Lack of evidence of increased mortality among patients with atrial fibrillation taking digoxin: findings from post hoc propensity-matched analysis of the AFFIRM trial
Open accessAbstract
AIMS: Digoxin is recommended for long-term rate control in paroxysmal, persistent, and permanent atrial fibrillation (AF). While some analyses suggest an association of digoxin with a higher mortality in AF, the intrinsic nature of this association has not been examined in propensity-matched cohorts, which is the objective of the current study. METHODS AND RESULTS: In Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM), 4060 patients with paroxysmal and persistent AF were randomized to rate (n = 2027) vs. rhythm (n = 2033) control strategies. Of these, 1377 received digoxin as initial therapy and 1329 received no digoxin at baseline. Propensity scores for digoxin use were estimated for each of these 2706 patients and used to assemble a cohort of 878 pairs of patients receiving and not receiving digoxin, who were balanced on 59 baseline characteristics. Matched patients had a mean age of 70 years, 40% were women, and 11% non-white. During the 3.4 years of the mean follow-up, all-cause mortality occurred in 14 and 13% of matched patients receiving and not receiving digoxin, respectively [hazard ratio (HR) associated with digoxin use: 1.06; 95% confidence interval (CI): 0.83-1.37; P = 0.640]. Among matched patients, digoxin had no association with all-cause hospitalization (HR: 0.96; 95% CI: 0.85-1.09; P = 0.510) or incident non-fatal cardiac arrhythmias (HR: 0.90; 95% CI: 0.37-2.23; P = 0.827). Digoxin had no multivariable-adjusted or propensity score-adjusted associations with these outcomes in the pre-match cohort. CONCLUSIONS: In patients with paroxysmal and persistent AF, we found no evidence of increased mortality or hospitalization in those taking digoxin as baseline initial therapy.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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 [550]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
The central role of the propensity score in observational studies for causal effects
ROSENBAUM, P. R., & RUBIN, D. B. (1983) · Biometrika · doi:10.1093/biomet/70.1.41 · Cited by 31,241 · see citing works
Guidelines for the management of atrial fibrillation
Authors/Task Force Members, Camm, A. J., Kirchhof, P. F., Lip, G. Y. H., Schotten, U., Savelieva, I., Ernst, S., Gelder, I. C. V., Al‐Attar, N., Hindricks, G., et al. (2010) · European Heart Journal · doi:10.1093/eurheartj/ehq278 · Cited by 5,875 · see citing works
A comparison of rate control and rhythm control in patients with atrial fibrillation
(2002) · New England Journal of Medicine · doi:10.1056/nejmoa021328 · Cited by 4,405 · 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
Feinberg, W. M. (1995) · Archives of Internal Medicine · doi:10.1001/archinte.155.5.469 · Cited by 2,282 · see citing works
Using Propensity Scores to Help Design Observational Studies: Application to the Tobacco Litigation
Rubin, D. B. (2001) · Health Services and Outcomes Research Methodology · doi:10.1023/a:1020363010465 · Cited by 2,228 · see citing works
Evaluating medication effects outside of clinical trials: new-user designs
Ray, W. A. (2003) · American Journal of Epidemiology · doi:10.1093/aje/kwg231 · Cited by 1,646 · see citing works
Wann, L. S., Curtis, A. B., January, C. T., Ellenbogen, K. A., Lowe, J. E., Estes, N. A. M., Page, R. L., Ezekowitz, M. D., Slotwiner, D. J., Jackman, W. M., et al. (2010) · Circulation · doi:10.1161/cir.0b013e3181fa3cf4 · Cited by 1,338 · see citing works
Normand, S., Landrum, M., Guadagnoli, E., Ayanian, J. Z., Ryan, T. J., Cleary, P., & McNeil, B. J. (2001) · Journal of Clinical Epidemiology · doi:10.1016/s0895-4356(00)00321-8 · Cited by 1,256 · see citing works
The AFFIRM Investigators (2004) · Circulation · doi:10.1161/01.cir.0000121736.16643.11 · Cited by 1,202 · see citing works
Time-dependent covariates in the Cox proportional-hazards regression model.
