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Background:To date, there is no data on switching to dual pathway inhibition (DPI) patients who have completed a guideline-recommended dual antiplatelet therapy (DAPT) regimen. Objectives: To assess the feasibility of switching from DAPT to DPI and to compare the pharmacodynamic (PD) profiles of these treatments. Methods: This was a prospective, randomized, PD study conducted in 90 patients with chronic coronary syndrome (CCS) on DAPT with aspirin (81mg/qd) plus a P2Y12 inhibitor [clopidogrel (75 mg/qd; n=30), ticagrelor (90mg/bid; n=30), or prasugrel (10mg/qd; n=30)]. Patients in each cohort were randomized to maintain DAPT or switch to DPI (aspirin 81mg/qd plus rivaroxaban 2.5mg/bid). PD assessments included: VerifyNow P2Y12 reaction units; light transmittance aggregometry following stimuli with adenosine diphosphate (ADP), tissue factor (TF), and a combination of collagen, ADP, and TF (CATF, maximum platelet aggregation %); thrombin generation (TG). Assays were performed at baseline and 30 days post-randomization. Results: Switching from DAPT to DPI occurred without major side effects. DAPT was associated with enhanced P2Y12 inhibition, while DPI with reduced TG. Platelet-mediated global thrombogenicity (primary endpoint) showed no differences between DAPT and DPI in the ticagrelor (14.5% [0.0–63.0] vs. 20.0% [0.0–70.0]; p=0.477) and prasugrel (20.0% [0.0–66.0] vs. 4.0% [0.0–70.0]; p=0.482), but not clopidogrel (27.0% [0.0–68.0] vs. 53.0% [0.0–81.0]; p=0.011), cohorts. Conclusion: In patients with CCS, switching from different DAPT regimens to DPI was feasible, showing enhanced P2Y12 inhibition with DAPT and reduced TG with DPI, with no differences in platelet-mediated global thrombogenicity between DPI and ticagrelor- and prasugrel, but not clopidogrel-, based DAPT.

Objectives To rule out a drug-drug interaction (DDI) among cangrelor-treated patients who have been pre-treated with ticagrelor. Background There are no studies specifically designed to rule out a DDI when cangrelor is used among patients who have been pre-treated with ticagrelor. Methods In this prospective, randomized, double-blind, placebo-controlled, cross-over, pharmacokinetic (PK) and pharmacodynamic (PD) study, patients with coronary artery disease (n = 20) were pre-treated with a 180-mg ticagrelor loading dose (LD) and after 1 hour randomized to placebo or cangrelor (bolus and infusion for 2 hours). Patients crossed over after 1-4 weeks of washout. PK analysis included ticagrelor plasma levels and its active metabolite. PD assessments included: VerifyNow P2Y12 reaction units (PRU), light transmittance aggregometry vasodilatorstimulated phosphoprotein, and Total Thrombus-Formation Analysis System. PK/PD assessments were performed at 7-time points. Results Compared to placebo, adding cangrelor to patients pre-treated with ticagrelor resulted in a significant reduction in PRU at 30 min and 1 hour after starting infusion. At 2 hours after stopping cangrelor/placebo infusion, PRU was low and similar in both groups (16.9 vs. 12.6; mean difference: 4.3; 95%CI: -28.6; 37.3), meeting the non-inferiority primary endpoint (predefined non-inferiority margin 45 PRU). Consistent findings were shown with all PD assays. PK tracked PD findings with no differences between groups in plasma levels of ticagrelor and its metabolite. Conclusions Compared with placebo, the use of cangrelor in patients pre-treated with ticagrelor results in enhanced platelet inhibition with no differences in PK/PD profiles after discontinuation of drug infusion indicating the absence of a DDI.

Aims To assess the feasibility of switching from dual antiplatelet therapy (DAPT) to dual pathway inhibition (DPI) and to compare the pharmacodynamic (PD) profiles of these treatment regimens. Methods and results This was a prospective, randomized, PD study conducted in 90 patients with chronic coronary syndrome (CCS) on DAPT with aspirin (81 mg/qd) plus a P2Y12 inhibitor [clopidogrel (75 mg/qd; n = 30), ticagrelor (90 mg/bid; n = 30), or prasugrel (10 mg/qd; n = 30)]. Patients in each cohort were randomized to maintain DAPT or switch to DPI (aspirin 81 mg/qd plus rivaroxaban 2.5 mg/bid). PD assessments included: VerifyNow P2Y12 reaction units; light transmittance aggregometry following stimuli with adenosine diphosphate (ADP), tissue factor, and a combination of collagen, ADP, and TF (CATF, maximum platelet aggregation %); thrombelastograph coagulation analyzer; thrombin generation (TG). Assays were performed at baseline (on DAPT) and 30 days post-randomization (trough and peak). Switching from DAPT to DPI occurred without major side effects. DAPT was associated with enhanced P2Y12 inhibition, while DPI with reduced TG. Platelet-mediated global thrombogenicity (primary endpoint) showed no differences between DAPT and DPI in the ticagrelor (14.5% [0.0–63.0] vs. 20.0% [0.0–70.0]; p = 0.477) and prasugrel (20.0% [0.0–66.0] vs. 4.0% [0.0–70.0]; p = 0.482), but not clopidogrel (27.0% [0.0–68.0] vs. 53.0% [0.0–81.0]; p = 0.011), cohorts. Conclusion In patients with CCS, switching from different DAPT regimens to DPI was feasible, showing enhanced P2Y12 inhibition with DAPT and reduced TG with DPI, with no differences in platelet-mediated global thrombogenicity between DPI and ticagrelor- and prasugrel, but not clopidogrel-, based DAPT.

To rule out a drug-drug interaction (DDI) among cangrelor-treated patients who have been pre-treated with ticagrelor.There are no studies specifically designed to rule out a DDI when cangrelor is used among patients who have been pre-treated with ticagrelor.In this prospective, randomized, double-blind, placebo-controlled, cross-over, pharmacokinetic (PK) and pharmacodynamic (PD) study, patients with coronary artery disease (n=20) were pre-treated with a 180-mg ticagrelor loading dose (LD) and after 1 hour randomized to placebo or cangrelor (bolus and infusion for 2 hours). Patients crossed over after 1-4 weeks of washout. PK analysis included ticagrelor plasma levels and its active metabolite. PD assessments included: VerifyNow P2YCompared to placebo, adding cangrelor to patients pre-treated with ticagrelor resulted in a significant reduction in PRU at 30 min and 1 hour after starting infusion. At 2 hours after stopping cangrelor/placebo infusion, PRU was low and similar in both groups (16.9 vs. 12.6; mean difference: 4.3; 95%CI: -28.6; 37.3), meeting the non-inferiority primary endpoint (pre-defined non-inferiority margin 45 PRU). Consistent findings were shown with all PD assays. PK tracked PD findings with no differences between groups in plasma levels of ticagrelor and its metabolite.Compared with placebo, the use of cangrelor in patients pre-treated with ticagrelor results in enhanced platelet inhibition with no differences in PK/PD profiles after discontinuation of drug infusion indicating the absence of a DDI.

