Balancing Beats and Bleeding: The Evolving Landscape of Atrial Fibrillation and Anticoagulation in the Past Two Decades

Abstract

Background

Anticoagulation has been the cornerstone for stroke prevention in patients with atrial fibrillation (AF). This study aims to describe the research trends and research hotspots in anticoagulation and AF.

Methods

Publications on AF and anticoagulation were retrieved from the Web of Science Core Collection from 2004 to 2024 for bibliometric analyses.

Results

A total of 12,551 articles were retrieved. The number of publications increased each year, reaching its peak in 2021. The United States has the largest number of published articles (country appearances, 18,181), followed by Italy (6525) and Japan (6,235). The most productive institutions were Harvard University (658), McMaster University (570), and the University of Birmingham (550). LIP GYH was the most prolific author, with 707 articles published. ‘Circulation’ has the highest H-index (77), followed by the ‘Thrombosis and Hemostasis’ (73), ‘Journal of the American College of Cardiology’ (72). The keyword analysis revealed that the research focused on warfarin, stroke, dabigatran, direct oral anticoagulants, rivaroxaban, antithrombotic therapy, prevention, safety, apixaban, and venous thromboembolism.

Conclusions

Research in AF and anticoagulation has expanded rapidly. Coagulation contact phase (such as coagulation factor XI and XII) inhibitors have emerged as a promising future therapeutic target, and there is a critical need for global collaboration to validate these strategies across diverse populations.

Keywords

atrial fibrillation anticoagulation bibliometric analysis;coagulation factor XII;stroke

Introduction

Atrial fibrillation (AF) is the most common arrhythmia and affects the health of millions of people worldwide.¹ Its prevalence and incidence increase significantly with age.^2,3 AF is an important independent risk factor for thromboembolic events, especially stroke, which has prompted anticoagulation therapy to become a core component of AF management strategies.^4,5 Oral anticoagulation therapy, such as vitamin K antagonists or direct oral anticoagulants (DOACs), remains an effective treatment for stroke prevention in patients with AF.^6,7 Recently, the use of DOACs, including the direct thrombin inhibitor dabigatran and activated factor X (Xa) inhibitors such as apixaban, edoxaban, and rivaroxaban, has rapidly increased in clinical practice.⁸ The effectiveness and safety of DOACs in preventing AF-related thromboembolic events have been extensively studied.^9,10 In the past two decades, research on AF and anticoagulation has developed rapidly, but a comprehensive bibliometric analysis is still lacking. Therefore, summarizing and sorting the research progress in this field will help to provide suggestions for better prevention and treatment of AF and reduce the occurrence of related complications. By analyzing the bibliometric characteristics of AF and anticoagulant therapy in the past 20 years, this study aims to (i) analyze the development history, difficult problems, and research hotspots in the field of AF and anticoagulation and (ii) reveal the cutting-edge research trends of AF and anticoagulation in the past two decades.

Methods

Search Strategy

The first key step in bibliometric research is to construct an effective search query that can retrieve as many articles as possible and exclude irrelevant ones. The search strategy of Web of Science Core Collection (WoSCC) (Supplementary Table 1) included all fields with the keywords “Atrial fibrillation” and “Anticoagulation”. Journal articles related to AF and anticoagulation published over the last 20 years (March 24, 2004, to March 24, 2024) were retrieved on March 24, 2024. The search results were limited to articles and review articles published between 2004 and 2024, and the language was limited to English. Article types such as conference abstracts, corrections, and letters were excluded.

Validation

The validation of the search queries was based on two approaches. In the first approach, 100 randomly selected retrieved articles were reviewed for validation to ensure that they fit the scope of AF and anticoagulation. This approach was adopted to eliminate false-positive results by excluding articles focusing on other diseases and therapies.¹¹ In the second approach, the number of citations for the top 5 highly cited authors obtained from the extracted data was compared with the number of citations obtained from their Google Scholar profiles. Comparisons were made via the Pearson correlation test (Supplementary Table 2). The results indicate that the correlation coefficient between the two is positive and that there is a significant and strong correlation, which proves the validity of the search query.¹²

Bibliometric Indicators

Bibliometric data were extracted from each selected article. Information such as journal name, journal impact factor, publication year, country, affiliated unit, keywords, citing references, and cited references was extracted from the RIS, BibTeX, and TXT formats.

Bibliometric information from RStudio, CiteSpace 6.3 R1, and VOSviewer 1.6.20 was used for bibliometric analysis.

