SMART-DATE - 6 vs 12 months of DAPT after PCI for ACS

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Hahn JY, et al. 6-month versus 12-month or longer dual antiplatelet therapy after percutaneous coronary intervention in patients with acute coronary syndrome (SMART-DATE): a randomised, open-label, non-inferiority trial. Lancet 2018 [epub]

Bottom line: In patients with ACS who underwent PCI, shorter DAPT (~6 months) increased the risk of recurrent MI (NNH 100) without any clear reduction in bleeding versus a standard DAPT duration of 12+ months.

Patients (n=2712)

  • Setting: South Korea from Sept 2012 to Dec 2015
  • Included:
    • ACS (STEMI, NSTEMI or unstable angina)
    • At least 1 lesions in a native coronary vessel with stenosis >50% amenable to PCI with stents
  • Excluded: Contraindication to antiplatelets, drug-eluting stent coating, or contrast media; Active bleeding, major bleeding within 3 months, or major surgery within 2 months; History of bleeding diathesis or known coagulopathy; Planned elective surgical procedure within next 12 months
  • Baseline characteristics:
    • Age 62 y
    • Women 25%
    • ACS subtype: STEMI 38%, NSTEMI 31%, unstable angina 31%
    • Prior MI 2%, previous revasc 5%
    • Angiography: Multivessel CAD 45%, left main 2%, LAD 59%, bifurcation lesion 9%
    • Other PMHx: Smoker 39%, HTN 49%, diabetes 27%

Intervention & control

  • Intervention: Short DAPT duration (x6 months)
    • Median DAPT duration 6.1 months
    • Adherence to study protocol: 74%
    • Used clopidogrel as P2Y12 inhibitor: 80%
  • Control: Standard DAPT duration (x12+ months)
    • Median DAPT duration 17.7 months
    • Adherence to study protocol: 96%
    • Used clopidogrel as P2Y12 inhibitor: 82%
  • Both groups: DAPT consisted of ASA + P2Y12 inhibitor at standard doses

Results (from PCI to 18 months after PCI)

Efficacy

  • 1o outcome (composite of all-cause mortality, MI, stroke): DAPTx6months 4.7%, x12+ months 4.2%, hazard ratio (HR) 1.13 (0.79-1.62)
    • Absolute risk difference 0.5% (upper limit 1.8% < 2.0% non-inferiority margin, p=0.03 for non-inferiority)
    • Post-hoc landmark analysis from month 6 to 18: HR 1.69 (0.97-2.94)
  • Death: 2.6% vs 2.9%, HR 0.90 (0.57-1.42)
  • MI: 1.8% vs 0.8%, HR 2.41 (1.15-5.05) - number needed to harm (NNH) 100
    • Post-hoc landmark analysis from month 6 to 18: HR 5.06 (1.46-17.47)
  • Stroke: 0.8% vs 0.9%
  • Stent thrombosis: 1.1% vs 0.7%

Safety

  • BARC 2-5 bleeding: 2.7% vs 3.9%, HR 0.69 (0.45-1.05)
  • Major bleeding: 0.5% vs 0.8%, HR 0.60 (0.22-1.65)

Generalizability

  • This trial enrolled a generally representative group of Asian patients with ACS undergoing PCI predominantly treated with DAPT consisting of ASA + clopidogrel
  • Study investigators were hesitant to comply with the study protocol; 26% of patients in the 6-month group continued to receive DAPT beyond 6 months
  • Although the authors claimed to randomize at the time of PCI rather than 6 months later in order to avoid "selection bias, resulting in enrolment of low-risk patients," it's likely that any "high-risk patients" would not have been considered & therefore not enrolled into this trial.

Risk of bias

  • Low risk of allocation bias
    • Web-based randomization;
    • Computer-generated block randomization;
    • Stratified by (1) enrolment site, (2) ACS subtype, (3) diabetes (y/n), (4) type of P2Y12 inhibitor after prasugrel/ticagrelor became available, & randomized to 1 of 3 drug-eluting stents (eluting everolimus [Xience Prime], zotarolimus [Resolute Integrity], or biolimus [BioMatrix Flex]).
  • High risk of performance & detection bias
    • Randomization occurred immediately after PCI rather than at month 6, allowing for differences in performance & collection of outcomes prior to patients receiving allocated treatment (stopping or continuing DAPT at 6 months);
    • Participants & personnel not blinded to treatment allocation;
    • 26% of patients in 6-month group did not comply with the study intervention of stopping DAPT at month 6.
  • Low risk of attrition bias
    • 2.5% loss-to-follow-up (3.0% vs 1.9%);
    • ITT analysis.
  • Non-inferiority design not clearly justified
    • Wide non-inferiority margin of 2.0% absolute risk difference justified based on feasibility (assuming 4.5% incidence of 1o outcome @ 18 months in 12-month group);
    • Non-inferiority criteria based on above wide non-inferiority margin met for primary outcome, however, MI - key component of this composite - was clinically and statistically significantly higher in the short DAPT group;
    • Inclusion of period from PCI to month 6, when both groups were intended to receive DAPT, biases the results toward non-inferiority. The post-hoc landmark analysis evaluating outcomes from month 6 to 18 demonstrates a greater difference between groups, supporting the conclusion that DAPT x6 months is inferior to 12+ months;
    • Similar results between ITT & per-protocol analysis, although with the above limitations.