Greater Platelet Inhibition Research Articles

Ticagrelor or prasugrel versus clopidogrel in patients with coronary heart disease

Abstract Introduction Antiplatelet therapy is pivotal in the management of coronary heart disease (CHD), especially after percutaneous coronary intervention (PCI). Clopidogrel has long been the cornerstone of dual antiplatelet therapy. However, newer agents like prasugrel and ticagrelor boast of faster onset of action and greater platelet inhibition, which may translate to improved outcomes. Purpose Our hypothesis is that prasugrel or ticagrelor are superior to clopidogrel in reducing cardiovascular mortality in chronic CHD patients. Methods We conducted a retrospective cohort study using the TriNetX network database, including patients with chronic CHD on dual antiplatelet therapy. A total of 1,420,165 patients on clopidogrel and 197,783 on prasugrel or ticagrelor were identified. We assessed the primary composite endpoint of cardiovascular mortality over a 5-year follow-up period, using event-free survival as our main outcome measure. Results The 5-year follow-up data revealed a significant difference in event-free survival between the groups. Patients on prasugrel or ticagrelor had a markedly higher event-free survival rate of 83.156% compared to 73.209% for those on clopidogrel. The Log Rank test showed a confidence interval of 1.544 to 1.592 with a highly significant p-value of <0.0001. Discussion The data suggest a clear benefit of prasugrel or ticagrelor over clopidogrel for event-free survival in CHD patients. This could be attributed to the more potent antiplatelet effects of these drugs, leading to reduced thrombotic events. Given the substantial sample size and robustness of the data, the findings advocate for a paradigm shift in the choice of more potent antiplatelet agents in clinical practice. Conclusion Our analysis supports the hypothesis that prasugrel or ticagrelor are associated with significantly lower cardiovascular mortality compared to clopidogrel in patients with chronic coronary heart disease.5-year Kaplan-Meier curves for mortality

Platelet and Monocyte Activation After Transcatheter Aortic Valve Replacement (POTENT-TAVR): A Mechanistic Randomized Trial of Ticagrelor Versus Clopidogrel

BackgroundInflammation and thrombosis are often linked mechanistically and are associated with adverse events after transcatheter aortic valve replacement (TAVR). High residual platelet reactivity (HRPR) is especially common when clopidogrel is used in this setting, but its relevance to immune activation is unknown. We sought to determine whether residual activity at the purinergic receptor P2Y12 (P2Y12) promotes prothrombotic immune activation in the setting of TAVR. MethodsThis was a randomized trial of 60 patients (enrolled July 2015 through December 2018) assigned to clopidogrel (300mg load, 75mg daily) or ticagrelor (180mg load, 90 mg twice daily) before and for 30 days following TAVR. Co-primary endpoints were P2Y12-dependent platelet activity (Platelet Reactivity Units; VerifyNow) and the proportion of inflammatory (cluster of differentiation [CD] 14+/CD16+) monocytes 1 day after TAVR. ResultsCompared to clopidogrel, those randomized to ticagrelor had greater platelet inhibition (median Platelet Reactivity Unit [interquartile range]: (234 [170.0-282.3] vs. 128.5 [86.5-156.5], p < 0.001), but similar inflammatory monocyte proportions (22.2% [18.0%-30.2%] vs. 25.1% [22.1%-31.0%], p = 0.201) 1 day after TAVR. Circulating monocyte-platelet aggregates, soluble CD14 levels, interleukin 6 and 8 levels, and D-dimers were also similar across treatment groups. HRPR was observed in 63% of the clopidogrel arm and was associated with higher inflammatory monocyte proportions. Major bleeding events, pacemaker placement, and mortality did not differ by treatment assignment. ConclusionsResidual P2Y12 activity after TAVR is common in those treated with clopidogrel but ticagrelor does not significantly alter biomarkers of prothrombotic immune activation. HRPR appears to be an indicator (not a cause) of innate immune activation in this setting.

TIcagrelor in Rotational Atherectomy to Reduce TROPonin Enhancement: The TIRATROP Study, A Randomized Controlled Trial.

