1 INTRODUCTION

Aortic stenosis is a common kind of valvular heart disease, affecting 2%–7% of older population.1, 2 Currently, transcatheter aortic valve implantation (TAVI) has been proved as an effective therapy to replace the conventional surgery for patients with severe aortic stenosis.3 However, some postoperative adverse events of TAVI cannot be ignored. Especially, thrombotic events commonly occur, with 1% being myocardial infarction (MI) and 3% being ischemic stroke, which lead to a high mortality.4, 5 Therefore, more attention should be paid to the thrombotic events after TAVI for the improvement of prognosis.

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 TAVI6; 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 meta-analysis 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.

2 METHODS 2.1 Literature search strategy

We searched for available literatures from PubMed, Embase, Cochrane Library and Web of Science, and the deadline for searching studies was April 1, 2021. The literature retrieval was independently conducted by two researchers (S. Q. Y. and S. Y. Z.). Search strategies included: “Transcatheter Aortic Valve Implantation” OR “Transcatheter Aortic Valve Replacement” AND “single antiplatelet therapy” OR “dual antiplatelet therapy” OR “Dual Anti-Platelet Therapy” OR “Anti-Platelet Therapies, Dual” OR “Anti-Platelet Therapy, Dual” OR “Dual Anti Platelet Therapy” OR “Dual Anti-Platelet Therapies” OR “Aspirin” OR “Acetylsalicylic Acid” OR “Acid, Acetylsalicylic” OR “2-(Acetyloxy)benzoic Acid” OR “Acylpyrin” OR “Aloxiprimum” OR “Colfarit” OR “Dispril” OR “Easprin” OR “Ecotrin” OR “Endosprin” OR “Magnecyl” OR “Micristin” OR “Polopirin” OR “Polopiryna” OR “Solprin” OR “Solupsan” OR “Zorprin” OR “Acetysal” OR “Clopidogrel” OR “SC 25989C” OR “SC 25990C” OR “SR 25989” OR “Clopidogrel-Mepha” OR “Clopidogrel Mepha” OR “Clopidogrel Sandoz” OR “Iscover” OR “Clopidogrel Napadisilate” OR “Clopidogrel Hydrochloride” OR “PCR 4099” OR “PCR-4099” OR “Clopidogrel Besylate” OR “Clopidogrel Besilate” OR “Clopidogrel, (+)(S)-isomer” OR “Plavix” OR “Clopidogrel Bisulfate” OR “Hydrochloride, Prasugrel” OR “Prasugrel HCl” OR “HCl, Prasugrel” OR “CS 747” OR “747, CS” OR “CS-747” OR “CS747” OR “Prasugrel” OR “Efient” OR “Effient” OR “LY 640315” OR “640 315, LY” OR “LY640315” OR “LY-640315” OR “Ticagrelor” OR “Brilique” OR “AZD 6140” OR “AZD6140” OR “AZD-6140” OR “Brilinta” OR “3-(7-((2-[3,4-difluorophenyl]cyclopropyl)amino)-5-(propylthio)-3H-(1-3)-triazolo(4,5-d)pyrimidin-3-yl)-5-(2-hydroxyethoxy) cyclopentane-1,2-diol”.

2.2 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.

2.3 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.

2.4 Outcome variable measurement 2.4.1 Primary outcomes Mortality and myocardial infarction (MI) events: all-cause death, cardiovascular death, and MI. Stroke events: all stroke, disabling stroke, minor stroke, and transient ischemic attack. Bleeding events: all-cause bleeding, life-threatening bleeding, major bleeding, and minor bleeding. 2.4.2 Secondary outcomes 2.5 Methodological quality appraisal

Two independent investigators (S. Q. Y. and S. Y. Z.) were responsible for quality assessment. Jadad scale15 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).

2.6 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 I2 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 (I2 < 50%), and the random-effect model was used when the heterogeneity was high (I2 ≥ 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 (I2 ≥ 50%). Sensitivity analysis was performed for all outcomes and publication bias was assessed by Begg's test.

3 RESULTS 3.1 Study selection and baseline characteristics

A total of 5008 studies were identified using the four English databases. Among which, 401 studies were eliminated as duplicates. After evaluating titles and abstracts, 4581 studies were excluded. The residual 26 texts were further assessed; of these, 15 texts were removed because of the incomplete data (n = 10) and control groups not meeting the requirements (n = 5). Finally, 11 studies (4 RCTs and 7 cohort studies)7, 12, 14, 17-24 were included, and the flow chart of study selection was shown in Figure 1. Totally, 4804 patients were enrolled, including 2257 patients in SAPT group and 2547 patients in DAPT group. Moreover, according to the evaluation results of Jadad and revised NOS, 9 studies were of high quality and 2 studies were of low quality. Table 1 summarizes the baseline characteristics and quality assessment score of included studies.

