One-month DAPT after biodegradable-polymer everolimus-eluting stent implantation in patients at high-bleeding risk: an individual patient data pooled analysis of the SENIOR and POEM trials

Abstract Aims Dual antiplatelet therapy (DAPT) can be shortened up to 1 month in high-bleeding risk (HBR) patients receiving a contemporary biodegradable-polymer sirolimus-eluting stent. We aimed to summarize the evidence on a similar DAPT regimen after biodegradable-polymer everolimus-eluting stent (EES) implantation in patients at HBR. Methods and results We pooled the individual participant data from the available trials evaluating this strategy, namely, the SENIOR and the POEM trials. Inclusion criteria were ≥1 biodegradable-polymer EES implantation and ≤1-month duration of DAPT. The primary endpoint was the 1-year composite of cardiovascular death, myocardial infarction, or stroke. Major bleeding was defined as Bleeding Academic Research Consortium (BARC) type 3–5 bleeding. Landmark analyses were performed at 1 month, the time point for intended DAPT interruption. We included 766 participants (age 77.5 ± 8.2 years, women 31.9%), 323 from the SENIOR and 443 from the POEM trial. The primary endpoint occurred in 45 participants (6.0%; 95% confidence interval [CI], 4.3–7.7%) through 1 year of follow-up, with 21 (2.8%; 95% CI, 1.6–3.9%) events during the first month and 24 (3.4%; 95% CI, 2.0–4.7%) thereafter. The incidences of cardiovascular death, myocardial infarction, and stroke were 2.2% (95% CI, 0.36–2.50%), 3.1% (95% CI, 1.8–4.3%), and 1.2% (95% CI, 0.4–2.0%), respectively. BARC type 3–5 bleeding ocuurred in 1.1% (95% CI, 0.3–1.8%) at 1 month and 2.9% (95% CI, 1.6–4.1%) at 1 year. Conclusion HBR patients receiving biodegradable-polymer EES had few ischemic and bleeding events when given 1 month of DAPT. One-month DAPT after biodegradable-polymer EES implantation seems safe in patients at HBR.


Introduction
Dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) reduces the occurrence of ischemic events at the cost of a higher risk of bleeding.However, bleeding events during DAPT can have a prognostic impact comparable to that associated with ischemic events. 1,2These findings are remarkable considering that up to 40% of patients undergoing PCI are deemed to be at high bleeding risk (HBR). 3Antiplatelet strategies balancing the antithrombotic requirements with the associated risk of bleeding can improve the outcome of these patients. 4everal randomized trials have shown that contemporary drugeluting stents (DES) allow short DAPT as device-related ischemic events were generally comparable with more prolonged regimens. 5Of note, short DAPT was associated with reduced bleeding in some of these trials. 5Recently, the MASTER-DAPT trial demonstrated that DAPT could be shortened up to 1 month in HBR patients receiving a contemporary biodegradable-polymer sirolimus-eluting stent (SES, Ultimaster, Terumo, Japan), allowing fewer bleeding and similar thrombotic events compared with standard DAPT duration. 6It is unclear if these results can be generalized to other contemporary DES.
The Synergy everolimus-eluting stent (EES) (Boston Scientific Corporation, USA) is a thin-strut (74-81 μm) platinum-chromium metal alloy platform coated with an ultrathin (4 μm) biodegradable poly(DL-lactide-co-glycolide) polymer on the abluminal side. 7These features may allow rapid stent reendothelialization and low thrombogenicity, both key characteristics to shorten DAPT. 8,9In the SENIOR trial, the Synergy EES was proven superior in terms of a composite of major adverse cardiac and cerebrovascular events (MACCE) to thin-strut bare-metal stents (BMS) in elderly patients. 10In this trial, the intended DAPT duration was 1 month for participants with chronic and 6 months for those with acute coronary syndrome. 102][13] However, the study was underpowered due to a lower-than-anticipated number of enrolled participants.
We aimed to summarize the available evidence on 1-month DAPT after Synergy EES stent implantation in participants at HBR by pooling together the trials evaluating this strategy.

