P2Y12 Inhibitors Research Articles

In vitro comparison of platelet aggregation between zalunfiban and selatogrel in healthy donors

Abstract Background Two subcutaneously injected antiplatelet drugs, zalunfiban and selatogrel, are under development for prehospital administration for STEMI and (N)STEMI, respectively. Zalunfiban is a glycoprotein IIb/IIIa inhibitor that produces high-grade inhibition of platelet aggregation induced by ADP or a thrombin receptor activating peptide (TRAP) within 15 minutes. Selatogrel is a P2Y12 inhibitor that produces high-grade inhibition of platelet aggregation initiated by ADP within 15 minutes. We have studied the relative potencies of the drugs at levels achievable in vivo in inhibiting platelet aggregation. Since trisodium citrate (TSC) has been reported to enhance the antiplatelet effect of zalunfiban and inhibit the antiplatelet effect off selatogrel, aggregation studies were performed with both blood anticoagulated with TSC and the non-chelating anticoagulant PPACK. Whereas both ADP and thrombin are present at the site of vascular injury within seconds, we tested the effects of both ADP and TRAP. Purpose To compare directly the effects of zalunfiban and selatogrel on ADP- and TRAP-induced platelet aggregation. Methods Light transmission platelet aggregometry was performed within 4 hours of blood collection (BioData PAP-8E). Whole blood from healthy donors not taking aspirin (N=10) was anticoagulated with 3.2% TSC and 100 μM PPACK. Platelet-rich plasma (PRP) was prepared and adjusted to a platelet count of 250,000/µl. Three clinically relevant incremental concentrations of zalunfiban and selatogrel were added to PRP and platelet aggregation was initiated with 20 μM ADP or 20 μM TRAP. Tracings were recorded for at least 10 minutes after agonist addition. Platelet aggregation was quantified based on the instrument’s measurement of the primary slope (PrSl) of aggregation, which is a measure of the change in light transmission per unit time sustained over at least a 15 second period. Results In TSC-anticoagulated PRP, zalunfiban was more effective in inhibiting the PrSl of both ADP- and TRAP-induced platelet aggregation at all drug concentrations [Figure 1, panel A and B]. In PPACK-anticoagulated PRP, selatogrel showed greater inhibition of ADP-induced platelet aggregation at the lowest concentration tested, similar inhibition at the intermediate concentration, and slightly less inhibition at the highest doses. In sharp contrast, with TRAP-induced aggregation, zalunfiban demonstrated dose-related inhibition, reaching greater than 80% inhibition at the highest dose, whereas selatogrel produced less than 20% inhibition at all three doses. Conclusion Selatogrel is a potent inhibitor of ADP-induced platelet aggregation, but has low impact on TRAP-induced platelet aggregation, whereas zalunfiban is a potent inhibitor of both ADP and TRAP-induced platelet aggregation. The difference between the drugs needs to be considered in light of the known generation of thrombin at the site of vascular injury within seconds.Comparison of Platelet Inhibition

Percutaneous coronary intervention and medical therapy versus medical therapy alone in chronic coronary syndrome: A hierarchical win-ratio analysis from SCAAR

Abstract Background Revascularization of patients with chronic coronary syndrome (CCS) using percutaneous coronary intervention (PCI) is frequently done. However, the role of a PCI in this subgroup of patients with coronary artery disease remains controversial. Purpose The objective is to determine whether PCI plus medical therapy is associated with better outcomes for patients with CCS, compared to medical therapy only. Methods We conducted a population-based nationwide observational study. Using the Swedish Coronary Angiography and Angioplasty registry (SCAAR) we identified all patients with CCS undergoing coronary angiography between 2010-2020. Patients with obstructive coronary artery disease, defined as having at least one stenosis with ≥50% luminal obstruction were included. Patients were stratified into two groups according to their received treatment with PCI plus medical therapy or medical therapy only. Propensity score (PS) matching was used to match the two groups on their baseline characteristics. Outcome was assessed with win-ratio and the primary endpoint was net adverse clinical event (NACE) within 5-years. In the win-ratio analysis, the components of NACE were ranked (1) all-cause mortality, (2) stroke, (3) bleeding and (4) myocardial infarction. Subgroup analysis was also performed. Results After propensity score matching, two groups comprising 16,937 patients each, were formed. Baseline characteristics were comparable between the two groups (Table 1). However, patients who underwent PCI were more likely to receive dual antiplatelet therapy with aspirin and a P2Y12 inhibitor, while those treated with medical therapy were more commonly prescribed nitrates. Additionally, statins were prescribed more frequently to patients treated with PCI. The hierarchical outcome analysis showed no statistically significant difference between the two groups (win-ratio: 0.98; 95% confidence interval: 0.94-1.02; p=0.345). Subgroup analyses of men, women, patients aged 75 years and older, diabetic patients, and non-diabetic patients showed no significant differences in outcome between the two groups. Conclusion In this study, which aimed to assess the outcomes of patients with CCS using a hierarchical approach, revascularization with PCI did not result in better outcomes when compared to medical therapy alone. These findings suggest that for patients with CCS, medical therapy may be just as effective as PCI in improving outcomes.Baseline characteristicsWin-ratio

Impact of transfusion on platelet aggregation and biomarkers in myocardial infarction patients with anemia: an ancillary study of the randomized REALITY trial

