The evolution of P2Y12 inhibitor therapy for the treatment of cardiovascular disease: from broad use to personalized medicine.

It has been established that atherosclerotic plaque rupture with resultant intravascular thrombosis leads to compromised or absent blood flow in arteries resulting in stroke, acute coronary syndromes, or major limb ischemia depending on the vascular bed affected. Dual antiplatelet therapy (DAPT) with aspirin and a P2Y¹² inhibitor has been the mainstay of treatment for acute coronary syndromes, percutaneous interventions, peripheral vascular disease, and acute stroke. ^{1, 2} The role of dual antiplatelet therapy in cardiovascular disease began with the STent Anticoagulation Restenosis Study (STARS) trial ³ in which the combination of aspirin and ticlopidine was the best therapy for coronary artery stenting when compared to aspirin alone or warfarin. DAPT was further imbedded in the therapeutic armamentarium of acute coronary syndrome after the Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial (CURE) trial ⁴ in an overall ACS population and the PCI-CURE ⁵ and Clopidogrel for the Reduction of Events During Observation (CREDO) ⁶ trials in PCI patients where DAPT was better than single antiplatelet therapy (SAPT) with aspirin alone in reducing ischemic events. By the early 2000s, almost all patients with a cardiovascular event were treated with a combination of aspirin and clopidogrel. It became evident that not all patients had adequate platelet inhibition with clopidogrel and this "nonresponse" was linked to an increase in adverse cardiac events. Investigation into the pharmacokinetics of clopidogrel demonstrated that clopidogrel was a pro-drug needing conversion to an active metabolite through a 2-step process using the cytochrome p450 2C19 enzyme (cyp2C19). ⁷ As the mechanism of clopidogrel platelet inhibition was elucidated, it became clear that there were groups of patients who did not have significant reduction of platelet aggregation with clopidogrel. ^8-10 At that time, a number of studies showed that between 16 - 50% of patients taking clopidogrel did not have adequate platelet inhibition in response to clopidogrel therapy. ¹¹

It was established that there were several alleles of cyp2C19 which affected the metabolism of clopidogrel and, therefore, its effectiveness at inhibiting the ADP pathway for platelet aggregation. The different alleles of cyp2C19 were classified into loss of function (LOF), wild type, and gain of function (GOF) alleles. ¹² However, at that time, performing platelet aggregation studies became simplified using point-of-care testing (POCT) dedicated to platelet function PFA-100, VerifyNow System, Multiplate Electrode Aggregometry [MEA]) while genetic testing was still cumbersome. Therefore, multiple studies were completed trying to correlate outcomes with levels of platelet aggregation using these platelet function testing (PFT) devices. Subsequently, a consensus statement from investigators involved in these studies was put forward a suggested level of platelet aggregation by the various devices above which patient had an increased risk for ischemic events or below which patients were at an increased risk for bleeding events ¹³.

Once it was appreciated that clopidogrel may not be effective at all populations, newer drugs blocking the P2Y12 pathway for platelet aggregation came forward as an alternative. These drugs, prasugrel (Effient) and ticagrelor (Brilinta), were shown to have a greater degree of platelet inhibition and appeared to be minimally affected by any genetic changes in their metabolic pathway. These characteristics would give prasugrel and ticagrelor an advantage over clopidogrel in reducing ischemic events as demonstrated in the TRITON-TIMI 38 ¹⁴ and PLATO ¹⁵ trials. However, the greater platelet inhibition resulting in reduced major adverse cardiac events (MACE) came at a price of increase bleeding events ^{14, 15}. As the initial studies of DAPT in ACS and PCI patients evaluated outcomes after 1 year of therapy, investigators began evaluating if shorter course of DAPT would reduce MACE without the increased risk of bleeding. Multiple studies have been completed using reduced duration of DAPT and most have shown no detriment on MACE with reduction in bleeding events ¹⁶. Another strategy that has emerged in recent years called "de-escalation" which changes therapy from a potent P2Y12 inhibitor to clopidogrel or changes therapy form DAPT to SAPT using a single antiplatelet agent of either aspirin only or P2Y12 receptor inhibitor only. ¹⁷ These studies have shown that SAPT appears to be as effective as DAPT in long term care with less bleeding. These regimens usually use DAPT for 3-6 months in patients with a lower risk of ischemic events and a risk of bleeding. Recently, the ULTIMATE- DAPT trial demonstrated similar MACE with reduced bleeding when participants were treated with 1 month of DAPT consisting of aspirin and ticagrelor followed by 11 months of DAPT or SAPT with only ticagrelor ¹⁸.

