Sodium thiosulfate ineffective at cardiac protection

The first-in-human clinical trial to test sodium thiosulfate to reduce infarct size after heart attacks in humans did not show benefits for any of the primary or secondary endpoints in the GIPS-IV trial at 4 months, despite promising preclinical evidence.

The multicentre, double-blind, randomised-controlled, phase 2 GIPS-IV trial (NCT02899364), presented by the study’s lead author, Dr Marie-Sophie de Koning (University Medical Center Groningen, the Netherlands), explored the feasibility of sodium thiosulfate for the preservation of cardiac function after ST-elevation myocardial infarction (STEMI) [1].

The rationale behind this trial was that the strong antioxidant sodium thiosulfate produces hydrogen sulfide, which in turn has been shown to reduce ischaemia-reperfusion injury after a heart attack in an abundance of preclinical evidence. Sodium thiosulfate became the leading candidate donor for hydrogen sulfide because it has already demonstrated to be safe and effective in humans for other indications.

GIPS-IV enrolled 380 patients treated for a first myocardial infarction (MI). Participants were randomly allocated to receive 2 infusions of either sodium thiosulfate or placebo: 1 upon admission to the cardiac catheterisation laboratory and the other 6 hours later. The primary endpoint was a reduction of the myocardial infarct size at 4 months, as measured with a cardiac MRI. Key secondary endpoints included left ventricular ejection fraction and NT-proBNP levels at 4 months, and peak creatine kinase-MB during MI.

At 4 months, the trial did not meet its primary or secondary endpoints (see Figure). Dr de Koning explained, “We knew that ischaemia-reperfusion injury is one of the most challenging targets of therapy because many compounds have failed so far, but there was a lot of very promising experimental evidence that this compound could work. We were disappointed that, despite a very well-conducted trial, we did not see any effect on infarct size or any of the secondary endpoints."

Figure: No statistical difference between patients receiving sodium thiosulfate or placebo in infarct size in the GIPS-IV study [1]

STS, sodium thiosulfate.

Safety was adequate; major adverse cardiovascular events were comparable in both study arms. Rates of the known side effects of STS, i.e. nausea and vomiting, were increased after administration of study medication in the sodium thiosulfate group.

"Based on this study, we now have evidence that sodium thiosulfate is not working,” Dr de Koning said. "However, we cannot exclude that sodium thiosulfate could make a bigger difference in regions of the world where the quality or efficiency of heart attack treatments are lower than in the Netherlands, where patients may experience a higher infarct size overall, and thus stand to benefit more from treatments that may reduce the damage to the heart muscle."

Although sodium thiosulfate showed no benefits for reducing injury to damaged areas of the heart muscle 4 months following a heart attack, Dr de Koning concluded by saying, “It's too early to tell whether hydrogen sulfide as a whole doesn't work for ischaemia-reperfusion injury. It's possible that what's needed is a stronger hydrogen sulfide donor compound or a prolonged administration after reperfusion.”

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   1. De Koning MS, et al. The Groningen Intervention Study For The Preservation Of Cardiac Function With Sodium Thiosulfate After St-segment Elevation Myocardial Infarction (GIPS-IV). Abstract 410–12, ACC 2022, 2–4 April, Washington DC, USA.

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Posted on 15 June, 202224 June, 2022