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STOPDAPT-3 Trial

CardioNerds Journal Club is a monthly forum for CardioNerds to discuss and breakdown recent publications on twitter and are produced with a corresponding infographic and detailed blog post. For more information, check out the CardioNerds Journal Club Page. This Journal Club focuses on the STOPDAPT-3 Trial

Table of contents for the The STOPDAPT-3 Trial summary:

August 9, 2024

An Aspirin-Free Versus Dual Antiplatelet Strategy for Coronary Stenting:

STOPDAPT-3 Randomized Trial

Masahiro Natsuaki, MD; Hirotoshi Watanabe , MD; Takeshi Morimoto , MD; Ko Yamamoto , MD;

Yuki Obayashi , MD; Ryusuke Nishikawa , MD; Kenji Ando , MD; Takenori Domei, MD; Satoru Suwa, MD; Manabu Ogita , MD; et al.

https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.123.066720

Randomized Control TrialPopulationInterventionOutcomes
  TICO3 20203056 patients with ACS treated with DESTicagrelor monotherapy (90mg BID) after 3-month DAPT -or-  ticagrelor-based 12-month DAPTThe primary outcome (1-year NACE, defined as a composite of major bleeding and adverse cardiac and cerebrovascular events: death, myocardial infarction, stent thrombosis, stroke, or target-vessel revascularization) occurred in 59 patients (3.9%) receiving ticagrelor monotherapy after 3-month DAPT and in 89 patients (5.9%) receiving ticagrelor-based 12-month DAPT (HR 0.66 [95% CI 0.48-0.92]; P = .01). This was a modest but statistically significant reduction in a composite outcome of major bleeding and cardiovascular events at 1 year. However, it should be noted that this was driven by statistically significant reduction in bleeding (HR 0.56 [95% CI 0.34-0.91]; P = .02), with no significant difference in adverse cardiac and cerebrovascular events (HR 0.69 [95% CI, 0.45-1.06]; P = .09).
TWILIGHT4 20207119 patients with high-risk features who had PCI with DES and had now received 3 months of DAPT with ticagrelor plus aspirin, had been adherent and event-freeTicagrelor plus placebo -or-  ticagrelor plus aspirin for 12 monthsThe primary outcome (BARC Type 2, 3, or 5) occurred in 3.6% of NSTE-ACS patients receiving monotherapy and in 7.6% receiving dual therapy (HR 0.47 [95% CI 0.36-0.67; P < 0.001). In patients without NSTE-ACS, the primary outcome was also reduced in the monotherapy group (4.8% vs. 6.2%; HR 0.76 [95% CI 0.54-1.06; P = 0.11).   The secondary outcome (composite of all-cause death, myocardial infarction, or stroke) among those with NSTE-ACS (4.3% vs. 4.4%; HR 0.97; 95% CI 0.74-1.28; P = 0.84) and without (3.1% vs. 3.2%; HR 0.96; 95% CI 0.61-1.49; P = 0.85) NSTE-ACS were similar between treatment arms irrespective of clinical presentation.   Among patients with or without NSTE-ACS who have completed an initial 3-month course of DAPT following PCI with DES, ticagrelor monotherapy reduced clinically meaningful bleeding events without increasing ischaemic risk as compared with ticagrelor plus aspirin. The benefits of ticagrelor monotherapy with respect to bleeding events were more pronounced in patients with NSTE-ACS.
T-PASS5 20242850 patient with ACS treated with DESTicagrelor monotherapy after <1 month of DAPT -or- 12 months of ticagrelor-based DAPTThe primary end point (net clinical benefit as a composite of all-cause death, myocardial infarction, definite or probable stent thrombosis, stroke, and major bleeding at 1 year after the index procedure in the intention-to-treat population) occurred in 40 patients (2.8%) in the group receiving ticagrelor monotherapy after <1-month DAPT, and in 73 patients (5.2%) in the ticagrelor-based 12-month DAPT group (HR 0.54 [95% CI, 0.37-0.80]; P<0.001 for noninferiority; P=0.002 for superiority). The occurrence of major bleeding was significantly lower in the ticagrelor monotherapy after <1-month DAPT group compared with the 12-month DAPT group (1.2% versus 3.4%; HR 0.35 [95% CI, 0.20-0.61]; P<0.001). This study provides evidence that stopping aspirin within 1 month for ticagrelor monotherapy is both noninferior and superior to 12-month DAPT for the 1-year composite outcome of death, myocardial infarction, stent thrombosis, stroke, and major bleeding, primarily because of a significant reduction in major bleeding, among patients with acute coronary syndrome receiving drug-eluting stent implantation
SMART-CHOICE7 20192993 patients treated with DESAspirin plus a P2Y12 inhibitor for 3 months then P2Y12 inhibitor alone -or- DAPT for 12 monthsThe primary end point was major adverse cardiac and cerebrovascular events (a composite of all-cause death, myocardial infarction, or stroke) at 12 months after the index procedure. At 12 months, major adverse cardiac and cerebrovascular events occurred in 42 patients in the P2Y12 inhibitor monotherapy group and in 36 patients in the DAPT group (2.9% vs 2.5%; difference, 0.4% [1-sided 95% CI, -∞% to 1.3%]; P = .007 for noninferiority). There were no significant differences in all-cause death (21 [1.4%] vs 18 [1.2%]; HR 1.18[95% CI 0.63-2.21]; P = .61), myocardial infarction (11 [0.8%] vs 17 [1.2%]; HR 0.66 [95% CI, 0.31-1.40]; P = .28), or stroke (11 [0.8%] vs 5 [0.3%]; HR 2.23 [95% CI 0.78-6.43 P = .14) between the 2 groups. The rate of bleeding was significantly lower in the P2Y12 inhibitor monotherapy group than in the DAPT group (2.0% vs 3.4%; HR 0.58 [95% CI 0.36-0.92]; P = .02). There was no significant difference in the primary outcome but did show reduced rate of bleeding.
