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BACKGROUND: Early and complete restoration of target vessel patency in ST-elevation myocardial infarction (STEMI) is associated with improved outcomes. Oral P2Y12 inhibitors have failed to demonstrate either improved patency or reduced mortality when administered in the pre-hospital setting. Thus, there is a need for antiplatelet agents that achieve prompt and potent platelet inhibition, and that restore patency in the pre-hospital setting. Zalunfiban, a novel subcutaneously administered glycoprotein IIb/IIIa inhibitor designed for pre-hospital administration, has shown to achieve rapid, high-grade platelet inhibition that exceeds that of P2Y12 inhibitors. Whether pre-hospital administration of zalunfiban can improve clinical outcome is unknown.HYPOTHESIS: The present study is designed to assess the hypothesis that a single, pre-hospital injection of zalunfiban given in the ambulance, in addition to standard-of-care in patients with STEMI with intent to undergo primary percutaneous coronary intervention (PCI) will improve clinical outcome compared to standard-of-care with placebo.STUDY DESIGN: The ongoing CELEBRATE trial (NCT04825743) is a phase III, randomized, double-blinded, placebo-controlled, international trial. Patients with STEMI intended to undergo primary PCI will receive treatment with a single subcutaneous injection containing either zalunfiban dose 1 (0.110 mg/kg), zalunfiban dose 2 (0.130 mg/kg) or placebo, and the study drug will be administered in the ambulance before transportation to the hospital. A target of 2499 patients will be randomly assigned to one of the treatment groups in a 1:1:1 ratio, i.e., to have approximately 833 evaluable patients per group. The primary efficacy outcome is a ranked 7-point scale on clinical outcomes. The primary safety outcome is severe or life-threatening bleeding according to the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) criteria.SUMMARY: The CELEBRATE trial will assess whether a single pre-hospital subcutaneous injection of zalunfiban in addition to standard-of-care in patients with STEMI with intent to undergo primary PCI will result in improved clinical outcome.

Oral inhibitors of the platelet P2Y12 receptor are indispensable in the treatment of ST-elevation myocardial infarction (STEMI), improving outcomes and even reducing mortality in some studies. However, these drugs are limited by delayed absorption and suboptimal platelet inhibition at the time of primary percutaneous coronary intervention. Despite efforts to achieve faster and more sustained platelet inhibition, strategies such as prehospital administration, higher loading doses, and crushed formulations have not led to improved coronary reperfusion. Parenteral glycoprotein IIb/IIIa inhibitors act sooner and are more potent than oral P2Y12 inhibitors, but their use has been limited by the increased risk of major bleeding and thrombocytopenia. Hence, there is a clinical need to refine drugs that deliver rapid, effective, yet safe platelet inhibition in the setting of STEMI. Novel parenteral antiplatelet drugs, such as cangrelor, selatogrel, and zalunfiban, have been recently developed to achieve rapid, potent antiplatelet effects while preserving hemostasis. We provide a description of currently available parenteral antiplatelet agents and of those in clinical development for prehospital administration in STEMI patients.

Objective The long-term predictive performance of existing bleeding risk models in patients with various manifestations of cardiovascular disease (CVD) is not well known. This study aims to assess and compare the performance of relevant existing bleeding risk models in estimating the long-term risk of major bleeding in a cohort of patients with established CVD.Methods Seven existing bleeding risk models (PRECISE-DAPT, DAPT, Ducrocq et al, de Vries et al, S2TOP-BLEED, Intracra-nial B2LEED3S and HAS-BLED) were identified and externally validated in 7,249 patients with established CVD included in the Utrecht Cardiovascular Cohort-second manifestations of arterial disease study. Predictive performance was assessed in terms of discrimination and calibration, both at 10 years and the original prediction horizon of the models. Major bleeding was defined as Bleeding Academic Research Consortium type 3 or 5.Results After a median follow-up of 8.4 years (interquartile range 4.5-12.5), a total of 233 (3.2%) major bleeding events occurred. C-statistics for discrimination at 10 years ranged from 0.53 (95%CI 0.49-0.57) to 0.64 (95%CI 0.60-0.68). Calibration plots after recalibration to 10 years showed best agreement between predicted and observed bleeding risk for De Vries et al, S2TOP-BLEED, DAPT and PRECISE-DAPT.Conclusions The performance of existing bleeding risk models to predict long-term bleeding in patients with CVD varied. Discrimination and calibration were best for the models of de Vries et al, S2TOP-BLEED, DAPT and PRECISE-DAPT. Of these, recalibrated models requiring the least predictors may be preferred for use to personalize prevention with antithrom-botic therapy. (Am Heart J 2023;260:72-81.)

