Amyloidosis is a rare group of disorders characterized by the pathological deposition of amyloid fibrils, resulting in from misfolded proteins, within the intracellular and/or extracellular compartments of a variety of tissues and organs including the heart, kidneys, central nervous system, and digestive system [1]. Recent advances in non-invasive diagnostic modalities, such as cardiac magnetic resonance imaging and bone scintigraphy, have revolutionized the detection of cardiac amyloidosis, particularly transthyretin amyloid cardiomyopathy (ATTR-CM) [2]. These technologies have significantly increased diagnostic accuracy and recognition rates of this previously underdiagnosed condition [3]. Cardiac amyloidosis (CA) encompasses several types, with ATTR-CM and amyloid light-chain (AL) being the most common. ATTR-CM can be further classified into two subtypes, namely wild-type (ATTRwt) and hereditary ATTR (hATTR) amyloidosis [4].

CA primarily manifests as restrictive cardiomyopathy [5], characterized by signs and symptoms of right ventricular diastolic dysfunction, such as elevated jugular venous pressure, ascites, peripheral edema, and dyspnea. In CA patients, amyloid infiltration of the atrial myocardium leads to complex structural and electrical remodeling of the atria, increasing the risk of atrial fibrillation (AF) and predisposing patients to thromboembolism due to altered electrophysiological characteristics [6]. A previous study has reported a high prevalence of AF in CA patients, with rates of up to 40% in wtATTR and 11% in hATTR [7]. Therefore, preventing the formation of left atrial thrombus is crucial in CA patients with AF to reduce the risk of cardioembolic stroke.

Direct oral anticoagulants (DOACs), such as rivaroxaban, apixaban, dabigatran, and edoxaban, are newer anticoagulants that have gained recognition as viable alternatives to vitamin K antagonists (VKAs) such as warfarin. Recent guidelines from the American Heart Association [8] and the European Society of Cardiology [9] have shifted the preference towards DOACs. Currently, anticoagulation therapy is recommended for AF patients with CA, regardless of their CHA₂DS₂-VASc (Congestive heart failure, Hypertension, Age $\ge$75 years, Diabetes mellitus, Stroke or transient ischemic attack history, Vascular disease, Age 65–74 years, and Sex category) score [10]. However, managing anticoagulation in this population is challenging due to high bleeding risks and frequent renal impairment, complicating clinical decision-making.

There is a lack of comprehensive studies that directly compare the effectiveness and safety of DOACs with VKAs in AF patients with CA. To address this gap, our current systematic review aimed to comprehensively analyze the existing research on the use of DOACs compared with VKAs in patients with AF and CA.

Our systematic review followed the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA).

The present study investigated the effect of anticoagulation therapy—DOACs versus VKAs—in patients with CA and AF. In terms of embolic events, three of the included studies [13, 14, 15] reported no significant difference between DOACs and VKAs, while one study [16] found that DOACs were associated with a lower risk of stroke. Regarding bleeding complications, two studies [13, 14] observed similar rates between the DOAC and VKA cohorts, whereas the remaining two studies [15, 16] reported a higher frequency of bleeding events in the VKA group. In the pooled quantitative analysis, DOACs were associated with a reduced risk of thromboembolic events compared to VKAs, with no significant difference observed in the incidence of major bleeding. These findings support the safe and effective use of DOACs as a non-inferior alternative to VKAs in patients with CA and AF.

Renal function emerged as a significant confounding factor influencing outcomes in anticoagulation therapy. Patients with impaired renal function were more likely to be prescribed VKAs since DOACs such as edoxaban and dabigatran are contraindicated in patients with an estimated glomerular filtration rate (eGFR) below 15 and 30 mL/min respectively [17, 18]. Consequently, the VKA group inherently comprised individuals with poorer renal function, which predisposed them to a higher risk of bleeding. Therefore, the increased incidence of bleeding events in the VKA group may not be directly attributed to the drug itself, but rather to the confounding effects of reduced renal function. The association was underscored by the findings of Cariou et al. [15], where the apparent superiority of DOACs over VKAs in reducing all-cause mortality observed in univariate analysis was no longer significant after adjusting to age, cardiac, and renal function. Furthermore, in the ATTRwt subpopulation, reduced eGFR was identified as the sole variable significantly associated with all-cause mortality.

The cohort study by Mitrani et al. [14] included patients diagnosed prior to the Food and Drug Administration (FDA)’s approval of dabigatran, the first DOAC, in 2010. As a result, patients treated before 2010 would have received VKAs regardless of their kidney function as DOACs were not yet available. In contrast, more recent studies showed that patients with preserved renal function were more likely to be prescribed DOACs [13, 15, 16]. Therefore, the VKA arm in Mitrani et al.’s [14] cohort likely presented with superior renal function compared to those in newer studies, potentially contributing to the more balanced outcomes reported in this study. However, the study did not report the exact exact average eGFR for either group, limiting further comparisons.

In the study by Cariou et al. [15], two additional types of VKAs, fluindione and acenocoumarol, were used alongside warfarin. Fluindione is predominantly prescribed in France, accounted for 80% of VKA prescriptions in the country [19]. Fluindione is an indanedione derivative contrary to warfarin and acenocoumarol, which are coumarin derivatives [20]. It is regarded as an interesting alternative to warfarin due to its longer half-life, which might be a useful attribute in stabilizing the international normalized ratio (INR). Acenocoumarol is a drug that has some geographical tendencies, is more commonly used in specific European countries, such as Spain and the Netherlands [21], but rarely prescribed in North America or Asia. The half-life of this drug is shorter than warfarin, theoretically making adjustments of INR more challenging. A study suggests that warfarin’s longer half-life offers no significant clinical advantage [22], and acenocoumarol has been associated with more stable anticoagulation effects. Yet, the inclusion of these two less-studied VKAs raises the question of whether the findings achieved by Cariou et al. [15] could be extrapolated to warfarin or VKAs as a class, given their pharmacological differences.

