Atrial cardiomyocytes contribute to the inflammatory status associated with atrial fibrillation in right heart disease.

AIMS: Right heart disease (RHD), characterized by right ventricular (RV) and atrial (RA) hypertrophy, and cardiomyocytes' (CM) dysfunctions have been described to be associated with the incidence of atrial fibrillation (AF). Right heart disease and AF have in common, an inflammatory status, but the mechanisms relating RHD, inflammation, and AF remain unclear. We hypothesized that right heart disease generates electrophysiological and morphological remodelling affecting the CM, leading to atrial inflammation and increased AF susceptibility. METHODS AND RESULTS: Pulmonary artery banding (PAB) was surgically performed (except for sham) on male Wistar rats (225-275 g) to provoke an RHD. Twenty-one days (D21) post-surgery, all rats underwent echocardiography and electrophysiological studies (EPS). Optical mapping was performed in situ, on Langendorff-perfused hearts. The contractility of freshly isolated CM was evaluated and recorded during 1 Hz pacing in vitro. Histological analyses were performed on formalin-fixed RA to assess myocardial fibrosis, connexin-43 levels, and CM morphology. Right atrial levels of selected genes and proteins were obtained by qPCR and Western blot, respectively. Pulmonary artery banding induced severe RHD identified by RV and RA hypertrophy. Pulmonary artery banding rats were significantly more susceptible to AF than sham. Compared to sham RA CM from PAB rats were significantly elongated and hypercontractile. Right atrial CM from PAB animals showed significant augmentation of mRNA and protein levels of pro-inflammatory interleukin (IL)-6 and IL1ß. Sarcoplasmic-endoplasmic reticulum Ca2+-ATPase-2a (SERCA2a) and junctophilin-2 were decreased in RA CM from PAB compared to sham rats. CONCLUSIONS: Right heart disease-induced arrhythmogenicity may occur due to dysfunctional SERCA2a and inflammatory signalling generated from injured RA CM, which leads to an increased risk of AF.

The role of cellular senescence in profibrillatory atrial remodelling associated with cardiac pathology.

AIMS: Cellular senescence is a stress-related or aging response believed to contribute to many cardiac conditions; however, its role in atrial fibrillation (AF) is unknown. Age is the single most important determinant of the risk of AF. The present study was designed to (i) evaluate AF susceptibility and senescence marker expression in rat models of aging and myocardial infarction (MI), (ii) study the effect of reducing senescent-cell burden with senolytic therapy on the atrial substrate in MI rats, and (iii) assess senescence markers in human atrial tissue as a function of age and the presence of AF. METHODS AND RESULTS: AF susceptibility was studied with programmed electrical stimulation. Gene and protein expression was evaluated by immunoblot or immunofluorescence (protein) and digital polymerase chain reaction (PCR) or reverse transcriptase quantitative PCR (messenger RNA). A previously validated senolytic combination, dasatinib and quercetin, (D+Q; or corresponding vehicle) was administered from the time of sham or MI surgery through 28 days later. Experiments were performed blinded to treatment assignment. Burst pacing-induced AF was seen in 100% of aged (18-month old) rats, 87.5% of young MI rats, and 10% of young control (3-month old) rats (P ≤ 0.001 vs. each). Conduction velocity was slower in aged [both left atrium (LA) and right atrium (RA)] and young MI (LA) rats vs. young control rats (P ≤ 0.001 vs. each). Atrial fibrosis was greater in aged (LA and RA) and young MI (LA) vs. young control rats (P < 0.05 for each). Senolytic therapy reduced AF inducibility in MI rats (from 8/9 rats, 89% in MI vehicle, to 0/9 rats, 0% in MI D + Q, P < 0.001) and attenuated LA fibrosis. Double staining suggested that D + Q acts by clearing senescent myofibroblasts and endothelial cells. In human atria, senescence markers were upregulated in older (≥70 years) and long-standing AF patients vs. individuals ≤60 and sinus rhythm controls, respectively. CONCLUSION: Our results point to a potentially significant role of cellular senescence in AF pathophysiology. Modulating cell senescence might provide a basis for novel therapeutic approaches to AF.

