Skip to main content
The Egyptian Heart Journal
Download PDF

Direct comparison of non-vitamin K antagonist oral anticoagulant versus warfarin for stroke prevention in non-valvular atrial fibrillation: a systematic review and meta-analysis of real-world evidences

The Egyptian Heart Journal volume 73, Article number: 70 (2021) Cite this article

Abstract

Background

To overcome the several drawbacks of warfarin, non-vitamin K antagonist oral anticoagulants (NOACs) were developed. Even though randomized controlled trials (RCTs) provided high-quality evidence, the real-world evidence is still needed. This systematic review and meta-analysis proposed to measure the safety and efficacy profile between warfarin and NOACs in non-valvular atrial fibrillation (NVAF) patients in preventing stroke.

Results

We collected articles about the real-world studies comparing warfarin and NOACs for NVAF patients recorded in electronic scientific databases such as Embase, ProQuest, PubMed, and Cochrane. The pooled hazard ratio (HR) and 95% confidence interval (CI) were estimated using the generic inverse variance method. A total of 34 real-world studies, including 2287288 NVAF patients, were involved in this study. NOACs effectively reduced the stroke risk than warfarin (HR 0.77; 95% CI 0.69 to 0.87; p < 0.01). Moreover, NOACs effectively lowered all-cause mortality risk (HR 0.71; 95% CI 0.63 to 0.81; p < 0.01). From the safety aspect, compared to warfarin, NOACs significantly reduced major bleeding risk (HR 0.68; 95% CI 0.54 to 0.86; p < 0.01) and intracranial bleeding risk (HR 0.54; 95% CI 0.42 to 0.70; p < 0.01). However, NOACs administration failed to decrease gastrointestinal bleeding risk (HR 0.78; 95% CI 0.58 to 1.06; p = 0.12).

Conclusions

In NVAF patients, NOACs were found to be more effective than warfarin at reducing stroke risk. NOACSs also lowered the risk of all-cause mortality, cerebral hemorrhage, and severe bleeding in NVAF patients compared to warfarin.

Background

Atrial fibrillation (AF) puts the patients at high risk for stroke or other systemic thromboembolic events [1, 2]. Current guidelines from several cardiovascular societies recommend oral anticoagulant treatment for long-term stroke prevention strategy in AF patients [3,4,5,6]. Warfarin, a vitamin K antagonist (VKA), is an anticoagulant widely used worldwide. It effectively reduces stroke risk and mortality in AF patients [7]. However, warfarin has several drawbacks, such as the narrow therapeutic window, the requirement for stably achieved international normalized ratio (INR), the need for routine INR monitoring, the drug to food interaction, the drug to drug interaction, and drug dose adjustment [8]. A prior study revealed that an INR value below 2.0 was related to the increased risk of stroke, while an INR value above 3.0 was related to the increased bleeding risk [9]. It can be a serious problem in patients with old age, non-compliance with medication, and various comorbidities.

The non-vitamin K antagonist oral anticoagulants (NOACs), including apixaban, dabigatran, edoxaban, and rivaroxaban, were developed to overcome several drawbacks of warfarin. In the non-valvular atrial fibrillation (NVAF) population, several randomized controlled trials (RCTs) revealed that NOACs were associated with better or at least non-inferior than warfarin for systemic embolism and/or stroke prevention [10,11,12,13]. From the safety point of view, edoxaban, apixaban, and low-dose dabigatran were related to lower bleeding rates [11,12,13]. However, rivaroxaban and high-dose dabigatran were correlated with similar rates of bleeding [10, 11]. Even though RCTs provide good evidence, they are limited by the strict inclusion and exclusion criteria. The real-world data offer additional evidence in an extensive spectrum of the study population outside the strictly selected and controlled population involved in the RCTs [14]. Therefore, we conducted a systematic review and meta-analysis to measure the efficacy and safety profile between warfarin and NOACs in preventing stroke in NVAF patients.

Methods

Design

A systematic review and meta-analysis study was completed in January 2021 based on the guidance from preferred reporting items for systematic review and meta-analysis (PRISMA) [15]. We collected articles about the real-world studies comparing NOACs and warfarin in NVAF patients recorded in online databases such as Embase, ProQuest, PubMed, and Cochrane. Studies that satisfy the eligibility criteria were involved in the quality assessment of the study. The essential information was extracted only from high-quality studies. The exposure variable was anticoagulants treatment. We divided the patients into “NOACs group” and “warfarin group.” We also performed the “head to head” comparison between each NOAC (apixaban, dabigatran, edoxaban, or rivaroxaban) and warfarin. The stroke risk was our primary outcome. The secondary outcomes included the risk of: (1) all-cause mortality; (2) major bleeding; (3) intracranial bleeding; and (4) gastrointestinal bleeding. The pooled hazard ratio (HR) and 95% confidence interval (CI) were applied in determining the overall effect.

Search strategy

Until December 2020, articles comparing the safety and efficacy of NOACs and warfarin in NVAF were collected from electronic scientific databases such as Embase, ProQuest, PubMed, and Cochrane. We used the following keywords: “non-vitamin K antagonist oral anticoagulant” or “new oral anticoagulant” or “novel oral anticoagulant’ or “NOAC,” AND “direct oral anticoagulant” or “DOAC,” AND “vitamin K antagonist” or “VKA,” AND “warfarin,” AND “dabigatran,” AND “apixaban,” AND “edoxaban,” AND “rivaroxaban,” AND “non-valvular atrial fibrillation” or “non-valvular AF” or “NVAF,” AND “stroke,” AND “cerebrovascular accident” or “CVA,” AND “death” or “all-cause death,” AND “mortality” or “all-cause mortality,” AND “major bleeding” or “major hemorrhage,” AND “intracranial bleeding” or “intracranial hemorrhage,” AND “gastrointestinal bleeding” or “gastrointestinal hemorrhage” or “GI bleeding” or "GI hemorrhage." We also collected all relevant articles through the list of references from all accessed articles or Google Scholar. We did not apply the language restriction during the initial data searching process.

