Elsevier

American Heart Journal

Volume 237, July 2021, Pages 5-12
American Heart Journal

Trial Designs
Comparison of Outcomes with Midodrine and Fludrocortisone for Objective Recurrence in Treating Syncope (COMFORTS trial): Rationale and design for a multi-center randomized controlled trial

https://doi.org/10.1016/j.ahj.2021.03.002Get rights and content

Abstract

Background

The cornerstone of the treatment of vasovagal syncope (VVS) is lifestyle modifications; however, some patients incur life-disturbing attacks despite compliance with these treatments which underscores the importance of pharmacological interventions.

Methods

In this open-label multi-center randomized controlled trial, we are going to randomize 1375 patients with VVS who had ≥2 syncopal episodes in the last year into three parallel arms with a 2:2:1 ratio to receive midodrine, fludrocortisone, or no medication. All patients will be recommended to drink 2 to 3 liters of fluids per day, consume 10 grams of NaCl per day, and practice counter-pressure maneuvers. In medication arms, patients will start on 5 mg of midodrine TDS or 0.05 mg of fludrocortisone BD. After one week the dosage will be up-titrated to midodrine 30 mg/day and fludrocortisone 0.2 mg/day. Patient tolerance will be the principal guide to dosage adjustments. We will follow-up the patients on 3, 6, 9, and 12 months after randomization. The primary outcome is the time to first syncopal episode. Secondary outcomes include the recurrence rate of VVS, time interval between first and second episodes, changes in quality of life (QoL), and major and minor adverse drug reactions. QoL will be examined by the 36-Item Short Form Survey questionnaire at enrollment and 12 months after randomization.

Conclusion

The COMFORTS trial is the first study that aims to make a head-to-head comparison between midodrine and fludrocortisone, against a background of lifestyle modifications for preventing recurrences of VVS and improving QoL in patients with VVS.

Section snippets

Ethical considerations and registration

The protocol of this study corresponds to the 1964 Declaration of Helsinki and its later amendments. It has been approved by the ethics committee of Tehran Heart Center at Tehran University of Medical Sciences with the ID of IR.TUMS.THC.REC.1399.028 and will be approved by ethics committees at all participating centers. We will obtain written informed consent from all participants before inclusion in the study. This protocol has been registered at www.clinicaltrials.gov with the ID of

Discussion

In this communication, we presented the detailed protocol of the COMFORTS trial, a multi-center RCT aimed at investigating the efficacy of midodrine versus fludrocortisone with a background of lifestyle modifications for prevention of vasovagal attacks and improving QoL in patients with VVS.

Midodrine is a prodrug that acts through the activation of peripheral alpha-1-adrenergic receptors by its active metabolite, desglymidodrine. It counteracts the venodilation and venous pooling, a consequence

Conclusions

To the best of our knowledge, the COMFORTS trial is the first one which aimed at investigating the efficacy of midodrine, fludrocortisone, and lifestyle modifications for preventing vasovagal spells and improving QoL in patients with VVS. We believe that the results of this study will shed more light on the available pharmacological interventions to improve the outcomes of the patients with VVS.

Declarations of Competing Interest

None.

Acknowledgments

We would like to express our genuine appreciation for the productive suggestions of Professor Michele Brignole, who is the COMFORTS trial advisor and has encouraged us to conduct this study. We thank the invaluable supports and sincere efforts of the staff of the information technology department of Tehran Heart Center for developing the online platform of the study.

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    • Pharmacologic prevention of recurrent vasovagal syncope: A systematic review and network meta-analysis of randomized controlled trials

      2023, Heart Rhythm
      Citation Excerpt :

      The trial conducted by Sheldon et al40 could not determine the efficacy of fludrocortisone in reducing syncopal spells despite a significant effect found in post hoc analyses and following dose stabilization. Overall, it seems that the hypothesis of the superiority of fludrocortisone compared with other drugs, especially midodrine, should be strongly re-evaluated, such as the hypothesis supposed by the COMFORTS (Comparison of Outcomes with Midodrine and Fludrocortisone for Objective Recurrence in Treating Syncope) trial.62 Nonpharmacologic management of VVS should not be forgotten by clinicians.

    • Compression stockings for treating vasovagal syncope (COMFORTS-II) trial: Rationale and design of a triple-blind, multi-center, randomized controlled trial

      2022, American Heart Journal
      Citation Excerpt :

      The only non-pharmacological intervention that has been studied in proper RCTs are physical counter-pressure maneuvers,16 which are nevertheless applicable only when prodromes are experienced. Among the various pharmacological options investigated, the oral mineralocorticoid, fludrocortisone, and the alpha-1 adrenergic receptor agonist, midodrine, are most studied.5,19,34 Fludrocortisone did not reduce VVS recurrence in a multicenter trial (Prevention of Syncope Trial-2 [POST-2]), and was only effective in exploratory analysis among patients who tolerated the target 0.2 mg daily dose (only 61% of study population).

    These authors contributed equally as co-first authors.

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