MASTER DAPT

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Valgimigli M, et al. "Dual antiplatelet therapy after PCI in patients at high bleeding risk". The New England Journal of Medicine. 2021. 385(18):1643-1655.
PubMedFull textPDFClinicalTrials.gov

Clinical Question

Among adults meeting a certain definition of high bleed risk who underwent placement of a biodegradable polymer sirolimus-eluting DES, was abbreviated duration DAPT non-inferior for CVD/bleeding events and superior for bleeding events alone when compared to standard duration DAPT?

Bottom Line

Among adults meeting a certain definition of high bleed risk who underwent placement of a biodegradable polymer sirolimus-eluting, 3rd generation DES, abbreviated duration DAPT was non-inferior for a composite outcome of CVD & bleeding and superior for fewer bleeding events when compared to standard duration DAPT.

Major Points

When compared to bare metal stents (BMS), drug-eluting stents (DES) have lower incidence of restenosis because of inhibition of neointimal proliferation.[1] DES require extended courses of anti-thrombosis medications (e.g., antiplatelets, anticoagulants) to prevent in-stent thrombosis.[2] The backbone of therapy is dual-antiplatelet therapy (DAPT), but the duration of such medications is unclear. The 2014 DAPT trial showed that 30 months of DAPT after DES placement was associated with less in-stent thrombosis and a reduction in the composite outcome of lower mortality, MI, or stroke at the expense of more bleeding. (All-cause mortality was higher in the 30-month group, interestingly.) Third-generation DES released in the mid-2010s include bioresorbable coatings that lead to shorter-duration activity of the anti-proliferative medication embedded on the stent (e.g., 3-4 months).[3] This might lead to earlier endothelialization, which might in turn require shorter durations of DAPT. Shorter DAPT regimens might benefit those at higher risk of bleeding.

Published in 2021, the Management of High Bleeding Risk Patients Post Bioresorbable Polymer Coated Stent Implantation with an Abbreviated versus Standard DAPT Regimen (MASTER DAPT) randomized 4,579 patients who had undergone placement of the sponsor's 3rd generation DES a month prior were randomized to abbreviated DAPT vs. standard DAPT in an open-label fashion. All participants met one specific definition of high bleeding risk, detailed in the Inclusion Criteria section below. Participants in the abbreviated DAPT were transitioned to single antiplatelet therapy at 30 days post-PCI (with continuation of concurrent oral anticoagulation among those with an indication for this therapy). Those in the standard DAPT group continued DAPT for 6 months post-PCI (3 months if also requiring oral anticoagulation as well). The statistical analysis of the primary outcome was tremendously more complicated than most CVD RCTs, combining per-protocol, intention-to-treat, non-inferiority, and superiority analyses in multiple hierarchical, overlapping composite endpoints. Ultimately, there was no difference in CVD-related endpoints between groups, but there was lower bleeding among those in the abbreviated DAPT group.

This trial provides evidence that among adults meeting one specific definition of higher bleeding risk who underwent placement of one specific 3rd generation DES, shorter duration DAPT (i.e., switching to a single antiplatelet medication 1 month post-DES) might reduce bleeding risk but not CVD complications. This trial does not support blanket use of shorter durations of DAPT with other DES models (particularly, 1st or 2nd generation devices) or those with lower bleeding risk.

Guidelines

As of October 2021, no guidelines have been published that reflect the results of this trial.

Design

  • Multicenter, randomized, open-label, non-inferiority and superiority trial
  • N=4,579
    • Abbreviated DAPT (n=2,295)
    • Standard DAPT (n=2,284)
  • Setting: 140 sites in 30 countries
  • Enrollment: 2017-2019
  • Follow-up: 11 mo after randomization visit, which occurred 1 mo after PCI
  • Analysis: Intention-to-treat/superiority for bleeding outcomes; per-protocol/non-inferiority for net adverse clinical events and major adverse cardiac and cerebral events
  • Primary outcomes: Net adverse clinical events; also major or clinically relevant non-major bleeding

