A conversation between two interventionalists:

Subhash Banerjee, MD (VA North Texas and UT Southwestern Medical Center)
& Sunil V. Rao, MD (Durham VA and Duke University Medical Center)

S. Banerjee. With two new ADP receptor antagonists, Prasugrel and Ticagrelor proven better than Clopidogrel is it time for their widespread adoption in patients undergoing PCI? Well, given the history of being ahead of the curve, the interventional community probably has already identified scenarios or strategies to incorporate these agents into practice. Just as a factual reminder, Prasugrel is now available in U.S. and Ticagrelor is expected to be approved for use in U.S by the fourth quarter of 2010. Thus, most of the content of this discussion would be on Clopidogrel and Prasugrel. To provide a framework to this discussion, let me propose 3 scenarios: STEMI, NSTEMI and elective PCI with DES. The relative benefits, bleeding risk, optimal duration and cost are up for consideration.
Just to recap what is already known, these novel agents have come into existence primarily to address three important limitations of Clopidogrel (a pro-drug requiring a multi-step activation by hepatic cytochrome –P450): a long lag (4-5 days) to maximal platelet P2Y12 receptor inhibition with 75 mg daily maintenance dose (often can be shortened to no less than 8–12 hours with 300–600 mg of Clopidogrel load), unpredictable inter-individual variability and irreversibility of its pharmacodynamic effects on platelet function. Moreover, the strategy of testing for platelet inhibition to guide Clopidogrel dosing may still leave an unacceptably large (10%) number of patients without optimal inhibition despite a 2400 mg loading dose!

S.V. Rao. That’s right Subhash. We have a lot experience with Clopidogrel, but there certainly appear to be patients who are hypo-responders to it and perhaps there are patients who are hyper-responders. One thing I hope we can discuss is the disconnect between the studies showing higher residual platelet aggregation with Clopidogrel in some patients and the clinical events that patients experience.

S. Banerjee. The third generation ADP receptor blocker, Prasugrel is significantly less dependent on hepatic activation and reaches maximal plasma concentration in approximately 30 min after a 60 mg loading dose and has a much greater mean P2Y12 inhibition compared to Clopidogrel. This pharmacokinetic/dynamic benefit translates into clinical benefit, demonstrated by the TRITON TIMI 38 trial. Though, in my opinion the trial favored Prasugrel from the get go with a 300 mg clopidogrel load, predominantly given just before PCI. This may have played an important role in the early benefit seen in the TRITON TIMI 38 trial with Prasugrel over Clopidogrel with respect to stent thrombosis and overall MACE. Ticagrelor, in the PLATO trial, is deprived of this rapid initial gain when compared a to a much more realistic strategy of a 600 mg Clopidogrel load given > 2 hours prior to PCI in a majority of patients. As well known to most, long term bleeding risk was elevated with Prasugrel, especially for those >75 years, <60 kg and with prior history of stroke/TIA. Interestingly, the risk of bleeding in diabetics despite a clear benefit of Prasugrel was unexpectedly elevated on Clopidogrel, compared to non-diabetics. This risk remained unaltered on Prasugrel.The benefit and risk balance was best demonstrated for STEMI, diabetics and for those with coronary stent implants. Thus, would these facts indicate towards a universal adoption of Prasugrel and Ticagrelor (when available) for all patients presenting with STEMI treated with primary angioplasty?

S.V. Rao. I think it’s complicated. The problem with looking at these subgroups is the lack of statistical power. Trials are never powered for safety, bleeding in this case, so if we find no difference in bleeding is that real or is it because we’re looking at a subgroup? The other monkey wrench is the availability of the CURRENT OASIS 7 data, which shows that a combination of 325 mg of aspirin and 600 mg of clopidogrel followed by 150 mg daily for 7 days is superior to conventional dosing. So we actually have three choices to discuss, although only two are commercially available: prasugrel, ticagrelor, and high dose clopidogrel. I think it’s going to be very difficult to argue against ticagrelor since the PLATO trial showed a mortality benefit of ticagrelor over clopidogrel. The issues may be the twice daily dosing, which could affect adherence, and the dyspnea that patients experienced due to the adenosine-like effects. So to address your question, until we have ticagrelor available, centers will have to choose between 600 mg of clopidogrel, which is a familiar strategy, and prasugrel, which clearly has benefit. The more complex decisions come later, when one has to determine long-term therapy.

S. Banerjee. During STEMI, the pharmacokinetic advantage of Prasugrel can be best realized given the urgency and inability to load patients with Clopidogrel much in advance. For NSTEMI, pre-PCI Clopidogrel load may be much more reliably achieved; however the need for urgent, in-patient CABG in 15% of patients may make Ticagrelor a much prudent choice in the future. Are you in agreement?

S.V. Rao. I agree that in the setting of possible CABG, a reversible agent like Ticagrelor is probably the way to go. In fact, in the PLATO trial, the bleeding benefit of Ticagrelor was seen only in the patients undergoing CABG. After all, a reversible agent is helpful when it needs to be reversed! In the patients not undergoing CABG, there was more bleeding with Ticagrelor. This is what we would expect given its greater platelet inhibition. We just don’t know enough about Prasugrel in the setting of CABG since the TRITON trial was predominantly a PCI trial. So in the NSTEMI setting, I still think that clopidogrel is the best strategy. Once Ticagrelor is available, we’ll need to re-evaluate.

S. Banerjee. For elective PCI, we in U.S are in effect talking about Clopidogrel, Prasugrel or Ticagrelor load for patients scheduled for diagnostic catheterization, given the ubiquitous practice of ad hoc PCI. Well, if most of us do not adopt this approach and still perform ad hoc PCI, the only alternative is to rapidly load a patient with a third generation anti-platelet agent. This strategy seems even more attractive and cost-effective in the era of dwindling use of GP IIb/IIIa agents.

S.V. Rao. This is an area where we have very little data. I hesitate to extend the findings of either the TRITON or PLATO trial to the elective PCI population until we have more data. Especially with Prasugrel, where there are clear risks like fatal bleeding, and clear contraindications on the label, I think we have to be very careful. You’re correct that the use of IIb/IIIa inhibitors is rapidly decreasing in the elective PCI setting. From the available registry data, it appears that loading on the table with Clopidogrel doesn’t translate into an excessive risk of acute stent thrombosis in the elective PCI patient. So I think that is still the preferred approach. I would like to see trials of prasugrel and ticagrelor in the elective PCI setting before I would adopt that strategy. We may get some information from the TRILOGY trial that is looking at chronic medical therapy with prasugrel. My guess is that a fair proportion of those patients will end up getting elective PCI at some point during the study.

To conclude, it might be worth for each one of us to answer the following questions:
1.Should all STEMI and/or high-risk ACS patients be treated exclusively with Prasugrel over Clopidogrel?
a. Yes
b. No – I would say no

2.Do you believe that given the demonstrable benefit of Prasugrel over Clopidogrel, its use for ACS patients undergoing PCI is overall a cost-effective strategy?
a. Yes
b. No – I would say no. In clinical practice, we are going to see more high risk patients (high risk for bleeding that is) than were seen in the TRITON trial

3.Does the use of Prasugrel for ad hoc elective PCI hold promise?
a. Yes – perhaps, but it needs to be tested.
b. No
However, if you are far ahead of the curve and contemplating switching agents to maximize upfront benefit and minimize long-term hemorrhagic risks, stay tuned for our next piece.