FormalPara Key Summary Points

Why carry out this study?

Patients at high bleeding risk (HBR patients) represent an important subset of patients undergoing percutaneous coronary intervention (PCI).

In contemporty practice, it is unclear whether shortened dual antiplatelet therapy (DAPT) (1–3 months) confers safe ischemic outcomes and a reduction in bleeding events compared with prolonged DAPT (6–12 months).

What was learned from the study?

Among HBR patients after PCI, short-term DAPT was associated with a reduction in major bleeding events and similar ischemic outcomes compared to long-term DAPT. However, a higher risk of ischemic stroke and MI was seen in some subsets.

Future dedicated trials should investigate optimal strategies for patient-tailored DAPT in various clinical subgroups.

Introduction

Patients at high bleeding risk (HBR patients) represent an important patient subset in contemporary percutaneous coronary intervention (PCI) practice. Approximately 40% of patients undergoing PCI present with characteristics of HBR [1]. Drug-eluting stents (DES) have passed through considerable device iteration, consequently leading to modified designs with biodegradable or biocompatible polymers and thinner struts [2, 3]. These characteristics facilitate rapid endothelialization and enable a therapeutic strategy consisting of shorter durations of dual-antiplatelet therapy (DAPT). DAPT is generally indicated for 6–12 months after PCI [4], but some authors recently reported the safety of shorter durations of DAPT in HBR patients [5, 6].

However, it remains unclear whether short-term DAPT regimens after PCI with second-generation DES in HBR patients confer sufficient protection against ischemic events and enhance the benefits driven by the reduction in major bleeding events. This uncertainty arises from mixed results across studies with limited statistical power to detect low-frequency events, the discrepancy in studies regarding short- and long-term DAPT durations, and differences in the single antiplatelet therapy (SAPT) used thereafter.

The primary objective of this study was to systematically review and synthesize available data from studies including 1–3 months of DAPT and compare these to studies including prolonged DAPT (6–12 months), in HBR patients who underwent PCI in contemporary practice.

Methods

Literature Search

This study was conducted according to the proposal for conducting and reporting Meta-analyses of Observational Studies (MOOSE) [7] and Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PRISMA) [8]. A computerized search of the PubMed and Scopus databases was performed from January 2004 to December 2021 using the following search terms separately and in combination: “short DAPT,” “short dual antiplatelet therapy,” “percutaneous coronary intervention,” “PCI,” "HBR," and “high bleeding risk.” Bibliographies of the retrieved studies were screened for other relevant studies. The search was limited to articles published in the English language. The search strategy is shown in Electronic Supplementary Material (ESM) Table 1.

Study Selection

We performed a meta-analysis of studies that included patients fulfilling HBR criteria who underwent PCI with second-generation DES and compared different DAPT durations. The duration of therapy studied included short-term DAPT, defined as 1–3 months, and long-term DAPT duration, defined as 6–12 months. Studies addressing patients with a single HBR or those comparing short- versus long-term triple antithrombotic therapy (TAT) with oral anticoagulation and DAPT after PCI were excluded.

Data Extraction and Quality Assessment

The data were extracted by two independent investigators (NM, RH) and confirmed by a third investigator (MM). Discrepancies were settled by consensus. The bias risk of the included studies was assessed using the New-Castle Ottawa Scale for cohort studies [9], and the revised Cochrane risk assessment tool for RCTs [10].

Study Outcomes

The primary outcome of the current study was the incidence of major bleeding events as defined according to the Bleeding Academic Research Consortium (BARC) classification [11]. Secondary outcomes included probable/definite stent thrombosis, all-cause mortality, cardiovascular mortality, myocardial infarction (MI), and ischemic stroke. Definitions of HBR criteria, inclusion and exclusion criteria, major bleeding, and DAPT duration are shown in ESM Table 2.

Data Synthesis and Statistical Analysis

Categorical variables were reported as counts and proportions, and continuous variables as means and standard deviation. Results were displayed using forest plots illustrating the relative contribution of the variable to the summary estimate of individual trials. Odds ratios (ORs) and mean differences (MD) with 95% confidence intervals (CIs) are presented as summary statistics. Statistical heterogeneity was assessed by the I2 statistic (I2), with I2 > 50% considered to indicate substantial heterogeneity and I2 > 75% to indicate considerable heterogeneity [12]. We used the Der-Simonian and Laird random-effects and random-effects generic inverse variance methods to calculate OR and MD, respectively, as we anticipated a high degree of clinical and methodological heterogeneity. Tests were two-tailed, and a p value of ≤ 0.05 was considered to indicate statistical significance. In the case of statistical significance, the OR was used to calculate the number needed to treat (NNT) and the number needed to harm (NNH) [13].

Potential publication bias was assessed using Egger’s test by visual examination of the funnel plots [14]. A subgroup analysis for studies with aspirin as SAPT versus those with P2Y12 inhibitors as SAPT was performed regarding the primary outcome. The following sensitivity analyses were conducted: (1) including only studies that  recruited patients presenting with MI, and (2) including only studies with a 3-month (short) DAPT duration. Statistical analysis was conducted using Review Manager software version 5.4 (2020; The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen).

