Platelet response in practice: Applying new insights and tools for testing and treatment
PRASUGREL IN PRACTICE: HOW LOW CAN THE DOSE GO, AND IS THERE A GENDER EFFECT?
Dr. Bhatt: Let’s stick with this focus on dosing but turn back to discussion of prasugrel. In your presentation of the TRITON-TIMI 38 data, Dr. Sabatine, you proposed a potential prasugrel dosage modification, down to a 5-mg loading dose, in subgroups that were identified as being at high bleeding risk—namely, elderly patients and patients with low body weight. However, no outcomes data with 5 mg of prasugrel came out of TRITON-TIMI 38.10 Is this proposed modification based on pharmacokinetic extrapolation? Could clinicians be comfortable using 5 mg of prasugrel, assuming the drug receives regulatory approval and a 5-mg tablet would be available?
Dr. Sabatine: Of course, evidence at the grade A level would consist of a trial showing that patients who received a lower dose enjoyed the same benefit as those who got standard dosing in TRITON-TIMI 38—a 60-mg loading dose followed by 10 mg/day—with an acceptable risk profile. However, such a trial would be difficult and costly to conduct, and would take roughly half a decade to pull off. It is only through large trials like TRITON-TIMI 38 that you identify subgroups that respond differently, and then to go back and do a separate trial for those subgroups takes a great deal of time. It may not be practical.
I think the Food and Drug Administration is moving toward embracing careful pharmacokinetic/pharmacodynamic substudies within trials, with these substudies having adequate numbers of subjects to provide a sense for the ideal target dose and what an acceptable dose range would be, without limiting approval to a single dose. The analogy would be warfarin dosing, with the aim being to figure out an acceptable dose range, discover which patients fall outside that range, and then model the effect of a lower dose in those patients. Thus, approving a 5-mg dose of prasugrel based on TRITON-TIMI 38 would be a reasonable approach if this dose passed muster under pharmacokinetic/pharmacodynamic modeling. If this approach were taken, there would clearly be a need for postmarketing surveillance to confirm whether the modeling on the effects of the lower dose was borne out by actual outcomes.
Dr. Bhatt: The audience has posed another interesting question raised by TRITON-TIMI 38: Can you comment on the lesser effect of prasugrel in women?
Dr. Sabatine: It is true that there was not a statistically significant effect of prasugrel among women in TRITON-TIMI 38, but statistical tests among subgroups found no significant heterogeneity for the effect between men and women, and that is the relevant measure to determine any gender effect. Keep in mind that not all subgroups represent a univariate slice of the population. For example, women generally have lower body weight than men, and since prasugrel’s net clinical benefit was reduced in patients with lower body weight, that may explain some of the differing extent of effect between men and women.
Dr. Bhatt: That’s a good point about the lack of heterogeneity between men and women. In fact, a meta-analysis of clopidogrel data conducted by one of the fellows I work with revealed that men and women appear to benefit similarly from clopidogrel.12 There was a slight signal of excess bleeding in women, but there were more elderly women in the pooled population, which may have been a confounding factor. As best as anyone can tell, antiplate-let therapy works well in both men and women.
NAVIGATING MANAGEMENT ACROSS THE SPECTRUM OF CARE
Dr. Bhatt: I would like to explore a bit further how all of these issues translate across the spectrum of care, beginning in the emergency department, which we know is a key component of the entire ACS management strategy for a health care system. What should emergency medicine doctors do, given all of the potential options—clopidogrel, different loading doses of clopidogrel, prasugrel, glycoprotein IIb/IIIa inhibitors, even bivalirudin?
Dr. Peacock: It depends on the practice setting. Some emergency physicians work at community hospitals with no backup. They must have relationships with the larger centers to which they’ll be transferring patients, because ACS patients should not be staying at community hospitals. These emergency physicians must have close relationships with the physicians who will be receiving their patients, and they know the potential head-butting with surgeons surrounding early clopidogrel use better than anybody does. If they treat with clopidogrel in the emergency room, and it turns out that the patient needs to go to the catheterization laboratory, can the receiving hospital use platelet testing to shorten the standard 5-day interval from treatment to catheterization?
