Efficacy and safety of Ticagrelor over time in patients with prior MI in PEGASUS-TIMI 54
Selected in Journal of the American College of Cardiology by D. Milasinovic
Bonaca MP, Storey RF, Theroux P, Steg PG, Bhatt DL, Cohen MC, Im K, Murphy SA, Magnani G, Ophuis TO, Rudah M, Parkhomenko A, Isaza D, Kamensky G, Goudev A, Montalescot G, Jensen EC, Johanson P, Braunwald E, Sabatine MS
J Am Coll Cardiol. 2017 Sep 12;70(11):1368-1375
LinkRead the abstract
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Why this study – the rationale/objective?
Original data from PEGASUS-TIMI 54 trial showed that prolonged Ticagrelor 60mg or 90mg twice daily, up to 3 years, was associated with cumulative reduction in ischemic events in patients with a history of MI. The objective of the here presented subanalysis was to investigate the temporal distribution of adverse events in the follow-up, and the impact of Ticagrelor thereon.
How was it executed – the methodology?
- 21 162 patients with a history of spontaneous MI (median 1.7 years prior to study inclusion) were randomized to twice daily Ticagrelor 60mg or 90mg or placebo (in addition to low dose Aspirin).
- Patients were ≥50 years old, and had at least one additional high-risk feature (diabetes requiring medication, chronic renal failure, multivessel CAD, a second prior spontaneous MI, age ≥65), and the median follow-up was 33 months (28% of patients were followed-up ≥ 5 years from their index MI).
What is the main result?
- Ticagrelor 60 mg bid was associated with a 10-20% reduction in the risk of ischemic events (CV death, MI or stroke) across all time intervals (HR 0.82 in the first year, HR 0.90 in the second year, HR 0.79 in the third year of the follow-up). Similar results were obtained for Ticagrelor 90mg bid over placebo.
- TIMI major bleeding occurred more frequently in patients on Aspirin and Ticagrelor compared to Aspirin alone, throughout the follow-up, albeit with a decreasing rate (HR 3.22 in the first year, HR 2.07 in the second year, HR 1.65 in the third year, for Ticagrelor 60mg bid).
Critical reading and the relevance for clinical practice
In the introduction of this paper, the authors provide an analogy with Aspirin (which is given lifelong after MI, generally based on randomized two-year follow-up data), that may inspire a shift in thinking towards extending DAPT for an indefinite period of time in populations at higher-risk of ischemic events.
And the study data seem to be supportive, as Ticagrelor 60mg bid was consistently associated with reduced rates of ischemic events in all follow-up periods, and the initial 3-fold increase in bleeding risk seems to have subsided with time, albeit likely related to the selection of patients for the analysis, as at each landmark further from the baseline, only patients without intolerable bleeding were retained in the analysis.
Moreover, the accompanying editorial pointed out that when looking at annual absolute event rates, the net benefit was not present during the entire follow-up, but only after three years, when the bleeding rates subsided. When compared to some of the other secondary prevention drugs, Ticagrelor had a moderate effect on the reduction of ischemic events, in terms of numbers needed to treat (NNT).
Therefore, a selective approach may, at least for now, seem reasonable, using some of the available risk tools (e.g. DAPT, PRECISE DAPT score etc.) and evaluating the overall clinical context, before extending DAPT.