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Hypothesis: The potential therapeutic role of nicorandil in COVID-19.
Ashour, H, Elsayed, MH, Elmorsy, S, Harb, IA
Clinical and experimental pharmacology & physiology. 2020;(11):1791-1797
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Abstract
At present, there is yet no specific antiviral treatment or immunization against the newly identified human severe acute respiratory syndrome virus (SARS-CoV2) that results in a rapidly progressive pandemic coronavirus disease 2019 (COVID-19). We believe in a crucial need for a clinical strategy to counteract this viral pandemic based on the known pathogenesis throughout the disease course. Evidence suggests that exaggerated patient's inflammatory response and oxidative stress are likely to aggravate the disease pathology. The resulting endothelial dysfunction further induces fibrosis and coagulopathy. These disturbances can generate severe acute respiratory distress syndrome (ARDS) that can progress into respiratory and circulatory failure. Nicorandil is an anti-anginal vasodilator drug acts by increasing nitric oxide bioavailability and opening of the KATP channel. Recently, nicorandil has been recognized to possess multiple protective effects against tissue injury. Here, we address a possible modulatory role of nicorandil against COVID-19 pathogenesis. We hypothesise nicorandil would be an effective form of adjuvant therapy against COVID-19.
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Nicorandil prior to primary percutaneous coronary intervention improves clinical outcomes in patients with acute myocardial infarction: a meta-analysis of randomized controlled trials.
Xu, L, Wang, L, Li, K, Zhang, Z, Sun, H, Yang, X
Drug design, development and therapy. 2019;:1389-1400
Abstract
Background: Nicorandil prior to reperfusion by primary percutaneous coronary intervention (PCI) in patients with ST-segment elevated myocardial infarction (STEMI) has been suggested to be beneficial. However, results of previous randomized controlled trials (RCTs) were not consistent. We aimed to perform a meta-analysis to systematically evaluate the effect of periprocedural nicorandil in these patients. Methods: Related studies were obtained by searching PubMed, Embase and Cochrane's Library. Effects of perioperative nicorandil on the incidence of no-reflow phenomenon (NRP), corrected thrombolysis in myocardial infarction (TIMI) frame count (CTFC), wall motion score (WMS), left ventricular ejection fraction (LVEF), heart failure (HF) exacerbation of rehospitalization and incidence of major cardiovascular adverse events (MACE) were analyzed. Results: Eighteen RCTs with 2,055 patients were included. Treatment of nicorandil prior to PCI significantly reduced the incidence of NRP (risk ratio [RR]: 0.47, P<0.001), and reduced CTFC (weighed mean difference [WMD]: -4.54, P<0.001) immediately after PCI. Moreover, although nicorandil did not significantly affect WMS (WMD: 0.04, P=0.91), treatment of nicorandil significantly increased LVEF in STEMI patients undergoing primary PCI (WMD: 1.89%, P<0.001). In addition, nicorandil significantly reduced the risk of HF exacerbation or rehospitalization (RR: 0.44, P=0.001) and the incidence of MACE (RR: 0.68, P<0.001). Further analyses showed that effects of nicorandil on LVEF, HF exacerbation and MACE were consistent within one month after PCI and during follow-up. Conclusions: Periprocedural nicorandil improves coronary blood flow, cardiac systolic function and prognosis in STEMI patients receiving primary PCI.
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Effects of mitochondrial ATP-sensitive potassium channel activation (nicorandil) in patients with angina pectoris undergoing elective percutaneous coronary interventions: A meta-analysis of randomized controlled trials.
Zhu, H, Xu, X, Fang, X, Zheng, J, Chen, T, Huang, J
Medicine. 2019;(3):e14165
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Abstract
AIMS: Nicorandil, which is a mitochondrial ATP-sensitive potassium channel opener, is believed to improve perioperative myocardial injury (PMI) in patients undergoing percutaneous coronary intervention (PCI), but recent studies have shown that nicorandil treatment did not improve functional and clinical outcomes in patients with angina pectoris who underwent elective PCI. We performed a meta-analysis to investigate the protective effect of nicorandil on perioperative injury in patients with angina pectoris who underwent elective PCI. METHODS The Medline, EMBASE, and Cochrane databases were searched for randomized clinical trials examining the effects of nicorandil. Two investigators independently selected suitable trials, extracted data, and assessed trial quality. RESULTS Seven studies of patients undergoing elective PCI, comprising a total of 979 patients, were included in this review. The results showed that nicorandil did not reduce the levels of markers of myocardial injury (standardized mean difference [SMD] 0.31 [95%CI -0.6, 1.22] for creatine kinase-MB [CK-MB] and 1.29 [95%CI -2.18, 4.76] for troponin I [TNI]), perioperative complications (relative risk [RR] 0.91 [95%CI 0.46-1.81]), target vessel revascularization (RR 0.79 [95%CI 0.50-1.25]) or major adverse cardiac events (MACE) (RR 0.83 [95%CI 0.49-1.43]). Nicorandil did reduce the corrected TIMI frame count (SMD-0.30 [95%CI -0.52, -0.09]). CONCLUSION Although nicorandil did not reduce the overall incidence of perioperative complications and the incidence of major adverse cardiac events (MACE) in patients with angina pectoris who underwent elective PCI, it could still improve no reflow and slow coronary flow.