Abstract Importance Higher rates of thrombotic events have been reported in patients with myocardial infarction (MI) requiring blood transfusion. The impact of transfusion strategies on biomarkers of thrombosis and inflammation is still unknown. Objective Compare the impact of a liberal vs a restrictive transfusion strategy in anemic MI patients on P2Y12 mediated platelet reactivity and biomarkers of thrombosis and inflammation. Design and Setting: Prespecified ancillary study of the multicentric randomized REALITY trial, performed in 6 French centers between February 2018 and September 2019 (Figure). Patients randomized to a liberal (hemoglobin ≤10g/dL) or a restrictive (hemoglobin ≤8g/dL) transfusion strategy had platelet reactivity measured at baseline and after randomization. Participants: One hundred anemic acute MI patients from the REALITY trial (666 randomized patients). Measurements: Measurements of platelet reactivity included a centralized blinded VASP-PRI assay and PRU measured locally using encrypted VerifyNow assay. Biomarkers of thrombosis (P-selectin, PAI-1, vWF) and inflammation (TNF-α) were also measured. The primary endpoint was the change in the VASP-PRI (difference from baseline and post randomization) between the two randomized groups. Results Among 100 patients included (n=50 in each group), the most frequent P2Y12 inhibitors used was clopidogrel (48%) while 16% of the patients did not receive any P2Y12 inhibitors. Transfused patients received on average 2.4±1.6 units of packed red blood cells. We found no differences between groups in change in P2Y12-mediated platelet aggregation before and after randomization, measured either by the VASP PRI (difference 4.3%; 95% CI (-5.4% to 14.1%)) or by the PRU (difference 23.5; 95% CI (-20.8 to 67.8)). Similar results were found in transfused patients (n=71) regardless of the randomized group, VASP PRI (difference 1.6%; 95% CI (-6.7% to 10.0%)) or PRU (difference -17.6; 95% CI (-41.0 to 5.7)). We did not find an impact of transfusion strategy or transfusion itself in the levels of P-selectin, PAI-1, vWF and TNF-α. Conclusion and Relevance A liberal or a restrictive transfusion strategy does not impact platelet reactivity and biomarkers in MI patients with anemia, supporting the lack of clinically relevant difference in thrombotic risk between both strategies.

Abbreviated versus standard dual antiplatelet therapy time after PCI in high bleeding risk patients with acute coronary syndrome - a report from the SWEDEHEART registry

Abstract Background The use of a short duration of dual antiplatelet therapy (DAPT) has become increasingly common in patients with high bleeding risk (HBR). This study aimed to evaluate outcomes for an abbreviated DAPT strategy compared to standard DAPT time strategy for high bleeding risk-patients with acute coronary syndrome (ACS) treated with percutaneous coronary intervention (PCI). Methods A total of 22310 patients from the SWEDEHEART-registry with at least one high bleeding risk criteria who underwent PCI for ACS in Sweden between January 1, 2013, until January 15, 2021, were enrolled. Patients were grouped according to their planned DAPT time at discharge: standard DAPT with 12 months of any P2Y12 inhibitor and aspirin or an abbreviated DAPT duration (<6 months DAPT or 12-month single APT) and matched for intended P2Y12 inhibitor type (clopidogrel or prasugrel/ticagrelor). The primary outcome was net adverse clinical events (NACE) at one year defined as the first occurrence of cardiac mortality or hospitalization due to myocardial infarction, ischemic stroke or clinically significant bleeding. Major adverse cardiovascular events and the individual components of NACE were defined as secondary endpoints. Results No significant difference in NACE was observed between the abbreviated compared to standard DAPT time groups, Kaplan-Meier event rate: 12.9% (n = 584) vs 13.1% (n = 594) hazard ratio (HR) 0.99; 95% confidence interval (CI) 0.88-1.11, p=0.83. No differences were observed for MACE (HR 1.08; 95% CI 0.94-1.25) or any of the elements of the primary composite outcome. The results were consistent in all HBR-subgroups. Conclusion For patients with a high bleeding risk undergoing PCI due to an ACS, an abbreviated DAPT strategy was associated with comparable rates of NACE and MACE as compared to a standard DAPT time strategy. The results add real-world evidence that abbreviated DAPT-regimes can be a viable treatment option for patients with ACS with a high bleeding risk.

ARCANGELO: an observational, prospective study with acute coronary syndrome patients undergoing percutaneous coronary intervention who receive cangrelor transitioning to oral P2Y12 inhibitors

Abstract Background The use of oral platelet P2Y12 receptor inhibitors, to reduce the risk of thrombotic complications related to Percutaneous Coronary Intervention (PCI), have some limitations in the acute phase, e.g., the delayed onset of action and lack of bioavailability in critical patients. Cangrelor is the only intravenous P2Y12 inhibitor, which based on its quick onset and offset of action is a valid alternative option for antiplatelet therapy, particularly for patients who are unable to take oral medications or for whom oral administration is not adequate. Notably, during the clinical development program of cangrelor, ticagrelor and prasugrel were not marketed and, therefore, the pivotal studies were conducted only with transitioning to clopidogrel. The aim of ARCANGELO study was the evaluation of the safety and effectiveness of cangrelor when administered to patients with Acute Coronary Syndrome (ACS) undergoing PCI in a real-world setting, including patients who received cangrelor transitioning to either clopidogrel, prasugrel, or ticagrelor. Methods Adult patients eligible to PCI for ACS who received cangrelor and who consented to take part in the study in 28 Italian centers, were followed in the 30 days after PCI. Bleedings, major adverse cardiac events (MACEs), and adverse events were recorded. The primary outcome was the incidence of any bleedings, according to BARC (Bleeding Academic Research Consortium) criteria, at 30 days post-PCI. Results A total of 1,004 patients were enrolled and 995 (99.2%) patients were eligible for analysis. Median (IQR) age was 65 (56-73) years, and 771 (77.5%) patients were males. 597 (59.9%) patients had ST-segment Elevation Myocardial Infarction; 509 (51.2%) patients had multi-vessel vessel coronary artery disease. A radial artery access was used in 926 (93.1%) patients and drug-eluting stents were implanted in almost all patients (n=972, 97.7%). All 995 patients included in the analysis received 30 micrograms/kg by intravenous bolus and 4 micrograms/kg/min by intravenous infusion. 730 patients (73.4%) were then transitioned to ticagrelor, 127 (12.8%) to prasugrel, and 138 (13.9%) to clopidogrel. 52 (5.2%) (95% CI 3.9% - 6.8%) patients experienced at least one bleeding event up to 30 days post-PCI. Five patients (0.5%) experienced at least one BARC type 3-5 (moderate-severe) bleeding (all type 3). Fourteen (1.4%) patients presented with at least one MACEs during observation (6 [0.6%] death, 7 [0.7%] myocardial infarction, 2 [0.2%] stent thrombosis). Six (0.6%) patients experienced at least one Treatment-Emergent Adverse Events related to cangrelor. Conclusions The results of this large real-world evidence study confirm that the use of cangrelor in patients with ACS undergoing PCI and transition strategy to the currently used P2Y12 oral inhibitors is safe and effective in daily practice.

