P2Y12 Receptor Inhibitor Research Articles

Effectiveness and Safety of Prasugrel versus Ticagrelor in PCI-treated ACS/AMI Patients: Meta-analysis

Introduction: As per international guidelines the P2Y12 receptor inhibitor, ticagrelor or prasugrel is recommended over clopidogrel for patients with acute coronary syndrome (ACS). Aims: To determine the effectiveness and safety of Prasugrel versus ticagrelor in patients with ACS/AMI (acute myocardial infarction) who underwent percutaneous coronary intervention (PCI) through meta-analysis of clinical trials. Methods: We performed a meta-analysis of randomized and non-randomized trials [with search results up to April 2023 in the following databases: PubMed (MEDLINE) and Google Scholar comparing prasugrel and ticagrelor in PCI-treated acute ACS/ AMI patients for the following: Composite of 1-year all-cause death, non-fatal MI, or stroke; Composite of 1-year cardiovascular death, non-fatal MI, or stroke; and individual parameters (all-cause death, cardiovascular death, non-fatal MI and stroke) and major bleeding as Bleeding Academic Research Consortium (BARC) type 3 to 5 bleeding (more severe bleeding) at 1-year. 4 studies met the metanalysis inclusion criteria. It was conducted on the data of a total of 10479 patients (5079 in the prasugrel group and 5400 ticagrelor group). Results: Prasugrel and ticagrelor have insignificant differences for the pooled relative risks of the following: composite of 1-year all-cause death, non-fatal myocardial infarction (MI), or stroke 0.921 (95% CI, 0.719 to 1.181; p =0.518); composite of 1-year cardiovascular death, non-fatal MI, or stroke 0.830 (95% CI, 0.598 to 1.152; p =0.265); BARC type 3 to 5 bleeding (more severe bleeding) at 1-year was 0.988 (95% CI, 0.774 to 1.262; p =0.924); individual parameters (all-cause death, cardiovascular death, non-fatal myocardial infarction (MI) and stroke). There was either inconsistency/heterogeneity and minimal or no inconsistency/ heterogeneity for different parameters in the data. There was no publication bias for all trials. Conclusion: Prasugrel and ticagrelor have similar effects for their relative risks of the following; composite of 1-year all-cause death, non-fatal MI, or stroke; composite of 1-year cardiovascular death, non-fatal MI, or stroke; and individual parameters and BARC type 3 to 5 bleeding at 1 year in patients with ACS/AMI undergoing PCI.

Novel Platelet Function Analyzer 200 Predicts Blood Transfusion After Elective Cardiac Surgery in Patients Suspended on Dual Antiplatelet Therapy.

The value of platelet function test in timing of cardiac surgery remains uncertain. Researches on correlation between Platelet Function Analyzer 200 (PFA-200) and bleeding after elective cardiac surgery are still inadequate. The objective of this study was to investigate the predictive value of PFA-200 in blood transfusion after cardiac surgery. A total of 71 patients on aspirin and P2Y12 receptor inhibitors undergoing cardiac surgery in Fuwai Hospital were enrolled. Platelet function after discontinuing of antiplatelet drugs was assessed by PFA-200 using closure time (CT). PFA-200 results before surgery were included in the statistics. The primary endpoint was postoperative blood transfusion. Seventeen patients (21.9%) received blood transfusion after cardiac surgery. The preoperative PFA-200 CT value in the transfused group was significantly higher than that in the non-transfused group (147.24 ± 85.54 s vs 98.06 ± 61.59 s, P = .011). Using 106 seconds as the dividing point, the incidence of blood transfusion in the elevated PFA-200 (CT > 106 s) group was significantly higher than those in normal PFA-200 (CT ≤ 106 s) group (10/24 patients, 41.9% vs 7/47 patients, 14.7%, P = .012). Multivariate logistic regression analysis showed that PFA-200 CT value > 106 s was an independent predictor of postoperative blood transfusion (OR: 4.05, 95%CI: 1.19-13.86, P = .026). The platelet function test PFA-200 had a predictive value for postoperative blood transfusion in elective cardiac surgery and had a promising prospect in the timing of cardiac surgery.

Immature Platelet Fraction Predicts Adverse Events in Patients With Acute Coronary Syndrome: the ISAR-REACT 5 Reticulated Platelet Substudy.

Immature or reticulated platelets are associated with impaired efficacy of antiplatelet drugs and adverse events in cardiovascular patients. Their role as a predictive biomarker in patients with acute coronary syndrome treated with potent P2Y12 receptor inhibitors is not fully understood. We aimed to prospectively evaluate reticulated platelets as a predictor of the primary end point of the ISAR-REACT 5 trial consisting of death, myocardial infarction, or stroke at 1 year in patients with acute coronary syndrome randomized to prasugrel or ticagrelor. Immature platelet fraction (IPF) was assessed within 48 hours after randomization. Patients were divided based on the IPF median values: the IPFhigh group included patients with IPF>median and the IPFlow group included patients with IPF≤median. Platelet aggregation was assessed using the Multiplate Analyzer and was correlated to IPF. Five hundred seventy-seven patients were included in the study. IPF values in % (median [interquartile range]) within the first 48 hours did not differ between the two study groups: 3.6 (2.5-5.2)% in the prasugrel group and 3.6 (2.5-5.4)% in the ticagrelor group (P=0.882). The incidence of the primary end point was significantly higher in the IPFhigh (IPF>3.6%) group compared with the IPFlow (IPF≤3.6%) group: 13.0% versus 7.2% (HRadj, 1.74 [1.02-3.00]; P=0.044), independently from the assigned drug (Pint=0.159). No significant association between IPF and BARC 3 to 5 bleeding was observed. ADP-induced platelet aggregation correlated significantly with IPF in patients treated with prasugrel (r=0.22; P=0.005) while no correlation was detected in patients treated with ticagrelor (r=0.09; P=0.257). Independently from drug treatment, IPF was associated with the primary end point and therefore is a promising biomarker for the prediction of adverse cardiovascular events in patients with acute coronary syndrome treated with prasugrel or ticagrelor. https://www. gov; Unique identifier: NCT01944800.