Eligibility criteria

We involved all articles which met the inclusion criteria, including: (1) cohort or real-world studies compared warfarin and NOACs in NVAF patients; (2) studies with the purpose to investigate the efficacy and/or safety profile of NOACs and warfarin in NVAF patients for stroke prevention; (3) intervention group was NOACs (apixaban, dabigatran, edoxaban, and rivaroxaban); (4) control group was warfarin; (5) availability of data about stroke, all-cause mortality, major bleeding, intracranial bleeding, or gastrointestinal bleeding; and (6) effect estimates were in HR and 95% CI. We excluded articles with one or more theses following criteria: (1) duplications; (2) not published in English; (3) involved patients with venous thromboembolism (VTE); (4) did not specify the name of the drug; (5) did not use warfarin as VKA; and (6) outcomes of interest were not reported. Two investigators reviewed all included articles. Discussion between both investigators or consultation with the third investigator was done to resolve the disagreement.

Study quality assessment

We used the Newcastle-Ottawa scale (NOS) to evaluate the quality of the studies. It has three domains with a maximum score of 9. According to the NOS, a good quality cohort study was defined as a study with 3 to 4 stars in the selection domain, 1 to 2 stars in the comparability domain, and 2 to 3 stars in the outcome domain [16]. Two investigators performed the study quality assessment. Discrepancies between both investigators during study quality assessment were resolved by consultation or discussion with the third investigator. We only included high-quality real-world studies in this systematic review and meta-analysis.

Data extraction

Important information about (1) name of the first author; (2) date of publication; (3) enrolment period; (4) country; (5) data source; (6) type of anticoagulants; (7) number of participants; (8) CHA2DS2-VASc score; (9) HAS-BLED score; (10) follow up period duration; (11) primary statistical model; and (12) adjusted HR and 95% CI of stroke, all-cause mortality, major bleeding, intracranial bleeding, and gastrointestinal bleeding were extracted from each study. Four investigators conducted the data extraction process.

Statistical analysis

The meta-analysis was conducted using a combination of two software, Review Manager Version 5.3 (RevMan, Cochrane, Copenhagen, Denmark) and Comprehensive Meta-Analysis version 3.0 (CMA, New Jersey, USA). We conducted the meta-analysis based on the direction from the existing guideline [17]. We collected adjusted HR, 95% CI, and the number of participants in each group. Log HR was calculated using each study’s logarithms, while the standard error (SE) was obtained from the CI given by each study. We applied Begg’s test and Egger’s test for publication bias identification. The p value of < 0.05 for Begg’s test or Egger’s test represented the presence of publication bias [18,19,20]. The Q test was applied in identifying the heterogeneity among the involved studies. In the presence of heterogeneity (p value of heterogeneity < 0.1), we used the random-effect analysis model. On the contrary, in the absence of heterogeneity (p value of heterogeneity ≥ 0.1), we used the fixed-effect analysis model [21, 22]. The pooled HR and 95% CI were determined using the generic inverse variance method [23]. Statistically significant was considered if the p value of < 0.05. Three investigators conducted the statistical analysis process.

Results

Study selection and baseline characteristics

In the beginning, we had collected 2303 potentially eligible articles from electronic scientific databases. After duplicate removal, we had 794 articles. A total of 701 articles were excluded because of unrelated to our study. We performed full-text assessment in 93 studies, then a total of 59 studies were excluded due to (1) not published in English (n = 9); (2) involved patients with VTE (n = 19); (3) did not specify the name of the drug (n = 18); (4) did not use warfarin as VKA (n = 6); and (5) outcomes of interest were not reported (n = 7). Finally, 34 studies were involved in this study [24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57]. The study selection flowchart is presented in Fig. 1. In this study, we only involved high-quality studies assessed by NOS (Supplementary Table 1).

Fig. 1
figure 1

Flow diagram summarizing the selection process of included studies. RCT = randomized controlled trial, VKA = vitamin K antagonist VTE = venous thromboembolism

Full size image

A total of 2287288 NVAF patients receiving apixaban, dabigatran, edoxaban, rivaroxaban, or warfarin from 34 real-world studies were involved in our meta-analysis. We involved studies that had been done in various countries in America, Asia, and Europe [24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57]. The mean CHA2DS2-VASc score ranged from 2 to 4.7 [24,25,26,27,28,29,30, 33, 36, 39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55, 57] while the HAS-BLED score ranged from 1.27 to 3.9 [24,25,26, 28,29,30, 33, 39, 40, 42, 46, 47, 49,50,51,52,53,54,55]. The primary statistical method included propensity score matching [25, 27, 31,32,33,34,35, 39, 41, 44, 47, 49, 50, 53, 55,56,57], propensity score weighting [24, 26, 28,29,30, 37, 38, 42, 43, 45, 46, 51, 52], and Cox proportional hazard model [36, 40, 48, 54]. The follow-up period duration was long enough [24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57]. Table 1 represents the baseline characteristics of the all included studies.

Table 1 Baseline characteristics of the studies
Full size table

Heterogeneity and publication bias

Heterogeneity was represented by a p value of heterogeneity of < 0.1. It was found in almost all analyses, except for the risk of: (1) stroke between edoxaban and warfarin; (2) all-cause mortality between NOACs and warfarin; and (3) intracranial bleeding between rivaroxaban and warfarin. Therefore, in almost all analyses, the random-effect analysis model was used. The p value of Begg’s test and Egger’s test for all analyses were > 0.05, so, no publication bias was found in this study. The assessment of heterogeneity and publication is summarized in Table 2.

Table 2 Summary of the outcomes of interest
Full size table

Primary outcome

Stroke

Our primary outcome was the stroke risk reduction. Our result revealed that NOACs significantly reduced stroke risk in NVAF patients (HR 0.77; 95% CI 0.69 to 0.87; p < 0.01) compared to warfarin (Fig. 2). The subgroup analysis for the specific agent also revealed the consistent results. Apixaban (HR 0.73; 95% CI 0.64 to 0.84; p < 0.01), dabigatran (HR 0.87; 95% CI 0.81 to 0.94; p < 0.01), edoxaban (HR 0.67; 95% CI 0.60 to 0.76; p < 0.01), and rivaroxaban (HR 0.81; 95% CI 0.73 to 0.90; p < 0.01) significantly reduced stroke risk (Fig. 3).

