Serotonin Receptor Blockers in Ischemic Mitral Regurgitation (CYPRO-MR)

Laval University

Status and phase: Enrolling; Phase 2

Conditions: Ischemic Mitral Regurgitation

Treatments: Drug: Cyproheptadine 4 Mg Oral Tablet; Other: Placebo

Study type: Interventional

Funder types: Other

Identifiers

NCT05469165

22229

Details and patient eligibility

About

This study is intended to investigate the effect of cyproheptadine (a 5HT2B receptor blocker) on mitral regurgitation severity.

Full description

Ischemic mitral regurgitation (MR) is a common and morbid complication of myocardial infarction (MI), doubling heart failure and mortality with currently limited therapies. Its mechanisms have been previously linked to left ventricle (LV) remodeling with secondary deformation of otherwise normal mitral leaflets. Recent studies are introducing new mechanistic elements, allowing possibilities for potential pharmacotherapeutic approaches. Normal mitral leaflets have the capacity to enlarge and adapt to even the largest LV dilatation to prevent MR. However, this compensatory mechanism is insufficient after MI, and the leaflets are abnormally thick with fibrotic changes. Those fibrotic changes could be related to a variation in blood serotonin (5-HT) levels after MI, which has been previously reported. Serotonin is a known cause of valve fibrosis through its 5HT type 2B receptor. In sheep models, the investigators have tested the hypothesis that a 5HT type 2B receptor blocker (cyproheptadine) can prevent adverse remodeling in the valve after MI. Cyproheptadine treatment was associated with increased valve leaflet surface, attenuated leaflet thickening and collagen deposition. Importantly, treated animals had less MR compared to non-treated animals.

Thus the present study is a double-blind randomized trial to assess the effect of cyproheptadine on MR severity, mitral valve surface variation, and left ventricular size following MI. Serial imaging (3D echo and MRI) will assess valve adaptation, LV remodeling and MR.

Enrollment: 214 estimated patients

Sex: All

Ages: 18 to 80 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Patients 18-80 years old with a 1st episode of STEMI with documented coronary obstruction.
2. Left ventricle ejection fraction (LVEF)<50% and mitral tenting area ≥ 4 cm2, OR LVEF ≤ 40% and inferior/posterior wall motion anomaly, OR LVEF≤30% and wall motion in any territory.

Exclusion criteria

1. Inability to provide informed consent
2. Hemodynamic instability / cardiogenic shock / papillary muscle rupture
3. Prior mitral valve procedure/surgery
4. Permanent atrial fibrillation (limiting imaging and MR quantification)
5. Primary mitral disease (endocarditis, rheumatic, degenerative or congenital)
6. More than mild valvular disease (other than mitral) at baseline
7. Planned cardiac surgery (CABG or valve intervention) within 3 months
8. Contraindications for MRI
9. Ongoing treatment with selective serotonin reuptake inhibitor (SSRI)
10. Chronic use of sedative medication
11. Ongoing or planned pregnancy
12. Chronic renal failure with Estimated Glomerular Filtration Rate (eGFR) < 30 mL/min
13. Neurocognitive disorder
14. Symptom or prior episode of urinary obstruction or glaucoma (relative contraindications for cyproheptadine)

Trial design

Primary purpose: Prevention

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: Quadruple Blind

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214 participants in 2 patient groups, including a placebo group

Cyproheptadine 4 Mg Oral Tablet

Experimental group

Description:

Participants will receive cyproheptadine 4mg tablet orally three times a day for three months, with a daily increase of 4mg/dose if the previous dose was well tolerated, up to 0.5 mg/kg/day.

Treatment:

Drug: Cyproheptadine 4 Mg Oral Tablet

Placebo

Placebo Comparator group

Description:

Participants will receive a matched placebo orally three times a day for 3 months. Daily titration similar to the treatment arm.

Treatment:

Other: Placebo