Switching P2Y

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])

Aims Dual pathway inhibition (DPI) by adding a vascular dose of rivaroxaban to a single antiplatelet agent has emerged as a promising antithrombotic strategy. However, in most studies the antiplatelet agent of choice used in adjunct to a vascular dose of rivaroxaban was aspirin, and data on a P2Y12 inhibitor and how this DPI regimen compares with standard dual antiplatelet therapy (DAPT) are limited. Methods and results This investigation was a substudy analysis conducted in selected cohorts of patients with stable atherosclerotic disease enrolled from a larger prospective, open-label, parallel-group pharmacodynamic (PD) study. We analysed data from 40 patients treated with either clopidogrel- or ticagrelor-based DAPT first, and clopidogrel- or ticagrelor-based DPI thereafter. PD measures explored key pathways involved in thrombus formation and included markers of (1) P2Y12 reactivity, (2) platelet-mediated global thrombogenicity, (3) cyclooxygenase-1 activity, (4) thrombin receptor-activating peptide (TRAP)-induced platelet aggregation, (5) tissue factor (TF)-induced platelet aggregation, and (6) thrombin generation. Compared with DAPT, on a background of the same P2Y12 inhibitor (clopidogrel or ticagrelor), DPI was associated with reduced thrombin generation, increased markers of cyclooxygenase-1 activity and TRAP-induced platelet aggregation, and no differences in markers of P2Y12 signalling, platelet-mediated global thrombogenicity, and TF-induced platelet aggregation. In an analysis according to P2Y12 inhibitor type, ticagrelor reduced markers of platelet-mediated global thrombogenicity, P2Y12 signalling, and rates of high platelet reactivity compared with clopidogrel. Conclusion Compared with DAPT with aspirin and a P2Y12 inhibitor, the use of a P2Y12 inhibitor in adjunct to a vascular dose of rivaroxaban as part of a DPI strategy is associated with similar effects on platelet-mediated global thrombogenicity but reduced thrombin generation. A DPI strategy with ticagrelor is associated with enhanced antithrombotic efficacy, the clinical implications of which warrant larger scale investigations. Clinical trial registration ClinicalTrials.gov identifier: NCT03718429.

Aim Inhibition of thrombin-mediated signaling processes using a vascular dose of rivaroxaban in adjunct to antiplatelet therapy, known as dual-pathway inhibition (DPI), reduces atherothrombotic events in patients with stable atherosclerotic disease. However, there are limited data on the pharmacodynamic (PD) effects of this strategy and how it compares to standard dual antiplatelet therapy (DAPT). Methods and Results This investigation was conducted in selected cohorts of patients (n = 40) with stable atherosclerotic disease—enrolled within a larger prospective, open-label, parallel-group PD study—who were treated with either aspirin plus clopidogrel (DAPT), aspirin plus rivaroxaban 2.5 mg/bid (DPI), or DAPT plus rivaroxaban 2.5 mg/bid. Multiple PD assays providing a comprehensive assessment of markers of thrombosis were used. PD endpoints included platelet-mediated global thrombogenicity measured by light transmittance aggregometry (LTA) following stimuli with CATF (collagen-related peptide + adenosine diphosphate [ADP] + tissue factor [TF]), markers of P2Y12 reactivity, markers of platelet aggregation using LTA following several stimuli (arachidonic acid, ADP, collagen, TF, and thrombin receptor-activating peptide [TRAP]), thrombin generation, and thrombus formation. There was no difference in platelet-mediated global thrombogenicity between groups. Rivaroxaban significantly reduced thrombin generation and was associated with a trend toward reduced TF-induced platelet aggregation. Clopidogrel-based treatments reduced markers of P2Y12 signaling and TRAP-induced platelet aggregation. There were no differences between groups on markers of cyclooxygenase-1-mediated activity. Conclusion Compared with DAPT, DPI does not result in any differences in platelet-mediated global thrombogenicity, but reduces thrombin generation. These PD observations suggest that modulating thrombin generation—by means of factor Xa inhibition—in adjunct to antiplatelet therapy provides effective antithrombotic effects, supporting the efficacy and safety findings of a DPI strategy observed in clinical trials.

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.

Objectives The aim of this study was to assess if intravenous methylnaltrexone can counteract the effects of morphine on the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of ticagrelor. Background Morphine delays the onset of action of oral P2Y12 receptor inhibitors, including ticagrelor, by inhibiting gastric emptying and leading to delayed drug absorption. Methylnaltrexone is a peripheral opioid receptor antagonist that has the potential to prevent opioid-induced peripherally mediated side effects (e.g., gastric emptying inhibition) without affecting analgesia. Methods In this prospective, randomized, double-blind, placebo-controlled, crossover study, aspirin-treated patients with stable coronary artery disease (n = 30) were randomized to receive methylnaltrexone (0.3 mg/kg intravenous) or matching placebo. After methylnaltrexone or placebo administration, all patients received morphine (5 mg intravenous). This was followed 15 min later by a 180-mg loading dose of ticagrelor. Patients crossed over to the alternative study treatment after 7 ± 2 days of washout. PK and PD assessments were performed at 12 time points (6 pre- and 6 post-crossover). PK analysis included measurement of plasma levels of ticagrelor and its major active metabolite (AR-C124910XX). PD assessments included VerifyNow P2Y12, light transmittance aggregometry, and vasodilator-stimulated phosphoprotein. Results Only marginal changes in plasma levels of ticagrelor (and its major active metabolite) were observed with ticagrelor: maximum plasma concentration and area under the plasma concentration versus time curve from time 0 to the last measurable concentration were 38% and 30% higher, respectively, in patients receiving methylnaltrexone compared with those receiving placebo, but no differences in time to maximum plasma concentration were observed. There were no differences in P2Y12 reaction units by VerifyNow P2Y12 between groups at each time point, including 2 h (the primary endpoint; p = 0.261). Similarly, there were no differences in PD markers assessed by light transmittance aggregometry and vasodilator-stimulated phosphoprotein. Conclusions In patients with coronary artery disease receiving morphine, intravenous administration of the peripheral opioid receptor antagonist methylnaltrexone leads to only marginal changes in plasma levels of ticagrelor and its major metabolite, without affecting levels of platelet reactivity. (Effect of Methylnaltrexone on the PK/PD Profiles of Ticagrelor in Patients Treated With Morphine; NCT02403830)

