FormalPara Key Points

This was a systematic review and meta-analysis synthesizing 25 observational studies, including 681,022 participants, and investigating the efficacy and safety of direct oral anticoagulants (DOACs) versus warfarin.

DOACs were superior to warfarin in preventing venous thromboembolism recurrence.

DOACs were associated with better safety outcomes such as major bleeding, clinically relevant non-major bleeding, and gastrointestinal bleeding.

1 Introduction

Venous thromboembolism (VTE), which includes deep venous thrombosis (DVT) and pulmonary embolism (PE), is a well-known cause of disability and mortality, with a global incidence exceeding 10 million cases annually [1]. Accordingly, it is the third most common cardiovascular disease after acute myocardial infarction and stroke and is associated with enormous short- and long-term morbidities [2]. In addition to the current high prevalence of VTE, it is expected to exceed 1.8 million cases in the United States (US) alone by 2050 [3]. About two-thirds of reported VTE cases are diagnosed as DVT episodes that often develop in the deep leg veins. Others present with PE when clots travel through the heart to the pulmonary arteries [4]. Besides its effects on the population’s health, VTE imposes serious negative economic impacts [5]. In terms of treatment, VTE events have been successfully managed for decades using anticoagulants (ACs) to suppress the synthesis or function of various clotting factors [6].

Anticoagulation, the cornerstone of VTE treatment, is recommended for a duration of at least 3 months in most patients with DVT and/or PE [9]. The goal of AC therapy is to avoid fatal PE, prevent recurrence, and lower the risk of long-term problems, such as post-thrombotic syndrome, long-term exertional dyspnea, or chronic thromboembolic pulmonary hypertension. Guidelines recommend the use of AC over three phases: an initial phase (first week from diagnosis), a long-term phase (the following 3–6 months), and an extended phase, where anticoagulation therapy, in some circumstances, must be extended indefinitely for patients who exhibit a high risk of thrombosis and a low risk of bleeding [7,8,9,10].

For many years, warfarin has served as the unchallenged AC option for the management of patients with acute VTE events in the long-term phase [6]. However, the necessity for parenteral AC in the initial treatment phase, the need for frequent monitoring and dose adjustment, and the existence of many drug–drug and drug–food interactions are major drawbacks to using warfarin in practice [11]. In light of those limitations, direct oral ACs (DOACs) are recognized as a good alternative, allowing for fixed-dose administration and less frequent monitoring.

Multiple randomized clinical trials (RCTs) have been conducted to compare DOACs to warfarin in terms of safety and efficacy [12,13,14,15,16,17]. Each of these reports highlights the superiority of using any DOAC agent compared to warfarin in terms of efficacy. Despite the valuable evidence that RCTs provide, strict inclusion and exclusion criteria constrain their utility. In contrast, real-world data (RWD) offer a supplementary source of evidence, capturing the complexities and diversity present in real-world settings, including individuals who may not meet the criteria or be subject to the controlled conditions imposed in RCTs. Accordingly, we performed this systematic review and meta-analysis to bridge the gap by assessing the actual effectiveness and safety of DOACs compared to warfarin using data from real-world practice settings.

2 Methods

2.1 Search Strategy and Databases

A systematic literature search was conducted using PubMed and EMBASE from inception through June 2024 to identify observational studies that compared the outcomes of using DOACs versus warfarin in patients with acute VTE. The literature search was limited to peer-reviewed articles published in English. The search terms included venous thromboembolism, VTE, deep venous thromboembolism, DVT, pulmonary embolism, PE, rivaroxaban, edoxaban, apixaban, dabigatran, DOACs, vitamin K antagonists, VKA, and warfarin.

2.2 Study Selection, Data Extraction, and Quality Assessment

Studies were included if they were observational (i.e., non-randomized), evaluated DOACs and warfarin for acute VTE management, reported VTE recurrence, and/or noted bleeding-related outcomes. Case reports, economic evaluations, RCTs, and other study designs not reporting analyses of RWD were excluded. Studies were also excluded if their participants were restricted to patients who were morbidly obese, had active cancer, and/or had end-stage renal disease, including hemodialysis. In addition, studies that evaluated both atrial fibrillation and VTE patients were excluded if they did not report the VTE patients’ outcomes separately.

