 2006-2015, the percentage of digoxin prescriptions in atrial fibrillation patients has declined. Predictors of digoxin use in atrial fibrillation patients are female sex, congestive heart failure, and higher number of concurrent medications.
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22
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Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, Deswal A, Drazner MH, Dunlay SM, Evers LR, Fang JC, Fedson SE, Fonarow GC, Hayek SS, Hernandez AF, Khazanie P, Kittleson MM, Lee CS, Link MS, Milano CA, Nnacheta LC, Sandhu AT, Stevenson LW, Vardeny O, Vest AR, Yancy CW. 2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure. J Am Coll Cardiol 2022; 79:e263-e421. [PMID: 35379503 DOI: 10.1016/j.jacc.2021.12.012] [Citation(s) in RCA: 1257] [Impact Index Per Article: 419.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
AIM The "2022 AHA/ACC/HFSA Guideline for the Management of Heart Failure" replaces the "2013 ACCF/AHA Guideline for the Management of Heart Failure" and the "2017 ACC/AHA/HFSA Focused Update of the 2013 ACCF/AHA Guideline for the Management of Heart Failure." The 2022 guideline is intended to provide patient-centric recommendations for clinicians to prevent, diagnose, and manage patients with heart failure. METHODS A comprehensive literature search was conducted from May 2020 to December 2020, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from MEDLINE (PubMed), EMBASE, the Cochrane Collaboration, the Agency for Healthcare Research and Quality, and other relevant databases. Additional relevant clinical trials and research studies, published through September 2021, were also considered. This guideline was harmonized with other American Heart Association/American College of Cardiology guidelines published through December 2021. STRUCTURE Heart failure remains a leading cause of morbidity and mortality globally. The 2022 heart failure guideline provides recommendations based on contemporary evidence for the treatment of these patients. The recommendations present an evidence-based approach to managing patients with heart failure, with the intent to improve quality of care and align with patients' interests. Many recommendations from the earlier heart failure guidelines have been updated with new evidence, and new recommendations have been created when supported by published data. Value statements are provided for certain treatments with high-quality published economic analyses.
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23
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Gerakaris A, Mulita F, Koniari I, Artopoulou E, Mplani V, Tsigkas G, Abo-Elseoud M, Kounis N, Velissaris D. Digoxin Impact on Heart Failure Patients with Atrial Fibrillation. Med Arch 2022; 76:23-28. [PMID: 35422570 PMCID: PMC8976896 DOI: 10.5455/medarh.2022.76.23-28] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 02/25/2022] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Digoxin is a cardiac glycoside, derived from the plant Digitalis purpurea. For many years digitalis has been widely used in the treatment of heart failure (HF), owing to its cardiotonic and neurohormonal effects and atrial fibrillation (AF), due to its parasympathomimetic effect on the AV node. OBJECTIVE The aim of this paper is to evaluate the available evidence on the safety and efficacy of digoxin in patients with HF and AF, by reviewing the pertinent literature. METHODS We conducted a PubMed/MEDLINE and SCOPUS search to evaluate the currently available evidence on the administration of digoxin and its association with all-cause mortality risk in patients with AF and HF. RESULTS Several observational analyses of clinical trials and meta-analyses have shown conflicting results on the safety and efficacy of digoxin administration in patients with AF and HF. According to these results, digoxin should be avoided in patients without HF, as it is associated with worse outcomes. On the other hand, in patients with AF and HF digoxin should be used with caution. CONCLUSION The impact of digoxin on all-cause mortality and adverse effects in these patients remains unclear based on the current evidence. More trials at low risk of bias evaluating the effects of digoxin are needed.
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Affiliation(s)
- Andreas Gerakaris
- Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Francesk Mulita
- Department of Surgery, University Hospital of Patras, Patras, Greece
| | - Ioanna Koniari
- Manchester Heart Institute, Manchester University Foundation Trust, Manchester, United Kingdom
| | - Eleni Artopoulou
- Department of Internal Medicine, University Hospital of Patras, Patras, Greece
| | - Virginia Mplani
- Department of Cardiology, University Hospital of Patras, Patras, Greece
| | - Grigorios Tsigkas
- Department of Cardiology, University Hospital of Patras, Patras, Greece
| | - Mohammed Abo-Elseoud
- Manchester Heart Institute, Manchester University Foundation Trust, Manchester, United Kingdom
| | - Nicholas Kounis
- Department of Cardiology, University Hospital of Patras, Patras, Greece
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24
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Lauro FV, Maria LR, Francisco DC, Marcela RN, Virginia MAM, Magdalena AR, Tomas LG, Idalia AC. Synthesis and Biological Activity of the Pyridine-Hexacyclic-Steroid Derivative on a Heart Failure Model. Antiinflamm Antiallergy Agents Med Chem 2021; 21:34-45. [PMID: 34951373 DOI: 10.2174/1871523021666211222125403] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Revised: 09/09/2021] [Accepted: 11/02/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Several drugs with inotropic activity have been synthesized; however, there is very little information on biological activity exerted by steroid derivatives in the cardiovascular system. OBJECTIVE The aim of this research was to prepare a steroid-pyridine derivative to evaluate the effect it exerts on left ventricular pressure and characterize its molecular interaction. METHODS The first stage was carried out through the synthesis of a steroid-pyridine derivative using some chemical strategies. The second stage involved the evaluation of the biological activity of the steroid-pyridine derivative on left ventricular pressure using a model of heart failure in the absence or presence of the drugs, such as flutamide, tamoxifen, prazosin, metoprolol, indomethacin, and nifedipine. RESULTS The results showed that steroid-pyridine derivative increased left ventricular pressure in a dose-dependent manner (0.001-100 nM); however, this phenomenon was significantly inhibited only by nifedipine at a dose of 1 nM. These results indicate that positive inotropic activity produced by the steroid-pyridine derivative was via calcium channel activation. Furthermore, the biological activity exerted by the steroid-pyridine derivative on the left ventricle produces changes in cAMP concentration. CONCLUSION It is noteworthy that positive inotropic activity produced by this steroid-pyridine derivative involves a different molecular mechanism compared to other positive inotropic drugs. Therefore, this steroid could be a good candidate for the treatment of heart failure.
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Affiliation(s)
- Figueroa-Valverde Lauro
- Laboratory of Pharmaco-Chemistry, Faculty of Chemical Biological Sciences, University Autonomous of Campeche, Humberto Lanz Cárdenas S/N, Colonia Ex Hacienda Kalá, C.P. 24085, Campeche. Mexico
| | - López-Ramos Maria
- Laboratory of Pharmaco-Chemistry, Faculty of Chemical Biological Sciences, University Autonomous of Campeche, Humberto Lanz Cárdenas S/N, Colonia Ex Hacienda Kalá, C.P. 24085, Campeche. Mexico
| | - Díaz-Cedillo Francisco
- Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional. Prol. Carpio y Plan de Ayala s/n Col. Santo Tomas, D.F. C.P. 11340. Mexico
| | - Rosas-Nexticapa Marcela
- Facultad de Nutrición, Universidad Veracruzana, Médicos y Odontologos s/n C.P. 91010, Unidad del Bosque Xalapa Veracruz. Mexico
| | - Mateu-Armad Maria Virginia
- Facultad de Nutrición, Universidad Veracruzana, Médicos y Odontologos s/n C.P. 91010, Unidad del Bosque Xalapa Veracruz. Mexico
| | - Alvarez-Ramirez Magdalena
- Facultad de Nutrición, Universidad Veracruzana, Médicos y Odontologos s/n C.P. 91010, Unidad del Bosque Xalapa Veracruz. Mexico
| | - Lopez-Gutierrez Tomas
- Laboratory of Pharmaco-Chemistry, Faculty of Chemical Biological Sciences, University Autonomous of Campeche, Humberto Lanz Cárdenas S/N, Colonia Ex Hacienda Kalá, C.P. 24085, Campeche. Mexico
| | - Arakachi-Cruz Idalia
- Universidad Modelo Chetumal, Carretera Federal Chetumal, Sub-teniente López. S/N. Entre la glorieta al mestizaje y la glorieta de Sta. Elena, Chetumal, Quintana Roo. Mexico
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25
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Liu C, Lai Y, Guan T, Zeng Q, Pei J, Zhang S, Wu D, Wu D. Association of Digoxin Application Approaches With Long-Term Clinical Outcomes in Rheumatic Heart Disease Patients With Heart Failure: A Retrospective Study. Front Cardiovasc Med 2021; 8:711203. [PMID: 34616781 PMCID: PMC8488133 DOI: 10.3389/fcvm.2021.711203] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 08/16/2021] [Indexed: 12/03/2022] Open
Abstract
Objective: This retrospective, case–control study was executed to assess the effects of digoxin (DGX) use approaches [continuous use of DGX (cDGX) vs. intermittent use of DGX (iDGX)] on the long-term prognosis in rheumatic heart disease (RHD) patients with heart failure (HF). Methods: A total of 642 RHD patients were enrolled to this study after propensity matching. The associations of DGX application approaches with the risks of all-cause mortality, cardiovascular death (CVD), HF re-hospitalization (1-, 3-, and 5-year), and new-onset atrial fibrillation (AF) were analyzed by multivariate Cox proportional hazards or binary logistic regression models, respectively. Results: cDGX was associated with increased risks of all-cause mortality (adjusted HR = 1.84, 95% CI: 1.27–2.65, P = 0.001) and CVD (adjusted HR = 2.23, 95% CI: 1.29–3.83, P = 0.004) in RHD patients with HF compared to iDGX. With exception of 1-year HF re-hospitalization risk, cDGX was associated with increased HF re-hospitalization risk of 3-year (adjusted OR = 1.53, 95% CI: 1.03–2.29, P = 0.037) and 5-year (adjusted OR = 1.61, 95% CI: 1.05–2.50, P = 0.031) as well as new-onset AF (adjusted OR = 2.06, 95% CI: 1.09–3.90, P = 0.027). Conclusion: cDGX was significantly associated with increased risks of all-cause mortality, CVD, medium-/long-term HF re-hospitalization, and new-onset AF in RHD patients with HF.
