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Visual Abstract, Highlights • Our study supports the feasibility of using rapid CYP2C19 genotyping among both patients with stable and acute coronary syndrome undergoing diagnostic coronary angiography, with intent to undergo ad hoc PCI, in real-world clinical practice. • Rapid bedside genetic testing assay allows for very rapid turnaround times of results, with patients approached the same day of their procedure and availability of CYP2C19 genotypes within 1 h of sampling and before patients undergoing PCI. • Among carriers of CYP2C19 loss-of-function alleles undergoing PCI there were no differences in levels of platelet inhibition between prasugrel and ticagrelor (loading and maintenance dosing)., Summary The feasibility of rapid genetic testing in patients undergoing percutaneous coronary intervention (PCI) and the comparison of the pharmacodynamic effects of prasugrel versus ticagrelor among carriers of cytochrome P450 2C19 loss-of-function alleles treated with PCI has been poorly explored. Rapid genetic testing using the Spartan assay was shown to be feasible and provides results in a timely fashion in a real-world setting of patients undergoing coronary angiography (n = 781). Among patients (n = 223, 28.5%), carriers of at least 1 loss-of-function allele treated with PCI (n = 65), prasugrel, and ticagrelor achieve similar levels of platelet inhibition. (A Pharmacodynamic Study Comparing Prasugrel Versus Ticagrelor in Patients Undergoing PCI With CYP2C19 Loss-of-function [NCT02065479])

Summary: Vorapaxar reduces thrombotic cardiovascular events at the expense of increased bleeding. However, the differential pharmacodynamic (PD) effects of vorapaxar according to diabetes mellitus (DM) status are unknown. Moreover, although withdrawal of aspirin has emerged as a bleeding reduction strategy, the PD effects of stopping aspirin in patients treated with vorapaxar also are unknown. In this prospective PD investigation, vorapaxar was associated with reduced platelet-mediated thrombogenicity without affecting clot kinetics irrespective of DM status. However, platelet-mediated thrombogenicity increased after aspirin withdrawal, particularly among patients with DM. (Optimizing anti-Platelet Therapy In diabetes MellitUS-5 Study [OPTIMUS-5]; NCT02548650) Key Words: dual antiplatelet therapy, pharmacodynamics, platelets, thrombin, vorapaxar

In patients requiring dual antiplatelet therapy (DAPT) who also have an indication to be treated with oral anticoagulant (OAC) drugs, aspirin withdrawal reduces the risk of bleeding. There is limited data on the pharmacodynamic effects associated with adding a nonvitamin K antagonist OAC on a background of aspirin and a P2Y12 inhibitor as well as dropping aspirin. Seventy-five patients on DAPT (aspirin plus clopidogrel) were randomized to DAPT plus high-dose edoxaban (60 mg once daily, Group A), DAPT plus low-dose edoxaban (30 mg once daily, Group B), or DAPT only (Group C) for 10 ± 2 days (Phase I). Afterwards, Groups A and B interrupted aspirin and maintained clopidogrel plus edoxaban for 10 ± 2 days, while patients in Group C maintained DAPT (Phase II). Platelet aggregation and clot kinetics were assessed at baseline, end of Phase I, and end of Phase II using thrombelastography (TEG), light transmittance aggregometry (LTA), VerifyNow P2Y12, and serum thromboxane-B2. The primary endpoint was the comparison of maximum amplitude (MA) measured by TEG, a measure of clot strength, between patients on DAPT plus high-dose edoxaban and patients on DAPT only. Edoxaban prolonged in a dose-dependent manner speed of thrombin generation (TEG R; Group A: 7.7 [6.8–8.7] vs. Group B: 7.4 [6.4–8.5] vs. Group C: 6.3 [5.7–7.0]; p = 0.05) but did not affect other markers of clot kinetics, including TEG MA (Group A: 63 [61–64] vs. Group B: 65 [63–67] vs. Group C: 64 [63–65]; p = 0.10). After aspirin discontinuation, platelet reactivity assessed by LTA using thrombin receptor activating peptide as agonist increased to a greater extent with low-dose edoxaban. Stopping aspirin did not affect markers of P2Y12 reactivity and had no or marginal effects on clot kinetics, but increased markers sensitive to cyclooxygenase-1 blockade.

