The Effect of Digoxin on Mortality and Morbidity in Patients with Heart Failure

Perry, Gilbert J.; Brown, Edward J.; Thornton, Ruth B.; Shiva, T; Hubbard, James; Reddy, K. Rajender; Doherty, J E; Cardello, FP; Fast, Angela M.; Radford, MJ; Folger, J S; Bhaskar, Gyan; Zoble, RG; Sridharan,; Loungani, R R; Gheorghiade, Mihai; Hsieh, Alexander; Tommaso, Cristina Di; Mansuri, Muhammad Fasih; Guess, M A; Akhtar, Shehreen; Wagner, Ştefan; Hagan, Kobina; McIntyre, K M; Ruble, Paul E.; Moten, Marriyam; Riley, Alan; Pierpont, Gordon L.; Bhatt, Anand; Patel, Gauravkumar; Puram, B S; Eladasari, BR; Karnegis, James N.; Gillie, Edward; Crawford, M H; Graettinger, W F; Shah, Ami A.; Sacco, Joseph; Chaudhry, M A; Dolen, D; El-Sherif, N; Bekheit-Saad, Soad; Campos, E E; Greene, J G; Khanijo,; Kumar, Uday; Mallis, G.; Mookherjee, S; Dibner-Dunlap, Mark E.; Gupta, S.C.; Danisa, Kola; Thadani, Udho; Tan, Audrey R; Rajachar, M; Amidi, Morteza; OReilly, M V; Hassapoyannes, C A; Davies, M L; Kumar, V A; Okerson, D; Ramanathan, K.; Putatunda, B; Gollapudi, Anurekha; Montero, Anastasio; Mohanty, P K; Lui, Chun Tat; Thagirisa, S; Rw, Lee; Glatter, T R; Bodine, K; Roberts, Diana; Bertoglio, M; Dennish, GW; Sarma, R J; Gregoratos, Gabriel; Rausch, D C; Pitt, W A; Kennelly, BM; Fahrenholtz, D; Gordon, RobertS.; Horwitz, Leora I.; Rothbart, Robert M.; Nutting, Paul A.; Lutz, Lois; Copen, D L; Rashkow, Andrew; Babb, Joseph D.; VanVoorhees, Lucy; Silverman, Alan H.; Stillabower, M E; Ab, Miller; NguyenPho, H T; Safford, R E; Fishman, S; Neiman, J C; Stein, M.; Jc, Dominguez; Abernathy, G T; Nair, P.; Goodman, L S; Cook, T H; Wickemeyer, W. J.; Berkson, D M; Mathew, James; Richman, H G; Lubell, D L; Lang, Ruth; Zajac, E J; Rosenstein, Robert; Silver, M. A.; Shanes, J. G.; Kelly, K J; Pequignot, M H; Campbell, Ruth; Kirlin, P C; Ziperman, D B; Denny, D. Marty; Gamble, L; Weiss, M; Kaimal, P.K.; Dhurandhar, R W; Ventura, Héctor O.; Godley, ML; Pu, Charles T.; Schick, E C; Barbour, D J; Salmon, Daniel A.; Goldstein, M; Effron, MB; Fleg, J. L.; Baughman, K. L.; Weiss, Robert G.; Ericson, Katharina; Sturrock, W A; Heinsimer, James A.; Timmis, G C; Smith, Stuart A.; Shrestha, D D; Duvernoy, Wfc; Hickner, John; Lewis, B K; O’Brien, T. K.; Yarows, S A; Willens, H. J.; Mast, D; Johnson, T H; Rodeheffer, R T; Siefert, Mary Lou; Swenson, Lyle; Denes, Pablo; Gudapati, Ramesh; Charles, F; Rich, M W; Beckham,; Hamilton, W P; Abele, P.; Harper, D; OKelly, R L; Forker, A. D.; Kahl, F R; Garrou, B W; Klang, TE; Popio, Kenneth A.; Mohiuddin, Syed M.; Pollak, E M; Chiaramida, Anthony J.; Gregory, J J; Papa, L A; Abrams, Jonathan; Ung, Steven; Jutila, C K; Croke, R P; Chiaramida, Salvatore A.; Lucariello, Richard J.; Rim, D A; Goldberger, M H; Kohn, R M; Graham, Susan; Philbin, E.F.; Sheesley, Karen A.; Nafziger, Anne N.; Macina, Gregory; Hsueh, J T; Zoneraich, Samuel; Binder, Andrew; Weinstein, Cheryl E.; Morrison, J. M.; Cameron, Alan C.; Vanderbush, E.J.; Brown, Jim; Pande, P N; Lader, Ellis; Kay, Ronald