A Review on Different Solubility Enhancement Techniques of Ticagrelor

Ticagrelor is a BCS class IV drug that inhibits platelet action by reversibly binding to the P2Y12 receptor. One of the major challenges faced by the class IV (low solubility, low permeability) drug is the lower dissolution rate leading to low bioavailability. The bioavailability of the marketed formulation of ticagrelor is approximately 36%. Researchers have come up with various techniques to improve the BCS class II and IV drug formulations as an integral part of the development of the pharmaceutical sciences. An increase in solubility can be achieved by various methods such as Salt formation, Complexation, Micronization, Solid Dispersion, altering the pH, Co-solvency, co-crystals, polymeric micelles, etc. A highly efficacious technique is converting a crystalline drug to its amorphous form. An extensive literature search was conducted using various databases like science direct, Taylor and Francis, Springer to extract relevant articles. Keywords like “Ticagrelor”, “low permeability”, “P2Y12 receptor inhibitor” were used for the literature search. Relevant articles were screened and referred for further study. This article discusses the techniques employed to increase the solubility of ticagrelor, thus highlighting the research conducted and reported. The increase in bioavailability of ticagrelor could be seen when formulated as nanoparticles, co-crystals, ticagrelor loaded self-micro emulsifying and nano emulsifying drug delivery system, solid dispersion, etc. the conversion of the crystalline drug into amorphous drug is a highly recommended approach to increase the solubility of ticagrelor which can be seen in cases of co-crystals and solid dispersion formulation.

1031 IMPACT OF PRE-TREATMENT WITH A P2Y12 RECEPTOR INHIBITOR ON PERIPROCEDURAL MYOCARDIAL INFARCTION AND MYOCARDIAL INJURY IN NSTEMI

Abstract Background Dual antiplatelet therapy with aspirin and a P2Y12 receptor inhibitor is the standard of care in patients with acute coronary syndromes. The optimal timing of the administration of oral P2Y12 inhibitors has been largely debated, particularly among patients with non-ST-segment elevation myocardial infarction (NSTEMI). The latest European Society of Cardiology guidelines, based on recent scientific evidence, do not recommend routine pre-treatment with a P2Y12 inhibitor before coronary angiography. However, the impact of pre-treatment on the incidence of peri-procedural myocardial infarction (MI) and myocardial injury has never been explored. Purpose To evaluate the impact of pre-treatment with a P2Y12 receptor inhibitor on periprocedural myocardial infarction and injury in NSTEMI patients undergoing invasive treatment. Methods We evaluated all consecutive patients admitted to our coronary care unit from 2016 to 2021 affected by NSTEMI undergoing invasive management with percutaneous coronary intervention (PCI). We enrolled only patients with stable (≤ 20% variation) or falling pre-procedure baseline cardiac troponin (cTn) values. The entire population was divided into two groups: patients pre-treated with dual antiplatelet therapy (an oral P2Y12 inhibitor in adjunct to aspirin) before performing coronary angiography (upstream group) and patients who started an oral P2Y12 inhibitor only after PCI (downstream group). All patients received aspirin and anticoagulant therapy before coronary angiography. The primary endpoint was the incidence rate of periprocedural MI and myocardial injury according to the fourth universal definition of myocardial infarction. Finally, a safety endpoint of major and minor bleeding according to Thrombolysis in Myocardial Infarction (TIMI) criteria was evaluated for all bleeding episodes during hospitalization. Results A total of 878 patients with NSTEMI undergoing PCI and with pre-procedure stable cTn levels were analyzed: 615 (70%) constituted the upstream group. The mean age of the study population was 70.1±12.5 years and 71.3% were males. There were no significant differences regarding traditional cardiovascular risk factors, comorbidities, cTn and hemoglobin levels between the two groups. After PCI, the rate of periprocedural myocardial injury and MI did not significantly differ between the upstream and downstream groups (19.5% vs 24.7%, p=0.08 and 17.6% vs 19.4%, p=0.5, respectively). A trend of lower periprocedural myocardial injury and MI cumulative incidence was observed in the upstream group (37.1% vs 44.1%, p=0.051). Notably, major and minor bleedings during hospitalization occurred more frequently in the upstream group compared to the downstream one (5.2% vs 1.9%, p=0.02). Conclusions Among NSTEMI patients undergoing invasive management and with stable pre-procedure cTn levels, pretreatment with an oral P2Y12 inhibitor did not reduce the rate of periprocedural MI and myocardial injury but was associated with an increase in major and minor bleeding complications during hospitalization.