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NICORANDIL EFFICACY IN THE TREATMENT OF ISCHEMIC HEART DISEASE (REVIEW).
Gvishiani, M, Gabunia, L, Makharadze, T, Gongadze, N
Georgian medical news. 2018;(280-281):152-155
Abstract
Nicorandil is an antianginal agent with a dual mechanism of action. It belongs to ATP-senitive potassium channel openers which has the beneficial effect in angina pectoris, playing an significant role in the dilation of arteries, veins and coronary artery. It leads to the relaxation of vascular smooth muscle and causes vasodilatation of major epicardial vessels. This effect is crucial for reducing risks of further damage in cases when percutaneous coronary intervention (PCI) is necessary. Relevant new studies concluded that Nicorandil has antiarrhythmic and cardioprotective effects by improving reperfusion, ultimately leading to a reduction in microvascular damage caused by PCI. Furthermore, Nicorandil addition to the standard therapy of paitents with ischemic heart disease has demonstrated improved quality of life.
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Nicorandil improves clinical outcomes in patients with stable angina pectoris requiring PCI: a systematic review and meta-analysis of 14 randomized trials.
Li, Y, Liu, H, Peng, W, Song, Z
Expert review of clinical pharmacology. 2018;(9):855-865
Abstract
Clinical trials concerning the effects of nicorandil in stable coronary artery disease (CAD) remain controversial. This study sought to evaluate the clinical outcomes of nicorandil following elective percutaneous coronary intervention (PCI). Areas covered: A meta-analysis including eligible randomized controlled trials (RCTs) with data on the nicorandil in stable CAD from Pubmed, EMBase, and Cochrane library (up to March 2018) was conducted. The primary end points were postprocedural incidence of myocardial infarction (MI) and contrast-induced nephropathy (CIN). The second end point was major adverse cerebrovascular and cardiovascular events (MACCE). Fourteen RCTs with a total of 1947 elective CAD patients were selected. Nicorandil significantly reduced the incidence of MI [n = 8; relative risk (RR) = 0.58; P = 0.001; I2 = 33.7%], and CIN (n = 5; RR = 0.36; P < 0.00001; I2 = 15.4%). However, There was no lowered risk of MACCE in nicorandil-treated patients [n = 10; odds RR = 0.75; P = 0.19; I2 = 0.0%]. Subsequent trial sequential analyses confirmed the effect of nicorandil on MI and CIN in PCI. Expert commentary: The present systematic review and meta-analysis suggests that nicorandil could improve clinical outcomes in terms of perioperative MI and CIN. However, the effect of nicorandil on the MACCE risk is not obvious. Future high-quality, large-scale clinical trials should majorly concern about the long-term clinical effect of nicorandil.
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Nitrates for the prevention of cardiac morbidity and mortality in patients undergoing non-cardiac surgery.