Fisher, L., & Lin, D.-Y. (1999) · Annual Review of Public Health · doi:10.1146/annurev.publhealth.20.1.145 · Cited by 1,055 · see citing works
Lenient versus strict rate control in patients with atrial fibrillation
Van Gelder, I. C., Groenveld, H. F., Crijns, H. J. G. M., Tuininga, Y. S., Tijssen, J. G. P., Alings, A. M., Hillege, H. L., Bergsma-Kadijk, J. A., Cornel, J. H., Kamp, O., et al. (2010) · New England Journal of Medicine · doi:10.1056/nejmoa1001337 · Cited by 1,033 · see citing works
Clarke, R., Shipley, M. J., Lewington, S., Youngman, L. D., Collins, R., Marmot, M. G., & Peto, R. (1999) · American Journal of Epidemiology · doi:10.1093/oxfordjournals.aje.a010013 · Cited by 879 · see citing works
Fuster, V., Rydén, L. E., Cannom, D. S., Crijns, H. J., Curtis, A. B., Ellenbogen, K. A., Halperin, J. L., Kay, G. N., Le Huezey, J.-Y., Lowe, J. E., et al. (2011) · Circulation · doi:10.1161/cir.0b013e318214876d · Cited by 859 · 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
Ahmed, A., Rich, M. W., Fleg, J. L., Zile, M. R., Young, J. B., Kitzman, D. W., Love, T. E., Aronow, W. S., Adams, K. F., & Gheorghiade, M. (2006) · Circulation · doi:10.1161/circulationaha.106.628347 · Cited by 605 · see citing works
Self-citationThe Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study
Olshansky, B., Rosenfeld, L. E., Warner, A. L., Solomon, A. J., O’Neill, G., Sharma, A. D., Platia, E. V., Feld, G. K., Akiyama, T., Brodsky, M. A., et al. (2004) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2003.11.032 · Cited by 590 · see citing works
Goette, A., Staack, T., Röcken, C., Arndt, M., Geller, J. C., Huth, C., Ansorge, S., Klein, H. U., & Lendeckel, U. (2000) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(00)00611-2 · Cited by 583 · see citing works
Ahmed, A., Husain, A., Love, T. E., Gambassi, G., Dell’Italia, L. J., Francis, G. S., Gheorghiade, M., Allman, R. M., Meleth, S., & Bourge, R. C. (2006) · European Heart Journal · doi:10.1093/eurheartj/ehi890 · Cited by 469 · see citing works
Self-citationPropensity Scores in Cardiovascular Research
D’Agostino, R. B. (2007) · Circulation · doi:10.1161/circulationaha.105.594952 · Cited by 451 · see citing works
Prevention of Atrial Fibrillation by Renin-Angiotensin System Inhibition
Schneider, M. P., Hua, T. A., Böhm, M., Wachtell, K., Kjeldsen, S. E., & Schmieder, R. E. (2010) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2010.01.043 · Cited by 417 · see citing works
Ahmed, 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
Self-citationAn overview of the objectives of and the approaches to propensity score analyses
Heinze, G., & Jüni, P. (2011) · European Heart Journal · doi:10.1093/eurheartj/ehr031 · Cited by 379 · see citing works
Increased mortality among patients taking digoxin—analysis from the AFFIRM study
Whitbeck, M. G., Charnigo, R. J., Khairy, P., Ziada, K., Bailey, A. L., Zegarra, M. M., Shah, J., Morales, G., Macaulay, T., Sorrell, V. L., et al. (2013) · European Heart Journal · doi:10.1093/eurheartj/ehs348 · Cited by 279 · see citing works
Atrial Fibrillation Follow-Up Investigation of Rhythm Management—The AFFIRM Study Design
(1997) · The American Journal of Cardiology · doi:10.1016/s0002-9149(97)00082-9 · Cited by 277 · see citing works
Khand, A. U., Rankin, A. C., Martin, W., Taylor, J., Gemmell, I., & Cleland, J. G. F. (2003) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2003.07.020 · Cited by 271 · see citing works
Self-citationDanaei, G., Tavakkoli, M., & Hernán, M. Á. (2012) · American Journal of Epidemiology · doi:10.1093/aje/kwr301 · Cited by 265 · see citing works
(1988) · ASHE-ERIC Higher Education Report · doi:10.1002/aehe.3640170508 · Cited by 259 · see citing works
Miyasaka, Y., Barnes, M. E., Gersh, B. J., Cha, S. S., Bailey, K. R., Abhayaratna, W., Seward, J. B., Iwasaka, T., & Tsang, T. S. M. (2006) · European Heart Journal · doi:10.1093/eurheartj/ehi694 · Cited by 192 · see citing works
