The 2019 ESC Guidelines for the Diagnosis and Management of Chronic Coronary Syndromes present a clear definition of refractory angina, a condition characterized by persistent symptoms lasting beyond three months. In the presence of obstructive coronary artery disease (CAD), refractory angina is caused by reversible ischemia. These distressing symptoms prove resistant to control even with the escalation of medical therapy using second- and third-line pharmacological agents, as well as interventions like bypass grafting, stenting, or percutaneous coronary intervention (PCI) of chronic total coronary occlusion (1). Unfortunately, refractory angina affects a significant portion, ranging from 5% to 15%, of individuals living with angina pectoris (2, 3). As a consequence, it not only diminishes their quality of life but also raises the risk of mortality (4).

To gain further insights into the field of refractory angina, this study adopted CiteSpace software and performed a bibliometric analysis of research accomplishments over the past two decades. Leveraging the comprehensive Web of Science (WOS) database, the analysis aimed to identify key trends, renowned researchers, main research countries and institutions, as well as the emerging research hotspots in this domain. By delving into the collective knowledge generated by the scientific community, this investigation sought to shed light on the advancements made in understanding and addressing refractory angina.

This study employed CiteSpace software to conduct a comprehensive bibliometric analysis of publications in the field of refractory angina from 2003 to 2022. The analysis encompassed spatiotemporal distribution, author and institutional contributions, core literature, research hotspots, and trends in refractory angina research. The annual publication volume in this field demonstrated relative stability without significant growth, indicating that refractory angina has not experienced a sudden surge in popularity within cardiovascular disease research compared to other areas. The analysis of national cooperation networks revealed that the United States and European countries dominated research in the field of refractory angina, with limited participation from Asian and African countries. Japan and China were the sole Asian countries at the forefront of research. Similarly, top-ranked research institutions primarily consisted of universities and medical institutions from the United States and European countries, and there is barely collaboration between institutions. Author collaborative network analysis identified Henry TD as a pivotal researcher in the field of refractory angina, with a substantial number of publications and citations. Henry TD is renowned for his groundbreaking work in interventional cardiology and stem cell therapy in the United States. Another noteworthy author is Mannheimer C, who ranked first in terms of co-citation and was nearly twice as many as second place despite having fewer publications. Mannheimer C led the report on the treatment of refractory angina by the ESC Joint Study Group in 2002.

Keyword clustering and burst analysis revealed research trends and hotspots in refractory angina. Scientists focused on diseases related to refractory angina, such as unstable angina, myocardial ischemia, acute myocardial infarction, and heart failure. Recently, Kawasaki disease has gained attention as a prominent topic. Extensive clinical trials were conducted, and patient benefits, quality of life, and survival prognosis have always been emphasized in this field. The experimental hotspots and research hotspots in this field are both focused on the treatment of refractory angina. Scientists initially focused on medical therapy and angiogenesis. The ECS guidelines recommended the first-line treatment drugs as blocker and/or calcium channel blocker using alone or in combination to control angina, and long-acting nitrates, Ivabradine, Nicorandil, Ranolazine or Trimetazidine can be used as second-line personalized therapy (18, 28). However, clinical studies have failed to identify highly specific anti-angina drugs (29), and the effect of medical therapy for refractory angina is not ideal, though the medical therapy is an essential basic treatment for refractory angina. Angiogenesis, including PCI and plain old balloon angioplasty (POBA), exhibited positive effects in reducing angina frequency, improving quality of life and reducing the risk of adverse cardiovascular events (30–33). But patients with intractable angina pectoris may still experience angina pectoris symptoms after angiogenesis due to distal vascular disease, vasospasm, negative emotion, or other unknown reasons (28). Subsequently, scientists explored auxiliary treatment methods for refractory angina such as spinal cord stimulation and EECP. In 1987, Murphy et al. first reported that spinal cord stimulation can be used to treat refractory angina (34). In recent years, multiple clinical trials and large-scale meta-analysis have demonstrated significant therapeutic effects of spinal cord stimulation surgery. Patients treated with spinal cord stimulation surgery have a higher quality of life, and the long-term follow-up effect is significant (18, 35, 36). EECP is a non-invasive assistive circulatory device that helps increase cardiac blood flow, improve coronary artery supply, reduce cardiac ejection resistance, reduce myocardial oxygen consumption, and thus alleviate and eliminate symptoms of angina. EECP proved to be safe and effective in treating refractory angina through a large number of clinical trials (37–39). Besides, research has found that the relief rate of clinically refractory angina can reach as high as 72%, and more than half of RA patients have not experienced any recurrence of angina in this study (40). In recent years, stem cell therapy and coronary sinus reducer emerged as new treatment hotspots. CD34⁺ and CD133⁺ cell therapies are commonly seen in stem cell therapy. Although autologous stem cell therapy exhibited promise in reducing angina attacks and adverse cardiovascular events (17, 41), further investigation is necessary to ascertain its effectiveness for refractory angina (42). The coronary sinus reducer, initially proposed and applied to surgical procedures in the 1940s and 1950s (43, 44), then abandoned in the 1960s with the rise of bypass surgery, regained attention as a potential treatment option. Clinical trials confirmed its feasibility and safety (45–47), but additional research is needed to comprehend its mechanism of action, long-term benefits and individual adaptability (48).

