Aspirin for Carotid Stent Continue During Surgery Sdn

Nonstandard Abbreviations and Acronyms

DAPT	dual antiplatelet therapy
OAC	oral anticoagulation
ST	stent thrombosis

Clinical Perspective

What Is New?

Compared with dual antiplatelet therapy, early aspirin discontinuation after coronary stenting does not increase mortality and ischemic events but reduces bleedings.

What Are the Clinical Implications?

The timing of aspirin discontinuation and the role of a monotherapy with more‐potent antiplatelet drugs after coronary stenting warrant further investigation.

In patients treated with a percutaneous coronary intervention (PCI) for stable or unstable coronary artery disease (CAD), specialty guidelines recommend a dual antiplatelet therapy (DAPT) for prevention of thrombotic complications. DAPT regimens usually consist of aspirin and a P2Y12‐inhibitor prescribed for 1 to 12 months according to clinical indication and concomitant antithrombotic therapies.¹

The use of DAPT after coronary stenting has been standard of care since a series of clinical trials done in the 1990s showed that this was the most effective approach.², ³ The main downside is that DAPT exposes patients to the risk of bleeding complications for the duration of therapy. In this regard, the search for alternative antithrombotic regimens, ensuring adequate platelet inhibition while having a wide therapeutic window, remains a matter of broad clinical interest. Recent randomized trials investigated the risk:benefit ratio of early aspirin discontinuation while continuing P2Y12‐inhibitors as compared with DAPT across various risk categories of patients with stable or unstable CAD treated with contemporary PCI and stenting.⁴, ⁵, ⁶ Not surprisingly, by dropping aspirin from DAPT regimens the bleeding risk was reduced to some extent. However, whether this benefit is offset by an increased risk of thrombotic events remains poorly investigated. Indeed, no trial was powered to reliably detect or rule out the efficacy of P2Y12‐inhibitors alone in preventing thrombotic events in this setting.

Against this background, this systematic review and meta‐analysis of randomized trials investigates the clinical impact of early aspirin discontinuation versus DAPT in patients treated with coronary stenting.

Methods

We will make the data and methods used in the analysis available to any researcher for the purposes of reproducing the results and procedures upon reasonable request.

Data Sources and Searches

Relevant electronic scientific databases (including Medline, EMBASE, the CENTRAL [Cochrane Central Register of Controlled Trials], session abstracts, and websites) were searched for scientific communications without restricting language or publication status. We extrapolated further citations by inspecting the references listed in all eligible studies. The last search was performed on March 30, 2020. Search terms included the keywords and the corresponding Medical Subject Headings for: "aspirin," "antithrombotic therapy," "(dual) antiplatelet therapy," "clopidogrel," "ticagrelor," "prasugrel," "percutaneous coronary intervention," "stent," "trial," and "randomized trial." Inclusion criteria were the following: (1) randomized design, (2) allocation to antiplatelet therapy with or without concomitant oral anticoagulation (OAC), and (3) follow‐up duration ≥6 months. Trials in which the type, number, dose, or duration of OAC medications differed between treatment groups were ineligible.⁷, ⁸, ⁹

Study Selection

Two investigators (J.W. and G.N.) independently assessed publications for eligibility at title and/or abstract level. A third investigator (S.C.) helped to settle divergences. In case the studies met inclusion criteria, they entered further analysis.

Data Extraction, Quality Assessment, and Outcome Variables

Trial‐level data concerning overall number of patients, mean age, proportion of females, patients with diabetes mellitus, former or current smokers, acute coronary syndromes (ACS) at admission, history of previous myocardial infarction (MI) or cerebrovascular accident were extracted from each trial. The same investigators evaluated independently the presence of any bias in each study in accordance with The Cochrane Collaboration items.¹⁰ We did not assign composite quality scores.¹¹ The primary outcomes of this analysis were all‐cause death and MI. Secondary outcomes were stent thrombosis (ST), stroke, and major bleeding. We considered all end points occurred up to the maximum follow‐up duration in the intention‐to‐treat population, as per definitions reported in the original protocols.

