Safety and efficacy of direct oral anticoagulants compared to Vitamin K antagonists postpercutaneous coronary interventions in patients with atrial fibrillation: A systematic review and meta‐analysis

Abstract Background Atrial fibrillation (AF) and coronary artery disease (CAD) are commonly associated. Cotreatment with multiple antithrombotic agents can increase the risk of bleeding. We sought to evaluate patient‐centered outcomes in patients with AF on double therapy with direct oral anticoagulants (DOACs) compared to patients with standard triple therapy, [a vitamin K antagonist (VKA) plus dual antiplatelet therapy]. Methods We performed a literature search of randomized controlled trials (RCTs) reporting outcomes of patients receiving double therapy with DOACs compared to triple therapy with VKAs in patients with AF undergoing percutaneous coronary intervention (PCI). Patient‐centered outcomes were the International Society of Thrombosis and Hemostasis (ISTH) major or clinically relevant nonmajor bleeding (CRNB), all‐cause mortality, major adverse cardiovascular events (MACE), stent thrombosis, myocardial infarction, and stroke. Results Four RCTs (9602 patients) met our inclusion criteria. Compared to VKAs, DOACs were associated with significantly lower ISTH major bleeding/ CRNB (RR: 0.75, 95% CI: 0.67‐0.82, P < .00001, I 2 = 11%). There were no statistically significant differences in the efficacy outcomes, including myocardial infarction (RR: 0.99, 95% CI :0.79‐1.25, P = .96), stent thrombosis (RR: 0.97, 95% CI: 0.6‐1.55, P = .89), ischemic stroke (RR: 0.76, 95% CI: 0.5‐1.15, P = .19), all‐cause mortality (RR: 1.06, 95% CI: 0.85‐1.31, P = .61), and MACE (RR: 1.06, 95% CI: 0.91‐1.22, P = .97). Conclusion Compared with triple therapy with VKAS, double therapy with DOACs is associated with a reduced risk of bleeding and is as effective in patients with AF undergoing PCI.


| INTRODUC TI ON
One of the common comorbidities of coronary artery disease (CAD) is atrial fibrillation (AF). [1][2][3] Its prevalence is about 2% in the general population and increases with age. 2 Inflammation plays an important role in the development of both conditions, and they share associated risk factors, including diabetes mellitus, hypertension, sleep apnea, obesity, and smoking. 1,2,[4][5][6] Up to 30% of AF patients have concomitant CAD, of whom 5%-10% are PCI patients. 7,8 The management of CAD and AF is distinct, as anticoagulants are used in AF, and antiplatelet drugs are used in CAD. Hence, combination of antithrombotic therapy with anticoagulants and antiplatelet drugs may lead to excessive bleeding and result in serious complications. 1 These combinations include double therapy (an oral anticoagulant plus a P2Y12 inhibitor) or triple therapy (an oral anticoagulant plus dual antiplatelet therapy).
Over the past few decades, anticoagulation options have expanded rapidly, offering a wider amount of agents for thromboembolic disease prevention and management. 9 No anticoagulant can reduce the risk of thrombosis without increasing the risk of bleeding to a certain extent. The emergence of direct oral anticoagulants (DOACs) has completely reshaped the management of AF. 1,[10][11][12][13][14][15] The current American and European professional society guidelines recommend DOACs as the first-line treatment in AF. 16,17 Nevertheless, vitamin K antagonists (VKAs) are recommended when combined with dual antiplatelet therapy (DAPT). 18,19 This meta-analysis compares the safety and efficacy outcomes for four randomized controlled trials (RCTs) on double therapy with DOACs vs standard triple therapy with VKAs in AF and PCI. Previous meta-analyses assessed the safety and efficacy of DOACs in patients with AF who undergo PCI with comparing PIONEER AF-PCI and RE-DUAL PCI trials. 1 The present analysis compares two more recent trials (AUGUSTUS and ENTRUST) to assess the safety and efficacy of DOACs in patients with AF who have undergone PCI.

