Digoxin use in patients with atrial fibrillation and adverse cardiovascular outcomes: a retrospective analysis of the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF).
BACKGROUND
Digoxin is a widely used drug for ventricular rate control in patients with atrial fibrillation (AF), despite a scarcity of randomised trial data. We studied the use and outcomes of digoxin in patients in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF).


METHODS
For this retrospective analysis, we included and classified patients from ROCKET AF on the basis of digoxin use at baseline and during the study. Patients in ROCKET AF were recruited from 45 countries and had AF and risk factors putting them at moderate-to-high risk of stroke, with or without heart failure. We used Cox proportional hazards regression models adjusted for baseline characteristics and drugs to investigate the association of digoxin with all-cause mortality, vascular death, and sudden death. ROCKET AF was registered with ClinicalTrials.gov, number NCT00403767.


RESULTS
In 14,171 randomly assigned patients, digoxin was used at baseline in 5239 (37%). Patients given digoxin were more likely to be female (42% vs 38%) and have a history of heart failure (73% vs 56%), diabetes (43% vs 38%), and persistent AF (88% vs 77%; p<0·0001 for each comparison). After adjustment, digoxin was associated with increased all-cause mortality (5·41 vs 4·30 events per 100 patients-years; hazard ratio 1·17; 95% CI 1·04-1·32; p=0·0093), vascular death (3·55 vs 2·69 per 100 patient-years; 1·19; 1·03-1·39, p=0·0201), and sudden death (1·68 vs 1·12 events per 100 patient-years; 1·36; 1·08-1·70, p=0·0076).


CONCLUSIONS
Digoxin treatment was associated with a significant increase in all-cause mortality, vascular death, and sudden death in patients with AF. This association was independent of other measured prognostic factors, and although residual confounding could account for these results, these data show the possibility of digoxin having these effects. A randomised trial of digoxin in treatment of AF patients with and without heart failure is needed.


BACKGROUND
Janssen Research & Development and Bayer HealthCare AG.
Duke Heart Center, Duke University Medical Center, Durham, NC, USA.
Jeffrey B
JB
Washam
Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA.
Susanna R
SR
Stevens
Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA.
Yuliya
Y
Lokhnygina
Mount Sinai Medical Center, New York, NY, USA.
Jonathan L
JL
Halperin
Hospital of the University of Münster, Münster, Germany.
Günter
G
Breithardt
Massachusetts General Hospital, and Harvard Medical School, Boston, MA, USA.
Daniel E
DE
Singer
Stanford School of Medicine, Stanford, CA, USA.
Kenneth W
KW
Mahaffey
School of Medicine and Pharmacology, University of Western Australia, Perth, WA, Australia.
Graeme J
GJ
Hankey
Bayer HealthCare Pharmaceuticals, Whippany, NJ, USA.
Scott D
SD
Berkowitz
Janssen Research & Development, Raritan, NJ, USA.
Christopher C
CC
Nessel
University of Edinburgh, and Royal Infirmary of Edinburgh, Edinburgh, UK.
Keith A A
KA
Fox
Duke Translational Medicine Institute, Duke University Medical Center, Durham, NC, USA.
Robert M
RM
Califf
Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA.
Jonathan P
JP
Piccini
Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA. Electronic address: manesh.patel@duke.edu.
Manesh R
MR
Patel
D000368:Aged; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000009:adverse effects*; D000925:Anticoagulants / Q000627:therapeutic use; D001281:Atrial Fibrillation / Q000188:drug therapy* / Q000401:mortality*; D003645:Death, Sudden / Q000453:epidemiology; D003920:Diabetes Mellitus / Q000453:epidemiology; D004077:Digoxin / Q000008:administration & dosage / Q000009:adverse effects*; D065427:Factor Xa Inhibitors / Q000627:therapeutic use; D005260:Female; D006333:Heart Failure / Q000453:epidemiology; D006339:Heart Rate; D006801:Humans; D020766:Intracranial Embolism / Q000517:prevention & control; D008297:Male; D009025:Morpholines / Q000627:therapeutic use; D016016:Proportional Hazards Models; D016032:Randomized Controlled Trials as Topic; D012189:Retrospective Studies; D000069552:Rivaroxaban; D017678:Sex Distribution; D020521:Stroke / Q000517:prevention & control; D013876:Thiophenes / Q000627:therapeutic use; D014812:Vitamin K / Q000037:antagonists & inhibitors; D014859:Warfarin / Q000627:therapeutic use
D000889:Anti-Arrhythmia Agents; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D009025:Morpholines; D013876:Thiophenes; D014812:Vitamin K; D014859:Warfarin; D004077:Digoxin; D000069552:Rivaroxaban