Assessing the Impact of Morphine on Adverse Outcomes in ACS Patients Treated with P2Y12 Inhibitors: Insights from Multiple Real-World Evidence.

Purpose: Mechanistic studies showed that morphine may impair the antiplatelet effect of P2Y12 inhibitors. However, Several clinical studies with cardiovascular events as an outcome are contradictory, and the broader impact of this drug interaction on additional organ systems remains uncertain. With multisource data, this study sought to determine the effects of morphine interaction with P2Y12 inhibitors on major adverse outcomes comprehensively, and identify the warning indicators. Patients and Methods: Interaction signals were sought in 187,919 safety reports from the FDA Adverse Event Reporting System (FAERS) database, utilizing reporting odds ratios (repOR). In a cohort of 5240 acute coronary syndrome patients, the analyses were validated, and the biological effects of warning indicators were further studied with Mendelian randomization and mediation analysis. Results: Potential risk of renal system adverse events in patients cotreated with morphine is significantly higher in FAERS (repOR 4.83, 95% CI 4.42-5.28, false discovery rate adjusted-P =3.55*10-209). The analysis of in-house patient cohorts validated these results with an increased risk of acute kidney injury (adjusted OR: 1.65; 95% CI: 1.20 to 2.26), and we also found a risk of myocardial infarction in patients treated with morphine (adjusted OR: 1.55; 95% CI: 1.14 to 2.11). The Morphine group exhibited diminished Plateletcrit (PCT) levels post-surgery and lower PCT levels were associated with an increased risk of AKI. Conclusion: The administration of morphine in patients treated with P2Y12 receptor inhibitors should be carefully evaluated. PCT may serve as a potential warning indicator for morphine-related renal injury.

Safety, Tolerability, and Pharmacodynamics of AZD3366 (Optimized Human CD39L3 Apyrase) Alone and in Combination With Ticagrelor and Acetylsalicylic Acid: A Phase 1, Randomized, Placebo-Controlled Study.

BACKGROUND: ADP and ATP are importantly involved in vascular and thrombotic homeostasis, via multiple receptor pathways. Blockade of ADP P2Y12 receptors inhibits platelet aggregation and represents an effective cardiovascular disease prevention strategy. AZD3366 (APT102), a long-acting recombinant form of an optimized CD39L3 human apyrase, has effectively reduced ATP, ADP, and platelet aggregation and provided tissue protection in preclinical models, features that could be very beneficial in treating patients with cardiovascular disease. METHODS AND RESULTS: We conducted this phase 1, first-in-human study of single ascending doses of intravenous AZD3366 or placebo, including doses added to dual antiplatelet therapy with ticagrelor and acetylsalicylic acid. The primary objective was safety and tolerability; secondary and exploratory objectives included pharmacokinetics, pharmacodynamics (measured as inhibition of platelet aggregation), adenosine diphosphatase (ADPase) activity, and ATP/ADP metabolism. In total, 104 participants were randomized. AZD3366 was generally well tolerated, with no major safety concerns observed. ADPase activity increased in a dose-dependent manner with a strong correlation to AZD3366 exposure. Inhibition of ADP-stimulated platelet aggregation was immediate, substantial, and durable. In addition, there was a prompt decrease in systemic ATP concentration and an increase in adenosine monophosphate concentrations, whereas ADP concentration appeared generally unaltered. At higher doses, there was a prolongation of capillary bleeding time without detectable changes in the ex vivo thromboelastometric parameters. CONCLUSIONS: AZD3366 was well tolerated in healthy participants and demonstrated substantial and durable inhibition of platelet aggregation after single dosing. Higher doses prolonged capillary bleeding time without detectable changes in ex vivo thromboelastometric parameters. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04588727.

Review of the Ticagrelor Trials Evidence Base.

Ticagrelor is a platelet P2Y12 receptor inhibitor approved for use in patients with acute coronary syndromes, coronary artery disease, and low-moderate risk acute ischemic stroke or high-risk transient ischemic attack. Clinical trials have evaluated the efficacy and safety of ticagrelor on ischemic and bleeding outcomes for different indications and with varying treatment approaches. As a result, there is a large body of clinical evidence demonstrating different degrees of net clinical benefit compared with other platelet inhibitor drugs based on indication, patient characteristics, clinical presentation, treatment duration, and other factors. We provide a review of the major trials of ticagrelor in the context of other randomized trials of clopidogrel and prasugrel to organize the volume of available information, elevate corroborating and conflicting data, and identify potential gaps as areas for further exploration of optimal antiplatelet treatment.

One-Month Dual Antiplatelet Therapy Followed by P2Y12 Inhibitor Monotherapy After Biodegradable Polymer Drug-Eluting Stent Implantation　- The REIWA Region-Wide Registry.

