Direct oral anticoagulants versus vitamin K antagonists: Which one is more effective in atrial fibrillation

Abstract

Background

The optimal approach for anticoagulation in patients with bioprosthetic valves and atrial fibrillation (AF) remains a subject of debate. A meta-analysis using updated evidence to evaluate the efficacy and safety of direct oral anticoagulants (DOACs) compared to vitamin K antagonists (VKAs) in patients with AF and bioprosthetic valves to address this controversy.

Methods

A comprehensive search was conducted in multiple databases, including PubMed, Scopus, Web of Science, ProQuest, and the Cochrane Central Register of Controlled Trials, up until March 2023. The search aimed to identify relevant randomized controlled trials (RCTs) that examined the efficacy and safety outcomes of both direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) in patients with bioprosthetic valves and atrial fibrillation. The primary outcomes of interest were major bleeding and all-cause mortality.

Results

Our study demonstrated that despite the difference was not significant, the hazard of all-cause mortality was 2.5% higher in the DOAC group (HR = 1.03, 95% CI = [0.88, 1.19], p-value = .75). Similarly, the hazard of stroke (HR = 1.03, 95% CI = [0.87, 1.32], p-value = .71) and major bleeding (HR = 1.11, 95% CI = [0.89, 1.38], p-value = .36) were found to be respectively 3.2 and 10.7% higher in the DOAC group, although the difference was not significant. However, the hazard of intracranial hemorrhage was found to be 28.8 lower in the DOAC treatment group (HR = 0.71, 95% CI = [0.39, 1.31], p-value = .27), which again was not statistically significant.

Conclusions

Our meta-analysis demonstrates that in patients undergoing bioprosthetic valve surgery and presenting with AF afterward, DOAC and VKA are similar regarding life-threatening and all-cause mortality outcomes, including major bleeding, stroke, and intracranial hemorrhage.

Keywords

vitamin K antagonist atrial fibrillation direct oral anticoagulation bioprosthetic heart valve major bleeding

Introduction

Preventing thromboembolic events in patients with a bioprosthetic valve and atrial fibrillation (AF) requires anticoagulation administration, but the best treatment is a matter of debate. The most frequent side effects of cardiac surgery are atrial tachyarrhythmias including AF, and atrial flutter.^1,2 Even though patients with AF have a safe and effective treatment administration option of direct oral anticoagulants (DOACs), which are popular alternatives to vitamin K antagonists (VKAs) for anticoagulation, individuals with a low incidence of bleeding following aortic or mitral bioprosthetic implantation surgery are advised to adhere to VKAs anticoagulant therapy for at least 3 months, based on ACC/AHA guidelines (class IIa, level B-NR).^3,4 Vitamin K plays a crucial role as a essential cofactor in the liver’s production of coagulation factors, including II, VII, IX, and X, as well as the regulatory factors protein C and protein S involved in the coagulation process. Vitamin K epoxide reductase complex is a pivotal enzyme for activation of vitamin K in metabolic cycle of the body, which can be competitively inhibited by vitamin K antagonist drugs such as warfarin. It can reduce the functional reserve of vitamin K and thus inhibit the synthesis of active coagulation factors as a result it can lead to Serious adverse effects like bleeding and significant hemorrhage.^5,6

Direct oral anticoagulants (DOACs) include direct thrombin inhibitors such as Dabigatran and direct factor Xa inhibitors like Apixaban, Rivaroxaban, and Edoxaban. DOACs offer advantages over warfarin, including limited drug interactions, a wider therapeutic window, stable and predictable anticoagulation effects, and a rapid onset of action.⁷ However, the superiority of DOACs compared to vitamin K antagonists remains unclear.

Recent studies had conflicting results comparing DOACs to VKAs in terms of hemorrhagic complications.^8,9 The two recent meta-analyses have investigated the efficacy and safety of DOACs. In the study by Gerfer et al. DOACs appeared to be safe and effective alternative for VKAs within a relatively heterogeneous study population, which can be associated with the validity of the assessment.¹⁰ Furthermore, in another meta-analysis Yokoyama et al., however indicated that DOAC might decrease the risk of major bleeding without increasing risk of mortality, stroke or systemic embolism compared to VKAs, they used observational studies alongside RCTs which can lead to selection bias and confounders in design, and they did not measure intracranial hemorrhage (ICH) as an outcome.¹¹ In the present meta-analysis, we used only randomized clinical trials evidence in case of the efficacy and safety of DOAC therapy in patients with AF after bioprosthetic valve replacement or valve repair, and is among the first studies to analyse ICH as an outcome using the last studies and updated evidence.