Clinical profile, treatment strategy and prognostic value of intraventricular thrombus detection

Abstract Background The clinical course of patients with intraventricular thrombus (IVT) is highly variable. Controversy still exists about the length of anticoagulant treatment and its prognostic relevance. Purpose Our objective is to describe the epidemiology and clinical course of patients with IVT. Methods All patients with an echocardiographic finding of IVT in our tertiary hospital between 2005 and 2021 were retrospectively analyzed. Demographic, clinical, echocardiographic, and treatment variables were collected. Patients were followed-up to 24 months. Results A total of 195 patients with IVT were finally included. The 84.4% were male and the mean age was 65.4 ± 14.1 years. Baseline characteristics are shown in the Table. The diagnosis of IVT was mostly made in the context of an acute myocardial infarction (AMI) (55.9%), of which 60.5% had new-onset ST-segment elevation AMI and 23.5% evolved infarction. The thrombus finding was incidental in 38.0% of the cases while 5.6% debuted as stroke. Regarding the morphological characteristics, 40.5% of the thrombi were sessile, 31.2% mural shape, and 28.3% pedicled. At diagnosis, the LVEF was 38.6 ± 11.7% with an end-diastolic volume of 132.3 ± 64.2ml. Once diagnosed 86.7% of patients were on anticoagulation, 55.4% on 2PY12 inhibitor and 78.5% on acetylsalicylic acid. At 12 and 24 months, the proportion of anticoagulated patients was significantly reduced (62% and 59.4%, respectively). 24.9% continued with a P2Y12 inhibitor at 12 months and only 9% at 2 years. During follow-up, 24.4% of the patients had events at 6 months (2.4% AMI, 7.2% stroke, 2.4% systemic embolism and mortality was 14.7%). In this period there were 8.9% of hemorrhages. The proportion of ischemic events and mortality decreased at one year (5.6%) and at two years (12.1%). Complete IVT clearance was documented in 87% and the median time to resolution was 119 days [49.5-347.5]. IVT recurrence was observed in 10.7% of the cases, up to 50% detected before 2 years from diagnosis. Conclusions Most patients with IVT were diagnosed after an AMI. Despite current recommendations, more than 50% of patients continued anticoagulation at 2 years. A quarter developed events 6 months after diagnosis, and this proportion decreased significantly after this period. A recurrence rate of 10.7% was observed in our population.

Interactions between aspirin and ticagrelor during experimental human endotoxaemia

Abstract Introduction Dual antiplatelet therapy (DAPT) with aspirin 75-100mg once daily (OD) and the P2Y12 inhibitor ticagrelor is a standard treatment for acute coronary syndromes. De-escalating DAPT to ticagrelor monotherapy reduces bleeding risk yet appears to have minimal ischaemic penalty in most groups. The reason for this is unclear. P2Y12 inhibition can inhibit inflammatory processes relevant to atherothrombosis but aspirin may hypothetically counter these via platelet PGE2 inhibition. We studied the regimen-dependent effects of aspirin +/- ticagrelor in a human model of endotoxaemia. Endotoxin activates toll-like receptor 4, a key damage receptor in atherogenesis. Methods 72 healthy volunteers were randomised to receive either no aspirin or aspirin 20mg twice daily (BD), 75mg OD or 300mg OD for 10 days +/- a loading dose of ticagrelor on the last day prior to receiving intravenous endotoxin administration (2ng/kg). Blood was collected at 9 timepoints from 1h pre to 6h post endotoxin. Key cytokines and prostanoids in the blood/urine were measured by ELISA, platelet function by light transmittance aggregometry and platelet-leukocyte interaction by flow cytometry. Bleeding time was measured pre and 3h post endotoxin. After >5 weeks, in a 2nd period they received the same dose of aspirin as the 1st but received ticagrelor if they had not already, and vice versa, undergoing a 2nd endotoxin challenge at the end of the period. The primary endpoint was plasma tumour necrosis factor (TNF)-α. Results 72 participants were randomised (median 22.5yrs [range 18-59], 6F:66M). A total of 128 endotoxin challenges were performed. Endotoxaemia was associated with flu-like symptoms, pyrexia, tachycardia and relative hypotension but was safe. In those not receiving aspirin, plasma TNF-α was significantly lower when receiving ticagrelor vs. no ticagrelor, but in those receiving any dose of aspirin the significant effect of ticagrelor was abolished (Fig 1). All doses of aspirin fully suppressed arachidonic acid-induced PA with or without ticagrelor despite the thromboinflammatory stimulus of endotoxaemia (Fig 2A), and significantly augmented the inhibitory effect of ticagrelor on collagen-induced PA (2B). Aspirin 75mg OD and 300mg OD, but not 20mg BD, significantly prolonged bleeding time from baseline (2C). Ticagrelor significantly prolonged bleeding time in combination with any dose of aspirin or no aspirin. Aspirin dose-dependently inhibited PGE2 release. Conclusions All doses of aspirin tested prevented the ability of ticagrelor to significantly inhibit cytokine release during experimental endotoxaemia. Aspirin 20mg BD may offer improved bleeding risk with maintained antiplatelet effect compared to standard regimens. Where ticagrelor monotherapy is an option, dropping aspirin may allow ticagrelor to exert greater beneficial effect on inflammatory pathways relevant to atherothrombosis, potentially reducing ischaemic risk whilst also reducing bleeding risk.Figure 1Figure 2

Revealing concealed cardioprotection by platelet Mfsd2b-released S1P in human and murine myocardial infarction

