Observational cohort study of the safety of digoxin use in women with heart failure
Open accessAbstract
OBJECTIVES: This study aims to assess whether digoxin has a different effect on mortality risk for women than it does for men in patients with heart failure (HF). DESIGN: This study uses the UK-based The Health Information Network population database in a cohort study of the impact of digoxin exposure on mortality for men and women who carry the diagnosis of HF. Digoxin exposure was assessed based on prescribing data. Multivariable Cox proportional hazards models were used to assess whether there was an interaction between sex and digoxin affecting mortality hazard. SETTING: The setting was primary care outpatient practices. PARTICIPANTS: The study cohort consisted of 17 707 men and 19 227 women with the diagnosis of HF who contributed only time without digoxin exposure and 9487 men and 10 808 women with the diagnosis of HF who contributed time with digoxin exposure. MAIN OUTCOME MEASURES: The main outcome measure was all-cause mortality. RESULTS: The primary outcome of this study was the absence of a large interaction between digoxin use and sex affecting mortality. For men, digoxin use was associated with a HR for mortality of 1.00, while for women, the HR was also 1.00 (p value for interaction 0.65). The results of sensitivity analyses were consistent with those of the primary analysis. CONCLUSION: Observational data do not support the concern that there is a substantial increased risk of mortality due to the use of digoxin in women. This finding is consistent with previous observational studies but discordant with results from a post hoc analysis of a randomised controlled trial of digoxin versus placebo.
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The association between digoxin use and excess mortality in AF patients is likely due to selection and prescription biases rather than harm caused by digoxin, particularly as digoxin is commonly prescribed to sicker patients.
“Observational studies have associated digoxin use with excess mortality in AF patients, [547][548][549] but this association is likely due to selection and prescription biases rather than harm caused by digoxin, [550][551][552][553] particularly as digoxin is commonly prescribed to sicker patients.225”
From 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS (2016) · cites this paper as [551]
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Cox, D. R. (1972) · Journal of the Royal Statistical Society Series B: Statistical Methodology · doi:10.1111/j.2517-6161.1972.tb00899.x · Cited by 39,793 · see citing works
The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure
Pitt, B., Zannad, F., Remme, W. J., Cody, R., Castaigne, A., Perez, A., Palensky, J., & Wittes, J. (1999) · New England Journal of Medicine · doi:10.1056/nejm199909023411001 · Cited by 9,214 · see citing works
The SOLVD Investigators* (1991) · New England Journal of Medicine · doi:10.1056/nejm199108013250501 · Cited by 8,029 · see citing works
Austin, P. C. (2009) · Statistics in Medicine · doi:10.1002/sim.3697 · Cited by 6,758 · see citing works
The effect of digoxin on mortality and morbidity in patients with heart failure
(1997) · New England Journal of Medicine · doi:10.1056/nejm199702203360801 · Cited by 3,016 · see citing works
The Effect of Spironolactone on Morbidity and Mortality in Patients with Severe Heart Failure
Pitt, B., Zannad, F. M., Remme, W. J., Cody, R. J., Castaigne, A., Pérez, A. J. P., Palensky, J., & Wittes, J. T. (2000) · Survey of Anesthesiology · doi:10.1097/00132586-200006000-00059 · Cited by 2,927 · see citing works
Association of Serum Digoxin Concentration and Outcomes in Patients With Heart Failure
Rathore, S. S., Curtis, J. P., Wang, Y., Bristow, M. R., & Krumholz, H. M. (2003) · JAMA · doi:10.1001/jama.289.7.871 · Cited by 772 · see citing works
Sex-Based Differences in the Effect of Digoxin for the Treatment of Heart Failure
Rathore, S. S., Wang, Y., & Krumholz, H. M. (2002) · New England Journal of Medicine · doi:10.1056/nejmoa021266 · Cited by 688 · see citing works
Lewis, J. D., Schinnar, R., Bilker, W. B., Wang, X., & Strom, B. L. (2007) · Pharmacoepidemiology and Drug Safety · doi:10.1002/pds.1335 · Cited by 602 · see citing works
Self-citationAhmed, A., Rich, M. W., Love, T. E., Lloyd‐Jones, D. M., Aban, I., Colucci, W. S., Adams, K. F., & Gheorghiade, M. (2005) · European Heart Journal · doi:10.1093/eurheartj/ehi687 · Cited by 408 · see citing works
Maguire, A., Blak, B. T., & Thompson, M. (2009) · Pharmacoepidemiology and Drug Safety · doi:10.1002/pds.1688 · Cited by 301 · see citing works
Adams, K. F., Patterson, J. H., Gattis, W. A., O’Connor, C. M., Lee, C. R., Schwartz, T. A., & Gheorghiade, M. (2005) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2005.02.091 · Cited by 288 · see citing works
Contemporary Use of Digoxin in the Management of Cardiovascular Disorders
Gheorghiade, M., van Veldhuisen, D. J., & Colucci, W. S. (2006) · Circulation · doi:10.1161/circulationaha.105.560110 · Cited by 194 · see citing works
Declining public health burden of digoxin toxicity from 1991 to 2004
Haynes, K., Heitjan, D., Kanetsky, P., & Hennessy, S. (2008) · Clinical Pharmacology & Therapeutics · doi:10.1038/sj.clpt.6100458 · Cited by 49 · see citing works
Self-citationThe Effect of Gender on Outcome in Digitalis-Treated Heart Failure Patients
Domański, M., Fleg, J. L., Bristow, M. R., & Knox, S. (2005) · Journal of Cardiac Failure · doi:10.1016/j.cardfail.2004.07.002 · Cited by 47 · see citing works
Andrey, J. L., Romero, S., García-Egido, A., Escobar, M. A., Corzo, R., Garcia-Dominguez, G., Lechuga, V., & Gómez, F. (2011) · International Journal of Clinical Practice · doi:10.1111/j.1742-1241.2011.02771.x · Cited by 27 · see citing works
Digoxin therapy for heart failure: an update.
