The cardio protective effects of nicorandil have been widely reported10–12. However, the renal protective potential has only been studied in selective PCI or coronary angiography. Patients receiving primary PCI have an increased risk of CIN compared with those after selective PCI13, but CIN prevention are less frequently applied in primary PCI than in elective PCI. In this multi-center prospective randomized controlled trial study, we aimed to investigate the potential effect of intravenous nicorandil on postoperative contrast induced nephropathy in STEMI patients undergoing primary PCI. The negative conclusion (nicorandil is ineffective in preventing CIN) is showed in the PRINCIPLE study from Japan. The study enrolling149 patients with renal insufficiency undergoing elective PCI used a smaller dose of drug with a relative smaller sample size. There was no statistically significant difference in the CIN incidence between nicorandil group and control group (6.8% vs 6.6%, P = 0.794)14. The efficacy of nicorandil was verified by decreasing the incidence of CIN. This finding would suggest a new strategy for the prevention of CIN after primary PCI in patients with STEMI.
Previous studies have demonstrated that the incidence of CIN fluctuates from 6–22% in patients undergoing primary PCI1–4, and in our study, the incidence of CIN in the placebo group was more than 20%. Although the mechanism of CIN is not fully understood, it is believed that this complication is closely related to renal ischemic injury and the direct renal tubular cytotoxicity of contrast medium15. These two processes are possibly mediated by the release of reactive oxygen species, intracellular calcium overload and the imbalance of vasoconstrictors and vasodilators such as adenosine, endothelin-1, angiotensin II, serotonin, nitric oxide and prostaglandins16. The univariate logistic regression analysis also identified the beneficial effect of nicorandil by decreasing the odds of CIN. The possible explanations are as follows. On the one hand, nitrate helps to increase the production of nitric oxide in blood vessels and to decrease the generation of intracellular reactive oxygen species. On the other hand, the opening of intracellular KATP channel improves the intracellular calcium overload 17. The activation of the KATP channel can reduce renal injury due to ischemia and reperfusion by limiting the accumulation of reactive oxygen radicals18.
The purpose of primary PCI is to open culprit arteries as quickly as possible to protect more myocardium in STEMIs. However, even without residual stenosis, it is not always possible to achieve the recovery of blood flow and complete myocardial reperfusion, which is known as no-reflow phenomenon. In our study, postoperative TIMI grade in nicorandil group was significantly better than that in placebo group, demonstrating the possible immediate effect of nicorandil, which is consistent with previous researches19. The mechanism is also related to the nitrate-like and KATP agonist effects of nicorandil.
There were several limitations in our study. Firstly, the definition of CIN is based on the changes in serum creatinine. However, studies have reported that serum creatinine levels are susceptible to a number of factors, including food, age and weight20. Therefore, another biomarker, Cystatin C, which is cleared only in the kidney and would not be affected by age, sex, dietary, medications or inflammation21, could be used in future studies to evaluate CIN in early renal damage. Secondly, as a multi-center study, the number of patients was relatively small. Large amount of data and long follow-up time should be performed in future studies.