Abstract Background/Introduction Platelet activation on ruptured or eroded atherosclerotic lesions leads to thrombus formation and ischemic events. Hence, platelet inhibition is the cornerstone of primary and secondary prevention in patients with cardiovascular disease. Recently, non-canonical effects of platelets in multiple disease processes were revealed. However, others have demonstrated the opposite: a protective and regenerative role of platelets during myocardial healing. Sphingosine-1-phosphate (S1P) is an important bioactive lipid released from platelets upon activation and has potent cardioprotective properties in AMI when acutely administered or kept constitutively high due to pharmacological or genetic inhibition of its degradation. In humans, S1P levels in plasma are dynamically regulated during AMI. Purpose We hypothesized that platelets may be an important source of the S1P burst during AMI and that platelet-derived S1P is relevant for the extent of myocardial damage due to AMI. Methods We have addressed these questions in experimental AMI in mice lacking components of the S1P synthesis, release and signaling pathways. In additon, we conducted a hypothesis generating, prospective, monocentric, time-series, translational analysis in 127 patients with ST-elevation myocardial infarction (STEMI) to analyze the association between S1P plasma concentration and infarct size. Results Injection of cell-free supernatant of activated platelets (SNT+) prior AMI in mice led to decreased infarct size after 24 h of reperfusion as compared to supernatant of non-activated platelets (SNT-). This reduction of infarct size by SNT+ was associated with reduced neutrophil accumulation and reduced apoptosis after AMI. S1P-concentrations in SNT+ was 25% higher as compared to SNT-. S1P concentrations in SNT- of mice lacking Sphingosinkinase-1 (SphK1) were 70% lower and did not increase in SNT+. Accordingly, SNT+ of SphK1- deficient platelets failed to reduce infarct size. Deficiency of platelet S1P exporter Mfsd2b shows increased infarct size during in vivo AMI compared to littermate controls. SNT+ of WT mice led to improved outcome after ischemia in a model of Langendorff-perfused hearts. This was blunted by inhibition of S1P receptor 1 and genetic cardiomyocyte deficiency of S1PR1. Platelet S1P release during activation was reduced by P2Y12 inhibition but preserved during GPIIb/IIIa (tirofiban) inhibition. This translated to blunted cardioprotection by SNT+ of cangrelor treated platelets but sustained cardioprotection during tirofiban treatment. Plasma S1P concentrations was associated with cardiovascular death and infarct size in patients with ST-elevation myocardial infarction. Conclusion We have identified the mechanisms underlying platelet-associated cardioprotection and finally, revealed the importance of platelet-released S1P on admission in patients with ST-elevation myocardial infarction (STEMI) regarding to infarct size and long-term prognosis.

Effect of evolocumab on platelet function in patients with acute coronary syndromes. An analysis of the randomized, double-blind, placebo-controlled EVOPACS Trial

Abstract Background Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors substantially lower levels of low-density lipoprotein cholesterol (LDL-C) and favourably impact clinical outcomes in patients with acute coronary syndromes (ACS). Although PCSK9 inhibitors have been suggested in ex vivo studies to suppress platelet activation, the impact of evolocumab on platelet function in ACS patients receiving potent antiplatelet therapy remains largely unknown. Methods The EVOPACS trial was a randomized, double-blind, placebo-controlled trial assessing the use of evolocumab initiated in the acute phase of ACS. Patients presenting with ST-elevation myocardial infarction (STEMI) or Non-ST-elevation ACS (NSTE-ACS) were randomly allocated in a 1:1 ratio to either evolocumab 420mg SC or matching placebo at baseline (during hospitalization for index ACS event) and after 4 weeks. All patients received atorvastatin 40mg daily. Dual antiplatelet therapy consisting of aspirin and a potent P2Y12 inhibitor was initiated according to STEMI / NSTE-ACS guidelines, unless a less potent treatment was indicated (e.g. due to concomitant use of oral anticoagulation). Platelet function was measured at baseline (during index hospitalization) and after 8 weeks, using the Multiplate analyser. The main outcome for this analysis was the change from baseline to 8 weeks in adenosine diphosphate (ADP)-induced platelet aggregation. Results Serial platelet function measurements were available in 260 of all 308 enrolled patients, 124 in the evolocumab and 136 in the placebo group. Mean age was 60.2±11.0 years and 83% were men. Baseline clinical characteristics were well balanced between the two treatment groups. At discharge, the proportion of patients treated with ticagrelor, prasugrel, and clopidogrel was 73%, 11%, and 9% respectively, without differences between groups. Evolocumab significantly reduced LDL-C compared to placebo at 8 weeks (difference in mean percentage change -40.75%, 95% CI -45.39 to -36.11; p<0.001). Change in ADP-induced platelet aggregation between baseline and 8-week follow-up was -5.6±23.5 U (from 24.1±19.8 to 29.7±25.6 U) in the evolocumab group vs. -1.7±198.7 U (from 23.0±14.7 U to 24.7±19.1 U) in the placebo group (p=0.13). Similar results were found in a subgroup of 189 patients (86 in the evolocumab and 103 in the placebo group) treated with ticagrelor at discharge, showing a change in ADP-induced platelet aggregation of -2.7±19.5 U with evolocumab vs. -2.4±19.9 U with placebo (p=0.80). Conclusions In this randomized trial of ACS patients largely treated with a potent P2Y12 inhibitor, evolocumab initiated during index hospitalization on top of high-intensity statin therapy had no measurable effect on ADP-induced platelet aggregation. These findings suggest that the early therapeutic benefit of PCSK9 inhibitors in ACS patients is likely related to plaque regression/stabilization rather than changes in platelet activity.

Comparison of de-escalation of DAPT intensity or duration in East Asian and Western patients with ACS undergoing PCI: A systematic review and meta-analysis