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Affiliation(s)
- Cheng Liu
- Department of Cardiology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China.,Department of Cardiology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Yanxian Lai
- Department of Cardiology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China
| | - Tianwang Guan
- Department of Cardiology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Qingchun Zeng
- Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jingxian Pei
- Department of Cardiology, The Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Shenghui Zhang
- Department of Cardiology, Guangzhou First People's Hospital, South China University of Technology, Guangzhou, China
| | - Daihong Wu
- Department of Cardiology, Guangzhou First People's Hospital, Guangzhou Medical University, Guangzhou, China
| | - Deping Wu
- Guangzhou Center for Disease Control and Prevention, Guangzhou, China
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26
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Kempf T, Bauersachs J, Bavendiek U. Eisen und Digitalis bei Herzinsuffizienz. AKTUELLE KARDIOLOGIE 2021. [DOI: 10.1055/a-1472-0114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
ZusammenfassungNeben der medikamentösen Standardtherapie der Herzinsuffizienz (HI) gilt es, Patienten zu identifizieren, die von einer Eisensupplementation oder Therapie mit Digitalis profitieren können. Wir haben die aktuelle Evidenz für diese Therapien zusammengestellt und beschreiben, wie die HI-Therapie mit Eisen und Digitalis individualisiert werden kann. Eine Eisensupplementation verbessert Leistungsfähigkeit, Symptome und Lebensqualität bei Patienten mit symptomatischer Herzinsuffizienz und Eisenmangel. Die Daten aus der unlängst publizierten AFFIRM-AHF-Studie zeigen, dass eine Eisentherapie mit Eisencarboxymaltose zudem HI-Hospitalisationen verhindert. Die Therapie mit Digitalis sollte bei fortgeschrittenen Stadien der Herzinsuffizienz mit reduzierter systolischer Funktion trotz leitliniengerechter Pharmako- und Devicetherapie in Erwägung gezogen werden, insbesondere, wenn diese aufgrund von Komorbiditäten nur eingeschränkt möglich ist. Auch bei koexistentem Vorhofflimmern
ist Digitalis zur Herzfrequenzkontrolle von großem Wert. Serumkonzentrationen von Digitalis im niedrigen therapeutischen Bereich sind anzustreben.
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Affiliation(s)
- Tibor Kempf
- Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover, Deutschland
| | - Johann Bauersachs
- Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover, Deutschland
| | - Udo Bavendiek
- Klinik für Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover, Deutschland
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27
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Das BB, Moskowitz WB, Butler J. Current and Future Drug and Device Therapies for Pediatric Heart Failure Patients: Potential Lessons from Adult Trials. CHILDREN (BASEL, SWITZERLAND) 2021; 8:322. [PMID: 33922085 PMCID: PMC8143500 DOI: 10.3390/children8050322] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/27/2021] [Revised: 04/19/2021] [Accepted: 04/20/2021] [Indexed: 12/11/2022]
Abstract
This review discusses the potential drug and device therapies for pediatric heart failure (HF) due to reduced systolic function. It is important to realize that most drugs that are used in pediatric HF are extrapolated from adult cardiology practices or consensus guidelines based on expert opinion rather than on evidence from controlled clinical trials. It is difficult to conclude whether the drugs that are well established in adult HF trials are also beneficial for children because of tremendous heterogeneity in the mechanism of HF in children and variations in the pharmacokinetics and pharmacodynamics of drugs from birth to adolescence. The lessons learned from adult trials can guide pediatric cardiologists to design clinical trials of the newer drugs that are in the pipeline to study their efficacy and safety in children with HF. This paper's focus is that the reader should specifically think through the pathophysiological mechanism of HF and the mode of action of drugs for the selection of appropriate pharmacotherapy. We review the drug and device trials in adults with HF to highlight the knowledge gap that exists in the pediatric HF population.
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Affiliation(s)
- Bibhuti B. Das
- Heart Center, Department of Pediatrics, Mississippi Children’s Hospital, University of Mississippi Medical Center, Jackson, MS 39212, USA;
| | - William B. Moskowitz
- Heart Center, Department of Pediatrics, Mississippi Children’s Hospital, University of Mississippi Medical Center, Jackson, MS 39212, USA;
| | - Javed Butler
- Department of Medicine, University of Mississippi Medical Center, Jackson, MS 39212, USA;
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28
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Tai CJ, Yang YH, Tseng TG, Chang FR, Wang HC. Association Between Digoxin Use and Cancer Incidence: A Propensity Score-Matched Cohort Study With Competing Risk Analysis. Front Pharmacol 2021; 12:564097. [PMID: 33867973 PMCID: PMC8044813 DOI: 10.3389/fphar.2021.564097] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2020] [Accepted: 02/22/2021] [Indexed: 12/29/2022] Open
Abstract
Background: Previous studies neglected death as a critical competing risk while estimating the cancer risk for digoxin users. Therefore, the current study aims to assess the effectiveness of digoxin on cancer prevention by competing risk analysis. Methods: We performed a population-based retrospective cohort study using the Taiwan National Health Insurance Research database between 1998 and 2010. After one-to-one propensity score-matching from 36,160 patients with defined criteria, we enrolled 758 patients both in digoxin and β-blocker group for further analysis. Results: The results showed that the digoxin group had higher all-cause mortality than the β-blocker group in the 4- year (10.4 vs. 4.9%) and 8 years (13.6 vs. 7.0%) follow-up. The subdistribution HR of cancer incidence in the digoxin group compared to the β-blocker group was 1.99 (95% confidence interval [CI]: 1.22-3.01) and 1.46 (95% CI: 1.01-2.15) in the 4 years and 8 years follow-up, respectively. Conclusions: The result of our study showed the usage of digoxin has no benefit in cancer prevention compared with β-blocker. The possibility of β-blocker as a new drug candidate for cancer prevention needs further clinical evaluation. The current study also emphasized the necessity of competing risk analysis applying to similar clinical researches.