47 UNDER THE BRIDGE: OFF-LABEL CANGRELOR FOR PCI PATIENTS UNDERGOING NON CARDIAC SURGERY

Abstract Background Dual antiplatelet therapy (DAPT) reduces the risk of stent thrombosis after percutaneous intervention (PCI), but it is estimated that approximately 5 to 10% of PCI patients undergo major noncardiac surgeries within 12 months from the procedure, which requires DAPT interruption. The interruption of DAPT reduces the risk of perioperative bleeding, but increases the risk of stent thrombosis. Peri-operative “bridge” therapy with cangrelor, a reversible and competitive intravenous P2Y12 receptor inhibitor with rapid on/offset of action, may offer a solution for high-risk patients undergoing major noncardiac surgery who require DAPT interruption. However, the use of cangrelor for this indication is currently off-label. Clinical Scenario A 58-year-old man was admitted to ER with increasing dyspnea and oppressive chest pain on exertion. A diagnosis of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) was made and PCI of the left main-left anterior descendent artery segment and the right coronary artery was performed with implantation of four drug-eluting stents. DAPT was prescribed for 12 months with acetylsalicylic acid 100 mg daily and ticagrelor 90 mg twice daily. The day after the procedure, due to gross hematuria with clots formation; the hemoglobin level fell to 8 g/dL and a transfusion was required. Subsequent abdominal echocardiography revealed two bladder neoformations that required further endoscopic evaluation and transurethral resection of bladder tumor (TURBT). In preparation for such invasive procedure, DAPT required interruption despite the high risk of catastrophic consequences. Methods After ticagrelor interruption, cangrelor was started intravenously at a rate of 0.6 mcg/Kg/min for 5 days and stopped 2 hours before the TURBT procedure, which was performed with minimal blood loss and no ischemic complications. Cangrelor infusion was re-started 2 hours after surgery at the same initial rate and planned for 12 hours if no sudden bleeding occurred. The day after the TURBT procedure cangrelor was stopped and DAPT was re-initiated with aspirin 100 mg daily and clopidogrel 75 mg daily (after a 600 mg loading dose). The patient was discharged 2 days later without any new bleeding or ischemic event. Conclusions Premature discontinuation of DAPT is a strong predictor of stent thrombosis in patients undergoing PCI who require major noncardiac surgery. Cangrelor represents a viable option for managing high-risk individuals who require prolonged P2Y12 receptor blockade with rapid onset and offset of action despite discontinuation of oral therapy. This use is currently off-label due to lack of well powered randomized clinical trials of bridge therapy.

730 P2Y12 INHIBITORS MONOTHERAPY IN PATIENTS UNDERGOING COMPLEX VS NON-COMPLEX PERCUTANEOUS CORONARY INTERVENTION: A SYSTEMATIC REVIEW AND META-ANALYSIS

Abstract Background Monotherapy with P2Y12 inhibitors (P2Y12i) is emerging as alternative strategy to dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI). However, early withdrawal of aspirin as part of P2Y12i monotherapy regimens may pose concerns in high-risk patients, such as those undergoing complex PCI. Thus, we aimed to evaluate the efficacy and safety of P2Y12i monotherapy compared with standard DAPT according to PCI complexity. Methods We performed a meta-analysis of randomized trials using random effects models to combine hazard ratios (HRs) with 95% confidence intervals (CIs). No restrictions were applied to the type of P2Y12 receptor inhibitor or to the definition of complex PCI. Within-trial interactions were pooled to estimate heterogeneity between complex and noncomplex PCI strata. The study protocol was registered in the PROSPERO (CRD42021291027). Results After screening of 7,502 unique citations, we included in the analysis 5 randomized clinical trial enrolling 31,627 patients, of whom 8,328 (26.3%) underwent complex PCI (Table 1) Risk estimates for efficacy and safety outcomes associated with P2Y12i monotherapy and standard DAPT across studies included in the analysis, stratified by complex and noncomplex PCI, are reported in Figure 1. P2Y12i monotherapy compared with standard DAPT was associated with a similar risk of all-cause death, stent thrombosis, and stroke, with no evidence for interaction between complex and noncomplex PCI. We found heterogeneity in the treatment effect of P2Y12i monotherapy vs. standard DAPT with respect to myocardial infarction (P-interaction=0.027). Compared with standard DAPT, P2Y12i monotherapy decreased the risk of myocardial infarction in complex PCI (HR 0.77, 95%CI 0.60-0.99, P=0.042), but not in noncomplex PCI patients (HR 1.09, 95%CI 0.90-1.30, P=0.382). The risk of major bleeding was significantly reduced by P2Y12i monotherapy with a consistent treatment effect (P-interaction=0.699) in both complex and noncomplex PCI strata. Conclusions Patients undergoing complex PCI may derive more benefit and less harm from P2Y12i monotherapy after early aspirin withdrawal compared with standard DAPT, resulting in decreased risks of myocardial infarction and bleeding.

351 MULTIPLE PHARMACODYNAMIC ASSESSMENTS OF CANGRELOR EFFECTS IN ELECTIVE COMPLEX PCI: DATA FROM PHARMACODYNAMIC EFFECTS OF CANGRELOR IN PATIENTS WITH ACUTE OR CHRONIC CORONARY SYNDROME UNDERGOING PERCUTANEOUS CORONARY INTERVENTION REGISTRY