Abstract Background Guideline-recommended dual antiplatelet therapy (DAPT; aspirin plus prasugrel/ticagrelor) for 12 months in acute coronary syndromes (ACS) patients undergoing PCI, leads to an excess of bleeding. This led to studies to evaluate alternatives to 12 months of high-intensity DAPT, to balance thrombotic and bleeding risks. Several trials have investigated de-escalation strategies, either by reducing DAPT intensity, through switching from potent P2Y12 inhibitors prasugrel or ticagrelor to clopidogrel, or by shortening the duration of DAPT and continuing with single antiplatelet therapy. East Asian (EA) patients exhibit higher bleeding and lower ischaemic risk compared to non-East Asians (nEA) and most studies of "de-escalation" were conducted in EA patients. We sought to compare the safety and benefit of various DAPT "de-escalation" strategies in EA and nEA populations. Methods A systematic review and meta-analysis of randomized controlled trials assessing reduction of DAPT intensity or duration in ACS patients undergoing PCI, in EA and nEA, was performed using a non-random effects model. The study was registered on PROSPERO. The primary efficacy endpoint was the occurrence of net adverse cardiovascular events (NACE), namely the composite of ischaemic endpoints (including major adverse cardiovascular events [MACE] comprising all cause death, recurrent myocardial infarction [MI] and cerebrovascular accident); secondary endpoints were trial-defined MACE and major bleeding at longest follow-up. Results Twenty- trials assessed reduction of DAPT intensity (n=12) or duration (n=11). Of these 11 were conducted exclusively in EA patients while the remaining 7 were conducted predominantly in nEA patients. Overall, reduced DAPT intensity attenuated major bleeding (odds ratio [OR] 0.78, 95% confidence interval [CI] 0.65-0.94, p=0.009), without impacting NACE or MACE. In nEA, this increased MACE (OR 1.20, 95% CI 1.09-1.31, p<0.0001) without impacting NACE or bleeding; whilst in EA, it reduced major bleeding (OR 0.71, 95% CI 0.53-0.95, p=0.02) without affecting NACE or MACE. Overall, DAPT abbreviation reduced NACE (OR 0.90, 95% CI 0.82-0.99, p=0.03) due to major bleeding (OR 0.69, 95% CI 0.53-0.99, p=0.006), without impacting MACE. In nEA, this strategy did not impact NACE, MACE or major bleeding; whilst in EA, it reduced major bleeding (OR 0.60, 95% CI 0.4-0.91, p=0.02) without impacting NACE or MACE. Conclusion In EA, reduction in DAPT intensity or duration can minimise bleeding, without safety concerns. In nEA, reduction in DAPT intensity may incur an ischaemic penalty, whilst DAPT abbreviation has no overall benefit. Although standard DAPT favours patients at high ischaemic risk, while shorter or less intense DAPT may benefit those at high bleeding risk, many patients have overlapping risk factors. Individualisation of DAPT strategy may be preferable to personalise care based on both ethnicity and prevailing risks.

Ticagrelor versus Clopidogrel in diabetes patients afflicted with acute coronary syndrome stratified by renal function

Abstract Background Ticagrelor has been recommended in place of clopidogrel as part of dual antiplatelet therapy (DAPT) in diabetic patients with acute coronary syndrome (ACS). Chronic kidney disease (CKD) patients also have a worse prognosis in the setting of ACS, but the safety and efficacy data for the use of P2Y12 inhibitors in moderate to severe CKD patients (eGFR <60 mL/min/1.73m2) are insufficient. Purpose There has been limited data on the outcome of prescribing ticagrelor compared to clopidogrel in ACS-DM patients with chronic kidney disease (CKD). Methods This prospective, nationwide, multi-center, observational study, the Acute Coronary Syndrome-Diabetes Mellitus Registry (ACS-DM Registry) was compiled from consecutive patients between October 1, 2013 and September 30, 2016. The primary end point was repeated revascularisation and the composite outcome was CV death, repeat revascularisation and CV-related readmission, was stratified by renal function stages. The Cox proportional hazards models and propensity score models were applied to six-months, one-year, and two-year post ACS, respectively. Results There were 539 patients with moderate to severe CKD or on dialysis identified from ACS-DM Registry. There were 451 patients eligible for inclusion criteria of which 116 patients were taking ticagrelor and 335 patients were taking clopidogrel. At our two-year follow-up, the unadjusted incidence of primary end point resulted higher in Ticagrelor group (HR 2.09, 95% CI 1.37-3.18, p = 0.001). After adjustment, ticagrelor also had poor primary end point event and composite outcome as compared to clopidogrel (HR 2.24, 95% CI 1.36-3.68, p = 0.002; HR 1.63, 95% CI 1.06-2.48, p = 0.024, respectively). In regards to the repeated revascularisation issue, the clopidogrel was preferable within the eGFR strata (CKD stage III: HR 2.53, 95% CI 1.32-4.84, CKD stage IV: 1.06 (0.09-12.51), CKD stage V: 1.91 (0.80-4.59), P for interaction=0.684). Conclusions Cardiovascular benefits associated with ticagrelor may not be as significant as in the landmark trial. Our results show that patients taking ticagrelor was associated with increased CV events as compared to clopidogrel in ACS-DM patients with stage III-V CKD.propensity score matchingForest plots

Ticagrelor or Clopidogrel to reduce ischemic events after Percutaneous Coronary Intervention in chronic coronary syndrome in clopidogrel naive patient: the ALPHEUS Naive sub-study

Abstract Background The ALPHEUS trial showed a similar rate of type 4 myocardial infarction (MI) or major myocardial injury in elective PCI treated by clopidogrel or ticagrelor. Whether clopidogrel therapy at baseline might have affected these results is unknown. Purpose We evaluated the impact of ticagrelor versus clopidogrel loading dose in clopidogrel naïve patients as compared to patients already treated by clopidogrel in this pre-specified analysis. Methods We divided 1882 randomized patients with complete data on baseline clopidogrel into 2 groups according to presence of clopidogrel therapy > 7 days (long term clopidogrel = Clopi+) or its absence (clopidogrel naïve = Clopi-). The primary endpoint was the rate of PCI-related MI and myocardial injury as defined by the 3rd and 4th universal definition of MI evaluated within 48 h of PCI (or hospital discharge if earlier) and major and minor bleeding. Angiographic complications evaluated by the core laboratory (coronary slow flow, no flow, dissection, and thrombus) were also compared. Event rates were compared and the interaction of the allocated treatment in the randomized groups was evaluated. Results 1077 patients (57.2%) were Clopi- and 805 patients were Clopi+. Patients in the Clopi- group were less frequently male (78.0% vs 81.9%, p= 0.04) with less often dyslipidemia (57.8% vs 65.6%, p< 0.001) and peripheral artery disease (11.1% vs 14.4%, p= 0.03) and had less acute coronary syndrome in the last 12 months (3.4% vs 8.7% p= 0.002). The primary endpoint was less frequent in Clopi- as compared to tClopi+ (32.8% vs 40%, OR =0.73, CI [0.60-0.88], p=0.001). This difference was mainly driven by a lower rate of major myocardial injury 24.% vs 31.6% while the rate of type 4a MI and stent thrombosis were similar (8.4% vs 8.2%) and (0.4% vs 0.2%) respectively. Angiographic complication rate was similar in the Clopi- and the Clopi+ groups (14.6% vs 12.9%) OR=1.15 CI [0.88-1.5], p=0.31. Major bleedings were infrequent in the trial. (0.1% vs 0%), and minor bleeding did not differ significantly between Clopi- and Clopi+ patients (7.0% vs 4.8% OR=1.47, CI [0.99-2.19], p=0.06). At 30 days, no difference in any outcomes were reported between the two groups. Alike for the main trial results, in the Clopi- group, ticagrelor was not superior to clopidogrel in reducing periprocedural myocardial necrosis, p for interaction was 0.83. Conclusions Periprocedural MI and procedural angiographic complications were less frequent in clopidogrel naïve patients as compared to patients already on clopidogrel therapy, and not influenced by the potency of the P2Y12 inhibitor’s loading dose prior to PCI. These results globally suggest no benefit of a long term clopidogrel pretreatment in patients receiving a loading dose of P2Y12 in the 24 hours prior to PCI in chronic coronary syndrome undergoing elective PCI and support the use of clopidogrel as the standard of care.