Morris, S. A., Hatcher, H., & Reddy, D. K. (2006) · PubMed · Cited by 23 · see citing works
Brophy, J. M. (2005) · European Heart Journal · doi:10.1093/eurheartj/ehi686 · Cited by 22 · see citing works
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1 of the 20 references couldn’t be matched to a known paper.
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Hindricks, G., Potpara, T., Dagres, N., Arbelo, E., Bax, J., Blomström-Lundqvist, C., Boriani, G., Castellá, M., Dan, G., Dilaveris, P. E., et al. (2020) · European Heart Journal · doi:10.1093/eurheartj/ehaa612 · Cited by 2,605 · see citing works
2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS
Kirchhof, P. F., Benussi, S., Kotecha, D., Ahlsson, A., Atar, D., Casadei, B., Castellà, M., Diener, H., Heidbüchel, H., Hendriks, J., et al. (2016) · EP Europace · doi:10.1093/europace/euw295 · Cited by 6,438 · see citing works
2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS
Kirchhof, P., Benussi, S., Kotecha, D., Ahlsson, A., Atar, D., Casadei, B., Castella, M., Diener, H.-C., Heidbuchel, H., Hendriks, J., et al. (2016) · European Heart Journal · doi:10.1093/eurheartj/ehw210 · Cited by 6,418 · see citing works
2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS
Kirchhof, P., Benussi, S., Kotecha, D., Ahlsson, A., Atar, D., Casadei, B., Castella, M., Diener, H.-C., Heidbuchel, H., Hendriks, J., et al. (2016) · European Journal of Cardio-Thoracic Surgery · doi:10.1093/ejcts/ezw313 · Cited by 1,403 · see citing works
Atrial fibrillation in heart failure: what should we do?
Kotecha, D., & Piccini, J. P. (2015) · European Heart Journal · doi:10.1093/eurheartj/ehv513 · Cited by 371 · see citing works
Ziff, O. J., Lane, D. A., Samra, M., Griffith, M., Kirchhof, P., Lip, G. Y. H., Steeds, R. P., Townend, J., & Kotecha, D. (2015) · BMJ · doi:10.1136/bmj.h4451 · Cited by 341 · see citing works
Adverse Drug Reactions to Guideline-Recommended Heart Failure Drugs in Women
Bots, S. H., Groepenhoff, F., Eikendal, A. L. M., Tannenbaum, C., Rochon, P. A., Regitz‐Zagrosek, V., Miller, V. M., Day, D., Asselbergs, F. W., & den Ruijter, H. M. (2019) · JACC Heart Failure · doi:10.1016/j.jchf.2019.01.009 · Cited by 82 · see citing works
Vámos, M., Erath, J. W., Benz, A. P., Lópes, R. D., & Hohnloser, S. H. (2018) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2018.09.036 · Cited by 67 · see citing works
Rush, C. J., Campbell, R. T., Jhund, P. S., Petrie, M. C., & McMurray, J. J. V. (2018) · European Heart Journal · doi:10.1093/eurheartj/ehy407 · Cited by 49 · see citing works
Hindricks, G., Potpara, T. S., Dagres, N., Arbelo, E., Bax, J. J., Blomström-Lundqvist, C., Boriani, G., Castellá, M., Dan, G., Dilaveris, P. E., et al. (2021) · Revista Española de Cardiología · doi:10.1016/j.recesp.2020.10.022 · Cited by 24 · see citing works
Rodríguez‐Mañero, M., Otero-Raviña, F., García‐Seara, J., Zugaza-Gurruchaga, L., Rodríguez-García, J. M., Blanco-Rodríguez, R., Turrado, V. T., Fernández-Villaverde, J. M., Vidal-Pérez, R., & González‐Juanatey, J. R. (2014) · Revista Española de Cardiología · doi:10.1016/j.recesp.2014.01.015 · Cited by 18 · see citing works
van der Meer, H. G., Wouters, H., van Hulten, R., Pras, N., & Taxis, K. (2015) · BMJ Open · doi:10.1136/bmjopen-2015-009213 · Cited by 18 · see citing works