The retrieved literature was imported into the CiteSpace program to generate visualization diagrams. In network visualization maps, network density is a metric that can indicate the strength of cooperation or relevance between nodes, which is automatically calculated by the software. The value ranges from 0 to 1, with a higher network density indicating greater cooperation or relevance among nodes. For keyword clustering, repeated dichotomy was selected as the clustering method to create mountain visualizations. The retrieved literature was also exported to the VOSviewer program to create author collaboration network diagrams. The strength of author collaboration was represented as total link strength, which is automatically provided by VOSviewer. The influence of authors in the field of AF and anticoagulation research was assessed via metrics such as the H-index, G-index, and number of published articles. R programs were employed to determine the growth and quantitative distribution of the literature publication and citation data. Visual indicators such as the H-index and total citations were used to assess productive journals and influential articles.¹³ For co-authorship analysis at the country and institutional level, the “full counting” method was applied, where each participating country or institution receives full credit (a count of 1) for a collaborative publication. The H-index measures the number of published articles and their frequency of being cited and is used to evaluate the cumulative impact of a journal’s publications.

Results

Literature Publication and Citation

The past two decades published 12,551 papers (Supplementary Figure 1), primarily comprising 9,657 research articles (76.9%) and 2,894 review articles (23.1%) (Figure 1A). The number of literature had a steady growth, with particularly notable since 2018. The average annual number of publications consistently surpassed 1,000 articles, peaking at 1,357 articles in 2021 after reaching 1,285 in 2020 Figure 1B. The field’s citation impact appeared to peak in 2007, when the mean total citation per article was 120.36 and the mean total citation per year peaked at 6.69, marking the highest point in nearly 20 years Figure 1C. In terms of geographic trends, the literature in the top five countries has grown rapidly over the past decade, driven in large part by the largest increase in the United States (Figure 1D).

Productive Journals and Influential Articles

The double plot overlay in Figure 2A shows the distribution of relationships between journals. Specifically, it highlights two main connecting paths: one for research published in the ‘Medicine, Medical, Clinical’ cited in the journal ‘Molecular, Biology, Genetics’ and the other for research published in the ‘Medicine, Medical, Clinical’ cited in the journal ‘Health, Nursing, and Medicine’. In terms of scholarly impact, journals such as CIRCULATION and EUROPEAN HEART JOURNAL received a high number of citations, with 31,481 and 21,290 citations, respectively (Figure 2B). The CIRCULATION and JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY journal ranked as the most influential journal Figure 2C–D. At the individual article level, Supplementary Table 3 lists the top 10 most-cited papers, among which a 2009 paper by Professor Connolly et al in the NEW ENGLAND JOURNAL OF MEDICINE stands out with 8,160 citations.

Distribution of Authors

Figure 3A shows the annual publications of leading authors, with LIP GYH ranking first. The G-index is an indicator highlighting highly-cited papers by determining the highest rank where total citations exceed the rank squared. Figure 3B highlights the top 10 authors based on these metrics. LIP GYH takes the lead with an H-index of 99 and a G-index of 192, whereas the H-index of the other nine authors ranges from 35 to 47, and their G-index ranges from 57 to 94. Figure 3C depicts the collaboration between the authors, highlighting the strong collaboration between LIP GYH and the other authors. This individual prominence is also reflected in publication volume (Figure 3D), where the top ten authors collectively contributed more than 1,500 papers, with the top three authors alone accounting for over 900 of these publications. Notably, LIP GYH led with 707 publications and accounted for 46.4% of the output from the top 10 authors, followed by DEIRDRE A LANE with 120 (7.9%), and CAMM AJ with 97 (6.4%) (Table 1).

Table 1.

The Top 10 Authors’ Publication in Atrial Fibrillation and Anticoagulation

Rank	Authors	Articles	Articles fractionalized
1	LIP GYH	707	131.43
2	Deirdre A Lane	120	7.03
3	CAMM AJ	97	17.10
4	CONNOLLY SJ	93	8.60
5	YAMASHITA T	91	10.78
6	KORETSUNE Y	84	5.20
7	LOPES RD	84	9.36
8	OKUMURA K	84	7.54
9	DE CATERINA R	83	15.42
10	LI X	80	9.46

Distribution of Countries and Institutions

Figure 4A illustrates the global distribution of published research in this area, including literature from more than 28 countries. United States had the largest number of published articles (country appearances, including international collaborations,18,181), followed by Italy (6,525), Japan (6,235), China (6,120), and the United Kingdom (5,321) (Figure 4B).