STOPDAPT-28 20193045 patients treated with PCI1-month of DAPT followed by clopidogrel monotherapy -or- 12 months of DAPT with aspiring and clopidogrelThe primary end point was a composite of cardiovascular death, myocardial infarction (MI), ischemic or hemorrhagic stroke, definite stent thrombosis, or major or minor bleeding at 12 months. The major secondary cardiovascular end point was a composite of cardiovascular death, MI, ischemic or hemorrhagic stroke, or definite stent thrombosis and the major secondary bleeding end point was major or minor bleeding.   One-month DAPT was both noninferior and superior to 12-month DAPT for the primary end point, occurring in 2.36% with 1-month DAPT and 3.70% with 12-month DAPT (absolute difference, -1.34% [95% CI, -2.57% to -0.11%]; hazard ratio [HR], 0.64 [95% CI, 0.42-0.98]), meeting criteria for noninferiority (P < .001) and for superiority (P = .04). The major secondary cardiovascular end point occurred in 1.96% with 1-month DAPT and 2.51% with 12-month DAPT (absolute difference, -0.55% [95% CI, -1.62% to 0.52%]; HR, 0.79 [95% CI, 0.49-1.29]), meeting criteria for noninferiority (P = .005) but not for superiority (P = .34). The major secondary bleeding end point occurred in 0.41% with 1-month DAPT and 1.54% with 12-month DAPT (absolute difference, -1.13% [95% CI, -1.84% to -0.42%]; HR, 0.26 [95% CI, 0.11-0.64]; P = .004 for superiority).   Among patients undergoing PCI, 1 month of DAPT followed by clopidogrel monotherapy, compared with 12 months of DAPT with aspirin and clopidogrel, resulted in a significantly lower rate of a composite of cardiovascular and bleeding events, meeting criteria for both noninferiority and superiority.
GLOBAL LEADERS9 201815968 patients treated PCI with DES for either stable CAD or ACSAspirin plus ticagrelor for 1 month followed by 23 months of ticagrelor monotherapy -or- Standard DAPT with clopidogrel or ticagrelor for 12 months followed by aspirin monotherapy for another 12 monthsThe primary endpoint at 2 years was a composite of all-cause mortality or non-fatal centrally adjudicated new Q-wave myocardial infarction. The secondary safety endpoint was site-reported bleeding assessed according to the Bleeding Academic Research Consortium criteria (grade 3 or 5).   304 (3.81%) participants in the experimental group had died or had a non-fatal centrally adjudicated new Q-wave myocardial infarction, compared with 349 (4.37%) participants in the control group (rate ratio 0.87 [95% CI 0.75-1.01]; p=0.073]). There was no evidence for a difference in treatment effects for the primary endpoint across prespecified subgroups of acute coronary syndromes and stable coronary artery disease (p=0.93). Grade 3 or 5 bleeding occurred in 163 participants in the experimental group and 169 in the control group (2.04% vs 2.12%; rate ratio 0.97 [95% CI 0.78-1.20]; p=0.77).   Ticagrelor in combination with aspirin for 1 month followed by ticagrelor alone for 23 months was not superior to 12 months of standard dual antiplatelet therapy followed by 12 months of aspirin alone in the prevention of all-cause mortality or new Q-wave myocardial infarction 2 years after percutaneous coronary intervention. There was no statistically significant differences in the primary or secondary outcomes between the groups. 
MASTER-DAPT11 20214434 patients treated with DES who had already received 1 month of DAPT and were considered at high bleeding riskImmediately discontinue DAPT and continue with single antiplatelet therapy -or- Continue DAPT for at least 2 additional months (standard therapy) with continuation of single antiplatelet therapy afterThe three ranked primary outcomes were net adverse clinical events (a composite of death from any cause, myocardial infarction, stroke, or major bleeding), major adverse cardiac or cerebral events (a composite of death from any cause, myocardial infarction, or stroke), and major or clinically relevant nonmajor bleeding; cumulative incidences were assessed at 335 days.   NACE occurred in 165 patients (7.5%) in the abbreviated-therapy group and in 172 (7.7%) in the standard-therapy group ([95% CI −1.80-1.33]; P<0.001 for noninferiority). A total of 133 patients (6.1%) in the abbreviated-therapy group and 132 patients (5.9%) in the standard-therapy group had a major adverse cardiac or cerebral event ([95% CI −1.29-1.51]; P=0.001 for noninferiority). Among the 4579 patients in the intention-to-treat population, major or clinically relevant nonmajor bleeding occurred in 148 patients (6.5%) in the abbreviated-therapy group and in 211 (9.4%) in the standard-therapy group ([ 95% CI, −4.40- −1.24]; P<0.001 for superiority).   One month of dual antiplatelet therapy was noninferior to the continuation of therapy for at least 2 additional months with regard to the occurrence of net adverse clinical events and major adverse cardiac or cerebral events; abbreviated therapy also resulted in a lower incidence of major or clinically relevant nonmajor bleeding.