| Protocol and registration
The protocol detailing the methods of the systematic review and meta-analysis was registered on the International Prospective Register of Systematic Reviews. The current meta-analysis was performed using the guidelines set by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). 20 Given the nature of the study, the meta-analysis was exempted from institutional review.

| Study identification and search strategy
We performed a search for RCTs using OVID versions of Medline

| Study selection
Two reviewers (PA and JZL) performed initial screening of the search results for inclusion into the meta-analysis. The first step involved title and abstract screening. The second step involved comprehensive review of the entire manuscripts. Inconsistencies in screening were resolved with consensus or when consensus could not be achieved, a third reviewer (JS) casted the deciding vote.

| Eligibility criteria
We selected all published RCTs, including any adult (age > 18 years) population with AF who underwent PCI comparing double therapy with DOAC to triple therapy with VKA following PCI. All classes of DOAC were included. No restrictions on study selection based on outcomes were used.

| Data extraction and quality assessment
For each included study, we extracted: (a) Characteristics of study participants including age, gender, race, type of AF, index event, medical history, type of stent, antiplatelet at randomization, type of oral anticoagulant before PCI, and the study's inclusion and exclu-

| Risk of bias
Validity of eligible RCTs was ascertained by pairs of reviewers, independently and determined the adequacy of concealment of allocation and randomization, blinding of patients, collectors, data, outcome assessors, health care providers, and extent of loss to follow-up (ie, proportion of patients in whom the investigators were not able to ascertain outcomes). To explore heterogeneity (variability) in study results, the hypotheses that effect size may vary according to the quality of RCTs were specified before performing the analysis. For each study, the effect by inverse of the standard error was plotted for each study. The assessment of symmetry of "funnel plots" was performed visually.

| Method of analysis
The meta-analysis was performed by computing risk ratios (RRs) using the random effects model based on underlying statistical heterogeneity. We calculated the RR and 95% confidence inter-

| Study selection
A total of 59 Citations were identified using Medline, EMBASE, SCOPUS, Web of Science, and Cochrane databases. A total of four RCTs were selected to be included in the evaluation. [22][23][24][25] Based on the title and abstracts, 46 studies were excluded. The rest of the publications were studied in detail, and four studies met the inclusion criteria mentioned above. The PRISMA diagram for the systematic review is shown in Figure 1. Kappa for agreement on full text, and abstract inclusion was 0.89 (95% CI: 0.86-0.94).

| Study and patient characteristics
The study characteristics are summarized in Table 1. The included trials were published between 2016 and 2019. All of the trials were multicentered and had a follow-up duration of 6 months to 12 months. The baseline characteristics of each RCT are provided in the Data S1. A total of 6733 patients were included in this meta-analysis, with the sample size in each trial ranging from 1393 to 2307. The mean age of patients was between 68 and 70 years. The patients were predominantly white (91.7%-94.1%), and ACS prevalence ranged from 30% to 52%. Comorbidities like diabetes, hypertension, hypercholesterolemia, F I G U R E 1 PRISMA flow chart of the RCT selection for the meta-analysis and peripheral artery disease, ranged from 5% to 88%. Most of the patients had a CHA2DS2-VASc score > 3 and a HAS-BLED score > 2.5. All patients had undergone PCI, except for AUGUSTUS, in which patients have had an acute coronary syndrome or have undergone PCI. Time to randomization varied from 3 to 14 days between the groups. The raw safety and efficacy outcomes of the trials are shown in the Data S1. The Jadad scale for randomized controlled trials was used to determine the quality of the studies 26 and is shown in the Data S1.
Three of the four trials were open-label, and blinding was not performed, except for AUGUSTUS. The outcomes were determined in a blinded manner and randomization was adequate.

