Clinical trial NCT03803215: Theophylline for Low Adenosine Syncope
Official title: Theophylline in Patients With Unexplained Syncope and Low Adenosine. Study Verified by ICM, Controlled by Propensity-score Matching
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Syncope
Keywords: theophylline
asystole
implantable loop recorder
Lead sponsor: Centro Prevenzione Malattie Cardiovascolari N. e V. Corbella
Sponsor class: OTHER
Collaborators: name: Gruppo Italiano Multidisciplinare per lo Studio della Sincope
First posted: 2019-01-14
Enrollment: 77
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: CASE_CONTROL
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Patients who have received an implantable cardiac monitor (ICM) for diagnosis of unexplained or atypical reflex syncope

Brief summary: The study aims at assessing that theophylline is effective in patients with no prodromes, normal heart and with low values of plasmatic adenosine compared with a propensity-score matched untreated control population who have received an implantable cardiac monitor (ICM) for diagnosis of unexplained or atypical reflex syncope.

Detailed description: Theophylline has been used for 3 decades in ordinary medical practice to tentatively prevent syncopal recurrences in patients affected by neurally-mediated syncope. Observational studies report a recurrence rate with this drug ranging between 12% and 22%. Theophylline was much more effective in selected patients with syncope without prodromes and normal heart who had ECG documentation of long pauses at the time of syncopal attack and low values of baseline plasmatic adenosine. Since theophylline is a non-selective antagonist of purinergic receptors, it has been hypothesized that purinergic receptors are involved in the mechanism of syncope in such patients. Conversely, theophylline was suspected to be ineffective (or less effective) in patients affected by other forms of neurally-mediated syncope.

The present study aims at assessing that theophylline is effective in patients with no prodromes, normal heart and with low values of plasmatic adenosine compared with a propensity-score matched untreated control population.

This will be a multicenter, non interventional study, verified by ICM, with 2 predefined subgroups:

Subgroup #1

* Low adenosine group: Patients with Low Adenosine values (\<0.40 μmol/L)
* Normal/high adenosine (≥0.40 μmol/L) group: any other patient Subgroup #2
* Patients with no prodromes or very short prodromes (≤5 sec), normal heart and normal ECG (No prodrome group)
* Any other form of atypical neurally-mediated syncope with prodromes \>5 sec. Remote or in-hospital periodic follow-up will be done according to centre's clinical practice for ICM monitoring.

Patients will be followed up until the first primary endpoint event with a maximum follow-up of 24 months since start of theophylline treatment.

Eligibility criteria: Inclusion Criteria:

1. Male or female gender with age \>18 years
2. Unexplained syncope without prodrome or neurally-mediated syncope with atypical prodrome, with normal heart and normal ECG
3. Two syncopes /last year or 3 syncopes /last 2 years before start of theophylline treatment
4. Having received an ICM according to conventional guideline-based indications
5. Being treated with oral theophylline therapy, while been waiting for ICM diagnosis
6. Having signed a written informed consent to the study participation and to the treatment of personal data

Exclusion Criteria:

1. Typical vaso-vagal syncope with long prodromes and situational syncope
2. Any other form of syncope/T-LOC different from reflex syncope
3. Pregnant or breast-feeding patients -

Primary outcomes:
measure: Asystolic syncope
timeFrame: 24 months
Secondary outcomes:
measure: Time to first syncope recurrence
timeFrame: 24 months
measure: Asystolic syncope in the subgroup with low adenosine plasmatic values
timeFrame: 24 months
measure: Asystolic syncope in patients without prodrome, normal heart and normal ECG
timeFrame: 24 months
Other outcomes:
Locations:
city: Lavagna
country: Italy
facility: Department of Cardiology, Ospedali del Tigullio
Study officials:
affiliation: Department of Cardiology, Ospedali del Tigullio
name: Michele Brignole, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Brignole M, Iori M, Strano S, Tomaino M, Rivasi G, Ungar A, Carretta D, Solari D, Napoli P, Deharo JC, Guieu R. Theophylline in patients with syncope without prodrome, normal heart, and normal electrocardiogram: a propensity-score matched study verified by implantable cardiac monitor. Europace. 2022 Jul 21;24(7):1164-1170. doi: 10.1093/europace/euab300.