Efficacy and Safety of Nicorandil in the Treatment of Stable Angina Pectoris.

Background: Stable angina pectoris (SAP) is an ischemic heart disease caused by coronary artery stenosis, which usually occurs during physical activity or emotional excitement. For this type of angina pectoris, reducing the oxygen demand of the heart and increasing the coronary blood flow are the key goals of treatment. Objective: To analyze nicorandil's application effect and adverse reactions in patients with SAP. Methods: Sixty patients with stable angina pectoris admitted to our hospital from December 2020 to May 2022 were randomly selected and included in this study. They were divided into nicorandil group (n=30) and conventional group (n=30). The clinical efficacy, duration of chest pain, number of heart attacks per week, cardiac function indexes, improvement of exercise tolerance, occurrence of adverse reactions, and Seattle Angina Scale (SAQ) score were observed. Results: The effective rate of nicorandil group was 93.33%, which was much higher than that of conventional group (73.33%, P < .05). The results showed that the nicorandil group was significantly better than the conventional group in clinical efficacy, duration of chest pain, number of attacks per week, cardiac function index, improvement of exercise tolerance, occurrence of adverse reactions and SAQ score (P < .05). Conclusions: Nicorandil can improve the clinical symptoms of SAP patients, significantly reduce the duration and frequency of chest pain attacks, and enhance cardiac function indicators. It can be used as an effective drug choice to reduce the frequency and intensity of angina pectoris attacks and is worthy of wide clinical application.

Utility and optimal dose of nicorandil for physiological assessment of the femoropopliteal artery.

BACKGROUND: Nicorandil is widely used as a vasodilator for the physiological assessment of coronary arteries because of its usefulness and safety; however, there are no data on its use in peripheral arteries. AIMS: To identify the utility of nicorandil and its appropriate dose for the physiological assessment on the femoropopliteal artery. METHODS: We retrospectively enrolled patients from three institutes in which physiological assessment was carried out with various doses of nicorandil before treatment. Twenty-four femoropopliteal artery stenotic lesions from 22 patients were included. The nicorandil doses used were 2, 4, and 6 mg. Twenty-two lesions were also assessed using 30 mg of papaverine. The pressure gradient (PG) and peripheral fractional flow reserve (pFFR) were calculated based on the mean and systolic pressure levels. We examined the correlation of each parameter with the peak systolic velocity ratio (PSVR) based on the duplex ultrasound images using Spearman's rank correlation coefficient. Systemic blood pressure was assessed for safety. RESULTS: The correlations were higher for mean pressure-based parameters than for systolic pressure-based parameters. As the nicorandil dose increased, the correlations among PG, pFFR, and PSVR also increased (mean pressure-based PG: 2 mg, r = 0.360; 4 mg, r = 0.498; 6 mg, r = 0.694, mean pressure-based pFFR: 2 mg, r = -0.479; 4 mg, r = -0.469; 6 mg, r = -0.641). The blood pressure after the administration of 6 mg of nicorandil was low, and the median systemic mean pressure was 65 mmHg. CONCLUSION: A 4 mg dose of nicorandil is effective and safe for the mean pressure-based physiological assessment of lesions in the femoropopliteal artery.

Combination of Nicorandil and Beta-Adrenergic Receptor Blockers in Patients with Coronary Artery Disease: A Real-World Observational Study.

BACKGROUND: The effect of combined nicorandil and beta-adrenergic receptor blockers (BBs) compared with that of BBs alone on long-term clinical outcomes in patients with coronary artery disease (CAD) remains undetermined. METHODS: A multicenter retrospective cohort study was performed. Adult patients who had been hospitalized for CAD and treated for angina with a combination of nicorandil and BBs or BBs alone were included. The effect of different treatments on the cumulative incidence of major adverse cardiovascular event (MACE) and their components within a follow-up duration of 2.5 years were analyzed using Kaplan-Meier survival curves. An inverse probability of treatment weighting (IPTW) method was used to adjust for the possible effect of confounding factors. RESULTS: A total of 137,714 patients were screened, of whom 16,912 individuals (mean age: 61.5 years, men: 67.1%) were successfully enrolled. Among the enrolled participants, 4669 received the combined treatment of nicorandil and BBs, while 12,243 received BBs alone. After IPTW, the results demonstrated that the combined treatment was associated with a significantly reduced incidence of MACE (hazard ratio [HR] 0.79, 95% conidence interval [CI] 0.72-0.87) and stroke (HR 0.48, 95% CI 0.42-0.54) but not of MI (HR 1.03, 95% CI 0.92-1.15) or all-cause mortality (HR 0.93, 95% CI 0.64-1.37). Sensitivity analyses revealed similar results. CONCLUSIONS: A combined antiangina treatment of nicorandil and BBs may be more effective than treatment of BBs alone in reducing the long-term incidence of MACE in patients with CAD.

