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Acute coronary syndromes -- Did prasugrel & ticagrelor offer same benefits as clopidogrel?

This article by Dr. Alfredo E Rodriguez et al. is published in Current Pharmaceutical Design, Volume 24, 2018

Bentham Science Publishers

In patients presenting with acute coronary syndromes (ACS) either with or without ST-segment elevation MI (STEMI and NSTEMI), dual antiplatelet therapy (DAPT) is recommended for at least 1 year independently of whether revascularization is performed.

Randomized clinical trials (RCT) in ACS patients with more potent P2Y12 inhibitors such as prasugrel and ticagrelor have been conducted and compared with clopidogrel. Most of these trials showed a significant reduction of adverse events with each of them, compared to clopidogrel, however, they also showed limitations, that we were discussed in this presentation.

The purpose of this review is to search all clinical data from these two new compounds in order to accumulate the potential advantages and disadvantages of each new drug.

These days, DAPT therapy emerged with a main role to reduce cardiac adverse events after percutaneous coronary interventions (PCI) in patients with ACS. The use of DAPT became even more relevant with the introduction of DES in routine clinical practice. The guidelines of how long DAPT therapy would be recommended after PCI have changed in the last few years from indefinitely to mandatory only during the first 6 months, although in the majority of cases, it is tailored according to patient and lesion subset.

New and more potent P2Y12 platelet aggregation inhibitors are available and these are compared to the first ones in RCT and observational studies in the broad spectrum of ACS with or without PCI.

Current indications for advantages and disadvantages of prasugrel and ticagrelor compared to clopidogrel in patients with ACS were drawn following the results of two main RCT: TRITON TIMI 38 (prasugrel vs. clopidogrel) and PLATO (ticagrelor vs. clopidogrel). Both drugs compared to clopidogrel reduce major adverse cardiac events (MACE), although with the penalty of major bleeding. Ticagrelor also reduced cardiovascular death and all-cause mortality and prasugrel early and late stent thrombosis. Treatment with prasugrel also needed certain limitations in patients with low weight and previous cerebrovascular accident.

When we analyse data from the PLATO study, all findings appear to be strong in favour of ticagrelor over clopidogrel. However, there are several controversies with trial design and results in the PLATO study, which were well reported and discussed in the manuscript, such as monitoring data, geographic disparities, discrepancies in vital status between ticagrelor and clopidogrel, inconsistencies in follow-up, etc., and even though some of them were rebutted by trial organizers, it was pretty difficult to fully understand and extrapolate the main conclusions of this trial to our clinical practice. Furthermore, we have to take into account that beyond PLATO results, other RCT such as PHILO and DISPERSE II reported negative or mixed results of ticagrelor over clopidogrel which are in agreement with negative results observed in USA sites of the PLATO trial.

In the manuscript we review data from large observational registries and meta-analysis where all of them shown that in patients with STEMI prasugrel was highly significant superior to ticagrelor and clopidogrel in reducing MACE including all-cause of death (p<0.001) and cardiovascular death at 1-month (p<0.001) and cardiovascular death at one year (p<0.001).

Additionally, no higher bleeding risk with prasugrel was seen.

However, we have to take into account that all findings from non-randomized data should be taken with caution, and we cannot discard co-founding factors which would explain the differences results among the P2Y12 inhibitors.

The rapid onset of action and faster inhibition of residual platelet reactivity of prasugrel might explain the findings in favour of prasugrel observed only in patients with STEMI. In fact, inhibition of platelet reactivity in patients with STEMI appears to be different from those found in healthy volunteers or patients with stable angina. However, the only RCT available in patients with STEMI comparing both drugs didn't find any advantage either in-hospital or at 30 days, although, small sample size of this study didn't allow any major conclusion.

Finally, with long-term DAPT treatment, either clopidogrel, prasugrel or ticagrelor, a number of side effects were reported, such as high risk of bleeding, dyspnea, arrhythmias included more incidence of cancer and non-cardiac death. Thus, some of these side effects are a cause of concern and so, a shorter exposure to DAPT should be preferred.

CONCLUSIONS

1. Both prasugrel and ticagrelor provide a significant reduction of adverse events compared to clopidogrel in patients with ACS, with a significant increase of bleeding risk.

2. In patients with STEMI undergoing PCI, indirect data from multicentre registries and meta-analysis, prasugrel and ticagrelor show that both are superior to clopidogrel in reducing cardiac adverse events, however, prasugrel was also more effective in reduced MACE, overall mortality and cardiovascular death at 1-month and one year compared to ticagrelor. This data in favour to prasugrel is consistently significant throughout all observational studies and meta-analysis. However, in the absence of large RCT with a direct comparison between prasugrel and ticagrelor it would be now difficult and inappropriate to draw a definitive statement in this regard.

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