Relavent Guidlines

2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines6

2023 ESC Guidelines for the management of acute coronary syndromes: Developed by the task force on the management of acute coronary syndromes of the European Society of Cardiology (ESC)10

Study Rationale

    The optimal duration of DAPT after PCI remains highly debated. There is a balance between decreasing cardiovascular events and causing bleeding. This study seeks to elucidate the efficacy and safety monotherapy vs DAPT within 1 month of PCI.  

    Objectives

      The study aims to assess patients with ACS or high bleeding risk to prasugrel monotherapy vs DAPT with aspirin and prasugrel. The coprimary endpoints were major bleeding (Bleeding Academic Research Consortium 3 or 5) for superiority and cardiovascular events (a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or ischemic stroke) for noninferiority with a relative 50% margin.

      Trial

      • A physician-initiated, prospective, multicenter, open-label, adjudicator-blinded randomized clinical trial involving 72 centers in Japan
        • 6002 patients screened and 5966 patients enrolled from January 2021 to April 2023; 2984 patients in the no-aspirin group and 2982 patients in the DAPT group

      Intervention

      Randomly assigned 1:1 to no-aspirin vs DAPT group

        Enrollment Criteria

        • Included patients with ACS regardless of high risk bleeding (as defined by ARC criteria) or non-ACS with high risk bleeding with minimal exclusion criteria. Exclusion criteria of this study were the following; (1) patients with a known allergy to the study drugs, and (2) patients who were enrolled in the ongoing prospective clinical trials

        Outcomes

        • Primary Outcomes: (1) Coprimary bleeding end point defined as the Bleeding Academic Research Consortium (BARC) type 3 or 5, and (2) coprimary cardiovascular end point defined as a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or ischemic stroke.
          • Secondary Outcomes:  Composite of the coprimary bleeding and cardiovascular end points representing net adverse clinical outcomes. Myocardial infarction and stent thrombosis were defined by the ARC criteria. Stent thrombosis was applied to the stents implanted at the index procedure of this trial.

        Statistical Analysis

        • Sample size was initially planned for 3110 patients, revised to 6000 based on observed event rates and the need for sufficient power to detect differences.
          • Kaplan-Meier estimates and log-rank tests for cumulative incidence were used for analysis. Cox proportional hazards model estimated the hazard ratios.
          • Significance levels were defined as a two-sided P-value for superiority in bleeding endpoints and a one-sided P-value for noninferiority in cardiovascular endpoints.
          • The sensitivity analysis included full analysis set and per-protocol population, with adjustments for discontinuations and subgroup analyses.