Fig. 2
figure 2

Comparison of NOACs versus warfarin for A stroke, B all-cause mortality, C major bleeding, D intracranial bleeding, and E gastrointestinal bleeding. CI = confidence interval; NOACs = non-vitamin K antagonist oral anticoagulants

Full size image
Fig. 3
figure 3

Comparison of stroke between NOACs and warfarin stratified by each agent. A Apixaban, B dabigatran, C edoxaban, and D rivaroxaban. CI = confidence interval, NOACs = non-vitamin K antagonist oral anticoagulants

Full size image

Secondary outcomes

All-cause mortality

NOACs administration successfully reduced all-cause mortality risk than warfarin (HR 0.71; 95% CI 0.63 to 0.81; p < 0.01) (Fig. 2). From the subgroup analysis, we found that apixaban (HR 0.69; 95% CI 0.49 to 0.98; p = 0.04), dabigatran (HR 0.67; 95% CI 0.57 to 0.80; p < 0.01), and edoxaban (HR 0.52; 95% CI 0.31 to 0.85; p = 0.01) were also related to lower all-cause mortality risk than warfarin (Fig. 4). However, the all-cause mortality risk between rivaroxaban and warfarin was not different significantly (HR 0.91; 95% CI 0.70 to 1.18; p = 0.47) (Fig. 4).

Fig. 4
figure 4

Comparison of all-cause mortality between NOACs and warfarin stratified by each agent. A apixaban, B dabigatran, C edoxaban, and D rivaroxaban. CI = confidence interval, NOACs = non-vitamin K antagonist oral anticoagulants

Full size image

Major bleeding

NOACs effectively reduced major bleeding risk (HR 0.68; 95% CI 0.54 to 0.86; p < 0.01) than warfarin (Fig. 2). The subgroup analysis also revealed the consistent results. Apixaban (HR 0.57; 95% CI 0.53 to 0.63; p < 0.01), dabigatran (HR 0.75; 95% CI 0.67 to 0.83; p < 0.01), edoxaban (HR 0.55; 95% CI 0.45 to 0.66; p < 0.01), and rivaroxaban (HR 0.90; 95% CI 0.82 to 0.98; p = 0.01) was associated with major bleeding risk reduction (Fig. 5).

Fig. 5
figure 5

Comparison of major bleeding between NOACs and warfarin stratified by each agent. A apixaban, B dabigatran, C edoxaban, and D rivaroxaban. CI = confidence interval, NOACs = non-vitamin K antagonist oral anticoagulants

Full size image

Intracranial bleeding

NOACs administration was correlated with the lower risk for intracranial bleeding (HR 0.54; 95% CI 0.42 to 0.70; p < 0.01) than warfarin (Fig. 2). The similar results were also found in the agent-specific level. Apixaban (HR 0.57; 95% CI 0.48 to 0.68; p < 0.01), dabigatran (HR 0.44; 95% CI 0.38 to 0.52; p < 0.01), edoxaban (HR 0.44; 95% CI 0.26 to 0.76; p < 0.01), and rivaroxaban (HR 0.69; 95% CI 0.64 to 0.74; p < 0.01) effectively reduced major bleeding risk (Fig. 6).

Fig. 6
figure 6

Comparison of intracranial bleeding between NOACs and warfarin stratified by each agent. A apixaban, B dabigatran, C edoxaban, and D rivaroxaban. CI = confidence interval, NOACs = non-vitamin K antagonist oral anticoagulants

Full size image

Gastrointestinal bleeding

The analysis results for gastrointestinal bleeding were different from major bleeding and intracranial bleeding. Overall, NOACs did not significantly reduce the gastrointestinal bleeding risk (HR 0.78; 95% CI 0.58 to 1.06; p = 0.12) (Figure 2). The subgroup analysis demonstrated conflicting results. Compared with warfarin, apixaban (HR 0.58; 95% CI 0.51 to 0.67; p < 0.01) and edoxaban (HR 0.62; 95% CI 0.44 to 0.87; p < 0.01) were related with the gastrointestinal bleeding risk reduction (Fig. 7). However, the administration of dabigatran (HR 0.99; 95% CI 0.87 to 1.12; p =0.88) and rivaroxaban (HR 1.00; 95% CI 0.86 to 1.17; p = 0.97) failed to reduce gastrointestinal bleeding risk (Fig. 7). All outcomes are summarized in Table 2.

Fig. 7
figure 7

Comparison of gastrointestinal bleeding between NOACs and warfarin stratified by each agent. A apixaban, B dabigatran, C edoxaban, and D rivaroxaban. CI = confidence interval, NOACs = non-vitamin K antagonist oral anticoagulants

Full size image

Discussion

Our systematic review and meta-analysis study, including more than 2.2 million NVAF patients, assessed the safety and efficacy profile of warfarin and NOACs for stroke prevention in the real-world population. We analyzed the results of the real-world studies regarding anticoagulant treatment for NVAF in several countries across America, Asia, and Europe. Our study sample is smaller than the study conducted by Wang et al., which included more than 2.3 million patients [58]. However, Wang et al. only assessed the bleeding risk generally. They did not analyze the specific outcome for safety and efficacy profiles [58]. In this study, we tried to analyze the efficacy (stroke risk and all-cause mortality risk) and safety (intracranial bleeding risk, gastrointestinal bleeding risk, and major bleeding risk) profiles specifically.

The efficacy endpoint of our study included stroke risk (primary outcome) and all-cause mortality risk. In our study, NOACs effectively reduced stroke risk compared to warfarin. Our finding was similar to previous meta-analysis studies [59, 60]. In subgroup analysis, apixaban, dabigatran, and rivaroxaban also showed significant stroke risk reduction. These results supported the findings of the prior meta-analysis study [61]. However, our study provided new real-world evidence about the benefit of edoxaban for stroke risk reduction compared to warfarin. Our study also revealed that NOACs effectively reduced all-cause mortality compared to warfarin. This result was not different from the previous meta-analysis studies of RCTs [60, 62]. Our analysis on apixaban, dabigatran, and edoxaban showed the benefit of all-cause mortality risk reduction. Our results were similar to the results of previous studies [61, 63]. However, we failed to provide evidence of the advantage of rivaroxaban to reduce all-cause mortality risk.