Abstract Aims Complex percutaneous coronary intervention (PCI) patients have greater risk of peri-procedural complications, with potential to be associated with poor short-term and late prognosis. Cangrelor is an intravenous P2Y12 receptor inhibitor characterized by rapid onset and offset effect of platelet inhibition which reduced the risk of thrombotic complications. Cangrelor use is currently approved in patients naïve from oral P2Y12 inhibitors with chronic (CCS) or acute coronary syndrome (ACS) undergoing PCI with a IIb recommendation by European guidelines. Yet, the process of switching from cangrelor to oral P2Y12 inhibitor remains uncertain. Methods and Results POMPEII study (NCT04790032) is a prospective registry conducted at Federico II University of Naples enrolling all patients undergoing PCI and receiving cangrelor administration. Pharmacodynamic (PD) assessments were performed at baseline, at 30 minutes, 3 hours and 4-6 hours after cangrelor initiation with 3 assays: 1) the gold standard light transmittance aggregometry (LTA) (20- and 5-µM adenosine diphosphate [ADP] stimuli); 2) VerifyNow P2Y12-test; 3) Multiplate electrode aggregometry (MEA), ADP-test. We enrolled 41 patients undergoing elective complex PCI. All patients were P2Y12 inhibitor naïve and received aspirin, unfractionated heparin, and cangrelor (30-µg/kg bolus followed by 4-µg/kg/min infusion for 2 hours) prior to the start of PCI per standard of care. All patients showed low P2Y12 reactivity at 30 minutes during cangrelor infusion with a mean inhibition of platelet aggregation (IPA, %) of 55.7±18.0% at LTA 20-µM ADP test (34% with IPA ≤50%, 19.5% with IPA≥70%, 4.9% with IPA ≥80% and none IPA ≥90%). High residual platelet reactivity (HRPR) was observed in 1 case (2.4%) as shown by LTA (both 20- and 5-µM ADP stimuli) but not confirmed by VerifyNow and MEA. HRPR was observed in 55% at at 3h and 22.5% at 4-6h at LTA 20-µM and consistently with other assays. All patients with HRPR after cangrelor stop had received clopidogrel as switching drug, while no HRPR was observed in the 4 patients switching to ticagrelor. Conclusions Cangrelor showed to be effective and safe in patients undergoing complex PCI at high thrombotic risk. The switch from cangrelor to clopidogrel could expose patients to a variable period of on-treatment HRPR with inadequate platelet inhibition probably due to the fast offset of cangrelor effect and delay of oral drug effect, while the use of ticagrelor soon after cangrelor start might be ideal to cover the gap. This might be of relevance in such a delicate clinical setting.

Pretreatment with a P2Y12 receptor inhibitor and delay to coronary artery bypass surgery in patients with non-ST segment elevation acute coronary syndrome.

2020 ESC guidelines for non-ST elevation acute coronary syndromes (NSTE-ACS) recommend against the pretreatment with P2Y12 receptor inhibitors (P2Y12i) in patients undergoing early invasive management (<24 h). The rationale is, in part, to prevent bleeding complications and the delay of coronary artery bypass graft surgery (CABG) in patients with suitable coronary anatomy. This study aimed to analyze the theoretical impact of pretreatment with a P2Y12i on delay to CABG surgery in a real-world population with NSTE-ACS. Single-center retrospective cohort of consecutive patients with NSTE-ACS undergoing invasive evaluation in 2019. Those with previous CABG or nonobstructive coronary disease were excluded. The total cohort included 262 patients (mean age 68±12 years, 69% male, 15% with unstable angina and mean GRACE score 134±35). Median time from FMC to angiography was 2 (1-4) days. Overall, 168 (64%) patients underwent percutaneous coronary intervention, 47 (18%) were proposed for CABG and the remainder received conservative management. All patients considered for CABG received pretreatment with P2Y12i (clopidogrel or ticagrelor). The median time from angiography to CABG was 12 (7-15) days. Six patients experienced recurrent angina (13%) and 2 (4%) died before surgery due to refractory ventricular fibrillation. Those who underwent CABG under P2Y12i effect were more likely to receive blood and platelets transfusions (64.7% vs. 28.6%, P=0.017 and 82.4% vs. 21.4%, P<0.001, respectively), although there were no differences regarding major bleeding. Pretreatment with P2Y12i was a potential but not the sole driver of CABG delay in our cohort. Adopting the new recommendations of withholding pretreatment might decrease this delay, but other factors must be considered.

Performance Evaluation of a New Microfluidic Platelet Function Test Platform

To evaluate the performance of a microfluidic platelet function test platform (MPFTP) previously established by our research group. The effects of flow shear rate and storage time on platelet function test were analyzed taking the MPFTP as the object. The intra-assay variability of the MPFTP was evaluated. The function of platelet in peripheral venous blood from 24 healthy volunteers was assessed using the MPFTP and light transmission turbidity, either in the presence of 20 μmol/L acetylsalicylic acid (AS, an inhibitor of cyclooxygenase 1) or 50 μmol/L 5-phospho-2-methylthioadenosine (2-MeSAMP, a P2Y12 receptor inhibitor). The diagnostic performance of both methods in assaying platelet function inhibition by AS and 2-MeSAMP was analyzed by using receiver operating characteristic (ROC) curve. Under the flow shear rate of 1 500 s-1, our MPFTP could dynamically monitor platelet adhesion and aggregation, as well as quantify platelet function. Platelet aggregation increased with the increase of flow shear rate, while sample storage at room temperature for up to 5 h did not affect results of platelet function test. The intra-assay variability coefficient of variation of the MPFTP was <15%. The area under the curve of ROC showed that this platform had good diagnostic performance in the identification of platelet function inhibition by AS and 2-MeSAMP. This MPFTP shows good analytical performance for the assay of platelet function and can be developed into a new clinical platelet function test device in the future.

