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Review Article
Novel anticoagulants in the management of atrial fibrillation: A comprehensive comparative analysis
expand article infoMazen M. Jwaid‡, Mohammed J. Alwan§, Isam Ihsan‡, Maher M. Jwaid§, Yasir F. Muhsin‡, Hany A. Al-hussaniy|#, Mohammed K. Al iraqi |
‡ University of Baghdad, Baghdad, Iraq
§ Al-Hadi University College, Baghdad, Iraq
| Dr. Hany Akeel Institute, Iraqi Medical Research Center, Baghdad, Iraq
¶ Damascus University, Damascus, Syria
# Bilad Alrafidain University College, Baqubah, Iraq

Corresponding author: Mazen M. Jwaid ( mazen.m@copharm.uobaghdad.edu.iq )

Academic editor: Plamen Peikov
© 2024 Mazen M. Jwaid, Mohammed J. Alwan, Isam Ihsan, Maher M. Jwaid, Yasir F. Muhsin, Hany A. Al-hussaniy, Mohammed K. Al iraqi .
This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Citation: Jwaid MM, Alwan MJ, Ihsan I, Jwaid MM, Muhsin YF, Al-hussaniy HA, Al iraqi MK (2024) Novel anticoagulants in the management of atrial fibrillation: A comprehensive comparative analysis. Pharmacia 71: 1-6. https://doi.org/10.3897/pharmacia.555.e113097
Open Access

Abstract

Background: Atrial fibrillation (AF) stands as the most prevalent cardiac arrhythmia, with associated risks of stroke and systemic thromboembolism. While vitamin K antagonists, specifically warfarin, have historically been the mainstay for stroke prevention in AF, they come with inherent limitations.

Aim: This review seeks to offer a comprehensive analysis of the efficacy, safety, and clinical advantages of novel oral anticoagulants (NOACs) compared to traditional warfarin in AF management.

Method: A meticulous examination of pivotal clinical trials, meta-analyses, and recent research publications was conducted. Four NOACs, namely Dabigatran, Rivaroxaban, Apixaban, and Edoxaban, were compared against warfarin, focusing on parameters like stroke prevention, risk of bleeding, patient compliance, and drug interactions.

Results: NOACs, as a collective group, demonstrated a comparable or superior efficacy profile in stroke prevention compared to warfarin. They also showcased a more predictable therapeutic range, fewer drug and food interactions, and, in certain cases, a better safety profile. The challenges associated with frequent monitoring and dose adjustments inherent to warfarin therapy were notably absent with NOACs.

Conclusion: NOACs present a robust alternative to warfarin for AF management, demonstrating comparable efficacy and, in certain aspects, heightened safety and practicality. However, the choice of anticoagulant should remain individualized, taking into account patient-specific factors and clinician expertise.

Keywords

Atrial fibrillation (AF), Novel oral anticoagulants (NOACs), Dabigatran, Apixaban, Edoxaban

Introduction

Atrial fibrillation (AF) stands as a paramount challenge in cardiological management due to its association with increased morbidity and mortality (Benjamin et al. 1998; Al-Kelaby et al. 2023). As the most common clinical cardiac arrhythmia, AF is characterized by rapid and irregular heart rhythms, which can lead to complications such as stroke and heart failure (Caramelli et al. 2022).

Historically, vitamin K antagonists, prominently warfarin, have been employed as the principal agents for stroke prevention in AF patients (Ruff et al. 2016; Mahmood et al. 2023; Sood et al. 2023). While effective, their use has been challenged by various factors such as unpredictable pharmacokinetics, potential food and drug interactions, and the constant need for monitoring the international normalized ratio (INR) (Pandya and Bajorek 2017; Situ et al. 2023). These challenges have spurred the scientific community’s quest for newer, more efficient, and safer alternatives.

Emerging from this need, the last decade witnessed the development and clinical adoption of novel oral anticoagulants (NOACs). Touted for their potential in offering a balanced profile of efficacy, safety, and convenience, NOACs such as Dabigatran, Rivaroxaban, Apixaban, and Edoxaban have revolutionized anticoagulant therapy in AF (Nielsen et al. 2022; Altalebi et al. 2023).

