Cardiocerebral Protective Effects of Nicorandil Beyond Antiangina: Insights From a Series of Real-World Studies

Coronary heart disease (CHD) is a chronic, systemic disease and the primary global cause of death, affecting more than 100 million individuals worldwide.[1] It is associated with various symptoms, a deterioration in clinical outcomes, and increasing healthcare expenditures.[2] Patients with CHD are at elevated long-term risk of major adverse cardiovascular events (MACEs), which typically include new-onset or recurrent myocardial infarction, stroke, and cardiovascular mortality.[3,4] Angina pectoris is a predominant clinical presentation in patients with CHD; it is the primary reason for which patients seek medical help.[5] Antianginal medications can relieve chest pain, improve patients’ quality of life, potentially prevent cardiovascular events, and improve prognoses.[6] First-line antianginal medications include β-blockers, calcium channel blockers, and nitrates. In addition, current guidelines recommend the consideration of second-line drugs, such as nicorandil, ranolazine, and trimetazidine, for patients with contraindications, resistance, or intolerance to first-line treatments.[6] However, the long-term effects of these drugs and the benefits they provide beyond cardioprotection remain undetermined. Although various medications reduce cardiovascular events,[7] they show limited efficacy in alleviating angina.[8] In randomized trials exploring antianginal strategies for patients with CHD, the symptoms of angina are often improved[9,10]; however, many patients require a minimum of 2 types of antianginal drugs to achieve this.[10–12] The 2018 Guideline on the Diagnosis and Treatment of Stable Coronary Artery Disease recommends using nicorandil for symptom relief when β-blockers are contraindicated, ineffective, or cause adverse reactions.[13] The clinical effectiveness of nicorandil relative to other antianginal drugs, such as nitrate and nitroglycerin, in patients with stable angina has been evaluated. A single-center randomized trial including 54 patients experiencing the coronary slow-flow phenomenon and frequent angina showed that nicorandil was safe and provided superior symptomatic relief relative to nitroglycerin, with greater reductions in angina frequency and pain intensity.[14] Furthermore, a multicenter open-label randomized controlled trial of 402 patients with stable CHD revealed that combined treatment with oral nicorandil and standard medications for CHD, including aspirin, β-blockers, calcium channel blockers, angiotensin-converting enzyme inhibitors, long-acting nitrates, and statins, for 12 weeks significantly reduced the number of ischemic attacks compared to standard treatment.[15] These results suggest that the combined use of nicorandil and other first-line antianginal treatments decreased the incidence of myocardial infarction and cardiovascular morbidity in patients with stable angina. Therefore, given the requirement for combined drug administration to achieve satisfactory control, further exploration of the effectiveness and safety of different combinations of antianginal drugs in clinical practice is essential. The collective evidence from recent real-world observational studies provides valuable insights into the roles of some antianginal medications in the long-term management of CHD. A series of real-world retrospective studies conducted with data from Chinese hospital systems covering a 3-year period and encompassing more than 100,000 patients with CHD has provided insights into the management of angina in actual clinical practice. In a retrospective analysis of 11,101 patients with CHD, Shen et al[16] reported that the combined use of nicorandil and trimetazidine was associated with a significant reduction in the risks of MACEs (hazard ratio (HR) = 0.85) and stroke (HR = 0.58) over 3 years compared with trimetazidine monotherapy. A separate analysis of data from 16,912 patients with CHD showed that the combined use of nicorandil and β-blockers was associated with significant decreases in the occurrence of MACEs (HR = 0.79) and stroke (HR = 0.48) within 2.5 years compared with the use of β-blockers alone.[17] These findings indicate that the synergistic use of nicorandil with first-line antianginal drugs is a viable and efficacious strategy for the reduction of MACEs and stroke. Similarly, Cheng et al[18] reported that combination therapy with nicorandil and dihydropyridine calcium channel blockers was associated with the reduced risk of MACEs (HR = 0.80) and stroke (HR = 0.55) over 3 years, especially in patients with diabetes.[18] This study confirmed the long-term clinical advantages of using nicorandil with dihydropyridine calcium channel blockers in patients with CHD, echoing the European Society of Cardiology’s endorsement of nicorandil due to its antianginal properties and beneficial impact in patients with CHD while enriching real-world evidence. These 3 retrospective analyses show that combined treatment with nicorandil and other first-line antianginal medications is associated with a reduced risk of stroke, providing valuable insights for clinical practice. Preclinical studies suggest that nicorandil exerts neuroprotective effects by mitigating neuroinflammation in the presence of cerebral ischemic injury. For instance, nicorandil protected against oxygen-glucose deprivation-induced inflammation in microglial cells by inhibiting activation of the inflammasome and toll-like receptor-4 signal transduction.[19] In addition, nicorandil attenuated neuroinflammation and endoplasmic reticulum stress in astrocytes.[20] Furthermore, it improved ischemia-induced blood-brain barrier disruption and brain edema in murine models, potentially through the upregulation of nuclear factor erythroid 2-related factor 2.[6,21] The correct dosage of nicorandil can improve cerebral blood flow without causing significant changes in hemodynamic profiles.[22] Further research is needed to validate these findings and elucidate the molecular mechanisms underlying the potential benefits of nicorandil in stroke prevention. It is essential to note the limitations inherent to retrospective observational studies, including the inability to establish causality and the potential introduction of bias. Although propensity score matching or inverse probability of treatment weighting was used in these studies, these methods cannot account for all potential confounding factors, and unidentified factors may have influenced the results. Consequently, the findings should be interpreted with caution and viewed as a foundation for future randomized controlled trials. Additionally, recall and selection biases may have affected the results. These studies relied on data on medication prescriptions at discharge, which may not reflect actual drug use over time due to factors such as variable medication compliance and changes in medication regimens. Furthermore, it is noteworthy that the 3 large retrospective studies cited stem from the same research team, raising concerns regarding the validation of the stroke prevention effects of nicorandil by independent sources. Therefore, future trials are crucial to validate the long-term benefits of nicorandil use in combination with other treatments and to determine the optimal patient populations for these treatment strategies. In conclusion, the studies discussed in this commentary contribute to the clinical dialogue on the management of CHD, especially in those with ischemic cerebrovascular disease, and provide a strong impetus for further investigation into the therapeutic role of nicorandil. As the global burden of atherosclerotic disease continues to rise, the search for effective and well-tolerated therapies is more critical than ever. The potential of nicorandil, supported by real-world evidence, offers a promising avenue for improving the long-term outcomes and quality of life of patients with CHD beyond cardioprotection. Acknowledgments The authors acknowledge Chugai Pharma China Co., Ltd for providing editing and proofreading support. Funding None. Author contributions Qifan Li drafted the manuscript and Liu He reviewed and revised the manuscript. Both authors read and approved the final manuscript. Conflicts of interest None.