New England Journal of Medicine AUGUST 28, 2021

Management of High Bleeding Risk Patients Post Bioresorbable Polymer Coated Stent Implantation With an Abbreviated Versus Standard DAPT Regimen (MASTER-DAPT)

Marco Valgimigli, et al.

Bottom Line

In patients at high bleeding risk who underwent percutaneous coronary intervention with a specific biodegradable-polymer sirolimus-eluting stent, an abbreviated 1-month dual antiplatelet therapy regimen was noninferior to standard-duration therapy for ischemic outcomes and superior for reducing major or clinically relevant nonmajor bleeding.

Key Findings

1. The abbreviated DAPT regimen (1 month) was noninferior to standard DAPT (3+ months) regarding net adverse clinical events (NACE), which occurred in 7.5% of the abbreviated group and 7.7% of the standard group (P<0.001 for noninferiority).

2. Major adverse cardiac or cerebral events (MACCE) were also similar between groups, occurring in 6.1% of patients receiving abbreviated therapy compared to 5.9% in the standard therapy group (P=0.001 for noninferiority).

3. Abbreviated DAPT demonstrated superiority regarding bleeding, with major or clinically relevant nonmajor bleeding occurring in 6.5% of the abbreviated group compared to 9.4% in the standard group, representing a significant absolute risk reduction of 2.82 percentage points (95% CI -4.40 to -1.24; P<0.001).

Study Design

Design

RCT

Open-Label

Sample

4,579

Patients

Duration

15 mo

Median

Setting

Multicenter, 30 countries

Population Patients at high bleeding risk who underwent successful PCI of all coronary artery stenoses with a biodegradable-polymer sirolimus-eluting stent and remained free from ischemic and bleeding events at the time of enrollment (30 to 44 days post-PCI).

Intervention Abbreviated DAPT (discontinuation of DAPT immediately at the time of randomization, approximately 1 month post-PCI).

Comparator Standard DAPT (continuation of DAPT for at least 2 additional months).

Outcome Net adverse clinical events (all-cause mortality, myocardial infarction, stroke, or major bleeding), major adverse cardiac or cerebral events (all-cause mortality, myocardial infarction, or stroke), and major or clinically relevant nonmajor bleeding.

Study Limitations

• The study mandated the use of a specific biodegradable-polymer sirolimus-eluting stent (Ultimaster), limiting the generalizability of results to other stent platforms.

• The trial was open-label, which may introduce potential bias, although objective outcome definitions were employed to mitigate this risk.

• The findings are specifically applicable to a high-bleeding-risk population and should not be extrapolated to patients at low bleeding risk without further evidence.

Clinical Significance

This trial supports an abbreviated 1-month dual antiplatelet therapy strategy for patients at high bleeding risk undergoing percutaneous coronary intervention, allowing for a reduction in bleeding events without compromising ischemic protection, provided a contemporary biodegradable-polymer stent is utilized.

Historical Context

The MASTER-DAPT trial addressed the clinical dilemma of balancing the high ischemic risk of stent thrombosis against the significant bleeding risk in patients undergoing coronary intervention. By focusing on a high-bleeding-risk population and utilizing modern, safer stent technology, it provided a evidence-based pivot away from the traditionally mandated long-term dual antiplatelet therapy durations that were common in earlier clinical practice.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the physiological rationale for dual antiplatelet therapy (DAPT) following stent implantation, and why does shortening the duration specifically benefit patients with high bleeding risk (HBR)?

Key Response

DAPT (typically aspirin and a P2Y12 inhibitor) is required to prevent stent thrombosis while the metallic struts undergo endothelialization. In HBR patients, prolonged platelet inhibition increases the risk of major gastrointestinal or intracranial hemorrhage. MASTER-DAPT demonstrates that with modern biodegradable-polymer stents, the 'ischemic window' requiring intensive DAPT may be shorter than previously thought, allowing for reduced bleeding without a significant rise in clotting events.

Resident

The MASTER-DAPT trial utilized specific criteria to define 'High Bleeding Risk' (HBR). How should a clinician apply these criteria (such as the ARC-HBR) when deciding to discontinue DAPT after only 30 days in a post-PCI patient?

Key Response

Clinicians should identify HBR using validated criteria: age ≥75, requirement for long-term oral anticoagulation, renal failure (CrCl <40 ml/min), or recent major bleeding. MASTER-DAPT suggests that if a patient meets at least one major or two minor HBR criteria, transitioning to single antiplatelet therapy at 1 month is superior for reducing bleeding (BARC 2, 3, or 5) while remaining noninferior for MACCE compared to the standard 3-6 month regimen.