        Notable Baseline Characteristics

        • Of 6002 patients who underwent randomization, 5966 were included; those who were excluded did not receive PCI, were enrolled in another trial, or withdrew their consent
        • The baseline characteristics and medications were well balanced between the 2 groups, except for the lower prevalence of proton pump inhibitor use at discharge in the no-aspirin group than in the DAPT group (83.0% and 92.4%)
        • Mean age 71.6; 76.6% were male
        • 75% ACS, 25% non-ACS (stable CAD)

        Primary Outcome

        • At 1 month, the no-aspirin group was not superior to the DAPT group for the coprimary bleeding end point (4.47% and 4.71%; HR, 0.95 [95% CI, 0.75–1.20]; P superiority=0.66)
          •  The most frequent cause of bleeding was access site bleeding related to either PCI or non-PCI access site followed by cardiac tamponade, gastrointestinal bleeding, and other PCI-related bleeding
        • The 1-month incidence of the coprimary cardiovascular end point was 4.12% in the no-aspirin group and 3.69% in the DAPT group (HR, 1.12 [95% CI, 0.87–1.45];  P noninferiority=0.01)

        Secondary Outcomes

        • There was no between-group difference in the incidence of all-cause death (2.28% and 2.11%; HR, 1.08 [95% CI, 0.77–1.52]) and major secondary end point representing net adverse clinical outcomes (7.14% and 7.38%; HR, 0.97 [95% CI, 0.80– 1.17]); the 1-month incidences of coronary events were 1.15% and 0.57% (HR, 1.83 [95% CI, 1.01–3.30]) for any unplanned coronary revascularization, 0.37% and 0.17% (HR, 2.20 [95% CI, 0.77–6.34]) for unplanned non–target-lesion revascularization, 0.71% and 0.44% (HR, 1.62 [95% CI, 0.81–3.23]) for definite or probable stent thrombosis, and 0.58% and 0.17% (HR, 3.04 [95% CI, 1.26–9.23]) for subacute definite or probable stent thrombosis in the no-aspirin group and in the DAPT group, respectively
        End PointExperimental (No-aspirin)Standard (DAPT)[Risk Association]P value
        Coprimary bleeding end point: BARC 3 or 5 bleeding133 (4.47%)140 (4.71%)HR  0.95 (0.75–1.20)0.66
        Coprimary cardiovascular end point: A composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or ischemic stroke123 (4.12%)110 (3.69%)HR 1.12 (0.87–1.45)0.01
        Major secondary endpoint: A composite of cardiovascular death, myocardial infarction, definite stent thrombosis, ischemic stroke, or BARC 3 or 5 bleeding213 (7.14%)220 (7.38%)HR 0.97 (0.80–1.17)N/A

        Adverse Events

        • As defined by the major secondary endpoint

        The trial was designed to assess the safety and efficacy of prasugrel monotherapy compared to DAPT within 1 month of PCI

        • The aspirin-free strategy using low-dose prasugrel compared with the DAPT strategy was not superior for major bleeding and noninferior for cardiovascular events within 1 month after PCI
        • However, the aspirin-free strategy was associated with a signal suggesting an excess of coronary events (3-fold higher rate of subacute definite or probable stent thrombosis in the no-aspirin arm (0.58% versus 0.17%; hazard ratio, 3.04 [95% CI, 1.26–9.23]), despite the use of intravascular imaging for optimization of stent deployment in 93% of patients)
        • There have been multiple recent studies dedicated to duration of DAPT, which mixed outcomes; current guidelines recommend at least 1 month of DAPT, longer if able. High risk bleeding patient may need shorter duration, while patient with complex CAD may need longer duration
        • Shared decision making, individual treatment plans will continue to be paramount in deciding post-PCI DAPT

        Limitations & Considerations

        This study was open-label, which may have influenced the treatment after assignment