Flow chart of study selection

TABLE 1. Baseline characteristics of included studies Author Year of publication Country Study design Groups Total Age (years) Male/female Follow-up (months) Quality of literatures Outcomes Ussia 2011 Italy RCT SAPT 39 81 ± 4 16/23 6 4 a, b, c, e, f, g, i, j, k DAPT 40 80 ± 6 20/20 Poliacikova 2013 UK Cohort SAPT 91 82 49/42 6 4 a, c, d, h DAPT 58 81.6 32/26 Durand 2013 France Cohort SAPT 164 82.7 ± 6.3 90/74 6 5 a, c, d, e, f, g, h, i, j, k, l DAPT 128 84.6 ± 5.8 50/78 Stabile 2014 Italy RCT SAPT 60 81.1 ± 4.8 24/36 6 6 a, b, c, e, f, j, k, l DAPT 60 80.2 ± 5.7 16/44 Czerwińska-Jelonkiewicz 2016 Poland Cohort SAPT 124 79.14 ± 7.39 56/68 12 6 c, i DAPT 352 78.92 ± 7.24 NA D'Ascenzo 2017 Italy Cohort SAPT 605 81 ± 4 256/349 12 4 a, d, h, i, j, k DAPT 605 81 ± 5 269/336 Ichibori 2017 Japan Cohort SAPT 78 83 ± 6 28/50 12 5 i, l DAPT 66 84 ± 6 24/42 Mangieri 2017 Italy Cohort SAPT 108 84.3 ± 7.1 46/62 12 6 a, b, c, d, i, j, k, l DAPT 331 82.9 ± 8.2 117/214 Rodés-Cabau 2017 Canada RCT SAPT 111 79 ± 9 59/52 3 4 a, c, d, e, f, g, i, j DAPT 111 79 ± 9 70/41 Brouwer 2020 Netherlands RCT SAPT 331 80.4 ± 6.2 167/164 12 5 a, b, c, d, e, f, h, i, j, k DAPT 334 79.5 ± 6.4 174/160 Hioki 2021 Japan Cohort SAPT 546 85 (81–88) 151/395 12 5 a, b DAPT 462 84 (81–87) 147/315 Note: Data presented as mean ± SD or n. RCT, randomized control trail; SAPT, single antiplatelet therapy; DAPT, dual antiplatelet therapy; a, all-cause death; b, cardiovascular death; c, myocardial infarction; d, all stroke; e, disabling stroke; f, minor stroke; g, transient ischemic attack; h, all-cause bleeding; i, life-threatening bleeding; j, major bleeding; k, minor bleeding; l, acute kidney injury. 3.2 Mortality and MI events

Table 2 shows no significant difference in all-cause death between the two groups (RR: 0.90, 95% CI: 0.77–1.05, p = .183) (Figure 2A). The cardiovascular death of the two groups was not statistically significant (RR: 0.71, 95% CI: 0.45 to 1.11, p = .132) (Figure 2B). Also, the incidence of MI in SAPT group showed no statistical difference from DAPT group (RR: 0.70, 95% CI: 0.35–1.39, p = .306) (Figure 2C).

TABLE 2. Meta-analysis results of outcomes between SAPT and DAPT Outcomes RR (95% CI) p I2 Mortality and MI events All-cause death 0.90 (0.77, 1.05) .183 30.4 Cardiovascular death 0.71 (0.45, 1.11) .132 43.3 Myocardial infarction 0.70 (0.35, 1.39) .306 0.0 Stroke events All stroke 0.69 (0.45, 1.08) .102 0.0 Disabling stroke 0.88 (0.39, 1.99) .763 0.0 Minor stroke 0.73 (0.37, 1.43) .354 0.0 Transient ischemic attack 0.90 (0.13, 6.23) .911 0.0 Bleeding events All-cause bleeding 0.51 (0.44, 0.61) <.001 47.5 Life-threatening bleeding 0.55 (0.28, 1.08) .083 73.8 Major bleeding 0.53 (0.32, 0.86) .011 58.7 Minor bleeding 0.58 (0.34, 0.98) .044 63.3 Acute kidney injury 0.83 (0.32, 2.15) .699 65.1 Abbreviations: CI, confidence interval; DAPT, dual antiplatelet therapy; MI, myocardial infarction; RR, relative risk; SAPT, single antiplatelet therapy.