An inflammation resolution-promoting intervention prevents atrial fibrillation caused by left ventricular dysfunction.

AIMS: Recent studies suggest that bioactive mediators called resolvins promote an active resolution of inflammation. Inflammatory signalling is involved in the development of the substrate for atrial fibrillation (AF). The aim of this study is to evaluate the effects of resolvin-D1 on atrial arrhythmogenic remodelling resulting from left ventricular (LV) dysfunction induced by myocardial infarction (MI) in rats. METHODS AND RESULTS: MI was produced by left anterior descending coronary artery ligation. Intervention groups received daily intraperitoneal resolvin-D1, beginning before MI surgery (early-RvD1) or Day 7 post-MI (late-RvD1) and continued until Day 21 post-MI. AF vulnerability was evaluated by performing an electrophysiological study. Atrial conduction was analysed by using optical mapping. Fibrosis was quantified by Masson's trichrome staining and gene expression by quantitative polymerase chain reaction and RNA sequencing. Investigators were blinded to group identity. Early-RvD1 significantly reduced MI size (17 ± 6%, vs. 39 ± 6% in vehicle-MI) and preserved LV ejection fraction; these were unaffected by late-RvD1. Transoesophageal pacing induced atrial tachyarrhythmia in 2/18 (11%) sham-operated rats, vs. 18/18 (100%) MI-only rats, in 5/18 (28%, P < 0.001 vs. MI) early-RvD1 MI rats, and in 7/12 (58%, P < 0.01) late-RvD1 MI rats. Atrial conduction velocity significantly decreased post-MI, an effect suppressed by RvD1 treatment. Both early-RvD1 and late-RvD1 limited MI-induced atrial fibrosis and prevented MI-induced increases in the atrial expression of inflammation-related and fibrosis-related biomarkers and pathways. CONCLUSIONS: RvD1 suppressed MI-related atrial arrhythmogenic remodelling. Early-RvD1 had MI sparing and atrial remodelling suppressant effects, whereas late-RvD1 attenuated atrial remodelling and AF promotion without ventricular protection, revealing atrial-protective actions unrelated to ventricular function changes. These results point to inflammation resolution-promoting compounds as novel cardio-protective interventions with a particular interest in attenuating AF substrate development.

Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology 2023 Focused Update of the Guidelines for the Use of Antiplatelet Therapy.

Antiplatelet therapy (APT) is the foundation of treatment and prevention of atherothrombotic events in patients with atherosclerotic cardiovascular disease. Selecting the optimal APT strategies to reduce major adverse cardiovascular events, while balancing bleeding risk, requires ongoing review of clinical trials. Appended, the focused update of the Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology guidelines for the use of APT provides recommendations on the following topics: (1) use of acetylsalicylic acid in primary prevention of atherosclerotic cardiovascular disease; (2) dual APT (DAPT) duration after percutaneous coronary intervention (PCI) in patients at high bleeding risk; (3) potent DAPT (P2Y12 inhibitor) choice in patients who present with an acute coronary syndrome (ACS) and possible DAPT de-escalation strategies after PCI; (4) choice and duration of DAPT in ACS patients who are medically treated without revascularization; (5) pretreatment with DAPT (P2Y12 inhibitor) before elective or nonelective coronary angiography; (6) perioperative and longer-term APT management in patients who require coronary artery bypass grafting surgery; and (7) use of APT in patients with atrial fibrillation who require oral anticoagulation after PCI or medically managed ACS. These recommendations are all on the basis of systematic reviews and meta-analyses conducted as part of the development of these guidelines, provided in the Supplementary Material.

Genetic-Guided Oral P2Y12 Inhibitor Selection and Cumulative Ischemic Events After Percutaneous Coronary Intervention.

