Impact of Society Guidelines on Trends in Use of Newer P2Y12 Inhibitors for Patients With Acute Coronary Syndromes Undergoing Percutaneous Coronary Intervention.

BACKGROUND: Over the past decade, major society guidelines have recommended the use of newer P2Y12 inhibitors over clopidogrel for those undergoing percutaneous coronary intervention for acute coronary syndrome. It is unclear what impact these recommendations had on clinical practice. METHODS AND RESULTS: All percutaneous coronary intervention procedures (n=534 210) for acute coronary syndrome in England and Wales (April 1, 2010, to March 31, 2022) were retrospectively analyzed, stratified by choice of preprocedural P2Y12 inhibitor (clopidogrel, ticagrelor, and prasugrel). Multivariable logistic regression models were used to examine odds ratios of receipt of ticagrelor and prasugrel (versus clopidogrel) over time, and predictors of their receipt. Overall, there was a significant increase in receipt of newer P2Y12 inhibitors from 2010 to 2020 (2022 versus 2010: ticagrelor odds ratio, 8.12 [95% CI, 7.67-8.60]; prasugrel odds ratio, 6.14 [95% CI, 5.53-6.81]), more so in ST-segment-elevation myocardial infarction than non-ST-segment-elevation acute coronary syndrome indication. The most significant increase in odds of receipt of prasugrel was observed between 2020 and 2022 (P<0.001), following a decline/plateau in its use in earlier years (2011-2019). In contrast, the odds of receipt of ticagrelor significantly increased in earlier years (2012-2017, Ptrend<0.001), after which the trend was stable (Ptrend=0.093). CONCLUSIONS: Over a 13-year-period, there has been a significant increase in use of newer P2Y12 inhibitors, although uptake of prasugrel use remained significantly lower than ticagrelor. Earlier society guidelines (pre-2017) were associated with the highest rates of ticagrelor use for non-ST-segment-elevation acute coronary syndrome and ST-segment-elevation myocardial infarction cases while the ISAR-REACT 5 (Prospective, Randomized Trial of Ticagrelor Versus Prasugrel in Patients With Acute Coronary Syndrome) trial and later society guidelines were associated with higher prasugrel use, mainly for ST-segment-elevation myocardial infarction indication.

An Aspirin-Free Strategy for Immediate Treatment Following Complex Percutaneous Coronary Intervention.

BACKGROUND: There was no study evaluating the effects of an aspirin-free strategy in patients undergoing complex percutaneous coronary intervention (PCI). OBJECTIVES: The authors aimed to evaluate the efficacy and safety of an aspirin-free strategy in patients undergoing complex PCI. METHODS: We conducted the prespecified subgroup analysis based on complex PCI in the STOPDAPT-3 (ShorT and OPtimal duration of Dual AntiPlatelet Therapy after everolimus-eluting cobalt-chromium stent-3), which randomly compared low-dose prasugrel (3.75 mg/d) monotherapy to dual antiplatelet therapy (DAPT) with low-dose prasugrel and aspirin in patients with acute coronary syndrome or high bleeding risk. Complex PCI was defined as any of the following 6 criteria: 3 vessels treated, ≥3 stents implanted, ≥3 lesions treated, bifurcation with 2 stents implanted, total stent length >60 mm, or a target of chronic total occlusion. The coprimary endpoints were major bleeding events (Bleeding Academic Research Consortium 3 or 5) and cardiovascular events (a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or ischemic stroke) at 1 month. RESULTS: Of the 5,966 study patients, there were 1,230 patients (20.6%) with complex PCI. Regardless of complex PCI, the effects of no aspirin relative to DAPT were not significant for the coprimary bleeding (complex PCI: 5.30% vs 3.70%; HR: 1.44; 95% CI: 0.84-2.47; P = 0.18 and noncomplex PCI: 4.26% vs 4.97%; HR: 0.85; 95% CI: 0.65-1.11; P = 0.24; P for interaction = 0.08) and cardiovascular (complex PCI: 5.78% vs 5.93%; HR: 0.98; 95% CI: 0.62-1.55; P = 0.92 and noncomplex PCI: 3.70% vs 3.10%; HR: 1.20; 95% CI: 0.88-1.63; P = 0.25; P for interaction = 0.48) endpoints without significant interactions. CONCLUSIONS: The effects of the aspirin-free strategy relative to standard DAPT for the cardiovascular and major bleeding events were not different regardless of complex PCI. (ShorT and OPtimal duration of Dual AntiPlatelet Therapy after everolimus-eluting cobalt-chromium stent-3 [STOPDAPT-3]; NCT04609111).

