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Abstract

Background

Cerebral venous thrombosis (CVT) is a rare but severe type of stroke, typically treated with vitamin K antagonists (VKAs). This study compares different direct oral anticoagulants (DOACs) with VKAs for the management of CVT.

Methods

PubMed, Cochrane Central, and ScienceDirect were searched up to May 2025. A network meta-analysis using a frequentist approach was performed in RStudio version 4.3.3. P-scores were used to rank treatments. The evaluated outcomes included full recanalization, recurrent venous thromboembolism (VTE), major hemorrhage, intracranial hemorrhage (ICH), and mortality. The Cochrane Risk of Bias (RoB 2.0) tool and the Newcastle-Ottawa Scale (NOS) were employed to assess the quality of randomized controlled trials (RCTs) and observational studies.

Results

Our analysis included 16 studies involving 1403 patients. We found that various DOACs, including apixaban, dabigatran, and rivaroxaban, had rates of full recanalization, VTE recurrence, major hemorrhage, ICH, and mortality comparable to those of VKAs. VKAs showed the highest likelihood of full recanalization, with a P-score of 0.70, whereas apixaban had the lowest, with a P-score of 0.04. For reducing recurrent VTE rates, apixaban was the most effective (P-score = 0.83), and dabigatran the least (P-score = 0.04). Apixaban also led to the greatest reduction in ICH risk (P-score = 0.70), while rivaroxaban had the lowest likelihood (P-score = 0.29). Regarding major hemorrhage, apixaban had the highest probability of reduction (P-score = 0.81), with VKAs performing worst (P-score = 0.26). Lastly, apixaban ranked highest for reducing mortality (P-score = 0.78), whereas VKAs ranked lowest (P-score = 0.39).

Conclusion

DOACs showed no significant differences in rates of full recanalization, VTE recurrence, major hemorrhage, ICH, or mortality compared with VKAs. Apixaban had the highest probability of reducing VTE recurrence, mortality, and hemorrhagic events, whereas VKAs had the highest probability of achieving full recanalization.

Keywords

cerebral venous thrombosis direct oral anticoagulants vitamin k antagonists systematic review network meta-analysis

Introduction

Cerebral venous thrombosis (CVT) is a serious, although uncommon, potentially life-threatening cerebrovascular disease contributing 0.5–1% of all strokes, and is more common in young adults, particularly in females.^1–3 The primary therapeutic objective is to inhibit thrombus growth, achieve recanalization, and minimize morbidity and mortality, which has often been addressed using vitamin K antagonists (VKAs), such as warfarin.^1–4 More recently, direct oral anticoagulants (DOACs), such as dabigatran, rivaroxaban, and apixaban, have been established as a potentially viable alternative due to their predictable pharmacokinetics, decreased interactions, and the absence of the need for routine monitoring.^5,6

Recent literature has demonstrated that the use of DOACs is at least as effective and safe as VKAs in CVT, with similar recanalization rates, mortality, and functional outcomes.^1,2,7 Additionally, there is evidence of reduced cases of intracranial bleeding and improved patient compliance with the use of DOACs.^8–10 Although several head-to-head studies have individually compared specific DOACs with VKAs, there has been no indication of superiority in terms of efficacy or safety for any individual agent.^1,5

Despite the emerging empirical data, significant gaps remain. The best anticoagulant choice, the length of therapy, and the patient subgroups who will benefit most from DOAC administration are all areas of uncertainty. DOACs are increasingly popular in current clinical practice, and the available literature does not provide sufficient detail to make accurate comparative assessments. Our systematic review and network meta-analysis represent an effort to subclassify DOACs based on their efficacy and safety profiles, thereby enabling indirect comparisons between DOACs and VKAs for CVT.

Methods

This systematic review and network meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines¹¹ and followed the Cochrane Handbook for Systematic Reviews and Interventions.¹² The protocol for this review was registered on PROSPERO under the ID: CRD420251145782.

Literature Search

Electronic databases, including PubMed, Cochrane Central, and ScienceDirect, were searched till May 2025. The bibliographies of the included studies were also searched for potential articles. The MeSH terms and keywords used were “Factor Xa Inhibitors,” “Direct-Acting Oral Anticoagulant,” “Dabigatran,” “Rivaroxaban,” “Apixaban,” “Warfarin,” “Vitamin K antagonist,” and “cerebral venous thrombosis.” The detailed search strategies used in each database are provided in Supplementary Table 1 .

Study Selection and Eligibility Criteria

Two authors (H.K. and K.F.) independently searched the databases and retrieved articles. After removing duplicates, the remaining articles underwent primary screening of titles and abstracts. The articles obtained from the initial screening were then subjected to a secondary full-text review. Any discrepancies in the study selection process were resolved by a third author (M.H.W.). The detailed study selection process is outlined in the PRISMA flowchart ( Figure 1 ).

Figure 1.

PRISMA flowchart of the study selection process.

Adult patients aged 18 and above with a confirmed diagnosis of CVT were included in the study. The interventions involved DOACs, including apixaban, rivaroxaban, and dabigatran. The comparison arm used VKAs. The study designs included randomized controlled trials (RCTs) and observational studies. Patients under 18, those with infections, cancer, pregnancy, or higher bleeding risk, and studies like reviews, case reports, and editorials were excluded. Studies comparing DOACs with VKA but not specifying which DOAC (such as apixaban, rivaroxaban, or dabigatran) were excluded. Additionally, studies involving multiple DOACs in the intervention group that did not separate outcomes by individual DOAC were also excluded.

