TOPIC - Continuing ticagrelor/prasugrel vs switching to clopidogrel 1 month after ACS

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Benefit of switching dual antiplatelet therapy after acute coronary syndrome: The TOPIC (timing of platelet inhibition after acute coronary syndrome) randomized study. Eur Heart J 2017 [online]

Bottom line: In patients with ACS who underwent PCI & tolerated prasugrel/ticagrelor x1 month, discontinuing prasugrel/ticagrelor & switching to a pill that combines ASA+clopidogrel reduced the risk of mainly minor bleeding over the subsequent 11 months.

TOPIC was underpowered to evaluate ischemic events, & is inadequate to inform practice or change routine care. Based on results from PLATO, employing this strategy would result in an increased risk of death/MI/stroke, particularly during the crossover period between stopping ticagrelor & waiting for clopidogrel to achieve its full antiplatelet effect (up to 7 days).

 

Patients (n=645)

  • Included: 
    • Adults with ACS, & PCI within 3 days of ACS admission initially treated with prasugrel/ticagrelor
    • No major adverse event in 1st month (including ischemia or bleed)
  • Key exclusion: Major bleed (BARC criteria) in last year, long-term use of anticoagulation
  • Baseline characteristics
    • Age ~60 y
    • Male ~83%
    • ACS type: STEMI ~40%, NSTE-ACS 60%
    • Previous CAD 30%
    • CV risk factors: Smoker ~45%, HTN ~50%, T2DM ~25%
    • Meds
      • P2Y12 inhibitor: Prasugrel ~55%, ticagrelor ~45%
      • ACE inhibitor or ARB ~75%
      • Beta-blocker ~70%
      • Statin ~95%
      • PPI 100%

Interventions

ASA 75 mg/d + ticagrelor/prasugrel (clinician selection) x1 month, then randomized to:

  • I ("switch"): Switch to clopidogrel 75 mg/d + ASA 75 mg/d (combined in 1 pill) x11 months (total 1 year on DAPT)
    • The published report does not specify what strategy was used to perform the switch to clopidogrel. This is critical as clopidogrel 75 mg/d takes 5-7 days to achieve its full antiplatelet effect
    • 86% still receiving at 1 year (~6% switched back to ticagrelor/prasugrel, ~6% on ASA only, <1% on no antiplatelet)
  • C ("continue"): Continue ticagrelor/prasugrel + ASA 75 mg/d (not combined into 1 pill) x11 months (total 1 year on same P2Y12 inhibitor)
    • 75% still receiving at 1 year (~17% switched to clopidogrel, ~7% on ASA only, <1% on no antiplatelet)

Results @ 1 year

 

Generalizability

  • P: This trial applies to ACS patients who tolerated ticagrelor/prasugrel for 1 month without issue, including recurrent coronary event or clinically-important bleeding
  • I/C:
    • The "switch" intervention was actually 2 distinct interventions:
      1. Consolidation of multiple pill administrations into a single tablet
        • For initial ticagrelor users, simplified from 3 tabs/day to 1
        • For initial prasugrel users, simplified from 2 tabs/day to 1
      2. Switch to lower-potency antiplatelet agent (clopidogrel)
      • Reduced bleeding rates in this trial are a combined result of decreased antiplatelet potency, as well as more consistent adherence due to decreased pill burden and simplification of administration regimen. This also reduces any apparent benefit on ischemic outcomes with the prasugrel/ticagrelor continuation, since non-adherence dulls their efficacy
    • Use of either prasugrel or ticagrelor in the control group complicates this further, as these agents have different efficacy/safety profiles (ticagrelor generally considered more efficacious + safer), & administration methods (ticagrelor is dosed BID)

Internal validity

  • Use of inappropriate composite primary outcome
    • Includes biologically disparate events (both ischemic/efficacy & bleeding/safety events)
    • Largely driven by the least "clinically important" outcome (bleeding requiring medical evaluation)
    • Inadequate power to evaluate more important components (CV/overall death, stroke, revascularization), & cannot rule in/out a difference nor determine consistency between different components
  • Enrolment occurred in a single center in France 2014-2016
    • Single-center trials systematically overestimate benefits compared to multi-center trials, likely related issues in minimizing typical bias domains (allocation, performance & detection)
  • Unclear risk of allocation bias
    • Allocation concealed by sequentially-numbered sealed envelopes: Application of this strategy varies, and is prone to manipulation
  • High risk of performance and detection bias
    • Patients, caretakers and clinicians not blinded to study intervention
    • "Switch" intervention simpler, easier to adhere to
    • Adjudicated by physician unaware of allocated intervention, though reporting of events to adjudicators may have been biased (particularly the subjective BARC 2 bleeds)
  • Low risk of attrition bias (intention-to-treat analysis with 2% loss-to-follow-up at 1 year)
  • Potential selective outcome reporting
    • Reporting of coronary events limited to those "requiring unplanned hospitalization for urgent coronary revascularization," but investigators did not report ACS events not requiring revascularization