G.; Bloomfield, D; Costantino, Thomas; Heiselman, DE; Radwany, Steven; Smith, Stacy; Hobbs, R E; Fraker, T D; Frerking, T R; DeLeon, A C; Christie, L G; Toren, Michael; Grover, John W.; McBarron, F D; Harris, D E; McLean, R W; Morris, L; Zatuchni, Jacob; Boehmer, J P; Clemson, B.S; Lipshutz, H; Small, R S; Ufret, R.; LugoRodriquez, JE; Khan, AH; Yousefian, Mahzad; Friesinger, G C; Ely, Debra; Farmer, JA; Young, J. B.; Payne, R M; Fowles, R E; Ab, Lee; Shalev, Yoseph; AlBitar,; Schroeder, G S; Radant, L; Hankey, T L; Rezkalla, Shereif H.; Groden, D L; Kk, Teo; Humen, D.; Wong, Douglas; Greenwood, P V; Talibi, T; Hui, William; Klinke, W. Peter; Mpj., Senaratne; Goeres, M; Hughes, D.; Mar., Sayeed; Roth, D. L.; Belenkie,; Manyari, D E; Borgersen, K; Read, Laura L.; Kinloch, David; Reid, R; Barber, N C; Horner, B A; Kenefick, G; Kuritzky, R A; Imrie,; Wagner, KR; Rabkin, S.; Mizgala, H F; Tarry, L; Dodek, Arthur; Kornder, J M; Ashton, Thomas; Barr, Daniel M.; Dufton, J; Sweeny, Robert J.; Morris, Andrew L.; Bessoudo, Ricardo; Marr, D; Milton, Marilyn Daisy; Thompson, Brenda; Robinson, Stewart; Sussex, B A; Tobin, M.; McMahon, DP; Folkins, D; Crowell, Rebecca; Lalonde, LD; Koilpillai, Chris; Hatheway, R J; OReilly, MG; Machel, T; Hack,; Stewart, J. W.; Tanser, P H; Sullivan, Barbara L.; Hagar, S; Quinn, Beverly; Baird, M G; Williams, W L; Lemay, Mathieu; Higginson, Lyall; Turek, Michèle; Sochowski, R A; Weeks, A. M.; Jacobs, M H; Baigrie, Ronald S.; DeVilla, M A; Vértes, Gergely; Bozek, B; Goode, J E; Ricci, A; Swan, J; Fell, D.; LevinoffRoth, S N; Jmo., Arnold; Patrick, Lorna; Southern, R F; Rinne, Claus; Brisbin, D; DeYoung, J. Paul; Baitz, T; Vizel, Saul; Minkowitz, J; Letarte, Peter B.; Chan, YK; Kwok, K K; Nawaz, Shah; Ganjavi, F; Yao, Louis; Misterski, J; Raco, D L; Hess, A R; Kuruvilla, G; Silverberg, L; Borts, David J.; Fulop, J C; Weingert, M E; Carter, RP; Sahay, BM; Hickey, J E; Lalonde, Guy; Gosselin, Gilbert; Bourassa, Martial G.; Goulet, Claude; Joyal, Michel; Méthé, M; Honos, George; Fitchett, David; Serpa, Augusto Sarquis; Sestier, F; Roberge, G; Latour, Y; Rondeau, Cherie; Gossard, Denis; Jhf., Lenis; Brossoit, R; Simard, Louis; Delage, F; Auger, Pierre; Saulnier, D; Talbot, Paul; Beaudoin, Jonathan; Campeau, Joseph D.; Pruneau, Genevieve M.; Tamilia, Michael; Boutros, G; Comeau, B; Starra, R; StHilaire, R; Veilleux, Jennifer C.; Mercier, Mariette; Poulin, J F; MacLellan, Keith; Lepage, Serge; Rouleau, J L; Bruinsma, Nienke; Lévesque, Claude; DeLarochellière, Robert; Leblanc, Marie-Hélène; Kouz, Simon; Kiwan, G S; Laforest, Marie-Eve; Brooks, Joel; Bouchard, Gianna; Gervais, P B; Brophy, James M.; Gagnon, Julien; Habib, Naomi; Basu, A K; Lutterodt, A T; Khouri, Michel G.; Gorlin, Richard; Egan, Debra; Garg, Rekha; Yusuf, Salim; Montague, Terrence J.; Smith, T W; Cohn, J. N.; Dagenais, G. R.; Davies, RA; Johnstone, D E; Fye, Carol L.; Sather,; Deykin, Daniel; Francis, Gary S.; Collins, J.F.; Williford, WO; Singh, B N

doi:10.1056/nejm199702203360801

Cited by 2,596 publications

(288 citation statements)