Data Extraction and Endpoint Definitions

Two authors (Z.U.A. and J.P.R.) independently extracted data on baseline variables and outcomes. The baseline variables included study ID, location, study design, mean age, sample size, intervention group, control group, gender distribution, follow-up duration, anticoagulation therapy duration, and incidence of headache, seizures, papilledema, and hypertension. The efficacy endpoints included full recanalization and recurrent venous thromboembolism (VTE), while the safety endpoints encompassed major hemorrhage, mortality, and intracranial hemorrhage (ICH). Any discrepancies during data extraction were resolved by a third author (M.H.W.).

Full recanalization was defined as the complete recanalization of the vein or sinus that was blocked, with no remaining thrombus present. Recurrent VTE is defined as any venous thromboembolic event happening after the initial anticoagulation treatment, which may involve recurrence at the same site (eg, CVT) or in different parts of the venous system (such as deep venous thrombosis). Major hemorrhage and intracranial hemorrhage (ICH) were defined using the International Society on Thrombosis and Hemostasis (ISTH) criteria.¹³ According to ISTH, major bleeding includes fatal bleeding, symptomatic bleeding in critical areas or organs, a decrease in hemoglobin levels by at least 2 g/dL or 20 g/L, or a transfusion of at least 2 units of blood during hospitalization.

Risk of Bias

Two authors (K.F. and A.L.F.C.) independently assessed the risk of bias. For the included RCTs, risk of bias was assessed using the Cochrane Risk of Bias (RoB 2.0) tool,¹⁴ whereas the Newcastle Ottawa Scale (NOS)¹⁵ was used to assess the risk of bias in observational studies. The RoB 2.0 tool evaluates bias across five domains, including randomization process bias, deviations from intended interventions, missing outcome data bias, outcome measurement bias, and selection of reported results bias. It rates the overall risk of bias as low, some concerns, or high. In contrast, the NOS assesses bias across three main domains: selection, comparability, and outcome. The selection domain evaluates four key aspects, including S1 (Representativeness of the Exposed Cohort), S2 (Selection of the Non-exposed Cohort), S3 (Ascertainment of Exposure), and S4 (Whether the outcome was absent at the beginning of the study). The comparability domain assesses two main aspects: whether the study controls for age and sex, and whether it accounts for other factors. The outcome domain evaluates three key aspects, including O1 (Assessment of Outcome), O2 (Follow-up long enough for Outcomes to occur), and O3 (Adequacy of follow-up of Cohorts). The maximum scores are 4 for the selection domain, 2 for the comparability domain, and 3 for the outcome domain, yielding a maximum total score of 9 per study. Studies scoring 7–9 are regarded as high quality; those scoring 4–6 are considered fair; and those scoring 0–3 are deemed poor quality.

Statistical Analysis

Using RStudio version 4.3.3 along with the “meta” and “netmeta” packages, we conducted a network meta-analysis employing a frequentist approach. We pooled risk ratios (RRs) and 95% confidence intervals (CIs) to estimate the network effects for dichotomous outcomes. We assessed heterogeneity using the Cochran's Q test and Higgins I² statistics,¹⁶ with P values less than 0.05 indicating statistical significance. Forest plots and league tables were made to visualize the network structure. We created network plots with NMAStudio, where each node represents an intervention, and the line thickness connecting two nodes shows the number of studies comparing them. To measure inconsistency between direct and indirect estimates, we conducted a split-node analysis. We ranked interventions using P-scores, with 1 indicating the highest probability of being most effective or safe and 0 the lowest. We depicted the ranking of interventions for different endpoints using rankograms. We assessed publication bias visually through funnel plots and statistically using Egger's regression test.¹⁷

Results

Search Results

Our initial search of databases, including PubMed, Cochrane Central, and ScienceDirect, yielded a total of 547 articles. After removing duplicates (n = 126), we were left with 421 articles, which we screened based on their titles and abstracts. From those, 94 articles made it to the secondary screening stage, where we reviewed the full texts and selected 16 studies^6,18–32 to include in the network meta-analysis. The entire selection process is outlined in the PRISMA flowchart ( Figure 1 ).

Study Characteristics

Sixteen studies,^6,18–32 encompassing a total of 1403 patients were included. Among them six were RCTs and the remainder were observational. Participants’ ages ranged from 26 to 50 years. Reported incidence rates included headaches (56% to 100%), seizures (8% to 60%), papilledema (7% to 64%), and hypertension (8% to 68%). The intervention group received anticoagulants such as rivaroxaban, apixaban, and dabigatran, while the control group was treated with warfarin. Gender distribution varied, with males ranging from 18% to 61% and females from 39% to 82%. Follow-up periods and anticoagulation durations ranged from 3 to 12 months. Tables 1A and B provide detailed baseline characteristics of the included studies and patients.

Table 1A.

Baseline Characteristics of the Included Studies.

