Mechanism-based Therapy of Hypotensive Syncope (2STEPtherapy)

The aim of this study is to assess the efficacy of a therapeutic strategy aimed to increase 24-hour systolic blood pressure (SBP) values, assessed by 24-hour ambulatory blood pressure monitoring (ABPM), in reducing syncope recurrences in patients affected by hypotensive syncope during one year of follow-up.

Study Overview

• Status: Recruiting
• Conditions: Syncope, Vasovagal, Neurally-Mediated

Detailed Description

This multicentre, prospective, observational, pragmatic study on long-term therapy of hypotensive syncope consists of two distinct twin substudies to be undergone in parallel:

1. the Drug-deprescribing substudy wants to assess a strategy aimed to increase BP by deprescribing of hypotensive drugs in hypertensive patients affected by drug-related syncope, and;
2. the Drug-addition substudy wants to assess a therapeutic strategy aimed at increasing BP with fludrocortisone in syncopal patients with drug-unrelated permanent or intermittent hypotension.

Inclusion criteria

1. Patients >18-year-old with a clinical diagnosis of severe, recurrent reflex syncope, refractory to education and life-style measures (according to the criteria of ESC guidelines) AND a diagnosis of hypotensive syncope defined as:

   • Persistent or intermittent hypotension during 24-hour ABPM (ABPM1) AND/OR
   • Reproduction of syncope during the Short Cardiovascular Autonomic Function Assessment (SCAFA) that consists in carotid sinus massage (CSM), 3-min active stand test, and head-up tilt test (TT) performed one after another in an uninterrupted sequence as a single procedure in a tilt table.
2. Clinical indication to deprescribing of antihypertensive drugs or to prescribing of fludrocortisone therapy, as appropriate, according to the clinical practice of the investigator Exclusion criteria

1. Age <18 years 2. Cardioinhibitory reflex syncope during SCAFA tests 3. Competing causes of syncope 4. Severe cardiac disease, previous stroke or transient ischaemic attack. 5. Patients who refused drug therapy 6. Non-severe forms of syncope, i.e., patients with rare and mild episodes occurring in low-risk situations in the presence of distinct and preventable triggers.

7. Contraindication to fludrocortisone Therapy The strategy of deprescribing (withdrawal or dose reduction) is empirically based on the usual clinical practice of the investigators and is targeted to achieve an absolute value ≥134 mmHg and/or an increase ≥12 mmHg of 24-hour SBP.

The initial recommended dose of fludrocortisone is 0.2 md/day, accepted range is 0.1 to 0.3 mg and is targeted to achieve an absolute value of ≥116 mmHg and/or an increase of ≥9 mmHg of 24-hour SBP.

30-day optimization period A period up to 30 days is allowed to optimize therapy, if necessary, with the goal to achieve the above targets of mean 24-hour SBP during an ABPM performed at the end of this period (ABPM2). Subsequent follow-up visits are performed at 4, 8 and 12 months.

Primary endpoints

• The primary endpoint of the Drug-deprescribing subgroup is the comparison of syncopal recurrences (time to first recurrence and syncope burden) at one year in patients who achieved a mean absolute value of ≥134 mmHg and/or an increase ≥12 mmHg of 24-hour SBP on ABPM2 (Target) with those of patients who did not (No target).
• The primary endpoint of the Drug-addition subgroup is the comparison of syncopal recurrences (time to first recurrence and syncope burden) at one year in patients who achieved a mean absolute value of ≥116 mmHg and an increase of ≥9 mmHg of 24-hour SBP on ABPM2 (Target) with those of patients who did not (No target).

Secondary endpoints

• Comparison between the burden of syncope and presyncope during the year before with that during the year after enrolment
• Exploratory analyses with the aim to identify eventual different targets that are better predictor of efficacy of therapy.