Methods

Data collection process and search strategy

This meta-analysis was carried out following the “Preferred Reporting Items for Systematic Reviews and Meta-Analyses” (PRISMA) protocol and was registered at PROSPERO (International Prospective Register of Systematic Reviews, ID = CRD42022360324)¹² We searched for studies comparing DOAC to VKA in individuals with AF following bioprosthetic valve replacement or repair. On March 15, 2023, an electronic search was conducted through the databases PubMed, Scopus, ProQuest, Web of Science, and Cochrane Central Register of Controlled Trials using the following terms in addition to Boolean operators: (“Cardiac Surgical Procedures” OR “cardiac surgery” OR “CABG” OR “Heart Valve Prosthesis Implantation”) AND (“Atrial Fibrillation”) AND (“Anticoagulants” OR “anti-xa” OR “direct xa inhibitor” OR “thrombin inhibitor” OR “doac” OR “direct oral anticoagulant” OR “oral anticoagulant”). Moreover, the search strategy is detailed in the Supplemental Material.

Study selection and the process of data extraction

Randomized controlled trial studies (RCTs) as design and patients who had undergone bioprosthetic heart valve replacement with or without AF, in which enrolled patients were separated into DOAC and VKA groups, were used as inclusion criteria for the research. Also, studies combining antiplatelet treatment and comparing oral VKA anticoagulation with DOAC were included. All patients with a medical history of paroxysmal, chronic, or permanent AF were also included. To reduce heterogeneity, studies that exclusively included patients who underwent surgical valve replacement and did not have AF or those with a lower than 50% AF occurrence after surgery in the DOAC or VKA group were excluded. Also, case series, case reports, systematic reviews, meta-analyses, and studies reported on individuals with mechanical heart valve procedures or pregnant or lactating women were excluded. The study selection was completed based on a blind screening of titles and abstracts by two authors independently and blindly; Any controversy was resolved by the third author, and then each paper was briefly read by the rest of the authors to exclude unrelated and duplicate studies.

The included studies were retrieved, along with their names, period, type of exposure, sample size, length of follow-up, designs, patient characteristics (such as gender and age), and type of valve operation. Also, as mentioned above, the risk of bias assessment was performed by two blinded authors, and identically, any disagreements were addressed by the third author. Trials were evaluated for their potential for bias using a method developed by the Cochrane Collaboration assessment tool¹³ (Figure 1).

Figure 1.

Study selection process flow diagram. *Consider, if feasible, reporting the number of records identified from each database or register searched (rather than the total number across all databases/registers). **If automation tools were used, indicate how many records were excluded by a human and how many were excluded by automation tools.

Outcomes

Death from a heart attack, blood clot, or stroke was considered the primary efficacy outcome. The primary safety outcome was demonstrated as major bleeding (defined according to the International Society of Thrombosis and Hemostasis (ISTH) criteria). The secondary outcomes were myocardial infarction and intracranial hemorrhage. The primary and secondary outcome combinations were computed to measure the overall clinical result. We analyzed the reported outcomes separately for individuals who underwent biological prostheses and/or valve repair and for patients with biological valve replacements.

Data synthesis

Descriptive data were presented as mean ± standard deviation (SD), frequency, and percentage. A Fixed effects model (ES) was performed to estimate the pooled hazard ratio and 95% confidence interval representing the difference in study outcomes between the intervention groups. The I² (More than 50%) and χ² (p < .05) statistics were used to evaluate the statistical heterogeneity. Begg’s and Egger’s tests (p < .10) and the funnel plot were used to investigate an existing publication bias. Analyses were performed using the STATA statistical package (Version 17).

Results

Study selection and characteristics

A total of 940 published papers were collected after the primary screening. Ultimately, nine studies^14–22 were included as a whole, and they were accounted for qualitative analysis. Five of them^{15,16,20–22} were also considered for quantitative analysis as they were conducted in RCT study design, with 1452 people in the DOAC group and 1436 in the Warfarin group, 2888 patients with AF who underwent bioprosthetic valve implantation or valve repair. After eliminating 99 duplicate documents, 799 non-RCTs studies failed to meet the inclusion criteria. Figure 1 clarifies the screening process. All the five selected studies in quantitative analysis^{15,16,20–22} demonstrated an appropriate randomization approach; one adopted allocation concealment and utilized a double-blind method¹⁶ and consequently, all were free of any other biases. Figure 2 shows the study methodology assessment. A glance at the quality assessment of studies provided reveals striking differences between the Guimaerez et al. study reaching the highest quality as it was free of any biases and the details provided were clarified enough¹⁶ and the Van Mieghem et al., Duraes et al. studies touching the lowest quality as participants and personnel were not blinded and patients may have been informed of the group they are classified in.^15,20

Figure 2.

