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.
ABSTRACT: 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.
Project description:We performed a network meta-analysis to investigate the optimal antithrombotic regime by indirectly comparing new antithrombotic regimes (new P2Y12 inhibitors plus aspirin or novel oral anticoagulants on top of traditional dual antiplatelet therapy [DAPT]) in patients with acute coronary syndrome (ACS).A systematic search of MEDLINE, EMBASE, and the Cochrane databases was performed to identify all phase 3 randomized controlled trials (RCTs) involving novel oral anticoagulants or oral P2Y12 inhibitors in patients with ACS. Major adverse cardiac events (MACE) were regarded as the efficacy endpoint, and thrombolysis in myocardial infarction (TIMI) major bleeding events were used as the safety endpoint. The net clinical benefit was calculated as the sum of MACE and TIMI major bleeding events.Five phase 3 RCTs with 64,476 ACS patients were included. Although there were no significant differences among new antithrombotic regimes, rivaroxaban 5 mg twice daily plus traditional DAPT might be the most effective in reducing the incidence of MACE, accompanying the highest risk of TIMI major bleeding. Ticagrelor plus aspirin presented slight advantage on the net clinical benefit over other new antithrombotic regimes, with the highest probability of being the best regimes for net clinical benefit (35.0%), followed by prasugrel plus aspirin (28.0%), and rivaroxaban 2.5 mg twice daily plus traditional DAPT (19.5%).Novel antithrombotic regime with ticagrelor plus aspirin brings a larger clinical benefit in comparison with other regimes, suggesting that it may be the optimal antithrombotic regime for patients with ACS.
Project description:Whether newer P2Y12 inhibitors are more efficacious and safer than clopidogrel and whether there is a superior one remain uncertain. We compared the effect of P2Y12 inhibitors on clinical outcomes in patients with acute coronary syndrome (ACS). Randomized controlled trials comparing clopidogrel, prasugrel, ticagrelor, or cangrelor, in combination with aspirin were searched. Sixteen trials with altogether 77,896 patients were included. Compared to clopidogrel, cardiovascular mortality was reduced with prasugrel (OR 0.85, 95% CI 0.75-0.97) and ticagrelor (0.82, 0.73-0.93). Myocardial infarction (0.75, 0.63-0.89) and major adverse cardiovascular events (0.80, 0.69-0.94) were reduced by prasugrel. Stent thrombosis was reduced by prasugrel (0.49, 0.38-0.63), ticagrelor (0.72, 0.57-0.90), and cangrelor (0.59, 0.43-0.81). It was reduced more by prasugrel than ticagrelor (0.69, 0.51-0.93). There were more major bleeds with prasugrel (1.24, 1.05-1.48). Thrombolysis in Myocardial Infarction (TIMI) major bleeding was increased with prasugrel compared to clopidogrel (1.36, 1.11-1.66) and ticagrelor (1.33, 1.06-1.67). TIMI minor bleeding was increased with prasugrel (1.44, 1.16-1.77) and cangrelor (1.47, 1.01-2.16) compared to clopidogrel while it was increased with prasugrel compared to ticagrelor (1.32, 1.01-1.72). Prasugrel is preferable to those ACS patients at low bleeding risk to reduce cardiovascular events whereas ticagrelor is a relatively safe antiplatelet drug of choice for most patients.
Project description:Diabetes mellitus (DM) is a metabolic disorder associated with accelerated atherogenesis and an increased risk of atherothrombotic complications. Multiple mechanisms contribute to the pro-thrombotic status which characterizes DM patients underscoring the importance of antiplatelet therapies used for secondary prevention in these patients. For many years, dual antiplatelet therapy (DAPT) with aspirin and the P2Y12 inhibitor clopidogrel has represented the mainstay of treatment following an acute coronary syndrome (ACS) or in patients undergoing percutaneous coronary interventions (PCI). Although DAPT reduces the incidence of atherothrombotic recurrences, these rates remain high in DM patients underscoring the need for more efficacious therapies. Oral platelet P2Y12 receptor inhibitors with enhanced potency, such as prasugrel and ticagrelor, as well as antiplatelet therapies such as vorapaxar inhibiting the thrombin-mediated platelet signaling pathway, constitute treatment opportunities for patients with DM and have shown to be associated with a greater reduction in ischemic recurrences, albeit at the cost of more bleeding. This article reviews currently available antiplatelet agents and delivers an update on the advances and drawbacks of these agents used for secondary prevention in DM patients experiencing an ACS or undergoing PCI.
