Effectiveness of Nicorandil in Heart Failure: A Meta-Analysis

By Tongge Mu, Kaixuan Tang, Yan Sun

Affiliations

1. School of Medicine, Shandong University of Traditional Chinese Medicine, Jinan, China

doi: 10.29271/jcpsp.2025.06.755

ABSTRACT
This meta-analysis aims to evaluate the effectiveness of nicorandil in treating heart failure by synthesising evidence from diverse studies. The study period spanned from 12/01/2023 to 28/02/2024. Observational and randomised controlled trials have been conducted to study the cardiovascular outcomes associated with nicorandil. The findings consistently show that nicorandil, administered either intravenously or orally, significantly reduces major adverse cardiovascular events (MACEs), lowers NT-proBNP levels, and improves left ventricular ejection fraction, indicating enhanced cardiac function. Nicorandil emerges as a promising adjunctive therapy in heart failure management, potentially improving patient outcomes and decreasing the risk of MACEs. However, the exact role of this therapy in heart failure treatment requires further research.

Key Words: Nicorandil, Heart failure, Major adverse cardiovascular events (MACEs), Cardiac function, Meta-analysis.

INTRODUCTION

Heart failure (HF) is a chronic syndrome characteristed by either reduced (HFrEF) or preserved (HFpEF) left ventricular ejection fraction (LVEF), reflecting its progressive nature.¹ HF has emerged as a pressing healthcare concern, assuming epidemic proportions in both developed and developing nations.² Among individuals aged 70 years and older, the prevalence exceeds 10%, while approximately 1-2% of adults in developed nations are affected by this condition.³ In conjunction with dyspnoea and fatigue, individuals with HF commonly experience physical manifestations, including abnormal crackling sounds in the lungs (pulmonary rales), swelling in the extremities (peripheral oedema), and enlargement of the jugular veins.¹

Advances in medical therapies, particularly for acute coronary syndromes and congenital heart disease, have substantially reduced the short-term mortality related to HF. Moreover, the extensive utilisation of oral therapies and medical devices aimed at modifying the disease has significantly enhanced the long-term survival rates of individuals diagnosed with HFrEF. Despite these advancements in evidence-based therapies, patients with chronic HF inevitably progress to advanced stages of the disease. An estimated 1-10% of the overall HF population falls into the category of advanced HF.^4,5

 Nicorandil, a pharmacological agent known for its vasodilatory properties, has garnered attention in the context of cardiovascular health. Its unique combination of ATP-sensitive potassium channel opening and nitric oxide donation results in multifaceted effects on vascular and myocardial function.^6,7 These effects encompass not only enhanced coronary blood flow, reduced cardiac preload and afterload, and antianginal benefits but also extend to cardioprotective mechanisms.⁸ Experimental research has revealed its role in preserving mitochondrial integrity, mitigating oxidative stress, and modulating various cellular processes.^9,10 In light of its promising cardioprotective attributes, nicorandil has emerged as a potential therapy for HF. However, the clinical evidence supporting its use in HF remains a subject of ongoing investigation.¹¹ The aim of this meta-analysis was to provide a comprehensive assessment of the efficacy of nicorandil in HF management.

METHODOLOGY

This study adhered to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines.¹² The data utilised in this study were sourced from publicly accessible research publications and constituted the outcome of a meta- analysis involving both observational investigations and RCTs. Consequently, there was no requirement for additional ethical approval for the conduct of this research.

This investigation focused on gathering and analysing data from RCTs and observational studies comparing the efficacy of interventions related to this research question. Multiple electronic databases were searched, including EMBASE, PubMed, and the Cochrane Central Register of Controlled Trials, to locate relevant studies. The Boolean operator 'AND' was employed to combine results from different search themes. Moreover, the search was supplemented by manually examining the reference lists of the included studies, meta- analyses, and review articles, thereby augmenting the comprehensiveness of the inquiry. Additionally, efforts were made to obtain any missing data or clarifications by contacting the authors of the identified studies when necessary. An initial selection of studies was performed by two independent reviewers, with any discrepancies resolved by discussion and, if necessary, by a third reviewer. For inclusion in this review, specific criteria had to be met including patients with a confirmed diagnosis of acute or chronic heart failure; a comparison between nicorandil and either placebo or no nicorandil treatment was conducted; the study reported one or more of the following outcome measures: MACEs, NT-proBNP, or LVEF; the publications were exclusively available in the English language; the study encompassed RCTs or observational studies. Studies were excluded if they were incomplete, inaccurate, with missing data, with the absence of relevant outcomes; studies did not align with the intervention strategy; research articles being meta-analyses, reviews, animal studies, or case reports; and duplicate publications. Trials where nicorandil was also administered in the control group were excluded.