(a) Risk of bias graph, (b) Risk of bias summary.

Of the nine selected studies, three^16,20,21 employed Cox regression model adjustment, whereas the others^15,22 used the Fisher exact test. The study details are indicated in Table 1, and the basic information about the population is shown in Table 2.

Table 1.

Study details.

Author	Publication year	Design	Gender	Sample size	Exposure	Period	Approach	Length of follow-up	Types of adjustment
Mannacio et al.¹⁸	2022	Cohort	Both	1032	DOACs and warfarin	From 2013 to 2019	SAVR	38 months	PSM
Seeger et al.¹⁹	2017	Cohort	Both	617	Epixaban and warfarin	From 2013 to 2014	TAVR	1 year	N/A
Butt et al.¹⁴	2021	Cohort	Both	735	DOACs and warfarin	From 2012 to 2017	TAVR	23 months	Cox regression model
Kawashima et al.¹⁷	2020	Cohort	Both	403	DOACs and warfarin	From October 2013 to May 2017	TAVR	568 days	IPTW
Guimaraes et al.¹⁶	2019	RCT	Both	156	Apixaban and warfarin	From December 31, 2006 to May 25, 2011	SAVR, SMVR, DVR	12 months	Cox regression model
Guimaraes et al.²¹	2020	RCT	Both	1005	Rivaroxaban and warfarin	From April 14, 2016, through July 22, 2019	SMVR	20 months	Cox regression model
Van Miegham et al.²⁰	2021	RCT	Both	1426	Endoxaban and warfarin	From April 2017 through January 2020	TAVR	17(Endoxaban)-18(VKA)months	Cox proportional-hazard regression
Shim et al.²²	2021	RCT	Both	218	Endoxaban and warfarin	From December 2017 to September 2019	SMVR, SAVR	3 months	Fisher exact test
Duraes et al.¹⁵	2016	RCT	Both	27	Dabigatran and warfarin	Between August 2013 and November 2014	TAVR, SMVR	90 days	Fisher exact test

RCT, randomized controlled trial; DVR, dual valve replacement; N/A, not available; SMVR, surgical mitral valve replacement; DOAC, Direct oral anticoagulant; PSM, propensity score matched; MVR, mitral valve replacement; AVR, aortic valve replacement; SAVR, surgical aortic valve replacement; TAVR, transcatheter aortic valve replacement; IPTW, Inverse probability of treatment weighting.

Table 2.

Basic information of the population.