Given the burgeoning interest and the clinical significance of NOACs, this comprehensive review endeavors to explore the depth and breadth of their role in AF management, drawing comparisons with the traditional stalwart, warfarin.

Materials and methods

A systematic review of the literature was conducted, focusing on comparative analyses of NOACs and warfarin in the management of AF.

Data sources and searches

A comprehensive literature search was undertaken using databases like PubMed, Medline, Scopus, and Google Scholar. The search strategy incorporated terms such as “atrial fibrillation”, “NOACs”, “warfarin”, “anticoagulation”, and “stroke prevention” (Eikelboom et al. 2011).

Study selection

Only randomized controlled trials (RCTs), meta-analyses, and comprehensive reviews published in English between 2010 and 2022 were considered. Studies were selected based on their relevance to the topic, sample size, and the quality of data presented.

Data extraction

Data pertaining to the efficacy, safety, patient compliance, and drug interactions of NOACs and warfarin were extracted. Specific endpoints like stroke prevention, systemic embolism, major bleeding events, and all-cause mortality were noted.

Results

Our meticulous review of the literature provided a wealth of data, systematically evaluating the therapeutic outcomes associated with NOACs and their comparison with warfarin in AF management.

Efficacy in stroke prevention

All four NOACs – Dabigatran, Rivaroxaban, Apixaban, and Edoxaban – demonstrated a robust profile in preventing stroke events compared to warfarin. In the RE-LY trial, Dabigatran, at a dose of 150mg twice daily, was associated with lower rates of stroke and systemic embolism than warfarin (Gregory 2016). Similarly, the ROCKET-AF trial found that Rivaroxaban was non-inferior to warfarin in preventing stroke or systemic embolism among patients with AF (Ruff et al. 2014; Al-Kuraishy et al. 2022a).

Apixaban’s significant reduction in stroke or systemic embolism events compared to warfarin was another notable outcome from the ARISTOTLE trial[9]. Edoxaban’s performance in the ENGAGE AF-TIMI 48 trial reinforced the same, showing it was non-inferior to warfarin in terms of the primary safety outcome and superior in preventing hemorrhagic strokes (González-Pérez et al. 2022).

Risk of bleeding

Bleeding risks have always been a concern with anticoagulant therapy. The comparative studies between NOACs and warfarin yielded varying results. Apixaban and Edoxaban both demonstrated a statistically significant reduction in major bleeding events compared to warfarin (Gencer et al. 2022). In contrast, Dabigatran (at the 150mg dose) and Rivaroxaban showed similar major bleeding rates as warfarin, but with a reduced risk of life-threatening or intracranial hemorrhage (Alkuraishy et al. 2017; Själander et al. 2018; Waranugraha et al. 2021).

Patient compliance

The predictable therapeutic profile, reduced drug and food interactions, and the non-necessity of regular INR monitoring positioned NOACs favorably in terms of patient compliance. A cohort study revealed that patients on NOACs had a higher persistence rate at one year compared to those on warfarin (Mueck et al. 2014). This could translate to better therapeutic outcomes, given the direct relationship between adherence to medication and its efficacy.

Drug interactions

Warfarin’s extensive drug and food interactions have been a significant limitation in its clinical use. NOACs, by and large, demonstrated fewer such interactions. However, certain drugs like Rivaroxaban did show significant interactions with agents like ketoconazole or ritonavir, necessitating caution in co-prescription (Al-Kuraishy et al. 2022b).

Renal implications

Dabigatran’s reliance on renal excretion necessitates dose adjustments in patients with impaired renal function (Stangier 2008; Austin et al. 2018). While Rivaroxaban, Apixaban, and Edoxaban also undergo renal clearance, their dependence is comparatively lower, making them a preferable option in cases of moderate renal impairment (Raghavan et al. 2009; Parasrampuria et al. 2015).

Economic evaluation

While NOACs are generally pricier than warfarin, a cost-effectiveness analysis that considered factors like monitoring costs, complications, and quality-adjusted life years (QALYs) suggested that NOACs could be cost-effective in specific populations, especially when the indirect costs of warfarin therapy, such as regular clinic visits and dietary restrictions, were accounted for (Wang et al. 2014).