BACKGROUND: Genetic-guided P2Y12 inhibitor selection has been proposed to reduce ischemic events by identifying CYP2C19 loss-of-function (LOF) carriers at increased risk with clopidogrel treatment after percutaneous coronary intervention (PCI). A prespecified analysis of TAILOR-PCI (Tailored Antiplatelet Therapy Following PCI) evaluated the effect of genetic-guided P2Y12 inhibitor therapy on cumulative ischemic and bleeding events. OBJECTIVES: Here, the authors detail a prespecified analysis of cumulative endpoints. The primary endpoint was cumulative incidence rate of ischemic events at 12 months. Cumulative incidence of major and minor bleeding was a secondary endpoint. Cox proportional hazards models as adapted by Wei, Lin, and Weissfeld were used to estimate the effect of this strategy on all observed events. METHODS: The TAILOR-PCI trial was a prospective trial including 5,302 post-PCI patients with acute and stable coronary artery disease (CAD) who were randomized to genetic-guided P2Y12 inhibitor or conventional clopidogrel therapy. In the genetic-guided group, LOF carriers were prescribed ticagrelor, whereas noncarriers received clopidogrel. TAILOR-PCI's primary analysis was time to first event in LOF carriers. RESULTS: Among 5,276 patients (median age 62 years; 25% women; 82% acute CAD; 18% stable CAD), 1,849 were LOF carriers (903 genetic-guided; 946 conventional therapy). The cumulative primary endpoint was significantly reduced in the genetic-guided group compared with the conventional therapy (HR: 0.61; 95% CI: 0.41-0.89; P = 0.011) with no significant difference in cumulative incidence of major or minor bleeding (HR: 1.36; 95% CI: 0.67-2.76; P = 0.39). CONCLUSIONS: Among CYP2C19 LOF carriers undergoing PCI, a genetic-guided strategy resulted in a statistically significant reduction in cumulative ischemic events without a significant difference in bleeding. (Tailored Antiplatelet Therapy Following PCI [TAILOR-PCI]; NCT01742117).

The Ongoing Saga of the Evolution of Percutaneous Coronary Intervention: From Balloon Angioplasty to Recent Innovations to Future Prospects.

The advances in percutaneous coronary intervention (PCI) have been, above all, dependent on the work of pioneers in surgery, radiology, and interventional cardiology. From Grüntzig's first balloon angioplasty, PCI has expanded through technology development, improved protocols, and dissemination of best-practice techniques. We can nowadays treat more complex lesions in higher-risk patients with favourable results. Guide wires, balloon types and profiles, debulking techniques such as atherectomy or lithotripsy, stents, and scaffolds all represent evolutions that have allowed us to tackle complex lesions such as an unprotected left main coronary artery, complex bifurcations, or chronic total occlusions. Best-practice PCI, including physiology assessment, imaging, and optimal lesion preparation are now the gold standard when performing PCI for sound indications, and new technologies such as intravascular lithotripsy for lesion preparation, or artificial intelligence, are innovations in the steps of 4 decades of pioneers to improve patient care in interventional cardiology. In the present review, major innovations in PCI since the first balloon angioplasty and also uncertainties and obstacles inherent to such medical advances are described.

Coronary Stenting: Reflections on a 35-Year Journey.

Stenting was introduced as a therapy for coronary artery disease 35 years ago, and is currently the most commonly performed minimally invasive procedure globally. Percutaneous coronary revascularization, initially with plain old balloon angioplasty and later with stenting, has dramatically affected the outcomes of acute myocardial infarction and acute coronary syndromes. Coronary stenting is probably the most intensively studied therapy in medicine on the basis of the number of randomized clinical trials for a broad range of indications. Continuous improvements in stent materials, design, and coatings concurrent with procedural innovations have truly been awe-inspiring. The story of stenting is replete with high points and some low points, such as the initial experience with stent thrombosis and restenosis, and the more recent disappointment with bioabsorbable scaffolds. History has shown rapid growth of stent use with expansion of indications followed by contraction of some uses in response to clinical trial evidence in support of bypass surgery or medical therapy. In this review we trace the constantly evolving story of the coronary stent from the earliest experience until the present time. Undoubtedly, future iterations of stent design and materials will continue to move the stent story forward.

Infections Deaths in the PLATO Trial.

