Effects of single versus dual antiplatelet therapy on the adverse events after transcatheter aortic valve implantation: A meta‐analysis

Abstract Dual antiplatelet therapy (DAPT) was currently recommended for transcatheter aortic valve implantation (TAVI) postoperative management in clinical application. However, POPular‐TAVI trial showed DAPT increased the incidence of adverse events compared to single antiplatelet therapy (SAPT). Herein, we performed a meta‐analysis to investigate the effect of SAPT versus DAPT on the adverse events after TAVI. Eleven studies were available from PubMed, Embase, Cochrane Library, and Web of Science from inception to April 1, 2021. The pooled effect size was presented as relative risk (RR) with 95% confidence intervals (CIs). The sensitivity analysis was used to assess the stability of analysis results, and Begg's test was applied to evaluate the publication bias. The Cochran Q test and the I 2 statistic were used to evaluate the heterogeneity, and the source of heterogeneity was explored by meta‐regression. A total of 4804 patients were obtained, with 2257 in SAPT group and 2547 in DAPT group. Compared to the DAPT, SAPT was associated with the decreased risk of all‐cause bleeding (RR: 0.51, 95% CI: 0.44–0.61), major bleeding (RR: 0.53, 95% CI: 0.32–0.86), and minor bleeding (RR: 0.58, 95% CI: 0.34–0.98). There were no significant differences in mortality and myocardial infarction events, stroke events, and acute kidney injury between the two groups. SAPT was superior to DAPT in decreasing all‐cause bleeding, major bleeding, and minor bleeding, suggesting that SAPT could be preferentially recommended for TAVI postoperative management in most patients without another indication for DAPT and oral anticoagulation.

The American College of Cardiology/American Heart Association (ACC/AHA) guidelines suggest dual antiplatelet therapy (DAPT) for thrombotic events. 6 Patients are recommended with aspirin and clopidogrel for the first 3-6 months after TAVI 6 ; however, this therapy is lack of clear clinical evidence. Currently, single antiplatelet therapy (SAPT) that use aspirin alone is applied as an alternative antithrombotic treatment regimen after TAVI. 7 Previous studies have compared the effects of SAPT and DAPT on the adverse events after TAVI, but the results remained controversial. 8,9 Hu et al. and Ahmad et al. reported that DAPT reduced the risk of thrombotic events and helped to mitigate stoke. 10,11 POPular-TAVI trial assessed the safety between SAPT and DAPT, and results indicated DAPT was associated with a higher incidence of bleeding events. 12 Ichibori et al. reported the similar finding that DAPT increased the risk of bleeding compared to SAPT. 7 Rodés-Cabau et al found that SAPT deceased the occurrence of major adverse events compared to the DAPT. 13 Ussia et al. reported that there was no significant difference between SAPT and DAPT in death, transient ischemic attack, and bleeding events. 14 Given that there is no consensus now, we perform a metaanalysis to compare the effects of SAPT and DAPT on the postoperative adverse events of TAVI. Meta-regression to explore source of heterogeneity and subgroup analysis based on study design and follow-up time are also performed.

| Inclusion and exclusion criteria
Studies were included based on the following criteria: (1) severe aortic stenosis patients undergoing TAVI; (2) the experimental group receiving SAPT (aspirin) and the control group receiving DAPT (aspirin plus clopidogrel); (4) randomized controlled trails (RCTs) or cohort studies; (5) studies published in English.
Studies were excluded according to the following criteria: (1) animal experiments; (2) studies without complete data; (3) conference reports, case reports, editorial materials, letters, protocols, meta-analyses, and reviews.

| Data extraction
Data from the eligible studies were independently extracted by two investigators (S. Q. Y. and S. Y. Z.), and a third investigator (C. L. Y.) participated to resolve disagreements. The data requested to be extracted were name of the first author, year of publication, country, study design, groups, total number of participants, age, sex, follow-up time and outcomes.

| Methodological quality appraisal
Two independent investigators (S. Q. Y. and S. Y. Z.) were responsible for quality assessment. Jadad scale 15 and revised Newcastle-Ottawa Scale (NOS) 16 were separately used to assess the quality of RCTs and cohort studies. The total score of Jadad scale was 7, and studies with 1-3 points were considered as low quality and 4-7 points were considered as high quality. The total score of NOS was 10, and studies were divided into low quality (<5 points) and high quality (≥5 points).

