TRILOGY-ACS Trial: recommendations should remain unchanged.

Background

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:

• In the CURE trial - Clopidogrel in Unstable angina to prevent Recurrent Events, (2001), the 12,562 patients enrolled all had NSTE-ACS associated with elevated cardiac markers or ST-segment depression on ECG or age >60 years with prior coronary artery disease (CAD) history. Patients were then randomised to either a loading dose of 300 mg clopidogrel followed by 75 mg daily maintenance for 9–12 months in addition to aspirin, or with aspirin + placebo during the same time period. Patients in the clopidogrel + aspirin arm had a reduced incidence of the combined end point of cardiovascular death, non-fatal myocardial infarction (MI) and stroke compared with aspirin alone (9.3% vs 11.4%; RR 0.80; P < 0.001) but at the expense of more major bleeding (16.5% vs 18.8%; RR 0.86; P < 0.001)(1-3).

1) Prasugrel in invasively-treated ACS patients – TRITON-TIMI 38

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.

• In TRITON-TIMI 38 (4) – (TRrial to assess Improvement in Therapeutic Outcomes by optimizing platelet inhibitioN with prasugrel-ThrombolysIs in Myocardial Infarction 38), prasugrel was tested against clopidogrel for a duration of 15 months in combination with aspirin in both ST elevation myocardial infarction (STEMI) and NSTE-ACS. The objective of the trial was to assess the benefit-risk balance of switching from clopidogrel to a more potent platelet inhibitor - prasugrel, in a population of invasively-treated patients only. Prasugrel therapy was associated with significantly reduced rates of cardiovascular death/myocardial infarction/stroke, (9.9% vs12.1%; RR 0.81; P < 0.001) and also stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding (0.4% vs 0.1%; RR 4.19 ; P <0.002).

2) Ticagrelor in a broad ACS patient population treated invasively or medically only - PLATO

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).

• PLATO: In this multicenter, double-blind, randomized trial, ticagrelor (180-mg loading dose, 90 mg twice daily thereafter was compared with clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624 patients admitted to the hospital with an acute coronary syndrome, with or without ST-segment elevation. At 12 months, the primary end point — a composite of death from vascular causes, myocardial infarction, or stroke — had occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those receiving clopidogrel (hazard ratio, 0.84; 95% confidence interval [CI], 0.77 to 0.92; P<0.001). Predefined hierarchical testing of secondary end points showed significant differences in the rates of other composite end points, as well as myocardial infarction alone (5.8% in the ticagrelor group vs 6.9% in the clopidogrel group, P = 0.005) and death from vascular causes (4.0% vs 5.1%, P = 0.001) but not stroke alone (1.5% vs 1.3%, P = 0.22). The rate of death from any cause was also reduced with ticagrelor (4.5%, vs 5.9% with clopidogrel; P<0.001). No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P = 0.43), but ticagrelor was associated with a higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs 3.8%, P = 0.03), including more instances of fatal intracranial bleeding and fewer of fatal bleeding of other types.
• In a PLATO substudy, the 5216 (28%) of 18,624 patients admitted to hospital for acute coronary syndrome were specified as planned for non-invasive management. Patients were randomised to treatment with ticagrelor (n=2601) or clopidogrel (2615). The primary composite end point of cardiovascular death, myocardial infarction, and stroke was lower with ticagrelor than with clopidogrel (12.0% (n=295) v 14.3% (346); hazard ratio 0.85, 95% confidence interval 0.73 to 1.00; P=0.04). Overall mortality was also lower (6.1% (147) v 8.2% (195); 0.75, 0.61 to 0.93; P=0.01). The incidence of total major bleeding (11.9% (272) v 10.3% (238); 1.17, 0.98 to 1.39; P=0.08) and non-coronary artery bypass grafting related major bleeding (4.0% (90) v 3.1% (71); 1.30, 0.95 to 1.77; P=0.10) was numerically higher with ticagrelor than with clopidogrel.

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.

3) Prasugrel in high-risk NSTEMI and unstable patients selected for medical management only - TRILOGY-ACS

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.

• The TRILOGY trial - the TarGeted platelet Inhibition to cLarify the Optimal strateGY to medically manage acute coronary syndromes trial - (7,8) published in 2012 studied aspirin and prasugrel in high-risk NSTEMI and unstable angina (UA) patients selected for medical management treatment only, within 10 days of their index event. It was a randomised, double-blind, double-dummy, active-control, event-driven trial, with a sample size (n=9326) and follow-up (median >14 months) that was powered to detect a clinically significant difference (22% relative risk reduction) in the primary end point of cardiovascular (CV) death, myocardial infarction (MI) and stroke in subjects <75 years of age for up to 30 months with prasugrel. The study population was at high risk, including NSTEMI or UA with >1 mm of ST depression plus 1 of 4 additional risk criteria: age ≥60 years, diabetes, prior MI, prior revascularisation (percutaneous coronary interventions (PCI) or coronary artery bypass grafting (CABG)). Geographical diversity was satisfactory (33.1% of patients from Central/Eastern Europe) and 22.3% of patients were 75 years of age or above (5, 6). Prasugrel maintenance dose was adjusted to 5 mg (instead of 10 mg) for patients ≥75 years which was a dose which had not been previously tested in such a population) as well as in patient below 60 kg of body weight (5, 6) as which had been previously done in TRITON-TIMI 38 (4).

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).

4) Cross-trial comparison of ticagrelor and prasugrel in medically-treated NSTE-ACS patients

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.

Conclusions

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:

• Ticagrelor is superior to clopidogrel in NSTE-ACS patients initially intended for non-invasive management. 
• Prasugrel is not superior to clopidogrel in NSTE-ACS patients initially intended for non-invasive management.

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:

• Ticagrelor, for patients at moderate-high risk of ischemic events regardless the initial invasive or non-invasive treatment strategy.
• Prasugrel, in patients in whom coronary anatomy is known and are proceeding to percutaneous coronary interventions. 

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).