Clinical trial NCT03274752: Paroxetine-mediated GRK2 Inhibition to Reduce Cardiac Remodeling After Acute Myocardial Infarction
Official title: Paroxetine-mediated GRK2 Inhibition to Reduce Cardiac Remodeling After Acute Myocardial Infarction (CARE-AMI): a Randomized Controlled Pilot Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Cardiac Remodeling
Myocardial Infarction
Keywords: Paroxetine
Lead sponsor: Insel Gruppe AG, University Hospital Bern
Sponsor class: OTHER
First posted: 2017-09-07
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study evaluates the off-target effect of paroxetine to reverse cardiac remodeling and improve left ventricular ejection fraction in patients after acute myocardial infarction. Half of the participants will receive paroxetine, while the other half will receive placebo treatment.

Detailed description: Cardiac remodeling is characterized by a composite of structural, geometric, molecular, and functional changes of the myocardium, and is an important determinant of heart failure and cardiovascular outcome in survivors of acute myocardial infarction. Progression of heart failure secondary to the remodeling process results from dysregulation of the G protein-coupled receptor (GPCR). Excessive adrenergic drive in patients with heart failure results in an enhanced activation of GPCR kinases (GRKs) that is considered to have a central role in adverse cardiac remodeling after ischemic injury. The selective Serotonin reuptake inhibitor paroxetine specifically binds to the catalytic domain of GRK2 as an off-target effect, and has been shown to reverse cardiac remodeling and increase left ventricular ejection fraction in a mouse model. The effect was observed at serum levels achieved with standard dosages of paroxetine, and was robust in mice with and without concomitant heart failure treatment, respectively.

Eligibility criteria: Inclusion Criteria:

* Anterior wall ST-segment elevation myocardial infarction
* Primary percutaneous coronary intervention (PCI) within 24 hours of symptom onset
* Left ventricular ejection fraction ≤ 45% within 48-96 hours after primary PCI (transthoracic echocardiography)

Exclusion Criteria:

* Female patients at reproductive age (\<50 years)
* Known intolerance to paroxetine
* Inability to provide informed consent
* Currently participating in another trial before reaching first endpoint
* Current medical therapy with MAO-blocker (during, 14 days before, and 14 days after treatment with MAO-blocker), lithium, thioridazide, or pimozide
* Concomitant tamoxifen intake
* Previous myocardial infarction
* Previous revascularization procedure (percutaneous coronary intervention or coronary artery bypass grafting).
* Contraindication to cardiac magnetic resonance imaging
* Obvious or questionable inability to appropriately cooperate (alcohol, drugs etc.)
* Relevant nephropathy or hepatopathy

Primary outcomes:
measure: Difference in the change of left ventricular ejection fraction (LVEF)
timeFrame: 12 weeks after randomization
Secondary outcomes:
measure: Difference in change in left left-ventricular end-diastolic volume (LVEDV)
timeFrame: 12 weeks after randomization
measure: Difference in change in left left-ventricular end-systolic volume (LVESV)
timeFrame: 12 weeks after randomization
measure: Difference in late-enhancement
timeFrame: 12 weeks after randomization
measure: Difference in LVEF between baseline and 12 weeks, and 12 months, respectively
timeFrame: 12 months after randomization
measure: Major adverse cardiac events
timeFrame: 12 weeks and 12 months after randomization
measure: Clinical symptoms of heart failure
timeFrame: 12 weeks and 12 months after randomization
Other outcomes:
Locations:
city: Bern
country: Switzerland
facility: Bern University Hospital, Department of Cardiology
Study officials:
affiliation: Bern University Hospital, Department of Cardiology, Freiburgstrasse 10, CH-3010 Bern, Switzerland
name: Thomas Pilgrim, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Schumacher SM, Gao E, Zhu W, Chen X, Chuprun JK, Feldman AM, Tesmer JJ, Koch WJ. Paroxetine-mediated GRK2 inhibition reverses cardiac dysfunction and remodeling after myocardial infarction. Sci Transl Med. 2015 Mar 4;7(277):277ra31. doi: 10.1126/scitranslmed.aaa0154.
citation: Sutton MG, Sharpe N. Left ventricular remodeling after myocardial infarction: pathophysiology and therapy. Circulation. 2000 Jun 27;101(25):2981-8. doi: 10.1161/01.cir.101.25.2981. No abstract available.
citation: Pilgrim T, Bernhard B, Furholz M, Vollenbroich R, Babongo Bosombo F, Losdat S, Reusser N, Windecker S, Stortecky S, Siontis GCM, Hunziker L, Lanz J, Dobner S. Paroxetine-Mediated G-Protein Receptor Kinase 2 Inhibition in Patients With Acute Anterior Myocardial Infarction: Final 1-Year Outcomes of the Randomized CARE-AMI Trial. J Am Heart Assoc. 2022 Sep 6;11(17):e026362. doi: 10.1161/JAHA.122.026362. Epub 2022 Aug 24. No abstract available.
citation: Pilgrim T, Vollenbroich R, Deckarm S, Grani C, Dobner S, Stark AW, Erne SA, Babongo Bosombo F, Fischer K, Stortecky S, Reusser N, Furholz M, Siontis GCM, Heg D, Hunziker L, Windecker S, Lanz J. Effect of Paroxetine-Mediated G-Protein Receptor Kinase 2 Inhibition vs Placebo in Patients With Anterior Myocardial Infarction: A Randomized Clinical Trial. JAMA Cardiol. 2021 Oct 1;6(10):1171-1176. doi: 10.1001/jamacardio.2021.2247.