BACKGROUND: The safety and feasibility of using 1-month dual antiplatelet therapy (DAPT) followed by P2Y12inhibitor monotherapy for patients after percutaneous coronary intervention (PCI) with thin-strut biodegradable polymer drug-eluting stents (BP-DES) in daily clinical practice remain uncertain.Methods and Results: The REIWA region-wide registry is a prospective study conducted in 1 PCI center and 9 local hospitals in northern Japan. A total of 1,202 patients who successfully underwent final PCI using BP-DES (Synergy: n=400; Ultimaster: n=401; Orsiro: n=401), were enrolled in the registry, and received 1-month DAPT followed by P2Y12inhibitor (prasugrel 3.75 mg/day or clopidogrel 75 mg/day) monotherapy. The primary endpoint was a composite of cardiovascular and bleeding events at 12 months, including cardiovascular death, myocardial infarction (MI), definite stent thrombosis (ST), ischemic or hemorrhagic stroke, and Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding. Based on the results of a previous study, we set the performance goal at 5.0%. Over the 1-year follow-up, the primary endpoint occurred in 3.08% of patients, which was lower than the predefined performance goal (Pnon-inferiority<0.0001). Notably, definite ST occurred in only 1 patient (0.08%) within 1 year (at 258 days). No differences were observed in the primary endpoint between stent types. CONCLUSIONS: The REIWA region-wide registry suggests that 1-month DAPT followed by P2Y12inhibitor monotherapy is safe and feasible for Japanese patients with BP-DES.

Antiplatelet Treatment Preferences of a Group of Cardiologists from Türkiye: A Survey Research Study.

OBJECTIVE: Deciding on the optimal duration of dual antiplatelet treatment (DAPT) remains a complex decision. This survey aims to explore the preferences for antiplatelet therapy and the daily routine regarding DAPT duration in coronary artery disease among a group of cardiologists in Türkiye. METHOD: Using an online questionnaire with 38 questions, the preferences of 314 cardiologists were collected. Qualitative descriptive characteristics of the answers received from the participants were examined. RESULTS: Participating cardiologists mostly worked in training and research hospitals (51.59%) and university hospitals (21.66%). Participants primarily favored ticagrelor in patients undergoing PCI with a diagnosis of STEMI and NSTE-ACS (69.75% and 55.73% respectively). Clopidogrel was the most preferred P2Y12 treatment in patients with chronic coronary syndrome (CCS) after PCI (94.90%). Pre-treatment with a loading dose of a P2Y12 receptor inhibitor was administered to 57.01% of patients with NSTE-ACS, irrespective of the planned treatment strategy. In NSTE-ACS patients with low bleeding risk treated with PCI, 83.12% of participants recommended DAPT for 12 months and 14.65% for >12 months. In high-bleeding-risk NSTE-ACS patients treated with PCI, DAPT durations of six months (74.52%), three months (19.75%), and one month (5.73%) were chosen. Among CCS patients treated with PCI without an increased risk of bleeding, 12 months of DAPT was preferred by 68.15% of participants. Most participants (70.70%) were switching to a more potent P2Y12 receptor inhibitor therapy in emergency department clopidogrel-loaded patients with ACS. CONCLUSION: The aim of this survey to capture a snapshot of the preferences of a group of cardiologists in Türkiye regarding DAPT treatment and duration. The responses were both in accordance and in conflict with the current guidelines.

Ticagrelor Induced Cheyne-Stokes Respiration and Asystolic Ventricular Standstill: A Case Report.

Ticagrelor is a potent, direct-acting, and reversible P2Y12­adenosine diphosphate receptor blocker. It has a rapid onset of action and an intense and consistent platelet reactivity inhibition that has been demonstrated to be superior to clopidogrel in decreasing major adverse events in acute coronary syndrome (ACS). Although ticagrelor is well tolerated in ACS patients, it has side effects, such as dyspnea and bradyarrhythmia, as reported in the Platelet Inhibition and Patient Outcomes (PLATO) study. Furthermore, it was reported that ticagrelor's bradyarrhythmic potential was transient and not clinically significant beyond the acute initiation phase. Nor was there a difference in rates of syncope or need for pacemaker insertion during 30 days of follow-up. Here we report a case of ticagrelor associated with Cheyne-Stokes respiration and asystolic ventricular standstill in a patient with ACS who required resuscitation and insertion of a temporary pacemaker.

Net clinical benefit of extended dual pathway inhibition according to baseline risk in patients with chronic coronary syndrome: a COMPASS substudy.