| Statistical analysis
Stata 15.1 (Stata Corporation, College Station, TX) was applied for statistical analysis, and p < .05 was considered as statistical significance.
The relative risk (RR) with 95% confidence intervals (CIs) was calculated to analyze the binary outcome. The Cochran Q test and the I 2 statistic were used to assess between-study heterogeneity for each outcome effect size. To combine the effect amount, the fixed-effect model was used when the heterogeneity was low (I 2 < 50%), and the random-effect model was used when the heterogeneity was high (I 2 ≥ 50%). Based on study design and follow-up time, subgroup analysis was used to assess the incidence of major bleeding and minor bleeding in SAPT and DAPT groups. Meta-regression was performed to explore sources of inconsistency (I 2 ≥ 50%). Sensitivity analysis was performed for all outcomes and publication bias was assessed by Begg's test.

| Study selection and baseline characteristics
A total of 5008 studies were identified using the four English databases.

| Stroke events
For stroke events, results were shown in Table 2, indicating that no statistical significance was found between the two groups in the inci-    Figure 4B). Moreover, patients accepting SAPT had a lower incidence of major bleeding (RR: 0.53, 95% CI: 0.32-0.86, p = .011) ( Figure 4C).

| Acute kidney injury
The results of meta-analysis were summarized in Table 2. Four studies were included to compare the effect of SAPT and DAPT on acute kidney injury, and random-effect model was used. The pooling data suggested that no remarkable significance was observed between the two groups in the occurrence of acute kidney injury (RR: 0.83, 95% CI: 0.32-2.15, p = .699) ( Figure 5).

| Meta-regression and subgroup analysis
To explore the source of heterogeneity among studies for lifethreatening bleeding, major bleeding and minor bleeding, meta-regression analysis was performed based on study design and follow-up time. The results showed that heterogeneity among the studies was not associated with study design and follow-up time (   Figure 6D).

| Sensitivity analysis and publication bias
Sensitivity analysis was implemented via sequentially removed single study and reanalyzing the remaining dataset to test the strength of results. The stability and reliability of this meta-analysis were confirmed by the similar heterogeneity before and after the study removal ( Table 2). In addition, the result of Begg's test showed no publication bias in the analysis of all-cause death (Z = À0.10, p = 1.000).

| DISCUSSION
Our meta-analysis included 11 studies comparing the effects of SAPT The successful clinical introduction of TAVI is of great importance in the treatment of severe aortic stenosis. 25 Because of the frequent transcatheter heart valve thrombosis, concern for antithrombotic therapy after TAVI has been increasingly important. Current clinical practice of post-TAVI antithrombotic therapy is still based on The results of metaregression analysis based on study design and follow-up time showed the similar results. Ussia et al. found that no differences in the major ischemic stroke between the two groups. 14 Stabile et al. showed that the incidence of major stroke was similar in the two groups. 22 Our results showed no differences between the groups in the stroke events, including all stroke, disabling stroke, minor stroke, and transient ischemic attack. A retrospective review from a F I G U R E 6 Forrest plots of study design (A) and follow-up time (B) for major bleeding, and study design (C) and follow-up time (D) for minor bleeding dedicated TAVI database of a single high-volume center in Milan reported that no significant difference was found in all-cause mortality and cardiovascular mortality between DAPT and SAPT. 19 Moreover, the incidence of thromboembolic events of MI in the two groups showed no significant difference. 7 Accordingly, our results found that the incidence of all-cause death, cardiovascular death and MI was not significantly different in the two groups. Moreover, the significance in life-threating bleeding between the two groups was not found in our meta-analysis, which was in accordance with the studies from D'Ascenzo et al. and Ullah et al. 20,31 Also, our study found the similar result as the reports of Durand et al. and Stabile et al. that DAPT was not superior to SAPT in acute kidney injury. 22 23 Although SAPT was not superior to DAPT in decreasing the risk of mortality and MI events, stroke events, life-threatening bleeding, and acute kidney injury, the use of SAPT avoided drug abuse and mitigated the economic burden of patients and their families. In addition, clopidogrel caused more damage to patients' body with a higher risk of diarrhea and rash than aspirin, 32 supporting that DAPT with clopidogrel plus aspirin brought more toxicity than SAPT with aspirin alone.
Our meta-analysis showed a clear benefit of SAPT for TAVI postoperative management. In addition, meta-regression based on study design and follow-up time was performed to explore the heterogeneity. However, some limitations were existed. First, our study combined RCTs and cohort studies, and the heterogeneity might exist among the included studies. Second, our study was lack of adjustment for confounders in baseline characteristics and comorbidities of the included patients across groups.
In conclusion, our meta-analysis indicated that SAPT decreased the incidence of all-cause bleeding, major bleeding and minor bleeding. Although SAPT was not superior to DAPT in life-threatening bleeding, mortality and MI events, stroke events, and acute kidney injury, it avoided the drug abuse, and mitigated the damage to patients' bodies and the economic burden to their family members.
Based on available data, SAPT was preferred after TAVI for most patients who were absent another indication for DAPT or oral anticoagulation.