Ethical approval was not required for this study as it is a study-level meta-analysis of published data. This article is based on previously conducted studies and does not contain any new studies with human participants or animals performed by any of the authors.

Results

The study selection process is shown in ESM Fig. 1. The search of the databases identified six studies as meeting the inclusion requirements: one RCT [15], two RCT subanalyses [16, 17], and three prospective propensity-matched studies [11, 18]. The study cohorts from the Xience 28 and Xience 90 studies [11] were reported in a single publication.

Characteristics of the included studies are shown in Table 1. Publication bias assessment is shown in ESM Fig. 2. Bias assessment as per Cochrane New-castle Ottawa scale and revised Cochrane risk assessment tool is shown in ESM Tables 3 and 4.

Table 1 Characteristics of the included studies
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In the studies included in this meta-analysis, 7725 patients received short-term DAPT and 7470 patients received long-term DAPT. Patient characteristics are shown in ESM Table 5.

Clinical Outcomes

During the 12 months of follow-up, the short-term DAPT strategy was associated with a reduction in major bleeding events compared with the long-term DAPT strategy (2.27% vs. 3.20%, respectively; OR 0.63, 95% CI 0.42–0.95; p = 0.03, I2 = 71) (NNT = 86).

Both short- and long-term DAPT strategies were associated with a similar risk of definite/probable stent thrombosis (0.40% vs. 0.31%, respectively; OR 1.30, 95% CI 0.76–2.23; p = 0.34, I2 = 0%), all-cause mortality (3.1% vs. 2.9%, respectively; OR 1.05, 95% CI 0.87–1.27; p = 0.59, I2 = 0%), cardiovascular mortality (1.7% vs. 1.8%, respectively; OR 0.92, 95% CI 0.72–1.18; p = 0.53, I2 = 0%), MI (2.4% vs. 2.0%, respectively; OR 1.17, 95% CI 0.94–1.45; p = 0.16, I2 = 0%), and ischemic stroke (0.73% vs. 0.63%, respectively; OR 1.10, 95% CI 0.57–2.10; p = 0.78, I2 = 43%) (Figs. 1, 2).

Fig.1
figure 1

Summary of the outcomes of short- versus long-term dual antiplatlet therapy (DAPT) in patients at high bleeding risk undergoing percutaneous coronary intervention. a Major bleeding, b probable/definite stent thrombosis, c all-cause death, d cardiovascular death. CI Confidence interval

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Fig.2
figure 2

Summary of the outcomes of short- versus long-term DAPT in patients at high bleeding risk undergoing percutaneous coronary intervention. a Myocardial infarction, b ischemic stroke

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In a subgroup analysis, we compared trials employing SAPT with aspirin to trials employing SAPT with P2Y12 inhibitor; the results did not show any significant treatment-by-subgroup interaction regarding the primary outcome. Major bleeding events in studies employing SAPT with aspirin was 2.56% in the short-term DAPT arm versus 3.38% in the long-term DAPT arm (OR 0.77, 95% CI 0.49–1.21; p = 0.25, I2 = 66); in studies employing SAPT with P2Y12 inhibitor, the incidence of major bleeding events was 1.87% in the short-term DAPT arm versus 2.98% in the long-term DAPT arm (OR 0.41, 95% CI 0.15–1.14; p = 0.09, I2 = 81) (p-interaction = 0.27) (ESM Fig. 3).

A sensitivity analysis of studies that recruited patients primarily presenting with acute MI showed a trend towards higher re-infarction rates (2.55% vs. 2.03%; OR 1.25, 95% CI 0.98–1.59; p = 0.07, I2 = 0), with a significant reduction in major bleeding events (2.15% vs. 3.40%; OR 0.55, 95% CI 0.36–0.84; p = 0.005, I2 = 64) (NNT 67) associated with the short-term DAPT strategy at the 1-year follow-up (ESM Fig. 4).

Furthermore, short- and long-term DAPT strategies had comparable outcomes when only studies comparing 3-month, short-term DAPT to 12-month, long-term DAPT duration were included, albeit with more ischemic stroke rates in the short-term DAPT arm (1.06% vs. 0.42%, respectively; OR 2.37, 95% CI 1.15–4.87; p = 0.02, I2 = 0%) (NNH 176) (ESM Fig. 5).

Discussion

In the meta-analysis reported here we compared the clinical outcomes of patients fulfilling HBR criteria who were treated with short- versus long-term DAPT after PCI. The major findings of our study include: (1) short duration of DAPT (1–3 months) was associated with a lower risk of major bleeding events (NNT = 86), with comparable cardiovascular ischemic events at 12 months; (2) major bleeding events were similar with either aspirin or P2Y12 inhibitors as SAPT; (3) there was an indication of more frequent recurrent MI in studies  recruiting patients undergoing PCI after presenting with MI and treated with a short-term DAPT strategy; and (4) when limiting the analysis to 3 versus 12 months of DAPT after PCI, there was a high risk of ischemic stroke in the short-term DAPT arm (NNH = 176).

