Author + information
- David P. Faxon, MD∗ ()
- ↵∗Address for correspondence:
Dr. David P. Faxon, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02108.
Prolonged dual antiplatelet therapy after stent placement is the standard of care for all patients due to a significant reduction in major cardiovascular events largely due to prevention of early and late stent thrombosis. The combination of the P2Y12 platelet inhibitor clopidogrel and aspirin has been the preferred therapy. However, it has been recognized that 10% to 40% of patients have resistance to clopidogrel, which results in an inadequate reduction in platelet aggregation (high on treatment platelet reactivity [HPR]) and results in significant increase in major adverse cardiac events following percutaneous coronary intervention (PCI) (1). A number of genetic polymorphisms of cytochrome 450 enzyme system, a key modulator of the conversion of the clopidogrel pro-drug into the active compound have been identified. In particular CYP2C19∗2 loss-of-function (LOF) allele is associated with slow metabolism of clopidogrel whereas CYP2C19∗1/∗1 or CYP2C19∗17 are gain-of-function alleles associated with more rapid metabolism. Other polymorphisms such as the membrane transporter ABCB1 have been shown to alter clopidogrel metabolism as well. Unlike clopidogrel, the newer P2Y12 inhibitors, prasugrel and ticagrelor, do not have this limitation. Prasugrel is more potent than clopidogrel, is absorbed faster, and is metabolized into the active metabolite primarily by the P450 enzymes CYP3A4 and 2B6. Ticagrelor is an adenosine triphosphate analog that is not a pro-drug and binds reversibly to the P2Y12 receptor. They both have been shown in large randomized trials to reduce major adverse events to a greater extent than clopidogrel does, although at the expense of more bleeding. Both the American Heart Association and European Society of Cardiology guidelines recommend ticagrelor and prasugrel as preferred agents in patients with acute coronary syndromes (ACSs), whereas clopidogrel is recommended in patients with stable angina and those requiring oral anticoagulation (Class I, Level of Evidence: B). The limitation of prasugrel and ticagrelor is that they are more expensive and both increase bleeding risk, which is an independent risk for adverse outcomes.
Tailored therapy using prasugrel or ticagrelor in patients with HPR on clopidogrel and clopidogrel in those without HPR might be a way to maximize effectiveness and safety. Platelet testing has not been common practice because it takes at least 24 h to reach a steady state and this exposes the patient to risk because the greatest risk of thrombotic complications is early after PCI. Genetic testing is an attractive alternative because it could be done prior to initiating therapy. This has not been feasible in the past due to a prolonged assay time and the lack of availability of testing. Recently a rapid bedside genetic test (Spartan RX; Spartan Bioscience Inc., Ottawa, Ontario, Canada) for CYP2C19∗1, ∗2, ∗3, and ∗17 has been developed that allows determination of CY2C19 LOF alleles within an hour. This allows genetic testing to be done prior to PCI even in ACS.
The POPular Genetics (Patient Outcome After Primary PCI Genetics Study) was a large trial comparing genotype-guided use versus standard use of prasugrel of ticagrelor in patients with primary PCI (2). The genotyping was done at a central lab or using the Spartan Xl device. It showed that a genotype-guided strategy with use of clopidogrel in patients without CYP2C19 LOF alleles and ticagrelor or prasugrel in those with LOF was noninferior for thrombotic events and had a lower incidence of bleeding. Likewise the PHARMCLO (Pharmacogenetics of Clopidogrel in Acute Coronary Syndromes) trial also showed that in patients with ACS, a pharmacogenomic approach compared with a standard approach resulted in lower major adverse cardiac event rates (15% vs. 25%) and lower bleeding (3). This trial was underpowered and should be interpreted cautiously. These and other studies have led to increased enthusiasm to use of a genotype-guided approach.