Zhao, N, Xu, J, Singh, B, Yu, X, Wu, T, Huang, Y
The Cochrane database of systematic reviews. 2016;(8):CD010726
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Abstract
BACKGROUND Cardiac complications are not uncommon in patients undergoing non-cardiac surgery, especially in patients with coronary artery disease (CAD) or at high risk of CAD. Perioperative cardiac complications can lead to mortality and morbidity, as well as higher costs for patient care. Nitrates, which are among the most commonly used cardiovascular drugs, perform the function of decreasing cardiac preload while improving cardiac blood perfusion. Sometimes, nitrates are administered to patients undergoing non-cardiac surgery to reduce the incidence of cardiac complications, especially for patients with CAD. However, their effects on patients' relevant outcomes remain controversial. OBJECTIVES • To assess effects of nitrates as compared with other interventions or placebo in reducing cardiac risk (such as death caused by cardiac factors, angina pectoris, acute myocardial infarction, acute heart failure and cardiac arrhythmia) in patients undergoing non-cardiac surgery.• To identify the influence of different routes and dosages of nitrates on patient outcomes. SEARCH METHODS We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and the Chinese BioMedical Database until June 2014. We also searched relevant conference abstracts of important anaesthesiology or cardiology scientific meetings, the database of ongoing trials and Google Scholar.We reran the search in January 2016. We added three potential new studies of interest to the list of 'Studies awaiting classification' and will incorporate them into our formal review findings for the review update. SELECTION CRITERIA We included randomized controlled trials (RCTs) comparing nitrates versus no treatment, placebo or other pharmacological interventions in participants (15 years of age and older) undergoing non-cardiac surgery under any type of anaesthesia. DATA COLLECTION AND ANALYSIS We used standard methodological procedures as expected by Cochrane. Two review authors selected trials, extracted data from included studies and assessed risk of bias. We resolved differences by discussion and, when necessary, sought help and suggestions from a third review author. We used a random-effects model for data analysis. MAIN RESULTS We included 27 randomized controlled trials (RCTs) (8244 participants analysed). Investigators reported 12 different comparisons of three different nitrates (nitroglycerin, isosorbide dinitrate and nicorandil) versus no treatment, placebo or other pharmacological interventions. All participants were older than 15 years of age. More than half of the trials used general anaesthesia. Surgical procedures in most trials were at low to moderate risk for perioperative cardiac complications. Only two comparisons including three studies reported the primary outcome - all-cause mortality up to 30 days post operation. Researchers reported other morbidity outcomes and adverse events in a variable and heterogeneous way, resulting in limited available data for inclusion in the meta-analysis. We determined that the overall methodological quality of included studies was fair to low, in accordance with risk of bias in most domains.In summary, we found no difference in the primary outcome - all-cause mortality up to 30 days post operation - when nitroglycerin was compared with no treatment (one study, 60 participants, 0/30 vs 1/30; (risk ratio (RR) 0.33, 95% confidence interval (CI) 0.01 to 7.87, very low-quality evidence based on GRADE criteria) or with placebo (two studies, 89 participants, 1/45 vs 0/44; RR 2.81, 95% CI 0.12 to 63.83, very low-quality evidence). Regarding our secondary outcomes, we noted no statistically significant differences in angina pectoris, acute myocardial infarction, acute heart failure, cardiac arrhythmia or cardiac arrest in any comparisons. In comparisons versus nitroglycerin, although more events of cardiac ischaemia were observed in participants receiving no treatment or placebo, we found no statistically significant differences in any comparisons, except the comparison of nicorandil versus placebo. One study revealed a potential dose-dependent protective effect of nicorandil for cardiac ischaemia.Adverse events were reported in a heterogeneous way among the comparisons. In general, more participants treated with nitrates had hypotension, tachycardia and headache, but investigators reported no statistically significant differences between groups in any comparisons. AUTHORS' CONCLUSIONS This systematic review suggests that nitroglycerin or isosorbide dinitrate is not associated with improvement in mortality and cardiac complications among patients undergoing non-cardiac surgery. Limited evidence suggests that nicorandil may reduce the risk of cardiac ischaemia in participants undergoing non-cardiac surgery. Additional studies are needed to consolidate the evidence.However, the data included in many of the analyses in this review are sparse - that is, adequate data are few - resulting in very low power to detect differences between nitrates and comparators. Thus, a more objective conclusion would state that available evidence is insufficient to show whether nitrates are associated with improvement in mortality and cardiac complications among patients undergoing non-cardiac surgery.Over the past decade, no high-quality studies have focused on association of cardiac mortality and morbidity with use of nitrates during non-cardiac surgery. This review underlines the need for well-designed trials in this field.
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Nicorandil, Gastrointestinal Adverse Drug Reactions and Ulcerations: A Systematic Review.
Pisano, U, Deosaran, J, Leslie, SJ, Rushworth, GF, Stewart, D, Ford, I, Watson, AJ
Advances in therapy. 2016;(3):320-44
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Abstract
INTRODUCTION Nicorandil is a popular anti-anginal drug in Europe and Japan. Apart from some common adverse drug reactions (ADR), its safety is satisfactory. Several reports have suggested a link between nicorandil, gastrointestinal (GI) ulceration and fistulas. The review aims to critically appraise, synthesize and present the available evidence of all known GI ADR per anatomical location. METHODS The study complied with the PRISMA statement. Literature and pharmacovigilance databases were used to provide rate and/or calculate parameters (median age, median dose, history of symptoms, length of therapy and healing time after withdrawal of the drug). Differences in distribution of quantitative variables were analyzed via Mann-Whitney test. Correlation between quantitative variables was assessed with a Spearman's correlation coefficient. A p value <0.05 was significant. RESULTS Oral ulcerations occur in 0.2% of the subjects, anal ulcerations are present between 0.07% and 0.37% of patients. Oral and distal GI involvements are the most common ADR (28-29% and 27-31% of all GI ADR, respectively). The hepatobiliary system, the pancreas and salivary glands are not affected by nicorandil exposure. The time to develop oral ulcerations is 74 weeks among people on <30 mg/day compared to only 7.5 weeks in individuals on higher regimens (p = 0.47). There is a significant correlation between dose and ulcer healing time (Spearman's 0.525, p < 0.001). CONCLUSIONS Ulcerative disease is a very commonly reported GI ADR. A delayed ulcerative tendency supports the hypothesis of an ulcerogenic metabolite. Nicorandil seems to act as a cause of the ulcerations, but appears to also work in synergy with other promoting factors. Whether the action of the metabolites relies on a specific mechanism or a simple chemical ulceration is still to be established.