СРАВНЕНИЕ ЭФФЕКТИВНОСТИ И БЕЗОПАСНОСТИ ИНГИБИТОРОВ P2Y12 РЕЦЕПТОРОВ У ПАЦИЕНТОВ С ИНВАЗИВНОЙ СТРАТЕГИЕЙ ВЕДЕНИЯ ОСТРОГО КОРОНАРНОГО СИНДРОМА

Dual antiplatelet therapy (DAPT) using of acetylsalicylic acid and antagonists of platelet’s P2Y12 receptors is included in standards for treatment of patients with acute coronary syndrome (ACS) who underwent percutaneous coronary intervention (PCI). Clopidogrel, prasugrel, and ticagrelor are the P2Y12 receptor inhibitors used as a component of DAPT. The aim of this review is to determine the most effective and the safest P2Y12 receptor inhibitor for treating patients with an invasive treatment strategy of ACS. The TRITON study compared clopidogrel and pragugrel efficacy and safety had demonstrated a significantly higher efficiency in reducing the risk of reaching the primary endpoint (including cardiovascular death, myocardial infarction and stroke) for prasugrel, but at the same time, the prasugrel group was reliably recorded higher rate of major bleeding. Comparison of the efficacy and safety of clopidogrel and ticagrelor was carried out in the PLATO study, where ticagrelor was shown to be more effective in reducing cardiovascular deaths and myocardial infarction, while the safety of the drugs was comparable. A subsequent ISAR-REACT 5 study proved higher efficacy of prasugrel compared to ticagrelor in reducing the risk of reaching a primary endpoint with comparable safety to the major bleeding risk. Baseline data represents that the most effective drug among P2Y12 receptor inhibitors as a component of DAPT for patients with an invasive treatment strategy is prasugrel, and the safest is clopidogrel, which can be considered in elderly patients.

Impact of Close Surveillance on Dual-Antiplatelet Therapy Compliance in Myocardial Infarction Patients Post-Percutaneous Coronary Intervention

BackgroundDual-antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor is the mainstay regimen for acute coronary syndrome (ACS) patients after percutaneous coronary intervention (PCI). We aimed to investigate DAPT compliance and switching patterns in ACS patients prescribed ticagrelor and aspirin. Secondly, we evaluated the impact of a pilot strategy of close surveillance telephone calls. MethodsThe study enrolled 150 consecutive ACS patients who underwent PCI and were prescribed DAPT (aspirin and ticagrelor). This cohort, the “close surveillance arm,” then received telephone calls from a healthcare professional to inquire about DAPT for up to one year. These findings, and clinical outcomes, were then compared to a “historical arm” of ACS patients (n = 505) who received PCI and were prescribed DAPT before initiation of the program. Finally, healthcare providers were surveyed about their experience with prescribing DAPT. ResultsThe rate of ticagrelor cessation trended lower in the close surveillance arm (22.00 % versus 31.70 %, p = 0.0783). The most common reasons for ticagrelor cessation were adverse medication reaction (dyspnea), bleeding, and financial burden. Nevertheless, the adverse events were few and similar between the two groups during follow-up. Over 96 % of healthcare providers surveyed stated that they worry about their patients' DAPT compliance post-PCI. ConclusionNoncompliance and switching medications are still common for patients who undergo PCI for ACS. A close surveillance program identified patients at risk for medication cessation or switching and could potentially mitigate this phenomenon and improve quality of care.

СРАВНЕНИЕ ЭФФЕКТИВНОСТИ И БЕЗОПАСНОСТИ ИНГИБИТОРОВ P2Y12 РЕЦЕПТОРОВ У ПАЦИЕНТОВ С ИНВАЗИВНОЙ СТРАТЕГИЕЙ ВЕДЕНИЯ ОСТРОГО КОРОНАРНОГО СИНДРОМА

Dual antiplatelet therapy (DAPT) using of acetylsalicylic acid and antagonists of platelet’s P2Y12 receptors is included in standards for treatment of patients with acute coronary syndrome (ACS) who underwent percutaneous coronary intervention (PCI). Clopidogrel, prasugrel, and ticagrelor are the P2Y12 receptor inhibitors used as a component of DAPT. The aim of this review is to determine the most effective and the safest P2Y12 receptor inhibitor for treating patients with an invasive treatment strategy of ACS.&#x0D; The TRITON study compared clopidogrel and pragugrel efficacy and safety had demonstrated a significantly higher efficiency in reducing the risk of reaching the primary endpoint (including cardiovascular death, myocardial infarction and stroke) for prasugrel, but at the same time, the prasugrel group was reliably recorded higher rate of major bleeding.&#x0D; Comparison of the efficacy and safety of clopidogrel and ticagrelor was carried out in the PLATO study, where ticagrelor was shown to be more effective in reducing cardiovascular deaths and myocardial infarction, while the safety of the drugs was comparable.&#x0D; A subsequent ISAR-REACT 5 study proved higher efficacy of prasugrel compared to ticagrelor in reducing the risk of reaching a primary endpoint with comparable safety to the major bleeding risk.&#x0D; Baseline data represents that the most effective drug among P2Y12 receptor inhibitors as a component of DAPT for patients with an invasive treatment strategy is prasugrel, and the safest is clopidogrel, which can be considered in elderly patients.

Comparison of the efficacy and safety between different oral P2Y12 receptor inhibitors in patients with acute coronary syndrome: a systematic review and meta-analysis