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Affiliation(s)
- Chi-Jung Tai
- Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Family Medicine, Pingtung Hospital, Ministry of Health and Welfare, Pingtung, Taiwan
| | - Yi-Hsin Yang
- School of Pharmacy, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
- National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
| | - Tzyy-Guey Tseng
- Department of Family Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Fang-Rong Chang
- Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Hui-Chun Wang
- Graduate Institute of Natural Products, College of Pharmacy, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Marine Biotechnology and Resources, National Sun Yat-sen University, Kaohsiung, Taiwan
- Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung, Taiwan
- Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
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29
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Bhatt AS, Abraham WT, Lindenfeld J, Bristow M, Carson PE, Felker GM, Fonarow GC, Greene SJ, Psotka MA, Solomon SD, Stockbridge N, Teerlink JR, Vaduganathan M, Wittes J, Fiuzat M, O'Connor CM, Butler J. Treatment of HF in an Era of Multiple Therapies: Statement From the HF Collaboratory. JACC-HEART FAILURE 2020; 9:1-12. [PMID: 33309582 DOI: 10.1016/j.jchf.2020.10.014] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Revised: 10/22/2020] [Accepted: 10/26/2020] [Indexed: 01/14/2023]
Abstract
The treatment of heart failure with reduced ejection fraction (HFrEF) has changed considerably over time, particularly with the sequential development of therapies aimed at antagonism of maladaptive biologic pathways, including inhibition of the sympathetic nervous system and the renin-angiotensin aldosterone system. The sequential nature of earlier HFrEF trials allowed the integration of new therapies tested against the background therapy of the time. More recently, multiple heart failure therapies are being evaluated simultaneously, and the number of therapeutic choices for treating HFrEF has grown considerably. In addition, implementation science has lagged behind discovery science in heart failure. Furthermore, given there are currently >200 ongoing clinical trials in heart failure, further complexities are anticipated. In an effort to provide a decision-making framework in the current era of expanding therapeutic options in HFrEF, the Heart Failure Collaboratory convened a multi-stakeholder group, including patients, clinicians, clinical investigators, the U.S. Food and Drug Administration, industry, and payers who met at the U.S. Food and Drug Administration campus on March 6, 2020. This paper summarizes the discussions and expert consensus recommendations.
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Affiliation(s)
- Ankeet S Bhatt
- Cardiology Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - William T Abraham
- Division of Cardiovascular Medicine, The Ohio State University, Columbus, Ohio, USA
| | - JoAnn Lindenfeld
- Cardiology Division, Vanderbilt University, Nashville, Tennessee, USA
| | - Michael Bristow
- Division of Cardiology, University of Colorado, Aurora, Colorado, USA
| | - Peter E Carson
- Department of Cardiology, Washington Veterans Affairs Medical Center, Washington, DC
| | - G Michael Felker
- Duke Clinical Research Institute and Division of Cardiology, Duke University, Durham, North Carolina, USA
| | - Gregg C Fonarow
- Department of Internal Medicine, University of California-Los Angeles, Los Angeles, California, USA
| | - Stephen J Greene
- Duke Clinical Research Institute and Division of Cardiology, Duke University, Durham, North Carolina, USA
| | | | - Scott D Solomon
- Cardiology Division, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | | | - John R Teerlink
- Section of Cardiology, San Francisco Veterans Affairs Medical Center and School of Medicine, University of California San Francisco, San Francisco, California, USA
| | | | | | - Mona Fiuzat
- Duke Clinical Research Institute and Division of Cardiology, Duke University, Durham, North Carolina, USA
| | | | - Javed Butler
- Department of Medicine, University of Mississippi, Jackson, Mississippi, USA.
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30
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Bello MVDO, Bacal F. Heart Failure – Pathophysiology and Current Therapeutic Implications. INTERNATIONAL JOURNAL OF CARDIOVASCULAR SCIENCES 2020. [DOI: 10.36660/ijcs.20200056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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31
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Ott P, Marcus FI. The Role of Digoxin in the Treatment of Chronic Congestive Heart Failure. J Cardiovasc Pharmacol Ther 2020; 1:259-264. [PMID: 10684425 DOI: 10.1177/107424849600100310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
It is now well established that digoxin is an effective drug for the treatment of heart failure. Since treatment with angiotensin-converting enzyme (ACE) inhibitors reduces mortality in congestive heart failure, digoxin should be added to ACE inhibitors in patients with moderate or severe heart failure. The beneficial effects of digoxin may be due, in part, to its well-documented sympathoinhibitory effects that can avert the adverse effects of long-term excessive sympathetic adrenergic stimulation in heart failure.
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Affiliation(s)
- P Ott
- Section of Cardiology, University of Arizona Health Sciences Center, Tucson, Arizona, USA
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32
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Digoxin, mortality, and cardiac hospitalizations in patients with atrial fibrillation and heart failure with reduced ejection fraction and atrial fibrillation: An AF-CHF analysis. Int J Cardiol 2020; 313:48-54. [PMID: 32320783 DOI: 10.1016/j.ijcard.2020.04.047] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/18/2020] [Revised: 04/02/2020] [Accepted: 04/16/2020] [Indexed: 12/22/2022]
Abstract
BACKGROUND Recent publications have raised serious concerns regarding the safety of digoxin for atrial fibrillation (AF). However, the subgroup of patients with reduced ejection fraction and AF have been speculated to derive clinical benefit from digoxin. We aimed to assess the impact of digoxin on mortality and cardiovascular hospitalizations in the Atrial Fibrillation and Congestive Heart Failure (AF-CHF) trial since all AF-CHF patients had an ejection fraction ≤35% and AF. METHODS AND RESULTS Using marginal structural modeling, a contemporary statistical method that overcomes limitations of traditional modeling techniques and reduces bias, we assessed the impact of digoxin on the pre-specified primary and secondary outcomes of the AF-CHF trial, i.e., all-cause, cardiac and arrhythmic death as well as cardiovascular hospitalization. Among 1376 patients, 869 (65%) were on digoxin at one-year follow-up. Over a mean (SD) follow-up of 37 (19) months (maximum 74 months), 445 (32%) patients died, 357 (26%) from cardiovascular causes and 159 (12%) from arrhythmic death. Digoxin was significantly associated with all-cause, cardiac, and arrhythmic death, with estimated hazard ratios (HR) of 1.39 (95% confidence interval [CI] 1.11-1.73, P = 0.004), 1.44 (95% CI 1.13-1.82, P = 0.003), and 2.03 (95% CI 1.63-2.54, P < 0.0001), respectively. Digoxin was not associated with cardiovascular hospitalizations [HR 1.12 (95% CI 0.91-1.37), P = 0.29]. CONCLUSION Digoxin is associated with increased all-cause mortality among patients with combined heart failure with reduced ejection fraction and AF, which is predominantly driven by arrhythmic deaths. In contrast, cardiovascular hospitalizations were not impacted by digoxin.
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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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Zhou J, Cao J, Jin X, Zhou J, Chen Z, Xu D, Yang X, Dong W, Li L, Fan Y, Chen L, Zhong Q, Fu M, Hu K, Ge J. Digoxin is associated with worse outcomes in patients with heart failure with reduced ejection fraction. ESC Heart Fail 2020; 7:138-146. [PMID: 31994361 PMCID: PMC7083440 DOI: 10.1002/ehf2.12539] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 09/02/2019] [Accepted: 09/17/2019] [Indexed: 11/10/2022] Open
Abstract
AIMS The aim of this study was to investigate the impact of digoxin use on the outcomes of patients with heart failure with reduced ejection fraction (HFrEF) and its possible interaction with atrial fibrillation or use of currently guideline-recommended treatments in the real world in China. METHODS AND RESULTS Patients hospitalized with HFrEF from 45 hospitals participating in the China National Heart Failure Registration Study (CN-HF) were enrolled to assess the all-cause mortality, HF mortality, all-cause re-hospitalization, and HF re-hospitalization associated with digoxin use. Eight hundred eighty-two eligible HFrEF patients in the CN-HF registry were included: 372 patients with digoxin and 510 patients without digoxin. Among them, 794 (90.0%) patients were followed up for the endpoint events, with a median follow-up of 28.6 months. Kaplan-Meier survival analysis showed that the all-cause mortality (P < 0.001) and all-cause re-hospitalization (P = 0.020) were significantly higher in digoxin group than non-digoxin group, while HF mortality (P = 0.232) and HF re-hospitalization (P = 0.098) were similar between the two groups. The adjusted Cox proportional-hazards regression analysis demonstrated that digoxin use remained as an independent risk factor for increased all-cause mortality [hazard ratio (HR) 1.76; 95% confidence interval (CI) 1.27-2.44; P = 0.001] and all-cause re-hospitalization (HR 1.27; 95% CI 1.03-1.57; P = 0.029) in HFrEF patients and the predictive value of digoxin for all-cause mortality irrespective of rhythm or in combination with other guideline-recommended therapies. CONCLUSIONS Digoxin use is independently associated with increased risk of all-cause mortality and all-cause re-hospitalization in HFrEF patients.