AL and ATTR amyloidosis are two distinct conditions within the amyloidosis spectrum, each exhibiting distinct characteristics, particularly in terms of thromboembolic risk [23]. AL amyloidosis results from neoplastic plasma cells producing misfolded unstable free light chains [23] that could deposit in virtually any organ, and are not limited to the heart. Common extracardiac manifestations include renal failure, elevated liver enzymes, gastrointestinal symptoms, macroglossia, and autonomic dysfunction [24]. In AL patients, renal dysfunction is often a direct consequence of disease progression rather than heart failure. Nephrotic syndrome, associated with urinary loss of anticoagulant factors (e.g., antithrombin, protein S), immunomodulatory drug use, high free light chain levels, and elevated beta-2 microglobulin levels, collectively increase thromboembolic risk. At the same time, renal failure and increased vessel fragility caused by amyloid deposition elevate the risk of bleeding [25].

On the other hand, ATTR amyloidosis follows a distinct pathogenic pathway, primarily involving cardiac amyloid deposition [26]. Transthyretin, a tetrameric protein produced by the liver, functions as a transporter for thyroxine and retinol-binding protein. Mutations in the amyloidogenic genes destabilize the tetramer structure, leading to abnormal protein misfolding [27], aggregation, and fibril formation. In wild-type ATTR amyloidosis, the misfolded non-mutated transthyretin proteins assemble into soluble oligomers, which are prone to forming amyloid fibrils [27]. These insoluble fibrils accumulate in various organs, particularly in the elderly, resulting in wild-type amyloidosis [27]. Unlike AL amyloidosis, ATTR typically does not involve other vital organs or the use of immunomodulatory drugs, resulting in comparatively lower thrombotic and bleeding risks.

DOACs are contraindicated in patients receiving chemotherapy regimens containing dexamethasone. Both rivaroxaban and apixaban are primarily metabolized by CYP3A4 in the liver. Dexamethasone, a known Cytochrome P450 3A4 (CYP3A4) inducer, increases the enzyme’s expression, thereby accelerating the metabolism of these DOACs [28]. This reduces anticoagulant levels, potentially leading to subtherapeutic anticoagulation [28]. In the study by Cariou et al. [15], 69 patients with AL amyloidosis were anticoagulated, and only 15 receiving DOACs, indicating that AL patients were more likely to be on warfarin. While the study did not provide specific information about chemotherapy in this cohort, the potential drug-drug interaction between DOACs and dexamethasone likely contributed to this treatment pattern.

AL amyloidosis presents with higher prothrombotic and bleeding risks, explaining the greater proportion of AL patients managed with warfarin. However, warfarin is generally considered less effective and more challenging to manage compared to DOACs. In contrast, ATTRwt develops as an age-related condition [29], and its diagnosis typically occurs at a significantly older age AL amyloidosis. Chronic kidney disease (CKD) is often associated with an advanced age [30], results in poorer renal function in the ATTRwt population. Although AL amyloidosis directly impacts renal function due to amyloid deposition, the overall renal function in ATTRwt patients is often worse due to the higher prevalence of age-related CKD in this group.

DOACs offer several advantages over VKAs such as warfarin, including a wider therapeutic window, shorter half-life, and reduced need for frequent INR monitoring [31]. Maintaining a stable and therapeutic INR is a significant problem when administering VKAs in CA patients, which highly depends on the center and patient’s adherence. In the study by Mitrani et al. [14], 87.5% of the patients in the VKA group had a labile INR during follow-up, and all ischemic events or major bleeding episodes occurred in patients with unstable INR levels. Similarly, in the multicenter study by Vilches et al. [13], labile INR was observed in 18.7% of patients treated with VKAs and was associated with a higher rate of embolic events. However, limitations in data, such as missing information on INR stability and ejection fraction, reduce the credibility and generalizability of these findings.

Once considered incurable, ATTR-CM has seen significant advancements with the development of novel disease-modifying therapies over the past decades. In 2019, the FDA approved the first and only agent for ATTR-CM, tafamidis [32]. As additional promising therapies are anticipated to gain approval and enter the market, there is a growing need to evaluate potential drug-drug interactions between these emerging agents and commonly used anticoagulants. However, none of the existing studies have reported data on the use of chemotherapy or targeted therapy agents in their patient populations. Future trials would benefit from including such details in their population demographics to provide more comprehensive insights into these interactions.

Existing studies support the use of DOACs as a non-inferior therapeutic option compared to VKAs for preventing thromboembolism in patients with AF and CA. DOACs offer practical advantages, such as reduced monitoring requirements and a lower likelihood of labile anticoagulation. However, the evidence remains limited by the retrospective nature of current studies and the lack of RCTs. Further prospective trials are essential to confirm these findings and to establish robust clinical guidelines tailored to the unique challenges of anticoagulation in this high-risk population.

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Conception and design (TZ, WZ, YC), analysis and interpretation of the data (QN, SL); the drafting of the paper (QN, SL), revising it critically for intellectual content (SL, WZ); and the final approval of the version to be published (YC, TZ, WZ). All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

Not applicable.

This research received no external funding.

The authors declare no conflict of interest. Wengen Zhu is serving as one of the Editorial Board members of this journal. We declare that Wengen Zhu had no involvement in the peer review of this article and has no access to information regarding its peer review. Full responsibility for the editorial process for this article was delegated to Jan Slezak.