Two independent reviewers undertook the data extraction process. Whenever necessary, a third reviewer was consulted to resolve disagreements. Information gathered encompassed critical details such as the authors of the literature, publication year, study design, type of HF, patient demographics including sample size, mean age, gender distribution, LVEF, hypertension, diabetes, outcomes, as well as comprehensive treatment information including therapeutic indications, medicine types, dosages, and duration of follow-up. This research primarily focused on three crucial outcomes: MACEs, NT-proBNP, and LVEF. In instances where outcome data were unclear or inaccessible within the articles, diligent efforts were made to establish contact with the respective study authors via email, issuing a reminder if required.

The Newcastle-Ottawa scale was employed to evaluate the quality of the comparative observational studies included in the analysis. Research scoring 7-9 points is classified as high- quality, while 4-6 points indicate medium-quality, and below 4 points represent low-quality research. The comprehensive quality assessment results for the included RCT studies are presented using the Cochrane risk of bias assessment tool.

In statistical analysis, the focus was on MACE incidence as the primary endpoint, while NT-proBNP and LVEF improvement were considered secondary endpoints. Statistical analyses were performed utilising Review Manager 5.3, a reputable software developed by the Cochrane Collaboration in Copenhagen, Denmark. Hazard ratio (HR) with corresponding 95% confidence interval (CI) was employed to elucidate dichotomous data for each study, specifically focusing on MACEs. Regarding continuous outcomes, the meta-analysis results were evaluated by calculating the mean difference (MD) along with its corresponding 95% CI. To gauge heterogeneity among the trials, the I² statistic was utilised, where values below 25%, between 25% and 50%, and above 50% were indicative of mild, moderate, and severe heterogeneity, respectively.¹³ Pooling of the trial results was carried out using the random-effects model, and between-study variance was estimated via DerSimonian and Laird regression. A significance level of  p <0.05 was utilised for all statistical analyses, employing two-tailed tests.

RESULTS

From the initial search, 59 records from PubMed, 189 records from Embase, and 10 records from the Cochrane Library were initially identified as promising. Following the removal of duplicates and a meticulous review of titles and abstracts, 21 full- text articles were identified that warranted a comprehensive evaluation for eligibility. Among the identified articles, two did not align with the interventional strategy, five failed to fulfil the inclusion criteria, and two exhibited inadequate data documentation. In the end, a total of 12 articles (comprising 8 RCTs and 4 observational studies) involving 1,524 patients were identified and subjected to analysis.^14-25 The flowchart outlines the process of study selection (Figure 1).

Figure 1: Diagram illustrating the search strategy for the study.

A comprehensive overview of the characteristics of the studies included in this analysis was provided (Table I). This encompassed 8 randomised controlled trials (RCTs) and 4 observational studies. In this study, a total of 1,524 patients with HF were included, comprising 585 in the nicorandil group and 939 in the control group. Additionally, the sample sizes varied, ranging from 6 to 324 participants. The follow-up durations for these studies varied from one day to three years.

In the studies included, where baseline data were available for both the nicorandil and control groups, similarities were observed between the two groups regarding age, gender, LVEF, and the prevalence of hypertension and diabetes.

Table I: The characteristics of the included studies.

Studies	Design	Type of HF	Follow-up	Nicorandil	Nicorandil, n	Control, n	Outcomes
Galie et al.25 1990	RCT	CHF	3 days	Oral, 40 mg/day or 60 mg/day	9	9	Echocardiograph parameters
Harada et al.22 2017	RCT	AHF	60 days	IV, 0.2 mg/kg + 0.2 mg/kg/h	50	56	Echocardiograph parameters, mortality, and rehospitalisation
Ishihara et al.18 2012	OB	AHF	180 days	IV, 0.1–0.2 mg/kg + 0.1 mg/kg/h	78	324	Mortality and rehospitalisation
Kasama et al.19 2014	OB	CHF	6 months	Oral, 15 mg/day	85	85	Echocardiograph parameters, MACEs
Kasama et al.17 2015	RCT	AHF	28 days	IV, 4-12 mg/h	35	35	Echocardiograph parameters, NT-proBNP
Masahito et al.23 2011	RCT	AHF	24 hours	IV, 0.2 mg/kg + 0.2 mg/kg/h	59	59	Echocardiograph parameters
Masahito et al.21 2012	RCT	AHF	60 days	IV, 0.2 mg/kg + 0.2 mg/kg/h	43	48	Echocardiograph parameters, mortality, and rehospitalisation
Shirakabe et al.20 2010	RCT	AHF	7 days	IV, 0.1 mg/kg + 0.06–0.1 mg/kg/h	16	15	Echocardiograph parameters, BNP/NT-proBNP, and mortality
Yamada et al.24 2009	RCT	CHF	3 years	Oral, 30 mg/day	11	11	Echocardiograph parameters, NT-proBNP
Yokota et al.16 1987	OB	CHF	NA	Oral, 15 mg/day	9	6	Echocardiograph parameters
Yoshihisa et al.14 2017	OB	NA	963 days	Oral, 15 mg/day	116	218	Mortality
Zhang et al.15 2022	RCT	AHF	90 days	IV, 0.2 mg/kg + 0.2 mg/kg/h	74	73	Echocardiograph parameters, NT-proBNP, and rehospitalisation
HF, Heart failure; AHF, Acute HF; CHF, Chronic HF; IV, Intravenous injection; MACEs, Major adverse cardiovascular event; NA, Not available; OB, Observational studies; RCT, Randomised controlled trials.