AIMS: Guidelines recommend extended dual pathway inhibition (DPI) with aspirin and rivaroxaban in patients with chronic coronary syndrome (CCS) at high ischaemic risk. The CHADS-P2A2RC score improves risk prediction and enables antithrombotic treatment allocation in these patients. This study evaluated the net clinical benefit of DPI treatment according to baseline risk as classified by the CHADS-P2A2RC score in patients with CCS included in the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial. METHODS AND RESULTS: COMPASS patients with CCS (n = 14 670), randomized to aspirin alone or DPI, were stratified according to cardiovascular risk using the CHADS-P2A2RC score. Endpoints were major adverse cardiovascular events (MACE), all-cause death, fatal/critical organ bleeding, and composite adverse events (MACE and bleeding). Net clinical benefit was the 30-month risk difference of MACE and bleeding. Thirty-month incidences of MACE [7.9% vs. 3.9%, hazard ratio (HR) 2.01, 95% confidence interval (CI) 1.83-2.18] and fatal/critical organ bleeding (1.2% vs. 0.8%, HR 1.49, 95% CI 1.06-1.92) were higher in high-risk (CHADS-P2A2RC ≥ 4) than in low/moderate-risk (CHADS-P2A2RC < 4) patients. DPI reduced MACE (low/moderate risk: HR 0.62, 95% CI 0.47-0.82; high risk: HR 0.82, 95% CI 0.68-0.99, P for interaction 0.09) and all-cause death (low/moderate risk: HR 0.65, 95% CI 0.46-0.91; high risk: HR 0.81, 95% CI 0.65-1.00, P for interaction 0.29), without substantially increasing fatal/critical organ bleeding (low/moderate risk: HR 1.35, 95% CI 0.72-2.53; high risk: HR 1.18, 95% CI 0.73-1.90, P for interaction 0.73). DPI provided net clinical benefit of similar magnitude in low/moderate-risk (-1.81%, 95% CI -3.00 to -0.62) and high-risk (-1.96%, 95% CI -3.60 to -0.33) CCS patients. CONCLUSION: As classified by the CHADS-P2A2RC score, low/moderate- and high-risk patients with CCS derived similar net clinical benefit and reduction in all-cause death from DPI treatment.

Comparative effectiveness and safety of prasugrel and ticagrelor in patients of acute coronary syndrome undergoing percutaneous transluminal coronary angioplasty: A propensity score-matched analysis.

Evidence on comparative effectiveness and safety of prasugrel and ticagrelor post-percutaneous transluminal coronary angioplasty is scarce in Indian population. In a 1:1 propensity score-matched cohort with 71 individuals in each group, the incidence of a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or coronary revascularization was not significantly different in prasugrel and ticagrelor group (7.04% vs 9.86%; absolute difference, 2.8%; HR, 0.65; 95% CI, 0.21-2.1; p = 0.49). There was no significant difference in bleeding (5.63% vs 9.86%; absolute difference, -4.20%; 95% CI, -13.0%-4.5%) and dyspnea (7.04% vs 12.7%; absolute difference, -5.60%; 95% CI, -15.4%-4.1%).

Monotherapy with P2Y12-inhibitors after dual antiplatelet therapy: Filling gaps in evidence.

BACKGROUND: Whether P2Y12 inhibitor monotherapy (P2Y12-I) is superior to aspirin following DAPT discontinuation post-PCI remains to be established. METHODS: We updated our prior network meta-analysis where P2Y12-I and aspirin had been compared with DAPT or directly with each other. The focus is specifically on the available direct evidence, now consisting of the three head-to-head comparisons of P2Y12-I and aspirin in event-free PCI patients after DAPT. We include a Trial Sequential Analysis of the direct evidence based on meta-analytical literature. RESULTS: The main finding reveals a 39% significantly lower risk of myocardial infarction with P2Y12-I (RR 0.61, 95% CI 0.47-0.78, p = 0.0001, I2 = 0%) with no difference in bleeding. Trial Sequential Analysis demonstrates clinically meaningful evidence for a reduction in the incidence of myocardial infarction with P2Y12-I that is also supported by statistical significance. CONCLUSIONS: Accruing data highlight that P2Y12-I following DAPT discontinuation after PCI is associated with lower risk for MI and a similar risk for bleeding as compared with ASA. In light of potential limitations to the widespread adoption of life-long P2Y12-I treatment, clinicians should consider identifying selected patients who are expected to derive the highest benefit.

Impact of Preloading Strategy With Ticagrelor on Periprocedural Myocardial Injury in Patients With Non-ST Elevation Myocardial Infarction Undergoing Early Invasive Strategy.

ABSTRACT: Pretreatment with an oral P2Y12 receptor blocker (before coronary angiography) versus treatment in the catheterization laboratory has been a matter of debate in patients presenting with non-ST segment elevation myocardial infarction (NSTEMI). The primary aim of this study was to assess the impact of an immediate preloading strategy with ticagrelor on periprocedural myocardial injury in patients with NSTEMI treated with an early invasive strategy. NSTEMI patients who underwent coronary angiography and subsequent percutaneous coronary intervention (PCI) within 24 hours after hospital admission were divided into 2 groups: the first group (pretreatment group) included patients who received ticagrelor pretreatment as soon as possible after admission and the second group (no pretreatment group) included patients who received a loading dose of ticagrelor after coronary angiography. The pretreatment group included 232 patients, and the no pretreatment group included 87 patients. Male patients represented the majority of the patients. The 2 groups were similar in baseline characteristics, except for a greater incidence of hypertension ( P = 0.014) and higher hemoglobin levels ( P = 0.01) in the pretreatment group in comparison with the no pretreatment group. Patients in the ticagrelor pretreatment group had less myocardial injury until coronary angiography based on troponin measurements collected at 12 hours after admission ( P = 0.025). Patients in the ticagrelor pretreatment group also had fewer periprocedural myocardial injuries based on troponin measurements taken between 12 and 24 hours after the PCI ( P = 0.026 and P = 0.022, respectively). Our findings suggested that ticagrelor pretreatment reduces periprocedural myocardial injury in NSTEMI patients who underwent PCI within 24 hours after admission.