Refractory cardiac arrest caused by type I Kounis syndrome treated with adrenaline and nicorandil: A case report.

RATIONALE: Kounis syndrome is a rare but life-threatening anaphylactic reaction that can lead to acute coronary syndrome and cardiac arrest, and requires prompt diagnosis. Adrenaline, which is used to treat anaphylaxis, may cause coronary vasoconstriction and worsen ischemia, whereas coronary vasodilators may dilate systemic vessels and exacerbate hypotension. Delayed diagnosis of Kounis syndrome and inadequate therapeutic intervention may thus lead to a poor outcome. PATIENT CONCERNS: A 59-year-old man was treated for sepsis due to a liver abscess. Following administration of daptomycin, the patient developed severe anaphylactic shock leading to refractory cardiac arrest. Because conventional cardiopulmonary resuscitation was ineffective, extracorporeal cardiopulmonary resuscitation was considered as an alternative approach. DIAGNOSES: On bedside monitoring during cardiopulmonary resuscitation, unexpected ST-segment elevation was found on lead II electrocardiogram. Accordingly, the patient was clinically diagnosed with Kounis syndrome. INTERVENTIONS: Nicorandil (6 mg/h), a coronary vasodilator with minimal blood pressure effects, was administered along with high doses of vasopressors, including adrenaline 0.2 µg/kg/min. OUTCOMES: After the initiation of nicorandil administration, the patient achieved return of spontaneous circulation and did not require extracorporeal cardiopulmonary resuscitation. Based on the elevated serum tryptase level, normal creatine kinase-MB range, and lack of stenosis on coronary angiography, the patient was definitively diagnosed with type I (coronary vasospasm) Kounis syndrome. He was subsequently transferred to the referring hospital without neurological sequelae. LESSONS: If anaphylaxis leads to refractory shock and cardiac arrest, ischemic changes on the electrocardiogram should be investigated to identify underlying Kounis syndrome. In addition to adrenaline, coronary dilators are the definitive treatment. Nicorandil may be a useful treatment option because of its minimal effect on blood pressure.

Effects of nicorandil on QT prolongation and myocardial damage caused by citalopram in rats.

Citalopram is a selective serotonin re-uptake inhibitor (SSRI) antidepressant; it exhibits the greatest cardiotoxic effect among SSRIs. Citalopram can cause drug-induced long QT syndrome (LQTS) and ventricular arrhythmias. We investigated the protective effect of nicorandil, a selective mitochondrial KATP (mito-KATP) channel opener, on LQTS and myocardial damage caused by citalopram in male rats. In a preliminary study, we determined that the minimum citalopram dose that prolonged the QT interval was 102 mg/kg injected intraperitoneally. For the main study, rats were divided randomly into five experimental groups: untreated control, normal saline + citalopram, nicorandil + citalopram, 5-hydroxydecanoate (5-HD) + citalopram, 5-HD + nicorandil + citalopram. Biochemical and histologic data from blood and heart tissue samples from six untreated control rats were evaluated. Electrocardiographic parameters including QRS duration, QT interval, corrected QT interval (QTc) and heart rate (HR) were assessed, and biochemical parameters including malondialdehyde, reduced glutathione, glutathione peroxidase, superoxide dismutase were measured. We also performed histomorphologic and immunohistochemical examination of heart tissue. Citalopram prolonged QT-QTc intervals significantly and increased significantly the histomorphologic score and proportion of apoptotic cells, but produced no differences in the oxidant and antioxidant parameters. Nicorandil did not prevent citalopram induced QT-QTc interval prolongation and produced no significant changes in oxidant and antioxidant parameters; however, it did reduce histologic damage and apoptosis caused by citalopram.

