Jenica N Upshaw1, David van Klaveren2, Marvin A Konstam3, David M Kent4. 1. The CardioVascular Center, Tufts Medical Center, Boston, Mass. Electronic address: jupshaw@tuftsmedicalcenter.org. 2. The Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, Mass; The Medical Statistics Department, Leiden University Medical Center, The Netherlands. 3. The CardioVascular Center, Tufts Medical Center, Boston, Mass. 4. The Institute for Clinical Research and Health Policy Studies, Tufts Medical Center, Boston, Mass.
Abstract
BACKGROUND: Digoxin has been shown to reduce heart failure hospitalizations with a neutral effect on mortality. It is unknown whether there is heterogeneity of treatment effect for digitalis therapy according to predicted risk of heart failure hospitalization. METHODS AND RESULTS: We conducted a post hoc analysis of the Digitalis Investigator Group (DIG) studies, randomized controlled trials of digoxin vs placebo in participants with heart failure and left ventricular ejection fraction ≤45% (main DIG study, n = 6800) or >45% (ancillary DIG study, n = 988). Using a previously derived multistate model to risk-stratify DIG study participants, we determined the differential treatment effect on hospitalization and mortality outcomes. There was a 13% absolute reduction in the risk of any heart failure hospitalizations (39% vs 52%; odds ratio 0.58; 95% confidence interval 0.47-0.71) in the digoxin vs placebo arms in the highest-risk quartile, compared with a 3% absolute risk reduction for any heart failure hospitalization (17% vs 20%; odds ratio 0.84; 95% confidence interval, 0.66-1.08) in the lowest-risk quartile. There were 12 fewer total all-cause hospitalizations per 100 person-years in the highest-risk quartile compared with an increase of 8 hospitalizations per 100 person-years in the lowest-risk quartile. There was neutral effect of digoxin on mortality in all risk quartiles and no interaction between baseline risk and the effect of digoxin on mortality (P = .94). CONCLUSIONS: Participants in the DIG study at higher risk of hospitalization as identified by a multistate model were considerably more likely to benefit from digoxin therapy to reduce heart failure hospitalization.
BACKGROUND: Digoxin has been shown to reduce heart failure hospitalizations with a neutral effect on mortality. It is unknown whether there is heterogeneity of treatment effect for digitalis therapy according to predicted risk of heart failure hospitalization. METHODS AND RESULTS: We conducted a post hoc analysis of the Digitalis Investigator Group (DIG) studies, randomized controlled trials of digoxin vs placebo in participants with heart failure and left ventricular ejection fraction ≤45% (main DIG study, n = 6800) or >45% (ancillary DIG study, n = 988). Using a previously derived multistate model to risk-stratify DIG study participants, we determined the differential treatment effect on hospitalization and mortality outcomes. There was a 13% absolute reduction in the risk of any heart failure hospitalizations (39% vs 52%; odds ratio 0.58; 95% confidence interval 0.47-0.71) in the digoxin vs placebo arms in the highest-risk quartile, compared with a 3% absolute risk reduction for any heart failure hospitalization (17% vs 20%; odds ratio 0.84; 95% confidence interval, 0.66-1.08) in the lowest-risk quartile. There were 12 fewer total all-cause hospitalizations per 100 person-years in the highest-risk quartile compared with an increase of 8 hospitalizations per 100 person-years in the lowest-risk quartile. There was neutral effect of digoxin on mortality in all risk quartiles and no interaction between baseline risk and the effect of digoxin on mortality (P = .94). CONCLUSIONS: Participants in the DIG study at higher risk of hospitalization as identified by a multistate model were considerably more likely to benefit from digoxin therapy to reduce heart failure hospitalization.
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