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

Aims Patients with diabetes mellitus (DM) and chronic kidney disease (CKD) are at increased risk of atherothrombotic events. Ticagrelor reduces ischaemic events compared to clopidogrel, with the greatest risk reduction in patients with both DM and CKD. How CKD status affects the pharmacodynamic (PD) and pharmacokinetic (PK) profiles of different ticagrelor maintenance dose regimens in patients with DM is unknown. Methods and results In this randomized, crossover study, patients with DM on treatment with dual antiplatelet therapy (aspirin and clopidogrel) were stratified according to CKD status and randomized to ticagrelor 90 or 60 mg bid. PK/PD assessments were performed at baseline, after 7–10 days of ticagrelor (peak and trough), and after 7–10 days of alternative ticagrelor regimen (peak and trough). PK assessments included plasma concentrations of ticagrelor and its major metabolite. PD assessments included vasodilator-stimulated phosphoprotein (VASP)–platelet reactivity index (PRI), VerifyNow P2Y12, and light transmittance aggregometry (LTA). A total of 92 patients with DM (CKD, n = 44; non-CKD, n = 48) were randomized. Levels of platelet reactivity were lower with the 90 mg compared with the 60 mg ticagrelor dose, which was statistically significant in non-CKD but not in CKD patients for most PD measures. There were no significant differences in the primary endpoint (trough levels of VASP–PRI following ticagrelor 90 mg dosing) between cohorts (31 ± 20 vs. 25 ± 14; P = 0.105). VerifyNow and LTA provided similar findings. PK assessments tracked PD profiles showing increased plasma concentrations of ticagrelor and its major metabolite in CKD compared to non-CKD patients. Conclusion In patients with DM, although ticagrelor maintenance dose regimens (60 and 90 mg) yield potent P2Y12 inhibition, levels of platelet reactivity tended to be higher and subject to broader variability in non-CKD compared with CKD patients. Clinical trial registration http://www.clinicaltrials.gov Unique Identifier: NCT02539160.

Background: Diabetes mellitus (DM) is a key risk factor for the development of chronic kidney disease (CKD) and patients having both risk factors have increased risk of atherothrombotic events, underscoring the importance of antiplatelet therapy. Ticagrelor reduces ischemic events compared with clopidogrel, with the greatest risk reduction in patients with both DM and CKD. However, how CKD status affects the pharmacodynamic (PD) and pharmacokinetic (PK) profiles of different ticagrelor dosing regimens in DM patients is unknown. Methods: This was a prospective, randomized, cross-over study testing the PD/PK profiles of ticagrelor 90mg bid and 60mg bid among DM patients with and without CKD. All patients had coronary artery disease and were on dual antiplatelet therapy with aspirin (81mg qd) and clopidogrel (75mg qd). PD and PK assessments were performed at 3 visits: baseline, after 7-10 days of ticagrelor therapy (pre-crossover; peak and trough), and after 7-10 days of alternative ticagrelor regimen (post-crossover; peak and trough). Results: A total of 92 patients were randomized (CKD-, n=48; CKD+, n=44). Platelet reactivity as assessed by multiple assays (VASP-PRI; VerifyNow P2Y12; LTA) was increased with 60mg compared with 90 mg, which was statistically significant in CKD- but not in CKD+ patients for most PD measures (Figure). Although trough levels of platelet reactivity were numerically lower in CKD+ patients compared with CKD-, there was no significant difference in the pre-defined primary endpoint (trough levels of VASP-PRI following ticagrelor 90 mg dosing) between DM subjects with and without CKD (31±20 vs 25±14; mean difference= 6.4; 95% CI: -1.1 to 14.3; p=0.105; primary endpoint; Figure). PK assessments tracked PD profiles. Conclusions: In patients with DM, platelet inhibition by ticagrelor is similar irrespective of CKD status. However, the PD effects of the 60mg ticagrelor regimen is reduced compared with the 90mg regimen in patients without CKD.

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.

Objectives: This study sought to assess the pharmacodynamic (PD) effects of switching to ticagrelor patients who were treated with prasugrel after undergoing percutaneous coronary intervent...

Background Platelet inhibitory effects induced by oral P2Y 12 receptor antagonists are delayed in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI), which may be attributed to impaired absorption affecting drug pharmacokinetics (PK) and pharmacodynamics (PD). Crushing tablets has been suggested to lead to more favorable PK/PD profiles. To date, no studies have investigated the PK/PD effects of crushing prasugrel. Objectives This study sought to determine whether crushing prasugrel is associated with more favorable drug bioavailability and platelet inhibitory effects compared with whole tablets in STEMI patients undergoing PPCI. Methods Our prospective, randomized, open-label study assessed STEMI patients undergoing PPCI (n = 52) who were treated with a prasugrel 60-mg loading dose (LD) either as whole or crushed tablets. PK/PD analyses were performed at 7 time points. PD effects were measured as P2Y 12 reaction units and platelet reactivity index, and PK by plasma levels of prasugrel’s active metabolite. Results Compared with whole tablets, crushed prasugrel led to reduced P2Y 12 reaction units by 30 min post-LD, which persisted at 1, 2 (164 vs. 95; least square mean difference = 68; 95% confidence interval: 10 to 126; primary endpoint), and 4 h post-LD. Significant differences were no longer present at 6 h post-LD. Parallel findings were shown with platelet reactivity index. Accordingly, high on-treatment platelet reactivity rates were reduced with crushed prasugrel. PK analyses showed a >3-fold faster absorption with crushed compared with whole prasugrel. Conclusions In STEMI patients undergoing PPCI, crushed prasugrel leads to faster drug absorption, and consequently, more prompt and potent antiplatelet effects compared with whole tablet ingestion. (Pharmacological Effects of Crushing Prasugrel in STEMI Patients; NCT02212028 )

Impact of chronic kidney disease on platelet P2Y12 receptor signalling in patients with type 2 diabetes mellitus