			Sample Size
Study ID	Location	Study Design	Total	DOACs	VKA	Intervention	Control	Gender distribution (Male/Female)%	Follow-Up Duration	Anticoagulation Therapy Duration
Alkhawam et al¹⁸	Syria	RCT	71	37	34	Rivaroxaban	Warfarin	31/69	6 months	6 months
Bajko et al¹⁹	Romania	Observational Study	85	5	80	Rivaroxaban	Warfarin	34/66	6 months	6 months
Dong et al²⁰	China	Observational Study	157	62	95	Apixaban	Warfarin	45/55	6 months	3–12 months
Esmaeili et al²¹	Iran	Observational Study	36	23	13	Rivaroxaban	Warfarin	19/81	12 months	12 months
Fei-hu et al²²	China	Observational Study	52	25	27	Rivaroxaban	Warfarin	44/56	-	3 months
Ferro et al²³	Multi-centered	RCT	120	60	60	Dabigatran	Warfarin	45/55	6 months	6 months
Field et al²⁴	Canada	RCT	53	26	27	Rivaroxaban	Warfarin	44/66	12 months	6 months
Geisbüsch et al²⁵	Germany	Observational Study	16	7	9	Rivaroxaban	Warfarin	19/81	8 months	9 months
Jiang et al²⁶	China	Observational Study	83	38	45	Rivaroxaban	Warfarin	61/39	3 months	3–12 months
Khorvash et al²⁷	Iran	RCT	50	25	25	Rivaroxaban	Warfarin	28/72	6 months	3 months
Ma et al²⁸	China	RCT	89	44	45	Dabigatran	Warfarin	51/49	6 months	-
Maqsood et al²⁹	Pakistan	RCT	45	21	24	Rivaroxaban	Warfarin	18/82	12 months	12 months
Pan et al³⁰	China, USA	Observational Study	82	33	49	Rivaroxaban	Warfarin	33/67	6 months	6 months
Phan et al⁶	United States	Observational Study	31	31	-	Apixaban, Rivaroxaban, Dabigatran	-	29/71	6 months	6 months
Simaan et al³¹	Israel	Observational Study	403	48	355	Apixaban	Warfarin	34/66	12 months	-
Saeed et al³²	Pakistan	Observational Study	30	15	15	Rivaroxaban	Warfarin	30/70	6 months	-

Note: RCT: Randomized Controlled Trial; DOACs: Direct oral anticoagulants; VKA: Vitamin K antagonist.

Table 1B.

Baseline Characteristics of Included Patients.

Study ID	Age, Mean ± SD		Headache		Seizures		Papilledema		Hypertension
Study ID	DOACs	VKA	DOACs	VKA	DOACs	VKA	DOACs	VKA	DOACs	VKA
Alkhawam et al¹⁸	33.72 ± 9.25	28.5 ± 3.75	37 (100%)	34 (100%)	19 (51.4%)	19 (55.9%)	-	-	-	-
Bajko et al¹⁹	-	-	3 (60%)	66 (82.5%)	3 (60%)	35 (43.7%)	-	-	-	-
Dong et al²⁰	-	-	39 (63%)	88 (93%)	-	-	-	-	20(32.26%)	30(31.53%)
Esmaeili et al²¹	36 ± 11.15	34 ± 11.22	-	-	-	-	-	-	-	-
Fei-hu et al²²	35.80 ± 3.15	34.37 ± 3.02	-	-	-	-	-	-	-	-
Ferro et al²³	-	-	54 (90.0%)	55 (91.7%)	13 (21.7%)	16 (26.7%)	10 (16.7%)	4 (6.7%)	-	-
Field et al²⁴	49.92 ± 21.37	48.33 ± 14.87	23 (88.5%)	24 (88.9%)	13 (50.0%)	10 (37.0%)	-	-	-	-
Geisbüsch et al²⁵	38.75 ± 20.88	43.0 ± 17.40	6 (85.71%)	5 (55.56%)	2 (28.57%)	4 (44.44%)	-	-	-	-
Jiang et al²⁶	38.95 ± 14.38	40.89 ± 13.171	30(78.9%)	40(88.9%)	9(23.7%)	14(31.1%)	-	-	3(7.9%)	7(15.6%)
Khorvash et al²⁷	41.20 ± 11.35	40.76 ± 11.72	88%	92%	24%	8%	64%	64%	-	-
Ma et al²⁸	-	-	95.50%	82.20%	22.70%	40.00%	36.40%	44.40%	68.20%	62.20%
Maqsood et al²⁹	26 ± 5.6	27 ± 7.6	18 (86%)	22 (92%)	11 (52%)	12 (50%)	11 (52%)	12 (50%)	-	-
Pan et al³⁰	37.1 ± 13.8	34.1 ± 14.0	-	-	-	-	-	-	-	-
Phan et al⁶	45.78 ± 20.98	-	-	-	-	-	-	-	10 (32%)	-
Simaan et al³¹	41.5 ± 18.8	41.1 ± 18.0	43 (89.6%)	269 (75.6%)	11 (22.9%)	74 (20.8%)	27.10%	27.70%	6 (12.5%)	49 (13.8%)
Saeed et al³²	31.47 ± 9.2	35.87 ± 10.8	-	-	-	-	-	-	-	-

Note: DOACs: Direct oral anticoagulants; VKA: Vitamin K antagonist.

Risk of Bias

To assess risk of bias in RCTs, we used the Cochrane RoB 2.0 tool; for observational studies, we used the NOS. The risk of bias in RCTs was evaluated as high by Ferro et al²³ and Maqsood et al²⁹ mainly due to bias arising from the randomization process. The remaining four RCTs raised some concerns. The traffic light plot from the RoB 2.0 tool is included in Supplementary Figure 1 . In observational studies, most studies scored between 7 and 9 and are of good quality, except for three studies, Esmaeili et al,²¹ Bajko et al,¹⁹ and Fei-hu et al,²² which scored between 5 and 6, and are of fair quality. The overall quality of the studies included in this network meta-analysis is moderate, indicating sound methodological rigor. The details of the bias assessment using the NOS are outlined in Supplementary Table 2 .