Prehospital crushed versus integral prasugrel loading dose in STEMI patients with a large myocardial area.

BACKGROUND: The effect of administering a crushed prasugrel loading dose is uncertain in patients presenting with a large myocardial infarction and ST-segment elevation myocardial infarction (STEMI). AIMS: The aim of this study was to investigate if patients with a large myocardial infarction may benefit from prehospital administration of a crushed prasugrel loading dose. METHODS: Patients from the CompareCrush trial with an available ambulance electrocardiography (ECG) were included in the study. An independent core laboratory confirmed a prehospital large myocardial area. We compared pre- and postprocedural angiographic markers, including Thrombolysis in Myocardial Infarction (TIMI) 3 flow in the infarct-related artery, high thrombus burden, and myocardial blush grade 3, in STEMI patients with and without a prehospital large myocardial area. RESULTS: Ambulance ECG was available for 532 patients, of whom 331 patients were identified with a prehospital large myocardial area at risk. Crushed prasugrel significantly improved postprocedural TIMI 3 flow rates in STEMI patients with a prehospital large myocardial area at risk (92% vs 79%, odds ratio [OR] 3.00, 95% confidence interval [CI]: 1.50-6.00) but not in STEMI patients without a prehospital large myocardial area at risk (91% vs 95%, OR 0.47, 95% CI: 0.14-1.57; pinteraction=0.009). CONCLUSIONS: Administration of crushed prasugrel may improve postprocedural TIMI 3 flow in STEMI patients with signs of a large myocardial area at risk on the ambulance ECG. The practice of crushing tablets of prasugrel loading dose might, therefore, represent a safe, fast and cost-effective strategy to improve myocardial reperfusion in this high-risk STEMI subgroup undergoing primary percutaneous coronary intervention.

[Antithrombotic therapy in acute coronary syndrome]. / Antithrombotische Therapie beim akuten Koronarsyndrom.

Dual antiplatelet therapy (DAPT) is the cornerstone of maintenance medication following acute coronary syndromes (ST elevation myocardial infarction, non-ST elevation myocardial infarction, unstable angina). Over the last decade, P2Y12 inhibition in addition to low-dose acetylsalicylic acid has been intensively debated. In patients with acute coronary syndromes, balancing the reduction in cardiovascular events and increase in major bleeding during treatment with more potent P2Y12 inhibitors such as prasugrel and ticagrelor is still an issue. A special focus is on patients already treated with oral anticoagulants for stroke prevention in atrial fibrillation who require additional platelet inhibition following coronary stenting. This article summarizes the major recommendations given in the most recent Guideline for "Acute Coronary Syndromes" published by the European Society of Cardiology (ESC). The recommendations finally address strategies to reduce an increased bleeding risk based on clinical predictors.

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.

Low-dose prasugrel versus standard-dose ticagrelor in east Asian patients with acute coronary syndrome.

Low-dose prasugrel demonstrated a similar effectiveness profile to clopidogrel in East Asian ACS patients, but its comparison with another new-generation potent P2Y12 inhibitor, ticagrelor, remains unclear. To compare the effectiveness and safety of low-dose prasugrel against those of standard-dose ticagrelor in East Asian patients with ACS. This retrospective cohort study used Taiwan's National Health and Welfare Database. This study included ACS patients who underwent percutaneous coronary intervention and, at discharge between January 1, 2018 and December 31, 2020, were prescribed with low-dose prasugrel plus aspirin or standard-dose ticagrelor plus aspirin. Stabilized inverse probability of treatment weighting was used to balance the covariates across these two groups. The primary effectiveness outcome was a composite of acute myocardial infarction, ischemic stroke, and cardiovascular death; the secondary effectiveness outcome was each of the individual components of the primary outcome, transient ischemic attack, and repeat revascularization. The primary safety outcome was a composite of intracranial hemorrhage and gastrointestinal bleeding, and the two secondary safety outcomes were intracranial hemorrhage and gastrointestinal bleeding. A total of 24,807 patients were included in this study. Among them, 1,493 were low-dose prasugrel users and 23,314 were standard-dose ticagrelor users. No significant differences were found in primary effectiveness [HR: 0.97 (0.74-1.28)] or primary safety outcomes [HR: 1.22 (0.73-2.01)] between the two study groups. For East Asian patients with ACS, low-dose prasugrel provides comparable effectiveness without increasing bleeding risk compared to standard-dose ticagrelor. Low-dose prasugrel may be an appropriate alternative for East Asian populations.