Abstract Introduction Dual antiplatelet therapy (DAPT) with aspirin and a P2Y12 receptor inhibitor for at least 1 month is the mainstay of therapy after an acute coronary syndrome (ACS). Despite several randomized controlled trials (RCTs) having compared different DAPT regimens after an ACS, the choice of the optimal P2Y12 receptor inhibitor is still debated. Purpose We aimed to compare the efficacy and safety profiles of the new P2Y12 receptor inhibitors (prasugrel and ticagrelor) versus clopidogrel in patients with ACS through a meta-analysis of RCTs. Methods We performed an extensive literature search, from January 1970 to December 2021 using PubMed database. Studies were eligible if they were RCTs directly comparing different oral P2Y12 receptor inhibitors in patients with ACS. Data on study methods, patient characteristics, and outcomes of interest (all-cause and cardiovascular death, recurrent myocardial infarction, stroke, major and non-major bleeding) were extracted from the original publications. We performed a meta-analysis using a random-effects model with the Mantel–Haenszel method. The effect measures of each study included were calculated and reported as odds ratio (OR) with 95% confidence interval (CI), visually presented in forest plots. A two-sided p-value &amp;lt;0.05 was considered statistically significant. Heterogeneity was tested using the I2-statistic. Results A total of 117 studies were available for the analysis; after full reading 11 studies were eligible to be analyzed. The 11 studies reported data on 50,722 patients: 25,424 [50.1%] taking a new oral P2Y12 receptor inhibitor and 25,298 [49.9%] taking clopidogrel. Patients receiving ticagrelor or prasugrel showed a lower risk of all-cause mortality (OR 0.88, 95% confidence interval [CI] 0.80–0.97, I2=8%), cardiovascular mortality (OR 0.88, 95% CI 0.81–0.95, I2=0%), and recurrent myocardial infarction (OR 0.86, 95% CI 0.76–0.97, I2=43%) compared to those receiving clopidogrel. The two groups did not differ significantly concerning the risk of stroke (OR 0.98, 95% CI 0.82–1.17, I2=0%), major bleeding (OR 1.05, 95% CI 0.97–1.15, I2=0%), or non-major bleeding (OR 1.36, 95% CI 0.85–2.20, I2=67%). By restricting the analysis to the studies comparing ticagrelor versus clopidogrel, the ticagrelor group showed a lower risk of all-cause mortality (OR 0.79, 95% CI 0.70–0.90, I2=0%), but a higher risk of non-major bleeding (OR 1.67, 95% CI 1.05–2.66, I2=30%). There was no significant difference between ticagrelor and clopidogrel in terms of cardiovascular death (OR 0.87, 95% CI 0.73–1.05, I2=0%), stroke (OR 1.06, 95% CI 0.85–1.13, I2=0%), or major bleeding (OR 1.02, 95% CI 0.93–1.12, I2=0%). Conclusions In patients with an ACS, a DAPT strategy with aspirin plus either prasugrel or ticagrelor is associated with a reduced risk of all-cause and cardiovascular mortality as well as of recurrent myocardial infarction compared to aspirin plus clopidogrel, without an increased risk of bleeding. Funding Acknowledgement Type of funding sources: None.

Safety of intravenous cangrelor infusion during percutaneous coronary intervention in a real-world cohort of non-pretreated NSTEACS patients

Abstract Background and purpose Since publication of latest ESC guidelines in 2020, pretreatment with an oral P2Y12 receptor inhibitor (P2Y12i) is no longer systematically recommended in patients with non-ST elevation acute coronary syndrome (NSTEACS) [1]. Therefore, from now on, NSTEACS patients will arrive to the cathlab to a larger extent without having a loading dose of an oral P2Y12i administered. Cangrelor, a potent intravenous P2Y12i, is an emerging option that provides a rapid onset of platelet inhibition, but it has not been widely used yet [2]. We aimed to evaluate safety of cangrelor real-world use in NSTEACS patients who had not received an oral P2Y12i before percutaneous coronary intervention (PCI). Methods Development of periprocedural thrombotic complications, ischaemic and bleeding events at 30 days was retrospectively evaluated in a cohort of non-pretreated NSTEACS patients referred to PCI. Comparison among those who underwent intravenous infusion of cangrelor and those who received a loading dose of an oral P2Y12i (ticagrelor, prasugrel or clopidogrel) at the moment of PCI was performed. Results Between January and December of 2020, 155 non-pretreated NSTEACS patients were referred to our cathlab; of whom, 89 underwent PCI and were included in the analysis (18.0% with unstable angina, 82.0% with NSTEMI). Mean age was 66.0±14.3 years, 21 (23.6%) were female and the mean GRACE risk score was 112±34. PCI was performed ad-hoc (immediately after diagnostic catheterization) in 81 patients (91.0%), whereas 15 patients (16.9%) required PCI to be done in more than two times. Procedure was performed exclusively by radial or cubital artery access in 78 patients (87.6%). Regarding antiplatelet drug administration, cangrelor was used in 14 patients (15.7%), prasugrel in 35 (39.3%), ticagrelor in 29 (32.6%) and clopidogrel in 11 (12.4%). No significant differences were found among patients in terms of development of ischaemic events at 30 days (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or stent thrombosis) or periprocedural thrombotic events (no-reflow, bailout use of anti-IIb/IIIb or intraprocedural stent thrombosis). The use of cangrelor did not raise the incidence of bleeding events at 30 days (7.1% vs. 15.1%, p=0.682) [Table 1]. Cangrelor tended to be more frequently used in high-risk NSTEMI patients (20.8% vs. 12.9%, p=0.357) and in case of complex PCI (26.3% vs. 7.8%, p=0.018) [Figure 1]. After controlling by both variables, cangrelor did not significantly increase the risk of bleeding or ischaemic events at 30 days either. Conclusions Intravenous infusion of cangrelor during PCI in non-pretreated NSTEACS patients shows no differences in terms of thrombotic or bleeding events in comparison to the administration of a loading dose of an oral P2Y12i. Our results also suggest that cangrelor could be a safe option in patients with high thrombus burden who require complex PCI. Funding Acknowledgement Type of funding sources: None.

Time to coronary angiography in a real-life cohort of NSTEACS patients: are guidelines too optimistic?

