DAPT - Comparison of 12 vs >12 of DAPT after drug-eluting stent placement

in

Mauri L, et al. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014;371:2155-66.

Bottom line: In patients who go 1 year after drug-eluting stent placement with good adherence to DAPT without a CV or bleeding event, extending DAPT for another 18 months will reduce the risk of MI (NNT 50), but increase the risk of death (NNH 200) & moderate-to-severe bleeding (NNH 112). Benefits are far less impressive in patients receiving 2nd generation drug-eluting-stents, which are the sole drug-eluting stents implanted in current practice.

 

Context

  • Concerns were raised in 2006 about an increased risk of late (month 1-12 after stent placement) & very late (>1 year) stent thrombosis with 1st generation drug-eluting stents (Cypher, Taxus) versus bare-metal stents
    • DAPT duration recommendations at the time were 3-6 months
    • End of 2006: Label change & AHA recommendations for 12 months of DAPT after drug-eluting stent placement
    • True ideal duration of DAPT unknown; further reduction of very late stent thrombosis & resulting MI with durations >12 months?
  • From 2008 onward, newer "2nd generation" drug-eluting stents with faster endothelial healing over the stent & decreased thrombogenicity entered the market
    • Includes everolimus-eluting (Xience) & zotarolimus-eluting (Endeavor, Resolute) stents

Issues with internal validity?

  • Low risk of allocation, performance and detection bias: Randomized, allocation-concealed, double-blind trial analyzed using the intention-to-treat population
  • Unclear risk of attrition bias: ~5% of patients were lost-to-follow-up or withdrew consent

Patients (n=9961)

  • Inclusion
    • >18 y/o
    • PCI with drug-eluting stent placement
    • Received 12 months of DAPT after stent placement
    • Adherence 80%+ during 1st year of DAPT
    • No adverse events during 1st year of DAPT (MI, stroke, repeat coronary revascularization, stent thrombosis, major bleed)
  • Exclusion
    • Life expectancy <3 y
    • Planned surgery in next 30 months requiring antiplatelet discontinuation >14 days
    • Stent diameter <2.25 mm or >4.0 mm
    • Need for oral anticoagulation
    • Switched P2Y12 inhibitor type or dose in first 6 months of DAPT
  • 22.866 screened (11% had events within 1 year) -> 9961 randomized -> 9499 analyzed
  • "Average" patient
    • Age 62 y
    • Female 25%
    • White 91%
    • Indication for PCI: STEMI (10%), NSTEMI (15%), unstable angina (17%), stable angina (38%), other (20%)
    • CV history
      • Prior MI 22%
      • Prior PCI 31%
      • Prior CABG 11%
      • Stroke/TIA 3%
      • HF <5%
      • PAD 6%
    • CV risk factors
      • Current smoker 25%
      • HTN 75%
      • Diabetes 31%
    • PCI characteristics
      • Type of stent
        • 1st generation: Paclitaxel (27%), sirolimus (11%)
        • 2nd generation: Everolimus-eluting (47%), zotarolimus (13%)
      • Other PCI characteristics
        • Treated vessel: Left main (<1%), LAD (41%), RCA (33%), LCx (22%), graft (3%)
        • 1.5 stents
        • Minimum diameter <3 mm 47%
        • Total length 28 mm

Intervention

  • I: DAPT with clopidogrel (2/3) or prasugrel (1/3) x30 months
    • Investigator's choice: Clopidogrel 75 mg/d or prasugrel 10 mg/d (5 mg/d if weight <60 kg)
  • C: DAPT x12 months, then matching placebo
  • Co-interventions
    • Drug-eluting stents used in this trial: 1st generation (Cypher, TAXUS), 2nd generation (Endeavor, Xience)
    • ASA 75-162 mg/d

Generalizability

  • Population: Limited to a relatively low-risk population; individuals with stent placement (for ACS or stable angina) without any CV or bleeding event x12 months
    • Patients with a CV event in this timeframe would inherently be at higher risk & therefore have a larger absolute benefit from prolonged DAPT
    • Patients with a bleeding event in this timeframe would inherently be at higher bleed risk, & therefore have a higher risk of harm from prolonged DAPT
  • Intervention: Most used clopidogrel, but ~1/3 of patients used prasugrel (investigator's choice)
    • Ticagrelor not used in this trial, but risk/benefit of prolonged ticagrelor-based DAPT likely similar to prasugrel (extrapolating from PLATO & PEGASUS ), with additional adverse events with ticagrelor (dyspnea & gout)

Results during months 12-30 from stent placement (randomized period)

  • Death, MI, stroke (primary outcome 1): 4.3% with DAPT x30 months, 5.9% with DAPT x12 months, hazard ratio 0.71 (0.59-0.85)
    • Death: 2.0% vs  1.5% (NNH 200, p=0.05)
    • MI: 2.1% vs 4.1% (NNT 50), HR 0.47 (0.37-0.61)
      • Stroke: 0.8% vs 0.9% (p=0.32)
  • Stent thrombosis, definite or probable (primary outcome 2): 0.4% vs 1.4% (NNT 100), HR 0.29 (0.17-0.48)
    • Safety
      • Discontinued study drug: 21.4% vs 20.3% (p=0.18)
      • Moderate-severe bleed (GUSTO definition): 2.5% vs 1.6% (NNH 112)
  • Subgroup analyses: Newer stents have lower risk of CV events & stent thrombosis, as well as lower relative & absolute benefit from prolonged DAPT
    • Benefit of prolonged DAPT on CV events based on stent type:
      • 1st generation NNT <32
      • 2nd generation NNT >77

Other consideration

  • 11 RCTs (n=33,051) have compared DAPT durations ranging from 3 to 48 months following drug-eluting stent placement
    • In 1 meta-analysis of 10 RCTs, "longer" vs "shorter" DAPT duration resulted in
      • Decreased risk of MI by -0.8%/year (NNT 125)
      • Increased risk of 
        • Death by +0.2%/year (NNH 500)
        • Major bleed by +0.6%/year (NNH 167)
  • Subgroups analyses