Early Trimetazidine Therapy in Patients Undergoing Primary Percutaneous Coronary Intervention for ST Segment Elevation Myocardial Infarction Reduces Myocardial Infarction Size.

PURPOSE: Trimetazidine, a metabolic agent with anti-ischemic effects, was reported to reduce reperfusion injury in animal models. In this randomized double-blind placebo-controlled trial, we investigated the effects of trimetazidine on the reduction of infarction size in patients undergoing revascularization for ST segment elevation myocardial infarction (STEMI). METHODS: Patients with STEMI randomly received trimetazidine (n = 87) or placebo (n = 86) before primary percutaneous coronary intervention (PCI), and subsequently received oral trimetazidine or placebo for 12 months after reperfusion. The predefined primary endpoint was infarction size on cardiac magnetic resonance (CMR) performed at 7 days after primary PCI. The trial was registered on www. CLINICALTRIALS: gov (registration number: NCT02826616). RESULTS: The clinical characteristics of the patients in both groups were well-matched at baseline. At 7 days after primary PCI, the percentage and absolute infarction size in the trimetazidine group were significantly smaller than those in the control group (22% ± 12% [n = 74] vs. 27% ± 13% [n = 74], p = 0.011 and 28 ± 18 g [n = 74] vs. 35 ± 19 g [n = 74], p = 0.022, respectively), and the incidence of myocardial microvascular obstruction (MVO) measured by CMR was significantly reduced in the trimetazidine group (29.7% [22/74] vs. 52.7% [39/74], p = 0.005). The myocardial salvage index (MSI) measured by CMR was significantly higher in the trimetazidine group (48% ± 20% vs. 39% ± 20%, p = 0.008). The incidence of readmission due to aggravated heart failure did not differ significantly between the trimetazidine group and the control group (8.0% vs. 14.0%, p = 0.234). CONCLUSIONS: In patients with STEMI undergoing primary PCI, early trimetazidine before reperfusion reduced myocardial infarction size and MVO, and improved MSI.

Effects of Nicorandil Administration on Infarct Size in Patients With ST-Segment-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: The CHANGE Trial.

Background Nicorandil was reported to improve microvascular dysfunction and reduce reperfusion injury when administered before primary percutaneous coronary intervention. In this multicenter, prospective, randomized, double-blind clinical trial (CHANGE [Effects of Nicorandil Administration on Infarct Size in Patients With ST-Segment-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention]), we investigated the effects of nicorandil administration on infarct size in patients with ST-segment-elevation myocardial infarction treated with primary percutaneous coronary intervention. Methods and Results A total of 238 patients with ST-segment-elevation myocardial infarction were randomized to receive intravenous nicorandil (n=120) or placebo (n=118) before reperfusion. Patients in the nicorandil group received a 6-mg intravenous bolus of nicorandil followed by continuous infusion at a rate of 6 mg/h. Patients in the placebo group received the same dose of placebo. The predefined primary end point was infarct size on cardiac magnetic resonance (CMR) imaging performed at 5 to 7 days and 6 months after reperfusion. CMR imaging was performed in 201 patients (84%). Infarct size on CMR imaging at 5 to 7 days after reperfusion was significantly smaller in the nicorandil group compared with the placebo (control) group (26.5±17.1 g versus 32.4±19.3 g; P=0.022), and the effect remained significant on long-term CMR imaging at 6 months after reperfusion (19.5±14.4 g versus 25.7±15.4 g; P=0.008). The incidence of no-reflow/slow-flow phenomenon during primary percutaneous coronary intervention was much lower in the nicorandil group (9.2% [11/120] versus 26.3% [31/118]; P=0.001), and thus, complete ST-segment resolution was more frequently observed in the nicorandil group (90.8% [109/120] versus 78.0% [92/118]; P=0.006). Left ventricular ejection fraction on CMR imaging was significantly higher in the nicorandil group than in the placebo group at both 5 to 7 days (47.0±10.2% versus 43.3±10.0%; P=0.011) and 6 months (50.1±9.7% versus 46.4±8.5%; P=0.009) after reperfusion. Conclusions In the present trial, administration of nicorandil before primary percutaneous coronary intervention led to improved myocardial perfusion grade, increased left ventricular ejection fraction, and reduced myocardial infarct size in patients with ST-segment-elevation myocardial infarction. Registration URL: http://www.clinicaltrials.gov. Unique identifier: NCT03445728.

Protective Effect of Nicorandil on Cardiac Microvascular Injury: Role of Mitochondrial Integrity.

A major shortcoming of postischemic therapy for myocardial infarction is the no-reflow phenomenon due to impaired cardiac microvascular function including microcirculatory barrier function, loss of endothelial activity, local inflammatory cell accumulation, and increased oxidative stress. Consequently, inadequate reperfusion of the microcirculation causes secondary ischemia, aggravating the myocardial reperfusion injury. ATP-sensitive potassium ion (KATP) channels regulate the coronary blood flow and protect cardiomyocytes from ischemia-reperfusion injury. Studies in animal models of myocardial ischemia-reperfusion have illustrated that the opening of mitochondrial KATP (mito-KATP) channels alleviates endothelial dysfunction and reduces myocardial necrosis. By contrast, blocking mito-KATP channels aggravates microvascular necrosis and no-reflow phenomenon following ischemia-reperfusion injury. Nicorandil, as an antianginal drug, has been used for ischemic preconditioning (IPC) due to its mito-KATP channel-opening effect, thereby limiting infarct size and subsequent severe ischemic insult. In this review, we analyze the protective actions of nicorandil against microcirculation reperfusion injury with a focus on improving mitochondrial integrity. In addition, we discuss the function of mitochondria in the pathogenesis of myocardial ischemia.

Effects of nicorandil on myocardial infarct size in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: study design and protocol for the randomized controlled trial.

Previous studies have shown that nicorandil has a protective effect on cardiomyocytes. However, there is no study to investigate whether perioperative intravenous nicorandil can further reduce the myocardial infarct size in patients with ST-segment elevation myocardial infarction (STEMI) compared to the current standard of percutaneous coronary intervention (PCI) regimen. The CHANGE (China-Admini stration of Nicorandil Group) study is a multicenter, prospective, randomized, double-blind and parallel-controlled clinical study of STEMI patients undergoing primary PCI in China, aiming to evaluate the efficacy and safety of intravenous nicorandil in ameliorating the myocar dial infarct size in STEMI patients undergoing primary PCI and provide evidence-based support for myocardial protection strategies of STEMI patients.