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Effect of nicorandil in patients with heart failure: a systematic review and meta-analysis.
Zhao, F, Chaugai, S, Chen, P, Wang, Y, Wang, DW
Cardiovascular therapeutics. 2014;(6):283-96
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BACKGROUND AND PURPOSE It is unclear whether nicorandil, a metabolic therapeutic drug, can be applied clinically to therapy of heart failure (HF). This meta-analysis evaluated therapeutic effects of nicorandil on HF patients. EXPERIMENTAL APPROACH We performed a systematic review and meta-analysis of published studies evaluating effect of nicorandil on HF patients. Studies were stratified according to controlled versus uncontrolled designs and analyzed using random-effects meta-analysis models. KEY RESULTS We identified a total of 20 studies with a total of 1222 patients. In five randomized controlled studies, nicorandil treatment resulted in reduction in all-cause mortality and hospitalization for cardiac causes (HR: 0.35, P < 0.001) and improved cardiac pump function (SMD: 0.31, P = 0.02). In 15 observational studies, nicorandil therapy increases cardiac pump function (SMD: 0.75, P < 0.001), improves NYHA functional class (WMD: -1.33, P < 0.001), decreases PCWP (WMD: -6.86 mm Hg, P < 0.001), and pulmonary arterial pressure (SMD: -0.84, P < 0.001). CONCLUSIONS AND IMPLICATIONS The use of nicorandil in HF patients exerts substantial beneficial effects, suggesting that it may be an additional therapeutic agent for HF.
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All-cause mortality and cardiovascular events with nicorandil in patients with IHD: systematic review and meta-analysis of the literature.
Luo, B, Wu, P, Bu, T, Zeng, Z, Lu, D
International journal of cardiology. 2014;(3):661-9
Abstract
BACKGROUND Nicorandil is able to protect the cardiomyocytes from ischemic damage, but clear benefits of nicorandil in all-cause mortality and cardiovascular events were not consistently reported in patients with ischemic heart disease (IHD). MATERIALS AND RESULTS Cochrane, PubMed, EMBASE, CBM, CNKI and Wangfang databases were searched for randomized controlled trials. Data on all-cause mortality and cardiovascular events were collected. Nicorandil groups were pooled to perform a comparison with control groups and to get the pooled odds ratios (ORs) and associated 95% confidence intervals (CIs) for all-cause mortality, relative risks (RRs), and associated 95% CIs for cardiovascular events. STATA 11.0 software was used for all-cause mortality and cardiovascular events statistics. We retrieved 17 randomized controlled studies enrolling a total of 7305 patients. The addition of nicorandil treatment significantly reduced cardiovascular events (13.83% versus 18.01%; RR, 0.77; 95% CI, 0.69 to 0.86). No differences in all-cause mortality (3.83% versus 4.70%; OR, 0.81; 95% CI, 0.64 to 1.02), and repeat revascularization rate (13.06% versus 13.54%; RR, 0.95; 95% CI, 0.70 to 1.29) were observed. There was a weak linear association between cardiovascular events and nicorandil in IHD with diabetes (P=0.099). CONCLUSIONS The results suggest that nicorandil as an adjunct therapy to IHD is associated with reduced cardiovascular events in patients with IHD.
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[Nicorandil in the treatment of patients with ischemic heart disease].
Minushkina, LO, Sidorenko, BA
Kardiologiia. 2013;(5):69-73
Abstract
Adequate drug therapy of stable ischemic heart disease directed at reduction and prevention of main clinical symptoms of the disease, increase of exercise tolerance to physical effort, improvement of quality of life and prognosis remains an actual problem. Nicorandil combines properties of an antianginal drug and cardioprotective effects. Its pharmacological action is related to capabilities to be an nitrous oxide donor and to activate ATP-dependent potassium channels. In this review we present data on mechanism of action of nicorandil, on its clinical effectiveness, and on comparison with antianginal drugs of other groups. We have also analyzed experience of the use of nicorandil in patients with acute coronary syndrome and in conjunction with during invasive interventions.