Fellow

In the context of the MASTER-DAPT findings, how should the presence of complex PCI (e.g., multi-vessel disease, bifurcation stenting, or long lesions) influence the decision to pursue a 1-month abbreviated DAPT strategy in an HBR patient?

Key Response

Sub-analyses of MASTER-DAPT indicate that the benefits of abbreviated DAPT for bleeding reduction, and its noninferiority for ischemic events, persisted even in patients who underwent complex PCI. This suggests that in the HBR population, the patient's intrinsic bleeding risk may be a more significant driver of adverse outcomes than the anatomical complexity of the procedure, provided that contemporary drug-eluting stents are used.

Attending

MASTER-DAPT showed noninferiority for Net Adverse Clinical Events (NACE). How does this shift the 'Ischemic vs. Bleeding' paradigm when managing elderly patients with multiple comorbidities who present with Acute Coronary Syndrome (ACS)?

Key Response

Historically, ACS dictated at least 12 months of DAPT. MASTER-DAPT included ACS patients (about 50%) and showed that even in this higher-risk group, bleeding events are potent drivers of mortality. This trial empowers attendings to prioritize 'bleeding-first' stratification in the HBR subset, acknowledging that the 'ischemic penalty' of stopping DAPT early is offset by the significant 'survival/safety dividend' of avoiding major bleeds.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

Critically evaluate the implications of the choice of a 3.6% noninferiority margin for the NACE endpoint; to what extent does the use of a specific biodegradable-polymer stent (Ultimaster Tansei) limit the generalizability of these statistical findings to other contemporary thin-strut DES?

Key Response

The noninferiority margin is relatively wide, which can sometimes overstate safety. Furthermore, since only one stent type was used, the results technically only validate that specific hardware. However, the 'biodegradable polymer' feature is hypothesized to reduce chronic inflammation and accelerate healing, which is the biological basis for the 1-month safety. Building on this would require a head-to-head 'stent-type by DAPT-duration' interaction analysis to see if the strategy is truly stent-agnostic.

Journal Editor

As a reviewer, what are the primary concerns regarding the open-label design of MASTER-DAPT, specifically relating to the adjudication of 'clinically relevant nonmajor bleeding'?

Key Response

Open-label trials are highly susceptible to ascertainment bias. Patients and providers aware of the treatment assignment might differentially report or manage minor bleeding events. While 'Major Bleeding' (BARC 3 or 5) is harder to bias, 'clinically relevant nonmajor bleeding' is subjective. However, the use of a blinded independent clinical events committee and the consistent results across ischemic endpoints (which are harder to bias) lend significant weight to the trial's validity.

Guideline Committee

Does MASTER-DAPT provide sufficient evidence to move the 1-month DAPT recommendation for HBR patients from a Class IIa (should be considered) to a Class I (recommended) level in future ACS and CCS guidelines?

Key Response

Current ESC guidelines (2023) already moved toward 1-month DAPT as a Class IA recommendation for HBR patients based on MASTER-DAPT and similar trials (e.g., LEADERS FREE, ONYX ONE). The committee must now harmonize this with ACS guidelines, where the duration was traditionally longer. The strength of MASTER-DAPT lies in its large-scale randomized design and use of the NACE endpoint, which integrates the 'net' clinical benefit essential for guideline-level policy changes.

Clinical Landscape

Noteworthy Related Trials

2015

LEADERS FREE Trial

n = 2,466 · NEJM

Tested

Polymer-free drug-coated stent

Population

Patients at high bleeding risk

Comparator

Bare-metal stent

Endpoint

Composite of cardiac death, myocardial infarction, or stent thrombosis

Key result: The polymer-free drug-coated stent was superior to the bare-metal stent in both safety and efficacy endpoints.

2018

GLOBAL LEADERS Trial

n = 15,968 · Lancet

Tested

23 months of ticagrelor plus 1 month of DAPT

Population

All-comers undergoing PCI

Comparator

12 months of standard DAPT followed by aspirin monotherapy

Endpoint

All-cause mortality or new Q-wave myocardial infarction

Key result: The experimental regimen did not meet superiority over the standard DAPT regimen in the overall trial population.

2019

STOPDAPT-2 Trial

n = 3,045 · JAMA

Tested

1 month of DAPT followed by clopidogrel monotherapy

Population

Patients undergoing PCI

Comparator

12 months of standard DAPT

Endpoint

Composite of cardiovascular and bleeding events

Key result: Short-term DAPT followed by clopidogrel monotherapy was noninferior to standard 12-month DAPT in terms of ischemic and bleeding outcomes.

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