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Prof. Raffaele De Caterina,
When moderate/high risk patients with non-ST elevation (NSTE) acute coronary syndromes (ACS) are not treated invasively, the PLATO trial (2009 and 2011) has shown that added to aspirin ticagrelor is superior to clopidogrel and can be recommended in these patients – as well as in invasively-treated patients. Only for patients treated invasively, after their coronary anatomy is known, aspirin and prasugrel are also recommended - on the basis of the TRITON-TIMI 38 trial (2007). The TRILOGY-ACS trial has now shown that prasugrel is not superior to clopidogrel in NSTE myocardial infarction and unstable angina in patients without revascularisation. Thus, all recommendations stay the same.
Despite the recommendation that moderate/high risk patients with non-ST elevation acute coronary syndromes (NSTE-ACS) be treated invasively on the basis that intervention relieves symptoms, shortens hospital stay, and improves prognosis, approximately half of moderate/high risk patients with NSTE-ACS do not undergo early revascularisation and are treated only medically. Such medically-only treated patients usually have more comorbidities, a higher risk of bleeding, and a worse global outcome than invasively treated patients. Reasons for not selecting patients for intervention are diverse; they may include prior intervention, poor renal function, diabetes, complex coronary anatomy or advanced age. This population has not been well represented in trials. Nevertheless, standard practice has been, until a few years ago, to treat such patients with a combination of aspirin and clopidogrel for one year, essentially as a result of the findings of the CURE trial:
When ST elevation myocardial infarction (STEMI) patients and NSTE-ACS patients are treated invasively, on the other hand, a more recent approach tested in the TRITON-TIMI 38 trial (2007) has been to treat them with a combination of aspirin and prasugrel for one year, which has resulted in the approval for prasugrel use at PCI in the setting of ACS.
The other P2Y12 inhibitor tested against clopidogrel in the ACS population, ticagrelor, was studied in the PLATO trial that was designed to test the hypothesis that ticagrelor compared with clopidogrel would result in a lower risk of recurrent thrombotic events in a broad patient population with ACS (5). Indeed, it showed that ticagrelor was superior to clopidogrel in the overall ACS population, comprising both STEMI and NSTE-ACS patients. A sub-analysis of PLATO showed that ticagrelor was superior to clopidogrel even in NSTE-ACS patients initially intended for non-invasive management (6).
Therefore, in patients who have an acute coronary syndrome with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non–procedure-related bleeding. One question left to ask was: what about prasugrel in non-invasively treated patients? To study this population and address this gap, as well as to resolve the issue of the prohibitively high risk of bleeding in TRITON-TIMI 38 for patients ≥75 years of age (4) assessment of prasugrel (at a lower dose in patients ≥75 years of age) in NSTE-ACS patients was warranted.
The main trial hypothesis of the TRILOGY-ACS trial is that long-term use of prasugrel would reduce adverse cardiovascular outcomes in patients with non-ST-elevation acute coronary syndromes selected for medical management without revascularisation, compared with clopidogrel.
Results did not support the trial main hypothesis. The primary efficacy end point - cardiovascular death, MI and stroke in patients under 75 years - was not statistically different between the two arms of the study. Statistical significance was also not achieved for other efficacy end points including CV death; MI; stroke; all-cause death; CV death+MI; recurrent hospitalisation for UA; All-cause death, MI or stroke; and for the net clinical benefit end point, including major bleeding (8). However, none of the safety bleeding end points were statistically different between the two arms, including in patients >75 years of age - here indicating the success of the modified regimen in terms of safety. There was also no prohibitively high risk of bleeding as in the TRITON-TIMI trial, but moderate/minor bleeding was still higher in the prasugrel group, as a reflection of the increased antiplatelet effect of prasugrel vs clopidogrel (8). Nevertheless, there was an apparent separation of the curves after 12 months (8), which is triggering interesting speculations and would be worth further investigation. No previous trial had tested a P2Y12 inhibitor with such a long follow-up.In comparing with the TRILOGY-ACS trial, one can note that there were more crossover to revascularisation therapy cases in the PLATO cohort initially managed medically (6). This result is in line with the fact that substudy of the PLATO trial involved a subgroup of a larger study intending to treat all comers in ACS), whereas TRILOGY included only purely medically treated patients at randomisation (7,8); crossover to revascularisation was 40.0 % in the PLATO substudy and 7.9% in TRILOGY (Table 1). Nevertheless, these differences do not apparently account for the different outcomes. Indeed, the PLATO substudy authors state that, in the 3,948 patients who did not actually undergo revascularisation during their hospital admission - despite the initially intended intervention strategy, ticagrelor reduced the primary outcome, a composite of death from cardiovascular causes, MI, or stroke compared with clopidogrel which was consistent with the overall results of PLATO (5), from 15.2% (726) to 12.2% (224) (HR 0.81, CI 0.68 to 0.97).
