Abstract 662 A score for simple and safe digitoxin dosing in heart failure based on data from the DIGIT-HF-trial

Background:
The cardiac glycoside digitoxin is a therapeutic option for patients with heart failure with reduced ejection fraction (HFrEF). Pharmacokinetic data for simple and safe dosing of digitoxin in HFrEF patients are not available. The present study aimed to develop a score for simple dosing when starting digitoxin in HFrEF patients employing first data from the DIGIT-HF trial.

Methods and results:
The DIGIT-HF trial is a randomized, double-blind, placebo-controlled trial investigating the impact of digitoxin on the risk of hospitalization for worsening heart failure and mortality in patients with advanced HFrEF. Digitoxin treatment was titrated by a standardized dosing protocol to achieve serum concentrations within a predefined low therapeutic range of 10.0-23.6 nmol/l. Patients randomized to digitoxin started with a digitoxin dose of 0.07 mg once daily. For dose titration, digitoxin serum concentrations were determined 6 weeks after treatment start. Digitoxin was reduced from 0.07 mg to 0.05 mg once daily if a digitoxin serum concentration of >23 nmol/l was found.

The aim of this sub-analysis was to identify variables associated necessitating a dose reduction of digitoxin. We analyzed 317 DIGIT-HF patients randomized to digitoxin with available digitoxin serum concentration levels at 6 weeks. Patients in whom the digitoxin dose was not changed or increased (n=181) were compared with patients receiving a dose reduction (n=136) using univariate/multivariable logistic regression analysis. Female sex, older age, lower BMI, and lower eGFR were associated with dose reduction and selected for score development. Specifically, in the multivariable logistic regression model there was a higher necessity of dose reduction for women (OR 3.10, 95% CI 1.66-5.81), patients with eGFR <50 ml/min (OR 2.45, 95% CI 1.40-4.32), or BMI <27 kg/qm (OR 3.05, 95% CI 1.83-5.08). The effect for older patients (age ≥75 years) was fairly modest and not statistically significant in the multivariable model, most likely due to collinearity between age and eGFR. Finally, female sex, age ≥75 years, eGFR <50 ml/min, and BMI <27 kg/qm each were assigned one point for the Digitoxin-Dosing-Score. A score of ≥1 indicated the need of a dose reduction from 0.07 mg to 0.05 mg digitoxin with sensitivity of 83.1% and specificity of 49%. This was confirmed in a validation data set including 64 patients randomized to digitoxin (sensitivity/specificity: 87.5/37.5%). The high sensitivity of the score is of particular importance, because overdosing must be excluded during the early phase of treatment initiation. By contrast, specificity is neglectable in that respect, because digitoxin serum concentrations have to be determined after start of treatment in any case enabling uncomplicated dose uptitration if required.

Conclusion:
A Digitoxin-Dosing-Score consisting of variables that can easily be obtained in clinical routine (female sex, eGFR, BMI, age) enables simple and safe initiation of digitoxin treatment avoiding overdosing and concomitant side effects in patients with HFrEF.

Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5
A score for simple and safe digitoxin dosing in heart failure based on data from the DIGIT-HF-trial
U. Bavendiek¹, A. Großhennig², J. Schwab³, D. Berliner¹, X. Liu², L. S. Maier⁴, T. Gaspar⁵, A. Rieth⁶, S. Philipp⁷, R. Hambrecht⁸, R. Westenfeld⁹, T. Münzel¹⁰, S. Winkler¹¹, M. Hülsmann¹², D. Westermann¹³, R. Lichtinghagen¹⁴, H. E. von der Leyen¹⁵, S. Zimmermann¹⁶, C. G. Veltmann¹, M. Böhm¹⁷, S. Störk¹⁸, A. Koch², J. Bauersachs¹, für die Studiengruppe: DIGIT-HF
¹Kardiologie und Angiologie, Medizinische Hochschule Hannover, Hannover; ²Biometrie, Medizinische Hochschule Hannover, Hannover; ³Klinik für Innere Medizin 8, Schwerpunkt Kardiologie, Universitätsklinik der Paracelsus Medizinischen Privatuniversität, Nürnberg; ⁴Klinik und Poliklinik für Innere Med. II, Kardiologie, Universitätsklinikum Regensburg, Regensburg; ⁵Abteilung für Invasive Elektrophysiologie, Herzzentrum Dresden GmbH an der TU Dresden, Dresden; ⁶Abteilung für Kardiologie, Kerckhoff Klinik GmbH, Bad Nauheim; ⁷Klinik für Innere Med., Kardiologie und Intensivmedizin, Elbe Kliniken in Stade, Stade; ⁸Innere Medizin I, Klinikum Links der Weser, Bremen; ⁹Klinik für Kardiologie, Pneumologie und Angiologie, Universitätsklinikum Düsseldorf, Düsseldorf; ¹⁰Kardiologie 1, Zentrum für Kardiologie, Universitätsmedizin der Johannes Gutenberg-Universität Mainz, Mainz; ¹¹Klinik f. Innere Medizin / Kardiologie, Unfallkrankenhaus Berlin, Berlin; ¹²Kardiologie, Universitätsklinik für Innere Medizin II, Wien, AT; ¹³Allgemeine und Interventionelle Kardiologie, Universitäres Herz- und Gefäßzentrum Hamburg GmbH, Hamburg; ¹⁴Klinische Chemie, Medizinische Hochschule Hannover, Hannover; ¹⁵Hannover Clinical Trial Center, Medizinische Hochschule Hannover, Hannover; ¹⁶Clinical Trial Services, Medizinische Hochschule Hannover, Hannover; ¹⁷Innere Medizin III - Kardiologie, Angiologie und internistische Intensivmedizin, Universitätsklinikum des Saarlandes, Homburg/Saar; ¹⁸Deutsches Zentrum für Herzinsuffizienz, Universitätsklinikum Würzburg, Würzburg;
Background: The cardiac glycoside digitoxin is a therapeutic option for patients with heart failure with reduced ejection fraction (HFrEF). Pharmacokinetic data for simple and safe dosing of digitoxin in HFrEF patients are not available. The present study aimed to develop a score for simple dosing when starting digitoxin in HFrEF patients employing first data from the DIGIT-HF trial. Methods and results: The DIGIT-HF trial is a randomized, double-blind, placebo-controlled trial investigating the impact of digitoxin on the risk of hospitalization for worsening heart failure and mortality in patients with advanced HFrEF. Digitoxin treatment was titrated by a standardized dosing protocol to achieve serum concentrations within a predefined low therapeutic range of 10.0-23.6 nmol/l. Patients randomized to digitoxin started with a digitoxin dose of 0.07 mg once daily. For dose titration, digitoxin serum concentrations were determined 6 weeks after treatment start. Digitoxin was reduced from 0.07 mg to 0.05 mg once daily if a digitoxin serum concentration of >23 nmol/l was found. The aim of this sub-analysis was to identify variables associated necessitating a dose reduction of digitoxin. We analyzed 317 DIGIT-HF patients randomized to digitoxin with available digitoxin serum concentration levels at 6 weeks. Patients in whom the digitoxin dose was not changed or increased (n=181) were compared with patients receiving a dose reduction (n=136) using univariate/multivariable logistic regression analysis. Female sex, older age, lower BMI, and lower eGFR were associated with dose reduction and selected for score development. Specifically, in the multivariable logistic regression model there was a higher necessity of dose reduction for women (OR 3.10, 95% CI 1.66-5.81), patients with eGFR <50 ml/min (OR 2.45, 95% CI 1.40-4.32), or BMI <27 kg/qm (OR 3.05, 95% CI 1.83-5.08). The effect for older patients (age ≥75 years) was fairly modest and not statistically significant in the multivariable model, most likely due to collinearity between age and eGFR. Finally, female sex, age ≥75 years, eGFR <50 ml/min, and BMI <27 kg/qm each were assigned one point for the Digitoxin-Dosing-Score. A score of ≥1 indicated the need of a dose reduction from 0.07 mg to 0.05 mg digitoxin with sensitivity of 83.1% and specificity of 49%. This was confirmed in a validation data set including 64 patients randomized to digitoxin (sensitivity/specificity: 87.5/37.5%). The high sensitivity of the score is of particular importance, because overdosing must be excluded during the early phase of treatment initiation. By contrast, specificity is neglectable in that respect, because digitoxin serum concentrations have to be determined after start of treatment in any case enabling uncomplicated dose uptitration if required. Conclusion: A Digitoxin-Dosing-Score consisting of variables that can easily be obtained in clinical routine (female sex, eGFR, BMI, age) enables simple and safe initiation of digitoxin treatment avoiding overdosing and concomitant side effects in patients with HFrEF.
https://dgk.org/kongress_programme/jt2022/aV195.html