This high productivity is coupled with a central role in international cooperation, as research is focused mainly on the United States. Reflecting this collaborative trend, the number of papers published with multinational cooperation (Figure 4C) is much greater than that published in single countries, and they are more biased toward multinational cooperation. Figure 4D further visualizes the international cooperation between the top five countries in the field, with the United States holding a large position, followed by the United Kingdom. Moving from the national to the institutional level, Harvard University, McMaster University, the University of Birmingham, Aalborg University, and the University of Liverpool are in core positions Figure 4E. They actively engage in multi-party cooperation, playing pivotal roles within the overall collaborative network. This collaborative strength is mirrored in their productivity, as Figure 4F shows that the top 10 institutions by number of published papers on AF and anticoagulation from 2004 to 2024 are: Harvard University (658), McMaster University (570), and the University of Birmingham (550), among others.

Keyword Analysis

Keyword analysis reveals the thematic structure and evolution of the field. The keywords “atrial fibrillation,” “warfarin,” and “stroke” appear with high frequency Figure 5A–B. A total of 177 keywords were extracted, among which 13 appeared more than 1,000 times, 27 appeared more than 500 times, and 73 appeared more than 200 times. Supplementary Table 4 presents the co-occurrences of the top 10 keywords, including Warfarin (4,599), Stroke (3,841), and Dabigatran (2,202) as the most frequent.

Figure 5C divides 177 keywords into 14 thematic clusters. The red-colored cluster centers on efficacy and safety, and is closely associated with stroke. The green-colored area mainly involves predicting stroke and antiplatelet therapy. The purple-colored area, centered around catheter ablation and left atrial appendage occlusion, enriches the research dimensions of AF and anticoagulation therapy. Regarding the field’s evolution, Figure 5D shows the citation bursts from 2004 to 2024, which help identify trending topics and cutting-edge directions. From 2004 to 2014, direct thrombin inhibitors were the strongest keywords. Figure 5E–F provides a summary heatmap and clusters that illustrates a high-density cluster comprising stroke, warfarin, DOACs, bleeding, rivaroxaban, and dabigatran.

Discussion

Analysis of Characteristics of the Studies

Our analysis reveals a substantial upward trend in AF and anticoagulation research over the past two decades. The key drivers of this growth since 2010 appear to be the recognition of warfarin’s limitations and the emergence of DOACs, offering more effective thromboprophylaxis.¹⁴ Geographically, the United States has maintained a dominant position in publications and international cooperation. This dominance is reflected in the fact that five of the top 10 most productive institutions are from the US, including the top-ranked Harvard University. European nations, particularly Italy, the UK, and Germany, also form a core collaborative network. However, our analysis also highlights the rapid emergence of research from Asia, with Japan (3rd) and China (4th) being the top contributors. This surge, especially from China reflects the growing clinical burden of AF in Asia and an increasing focus on guideline implementation and evidence generation within these specific populations.

Historical Evolution of AF and Anticoagulation

Keyword analysis reveals significant insights into the historical evolution of AF and anticoagulation research over time. The analysis delineates the formation of 14 clusters on the basis of keyword clustering.

From 2004 to 2011 no more than 300 papers published annually, and keywords focused mainly on anticoagulant therapy, VTE, and deep vein thrombosis. This is likely attributable to the fact that atrial fibrillation is the leading cause of cardioembolic stroke in adults,¹⁵ and that anticoagulant therapy has demonstrated efficacy in preventing AF-associated ischemic stroke and thromboembolism.^16,17 Most studies evaluated outcomes such as ischemic or hemorrhagic stroke and systemic embolism to compare the efficacy and safety of warfarin with other anticoagulant agents. During this period, anticoagulation relied primarily on vitamin K antagonists such as warfarin.¹⁸ However, warfarin’s narrow therapeutic index, variable dose-response, and the need for strict INR monitoring limited optimal management. These limitations prompted efforts to optimize oral anticoagulation strategies.^19,20

Notably, in 2010, the refinement of clinical risk stratification tools further advanced stroke prevention strategies for atrial fibrillation. The development of the CHA₂DS₂-VASc score proposed by Lip et al provided a simplified yet powerful tool for evaluating stroke and thromboembolic risks in patients with AF.²¹ Similarly, the HAS-BLED score established by Pisters et al allowed clinicians to assess bleeding risks associated with anticoagulant therapy.²² These complementary risk models have greatly influenced current clinical guidelines and promoted individualized management of anticoagulation in AF.^6,23-25