Our study revealed that NOACs were correlated with a lower risk of intracranial bleeding and major bleeding than warfarin. Our findings supported the previous evidence from the meta-analysis of RCTs comparing NOACs and warfarin [62]. In subgroup analysis, apixaban, dabigatran, edoxaban, and rivaroxaban also showed similar results for major bleeding and intracranial bleeding. Our findings on the meta-analysis of apixaban, dabigatran, edoxaban, and rivaroxaban were consistent with the prior meta-analysis studies [61, 63, 64]. In our study, the gastrointestinal bleeding risk between NOACs and warfarin was not significantly different. Our result was different from the previous meta-analysis studies. A meta-analysis of RCTs from Ruff et al. demonstrated that NOACs were related to greater gastrointestinal bleeding risk [62]. However, in the meta-analysis of real-world studies from Chan et al., NOACs significantly decreased gastrointestinal bleeding risk [63]. Our study revealed that apixaban and edoxaban effectively reduced gastrointestinal bleeding risk. However, our study also revealed that the bleeding risks between dabigatran and rivaroxaban were not different significantly. Our results on apixaban and edoxaban supported the results of previous real-world meta-analysis studies [61, 63]. The previous meta-analysis studies on dabigatran and rivaroxaban showed conflicting results. A meta-analysis study from Chan et al. [63] showed that dabigatran and rivaroxaban did not significantly reduce the gastrointestinal bleeding risk, while a meta-analysis study from Xue et al. showed that dabigatran and rivaroxaban reduced gastrointestinal bleeding risk [61]. Those two previous meta-analyses included only the real-world data from Asian countries [61, 63]. However, our study provided real-world evidence beyond the Asian population.

Our study demonstrated that NOACS, including apixaban, dabigatran, edoxaban, and rivaroxaban, consistently revealed a significant decrease in the risk of stroke, all-cause mortality, major bleeding, and intracranial bleeding in the real-world setting. The situation in the real-world setting was quite different than in the RCTs. In RCTs, the mean time in the therapeutic range (TTR) of INR 2.0 to 3.0 ranged from 55 to 64% [10,11,12]. However, in most of the real-world studies, the TTR could not be recorded [24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50, 52,53,54,55, 57]. Real-world studies usually have a role in providing complementary sources of knowledge, and their results are fruitful to validate the findings from RCTs. Our study also revealed that NOACs failed to minimize the risk of gastrointestinal bleeding. The possible explanations were the unavailability of the data about: (1) patients' age; (2) the underlying gastrointestinal disease; and (3) the administration of gastroprotective agents. Moreover, the mean HAS-BLED score among the included studies also varied. That could be the essential confounding factor.

In daily clinical practice, NOACs offer more benefit than warfarin due to: (1) rapid onset of action; (2) fixed dosing; (3) few drug to drug interactions; (4) few drug to food interactions; (5) no routine laboratory monitoring; and (6) short blood-thinning effect. However, NOACs also have several drawbacks, such as the high cost and the unavailability of reversal agents [65, 66]. According to our results, we recommend NOACs as the first choice for stroke prevention in NVAF patients.

There were several limitations of our systematic review and meta-analysis study. First, almost all involved studies did not provide data about the treatment regimen’s compliance or persistence. Second, the TTR of warfarin users was not reported in almost all studies. The favorable safety and efficacy profile of NOACs might have been at least partly because of low TTR in warfarin users. Third, we did not conduct subgroup analysis comparing warfarin with a low or high dose of NOACs because of the limited available data. Fourth, among the involved studies, the precise inclusion or exclusion criteria and outcomes definitions varied. Last, even though we involved studies that reported the adjusted HR and 95% CI using either propensity score matching, propensity score weighting, or multi-variate Cox regression, the residual confounding factors with unmeasured variables could not be excluded from this study due to the characteristic of real-world data.

Conclusions

In conclusion, our study demonstrated that NOACs had more efficacy than warfarin in preventing stroke in NVAF patients. NOACs were also related to a lower risk of all-cause mortality, intracranial bleeding, and major bleeding than warfarin. Among NOACs, apixaban and edoxaban might have a better safety and efficacy profile compared to warfarin. A head-to-head RCT that directly compares the specific type of NOACs is needed.

Availability of data and materials

Data used in our study were presented in the main text and supplementary material.

Abbreviations

AF:

Atrial fibrillation

CHA2DS2-VASc:

Congestive heart failure, Hypertension, Age, Diabetes, previous Stroke/transient ischemic attack, VAScular disease

CI:

Confidence interval

CMA:

Comprehensive Meta-Analysis

CVA:

Cerebrovascular accident

DOAC:

Direct oral anticoagulant

GI:

Gastrointestinal

HAS-BLED:

Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly, Drugs/alcohol concomitantly

HR:

Hazard ratio

INR:

International normalized ratio

NOAC:

Non-vitamin K antagonist oral anticoagulant

NOS:

Newcastle-Ottawa scale

NVAF:

Non-valvular atrial fibrillation

PRISMA:

Preferred reporting items for systematic review and meta-analysis

RCT:

Randomized controlled trials

SE:

Standard error

VKA:

Vitamin K antagonist

VTE:

Venous thromboembolism

References

  1. Ceornodolea AD, Bal R, Severens JL (2017) Epidemiology and management of atrial fibrillation and stroke: review of data from four European countries. Stroke Res Treat 2017:1–12. https://doi.org/10.1155/2017/8593207

    Article  Google Scholar 

  2. Pistoia F, Sacco S, Tiseo C, Degan D, Ornello R, Carolei A (2016) The epidemiology of atrial fibrillation and stroke. Cardiol Clin 34(2):255–268. https://doi.org/10.1016/j.ccl.2015.12.002

    Article  PubMed  Google Scholar 

  3. Brieger D, Amerena J, Attia J, Bajorek B, Chan KH, Connell C, Freedman B, Ferguson C, Hall T, Haqqani H, Hendriks J, Hespe C, Hung J, Kalman JM, Sanders P, Worthington J, Yan TD, Zwar N (2018) National Heart Foundation of Australia and the Cardiac Society of Australia and New Zealand: Australian Clinical Guidelines for the Diagnosis and Management of Atrial Fibrillation 2018. Heart Lung Circ 27(10):1209–1266. https://doi.org/10.1016/j.hlc.2018.06.1043

    Article  PubMed  Google Scholar 

  4. Chiang C-E, Okumura K, Zhang S, Chao TF, Siu CW, Wei Lim T, Saxena A, Takahashi Y, Siong Teo W (2017) 2017 consensus of the Asia Pacific Heart Rhythm Society on stroke prevention in atrial fibrillation. J Arrhythmia 33(4):345–367. https://doi.org/10.1016/j.joa.2017.05.004

