Rationale and Design of the Groningen Intervention Study for the Preservation of Cardiac Function with Sodium Thiosulfate after St-segment Elevation Myocardial Infarction (GIPS-IV) trial

Marie-Sophie Ly De Koning,Paulien Van Dorp,Solmaz Assa,Minke Ht Hartman,Michiel Voskuil,Rutger L Anthonio,Duco Veen,Gabija Pundziute-Do Prado,Tim Leiner,Harry Van Goor,Peter Van Der Meer,Dirk J Van Veldhuisen,Robin Nijveldt,Erik Lipsic,Pim Van Der Harst

doi:10.1016/j.ahj.2021.08.012

Abstract

Ischemia and subsequent reperfusion cause myocardial injury in patients presenting with ST-segment elevation myocardial infarction (STEMI). Hydrogen sulfide (H2S) reduces "ischemia-reperfusion injury" in various experimental animal models, but has not been evaluated in humans. This trial will examine the efficacy and safety of the H2S-donor sodium thiosulfate (STS) in patients presenting with a STEMI. The Groningen Intervention study for the Preservation of cardiac function with STS after STEMI (GIPS-IV) trial (NCT02899364) is a double-blind, randomized, placebo-controlled, multicenter trial, which will enroll 380 patients with a first STEMI. Patients receive STS 12.5 grams intravenously or matching placebo in addition to standard care immediately at arrival at the catheterization laboratory after providing consent. A second dose is administered 6 hours later at the coronary care unit. The primary endpoint is myocardial infarct size as quantified by cardiac magnetic resonance imaging 4 months after randomization. Secondary endpoints include the effect of STS on peak CK-MB during admission and left ventricular ejection fraction and NT-proBNP levels at 4 months follow-up. Patients will be followed-up for 2 years to assess clinical endpoints. The GIPS-IV trial is the first study to determine the effect of a H2S-donor on myocardial infarct size in patients presenting with STEMI.

Highlights

Background and rationaleAcute myocardial infarction (MI) results in myocardial injury and increases the risk of future heart failure and early mortality.[1]
We considered an absolute reduction of 3% (33% relative) relevant
The GIPS-IV study is the first clinical trial to investigate the effect of the H2S-donor sodium thiosulfate (STS) on myocardial infarct size in patients presenting with acute MI

Summary

Introduction

Acute myocardial infarction (MI) results in myocardial injury and increases the risk of future heart failure and early mortality.[1] Timely reperfusion by percutaneous coronary intervention (PCI) is an effective treatment to improve outcomes. Reperfusion has been hypothesized to contribute to the myocardial injury.[2,3,4] It has been estimated that the contribution of this “ischemiareperfusion (I/R) injury” can be as much as 50% of myocardial infarct size.[2] The underlying mechanisms that have been associated to I/R injury include intracellular pH changes, calcium overload, cardiomyocyte hypercontracture, myocardial inflammation, oxidative stress generation, and mitochondrial permeability transition pore opening.[2,4] Apart from cardiomyocyte cell death, the coronary microcirculation undergoes irreversible injury from I/R.5. Intervening in the I/R injury mechanisms may potentially reduce myocardial infarct size, decrease adverse cardiac remodeling, improve cardiac function, and eventually clinical outcomes.[6] to date, effective therapies targeting I/R in humans are lacking

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