Ahmed, A., Zannad, F. M., Love, T. E., Tallaj, J. A., Gheorghiade, M., Ekundayo, O. J., & Pitt, B. (2007) · European Heart Journal · doi:10.1093/eurheartj/ehm091 · Cited by 185 · see citing works
Self-citationRosenbaum, P. (2002) · Springer series in statistics · doi:10.1007/978-1-4757-3692-2_4 · Cited by 172 · see citing works
Baseline characteristics of patients with atrial fibrillation: The AFFIRM Study
The AFFIRM Investigators (2002) · American Heart Journal · doi:10.1067/mhj.2002.122875 · Cited by 172 · see citing works
van Veldhuisen, D. J., Veld, A. J. M. I., Dunselman, P. H. J. M., Lok, D. J. A., Dohmen, H. J. M., Poortermans, J. C., Withagen, A. J. A. M., Pasteuning, W. H., Brouwer, J., & Lie, K. I. (1993) · Journal of the American College of Cardiology · doi:10.1016/0735-1097(93)90579-p · Cited by 166 · see citing works
Austin, P. C. (2008) · Circulation Cardiovascular Quality and Outcomes · doi:10.1161/circoutcomes.108.790634 · Cited by 153 · see citing works
Filippatos, G. S., Ahmed, M. I., Gladden, J. D., Mujib, M. U., Aban, I., Love, T. E., Sanders, P. W., Pitt, B., Anker, S. D., & Ahmed, A. (2011) · European Heart Journal · doi:10.1093/eurheartj/ehq473 · Cited by 146 · see citing works
Self-citationGheorghiade, M., Hall, V. B., Jacobsen, G., Alam, M., Rosman, H., & Goldstein, S. (1995) · Circulation · doi:10.1161/01.cir.92.7.1801 · Cited by 121 · see citing works
Self-citationAhmed, A., Pitt, B., Rahimtoola, S. H., Waagstein, F., White, M., Love, T. E., & D, E. B. M. (2007) · International Journal of Cardiology · doi:10.1016/j.ijcard.2006.12.001 · Cited by 119 · see citing works
Self-citationGheorghiade, M., Patel, K., Filippatos, G. S., Anker, S. D., van Veldhuisen, D. J., Cleland, J. G. F., Metra, M., Aban, I., Greene, S. J., Adams, K. F., et al. (2013) · European Journal of Heart Failure · doi:10.1093/eurjhf/hft010 · Cited by 115 · see citing works
Self-citationAhmed, A., Waagstein, F., Pitt, B., White, M., Zannad, F. M., Young, J. B., & Rahimtoola, S. H. (2008) · The American Journal of Cardiology · doi:10.1016/j.amjcard.2008.06.068 · Cited by 88 · see citing works
Self-citationAhmed, M. I., White, M., Ekundayo, O. J., Love, T. E., Aban, I., Liu, B., Aronow, W. S., & Ahmed, A. (2009) · European Heart Journal · doi:10.1093/eurheartj/ehp222 · Cited by 79 · see citing works
Self-citationRenin-Angiotensin Inhibition in Systolic Heart Failure and Chronic Kidney Disease
Ahmed, A., Fonarow, G. C., Zhang, Y., Sanders, P. W., Allman, R. M., Arnett, D. K., Feller, M. A., Love, T. E., Aban, I., Levesque, R., et al. (2012) · The American Journal of Medicine · doi:10.1016/j.amjmed.2011.10.013 · Cited by 77 · see citing works
Self-citationAhmed, A. (2007) · The Journals of Gerontology Series A · doi:10.1093/gerona/62.3.323 · Cited by 59 · see citing works
Self-citationPatel, K., Fonarow, G. C., Kitzman, D. W., Aban, I., Love, T. E., Allman, R. M., Gheorghiade, M., & Ahmed, A. (2012) · European Journal of Heart Failure · doi:10.1093/eurjhf/hfs101 · Cited by 41 · see citing works
Self-citationRenin-Angiotensin Inhibition in Diastolic Heart Failure and Chronic Kidney Disease
Ahmed, A., Rich, M. W., Zile, M. R., Sanders, P. W., Patel, K., Zhang, Y., Aban, I., Love, T. E., Fonarow, G. C., Aronow, W. S., et al. (2013) · The American Journal of Medicine · doi:10.1016/j.amjmed.2012.06.031 · Cited by 35 · see citing works
Self-citationA propensity-matched study of outcomes of chronic heart failure (HF) in younger and older adults
Wahle, C., Adamopoulos, C., Ekundayo, O. J., Mujib, M. U., Aronow, W. S., & Ahmed, A. (2008) · Archives of Gerontology and Geriatrics · doi:10.1016/j.archger.2008.06.009 · Cited by 30 · see citing works
Self-citationLow-dose digoxin in patients with heart failure
van Veldhuisen, D. J. (2002) · Journal of the American College of Cardiology · doi:10.1016/s0735-1097(02)01710-2 · Cited by 25 · see citing works
Digoxin for patients with atrial fibrillation and heart failure: paradise lost or not?