Development of a routine bedside CYP2C19 genotype assessment program for antiplatelet therapy guidance in a community hospital catheterization laboratory.

Genotype based personalized antiplatelet therapy in the setting of percutaneous coronary intervention (PCI) has been studied in clinical trials. Despite the demonstrated risk associated with CYP2C19 loss-of-function (LoF) carriage in clopidogrel-treated PCI patients, real-world implementation of genotyping for PCI has been low. The goal of the current study was to provide CYP2C19 genotype information to the interventionalist prior to the completion of the catheterization to facilitate immediate personalized antiplatelet therapy. Routine personalization of P2Y12 inhibitor therapy for PCI in a community hospital cardiac catheterization laboratory by POC genotyping with the SpartanRx system was first offered in February 2017. A best practice advisory (BPA) based on the Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2C19 genotype and clopidogrel therapy was placed in the electronic health record prescription medication ordering system. By December 2019, 1,052 patients had CYP2C19 genotype testing, 429 patients underwent PCI with genotype guided antiplatelet therapy, and 250 patients underwent PCI without genotype testing and received antiplatelet therapy at the discretion of the treating physician. BPA compliance was 93. 87% of LoF allele carriers were prescribed ticagrelor or prasugrel whereas 96% of non-LoF allele carriers were prescribed clopidogrel. The genotyping results were available within 1 h and made immediately available for decision making by the interventional cardiologist. POC CYP2C19 genotyping is feasible in a community hospital catheterization laboratory and is associated with high rate of best practice compliance.Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03040622.

Prasugrel Single Antiplatelet Therapy versus Aspirin and Clopidogrel Dual Antiplatelet Therapy for Flow Diverter Treatment for Cerebral Aneurysms: A Retrospective Multicenter Study.

BACKGROUND AND PURPOSE: The optimal antiplatelet regimen after flow diverter treatment of cerebral aneurysms is still a matter of debate. A single antiplatelet therapy might be advantageous in determined clinical scenarios. This study evaluated the efficacy and safety of prasugrel single antiplatelet therapy versus aspirin and clopidogrel dual antiplatelet therapy. MATERIALS AND METHODS: We performed a post hoc analysis of 4 retrospective multicenter studies including ruptured and unruptured aneurysms treated with flow diversion using either prasugrel single antiplatelet therapy or dual antiplatelet therapy. Primary end points were the occurrence of any kind of procedure- or device-related thromboembolic complications and complete aneurysm occlusion at the latest radiologic follow-up (mean, 18 months). Dichotomized comparisons of outcomes were performed between single antiplatelet therapy and dual antiplatelet therapy. Additionally, the influence of various patient- and aneurysm-related variables on the occurrence of thromboembolic complications was investigated using multivariable backward logistic regression. RESULTS: A total of 222 patients with 251 aneurysms were included, 90 (40.5%) in the single antiplatelet therapy and 132 (59.5%) in the dual antiplatelet therapy group. The primary outcome-procedure- or device-related thromboembolic complications-occurred in 6 patients (6.6%) of the single antiplatelet therapy and in 12 patients (9.0%) of the dual antiplatelet therapy group (P = .62; OR, 0.712; 95% CI, 0.260-1.930). The primary treatment efficacy end point was reached in 82 patients (80.4%) of the single antiplatelet therapy and in 115 patients (78.2%) of the dual antiplatelet therapy group (P = .752; OR, 1.141; 95% CI, 0.599-2.101). Logistic regression showed that non-surface-modified flow diverters (P = .014) and fusiform aneurysm morphology (P = .004) significantly increased the probability of thromboembolic complications. CONCLUSIONS: Prasugrel single antiplatelet therapy after flow diverter treatment may be as safe and effective as dual antiplatelet therapy and could, therefore, be a valid alternative in selected patients. Further prospective comparative studies are required to validate our findings.