Rodríguez‐Mañero, M., Otero-Raviña, F., García‐Seara, J., Zugaza-Gurruchaga, L., Rodríguez-García, J. M., Blanco-Rodríguez, R., Turrado, V. T., Fernández-Villaverde, J. M., Vidal-Pérez, R., & González‐Juanatey, J. R. (2014) · Revista Española de Cardiología (English Edition) · doi:10.1016/j.rec.2014.01.014 · Cited by 16 · see citing works
Maury, P., Rollin, A., Galinier, M., & Juillière, Y. (2014) · Research Reports in Clinical Cardiology · doi:10.2147/rrcc.s44919 · Cited by 16 · see citing works
Muk, B., Vámos, M., Bógyi, P., Szabo, B. A., Dékány, M., Vágány, D., Majoros, Z., Borsányi, T., Duray, G. Z., Kiss, R. G., et al. (2020) · Clinical Cardiology · doi:10.1002/clc.23500 · Cited by 10 · see citing works
Sex differences in hepatic enzymes and transporters involved in pharmacokinetics
Behal, M., McCalla, Z., & Wang, X. (2025) · Liver Research · doi:10.1016/j.livres.2025.10.003 · Cited by 9 · see citing works
Koniari, I. C., Artopoulou, E., Velissaris, D., Kounis, N. G., & Tsigkas, G. (2021) · PubMed Central · doi:10.11909/j.issn.1671-5411.2021.05.003 · Cited by 8 · see citing works
Kitapçı, M. T. (2023) · The Anatolian Journal of Cardiology · doi:10.14744/anatoljcardiol.2023.2618 · Cited by 7 · see citing works
Concerns about the use of digoxin in acute coronary syndromes
Bugiardini, R., Cenko, E., Yoon, J., van der Schaar, M., Kedev, S. A., Gale, C. P., Vasiljević, Z., Bergami, M., Miličić, D., Zdravkovic, M. D., et al. (2021) · European Heart Journal - Cardiovascular Pharmacotherapy · doi:10.1093/ehjcvp/pvab055 · Cited by 6 · see citing works
2018 Korean Heart Rhythm Society Guidelines for The Rate Control of Atrial Fibrillation
Lim, W., Choi, E., Joung, B., & Choi, K. (2018) · Korean Journal of Medicine · doi:10.3904/kjm.2018.93.2.133 · Cited by 2 · see citing works
Liu, X., Zhang, H., Cheng, W., Fan, Q., Lu, Z., Zheng, X., & Zhang, G. (2023) · Frontiers in Pharmacology · doi:10.3389/fphar.2023.1291896 · Cited by 1 · see citing works
Atrial Fibrillation Ablation Should Be First-Line Therapy in Heart Failure Patients: CON
Khaji, A., Hanley, C. M., & Kowey, P. R. (2019) · Cardiology Clinics · doi:10.1016/j.ccl.2019.01.005 · Cited by 1 · see citing works
Yazdi, M., Shafie, D., Givi, M., Garakyaraghi, M., Sarrafzadegan, N., & Yadegarfar, G. (2022) · PubMed Central · doi:10.48305/arya.v18i0.2329
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- Authors
- Flory, J. H., Ky, B., Haynes, K., M Brunelli, S., Munson, J., Rowan, C., Strom, B. L., & Hennessy, S.
- Affiliations
- NewYork–Presbyterian Hospital (US)
- University of Pennsylvania (US)
- Dartmouth–Hitchcock Medical Center (US)
- IQVIA (United States) (US)
- Corresponding author
- Flory, James H
- Venue
- BMJ Open
- Publisher
- BMJ
- Published
- 2012
- Volume
- 2
- Issue
- 2
- Pages
- e000888
- ISSN
- 2044-6055 (ISSN-L)
- PMC
- PMC3332247
- OpenAlex
- W2168337780
- Cited by
- 27
- References
- 20
- Citations by year
- 2025: 1 · 2024: 1 · 2023: 4 · 2022: 1 · 2021: 4 · 2020: 2 · 2019: 2 · 2018: 3 · 2016: 3 · 2015: 3 · 2014: 3
- FWCI
- 1.23
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- BMJ Open (publishedVersion, cc-by-nc)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Health Sciences › Medicine › Geriatrics and Gerontology › Pharmaceutical Practices and Patient Outcomes
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Atrial Fibrillation Management and Outcomes
- Keywords
- digoxin, heart failure, sex differences, mortality risk, drug safety, women, sex-stratified analysis, prescribing patterns
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