van Veldhuisen, D. J., Gelder, I. C. V., Ahmed, A., & Gheorghiade, M. (2013) · European Heart Journal · doi:10.1093/eurheartj/ehs483 · Cited by 24 · see citing works
Self-citationCleland, J. G. F., & Cullington, D. (2009) · Circulation Heart Failure · doi:10.1161/circheartfailure.109.859322 · Cited by 22 · see citing works
Self-citationNo Impact of Atrial Fibrillation on Mortality Risk in Optimally Treated Heart Failure Patients
Tveit, A., Flønæs, B., Aaser, E., Korneliussen, K., Frøland, G., Gullestad, L. L., & Grundtvig, M. (2011) · Clinical Cardiology · doi:10.1002/clc.20939 · Cited by 18 · see citing works
In search of the right word: a statement of the HEART Group on scientific language
Lüscher, T. F. (2013) · European Heart Journal · doi:10.1093/eurheartj/ehs387 · Cited by 12 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Cleland JG, Cullington D. Digoxin: quo vadis? Circ Heart Fail 2009;2:81 -85.
Cited by
Sorted by citations
2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure
Ponikowski, P., Voors, A. A., Anker, S. D., Bueno, H., Cleland, J. G. F., Coats, A. J. S., Falk, V., González-Juanatey, J. R., Harjola, V.-P., Jankowska, E. A., et al. (2016) · European Heart Journal · doi:10.1093/eurheartj/ehw128 · Cited by 11,429 · see citing works
Self-citation2016 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 Diagnosis and Treatment of Acute and Chronic Heart Failure
Ponikowski, P., Voors, A. A., Anker, S. D., Bueno, H., Cleland, J. G. F., Coats, A. J. S., Falk, V., González-Juanatey, J. R., Harjola, V.-P., Jankowska, E. A., et al. (2016) · European Journal of Heart Failure · doi:10.1002/ejhf.592 · Cited by 5,866 · see citing works
Self-citation2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation
January, C. T., Wann, L. S., Alpert, J. S., Calkins, H., Cigarroa, J. E., Cleveland, J. C., Conti, J. B., Ellinor, P. T., Ezekowitz, M. D., Field, M. E., et al. (2014) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2014.03.022 · Cited by 2,955 · 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
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
Increased Mortality Associated With Digoxin in Contemporary Patients With Atrial Fibrillation
Turakhia, M. P., Santangeli, P., Winkelmayer, W. C., Xu, X., Ullal, A. J., Than, C. T., Schmitt, S., Holmes, T. H., Frayne, S. M., Phibbs, C. S., et al. (2014) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2014.03.060 · Cited by 208 · see citing works
- Authors
- Gheorghiade, M., Fonarow, G. C., van Veldhuisen, D. J., Cleland, J. G. F., Butler, J., Epstein, A. E., Patel, K., Aban, I. B., Aronow, W. S., Anker, S. D., & Ahmed, A.
- Affiliations
- Northwestern University (US)
- University of California, Los Angeles (US)
- Hull York Medical School (GB)
- Emory University (US)
- University of Pennsylvania (US)
- University of Alabama at Birmingham (US)
- New York Medical College (US)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
- Corresponding author
- Ahmed, A.
- ORCID
- Venue
- European Heart Journal
- Publisher
- Oxford University Press (OUP)
- Published
- 2013-04-16
- Volume
- 34
- Issue
- 20
- Pages
- 1489-1497
- ISSN
- 0195-668X (ISSN-L)
- 1522-9645
- PMC
- PMC3659306
- OpenAlex
- W2128605957
- Cited by
- 192
- References
- 51
- Citations by year
- 2026: 3 · 2025: 4 · 2024: 5 · 2023: 7 · 2022: 9 · 2021: 18 · 2020: 12 · 2019: 13 · 2018: 11 · 2017: 13 · 2016: 25 · 2015: 29 · 2014: 27 · 2013: 14
- FWCI
- 21.55
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- European Heart Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Touro Scholar (Touro College) (submittedVersion)
- HighWire Press Open Archive (submittedVersion)
- University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion)
- Funders
- National Institute for Health and Care Research (NF-SI-0611-10227)
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01-HL085561-S, R01HL097047, R01HL085561)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Atrial Fibrillation Management and Outcomes
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Heart Failure Treatment and Management
- Health Sciences › Medicine › Geriatrics and Gerontology › Pharmaceutical Practices and Patient Outcomes
- Keywords
- digoxin, atrial fibrillation, all-cause mortality, hospitalization, cardiac arrhythmias, rate control, rhythm control, paroxysmal atrial fibrillation, persistent atrial fibrillation, AFFIRM trial, propensity score matching
- MeSH terms
- Aged, Anti-Arrhythmia Agents, Atrial Fibrillation, Cause of Death, Digoxin, Female, Heart Failure, Hospitalization, Humans, Male, Treatment Outcome, Kaplan-Meier Estimate, Propensity Score
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