Background Cardiovascular benefits of aggressive dual antiplatelet therapy may be associated with extra risks including bleeding, cancer, and infections discovered first for prasugrel in the TRial to assess Improvement in Therapeutic Outcomes by optimizing platelet InhibitioN with prasugrel (TRITON) trial. Ticagrelor in PLATO also caused slightly more infections but surprisingly less sepsis-related deaths (SRD) than clopidogrel. However, verified infection fatalities in PLATO were lacking from the public domain. We obtained the complete Food and Drug Administration (FDA)-issued primary causes death list, matched it with the few local site records dataset and analyzed the patterns of infections and deaths reported in PLATO. Methods Among infections, the FDA spreadsheet contains only two primary death codes for pneumonia (12-2) and SRD (12-8). We obtained local evidence for two pneumonia and two SRD and matched those with the FDA records. We assessed how SRD patterns were reported among nonvascular death's dataset. Results The FDA PLATO records indicate that clopidogrel caused numerically less ( n = 8) primary pneumonia deaths than ticagrelor ( n = 10) but over three times more SRD ( n = 23/7). Among matched verifiable outcomes, both pneumonia deaths were correct, but two clopidogrel SRD were incorrect. Of the remaining 21 clopidogrel SRD, 6 were reported as two separate closed paired entries in Brazil (lines 76 and 78 and 86 and 88) and India (lines 436 and 440), suggesting last minute addition of potentially incorrect SRD reports. Four ticagrelor SRD (lines 24,193,467 and 650) were "compensated" with close or next in line clopidogrel SRD entries (lines 22,195,468 and 651). Conclusion The FDA-issued evidence suggests no benefit of ticagrelor in preventing deaths from infections with slightly more pneumonia deaths, with possible misreporting of SRD in PLATO. These findings require an in-depth precise review of sepsis deaths in this trial.

FDA PLATO deaths list challenges aspirin dose-ticagrelor interaction.

No abstract present.

Misreported Cancer Deaths in PLATO Trial.

The potential link between antiplatelet agents and anticoagulants with excess cancer deaths (CD) was reported first for prasugrel (TRITON, DAPT), clopidogrel (DAPT), vorapaxar (TRACER), apixaban (APPRAISE-2), and later ticagrelor (PEGASUS). However, verified CD in the ticagrelor indication-seeking PLATO were not public. We obtained the complete list of deaths and their primary causes in PLATO, matched that dataset against local site records, and analyzed the patterns of CD reporting. The FDA-issued spreadsheet contains 31 precisely detailed CD (PLATO code 12-3). We obtained local site evidence for four CD and matched them with FDA-reported. We also assessed the patterns of how CD were reported among non-vascular death database column "S" by scrolling the FDA Excel file down among 938 PLATO entries. Clopidogrel CD (n = 17) were reported exclusively by sponsor, while independent CRO's reported only ticagrelor CD (3 out of 14 PLATO total). Among four matched verified outcomes, one ticagrelor CD was correct, second ticagrelor CD was unreported, and two (ticagrelor and clopidogrel) CD were reported inaccurately. Of the remaining 16 clopidogrel CD six were reported as three separate next in line paired entries in Denmark (236-237), Poland (597-598), Romania (679-680), and as two more fatalities in South Africa (786) and Spain (789), while patients 787 and 788 received ticagrelor out of 938 records suggesting possible late addition of incorrect clopidogrel CD reports. We conclude that some CD were misreported in PLATO, favoring ticagrelor. Such mismatch may require reevaluation of this critical outcome in the trial focusing on the exact death cause reported by site investigators.

The FDA and PLATO Investigators death lists: Call for a match.

PURPOSE: The FDA-issued PLATO trial dataset revealed that some primary death causes (PDCs) were inaccurately reported favouring ticagrelor. However, the PLATO Investigators operated the shorter death list of uncertain quality. We compared if PDC match when trial fatalities were reported to the FDA and by the PLATO Investigators. METHOD: The FDA list contains precisely detailed 938 PLATO deaths, while shorter investigators dataset consists of 905 deaths. We matched four vascular (sudden, post-MI, heart failure and stroke), and three non-vascular (cancer, sepsis and suicide) PDC between death lists. RESULTS: There were more sudden deaths in the shorter list than in the FDA dataset (161 vs 138; P < .03) and post-AMI (373 vs 178; P < .001) but fewer heart failure deaths (73 vs 109; P = .02). Stroke numbers match well (39 vs 37; P = NS) with only two ticagrelor cases removed. Cancer matched well (32 vs 31; P = NS), and sepsis cases were identical (30 vs 30; P = NS). However, two extra clopidogrel suicides in the shorter list are impossible to comprehend. CONCLUSIONS: The PLATO trial PDCs were mismatched between FDA and investigators sets. We are kindly asking the ticagrelor sponsor or/and concerned PLATO Investigators to clarify the PDC dataset match.