Initially, four researchers (WAA, SAA, SMA, and AMA) independently screened the studies under consideration for eligibility based on titles and abstracts. The Rayyan software was used to combine the search results and remove duplicates [18]. All identified studies were assessed for final inclusion based on a full-text review by two other senior authors (MSA and ARA), and any disagreements were resolved by consensus among these two senior authors. Four investigators (WAA, SAA, SMA, and AMA) extracted the following data from the included studies into an Excel sheet: the primary author’s last name, year of publication, number of centers, patients’ baseline characteristics, study arms, study period, key inclusion and exclusion criteria, and the reported effectiveness and safety outcomes with their related definitions. Two additional investigators (RSA and MAA) checked and validated the extracted data.

2.3 Data Synthesis and Analysis

The effectiveness outcome of the analysis estimated the risk of VTE recurrence among the DOACs group relative to the use of warfarin via the hazard ratio (HR) or odds ratio (OR) with a corresponding 95% confidence interval (CI). The safety outcomes included major bleeding, clinically relevant non-major bleeding, intracranial hemorrhage, gastrointestinal bleeding, and all-cause mortality. The meta-analysis was performed with a random-effects model using Comprehensive Meta-Analysis (CMA) software version 3. Forest plots were used to summarize the results, including the heterogeneity I2 statistics using the restricted maxim likelihood method (REML) [19]. We also ran a sensitivity analysis by eliminating one study at a time to examine the effect on the pooled analysis and heterogeneity score when a substantial degree of heterogeneity was detected (I2 > 75%). Publication bias was assessed via Egger’s test. Lastly, this meta-analysis was prepared in accordance with the preferred reporting system for meta-analysis of observational studies (MOOSE) [20].

2.4 Quality Assessment and Publication Bias

The Newcastle–Ottawa Scale (NOS), which consists of eight criteria encompassing three domains—selection, comparability, and outcome—is a useful tool for assessing the quality of nonrandomized studies. The NOS scale has a maximum of nine stars, with low-quality studies receiving one to three stars, average-level studies receiving four to six stars, and high-quality studies receiving seven to nine stars [21]. Two of the team’s investigators (WAA and SMA) independently applied the NOS scale to rate the quality of the included studies independently, and any disagreements were resolved by consensus among these two authors.

3 Results

3.1 Study Selection and Baseline Characteristics

A total of 33,777 publications were initially identified from the PubMed (n = 10,351) and EMBASE (n = 23,426) databases. After removing 3556 duplicates, the remaining 30,221 articles were subjected to title and abstract screening. Among the latter, 300 were selected for full-text review, and 275 studies were excluded at this stage for various reasons. Ultimately, the selection process yielded 25 studies to be included in the current meta-analysis [22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46]. Figure 1 presents the flowchart for the literature retrieval process. The sample sizes for the included studies ranged between 107 and 155,119 patients, and 680,695 patients were included in the analysis. All included studies were retrospective in nature except for one prospective study. Most of the studies were conducted in the US using data retrieved from hospitals or claims (Table 1). The NOS score for all included studies was eight or nine stars (Figure S1, see the electronic supplementary material); additionally, the results from conducting Egger’s test for all outcomes did not suggest a potential for publication bias (Table S1).

Fig. 1
figure 1

Flow diagram for studies included in the systematic review and meta-analysis

Full size image
Table 1 Characteristics of studies included in the meta-analysis
Full size table

3.2 Effectiveness Outcomes

The use of DOACs for the treatment of acute VTE was associated with a 24% reduction in the risk of recurrent VTE events compared to the use of warfarin (HR 0.76, 95% CI 0.69–0.85), but a significant degree of heterogeneity was observed (I2 = 83.9%). Likewise, the incidence of recurrent VTE in patients treated with DOACs was lower compared to patients treated with warfarin based on studies that reported the number of events per arm (OR 0.72, 95% CI 0.64–0.80; I2 = 78.48%). The forest plots for the effectiveness outcomes are displayed in Fig. 2.

Fig. 2
figure 2

Comparison of the risk of recurrent VTE for patients on DOACs compared to patients on warfarin using random-effects model. A Studies that reported hazard ratios (I2 = 83.9%). B Studies that reported number of events per arm (I2 = 78.48%). CI confidence interval, DOAC direct oral anticoagulant

Full size image

3.3 Safety Outcomes

The use of DOAC agents was significantly associated with a 23% reduction in the risk of major bleeding compared to warfarin (HR 0.77, 95% CI 0.72–0.83); however, as with the risk of recurrent VTE events, high heterogeneity was found (I2 = 53.82%). Similarly, the risk of major bleeding events in patients treated with DOACs was lower compared to patients treated with warfarin based on studies reporting the number of events per arm (OR 0.70, 95% CI 0.63–0.77; I2 = 66.04%). The forest plots for major bleeding are presented in Fig. 3.