Forrest plots of all-cause death (A), cardiovascular death (B), and myocardial infarction (C)

3.3 Stroke events

For stroke events, results were shown in Table 2, indicating that no statistical significance was found between the two groups in the incidence of all stroke (RR: 0.69, 95% CI: 0.45–1.08, p = .102) (Figure 3A), disabling stroke (RR: 0.88, 95% CI: 0.39–1.99, p = .763) (Figure 3B), minor stroke (RR: 0.73, 95% CI: 0.37–1.43, p = .354) (Figure 3C), and transient ischemic attack (RR: 0.90, 95% CI: 0.13–6.23, p = .911) (Figure 3D).

Forrest plots of all stroke (A), disabling stroke (B), minor stroke (C), and transient ischemic attack (D)

3.4 Bleeding events

Table 2 displays the analysis results of bleeding events between the two groups. Compared to DAPT, SAPT group showed a 49% reduction in all-cause bleeding (RR: 0.51, 95% CI: 0.44–0.61, p < .001) (Figure 4A), while it was not significantly correlated with the decreased risk of life-threatening bleeding (RR:0.55, 95% CI: 0.28–1.08, p = .083) (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). Similarly, SAPT decreased the risk of minor bleeding compared with DAPT (RR: 0.58, 95% CI: 0.34–0.98, p = .044) (Figure 4D).

Forrest plots of all-cause bleeding (A), life-threatening bleeding (B), major bleeding (C), and minor bleeding (D)

3.5 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).

Forrest plot of acute kidney injury

3.6 Meta-regression and subgroup analysis

To explore the source of heterogeneity among studies for life-threatening 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 (Table 3). Results of SAPT versus DAPT on adverse outcomes in different subgroups were shown in Table 4. SAPT decreased the risk of major bleeding compared to DAPT in RCT articles (RR: 0.42, 95% CI: 0.23–0.79, p = .007), while cohort studies presented no differences between the two groups (RR: 0.54, 95% CI: 0.26–1.13, p = .100) (Figure 6A). Our findings also showed that the incidence of major bleeding was lower in SAPT group at 6 months follow-up (RR: 0.33, 95% CI: 0.12–0.96, p = .041), but no significance at 3 months (RR: 0.60, 95% CI: 0.15–2.45, p = .477) and 12 months (RR: 0.60, 95% CI: 0.33–1.09, p = .096) (Figure 6B). Either cohort studies (RR: 0.52, 95% CI: 0.19–1.41, p = .198) or RCTs (RR: 0.64, 95% CI: 0.39–1.07, p = .087) did not show the significance between the two groups regarding to minor bleeding (Figure 6C). Similarly, the difference was not found at follow-up of 6 months (RR: 0.57, 95% CI: 0.22–1.49, p = .250) or 12 months (RR: 0.58, 95% CI: 0.29–1.16, p = .123) (Figure 6D).

TABLE 3. The results of meta-regression analysis based on study design and follow-up time Variables Coef SE t p 95% CI Life-threatening bleeding Study design (Cohort study vs. RCT) −0.004 1.237 −0.00 .998 −3.438 3.430 Follow-up (6 months vs. 3 months) 0.458 2.095 0.22 .837 −5.357 6.274 Follow-up (12 months vs. 3 months) 0.984 2.032 0.48 .653 −4.656 6.625 Constant 0.143 1.667 0.09 .936 −4.487 4.772 Major bleeding Study design (Cohort study vs. RCT) 0.213 0.469 0.45 .681 −1.280 1.706 Follow-up (6 months vs. 3 months) −0.320 0.949 −0.34 .758 −3.341 2.701 Follow-up (12 months vs. 3 months) −0.083 0.879 −0.09 .931 −2.880 2.714 Constant 0.600 0.765 0.78 .490 −1.834 3.034 Minor bleeding Study design (Cohort study vs. RCT) −0.062 0.472 −0.13 .904 −1.563 1.440 Follow-up (12 months vs. 6 months) −0.034 0.559 −0.06 .955 −1.812 1.744 Constant 0.745 0.534 1.39 .258 −0.956 2.446 Abbreviations: CI, confidence interval; RCT, randomized control trail. TABLE 4. The effects of DAPT versus SAPT on the adverse events based on different study designs and follow-up time Outcomes RR (95% CI) p I2 Major bleeding Study design RCT 0.42 (0.23, 0.79) .007 0.0 Cohort study 0.54 (0.26, 1.13) .100 82.4 Follow-up 3 months 0.60 (0.15, 2.45) .477 NA 6 months 0.33 (0.12, 0.96) .041 20.9 12 months 0.60 (0.33, 1.09) .096 77.6 Minor bleeding Study design RCT 0.64 (0.39, 1.07) .087 8.5 Cohort study 0.52 (0.19, 1.41) .198