Nicorandil: What is Beyond the Anti-Anginal Action?

Mohamed Shehata, MD, FESC, FSCAI

Faculty of Medicine Department of Cardiology Ain Shams University Hospital Abbasia Square, Cairo 11741, Egypt; Tel. +201223224282; Fax: +2022564304; E-mail: smarttmann@hotmail.com

Incidence of Contrast Induced Nephropathy (CIN) among ischemic heart disease patients subjected to coronary catheterization is highly dependent on the kidney function before contrast media administration and relevant risk factors, of which diabetes mellitus is the most important one.¹ Incidence of CIN ranges from <2% in the general population up to 50% in patients with Advanced Kidney Disease (AKD)2 and it is the third most common cause of hospital acquired renal failure.³ Development of contrast media started by the first ionic, high-osmolar contrast agent (sodium acetrizoate) brought by Vernon Wallingford in 1953 and continued till development of the second generation non-ionic media in 1980’s.¹ The exact mechanisms underlying CIN are still unclear. However, it was postulated that in addition to their direct toxic effects on renal tubular epithelial cells, contrast media trigger acute renal ischemia by inducing an imbalance between vasodilatory and vasoconstrictive factors.⁴ Scientific research for identification of renoprotective agents that can prevent CIN is continuously going on. No pharmacological approach has yet been shown to provide consistent protection. Furosemide, dopamine, atrial natriuretic peptide, sodium bicarbonate, sodium chloride, mannitol, endothelin receptor antagonists, ascorbic acid, fenoldopam, theophylline, N-acetylcysteine, trimetazidine and statins were all previously evaluated in prospective, randomized trials, showing positive or controversial results.^5,6,7.

Nicorandil is an anti-anginal medication that has the dual properties of a K+ATP channel agonist and a Nitric Oxide (NO) donor.⁸ It was reported that activation of the K+ATP channel reduced renal injury (due to ischemia and reperfusion) by preventing accumulation of reactive oxygen radicals. These data suggest that nicorandil may protect the kidney against ischemic injury associated with the use of contrast media by decreasing calcium inflow to the tubular cells, inhibiting the accumulation of reactive oxygen species, suppressing synthesis of endothelin-1, and inducing NO production.⁹

Two prominent studies reported contradicting results concerning feasibility of using Intravenous (IV) nicorandil as a CIN-preventing agent.^10,11 The first one is the PRINCIPLE study (a randomized controlled multicenter study), that was conducted on a total of 166 patients (nicorandil n=81; control n=85) with an estimated glomerular filtration rate <60 mL/ min. Nicorandil (12 mg dissolved in 100 mL of 0.9% saline) was administered intravenously for 30 minutes just prior to coronary angiography in the nicorandil group. The same volume of only saline was given to the control group. An iso-osmolar, non-ionic contrast medium, was used. The primary endpoint was the incidence of CIN, defined as >0.5 mg/dL increase or >25% rise in serum creatinine level within 48 hours of contrast exposure compared to baseline. The incidence of CIN did not differ between both groups (6.8% vs. 6.6%, p=0.794). It was concluded that prophylactic IV infusion of nicorandil did not decrease the incidence of CIN in patients with renal dysfunction undergoing coronary angiography. Authors assumed that IV nicorandil might be effective when administered at a different dosing regimen. Additionally, the majority (>75%) of the patients included in their study belonged to relatively lower CIN risk groups. percutaneous coronary intervention (PCI) was performed in 38.9% of the patients, and only 24.8% of the included patients required contrast media volume ≥150 mL. These data most probably led to an incidence of CIN that was much lower than what was assumed for the calculation of the study sample size i.e. underpowered study.¹⁰

The other study was recently conducted by Nawa, et al.¹¹ It was a prospective randomized single center trial applying the same definition of CIN. They included 213 patients undergoing elective PCI and with a high serum cystatin C level (greater than 0.95 mg/dL in males and 0.87 mg/dL in females). Patients were randomized in to a saline group (n=107) or a nicorandil group (n=106, 96 mg of nicorandil was dissolved in 100 mL of 0.9% saline then infused in addition to saline for 4h before and 24 h after PCI). A low-osmolar, non-ionic, contrast medium, was used. All patients showed an estimated glomerular filtration rate p<0.02). Univariate regression analysis revealed nicorandil IV infusion to be the only significant predictor of CIN development. The study still face the limitation of utilizing the uncommonly used indicator of renal dysfunction; cystatin C, in addition to being a single center study.¹¹