Project description:<b>Objectives: </b>The objective of this study is to examine the temporal trend of antiplatelet prescribing pattern during index hospitalisation discharge in Hong Kong (HK) acute coronary syndrome (ACS) population.<br><br><b>Design: </b>The study is a retrospective observational cohort study.<br><br><b>Setting: </b>The study retrieved data from electronic health record from Hospital Authority (HA), HK.<br><br><b>Participants: </b>The study included patients aged 18 years old or above, who were admitted to seven institutions under HA with diagnosis of ACS during 2008-2017.<br><br><b>Primary and secondary outcome measures: </b>The primary outcome was the frequency of antiplatelet therapy prescription at the point of index hospitalisation discharge each year during 2008-2017. Association between demographics, baseline comorbidities, procedures and antiplatelet prescription were examined as secondary outcome using multivariate logistic regression model, with commonly used antiplatelet groups selected for comparison.<br><br><b>Results: </b>Among the included 14?716 patients, 5888 (40.0%) discharged with aspirin alone, 6888 (46.8%) discharged with dual antiplatelet therapy (DAPT) with clopidogrel, and 973 (6.6%) discharged with DAPT with prasugrel/ticagrelor. Prescribing rate of aspirin alone decreased substantially from 56.8% in 2008 to 27.5% in 2017. Utilisation of DAPT with clopidogrel increased from 33.7% in 2008 to 52.7% in 2017. Use of DAPT with prasugrel/ticagrelor increased from 0.3% in 2010 to 15.3% in 2017. Compared with those prescribed with DAPT with clopidogrel, male patients (adjusted OR (aOR) 1.34, 95%?CI 1.09 to 1.65), patients with non-ST-elevation myocardial infarction (aOR 2.50, 1.98 to 3.16) or ST-elevation myocardial infarction (aOR 3.26, 2.59 to 4.09), use of glycoprotein IIb/IIIa (aOR 3.03, 2.48 to 3.68) or undergoing percutaneous coronary intervention (aOR 3.85, 3.24 to 4.58) or coronary artery bypass graft (aOR 6.52, 4.63 to 9.18) during index hospitalisation, concurrent use of histamine-2 receptor antagonists (aOR 1.35, 1.10 to 1.65) or proton pump inhibitors (aOR 3.57, 2.93 to 4.36) during index hospitalisation discharge were more likely to be prescribed with DAPT with prasugrel/ticagrelor. Patients with older age (aOR 0.97, 0.96 to 0.97), diabetes (aOR 0.68, 0.52 to 0.88), chronic kidney disease (aOR 0.43, 0.22 to 0.85) or concurrent use of oral anticoagulant (aOR 0.16, 0.07 to 0.42) were more likely to received DAPT with clopidogrel.<br><br><b>Conclusions: </b>Use of DAPT with prasugrel/ticagrelor was suboptimal yet improving during 2008-2017 in HK patients with ACS. Considering DAPT, predictors for clopidogrel prescription, compared with prasugrel/ticagrelor, were consistent with identified risk factors of bleeding.
Project description:We assessed the effectiveness of dual antiplatelet therapy (DAPT) post elective or urgent (i.e., post acute coronary syndrome [ACS]) coronary artery bypass graft surgery (CABG).We systematically searched MEDLINE, EMBASE, and the Cochrane Registry from inception to August 2015. Randomized controlled trials (RCTs) in adults undergoing CABG comparing either dual vs. single antiplatelet therapy or higher- vs. lower-intensity DAPT were identified.Nine RCTs (n?=?4,887) with up to 1y follow-up were included. Five RCTs enrolled patients post-elective CABG (n?=?986). Two multi-centre RCTs enrolled ACS patients who subsequently underwent CABG (n?=?2,155). These 7 RCTs compared clopidogrel plus aspirin to aspirin alone. Two other multi-centre RCTs reported on ACS patients who subsequently underwent CABG comparing higher intensity DAPT with either ticagrelor (n?=?1,261) or prasugrel (n?=?485) plus aspirin to clopidogrel plus aspirin. Post-operative anti-platelet therapy was started when chest tube bleeding was no longer significant, typically within 24-48 h. There were no differences in all-cause mortality in clopidogrel plus aspirin vs. aspirin RCTs; conversely, all-cause mortality was significantly lower in ticagrelor and prasugrel vs. clopidogrel RCTs (risk ratio[RR] 0.49, 95% confidence interval[CI] 0.33-0.71, p?=?0.0002; 2 RCTs, n?=?1695; I(2) ?=?0%; interaction p?<?0.01 compared to clopidogrel plus aspirin vs aspirin RCTs). There were no differences in myocardial infarctions, strokes, or composite outcomes. Overall, major bleeding was not significantly increased (RR 1.31, 95% CI 0.81-2.10, p?=?0.27; 7 RCTs, n?=?4500). There was heterogeneity (I(2) ? =?42%) due almost entirely to higher bleeding reported for the prasugrel RCT which included mainly CABG-related major bleeding (RR 3.15, 95% CI 1.45-6.87, p?=?0.004; 1 RCT, n?=?437).Most RCT data for DAPT post CABG is derived from subgroups of ACS patients in DAPT RCTs requiring CABG who resume DAPT post-operatively. Limited RCT data with heterogeneous trial designs suggest that higher intensity (prasugrel or ticagrelor) but not lower intensity (clopidogrel) DAPT is associated with an approximate 50% lower mortality in ACS patients who underwent CABG based on post-randomization subsets from single RCTs. Large prospective RCTs evaluating the use of DAPT post-CABG are warranted to provide more definitive guidance for clinicians.