Most of the treatment methods mentioned earlier, such as EECP and stem cell therapy, necessitate repetitive applications to maintain lasting effects, with coronary sinus reducer therapy being the only option that may exert permanent, rather than temporary, effects (49). Additionally, internal mammary artery occlusion therapy is currently garnering significant attention as a promising method with potential permanent effects (50). However, due to the limited number of literature on related topic words, this treatment method was not reflected in the data obtained in this study. Nonetheless, ample evidence suggests that the blood supply to the heart can be supplemented by non-coronary collateral circulation, which originates from surrounding arteries (51). One of the vital thoracic branches that establish connections with the heart is the pericardiophrenic branch of the internal mammary artery (52). The principle behind internal mammary artery occlusion is to ligate the internal mammary artery, creating a local hypertensive environment and increasing perfusion pressure in the channel leading to the heart (53). Meanwhile, angiogenic growth factors are applied to the internal mammary artery to enhance the development of new collateral branches, thereby promoting improved blood flow to the heart (54). Researches had shown that internal mammary artery occlusion can increase the blood supply of extracardiac ipsilateral coronary arteries, leading to reduced ischemia in dependent myocardial regions and alleviating angina symptoms in patients (55, 56). Although internal mammary artery occlusion has not yet gained widespread recognition as a standard treatment method and requires further evidence-based research, it is considered a novel approach for refractory angina or a potential alternative to coronary sinus reducer therapy due to its significant anti-myocardial ischemia effect (57). Overall, the treatment of refractory angina is still in the exploratory stage, and further studies are required to establish authoritative guidelines and evaluate long-term efficacy and cost-effectiveness.

Reference co-citation analysis identified five key publications that made significant contributions to the development of refractory angina. Eddicks in 2007 conducted the first placebo-controlled randomised study on thoracic spinal cord stimulation confirming that it can alleviate symptoms in patients with refractory angina (21). Taylor's meta-analysis in 2009 on spinal cord stimulation demonstrated its safety and efficacy as an alternative treatment method (25). McGillion, in 2012, led the Canadian Cardiovascular Society and the Canadian Pain Society in jointly publishing a practical guideline for the management of patients with refractory angina, provided evidence-based treatment recommendations for refractory angina (24). Subsequently, a guideline for the management of stable coronary artery disease published by the European Society of Cardiology in 2013, outlined treatment options for stable coronary artery disease and included recommendations for refractory angina (1). Lastly, Verheye's 2015 clinical trial on the coronary sinus reducer confirmed its effectiveness in improving symptoms and quality of life (9). These five articles serve as significant milestones in refractory angina research, especially three trial articles, aligning with recent research hotspots. However, the treatment of refractory angina necessitates further investigation, and the development of authoritative guidelines remains limited. High-quality randomized controlled trials, long-term evidence of benefits, and cost-effectiveness studies are crucial to advancing the field. This research aims to support clinical doctors and cardiovascular disease patients in enhancing their understanding of refractory angina.

This study has several limitations. Firstly, the research content is limited to the analysis of literature published between 2003 and 2022, excluding earlier publications. Additionally, the analysis focused solely on English-language papers, potentially overlooking relevant research published in other languages. Furthermore, the study solely relied on the SCI-E database of WOS, which restricts the range of literature types considered. Secondly, the CiteSpace software utilized in the analysis has certain limitations, such as a network size limit of 500, which may impact the analysis results. Despite these limitations, this study offers a comprehensive analysis and summary of achievements in the field of refractory angina over the past two decades, contributing to scholars' understanding of its development status.

Refractory angina, a condition characterized by persistent angina symptoms despite optimal medical therapy and revascularization, presents ongoing challenges in the field of cardiovascular medicine. While advancements have been made in understanding the underlying mechanisms and exploring potential treatment options, the outlook for refractory angina remains complex and multifaceted. In recent years, there have been notable developments in the field of refractory angina research. Scientists and clinicians have focused on expanding their knowledge of the disease, identifying novel therapeutic approaches, and evaluating their efficacy. This has led to the emergence of new treatment modalities and a better understanding of the disease process. One promising avenue of research lies in the exploration of alternative treatment methods beyond conventional medical therapy and revascularization such as spinal cord stimulation, EECP, and coronary sinus reducer, showing promise in the management of refractory angina. Advancements in regenerative medicine, particularly stem cell therapy, have also garnered attention in the field of refractory angina. In addition, some emerging methods for treating myocardial ischemia, such as internal mammary artery occlusion, can also try to treat refractory angina. Despite these advancements, it is important to acknowledge the remaining challenges in the management of refractory angina. The heterogeneity of the patient population and the complex underlying pathophysiology contribute to the variability in treatment response and outcomes. There is a need for further research to better understand patient selection criteria, optimal timing and sequencing of interventions, and long-term outcomes. Furthermore, the development of comprehensive and evidence-based guidelines for the management of refractory angina is crucial. Currently, treatment decisions are often based on expert opinion and individualized patient considerations. Establishing standardized guidelines will provide clinicians with a framework to navigate the complexities of treatment selection and optimize patient care.