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%).

Comparison of ticagrelor and clopidogrel in anemic patients with acute coronary syndrome: efficacy and safety outcomes over one year.

OBJECTIVE: This retrospective study aimed to investigate the potential impact of ticagrelor and clopidogrel treatment on cardiovascular outcomes in patients with anemia and acute coronary syndrome (ACS) and to provide insights into the optimal therapeutic approach for this vulnerable patient population. METHODS: A retrospective research design was employed, involving patients diagnosed with ST-segment elevation myocardial infarction (STEMI) or non-ST-segment elevation myocardial infarction (NSTEMI) between 2014 and 2021. Inclusion criteria required a hemoglobin level below 12 mg/dL and a minimum 12-month P2Y12 inhibitor treatment. Comprehensive clinical, biochemical, and echocardiographic data were collected from the hospital's electronic repository. The primary efficacy endpoint was major adverse cardiovascular events (MACE), encompassing total mortality, cardiovascular mortality, reinfarction, ischemic stroke, and hemorrhagic stroke. Major hemorrhage was the primary safety endpoint. Secondary outcomes included total mortality, cardiovascular mortality, reinfarction, ischemic stroke, and hemorrhagic stroke, individually. RESULTS: Patients treated with ticagrelor (n = 118) and clopidogrel (n = 538) were compared. No significant difference was observed in major adverse cardiovascular events (MACE) and major bleeding between ticagrelor and clopidogrel treatment groups (MACE: clopidogrel 10.0% vs. ticagrelor 11.0%, p = 0.75; major bleeding: clopidogrel 2.8%, ticagrelor 2.5%, p = 0.88). Patients with hemoglobin levels ≤ 8 mg/dL demonstrated significantly higher MACE and major bleeding rates in the ticagrelor group (p = 0.008 and p = 0.002, respectively). Among patients aged ≥ 75 years, ticagrelor treatment was associated with a higher risk of major bleeding (p = 0.04). CONCLUSIONS: Ticagrelor and clopidogrel exhibited comparable efficacy and safety outcomes in anemic ACS patients over a one-year period. Although ticagrelor demonstrated superiority in reducing ischemic events, it is crucial to recognize the limitations of retrospective studies in informing clinical practice. This study offers valuable insights into tailoring antiplatelet therapy for anemic ACS patients and provides guidance for personalized treatment strategies, acknowledging the hypothesis-generating nature of retrospective analyses.

Genetic-Guided Pharmacotherapy for Coronary Artery Disease: A Systematic and Critical Review of Economic Evaluations.

BACKGROUND: Genetic-guided pharmacotherapy (PGx) is not recommended in clinical guidelines for coronary artery disease (CAD). We aimed to examine the extent and quality of evidence from economic evaluations of PGx in CAD and to identify variables influential in changing conclusions on cost-effectiveness. METHODS AND RESULTS: From systematic searches across 6 databases, 2 independent reviewers screened, included, and rated the methodological quality of economic evaluations of PGx testing to guide pharmacotherapy for patients with CAD. Of 35 economic evaluations included, most were model-based cost-utility analyses alone, or alongside cost-effectiveness analyses of PGx testing to stratify patients into antiplatelets (25/35), statins (2/35), pain killers (1/35), or angiotensin-converting enzyme inhibitors (1/35) to predict CAD risk (8/35) or to determine the coumadin doses (1/35). To stratify patients into antiplatelets (96/151 comparisons with complete findings of PGx versus non-PGx), PGx was more effective and more costly than non-PGx clopidogrel (28/43) but less costly than non-PGx prasugrel (10/15) and less costly and less effective than non-PGx ticagrelor (22/25). To predict CAD risk (51/151 comparisons), PGx using genetic risk scores was more effective and less costly than clinical risk score (13/17) but more costly than no risk score (16/19) or no treatment (9/9). The remaining comparisons were too few to observe any trend. Mortality risk was the most common variable (47/294) changing conclusions. CONCLUSIONS: Economic evaluations to date found PGx to stratify patients with CAD into antiplatelets or to predict CAD risk to be cost-effective, but findings varied based on the non-PGx comparators, underscoring the importance of considering local practice in deciding whether to adopt PGx.