Furthermore, this period witnessed a paradigm shift driven by landmark randomized controlled trials. The RE-LY trial (2009) demonstrated that dabigatran reduced the risk of stroke or systemic embolism compared with warfarin.²⁶ In 2011, both the ARISTOTLE and ROCKET AF trials confirmed the superiority or non-inferiority of apixaban and rivaroxaban, respectively, compared to warfarin.^27,28 Collectively, these studies demonstrated the significant efficacy and safety of DOACs in patients with atrial fibrillation, establishing them as a compelling alternative to traditional anticoagulation.²⁹ These pivotal studies not only fueled a surge in annual publication volume but also catalyzed the update of clinical practice guidelines worldwide.^30-33

In recent years, emphasis has shifted toward individualized anticoagulation strategies, particularly in specific regional and high-risk populations. Our bibliometric analysis demonstrated a rapid increase in AF-related research from Asia, with Japan and China ranking among the leading contributors. This trend reflects the growing epidemiological burden of AF in Asia, driven largely by population aging and distinct risk profiles.^34,35 Despite the substantial need for stroke prevention, registry data from Korea and China have documented significant underuse of warfarin, especially in community settings.^36,37 Concerns regarding bleeding, particularly intracranial hemorrhage (ICH), and challenges in INR control have contributed to these treatment gaps.³⁸ This so-called ‘Asian paradox’ has been partially attributed to population-specific pharmacogenomic profiles.^39,40 It is well-established that polymorphisms in genes like VKORC1 and CYP2C9 are distributed differently in Asian populations, including in Han Chinese patients, leading to higher warfarin sensitivity and a narrower therapeutic range.^39,40 The introduction of DOACs, therefore, had particular clinical relevance in this region. Regional trials such as J-ROCKET AF,⁴¹ together with East Asian subgroup analyses from global studies,⁴² established population-specific evidence. Subsequent real-world registries consistently demonstrated improved safety profiles,⁴³ notably reduced intracranial hemorrhage, supporting a gradual shift toward DOAC-based strategies.³⁶ In summary, research originating from Asia has not only addressed critical local evidence gaps but has also provided indispensable insights into pharmacogenomics and individualized anticoagulation strategies that are of global relevance.

Research Hotspots and Trends in AF and Anticoagulants

Our study identified warfarin, stroke, and dabigatran as the most frequent keywords in AF and anticoagulation research, reflecting sustained attention to drug selection, efficacy, and safety. We revealed that the current research hotspots in AF and anticoagulation are focused on three aspects: (1) The clinical paradigm shift from warfarin to DOACs is now firmly established as the predominant standard of care; (2) the safety of anticoagulant therapy, particularly regarding the management of bleeding risks, remains a persistent clinical challenge and (3) the contact phase of coagulation is a possible new target for anticoagulant therapy.

The transition from warfarin to DOACs is now firmly embedded in clinical practice.⁴⁴ Large-scale trials have demonstrated the superiority of DOACs in stroke prevention for AF, although bleeding remains the principal complication. While anticoagulation therapy is unequivocally effective for stroke prevention in atrial fibrillation, achieving an optimal balance between thromboembolic protection and bleeding risk remains particularly challenging in patients with polypharmacy⁴⁵ and multimorbidity.⁴⁶ In high-risk populations—such as those with advanced chronic kidney disease,⁴⁷ cardiorenal interactions,⁴⁸ or post-valve replacement status—the risk-benefit profile of DOAC therapy requires careful individualized assessment.⁴⁹ Meanwhile, emerging evidence highlights the role of molecular mechanisms involved in cardiac remodeling in cardiovascular diseases, which may also contribute to the development of atrial fibrillation.⁵⁰ Therefore, continuous evaluation of both thrombotic and bleeding risks is essential to optimize outcomes. Although next-generation anticoagulants have expanded therapeutic options, bleeding management remains a central component of comprehensive AF care.