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Affiliation(s)
- Jingmin Zhou
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai, 200032, China
| | - Juan Cao
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai, 200032, China.,North Sichuan Medical College, Department of Cardiology, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Xuejuan Jin
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai, 200032, China
| | - Jun Zhou
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai, 200032, China
| | - Zhenyue Chen
- Department of Cardiology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China
| | - Dingli Xu
- Department of Cardiology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xinchun Yang
- Heart Center, Beijing Chaoyang Hospital affiliated to Capital Medical University, Beijing, China
| | - Wei Dong
- Department of Cardiology, Chinese People's Liberation Army General Hospital, Beijing, China
| | - Liwen Li
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China
| | - Yuyuan Fan
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai, 200032, China.,North Sichuan Medical College, Department of Cardiology, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Li Chen
- North Sichuan Medical College, Department of Cardiology, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Qiaoqing Zhong
- Department of Cardiology, First People's Hospital of Chenzhou, Chenzhou, China
| | - Micheal Fu
- Section of Cardiology, Department of Medicine, Sahlgrenska University Hospital/Östra Hospital, University of Gothenburg, Gothenburg, Sweden
| | - Kai Hu
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai, 200032, China
| | - Junbo Ge
- Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 180 Fenglin Road, Shanghai, 200032, China
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Tkacheva ON, Ostroumova OD, Kotovskaya YV, Kochetkov AI, Pereverzev AP, Krasnov GS. [Treatment of chronic heart failure: is deprescribing possible?]. ACTA ACUST UNITED AC 2020; 60:126-136. [PMID: 32375625 DOI: 10.18087/cardio.2020.3.n779] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Revised: 10/17/2019] [Accepted: 10/18/2019] [Indexed: 11/18/2022]
Abstract
Deprescribing is a scheduled withdrawal, dose reduction, or replacement of a medicine with a safer one. Several groups of medicinal products (MPs) are used simultaneously in the treatment of chronic heart failure. This increases the risk of adverse drug reactions, particularly in elderly and senile patients. A systematic search for literature allowed evaluating possibilities of deprescribing for the following pharmaceutic groups: 1) MPs influencing the renin-angiotensin-aldosterone system; 2) beta-blockers; 3) digoxin; and 4) diuretics. Three systematic reviews and several studies were analyzed to determine the most feasible and potentially optimal regimens of deprescribing in CHF. It was established that in CHF, deprescribing has a very limited potential for use due to the documented, obvious effect of some MP groups on prediction and severity of clinical symptoms in CHF patients.
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Affiliation(s)
- O N Tkacheva
- Russian Clinical and Research Center of Gerontology, N.I. Pirogov Russian National Research Medical University
| | - O D Ostroumova
- Russian Clinical and Research Center of Gerontology, N.I. Pirogov Russian National Research Medical University
| | - Yu V Kotovskaya
- Russian Clinical and Research Center of Gerontology, N.I. Pirogov Russian National Research Medical University
| | - A I Kochetkov
- Russian Clinical and Research Center of Gerontology, N.I. Pirogov Russian National Research Medical University
| | - A P Pereverzev
- Russian Clinical and Research Center of Gerontology, N.I. Pirogov Russian National Research Medical University
| | - G S Krasnov
- Russian Clinical and Research Center of Gerontology, N.I. Pirogov Russian National Research Medical University
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Ahmed MM, Roukoz H, Trivedi JR, Bhan A, Ravichandran A, Dhawan R, Cowger J, Bhat G, Birks EJ, Slaughter MS, Gopinathannair R. Questionable utility of digoxin in left-ventricular assist device recipients: A multicenter, retrospective analysis. PLoS One 2019; 14:e0225628. [PMID: 31765397 PMCID: PMC6876793 DOI: 10.1371/journal.pone.0225628] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Accepted: 10/29/2019] [Indexed: 11/19/2022] Open
Abstract
Background While clinical experience with left ventricular assist devices (LVAD) continues to grow and evolve, little is known regarding the ongoing use of certain medications in this population. We sought to evaluate the utility of digoxin in LVAD recipients and its association with outcomes. Methods A total of 505 patients who underwent continuous-flow LVAD implantation at 5 centers from 2007–2015 were included. Patients were divided into 4 groups: not on digoxin at any time (ND; n = 257), received digoxin pre implant (PreD; n = 144), received digoxin pre and post implant (ContD; n = 55), and received digoxin only post implant (PostD; n = 49). Survival and all-cause readmission were compared between the 4 groups. Results There was no difference in survival at 1 year nor at 3 years between groups (ND = 88%, 66%, respectively; PreD = 85%, 66%; ContD = 86%, 57%; PostD = 90%, 51%; p = 0.7). Readmission per 100 days also was not different between groups (ND = 0.5, PreD = 0.6, ContD = 0.5, PostD = 0.7; p = 0.1). Conclusions In this large, multicenter cohort, use of digoxin was not associated with any significant benefit in regard to mortality or hospitalization in patients supported with a continuous-flow LVAD. Importantly, its discontinuation post implant did not worsen all-cause hospitalization or survival.
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Affiliation(s)
- Mustafa M. Ahmed
- Division of Cardiovascular Medicine, Department of Medicine, University of Florida, Gainesville, FL, United States of America
- * E-mail:
| | - Henri Roukoz
- Cardiovascular Division, Electrophysiology Section, University of Minnesota, Minneapolis, MN, United States of America
| | - Jaimin R. Trivedi
- Department of Cardiovascular and Thoracic Surgery, University of Louisville, Louisville, KY, United States of America
| | - Adarsh Bhan
- Heart Institute, Advocate Christ Medical Center, Oak Lawn, IL, United States of America
| | - Ashwin Ravichandran
- St. Vincent Heart Center of Indiana, Indianapolis, IN, United States of America
| | - Rahul Dhawan
- University of Nebraska, Omaha, Nebraska, United States of America
| | - Jennifer Cowger
- Henry Ford Hospital, Detroit, Michigan, United States of America
| | - Geetha Bhat
- Heart Institute, Advocate Christ Medical Center, Oak Lawn, IL, United States of America
| | - Emma J. Birks
- Division of Cardiovascular Medicine, University of Louisville, Louisville, Kentucky, United States of America
| | - Mark S. Slaughter
- Department of Cardiovascular and Thoracic Surgery, University of Louisville, Louisville, KY, United States of America
| | - Rakesh Gopinathannair
- Kansas City Heart Rhythm Institute and Research Foundation, Overland Park, Kansas, United States of America
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Picollo CT, Santos AAD, Antonio EL, Silva JMA, Bocalini D, Serra AJ, Ihara SSM, Tucci PJF. Digitoxin Attenuates Heart Failure, Reduces Myocardial Hypertrophy, and Preserves the Calcium-Binding Proteins in Infarcted Rats. J Cardiovasc Pharmacol Ther 2019; 25:265-272. [PMID: 31714152 DOI: 10.1177/1074248419887708] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
We previously showed that digitoxin prolongs the survival of rats with heart failure due to myocardial infarction (MI). In this study, we evaluated the effect of digitoxin on myocardial structure, ventricular function, and proteins involved in calcium kinetics. Seventy-two rats with MI >35% of the left ventricle were randomly assigned to 4 treatment groups: sham (n = 15), digitoxin (n = 11), infarction (n = 20), and infarction + digitoxin (n = 26). The rats were assessed 120 days after surgery by echocardiogram, hemodynamics, papillary muscle mechanics, collagen content, cardiomyocyte nuclear volume, and Western blot analysis of proteins involved in calcium kinetics. Digitoxin was administered via the rat chow. Two-way analysis of variance was used for comparisons. Myocardial infarction caused inotropic impairment, pulmonary congestion, increase of nuclear volume, myocardial collagen, and Na+/Ca2+ exchanger levels, and decreased SERCA2 and phosphorylated phospholamban levels. Treatment with digitoxin showed improvements in cardiac remodeling, inotropism, ventricular performance, pulmonary congestion, collagen accumulation, nuclear volume, and proteins involved in calcium kinetics. In rats with heart failure due to MI, long-term treatment with digitoxin attenuates congestive heart failure, mitigates myocardial remodeling and contractile impairment, and preserves myocardial levels of proteins involved in calcium kinetics.