Because rotational atherectomy (RA) is associated with arterial trauma and platelet activation, patients treated with RA may benefit from more potent antiplatelet drugs. The aim of this trial was to assess the superiority of ticagrelor over clopidogrel in reducing post procedure troponin release. TIRATROP (TIcagrelor in Rotational Atherectomy to reduce TROPonin enhancement) is a multicenter double-blind randomized controlled trial that included 180 patients with severe calcified lesions requiring RA who received either clopidogrel (300 mg loading dose, then 75 mg/d) or ticagrelor (loading dose 180 mg then 90 mg twice daily). Blood samples were collected at the beginning (T0), and 6, 12, 18, 24 and 36 h after the procedure. Primary end point was troponin release within the first 24 h using area under the curve analysis (troponin level as a function of time). The mean age of patients was 76 ± 10 years, 35% had diabetes. RA was used to treat 1, 2 or 3 calcified lesions in 72%, 23% and 5% of patients, respectively. Troponin release within the first 24 h was similar in both the ticagrelor (adjusted mean ±SD of ln AUC 8.85 ± 0.33) and the clopidogrel (8.77 ± 0.34, p = 0.60) arms. Independent predictors for troponin enhancement were acute coronary syndrome presentation, renal failure, elevated C-Reactive protein and multiple lesions treated with RA. Troponin release did not differ among treatment arms. Our results suggest that greater platelet inhibition does not affect periprocedural myocardial necrosis in the setting of RA.

Intensified antiplatelet therapy in patients after percutaneous coronary intervention with high on-treatment platelet reactivity: the OPTImal Management of Antithrombotic Agents (OPTIMA)-2 Trial.

High on-treatment platelet reactivity (HOPR) is associated with increased risk of cardiovascular events in patients undergoing percutaneous coronary intervention (PCI). We randomised post-PCI patients with HOPR after 5days of standard dual antiplatelet therapy (DAPT) to intensified therapy with aspirin 100mg once daily in combination with either clopidogrel 150mg once daily, clopidogrel 75mg once daily plus cilostazol 100mg twice daily, ticagrelor 90mg twice daily, or standard therapy with clopidogrel 75mg once daily (STD) for 1month, after which all patients were switched to standard DAPT for a further 11months. The primary outcome was residual HOPR rate at 1month. We screened 1724 patients with light transmission aggregation studies and randomised 434 with HOPR. At 1month the proportion of patients with persistent HOPR was significantly lower in the intensified therapy groups compared with STD group. Compared to the group receiving STD therapy, those receiving intensified therapy had significantly lower rate of major adverse cardiovascular events (MACE) at both 1month and 12months with no significant increase in bleeding. In patients with post-PCI HOPR, 1month of intensified antiplatelet therapy provides greater platelet inhibition and improves outcomes without increasing bleeding. Clinical Trial Registration URL: http://www.clinicaltrials.gov; Unique Identifier: NCT01955200.

Effects of Monotherapy with Clopidogrel vs. Aspirin on Vascular Function and Hemostatic Measurements in Patients with Coronary Artery Disease: The Prospective, Crossover I-LOVE-MONO Trial.

Objectives: To evaluate the effect of clopidogrel vs. aspirin monotherapy on vascular function and hemostatic measurement. Background: Monotherapy with P2Y12 receptor inhibitor vs. aspirin can be a useful alterative to optimize clinical efficacy and safety in high-risk patients with coronary artery disease (CAD). Methods: We performed a randomized, open-label, two-period crossover study in stented patients receiving at least 6-month of dual antiplatelet therapy (DAPT). Thirty CAD patients with moderate-to-high ischemic risk were randomly assigned to receive either 75 mg of clopidogrel or 100 mg of aspirin daily for 4 weeks, and were crossed over to the other strategy for 4 weeks. Vascular function was evaluated with reactive hyperemia-peripheral arterial tonometry (RH-PAT) and brachial-ankle pulse wave velocity (baPWV). Hemostatic profiles were measured with VerifyNow and thromboelastography (TEG). The primary endpoint was the reactive hyperemia index (RHI) during clopidogrel or aspirin monotherapy. Results: Clopidogrel vs. aspirin monotherapy was associated with better endothelial function (RHI: 2.11 ± 0.77% vs. 1.87 ± 0.72%, p = 0.045), lower platelet reactivity (130 ± 64 vs. 214 ± 50 P2Y12 reaction unit [PRU], p < 0.001) and prolonged reaction time (TEG R: 5.5 ± 1.2 vs. 5.1 ± 1.1 min, p = 0.037). In multivariate analysis, normal endothelial function (RHI ≥ 2.1) was significantly associated with clot kinetics (TEG angle ≤ 68 degree) and ‘PRU ≤ 132’. ‘PRU ≤ 132’ was achieved in 46.2% vs. 3.8% during clopidogrel administration vs. aspirin monotherapy (odds ratio 21.4, 95% confidence interval 2.7 to 170.1, p < 0.001). Conclusions: In CAD patients, clopidogrel vs. aspirin monotherapy was associated with better endothelial function, greater platelet inhibition and lower coagulation activity, suggesting pleiotropic effects of clopidogrel on endothelial function and hemostatic profiles.