Project description:To examine the effect of de-escalation of P2Y12 inhibitor in dual antiplatelet therapy (DAPT) on major adverse cardiovascular events (MACE) and bleeding complications after acute myocardial infarction (AMI) in Taiwanese patients undergoing percutaneous coronary intervention (PCI). Patients who had received PCI during hospitalization for AMI (between 2013 and 2016) and were initially treated with aspirin and ticagrelor and without adverse events after 3 months of treatment were retrospectively evaluated. In total, 1,901 and 8,199 patients were identified as "de-escalated DAPT" (switched to aspirin and clopidogrel) and "unchanged DAPT" (continued on aspirin and ticagrelor) cohorts, respectively. With a mean follow-up of 8 months, the incidence rates (per 100 person-year) of death, AMI readmission and MACE were 2.89, 3.68, and 4.91 in the de-escalated cohort and 2.42, 3.28, and 4.72 in the unchanged cohort, respectively, based on an inverse probability of treatment weighted approach that adjusting for baseline characteristics of the patients. Multivariate Cox regression analyses showed the two groups had no significant differences in the hazard risk of death, AMI admission, and MACE. Additionally, there was no observed difference in the risk of bleeding, including major or clinically relevant non-major bleeding. The real-world data revealed that de-escalation of P2Y12 inhibitor in DAPT was not associated with a higher risk of death or AMI readmission in Taiwanese patients with AMI undergoing successful PCI.
Project description:Objective:To ascertain whether different oral P2Y12 inhibitors might affect rates of acute stent thrombosis and 30-day outcomes after primary percutaneous coronary intervention (pPCI). Methods:The European Ambulance Acute Coronary Syndrome Angiography (EUROMAX) randomised trial compared prehospital bivalirudin with heparin with optional glycoprotein IIb/IIIa inhibitor treatment in patients with ST-segment elevation myocardial infarction triaged to pPCI. Choice of P2Y12 inhibitor was at the investigator's discretion. In a prespecified analysis, we compared event rates with clopidogrel and newer oral P2Y12 inhibitors (prasugrel, ticagrelor). Rates of the primary outcome (acute stent thrombosis) were examined as a function of the P2Y12 inhibitor used for loading and 30-day outcomes (including major adverse cardiac events) as a function of the P2Y12 inhibitor used for maintenance therapy. Logistic regression was used to adjust for differences in baseline characteristics. Results:Prasugrel or ticagrelor was given as the loading P2Y12 inhibitor in 49% of 2198 patients and as a maintenance therapy in 59%. No differences were observed in rates of acute stent thrombosis for clopidogrel versus newer P2Y12 inhibitors (adjusted OR 0.50, 95% CI 0.13 to 1.85). After adjustment, no difference was observed in 30-day outcomes according to maintenance therapy except for protocol major (p=0.029) or minor (p=0.025) bleeding and Thrombolysis In Myocardial Infarction minor bleeding (p=0.002), which were less frequent in patients on clopidogrel. Consistent results were observed in the bivalirudin and heparin arms. Conclusions:The choice of prasugrel or ticagrelor over clopidogrel was not associated with differences in acute stent thrombosis or 30-day ischaemic outcomes after pPCI. Trial registration number:NCT01087723.