Association of inflammatory activation with acute stent thrombosis

Abstract Background Acute stent thrombosis (ST) is a rare but deleterious event. Acute infection and inflammation may lead to activation of the coagulation system and of platelets. Coronary angiography with stent implantation is often deferred because of increased inflammatory markers. Purpose The aim of this study was to investigate whether an acute inflammatory state is associated with increased risk of early stent thrombosis. Methods Within a prospective single-center registry, the association between pre-procedural acute inflammatory activation, defined as C-reactive protein (CRP) plasma levels >5mg/dL or leukocytes >12 G/L, and occurrence of early stent thrombosis within 30 days after PCI was evaluated. Results We included 11327 patients that underwent coronary stenting. 3964 (35%) were treated for acute coronary syndrome (ACS) and 7363 (65%) had chronic coronary artery disease. The number of definite early ST within 30 days was 91 (0.8 %). Leukocyte count and plasma levels of C-reactive protein (CRP) were available in 6880 patients (87 patients with ST). 1715 patients showed signs of an acute inflammatory state as defined by a leukocyte count > 12 G/L or plasma levels of CRP > 5mg/dL. Stent implantation in patients with acute inflammation was associated with significant increased risk for ST (HR 3.01; p<0.0000001) independent of age, gender, kidney function, number and type of stents, presence of multivessel disease, choice of P2Y12 inhibitor and clinical presentation. This was the case in patients with (HR 2.48; p<0.001) and without acute coronary syndromes (HR 3.59; p<0.001). The incidence of ST in patients with ACS with and without signs of inflammation was 2.7% vs. 1.1% (p<0.001) and in patients with chronic coronary artery disease with and without inflammation was 2.3% vs 0.7% (p<0.001) Conclusions An acute inflammatory state as defined by a leukocyte count > 12 G/L or plasma levels of CRP > 5mg/dL at time of stent implantation was associated with a significant increased risk of acute ST. In particular in patients with chronic coronary artery disease acute inflammatory activation should lead to a deferral of elective interventions. In patients with ACS and increased inflammatory parameters, in which acute PCI is mandatory, future studies are needed, whether more intensive therapy could reduce risk of early ST in this particular high-risk cohort.

One-month dual antiplatelet therapy following stent implantation in patients with acute coronary syndromes and high bleeding risk

Abstract Background/introduction There is a paucity of data regarding the safety of a one-month dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI) in patients at high bleeding risk (HBR) presenting with acute coronary syndromes (ACS). Purpose We aimed to compare the clinical outcomes of patients at HBR with ACS or chronic coronary syndromes (CCS) treated with PCI using bioresorbable-polymer everolimus-eluting stent followed by one-month DAPT. Methods This is a pre-specified sub-analysis of the POEM trial, an interventional, prospective, multicenter, single-arm trial, that evaluated the safety of PCI with bioresorbable-polymer everolimus-eluting stent followed by one-month DAPT in patients with HBR against an objective performance criterion (OPC). The OPC was derived from the reported 1-year primary endpoint rate of 9.4% observed in the LEADERS FREE trial. According to the POEM protocol, patients were treated with one-month DAPT. In case of need for anticoagulation, patients received an oral anticoagulant in addition to a P2Y12 inhibitor for one month, followed by oral anticoagulation only after that. The primary endpoint was a composite of cardiac death, myocardial infarction, or definite/probable stent thrombosis at 12 months. Results 263 (59.4%) patients with CCS and 180 (40.6%) patients with ACS were included. Most of the HBR inclusion criteria were comparable between the two groups, Figure 1. At one year, the rates of the primary outcome were 4.3% (95% CI, 2.4-7.6%) and 5.7% (95% CI, 3.1-10.3%) among patients with CCS and ACS, respectively. Both 1-sided 97.5% upper confidence limits of the risk difference between the primary outcome and the prespecified OPC of 9.4% were below the non-inferiority margin of 3.85 % (CCS: -1.8 %; ACS: 0.9 %), Figure 2. No significant difference was evident between CCS and ACS patients for each isolated component of the primary endpoint (cardiac death: 1.7% vs. 2.0%, p= 0.857; myocardial infarction: 3.9% vs. 3.1%, p= 0.934; definite/probable stent thrombosis: 1.2% vs. 0.8%, p= 0.689). The risk for Bleeding Academic Research Consortium (BARC) type 1-5 or type 3-5 bleedings was also similar between CCS and ACS patients (4.3% vs. 5.2%, p=0.677, and 1.6% vs. 2.9%, p=0.351, respectively). Conclusions Among HBR patients with ACS who underwent PCI with BP-EES, a one-month DAPT strategy is associated with a similar risk of ischemic and bleeding events compared to those with CCS. These findings support the hypothesis that DAPT should be tailored to patients’ bleeding risk profiles and that a one-month strategy might be safely applied also in a particular setting of ACS.Figure 1.HBR inclusion criteria.Figure 2.Primary endpoint analysis.