Data Synthesis and Statistical Analysis

Hazard ratios (HRs) and 95% CIs served as summary statistics to compare the outcomes of interest associated with either early aspirin discontinuation (experimental therapy) or standard DAPT (control therapy). A random effects model with the inverse variance weighting (stratified according to concomitant OAC therapy) served to pool trial‐level logHRs and corresponding SEs. We considered time‐to‐event data during the entire duration of follow‐up in each included trial (primary analysis), and after therapies in the treatment groups actually diverged (posing a landmark at aspirin discontinuation in the experimental group). The I² statistic and (95% CIs) informed on the heterogeneity between the trials: I² values ≈25%, 50%, and 75% were considered to indicate low, moderate, or high heterogeneity, respectively.¹⁰ In addition, we estimated the between‐study variance (tau²) according to DerSimonian‐Laird and derived the 95% prediction interval of pooled estimates.¹² In case of statistical significance in the primary analysis, the number needed to treat or to harm with (95% CI) was provided. We performed 3 sensitivity analyses.

The Breslow‐Day χ² test for subgroup differences addressed the impact of concomitant OAC therapy on outcomes of interest. The same statistical method was useful to calculate the treatment‐by‐subgroup interaction between primary outcomes and (1) the P2Y12‐inhibitor predominantly used in the experimental group (clopidogrel versus ticagrelor); (2) the time point of aspirin discontinuation (immediately versus 1 month versus 3 months after coronary stenting) as per individual protocol in each trial; (3) the predominant geographic area of enrollment (Asia versus Western countries).
An influence analysis assessed the changes in the direction of the summary estimates for primary outcomes computed omitting 1 study at a time.
A random‐effect meta‐regression analysis assessed the impact proportion of patients with ACS at admission on the pooled estimates for primary outcomes.

We calculated the power of our meta‐analysis to detect a 30% relative risk difference for main outcomes with early aspirin discontinuation conditional on the observed precision of the pooled estimate.¹³ We set the 30% threshold as benchmark because it corresponds to the average relative risk difference threshold (range 20%–58%) supporting the power of individual study designs included in this meta‐analysis. The possibility of small study effects resulting from publication bias or other biases was examined for the primary outcomes by visual inspection of funnel plots of the HRs of individual trials against their SEs and by a linear regression test for funnel plot asymmetry.

This study was reported in compliance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) statement (Table S1).¹⁴ All analyses were performed by using the package meta in R (version 3.6.0; R Foundation for Statistical Computing, Vienna, Austria). No extramural funding was used to support this work. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the paper, and its final contents. Ethical approval was not required for this study.

Results

Eligible Studies

The flow diagram for the trial selection process is shown in Figure 1. After application of inclusion/exclusion criteria, 7 trials (6 published as full‐length manuscripts⁴, ⁵, ⁶, ¹⁵, ¹⁶, ¹⁷ and 1 available as a meeting presentation¹⁸) were included in the meta‐analysis. No disagreements required solution by the third reviewer. In the selected trials, a total of 37 303 patients were randomly allocated to experimental (n=18 638) or control therapy (n=18 665) after coronary stenting. Two trials included patients with PCI with a planned OAC therapy. The WOEST (What is the Optimal Antiplatelet and Anticoagulant Therapy in Patients with Oral Anticoagulation and Coronary Stenting) trial included patients with any indication for OAC.¹⁵ Conversely, the Aspirin Placebo in Patients with Atrial Fibrillation and Acute Coronary Syndrome or Percutaneous Coronary Intervention (AUGUSTUS) trial included only patients with an indication for OAC because of atrial fibrillation.⁶ The AUGUSTUS trial included a total of 1097 patients with medically treated ACS: since the current study focused on patients receiving experimental or control therapy after coronary stenting, we obtained from this latter study time‐to‐event data of the PCI stratum to derive summary risk estimates.¹⁹ Thus, we analyzed the aggregate data of 7 trials in which a total of 36 206 PCI patients were allocated to experimental (n=18 088) or control therapy (n=18 118).

**Figure 1. PRISMA flow chart for the trial selection process.**
ACS indicates acute coronary syndrome; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta‐Analyses; and RCTs, randomized controlled trials.

The main characteristics of the trials included are shown in Table S2. All trials had a multicenter design and included patients with obstructive chronic/stable or unstable CAD receiving coronary stenting.