Fig. 3
figure 3

Comparison of the risk of major bleeding for patients on DOACs compared to patients on warfarin using random-effects model. A Studies that reported hazard ratios (I2 = 53.82%) B Studies that reported number of events per arm (I2 = 66.04%). CI confidence interval, DOAC direct oral anticoagulant

Full size image

Compared to warfarin, DOACs were significantly associated with a lower risk of clinically relevant non-major bleeding (HR 0.82, 95% CI 0.77–0.88; I2 = 75.5%). This outcome was also observed in studies reporting the number of events per arm (OR 0.82, 95% CI 0.72–0.94; I2 = 92.2%). Figure 4 presents the forest plots for the clinically relevant non-major bleeding.

Fig. 4
figure 4

Comparison of the risk of clinically relevant non-major bleeding for patients on DOACs compared to patients on warfarin using random-effects model. A Studies that reported hazard ratios (I2 = 75.48%). B Studies that reported number of events per arm (I2 = 92.19%). CI confidence interval, DOAC direct oral anticoagulant

Full size image

The risk of gastrointestinal bleeding was also lower in the DOACs group compared to the warfarin group (HR 0.75, 95% CI 0.68–0.83) and exhibited no heterogeneity (I2 = 0%). Similarly, studies reporting the number of events per arm also demonstrated a lower risk (OR 0.69, 95% CI 0.60–0.81, I2 = 18.73%). The results for gastrointestinal bleeding can be found in Fig. 5.

Fig. 5
figure 5

Comparison of the risk of gastrointestinal bleeding for patients on DOACs compared to patients on warfarin using random-effects model. A Studies that reported hazard ratios (I2 = 0%). B Studies that reported number of events per arm (I2 = 18.73%). CI confidence interval, DOAC direct oral anticoagulant

Full size image

The risk of intracranial hemorrhage was significantly lower in the DOACs group compared to the warfarin group (HR 0.69, 95% CI 0.52–0.91; I2 = 38.9%). However, no significant differences were observed in the incidence of intracranial hemorrhage among studies reporting the number of events per arm (OR 0.69, 95% CI 0.53–0.91; I2 = 2.39%). For the forest plots for the risk of intracranial hemorrhage, please see Fig. 6.

Fig. 6
figure 6

Comparison of the risk of intracranial hemorrhage for patients on DOACs compared to patients on warfarin using random-effects model. A Studies that reported hazard ratios (I2 = 38.89%). B Studies that reported number of events per arm (I2 = 2.39%). CI confidence interval, DOAC direct oral anticoagulant

Full size image

Four studies reported the HR for all-cause mortality in patients receiving DOACs and warfarin, and no significant difference was found in the risk of all-cause mortality between the two groups (HR 0.96, 95% CI 0.83–1.10). In addition, six studies reported the number of events per arm, with no significant difference in the incidence of all-cause mortality among patients treated with DOACs or warfarin (OR 0.75, 95% CI 0.61–0.94). The forest plots for all-cause mortality are illustrated in Fig. 7.

Fig. 7
figure 7

Comparison of the risk of all-cause mortality for patients on DOACs compared to patients on warfarin using random-effects model. A Studies that reported hazard ratios (I2 = 59.25%). B Studies that reported number of events per arm (I2 = 77.87%). CI confidence interval, DOAC direct oral anticoagulant

Full size image

Among studies reporting HR and OR for the risk of recurrent VTE and clinically relevant non-major bleeding, significant heterogeneity was seen (I2 > 75%). According to the sensitivity analysis, the pooled estimates did not differ significantly from the primary analyses (Figures S2–S5). However, eliminating Kohn et al. and Zakai et al. from studies reporting HRs (HR 0.77, 95% CI 0.70–0.84, I2 = 67.3%; not presented in figures), and eliminating Dawwas et al. from studies reporting ORs (OR 0.76, 95% CI 0.70–0.82, I2 = 55.36 %) for the risk of recurrent VTE reduced the heterogeneity to less than 75%. Similarly, excluding Perino et al. from studies reporting HRs (HR 0.80, 95% CI 0.77–0.84; I2 = 37.0%) and ORs (OR 0.77, 95% CI 0.72–0.82; I2 = 50.7%) for the risk of clinically relevant non-major bleeding reduced heterogeneity to less than 75%.