Objectives The goal of this study was to assess the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of escalating ticagrelor loading dose (LD) regimens in primary percutaneous coronary intervention (PPCI). Background Patients with ST-segment elevation myocardial infarction undergoing PPCI frequently have suboptimal platelet inhibition in the early hours after ticagrelor LD. The use of high ticagrelor LD regimens has been hypothesized to optimize platelet inhibition in PPCI. Methods This was a prospective, randomized study of escalating ticagrelor LD regimens (180 mg, 270 mg, or 360 mg) in PPCI (N = 52). PK/PD analyses were performed before and 30 min, 1, 2, 4, 8, and 24 h post-LD. PK assessments included exposure to ticagrelor and its metabolite (AR-C124910XX). PD assessments included P2Y12 reaction units (PRU) measured by VerifyNow P2Y12 and platelet reactivity index (PRI) measured by vasodilator-stimulated phosphoprotein (VASP). Results Platelet reactivity was elevated during the first 2 h post-LD. There were no differences in PRU between groups during the study time course (p = 0.179). There were no significant differences in PRU levels across groups at all time points, except at 1 h (p = 0.017) where platelet reactivity was lowest with a 270-mg LD. No differences were found between the 180-mg and 360-mg groups (primary endpoint; p > 0.999). High on-treatment platelet reactivity rates were not different across groups, except at 1 hour (p = 0.038). Parallel PD findings were observed with VASP-PRI. PK analysis showed a delay in ticagrelor absorption and generation of AR-C124910XX, irrespective of dose. Although morphine was associated with a delay in ticagrelor PK/PD, it was not an independent predictor of high on-treatment platelet reactivity. Conclusions ST-segment elevation myocardial infarction patients undergoing PPCI frequently exhibit impaired response to ticagrelor in the early hours after drug administration, which cannot be overcome by increasing LD regimens. These PD findings are largely attributed to an impaired PK profile, indicating a delay in drug absorption compared with that reported in stable clinical settings. (High Ticagrelor Loading Dose in STEMI; NCT01898442)

Smokers have a greater relative benefit of clopidogrel therapy compared with nonsmokers, likely attributed to its enhanced pharmacodynamic (PD) effects. However, to date, all PD studies have been conducted in patients on dual antiplatelet therapy with aspirin and clopidogrel, and it is unknown whether clopidogrel monotherapy can offer more effective antithrombotic effects compared with aspirin alone among smoking patients. Sixty aspirin-treated (81 mg/day) patients with vascular disease, classified as nonsmokers, light smokers, and heavy smokers according to cotinine serum levels, were enrolled. Patients were switched to clopidogrel (75 mg/day) monotherapy for 7-10 days. PD assessments were performed before and after switch by multiple electrode aggregometry (MEA) and kaolin-activated thromboelastography (TEG). Complete PD data were obtained in 57 patients (nonsmokers, n = 27; light smokers, n = 13; heavy smokers, n = 17). On treatment platelet reactivity following MEA, adenosine diphosphate (ADP) + prostaglandin E1 (PGE1) and thrombin receptor-activating peptide (TRAP) stimuli were significantly lower among heavy smokers following switch to clopidogrel. A significant inverse effect was observed with MEA arachidonic acid (ASPI), while neutral findings were shown with MEA collagen (COLL) stimulus. Thrombin and fibrin activity assessed by clot generation parameters were all nonsignificantly different but showed trends towards enhanced antithrombotic activity with clopidogrel among heavy smokers. In heavy smokers with vascular disease manifestations, clopidogrel is associated with enhanced platelet inhibitory effects, affecting purinergic and non-purinergic pathways, compared with aspirin as measured by MEA. Moreover, among smokers, clopidogrel offers trends towards enhanced effects on parameters of clot generation measured by TEG.

Background: Patients with diabetes mellitus (DM) are at increased risk of atherothrombotic events, underscoring the importance of effective platelet inhibiting therapies. Prasugrel and ticagrelor reduce thrombotic complications to a greater extent than clopidogrel. Subgroup analyses of pivotal clinical trials testing prasugrel and ticagrelor versus clopidogrel showed DM patients to have benefits that were consistent with the overall trial populations, although the magnitude of the ischemic risk reduction appeared to be enhanced with prasugrel. Whether these findings may be attributed to differences in the pharmacodynamic profiles of these drugs in DM patients remains poorly explored and represented the aim of this study. Methods: In this prospective, randomized, double-blind, double-dummy, crossover pharmacodynamic study, aspirin-treated DM patients (n=50) with coronary artery disease were randomly assigned to receive prasugrel (60 mg loading dose [LD]/10 mg maintenance dose once daily) or ticagrelor (180 mg LD/90 mg maintenance dose twice daily) for 1 week. Pharmacodynamic assessments were conducted using 4 different assays, including VerifyNow P2Y12, vasodilator-stimulated phosphoprotein, light transmittance aggregometry, and Multiplate, which allowed us to explore ADP- and non–ADP-induced (arachidonic acid-, collagen-, thrombin receptor-activating, peptide-induced) platelet signaling pathways. The acute (baseline, 30 minutes, and 2 hours post-LD) and maintenance (1 week) effects of therapy were assessed. The primary end point of the study was the comparison of P2Y 12 reaction units determined by VerifyNow P2Y12 at 1 week between prasugrel and ticagrelor. Results: ADP- and non–ADP-induced measures of platelet reactivity reduced significantly with both prasugrel and ticagrelor LD and maintenance dose. P2Y 12 reaction units defined by VerifyNow were similar between prasugrel and ticagrelor at 30 minutes and 2 hours post-LD. At 1 week, P2Y 12 reaction units were significantly lower with ticagrelor than with prasugrel (52 [32–72] versus 83 [63–103]; least-square means difference: –31; 95% confidence interval, –57 to –4; P =0.022; primary end point). Pharmacodynamic assessments measured by vasodilator-stimulated phosphoprotein, light transmittance aggregometry, and Multiplate were similar between prasugrel and ticagrelor at each time point, including at 1 week. Rates of high on-treatment platelet reactivity were similar between groups with all assays at all time points. Conclusions: In DM patients with coronary artery disease, ticagrelor exerts similar or greater inhibition of ADP-induced platelet reactivity in comparison with prasugrel in the acute and chronic phases of treatment, whereas the inhibition of measures of non–ADP-induced platelet reactivity was not significantly different between the 2 agents. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01852214.

Objectives To report a series of consecutive patients that developed retroperitoneal hemorrhage (RPH) and persistent hypotension treated with endovascular approach. Background RPH is a rare complication of percutaneous cardiovascular interventions associated with high morbidity and mortality. The standard approach to treat this complication has been a conservative management for stable patients, and urgent vascular surgery for those with persistent hypovolemic shock. Percutaneous endovascular treatment has evolved as an alternative treatment option. Methods We implemented a management algorithm for patients with suspected RPH and persistent hypotension which embraced systematic use of emergency endovascular evaluation and treatment following clinical assessment without the use of non-invasive diagnostic testing. We report a series of 8 consecutive patients that developed RPH with persistent hypotension. Results Successful percutaneous treatment was achieved in all cases with the use of a covered stent. No patient required vascular surgery. The average blood transfusion was 3.4 ± 2.7 units per patient. There were no deaths; one patient experienced acute stent thrombosis that was successfully treated via endovascular approach. At 1-year follow-up, no further events were reported. Conclusion The incorporation of a standardized protocol using only clinical evaluation followed by emergency percutaneous approach without delays attributed to non-invasive diagnostic work-up showed to be feasible and associated with favorable outcomes. © 2016 Wiley Periodicals, Inc.