Patients allocated to experimental therapy received aspirin 75 to 200 mg once daily for a period of time ranging between 1 and 3 months in 5 trials,⁴, ⁵, ¹⁶, ¹⁷, ¹⁸ with clopidogrel 75 mg once daily or ticagrelor 90 mg twice daily as predominant P2Y12‐inhibitors. In 3 trials,⁶, ¹⁶, ¹⁷ a proportion of patients ranging between 0.7% and 39.6% received 3.75 to 10 mg prasugrel once daily according to clinical indication.

Patients assigned to control therapy received DAPT consisting of clopidogrel 75 mg once daily or ticagrelor 90 mg twice daily in combination with aspirin 75 to 200 mg once daily. Patients with an indication for OAC received either vitamin K antagonist or either apixaban or vitamin K antagonist in a random fashion in 2 trials.⁶, ¹⁵ Comparative Effectiveness of 1 Month of Ticagrelor Plus Aspirin Followed by Ticagrelor Monotherapy Versus a Current‐day Intensive Dual Antiplatelet Therapy in All‐comers Patients Undergoing Percutaneous Coronary Intervention With Bivalirudin and BioMatrix Family Drug‐eluting Stent Use (GLOBAL LEADERS) trial had a peculiar design which deserves further description. The experimental therapy consisted of ticagrelor 90 mg twice daily in combination with aspirin 75 to 150 mg once daily for 1 month followed by ticagrelor monotherapy for 23 months. The control therapies consisted of clopidogrel 75 mg once daily or ticagrelor 90 mg twice daily (according to clinical presentation) in combination with aspirin 75 to 150 mg once daily for 12 months followed by aspirin 75 to 150 mg once daily for an additional 12 months.⁴ Finally, the Ticagrelor With Aspirin or Alone in High‐Risk Patients After Coronary Intervention (TWILIGHT) trial randomized patients without bleeding or ischemic events 3 months after PCI to either continue ticagrelor as standalone therapy or DAPT (experimental and control therapy, respectively).⁵

In 3 trials the predominant diagnosis at admission was ACS or stabilized MI.⁵, ¹⁶, ¹⁸ In the experimental group, the adherence to assigned antiplatelet regimen at the longest available follow‐up ranged between 77.6% and 87.1%. All patients received ancillary therapies for acute or chronic manifestations of CAD in accordance with standard of care.

Baseline characteristics are shown in Table. Patients were more often male, had a median age of 65.1 years (interquartile range, 64.5–69.9), more than a third of them had diabetes mellitus, and nearly one‐fourth of them had a history of smoking at the time of inclusion in the primary trials. Approximately 50% of patients included presented with ACS. A previous MI was reported in 25.3% of patients, and 6.4% of patients have had cerebrovascular accidents before enrollment. The weighted median follow‐up available for the assessment of outcomes of interest was 12 months (mean 12.8±5.3).

John Wiley & Sons, Ltd

**Table 1. Main Characteristics of Patients Enrolled Among Trials Included in the Study**
Trial	Patients, n	Age, y	Females, %	Diabetes Mellitus, %	Smoking, %	ACS, %	Previous MI, %	Previous CVA, %
With oral anticoagulation
AUGUSTUS (PCI stratum)⁶, ⁷, ⁸, ⁹, ¹⁰, ¹¹, ¹², ¹³, ¹⁴, ¹⁵, ¹⁶, ¹⁷, ¹⁸, ¹⁹	3498	70.6	904 (25.8)	1320 (37.7)	N/R	1714 (48.9)	N/R	466 (13.3)
WOEST¹⁵	573*	69.9	115 (20.4)	140 (24.9)	102 (18.1)	155 (27.5)	196 (34.8)	99 (17.6)
Without oral anticoagulation
GLOBAL LEADERS⁴	15 968	64.5	3714 (23.2)	4038 (25.2)	4169 (26.1)	7487 (46.8)	3710 (23.2)	421 (2.6)
SMART CHOICE¹⁶	2993	64.5	795 (26.5)	1122 (37.4)	791 (26.4)	1741 (58.1)	783 (26.1)	201 (6.7)
STOP DAPT 2¹⁷	3009	68.6	672 (22.3)	1159 (38.5)	710 (23.5)	1148 (38.1)	741 (24.6)	186 (6.1)
TICO¹⁸	3056	61.0	628 (20.5)	835 (27.3)	1142 (37.3)	3056 (100)	113 (3.7)	126 (4.1)
TWILIGHT⁵	7199	65.1	1698 (23.5)	2620 (36.3)	1548 (21.5)	4614 (64.1)	2120 (29.4)	N/R