    Article  Google Scholar 

  5. January CT, Wann LS, Calkins H, Chen LY, Cigarroa JE, Cleveland JC Jr, Ellinor PT, Ezekowitz MD, Field ME, Furie KL, Heidenreich PA, Murray KT, Shea JB, Tracy CM, Yancy CW (2019) 2019 AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. J Am Coll Cardiol 74(1):104–132. https://doi.org/10.1016/j.jacc.2019.01.011

    Article  PubMed  Google Scholar 

  6. Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C, Boriani G, Castella M, Dan GA, Dilaveris PE, Fauchier L, Filippatos G, Kalman JM, la Meir M, Lane DA, Lebeau JP, Lettino M, Lip GYH, Pinto FJ, Thomas GN, Valgimigli M, van Gelder IC, van Putte BP, Watkins CL, ESC Scientific Document Group, Kirchhof P, Kühne M, Aboyans V, Ahlsson A, Balsam P, Bauersachs J, Benussi S, Brandes A, Braunschweig F, Camm AJ, Capodanno D, Casadei B, Conen D, Crijns HJGM, Delgado V, Dobrev D, Drexel H, Eckardt L, Fitzsimons D, Folliguet T, Gale CP, Gorenek B, Haeusler KG, Heidbuchel H, Iung B, Katus HA, Kotecha D, Landmesser U, Leclercq C, Lewis BS, Mascherbauer J, Merino JL, Merkely B, Mont L, Mueller C, Nagy KV, Oldgren J, Pavlović N, Pedretti RFE, Petersen SE, Piccini JP, Popescu BA, Pürerfellner H, Richter DJ, Roffi M, Rubboli A, Scherr D, Schnabel RB, Simpson IA, Shlyakhto E, Sinner MF, Steffel J, Sousa-Uva M, Suwalski P, Svetlosak M, Touyz RM, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C, Boriani G, Castella M, Dan GA, Dilaveris PE, Fauchier L, Filippatos G, Kalman JM, la Meir M, Lane DA, Lebeau JP, Lettino M, Lip GYH, Pinto FJ, Neil Thomas G, Valgimigli M, van Gelder IC, Watkins CL (2021) 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS). Eur Heart J 42(5):373–498. https://doi.org/10.1093/eurheartj/ehaa612

    Article  PubMed  Google Scholar 

  7. Hart RG, Pearce LA, Aguilar MI (2007) Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 146(12):857–867. https://doi.org/10.7326/0003-4819-146-12-200706190-00007

    Article  PubMed  Google Scholar 

  8. Caterina R, Husted S, Wallentin L, Andreotti F, Arnesen H, Bachmann F, Baigent C, Huber K, Jespersen J, Kristensen S, Lip GYH, Morais J, Rasmussen L, Siegbahn A, Verheugt FWA, Weitz JI (2013) Vitamin K antagonists in heart disease: current status and perspectives (Section III): position paper of the ESC Working Group on Thrombosis – Task Force on Anticoagulants in Heart Disease. Thromb Haemost 110(12):1087–1107. https://doi.org/10.1160/TH13-06-0443

    Article  CAS  PubMed  Google Scholar 

  9. Hylek EM (1996) An analysis of the lowest effective intensity of prophylactic anticoagulation for patients with nonrheumatic atrial fibrillation. N Engl J Med 335(8):540–546. https://doi.org/10.1056/NEJM199608223350802

    Article  CAS  PubMed  Google Scholar 

  10. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KAA, Califf RM, the ROCKET AF Steering Committee (2011) Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 365(10):883–891. https://doi.org/10.1056/NEJMoa1009638

    Article  CAS  PubMed  Google Scholar 

  11. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener HC, Joyner CD, Wallentin L (2009) Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 361(12):1139–1151. https://doi.org/10.1056/NEJMoa0905561

    Article  CAS  PubMed  Google Scholar 

  12. Granger CB, Alexander JH, McMurray JJV et al (2011) Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 365(11):981–992. https://doi.org/10.1056/NEJMoa1107039

    Article  CAS  PubMed  Google Scholar 

  13. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Špinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM (2013) Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 369(22):2093–2104. https://doi.org/10.1056/NEJMoa1310907

    Article  CAS  PubMed  Google Scholar 

  14. Freedman B, Potpara TS, Lip GYH (2016) Stroke prevention in atrial fibrillation. Lancet 388(10046):806–817. https://doi.org/10.1016/S0140-6736(16)31257-0

    Article  PubMed  Google Scholar 

  15. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JPA, Clarke M, Devereaux PJ, Kleijnen J, Moher D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 6(7):e1000100. https://doi.org/10.1371/journal.pmed.1000100

    Article  PubMed  PubMed Central  Google Scholar 

  16. Wells G, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Accessed February 22, 2021. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp

  17. Cleophas TJ, Zwinderman AH (2017) Modern meta-analysis: review and update of methodologies. Springer International Publishing. https://doi.org/10.1007/978-3-319-55895-0

  18. Begg CB, Mazumdar M (1994) Operating Characteristics of a Rank Correlation Test for Publication Bias. Biometrics. 50(4):1088–1101. https://doi.org/10.2307/2533446

    Article  CAS  PubMed  Google Scholar 

  19. Egger M, Smith GD, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ. 315(7109):629–634. https://doi.org/10.1136/bmj.315.7109.629

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Waranugraha Y, Rizal A, Setiawan D, Aziz IJ (2021) The benefit of atrioventricular junction ablation for permanent atrial fibrillation and heart failure patients receiving cardiac resynchronization therapy: an updated systematic review and meta-analysis. Indian Pacing Electrophysiol J 21(2):101–111. https://doi.org/10.1016/j.ipej.2020.12.005

    Article  PubMed  PubMed Central  Google Scholar 

  21. Fletcher J (2007) What is heterogeneity and is it important? BMJ. 334(7584):94–96. https://doi.org/10.1136/bmj.39057.406644.68

    Article  PubMed  PubMed Central  Google Scholar 

  22. Waranugraha Y, Rizal A, Setiawan D, Aziz IJ (2021) Additional complex fractionated atrial electrogram ablation does not improve the outcomes of non-paroxysmal atrial fibrillation: A systematic review and meta-analysis of randomized controlled trials. Indian Heart J 73(1):63–73. https://doi.org/10.1016/j.ihj.2020.11.004