Item	Guimaraes 2019		Van mieghem 2021		Guimaraes 2020		Duraes 2016		Shim 2021
Item	DOAC	VKA	DOAC	VKA	DOAC	VKA	DOAC	VKA	DOAC	VKA
Number (n)	87	69	713	713	500	505	15	12	109	109
Age (mean ± SD)	72 ± 7	74 ± 4	82.1 ± 5.4	82.1 ± 5.5	59.4 ± 2.4	59.2 ± 11.8	48.8 ± 10.4	45.7 ± 6	67.0 ± 12.3	67.7± 10.0
Female (n, %)	34 (39.1%)	27 (39.1%)	347 (48.7)	331 (46.4)	311 (62.2)	296 (58.6)	10 (66.7)	7 (58.3)	57 (52)	47 (43)
BMI (kg/m²)	26 (24, 31)	27 (24, 32)	27.5 ± 5.7	27.9 ± 5.4	26.6 (23.4–29.9)	25.5 (22.8–29.3)	N/A	N/A	N/A	N/A
CHADS2 score (mean ± SD)	2.7 ± 1.5	2.5 ± 1.3	4.5 ± 1.4	4.5 ± 1.3	2.7 ± 1.5	2.5 ± 1.3	N/A	N/A	2.8 ± 1.6	2.6 ±1.5
HAS-BLED score (mean ± SD)	1.6 ± 0.6	1.6 ± 0.9	N/A	N/A	1.6 ± 0.6	1.6 ± 0.9	0 (0–1)	0 (0–1)	1.7± 1.0	1.5 ± 1.0
Diabetes (n, %)	19 (21.8%)	17 (24.6%)	270 (37.9)	257 (36.0)	74 (14.8)	64 (12.7)	1 (7.1)	0 (0)	23 (21)	22 (20)
Hypertension (n, %)	68 (78.2%)	64 (92.8%)	647 (90.7)	657 (92.1)	308 (61.6)	302 (59.8)	7 (46.7)	6 (50)	65 (60)	63 (58)
Prior stroke (n, %)	24 (27.6%)	12 (17.4%)	123 (17.3)	116 (16.3)	63 (12.6)	66 (13.1)	4 (26.7)	4 (33.3)	10 (9)	6 (6)
Prior MI (n, %)	16 (18.4%)	10 (14.5%)	97 (13.6)	101 (14.2)	24 (4.8)	24 (4.8)	N/A	N/A	9 (8)	5 (5)
End points
Major bleeding (n, %)	7 (8)	7 (10.1)	98 (9.7)	68 (7.0)	7 (1.4)	13 (2.6)	1 (6.7)	2 (16.7)	3 (2.75)	1 (0.92)
Stroke (n, %)	4 (4.6)	2 (2.8)	29 (2.7)	35 (3.5)	3 (0.6)	12 (2.4)	0 (0)	1 (8.3)
Death (n, %)	7 (8)	6 (8.6)	85 (7.8)	93 (9.1)	20 (4.0)	20 (4.0)	0 (0)	1 (8.3)	0 (0)	0 (0)
Myocardial infarction (n, %)	1 (1.1)	1 (1.4)	12 (1.1)	7 (0.7)	N/A	N/A	N/A	N/A	N/A	N/A
Intracranial hemorrhage (n %)	1 (0)	2	16 (1.5)	21 (2.1)	0 (0)	5 (1)	N/A	N/A	1 (0.9)	1 (0.9)

Results synthesis

The results of the Hazard ratio (HR) for the incidence outcomes are included due to the heterogeneity of the fixed effects model. Based on this HR model, none of the pooled HRs were statistically significant for all outcomes. The funnel plot and forest plot figures for all-cause death, intracranial hemorrhage, major bleeding, and stroke variables were calculated, respectively, according to the studies involved (Figure 3. A, B: All-cause death; C, D: Intracranial hemorrhage; E, F: Major bleeding; G, H: Stroke).

Figure 3.

(a) Funnel plot for death outcome, (b) Forrest plot for death outcome, (c) Funnel plot for intracranial hemorrhage outcome, (d) Forest plot for intracranial hemorrhage outcome, (e) Funnel plot for major bleeding outcome, (f) Forrest plot in the major bleeding outcome, (g) Funnel plot for Stroke outcome, (h) Forrest plot for Stroke outcome.

Primary analysis regarding death and secondary analysis

As illustrated in the forest plots, no significant difference between the therapies was identified regarding the study’s outcomes (Figure 3). Based on the findings, despite the fact that difference was not significant, the hazard of all-cause mortality was 2.5% higher in the DOAC group (HR = 1.03; 95% CI = [0.88, 1.19], p-value = .75). Similarly, the hazard of stroke (HR = 1.03, 95% CI = [0.87, 1.32], p-value = .71) and major bleeding (HR = 1.11, 95% CI = [0.89, 1.38], p-value = .36) were found to be respectively 3.2 and 10.7% higher in the DOAC group. However, the difference was not significant. The hazard of intracranial hemorrhage was found to be 28.8 lower in the DOAC treatment group (HR = 0.71, 95% CI = [0.39, 1.31], p-value = .27), which again was not statistically significant. Begg’s and Egger’s tests revealed there was no significant publication bias in any of the study outcomes. Moreover, no severe asymmetry was detected in the funnel plots.

Discussion

In this meta-analysis, we mainly provided evidence that there was no significant difference between the administration of DOACs and VKAs in patients with AF and prosthetic valves. More exclusively, we found no significant difference between these two prophylactic strategies in thromboembolic strokes, bleeding, all-cause mortality, and intracranial hemorrhage.