The main discrepancy between both studies, concerning methodology, can be summarized in two points. The first one is that all patients in the second study underwent PCI, which means a higher mean contrast volume (140 ml vs. 125 ml). The second one is related to nicorandil infusion regimen. It is assumed that the detrimental effect of the relatively high contrast volume was negated by more intensive exposure to IV nicorandil in the second study.

The recently published study by Nawa, et al.¹¹ opens the door for more research work targeting the same subject. Many future perspectives can be addressed, for example; could a more intensive dosing regimen bring more reduction in CIN incidence? Does it worth tackling patients with more severe renal dysfunction? What about using an intensive oral dosing regimen instead of IV infusion? Answers are expected in the near future.

CONFLICTS OF INTEREST

The author has no financial interest in or financial conflict with the subject matter discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

1. Geenen RW, Kingma HJ, van der Molen AJ. Contrast-induced nephropathy: pharmacology, pathophysiology and prevention. Insights Imaging. 2013; 4: 811-820. doi: 10.1007/s13244-013-0291-3

2. Thomsen HS, Morcos SK, Barrett BJ. Contrast-induced nephropathy: the wheel has turned 360 degrees. Acta Radiol. 2008; 49: 646-657. doi: 10.1080/02841850801995413

3. Stacul F, Van der Molen AJ, Reimer P, et al. Contrast induced nephropathy: updated ESUR contrast media safety committee guidelines. Eur Radiol. 2011; 21: 2527-2541. doi: 10.1007/s00330-011-2225-0

4. Persson PB, Hansell P, Liss P. Pathophysiology of contrast medium-induced nephropathy. Kidney Int. 2005; 68: 14-22. doi: 10.1111/j.1523-1755.2005.00377.x

5. Kelly AM, Dwamena B, Cronin P, Bernstein SJ, Carlos RC. Meta-analysis: effectiveness of drugs for preventing contrast-induced nephropathy. Ann Intern Med. 2008; 148: 284-294. doi: 10.7326/0003-4819-148-4-200802190-00007

6. Shehata M, Hamza M. Impact of high loading dose of atorvastatin in diabetic patients with renal dysfunction undergoing elective percutaneous coronary intervention: a randomized controlled trial. Cardiovasc Ther. 2015; 33: 35-41. doi: 10.1111/1755-5922.12108

7. Shehata M. Impact of trimetazidine on incidence of myocardial injury and contrast-induced nephropathy in diabetic patients with renal dysfunction undergoing elective percutaneous coronary intervention. Am J Cardiol. 2014; 114: 389-394. doi: 10.1016/j. amjcard.2014.04.052

8. Taira N. Nicorandil as a hybrid between nitrates and potassium channel activators. Am J Cardiol. 1989; 63: 18J-24J.

9. Sun Z, Zhang X, Ito K, et al. Amelioration of oxidative mitochondrial DNA damage and deletion after renal ischemic injury by the K+ATP channel opener diazoxide. Am J Physiol Renal Physiol. 2008; 294: F491-F498. doi: 10.1152/ajprenal.00263.2007

10. Ko YG, Lee BK, Kang WC, et al. Preventive effect of pretreatment with intravenous nicorandil on contrast-induced nephropathy in patients with renal dysfunction undergoing coronary angiography (PRINCIPLE Study). Yonsei Med J. 2013; 54: 957-964. doi: 10.3349/ymj.2013.54.4.957

11. Nawa T, Nishigaki K, Kinomura Y, et al. Continuous intravenous infusion of nicorandil for 4 hours before and 24 hours after percutaneous coronary intervention protects against contrast-induced nephropathy in patients with poor renal function. Int J Cardiol. 2015; 195: 228-234. doi: 10.1016/j.ijcard.2015.05.078