Clinical Outcomes

All trials had sufficient statistical power for bleeding or composite clinical end points, which included mortality and MI in most of them. One trial reported outcome data beyond 12 months.⁴ The definitions of outcomes are reported in Table S3 and the risk of bias among studies is reported in Table S4.

Primary Outcomes

Overall, all‐cause deaths occurred in 981 patients (2.7%; Figure 2A).⁴, ⁵, ⁶, ¹⁵, ¹⁶, ¹⁷, ¹⁸, ¹⁹ The outcome of all‐cause death occurred in 2.5% of patients assigned to experimental and 2.9% of patients assigned control therapy (HR, 0.91; 95% CI, 0.75–1.11; P=0.37). The random‐effects meta‐analysis had 94.7% power to detect a 30% relative risk difference of all‐cause death associated with experimental therapy. The 95% prediction interval for this outcome contained the null (0.58; 1.45) and there was moderate heterogeneity. Notably, there was no impact of concomitant OAC therapy with the risk of all‐cause death (P for interaction [P _int]=0.72). Cardiac death occurred in 128 patients (0.8%, data available for 16 740 participants). The risk of cardiac death in patients assigned to either experimental or control therapy was not significantly different (0.6% versus 0.9%; HR, 0.73 [0.52–1.04], P=0.08).

The outcome of MI occurred in 896 patients (2.5%; Figure 2B).⁴, ⁵, ⁶, ¹⁵, ¹⁶, ¹⁷, ¹⁸, ¹⁹ The risk of MI in patients assigned to either experimental or control therapy was not significantly different (2.5% versus 2.5%; HR, 1.02 [0.85–1.22], P=0.81). The random‐effects meta‐analysis had 97.4% power to detect a 30% risk difference of MI associated with experimental therapy. The 95% prediction interval for this outcome contained the null (0.71; 1.48). There was no impact of concomitant OAC therapy with the risk of MI (P _int=0.64).

Secondary Outcomes

ST occurred in 213 patients (0.6%) (Figure 3A through 3C).⁴, ⁵, ⁶, ¹⁵, ¹⁶, ¹⁷, ¹⁸, ¹⁹ In patients assigned to either experimental or control therapy, the risk of ST was not significantly different (0.6% versus 0.6%; HR, 1.02 [0.87–1.20], P=0.83).

Stroke occurred in 282 patients (0.8%). In patients assigned to either experimental or control therapy, the risk of stroke was not significantly different (0.8% versus 0.8%; HR, 1.01 [0.68–1.49], P=0.96), with moderate to high heterogeneity.

Major bleeding occurred in 812 patients (2.2%). Patients assigned to experimental therapy had a lower risk of major bleeding compared with control therapy (1.8% versus 2.7%; HR, 0.58 [0.43–0.77], P<0.01), with high heterogeneity. The number needed to treat to avoid 1 case of major bleeding with experimental therapy was 88 patients (64; 161). We found no impact of concomitant OAC therapy with the risk of ST, stroke, or major bleeding in patients assigned to either experimental or control therapy (P _int≥0.69).

Landmark Analysis

After aspirin discontinuation, the risk of all‐cause death (HR, 0.92 [0.74–1.15], P=0.47), MI (HR, 1.01 [0.81–1.27], P=0.92), ST (HR, 1.02 [0.73–1.43], P=0.90), and stroke (HR, 1.10 [0.69–1.74], P=0.70) was not significantly different in patients assigned to either experimental or control therapy. In contrast, the risk of major bleeding was lower with the experimental compared with control therapy (HR, 0.53 [0.38–0.74], P<0.01). The concomitant OAC therapy did not impact the risk estimates for the abovementioned outcomes (P _int≥0.56).

