Publications

The DIGIT-HF trial: Key amendments of study design.

Abstract

Not specified

Authors: U. Bavendiek, D. Berliner, N. H. Thomas, X. Liu, J. Schwab, A. Rieth, L. S. Maier, S. Schallhorn, E. Angelini, F. Rathje, M. A. Sandu, W. Geller, T. Gaspar, R. Hambrecht, M. Zdravkovic, S. Philipp, D. Kosevic, G. Nickenig, D. Scheiber, S. Winkler, P. M. Becher, P. Lurz, M. Hulsmann, C. Schroder, A. Seltmann, H. von der Leyen, C. Veltmann, S. Stork, M. Bohm, A. Koch, J. Bauersachs

Date Published: 22nd Jan 2025

Publication Type: Journal

Rationale and design of the DIGIT-HF trial (DIGitoxin to Improve ouTcomes in patients with advanced chronic Heart Failure): a randomized, double-blind, placebo-controlled study.

Abstract (Expand)

AIMS: Despite recent advances in the treatment of chronic heart failure (HF), mortality and hospitalizations still remain high. Additional therapies to improve mortality and morbidity are urgently … needed. The efficacy of cardiac glycosides - although regularly used for HF treatment - remains unclear. DIGIT-HF was designed to demonstrate that digitoxin on top of standard of care treatment improves mortality and morbidity in patients with HF and a reduced ejection fraction (HFrEF). METHODS: Patients with chronic HF, New York Heart Association (NYHA) functional class III-IV and left ventricular ejection fraction (LVEF) </= 40%, or patients in NYHA functional class II and LVEF </= 30% are randomized 1:1 in a double-blind fashion to treatment with digitoxin (target serum concentration 8-18 ng/mL) or matching placebo. Randomization is stratified by centre, sex, NYHA functional class (II, III, or IV), atrial fibrillation, and treatment with cardiac glycosides at baseline. A total of 2190 eligible patients will be included in this clinical trial (1095 per group). All patients receive standard of care treatment recommended by expert guidelines upon discretion of the treating physician. The primary outcome is a composite of all-cause mortality or hospital admission for worsening HF (whatever occurs first). Key secondary endpoints are all-cause mortality, hospital admission for worsening HF, and recurrent hospital admission for worsening HF. CONCLUSION: The DIGIT-HF trial will provide important evidence, whether the cardiac glycoside digitoxin reduces the risk for all-cause mortality and/or hospital admission for worsening HF in patients with advanced chronic HFrEF on top of standard of care treatment.

Authors: U. Bavendiek, D. Berliner, L. A. Davila, J. Schwab, L. Maier, S. A. Philipp, A. Rieth, R. Westenfeld, C. Piorkowski, K. Weber, A. Hanselmann, M. Oldhafer, S. Schallhorn, H. von der Leyen, C. Schroder, C. Veltmann, S. Stork, M. Bohm, A. Koch, J. Bauersachs

Date Published: 21st Mar 2019

Publication Type: Journal

Simple and safe digitoxin dosing in heart failure based on data from the DIGIT-HF trial.

Abstract (Expand)

BACKGROUND: The present study aimed to develop a simple dosing score when starting the cardiac glycoside digitoxin in heart failure with reduced ejection fraction (HFrEF) employing first data from the … randomized, double-blinded DIGIT-HF trial. METHODS AND RESULTS: In DIGIT-HF, digitoxin was started with a dose of 0.07 mg once daily (o.d.) in all patients. For score derivation, 317 patients were analyzed who had been randomized to digitoxin. In these patients, after scheduled determination of serum levels at study week 6, the digitoxin dose had remained unchanged or had been reduced to 0.05 mg o.d. (97% of patients) to achieve serum concentrations within a predefined range (10.5-23.6 nmol/l). In logistic regression analyses, sex, age, body mass index (BMI), and estimated glomerular filtration rate (eGFR) were associated with need for dose reduction and, therefore, selected for further developing the dosing score. Optimal cut-points were derived from ROC curve analyses. Finally, female sex, age >/= 75 years, eGFR < 50 ml/min/1.73 m(2), and BMI < 27 kg/m(2) each were assigned one point for the digitoxin dosing score. A score of >/= 1 indicated the need for dose reduction with sensitivity/specificity of 81.6%/49.7%, respectively. Accuracy was confirmed in a validation data set including 64 patients randomized to digitoxin yielding sensitivity/specificity of 87.5%/37.5%, respectively. CONCLUSION: In patients with HFrEF, treatment with digitoxin should be started at 0.05 mg o.d. in subjects with either female sex, eGFR < 50 ml/min/1.73m(2), BMI < 27 kg/m(2), or age >/= 75 years. In any other patient, digitoxin may be safely started at 0.07 mg o.d.