Impact of trial results and guidelines on the practice of Primary PCI over 14 years

Abstract Aim We aimed to present an overview of changes in daily practice of primary PCI in relation to on the growing evidence in device and adjunctive pharmacologic therapy. Methods and results Clinical outcomes, data on treatment as well as characteristics of 19,054 patients prospectively enrolled in a nation-wide registry of primary PCI between 2005 and 2018 were analysed. A year-by-year trend analysis was done to show the dynamic of changes following landmark trial publications and new guideline recommendations. Patient characteristics remained stable except a slight increase of patients needing resuscitation (from 8% to 12%) and treatment delays showed improvements over time. The prescription of new P2Y12 Inhibitors rapidly increased after approval in 2009. Femoral access was predominant in 2011 (over 90%) followed by a steady decrease to under 30% in 2018. The use of thrombus aspiration increased since 2008 with a maximum in 2013 followed by a decrease after publication of two negative randomised trials. Mortality was in average 6%. Conclusion Trial results and guideline recommendations had a strong impact on the practice of PPCI in this national registry. Despite improved treatments, the average in-hospital mortality of 6% indicates the necessity of continuous reassessment of treatment delays and other quality indicators to further improve patient outcome after STEMI.Changes over time

Pharmacodynamic and pharmacokinetic profiles associated with switching from cangrelor to prasugrel in patients undergoing percutaneous coronary intervention: the SWAP-6 study

Abstract Background Cangrelor is an intravenous P2Y12 inhibitor used in patients undergoing coronary intervention (PCI). Preliminary studies have shown the potential for a drug-drug interaction (DDI) when transitioning from cangrelor to oral P2Y12 inhibition with prasugrel. However, to date this has not been prospectively tested in patients undergoing PCI. Purpose To rule out a DDI when cangrelor and prasugrel are concomitantly administered in patients undergoing PCI. Methods SWAP-6 is a prospective, randomized, 3-arm, open-label, pharmacokinetic (PK) and pharmacodynamic (PD) study conducted in patients undergoing PCI (n=77). Patients were randomized to either a) prasugrel only administered at the start of PCI; b) cangrelor plus prasugrel concomitantly administered at the start of PCI; c) cangrelor administered at the start of PCI plus prasugrel administered at the end of the cangrelor infusion. Cangrelor (30 μg/kg bolus followed by 4 μg/kg/min infusion) was maintained for 2 hours and all patients were on a background of aspirin therapy. Prasugrel was administered as a 60 mg loading dose. PK analysis included plasma levels of prasugrel active metabolite, and PD assessments included VerifyNow PRU, total thrombus-formation analysis system (T-TAS), and vasodilator-stimulated phosphoprotein (VASP), at baseline and 6 time points after prasugrel/cangrelor administration. The primary end point was non-inferiority in PRU measured at 4 hours after prasugrel/cangrelor loading (2 hours after stopping cangrelor infusion) of cangrelor plus prasugrel concomitantly administered versus prasugrel only. The noninferiority margin was defined as 45 PRU. Results Cangrelor achieved lower PRU levels than prasugrel only as early as 30 minutes and up to 2 hours after bolus administration (Figure). At 3 hours after prasugrel/cangrelor loading, PRU levels were higher with cangrelor compared to prasugrel only. At 4 hours after loading (2 hours after stopping cangrelor infusion), PRU levels were significantly lower with prasugrel only compared to cangrelor and prasugrel concomitantly administered (LSM difference 130; 95% CI: 85-176), failing to meet the prespecified noninferiority primary end point (Figure). At this time point, cangrelor followed by prasugrel at the end of the infusion had higher PRU than prasugrel only, but lower than cangrelor and prasugrel concomitantly. Platelet reactivity by T-TAS and VASP showed consistent findings. PK analysis tracked PD results (data not shown). Conclusions In patients undergoing PCI, cangrelor is associated with more potent platelet inhibition than prasugrel alone. However, concomitant administration of prasugrel with cangrelor leads to a marked increase in platelet reactivity after stopping cangrelor infusion, supporting the presence of a DDI. This underscores the importance of administering prasugrel not until the end of cangrelor infusion, a strategy which mitigates the increase in platelet reactivity.

Periprocedural management of direct oral anticoagulants in patients with atrial fibrillation and active cancer

BackgroundCancer and atrial fibrillation (AF) are common concurrent disorders. Direct oral anticoagulants (DOACs) are prescribed to prevent stroke in patients with AF. Patients with cancer often undergo invasive procedures for diagnostic or therapeutic purposes, necessitating interruption of anticoagulation. There are limited data to guide best periprocedural anticoagulation management practices in the setting of active cancer. ObjectivesTo describe patient characteristics, periprocedural management, and clinical outcomes in DOAC-treated patients with AF according to active cancer status. MethodsWe conducted descriptive and comparative analyses using data from the PAUSE study. Multivariable logistic regression was used to determine whether active cancer status was an independent risk factor for bleeding outcomes. Covariates were selected a priori based on biological rationale and preexisting knowledge. ResultsPatients with active cancer were older (P < .001), more likely to be thrombocytopenic (P = .026), have moderate renal dysfunction (P = .005), and more likely to receive low-dose DOAC therapy (P < .001). A greater proportion of patients with active cancer underwent a high-bleed-risk procedure (P < .001), with longer periprocedural DOAC-interruption intervals (P <.001) and lower preprocedural residual DOAC levels (P = .002). Active cancer was an independent predictor for surgical major bleeding (OR = 2.45; 95% CI, 1.08-5.14) after adjusting for study center, procedure category and bleed risk, thrombocytopenia, hypertension, and the use of a P2Y12 inhibitor. ConclusionsActive cancer status is associated with an increased risk of surgical major bleeding among DOAC-treated patients with AF undergoing interruption of anticoagulation for elective invasive procedures.