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Affiliation(s)
- Camila T Picollo
- Cardiology Division, Department of Medicine, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Alexandra A Dos Santos
- Cardiology Division, Department of Medicine, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Ednei L Antonio
- Cardiology Division, Department of Medicine, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Jairo M A Silva
- Cardiology Division, Department of Medicine, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | | | - Andrey Jorge Serra
- Cardiology Division, Department of Medicine, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Silvia S M Ihara
- Department of Pathology, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Paulo J F Tucci
- Cardiology Division, Department of Medicine, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
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Long L, Zhao HT, Shen LM, He C, Ren S, Zhao HL. Hemodynamic effects of inotropic drugs in heart failure: A network meta-analysis of clinical trials. Medicine (Baltimore) 2019; 98:e18144. [PMID: 31764856 PMCID: PMC6882628 DOI: 10.1097/md.0000000000018144] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Revised: 10/12/2019] [Accepted: 10/30/2019] [Indexed: 11/27/2022] Open
Abstract
BACKGROUND There is currently no consensus on the appropriate selection of inotropic therapy in ventricular dysfunction. The objective of the study was to detect the effects of different inotropes on the hemodynamics of patients who developed low cardiac output. METHODS PubMed, Embase, and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched (all updated December 31, 2017). The inclusion criteria were as follows: low cardiac index (CI < 2.5 L/min/m) or New York Heart Association class II-IV, and at least 1 group receiving an inotropic drug compared to another group receiving a different inotropic/placebo treatment. The exclusion criteria were studies published as an abstract only, crossover studies, and studies with a lack of data on the cardiac index. RESULTS A total of 1402 patients from 37 trials were included in the study. Inotropic drugs were shown to increase the cardiac index (0.32, 95%CI:0.25, 0.38), heart rate (7.68, 95%CI:6.36, 9.01), and mean arterial pressure (3.17, 95%CI:1.96, 4.38) than the placebo. Overall, the pooled estimates showed no difference in terms of cardiac index, heart rate, mean arterial pressure, systemic vascular resistance, and mean pulmonary arterial pressure among the groups receiving different inotropes. CONCLUSIONS Our systematic review found that inotrope therapy is not associated with the amelioration of hemodynamics. An accurate evaluation of the benefits and risks, and selection of the correct inotropic agent is required in all clinical settings.
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Affiliation(s)
| | - Hao-tian Zhao
- Department of Ultrasound, Hebei General Hospital, Hebei, China
| | | | - Cong He
- Department of Intensive Care Unit
| | - Shan Ren
- Department of Intensive Care Unit
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Malik A, Masson R, Singh S, Wu WC, Packer M, Pitt B, Waagstein F, Morgan CJ, Allman RM, Fonarow GC, Ahmed A. Digoxin Discontinuation and Outcomes in Patients With Heart Failure With Reduced Ejection Fraction. J Am Coll Cardiol 2019; 74:617-627. [PMID: 31370952 PMCID: PMC10465068 DOI: 10.1016/j.jacc.2019.05.064] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2019] [Revised: 05/23/2019] [Accepted: 05/28/2019] [Indexed: 11/26/2022]
Abstract
BACKGROUND The deleterious effects of discontinuation of digoxin on outcomes in ambulatory patients with chronic heart failure (HF) with reduced ejection fraction (HFrEF) receiving angiotensin-converting enzyme inhibitors are well-documented. OBJECTIVES The authors sought to determine the relationship between digoxin discontinuation and outcomes in hospitalized patients with HFrEF receiving more contemporary guideline-directed medical therapies including beta-blockers and mineralocorticoid receptor antagonists. METHODS Of the 11,900 hospitalized patients with HFrEF (EF ≤45%) in the Medicare-linked OPTIMIZE-HF (Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure) registry, 3,499 received pre-admission digoxin, which was discontinued in 721 patients. Using propensity scores for digoxin discontinuation, estimated for each of the 3,499 patients, a matched cohort of 698 pairs of patients, balanced on 50 baseline characteristics (mean age 76 years; mean EF 28%; 41% women; 13% African American; 65% on beta-blockers) was assembled. RESULTS Four-year post-discharge, digoxin discontinuation was associated with significantly higher risks of HF readmission (hazard ratio [HR]: 1.21; 95% confidence interval [CI]: 1.05 to 1.39; p = 0.007), all-cause readmission (HR: 1.16; 95% CI: 1.04 to 1.31; p = 0.010), and the combined endpoint of HF readmission or all-cause mortality (HR: 1.20; 95% CI: 1.07 to 1.34; p = 0.002), but not all-cause mortality (HR: 1.09; 95% CI: 0.97 to 1.24; p = 0.163). Discontinuation of digoxin was associated with a significantly higher risk of all 4 outcomes at 6 months and 1 year post-discharge. At 30 days, digoxin discontinuation was associated with higher risks of all-cause mortality (HR: 1.80; 95% CI: 1.26 to 2.57; p = 0.001) and the combined endpoint (HR: 1.36; 95% CI: 1.09 to 1.71; p = 0.007), but not of HF readmission (HR: 1.19; 95% CI: 0.90 to 1.59; p = 0.226) or all-cause readmission (HR: 1.03; 95% CI: 0.84 to 1.26; p = 0.778). CONCLUSIONS Among hospitalized older patients with HFrEF on more contemporary guideline-directed medical therapies, discontinuation of pre-admission digoxin therapy was associated with poor outcomes.
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Affiliation(s)
- Awais Malik
- Veterans Affairs Medical Center, Washington, DC; Georgetown University, Washington, DC
| | - Ravi Masson
- Veterans Affairs Medical Center, Washington, DC; Georgetown University, Washington, DC
| | - Steven Singh
- Veterans Affairs Medical Center, Washington, DC; Georgetown University, Washington, DC
| | - Wen-Chih Wu
- Veterans Affairs Medical Center, Providence, Rhode Island; Brown University, Providence, Rhode Island
| | | | | | | | - Charity J Morgan
- Veterans Affairs Medical Center, Washington, DC; University of Alabama at Birmingham, Birmingham, Alabama
| | - Richard M Allman
- University of Alabama at Birmingham, Birmingham, Alabama; George Washington University, Washington, DC
| | - Gregg C Fonarow
- University of California, Los Angeles, Los Angeles, California
| | - Ali Ahmed
- Veterans Affairs Medical Center, Washington, DC; Georgetown University, Washington, DC; George Washington University, Washington, DC.
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Uretsky BF, Vallurupalli S. Is the Digitalis Leaf Still Withering? J Am Coll Cardiol 2019; 74:628-630. [DOI: 10.1016/j.jacc.2019.06.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Accepted: 06/10/2019] [Indexed: 10/26/2022]
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Malhamé I, Gandhi C, Tarabulsi G, Esposito M, Lombardi K, Chu A, Chen KK. Maternal monitoring and safety considerations during antiarrhythmic treatment for fetal supraventricular tachycardia. Obstet Med 2019; 12:66-75. [PMID: 31217810 PMCID: PMC6560838 DOI: 10.1177/1753495x18808118] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2018] [Accepted: 09/25/2018] [Indexed: 11/16/2022] Open
Abstract
Fetal tachycardia is a rare complication during pregnancy. After exclusion of maternal and fetal conditions that can result in a secondary fetal tachycardia, supraventricular tachycardia is the most common cause of a primary sustained fetal tachyarrhythmia. In cases of sustained fetal supraventricular tachycardia, maternal administration of digoxin, flecainide, sotalol, and more rarely amiodarone, is considered. As these medications have the potential to cause significant adverse effects, we sought to examine maternal safety during transplacental treatment of fetal supraventricular tachycardia. In this narrative review we summarize the literature addressing pharmacologic properties, monitoring, and adverse reactions associated with medications most commonly prescribed for transplacental therapy of fetal supraventricular tachycardia. We also describe maternal monitoring practices and adverse events currently reported in the literature. In light of our findings, we provide clinicians with a suggested maternal monitoring protocol aimed at optimizing safety.
