A non-interventional comparative study of the 20:1 combination of cafedrine/theodrenaline versus ephedrine for the treatment of intra-operative arterial hypotension: the ‘HYPOTENS’ study design and rationale

Abstract

Objective: To compare the effectiveness of 20:1 cafedrine/theodrenaline approved for use in Germany to ephedrine in the restoration of arterial blood pressure and on post-operative outcomes in patients with intra-operative arterial hypotension of any origin under standard clinical practice conditions.

Methods and results: ‘HYPOTENS’ is a national, multi-center, prospective, open-label, two-armed, non-interventional study. Effectiveness and post-operative outcome following cafedrine/theodrenaline or ephedrine therapy will be evaluated in two cohorts of hypotensive patients. Cohort A includes patients aged ≥50 years with ASA-classification 2–4 undergoing non-emergency surgical procedures under general anesthesia. Cohort B comprises patients undergoing Cesarean section under spinal anesthesia. Participating surgical departments will be assigned to a treatment arm by routinely used anti-hypotensive agent. To minimize bias, matched department pairs will be compared in a stratified selection process. The composite primary end-point is the lower absolute deviation from individually determined target blood pressure (IDTBP) and the incidence of heart rate ≥100 beats/min in the first 15 min. Secondary end-points include incidence and degree of early post-operative delirium (cohort A), severity of fetal acidosis in the newborn (cohort B), upper absolute deviation from IDTBP, percentage increase in systolic blood pressure, and time to IDTBP.

Conclusion: This open-label, non-interventional study design mirrors daily practice in the treatment of patients with intra-operative hypotension and ensures full treatment decision autonomy with respect to each patient’s individual condition. Selection of participating sites by a randomization process addresses bias without interfering with the non-interventional nature of the study. First results are expected in 2018. ClinicalTrials.gov identifier: NCT02893241; DRKS identifier: DRKS00010740.

Keywords:

• Intraoperative hypotension
• arterial hypotension
• cafedrine/theodrenaline
• ephedrine
• non-interventional trial
• study design
• Akrinor

Transparency

Declaration of funding

The ‘HYPOTENS’ study is funded by Teva ratiopharm GmbH, Ulm, Germany.

Declaration of financial/other interests

L.E. reports honoraria from Baxter Deutschland GmbH, Fresenius Kabi Deutschland GmbH, Grünenthal GmbH, Sintetica GmbH, and Teva ratiopharm GmbH. G.G. has received honoraria from Teva ratiopharm. S.H. is an employee of Teva ratiopharm GmbH. K.M. is an employee of Teva GmbH. T.K. receives payments from the sponsor for statistical services (design and analysis) as part of this this study. T.K. received honoraria for consulting from Teva ratiopharm GmbH. P.F. has received honoraria for consulting from Teva ratiopharm GmbH, Acacia Ltd, and BBraun. He has received honoraria for lecturing from Fresenius Kabi Deutschland GmbH, Grünenthal GmbH, Baxter Deutschland GmbH, and Medtronic GmbH. Peer reviewers on this manuscript have received an honorarium from CMRO for their review work, but have no other relevant financial relationships to disclose.

Acknowledgments

Editorial assistance for manuscript preparation was provided by Physicians World Europe GmbH, Mannheim, Germany, with financial support from Teva ratiopharm GmbH, Ulm, Germany.

Ethics and Clinical Trial Registration

The leading ethic committee of the Medical Faculty of the Philipps-University Marburg (chairman: Professor Dr G. Richter) approved this trial on April 15, 2016 (Az.14/16). All participating clinics will be approved by the responsible ethics committees and trained following allocation. The trial was registered at ClinicalTrials.gov identifier: NCT02893241 and DRKS identifier: DRKS00010740.