Population

Inclusion Criteria

Inclusion criteria after index PCI

  • Aged ≥18 years with ≥1 high bleeding risk criteria, which include:
    • Need for oral anticoagulant for ≥12 months, or chronic treatment with steroids or NSAIDs
    • Non-access site bleeding requiring medical attention in prior year
    • Prior hospitalization for bleeding episodes that wasn't otherwise definitively treated.
    • Aged ≥75 years
    • Systemic conditions with high bleeding risk (e.g., thrombocytopenia with plt <100k or known coagulation disorder conferring bleeding risk)
    • Hgb <11 g/dL or transfusion in the prior 4 weeks
    • High-bleed risk malignancy (e.g., GI, GU/renal, pulmonary)
    • Stroke or TIA in prior 6 mo
    • PRECISE-DAPT score ≥25
      • This score's covariates include age, hgb, wbc, and CrCl
  • Successful treatment of coronary lesions with a specific DES sold by the study sponsor. This stent had a biodegradable polymer and sirolimus-eluting.
  • No remaining lesions that would warrant DAPT therapy, per the treating physician's judgement
    • No further PCI planned

Inclusion criteria at 1-mo randomization visit (30-44 days after index PCI)

  • ≥1 high bleeding risk criteria or on basis of post-PCI actionable nonaccess-site related bleeding episode
  • Uneventful 30 day clinical course from a CVD perspective.
  • If not on oral anticoagulant:
    • On DAPT with ASA+P2Y12 inhibitor
    • with one type of P2Y12 inhibitor for ≥7 days
  • If on oral anticoagulant:
    • On the same type of oral anticoagulant for ≥7 days
    • On clopidogrel for ≥7 days

Exclusion Criteria

  • Treated with stent other than a specific stent sold by the study sponsor
  • In-stent restenosis or stent thrombosis at index PCI or in prior 6 mo
  • Prior treatment of a lesion with bioresorbable scaffold
  • Issues with consent or compliance
  • Active bleeding at randomization visit
  • <1 year life expectancy, hypersensitivity to study agents
  • Planned/likely upcoming PCI
  • Participation in another trial
  • Pregnant or breastfeeding women

Baseline Characteristics

From the abbreviated DAPT group.

  • Demographics: Age 76y, 69% male sex
  • Anthropometrics: BMI 27 kg/m2
  • Presentation: Stable angina 40%, silent ischemia 11%, NSTEMI 26%, UA 11%, MI (Killip class II, III, or IV) 11%, cardiac arrest 1%
  • PMH: Prior bleeding 7%, MI 19%, stroke 12%, FH of CAD 24%, hypertension 77%, DM 33%, HLD 67%, current smoker 10%, previously smoker 38%, PVD 11%, carotid artery disease 5%, HF 19%, lung disease 11%, CKD 18%, liver disease 1%, AF 34%
  • PSH: PCI 26%, CABG 7%
  • Labs and other data: Hgb 12 g/L, WBC 9.3x10-9/L, CrCl 77 mL/min/1.73/m2, LVEF 53%
  • Medications: Oral anticoagulant 37%

Interventions

  • Randomization to a group at the time of their randomization visit, which occurred 1 mo after PCI (add 1 mo to each of the below durations to determine duration of time since PCI):
    • Abbreviated DAPT:
      • If not on oral anticoagulation: DAPT discontinued and a single antiplatelet was continued for 11 mo.
      • If on oral anticoagulation: DAPT discontinued and ASA or clopidogrel was continued for 5 mo. Oral anticoagulation was continued for at least 11 mo.
    • Standard DAPT:
      • If not on oral anticoagulation: ASA was continued for 11 months. The P2Y12 inhibitor taken at randomization was continued for 5-11 mo.
      • If on oral anticoagulation: ASA and clopidogrel was continued for 2-11 months. Aspirin or clopidogrel monotherapy is continued until 11 months. Oral anticoagulation was continued for at least 11 mo.
  • Study medications were:
    • Aspirin 75-162 mg/day
    • Clopidogrel 75 mg/day
    • Prasugrel 10 mg/day (dose reduced to 5 mg/day by weight or age thresholds, or by regional standard dose)
    • Ticagrelor 90 mg BID
    • VKA per INR based upon typical guidelines
    • DOAC (eg, rivaroxaban, edoxaban, apixaban, dabigatran) based upon local dosing
      • Note: switching between VKA or DOAC were generally not allowed.
  • The statistical analysis prespecified that some components of the primary outcome be analyzed as intention-to-treat, while others were analyzed as per-protocol. Details related to specific definitions of what constituted the populations in the per-protocol analysis and extended details about the analytical plan are on page 21 of the supplemental appendix.[4]

Outcomes

Presented as abbreviated DAPT vs. standard DAPT. The analysis plan specified which analysis type (per-protocol vs. intention-to-treat) would be used, and the corresponding types are presented for the primary analyses. Per-protocol and intention-to-treat analyses are shown for each outcome in Table 2 on pgs 1650-1651. For the primary outcome, per-protocol analyses were for non-inferiority, the intention-to-treat analysis was for superiority.