Background: The platelet inhibitory effects induced by oral P2Y 12 receptor antagonists are delayed in patients with ST-segment–elevation myocardial infarction undergoing primary percutaneous coronary intervention (P-PCI). In turn, this leads to a gap in platelet inhibition, exposing patients to an increased risk of early thrombotic complications and underscoring the need to define strategies associated with more effective platelet inhibition in the peri–primary percutaneous coronary intervention period. Cangrelor is an intravenous P2Y 12 inhibitor with prompt and potent antiplatelet effects. However, to date, there are limited data on the effects of cangrelor used in combination with ticagrelor in patients undergoing primary percutaneous coronary intervention. Moreover, questions have emerged on the potential for drug–drug interactions during the transition from cangrelor to oral P2Y 12 inhibitors. Methods: This was a prospective, randomized, double-blind, placebo-controlled pharmacodynamic study conducted in patients undergoing primary percutaneous coronary intervention (n=50) who were randomized to treatment with either cangrelor or matching placebo (bolus followed by 2-hour infusion). All patients received ticagrelor 180-mg loading dose administered as crushed tablets at the time of cangrelor/placebo bolus administration. Pharmacodynamic analyses were performed at 8 time points. Pharmacodynamic effects were measured as P2Y 12 reaction units by VerifyNow and platelet reactivity index by vasodilator-stimulated phosphoprotein. Results: Compared with placebo, cangrelor was associated with reduced P2Y 12 reaction units as early as 5 minutes after bolus, which persisted during the entire duration of drug infusion, including at 30 minutes (63 [32–93] versus 214 [183–245]; mean difference, 152 [95% CI, 108–195]; P Conclusions: In patients undergoing primary percutaneous coronary intervention, cangrelor is an effective strategy to bridge the gap in platelet inhibition associated with the use of oral P2Y 12 inhibition induced by ticagrelor. Ticagrelor can be administered as a crushed formulation concomitantly with cangrelor without any apparent drug–drug interaction. The clinical implications of these pharmacodynamic findings warrant investigation in an adequately powered clinical trial. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03247738

Background Vorapaxar as an adjunct to dual antiplatelet therapy ( DAPT ) reduces thrombotic events in patients with prior myocardial infarction at the expense of increased bleeding. Withdrawal of aspirin has emerged as a bleeding reduction strategy. The pharmacodynamic effects of vorapaxar with potent P2Y 12 inhibitors as well as the impact of dropping aspirin is unexplored and represented the aim of the VORA‐PRATIC (Vorapaxar Therapy in Patients With Prior Myocardial Infarction Treated With Newer Generation P2Y 12 Receptor Inhibitors Prasugrel and Ticagrelor) study. Methods and Results Post–myocardial infarction patients (n=130) on standard DAPT (aspirin+prasugrel or ticagrelor) were randomized to 1 of 3 arms: (1) triple therapy: aspirin+prasugrel/ticagrelor+vorapaxar; (2) dual therapy (drop aspirin): prasugrel/ticagrelor+vorapaxar; (3) DAPT : aspirin+prasugrel/ticagrelor. Pharmacodynamic assessments were performed at 3 time points (baseline and 7 and 30 days). Vorapaxar reduced CAT (collagen‐ADP‐TRAP)–induced platelet aggregation, a marker of platelet‐mediated global thrombogenicity (triple therapy versus DAPT at 30 days: mean difference=–27; 95% CI ,–35 to –19; P DAPT at 30 days: mean difference=–15; 95% CI ,–23 to –7; P P P 12 reactivity. Markers sensitive to aspirin‐induced effects increased ( P Conclusions In post–myocardial infarction patients treated with potent P2Y 12 inhibitors, vorapaxar reduces platelet‐driven global thrombogenicity, an effect that persisted, albeit attenuated, in the absence of aspirin and without affecting markers of P2Y 12 reactivity or clot kinetics. The clinical implications of these PD observations warrant future investigation. Registration URL : https://www.clini​caltr​ials.gov . Unique identifier: NCT 02545933.

Background: Switching between different classes of P2Y 12 inhibitors, including de-escalation from ticagrelor to clopidogrel, commonly occurs in clinical practice. However, the pharmacodynamic profiles of this strategy have been poorly explored. Methods: This was a prospective, randomized, open-label study conducted in patients on maintenance dosing (MD) of aspirin (81 mg/d) and clopidogrel (75 mg/d). After a 7-day run-in with ticagrelor (180 mg loading dose [LD] followed by 90 mg twice daily MD), patients (n=80) were randomized into 1 of 4 groups: group A, clopidogrel 600 mg LD 24 hours after the last MD of ticagrelor (C-600 mg-24h); group B, clopidogrel 600 mg LD 12 hours after the last MD of ticagrelor (C-600 mg-12h); group C, clopidogrel 75 mg/d MD 24 hours after the last MD of ticagrelor (C-75 mg-24h); and group D, ticagrelor 90 mg twice daily MD (T-90 mg twice daily). MD of the randomized treatment was maintained for 10±3 days. Pharmacodynamic assessments were performed at baseline, after run-in, and at 2, 24, 48, and 72 hours and 10 days with P2Y 12 reaction units by VerifyNow; platelet reactivity index was assessed by vasodilator-stimulated phosphoprotein; and maximal platelet aggregation was determined by light transmittance aggregometry. Results: T-90 mg twice daily led to lower platelet reactivity than any clopidogrel regimen using all assays at all time points. P2Y 12 reaction unit levels were similar between the C-600 mg-24h (group A) and the C-75 mg-24h (group C) ( P =0.29), including at 48 hours (primary end point; least mean difference, −6.9; 95% confidence interval, −38.1 to 24.3; P =0.66). P2Y 12 reaction unit levels were lower with C-600 mg-12h (group B) than with C-75 mg-24h (group C; P =0.024). Maximal platelet aggregation over time was lower with both C-600 mg-24h (group A; P =0.041) and C-600 mg-12h (group B; P =0.028) compared with C-75 mg-24h (group C). Platelet reactivity index profiles paralleled those observed with P2Y 12 reaction units. There were no pharmacodynamic differences for all tests between C-600 mg-24h (group A) and C-600 mg-12h (group B). In group C (C-75 mg-24h), platelet reactivity increased compared with baseline as early as 24 hours, reaching statistical significance at 48 and 72 hours and up to 10 days. These pharmacodynamic findings were delayed and blunted in magnitude with the administration of an LD, regardless of the timing of administration. Conclusions: De-escalation from ticagrelor to clopidogrel therapy is associated with an increase in platelet reactivity. The use of an LD before the initiation of an MD regimen of clopidogrel mitigates these observations, although this is not affected by the timing of its administration after ticagrelor discontinuation. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02287909.