Network Meta-Analysis

Efficacy Endpoints

Full Recanalization

Eight studies, including four interventions and 10 pairwise comparisons, were included in the network meta-analysis of full recanalization. Compared to VKA, none of the interventions, including apixaban (RR = 0.36; 95%CI:[0.11, 1.17]; p = 0.09), dabigatran (RR = 0.98; 95%CI:[0.72, 1.34]; p = 0.90) and rivaroxaban (RR = 0.98; 95%CI:[0.83, 1.16]; p = 0.82) caused significant change in the rate of full recanalization (Figure 2A and 3A). The network plot of full recanalization is shown in Figure 4A . Based on P-scores, VKA had the highest probability of achieving full recanalization (P-score = 0.70), whereas apixaban had the lowest (P-score = 0.04). Details on treatment ranking are provided in Table 2 and Figure 5A . No heterogeneity was detected among the included studies (τ² < 0.0001; I² = 0%).

Figure 2.

Forest plots (A) Full recanalization (B) Recurrent venous thromboembolism (C) Mortality (D) Major hemorrhage.

Figure 3.

League table (A) Full recanalization (B) Recurrent venous thromboembolism (C) Mortality (D) Major hemorrhage.

Figure 4.

Network plot (A) Full recanalization (B) Recurrent venous thromboembolism (C) Mortality (D) Major hemorrhage.

Figure 5.

Rankograms (A) Full recanalization (B) Recurrent venous thromboembolism (C) Mortality (D) Major hemorrhage.

Table 2.

Treatment Ranking Based on P-Score.

Full Recanalization			Recurrent VTE			Major Hemorrhage			Intracranial Hemorrhage			Mortality
Intervention	P-Score	Rank	Intervention	P-Score	Rank	Intervention	P-Score	Rank	Intervention	P-Score	Rank	Intervention	P-Score	Rank
VKA	0.70	first	Apixaban	0.83	first	Apixaban	0.81	first	Apixaban	0.70	first	Apixaban	0.78	first
Dabigatran	0.63	second	Rivaroxaban	0.71	second	Rivaroxaban	0.51	second	Dabigatran	0.58	second	Dabigatran	0.43	second
Rivaroxaban	0.62	third	VKA	0.41	third	Dabigatran	0.42	third	VKA	0.43	third	Rivaroxaban	0.393	third
Apixaban	0.04	fourth	Dabigatran	0.04	fourth	VKA	0.26	fourth	Rivaroxaban	0.29	fourth	VKA	0.392	fourth

Note: VKA: Vitamin K antagonists; VTE: Venous thromboembolism.

Recurrent Venous Thromboembolism

Twelve studies, including four interventions and 14 pairwise comparisons, were included in the network meta-analysis. Compared to VKA, none of the interventions including apixaban (RR = 0.32; 95%CI:[0.04, 2.80]; p = 0.30), dabigatran (RR = 2.34; 95%CI:[0.75, 7.27]; p = 0.14) and rivaroxaban (RR = 0.58; 95%CI:[0.21, 1.63]; p = 0.30) significantly changed the rate of recurrent VTE (Figure 2B and 3B). The network plot of recurrent VTE is shown in Figure 4B . Based on the P-scores, the apixaban was ranked best (P-score = 0.83), whereas the dabigatran was ranked worst (P-score = 0.04). The details of treatment ranking are given in Table 2 and Figure 5B . No heterogeneity was detected among the studies (τ² < 0.0001; I² = 0%).

Safety Endpoints

Mortality

Fourteen studies, including four interventions and 14 pairwise comparisons, were included in the network meta-analysis of mortality. Compared to VKA, none of the interventions, including apixaban (RR = 0.42; 95%CI:[0.07, 2.35]; p = 0.32), dabigatran (RR = 1.01; 95%CI:[0.06, 15.95]; p = 0.99) and rivaroxaban (RR = 1.01; 95%CI:[0.37, 2.78]; p = 0.98) significantly changed the rate of mortality (Figure 2C and 3C). The network plot of mortality is given in Figure 4C . Based on P-scores, apixaban had the best probability of reducing mortality (P-score = 0.78), whereas the VKA had the worst (P-score = 0.39). Details on the treatment ranking are provided in Table 2 and Figure 5C . No heterogeneity was detected among the studies (τ² < 0.0001; I² = 0%).

Major Hemorrhage

Nine studies, including four interventions and 11 pairwise comparisons, were included in the network meta-analysis of major hemorrhage. Compared to VKA, none of the interventions, including apixaban (RR = 0.16; 95%CI:[0.004, 5.40]; p = 0.30), dabigatran (RR = 0.73; 95%CI:[0.12, 4.42]; p = 0.73) and rivaroxaban (RR = 0.61; 95%CI:[0.15, 2.52]; p = 0.50) significantly changed the rate of mortality (Figure 2D and 3D). The network plot of major hemorrhage is shown in Figure 4D . Based on P-scores, apixaban had the highest probability of reducing major hemorrhage (P-score = 0.81), whereas VKA had the lowest (P-score = 0.26). Details on the treatment ranking are provided in Table 2 and Figure 5D . No heterogeneity was detected among the studies (τ² < 0.0001; I² = 0%).