Table II: Assessment of comparative observational studies quality using the Newcastle-Ottawa scale.

Authors / studies	Year	Study quality (Newcastle-Ottawa scale)
		Selection	Comparability	Outcome/exposure	Total score
Ishihara et al.18	2012	***	**	**	7
Kasama et al.19	2014	***	**	**	7
Yokota et al.16	1987	****	**	**	8
Yoshihisa et al.14	2017	****	**	***	9

Table III: Assessment of bias risk in included randomised controlled trials.

Trials	Random sequence generation (selection bias)	Allocation concealment (selection bias)	Blinding of participants and personnel (performance bias)	Blinding of outcome assessment (detection bias)	Incomplete outcome data (attrition bias)	Selective reporting (reporting bias)	Other bias
Galie et al.25 1990	Unclear risk	Unclear risk	Low risk	Low risk	Low risk	Low risk	Low risk
Harada et al.22 2017	Unclear risk	Unclear risk	Unclear risk	Low risk	Low risk	Low risk	Low risk
Kasama et al.17 2015	Unclear risk	Unclear risk	Unclear risk	Low risk	Low risk	Low risk	Low risk
Shigekiyo et al.23 2011	Unclear risk	Unclear risk	Unclear risk	Unclear risk	Low risk	Low risk	Low risk
Shigekiyo et al.21 2012	Unclear risk	Unclear risk	Unclear risk	Unclear risk	Low risk	Low risk	Low risk
Shirakabe et al.20 2010	Unclear risk	Unclear risk	Unclear risk	Low risk	Low risk	Low risk	Low risk
Yamada et al.24 2009	Unclear risk	Unclear risk	Low risk	Unclear risk	Low risk	Low risk	Low risk
Zhang et al.15 2022	Unclear risk	Unclear risk	Unclear risk	Low risk	Low risk	Low risk	Low risk

Figure 2: Forest plots illustrating the impact of nicorandil on major adverse cardiac events based on a meta-analysis. Figure 3: Forest plots depicting the results of the meta-analysis assessing the impact of nicorandil on NT-proBNP. Figure 4: Forest plots depicting the results of the meta-analysis assessing the impact of nicorandil on left ventricular ejection fraction.

According to the assessment using the Newcastle-Ottawa scale for the comparative observational studies included, all studies that achieved a score of 7 points or above, indicating high quality (Table II). Based on the Cochrane risk of bias assessment tool, Table III provides comprehensive results of quality assessments for included RCTs. Two articles^24,25 provided information regarding the blinding of participants and personnel, while none of the studies described the methods used for random sequence generation and allocation concealment.

MACEs were defined as a composite outcome, encompassing all-cause mortality, new occurrences of acute myocardial infarction, any revascularisation, and re-hospitalisation rate due to congestive HF, and the presence of ventricular arrhythmias. The composite outcome of MACEs was established and documented in 4 of the included studies.^14,18,19,21 Statistical heterogeneity was detected in the meta-analysis, with an I² value of 55% (p = 0.14) for the intravenous subgroup and an I² value of 0% (p = 0.96) for the oral subgroup. The pooled findings indicated a notable decrease in the risk of MACEs associated with intravenous nicorandil (HR: 0.29, 95% CI: 0.10 to 0.88, p = 0.03), and oral nicorandil demonstrated a similar effect (HR: 0.51, 95% CI: 0.33 to 0.78, p = 0.002). The overall analysis indicated a significant association between nicorandil usage and a decreased risk of MACEs (HR: 0.41, 95% CI: 0.26 to 0.66, p = 0.0002; I² = 0%; Figure 2).

Three studies encompassed a total of 125 patients who were administered Nicorandil, while 123 were part of the control group. These studies displayed no statistical heterogeneity (p = 0.47, I² = 0%). The meta-analysis revealed a notable reduction in NT-proBNP levels (MD = -577.16, 95% CI: -880.94 to -273.37, p = 0.0002) following nicorandil administration, as depicted in Figure 3.