4 Discussion

Warfarin has traditionally been the primary therapeutic agent for managing VTE; however, the limitations associated with its use have highlighted the viability of DOACs as an alternative. According to the results of clinical trials, DOACs have demonstrated comparable efficacy and a superior safety profile to warfarin. Furthermore, real-world studies have uncovered compelling evidence supporting the superiority of DOACs, as demonstrated in this systematic review and meta-analysis, which aimed to assess the effectiveness and safety of DOACs versus warfarin in real-world practice. In comparison to warfarin, we found the use of DOACs to be significantly associated with a reduced risk of recurrent VTE, major bleeding, clinically relevant non-major bleeding, gastrointestinal bleeding, and intracranial hemorrhage.

Several previous systematic reviews and meta-analyses also examined the effectiveness and safety of DOACs compared to warfarin. A network meta-analysis reported that patients treated with DOACs for acute VTE events experienced similar efficacy and exhibited a better safety profile than patients treated with warfarin [47]. Another meta-analysis found that DOACs were associated with a decreased risk of bleeding in acute VTE [48]. In contrast with the present study, the previous meta-analyses pooled available data from RCTs only [47, 48]. Additionally, a network meta-analysis from RWD but in patients with non-valvular atrial fibrillation yielded results that aligned with our findings in patients with VTE, potentially providing some indirect evidence for this comparison; in particular, compared to patients using warfarin, the researchers associated patients using DOACs with better effectiveness outcomes (lower risk of stroke and systemic embolism) and a favorable safety profile (lower risk of major bleeding and intracranial bleeding). However, unlike our findings in patients with VTE, all-cause mortality was significantly lower in the DOAC group in that study [49].

The most frequently used DOACs in the current meta-analysis were apixaban and rivaroxaban, and findings from RWD support their use in patients with acute VTE. For instance, a large study from Saudi Arabia reported comparable VTE recurrence rates between apixaban and warfarin, but significantly fewer major bleeding events with apixaban [50]. Another analysis of data concerning hospital resource utilization and costs in the US revealed that apixaban treatment was associated with a shorter hospital stay, lower cost, and reduced risk of major bleeding-related readmissions compared to warfarin [51]. These observational studies collectively support our results that apixaban may be a more favorable option than warfarin in the treatment of acute VTE. Furthermore, the reports of a systematic review and meta-analysis comparing apixaban to warfarin support our finding regarding DOACs’ favorable safety profile [52]. In addition, a recently published meta-analysis demonstrated that rivaroxaban could significantly reduce the incidence of VTE and major bleeding events compared to warfarin [53]. However, in a direct comparison using RWD, Aryal et al. found that apixaban and rivaroxaban had equivalent effectiveness in terms of preventing recurrent VTE, while apixaban exhibited a lower risk of both major and minor bleeding [54]. Therefore, our findings support the recommendations in the guidelines from the American Society of Hematology (2020) and the American College of Chest Physicians (2021) [9, 10], which suggest using DOACs over warfarin for VTE therapy except for certain groups, such as cancer patients, where more data are still needed.

This meta-analysis yields noteworthy implications and recommendations for clinical practice. Our findings offer valuable insights into the safety and effectiveness profile for DOACs in real-world settings, revealing that DOACs actually demonstrate favorable effectiveness and a better safety profile in light of the lower risk of recurrent VTE and major bleeding events compared to warfarin. However, it is crucial to consider that the risk of bleeding can alternatively be influenced by individual patient characteristics, comorbidities, and concomitant medications. Consequently, clinicians should exercise caution, carefully assess patient-specific factors, and evaluate potential bleeding risks before initiating DOAC-based therapy.

Notably, we must also acknowledge that the current meta-analysis has certain limitations. The considerable variability observed among the included studies with regard to study designs, follow-up period duration, outcomes, and sample sizes potentially might have contributed to the substantial heterogeneity observed in our analysis. Although this systematic review and meta-analysis included data for more than 400,000 patients from observational studies around the globe, only two studies reported the mean International normalized ratio (INR) in the warfarin group. This omission could affect the effectiveness outcomes, as the INR might not have been at the therapeutic target during the treatment period. Therefore, the findings should be used with caution until large direct comparative studies can be conducted, including sub-group analyses, to support this evidence. Perhaps future studies might scrutinize more carefully patient-specific outcomes that could be based on differences in terms of sex, age group, and the presence of other comorbidities.

5 Conclusion

In conclusion, our meta-analysis of real-world studies provides valuable insights into the use of DOACs in clinical practice. The findings suggest that DOACs are generally effective in treating acute VTE events and are associated with a lower incidence of VTE recurrence compared to warfarin. In addition, DOACs demonstrate a reduced risk of bleeding events, suggesting a favorable safety profile. These findings support the use of DOACs as a viable treatment option for acute VTE management, offering improved outcomes with a lower risk of recurrence and bleeding-related complications.