This study sought to assess the pharmacodynamic (PD) effects of switching to ticagrelor patients who were treated with prasugrel after undergoing percutaneous coronary intervention in the setting of an acute coronary syndrome.In clinical practice, there is a frequent need to switch between P2Y12 receptor inhibitors. However, concerns on drug interactions have emerged when switching therapies. To date, the PD effects of switching from prasugrel to ticagrelor have yet to be investigated.This was a prospective, randomized, open-label, 3-arm, parallel-design study conducted in patients (n = 82) on maintenance dual antiplatelet therapy with aspirin (81 mg QD) and prasugrel (10 mg QD). Patients were randomized to continue prasugrel 10 mg QD or switch to ticagrelor 90 mg bid, with or without a 180 mg loading dose (LD), for 1 week. PD assessments included P2Y12 reaction units (PRU) by VerifyNow, platelet reactivity index by vasodilator-stimulated phosphoprotein (VASP), and platelet aggregation by light transmittance aggregometry (LTA) at a total of 6 time points: baseline, 2 h, 4 h, 24 h, 48 h, and 1 week after randomization.After switching to ticagrelor, PRU levels decreased as early as 2 h after drug administration. Mean PRU levels remained low during the study time course, without evidence of drug interactions. The primary endpoint of noninferiority of ticagrelor (2 arms combined) versus prasugrel measured by PRU at 1 week was met (least squares mean difference: -18; 95% confidence interval: -41 to 5). There was no increase in rates of high on-treatment platelet reactivity (PRU208), which were overall very low throughout the study time course. Similar levels of platelet reactivity were observed irrespective of the use of a ticagrelor LD. Parallel findings were observed with VASP and LTA.Switching from prasugrel to ticagrelor leads to transiently higher levels of platelet inhibition, irrespective of the use of a LD, without evidence of drug interactions. (Pharmacodynamic Evaluation of Switching From Prasugrel to Ticagrelor [SWAP3]; NCT02016170).

Objectives The purpose of this study is to assess the pharmacodynamic effects of different prasugrel dosing regimens in patients on maintenance prasugrel therapy. Background There are a growing number of patients on chronic prasugrel therapy regimens, leading to questions about the dosing regimen of prasugrel to administer if percutaneous coronary intervention is required. Methods This is a prospective pharmacodynamic study in patients (n = 64) receiving maintenance prasugrel therapy who were randomly allocated to a 10 mg, 30 mg, or 60 mg dose of prasugrel. Pharmacodynamic assessments using multiple assays were conducted at 3 timepoints (baseline and 1 h and 4 h after dosing). Results Intragroup comparisons showed that a 60 mg dose reduced the platelet reactivity index (PRI) after 1 h (p = 0.004) and 4 h (p Conclusions For patients on maintenance prasugrel therapy, a 60 mg dosing strategy is associated with faster and higher platelet inhibition compared with lower doses, as assessed by P2Y12 specific assays. (Impact of Prasugrel Re-load on Platelet Aggregation in Patients on Chronic Prasugrel Therapy; NCT01201772)

SummaryPatients with type 2 diabetes mellitus (T2DM) have impaired clopidogrel-induced antiplatelet effects, which may be in part attributed to their reduced sensitivity to insulin and consequently, results in upregulation of the P2Y12 signalling pathway. It has been hypothesised that insulin sensitising strategies may enhance clopidogrel-mediated P2Y12 inhibitory effects. The aim of this pilot pharmacodynamics (PD) study was to assess the impact of pioglitazone on clopidogrel-mediated P2Y12 inhibitory effects in patients with T2DM. This was a prospective, randomised, double-blind, placebo-controlled, cross-over PD study. Patients with T2DM and stable coronary artery disease on maintenance aspirin and clopidogrel were randomised to receive either pioglitazone 30 mg or matching placebo daily for 14 days. PD assessments were measured at baseline, 14 days after randomisation, at the end of the wash-out period, and 14 days after cross-over. The primary endpoint measure was maximal platelet aggregation (MPA) to 20 μM adenosine diphosphate (ADP) as assessed by light transmittance aggregometry (LTA). Flow cytometric analysis of vasodilator-stimulated phosphoprotein phosphorylation (VASP-PRI), and VerifyNow P2Y12 testing were also performed. A total of 15 randomised patients completed the study. MPA to 20 μM ADP (primary endpoint) was not significantly different with pioglitazone compared with placebo (49.53 ± 4.76 vs. 52.52 ± 3.89%; p = 0.594). Similarly, other PD measures did not differ significantly between the groups. In conclusion, in patients with T2DM on maintenance aspirin and clopidogrel therapy, the adjunctive use of pioglitazone does not result in enhanced inhibition of platelet P2Y12 mediated signalling.

SummaryCilostazol is a platelet inhibitor which when added to aspirin and clopidogrel has shown to reduce the risk of recurrent ischaemic events without an increase in bleeding. These clinical benefits have shown to be more pronounced in patients with diabetes mellitus (DM). However, it remains unknown whether cilostazol exerts different pharmacodynamic effects in patients with and without DM. This was a randomised, double-blind, placebo-controlled, cross-over pharmacodynamic study comparing platelet function in patients with and without DM on aspirin and clopidogrel therapy. Patients (n=111) were randomly assigned to either cilostazol 100 mg or placebo twice daily for 14 days and afterwards crossed-over treatment for another 14 days. Platelet function was performed at baseline, 14 days post-randomisation, and 14 days post-cross-over. Functional testing to assess P2Y12 signalling included flow cytometric analysis of phosphorylation status of vasodilatorstimulated phosphoprotein measured by P2Y12 reactivity index (PRI), light transmittance aggregometry and VerifyNow. Thrombin generation processes were also studied using thrombelastography. Significantly lower PRI values were observed following treatment with cilostazol compared with placebo both in DM and non-DM groups (p < 0.0001). The absolute between-treatment differences of PRI between groups was a 35.1% lower in patients with DM (p=0.039). Similar results were obtained using all other functional measures assessing P2Y12 signalling. Thrombin generation was not affected by cilostazol. Cilostazol reduces platelet reactivity both in patients with and without DM, although these pharmacodynamic effects are enhanced in patients with DM. Despite the marked platelet inhibition, cilostazol does not alter thrombin-mediated haemostatic processes, which may explain its ischaemic benefit without the increased risk of bleeding.