Background Postsurgical thoracic aortic pseudoaneurysms (PTAPs) are a potentially lethal complication after cardiac or aortic surgery. Surgical management can pose a challenge with high in-hospital mortality rates. Transcatheter closure is a less-invasive alternative treatment option for selected patients, although current experience is limited. Aims We aimed to evaluate procedural and imaging outcomes of our first 11 cases of transcatheter PTAP closure with the use of closure devices. Methods Patients with a high operative risk who underwent transcatheter PTAP closure at our centre from 2019 to 2021 were retrospectively included. Suitability was evaluated on preprocedural computed tomography (CT) scans and three-dimensional (3D) reconstructions. All procedures were performed in the catheterisation laboratory. Intraprocedural aortography and postprocedural CT scans with 3D reconstructions were used to evaluate PTAP occlusion. Results Eleven consecutive patients with a high operative risk and a history of cardiac/aortic surgery who underwent transcatheter PTAP closure were included. PTAPs were predominantly located at the proximal or distal anastomosis of a supracoronary ascending aortic vascular graft or Bentall prosthesis (82%). Implanted closure devices included Amplatzer Valvular Plug III (82%), Amplatzer septal occluder (9%) and Occlutech atrial septal defect occluder (9%). No periprocedural complications occurred. After device deployment, residual flow was absent on aortography in 64% and minimal residual flow was present in 36% of patients. Subtotal or total occlusion of the PTAP on follow-up CT ranged between 45% and 73%. Conclusions Although subtotal or total occlusion of the PTAP was found at follow-up in only 45–73% of cases, transcatheter PTAP closure guided by preprocedural 3D reconstructions can offer a valuable minimally invasive primary treatment option for patients who otherwise would face a high-risk reoperation.

Introduction: P2Y(12)-inhibitor monotherapy following 1-3 months of dual antiplatelet therapy (DAPT) reduces (major) bleeding without an apparent increase in ischemic events and has therefore emerged as an alternative to 6-12 months of DAPT following percutaneous coronary intervention (PCI). However, there are important differences between the available P2Y(12)-inhibitors (clopidogrel, prasugrel, and ticagrelor) as agents of choice for P2Y(12)-inhibitor monotherapy.Areas covered: This review critically appraises the evidence for P2Y(12)-inhibitor monotherapy after PCI using either clopidogrel, prasugrel, or ticagrelor. Furthermore, we discuss ongoing trials and future directions for research.Expert opinion: P2Y(12)-inhibitor monotherapy following 1-3 months of DAPT is an alternative to 6-12 months of DAPT following PCI. Ticagrelor may be considered the current preferred option due to its reliable effect on platelet reactivity and its predominant use in clinical trials. Prasugrel could serve as a useful substitute for those not tolerating ticagrelor, but more research into prasugrel monotherapy is warranted. Alternatively, clopidogrel can be used, although there are concerns of high platelet reactivity, especially when genotyping and/or platelet function testing are not used. Future research will need to address the minimal duration of DAPT before switching to P2Y(12)-inhibitor monotherapy and what the optimal antithrombotic therapy beyond 12 months is.