Intravenous nicorandil for patients with acute decompensated heart failure: a meta-analysis of randomized controlled trials.

OBJECTIVES: Pilot studies have suggested the potential benefits of intravenous nicorandil for patients with acute decompensated heart failure (ADHF). However, clinical evidence remains limited. The aim of the study was to summarize the efficacy and safety of intravenous nicorandil for the treatment of ADHF. DESIGN: A systematic review and meta-analysis was performed. The search for relevant randomised controlled trials (RCTs) was conducted in PubMed, Embase, Cochrane's Library, Wanfang, and CNKI databases. A random-effects model was employed to combine the results. RESULTS: Eight RCTs contributed to the meta-analysis. Pooled results showed that acute treatment with intravenous nicorandil could significantly improve the symptom of dyspnea at 24 h after treatment, as evidenced by the five-point Likert scale for dyspnea after treatment (mean difference [MD]: -0.26, 95% confidence interval [CI]: -0.40 to -0.13, p < 0.001). Furthermore, nicorandil significantly reduced serum B natriuretic peptide (MD: -30.03 ng/dl, 95% CI: -47.00 to -13.06, p < 0.001), and N-terminal proBNP (MD: -138.69, 95% CI: -248.06 to -29.31, p = 0.01). In addition, nicorandil significantly improved ultrasonic parameters including left ventricular ejection fraction and E/e' at discharge. Moreover, during the follow-up duration of up to 90 days, intravenous nicorandil significantly reduced the incidence of major adverse cardiovascular events (risk ratio [RR]: 0.55, 95% CI: 0.32 to 0.93, p = 0.03). The incidence of treatment-related adverse events was not significantly different between nicorandil and controls (RR: 1.22, 95% CI: 0.69 to 2.15, p = 0.49). CONCLUSIONS: Results of this study suggest that intravenous nicorandil may be an effective and safe treatment for patients with ADHF.

Protective Effect of Nicorandil on Contrast-Induced Acute Kidney Injury After Emergency Percutaneous Coronary Intervention.

Objective: To investigate the protective effect of nicorandil on contrast-induced acute kidney injury (CIAKI) in patients with acute ST-segment elevation myocardial infarction (STEMI) after emergency percutaneous coronary intervention (PCI). Methods: This is a single-center, retrospective control study. A total of 156 patients with STEMI were divided into the nicorandil group (n = 55) and the control group (n = 101). The incidence of CIAKI, defined as an increase of >25% or absolute values > 44.2 µmol/L in serum creatinine (Scr) from baseline within 72 h of exposure to a contrast agent after exclusion of other causes, was the primary endpoint. The secondary endpoints were: (1) changes of Scr, estimated glomerular filtration rate (eGFR), uric acid, and ß2-microglobulin at 24/48/72 h and 5 to 7 days after PCI; (2) the peak value difference of creatine kinase isoenzymes (CK-MB) after PCI; (3) adverse events within 6 months after PCI. Results: The overall incidence of CIAKI was 21.8%; the incidence of CIAKI in the nicorandil group was significantly lower (12.7% [7/55]) than in the control group (26.7% [27/101]) (P = .043). Compared with the control group, Scr, uric acid, and ß2-microglobulin levels were lower, and the level of eGFR was higher in nicorandil group (P all < .05). The peak value of CK-MB in the nicorandil group was lower than that in the control group (105.30 [56.61, 232.04] vs 178.00 [77.08, 271.91]U/L, P = .042). There was no significant difference in adverse events between the 2 groups within 6 months after PCI. Moreover, multivariate logistic regression analysis showed that hypertension and diabetes were independent risk factors for CIAKI, while nicorandil treatment was a protective factor. Conclusion: Our data suggest that intravenous nicorandil after emergency PCI has a protective effect on the occurrence of CIAKI in STEMI patients.

Cardioprotective and Antianginal Efficacy of Nicorandil: A Comprehensive Review.