Cardioembolic events and death predictors in patients with intraventricular thrombus

Abstract Background There is poor evidence about the optimal medical treatment and length of anticoagulation for the management of intraventricular thrombus (IVT). Current ESC guidelines recommend continuation of anticoagulation for up to 6 months. Purpose The objective of this study was to identify predictors of events during follow-up in patients with IVT in order to infer the best therapy in this clinical scenario. Methods All patients with IVT in our tertiary hospital between 2005 and 2021 were retrospectively analyzed. Patients were classified into 2 groups, according to whether they developed (group 1) or not (group 2) the combined event of death, myocardial infarction, stroke or embolism during the first 6 months. A multivariate logistic regression analysis was performed to identify independent risk factors of clinical events. Results 195 patients were included, of whom 40 (24.1%) presented the combined event at 6 months. There were no differences in age (68.5±15.6 vs 65±13.7 years; p=0.167) or gender distribution (80% men vs 84.9%; p=0.463) between the groups. A history of peripheral vascular disease (22% vs 7.1%; p=0.007), atrial fibrillation (AF) (22% vs 6.3%; p= 0.004) and stroke (34.2% vs 11.8%; p=0.001) were more frequent in group 1. The echocardiogram showed more frequently a mobile thrombus (43.2% vs 23%; p=0.017) with the presence of outgrowths (19.4% vs 5.6%; p=0.012) in the group with events. In addition, these patients had worse ventricular function (LVEF 33.6% vs 40.4%; p=0.002). Regarding treatment, the use of P2Y12 inhibitors was lower in group 1 (36.6% vs. 58.3%, p=0.016). There were no differences in the use of anticoagulants (85.4% vs 87.4%, p=0.737) or in the time until the thrombus clearance (median 119 vs 147 days, p=0.152). The presence of outgrowths in the thrombus, the ejection fraction, and a history of stroke were independently associated with the development of events at 6 months (Table). Considering a cut-off point of one-year follow-up instead, only 7 patients more had events. The presence of outgrowths was the only factor that maintained the independent association with the development of events (OR 9.3 (95%CI 1.6-54.7); p=0.01) during this time frame. Conclusions Cardiovascular events after IVT diagnosis are concentrated in the first 6 months. The presence of outgrowths attached to the thrombus, the lower ejection fraction, and a history of stroke were independent predictors of events at 6 months. In addition, the presence of outgrowths maintained its strong association at one year. Therefore, a more aggressive antithrombotic treatment may be considered in the presence of these factors.

The impact of ticagrelor therapy on CABG-related bleeding in patients with STEMI managed with pPCI

Abstract Background Patients on double antiplatelet treatment who need early in-hospital coronary artery bypass grafting (CABG) are at high risk of major bleeding. However, recent studies have demonstrated that early CABG surgery within 7 days of discontinuation of p2Y12 inhibitors are safe with respect to bleeding events in patients with acute coronary syndrome. Purpose In this study, we aimed to investigate the impact of ticagrelor preloading on CABG related bleeding in patients with ST-segment elevation myocardial infarction (STEMI) initially managed with primary percutaneous coronary intervention (pPCI). Methods Patients with the diagnosis of STEMI who were managed with pPCI and underwent subsequent early (4-7 days following pPCI) or delayed (&amp;gt; 7 days following pPCI) CABG surgery were included. All study patients were preloaded with ticagrelor 180 mg prior to pPCI procedure. Patients’ demographics, clinical variables and short-term cardiovascular outcomes were recorded. Results The study cohort included 98 patients. Fifty-four (54%) patients underwent early and 44(45%) patients underwent delayed CABG surgery. Left main coronary artery involvement and presence of chronic total occlusion in the non-infarct related artery were 26.5% and 25.5%. CABG-related bleeding occurred in 22 (22.4%) patients. There was no significant difference with respect to total ticagrelor dose and timing of the surgery between patients with or without CABG-related bleeding (p: 0.165 and p:0.142). Multivariate analyses demonstrated that only preoperative hemoglobin level was an independent predictor of CABG-related bleeding (OR:0.720, p: 0.034).There were three deaths within the 30 days of surgery, all occurring in patients with CABG-related bleeding. However, CABG-related bleeding was not associated with long-term cardiovascular events during the follow-up. Conclusion Our results indicated that discontinuation of ticagrelor therapy 3 days prior to surgery is sufficient to avoid CABG-related bleeding. Moreover, early CABG following STEMI does not increase the risk of long-term cardiovascular events.

Abstract 14153: P2Y12 Inhibitors and Quality of Life Outcomes in Critically Ill Patients Hospitalized for COVID-19: A Pre-Specified Secondary Analysis of the ACTIV4a Randomized Clinical Trial

Background: Post-acute sequela of COVID-19 (PASC) is a complication of SARS-CoV-2 causing persistent symptoms and impaired functional status. We studied the effect of P2Y12 inhibitors on health-related Quality of Life (QoL) at 90 days in critically ill patients hospitalized for COVID-19. Methods: Adults hospitalized for COVID-19 who were randomized in the P2Y12 inhibitor domain of ACTIV-4a platform trial between February 2021 and June 2022. Participants were to receive usual care and either P2Y12 inhibitor (ticagrelor preferred) or no P2Y12 inhibitor for 14-days or until hospital discharge, whichever was sooner. The QoL primary outcome was determined by the EQ-5D-5L utility and visual analog scores, standardized and validated instruments. A Bayesian model estimated difference in health related QoL by randomization status adjusting for risk factors. Results: Among 1,502 participants, 860 critically ill patients were administered English and Spanish translations of EQ-5D-5L at 90-days. Median age was 57 years (IQR: 47, 65), 37% were female, 49% were under-represented minorities, and 10% resided in Spain. In those assigned to P2Y12 inhibitor, the mean EQ-5D-5L utility score was better in those assigned to usual care (adjusted difference: 0.08, 95% CrI: 0.03, 0.13; posterior probability of superiority [defined as a mean difference &gt; 0] was 99.9%). Better health related QoL was also observed with assignment to P2Y12 inhibitors; EQ-5D-5L visual analog score adjusted difference: 5.30 (95% Crl: -0.49, 10.84), probability of superiority: 96.4% (table 1). Conclusion: In secondary analysis of an international randomized trial of critically ill participants with COVID-19, treatment with a P2Y12 inhibitor vs usual care was associated with improved quality of life at 90-days and may decrease symptoms of PASC following hospital discharge.