Antidotes and reversal agents for novel anticoagulants

One of the challenges that arose with the introduction of novel oral anticoagulants (NOACs) in managing atrial fibrillation was the lack of specific antidotes or reversal agents for these drugs. Unlike the traditional anticoagulant warfarin, which can be reversed with vitamin K or fresh frozen plasma, NOACs presented a new paradigm where immediate reversal, especially in emergencies, became a concern (Dobesh and Fanikos 2015; Al-Hussainy et al. 2022).

Dabigatran (Pradaxa)

Dabigatran, a direct thrombin inhibitor, was one of the first NOACs introduced. Its antidote, Idarucizumab (Praxbind), is a humanized monoclonal antibody fragment (Fab) that binds specifically to dabigatran, neutralizing its anticoagulant effect (Connolly et al. 2017; Jones et al. 2023). This has been a crucial development, especially for patients needing urgent surgery or those who present with uncontrolled bleeding while on dabigatran (Glund et al. 2014; Alzobaidy et al. 2021; Al-Hussaniy et al. 2022b).

Factor Xa inhibitors

Factor Xa inhibitors include rivaroxaban (Xarelto), apixaban (Eliquis), and edoxaban (Lixiana/Savaysa). The primary reversal agent for these drugs is Andexanet alfa (Andexxa). It is a recombinant, modified Factor Xa molecule that acts as a decoy receptor, binding the Factor Xa inhibitors, and preventing them from exerting their anticoagulant effect (Powell et al. 2019; Al-Hussaniy et al. 2023a, b).

Another approach has been the use of Ciraparantag (PER977), which reverses anticoagulation from both factor Xa inhibitors and direct thrombin inhibitors by binding to these drugs directly, making them unavailable to bind to their target enzymes (Ansell et al. 2021; Al-Hussaniy et al. 2022a; Awad et al. 2022; Salim Mahmood et al. 2022).

Current limitations

While these antidotes represent significant advancements, they are not without limitations. Their high cost, availability, and the need for specialized hospital storage can be limiting factors. Additionally, while they can effectively reverse anticoagulation, the restoration of hemostasis is not instantaneous, which can be a crucial factor in life-threatening bleeds (Al-hassany et al. 2021; Al-Kuraishy et al. 2022c).

Future prospects

Research is ongoing to discover more effective and affordable antidotes for NOACs, especially as their use becomes more widespread. There is also interest in developing reversal agents that can act on multiple pathways, offering a more universal approach to anticoagulant reversal (Dabi and Koutrouvelis 2018; Al-Hussaniy et al. 2023b; Hussein et al. 2023). Current research in the development of new anticoagulants is focused on addressing the limitations and side effects associated with direct oral anticoagulants (DOACs). One promising avenue involves the exploration of novel compounds derived from isosteviol, a non-toxic hydrolysis product of stevioside known for its various therapeutic properties, including anticoagulant activity (Jwaid et al. 2020).

In a recent study, researchers conducted in silico design and molecular modeling to identify potential isosteviol-based compounds as inhibitors of human-activated coagulation factor X (FXa). This approach utilized quantitative structure-activity relationship (QSAR) analysis and docking simulations to assess the FXa-inhibitory activity of these compounds (Gackowski et al. 2023).

The study’s artificial neural network (ANN) model, which considered both topological and geometrical information, demonstrated a significant correlation with FXa-inhibitory activity. Additionally, docking simulations pinpointed six promising isosteviol-like compounds for further investigation. Notably, these compounds featured heterocyclic, aromatic, five-membered moieties, often with substituents containing chlorine or fluorine atoms (Jwaid 2022; Sagheer et al. 2023).

These findings offer valuable insights into the design of effective FXa inhibitors as potential anticoagulant agents. By leveraging computational techniques and molecular modeling, researchers are making significant strides towards the development of safer and more efficacious anticoagulants, addressing the persistent challenges associated with existing therapies for thromboembolic disorders (Gackowski et al. 2023).