        • There was increased use of proton-pump inhibitors in the DAPT group
        • Was not powered enough to evaluate coronary events, but small signal suggesting an excess of coronary events with the no-aspirin strategy relative to the DAPT strategy was based on the small number of patients with event in a few secondary end points
        •  Reduced dosed of prasugrel (loading 20mg, maintenance 3.75mg) were used; these are only approved in Japan
          • There is some evidence that suggests that the levels of prasugrel active metabolite obtained with the prasugrel 20/3.75-mg regimen would be insufficient to deliver a high level of platelet P2Y12 receptor blockade in the majority of patients, thereby risking markedly suboptimal levels of receptor blockade2
        • 12% of patients were also receiving an oral anticoagulant drug at hospital discharge

        • Only 25% women
        1. Natsuaki M, Watanabe H, Morimoto T, et al. An Aspirin-Free Versus Dual Antiplatelet Strategy for Coronary Stenting: STOPDAPT-3 Randomized Trial. Circulation. 2024;149:585-600.
        2. Storey R. Antiplatelet Therapy After PCI: The Art and Science of De-Escalation. Circulation. 2024;149(8):601-604.
        3. Kim B, Hong S, Cho Y, et al. Effect of Ticagrelor Monotherapy vs Ticagrelor With Aspirin on Major Bleeding and Cardiovascular Events in Patients With Acute Coronary Syndrome: The TICO Randomized Clinical Trial. JAMA. 2020;323(23):2407-2416.
        4. Baber U, Dangas G, Angiolillo D. Ticagrelor alone vs. ticagrelor plus aspirin following percutaneous coronary intervention in patients with non-ST-segment elevation acute coronary syndromes: TWILIGHT-ACS. Eur Heart J. 2020;41(37):3533-3545.
        5. Hong S, Lee S, Suh Y, et al. Stopping Aspirin Within 1 Month After Stenting for Ticagrelor Monotherapy in Acute Coronary Syndrome: The T-PASS Randomized Noninferiority Trial. Circulation. 2024;149:562-573.
        6. Lawton J, Tamis-Holland J, Bangalore S, et al. 2021 ACC/AHA/SCAI Guideline for Coronary Artery Revascularization: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2021;145(3):e18-e114.
        7. Hahn J, Song Y, Oh J, et al. Effect of P2Y12 Inhibitor Monotherapy vs Dual Antiplatelet Therapy on Cardiovascular Events in Patients Undergoing Percutaneous Coronary Intervention: The SMART-CHOICE Randomized Clinical Trial. JAMA. 2019;321(24):2428-2437.
        8. Watanabe H, Domei T, Morimoto T, et al. Effect of 1-Month Dual Antiplatelet Therapy Followed by Clopidogrel vs 12-Month Dual Antiplatelet Therapy on Cardiovascular and Bleeding Events in Patients Receiving PCI: The STOPDAPT-2 Randomized Clinical Trial. JAMA. 2019;321(24):2414-2427.
        9. Vranckx P, Valgimigli M, Jüni P, et al. Ticagrelor plus aspirin for 1 month, followed by ticagrelor monotherapy for 23 months vs aspirin plus clopidogrel or ticagrelor for 12 months, followed by aspirin monotherapy for 12 months after implantation of a drug-eluting stent: a multicentre, open-label, randomised superiority trial. Lancet. 2018;392(10151):940-949.
        10. Byrne R, Rossello X, Coughlan J, et al. 2023 ESC Guidelines for the management of acute coronary syndromes: Developed by the task force on the management of acute coronary syndromes of the European Society of Cardiology (ESC). European Heart Journal. 2023;44(38):3720-3826.
        11. Valgimigli M, Rigoli E, Heg D, et al. Dual Antiplatelet Therapy after PCI in Patients at High Bleeding Risk. N Engl J Med. 2021;385(18):1643-1655.

          Summary by:

          Elizabeth Davis, Cardiology Fellow, University of Texas Medical Branch, @EliDavisMD

          Visual abstract by:

          Yeo Yong Hao, Med-Peds Resident, Corewell Health William Beaumont University Hospital, @YeoYongHao

          Trial Tweets, Promotion, & Archive by:

          Mariana Garcia, Internal Medicine Resident, University of Wisconsin Madison, @MarianaGarcia_a

          Moderator of Twitter during CardsJC by:

          Jake Roberts, internal Medicine Resident, UCLA, @JakeRoberts_MD

          Interns:

          Tina Reddy, Internal Medicine Resident, Osler Residency at John Hopkins Hospital, @TinaKReddy

          Diane Masket, Internal Medicine Resident, University of Chicago Northshore, @DianeMasket

          Under the guidance of House Chief:

          Claire Cambron, Cardiology Fellow, Oregon Health & Science University, @ClaireCambron

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