The previously referred pre-specified sub-analysis of the PLATO - PLAtelet inhibition paTient Outcome - Study published in 2011 (6) was performed in a population half that of TRILOGY-ACS's (5,216 vs 9,326) with a shorter follow-up (median 9.2 months vs 14.8 months), and with a slightly lower risk profile: there were fewer women and patients with hypertension, diabetes or previous MI (Table 1). Ticagrelor use was associated with a significantly lower occurrence of cardiovascular death, MI and stroke - its primary end point -, and with less mortality by all causes (HR 0.75; 95% CI 0.61-0.93), compared with clopidogrel (Table 2). Although these comparisons between different trials may be faulty for several reasons, they do suggest a difference in outcome with the use of the two drugs. Such reasons may involve additional properties of ticagrelor, such as – as suggested – an adenosine-like effect.
The PLATO subanalysis and TRILOGY-ACS investigated two newer ADP receptor/P2Y12 inhibitors in medically treated NSTE-ACS in head-to-head comparison with clopidogrel. However they have apparently provided different outcomes:
These results are consistent with current ESC Guidelines on NSTE-ACS (2) that state that the following drug, in combination with aspirin should be preferred over clopidogrel:
Such recommendations should not change as the result of TRILOGY-ACS.In a context where up to a quarter of patients are non-responders to clopidogrel (see previous e-journal article on anti-platelet therapy and the Madonna trial), prasugrel however is worth investigating in subsets of ACS patients not optimally responding to clopidogrel.Table 1. Main study characteristics of novel P2Y12 antagonists vs clopidogrel in medically treated ACS (6,8).
Table 2. Main study outcomes of novel P2Y12 antagonists vs clopidogrel in medically treated ACS (6,8).
1.Noninvasive, medical management for non-ST-elevation acute coronary syndromes.Chan MY, Becker RC, Harrington RA, Peterson ED, Armstrong PW, White H, Fox KA, Ohman EM, Roe MT. Am Heart J 2008;155:397-407.2.ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC).Hamm CW, Bassand JP, Agewall S, Bax J, Boersma E, Bueno H, Caso P, Dudek D, Gielen S, Huber K, Ohman M, Petrie MC, Sonntag F, Uva MS, Storey RF, Wijns W, Zahger D, Bax JJ, Auricchio A, Baumgartner H, Ceconi C, Dean V, Deaton C, Fagard R, Funck-Brentano C, Hasdai D, Hoes A, Knuuti J, Kolh P, McDonagh T, Moulin C, Poldermans D, Popescu BA, Reiner Z, Sechtem U, Sirnes PA, Torbicki A, Vahanian A, Windecker S, Achenbach S, Badimon L, Bertrand M, Botker HE, Collet JP, Crea F, Danchin N, Falk E, Goudevenos J, Gulba D, Hambrecht R, Herrmann J, Kastrati A, Kjeldsen K, Kristensen SD, Lancellotti P, Mehilli J, Merkely B, Montalescot G, Neumann FJ, Neyses L, Perk J, Roffi M, Romeo F, Ruda M, Swahn E, Valgimigli M, Vrints CJ, Widimsky P. Eur Heart J 2011;32:2999-3054.3 - Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK; Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators.N Engl J Med. 2001 Aug 16;345(7):494-502. Erratum in: N Engl J Med 2001 Dec 6;345(23):1716. N Engl J Med 2001 Nov 15;345(20):1506. 4.Prasugrel versus clopidogrel in patients with acute coronary syndromes.
6.Ticagrelor versus clopidogrel in patients with acute coronary syndromes intended for non-invasive management: substudy from prospective randomised PLATelet inhibition and patient Outcomes (PLATO) trial.James SK, Roe MT, Cannon CP, Cornel JH, Horrow J, Husted S, Katus H, Morais J, Steg PG, Storey RF, Stevens S, Wallentin L, Harrington RA. BMJ 2011;342:d3527.7.Study design and rationale of a comparison of prasugrel andclopidogrel in medically managed patients with unstable angina/non-ST-segment elevation myocardial infarction: the TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes (TRILOGY ACS) trial.Chin CT, Roe MT, Fox KA, Prabhakaran D, Marshall DA, Petitjean H, Lokhnygina Y, Brown E, Armstrong PW, White HD, Ohman EM. Am Heart J 2010;160:16-22 e1.8. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. Roe MT, Armstrong PW, Fox KA, White HD, Prabhakaran D, Goodman SG, Cornel JH, Bhatt DL, Clemmensen P, Martinez F, Ardissino D, Nicolau JC, Boden WE, Gurbel PA, Ruzyllo W, Dalby A,McGuire DK, Leiva-Pons JL, Parkhomenko A, Gottlieb S, Topacio GO, Hamm C, Pavlides G, Goudev AR, Oto A, Tseng CD, Merkely B, Gasparovic V, Corbalan R, Cinteza M, McLendon RC, Winters KJ, Brown EB, Lokhnygina Y, Aylward PE, Huber K, Hochman JS, Ohman EM. N Engl J Med 2012;367:1297-309
Raffaele De Caterina, MD, PhD, FESC – “G. d’Annunzio” University – Chieti, ItalyAuthor's disclosures: None declared.