Project description:OBJECTIVE:Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor is the cornerstone of treatment in patients with acute coronary syndromes (ACS) and in those undergoing percutaneous coronary intervention (PCI). In current clinical situation, availability of different oral P2Y12 inhibitors (clopidogrel, prasugrel, and ticagrelor) has enabled physicians to switch among therapies owing to specific clinical scenarios. Although optimum time, loading dose and interval of transition between P2Y12 inhibitors is still controversial and needs further evidence, switching between oral inhibitors frequently occurs in clinical practice for several reasons. DATA SOURCES:This review was based on data in articles published in PubMed up to June 2018, with the following keywords "antiplatelet therapy", "ACS", "PCI", "ticagrelor", and "clopidogrel". STUDY SELECTION:Original articles and critical reviews on de-escalation strategy in ACS patients after PCI were selected. References of the retrieved articles were also screened to search for potentially relevant papers. RESULTS:Safety concerns associated with switching between antiplatelet agents, has prompted the use of clopidogrel for patients with ACS especially after PCI as a de-escalation strategy. Practical considerations for de-escalating therapies in patients with ACS such as reducing dose of P2Y12 inhibitors or shortening duration of DAPT (followed by aspirin or P2Y12 receptor inhibitor monotherapy) as potential options are yet to be standardized and validated. CONCLUSIONS:Current review will provide an overview of the pharmacology of common P2Y12 inhibitors, definitions of de-escalation and different de-escalating strategies and its outcomes, along with possible direction to be explored in de-escalation.
Project description:OBJECTIVE:To evaluate the clinical utility of individualising dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) in an all-comers population, including ST-elevation myocardial infarction (STEMI) patients. SETTING:Tertiary care single centre registry. PARTICIPANTS:1008 consecutive PCI patients with stent implantation, without exclusion criteria. INTERVENTION:Peri-interventional individualisation of DAPT, guided by multiple electrode aggregometry (MEA), to overcome high on-treatment platelet reactivity (HPR) to ADP-induced (?50 U) and arachidonic acid (AA)-induced aggregation (>35 U). OUTCOME MEASURES:The primary efficacy end point was definite stent thrombosis (ST) at 30 days. The primary safety end point was thrombolysis in myocardial infarction (TIMI) major and minor bleeding. Secondary end points were probable ST, myocardial infarction, cardiovascular death and the combined end point: major cardiac adverse event (MACE). RESULTS:53% of patients presented with acute coronary syndrome (9% STEMI, 44% non-ST-elevation). HPR to ADP after 600 mg clopidogrel loading occurred in 30% of patients (73±19 U vs 28±11 U; p<0.001) and was treated by prasugrel or ticagrelor (73%), or clopidogrel (27%) reloading (22±12 U; p<0.001). HPR to ADP after prasugrel loading occurred in 2% of patients (82±26 U vs 19±10 U; p<0.001) and was treated with ticagrelor (34±15 U; p=0.02). HPR to AA occurred in 9% of patients with a significant higher proportion in patients with HPR to ADP (22% vs 4%, p<0.001) and was treated with aspirin reloading. Definite ST occurred in 0.09% of patients (n=1); probable ST, myocardial infarction, cardiovascular death and MACE occurred in 0.19% (n=2), 0.09% (n=1) and 1.8% (n=18) of patients. TIMI major and minor bleeding did not differ between patients without HPR and individualised patients (2.6% for both). CONCLUSIONS:Individualisation of DAPT with MEA minimises early thrombotic events in an all-comers PCI population to an unreported degree without increasing bleeding. A randomised multicentre trial utilising MEA seems warranted. TRIAL REGISTRATION NUMBER:http://www.clinicaltrials.gov; NCT01515345.
Project description:Dual antiplatelet therapy, composed of aspirin plus a P2Y12 -receptor antagonist, is the cornerstone of treatment for patients with acute coronary syndrome (ACS). A number of U.S. Food and Drug Administration-approved P2Y12 -receptor antagonists are available for treating patients with ACS, including the thienopyridine compounds clopidogrel and prasugrel. Ticagrelor, the first of a new class of antiplatelet agents, is a noncompetitive, direct-acting P2Y12 -receptor antagonist. Unlike the thienopyridine compounds, ticagrelor does not require metabolism for activity. Also, whereas clopidogrel and prasugrel are irreversible inhibitors of the P2Y12 receptor, ticagrelor binds reversibly to inhibit receptor signaling and subsequent platelet activation. In pharmacodynamic studies, ticagrelor demonstrated faster onset and more potent inhibition of platelet aggregation than clopidogrel. These properties of ticagrelor may contribute to reduced rates of thrombotic outcomes compared with clopidogrel, as demonstrated in a phase III clinical trial. However, in addition to bleeding, distinctive adverse effects of this new chemical entity have not been reported with the thienopyridine P2Y12 -receptor inhibitors. Although ticagrelor represents an advancement in P2Y12 -receptor inhibition therapy, a thorough understanding of this compound as an antiplatelet therapy remains to be elucidated.