Acute coronary syndromes (ACS) have been associated with the occurrence of cardiovascular (CV) events. Moderate- to high-risk ACS are generally managed by an early invasive approach, where coronary angiography is followed by percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). However, ACS and the use of PCI or CABG are associated with a high risk of thrombotic complications. To reduce this risk, patients with ACS or those undergoing PCI may be treated with anticoagulants and/or antiplatelets. The efficacy of oral antiplatelets agents such as aspirin and clopidogrel (an irreversible P2Y12 receptor antagonist) in terms of reducing the risk of CV events is well established.1,2 Cardiologists generally consider dual therapy with aspirin plus clopidogrel as a gold standard treatment in patients with unstable angina (UA)/non-ST-segment-elevation myocardial infarction (NSTEMI) ACS, those with STEMI ACS and those undergoing PCI. Nevertheless, there is still a need to further reduce the risk of CV events than is offered by the above-mentioned therapies and to optimise the safety and efficacy profile of antiplatelet therapies. An interview was carried out with Professor Franz-Josef Neumann to gain a better understanding of the unmet needs and current challenges still faced with oral antiplatelet therapies in ACS in light of the results of recent major clinical trials.
Interviewer: For patients with acute coronary syndromes undergoing percutaneous coronary intervention, what is the role of oral antiplatelet therapy?
Professor Neumann: The role of oral antiplatelet therapy in these patients is to reduce the risk of peri-interventional and long-term cardiac complications, which can include death and MI.
Are there any special considerations depending on the type of acute coronary syndrome, such as ST-segment elevation or non-ST-segment elevation?
In general, oral antiplatelets are efficacious independent of the type of ACS. However, there is inconsistent evidence for the efficacy of the glycoprotein (GP) IIb/IIIa inhibitors depending on the type of ACS. For non-MI ACS, there is not a lot of evidence to show the efficacy of glycoprotein (GP) IIb/IIIa inhibitors, while there is some evidence in favour of GPIIb/IIIa inhibitors in NSTEMI ACS. Lastly, there is conflicting evidence in STEMI ACS, with older studies showing benefit in terms of prevention of MI and of death, but newer studies not demonstrating any such benefit.
Could you please quickly run through the benefits associated with the use of antiplatelets, including aspirin and clopidogrel? What are the unmet needs and challenges faced with the use of these agents?
The benefits of antiplatelets are to reduce major cardiac complications including death and large MI. A current unmet need is to find the optimal balance between the prevention of thrombotic events and the induction of bleeding events, and I think that the challenge is to define the optimal level of platelet inhibition that is needed in the various ACS and also at various stages of the disease.
Cardiologists want a rapid onset of action with oral antiplatelets when treating STEMI. What do studies such as ALBION and PRINCIPLE-TIMI 44 demonstrate in terms of dosage, efficacy and/or onset of action of the current gold standard, clopidogrel, in this acute setting?
The onset of action has been investigated by the Platelet Activation and Aggregation-Thrombolysis in Myocardial Infarction 443 (PRINCIPLE-TIMI 44) study, and the results showed a faster onset of action with prasugrel (an irreversible P2Y12 receptor antagonist) compared with clopidogrel and also a stronger and more consistent effect of the loading dose. The Assessment of the Best Loading Dose of clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis (ALBION 4) study tended to suggest that a 900mg loading dose of clopidogrel is somewhat more effective than 600mg (in NSTEMI patients undergoing PCI), but most of the comparisons between 600 and 900mg clopidogrel in ALBION were statistically insignificant. There are also data from a study by von Beckerath,5 which showed no major difference between 600 and 900mg loading doses of clopidogrel in terms of platelet inhibition as well as the formation of active metabolite. Therefore, the reach of increasing the dose of clopidogrel is limited and the reason is probably that clopidogrel itself and also some of its metabolites inhibit cytochromes that are needed for the formation of active metabolite.
Considering the results of recent studies such as CURRENT-OASIS 7 and TRITON-TIMI 38, what conclusions can be drawn regarding the dosing and timing of antiplatelet/anticoagulant treatment among ACS or STEMI patients?
The Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events/Optimal Antiplatelet Strategy for Interventions (CURRENT 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, which are more effective pharmacodynamically and more efficacious clinically.
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.