Methods
The data underlying this article will be shared upon reasonable request to the corresponding author.

Study design and population
We pooled individual participant data from the SENIOR and POEM trials because they evaluated a strategy of 1-month DAPT following PCI with the implantation of the Synergy EES.Supplementary material online, Table S1 summarizes and compares the characteristics of both trials, including the main inclusion and exclusion criteria.The institutional review board of each centre approved the protocols of corresponding studies, which were conducted following the ethical principles of the Declaration of Helsinki.Participants were required to provide written informed consent before participating in each study.

Data collection and harmonization
The Cardiovascular European Research Center (Massy, France), an independent research organization, was the data coordinating centre.Individual participant data included baseline clinical characteristics and demographics, procedural features, relevant discharge information, and clinical outcomes at follow-up.These data were anonymized, extracted, transferred in preformatted electronic spreadsheets, and finally merged into a core study dataset.Inclusion criteria were 1) the implantation of at least one Synergy EES and 2) an intended DAPT duration equal to or less than 1 month.The implantation of at least one BMS represented the sole exclusion criterion.

Study endpoints
The primary endpoint was MACCE, a composite of cardiovascular death, myocardial infarction, or stroke at 12 months.Secondary endpoints at 12 months included all-cause death, cardiovascular death, noncardiovascular death, myocardial infarction, stent thrombosis, target-vessel revascularization, target-lesion revascularization, major/severe (i.e.type 3-5) bleeding according to Bleeding Academic Research Consortium (BARC) criteria, net adverse cardiac and cerebrovascular event (NACCE), a composite of cardiovascular death, myocardial infarction, stroke, or BARC type 3-5 bleeding.Details on clinical event adjudication and study definitions used in each trial are provided in Supplementary material online, Table S1.The outcome definitions were consistent across the included studies: myocardial infarction was defined according to the third Universal Definition of Myocardial Infarction, 14 stent thrombosis according to the Academic Research Consortium (ARC) definitions, 15 and bleeding according to the BARC definitions. 16

Statistical analysis
Categorical data are reported as counts and proportions.Continuous variables are reported as mean ± standard deviation or median (interquartile range), as appropriate.The cumulative distribution of outcomes from the index PCI to 1-year follow-up was computed using the Kaplan-Meier method.Landmark analyses were performed at 1 month, which was the time point for intended DAPT interruption.The associations between main outcomes and baseline conditions were assessed by multivariable Cox proportional hazards regression model employed on datasets (n = 5) generated by chained equation multiple imputation.The results were combined using Rubin's rules and expressed as hazard ratios (HRs) and 95% confidence intervals (CIs).Least absolute shrinkage and selection operator across imputed datasets allowed identifying the candidate variable to include in the final multivariable model.The log-rank test was used to compare cumulative incidences of event in chronic and acute coronary syndrome subgroups.Finally, we conducted a sensitivity analysis, including only those participants who fulfilled the ARC-HBR criteria, and a per-protocol analysis, excluding participants who extended DAPT beyond 1 month.Supplementary material online, Table S2 illustrates the list of major and minor ARC-HBR criteria and their respective definitions adapted to the current study database.A two-sided P-value of <0.05 was considered statistically significant.All statistical analyses were performed by using R 4.3.1.