Authors: U. Bavendiek, A. Grosshennig, J. Schwab, D. Berliner, X. Liu, L. Maier, T. Gaspar, A. Rieth, S. Philipp, R. Hambrecht, R. Westenfeld, T. Munzel, S. Winkler, M. Hulsmann, D. Westermann, M. Zdravkovic, R. Lichtinghagen, H. von der Leyen, S. Zimmermann, C. Veltmann, M. Bohm, S. Stork, A. Koch, J. Bauersachs

Date Published: 21st Jul 2023

Publication Type: Journal

DIGitoxin to Improve ouTcomes in patients with advanced chronic Heart Failure (DIGIT-HF): Baseline characteristics compared to recent randomized controlled heart failure trials.

Abstract (Expand)

AIMS: This report presents the baseline characteristics of patients enrolled in the DIGIT-HF trial and compares them with participants from recent trials with improved outcomes in patients with heart … failure (HF) and a reduced ejection fraction (HFrEF). METHODS AND RESULTS: DIGIT-HF, a randomized, double-blind, placebo-controlled, multicentre trial enrolling patients with symptomatic HFrEF (New York Heart Association [NYHA] functional class II and left ventricular ejection fraction [LVEF] </=30%, or NYHA class III-IV and LVEF </=40%), compares the efficacy and safety of digitoxin versus placebo in addition to standard treatment. Most baseline characteristics of the intention-to-treat population (1212 patients, mean age 66 +/- 11 years, 20% women, mean LVEF 29 +/- 7%) were similar to those in recent HFrEF trials. The distribution of NYHA class II, III, and IV was 30%, 66% and 4%, respectively, and indicates that the patients were sicker than in comparator HFrEF trials. Less patients had atrial fibrillation (27%) than those in recent HFrEF trials, but prescription rates of background therapy with beta-blockers (96%), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers/angiotensin receptor-neprilysin inhibitors (95%), mineralocorticoid receptor antagonists (76%), and diuretics (87%) were high and similar. Overall, 40% of patients were on angiotensin receptor-neprilysin inhibitors, 19% on sodium-glucose cotransporter 2 inhibitors, and 9% on ivabradine. Rates of implantable cardioverter-defibrillator (ICD, 64%) and cardiac resynchronization therapy (CRT, 25%) devices were much higher than in recent HFrEF trials. CONCLUSIONS: Patients included in DIGIT-HF display a more severe HF symptom burden and higher rates of ICD/CRT implants compared to participants in recent HFrEF trials, while pharmacotherapy was largely similar. CLINICAL TRIAL REGISTRATION: EudraCT (2013-005326-38).

Authors: U. Bavendiek, N. H. Thomas, D. Berliner, X. Liu, J. Schwab, A. Rieth, L. S. Maier, S. Schallhorn, E. Angelini, S. Soltani, F. Rathje, M. A. Sandu, W. Geller, T. Gaspar, R. Hambrecht, M. Zdravkovic, S. Philipp, D. Kosevic, G. Nickenig, D. Scheiber, S. Winkler, P. M. Becher, P. Lurz, M. Hulsmann, M. von Karpowitz, C. Schroder, B. Neuhaus, A. Seltmann, H. von der Leyen, C. Veltmann, S. Stork, M. Bohm, A. Koch, A. Grosshennig, J. Bauersachs

Date Published: 19th May 2025

Publication Type: Journal

Cannabis-based medicine in treatment of patients with Gilles de la Tourette syndrome.

Abstract (Expand)

INTRODUCTION: Gilles de la Tourette syndrome (GTS) is a childhood onset disorder characterised by the presence of motor and vocal tics. The guidelines of both the American Academy of Neurology (AAN) … as well as the European Society for the Study of Tourette Syndrome (ESSTS) recommend behavioural therapy and pharmacotherapy, mainly with antipsychotics, as first line treatments for tics. In spite of these well-established therapeutic approaches, a significant number of patients are dissatisfied because of insufficient tic reduction or intolerable side effects. Previous studies have suggested that cannabis-based medicine (CBM) might be an alternative treatment in these patients. MATERIAL AND METHODS: Two reviewers (KS, NS) searched the electronic database of PubMed on 1 July, 2021 for relevant studies using the search terms: ('Tourette syndrome' [MeSH Terms] OR 'Gilles de la Tourette syndrome' [MeSH Terms] OR 'tic disorders' [MeSH Terms] OR 'tics' [MeSH Terms] OR 'tic disorders'[Title/Abstract]) AND ('cannabis-based medicine' [Title/Abstract] OR 'cannabis' [Title/Abstract] OR 'dronabinol' [Title/Abstract] OR 'nabiximols' [Title/Abstract] OR 'tetrahydrocannabinol' [Title/Abstract] OR 'THC' [Title/Abstract] OR 'cannabidiol' [Title/Abstract], limit: 'humans'. These studies were further reviewed for additional relevant citations. The titles and abstracts of the studies obtained through this search were examined by two reviewers (KS, NS) in order to determine article inclusion. Discrepancies were addressed by the reviewers through discussion and eventually conversation with the senior reviewer (KMV). RESULTS: Although the amount of evidence supporting the use of CBM in GTS is growing, the majority of studies are still limited to case reports, case series, and open uncontrolled studies. To date, only two small randomised controlled trials (RCTs) using tetrahydrocannabinol (THC, dronabinol) have been published demonstrating the safety and efficacy of this intervention in the treatment of tics in patients with GTS. On the other hand, another RCT with Lu AG06466 (formerly known as ABX-1431), a modulator of endocannabinoid neurotransmission, has failed to prove effective in the therapy of GTS. Accordingly, under the guidelines of both the ESSTS and the AAN, treatment with CBM is categorised as an experimental intervention that should be applied to patients who are otherwise treatment-resistant. CONCLUSIONS: Increasing evidence suggests that CBM is efficacious in the treatment of tics and psychiatric comorbidities in patients with GTS. The results of ongoing larger RCTs, such as CANNA-TICS (ClinicalTrials.gov Identifier: NCT03087201), will further clarify the role of CBM in the treatment of patients with GTS.