The scientific statement on genetic testing in all patients being treated with P2Y12 inhibition published in Circulation focuses on determining which patients will be responsive or not responsive to clopidogrel based on the testing for which cyp2C19 alleles the patient possesses ¹⁹. The authors present a thorough review of the genetics and pharmacodynamics of P2Y12 inhibition of platelet aggregation, particularly focusing on clopidogrel metabolism. The authors review multiple observational and a few randomized trials evaluating a genotype guided therapy versus a treat-all strategy using potent P2Y12 inhibitor strategy in ACS and PCI patients. The authors point out that a strategy determining the patient's genetic background can lead to more patient centered therapy with clopidogrel and the more potent P2Y12 inhibitors. A genotype driven strategy is predicted to improve ischemic outcomes without increasing bleeding and in at least 1 study was shown to have a dominant health economic impact. However, the authors also point out that not everyone with a LOF gene will be a nonresponder and not everyone with wild type or a GOF allele will be a responder to clopidogrel. The authors also point out there is minimal data comparing a genotype guided strategy with a pharmacodynamic strategy (measuring platelet aggregation in response to P2Y12 inhibitor therapy) to determine which strategy is more advantageous to predict reduced MACE with minimal bleeding. Given that various factors such as duration of therapy, timing of the test following a dose of medication, and dose of the medication given may affect the result of a PFT, the authors conclude that a broad genomic strategy with testing all patients with ACS or undergoing PCI may result in more effective treatment with reduced bleeding resulting in a better the cost benefit outcome for the patient. The authors also suggest that this strategy could be applied to patients with stroke or peripheral arterial disease who will also be treated with DAPT or SAPT using a P2Y12 inhibitor, as there are several trials which have evaluated this strategy ¹⁹.

However, although genotype may predict who will respond well to clopidogrel, it is not clear whether switching from a PFT strategy to a genotype guided antiplatelet therapy strategy will improve the diagnostic accuracy of patients who will benefit from treatment with a more potent antiplatelet agent such as ticagrelor or prasugrel compared with continuing on clopidogrel or who will benefit from de-escalation of antiplatelet therapy. As de-escalation strategies are becoming more routine, and patients being placed on P2Y12 inhibitor monotherapy most frequently receive clopidogrel, determination of the patient's ability to inhibit platelet aggregation becomes paramount. If the patient placed on clopidogrel monotherapy is a nonresponder, then it would be as if the patient was not receiving any antiplatelet therapy. In most institutions in the United States, it is easier to obtain results of a platelet aggregation test using VerifyNow than it is to obtain genomics on the patient. Currently, at my institution, in order to obtain a genetic test for cyp2C19 alleles, a comprehensive genomics test needs to be ordered from a commercial company with a 7-10 day turnaround for results or a cyp2C19 directed genetic profile can be obtained through the Mayo Clinic with a 2 -4 day response. In either case, the test needs to be outsourced and will take time to get results. However, a VerifyNow test for platelet aggregation is turned around the same day and will be at a lower charge to the patient. Until further there are studies evaluating the benefit of an all-comers genomic strategy versus a directed PFT, there will still be controversy as to which is more appropriate in the management of patients receiving P2Y12 inhibitor therapy.

Whether directed P2Y12 therapy is accomplished through genotype guided antiplatelet therapy or through PFT, it is becoming clear that patient profiling is needed to determine the best therapy for the patient. The current scientific statement clearly advocates genotype guided antiplatelet therapy although the authors acknowledge that implementation and cost may be a problem. As noted above, an updated consensus statement on platelet function and/or genetic testing from 2019 concluded "the robustness of the evidence, particularly when considering adequately powered randomized trials, still does not allow recommending the use of PFT or genetic testing routinely in clinical practice." ²⁰ The current scientific statement on genotype guided antiplatelet therapy concludes, "A precision medicine approach, based on cyp2C19 genetic testing results, in which LOF carriers are prescribed ticagrelor or prasugrel and non-carriers are prescribed clopidogrel, decreases the risk of ischemic events compared with universal clopidogrel and decreases the risk of bleeding compared with universal ticagrelor or prasugrel, and thus may offer a more balanced therapeutic approach. Given the totality of pharmacokinetic, pharmacodynamic and recent clinical trial data with recent meta-analyses findings, this writing group considers the evidence supportive of CYP2C19 genetic testing prior to prescribing clopidogrel or ticagrelor/prasugrel in patients with ACS and/or PCI can be beneficial." ¹⁹ Both the updated 2019 statement and the current Scientific Statement agree that evaluating patients in whom P2Y12 therapy will be instituted by either genotype guided antiplatelet therapy or PFT may lead to better outcomes with less bleeding demonstrating an in advantage for personalized medicine.