    Article  PubMed  Google Scholar 

  23. Borenstein M, Hedges LV, Higgins JPT, Rothstein HR, eds. Introduction to Meta-Analysis. Reprinted. Wiley; 2010.

  24. Adeboyeje G, Sylwestrzak G, Barron JJ et al (2017) Major bleeding risk during anticoagulation with warfarin, dabigatran, apixaban, or rivaroxaban in patients with nonvalvular atrial fibrillation. J Manag Care Spec Pharm 23(9):968–978. https://doi.org/10.18553/jmcp.2017.23.9.968

    Article  PubMed  Google Scholar 

  25. Amin A, Keshishian A, Trocio J, Dina O, le H, Rosenblatt L, Liu X, Mardekian J, Zhang Q, Baser O, Vo L (2017) Risk of stroke/systemic embolism, major bleeding and associated costs in non-valvular atrial fibrillation patients who initiated apixaban, dabigatran or rivaroxaban compared with warfarin in the United States Medicare population. Curr Med Res Opin 33(9):1595–1604. https://doi.org/10.1080/03007995.2017.1345729

    Article  CAS  PubMed  Google Scholar 

  26. Bang OY, On YK, Lee M-Y et al (2020) The risk of stroke/systemic embolism and major bleeding in Asian patients with non-valvular atrial fibrillation treated with non-vitamin K oral anticoagulants compared to warfarin: Results from a real-world data analysis. Ai T, ed. PLoS One 15(11):e0242922. https://doi.org/10.1371/journal.pone.0242922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Cha M-J, Choi E-K, Han K-D, Lee SR, Lim WH, Oh S, Lip GYH (2017) Effectiveness and safety of non-vitamin K antagonist oral anticoagulants in Asian patients with atrial fibrillation. Stroke. 48(11):3040–3048. https://doi.org/10.1161/STROKEAHA.117.018773

    Article  CAS  PubMed  Google Scholar 

  28. Chan Y, See L, Tu H et al (2018) Efficacy and safety of apixaban, dabigatran, rivaroxaban, and warfarin in Asians with nonvalvular atrial fibrillation. J Am Heart Assoc 7(8):e008150. https://doi.org/10.1161/JAHA.117.008150

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chan Y-H, Lee H-F, See L-C, Tu HT, Chao TF, Yeh YH, Wu LS, Kuo CT, Chang SH, Lip GYH (2019) Effectiveness and safety of four direct oral anticoagulants in Asian patients with nonvalvular atrial fibrillation. Chest. 156(3):529–543. https://doi.org/10.1016/j.chest.2019.04.108

    Article  PubMed  Google Scholar 

  30. Cho MS, Yun JE, Park JJ, Kim YJ, Lee J, Kim H, Park DW, Nam GB (2019) Outcomes after use of standard- and low-dose non–vitamin k oral anticoagulants in Asian patients with atrial fibrillation. Stroke. 50(1):110–118. https://doi.org/10.1161/STROKEAHA.118.023093

    Article  CAS  Google Scholar 

  31. Coleman CI, Peacock WF, Bunz TJ, Alberts MJ (2017) Effectiveness and safety of apixaban, dabigatran, and rivaroxaban versus warfarin in patients with nonvalvular atrial fibrillation and previous stroke or transient ischemic attack. Stroke. 48(8):2142–2149. https://doi.org/10.1161/STROKEAHA.117.017474

    Article  CAS  PubMed  Google Scholar 

  32. Costa OS, Beyer-Westendorf J, Ashton V, Milentijevic D, Moore KT, Bunz TJ, Coleman CI (2020) Effectiveness and safety of rivaroxaban versus warfarin in obese nonvalvular atrial fibrillation patients: analysis of electronic health record data. Curr Med Res Opin 36(7):1081–1088. https://doi.org/10.1080/03007995.2020.1762554

    Article  CAS  PubMed  Google Scholar 

  33. Deitelzweig S, Luo X, Gupta K, Trocio J, Mardekian J, Curtice T, Lingohr-Smith M, Menges B, Lin J (2017) Comparison of effectiveness and safety of treatment with apixaban vs. other oral anticoagulants among elderly nonvalvular atrial fibrillation patients. Curr Med Res Opin 33(10):1745–1754. https://doi.org/10.1080/03007995.2017.1334638

    Article  CAS  PubMed  Google Scholar 

  34. Graham DJ, Reichman ME, Wernecke M, Zhang R, Southworth MR, Levenson M, Sheu TC, Mott K, Goulding MR, Houstoun M, MaCurdy TE, Worrall C, Kelman JA (2015) Cardiovascular, bleeding, and mortality risks in elderly medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation. 131(2):157–164. https://doi.org/10.1161/CIRCULATIONAHA.114.012061

    Article  CAS  PubMed  Google Scholar 

  35. Graham DJ, Baro E, Zhang R et al (2019) Comparative stroke, bleeding, and mortality risks in older medicare patients treated with oral anticoagulants for nonvalvular atrial fibrillation. Am J Med 132(5):596–604.e11. https://doi.org/10.1016/j.amjmed.2018.12.023

    Article  PubMed  Google Scholar 

  36. Halvorsen S, Ghanima W, Fride Tvete I, Hoxmark C, Falck P, Solli O, Jonasson C (2017) A nationwide registry study to compare bleeding rates in patients with atrial fibrillation being prescribed oral anticoagulants. Eur Heart J - Cardiovasc Pharmacother 3(1):28–36. https://doi.org/10.1093/ehjcvp/pvw031

    Article  PubMed  Google Scholar 

  37. Hernandez I, Baik SH, Piñera A, Zhang Y (2015) Risk of Bleeding With Dabigatran in Atrial Fibrillation. JAMA Intern Med 175(1):18–24. https://doi.org/10.1001/jamainternmed.2014.5398

    Article  PubMed  PubMed Central  Google Scholar 

  38. Hsu C-C, Hsu P-F, Sung S-H, Tu ST, Yu BH, Huang CJ, Cheng HM (2018) Is there a preferred stroke prevention strategy for diabetic patients with non-valvular atrial fibrillation? Comparing warfarin, dabigatran and rivaroxaban. Thromb Haemost 118(01):072–081. https://doi.org/10.1160/TH17-02-0095