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Affiliation(s)
- Isabelle Malhamé
- Department of Medicine, Women and Infants Hospital, Providence, RI, USA
| | - Christy Gandhi
- Department of Medicine, Women and Infants Hospital, Providence, RI, USA
| | - Gofran Tarabulsi
- Department of Medicine, Women and Infants Hospital, Providence, RI, USA
| | - Matthew Esposito
- Department of Obstetrics and Gynecology, Women and Infants Hospital, Providence, RI, USA
| | - Kristin Lombardi
- Department of Pediatrics, Hasbro Children’s Hospital, Providence, RI, USA
| | - Antony Chu
- Department of Medicine, Rhode Island Hospital, Providence, RI, USA
| | - Kenneth K Chen
- Department of Medicine, Women and Infants Hospital, Providence, RI, USA
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Bavendiek U, Berliner D, Dávila LA, Schwab J, Maier L, Philipp SA, Rieth A, Westenfeld R, Piorkowski C, Weber K, Hänselmann A, Oldhafer M, Schallhorn S, von der Leyen H, Schröder C, Veltmann C, Störk S, Böhm M, Koch A, Bauersachs J. Rationale and design of the DIGIT-HF trial (DIGitoxin to Improve ouTcomes in patients with advanced chronic Heart Failure): a randomized, double-blind, placebo-controlled study. Eur J Heart Fail 2019; 21:676-684. [PMID: 30892806 PMCID: PMC6607489 DOI: 10.1002/ejhf.1452] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 01/31/2019] [Accepted: 02/06/2019] [Indexed: 12/11/2022] Open
Abstract
AIMS Despite recent advances in the treatment of chronic heart failure (HF), mortality and hospitalizations still remain high. Additional therapies to improve mortality and morbidity are urgently needed. The efficacy of cardiac glycosides - although regularly used for HF treatment - remains unclear. DIGIT-HF was designed to demonstrate that digitoxin on top of standard of care treatment improves mortality and morbidity in patients with HF and a reduced ejection fraction (HFrEF). METHODS Patients with chronic HF, New York Heart Association (NYHA) functional class III-IV and left ventricular ejection fraction (LVEF) ≤ 40%, or patients in NYHA functional class II and LVEF ≤ 30% are randomized 1:1 in a double-blind fashion to treatment with digitoxin (target serum concentration 8-18 ng/mL) or matching placebo. Randomization is stratified by centre, sex, NYHA functional class (II, III, or IV), atrial fibrillation, and treatment with cardiac glycosides at baseline. A total of 2190 eligible patients will be included in this clinical trial (1095 per group). All patients receive standard of care treatment recommended by expert guidelines upon discretion of the treating physician. The primary outcome is a composite of all-cause mortality or hospital admission for worsening HF (whatever occurs first). Key secondary endpoints are all-cause mortality, hospital admission for worsening HF, and recurrent hospital admission for worsening HF. CONCLUSION The DIGIT-HF trial will provide important evidence, whether the cardiac glycoside digitoxin reduces the risk for all-cause mortality and/or hospital admission for worsening HF in patients with advanced chronic HFrEF on top of standard of care treatment.
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Affiliation(s)
- Udo Bavendiek
- Department of Cardiology and AngiologyHannover Medical SchoolHannoverGermany
| | - Dominik Berliner
- Department of Cardiology and AngiologyHannover Medical SchoolHannoverGermany
| | | | - Johannes Schwab
- Department of Cardiology, Cardiovascular Center, Clinical Center NuernbergParacelsus Medical UniversityNuernbergGermany
| | - Lars Maier
- Department of Internal Medicine IIUniversity Medical Center RegensburgRegensburgGermany
| | - Sebastian A. Philipp
- Department of Cardiology and Intensive Care MedicineElbe Clinic StadeStadeGermany
| | - Andreas Rieth
- Department of Cardiology, Kerckhoff HeartRheuma and Thoracic CenterBad NauheimGermany
| | - Ralf Westenfeld
- Department of Cardiology, Pulmonology, and Vascular Medicine, Medical FacultyUniversity DuesseldorfDuesseldorfGermany
| | - Christopher Piorkowski
- Department of Electrophysiology, Heart CenterUniversity of Technology DresdenDresdenGermany
| | - Kristina Weber
- Department of BiostatisticsHannover Medical SchoolHannoverGermany
| | - Anja Hänselmann
- Department of Cardiology and AngiologyHannover Medical SchoolHannoverGermany
| | | | - Sven Schallhorn
- Department of Cardiology and AngiologyHannover Medical SchoolHannoverGermany
| | | | - Christoph Schröder
- Institute of Clinical PharmacologyHannover Medical SchoolHannoverGermany
| | - Christian Veltmann
- Department of Cardiology and AngiologyHannover Medical SchoolHannoverGermany
| | - Stefan Störk
- Department of Internal Medicine IUniversity Hospital WuerzburgWuerzburgGermany
| | - Michael Böhm
- Department of Internal Medicine IIIUniversity Hospital of the SaarlandHomburgGermany
| | - Armin Koch
- Department of BiostatisticsHannover Medical SchoolHannoverGermany
| | - Johann Bauersachs
- Department of Cardiology and AngiologyHannover Medical SchoolHannoverGermany
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Affiliation(s)
- James P. Stevenson
- Southern Adelaide Palliative Services Repatriation General Hospital Daw Park, South Australia, Australia
| | - David C. Currow
- Department of Palliative and Supportive Services Flinders University Bedford Park, South Australia, Australia
| | - Amy P. Abernethy
- Division of Medical Oncology Department of Medicine Duke University Medical Centre Durham, North Carolina, USA
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Chen SQ, Ding WH, Zhang N, Xiang Q, Cui YM, Zhao X. Influence of OATP1B1 and OATP1B3 mutations and glomerular filtration rate on trough serum digoxin concentration in the Chinese population: A prospective cohort study. Medicine (Baltimore) 2019; 98:e15088. [PMID: 30946364 PMCID: PMC6456138 DOI: 10.1097/md.0000000000015088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
Abstract
Polymorphisms of organic anion transporting polypeptides (OATPs) have been reported to affect trough serum digoxin concentration (SDC). However, the association of these polymorphisms with trough SDC in Chinese heart failure patients has not been studied. We aim to explore whether OATP1B1 388A>G, OATP1B1 521T>C, and OATP1B3 699G>A influence trough SDC in Chinese heart failure patients and to make clinical recommendations.Chinese patients (n = 104) diagnosed with heart failure under long-term digoxin therapy (0.125 mg daily) were enrolled in this study. Blood samples were collected for the analysis of trough SDC (immunofluorescence) and the polymorphisms of OATP1B1 388A>G, OATP1B1 521T>C, and OATP1B3 699G>A (PCR-RFLP and Sanger sequencing).Patients with glomerular filtration rate (GFR) under 30 mL/min had significantly higher trough SDC (1.20 ± 0.50 ng/mL) than recommended trough SDC for heart failure patients. Trough SDC was not significantly influenced by mutations of OATP1B1 388A>G (P = .890), 521T>C (P = .054), and OATP1B3 699G>A (P = .854). Patients with OATP1B1 521T>C mutant-type carrier had slightly higher trough SDC (0.98 ± 0.53 ng/mL) than those with wild-type carrier (0.74 ± 0.40 ng/mL) when they have repaired renal function.Heart failure patients with severe renal dysfunction (GFR<60 mL/min) and/or OATP1B1 521T>C mutant-type carriers are recommended a smaller dosage of digoxin and strict therapeutic drug monitoring.
