Ischaemic risk and efficacy of ticagrelor in relation to time from P2Y ₁₂ inhibitor withdrawal in patients with prior myocardial infarction: insights from PEGASUS-TIMI 54
Marc P. BonacaDeepak L. BhattPhilippe Gabríel StegRobert F. StoreyMarc CohenKyungAh ImTon Oude OphuisAndrzej BudajShinya GotoJosé López‐SendónRafael DíazAnthony J. DalbyFrans Van de WerfDiego ArdissinoGilles MontalescotPhilip E. AylwardGiulia MagnaniEva C. JensenPeter HeldEugene BraunwaldMarc S. Sabatine
Why the study?
It was hypothesized that patients who recently discontinued P2Y12 inhibition, even years after MI, may be at particular risk of MACE and derive particular benefit from continuation or reinitiation of therapy.
Does ticagrelor reduce major adverse cardiovascular events in patients with prior myocardial infarction depending on the time from previous P2Y12 inhibitor withdrawal?
Structured PICO
Does ticagrelor reduce major adverse cardiovascular events in patients with prior myocardial infarction depending on the time from previous P2Y12 inhibitor withdrawal?
P
Population
Patients with prior myocardial infarction (MI) and at least one additional risk factor from the PEGASUS-TIMI 54 trial, categorized by time from last P2Y12 inhibitor withdrawal (≤30 days, >30-360 days, >360 days).
I
Intervention
Ticagrelor (pooled doses)
C
Comparator
Placebo
O
Outcome
Major adverse cardiovascular event (MACE)composite
Continuing or briefly interrupting P2Y12 inhibition with ticagrelor yields greater ischemic benefit than re-initiating therapy after prolonged discontinuation in stable post-MI patients.
Key expert perspectives
Captured external expert commentary on this paper, strongest first. Original sources are linked where available.
“These findings suggest greater benefit in continuing P2Y12 inhibition beyond 12 months therapy without interruption than in re-initiating such therapy in patients who have remained stable for more than 2 years after their MI and more than 1 year off of a P2Y12 inhibitor.”
“This analysis pointed to important patterns with regards to common adverse events associated with ticagrelor in the context of clinical benefit. Physicians must consider the overall risks, including higher rates of bleeding and dyspnea particularly within the first year. For patients at increased risk for recurrent cardiovascular events in the long-term, ticagrelor can provide an important benefit.”
“This analysis demonstrates that the efficacy of ticagrelor was maintained over the duration of the trial, providing most benefit in patients who commenced the trial less than two years after a heart attack. These new insights are important, showing that the effectiveness of ticagrelor did not lessen over three years of treatment. This supports the benefit of continuing ticagrelor at a dose of 60mg for patients who tolerate ticagrelor 90mg for the first 12 months after MI.”
Implication
Account for time from last P2Y12 dose in ticagrelor prescribing; extends randomized evidence of time-dependent efficacy in secondary prevention.
Abstract
AIMS: Ticagrelor reduced major adverse cardiovascular event (MACE) by 15-16% in patients with prior myocardial infarction (MI) in PEGASUS-TIMI 54. We hypothesized that patients who recently discontinued P2Y12 inhibition, even years after MI, may be at particular risk of MACE and may derive particular benefit from continuation or reinitiation of therapy. METHODS AND RESULTS: Patients in PEGASUS-TIMI 54 were categorized by time from last P2Y12 inhibitor (days: ≤30, >30-360, >360). The risk of MACE and the efficacy of ticagrelor were compared across categories. In the placebo arm, patients who more recently stopped P2Y12 inhibitor therapy had a greater number of risk factors but still had a higher risk of MACE after multivariable adjustment [≤30 days, hazard ratio (HR)adj 1.47, 95% confidence interval (CI) 1.12-1.93, P = 0.0051; 30 days-1 year, HRadj 1.28, 95% CI 0.98-1.67, P = 0.073] compared with those who stopped >1 year prior (P-trend = 0.0097). The benefit of ticagrelor depended on the time from last dose, with HRs (95% CI) for ticagrelor (pooled doses) vs. placebo of 0.73 (0.61-0.87), 0.86 (0.71-1.04), and 1.01 (0.80-1.27), respectively, by category (P-trend for interaction < 0.001). The benefit in those ≤30 days of stopping was similar regardless of time from MI (<2 years, HR 0.73, 95% CI 0.60-0.89 vs. ≥2 years, HR 0.71, 95% CI 0.50-1.00). CONCLUSION: The benefit of ticagrelor for long-term secondary prevention in patients with prior MI and at least one additional risk factor appeared more marked in patients continuing on or re-starting after only a brief interruption of P2Y12 inhibition, when compared with patients who had proved themselves stable more than 2 years from their MI and off P2Y12 inhibitor therapy for more than a year. The increase in bleeding events with ticagrelor was similar regardless of this time interval. For clinicians considering a strategy of prolonged P2Y12 inhibitor therapy in high-risk patients, these data suggest greater benefit in the continuation of such therapy without interruption after MI, rather than re-initiating such therapy in patients who have remained stable for an extended period. Future analyses may help to clarify further the profile of post-MI patients most likely to benefit from uninterrupted dual antiplatelet therapy. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.clinicaltrials.gov NCT01225562.
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Cite This Study
Bonaca et al. (2015) studied this question.