Management of Acute Coronary Syndromes

Management of Acute Coronary Syndromes

Antiplatelet Effect of Different Loading Doses of Ticagrelor in Patients With Non–ST-Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: The APELOT Trial

BackgroundWe hypothesized that a high ticagrelor loading dose (LD) may improve platelet inhibition in patients with non–ST-elevation acute coronary syndrome (NSTE-ACS) undergoing percutaneous coronary intervention (PCI). MethodsThis interventional multicentre open-label trial randomized 278 patients with NSTE-ACS to a high (360 mg) or conventional (180 mg) ticagrelor LD. The primary outcome was the platelet reactivity index (PRI) 1 hour after administration of the LD. Secondary outcomes included PRI at 0.5 hour, 1 hour, 8 hours, and 24 hours; periprocedural myocardial infarction (PMI); major cardiac adverse events; and bleeding events. ResultsTwo hundred sixty-two patients completed the major end points. PRI was lower in the high-LD group than in the conventional-LD group at any time point (all, P < 0.05), including at 1 hour (12.2% vs 16.7%; P = 0.023). At 0.5 hour, the high-LD group showed a lower high-platelet reactivity rate (49.6% vs 60.2%; P = 0.013) and a higher low-platelet reactivity rate (24.8% vs 12.8%; P = 0.017) than did the conventional LD group. No significant differences in the bleeding rates were found between the 2 groups (14% vs 14.3%). Four cases of PMI and 1 death in each group, as well as 1 acute myocardial infarction in the conventional LD group, occurred. There was no stroke, target lesion revascularization, or target vessel revascularization. ConclusionsDoubling the ticagrelor LD achieved faster onset and greater platelet inhibition without an increase in adverse events in patients with NSTE-ACS undergoing PCI.

Administration of Ticagrelor and Double-Dose Clopidogrel Based on Platelet Reactivity Determined by VerifyNow-P2Y12 for Chinese Subjects After Elective PCI.

Previous studies have identified high on treatment platelet reactivity (HTPR) as a potent factor predicting ischemic events for patients with coronary heart disease. We assessed the efficacy and safety of ticagrelor (90 mg twice-daily) and double-dose of clopidogrel (150 mg once-daily) among Chinese patients for elective percutaneous coronary intervention. We enrolled 40 patients with HTPR from among 317 patients with non-ST-segment elevation acute coronary syndromes after a successful elective percutaneous coronary intervention (PCI). Platelet reactivity was measured by VerifyNow P2Y12 assay. Platelet reactivity was significantly lower for both groups when compared with baseline platelet reactivity after medication adjustment (all P < 0.001). The mean platelet reactivity units (PRU) was significantly lower for the ticagrelor group compared with that of the clopidogrel group over time (all P < 0.001). The differences in the rate of sustained HTPR at different time points between the two groups were significant (2 hours: 0% versus 60%; 8 hours: 5.6% versus 50%; 24 hours: 5.9% versus 43.8%, all P < 0.05). Genetic variation of CYP2C19*2 had no impact on PRU means or rate of HTPR in the ticagrelor group (P > 0.05). During the 30-day follow-up, no MACE occurred in any patient, and the overall risk of bleeding showed no difference between the two groups (35% versus 21%, P = 0.48). Our results suggest that ticagrelor may achieve a more rapid and greater platelet inhibition than double-dose clopidogrel. Further studies are still needed to assess the differences in efficacy and safety between ticagrelor and double-dose clopidogrel administration for Chinese patients post elective PCI.

