Siva Suryadevara

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).

Antiplatelet drug response variability and the role of platelet function testing: A practical guide for interventional cardiologists†

Antiplatelet therapy is the cornerstone of treatment for patients with acute coronary syndrome and is also of particular importance in those who undergo percutaneous coronary intervention with stent implantation. Dual antiplatelet therapy with aspirin and clopidogrel is associated with improvement in long‐term clinical outcomes in such patients and is presently the antiplatelet therapy of choice for secondary prevention of thrombotic events. However, a significant number of patients experience recurrent events despite antiplatelet therapy. Although poor patient compliance can account for some of these events, particularly in those patients who receive a drug‐eluting stent, increasing evidence indicates that there is variability in response to antiplatelet therapy and patients who have higher levels of platelet reactivity are at increased risk for recurrent ischemic events. However, the lack of a consistent definition of inadequate platelet response, as well as the lack of a standardized measurement technique, has made it difficult to define how to treat these patients. To translate findings associated with variability in platelet response into improved patient care, it is necessary to gain a better understanding of what variable platelet response is, how it is measured, who it should be measured in, and what its clinical relevance is. The objective of this review is to evaluate the data regarding interindividual response variability to antiplatelet therapy with the aim of providing practical considerations and where possible, recommendations, regarding this topic for interventional cardiologists.

Prasugrel: a novel platelet ADP P2Y12 receptor antagonist. A review on its mechanism of action and clinical development

Antiplatelet therapy is the cornerstone of treatment for patients who present with acute coronary syndrome (ACS) or undergo percutaneous coronary intervention (PCI). Clopidogrel, in combination with aspirin, is associated with improvement in long-term clinical outcomes in these patients and is currently the antiplatelet therapy of choice. However, a significant number of patients experience recurrent ischemic events, which have been in part attributed to variability in individual response profiles to currently recommended treatment regimens. The presence of variable degrees of responsiveness, thus inadequate platelet inhibition in some patients, underscores the need for novel agents with more potency and less variable platelet inhibitory effects. Prasugrel (CS-747; LY640315), a novel third-generation oral thienopyridine, is a specific, irreversible antagonist of the platelet adenosine diphosphate (ADP) P2Y12 receptor. Pre-clinical and early phase clinical studies have shown prasugrel to be characterized by more potent antiplatelet effects, lower interindividual variability in platelet response, and faster onset of activity compared with clopidogrel. Recent findings from large-scale Phase III testing showed prasugrel to be more efficacious in preventing ischemic events in ACS patients undergoing PCI; however, this is achieved at the expense of an increased risk of bleeding. This article reviews the currently available data regarding the efficacy and safety of prasugrel.

Effects of pioglitazone on platelet P2Y12-mediated signalling in clopidogrel-treated patients with type 2 diabetes mellitus

Patients 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.

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).

IMPACT OF MORPHINE ON PHARMACOKINETIC AND PHARMACODYNAMIC PROFILES OF TICAGRELOR IN PATIENTS WITH ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION UNDERGOING PRIMARY PERCUTANEOUS CORONARY INTERVENTION

In patients undergoing primary percutaneous coronary intervention (PPCI), morphine delays the pharmacodynamic (PD) effects of P2Y12 inhibitors, including prasugrel and ticagrelor. However, to date studies with novel P2Y12 inhibitors have been limited to PD assessments. The impact of morphine on

Pharmacodynamic Effects of Switching From Ticagrelor to Clopidogrel in Patients With Coronary Artery Disease: Results of the SWAP-4 Study

Background: Switching between different classes of P2Y12 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 P2Y12 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. P2Y12 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). P2Y12 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 P2Y12 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.

CANGRELOR AS AN ANTIPLATELET BRIDGING STRATEGY IN PATIENTS WITH CORONARY ARTERY DISEASE UNDERGOING CARDIAC AND NON-CARDIAC SURGERY

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

OPERATOR RADIATION EXPOSURE AND PHYSICAL DISCOMFORT DURING A RIGHT VERSUS LEFT RADIAL APPROACH FOR CORONARY INTERVENTIONS: A RANDOMIZED EVALUATION

Compared with a femoral approach, studies have shown increased radiation exposure with transradial approach (TRA). Right radial approach (RRA) is preferred over a left radial approach (LRA) due to perceived increased operator discomforts with LRA. However, no randomized study has evaluated these