Abstract Background and purpose In 2020, new recommendations against routine use of pretreatment in NSTEACS have been established, especially if an early invasive strategy (within first 24 hours) is planned [1]. These recommendations are mainly based on evidence from clinical trials that have included short intervals of time to coronary angiography (CA) [2,3]. However, this timing seems hard to achieve in daily clinical practice, above all, when high-risk NSTEACS patients are now advised for an early invasive strategy. We aimed to assess the feasibility of these recommendations in real-world clinical practice. Methods We performed a retrospective analysis of a real-life cohort of NSTEACS patients referred to CA in a tertiary-level hospital between January and December 2020. Results We analysed 347 consecutive NSTEACS patients referred to CA (21.7% unstable angina, 78.3% NSTEMI). Percutaneous coronary intervention was performed in 60.5% and the radial or cubital artery access were exclusively used in 86.7%. Median time from hospital admission to CA was 39.4 hours (IQR: 20.7–67.0 hours) and 31.4% patients had the CA performed within first 24 hours (Figure 1). Main differences regarding clinical and risk-related variables among those patients who underwent CA before and after first 24 hours are shown in Table 1. More patients with NSTEMI and dynamic changes in ECG tended to be referred earlier to CA, while those with impaired renal function were more likely to receive a delayed strategy. There were 282 patients (82.7%) who met the high-risk criteria from current ESC guidelines on NSTEACS (GRACE risk score &amp;gt;140, ST transient elevation or depression in ECG, raise of cardiac troponin levels above the 99th percentile of the upper reference limit, cardiogenic shock or cardiac arrest at presentation); of whom, only 95 (33.7%) were referred to CA in the first 24 hours. No differences were found according to patients being admitted to PCI or non-PCI centres (32.1% vs. 30.9% had the CA performed within first 24 hours, p=0.81) or receiving pretreatment with a P2Y12 receptor inhibitor or not (31.7% vs. 31.0% of the CA ≤24 hours group; p=0.87). Conclusion Evidence from this real-life registry shows that median time from admission to CA is far from current recommendations for high-risk NSTEACS patients. This might represent an important limitation at the moment of translating guidelines to daily clinical practice, especially those who presume patients to have a CA performed within first 24 hours. Funding Acknowledgement Type of funding sources: None.

To pretreat or not no pretreat with dual antiplatelet therapy in non-ST elevation acute coronary syndrome patients: that is the question

Abstract Background The timing for the initiation of dual antiplatelet treatment (DAPT) in patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) is controversial and the 2020 ESC guidelines suppressed the recommendation of routine pre-treatment. The aim of our study was to assess the effect of pretreatment on clinical outcomes according to the available evidence. Methods We conducted a meta-analysis of the main studies on pretreatment with P2Y12 receptor inhibitors in patients with NSTE-ACS. After a systematic review, we included four randomized clinical trials (PCI-CURE, ACCOAST, ISAR-REACT 5, and DUBIUS), and one observational study (SCAAR). Data was analyzed using the inverse variance method, using a fixed effects model since no statistically significant heterogeneity was observed. Results A total of 75,345 patients were included, 65,134 patients who followed a systematic pretreatment strategy with DAPT and 10,211 patients with a simple antiplatelet strategy with acetylsalicylic acid (ASA) and administration of a second antiplatelet during angiography and prior to angioplasty. No significant differences were observed in cardiovascular mortality (odds ratio [OR] 1.20; 95% confidence interval [CI] 0.90 to 1.60; P=0.2184) or acute stent thrombosis (OR 0.88; 95% CI, 0.65 to 1.18; p=0.3866). However, a significant increase in major bleeding was observed (OR 1.42; 95% CI, 1.15 to 1.75; p=0.0011). Conclusions Routine pretreatment with DAPT in patients with suspected NSTE-ACS is not associated with a decrease in cardiovascular death or an increase in acute stent thrombosis and, however, it is associated with a significant increase in major bleeding. Funding Acknowledgement Type of funding sources: None.

P2Y12 inhibitors monotherapy in patients undergoing complex vs. non-complex percutaneous coronary intervention: a meta-analysis of randomized trials

Abstract Background Monotherapy with P2Y12 inhibitors (P2Y12i) is emerging as alternative strategy to dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI). However, early withdrawal of aspirin as part of P2Y12i monotherapy regimens may pose concerns in high-risk patients, such as those undergoing complex PCI. Purpose To evaluate the efficacy and safety of P2Y12i monotherapy after a short course of DAPT (1- to 3-month) compared with standard DAPT (≥12-month) according to PCI complexity. Methods We performed a meta-analysis of randomized trials using random effects models to combine hazard ratios (HRs) with 95% confidence intervals (CIs). No restrictions were applied to the type of P2Y12 receptor inhibitor (clopidogrel, prasugrel, or ticagrelor) or to the definition of complex PCI. Within-trial interactions were pooled to estimate heterogeneity between complex and noncomplex PCI strata. The study protocol was registered in the PROSPERO (CRD42021291027). Results We screened 7,502 unique citations, of which 2,948 were screened at title and abstract level and 576 were judged potentially eligible for full-text assessment. We included in the analysis five trials (1–5) enrolling 31,627 patients, of whom 8,328 (26.3%) underwent complex PCI; characteristics of trials and patient populations are summarized in Table 1. Risk estimates for efficacy and safety outcomes associated with P2Y12i monotherapy and standard DAPT across studies included in the analysis, stratified by complex and noncomplex PCI, are reported in Figure 1. P2Y12i monotherapy compared with standard DAPT was associated with a similar risk of all-cause death, stent thrombosis, and stroke, with no evidence for interaction between complex and noncomplex PCI. We found heterogeneity in the treatment effect of P2Y12i monotherapy vs. standard DAPT with respect to myocardial infarction (P-interaction=0.027). Compared with standard DAPT, P2Y12i monotherapy decreased the risk of myocardial infarction in complex PCI (HR 0.77, 95% CI 0.60–0.99, P=0.042), but not in noncomplex PCI patients (HR 1.09, 95% CI 0.90–1.30, P=0.382). The risk of major bleeding was significantly reduced by P2Y12i monotherapy with a consistent treatment effect (P-interaction=0.699) in both complex and noncomplex PCI strata. Conclusions Patients undergoing complex PCI may derive more benefit and less harm from P2Y12i monotherapy after early aspirin withdrawal compared with standard DAPT, resulting in decreased risks of myocardial infarction and bleeding. Funding Acknowledgement Type of funding sources: None.