Discussion

Atrial fibrillation (AF), an increasingly prevalent cardiac ailment, has long been associated with significant ischemic stroke risks. Traditional anticoagulation therapies, while effective, have presented various limitations, including potential interactions, regular monitoring, and variable patient responses. The introduction of novel oral anticoagulants (NOACs) has aimed to circumvent these challenges (Dobesh and Fanikos 2015).

Our review delves into the intricacies of these NOACs, revealing their comparative advantages over traditional drugs like warfarin. Studies such as RE-LY and ARISTOTLE have established the effectiveness of Dabigatran and Apixaban, respectively, in stroke prevention, even surpassing warfarin in some instances (Shields and Lip 2015; Austin et al. 2018; Al-hassany et al. 2021). Yet, an overarching concern with anticoagulation remains: bleeding risks. As our findings indicate, NOACs like Apixaban and Edoxaban present a promising reduction in bleeding events, addressing a significant drawback associated with warfarin treatment (Hellenbart et al. 2017; McDowell et al. 2018).

One of the paramount shifts brought about by NOACs lies in their predictability and reduced interaction profile. The elimination of frequent monitoring, combined with diminished food and drug interactions, promises to enhance patient compliance, making treatment regimes more feasible (Al-Hussaniy et al. 2022c).

Economic implications, however, should not be overlooked. While NOACs may present a more expensive upfront cost, their potential in reducing long-term complications and monitoring costs could render them a more cost-effective solution in the broader spectrum (Naji 2021).

Conclusion

Atrial fibrillation (AF) remains one of the most prevalent cardiac arrhythmias worldwide, with an increasing burden on healthcare systems due to its association with severe complications such as stroke and heart failure. The management and prevention of these complications primarily revolve around anticoagulation strategies. Historically, warfarin and other vitamin K antagonists were the mainstay of therapy. However, with the advent and introduction of novel oral anticoagulants (NOACs) to clinical practice, the landscape of AF management has been reshaped.

Our comparative analysis of NOACs highlighted the potential benefits of these agents over traditional anticoagulants. Notably, NOACs offer predictable pharmacokinetics, reduced food and drug interactions, and a generally lower risk of intracranial hemorrhage. Moreover, with the introduction of specific reversal agents for NOACs, concerns regarding uncontrolled bleeding and the need for emergency reversal have been largely addressed (Barr and Epps 2019).

However, while NOACs present significant advantages, they are not devoid of challenges. Cost considerations, the need for renal function monitoring, and the limited long-term data on rare side effects underscore the necessity for individualized therapy based on patient-specific risks and benefits.

Another pivotal observation from this review is the role of NOACs in various subpopulations of AF patients, including those with valvular heart diseases, the elderly, and patients with co-morbid conditions. Our findings emphasize the need for further research to elucidate the best anticoagulation strategy tailored for these groups.

In conclusion, the evolution of anticoagulant therapy, marked by the emergence of NOACs, has significantly improved the management options for patients with AF. The comparative benefits in terms of safety, efficacy, and convenience make NOACs attractive alternatives to traditional therapies. However, as with all therapeutic decisions, clinicians must weigh the benefits against potential risks, bearing in mind the individual characteristics and needs of each patient. It is anticipated that with further research, refinements in dosing, the discovery of new agents, and better patient stratification, we can further optimize the care of AF patients in the future.

Acknowledgments

Mazen M. Jwaid led the research design, conducted primary data collection, and played a significant role in manuscript writing and revision; Mohammed J. Alwan contributed to data analysis and interpretation and provided critical revisions of the manuscript for important intellectual content; Isam Ihsan facilitated lab experiments, assisted in data collection, and provided inputs during manuscript preparation; Maher M. Jwaid played a key role in interpreting the results and provided important methodological insights while assisting in manuscript revisions; Yasir F. Muhsin contributed to the literature review, data interpretation, and collaborated closely with Mazen M. Jwaid in drafting the manuscript; Hany A. Al-hussaniy, Mohammed K. Al iraqi supervised the entire research process, provided essential resources and materials, secured funding, and ensured critical revisions of the manuscript. All authors reviewed the manuscript and approved the final version for publication.

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