Sensitivity and Influence Analyses

The test for subgroup differences did not find a significant interaction between the risk for all‐cause death and MI and the use of clopidogrel or ticagrelor in the experimental arm (P=0.41 and 0.82), the discontinuation of aspirin immediately, 1 or 3 months after coronary stenting (P=0.84 and 0.76), and the predominant enrollment of patients from Asia or Western countries (P=0.57 and 0.25). By omitting 1 study at a time, the direction of the summary HRs for the primary outcomes did not display a significant modification (Figure S1A and S1B). The linear regression test discarded a funnel plot asymmetry for all‐cause death (P=0.54) and MI (P=0.48), respectively (Figure S2A and S2B). Finally, the treatment effect for all‐cause death (P=0.71) and MI (P=0.40) was not dependent on the proportion of patients with ACS at admission.

Discussion

This systematic review and meta‐analysis of aggregate study‐level data investigated the outcomes of ≈40 000 patients with CAD randomly assigned to either early aspirin discontinuation or DAPT after PCI with stent implantation. Importantly, the treatment groups in each included trial received identical antithrombotic regimens, apart from early aspirin discontinuation in the experimental group. After a median follow‐up of 12 months the main findings are as follows:

In comparison with DAPT, the risk of all‐cause death and MI with early aspirin discontinuation was not significantly different, but the risk of major bleeding was lower.
There are no significant differences with respect to ST and stroke associated with either early aspirin discontinuation or DAPT.

First, the results of this study are relevant in that they report a neutral treatment effect for mortality and MI and a lower risk of major bleeding with an antithrombotic regimen without aspirin. In fact, although the lower bleeding risk associated with the omission of aspirin among antithrombotic medications comes as no surprise,²⁰ this analysis showed no trade‐off between bleeding reduction and increased thrombotic risk. This is a pervasive feature of most trials of antithrombotic therapy and accordingly, adjudication of overall patient benefit can be challenging. In this respect, all‐cause death, the primary end point of the current study, might be a robust and sensitive indicator of net clinical benefit. Along the same line, the lack of significant difference in terms of ischemic risk in patients assigned to either early aspirin discontinuation or DAPT after contemporary stenting is reassuring. It is worth mentioning that the present study has sufficient statistical power to ascertain any clinically relevant benefit (or harm) in terms of mortality and MI associated with aspirin withdrawal in this setting.

Second, the magnitude of treatment effect for primary outcomes was not dependent on whether we considered time‐to‐event data from the entire follow‐up duration or after aspirin discontinuation in the experimental group. Indeed, in the majority of trials included, patients randomized at time of PCI received the same antithrombotic regimens for a period of time ranging between 1 and 3 months.⁴, ⁵, ⁶, ¹⁶, ¹⁷, ¹⁸ This is an important methodological aspect, because it provides evidence that the risk for ischemic and bleeding outcomes associated with early aspirin discontinuation is not dampened from events that occurred when treatment groups receive the same antithrombotic therapies. The analysis of landmark data, the increased statistical power for clinically relevant outcomes, the selection of trials in which antithrombotic regimens across groups were identical apart from per‐protocol aspirin withdrawal, and the inclusion of the latest available evidence concerning early aspirin dropping from DAPT after coronary stenting represent unique features of this study, which have some clinical relevance.

Third, the present meta‐analysis is quite consistent with another study assessing the role of aspirin in primary prevention, and which demonstrated no reduction of mortality, but increased rates of major bleedings.²¹ In contrast with this previous study, we did not confirm the benefit of antithrombotic regimens with aspirin in lowering nonfatal ischemic events. The findings from primary prevention studies may have implications for aspirin use in the setting of secondary prevention, as in patients with CAD undergoing coronary stenting. Indeed, the mechanism of atherothrombotic protection of aspirin is the same, regardless of use in the setting of primary or secondary prevention. In addition, ischemic events, mostly indicated to support the benefits of aspirin in primary prevention, may be even more frequent in the setting of secondary prevention because of poorer risk profile of patients predisposing to a higher risk of adverse events.