To the best of our knowledge, the current meta-analysis is the first to compare the outcomes of patients who received the short-term DAPT (1–3 months) accepted in contemporary clinical setting to outcomes in patients receiving long-term DAPT (6–12 months) after the use of contemporary second-generation drug-eluting stents. It should be noted that only studies that were primarily designed to investigate the HBR population receiving exclusively DAPT were included in the meta-analysis (studies including patients on triple anti-thrombotic therapy were excluded).

Unlike a previously published meta-analysis [19], we included only studies that were primarily designed for the HBR patient population with > 1 HBR criterion as the inclusion criterion. We believe that patients receiving TAT are a specific PCI population and that their number is decreasing over time. The routine use of TAT has been recently discouraged, and it is currently considered to be acceptable only in patients at high thrombotic risk and then only for the shortest possible period [20]. Studies comparing the durations of TAT after PCI were excluded from our meta-analysis to avoid heterogeneity.

Recently, less than or equal 3 months DAPT was equally effective with lower major bleeding events than 12 months DAPT after PCI in an all-comers population [21]. In the contrary to a previously reported meta-analysis [22], we included only studies comparing the contemporary accepted short-term DAPT duration (1–3 months) with DAPT of a prolonged duration (6–12 months).

It is plausible that the incidence of major bleeding would continue to rise with longer durations of DAPT. This meta-analysis showed that at the 1-year follow-up, the short-term DAPT strategy was associated with a 37% relative risk reduction (RRR) in major bleeding events compared with the prolonged DAPT strategy. The RRR even reached 45% among studies that included patients presenting with MI. Generally, major bleeding events result in higher mortality rates [23]. Nevertheless, in this analysis, the considerable reduction in major bleeding events did not lead to a significant reduction in mortality. One explanation for this result is a possible lack of statistical power to detect a concomitant significant reduction in death rates and the influence of competing risk due to ischemic events. Moreover, considerable heterogeneity was observed in terms of major bleeding events, possible due to differences in trial design and individual bleeding risk criteria. We find further dedicated randomized trials a necessity, with the aim to prove benefit of short-term DAPT in terms of decreased major bleeding events in HBR patients within different clinical subgroups.

Our sensitivity analysis revealed patients on aspirin as SAPT had comparable major bleeding rates as those on a P2Y12 inhibitor as SAPT, with no treatment-by-subgroup interaction [24].

DAPT in the PCI population reduces the risk of thrombotic occlusion of the stents until the vascular healing is completed; moreover, it protects the coronary vessel tree against the complications of atherosclerosis, thus reducing the incidence of thrombotic events in the non-treated coronary segments [25]. In our analysis, ischemic events were comparable between both groups at the 1-year follow-up. Our findings should be interpreted with caution as the study may have lacked the statistical power to identify a difference in ischemic events in high-risk subsets. The incidence of ischemic events might also be higher with prolonged follow-up, which we could not further analyze.

In our sensitivity analysis of studies that recruited  patients presenting with MI, patients receiving short-term DAPT showed a trend toward higher MI rates at the 1-year follow-up. This finding has been previously described and is currently represented in the guidelines [26, 27]. Patients with MI represent a high thrombotic milieu with the potential of pan coronary artery inflammation and a significantly higher risk of subsequent MIs [28, 29]. Notably, most of the studies included in our analysis did not report data on the completeness of revascularization after the index PCI. Thus, the increased rates of subsequent MI might be related to critical or sub-critical lesions left behind rather than problems with the recently implanted stent.

The role of DAPT is well established in the primary and secondary prevention of cerebrovascular events [30]. Our analysis found a higher rate of ischemic strokes with a 3-month short-term DAPT regimen compared to a 12-month DAPT strategy. This finding illustrates that the need for prolonged antithrombotic therapy after PCI may be related to preventing non-stent-related events. Notably, this finding was not revealed in our main analysis, possible due to the presence of studies comparing 1- and 6-month DAPT in which relative small difference between the short- and long-term DAPT duration would not allow us to distinguish an obvious difference in ischemic outcomes.

Our data suggest that short-term DAPT generally carries a lower risk for major bleeding events after PCI, but that the optimal DAPT duration after DES placement should be tailored to individual patients, especially those presenting with acute coronary syndrome and those at risk of cerebrovascular adverse events, after carefully balancing the risks of ischemic versus bleeding events.

Limitations

Our study has a number of limitations. First, the included studies had a considerable degree of heterogeneity regarding the primary outcome. Studies primarily addressing TAT after PCI were excluded from this analysis, but some patients included in the MASTER-DAPT trial did receive TAT. Secondly, five observational studies were included, which introduces the risk of selection bias and confounding. Finally, some variance was introduced by clinical endpoint definitions, especially in bleeding event endpoints.

Conclusions

Short-term DAPT after PCI in HBR patients was generally associated with a reduction in major bleeding events and similar ischemic outcomes after PCI with second-generation DES. However, subgroups of interest with differential responses to DAPT emerged with higher ischemic stroke rates and a trend towards recurrent MI at 1 year of follow-up. Future dedicated trials should investigate the optimal strategies for patient-tailored DAPT in various clinical subgroups.