Racial differences in P2Y12 inhibitor responsiveness in patients undergoing neuro-endovascular procedures: A cohort from the Middle East.

BACKGROUND: Data on P2Y12 inhibitors responsiveness from the middle east is scarce. We sought to investigate patient responsiveness to P2Y12 inhibitors within a cohort of major races that characterize the UAE population. The secondary objective was to assess risk factors for hyper and hypo-responsiveness in this population. METHODS: We conducted a cross-sectional study on adults who received either clopidogrel or ticagrelor treatments and had platelet responsiveness testing before undergoing neuro-endovascular interventions at our quaternary care hospital between March 2015 and April 2019. RESULTS: During the study period, 249 subjects met the inclusion criteria. Overall, 17.3 % were hyper-responsive and 25.7 % were hypo-responsive to P2Y12 inhibitors. When comparing between the P2Y12 inhibitors, rates of hyper-responsiveness were significantly higher to ticagrelor when compared to clopidogrel (11 versus 6 %, p = 0.02 respectively). Contrarily, hypo-responsiveness rates were significantly higher in clopidogrel treated patients compared to their ticagrelor treated counterparts (23 versus 2 %, p < .001 respectively). Patients of Middle-Eastern origin showed a significantly higher rate of hypo-responsiveness to both clopidogrel and ticagrelor when compared to other races (41.1 % and 26.7 %, P < 0.001 respectively). Asians showed the highest rates of hyper-responsiveness for both agents. Multivariate logistic regression analysis showed that proton pump inhibitors and statin combination, (OR: 6.39, 95 %CI [1.60, 25.392]), and Middle East vs. Indian subcontinent patients (OR: 4.67, 95 %CI [1.79-12.14]) were independent predictors of hypo-responsiveness to both P2Y12 inhibitors. CONCLUSION: This study demonstrated a high rate of hypo-responsiveness to P2Y12 inhibitors in a UAE cohort of patients undergoing neuro-endovascular procedures. In addition, therapeutic responsiveness to P2Y12 inhibitors varied markedly based on the racial background. Future larger studies are needed to evaluate genetic variations that may contribute to this rate of hypo-responsiveness in our population.

Population Pharmacokinetic/Pharmacodynamic Models for P2Y12 Inhibitors: A Systematic Review and Clinical Appraisal Using Exposure Simulation.

BACKGROUND AND OBJECTIVE: Recent research indicates a correlation between plasma concentration of P2Y12 inhibitors and clinical events, particularly bleeding, which significantly impeded their clinical therapeutic performance. It is therefore vital to delve into the factors that might affect the plasma concentration. The study aims to summarize population pharmacokinetics/pharmacodynamics (PopPKPD) models for commonly prescribed P2Y12 inhibitors (clopidogrel, prasugrel, and ticagrelor) and assess bleeding risk in specific individual groups. METHODS: The PopPKPD models of P2Y12 inhibitors were collected and summarized based on predetermined inclusion and exclusion criteria. The collected models were replicated in simulations, which were used to assess factors affecting plasma concentrations of P2Y12 inhibitors. Simulation results for special populations were compared to therapeutic window based on reported exposure-effect relationships (PK/PD-related bleeding and thrombotic clinical outcomes) to predict bleeding risk in special populations with different dosing regimens and cumulative covariates. RESULT: Finally, 12 studies were included for PK simulation, 7 of which that also included PD data were subjected to further analysis, with the majority being based on Phase I or II trials. Simulations showed that several covariates such as female gender, weight, elderly can significantly impact on exposure, with special populations reaching up to 179% of the general population. However, after dose adjustment, blood concentrations for special populations can reach approximately ±20% of general population exposure. Therefore, lowering the maintenance dose of ticagrelor from 90 to 60 mg bid was first recommended to reduce bleeding risk without significantly increasing ischemic risk, particularly in elderly, small-weight Asian females. CONCLUSION: Lowering the maintenance dose of ticagrelor from 90 to 60 mg bid effectively reduces bleeding risk without increasing thrombotic infarction risk in elderly, small-weight Asian females.

De-escalation of dual antiplatelet therapy for patients with acute coronary syndrome after percutaneous coronary intervention: a systematic review and network meta-analysis.

