Platelet response in practice: Applying new insights and tools for testing and treatment
ARE GUIDELINES DESTINED TO BECOME EVER MORE COMPLEX?
Dr. Bhatt: Here’s a comment and question from the audience that pulls together a lot of what we’ve discussed while also looking forward: The antiplatelet therapy guidelines are already complicated. If the ongoing studies of emerging antiplatelet drugs all have results that are qualitatively similar to those of the TRITON-TIMI 38 study of prasugrel—ie, better efficacy with more potent therapy but more bleeding—how do you foresee these antiplatelet drugs being used in clinical practice?
Dr. Sabatine: The contrast between the US guidelines and the European guidelines for ACS management is stark. The US guidelines—from the ACC and AHA1—are essentially an encyclopedia that includes nearly every trial of anti-platelet therapy in ACS along with complicated algorithms; they do a wonderful job of being complete. The European guidelines14 are probably one tenth the size of their US counterpart document, and they suggest treatments for various patient types; they are very simple.
In a sense, the US guidelines lay out the data and force practitioners to evaluate the trials and consider how our patients fit into the study populations. In this way they are analogous to current guidelines for anticoagulant therapy. Several anticoagulants have been compared with heparin in clinical trials. These newer anticoagulants appear to reduce the risk of ischemic events compared with heparin; some have lower rates of bleeding, while others have higher rates of bleeding. There have been few head-to-head studies of these agents, however, so we wind up with guidelines that are not definitive but rather suggest agents to “consider” in various settings.
It’s unlikely that a head-to-head trial will be conducted comparing prasugrel with the reversible P2Y12 antagonist AZD6140, assuming that both are approved for marketing. If the drugs appear equally efficacious in placebo-controlled trials, it will take consensus to determine the appropriate choice at your hospital, factoring in your patient profile, the cost of the drugs, and other variables. It’s more complicated when one agent is slightly more efficacious but causes more bleeding or, conversely, a little less efficacious but less apt to cause bleeding. In such cases, you may need to tailor therapy to the patient, trying to gauge bleeding risk. All of the emerging data appear to point to the importance of bleeding on outcomes: patients who bleed fare poorly, in part due to the bleeding itself and in part perhaps because they have a proclivity for bleeding.
THE FUTURE: MONITORING-BASED DOSING AND NICHE ANTIPLATELETS?
Dr. Bhatt: That’s a good observation. Let’s wrap up by having the other panelists share any final thoughts you may have.
Dr. Alexander: I’d like to return to the issue of measuring antiplatelet response and using it to guide therapy. Earlier we cited the examples of antihypertensive therapy and lipid-lowering therapy to support this model of monitoring-based treatment. Guidelines for dyslipidemia treatment recommend using LDL-C levels to guide therapy, but this practice is difficult to study in a randomized trial. In fact, none of the randomized trials of statins used LDL-C levels to guide therapy. They all studied fixed doses of statins versus placebo or fixed doses of another statin. Higher doses of statins were always beneficial compared with lower doses, and this finding was extrapolated into the guidelines as a justification to treat to target LDL-C levels.
Dr. Bhatt: It’s not even necessarily clear that LDL-C level is the best target, if you consider the JUPITER trial, in which patients received statin therapy based on their baseline level of high-sensitivity C-reactive protein, not their LDL-C level.15 It goes to show how incomplete our knowledge of a class of drugs may be, even decades after the drugs are introduced.
Dr. Kottke-Marchant: To speak to Dr. Alexander’s point, dose adjustment guided by platelet monitoring is a bit more problematic for antiplatelet drugs that are irreversible inhibitors, such as clopidogrel and aspirin, than for those that are reversible inhibitors, which are being developed and may eventually make more sense to use. From a drug development standpoint, a drug that requires monitoring and dose adjustment will not gain wide acceptance because it will increase medical costs and morbidity.
Dr. Bhatt: Yes, we know from experience with warfarin that doctors and patients don’t like the ongoing need for monitoring and testing.
Dr. Peacock: The drugs that are going to be adopted by the emergency department are those with the shortest half-lives, for several reasons: (1) using a drug with a short half-life won’t commit us to a particular course of action; (2) the potential for drug interactions is lower; and (3) in the event of an erroneous diagnosis, the consequence of misapplication may be mitigated by early recognition and termination of the drug. If we later decide that we’ve gone down the wrong therapeutic road or reached a wrong diagnosis, or if a complication occurs, we can turn off the therapy quickly. That level of flexibility is needed.
Dr. Kottke-Marchant: I think we are moving into an era of niche antiplatelet drugs. One might be used in a patient going to surgery, for example, and another for long-term therapy.
Dr. Peacock: One thing that I don’t have a feel for is how to transition from one drug to another. When you change drugs for a patient, it so often seems like it goes badly. If we’re eventually going to use drugs with ultra-short half-lives in the in the emergency department for the first day or two, and then switch patients to a pill for a week, a lot more platelet function testing may be needed.