References 10 publications

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“…Nevertheless, this study is based on the largest randomized controlled trial in patients with AF. Finally, the association between digoxin and worse clinical outcomes as demonstrated in the current analysis was not demonstrated in the only prospective trial with digoxin in patients with HF 29. However, this trial was limited to patients in sinus rhythm, and no conclusions can be made with regards to patients with AF.…”

Section: Discussionmentioning

confidence: 58%

Digoxin Use and Subsequent Clinical Outcomes in Patients With Atrial Fibrillation With or Without Heart Failure in the ENGAGE AF‐TIMI 48 Trial

Eisen

Ruff

Braunwald

et al. 2017

JAHA

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BackgroundDigoxin is widely used in patients with atrial fibrillation despite the lack of randomized controlled trials. Observational studies report conflicting results regarding its association with mortality, perhaps because of residual confounding by the presence of heart failure (HF).Methods and ResultsIn the ENGAGE AF‐TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation‐Thrombolysis in Myocardial Infarction 48) trial, clinical outcomes of patients with atrial fibrillation with and without HF were examined by baseline digoxin use during a median follow‐up of 2.8 years. HF was defined at baseline as prior or current clinical stage C or D HF. Of 21 105 patients enrolled, 6327 (30%) were treated with digoxin at baseline. Among patients without HF (n=8981), digoxin use (20%) was independently associated with sudden cardiac death (adjusted hazard ratio, 1.51; 95% CI, 1.10–2.08), with no significant interaction by age, sex, left ventricular ejection fraction, renal function, or concomitant medications (P>0.05 for each). Consistent results were observed using propensity matching (adjusted hazard ratio for sudden cardiac death, 1.90; 95% CI, 1.36–2.65). Among patients with HF (n=12 124), digoxin use (37%) was associated with an increase in all‐cause death, cardiovascular death, sudden cardiac death, and death caused by HF/cardiogenic shock (P<0.01 for each), but not with noncardiovascular death, stroke/systemic embolism, or myocardial infarction.ConclusionsIn this observational analysis of patients with atrial fibrillation without investigator‐reported HF, digoxin use was significantly associated with sudden cardiac death. While residual confounding cannot be excluded, the association between digoxin use and worse clinical outcomes highlights the need to examine digoxin use, particularly when prescribed to control heart rate in patients with atrial fibrillation in a randomized trial.Clinical Trial Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT00781391.

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Section: Discussionmentioning

confidence: 58%

Digoxin Use and Subsequent Clinical Outcomes in Patients With Atrial Fibrillation With or Without Heart Failure in the ENGAGE AF‐TIMI 48 Trial

Eisen

Ruff

Braunwald

et al. 2017

JAHA

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“…Based on the energetic consequences of calcium handling by the myocyte in an experimental animal model, a beneficial effect of digitalis in CHF may depend upon the stage of disease 37. In humans, digoxin did not decrease overall mortality in a large trial of human CHF patients, but did decrease the rate of hospitalization and worsening CHF 38. However, in a meta‐analysis of digoxin use and mortality risk in humans with AF, digoxin use was associated with a greater risk for mortality regardless of concomitant CHF 39.…”

Section: Discussionmentioning

confidence: 99%

Long‐term Outcome of Irish Wolfhound Dogs with Preclinical Cardiomyopathy, Atrial Fibrillation, or Both Treated with Pimobendan, Benazepril Hydrochloride, or Methyldigoxin Monotherapy