Authors: N. Szejko, K. Saramak, A. Lombroso, K. Muller-Vahl

Date Published: 29th Oct 2021

Publication Type: Journal

The CANNA-TICS Study Protocol: A Randomized Multi-Center Double-Blind Placebo Controlled Trial to Demonstrate the Efficacy and Safety of Nabiximols in the Treatment of Adults With Chronic Tic Disorders.

Abstract (Expand)

Background: Gilles de la Tourette syndrome (TS) is a chronic neuropsychiatric disorder characterized by motor and vocal tics. First-line treatments for tics are antipsychotics and tic-specific behavioral … therapies. However, due to a lack of trained therapists and adverse events of antipsychotic medication many patients seek alternative treatment options including cannabis. Based on the favorable results obtained from case studies on different cannabis-based medicines as well as two small randomized controlled trials using delta-9-tetrahydrocannabinol (THC), we hypothesize that the cannabis extract nabiximols can be regarded as a promising new and safe treatment strategy in TS. Objective: To test in a double blind randomized clinical trial, whether treatment with the cannabis extract nabiximols is superior to placebo in patients with chronic tic disorders. Patients and Methods: This is a multicenter, randomized, double-blind, placebo controlled, parallel-group, phase IIIb trial, which aims to enroll 96 adult patients with chronic tic disorders (TS or chronic motor tic disorder) across 6 centers throughout Germany. Patients will be randomized with a 2:1 ratio into a nabiximols and a placebo arm. The primary efficacy endpoint is defined as tic reduction of at least 30% (compared to baseline) according to the Total Tic Score of the Yale Global Tic Severity Scale (YGTSS-TTS) after 13 weeks of treatment. In addition, several secondary endpoints will be assessed including changes in different psychiatric comorbidities, quality of life, driving ability, and safety assessments. Discussion: This will be the first large, controlled study investigating efficacy and safety of a cannabis-based medicine in patients with TS. Based on available data using different cannabis-based medicines, we expect not only a reduction of tics, but also an improvement of psychiatric comorbidities. If the cannabis extract nabiximols is proven to be safe and effective, it will be a valuable alternative treatment option. The results of this study will be of high health-economic relevance, because a substantial number of patients uses cannabis (illegally) as self-medication. Conclusion: The CANNA-TICS trial will clarify whether nabiximols is efficacious and safe in the treatment of patients with chronic tic disorders. Clinical Trial Registration: This trial is registered at clinicaltrialsregister.eu (Eudra-CT 2016-000564-42) and clinicaltrials.gov (NCT03087201).

Authors: E. Jakubovski, A. Pisarenko, C. Fremer, M. Haas, M. May, C. Schumacher, C. Schindler, S. Hackl, L. Aguirre Davila, A. Koch, A. Brunnauer, C. L. Cimpianu, B. Lutz, L. Bindila, K. Muller-Vahl

Date Published: 16th Dec 2020

Publication Type: Journal

Oral iron supplementation with ferric maltol in patients with pulmonary hypertension.

Abstract (Expand)

Oral ferric maltol was well tolerated and effective in patients with pulmonary hypertension and iron deficiency anaemia. Restoration of iron stores corrected anaemia and resulted in improved right … ventricular function and exercise tolerance https://bit.ly/2zMwvxc

Authors: K. M. Olsson, J. Fuge, T. Brod, J. C. Kamp, J. Schmitto, T. Kempf, J. Bauersachs, M. M. Hoeper

Date Published: 24th May 2020

Publication Type: Journal

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