Previous meta-analysis investigations have compared DOAC and VKA in AF and bioprosthetic valve patients. In contrast to our findings, in a very recent study on a heterogeneous population, Grefer and colleagues concluded that DOAC was a promising alternative to VKA, reducing the risk of thromboembolic complications and intracranial hemorrhage.¹⁰ A biased meta-analysis of 4 RCTs and 6 observational studies also confirmed lower bleeding rates in the DOAC group, despite similar rates of all-cause mortality and embolic reactions.¹¹ In agreement, Pan et al.²³ showed the same effects of DOAC and VKA in embolic reactions. An analysis of patients suffering from native heart disease, prosthetic valves, and AF consistently demonstrated that new oral anticoagulants significantly reduced stroke, embolisms, and bleeding. Corresponding to our results, another study on individuals suffering from bioprosthetic heart valves revealed no difference between VKA and DOAC.^24,25

All similar studies had important limitations such as heterogeneity, a low number of patients, a combination of non-union studies, and low power of analysis that could lead to biased results. Respecting recent large trials, we performed this updated systematic review and meta-analysis to end all controversies surrounding aforementioned outcomes.

Lifelong anticoagulant therapy for patients with bioprosthetic valves and AF has been recommended.^26,27However, choosing the best anticoagulation strategy remains challenging according to the different mechanisms of thromboembolic events in AF and bioprosthetic valves²⁸ DOACs were recommended for anticoagulation therapy because they decreased the incidence of embolism and bleeding.^3,27,29 The safety and efficacy of apixaban, rivaroxaban, and dabigatran were proven for bioprosthetic valves 3 months after operation.^15,21,30 In a recent assessment of observational studies on AF patients with gastrointestinal bleeding (GIB), DOAC showed more promising effects in stroke and systemic embolic, all-cause mortality, and repetitive GIB compared to VKAs.³¹ Contrarily, Edoxaban showed an increased risk of GIB in patients undergoing transcatheter aortic valve implantation.²⁰ Also, early initiation of DOAC therapy before hospital discharge in the first 3 months post-operation is strongly associated with an increased risk of intracranial hemorrhage.³² Although a lower incidence of thromboembolic events could neutralize increased bleeding complications, the initiation time of DOAC therapy is a potential variable to the occurrence of negligible but unwanted complications. Further research should unravel the association between DOAC complications and therapy initiation time.

There is also evidence that DOAC therapy decreases the risk of bleeding compared to VKA therapy, and greater bleeding rates due to VKA therapy are likely to be related to target INR in prior studies^3,33 VKAs require precise INR monitoring during the treatment process compared to DOACs.³⁴ A lower INR (2.0–2.5) might result in less bleeding in comparison to a higher INR (>2.5), similar to nonvalvular AF patients. Moreover, considering INR rates as a variable in future studies could solve possible controversies.

We updated recent meta-analysis studies to improve evidence on alternative anticoagulant therapies in patients with AF and bioprosthetic valves.¹¹ As aforementioned, unlike previous studies, we included only RCTs without significant publication bias to avoid confounding variabilities.^10,11,35

Since our results approved similar efficacy and complications of DOAC and VKA as routine therapies for patients with AF and bioprosthetic valves, a net decision on therapy may require additional considerations of further patient-important factors, including cost, easier administration, the influence of diet, the possibility of regular monitoring, susceptibility to complications according to past medical histories such as GIB and hypercoagulability states, and last but not least, the initiation time of the therapy. Future large RCTs comparing these therapies, single or combined, are necessary to provide a final consensus treatment regarding patient discretion, safety, and efficacy.

Limitations

This study has considerable limitations. First, we did not evaluate the difference between the four DOAC regimens. As mentioned above, apixaban, dabigatran, rivaroxaban, and edoxaban have demonstrated different complications. Second, all patients who had undergone bioprosthetic valve implantation or valve repair were included, although ideal strategies could differ in each procedure. Third, different dosages of DOAC and time dependency of pre-and postoperative thromboembolic risk were not studied. Categorization could help further studies to build up the comparing analysis.

Conclusion

In conclusion, our meta-analysis demonstrates that in patients undergoing bioprosthetic valve surgery and presenting with AF afterward, the usage of DOAC and VKA is similar regarding life-threatening and all-cause mortality outcomes, including major bleeding and stroke.

Footnotes

Author contributions

Bazrafshan drissi H and Khodadadiyan A conceived and designed the study and drafted the manuscript. Jazi K, Bazroodi H and Sadeghi E contributed to the data analysis and manuscript edition. Mashayekh M, Gholamabbas G, played as a rule in study selection independently and blindly. Likewise, any discrepancy resolved by Khodadadiyan A. Rahmanian M and Bazrafshan M assisted in data collection, extraction, and management. Risk of bias assessment was performed by Khodadadiyan A and Bazroodi H, and any controversial subjects were addressed by Gholamabbas G. Mashayekh M, Gholamabbas G and Khodadadiyan A took active part in manuscript revision. All authors read and approved the final version.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Hamed Bazrafshan Drissi

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