Platelet Quiescence in Patients With Acute Coronary Syndrome Undergoing Coronary Artery Bypass Graft Surgery.

Background The optimal antiplatelet strategy for patients with acute coronary syndromes who require coronary artery bypass surgery remains unclear. While a more potent antiplatelet regimen will predispose to perioperative bleeding, it is hypothesized that through "platelet quiescence," ischemic protection conferred by such therapy may provide a net clinical benefit. Methods and Results We compared patients undergoing coronary artery bypass surgery who were treated with a more potent antiplatelet inhibition strategy with those with a less potent inhibition through a meta-analysis. The primary outcome was all-cause mortality after bypass surgery. The analysis identified 4 studies in which the antiplatelet regimen was randomized and 6 studies that were nonrandomized. Combining all studies, there was an overall higher mortality with weaker strategies compared with more potent strategies (odds ratio, 1.38; 95% CI, 1.03-1.85; P=0.03). Conclusions Our findings support the concept of platelet quiescence, in reducing mortality for patients with acute coronary syndrome requiring coronary artery bypass surgery. This suggests the routine up-front use of potent antiplatelet regimens in acute coronary syndrome, irrespective of likelihood of coronary artery bypass graft.

The inflammation-resolution promoting molecule resolvin-D1 prevents atrial proarrhythmic remodelling in experimental right heart disease.

AIMS: Inflammation plays a role in atrial fibrillation (AF), but classical anti-inflammatory molecules are ineffective. Recent evidence suggests that failure of inflammation-resolution causes persistent inflammatory signalling and that a novel drug-family called resolvins promotes inflammation-resolution. Right heart disease (RHD) is associated with AF; experimental RHD shows signs of atrial inflammatory-pathway activation. Here, we evaluated resolvin-therapy effects on atrial arrhythmogenic remodelling in experimental RHD. METHODS AND RESULTS: Pulmonary hypertension and RHD were induced in rats with an intraperitoneal injection of 60 mg/kg monocrotaline (MCT). An intervention group received daily resolvin-D1 (RvD1), starting 1 day before MCT administration. Right atrial (RA) conduction and gene-expression were analysed respectively by optical mapping and qPCR/gene-microarray. RvD1 had no or minimal effects on MCT-induced pulmonary artery or right ventricular remodelling. Nevertheless, in vivo transoesophageal pacing induced atrial tachyarrhythmias in no CTRL rats vs. 100% MCT-only rats, and only 33% RvD1-treated MCT rats (P < 0.001 vs. MCT-only). Conduction velocity was significantly decreased by MCT, an effect prevented by RvD1. RHD caused RA dilation and fibrosis. RvD1 strongly attenuated RA fibrosis but had no effect on RA dilation. MCT increased RA expression of inflammation- and fibrosis-related gene-expression pathways on gene-microarray transcriptomic analysis, effects significantly attenuated by RvD1 (334 pathways enriched in MCT-rats vs. control; only 177 dysregulated by MCT with RvD1 treatment). MCT significantly increased RA content of type 1 (proinflammatory) CD68-positive M1 macrophages without affecting type 2 (anti-inflammatory) M2 macrophages. RvD1-treated MCT-rat RA showed significant reductions in proinflammatory M1 macrophages and increases in anti-inflammatory M2 macrophages vs. MCT-only. MCT caused statistically significant increases in protein-expression (western blot) of COL3A1, ASC, CASP1, CASP8, IL1ß, TGFß3, CXCL1, and CXCL2, and decreases in MMP2, vs. control. RvD1-treatment suppressed all these MCT-induced protein-expression changes. CONCLUSION: The inflammation-resolution enhancing molecule RvD1 prevents AF-promoting RA remodelling, while suppressing inflammatory changes and fibrotic/electrical remodelling, in RHD. Resolvins show potential promise in combating atrial arrhythmogenic remodelling by suppressing ongoing inflammatory signalling.