Protease-Activated Receptor 4 Variant p.Tyr157Cys Reduces Platelet Functional Responses and Alters Receptor Trafficking.

Protease-activated receptor 4 (PAR4) is a key regulator of platelet reactivity and is encoded by F2RL3, which has abundant rare missense variants. We aimed to provide proof of principle that rare F2LR3 variants potentially affect platelet reactivity and responsiveness to PAR1 antagonist drugs and to explore underlying molecular mechanisms. We identified 6 rare F2RL3 missense variants in 236 cardiac patients, of which the variant causing a tyrosine 157 to cysteine substitution (Y157C) was predicted computationally to have the greatest effect on PAR4 structure. Y157C platelets from 3 cases showed reduced responses to PAR4-activating peptide and to α-thrombin compared with controls, but no reduction in responses to PAR1-activating peptide. Pretreatment with the PAR1 antagonist vorapaxar caused lower residual α-thrombin responses in Y157C platelets than in controls, indicating greater platelet inhibition. HEK293 cells transfected with a PAR4 Y157C expression construct had reduced PAR4 functional responses, unchanged total PAR4 expression but reduced surface expression. PAR4 Y157C was partially retained in the endoplasmic reticulum and displayed an expression pattern consistent with defective N-glycosylation. Mutagenesis of Y322, which is the putative hydrogen bond partner of Y157, also reduced PAR4 surface expression in HEK293 cells. Reduced PAR4 responses associated with Y157C result from aberrant anterograde surface receptor trafficking, in part, because of disrupted intramolecular hydrogen bonding. Characterization of PAR4 Y157C establishes that rare F2RL3 variants have the potential to markedly alter platelet PAR4 reactivity particularly after exposure to therapeutic PAR1 antagonists.

VERifyNow in DIabetes high-on-treatment platelet reactivity: a pharmacodynamic study on switching from clopidogrel to prasugrel

Introduction Diabetic patients with an acute coronary syndrome undergoing percutaneous coronary intervention frequently exhibit high platelet reactivity while on clopidogrel. We hypothesized that in diabetic patients undergoing percutaneous coronary intervention, who exhibit highplatelet-reactivity after standard treatment with clopidogrel, a 60-mg prasugrel loading dose is superior to standard treatment with clopidogrel for optimal P2Y12 inhibition within the first 24-36 h post-angioplasty.Methods VERDI was a prospective, randomized, single-centre, single-blind, parallel-design study (NCT01684813). Consecutive diabetic patients with an non-ST-segment elevation acute coronary syndrome undergoing percutaneous coronary intervention and loaded with clopidogrel were considered for platelet reactivity assessment immediately before angioplasty with the VerifyNow assay measured in P2Y12 reaction units (PRU). Fifty of 63 screened patients (79.4%) had high platelet reactivity (PRU ≥ 208) and were randomized to receive a 60-mg prasugrel loading dose (n = 25) versus clopidogrel standard dose (n = 25). Platelet function was assessed again 24 hours post-angioplasty.Results Prasugrel achieved greater platelet inhibition than clopidogrel 24 hours post-angioplasty (median [interquartile range], 38 [9-72] vs 285 [240-337], respectively; P < 0.001). The non-high-platelet-reactivity rate (PRU < 208) at 24 h post-angioplasty (primary end point) was higher with prasugrel; 25 patients (100%) in the prasugrel group achieved optimal antiaggregation vs 4 patients (16%) in the clopidogrel group (P < 0.001). No significant acute bleeding was documented in either group.Conclusion Among type 2 diabetic patients suffering an acute coronary syndrome with high-platelet-reactivity undergoing percutaneous coronary intervention, switching from clopidogrel to prasugrel was superior to standard treatment with clopidogrel for the achievement of optimal antiaggregation within the first 24 hours post-angioplasty.