• Study Type: Observational
• Enrollment (Estimated): 140

Contacts and Locations

• Study Contact: Name: Michele Brignole, MD Cardiologist; Phone Number: +3204391422; Email: m.brignole@auxologico.it
• Study Contact Backup: Name: Antonella Groppelli, MD; Phone Number: +393388732063; Email: a.groppelli@auxologico.it

Study Locations

• France
  • Marseille, France
    • Recruiting
    • University of marseille Aix en Provence
    • Contact: Jean Claude Deharo
• Italy
  • Florence, Italy
    • Recruiting
    • University of Florence
    • Contact: Andrea Ungar
    • Sub-Investigator: Andrea Ungar
  • Lavagna, Italy
    • Recruiting
    • ospdali del Tigullio
    • Contact: Roberto Maggi
  • Naples, Italy
    • Recruiting
    • Università della Campania Vamvitelli
    • Contact: Vincenzo Russo
  • MI
    • Milan, MI, Italy, 16149
      • Recruiting
      • IRCCS Istituto Auxologico Italiano
      • Contact: Michele Brignole; Phone Number: 3204391422; Email: mbrignole@outlook.it
      • Contact: Michele MB Brignole, MD; Phone Number: 3204391422; Email: mbrignole@outlook.it
      • Principal Investigator: Michele Brignole
• Netherlands
  • Amsterdam, Netherlands
    • Recruiting
    • AMC Universisty of Amsterdam
    • Contact: Frederik de Lange
• Spain
  • Barcelona, Spain
    • Not yet recruiting
    • University of Barcelona Vall d'Ebron
    • Contact: Jaume Pascual
• Sweden
  • Stockholm, Sweden
    • Recruiting
    • Karolinska Institut
    • Contact: Artur Fedorowski

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

• Sampling Method: Probability Sample

Study Population

1. Age <18 years
2. Cardioinhibitory reflex syncope during SCAFA tests
3. Competing causes of syncope
4. Severe cardiac disease, previous stroke or transient ischaemic attack.
5. Patients who refused drug therapy
6. Non-severe forms of syncope, i.e., patients with rare and mild episodes occurring in low-risk situations in the presence of distinct and preventable triggers.
7. Contraindication to fludrocortisone

Description

Inclusion Criteria:

• Patients >18-year-old with a clinical diagnosis of severe, recurrent reflex syncope, refractory to education and life-style measures (according to the criteria of ESC guidelines) AND a diagnosis of hypotensive syncope defined as:
• Persistent or intermittent hypotension during 24-hour ABPM (ABPM1) AND/OR

• Reproduction of syncope during the Short Cardiovascular Autonomic Function Assessment (SCAFA) that consists in carotid sinus massage (CSM), 3-min active stand test, and head-up tilt test (TT) performed one after another in an uninterrupted sequence as a single procedure in a tilt table.

  2. Clinical indication to deprescribing of antihypertensive drugs or to prescribing of fludrocortisone therapy, as appropriate, according to the clinical practice of the investigator

Exclusion Criteria:

-

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort

Drug deprescring and drug addition; This multicentre, prospective, observational, pragmatic study on long-term therapy of hypotensive syncope consists of two distinct twin substudies to be undergone in parallel: the Drug-deprescribing substudy wants to assess a strategy aimed to increase BP by deprescribing of hypotensive drugs in hypertensive patients affected by drug-related syncope, and;; the Drug-addition substudy wants to assess a therapeutic strategy aimed at increasing BP with fludrocortisone in syncopal patients with drug-unrelated permanent or intermittent hypotension.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to first syncope recurrenceSyncope	• The primary endpoint of the Drug-deprescribing subgroup is the comparison of syncopal recurrences (time to first recurrence and syncope burden) at one year in patients who achieved a mean absolute value of ≥134 mmHg and/or an increase ≥12 mmHg of 24-hour SBP on ABPM2 (Target) with those of patients who did not (No target). • The primary endpoint of the Drug-addition subgroup is the comparison of syncopal recurrences (time to first recurrence and syncope burden) at one year in patients who achieved a mean absolute value of ≥116 mmHg and an increase of ≥9 mmHg of 24-hour SBP on ABPM2 (Target) with those of patients who did not (No target).	4 months

Collaborators and Investigators

• Sponsor: Istituto Auxologico Italiano

Study record dates

Study Major Dates

• Study Start (Actual): May 1, 2024
• Primary Completion (Estimated): December 31, 2025
• Study Completion (Estimated): May 31, 2026

Study Registration Dates

• First Submitted: July 16, 2024
• First Submitted That Met QC Criteria: July 16, 2024
• First Posted (Actual): July 22, 2024

Study Record Updates

• Last Update Posted (Actual): July 22, 2024
• Last Update Submitted That Met QC Criteria: July 16, 2024
• Last Verified: July 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Autonomic Nervous System Diseases; Unconsciousness; Consciousness Disorders; Primary Dysautonomias; Orthostatic Intolerance; Syncope; Syncope, Vasovagal
• Other Study ID Numbers: 09C408

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No