Platelet P2Y12 inhibiting therapy in adjunct to vascular dose of rivaroxaban or aspirin: a pharmacodynamic study of dual pathway inhibition vs. dual antiplatelet therapy.

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.

Pharmacodynamic Profiles of Dual-Pathway Inhibition with or without Clopidogrel versus Dual Antiplatelet Therapy in Patients with Atherosclerotic Disease.

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.

Pharmacodynamic Effects of Vorapaxar in Prior Myocardial Infarction Patients Treated With Potent Oral P2Y12 Receptor Inhibitors With and Without Aspirin: Results of the VORA-PRATIC Study.

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 P2Y12 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 P2Y12 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<0.001; primary end point). This effect was attenuated but still significant in the absence of aspirin (dual therapy versus DAPT at 30 days: mean difference=-15; 95% CI,-23 to -7; P<0.001; between-group comparisons, P<0.05). Vorapaxar abolished TRAP-induced aggregation (P<0.001), without affecting thrombin generation and clot strength. There were no differences in markers of P2Y12 reactivity. Markers sensitive to aspirin-induced effects increased (P<0.001) in the dual-therapy arm. Conclusions In post-myocardial infarction patients treated with potent P2Y12 inhibitors, vorapaxar reduces platelet-driven global thrombogenicity, an effect that persisted, albeit attenuated, in the absence of aspirin and without affecting markers of P2Y12 reactivity or clot kinetics. The clinical implications of these PD observations warrant future investigation. Registration URL: https://www.clini​caltr​ials.gov. Unique identifier: NCT02545933.

Platelet Inhibition With Cangrelor and Crushed Ticagrelor in Patients With ST-Segment-Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention.

BACKGROUND: The platelet inhibitory effects induced by oral P2Y12 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 P2Y12 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 P2Y12 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 P2Y12 reaction units by VerifyNow and platelet reactivity index by vasodilator-stimulated phosphoprotein. RESULTS: Compared with placebo, cangrelor was associated with reduced P2Y12 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<0·001; primary end point). Parallel findings were shown with platelet reactivity index. Accordingly, high on-treatment platelet reactivity rates were reduced with cangrelor. After discontinuation of cangrelor/placebo infusion, there were no differences in levels of platelet reactivity between groups, ruling out a drug-drug interaction when cangrelor and ticagrelor are concomitantly administered. 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 P2Y12 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.

Pharmacodynamic Effects of Vorapaxar in Patients With and Without Diabetes Mellitus: Results of the OPTIMUS-5 Study.

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).

Should endovascular approach be the first line of treatment for retroperitoneal bleeding with hemodynamic shock following percutaneous intervention? A case series.

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.

Pharmacodynamic Comparison of Prasugrel Versus Ticagrelor in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease: The OPTIMUS (Optimizing Antiplatelet Therapy in Diabetes Mellitus)-4 Study.

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 P2Y12 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. P2Y12 reaction units defined by VerifyNow were similar between prasugrel and ticagrelor at 30 minutes and 2 hours post-LD. At 1 week, P2Y12 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.

Impact of timing from blood sampling to pharmacodynamic assessment on measures of platelet reactivity in patients treated with P2Y12 receptor inhibitors.

Several platelet function tests (PFT) are available to assess the pharmacodynamic (PD) effects of P2Y12 inhibitors. However, there are technical variances between PFT, and P2Y12 inhibitors differ in pharmacological properties. Manufactures of PFT recommend a time-frame within which assessments needs to be executed. However, if the timing from blood sampling to processing affects PD results is unknown. We conducted a prospective study assessing the impact of timing from blood sampling to processing on PD measures using three different PFT. We studied 60 aspirin-treated patients with coronary artery disease (CAD) on maintenance P2Y12 inhibiting therapy [clopidogrel 75 mg/day (n=20), prasugrel 10 mg/day (n=20) and ticagrelor 90 mg bid (n=20)]. PD assessments (trough levels) were performed by VerifyNow P2Y12 (VN), light transmittance aggregometry (LTA) and vasodilator-stimulated phosphoprotein (VASP) at 30 minutes, 2 and 4 hours post-sampling; VASP was also performed at 24 hours. P2Y12 reaction units (PRU) by VN significantly decreased over time with all P2Y12 inhibitors (clopidogrel p<0.001; prasugrel p=0.016; ticagrelor p<0.001). PRU at 30 minutes and 2 hours were similar, but decreased at 4 hours. LTA showed consistent findings with VN. Conversely, PD measures as assessed by VASP were stable over time (p>0.1 for all P2Y12 inhibitors). In conclusion, in CAD patients on maintenance therapy with P2Y12 inhibitors, timing from blood sampling to processing significantly influences PD measures as assessed by VN and LTA, but not by VASP.

Pharmacodynamic Effects of Switching From Prasugrel to Ticagrelor: Results of the Prospective, Randomized SWAP-3 Study.

OBJECTIVES: 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. BACKGROUND: 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. METHODS: 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. RESULTS: 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 (PRU >208), 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. CONCLUSIONS: 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).

A head-to-head pharmacodynamic comparison of prasugrel vs. ticagrelor after switching from clopidogrel in patients with coronary artery disease: results of a prospective randomized study.

AIMS: 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. METHODS AND RESULTS: 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 (P < 0.001 for all assays). Platelet reactivity was similar with prasugrel and ticagrelor with all assays at 30 min, 2 h, and 1 week (P > 0.05 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. CONCLUSION: 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. CLINICALTRIALSGOV IDENTIFIER: NCT01852175.

Effects of dabigatran on the cellular and protein phase of coagulation in patients with coronary artery disease on dual antiplatelet therapy with aspirin and clopidogrel. Results from a prospective, randomised, double-blind, placebo-controlled study.

There 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.

Impact of Escalating Loading Dose Regimens of Ticagrelor in Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention: Results of a Prospective Randomized Pharmacokinetic and Pharmacodynamic Investigation.

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).

Pharmacodynamic Effects of Ticagrelor Dosing Regimens in Patients on Maintenance Ticagrelor Therapy: Results From a Prospective, Randomized, Double-Blind Investigation.

OBJECTIVES: The aim of this study was to assess the impact of ticagrelor dosing regimens on pharmacodynamic (PD) profiles in patients on maintenance ticagrelor therapy. BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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).