Abstract 15727: Platelet Inhibition With Ticagrelor and Clopidogrel in Comatose Survivors of Out-of-Hospital Cardiac Arrest

Comatose survivors of out-of-hospital cardiac arrest (OHCA) nowadays frequently undergo immediate percutaneous coronary intervention (PCI) which is associated with the need for antiplatelet therapy with P2Y12 inhibitors. In the present study we investigated platelet inhibition in 19 comatose survivors of OHCA undergoing PCI and hypothermia (32-34 o C) who were randomized to clopidogrel 600 mg loading followed by 75 mg/day (n=6) or ticagrelor 180 mg loading followed by 90mg bid (n=13) administered as crushed and dissolved tablets via nasogastric tube. Platelet inhibition was measured by VerifyNow® and Multiplate® aggregometry at baseline, and 2, 4, 12, 22 and 48 hours after loading dose. VerifyNow® revealed greater platelet inhibition with ticagrelor becoming statistically significant 12 hours after the loading (Figure). Also Multiplate ADPtest revealed greater platelet inhibition after ticagrelor at 4 hours (21.5±13.9 vs. 38.7±16.8, p=0.03), 12 hours (15.4±12.0 vs. 36.3±8.7, p&lt;0.01) and 22 hours (14.3±6.1 vs. 26.3±4.3, p&lt;0.01). Accordingly, our preliminary results indicate that ticagrelor has faster and stronger antiplatelet effect than clopidogrel during the initial 48 hours of postresuscitation phase and maybe a P2Y12 of choice in comatose survivors of OHCA undergoing PCI.

Abstract 596: Platelet inhibition by Ticagrelor in African American versus Caucasian patients after Percutaneous Coronary Intervention

PLATO study showed that in acute coronary syndromes, treatment with Ticagrelor as compared with Clopidogrel significantly reduced the rate of death, myocardial infarction or stroke. In subgroup analysis based on race, no significant difference in primary end point was noted. However, African Americans (AA) comprised only 1.1% of study population. AA have greater mortality from coronary artery disease (CAD) and more likely to have high on-treatment platelet reactivity. Aim of our study is to compare the extent of platelet inhibition achieved by Ticagrelor and Clopidogrel in AA versus Caucasian patients undergoing percutaneous coronary intervention (PCI). Methods: 72 patients undergoing PCI during September to November 2014 were included in this study. All received Aspirin 325mg loading dose (LD) followed by 81mg maintenance dose, along with either Ticagrelor 180 mg LD followed by 90 mg twice-daily MD or Clopidogrel 600 mg LD followed by 75 mg once-daily MD. Platelet reactivity (PRU) was measured using the VerifyNow P2Y12 function assay 12-24h following MD and the average values calculated for each group. Results: 40 African American (55%) and 32 Caucasian (45%) patients were included. Ticagrelor was used in 45 (62.5%) and Clopidogrel was used in 27 patients (37.5%). Among Caucasians, 16 (50%) received Ticagrelor and 16 (50%) received Clopidogrel. Among AA, 27 patients (67%) received Ticagrelor, 13 patients (33%) received Clopidogrel. In the total study population, the average PRU achieved was lower for Ticagrelor (44) compared with Clopidogrel (183). Among patients who received Ticagrelor, significantly lower average PRU was seen in AA (33) compared to Caucasians (63). Among patients who received Clopidogrel, similar average PRU was seen in AA (181) and Caucasian (185) groups. After combining Ticagrelor and Clopidogrel groups, lower average PRU was achieved in AA (76) compared to Caucasians (126), the difference primarily attributable to Ticagrelor. Conclusion: Ticagrelor achieved greater platelet inhibition in AAs compared to Caucasians, while Clopidogrel achieved similar platelet inhibition in both racial groups. This potentially greater platelet inhibition by Ticagrelor in high risk AA group merits investigation in large-scale studies.

Platelet Reactivity After Receiving Clopidogrel Compared With Ticagrelor in Patients With Kidney Failure Treated With Hemodialysis: A Randomized Crossover Study