Effect of Genotype-Guided Oral P2Y12 Inhibitor Selection vs Conventional Clopidogrel Therapy on Ischemic Outcomes After Percutaneous Coronary Intervention: The TAILOR-PCI Randomized Clinical Trial.

Importance: After percutaneous coronary intervention (PCI), patients with CYP2C19*2 or *3 loss-of-function (LOF) variants treated with clopidogrel have increased risk of ischemic events. Whether genotype-guided selection of oral P2Y12 inhibitor therapy improves ischemic outcomes is unknown. Objective: To determine the effect of a genotype-guided oral P2Y12 inhibitor strategy on ischemic outcomes in CYP2C19 LOF carriers after PCI. Design, Setting, and Participants: Open-label randomized clinical trial of 5302 patients undergoing PCI for acute coronary syndromes (ACS) or stable coronary artery disease (CAD). Patients were enrolled at 40 centers in the US, Canada, South Korea, and Mexico from May 2013 through October 2018; final date of follow-up was October 2019. Interventions: Patients randomized to the genotype-guided group (n = 2652) underwent point-of-care genotyping. CYP2C19 LOF carriers were prescribed ticagrelor and noncarriers clopidogrel. Patients randomized to the conventional group (n = 2650) were prescribed clopidogrel and underwent genotyping after 12 months. Main Outcomes and Measures: The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia at 12 months. A secondary end point was major or minor bleeding at 12 months. The primary analysis was in patients with CYP2C19 LOF variants, and secondary analysis included all randomized patients. The trial had 85% power to detect a minimum hazard ratio of 0.50. Results: Among 5302 patients randomized (median age, 62 years; 25% women), 82% had ACS and 18% had stable CAD; 94% completed the trial. Of 1849 with CYP2C19 LOF variants, 764 of 903 (85%) assigned to genotype-guided therapy received ticagrelor, and 932 of 946 (99%) assigned to conventional therapy received clopidogrel. The primary end point occurred in 35 of 903 CYP2C19 LOF carriers (4.0%) in the genotype-guided therapy group and 54 of 946 (5.9%) in the conventional therapy group at 12 months (hazard ratio [HR], 0.66 [95% CI, 0.43-1.02]; P = .06). None of the 11 prespecified secondary end points showed significant differences, including major or minor bleeding in CYP2C19 LOF carriers in the genotype-guided group (1.9%) vs the conventional therapy group (1.6%) at 12 months (HR, 1.22 [95% CI, 0.60-2.51]; P = .58). Among all randomized patients, the primary end point occurred in 113 of 2641 (4.4%) in the genotype-guided group and 135 of 2635 (5.3%) in the conventional group (HR, 0.84 [95% CI, 0.65-1.07]; P = .16). Conclusions and Relevance: Among CYP2C19 LOF carriers with ACS and stable CAD undergoing PCI, genotype-guided selection of an oral P2Y12 inhibitor, compared with conventional clopidogrel therapy without point-of-care genotyping, resulted in no statistically significant difference in a composite end point of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia based on the prespecified analysis plan and the treatment effect that the study was powered to detect at 12 months. Trial Registration: ClinicalTrials.gov Identifier: NCT01742117.

A Critical Comparison of Canadian and International Guidelines Recommendations for Antiplatelet Therapy in Coronary Artery Disease.

Antiplatelet therapy for patients with coronary artery disease has evolved dramatically over the last decade. P2Y12 inhibitors offering more potent and consistent platelet inhibition than clopidogrel are now widely available, dual antiplatelet therapy (DAPT) duration can be tailored to individual ischemic and bleeding risks, and strategies to personalize antiplatelet therapy have been developed when concomitant oral anticoagulation (OAC) is indicated. Scientific societies from Canada, the United States, and Europe have all published updated recommendations addressing antiplatelet therapy in the recent years. The purpose of this review is to put the Canadian guidelines into perspective vis-à-vis international recommendations by highlighting similarities and critically analyzing differences. We focus on 3 major topics relevant for clinical practice: DAPT duration following drug-eluting stent implantation, DAPT following percutaneous coronary intervention in patients with concomitant indications for OAC, and DAPT management for noncardiac surgery following drug-eluting stent implantation. Although guidelines broadly agree on the majority of recommendations, the justifications for major differences were contrasted in the manuscript. Unanswered questions remain, including the place of aspirin in secondary prevention of coronary artery disease in the contemporary era, aspirin-free strategies early after percutaneous coronary intervention, and the safe minimal duration of DAPT with newer generation stents.