OBJECTIVES: To compare dual antiplatelet therapy (DAPT) de-escalation with five alternative DAPT strategies in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). DESIGN: We conducted a systematic review and network meta-analysis (NMA). Parallel-arm randomised controlled trials (RCTs) comparing DAPT strategies were included and arms of interest were compared via NMA. Partial ranking of each identified arm and for each investigated endpoint was also performed. SETTING AND PARTICIPANTS: Adult patients with ACS (≥18 years) undergoing PCI with indications for DAPT. SEARCH METHODS: A comprehensive search covered several databases (PubMed, Embase, Cochrane Central, MEDLINE, Conference Proceeding Citation Index-Science) from inception to 15 October 2023. Medical subject headings and keywords related to ACS, PCI and DAPT interventions were used. Reference lists of included studies were screened. Clinical trials registers were searched for ongoing or unpublished trials. INTERVENTIONS: Six strategies were assessed: T1 arm: acetylsalicylic acid (ASA) and prasugrel for 12 months; T2 arm: ASA and low-dose prasugrel for 12 months; T3 arm: ASA and ticagrelor for 12 months; T4 arm: DAPT de-escalation (ASA+P2Y12 inhibitor for 1-3 months, then single antiplatelet therapy with potent P2Y12 inhibitor or DAPT with clopidogrel); T5 arm: ASA and clopidogrel for 12 months; T6 arm: ASA and clopidogrel for 3-6 months. MAIN OUTCOME MEASURES: Primary outcome: Cardiovascular mortality. SECONDARY OUTCOMES: bleeding events (all, major, minor), stent thrombosis (ST), stroke, myocardial infarction (MI), all-cause mortality, major adverse cardiovascular events (MACE). RESULTS: 23 RCTs (75 064 patients with ACS) were included. No differences in cardiovascular mortality, all-cause death, recurrent MI or MACE were found when the six strategies were compared, although with different levels of certainty of evidence. ASA and clopidogrel for 12 or 3-6 months may result in a large increase of ST risk versus ASA plus full-dose prasugrel (OR 2.00, 95% CI 1.14 to 3.12, and OR 3.42, 95% CI 1.33 to 7.26, respectively; low certainty evidence for both comparisons). DAPT de-escalation probably results in a reduced risk of all bleedings compared with ASA plus full-dose 12-month prasugrel (OR 0.49, 95% CI 0.26 to 0.81, moderate-certainty evidence) and ASA plus 12-month ticagrelor (OR 0.52, 95% CI 0.33 to 0.75), while it may not increase the risk of ST. ASA plus 12-month clopidogrel may reduce all bleedings versus ASA plus full-dose 12-month prasugrel (OR 0.66, 95% CI 0.42 to 0.94, low certainty) and ASA plus 12-month ticagrelor (OR 0.70, 95% CI 0.52 to 0.89). CONCLUSIONS: DAPT de-escalation and ASA-clopidogrel regimens may reduce bleeding events compared with 12 months ASA and potent P2Y12 inhibitors. 3-6 months or 12-month aspirin-clopidogrel may increase ST risk compared with 12-month aspirin plus potent P2Y12 inhibitors, while DAPT de-escalation probably does not.

Impact of renal function on adverse bleeding events associated with dual antiplatelet therapy in patients with acute coronary syndrome.

It is believed, but not well established, that renal dysfunction increases the risk of adverse bleeding events associated with dual antiplatelet therapy (DAPT), especially in patients with acute coronary syndrome (ACS). The aim of this study is to estimate the impact of renal function on adverse bleeding events associated with DAPT in patients with ACS. A total of 1,264 ACS patients who received DAPT, clopidogrel (n = 530) or prasugrel (n = 734) in addition to aspirin, were assessed in a multicenter observational study. The relationship between renal function and bleeding event, defined as BARC 3 or 5, was determined using a marginal effect from the logit model and Royston-Parmar model. During an average 313.1 days of the observation period, defined as the duration of DAPT after admission until the implementation of a change in the regimen, bleeding events were observed in 7.4% of patients (n = 94). The estimated curves demonstrated that the probability of bleeding was positive correlated with renal dysfunction (6.0 to 8.6), regardless of the DAPT regimen used. This probability was consistently higher in clopidogrel (7.4 to 10.5) than in prasugrel (4.8 to 0.7). This trend was also shown in maintenance hemodialysis patients (6.7 vs. 10.3). Estimated cumulative incidences among individual stages of renal function were drawn. In conclusion, bleeding events increased with worsening renal function, and prasugrel is safer than clopidogrel as a component of DAPT throughout all levels of renal function, including hemodialysis patients after ACS.