Patients with kidney failure treated with maintenance hemodialysis (HD) are poor responders to clopidogrel. More beneficial platelet-inhibiting strategies in HD patients therefore are required. Single-center, prospective, randomized, crossover study. 25 HD patients in Seoul, Korea. Patients were randomly assigned to receive clopidogrel (300mg loading, 75mg once daily for maintenance dose) or ticagrelor (180mg loading, 90mg twice daily for maintenance dose) for 14 days, and after a 14-day washout period, crossover treatment for another 14 days. All patients received aspirin (100mg/d). Platelet function was evaluated predosing and at 1, 5, and 48 hours and 14 days after the first loading dose. During the offset phase, platelet function was assessed at 1 hour and 2, 4, and 14 days after the last dose by light transmittance aggregometry and the VerifyNow P2Y12 assay, and patients were genotyped for the CYP2C19*2 allele. Maximal extent of aggregation, inhibition of platelet aggregation (IPA), P2Y12 reaction units (PRUs), and percentage of inhibition were evaluated. We performed per-protocol analysis, excluding patients who did not complete the protocol. 9 patients did not complete the protocol (7 patients due to adverse events; 2, nonadherence). Higher IPA occurred with ticagrelor than with clopidogrel at 1, 5, and 48 hours and 14 days after loading. By 5 hours after loading, a greater proportion of patients in the ticagrelor group than in the clopidogrel group achieved IPA>50% (75% vs 12%, respectively; P<0.05) and IPA>70% (44% vs 0%, respectively; P<0.05). Rates (slope) of onset and offset of the antiplatelet effect were faster in patients receiving ticagrelor than for those receiving clopidogrel (P<0.05). Regardless of CYP2C19*2 allele, the ticagrelor group had significantly lower PRUs at all times than the clopidogrel group. Single-center study with a small number of patients, not a double-blind study, and not intention-to-treat analysis. Ticagrelor may result in more rapid and greater platelet inhibition than clopidogrel in patients with kidney failure receiving HD.

Antiplatelet Effect of Thienopyridine (Clopidogrel or Prasugrel) Pretreatment in Patients Undergoing Primary Percutaneous Intervention for ST Elevation Myocardial Infarction

Although previous retrospective studies have suggested the clinical benefits of clopidogrel pretreatment in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI), the antiplatelet effect of thienopyridines during a narrow door-to-balloon time frame has not been evaluated. Seventy-nine consecutive patients with STEMI were treated with either 600 mg of clopidogrel (n = 49) or 60 mg of prasugrel (n = 30) loading on admission. All patients underwent PPCI with a door-to-balloon time of 48 ± 20 minutes. Adenosine diphosphate (ADP)-induced platelet aggregation (PA) was determined by light transmission aggregometry before thienopyridine loading, at PPCI, and after 72 hours. Baseline ADP-induced PA was comparable in clopidogrel- and prasugrel-treated patients (79 ± 10% vs 76 ± 9%, p = 0.2). Although ADP-induced PA was reduced significantly in both clopidogrel- and prasugrel-treated patients (p <0.01 for both), it was significantly lesser in prasugrel-treated patients (63 ± 18% vs 74 ± 12%, p = 0.002). Yet, <50% of the prasugrel-treated patients achieved adequate platelet inhibition (ADP-induced PA <70%) at PPCI. Prasugrel-treated patients, compared with clopidogrel-treated patients, were more likely to have Thrombolysis In Myocardial Infarction myocardial perfusion grade of ≥2 (79% vs 49%, p = 0.01), lower Thrombolysis In Myocardial Infarction frame count (10.2 ± 5.7 vs 13.6 ± 7.2, p = 0.03), and a numerically greater incidence of early ST-segment resolution >50% (26 of 30 [87%] vs 35 of 49 [71%], p = 0.1), suggesting better myocardial reperfusion. In conclusion, overall, prasugrel compared with clopidogrel pretreatment resulted in greater platelet inhibition at PPCI, but even with prasugrel, only <50% of the patients achieved early adequate platelet response.

Angiographic Outcomes in the PLATO Trial (Platelet Inhibition and Patient Outcomes)

