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Published on: August 27, 2019
Mammalian Target of Rapamycin Inhibition in Patients With ST-Segment Elevation Myocardial Infarction
Barbara E Stähli1, Roland Klingenberg2, Dik Heg3
1Department of Cardiology, University Heart Center, University Hospital Zurich, University of Zurich, Zurich, Switzerland.
Background:
Early inflammation following acute ST-segment elevation myocardial infarction (STEMI) treated by primary percutaneous coronary intervention (PCI) affects myocardial infarct (MI) size and left ventricular remodeling. The mammalian target of rapamycin (mTOR) is involved in the enhanced inflammatory response and its inhibition has exerted beneficial effects on MI size in preclinical models of acute MI.
Objectives:
The CLEVER-ACS (Controlled Level Everolimus in Acute Coronary Syndromes) trial evaluated the effects of targeting inflammation by mTOR inhibition in patients with STEMI undergoing PCI.
Methods:
CLEVER-ACS was a randomized, multicenter, international, double-blind, placebo-controlled trial. A total of 150 patients with STEMI undergoing PCI were randomly assigned to oral everolimus (days 1-3: 7.5 mg daily; days 4-5: 5.0 mg daily) or placebo for 5 days. The primary endpoint was the change in MI size. The secondary endpoint was the change in microvascular obstruction (MVO) from baseline (12 hours to 5 days after PCI) to 30 days as assessed by cardiac magnetic resonance imaging.
Results:
The changes in MI size from baseline to 30 days, the primary endpoint, were -14.2 g (95% CI: -17.4 to -11.1 g) and -12.3 g (95% CI: -16.0 to -8.7 g) in the everolimus and placebo groups (P = 0.99). Corresponding changes in MVO were -4.8 g (95% CI: -6.7 to -2.9 g) and -6.3 g (95% CI: -8.7 to -4.0 g) in the everolimus and placebo groups (P = 0.14). Adverse events did not differ between the study groups.
Conclusions:
Among STEMI patients undergoing PCI, early mTOR inhibition with everolimus did not reduce MI size or MVO at 30 days. (CLEVER-ACS [Controlled Level Everolimus in Acute Coronary Syndromes; NCT01529554).
Insights
Early inflammation after myocardial infarction (MI) impacts heart damage. Targeting the mTOR pathway with everolimus in ST-segment elevation MI patients did not reduce MI size or microvascular obstruction.
Area of Science:
- Cardiology
- Pharmacology
- Immunology
Background:
- Inflammation post-ST-segment elevation myocardial infarction (STEMI) influences infarct size and cardiac remodeling.
- Mammalian target of rapamycin (mTOR) pathway inhibition shows promise in preclinical models for reducing MI size.
Purpose of the Study:
- To evaluate the efficacy of mTOR inhibition via everolimus in reducing myocardial infarct size and microvascular obstruction in STEMI patients undergoing primary percutaneous coronary intervention (PCI).
Main Methods:
- The randomized, double-blind, placebo-controlled CLEVER-ACS trial enrolled 150 STEMI patients undergoing PCI.
- Patients received either oral everolimus or placebo for 5 days.
- Primary endpoint: change in MI size; Secondary endpoint: change in microvascular obstruction (MVO) assessed by cardiac MRI at 30 days.
Main Results:
- Everolimus did not significantly reduce MI size compared to placebo (-14.2 g vs. -12.3 g; P=0.99).
- No significant difference was observed in the reduction of MVO between the everolimus and placebo groups (-4.8 g vs. -6.3 g; P=0.14).
- Adverse event rates were similar between the groups.
Conclusions:
- Early mTOR inhibition with everolimus did not improve myocardial infarct size or microvascular obstruction in STEMI patients treated with primary PCI.
- The findings suggest that targeting mTOR in this manner may not be beneficial for acute MI treatment in humans.
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