Intracranial Hemorrhage

Fourteen studies, including four interventions and 16 pairwise comparisons, were included in the network meta-analysis of ICH. Compared to VKA, none of the interventions, including apixaban (RR = 0.61; 95%CI:[0.13, 2.85]; p = 0.53), dabigatran (RR = 0.76; 95%CI:[0.14, 4.08]; p = 0.75) and rivaroxaban (RR = 1.21; 95%CI:[0.45, 3.27]; p = 0.70) significantly changed the rate of mortality (Supplementary Figures 2 and 3). The network plot of mortality is given in Supplementary Figure 4 . Based on P-scores, apixaban was ranked best (P-score = 0.70), whereas rivaroxaban was ranked worst (P-score = 0.29). Details on the treatment ranking are provided in Table 2 and Supplementary Figure 5 . No heterogeneity was detected among the studies (τ² < 0.0001; I² = 0%).

Inconsistency and Publication Bias

To examine the discrepancy between direct and indirect evidence, we conducted a split node analysis. The results of this analysis are presented in Figures 6A-D, Supplementary Figure 6 , and Supplementary Tables 3–7. We assessed publication bias by visually inspecting funnel plots and conducting Egger's regression test. The funnel plots showed no signs of asymmetry, and this was confirmed by Egger's regression test (Supplementary Figures 7–11).

Figure 6.

Split node analysis (A) Full recanalization (B) Recurrent venous thromboembolism (C) Mortality (D) Major hemorrhage.

Discussion

This network meta-analysis of patients with CVT found no statistically significant differences between DOACs (apixaban, rivaroxaban, and dabigatran) and VKAs regarding recurrent VTE, ful recanalization, major hemorrhage, ICH, or mortality. The P-score ranking indicated the comparative efficacy of the drugs: apixaban had the highest probability of reducing the risk of recurrent VTE, major and cerebral hemorrhage, and mortality, while VKAs had the highest probability of achieving full recanalization.

VKAs, particularly warfarin, have traditionally served as the primary anticoagulant treatment for CVT, as supported by data and clinical guidelines.^33–35 However, their application is constrained by the necessity for frequent monitoring, interactions with food, and narrow therapeutic windows. DOACs, including apixaban, rivaroxaban, and dabigatran, have emerged as attractive alternatives due to their predictable pharmacokinetics, and reduced interactions, resulting in increased examination of their comparative safety and efficacy in CVT.^36,37

Our investigation found no substantial differences between DOACs and VKAs in preventing recurrent VTE, consistent with prior meta-analyses. For instance, Xi Chen et al⁵ discovered that DOACs and standard therapy exhibited similarly low recurrence rates, with no discernible advantage for either cohort. Similarly, Yaghi et al¹ and Ranjan et al³⁸ saw comparable efficacy regarding recurrence.

Apixaban demonstrated the highest P-score, indicating that it has the best probability of providing protection against recurrent VTE, a conclusion corroborated by several trials.^39,40 Dabigatran received the lowest ranking, consistent with specific studies on strokes, indicating its weak anticoagulation profile.⁴¹ Our findings collectively demonstrate the overall equivalence of DOACs and VKAs in preventing recurrence, while suggesting that apixaban may offer a marginal advantage. This aligns with the clinical practice trend that prefers apixaban due to its safety and ease of administration.⁴²

Full recanalization of occluded venous sinuses is a significant indicator of sustained neurological enhancement. Our network meta-analysis revealed no significant differences between DOACs and VKAs in achieving full recanalization, consistent with previous findings. Xi Chen et al⁵ reported similar full recanalization rates, with 60.9% for DOACs and 69.4% for VKAs. Similarly, Yaghi et al¹ reported a pooled relative risk of 1.0, indicating no significant difference. Nonetheless, our analysis revealed that VKAs obtained the highest P-scores, while apixaban received the lowest. This suggests that VKA was more likely to promote full venous recanalization. Naik et al⁴ observed higher six-month recanalization rates with DOACs than with traditional anticoagulation, emphasizing that treatment context and follow-up intervals may substantially influence perceived efficacy. The divergence between Naik's findings and our ranking may suggest differences in population severity, which have a marked influence on outcomes. Although DOACs are equally effective, VKAs may remain the optimal option for achieving full recanalization.⁴³ The high VKA ranking for full recanalization likely stems from the monitored therapy, which ensures a high Time in Therapeutic Range (TTR) and persistently inhibits thrombin production, promoting thrombus resolution and leading to full recanalization.²³

Significant bleeding is a critical factor when choosing anticoagulants. Consistent with the collective findings of Yaghi et al¹ and Xi Chen et al,⁵ which indicated marginally reduced, yet statistically insignificant, bleeding rates with DOACs, our research revealed no significant difference in the risk of major hemorrhage between DOACs and VKAs. This conclusion is corroborated by Ranjan et al,³⁸ who also found no significant change. Apixaban had the highest probability of reducing major bleeding events, which aligns with empirical findings on apixaban's bleeding profile across various thromboembolic illnesses, demonstrating a consistently lower risk of bleeding compared to dabigatran or rivaroxaban. Given that numerous patients with CVT are young adults with extended life expectancies and functional outcomes, it is essential to avert hemorrhagic complications.⁴⁴

ICH is the most severe complication associated with anticoagulant therapy for CVT. No substantial difference was observed between DOACs and VKAs regarding it. Prior research has consistently reached this conclusion: Yaghi et al¹ found no significant differences, whereas Xi Chen et al⁵ reported nonsignificant reductions in ICH associated with DOACs. Apixaban had the highest probability of reducing ICH, consistent with the literature, suggesting that rivaroxaban is associated with a higher bleeding risk than apixaban. The data suggest that apixaban may represent the optimal balance between efficacy and safety in mitigating the risk of cerebral hemorrhage.⁴⁵

In our network meta-analysis, mortality rates showed no significant variations across anticoagulants, aligning with prior meta-analyses. Xi Chen et al⁵ and Ranjan et al³⁸ both found that the overall mortality rates were nearly the same in the DOAC and VKA cohorts. Naik et al⁴ demonstrated that there was no substantial disparity in mortality rates between DOACs and VKAs. Our ranking revealed that apixaban had the highest likelihood of reducing mortality, whereas VKAs had the lowest.