Background Although clopidogrel is the most widely used P2Y12 inhibitor, loss-of-function (LOF) allelic variants located within the hepatic cytochrome P450 (CYP) 2C19 gene lead to attenuated bioactivation, increased rates of high platelet reactivity (HPR), and worse outcomes in patients undergoing percutaneous coronary intervention (PCI). Drug regulating authorities have suggested using alternative P2Y12 inhibitors (i.e., prasugrel or ticagrelor) in these patients. However, tailoring antiplatelet therapy in clinical practice according to results of genetic testing has been limited due to lack of access to promptly available results. Moreover, there are no head-to-head pharmacodynamic (PD) comparisons of prasugrel vs ticagrelor among patients with CYP2C19 LOF alleles. Purpose The aim of this study was to evaluate the feasibility of using rapid genetic testing in clinical practice and to compare the PD effects of prasugrel vs ticagrelor in patients undergoing PCI with CYP2C19 LOF alleles. Methods This was a prospective, randomized study conducted in patients with stable coronary artery disease and non-ST elevation acute coronary syndrome scheduled for left heart catheterization (LHC) with the intent to undergo PCI. Patients underwent rapid genetic testing using the Spartan RX assay, which defines CYP2C19 genetic status within 1 hour, allowing patients to be genotyped the same day of their LHC. Patients who were carriers of at least one LOF (*2 or *3) allele were randomized to receive either prasugrel [60mg loading dose (LD) - 10mg/day maintenance dose (MD)] or ticagrelor (180mg LD - 90mg b.i.d MD). Blood samples for PD analysis by VerifyNow were collected at 5 time points: baseline (prior to PCI), 30 minutes, 2 hours, 24 hours (or at hospital discharge whichever came first), and 1–4 weeks post-LD. All patients were treated with aspirin. The primary endpoint of our study was the non-inferiority in platelet reactivity, measured as PRU, at 24 hours of prasugrel vs ticagrelor in LOF allele carriers. Results A total of 781 consecutive patients scheduled for LHC were genotyped, of whom 223 (28.5%) were carriers of at least one LOF. Of these, 65 patients underwent PCI and randomized to prasugrel (n=32) vs ticagrelor (n=33). PRU levels at 24 hours were 33 vs 36 (prasugrel vs ticagrelor; mean difference = −3; 95% CI: −28 to 22; p=0.814) meeting the primary endpoint of non-inferiority. Both prasugrel and ticagrelor significantly reduced PRU to a similar extent with no differences between groups at all other time points (Figure). Accordingly, HPR rates were low and similar between groups. PRU by VerifyNow Conclusion Rapid genetic testing using the Spartan assay is feasible providing results in a timely fashion in a real-world clinical practice of patients undergoing PCI. Among patients with CYP2C19 LOF carrier status, prasugrel and ticagrelor are associated with similar levels of platelet inhibition. Acknowledgement/Funding Genetic testing was provided by Spartan RX

The platelet inhibitory effects induced by oral P2YThis was a prospective, randomized, double-blind, placebo-controlled pharmacodynamic study conducted in patients undergoing primary percutaneous coronary intervention (n=50) who were randomized to treatment with either cangrelor or matching placebo (bolus followed by 2-hour infusion). All patients received ticagrelor 180-mg loading dose administered as crushed tablets at the time of cangrelor/placebo bolus administration. Pharmacodynamic analyses were performed at 8 time points. Pharmacodynamic effects were measured as P2YCompared with placebo, cangrelor was associated with reduced P2YIn patients undergoing primary percutaneous coronary intervention, cangrelor is an effective strategy to bridge the gap in platelet inhibition associated with the use of oral P2YURL: https://www.clinicaltrials.gov . Unique identifier: NCT03247738.

Although it is common to switch from ticagrelor (T) to clopidogrel (C), the pharmacodynamic (PD) profiles of such switching, and if affected by the dose and timing of C administration, have been poorly explored. Patients (n=80) on chronic aspirin and C therapy underwent a 7-day run-in with T [(