Finally, in the past decade the strategy of discontinuing P2Y12‐inhibitors in favor of aspirin after coronary stenting has been extensively investigated.²² However, although aspirin has been the cornerstone of antiplatelet therapy for a long time, there exists a clinical rationale for discontinuing its use in favor of P2Y12‐inhibitors. Aspirin increases the risk of bleeding complications and the majority of studies of aspirin in patients with PCI were conceived before the advent of other established medical therapies, including new P2Y12‐inhibitors.²³ For these reasons, we believe that investigations concerning the de‐escalation of antithrombotic therapies by discontinuing aspirin (instead of P2Y12‐inhibitors) in patients with PCI are worth pursuing. In this regard, future trials should address whether a monotherapy with the irreversible P2Y12‐inhibitor prasugrel, which was prescribed in a small proportion of patients in the current analysis, is superior to a monotherapy with clopidogrel or ticagrelor after coronary stenting.

Limitations

The current study has some limitations. First, the meta‐analysis was based on study‐level data. Although we believe that the questions under consideration can be reliably answered by a meta‐analysis of aggregate data, a meta‐analysis of individual participant data remains necessary. In this context, the fact that we observed no change in the direction of treatment effect for primary outcomes dependent on several features at trial level including the need for concomitant OAC therapy, the type of P2Y12‐inhibitor, the timing of aspirin discontinuation, and the proportion of patients with ACS remains speculative in nature. The analysis of individual data remains a prerequisite to disclose a variation of treatment effect according to several features at patient (clinical presentation, concomitant OAC), procedural (anatomical or interventional complexity, stent type), and pharmacological (safety and efficacy profiles of different P2Y12‐inhibitors and dosages, response to antithrombotic drugs) levels. Second, all patients were on aspirin therapy at the time of PCI and discontinuation occurred at various intervals postprocedure per individual trial protocols. Although we found no statistical interaction between the timing of aspirin discontinuation and the treatment effect for the primary outcomes, we cannot recommend a specific time‐point after coronary stenting at which aspirin could be dropped from DAPT. Third, the results associated with experimental versus control therapy observed in this analysis do not apply to patients with clinical and anatomical features different from those represented here. Notably, the number needed to avoid 1 case of major bleeding with the experimental therapy remains relatively high because of the inclusion of relatively low‐risk patients with obstructive chronic/stable or unstable CAD. Fourth, the median follow‐up duration was 12 months. An extended follow‐up would be desirable and we cannot exclude the possibility that significant differences may emerge at long term. Finally, the use of funnel plots does not accurately depict publication bias for such a small sample.

Conclusions

The present study shows that in patients treated with coronary stenting and assigned to early aspirin discontinuation versus standard DAPT, the risk of mortality and ischemic events is not significantly different but the risk of bleeding is lower. This finding may challenge the current antithrombotic treatment of patients receiving coronary stenting. However, the comparative safety and efficacy of a monotherapy with more‐potent antiplatelet drugs after coronary stenting remains to be addressed in randomized trials powered for clinically relevant ischemic and bleeding end points.

Sources of Funding

None.

Disclosures

Joner is a consultant for Biotronik and OrbusNeich. The remaining authors have no disclosures to report.

Acknowledgments

Wiebe, Ndrepepa, Kufner, Lahmann, Xhepa, Kuna, Voll, Gosetti, and Cassese were involved in study conception and design. Cassese performed the data analysis. Laugwitz, Joner, and Kastrati supervised the data analysis. Wiebe together with Ndrepepa, Kastrati, and Cassese wrote the first draft of the manuscript. Wiebe, Ndrepepa, Kufner, Lahmann, Xhepa, Kuna, Voll, Gosetti, Laugwitz, Joner, Kastrati, and Cassese were involved in data acquisition and revised the manuscript for important intellectual contents. All authors had full access to all the data, including statistical reports and tables and approved the manuscript for final submission. Open access funding enabled and organized by Projekt DEAL.

Footnotes

* Correspondence to: Salvatore Cassese, MD, PhD, Klinik für Herz‐ und Kreislauferkrankungen, Deutsches Herzzentrum München, Technische Universität München, Lazarettstrasse, 36 ‐ Munich, Germany. E‐mail: [email protected] mhn.de

For Sources of Funding and Disclosures, see page 10.

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Source: https://www.ahajournals.org/doi/full/10.1161/JAHA.120.018304