Clinical and procedural characteristics
After excluding 596 and 281 participants who received a BMS or more than 1 month of DAPT after PCI, the final study population included 766 participants, 323 originally enrolled in the SENIOR trial and 443 in the POEM trial (see Supplementary material online, Figure S1).
Table 1 reports clinical characteristics at baseline.Participants had a mean age of 77.5 ± 8.2, and women were 31.9%.The ischemic and bleeding risk of the population can be inferred by the prevalence of chronic kidney disease (CKD, 37.7%), diabetes mellitus (34.8%), prior PCI (34.7%), peripheral artery disease (18.7%), prior stroke (6.9%), and atrial fibrillation (35.1%).The most common clinical presentation was chronic coronary syndromes (71.2%), followed by non-ST segment elevation myocardial infarction (13.4%), unstable angina (10.8%), and lastly, ST-segment elevation myocardial infarction (4.6%).Almost all  One-month DAPT after biodegradable-polymer everolimus-eluting stent the participants (99.6%) had at least one minor ARC-HBR criterion, and 609 (79.5%) fulfilled the ARC criteria for HBR (see Supplementary material online, Table S3).Age and oral anticoagulation were the most common minor and major ARC-HBR criteria, respectively (see Supplementary material online, Figure S2).Table 2 reports the procedural characteristics.The left anterior descending artery was the most frequent target vessel being treated in 470 (44.5%) of the 1119 lesions.The mean number of lesions per patient was 1.4 ± 0.6.Complete revascularization and procedural success were achieved in 95.2% and 99.9% of the cases, respectively.
A total of 589 participants (92.2%) were discharged with clopidogrel as a P2Y12 inhibitor, while ticagrelor and prasugrel were prescribed in only 41 (6.4%) and 9 (1.4%) of them, respectively (see Supplementary material online, Table S4).More than 85% of participants dropped the P2Y12 inhibitor after the first month (see Supplementary material online, Figure S3), with a median duration of 31 (30-34) days.Following DAPT discontinuation, 94.4% of participants continued with aspirin, while 5.6% continued with P2Y12 inhibitor.
The per-protocol analysis and the subgroup analysis according to clinical presentation are reported in Supplementary material online, Tables S5 and S6, respectively.

Discussion
We provided comprehensive evidence on 1-month DAPT after Synergy EES stent by pooling 766 participants and 1119 lesions from the SENIOR and the POEM trials.In a population including approximately four out of five participants fulfilling the ARC-HBR criteria, the overall incidence of the primary and secondary endpoints was low.In particular, the rates of ischemic events occurring after the DAPT interruption (i.e.generally 1 month after the index PCI) compared favourably with those occurring within the first month (i.e. during DAPT).8][19] Among our participants, those suffering from CKD were at higher risk for MACCE and NACCE, while those with anaemia were at higher risk of BARC type 3-5 bleeding after adjusting for confounders.

High-bleeding risk patients
As of today, several definitions for the bleeding risk have been adopted in clinical trials.The POEM trial applied the same criteria of the LEADERS FREE and the ONYX ONE trial to select patients at HBR. 17,18 In all of them, the most represented criterion was age ≥ 75 years, followed by oral anticoagulation, anaemia, or CKD.In the SENIOR trial, the patients were eligible if aged 75 years or older.The Academic Research Consortium aimed to standardize and reduce the heterogeneity in the bleeding risk definition among patients undergoing PCI. 20However, this consensus was reached only in 2019 and still requires prospective application in clinical trials.In the present study, 79.5% of patients fulfilled the ARC-HBR criteria, which is double the prevalence observed in real-world PCI cohorts. 3As discussed in the following paragraph, this premise is necessary to consider an early DAPT interruption.