The PLATO (Platelet Inhibition and Patient Outcomes) angiographic substudy sought to compare the efficacy of ticagrelor versus clopidogrel with respect to angiographic outcomes before and after PCI in the setting of acute coronary syndrome. Greater platelet inhibition has been associated with improved angiographic outcomes before and after percutaneous coronary intervention (PCI). Therefore, it was hypothesized that treatment with ticagrelor, which achieves more rapid, higher, and more consistent platelet inhibition, would be associated with improved angiographic outcomes when compared with those of clopidogrel treatment. The angiographic cohort consists of 2,616 patients drawn from the 18,624-patient PLATO trial. Clopidogrel naïve or pre-treated patients were randomized to 180 mg of ticagrelor or 300 mg of clopidogrel (75 mg for clopidogrel pre-treated patients). PCI patients were administered, as per treatment group: 1) an additional 90 mg of ticagrelor if >24 h following the initial loading dose; or 2) an optional further 300 mg of clopidogrel or placebo (total 600 mg) prior to PCI. The substudy primary endpoint was the incidence of post-PCI TIMI (Thrombolysis In Myocardial Infarction) myocardial perfusion grade 3 (TMPG 3) among patients who received a study drug prior to PCI. In total, 21.3% of patients were pretreated with clopidogrel prior to randomization. There was a short time interval between randomization and PCI (median: 0.68 [interquartile range (IQR): 0.30 to 2.21] h) among all patients. Post-PCI TMPG 3 was similar between the ticagrelor and clopidogrel groups (47.1% vs. 46.9%; p = 0.96). Likewise, the following pre-PCI outcomes were similar in the ticagrelor and clopidogrel groups, respectively: TMPG 3 (30.5% vs. 31.2%), TIMI flow grade 3 (37.1% vs. 39.3%), corrected TIMI frame count (median: 100 vs. 71 frames), TIMI thrombus grade 0 (24.1% vs. 27.6%), minimum lumen diameter (median: 0.3 [IQR: 0.0 to 0.6] vs. 0.3 [IQR: 0.0 to 0.6] mm) and percentage of diameter stenosis (median: 89 [IQR: 78 to 100] vs. 89 [IQR: 77 to 100]). Neither coronary flow nor myocardial perfusion, evaluated on coronary angiograms performed before or following PCI procedures within a few hours after the start of oral antiplatelet treatment in the setting of acute coronary syndromes, demonstrated a difference with ticagrelor versus clopidogrel. (A Comparison of Ticagrelor [AZD6140] and Clopidogrel in Patients With Acute Coronary Syndrome [PLATO]; NCT00391872).

Management of Acute Coronary Syndromes

Management of Acute Coronary Syndromes

Effect of CYP2C19*2 and *17 Genetic Variants on Platelet Response to Clopidogrel and Prasugrel Maintenance Dose and Relation to Bleeding Complications

The present study was performed to compare the influence of cytochrome P459 2C19 (CYP2C19) *2 and *17 genetic variants on the platelet response to clopidogrel and prasugrel maintenance therapy and to assess the relation between platelet reactivity and bleeding complications. A total of 730 patients were included (517 patients treated with clopidogrel 150 mg/day and 213 discharged with prasugrel 10 mg). Platelet reactivity was assessed at 1 month with the platelet reactivity index vasodilator-stimulated phosphoprotein (PRI VASP). High on-treatment platelet reactivity was defined as PRI VASP >50% and low on-treatment platelet reactivity (LTPR) as PRI VASP <20%. The patients were classified according to their genotypes as poor metabolizers (*2/non *17), intermediate metabolizers (*2/*17 or non *2/non *17) and ultrametabolizers (non *2/*17). At 1 month, the prasugrel response was significantly better than the clopidogrel response in all groups of patients, with a lower incidence of high on-treatment platelet reactivity but a greater incidence of LTPR, regardless of the genetic variants. The genetic distribution had a significant effect on the mean PRI VASP values, the incidence of high on-treatment platelet reactivity, and LTPR with both clopidogrel and prasugrel (p <0.05 for all). LTPR identified a group of patients at a greater risk of bleeding (odds ratio 4.8, 95% confidence interval 2.7 to 8.3; p <0.0001). In conclusion, the present study showed that both clopidogrel and prasugrel have genetic modulation by CYP2C19 *2 and *17 alleles and that prasugrel provides greater platelet inhibition, regardless of the genotypes. In addition, LTPR was associated with a greater risk of bleeding.

Use of Ticagrelor in the Treatment of Acute Coronary Syndromes

Copyright: © 2013 Aronow WS. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Ticagrelor is a non-thienopyridine antiplatelet drug which is an oral, reversible, direct-acting inhibitor of the ADP receptor P2Y12 [1]. Plasma levels of ticagrelor peak rapidly 1.5 to 3.0 hours after administration with antiplatelet effects occurring within 2 hours after administration. Ticagrelor has a half life of 7 to 8.5 hours with the metabolite lasting up to 12 hours [2]. This combined with its reversible binding to the ADP receptor P2Y12 requires twice daily dosing [2]. The rapid reversibility is beneficial if a surgical procedure has to be performed but is a disadvantage in poorly compliant patients. A loading dose of ticagrelor 180 mg achieves faster and greater platelet inhibition than a 600 mg loading dose of clopidogrel and is faster in offset after drug discontinuation than is clopidogrel [3].