Comparison of CRUSADE and ORBIT bleeding risk scores in prediction of mayor bleeding in pacients with acute coronary syndrome

Abstract Introduction Mayor bleeding is the most important complication of antithrombotic treatment in acute coronary syndrome (ACS) and is even associated with higher mortality. The CRUSADE scrore has been developed to predict mayor bleeding in ACS and is one of the most used. however, it has a moderate predictive capacity and is relatively complex to calculate at the patient's bedside. On the other hand, different bleeding risk scores have been developed for atrial fibrillation witch have also been evaluated for ACS, for example HAS-BLED. Recently, the NICE guidelines suggest using the Orbit Bleeding score (ORBIT) to assess the risk of bleeding in atrial fibrillation due to its greater predictive capacity. Its usefulness in the context of ACS has been little studied. Purpose The aim of the study is to evaluate the usefulness of the ORBIT to predict major bleeding in patients with ACS compared to the CRUSADE Methods A obserbational retrsopective study was performed. Patients with diagnostico ACS in two coronary units of Argentina were included. All of them, received antocoagulation as a antithrombitic treatment. The CRUSADE and ORBIT scores were calculated with the clinical data on admission. The primary point of major bleeding, defined as a BARC classification 3 or 5, was analyzed. Multivariate analysis was performed by logistic regression. To establish the discrimination capacity of the scores, the area under the ROC curve (AUC) was evaluated and the comparison between the curves was carried out using the chi-square area homogeneity test. Results A total of 880 patients were included (68% with non-ST elevation ACS and 32% with ST elevation), the mean of age was 68±11 years and 35% were women. As antithrombotic treatment, 100% received aspirin, 96.3% received P2Y12 receptor inhibitors, 100% received anticoagulation with enoxaparin, and 9.5% received fibrinolytics. The primary end point of major bleeding occurred in 3.4% (n=30). In univariate analysis both CRUSADE and ORBIT were predictors of mayor bleeding, but in multivariate analysis only ORBIT was independent predictor of mayor bleeding. (ORBIT OR: 2.46 (95% CI 1,61 to 3,97), P&amp;lt;0.001. The table shows the univariate and multivariate analysis. The AUC of CRUSADE was 0.68 (95% CI 0.57–0.80) and the ORBIT was 0.80 (95% CI 0.72–0.90). The ORBIT score presented a higher AUC than the CRUSADE (p=0.03). See Figure 1. Conclusion The Orbit score was an independent predictor of major bleeding in patients with ACS, presenting a better predictive capacity than the CRUSADE. Funding Acknowledgement Type of funding sources: None.

Features of antiplatelet therapy with P2Y12 receptor inhibitors in patients with myocardial infarction according to the Russian Register of Acute Myocardial Infarction REGION-MI.

Aim To study specific features of administering platelet P2Y12 receptor inhibitors to patients with myocardial infarction (MI) in real-life clinical practice; to reveal a possible inconsistency of the therapy with clinical guidelines; to evaluate the patients' compliance with the medication at the outpatient stage; and to outline major direction for improving quality of the antiplatelet treatment.Material and methods REGION-MI is a multicenter prospective, observational study. The observational period is divided into 3 stages: during the stay in the hospital and at 3 and 12 months following the inclusion into the registry. Information about the drug therapy (used at the time of hospitalization, administered before the hospitalization, received in the hospital, and prescribed at discharge from the hospital) was recorded in the patient's individual registration card. Information about the antiplatelet treatment at 6 months following enrollment into the study was obtain by phone.Results The study included 4 553 patients. Dual antiplatelet therapy was administered after MI to 94.4 % patients: clopidogrel was administered to 52 %, ticagrelor to 42.2 %, and prasugrel to 11 patients (0.2 %). Ticagrelor was administered significantly more frequently in ST segment elevation myocardial infarction (STEMI) than in NSTEMI, 45 % and 33 %, respectively (p&lt;0.001); clopidogrel was also administered more frequently to patients with STEMI than with NSTEMI, 59 % and 50 %, respectively. According to ARC-HBR criteria, in MI and a high risk of bleeding, clopidogrel was administered more frequently than ticagrelor (p &lt;0.001). Ticagrelor was significantly more frequently administered to patients with MI and a low risk of bleeding than to patients with a high risk (p&lt;0.001). In STEMI and a low risk of bleeding, ticagrelor was administered somewhat more frequently than clopidogrel, 56 % and 44 %, respectively (р&lt;0.05). In NSTEMI and a low risk of bleeding, clopidogrel was administered more frequently than ticagrelor, 53 % and 47 %, respectively (p&lt;0.05). At 6 months post-MI, 94 % of patients continued taking one of the P2Y12 inhibitors.Conclusion According to data of the REGION-MI registry, the frequency of administering P2Y12 inhibitors to patients with acute MI was high, and the patients' compliance with this therapy was high at 6 months following MI. Although ticagrelor (the most available drug of all powerful platelet P2Y12 receptor inhibitors) has been prescribed more frequently in the recent years, a definite reserve exists for increasing the frequency of its administration. This is particularly important with a low risk of bleeding and the absence of requirement for anticoagulants. Thus, the prognosis for MI patients can be considerably improved.