The use of genotyping to determine the best antiplatelet agent relies on the prasugrel and ticagrelor being highly effective in those with CYP2C19 LOF alleles. This has not been previously studied. In this issue of JACC: Basic to Translational Science, Franchi et al. (4) identified 223 of 781 patients (28.5%) undergoing PCI who had CYP2C19 LOF alleles using rapid bedside genotyping. The patients were randomized to either prasugrel or ticagrelor, and platelet aggregation was measured serially over 24 h and then at 1 to 4 weeks. Both agents showed a rapid inhibition of platelet aggregation by 24 h without loss of effectiveness over time. The study further demonstrated that rapid genotyping was possible even in patients with ACS undergoing urgent catheterization.
Although CYP2C19 genotyping is feasible, is it the optimal way to identify nonresponders to clopidogrel? Studies have suggested that CYP2C19∗2 carrier status only explains a small fraction of HPR whereas clinical factors account for most of the variability in platelet function testing. Platelet function testing is the direct way to determine inadequate platelet inhibition regardless of the cause. Rapid bedside assay using the VerifyNow device (Accriva, San Diego, California) are readily available in many catheterization labs. The primary limitation is the need to wait for at least 24 h to determine effectiveness, another approach might be to start all patients on ticagrelor or prasugrel and then de-escalate to clopidogrel later. This was tested in the TROPICAL–ACS (Testing Responsiveness to Platelet Inhibition on Chronic Antiplatelet Treatment for Acute Coronary Syndromes) trial where patients were randomized to prasugrel or to the de-escalation group (5). The de-escalation patients had 1 week of prasugrel and then 1 week of clopidogrel. If the patients showed HPR after 1 week on clopidogrel, then they were switched back to prasugrel. In the guided de-escalation group, 39% were switched back. There was no difference in ischemic or bleeding outcomes between the groups. In a genotypic substudy of this trial, a good correlation was seen between CYP2C19 genotypes and on treatment platelet reactivity, but only 43% of patients with CYP2C19 LOF alleles were switched from clopidogrel back to prasugrel. This suggests that genotyping identifies a significant number of patients who have LOF alleles but have adequate platelet inhibition on clopidogrel and would not need to be switched.
The routine use of the more powerful agents in all patients is a simple solution but cost and side effects (particularly with ticagrelor) and increased bleeding is a concern. Cost has become less of an issue recently because prasugrel is now generic in the United States and the cost is only twice that of generic clopidogrel ($20 to $30 vs. $9 to $10 per month) whereas ticagrelor remains 35× more costly.
The relationship between genetic testing and platelet function is loose and neither test alone is adequate for optimizing therapy. For instance, 14% of patients on prasugrel in TROPICAL-ACS had high on-treatment platelet aggregation. Conversely, a significant percentage of patients on prasugrel and ticagrelor have excessive platelet inhibition that has been shown to increase bleeding. One option might be to do an initial screen with genetic testing that would identify those patients with CYP2C19 LOF alleles who would receive prasugrel or ticagrelor and those who do not have LOF alleles who would start clopidogrel. Based on trials, this would preserve efficacy in all patients. This is the approach that the on-going TAILOR-PCI trial (Tailored Antiplatelet Therapy Following PCI; NCT01742117) is studying using ticagrelor. The trial is planned to be presented shortly. An additional option to further reduce bleeding risk would be to de-escalate those patients with LOF on prasugrel or ticagrelor who have a high bleeding risk to clopidogrel after 1 month when the risk of ischemic events falls significantly. Platelet function testing could be done at this point to verify effectiveness. Another approach might be to not de-escalate but to discontinue aspirin at 3 months and continue the potent P2Y12 agent as was done in TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention). These approaches would maximize antiplatelet therapy while reducing bleeding in those at risk.
The future is to develop more personalized approach to therapy, and integrating rapid genetic testing into the choice of antiplatelet agents is the first step. Further study is clearly needed to determine the optimal integration that can improve efficacy and reduce adverse effects that is practical and cost-effective. Time will tell, but I am optimistic.
↵∗ Editorials published in JACC: Basic to Translational Science reflect the views of the authors and do not necessarily represent the views of JACC: Basic to Translational Science or the American College of Cardiology.
Dr. Faxon has reported that he has no relationships relevant to the contents of this paper to disclose.
The author attests they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
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