Association of Serum Digoxin Concentration and Outcomes in Patients With Heart Failure

Rathore, Saif S.; Curtis, Jeptha P.; Wang, Yongfei; Bristow, Michael R.; Krumholz, Harlan M.

doi:10.1001/jama.289.7.871

Cited by 664 publications

(351 citation statements)

References 33 publications

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“…Conflicting data exist regarding adverse outcomes that are associated with digoxin use in patients with AF 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16. While several retrospective studies and meta‐analyses have demonstrated an association between digoxin use and all‐cause mortality, cardiovascular death, and sudden cardiac death (SCD),6, 7, 8, 9, 10, 11, 12, 13 other studies have not found a compelling association 14, 15, 16.…”

Section: Introductionmentioning

confidence: 99%

“…While several retrospective studies and meta‐analyses have demonstrated an association between digoxin use and all‐cause mortality, cardiovascular death, and sudden cardiac death (SCD),6, 7, 8, 9, 10, 11, 12, 13 other studies have not found a compelling association 14, 15, 16. These contradictory results can be attributed to the nature of observational studies and to digoxin prescription biases.…”

Section: Introductionmentioning

confidence: 99%

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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: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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“…Serum digoxin concentration (SDC) is an important predictor of therapeutic and adverse effects of digoxin, and was measured in a random subset of DIG participants. [5][6][7]9 Of the 1666 patients continued on digoxin, 457 had low (0.5-0.9 ng/ml) and 340 had high (≥1.0 ng/ml) SDC after 1 month of therapy, and of the 1699 patients in the placebo group, whose digoxin was discontinued, 1674 were alive at 1 month. Two patients randomized to placebo were censored during the first month after randomization and none had any hospitalizations during that period.…”

Section: Methodsmentioning

confidence: 99%

Effects of Discontinuation of Digoxin Versus Continuation at Low Serum Digoxin Concentrations in Chronic Heart Failure

Ahmed¹,

Gambassi²,

Weaver³

et al. 2007

The American Journal of Cardiology

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Discontinuation of digoxin is associated with worsening heart failure (HF) symptoms. However, the long-term effects of discontinuation of chronic digoxin therapy on mortality and morbidity in HF have not been well studied. Of the 7788 Digoxin Investigation Group trial participants, 3365 were receiving digoxin before randomization. During the trial, digoxin was continued in 1666 patients and discontinued in 1699 patients. Using multivariable Cox regression analyses, we at first determined the effect of discontinuation of digoxin on mortality and hospitalization during 39.7 months of median follow up. Of the 1666 patients continued on digoxin, 457 had low (0.5-0.9 ng/ml) and 340 had high (≥1.0 ng/ml) serum digoxin concentrations (SDC) after 1 month of therapy and of the 1699 patients whose digoxin was discontinued, 1674 were alive at 1 month. We examined the effects of continuation of digoxin at low or high SDC. Compared with continuation of chronic digoxin therapy, discontinuation of digoxin was associated with significant increase in all-cause hospitalization (adjusted hazard ratio {AHR}=1.18; 95% confidence interval {CI}=1.09-1.28; P<0.0001) and HF hospitalization (AHR=1.35; 95% CI=1.20-1.51; P<0.0001), but had no effect on all cause mortality (AHR=1.06; 95% CI=0.95-1.19; P=0.272). Continuation of digoxin at low SDC, on the other hand, was associated with reduction in all-cause mortality (AHR=0.75; 95% CI=0.63-0.90; P=0.002), allcause hospitalization (AHR=0.80; 95% CI=0.71-0.91; P=0.001) and HF hospitalization (AHR=0.60; 95% CI=0.50-0.73; P<0.0001). In conclusion, continuation of chronic digoxin therapy at low SDC was associated with reduction in mortality and hospitalization in ambulatory chronic HF patients receiving background therapy with ACE inhibitors and diuretics. KeywordsHeart failure; digoxin; discontinuation; mortality; hospitalization The American College of Cardiology / American Heart Association (ACC/AHA) guideline for chronic heart failure (HF) recommends continuation of long-term digoxin therapy in HF patients who are already receiving this drug. 1 Discontinuation of digoxin is associated with worsening heart failure (HF) symptoms. 2-4 However, little is known about the long-term effect of discontinuation of chronic digoxin therapy on mortality and morbidity in patients with ambulatory chronic heart failure (HF). Even less is known about the effect of continuation of long-term digoxin therapy at low serum digoxin concentration (SDC). In the Digitalis Investigation Group (DIG) trial, 3365 (43%) of the 7788 patients were receiving digoxin at the time of enrollment. 5 These patients were randomized to discontinue (placebo arm) or continue (digoxin arm) their chronic digoxin therapy. Data on SDC were collected in a random subset of DIG participants and post hoc analysis using SDC data suggest that the effect of digoxin on outcomes in HF may be dependent on SDC. 6,7 These provide a unique opportunity to rapidly and efficiently determine the long-term effect of discontinuation of digoxin as we...

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“…All‐cause mortality was not significantly affected; however, fewer patients were hospitalized for worsening HF with a risk reduction of 28% (95% CI 21–34%, P < 0.001) (The Digitalis Investigation Group, 1997). A post hoc analysis of the Digitalis Investigation Group trial demonstrated a correlation between serum digoxin concentrations and crude all‐cause mortality, with significantly higher mortality in the toxic range and no benefit outside of the target range of 0.5 to 0.8 ng⋅mL −1 (Rathore et al ., 2003), stressing the importance of regular plasma monitoring. A randomized, placebo‐controlled trial investigating the addition of digoxin to conventional therapy is ongoing (EudraCT:2007‐006660‐30).…”

Section: Evidence‐based Pharmacological Agentsmentioning

confidence: 99%

Present and future pharmacotherapeutic agents in heart failure: an evolving paradigm

Loudon

Noordali

Gollop

et al. 2016

British J Pharmacology

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Many conditions culminate in heart failure (HF), a multi‐organ systemic syndrome with an intrinsically poor prognosis. Pharmacotherapeutic agents that correct neurohormonal dysregulation and haemodynamic instability have occupied the forefront of developments within the treatment of HF in the past. Indeed, multiple trials aimed to validate these agents in the 1980s and early 1990s, resulting in a large and robust evidence‐base supporting their use clinically. An established treatment paradigm now exists for the treatment of HF with reduced ejection fraction (HFrEF), but there have been very few notable developments in recent years. HF remains a significant health concern with an increasing incidence as the population ages. We may indeed be entering the surgical era for HF treatment, but these therapies remain expensive and inaccessible to many. Newer pharmacotherapeutic agents are slowly emerging, many targeting alternative therapeutic pathways, but with mixed results. Metabolic modulation and manipulation of the nitrate/nitrite/nitric oxide pathway have shown promise and could provide the answers to fill the therapeutic gap between medical interventions and surgery, but further definitive trials are warranted. We review the significant evidence base behind the current medical treatments for HFrEF, the physiology of metabolic impairment in HF, and discuss two promising novel agents, perhexiline and nitrite.

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Association of Serum Digoxin Concentration and Outcomes in Patients With Heart Failure

Cited by 664 publications

References 33 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

Effects of Discontinuation of Digoxin Versus Continuation at Low Serum Digoxin Concentrations in Chronic Heart Failure

Present and future pharmacotherapeutic agents in heart failure: an evolving paradigm

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