Vollmar¹,

Fox

2016

Veterinary Internal Medicne

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BackgroundDilated cardiomyopathy (DCM) is a common cause of morbidity and mortality in the Irish Wolfhound (IW). However, the benefit of medical treatment in IW dogs with preclinical DCM, atrial fibrillation (AF), or both has not been demonstrated.ObjectivesCompare the time to develop congestive heart failure (CHF) or sudden death in IW dogs with preclinical DCM, AF, or both receiving monotherapy with pimobendan, methyldigoxin, or benazepril hydrochloride.AnimalsSeventy‐five client‐owned IW dogs.MethodsIrish Wolfhound dogs were prospectively randomized to receive pimobendan (Vetmedin®)1, benazepril HCl (Fortekor®)2, or methyldigoxin (Lanitop®)3 monotherapy in a 1:1:1 ratio in a blinded clinical trial. The prospectively defined composite primary endpoint was onset of CHF or sudden death. To assure stringent evaluation of treatment effect, data from dogs complying with the study protocol were analyzed.ResultsSixty‐six IW fulfilling the study protocol included 39 males, 27 females; median (interquartile range) age, 4.0 years (3.0–5.0 years) and weight, 70.0 kg (63.0–75.0 kg). Primary endpoint was reached in 5 of 23 (21.7%) IW receiving pimobendan, 11 of 22 (50.0%) receiving benazepril HCl, and 9 of 21 (42.9%) receiving methyldigoxin. Median time to primary endpoint was significantly longer for pimobendan (1,991 days; 65.4 months) compared to methyldigoxin (1,263 days; 41.5 months; P = .031) or benazepril HCl‐(997 days; 32.8 months; P = .008) treated dogs.Conclusions and Clinical ImportanceIn IW dogs with preclinical DCM, AF or both, pimobendan monotherapy significantly prolonged time to onset of CHF or sudden death than did monotherapy with benazepril HCl or methyldigoxin.

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“…First, an analysis showed that digoxin was prescribed at the time of hospital discharge to a greater extent for patients with BpEF and pEF who died. Definitive evidence for digoxin efficacy in HF comes from the Digitalis Investigation Group's randomized clinical trial, which showed that although this medication does not improve survival, it appears to be associated with a reduced risk of hospitalization 30. The second observation was that patients from all 3 EF strata who were still alive 1 year after hospital discharge were treated with multiple cardiac medications at the time of hospital discharge.…”

Section: Discussionmentioning

confidence: 99%

Magnitude of and Prognostic Factors Associated With 1‐Year Mortality After Hospital Discharge for Acute Decompensated Heart Failure Based on Ejection Fraction Findings

Coles

Tisminetzky

Yarzebski

et al. 2015

JAHA

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BackgroundLimited data exist about the magnitude of and the factors associated with prognosis within 1 year for patients discharged from the hospital after acute decompensated heart failure. Data are particularly limited from the more generalizable perspective of a population‐based investigation and should be further stratified according to currently recommended ejection fraction (EF) findings.Methods and ResultsThe hospital medical records of residents of the Worcester, Massachusetts, metropolitan area who were discharged after acute decompensated heart failure from all 11 medical centers in central Massachusetts during 1995, 2000, 2002, 2004, and 2006 were reviewed. The average age of the 4025 study patients was 75 years, 93% were white, and 44% were men. Of these, 35% (n=1414) had reduced EF (≤40%), 13% (n=521) had borderline preserved EF (41–49%), and 52% (n=2090) had preserved EF (≥50%); at 1 year after discharge, death rates were 34%, 30%, and 29%, respectively (P=0.03). Older age, a history of chronic obstructive pulmonary disease, systolic blood pressure findings <150 mm Hg on admission, and hyponatremia were important predictors of 1‐year mortality for all study patients, whereas several comorbidities and physiological factors were differentially associated with 1‐year death rates in patients with reduced, borderline preserved, and preserved EF.ConclusionsThis population‐based study highlights the need for further contemporary research into the characteristics, treatment practices, natural history, and long‐term outcomes of patients with acute decompensated heart failure and varying EF findings and reinforces ongoing discussions about whether different treatment guidelines may be needed for these patients to design more personalized treatment plans.

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The Effect of Digoxin on Mortality and Morbidity in Patients with Heart Failure

Abstract: Digoxin did not reduce overall mortality, but it reduced the rate of hospitalization both overall and for worsening heart failure. These findings define more precisely the role of digoxin in the management of chronic heart failure.

Cited by 2,596 publications

References 10 publications

Digoxin Use and Subsequent Clinical Outcomes in Patients With Atrial Fibrillation With or Without Heart Failure in the ENGAGE AF‐TIMI 48 Trial

Digoxin Use and Subsequent Clinical Outcomes in Patients With Atrial Fibrillation With or Without Heart Failure in the ENGAGE AF‐TIMI 48 Trial

Long‐term Outcome of Irish Wolfhound Dogs with Preclinical Cardiomyopathy, Atrial Fibrillation, or Both Treated with Pimobendan, Benazepril Hydrochloride, or Methyldigoxin Monotherapy

Magnitude of and Prognostic Factors Associated With 1‐Year Mortality After Hospital Discharge for Acute Decompensated Heart Failure Based on Ejection Fraction Findings

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