Dr. Bhatt: Yes, that’s a rather useful, although not completely validated, way of using point-of-care platelet testing—to potentially reduce the time to surgery.
Dr. Peacock: Right. So if the policies for handling these types of transfer-related issues are worked out in advance, all players have a pathway to follow, which can allow quick action when necessary. If you don’t have these issues worked out in advance, you either lose many opportunities to act quickly in the emergency room or you risk taking actions that will cause problems later in the course of management.
Dr. Alexander: I totally agree. The key is to sit down with all the players involved—the surgeons, the interventional cardiologists, the intensivists, the emergency room personnel—and come up with strategies for different populations of patients. Write down the collective strategy and hang it on the wall so that everybody can be comfortable with it. The strategy can be reevaluated when prasugrel or other new antithrombotic drugs come on the market.
Dr. Peacock: The other environment is the academic center, which is even more challenging, but for different reasons. At a large academic center like the Cleveland Clinic, any of 25 different cardiologists may be taking call and receiving patients from the emergency department on a particular night. A lot of phone interaction is required to elicit the planned management strategy, including if and when the patient will be going to the cath lab. Individualizing care to a particular cardiologist then becomes a time-consuming challenge, especially in clinical situations where outcomes are time-dependent.
Dr. Alexander: Agreed. Management needs to be integrated across the entire spectrum of care. The anticoagulants that we plan to use in the cath lab will affect the antithrombotic regimen used upstream.
Dr. Kottke-Marchant: One circumstance where platelet function testing has been helpful is in determining the washout of the clopidogrel effect before surgery. At Cleveland Clinic, we have implemented platelet function testing in this circumstance instead of waiting a blanket 5 days after clopidogrel administration to go to surgery. A return to normal platelet function on platelet aggregation testing, depending on the cutoff value used, is an indicator that the patient can proceed to surgery.
Dr. Bhatt: That’s a logical approach. How should we be using antiplatelet therapy in the medically managed patient, Dr. Alexander?
Dr. Alexander: When I think of medical management, I include patients who don’t go to the cath lab, but also those who do, with regards to their management prior to and following their time in the cath lab.
In patients who don’t go to the cath lab for angiography, the ACC/AHA guidelines recommend aspirin and either clopidogrel, a glycoprotein IIb/IIIa inhibitor, or both.1 In making this choice, I consider the patient’s risk of bleeding and the dosing complexity of the regimen, especially with the use of glycoprotein IIb/IIIa inhibitors in a patient with renal insufficiency. In a patient at relatively low risk for bleeding, I often use both clopidogrel and a glycoprotein IIb/IIIa inhibitor, although this strategy does not have a lot of data to support it.
The more challenging population consists of patients who go to the cath lab but do not undergo PCI; this population is managed medically too. We often drop the ball with clopidogrel in this population. Many patients in whom PCI is not performed do not receive clopidogrel upstream, for all of the reasons we’ve discussed, and there is pretty good evidence that if clopidogrel is not instituted before hospital discharge, the patient is not likely to be receiving it at 30 days either. We have an obligation to treat these patients.
Treatment following bypass surgery is much murkier, and I don’t really know what we should be doing. The ACC/AHA guidelines suggest that clopidogrel be started in a patient with non-ST-elevation ACS after bypass surgery,1 but I believe the evidence to support that recommendation is pretty weak.
Dr. Bhatt: Well, the CURE trial did contain a sizeable group that underwent bypass surgery,7 and although this group was underpowered in some respects, it was still a very large group, so I personally favor treatment in those patients. We should mention that an ongoing trial called TRILOGY ACS is comparing clopidogrel and prasugrel specifically in patients who are being managed medically,13 so more data on this strategy will be emerging.