One-month DAPT after biodegradable-polymer EES
In the first period following PCI with stent implantation, the benefit of intensive antithrombotic therapy with DAPT generally outweighs the increased risk of bleeding.However, this advantage dissipates over time, favouring antithrombotic strategies that consider this trade-off.Based on the PRECISE-DAPT score, patients at HBR might benefit from an abbreviated DAPT duration of 3-6 months, while the others could receive a standard (12 months) or prolonged (>12 months) treatment without being exposed to significant bleeding liability. 4The MASTER DAPT suggested that DAPT duration could be further shortened to 1 month in HBR patients undergoing PCI with Ultimaster SES. 6,21Accordingly, most updated guidelines consider dropping one antiplatelet agent between aspirin and P2Y12 after 1 month in this selected group of patients. 22The main concern relates to the subsequent risk of ischemic events, such as myocardial infarction and stent thrombosis.Our study population exhibited characteristics associated with ischemic risk similar to those of an all-comers PCI cohort due to limited exclusion criteria (planned major surgery within a month, life expectancy less than 1 year, and cardiogenic shock as the PCI indication). 23,24he rates of ischemic and bleeding events occurring after the first month (i.e. the time point for intended DAPT interruption) were reassuring if compared with the rates occurring during the first month in the same population (Figure 1) and with those reported in the literature (Figure 3). 6,18,19Despite the absence of a comparator arm, the landmark analysis allowed for an internal comparison within the same population under similar conditions, except for the antithrombotic therapy.The incidence of all-cause death in this study was comparable to other studies (Figure 3).Such an outcome may reflect the baseline patient risk more than the treatment strategy itself.Conversely, the relatively low incidence of myocardial infarction and late stent thrombosis points to the safety of a short DAPT regimen following Synergy EES implantation.Specifically, the rate of late definite or probable stent thrombosis (i.e. between 1 and 12 months post-implantation) was 0.4% in our study compared to 0.3% in the XIENCE 28, 0.7% in the ONYX ONE, and 0.6% in the MASTER DAPT trial.Only the latter tested the non-inferiority of 1 month of DAPT compared to the continuation of therapy for at least two additional months in patients receiving Ultimaster SES.Still, these results suggest that this strategy might be applied to other biodegradable-polymer devices (i.e. the Synergy EES) and other contemporary DES (i.e. the Xience durable-polymer EES (Abbott, USA), the Resolute Onyx durable-polymer zotarolimus-ES (ZES, Medtronic, USA), and the BioFreedom polymer-free biolimus-ES (Biosensors International, Singapore).
The Synergy EES, similar to the Xience EES (81 μm), the Resolute Onyx ZES (81 μm), and the Ultimaster SES (80 μm), has very thin struts (74-81 μm) that reduce acute platelet aggregation associated with early ST and incomplete reendothelialization associated with late ST. 7,25The antiproliferative drug (i.e.everolimus) is completely released after 3 months, and the ultrathin and abluminal polymer is resorbed after an additional month. 8Of note, compared to a similar BMS, stent reendothelialization is not impacted by the presence of everolimus or the polymer, reaching a coverage rate of 87.5% (74.0-93.3%)above and 97.7% (96.9-98.0%) between the stent struts. 7In patients evaluated with optical coherence tomography, the intimal coverage was 94.5% ± 4.4% and 96.6% ± 2.7% after 3 and 6 months from Synergy EES implantation. 9In this period, intensive antithrombotic therapy can reduce the risk of ST proportional to this minor increase in reendothelialization.However, this may not be a significant advantage, but rather detrimental in patients at HBR, where the prognosis depends more on bleeding events.
We could not evaluate the impact of intravascular imaging to guide PCI and DAPT duration.Optical coherence tomography or of the primary endpoint (MACCE, a composite of cardiovascular death, myocardial infarction, or stroke) at 1 year (lower) and landmark analysis at 1 month (upper).
One-month DAPT after biodegradable-polymer everolimus-eluting stent intravascular ultrasound was used in about 5% of the POEM population.These rates align with European clinical practice according to a recent survey from the European Association of Percutaneous Cardiovascular Interventions. 26Despite evidence that intravascular imaging improves patient outcome, 27 short DAPT appears safe, irrespective of the procedure's complexity or intravascular ultrasound (IVUS) use. 28In the IVUS-ACS trial presented at ACC 2024, there was no evidence of interaction between the type of guidance (IVUS vs. angiography alone) and DAPT duration (1 vs. 12 months).However, this analysis remains exploratory, and until more evidence becomes available, intravascular imaging is advisable, irrespective of the intended DAPT duration.
Finally, we explored if 1 month of DAPT was associated with signs of harm in particular subgroups of patients.No differences in the risk of adverse events were found between chronic and acute coronary syndrome subgroups.We identified only CKD as an independent predictor of the primary endpoint and NACE.0][31] As a result, patients with CKD still represent a challenging population where the optimal DAPT duration requires further evaluation.