ABSTRACT: Angina pectoris remains a significant burden despite advances in medical therapy and coronary revascularization. Many patients (up to 30%) with angina have normal coronary arteries, with coronary microvascular disease and/or coronary artery vasospasm being major drivers of the myocardial demand-supply mismatch. Even among patients revascularized for symptomatic epicardial coronary stenosis, recurrent angina remains highly prevalent. Medical therapy for angina currently centers around 2 disparate goals, viz secondary prevention of hard clinical outcomes and symptom control. Vasodilators, such as nitrates, have been first-line antianginal agents for decades, along with beta-blockers and calcium channel blockers. However, efficacy in symptoms control is heterogenous, depending on underlying mechanism(s) of angina in an individual patient, often necessitating multiple agents. Nicorandil (NCO) is an antianginal agent first discovered in the late 1970s with a uniquely dual mechanism of action. Like a typical nitrate, it mediates medium-large vessel vasodilation through nitric oxide. In addition, NCO has adenosine triphosphate (ATP)-dependent potassium channel agonist activity (K ATP ), mediating microvascular dilatation. Hence, it has proven effective in both coronary artery vasospasm and coronary microvascular disease, typically challenging patient populations. Moreover, emerging evidence suggests that cardiomyocyte protection against ischemia through ischemic preconditioning may be mediated through K ATP agonism. Finally, there is now fairly firm evidence in favor of NCO in terms of hard event reduction among patients with stable coronary artery disease, following myocardial infarction, and perhaps even among patients with congestive heart failure. This review aims to summarize the mechanism of action of NCO, its efficacy as an antianginal, and current evidence behind its impact on hard outcomes. Finally, we review other cardiac and emerging noncardiac indications for NCO use.

Nicorandil Exerts Anticonvulsant Effects in Pentylenetetrazol-Induced Seizures and Maximal-Electroshock-Induced Seizures by Downregulating Excitability in Hippocampal Pyramidal Neurons.

N-(2-hydroxyethyl) nicotinamide nitrate (nicorandil), a nitrate that activates adenosine triphosphate (ATP)-sensitive potassium (KATP) channels, is generally used in the treatment of angina and offers long-term cardioprotective effects. It has been reported that several KATP channel openers can effectively alleviate the symptoms of seizure. The purpose of this study was to investigate the improvement in seizures induced by nicorandil. In this study, seizure tests were used to evaluate the effect of different doses of nicorandil by analysing seizure incidence, including minimal clonic seizure and generalised tonic-clonic seizure. We used a maximal electroshock seizure (MES) model, a metrazol maximal seizure (MMS) model and a chronic pentylenetetrazol (PTZ)-induced seizure model to evaluate the effect of nicorandil in improving seizures. Each mouse in the MES model was given an electric shock, while those in the nicorandil group received 0.5, 1, 2, 3 and 6 mg/kg of nicorandil by intraperitoneal injection, respectively. In the MMS model, the mice in the PTZ group and the nicorandil group were injected subcutaneously with PTZ (90 mg/kg), and the mice in the nicorandil group were injected intraperitoneally with 1, 3 and 5 mg/kg nicorandil, respectively. In the chronic PTZ-induced seizure model, the mice in the PTZ group and the nicorandil group were injected intraperitoneally with PTZ (40 mg/kg), and the mice in the nicorandil group were each given 1 and 3 mg/kg of PTZ at a volume of 200 nL. Brain slices containing the hippocampus were prepared, and cell-attached recording was used to record the spontaneous firing of pyramidal neurons in the hippocampal CA1 region. Nicorandil (i.p.) significantly increased both the maximum electroconvulsive protection rate in the MES model and the seizure latency in the MMS model. Nicorandil infused directly onto the hippocampal CA1 region via an implanted cannula relieved symptoms in chronic PTZ-induced seizures. The excitability of pyramidal neurons in the hippocampal CA1 region of the mice was significantly increased after both the acute and chronic administration of PTZ. To a certain extent, nicorandil reversed the increase in both firing frequency and proportion of burst spikes caused by PTZ (P < 0.05). Our results suggest that nicorandil functions by downregulating the excitability of pyramidal neurons in the hippocampal CA1 region of mice and is a potential candidate for the treatment of seizures.

Nicorandil and ranolazine overdose management.

