Platelet response in practice: Applying new insights and tools for testing and treatment
WHAT ROLE FOR GENOTYPING IN GUIDING ANTIPLATELET THERAPY?
Dr. Bhatt: Dr. Peacock alluded to a potential role for genetic testing. Dr. Sabatine, you have done a lot of interesting work with genotyping in the TRITON-TIMI 38 study of prasugrel and clopidogrel. What is the future role of genotyping in determining which antiplatelet therapy is best for which patient?
Dr. Sabatine: As I mentioned, cytochrome P450 enzymes play a critical role in the metabolism of clopidogrel. These enzymes are fairly polymorphic—mutations in their encoding genes are responsible for subtle changes in effect, unlike the traditional mutations that we think about for sickle cell disease, for example. A wealth of data has been published showing that genetic variants are associated with decreased functional activity of cytochrome P450 enzymes, demonstrating the pharmacologic importance of these variants.
Individuals who carry variant alleles appear to respond differently to clopidogrel. A variety of small studies show that those who carry specific variants—particularly in the CYP2C19 enzyme, but in other enzymes as well—appear to have a diminished response to clopidogrel. There are also data showing that individuals with a diminished response to clopidogrel have worse outcomes.4 Our group is studying the impact of genetic variants that decrease the functional activity of cytochrome P450 enzymes on clinical outcomes. (Editor’s note: This study has since been published by Mega et al.5)
The practical implication may lie in point-of-care genotyping, which appears possible and will be clinically useful if a strong link can be demonstrated between genotype and outcomes. If point-of-care genotyping becomes practical, it will raise the question of whether both genotyping and platelet aggregation testing are needed. I think they might indeed be complementary in risk prediction, as is the case with genetic variants that affect low-density lipoprotein cholesterol (LDL-C) levels. In the lipid arena, we have seen that genetic effects and lipid levels provide independent incremental information about risk. That’s because of the high degree of variation in LDL-C levels: an LDL-C measurement is a snapshot in time, yet a variety of factors can influence LDL-C levels. In contrast, genotype is an invariant factor. Similarly, in the platelet arena, platelet aggregation studies and genotyping may be synergistic in predicting an individual’s predisposition to events and response to medications.
Dr. Bhatt: While we’re discussing pathways of metabolism, the literature, though scant, suggests a potential interaction between proton pump inhibitors and clopidogrel. I was co-chair of a recent American College of Cardiology/ American Heart Association/American College of Gastro-enterology consensus document that endorsed liberal use of proton pump inhibitors in patients who are at gastrointestinal risk, including those on antiplatelet therapy.6 The gastroenterologists believed strongly that proton pump inhibitors were safe and in fact underused in these patients. What do you think about the clopidogrel–proton pump inhibitor interaction? Should we be concerned?
Dr. Sabatine: Proton pump inhibitors are not only substrates for, but also inhibitors of, CYP2C19, a key enzyme that helps transform clopidogrel into an active metabolite. For this reason, there has been interest in whether concomitant use of proton pump inhibitors would blunt the efficacy of clopidogrel. The same concern was raised about giving clopidogrel with certain statin drugs that are also metabolized by the cytochrome P450 system, and several studies have shown an effect of these statins on clopidogrel’s platelet inhibition. However, there is no evidence that coadministration of these statins has affected clinical outcomes with clopidogrel in clinical trials. So it may be that while competition for the cytochrome P450 system is one factor, it’s not enough of a factor to tip the scale and result in a clinical event. The same may be true of coadministration of proton pump inhibitors; meanwhile, we await definitive data that concomitant use with clopidogrel leads to higher rates of ischemic events.
DIAGNOSTIC UNCERTAINTY IN THE EMERGENCY SETTING
Dr. Bhatt: We heard about quite a few new antiplatelet drugs in Dr. Sabatine’s presentation, some of which will likely be taken up in clinical practice. Dr. Peacock, from an emergency department perspective, how will you integrate all these new agents with the numerous therapies already available? What should emergency departments do to come to grips with and ultimately take advantage of these different forms of therapy as well as emerging platelet function tests?
Dr. Peacock: The piece that’s unique or especially pertinent to the emergency department is diagnostic uncertainty. Diagnosis and management are easy when a patient has an ST-elevation MI because we all know what that looks like and we know what to do in response. To some extent non-ST-elevation MI is fairly simple too. ACS is a lot more difficult because we don’t have a good definition for unstable angina, and that’s where diagnosis and management become problematic. And with high-sensitivity troponins coming out now, the question of non-ST-elevation MI is going to get more and more confusing because we will have a lot more patients who meet criteria without having an acute coronary artery event.
So it is going to be important that studies be designed correctly. A lot of the studies reviewed today were efficacy studies, showing that a particular drug works well in a carefully defined population, but they were not efficiency studies: they did not take into account the real-world diagnostic uncertainty—and inevitable misdiagnoses—that emergency departments encounter before starting therapy.
Take the CURE trial, for example. It was a great study, showing that clopidogrel reduced the hazard ratio for major coronary events by 20% in patients with unstable angina,7 and the message was that everybody should be using clopidogrel. A close look at the study, however, reveals that about half the patients did not receive clopidogrel in the emergency department. When patients did receive it early, it was driven by the cardiologist, who was absolutely certain of the diagnosis. But if the study was not designed to test early use, then it is a big leap to extrapolate its findings to this circumstance.
Many of the patients in the CURE trial were enrolled the day after presentation, when their diagnosis was certain—ie, they had a rise in troponin after their symptoms. But when a patient first arrives in the emergency department, we are not certain of the diagnosis. And if we use a drug such as clopidogrel, with a duration of action as long as 5 days, we have committed the entire medical system to a certain course of management for that period of time. If we get the diagnosis wrong, this commitment could restrict management options for up to 5 days.
The question for emergency physicians becomes, “How long is long enough to know whether I can pull the trigger on a therapy and be correct?” With all the new drugs coming along, the way to answer this is to do efficiency studies in a real-world environment in addition to efficacy studies.
Dr. Alexander: Yes, one of the biggest limitations of antiplatelet drug studies to date is that they usually haven’t really addressed the timing of drug initiation. We often assume that if a drug is shown to be beneficial, then it should be started as soon as possible. As we just heard, that may have been an unfounded extrapolation from the CURE trial. The same sort of thing happened with the ISIS trial of aspirin in patients with ST-elevation MI.8 In response to the ISIS results, clinicians rushed to give patients aspirin right away even though many of the patients in the trial may have received their aspirin the day after presentation. For these reasons, the EARLY-ACS study,9 which is addressing a very simple question—whether early upstream use of glycoprotein IIb/IIIa inhibitors is beneficial—has been a challenging trial to complete.