Apixaban ranks higher across various efficacy and safety outcomes, including recurrent VTE, major hemorrhage, ICH, and mortality, due to its unique pharmacodynamic and pharmacokinetic characteristics. As a direct factor Xa inhibitor, apixaban shows consistent absorption, a short half-life, and minimal drug-food interactions, eliminating the need for routine INR monitoring and dose titrations compared with VKA.^46,47 This not only enhances patient compliance but also decreases bleeding complications due to its stable anticoagulant profile and rapid clearance.^6,20 These factors help establish a better safety margin compared to VKA. Apixaban's selective inhibition of factor Xa prevents clot formation by blocking both free and clot-bound factor Xa, thereby reducing thromboembolic events.^6,46,48 The highest probability ranking of Apixaban for reducing mortality may stem from its favorable net clinical benefit, driven by its lower risk of bleeding complications and thromboembolic events.

The 2024 AHA/ASA statement on diagnosing and managing CVT states that, while DOACs are considered a safe alternative, it remains uncertain whether follow-up scans (recanalization) should guide treatment duration.⁴⁹ Our network meta-analysis is aligned with this cautious approach by highlighting the disconnect between radiographic appearance and clinical probability rankings. Although our analysis shows similar efficacy and safety for DOACs and VKA, P-score rankings reveal different trends. VKA had the highest likelihood of full recanalization, but apixaban showed the most favorable scores for reducing mortality, thromboembolic events, and hemorrhagic outcomes. These results imply that the treatment most likely to “open” the vein (VKA) may not be the safest option overall (apixaban). Therefore, achieving a “perfect” MRI result (full recanalization) may not always be essential for patient recovery. Clinicians might prefer a drug with a better safety profile, even if it's less likely to fully clear the clot and achieve complete recanalization.

This research represents a comprehensive network meta-analysis that directly contrasts individual DOACs with VKAs in CVT across various outcomes. Our methodology provides a more advanced hierarchy than conventional pairwise analyses by incorporating both direct and indirect data. However, specific limitations require acknowledgment. Most studies had small samples and low event rates, making the identification of outcomes such as ICH or mortality difficult. Rankings based on P-scores indicate only the probability of being the best or worst in safety or efficacy and are not absolute, especially when no statistically significant difference is present; therefore, they should be interpreted with caution. Moreover, discrepancies in follow-up lengths and anticoagulation procedures may bring bias into the findings. Since CVT is a rare disease, results may be affected by small-study effects and publication bias, with studies showing significant or positive results more likely to be published. This could lead to an overestimation of treatment effects. Furthermore, smaller studies tend to report more extreme outcomes than larger, well-powered studies, which can also lead to inflated estimates of the treatment benefits. The strict exclusion criteria, especially the exclusion of studies that do not specify the DOAC or have unstratified data, could lead to selection bias. A formal analysis based on drug dosages was not feasible due to variations, such as dynamic VKA titration and DOAC dose adjustments based on patients’ age and renal function. Reliance on observational data and the scarcity of RCTs reduce the robustness of the conclusions. The small sample size may limit the statistical power of the analysis and the broader applicability of the results. Larger, high-powered RCTs are needed to further confirm and reinforce these findings. Prolonged monitoring is crucial for detecting delayed recanalization and recurring thrombotic events. Head-to-head studies comparing DOACs (eg, apixaban vs rivaroxaban) are needed to clarify intra-class differences observed in our rankings.

Conclusion

This network meta-analysis demonstrated that DOACs and VKAs were comparable with respect to full recanalization, VTE recurrence, ICH, major hemorrhage, and mortality. However, treatment ranking revealed that apixaban had the highest probability of reducing VTE recurrence, ICH, major hemorrhage, and mortality, whereas VKAs had the best likelihood of achieving full recanalization. Future high-quality RCTs are essential for validating these hierarchical patterns and guiding precision anticoagulation in CVT.

Supplemental Material

sj-docx-1-cat-10.1177_10760296261427166 - Supplemental material for Comparing Efficacy and Safety of Different Anticoagulants in Cerebral Venous Thrombosis: A Systematic Review and Network Meta-Analysis

Supplemental material, sj-docx-1-cat-10.1177_10760296261427166 for Comparing Efficacy and Safety of Different Anticoagulants in Cerebral Venous Thrombosis: A Systematic Review and Network Meta-Analysis by Muhammad Hassan Waseem, Zain ul Abideen, Jamir Pitton Rissardo, Muhammad Haris Khan, Kanza Farhan, Ana Leticia Fornari Caprara, Pawan Kumar Thada and Adam A. Dmytriw in Clinical and Applied Thrombosis/Hemostasis

Footnotes

ORCID iDs

Muhammad Hassan Waseem

Pawan Kumar Thada

Authors’ Contributions CRediT Roles

Study concept and design: MHW and ZUA; acquisition of data: ZUA, and MHK; analysis and interpretation of data: ZUA, and KF; drafting of the manuscript: JPR, ALFC, PKT and MHK; critical revision of the manuscript: MHW and AAD

Authors' Note

Adam A. Dmytriw is also affiliated at Nuffield Department of Surgical Sciences, Medical Sciences Division, University of Oxford, Oxford, UK.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

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

Data can be obtained by reasonable request directed to the authors.