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Affiliation(s)
| | - Wen-hui Ding
- Department of Cardiology, Peking University First Hospital, Beijing, China
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Llàcer P, Núñez J, Bayés-Genís A, Conde Martel A, Cabanes Hernández Y, Díez Manglano J, Álvarez Rocha P, Soler Rangel L, Gómez Del Olmo V, Manzano L, Montero Pérez-Barquero M. Digoxin and prognosis of heart failure in older patients with preserved ejection fraction: Importance of heart rate. Results from an observational and multicenter study. Eur J Intern Med 2019; 60:18-23. [PMID: 30360944 DOI: 10.1016/j.ejim.2018.10.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2018] [Revised: 09/06/2018] [Accepted: 10/16/2018] [Indexed: 12/28/2022]
Abstract
BACKGROUND The value of digoxin in heart failure (HF) remains controversial, particularly in patients with preserved ejection fraction (HFpEF). This study evaluated the 1-year risk of events after digoxin treatment for acute heart failure (AHF) in patients >70 years old with HFpEF. METHODS 1833 patients were included in this analysis (mean age, 82 years). The main endpoints were all-cause death and the composite of death and/or HF re-admission within 1 year. Cox regression analysis was used to evaluate the association between digoxin treatment and prognosis. RESULTS 401 patients received digoxin treatment; of these, 86% had atrial fibrillation. The mean baseline heart rate was 86 ± 22 bpm. At the 1-year follow-up, 375 patients (20.5%) died and 684 (37.3%) presented composite endpoints. Patients treated with digoxin showed higher rates of death (3.21 vs. 2.44 per 10 person-years, p = .019) and composite endpoint (6.72 vs. 5.18 per 10 person-years, p = .003). After multivariate adjustment, digoxin treatment remained associated with increased risks of death (HR = 1.46, 95% CI: 1.16-1.85, p = .001) and the composite endpoint (HR = 1.35, 95% CI: 1.13-1.61, p = .001). A distinctive prognostic effect of digoxin was found across the heart rate continuum; the risks for both endpoints were higher at lower heart rates and neutral at higher heart rates (p of the interactions = 0.007 and 0.03, respectively). CONCLUSIONS In older patients with HFpEF discharged after AHF, digoxin treatment was associated with increased mortality and/or re-admission, particularly in patients with lower heart rates.
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Affiliation(s)
- Pau Llàcer
- Internal Medicine Department, Hospital de Manises, Valencia, Spain.
| | - Julio Núñez
- Cardiology Department, Hospital Clínico Universitario, INCLIVA, Universitat de València, Valencia, Spain; CIBER Cardiovascular, Madrid, Spain
| | - Antoni Bayés-Genís
- CIBER Cardiovascular, Madrid, Spain; Heart Institute, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Department of Medicine, Autonomous University of Barcelona, Barcelona, Spain
| | - Alicia Conde Martel
- Internal Medicine Department, Hospital Universitario de Gran Canaria Dr. Negrín, Las Palmas, Spain
| | | | - Jesús Díez Manglano
- Internal Medicine Department, Hospital Universitario Miguel Servet, Zaragoza, Spain
| | - Pablo Álvarez Rocha
- Internal Medicine and Cardiology Department, Hospital de Clínicas Dr. Manuel Quintela, Montevideo, Uruguay
| | - Llanos Soler Rangel
- Internal Medicine Department, Hospital Universitario Infanta Sofía, Madrid, Spain
| | - Vicente Gómez Del Olmo
- Internal Medicine Department, Hospital Universitario Ramón y Cajal, University of Alcalá (IRYCIS), Madrid, Spain
| | - Luis Manzano
- Internal Medicine Department, Hospital Universitario Ramón y Cajal, University of Alcalá (IRYCIS), Madrid, Spain
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Abstract
The aim of this study is to perform a systematic review of the costing methodological approaches adopted by published cost-of-illness (COI) studies. A systematic review was performed to identify cost-of-illness studies of heart failure published between January 2003 and September 2015 via computerized databases such as Pubmed, Wiley Online, Science Direct, Web of Science, and Cumulative Index to Nursing and Allied Health Literature (CINAHL). Costs reported in the original studies were converted to 2014 international dollars (Int$). Thirty five out of 4972 studies met the inclusion criteria. Nineteen out of the 35 studies reported the costs as annual cost per patient, ranging from Int$ 908.00 to Int$ 84,434.00, while nine studies reported costs as per hospitalization, ranging from Int$ 3780.00 to Int$ 34,233.00. Cost of heart failure increased as condition of heart failure worsened from New York Heart Association (NYHA) class I to NYHA class IV. Hospitalization cost was found to be the main cost driver to the total health care cost. The annual cost of heart failure ranges from Int$ 908 to Int$ 40,971 per patient. The reported cost estimates were inconsistent across the COI studies, mainly due to the variation in term of methodological approaches such as disease definition, epidemiological approach of study, study perspective, cost disaggregation, estimation of resource utilization, valuation of unit cost components, and data sources used. Such variation will affect the reliability, consistency, validity, and relevance of the cost estimates across studies.
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Affiliation(s)
- Asrul Akmal Shafie
- Discipline of Social Administrative Pharmacy, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800, Minden, Penang, Malaysia.
| | - Yui Ping Tan
- Discipline of Social Administrative Pharmacy, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800, Minden, Penang, Malaysia
| | - Chin Hui Ng
- Discipline of Social Administrative Pharmacy, School of Pharmaceutical Sciences, Universiti Sains Malaysia, 11800, Minden, Penang, Malaysia
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Kalmanovich E, Audurier Y, Akodad M, Mourad M, Battistella P, Agullo A, Gaudard P, Colson P, Rouviere P, Albat B, Ricci JE, Roubille F. Management of advanced heart failure: a review. Expert Rev Cardiovasc Ther 2018; 16:775-794. [PMID: 30282492 DOI: 10.1080/14779072.2018.1530112] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
INTRODUCTION Heart failure (HF) has become a global pandemic. Despite recent developments in both medical and device treatments, HF incidences continues to increase. The current definition of HF restricts itself to stages at which clinical symptoms are apparent. In advanced heart failure (AdHF), it is universally accepted that all patients are refractory to traditional therapies. As the number of HF patients increase, so does the need for additional treatments, with an increased proportion of patients requiring advanced therapies. Areas covered: This review discusses extensive evidence for the effect of medical treatment on HF, although the data on the effect on AdHF is scare. Authors review the relevant literature for treating AdHF patients. Furthermore, mechanical circulatory devices (MCD) have emerged as an alternative to heart transplantation and have been shown to enhance quality of life and reduce mortality therefore authors also review the current literature on the different MCD and technologies. Expert commentary: More patients will need advanced therapies, as the access to heart transplantation is limited by the number of available donors. AdHF patients should be identified timely since the window of opportunities for advanced therapy is narrow as their morbidity is progressive and survival is often short.
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Affiliation(s)
- Eran Kalmanovich
- a Department of Cardiology , Montpellier University Hospital , Montpellier , France
| | - Yohan Audurier
- b Pharmacy Department , University Hospital of Montpellier , Montpellier , France
| | - Mariama Akodad
- a Department of Cardiology , Montpellier University Hospital , Montpellier , France
| | - Marc Mourad
- c Department of Anesthesiology and Critical Care Medicine , Arnaud de Villeneuve Hospital , Montpellier , France.,d PhyMedExp , University of Montpellier , Montpellier , France
| | - Pascal Battistella
- a Department of Cardiology , Montpellier University Hospital , Montpellier , France
| | - Audrey Agullo
- a Department of Cardiology , Montpellier University Hospital , Montpellier , France
| | - Philippe Gaudard
- c Department of Anesthesiology and Critical Care Medicine , Arnaud de Villeneuve Hospital , Montpellier , France.,d PhyMedExp , University of Montpellier , Montpellier , France
| | - Pascal Colson
- c Department of Anesthesiology and Critical Care Medicine , Arnaud de Villeneuve Hospital , Montpellier , France.,d PhyMedExp , University of Montpellier , Montpellier , France
| | - Philippe Rouviere
- e Department of Cardiovascular Surgery , University Hospital of Montpellier, University of Montpellier , Montpellier , France
| | - Bernard Albat
- e Department of Cardiovascular Surgery , University Hospital of Montpellier, University of Montpellier , Montpellier , France
| | - Jean-Etienne Ricci
- f Department of Cardiology , Nîmes University Hospital, University of Montpellier , Nîmes , France
| | - François Roubille
- a Department of Cardiology , Montpellier University Hospital , Montpellier , France.,d PhyMedExp , University of Montpellier , Montpellier , France
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48
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Alkhawam H, Abo-Salem E, Zaiem F, Ampadu J, Rahman A, Sulaiman S, Zaitoun A, Helmy T, Vittorio TJ. Effect of digitalis level on readmission and mortality rate among heart failure reduced ejection fraction patients. Heart Lung 2018; 48:22-27. [PMID: 30172414 DOI: 10.1016/j.hrtlng.2018.07.006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2018] [Revised: 07/06/2018] [Accepted: 07/11/2018] [Indexed: 12/28/2022]
Abstract
INTRODUCTION Digitalis has been used for over 200 years to treat patients with heart failure, and evidence supports its use to improve clinical symptoms and quality of life, but not survival. The objective of this retrospective study was to evaluate the effects of digitalis on readmission and mortality in patients with heart failure with reduced ejection fraction (HFrEF) who were receiving current guideline recommended medical therapy. METHODS We reviewed medical record data from a retrospective cohort study of 1047 patients admitted to the hospital from 2005 to 2014 with decompensated HFrEF. 244 received digitalis, at some point during patient trajectory, and 803 never received digitalis. The primary outcomes of interest were the length of stay in hospital, readmission rates after discharge at 1, 6, 12, and 24 months and the overall mortality rate, at the same time points. RESULTS We studied the effects of digitalis after adjusting for age, sex, race, potentially confounding comorbidities, and prescription medications. Digitalis treatment is associated with decreases in EF in patients with HFrEF (OR = -2.83, P < 0.001) and was associated with an increased readmission rate for any reason after discharge from the hospital at 6, 12, and 24 months, 53%, 34%, and 35%, respectively. No statistically significant difference was found between patients who received digitalis and those who did not (referent group) for the length of hospital stay and overall mortality rate. CONCLUSION Digitalis use is associated with increased re-admission rates for any reason following discharge from the hospital at 6, 12, and 24 months.