Primary Outcome

Composite primary outcome, in order of hierarchical testing
Net adverse clinical events (per-protocol): 7.5% vs. 7.7% (HR 0.97; 95% CI 0.78-1.20; P<0.001 for noninferiority)
Above is defined as all-cause mortality, MI, stroke, BARC type 3 or 5 major bleeding. BARC bleeding types can be found here
Major adverse cardiac or cerebral events (per-protocol): 6.1% vs. 5.9% (HR 1.02; 95% CI 0.80-1.30; P=0.001 for non-inferiority)
Above is defined as all-cause mortality, MI, or stroke.
Major or non-major clinically relevant bleeding (intention-to-treat): 6.5% vs. 9.4% (HR 0.68; 95% CI 0.55-0.84 P<0.001 for superiority)
Above is defined as BARC type 2, 3, or 5 bleeding.

Secondary Outcomes

Intention-to-treat shown for all following outcomes. HR shown when provided in the manuscript.

CVD mortality, MI, or stroke
4.5% vs. 4.5% (HR 1.00; 95% CI 0.76-1.32)
Death
All-cause mortality: 3.3% vs. 3.6% (HR 0.92; 95% CI 0.67-1.26)
CVD mortality: 1.6% vs. 2.0% (HR 0.92; 95% CI 0.83; 95% CI 0.54-1.29)
Non-CVD mortality: 1.3% vs. 1.2% (HR 1.03; 95% CI 0.61-1.73)
Stroke or TIA
0.8% vs. 1.4% (HR 0.53; 95% CI 0.29-0.95)
Stroke: 0.5% vs. 1.0% (HR 0.52; 95% CI 0.26-1.04)
Ischemic stroke: 0.5% vs. 0.8%
Hemorrhagic stroke: <0.1% vs. 0.2%
MI
2.7% vs. 2.2% (HR 1.22; 95% CI 0.84-1.78)
Definite or probable stent thrombosis
0.6% vs. 0.4% (HR 1.55; 95% CI 0.67-3.57)
Bleeding
Bleeding definitions can be found here.
By BARC type.
1 to 5: 8.9% vs. 13.5% (HR 0.64; 95% CI 0.54-0.76)
2: 4.5% vs. 6.8%
3 to 5: 2.3% vs. 2.6%
4: 0 vs. 0
5: 0.1% vs. 0.4%
TIMI bleeding
Minor or major: 1.8% vs. 2.1% (HR 0.85; 95% CI 0.56-1.28)
Minor: 0.7% vs. 0.9%
Major 1.1% vs. 1.2%
GUSTO bleeding
Moderate or severe: 2.1% vs. 2.3% (HR 0.93; 95% CI 0.63-1.38)
Moderate: 1.8% vs. 1.7%
Severe: 0.4% vs. 0.6%

Subgroup Analysis

There were not major differences for the components of the primary by the prespecified endpoints. Details about these analyses are on pages 50-52 of the supplemental appendix.[4]

Criticisms

  • Open label design.
  • Heterogenous duration of DAPT in the standard DAPT arm.
  • Duration of DAPT among those on oral anticoagulation (i.e., triple therapy) in both arms is longer than is recommended in the 2020 AF ESC guidelines.[5] These guidelines recommend ≤1 week of triple therapy, unless there is risk for stent thrombosis.
  • Only studied a biodegradable polymer and sirolimus-eluting stent sold by the study sponsor.

Funding

Terumo, the seller of the Ultimaster stent used in this trial.

Further Reading

  1. Dangas GD et al. In-stent restenosis in the drug-eluting stent era. J Am Coll Cardiol 2010. 56:1897-907.
  2. Bittl JA et al. Duration of Dual Antiplatelet Therapy: A Systematic Review for the 2016 ACC/AHA Guideline Focused Update on Duration of Dual Antiplatelet Therapy in Patients With Coronary Artery Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation 2016. 134:e156-78.
  3. Gherbesi E & Danzi GB The Ultimaster coronary stent system: 5-year worldwide experience. Future Cardiol 2020. 16:251-261.
  4. 4.0 4.1 Supplemental Appendix
  5. Hindricks G et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J 2021. 42:373-498.