Enhanced active metabolite generation and platelet inhibition with prasugrel compared to clopidogrel regardless of genotype in thienopyridine metabolic pathways

Clopidogrel response varies according to the presence of genetic polymorphisms. The CYP2C19*2 allele has been associated with impaired response; conflicting results have been reported for CYP2C19*17, ABCB1, and PON1 genotypes. We assessed the impact of CYP2C19, PON1, and ABCB1 polymorphisms on clopidogrel and prasugrel pharmacodynamic (PD) and pharmacokinetic (PK) parameters. Aspirin-treated patients (N=194) with coronary artery disease from two independent, prospective, randomised, multi-centre studies comparing clopidogrel (75 mg) and prasugrel (10 mg) were genotyped and classified by predicted CYP2C19 metaboliser phenotype (ultra metabolisers [UM] = *17 carriers; extensive metabolisers [EM] = *1/1 homozygotes; reduced metabolisers [RM] = *2 carriers). ABCB1 T/T and C/T polymorphisms and PON1 A/A, A/G and G/G polymorphisms were also genotyped. PD parameters were assessed using VerifyNow® P2Y12 and vasodilator stimulated phosphoprotein (VASP) expressed as platelet reactivity index (PRI) after 14 days of maintenance dosing. Clopidogrel and prasugrel active metabolite (AM) exposure was calculated in a cohort of 96 patients. For clopidogrel, genetic variants in CYP2C19, but not ABCB1 or PON1, affected PK and PD. For prasugrel, none of the measured genetic variants affected PK or PD. Compared with clopidogrel, platelet inhibition with prasugrel was greater even in the CYP2C19 UM phenotype. Prasugrel generated more AM and achieved greater platelet inhibition than clopidogrel irrespective of CYP2C19, ABCB1, and PON1 polymorphisms. The lack of effect from genetic variants on prasugrel AM generation or antiplatelet activity is consistent with previous studies in healthy volunteers and is consistent with improved efficacy in acute coronary syndrome patients managed with percutaneous coronary intervention.

Spaced administration of PA32540 and clopidogrel results in greater platelet inhibition than synchronous administration of enteric-coated aspirin and enteric-coated omeprazole and clopidogrel

A common regimen for patients requiring dual-antiplatelet therapy who are at risk for gastrointestinal complications is the synchronous administration of enteric-coated (EC) aspirin, a proton pump inhibitor, and clopidogrel, although proton pump inhibitors have the potential for pharmacodynamic interaction with clopidogrel. Spaced administration of a clopidogrel and a single-tablet formulation of aspirin and immediate-release omeprazole (PA32540) was considered as an alternative that might reduce this potential pharmacodynamic interaction. A randomized, open-label, crossover study was conducted in healthy subjects (n = 30). Two 7-day treatments were separated by 14-day washout periods: (a) PA32540 + clopidogrel (300 mg loading/75 mg maintenance) 10 hours later and (b) synchronous dosing of clopidogrel + EC aspirin (81 mg) + EC omeprazole (40 mg). The primary end point was the inhibition of platelet aggregation (20 μM adenosine diphosphate, maximal extent) after 7 days. CYP2C19 and ABCB1 genotypes were determined. Inhibition of platelet aggregation was greater with spaced PA32540 + clopidogrel therapy vs synchronous clopidogrel + EC aspirin + EC omeprazole therapy (P = .004). There was no difference in day 7 arachidonic acid-induced aggregation. The effect of spacing on pharmacodynamics was independent of genotype. PA32540 and clopidogrel spaced 10 hours apart had greater antiplatelet effects than did synchronously administered EC aspirin (81 mg), clopidogrel (75 mg), and EC omeprazole in healthy volunteers. These finding are directly relevant to the treatment for patients with high gastrointestinal risk who require dual-antiplatelet therapy and gastroprotection.