A man in his 60s was admitted to the emergency department with chest pain following an intentional overdose of nicorandil and ranolazine. He was known to have an extensive cardiac history and had taken his prescribed medication with suicidal ideation. On presentation, he was hypotensive with a blood pressure of 70/50 mm Hg despite fluid resuscitation. He was commenced on vasopressor support and transferred to the intensive care unit. Despite an adequate blood pressure on vasopressors, he suffered a ventricular fibrillation cardiac arrest. Return of spontaneous circulation with a Glasgow Coma Score of 15 was achieved following cardiopulmonary resuscitation and three direct current shocks. Following subsequent continuous overnight significant vasopressor dependence, a dose of glucagon was given, and within 2 hours, his vasopressor requirement ceased, maintaining an unsupported normal blood pressure. He remained stable and was subsequently discharged to the coronary care unit for monitoring.

Use of nicorandil is associated with increased risk of incident atrial fibrillation.

BACKGROUND: Nicorandil will activate ATP-sensitive potassium channel (KATP). However, activation of potassium channels plays an important role in the mechanism of atrial fibrillation (AF) or atrial flutter (AFL). Whether use of nicorandil might contribute to initiation and/or perpetuation of AF/AFL remained unknown. We determined the relationship between use of nicorandil and risk of atrial fibrillation and determined its molecular mechanism. METHODS: We performed a nested case-control study using a cohort from the National Health Insurance Research Database (NHIRD) of Taiwan. The association between nicorandil use and risk of atrial fibrillation/flutter was estimated by logistic regression model. We also performed molecular, cellular and animal studies to explain the association. RESULTS: A total of 715 individuals who experienced AF/atrial flutter were matched to 72,215 controls. New use of nicorandil was found to be associated with increased risk for AF/AFL (odds ratio [OR], 2.34; 95% CI 1.07-5.13) compared to nitrate use. We found the expression of KATP subunits Kir6.2 and SUR2A in human and rat left atrial tissues. Furthermore, nicorandil directly shortened action potential duration (APD) in rat left atrium and shortened the QT interval of cultured human induced pluripotent stem cell (iPSC) derived cardiomyocytes (iPSC-CMs). CONCLUSIONS: Use of nicorandil was found to be associated with increased risk of AF/AFL. We also showed the expression of KATP subunits in human atria, and a possible mechanism that use of nicorandil increases the risk of AF through activation of KATP and shortening of atrial APD.

[Ulcers in vulva and perineum induced by an anti-anginal drug].

Nicorandil is a type of nicotinamide ester used for the treatment of angina and ischaemic heart disease. A 67-year-old woman was referred to a pelvic floor unit with possible vulvar cancer. She had a painful 2 × 1.5 cm punched-out ulcer. A biopsy showed inflammation, but no evidence of malignancy, infection or dysplasia. She had angina which had been controlled with nicorandil for the past six years. After nearly two years of treatment and examinations nicorandil-induced ulceration was suspected and in liaison with cardiologist, the nicorandil treatment was discontinued. Within a few months, the pain settled, and her ulcers healed.

Clinical Implications of Nicorandil Combined with Trimetazidine in Patients with Coronary Heart Disease: A Real-World Observational Study.

INTRODUCTION: Coronary heart disease (CHD) remains the leading cause of mortality in China. The treatment strategies, especially for patients with ischemic angina pectoris, are still far from satisfactory. Hence, this study was carried out to evaluate the long-term potential of nicorandil in Chinese patients with CHD. METHODS: Adult patients with CHD were reviewed retrospectively from three hospitals in Central China to obtain relevant data. The primary outcome was the rate of major adverse cardiovascular events (MACE) which is the composite outcome of stroke, myocardial infarction (MI), and mortality at 3 years while the secondary outcomes included rates of MACE, stroke, MI, and mortality at 1 and 2 years. The rates of MACE were estimated using Kaplan-Meir survival curves and compared by log-rank test. The association between various treatment regimens and hazards of MACE was estimated using Cox proportional hazards model. All analyses were carried out using SAS 9.4. RESULTS: A total of 5504, 1674, and 3923 patients treated with the nicorandil-trimetazidine combination, nicorandil, and trimetazidine were included in the study, respectively. At 3-year follow-up, the rate of MACE [hazard ratio (HR) 0.85; 95% CI 0.74-0.97; P = 0.017] and stroke (HR 0.58, 95% CI 0.48-0.71; P < 0.0001) was lower in the combination group compared to trimetazidine group. Similarly, the rate of stroke was significantly lower (HR 0.69; 95% CI 0.52-0.93; P = 0.0146) at 3 years in the nicorandil group compared to the trimetazidine group. The rate of stroke (HR 0.65; 95% CI 0.52-0.83; P = 0.0004) was significantly lower among the combination group compared with the trimetazidine group at 1-year follow-up. Similarly, the rate of stroke was significantly lower at 1 year (HR 0.70; 95% CI 0.50-0.97; P = 0.03) but not at 2 years (HR 0.70; 95% CI 0.52-0.94; P = 0.0177), while the rate of other outcomes, though lower in the nicorandil group than the trimetazidine group, was not statistically significant at 1 and 2 years respectively. CONCLUSION: Nicorandil in combination with trimetazidine can be considered as an effective and potential treatment strategy in reducing the rate of MACE in patients with CHD in the Chinese population.