Study limitations
The present study should be interpreted in view of several limitations.First, our findings remain explorative because of the absence of a comparator arm, such as a different DAPT regimen or another DES.This lack of a control group limits our ability to draw definitive conclusions, and future randomized controlled trials with appropriate comparator Figure 2 Predictors of the primary endpoint (MACCE) at 1 year.Forest plot for the predictors of the primary endpoint (MACCE, a composite of cardiovascular death, myocardial infarction, or stroke) at 1 year on multivariate analysis.Anaemia was defined as a haemoglobin level < 11 g/dL.CKD was defined as an estimated glomerular filtration rate < 60 mL/min/1.73m 2 .Chronic kidney disease: CKD; HR: hazard ratio; BMI: body mass index; CI: confidence interval.

Figure 3
Findings in perspectives.Event rates observed between 1 and 12 months follow-up in contemporary DES trials treating HBR patients with a 1-month DAPT regimen following PCI.The Synergy biodegradable-polymer everolimus-eluting stent was used in the present study (i.e.POEM-SENIOR).The Ultimaster biodegradable-polymer sirolimus-eluting stent was used in the MASTER DAPT trial.The Xience durable-polymer everolimus-eluting stent was used in the XIENCE 28 trial.The Resolute Onyx durable-polymer zotarolimus-eluting stent and the BioFreedom polymerfree biolimus-eluting stent were used in the ONYX ONE trial.Event rates are Kaplan-Meier estimates, except for the XIENCE 28 reporting propensity score stratified mean rates.BARC: Bleeding Academic Research Consortium.
arms are needed to validate these findings.Second, the two original studies had different designs.In more detail, SENIOR was a randomized trial comparing two different stents, while POEM was a single-arm registry enrolling participants after the procedure, which might explain the procedural success rate of 99.9%.This might have resulted in the inclusion of lower-risk patients in the POEM trial.As a result, we cannot extrapolate our findings to patients with suboptimal PCI results.Nevertheless, choosing the optimal DAPT duration is a dynamic process that should not be decided upfront the procedure, but must consider every new piece of information, such as stent apposition or any ischemic or bleeding complications during or after the procedure.Third, we acknowledge the increased risk of a type II error because of the small sample size.Fourth, the follow-up loss at 1 year exceeded 6%, which is high for a monitored clinical trial.This ascertainment bias should be acknowledged when interpreting our results.Fifth, the bleeding risk definition used in our study does not fully align with the ARC-HBR criteria, which identify patients at an even higher risk of adverse events.This discrepancy represents a limitation of our study, shared with other HBR trials published to date.Therefore, dedicated future prospective studies are necessary to address this issue comprehensively.Finally, the representation of patients with acute coronary syndrome from the SENIOR was limited because most of them received 6 months of DAPT and were excluded from the present analysis.However, our subgroup analysis by clinical presentation did not raise concern regarding the application of our strategy in HBR patients following an acute coronary syndrome.

Lead author biography
Carlo Andrea Pivato was born in Padova, Italy.He studied medicine at Vita-Salute San Raffaele University in Milan, graduating cum laude.He completed his residency in cardiology at Humanitas University.He then undertook a research fellowship at the Icahn School of Medicine at Mount Sinai in New York.He is currently a PhD researcher at Humanitas University and a cardiologist at Humanitas Research Hospital.

Conclusion
HBR patients undergoing PCI with a biodegradable-polymer EES had few ischemic and bleeding events when given a DAPT of 1 month.One-month DAPT after biodegradable-polymer EES implantation can be a safe and effective strategy for patients with high bleeding risk, but further comparative studies are needed to validate these findings.

Table 3 Figure 1
Figure 1 Incidence of the primary endpoint (MACCE) through 1 year of follow-up.Kaplan-Meier curves showing the cumulative incidence (95% CI)

Table 2 Angiographic and procedural characteristics Patients = 766 Lesions = 1119
Values are mean ± SD or number (%).PCI, percutaneous coronary intervention.a Per patient.b Per lesion.