Pharmacodynamics, pharmacokinetics, and safety of single-dose subcutaneous administration of selatogrel, a novel P2Y12 receptor antagonist, in patients with chronic coronary syndromes.

AIMS: To study the pharmacodynamics and pharmacokinetics of selatogrel, a novel P2Y12 receptor antagonist for subcutaneous administration, in patients with chronic coronary syndromes (CCS). METHODS AND RESULTS: In this double-blind, randomized study of 345 patients with CCS on background oral antiplatelet therapy, subcutaneous selatogrel (8 mg, n = 114; or 16 mg, n = 115) was compared with placebo (n = 116) (ClinicalTrials.gov: NCT03384966). Platelet aggregation was assessed over 24 h (VerifyNow assay) and 8 h (light transmittance aggregometry; LTA). Pharmacodynamic responders were defined as patients having P2Y12 reaction units (PRU) <100 at 30 min post-dose and lasting ≥3 h. At 30 min post-dose, 89% of patients were responders to selatogrel 8 mg, 90% to selatogrel 16 mg, and 16% to placebo (P < 0.0001). PRU values (mean ± standard deviation) were 10 ± 25 (8 mg), 4 ± 10 (16 mg), and 163 ± 73 (placebo) at 15 min and remained <100 up to 8 h for both doses, returning to pre-dose or near pre-dose levels by 24 h post-dose. LTA data showed similarly rapid and potent inhibition of platelet aggregation. Selatogrel plasma concentrations peaked ∼30 min post-dose. Selatogrel was safe and well-tolerated with transient dyspnoea occurring overall in 7% (16/229) of patients (95% confidence interval: 4-11%). CONCLUSIONS: Selatogrel was rapidly absorbed following subcutaneous administration in CCS patients, providing prompt, potent, and consistent platelet P2Y12 inhibition sustained for ≥8 h and reversible within 24 h. Further studies of subcutaneous selatogrel are warranted in clinical scenarios where rapid platelet inhibition is desirable.

Management of Patients with Asymptomatic and Symptomatic Carotid Artery Disease: Update on Anti-Thrombotic Therapy.

The most common causes of ischaemic stroke are represented by carotid artery atherosclerotic disease (CAAD) and atrial fibrillation. While oral anticoagulants substantially reduce the incidence of thromboembolic stroke (< 1%/year), the rate of ischaemic stroke and other cardiovascular disease events in patients with CAAD remains high, ranging from 8.4 to 18.1 events per 100 patient-years. Similar to any other atherosclerotic disease, anti-thrombotic therapies are proposed for CAAD to reduce stroke and other cardiovascular events. The 2017 European Society of Cardiology (ESC)/European Society for Vascular Surgery (ESVS) guidelines recommend for patients with asymptomatic CAAD ≥60% the use of aspirin 75 to 100 mg once daily or clopidogrel 75 mg once daily at the exception of patient at very high bleeding risk. For patients with symptomatic CAAD ≥50%, the use of aspirin 75 to 100 mg once daily or clopidogrel 75 mg once daily is recommended. New perspectives for anti-thrombotic therapy for the treatment of patients with CAAD come from the novel dual pathway strategy combining a low-dose anticoagulant (i.e. rivaroxaban) and aspirin that may help reduce long-term ischaemic complications in patients with CAAD. This review summarizes current evidence and recommendations for the anti-thrombotic management of patients with symptomatic or asymptomatic CAAD or those undergoing carotid revascularization.

Ischemic and bleeding outcomes after coronary artery bypass grafting among patients initially treated with a P2Y12 receptor antagonist for acute coronary syndromes: Insights on timing of discontinuation of ticagrelor and clopidogrel prior to surgery.

