Challenges in Oral Antiplatelet Therapy
OASIS-7) trial,6 a comparison of different clopidogrel loading doses
in patients with ACS or STEMI managed with an early invasive strategy, was a negative study because the primary end-point (a composite of death/MI/stroke at 30 days) was negative. A subgroup analysis suggested that in PCI, 60mg loading doses are better than 300mg, but this is not too concrete as the evidence is based on a sub-analysis of a study (i.e. CURRENT-OASIS 7) that is primarily negative. Nevertheless, this finding matches current practice. In the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel Thrombolysis In Myocardial Infarction (TRITON-TIMI 38),7
prasugrel,
mostly given at the time of the intervention, was more effective than clopidogrel given at the time of intervention (in moderate- to high- risk ACS patients undergoing scheduled PCI). This reflects the faster onset of action as well as the stronger effect of prasugrel compared with clopidogrel.
Prasugrel has demonstrated more rapid onset with increased potency over clopidogrel. Are there any concerns about an increased risk of bleeding with prasugrel, as shown in the TRITON-TIMI 38 study?
Well, in the entire cohort of TRITON-TIMI 38, the risk of major bleeding was increased with prasugrel, but the balance of safety and efficacy was very much in favour of prasugrel, with 23 (mostly large) infarctions prevented for six bleeds induced per 1,000 patients treated. However, the bleeding risk with prasugrel has meant that there is a clear-cut contraindication for prasugrel in patients with previous stroke or transient ischaemic attack (TIA). Also,
in
TRITON-TIMI 38 there was no benefit of prasugrel in the elderly patients and in patients with a low bodyweight. Even though there are no clinical study data to support this, it has been suggested that the maintenance dose of prasugrel should be reduced in the elderly and those with a low bodyweight.
What about patients with diabetes who are predisposed to a prothrombotic risk? What approaches would a cardiologist generally take given the findings of TRITION-TIMI 38?
In TRITON-TIMI 38, the benefit of prasugrel in the population with diabetes was particularly large, and larger than that seen in those without diabetes. Also, there were no significant differences in the bleeding complications between prasugrel and clopidogrel in the diabetic populations, but this was not due to the fact that the bleeding rate with prasugrel was lower; rather, the bleeding rate with clopidogrel was higher in the diabetic population than in the non-diabetic population.
For the treatment of UA/NSTEMI, what do the guidelines actually recommend right now with respect to antiplatelet therapies?
The guidelines are all outdated because they do not cover the newer studies. For example, the European Society of Cardiology (ESC) guidelines8
are from 2007 so they do not cover the more recent
data. They recommend aspirin and clopidogrel and also give a statement on the use of GPIIb/IIIa inhibitors. They leave it more or less to the judgement of the doctor to weigh the risk and benefit depending on bleeding complications and severity of ACS. I think that given the current controversy on anti-GPIIb/IIIa, this is a very reasonable statement. Of course, the newer guidelines would include more recent drugs such as prasugrel and ticagrelor,
EUROPEAN CARDIOLOGY
which are more efficacious clinically.
effective pharmacodynamically and more
What are the remaining undetermined variables regarding the treatment of unstable angina/ ST-segment elevation?
We need to define the optimal level of platelet inhibition during PCI in the early phase of the disease after PCI and then for secondary prevention – that is one factor. The second factor is that we need to redefine the role of GPIIb/IIIa inhibitors in an era of very
efficient P2Y12 receptor inhibition with either thienopyridines or the newer reversible P2Y12 receptor blockers (e.g. prasugrel or ticagrelor).
What do the results of PLATO suggest regarding antiplatelet therapy and unstable angina patients or those more at risk of bleeding?
The Study of Platelet Inhibition and Patient Outcomes (PLATO)9 demonstrated the efficacy of ticagrelor compared with clopidogrel (in patients with NSTEMI ACS or with either STEMI with scheduled primary PCI) with respect to death, MI and stroke. In other words, ticagrelor was superior to clopidogrel in preventing these complications in the mixed population of acute ACS and acute MI, and this benefit was due to a significant reduction in MI and cardiac and all-cause death.
Non-CABG bleeding was increased by ticagrelor compared with clopidogrel, and this is not surprising. However, as a difference from prasugrel, the bleeding complications during CABG were not higher on ticagrelor than on clopidogrel. This is probably due to the reversibility of ticagrelor, which in this setting is an advantage compared with clopidogrel, which is irreversible. Thus, in the PLATO study there was no difference in the combined bleeding end-point of CABG bleeding and non-CABG bleeding with ticagrelor compared with clopidogrel.
What are the current views regarding dual antiplatelet therapy for primary PCI, and PCI in ACS?
Currently, among the newer P2Y12 receptor blockers, only prasugrel is approved in many countries and, where it is approved, it is preferable to clopidogrel for the large majority of patients except for the few patients with absolute or relative contraindications. Of course, aspirin continues to be the mainstay of antiplatelet therapy.
What about long-term usage following stent implantation?
For elective stent implantation we have no sound evidence that you need to administer clopidogrel for more than six months. Most of the studies10,11
have demonstrated only an early benefit for the first
six months. Now as far as the ACS are concerned, we see benefit with the longer-term (nine- to 15-month) administration of both prasugrel12
and ticagrelor,9 and this would suggest that a more
efficacious antiplatelet therapy for longer-term therapy is needed in this setting.
Finally, are there any other areas of research that you would like to see focused on in future?
Yes, as I said, I would like to see the exact definition of the optimal level of platelet inhibition in the various ACS and also at various stages of the disease. n
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