| Structure of the meta-analysis
The study compared four treatment regimens comparing double

| ISTH major or clinically relevant nonmajor bleeding (CRNB)
The data were available for all the four trials, randomizing 6,733 patients. 1,198 of 6,733 patients experienced either ISTH major bleeding or CRNB. The forest plots of the analysis are shown in

| All-cause mortality
The data were available for all the four trails, reporting data for 6729 patients. Two hundred and fifty of 6729 patients had died. The results are summarized in Figure 3. There was no statistically

| Major adverse cardiovascular events (MACE)
The data were available for all the four trails, reporting data for 6729 patients. Four hundred and ninety-eight of 6729 patients have experienced trial-defined MACE. The results are summarized in Figure 4.

| Ischemic stroke
The data were available for all the four trials, reporting data for 6729 patients. Seventy-one of 6729 patients experienced a stroke, and the results are summarized in Figure 5. There was no statistically significant difference in the risk of stroke (RR: 0.84, 95% CI: 0.52-1.34, P = .46). No evidence of heterogeneity was noted (I 2 = 0%).

| Myocardial infarction (MI)
The data were available for all the four trials, reporting data for 6729 patients. Two hundred and twelve of 6729 patients experienced an MI, and the results are summarized in Figure 6.
There was no statistically significant difference in the risk of MI

| Stent thrombosis
The data were available for all the four trials, reporting data for 6,729 patients. Seventy of 6729 patients experienced stent thrombosis, and the results are summarized in Figure 7. There was no statistically significant difference in the risk of stent thrombosis  who underwent PCI and the results showed a lower rate of clinically significant bleeding with rivaroxaban treatments than with VKA and DAPT, with no significant difference in rates of ischemic events or major adverse cardiovascular events. 23 The AUGUSTUS trial which was a prospective, multicenter, two-by-two factorial, and randomized clinical trial compared apixaban of 2.5 mg with a VKA and aspirin with placebo postacute coronary syndrome (ACS) or underwent PCI in patients with AF. The results showed that the antithrombotic regimen with apixaban had caused no significant differences in ischemic events but resulted in less bleeding and fewer hospitalizations when compared to a regimen including VKA, aspirin, or both. 24 ENTRUST AF PCI (randomized, multicenter, open-label trial) was performed to determine the safety of edoxaban plus P2Y12 inhibitor in patients with AF who had PCI and results showed that edoxaban-based regimen was noninferior to VKA regimen for bleeding, without having significant differences in ischemic events. 25 There is a delicate balance between the risk of bleeding and the risk of ischemia in patients with AF who develop ACS or undergo PCI. For these patients, an optimal regimen needs to be defined, with the primary considerations being double vs triple therapy and DOAC vs VKA. There are a range of studies and meta-analyses on modifying regimens for anticoagulation in this patient population. 1,7 Moreover, trials have shown that triple therapy after PCI is associated with a twofold increase in bleeding in the patients relative to double therapy, and post-PCI bleeding events are linked to worse MACE outcomes, possibly from the interruption in antithrombotic therapy during bleeding events. [28][29][30][31][32] It has been shown that double therapy is enough for most patients with AF, and ACS/ PCI and triple therapy may increase the risk of bleeding. 27,33,34 We have shown that double therapy with DOACs is safe and as effective as triple therapy with VKA. These results favor the use of

| Summary of evidence
The present analysis updates the summary of evidence by add-

| CON CLUS ION
DOACs are associated with less risk of ISTH major/ CRNB bleeding and are as effective as standard therapy in patients with AF undergoing PCI.

ACK N OWLED G EM ENTS
None.

CO N FLI C T O F I NTE R E S T S
The authors declare no conflict of interests for this article. The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). b GRADE Working Group grades of evidence: (a) High certainty: We are very confident that the true effect lies close to that of the estimate of the effect; (b) Moderate certainty: We are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different; (c) Low certainty: Our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect, (d) Very low certainty: We have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect c Rated down for imprecision as the 95% confidence interval overlaps with no effect and fails to exclude important benefit or important harm.