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Affiliation(s)
- Hassan Alkhawam
- Center for Comprehensive Cardiovascular Care, St Louis University, St Louis, MO, United States; Department of Medicine, Icahn School of Medicine at Mount Sinai (Elmhurst), Elmhurst, NY, United States.
| | - Elsayed Abo-Salem
- Center for Comprehensive Cardiovascular Care, St Louis University, St Louis, MO, United States
| | - Feras Zaiem
- Department of Pathology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, United States
| | - James Ampadu
- Center for Comprehensive Cardiovascular Care, St Louis University, St Louis, MO, United States
| | - Aleef Rahman
- School of Medicine, St. George's University, St. George's, Grenada
| | - Samian Sulaiman
- Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, United States
| | - Anwar Zaitoun
- Division of Cardiology, Saint John Hospital and Medical Center, Detroit, MI, United States
| | - Tarek Helmy
- Center for Comprehensive Cardiovascular Care, St Louis University, St Louis, MO, United States
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Katsi V, Georgiopoulos G, Laina A, Koutli E, Parissis J, Tsioufis C, Nihoyannopoulos P, Tousoulis D. Left ventricular ejection fraction as therapeutic target: is it the ideal marker? Heart Fail Rev 2018; 22:641-655. [PMID: 28601914 DOI: 10.1007/s10741-017-9624-5] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Heart failure (HF) consists the fastest growing clinical cardiac disease. HF patients are categorized on the basis of underlying left ventricular ejection fraction (LVEF) into HF with preserved EF (HFpEF), reduced LVEF (HFrEF), and mid-range LVEF (HFmrEF). While LVEF is the most commonly used surrogate marker of left ventricular (LV) systolic function, the implementation of two-dimensional echocardiography in estimating this parameter imposes certain caveats on current HF classification. Most importantly, LVEF could fluctuate in repeated measurements or even recover after treatment, thus blunting the borders between proposed categories of HF and enabling upward classification of patients. Under this prism, we sought to summarize possible procedures to improve systolic function in patients with HFrEF either naturally or by the means of pharmacologic and non-pharmacologic treatment and devices. Therefore, we reviewed established pharmacotherapy, including beta-blockers, inhibitors of renin-angiotensin-aldosterone axis, statins, and digoxin as well as novel treatments like sacubitril-valsartan, ranolazine, and ivabradine. In addition, we assessed evidence in favor of cardiac resynchronization therapy and exercise training programs. Finally, innovative therapeutic strategies, including stem cells, xanthine oxidase inhibitors, antibiotic regimens, and omega-3 polyunsaturated fatty acids, were also taken into consideration. We concluded that LVEF is subject to changes in HF after intervention and besides the aforementioned HFrEF, HFpEF, and HFmrEF categories, a new entity of HF patients with recovered LVEF should be acknowledged. An improved global and refined LV function assessment by sophisticated imaging modalities and circulating biomarkers is expected to render HF classification more accurate and indicate patients with viable-yet dysfunctional-myocardium and favorable characteristics as the ideal candidates for LVEF recovery by individualized HF therapy.
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Affiliation(s)
- V Katsi
- 1st Cardiology Department, National and Kapodistrian University of Athens, University Medical School, Hippokration Hospital, Vasilissis Sofias 114, 11528, Athens, Greece
| | - G Georgiopoulos
- 1st Cardiology Department, National and Kapodistrian University of Athens, University Medical School, Hippokration Hospital, Vasilissis Sofias 114, 11528, Athens, Greece.
| | - A Laina
- 1st Cardiology Department, National and Kapodistrian University of Athens, University Medical School, Hippokration Hospital, Vasilissis Sofias 114, 11528, Athens, Greece
| | - E Koutli
- 1st Cardiology Department, National and Kapodistrian University of Athens, University Medical School, Hippokration Hospital, Vasilissis Sofias 114, 11528, Athens, Greece
| | - J Parissis
- 1st Cardiology Department, National and Kapodistrian University of Athens, University Medical School, Hippokration Hospital, Vasilissis Sofias 114, 11528, Athens, Greece
| | - C Tsioufis
- 1st Cardiology Department, National and Kapodistrian University of Athens, University Medical School, Hippokration Hospital, Vasilissis Sofias 114, 11528, Athens, Greece
| | - P Nihoyannopoulos
- 1st Cardiology Department, National and Kapodistrian University of Athens, University Medical School, Hippokration Hospital, Vasilissis Sofias 114, 11528, Athens, Greece
| | - D Tousoulis
- 1st Cardiology Department, National and Kapodistrian University of Athens, University Medical School, Hippokration Hospital, Vasilissis Sofias 114, 11528, Athens, Greece
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50
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Ambrosy AP, Bhatt AS, Stebbins AL, Wruck LM, Fudim M, Greene SJ, Kraus WE, O'Connor CM, Piña IL, Whellan DJ, Mentz RJ. Prevalent digoxin use and subsequent risk of death or hospitalization in ambulatory heart failure patients with a reduced ejection fraction-Findings from the Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) randomized controlled trial. Am Heart J 2018; 199:97-104. [PMID: 29754673 DOI: 10.1016/j.ahj.2018.02.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/29/2017] [Accepted: 02/03/2018] [Indexed: 12/27/2022]
Abstract
BACKGROUND Despite more than 200 years of clinical experience and a pivotal trial, recently published research has called into question the safety and efficacy of digoxin therapy in heart failure (HF). METHODS HF-ACTION (ClinicalTrials.gov Number: NCT00047437) enrolled 2331 outpatients with HF and an EF ≤35% between April 2003 and February 2007 and randomized them to aerobic exercise training versus usual care. Patients were grouped according to prevalent digoxin status at baseline. The association between digoxin therapy and outcomes was assessed using Cox proportional hazard and inverse-probability weighted (IPW) regression models adjusted for demographics, medical history, medications, laboratory values, quality of life, and exercise parameters. RESULTS The prevalence of digoxin therapy decreased from 52% during the first 6 months of enrollment to 35% at the end of the HF-ACTION trial (P <0.0001). Study participants were 59± 13 years of age, 72% were male, and approximately half had an ischemic etiology of HF. Patients receiving digoxin at baseline tended to be younger and were more likely to report New York Heart Association functional class III/IV symptoms (rather than class II) compared to those not receiving digoxin. Patients taking digoxin had worse baseline exercise capacity as measured by peak VO2 and 6-min walk test and greater impairments in health status as reflected by the Kansas City Cardiomyopathy Questionnaire. The association between digoxin and the risk of death or hospitalization differed depending on whether Cox proportional hazard (Hazard Ratio 1.03, 95% Confidence Interval 0.92-1.16; P = .62) or IPW regression models (HR 1.08, 95% CI 1.00-1.17; P = .057) were used to adjust for potential confounders. CONCLUSION Although digoxin use was associated with high-risk clinical features, the association between digoxin therapy and outcomes was dependent on the statistical methods used for multivariable adjustment. Clinical equipoise exists and additional prospective research is required to clarify the role of digoxin in contemporary clinical practice including its effects on functional capacity, quality of life, and long-term outcomes.
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