Status

This manuscript has not been published previously and is not under consideration for publication elsewhere.

Supplemental Material

Supplemental material for this article is available online.

References

Yaghi

Saldanha

Misquith

, et al. Direct oral anticoagulants versus vitamin K antagonists in cerebral venous thrombosis: A systematic review and meta-analysis. Stroke. 2022;53:3014-3024.

Yao

Liao

Chen

. Comparison of novel oral anticoagulants and vitamin K antagonists in patients with cerebral venous Sinus thrombosis on efficacy and safety: A systematic review. Front Neurol. 2020;11:597623.

Al Rawahi

Almegren

Carrier

. The efficacy and safety of anticoagulation in cerebral vein thrombosis: A systematic review and meta-analysis. Thromb Res. 2018;169:135-139.

Naik

Smith

Dharnipragada

, et al. Endovascular and medical management of cerebral venous thrombosis: A systematic review and network meta-analysis. World Neurosurg. 2022;165:e197-e205.

Chen

Guo

Lin

. Efficacy and Safety of Direct Oral Anticoagulants in Cerebral Venous Thrombosis: Meta-Analysis of Randomized Clinical Trials. Clin Appl Thromb Hemost. 2024;30.

Phan

Hong

. Comparison of Direct Oral Anticoagulants for Treatment of Cerebral Venous Thrombosis - A Retrospective Cohort Study. Clin Appl Thromb Hemost. 2025;31.

Waseem

Abideen

Shoaib

, et al. Direct oral anticoagulants versus vitamin K antagonists in cerebral venous thrombosis: A systematic review and meta-analysis of 4,929 patients. Clin Appl Thromb Hemost. 2025;31:10760296251405416.

Coyle

Lynch

Higgins

, et al. Risk of intracranial hemorrhage associated with direct oral anticoagulation vs antiplatelet therapy: A systematic review and meta-analysis. JAMA Netw Open. 2024;7(12):e2449017-e2449017.

Lai

Lin

Hsu

Chu

. Comparing the effectiveness and safety of direct oral anticoagulants and warfarin in patients with cerebral venous thrombosis: A real-world study. J Stroke Cerebrovasc Dis. 2025;34(6):108290.

10.

Toorop

MMA

van Rein

Nierman

, et al. Self-reported therapy adherence and predictors for nonadherence in patients who switched from vitamin K antagonists to direct oral anticoagulants. Res Pract Thromb Haemost. 2020;4(4):586-593.

11.

Page

McKenzie

Bossuyt

, et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. Br Med J. 2021:372.

12.

Higgins

JPT

Thomas

Chandler

, et al. Cochrane handbook for systematic reviews of interventions. Cochrane Handbook for Systematic Reviews of Interventions. 2019:1-694.

13.

Schulman

Kearon

. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemostasis. 2005;3(4):692-694.

14.

Sterne

JAC

Savović

Page

, et al. Rob 2: A revised tool for assessing risk of bias in randomised trials. Br Med J. 2019:366.

15.

Wells

. 2014. The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Meta-Analyses.

16.

Higgins

JPT

Thompson

Deeks

Altman

. Measuring inconsistency in meta-analyses. Br Med J. 2003;327:557-560.

17.

Egger

Smith

Schneider

Minder

. Bias in meta-analysis detected by a simple, graphical test. Br Med J. 1997;315:629-634.

18.

Alkhawam

Okar

Hanafi

, et al. Rivaroxaban versus warfarin for the treatment of cerebral venous thrombosis (RWCVT): A randomized controlled trial in resource-limited setting. Stroke Res Treat. 2025;2025(1).

19.

Bajko

Maier

Motataianu

, et al. Rivaroxaban for the treatment of cerebral venous thrombosis: A single-center experience. Acta Neurol Belg. 2022;122(1):105-111.

20.

Dong

Liu

Jiang

Zhang

Liu

. Clinical efficacy of conventional heparin anticoagulation combined with apixaban in the treatment of patients with cerebral venous thrombosis and its effect on serum. Comput Math Methods Med. 2021;2021(1).

21.

Esmaeili

Abolmaali

Aarabi

, et al. Rivaroxaban for the treatment of cerebral venous thrombosis. BMC Neurol. 2021;21(1).

22.

Fei-hu

Xue

. Clinical observation of rivaroxaban and warfarin in the treatment of cerebral venous Sinus thrombosis. ACTA NEUROPHARMACOLOGICA. 2022;12(3):5.

23.

Ferro

Coutinho

Dentali

, et al. Safety and efficacy of dabigatran etexilate vs dose-adjusted warfarin in patients with cerebral venous thrombosis: A randomized clinical trial. JAMA Neurol. 2019;76(12):1457-1465.

24.