Cangrelor is an intravenous P2Y12 receptor inhibitor with rapid onset and offset of action making it an attractive agent for bridging particularly in stented patients undergoing surgery who need to be on dual anti-platelet therapy (DAPT). However, to date there is limited real-world experience on

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 [(

Bare-metal stents have undergone intense pathological and clinical examination, but histological characterization of drug-eluting stent (DES) restenosis (ISR) remains unknown. We report a series of cases (n=6) with intravascular ultrasound (IVUS) and pathological examinations over 8 months after DES deployment. Tissue samples were obtained using atherectomy devices in 5 cases and a thrombectomy catheter in 1 case. Histology revealed not only smooth muscle cell proliferation, which correlated with homogeneous hypoechoic tissue by IVUS in one case, but also demonstrated delayed healing features such as organized fibrin deposition in 3 cases (one with homogeneous echolucent tissue by IVUS), macrophage and T-lymphocyte infiltration in others. IVUS appearance of ISR components varied from echolucent to echodense images. This report suggests a variable histological and IVUS pattern of ISR after DES implantation. Further investigations are necessary to define the potentially pro-thrombotic histological features of ISR after DES implantation, and the relationship between the molecular mechanisms of thrombosis and DES restenosis.

Aims Patients with type 2 diabetes mellitus (T2DM) have reduced platelet inhibition compared with non-diabetics following P2Y12 receptor blockade. Whether inhibition of P2Y12 signalling can be enhanced by adjunctive treatment with cilostazol in T2DM patients is unknown. The aim of this pilot study was to assess the functional impact of cilostazol in T2DM patients on standard aspirin and clopidogrel treatment. Methods and results This was a prospective, double-blind, double-dummy, placebo-controlled, randomized, cross-over platelet function study. T2DM patients on dual antiplatelet therapy were assigned to receive cilostazol 100 mg or placebo twice daily for 14 days and afterwards crossed-over treatment assignments for another 14 days. Platelet function was performed at three time points: at baseline, 14 days after randomization, and 14 days after treatment cross-over. The P2Y12 reactivity index, determined through flow cytometric assessment of the phosphorylation status of the vasodilator-stimulated phosphoprotein, was the primary endpoint measure. In addition to this flow cytometric evaluation, light transmittance aggregometry and VerifyNow testing were performed. A total of 25 T2DM patients were randomized; five patients discontinued treatment due to side effects. The P2Y12 reactivity index was significantly lower following cilostazol treatment compared with placebo (36.3 ± 20 vs. 59.9 ± 16%; P = 0.0002). All other P2Y12-specific functional assessments showed enhanced inhibition of this signalling pathway following treatment with cilostazol. Conclusion Adjunctive treatment with cilostazol in T2DM patients on standard dual antiplatelet therapy enhances inhibition of platelet P2Y12 signalling.

Updated guidelines on percutaneous coronary intervention recommend increasing the dose of clopidogrel to 150 mg in high-risk patients if50% platelet inhibition is demonstrated. However, to date, the functional impact of this recommendation has been poorly explored. The aim of this study was to assess the functional implications associated with the use of clopidogrel 150 mg/day in patients with inadequate platelet inhibition while receiving standard 75 mg/day maintenance treatment. Patients with diabetes mellitus have a higher prevalence of inadequate clopidogrel-induced antiplatelet effects and stent thrombosis compared with those without diabetes and were selected for this analysis. Platelet inhibition was assessed using the VerifyNow P2Y12 assay in patients with type 2 diabetes receiving dual-antiplatelet therapy. Patients (n = 17) with50% platelet inhibition were treated with clopidogrel 150 mg/day for 1 month. Adenosine diphosphate-induced aggregation and the P2Y12 reactivity ratio were also assessed. Platelet function profiles were compared with that of a control group (n = 17) withor=50% inhibition. Platelet inhibition increased from 27.1 +/- 12% to 40.6 +/- 18% in patients treated with clopidogrel 150 mg/day (p = 0.009; primary end point). All other functional measures also showed enhanced clopidogrel-induced antiplatelet effects. The degree of platelet inhibition achieved after treatment with clopidogrel 150 mg/day varied broadly, and only 35% of patients yielded a degree of platelet inhibitionor=50%. Increasing the dose in patients with inadequate response to clopidogrel did not reach the same degree of antiplatelet effects as those achieved in patients with adequate response while receiving 75 mg/day. In conclusion, the use of a 150 mg maintenance dose of clopidogrel in patients with type 2 diabetes with50% platelet inhibition is associated with enhanced antiplatelet effects. However, the antiplatelet effects achieved are nonuniform, and a considerable number of patients persist with inadequate platelet inhibition.

Background and Purpose— Although current guidelines state that carotid endarterectomy is probably recommended before or concomitant to coronary artery bypass grafting (CABG) in patients with carotid stenosis, s ignificant controversies to this recommendation still persist. Carotid artery stenting has been recently introduced as an alternative revascularization modality in high-risk patients. The aim of this study was to define, based on the published information, if carotid artery stenting is beneficial in this setting. Methods— A search of MEDLINE and a manual search of the literature from selected articles were performed. A total of 6 studies with 277 patients reporting carotid stenting followed by staged CABG were available for this clinical outcome analysis. All were retrospective and single-center studies. Results— The mean age was 69 years; 78% were males. Asymptomatic carotid stenosis was present in 76% of patients. The mean time to CABG was 32 days. The incidence of stroke and death associated with the stent procedure was 4.7%. Only 6 patients (2.2%) developed stroke associated with CABG. The overall combined 30-day event rate after CABG, including all events during carotid artery stenting, were as follows: minor stroke, 2.9%; major stroke, 3.2%; mortality, 7.6%; and combined death and any stroke, 12.3%. Conclusions— In this pooled analysis, the combined incidence of death and stroke in patients undergoing carotid artery stenting and staged CABG remains elevated. These results confirm that the presence of carotid stenosis is per se a marker of risk that might persists independent of its treatment. A systematic or randomized evaluation appears warranted.