    Article  Google Scholar 

  39. Huybrechts KF, Gopalakrishnan C, Bartels DB, Zint K, Gurusamy VK, Landon J, Schneeweiss S (2020) Safety and effectiveness of dabigatran and other direct oral anticoagulants compared with warfarin in patients with atrial fibrillation. Clin Pharmacol Ther 107(6):1405–1419. https://doi.org/10.1002/cpt.1753

    Article  CAS  PubMed  Google Scholar 

  40. Kjerpeseth LJ, Selmer R, Ariansen I, Karlstad Ø, Ellekjær H, Skovlund E (2019) Comparative effectiveness of warfarin, dabigatran, rivaroxaban and apixaban in non-valvular atrial fibrillation: A nationwide pharmacoepidemiological study. Garcia de Frutos P, ed. PLoS One 14(8):e0221500. https://doi.org/10.1371/journal.pone.0221500

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kohsaka S, Katada J, Saito K, Jenkins A, Li B, Mardekian J, Terayama Y (2020) Safety and effectiveness of non-vitamin K oral anticoagulants versus warfarin in real-world patients with non-valvular atrial fibrillation: a retrospective analysis of contemporary Japanese administrative claims data. Open Heart 7(1):e001232. https://doi.org/10.1136/openhrt-2019-001232

    Article  PubMed  PubMed Central  Google Scholar 

  42. Larsen TB, Skjøth F, Nielsen PB, Kjældgaard JN, Lip GYH. Comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. BMJ. Published online June 16, 2016:i3189. doi:https://doi.org/10.1136/bmj.i3189

  43. Lauffenburger JC, Farley JF, Gehi AK, Rhoney DH, Brookhart MA, Fang G (2015) Effectiveness and safety of dabigatran and warfarin in real-world US patients with non-valvular atrial fibrillation: a retrospective cohort study. J Am Heart Assoc 4(4):e001798. https://doi.org/10.1161/JAHA.115.001798

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Lee S-R, Choi E-K, Han K-D, Jung J-H, Oh S, Lip GYH (2018) Edoxaban in Asian patients with atrial fibrillation. J Am Coll Cardiol 72(8):838–853. https://doi.org/10.1016/j.jacc.2018.05.066

    Article  CAS  PubMed  Google Scholar 

  45. Lee S-R, Choi E-K, Han K-D, Jung JH, Cha MJ, Oh S, Lip GYH (2019) Non–vitamin K antagonist oral anticoagulants in Asian patients with supranormal renal function. Stroke. 50(6):1480–1489. https://doi.org/10.1161/STROKEAHA.118.024264

    Article  CAS  PubMed  Google Scholar 

  46. Lee S-R, Choi E-K, Kwon S, Han KD, Jung JH, Cha MJ, Oh S, Lip GYH (2019) Effectiveness and safety of contemporary oral anticoagulants among Asians with nonvalvular atrial fibrillation. Stroke. 50(8):2245–2249. https://doi.org/10.1161/STROKEAHA.119.025536

    Article  CAS  PubMed  Google Scholar 

  47. Li X, Deitelzweig S, Keshishian A, Hamilton M, Horblyuk R, Gupta K, Luo X, Mardekian J, Friend K, Nadkarni A, Pan X, Lip GYH (2017) Effectiveness and safety of apixaban versus warfarin in non-valvular atrial fibrillation patients in “real-world” clinical practice: A propensity-matched analysis of 76,940 patients. Thromb Haemost 117(06):1072–1082. https://doi.org/10.1160/TH17-01-0068

    Article  PubMed  PubMed Central  Google Scholar 

  48. Lip GYH, Pan X, Kamble S, Kawabata H, Mardekian J, Masseria C, Bruno A, Phatak H (2016) Major bleeding risk among non-valvular atrial fibrillation patients initiated on apixaban, dabigatran, rivaroxaban or warfarin: a “real-world” observational study in the United States. Int J Clin Pract 70(9):752–763. https://doi.org/10.1111/ijcp.12863

    Article  CAS  PubMed  Google Scholar 

  49. Lip GYH, Keshishian A, Kamble S, Pan X, Mardekian J, Horblyuk R, Hamilton M (2016) Real-world comparison of major bleeding risk among non-valvular atrial fibrillation patients initiated on apixaban, dabigatran, rivaroxaban, or warfarin: A propensity score matched analysis. Thromb Haemost 116(11):975–986. https://doi.org/10.1160/TH16-05-0403

    Article  PubMed  Google Scholar 

  50. Maura G, Blotière P-O, Bouillon K, Billionnet C, Ricordeau P, Alla F, Zureik M (2015) Comparison of the short-term risk of bleeding and arterial thromboembolic events in nonvalvular atrial fibrillation patients newly treated with dabigatran or rivaroxaban versus vitamin K antagonists: a French Nationwide Propensity-Matched Cohort Study. Circulation. 132(13):1252–1260. https://doi.org/10.1161/CIRCULATIONAHA.115.015710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Mitsuntisuk P, Nathisuwan S, Junpanichjaroen A, et al. Real-world comparative effectiveness and safety of non-vitamin K antagonist oral anticoagulants vs. warfarin in a developing country. Clin Pharmacol Ther. Published online November 22, 2020:cpt.2090. doi:10.1002/cpt.2090

  52. Nielsen PB, Skjøth F, Søgaard M, Kjældgaard JN, Lip GYH, Larsen TB (2017) Effectiveness and safety of reduced dose non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. BMJ. 356:j510. https://doi.org/10.1136/bmj.j510

    Article  PubMed  PubMed Central  Google Scholar 

  53. Rutherford O-CW, Jonasson C, Ghanima W, Söderdahl F, Halvorsen S (2020) Comparison of dabigatran, rivaroxaban, and apixaban for effectiveness and safety in atrial fibrillation: a nationwide cohort study. Eur Heart J - Cardiovasc Pharmacother 6(2):75–85. https://doi.org/10.1093/ehjcvp/pvz086

    Article  PubMed  PubMed Central  Google Scholar 

  54. Staerk L, Fosbøl EL, Lip GYH, Lamberts M, Bonde AN, Torp-Pedersen C, Ozenne B, Gerds TA, Gislason GH, Olesen JB (2017) Ischaemic and haemorrhagic stroke associated with non-vitamin K antagonist oral anticoagulants and warfarin use in patients with atrial fibrillation: a nationwide cohort study. Eur Heart J 38:907–915. https://doi.org/10.1093/eurheartj/ehw496