Field

Dizonno

Almekhlafi

, et al. Study of rivaroxaban for cerebral venous thrombosis: A randomized controlled feasibility trial comparing anticoagulation with rivaroxaban to standard-of-care in symptomatic cerebral venous thrombosis. Stroke. 2023;54(11):2724-2736.

25.

Geisbüsch

Richter

Herweh

Ringleb

Nagel

. Novel factor xa inhibitor for the treatment of cerebral venous and sinus thrombosis: First experience in 7 patients. Stroke. 2014;45(8):2469-2471.

26.

Jiang

Chen

, et al. Efficacy and safety assessment of rivaroxaban for the treatment of cerebral venous sinus thrombosis in a Chinese population. Clin Appl Thromb Hemost. 2022•journals.sagepub.com. 2022;28.

27.

Khorvash

Farajpour-Khanaposhtani

Hemasian

Saadatnia

. Evaluation of rivaroxaban versus warfarin for the treatment of cerebral vein thrombosis: A case-control blinded study. Curr J Neurol. 2021;20(3):125-130.

28.

Bian

, et al. Dabigatran etexilate versus warfarin in cerebral venous thrombosis in Chinese patients (CHOICE-CVT): An open-label, randomized controlled trial. Int J Stroke. 2024;19(6):635-644.

29.

Maqsood

Imran Hasan Khan

Yameen

Aziz Ahmed

Hussain

. Use of oral rivaroxaban in cerebral venous thrombosis. J Drug Assess. 2020;10(1):1-6.

30.

Pan

Wang

Zhou

Ding

Meng

. Efficacy and safety of rivaroxaban in cerebral venous thrombosis: Insights from a prospective cohort study. J Thromb Thrombolysis. 2022•Springer. 2022;53(3):594-600.

31.

Simaan

Metanis

Honig

, et al. Efficacy and safety of Apixaban in the treatment of cerebral venous sinus thrombosis: a multi-center study. Front Neurol. 2024;15.

32.

Saeed

Ahmad

. Comparison of warfarin and rivaroxaban in treatment of cerebral venous sinus thrombosis. Indo Am J Pharm Sci. 2019;6:8487-8492.

33.

van de Munckhof

van Kammen

Tatlisumak

, et al. Direct oral anticoagulants versus vitamin K antagonists for cerebral venous thrombosis (DOAC-CVT): An international, prospective, observational cohort study. Lancet Neurol. 2025;24(3):199-207.

34.

Riva

Carrier

Gatt

Ageno

. Anticoagulation in splanchnic and cerebral vein thrombosis: An international vignette-based survey. Res Pract Thromb Haemost. 2020;4(7):1192-1202.

35.

Weimar

Beyer-Westendorf

Bohmann

, et al. New recommendations on cerebral venous and dural sinus thrombosis from the German consensus-based (S2k) guideline. Neurol Res Pract. 2024;6(1):1-11.

36.

Chen

Stecker

Warden

. Direct oral anticoagulant use: A practical guide to common clinical challenges. J Am Heart Assoc. 2020;9(13).

37.

Miceli

Ciaccio

Tuttolomondo

. Challenges and opportunities of direct oral anticoagulant (DOAC) therapy in complex clinical scenarios: A comprehensive review and practical guide. J Clin Med. 2025;14(9).

38.

Ranjan

Ken-Dror

Sharma

. Direct oral anticoagulants compared to warfarin in long-term management of cerebral venous thrombosis: A comprehensive meta-analysis. Health Sci Rep. 2024;7(2).

39.

Perry

. 2023. Apixaban is safer and more effective than rivaroxaban for non-valvular atrial fibrillation.

40.

Granger

Alexander

McMurray

JJV

, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-992.

41.

Shaji

Thomas

Saju

Abraham

Nayak

. Dabigatran: Clinical correlation of drug and its dose with risk of stroke and bleeding. Perspect Clin Res. 2023;14(1):26-31.

42.

Trkulja

. Safety of apixaban for venous thromboembolism prophylaxis: The evidence to date. Drug Health Patient Saf. 2016;8:25-38.

43.

Kim

Honig

Alimohammadi

Sepehry

Zhou

Field

. Recanalization and outcomes after cerebral venous thrombosis: a systematic review and meta-analysis. Res Pract Thromb Haemost. 2023;7(3).

44.

Dawwas

Brown

Dietrich

Park

. Effectiveness and safety of apixaban versus rivaroxaban for prevention of recurrent venous thromboembolism and adverse bleeding events in patients with venous thromboembolism: A retrospective population-based cohort analysis. Lancet Haematol. 2019;6(1):e20-e28.

45.

Schaefer

Errickson

Kong

, et al. A comparison of outcomes with apixaban, rivaroxaban, and warfarin for atrial fibrillation and/or venous thromboembolism. JACC: Advances. 2025;4(5).

46.

Byon

Garonzik

Boyd

Frost

. Apixaban: A clinical pharmacokinetic and pharmacodynamic review. Clin Pharmacokinet. 2019;58(10):1265.

47.

Nutescu

. Apixaban: A novel oral inhibitor of factor Xa. Am J Health Syst Pharm. 2012;69(13):1113-1126.

48.

Wong

Pinto

DJP

Zhang

. Preclinical discovery of apixaban, a direct and orally bioavailable factor Xa inhibitor. J Thromb Thrombolysis. 2011;31(4):478-492.

49.

Saposnik

Bushnell

Coutinho

, et al. Diagnosis and management of cerebral venous thrombosis: A scientific statement from the American Heart Association. Stroke. 2024;55(3):E77-E90.

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