Pharmacodynamic (PD) studies comparing prasugrel and ticagrelor have reached inconsistent findings. Therefore, a comprehensive investigation comparing the PD effects of prasugrel vs. ticagrelor after switching from clopidogrel therapy, exploring both loading dose (LD) and maintenance dose (MD) regimens represented the aim of this study.Patients (n = 110) with coronary artery disease were randomized to prasugrel (60 mg LD/10 mg MD q.d.) or ticagrelor (180 mg LD/90 mg MD b.i.d) therapy for 1 week. Pharmacodynamic assessments were conducted using three assays (vasodilator-stimulated phosphoprotein, VerifyNow P2Y12, and light transmittance aggregometry, LTA) at baseline, 30 min, 2, 24 h, and 1 week. The impact of initiating ticagrelor MD 12 vs. 24 h after LD administration was also assessed. Switching clopidogrel-treated patients to an LD of prasugrel or ticagrelor was associated with a reduction in platelet reactivity at 30 min and was sustained at all time points up to 1 week with the MD (P0.001 for all assays). Platelet reactivity was similar with prasugrel and ticagrelor with all assays at 30 min, 2 h, and 1 week (P0.05 for all time points), with the exception of LTA at 30 min (lower with prasugrel; P = 0.003). At 24 h, platelet reactivity was lower among patients initiating ticagrelor MD after 12 vs. 24 h post-LD. Rates of high platelet reactivity (HPR) were markedly reduced and similar between groups.Prasugrel and ticagrelor exert similar levels of P2Y12 inhibition achieving more potent PD effects and reduced HPR rates compared with clopidogrel which are reached promptly following LD and sustained with MD.NCT01852175.

SummaryThere is growing interest in understanding the effects of adding an oral anticoagulant in patients on dual antiplatelet therapy (DAPT). Vitamin K antagonists (VKAs) and clopidogrel represent the most broadly utilised oral anticoagulant and P2Y12 receptor inhibitor, respectively. However, VKAs can interfere with clopidogrel metabolism via the cytochrome P450 (CYP) system which in turn may result in an increase in platelet reactivity. Dabigatran is a direct acting (anti-II) oral anticoagulant which does not interfere with CYP and has favourable safety and efficacy profiles compared with VKAs. The pharmacodynamic (PD) effects on platelet reactivity and clot kinetic of adjunctive dabigatran therapy in patients on DAPT are poorly explored. In this prospective, randomised, double-blind, placebo-controlled PD study, patients (n=30) on maintenance DAPT with aspirin and clopidogrel were randomised to either dabigatran 150 mg bid or placebo for seven days. PD testing was performed before and after treatment using four different assays exploring multiple pathways of platelet aggregation and fibrin clot kinetics: light transmittance aggregometry (LTA), multiple electrode aggregometry (MEA), kaolin-activated thromboelastography (TEG) and turbidimetric assays. There were no differences in multiple measures of platelet reactivity investigating purinergic and non-purinergic signaling pathways assessed by LTA, MEA and TEG platelet mapping. Dabigatran significantly increased parameters related to thrombin activity and thrombus generation, and delayed fibrin clot formation, without affecting clot structure or fibrinolysis. In conclusion, in patients on DAPT with aspirin and clopidogrel, adjunctive dabigatran therapy is not associated with modulation of profiles of platelet reactivity as determined by several assays assessing multiple platelet signalling pathways. However, dabigatran significantly interferes with parameters related to thrombin activity and delays fibrin clot formation.

The goal of this study was to assess the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of escalating ticagrelor loading dose (LD) regimens in primary percutaneous coronary intervention (PPCI).Patients with ST-segment elevation myocardial infarction undergoing PPCI frequently have suboptimal platelet inhibition in the early hours after ticagrelor LD. The use of high ticagrelor LD regimens has been hypothesized to optimize platelet inhibition in PPCI.This was a prospective, randomized study of escalating ticagrelor LD regimens (180 mg, 270 mg, or 360 mg) in PPCI (N = 52). PK/PD analyses were performed before and 30 min, 1, 2, 4, 8, and 24 h post-LD. PK assessments included exposure to ticagrelor and its metabolite (AR-C124910XX). PD assessments included P2Y12 reaction units (PRU) measured by VerifyNow P2Y12 and platelet reactivity index (PRI) measured by vasodilator-stimulated phosphoprotein (VASP).Platelet reactivity was elevated during the first 2 h post-LD. There were no differences in PRU between groups during the study time course (p = 0.179). There were no significant differences in PRU levels across groups at all time points, except at 1 h (p = 0.017) where platelet reactivity was lowest with a 270-mg LD. No differences were found between the 180-mg and 360-mg groups (primary endpoint; p0.999). High on-treatment platelet reactivity rates were not different across groups, except at 1 hour (p = 0.038). Parallel PD findings were observed with VASP-PRI. PK analysis showed a delay in ticagrelor absorption and generation of AR-C124910XX, irrespective of dose. Although morphine was associated with a delay in ticagrelor PK/PD, it was not an independent predictor of high on-treatment platelet reactivity.ST-segment elevation myocardial infarction patients undergoing PPCI frequently exhibit impaired response to ticagrelor in the early hours after drug administration, which cannot be overcome by increasing LD regimens. These PD findings are largely attributed to an impaired PK profile, indicating a delay in drug absorption compared with that reported in stable clinical settings. (High Ticagrelor Loading Dose in STEMI; NCT01898442).

Intravascular ultrasound provides detailed information on vessel wall and plaque morphology. This report illustrates the use of three-dimensional volumetric IVUS reconstruction images to characterize different patterns of plaque morphology, including vulnerable and ruptured plaques, within a single coronary artery in a patient with unstable angina. Catheter Cardiovasc Interv 2004;61:376–380. © 2004 Wiley-Liss, Inc.

Treating unprotected left main disease and degenerated saphenous vein grafts by percutaneous intervention remains one of the more challenging situations facing interventional cardiologists. We present two cases showing how the use of sirolimus-eluting stents in combination with other novel techniques might alter treatment paradigms in the future.