An Aspirin-Free Versus Dual Antiplatelet Strategy for Coronary Stenting: STOPDAPT-3 Randomized Trial.

BACKGROUND: Bleeding rates on dual antiplatelet therapy (DAPT) within 1 month after percutaneous coronary intervention (PCI) remain high in clinical practice, particularly in patients with acute coronary syndrome or high bleeding risk. Aspirin-free strategy might result in lower bleeding early after PCI without increasing cardiovascular events, but its efficacy and safety have not yet been proven in randomized trials. METHODS: We randomly assigned 6002 patients with acute coronary syndrome or high bleeding risk just before PCI either to prasugrel (3.75 mg/day) monotherapy or to DAPT with aspirin (81-100 mg/day) and prasugrel (3.75 mg/day) after loading of 20 mg of prasugrel in both groups. The coprimary end points were major bleeding (Bleeding Academic Research Consortium 3 or 5) for superiority and cardiovascular events (a composite of cardiovascular death, myocardial infarction, definite stent thrombosis, or ischemic stroke) for noninferiority with a relative 50% margin. RESULTS: The full analysis set population consisted of 5966 patients (no-aspirin group, 2984 patients; DAPT group, 2982 patients; age, 71.6±11.7 years; men, 76.6%; acute coronary syndrome, 75.0%). Within 7 days before randomization, aspirin alone, aspirin with P2Y12 inhibitor, oral anticoagulants, and intravenous heparin infusion were given in 21.3%, 6.4%, 8.9%, and 24.5%, respectively. Adherence to the protocol-specified antiplatelet therapy was 88% in both groups at 1 month. At 1 month, the no-aspirin group was not superior to the DAPT group for the coprimary bleeding end point (4.47% and 4.71%; hazard ratio, 0.95 [95% CI, 0.75-1.20]; Psuperiority=0.66). The no-aspirin group was noninferior to the DAPT group for the coprimary cardiovascular end point (4.12% and 3.69%; hazard ratio, 1.12 [95% CI, 0.87-1.45]; Pnoninferiority=0.01). There was no difference in net adverse clinical outcomes and each component of coprimary cardiovascular end point. There was an excess of any unplanned coronary revascularization (1.05% and 0.57%; hazard ratio, 1.83 [95%CI, 1.01-3.30]) and subacute definite or probable stent thrombosis (0.58% and 0.17%; hazard ratio, 3.40 [95% CI, 1.26-9.23]) in the no-aspirin group compared with the DAPT group. CONCLUSIONS: The aspirin-free strategy using low-dose prasugrel compared with the DAPT strategy failed to attest superiority for major bleeding within 1 month after PCI but was noninferior for cardiovascular events within 1 month after PCI. However, the aspirin-free strategy was associated with a signal suggesting an excess of coronary events. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04609111.

The role of platelet P2Y12 receptors in inflammation.

Inflammation is a complex pathophysiological process underlying many clinical conditions. Platelets contribute to the thrombo-inflammatory response. Platelet P2Y12 receptors amplify platelet activation, potentiating platelet aggregation, degranulation and shape change. The contents of platelet alpha granules, in particular, act directly on leucocytes, including mediating platelet-leucocyte aggregation and activation via platelet P-selectin. Much evidence for the role of platelet P2Y12 receptors in inflammation comes from studies using antagonists of these receptors, such as the thienopyridines clopidogrel and prasugrel, and the cyclopentyltriazolopyrimidine ticagrelor, in animal and human experimental models. These suggest that antagonism of P2Y12 receptors decreases markers of inflammation with some evidence that this reduces incidence of adverse clinical sequelae during inflammatory conditions. Interpretation is complicated by pleiotropic effects such as those of the thienopyridines on circulating leucocyte numbers and of ticagrelor on adenosine reuptake. The available evidence suggests that P2Y12 receptors are prominent mediators of inflammation and P2Y12 receptor antagonism as a potentially powerful strategy in a broad range of inflammatory conditions. LINKED ARTICLES: This article is part of a themed issue on Platelet purinergic receptor and non-thrombotic disease. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.4/issuetoc.