BACKGROUND: Clinical outcomes in acute coronary syndrome patients treated with P2Y12 inhibitors who require urgent coronary artery bypass grafting (CABG) have not been well studied. METHODS: We examined clinical outcomes in acute coronary syndrome patients in relation to the timing of CABG following P2Y12 inhibitor discontinuation (<72 h, 72 h to five days, >5 days). The primary ischemic outcome was a composite of death, reinfarction, need for revascularization, or stroke. The primary safety outcome was bleeding of at least moderate severity as defined by a Universal Definition of Perioperative Bleeding class ≥2. RESULTS: Among 508 patients (95 ticagrelor, 413 clopidogrel), the timing of CABG following P2Y12 inhibitor discontinuation was <72 h in 32.1%, 72 h to five days in 23.2% and >5 days in 44.7%. Compared with CABG within 72 h, CABG 72 h to five days (adjusted odds ratio (OR) 0.35; 95% confidence interval (CI) 0.14-0.85; p=0.02) but not >5 days (adjusted OR 0.62; 95% CI 0.33-1.16; p=0.14) after P2Y12 inhibitor discontinuation was associated with lower odds of the primary ischemic outcome. Compared with CABG within 72 h, CABG 72 h to five days (adjusted OR 0.38; 95% CI 0.22-0.66; p=0.001) and >5 days (adjusted OR 0.33; 95% CI 0.20-0.53; p<0.001) after P2Y12 inhibitor discontinuation were associated with lower rates of Universal Definition of Perioperative Bleeding class ≥2 bleeding. CONCLUSIONS: CABG within 72 h after P2Y12 inhibitor discontinuation is associated with excess ischemia and bleeding. The rates of ischemic and bleeding events were comparable in patients undergoing CABG 72 h to five days compared with >5 days after P2Y12 inhibitor discontinuation.

Long-Term Survival Following Multivessel Revascularization in Patients With Diabetes: The FREEDOM Follow-On Study.

BACKGROUND: The FREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) trial demonstrated that for patients with diabetes mellitus (DM) and multivessel coronary disease (MVD), coronary artery bypass grafting (CABG) is superior to percutaneous coronary intervention with drug-eluting stents (PCI-DES) in reducing the rate of major adverse cardiovascular and cerebrovascular events after a median follow-up of 3.8 years. It is not known, however, whether CABG confers a survival benefit after an extended follow-up period. OBJECTIVES: The purpose of this study was to evaluate the long-term survival of DM patients with MVD undergoing coronary revascularization in the FREEDOM trial. METHODS: The FREEDOM trial randomized 1,900 patients with DM and MVD to undergo either PCI with sirolimus-eluting or paclitaxel-eluting stents or CABG on a background of optimal medical therapy. After completion of the trial, enrolling centers and patients were invited to participate in the FREEDOM Follow-On study. Survival was evaluated using Kaplan-Meier analysis, and Cox proportional hazards models were used for subgroup and multivariate analyses. RESULTS: A total of 25 centers (of 140 original centers) agreed to participate in the FREEDOM Follow-On study and contributed a total of 943 patients (49.6% of the original cohort) with a median follow-up of 7.5 years (range 0 to 13.2 years). Of the 1,900 patients, there were 314 deaths during the entire follow-up period (204 deaths in the original trial and 110 deaths in the FREEDOM Follow-On). The all-cause mortality rate was significantly higher in the PCI-DES group than in the CABG group (24.3% [159 deaths] vs. 18.3% [112 deaths]; hazard ratio: 1.36; 95% confidence interval: 1.07 to 1.74; p = 0.01). Of the 943 patients with extended follow-up, the all-cause mortality rate was 23.7% (99 deaths) in the PCI-DES group and 18.7% (72 deaths) in the CABG group (hazard ratio: 1.32; 95% confidence interval: 0.97 to 1.78; p = 0.076). CONCLUSIONS: In patients with DM and MVD, coronary revascularization with CABG leads to lower all-cause mortality than with PCI-DES in long-term follow-up. (Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes [FREEDOM]; NCT00086450).