The aim of this study was to assess the impact of ticagrelor dosing regimens on pharmacodynamic (PD) profiles in patients on maintenance ticagrelor therapy.Many patients on maintenance P2Y12-inhibiting therapies may require coronary revascularization procedures, raising a common clinical question with regard to the dosing regimen of the P2Y12-inhibiting agent to be used. To date, investigations assessing dosing regimens of P2Y12 receptor inhibitors in patients on maintenance therapy have been only assessed with thienopyridines, but not with ticagrelor.This was a prospective, randomized, double-blind, placebo-controlled study assessing the PD effects of 2 dosing regimens of ticagrelor in patients on standard aspirin and ticagrelor maintenance therapy. A total of 60 patients were randomized to either 90 mg (maintenance dose [MD] group) or 180 mg (loading dose [LD] group) dose of ticagrelor. PD assessments were conducted at 3 time points (baseline, 1 h and 4 h). PD assessments were defined according to the platelet reactivity index (PRI) (vasodilator-stimulated phosphoprotein phosphorylation assay), P2Y12 reaction unit (VerifyNow P2Y12 assay) and adenosine diphosphate-induced platelet aggregation by light transmittance aggregometry.There were no differences in baseline levels of platelet reactivity with all assays. Intergroup comparisons by means of repeated-measures analysis adjusted for baseline PRI values showed that the LD group had significantly lower PRI levels compared with the MD group during the overall study time course (p = 0.031). Consistent findings were found for P2Y12 reaction unit (p = 0.026) and light transmittance aggregometry (p = 0.004). Intragroup comparisons showed that a more prompt and sustained platelet inhibitory effect was achieved more consistently with an LD regimen compared with a MD regimen.In patients on maintenance ticagrelor therapy, a 180-mg LD regimen of ticagrelor is associated with more potent and prompt platelet inhibition compared with a 90-mg MD. (Impact of Ticagrelor Re-Load Pharmacodynamic Profiles; NCT01731041).

Introduction: In patients with established vascular disease, smoking is a strong independent risk factor for adverse outcomes, including mortality. Several investigations have shown that cigarette smoking induces cytochrome P450 enzymatic activity which in turn increases clopidogrel metabolism leading to enhanced pharmacodynamic (PD) effects compared with non-smokers. These findings may explain the heightened clinical benefits of clopidogrel in smokers compared with nonsmokers. Prasugrel has superior PD and clinical effects compared with clopidogrel. The aim of this study was to evaluate the impact of cigarette smoking on platelet P2Y 12 mediated effects among patients on maintenance prasugrel therapy. Methods: A total of 156 patients on maintenance prasugrel therapy (10mg/qd) for at least 7-days, in addition to aspirin (81mg/qd), who previously underwent a percutaneous coronary intervention in the setting of an acute coronary syndrome were studied. An objective assessment of smoking status was performed by measuring serum levels of cotinine (the major stable degradation product of nicotine metabolite). Cotinine levels >3 ng/ml identified patients as smokers. PD assessments to determine platelet P2Y 12 activity was performed by flow cytometric assessment of vasodilator-stimulated phosphoprotein (VASP). Results were reported as platelet reactivity index (PRI). A PRI>50% identified patients with high on-treatment platelet reactivity (HPR). Results: According to cotinine serum levels, patients were divided into smokers (n=55) and nonsmokers (n=101). PRI values in the overall population were not normally distributed (median [interquartile range (IQR)] 30 [19.1-38.9]) and 14.6% of patients had HPR. PRI levels were not significantly different between smokers and nonsmokers (33.7 [13.6-46.9] vs 28.8 [21.7-37.3], p= 0.56). There was no correlation between PRI values and cotinine levels (r=0.03; p=0.74). Accordingly, HPR rates were similar between smokers and nonsmokers (18.2% vs 12.9%; p=0.25). Conclusions: In patients on maintenance prasugrel therapy, cigarette smoking status, as objectively assessed by serum levels of cotinine, does not affect the degree of platelet P2Y 12 mediated inhibition.

Background: Thrombus formation represent the final step in the atherothrombotic process and occurs secondary to a complex interaction between platelets and coagulation factors. Increased platelet reactivity and enhanced clot formation can both determine predisposition to vascular events. Direct platelet inhibition by modern antiplatelet therapy is now effective at controlling the cellular component of coagulation but the fibrin network is not generally targeted in arterial disease. Our aim was to investigate the effects of dabigatran on fibrin network characteristics in individuals dual antiplatelet therapy (DAPT). Methods: This was a prospective, randomized, double-blind study conducted in 30 patients on maintenance (at least 30 days) DAPT with aspirin (81mg/day) and clopidogrel (75mg/day). Patients were randomized to receive either dabigatran 150mg bid or matching placebo for 7 days. Fibrin clot properties were studied using a validated turbidimetric assay and the following parameters were recorded: lag phase and time to full clot formation, both of which measure clotting potential; clot maximum absorbance, representing fibrin network density and fibre thickness; clot lysis time to assess fibrinolytic efficiency. Results: Dabigatran treatment was associated with an increase in lag phase, compared with baseline, of 1013±167 sec , whereas no difference was detected in placebo treated patients (-17±14 sec, p Conclusions: In patients on DAPT with aspirin and clopidogrel, additional treatment with dabigatran delays fibrin clot formation without affecting fibrinolysis. Therefore, triple therapy with dabigatran may be one option to reduce thrombosis potential in high risk individuals. Moreover, our assay, which can be conducted on stored samples, offers the opportunity to monitor response to dabigatran therapy.

Background: Clopidogrel is characterized by non-uniform pharmacodynamic (PD) effects leading to considerable rates of high on-treatment platelet reactivity (HPR), a marker of increased atherothrombotic risk. Prasugrel and ticagrelor have greater potency and more uniform PD effects compared with clopidogrel. The effects of switching from clopidogrel to prasugrel or ticagrelor and how this impacts HPR rates has been poorly explored. Methods: This was a prospective, randomized PD study conducted in patients with coronary artery disease on maintenance aspirin (81mg/qd) and clopidogrel (75mg/qd) therapy. Patients were randomized to switch to prasugrel (60mg loading dose/10mg maintenance dose qd) or ticagrelor (180mg loading dose/90mg maintenance dose bid) for 1 week. PD assessments were performed at 5 time points: before (while on clopidogrel) and 30 min, 2 hrs, 24 hrs and 1 week after switch. HPR was defined by a platelet reactivity index (PRI) > 50% assessed by VASP and platelet reaction unit (PRU) > 208 assessed by VerifyNow P2Y12 (VN). Results: A total of 110 patients were studied. HPR on clopidogrel therapy as defined by VASP-PRI was observed in 67.3% of the overall population. HPR rates were similarly distributed among patients subsequently randomized to prasugrel vs ticagrelor (69.8% vs 64.7%, p=0.57). After switching to prasugrel or ticagrelor, HPR rates significantly reduced as early as 30 min and continued to decrease consistently in both groups over the study time period. At 1 week, HPR was found in 13.7% and 15.6% of patients randomized to prasugrel and ticagrelor, respectively (p=0.80) (Figure). Parallel findings were observed when assessing HPR rates defined by VN-PRU (Figure). Conclusions: Switching from clopidogrel to a more potent P2Y 12 inhibiting agent significantly reduces HPR rates. Reduction in HPR rates occur to a similar extent between prasugrel and ticagrelor in both the acute and maintenance phases of therapy.