    Article  CAS  PubMed  Google Scholar 

  55. Villines TC, Schnee J, Fraeman K, Siu K, Reynolds MW, Collins J, Schwartzman E (2015) A comparison of the safety and effectiveness of dabigatran and warfarin in non-valvular atrial fibrillation patients in a large healthcare system. Thromb Haemost 114(12):1290–1298. https://doi.org/10.1160/TH15-06-0453

    Article  PubMed  Google Scholar 

  56. Yao X, Abraham NS, Sangaralingham LR, Bellolio MF, McBane RD, Shah ND, Noseworthy PA (2016) Effectiveness and safety of dabigatran, rivaroxaban, and apixaban versus warfarin in nonvalvular atrial fibrillation. J Am Heart Assoc 5(6):e003725. https://doi.org/10.1161/JAHA.116.003725

    Article  PubMed  PubMed Central  Google Scholar 

  57. Yu HT, Yang P-S, Kim T-H, Jang E, Kim D, Uhm JS, Kim JY, Pak HN, Lee MH, Lip GYH, Joung B (2018) Impact of renal function on outcomes with edoxaban in real-world patients with atrial fibrillation: a nationwide cohort study. Stroke. 49(10):2421–2429. https://doi.org/10.1161/STROKEAHA.118.021387

    Article  CAS  PubMed  Google Scholar 

  58. Wang YP, Kehar R, Iansavitchene A, Lazo-Langner A (2020) Bleeding risk in nonvalvular atrial fibrillation patients receiving direct oral anticoagulants and warfarin: a systematic review and meta-analysis of observational studies. TH Open 04(03):e145–e152. https://doi.org/10.1055/s-0040-1714918

    Article  Google Scholar 

  59. Capodanno D, Capranzano P, Giacchi G, Calvi V, Tamburino C (2013) Novel oral anticoagulants versus warfarin in non-valvular atrial fibrillation: A meta-analysis of 50,578 patients. Int J Cardiol 167(4):1237–1241. https://doi.org/10.1016/j.ijcard.2012.03.148

    Article  PubMed  Google Scholar 

  60. Hicks T, Stewart F, Eisinga A (2016) NOACs versus warfarin for stroke prevention in patients with AF: a systematic review and meta-analysis. Open Heart 3(1):e000279. https://doi.org/10.1136/openhrt-2015-000279

    Article  PubMed  PubMed Central  Google Scholar 

  61. Xue Z, Zhou Y, Wu C, Lin J, Liu X, Zhu W (2020) Non-vitamin K antagonist oral anticoagulants in Asian patients with atrial fibrillation: evidences from the real-world data. Heart Fail Rev 25(6):957–964. https://doi.org/10.1007/s10741-019-09878-y

    Article  CAS  PubMed  Google Scholar 

  62. Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, Camm AJ, Weitz JI, Lewis BS, Parkhomenko A, Yamashita T, Antman EM (2014) Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 383(9921):955–962. https://doi.org/10.1016/S0140-6736(13)62343-0

    Article  CAS  PubMed  Google Scholar 

  63. Chan Y-H, Lee H-F, Chao T-F, Wu CT, Chang SH, Yeh YH, See LC, Kuo CT, Chu PH, Wang CL, Lip GYH (2019) Real-world comparisons of direct oral anticoagulants for stroke prevention in asian patients with non-valvular atrial fibrillation: a systematic review and meta-analysis. Cardiovasc Drugs Ther 33(6):701–710. https://doi.org/10.1007/s10557-019-06910-z

    Article  CAS  PubMed  Google Scholar 

  64. Proietti M, Romanazzi I, Romiti GF, Farcomeni A, Lip GYH (2018) Real-world use of apixaban for stroke prevention in atrial fibrillation: a systematic review and meta-analysis. Stroke. 49(1):98–106. https://doi.org/10.1161/STROKEAHA.117.018395

    Article  CAS  PubMed  Google Scholar 

  65. Wadhera RK, Russell CE, Piazza G (2014) Warfarin versus novel oral anticoagulants: how to choose? Circulation. 130(22):e191–e193. https://doi.org/10.1161/CIRCULATIONAHA.114.010426

    Article  PubMed  Google Scholar 

  66. Mekaj A, Mekaj Y, Duci S, Miftari E (2015) New oral anticoagulants: their advantages and disadvantages compared with vitamin K antagonists in the prevention and treatment of patients with thromboembolic events. Ther Clin Risk Manag 11:967–977. https://doi.org/10.2147/TCRM.S84210

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the Faculty of Medicine, Universitas Brawijaya.

Funding

None.

Author information

Authors and Affiliations

  1. Department of Cardiology and Vascular Medicine, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia

    Yoga Waranugraha & Ardian Rizal

  2. Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia

    Mokhamad Fahmi Rizki Syaban, Icha Farihah Deniyati Faratisha, Nabila Erina Erwan & Khadijah Cahya Yunita

Authors
  1. Yoga Waranugraha
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ardian Rizal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mokhamad Fahmi Rizki Syaban
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Icha Farihah Deniyati Faratisha
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Nabila Erina Erwan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Khadijah Cahya Yunita
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Idea/concept: YW. Design: YW. Control/supervision: AR. Literature search: YW/AR/MFRS. Study quality assessment: YW/AR/MFRS. Data extraction: MFRS/IFDF/NEE/KCY. Statistical analysis: YW/IFDF/NEE. Results interpretation: YW/AR/KCY. Critical review/discussion: YW/AR/MFRS. Writing the article: YW/AR/ MFRS/IFDF/NEE/KCY. All authors have critically reviewed and approved the final draft and are responsible for the content and similarity index of the manuscript.

Corresponding author

Correspondence to Yoga Waranugraha.

Ethics declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

All authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Additional file 1:.

Supplementary Table 1. Newcastle-Ottawa Scale

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Waranugraha, Y., Rizal, A., Syaban, M.F.R. et al. Direct comparison of non-vitamin K antagonist oral anticoagulant versus warfarin for stroke prevention in non-valvular atrial fibrillation: a systematic review and meta-analysis of real-world evidences. Egypt Heart J 73, 70 (2021). https://doi.org/10.1186/s43044-021-00194-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s43044-021-00194-1

Keywords