The intrinsic (contact) pathway of coagulation, primarily involving factors XI (FXI) and XII (FXII), appears to contribute predominantly to thrombus propagation rather than physiological hemostasis. Given that a deficiency of FXI/FXII is associated with reduced thrombosis and a minimal bleeding tendency, targeting this pathway may allow for the partial separation of thrombosis from hemostasis. Accordingly, the contact phase has emerged as a promising therapeutic target.^51,52 Our research identified a clear trend toward coagulation contact phase factors (FXI and FXII) as novel therapeutic targets. These targets aim to ‘uncouple’ thrombosis from hemostasis, potentially providing robust antithrombotic protection with reduced bleeding risk.⁵³ Asundexian, by specifically inhibiting the intrinsic coagulation pathway, demonstrated a superior bleeding safety profile compared to apixaban both theoretically and in early Phase II clinical trials such as PACIFIC-AF, holding the promise of breaking the “therapeutic impasse” for elderly patients and those at high risk of bleeding.⁵⁴ However, with the release of data from large-scale Phase III clinical trials, this field faces new challenges and a pivotal turning point. The recently published OCEANIC-AF study revealed that while Asundexian significantly reduced severe bleeding events, it failed to meet the non-inferiority criteria for efficacy in preventing stroke or systemic embolism, leading to the trial’s early termination.⁵⁵ Taken together, while FXIa inhibitors confirm the mechanistic advantage of a reduced bleeding risk, current dosing strategies have not yet demonstrated sufficient efficacy to replace established DOAC regimens. Therefore, future research should focus on defining specific high-bleeding-risk populations and optimizing dosing strategies, rather than pursuing broad therapeutic substitution.

Strengths and Limitations

We first comprehensively maps two decades of global research on atrial fibrillation and anticoagulation, highlighting the transition from warfarin to DOACs, evolving safety considerations, and emerging interest in FXI/FXII inhibition as future therapeutic directions. It is important to acknowledge certain limitations inherent in this study. First, the reliance solely on the WoSCC may lead to the omission of relevant documents, as other databases encompass different journals and document types. Furthermore, by restricting the language to English, there is a possibility of overlooking research outcomes published in other languages, particularly in non-English-speaking regions where significant contributions to the field may originate. The inclusion of other databases, such as Scopus, Embase, or regional databases, would likely alter the productivity and citation rankings and enhance the visible impact of contributions from Asia. This broader inclusion might also reveal distinct regional research hotspots and perspectives not captured in the current analysis.

Conclusion

This bibliometric analysis showed a rapid, global expansion of research in AF and anticoagulation over the last 20 years, driven by the pivotal shift from warfarin to DOACs. Our findings provide a comprehensive map of the field’s evolution and highlight several actionable insights into its future trajectory. We demonstrate that the central research question has evolved from efficacy (DOACs vs. warfarin) to safety and optimization, suggesting that future research should prioritize bleeding risk stratification and management. Furthermore, our analysis identified a clear trend toward coagulation contact phase factors (FXI and FXII) as novel therapeutic targets. These inhibitors represent the next frontier in anticoagulant development, potentially offering antithrombotic protection with a reduced bleeding risk. Validating these novel strategies and optimizing safety in complex patients will require greater global collaboration to ensure findings are applicable across diverse populations, including those in rapidly contributing regions like Asia.

Supplemental Material

Supplemental Material - Supplemental Material for Balancing Beats and Bleeding: The Evolving Landscape of Atrial Fibrillation and Anticoagulation in the Past Two Decades

Supplemental Material for Balancing Beats and Bleeding: The Evolving Landscape of Atrial Fibrillation and Anticoagulation in the Past Two Decades by Boshui Huang, Chenhao Ouyang, Kaiyan Fan, Yifan Wu, Ran Mo, Wenli Gu, Jing Zhang, Jun Zhang, Xiang Gu, Wengen Zhu, Yuling Zhang, Jingfeng Wang, Yangxin Chen, Wenting Wang, Xiao Liu by Clinical and Applied Thrombosis/Hemostasis.

Footnotes

ORCID iDs

Wengen Zhu

Xiao Liu

Author Contributions

B.S-H, Y.F-W: Writing - original draft, Supervision. R-M: Methodology, Formal analysis, Data curation, Visualization, Software. K.Y-F, C.H-OY: Contributed to revision response, resubmission manuscript polishing & follow-up submission administration. W.L-G, J-Z, Jun-Z, X-G, W.G-Z, Y.L-Z, J.f-W, Y.X-C: Data Curation, Writing - Review & Editing. X-L and W.T-W: Conceptualization, Methodology, Writing - Review & Editing, Supervision, Project administration.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Academic Enhancement Support Program of Hainan Medical University (XSTS2025095); Hainan Province Clinical Medical Center; South Sea New Star Project of Hainan Province of China (NHXX-WJW-2025011); Hainan Provincial Natural Science Foundation of China (326MS0414).

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data Availability Statement

The datasets generated and analysed during the current study are available at the Web of Science, .

Supplemental Material

Supplemental material for this article is available online.

Appendix

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