Four studies encompassed a total of 183 individuals who were administered nicorandil, while the control group consisted of 180 participants. These investigations did not exhibit significant heterogeneity (p = 0.95, I² = 0%). Employing the random-effects model, a notable improvement in LVEF levels (MD = 3.43, 95% CI: 1.34 to 5.53, p = 0.001) was observed following the administration of nicorandil, as depicted in Figure 4.

DISCUSSION

In this comprehensive analysis of the effects of nicorandil on cardiovascular outcomes, compelling evidence was found to support its potential benefits in patients with HF. This comprehensive meta-analysis, incorporating a wide spectrum of studies including both observational studies and RCTs, demonstrated a significant decrease in MACEs associated with nicorandil administration, either intravenously or orally. Furthermore, these findings demonstrated that nicorandil effectively lowered NT-proBNP levels and improved LVEF, indicating improved cardiac function. These findings imply that nicorandil could serve as a promising supplementary therapy in HF management, providing clinicians with a valuable approach to enhance patient outcomes and mitigate the likelihood of adverse cardiovascular events.

Nicorandil, a cost-effective potassium ion channel medicine, possesses a versatile range of cardiovascular benefits. It operates through multiple mechanisms, including the opening of potassium ion channels, leading to the dilation of small arteries and veins, thus improving cardiac output and cardiac function.^6,7 Simultaneously, it reduces pulmonary artery wedge pressure and peripheral resistance, maintaining a balanced haemodynamic state. Its impact on blood pressure is modest. Beyond its vasodilatory effects, nicorandil demonstrates potential cardioprotective properties. It can reduce pre- and after-load, enhance myocardial perfusion, prevent calcium overload, scavenge free radicals, and even induce pharmacological preconditioning against ischaemia.^26-29 Additionally, it improves coronary microcirculation.³⁰ The diverse actions of nicorandil make it a valuable asset in treating cardiovascular conditions, promising improved patient outcomes in cardiology.

To the authors’ knowledge, only two prior meta-analyses have investigated the effectiveness of nicorandil in individuals suffering from HF.^31,32 Zhao et al. included a total of 20 studies, comprising 5 RCTs and 15 observational studies, involving a collective cohort of 1,222 patients in a systematic review and meta-analysis published in 2014.³¹ According to their thorough analysis, nicorandil was linked with a decline in overall mortality, a reduction in hospitalisations due to cardiac issues, and enhancements in cardiac pump function.³¹ It is worth noting that this meta-analysis was conducted in 2014. As innovative medications and therapeutic approaches have emerged in recent years, the treatment landscape for HF has evolved. Consequently, there is a notable absence of more recent meta-analyses addressing this topic in the current literature. In another meta-analysis published in 2023, Zhu and Xie conducted a comprehensive review that encompassed 8 RCTs involving a total of 764 patients suffering from acute decompensated HF.³² Notably, the focus of this analysis was solely on patients who received intravenous administration of nicorandil, with the exclusion of those who were treated with oral nicorandil.³² This specific inclusion criterion led to the omission of a subset of patients who might have demonstrated efficacy with oral nicorandil. In this meta-analysis, a comprehensive approach was adopted by including all categories of HF patients, encompassing both acute decompensated HF and chronic HF patients. This study’s inclusive criteria spanned a spectrum of study types, ranging from RCTs to observational studies. This study conducted a thorough and meticulous evaluation of the effects of nicorandil on patients with HF through rigorous selection criteria.

This extensive analysis of the effects of nicorandil on cardiovascular outcomes presents compelling evidence of its potential benefits for patients with HF. This meta-analysis, encompassing a diverse array of studies, ranging from randomised controlled trials to observational studies, consistently demonstrates that nicorandil, either administered intravenously or orally, reduces MACEs significantly. Additionally, nicorandil exhibits a favourable impact on cardiac function. These results imply that nicorandil could be a promising supplementary therapy in HF management, providing clinicians with a valuable strategy to enhance patient outcomes and mitigate the risk of adverse cardiovascular events. While acknowledging the potential of nicorandil, it is important to recognise the need for further well-designed trials to establish its definitive role in the evolving landscape of HF management. This study’s highlights the significance of continued research into this multifaceted potassium ion channel medicine, aiming to optimise its clinical utility and contribute to improved care for HF patients.

CONCLUSION

Nicorandil significantly reduces MACEs and improves cardiac function, as indicated by reduced NT-proBNP levels and enhanced LVEF. While nicorandil holds promise as an adjunctive therapy for HF, ongoing research is essential to solidify its clinical role in this evolving landscape.

COMPETING  INTEREST:
The authors declared no conflict of interest.

AUTHORS’ CONTRIBUTION:
TM, KT, YS: Conducted the statistical analyses and drafted the manuscript.
TM, YS: Conceived and designed the research, revised the manuscript, and responsible for screening the literature and conducting the quality rating.
All authors approved the final version of the manuscript to be published.

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