Nicorandil Decreases Renal Injury in Patients With Coronary Heart Disease Complicated With Type I Cardiorenal Syndrome.

ABSTRACT: Cardiorenal syndrome (CRS) is a group of disorders in which heart or kidney dysfunction worsens each other. This study aimed to explore the improvement effect of nicorandil on cardiorenal injury in patients with type I CRS. Patients with coronary heart disease complicated with type I CRS were enrolled. Based on the conventional treatment, the patients were prospectively randomized into a conventional treatment group and a nicorandil group, which was treated with 24 mg/d nicorandil intravenously for 1 week. Fasting peripheral venous blood serum and urine were collected before and at the end of treatment. An automatic biochemical analyzer and enzyme linked immunosorbent assay were used to detect B-type brain natriuretic peptide (BNP), serum creatinine (Scr) and cystatin C (Cys-C), renal injury index-kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and interleukin-18 (IL-18) levels. The left ventricular ejection fraction was measured by echocardiography. All measurements were not significantly different between the nicorandil and conventional treatment groups before treatment (all P > 0.05), and BNP, Scr, Cys-C, NGAL, KIM-1, and IL-18 were decreased in the 2 groups at the end of treatment (all P < 0.05). Compared with the conventional treatment group, BNP, Scr, Cys-C, NGAL, KIM-1, and IL-18 were more significantly decreased in the nicorandil group (all P < 0.05) and left ventricular ejection fraction was more significantly increased (P < 0.05). Therefore, nicorandil could significantly improve the cardiac and renal function of patients with type I CRS. This may prove to be a new therapeutic tool for improving the prognosis and rehabilitation of type I CRS.

Clinical outcomes of nicorandil administration in patients with acute ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: a systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Primary percutaneous coronary intervention is the treatment of choice in ST-segment elevation myocardial infarction and no-reflow phenomenon is still an unsolved problem. METHODS: We searched PubMed, EmBase, and Cochrane Central Register of Controlled Trials for relevant randomized controlled trials. The primary endpoint was the incidence of major adverse cardiac events and the secondary endpoint was the incidences of no-reflow phenomenon and complete resolution of ST-segment elevation. RESULTS: Eighteen randomized controlled trials were enrolled. Nicorandil significantly reduced the incidence of no-reflow phenomenon (OR, 0.46; 95% CI, 0.36-0.59; P < 0.001; I2 = 0%) and major adverse cardiac events (OR, 0.42; 95% CI, 0.27-0.64; P < 0.001; I2 = 52%). For every single outcome of major adverse cardiac events, only heart failure and ventricular arrhythmia were significantly improved with no heterogeneity (OR, 0.36; 95% CI, 0.23-0.57, P < 0.001; OR, 0.43; 95% CI, 0.31-0.60, P < 0.001 respectively). A combination of intracoronary and intravenous nicorandil administration significantly reduced the incidence of major adverse cardiac events with no heterogeneity (OR, 0.24; 95% CI, 0.13-0.43, P < 0.001; I2 = 0%), while a single intravenous administration could not (OR, 0.66; 95% CI, 0.40-1.06, P = 0.09; I2 = 52%). CONCLUSIONS: Nicorandil can significantly improve no-reflow phenomenon and major adverse cardiac events in patients undergoing primary percutaneous coronary intervention. The beneficial effects on major adverse cardiac events might be driven by the improvements of heart failure and ventricular arrhythmia. A combination of intracoronary and intravenous administration might be an optimal usage of nicorandil.