BackgroundThe cytochrome P450 (CYP) 2C9 enzyme plays a role in the metabolization of clopidogrel. Carriage of a CYP2C9 loss-of-function (LoF) allele has been associated with attenuated pharmacokinetics, leading to a diminished pharmacodynamic response and increased risk for developing stent thrombosis in patients treated with clopidogrel.MethodsIn this study, we aimed to determine the effect of the CYP2C9*2 and *3 LoF alleles on thrombotic events. Therefore, a post hoc analysis was performed in 878 patients with available CYP2C9 genotype status included in the POPular Genetics and POPular Age trials, which enrolled patients with ST-elevation myocardial infarction and non-ST-elevation myocardial infarction, respectively. The primary thrombotic outcome was a composite of cardiovascular death, myocardial infarction or stroke.ResultsA total of 526 (60%) patients were CYP2C9 LoF allele noncarriers and 352 (40%) were CYP2C9 LoF allele (*2 or *3) carriers. After correction for differences in baseline characteristics, there were no significant differences between CYP2C9 LoF allele carriers and noncarriers for the combined thrombotic outcome (6.3% vs. 5.9%, hazard ratio 1.16 [0.67-2.0], p = 0.60), or the individual thrombotic outcomes. Moreover, no differences were seen in the event rates for clinically relevant bleeding (Bleeding Academic Research Consortium [BARC] 2-5 bleeding) as well as major bleeding (BARC 3 or 5 bleeding).ConclusionsCarriers of a CYP2C9 *2 or *3 LoF allele presenting with acute coronary syndrome and treated with clopidogrel did not have an increased risk for thrombotic events compared with noncarriers. Given the limited number of poor metabolizers, no firm conclusions could be drawn with regard to the thrombotic risk for patients carrying two CYP2C9 LoF alleles.

Early recanalization of the infarct-related artery to achieve myocardial reperfusion is the primary therapeutic goal in patients with ST-elevation myocardial infarction (STEMI). To decrease the duration of ischaemia, continuous efforts have been made to improve pre-hospital treatment and to target the early period after symptom onset. In this period the platelet content of the fresh coronary thrombus is maximal and the thrombi are dynamic, and thus more susceptible to powerful antiplatelet agents. There have been substantial advances in antiplatelet therapy in the last three decades with several classes of oral and intravenous antiplatelet agents with different therapeutic targets, pharmacokinetics, and pharmacodynamic properties. New parenteral drugs achieve immediate inhibition of platelet aggregation, and fast and easy methods of administration may create the opportunity to bridge the initial gap in platelet inhibition observed with oral P2Y12 inhibitors. Moreover, potential future management of STEMI could directly involve patients in the process of care with self-administered antiplatelet agents designed to achieve rapid reperfusion. However, the potential anti-ischaemic benefits of potent antiplatelet agents will need to be balanced against their risk of increased bleeding. This study presents a comprehensive and updated review of pre-hospital antiplatelet therapy among STEMI patients undergoing primary percutaneous intervention and explores new therapies under development.

Transcatheter aortic valve replacement (TAVR) is a treatment option for symptomatic patients with severe aortic stenosis who are candidates for a bioprosthesis across the entire spectrum of risk. However, TAVR carries a risk for thrombotic and bleeding events, underscoring the importance of defining the optimal adjuvant antithrombotic regimen. Antithrombotic considerations are convoluted by the fact that many patients undergoing TAVR are generally elderly and present with multiple comorbidities, including conditions that may require long-term oral anticoagulation (OAC) (eg, atrial fibrillation) and antiplatelet therapy (eg, coronary artery disease). After TAVR among patients without baseline indications for OAC, recent data suggest dual-antiplatelet therapy to be associated with an increased risk for bleeding events, particularly early postprocedure, compared with single-antiplatelet therapy with aspirin. Concerns surrounding the potential for thrombotic complications have raised the hypothesis of adjunctive use of OAC for patients with no baseline indications for anticoagulation. Although effective in modulating thrombus formation at the valve level, the bleeding hazard has shown to be unacceptably high, and the net benefit of combining antiplatelet and OAC therapy is unproven. For patients with indications for the use of long-term OAC, such as those with atrial fibrillation, the adjunctive use of antiplatelet therapy increases bleeding. Whether direct oral anticoagulant agents achieve better outcomes than vitamin K antagonists remains under investigation. Overall, single-antiplatelet therapy and OAC appear to be reasonable strategies in patients without and with indications for concurrent anticoagulation. The aim of the present review is to appraise the current published research and recommendations surrounding the management of antithrombotic therapy after TAVR, with perspectives on evolving paradigms and ongoing trials. (J Am Coll Cardiol Intv 2021;14:1688-703) (c) 2021 by the American College of Cardiology Foundation.

Background: Little is known about the optimal antithrombotic therapy in patients with atrial fibrillation undergoing PCI for ST-elevation myocardial infarction (STEMI). Aims: The aim of this study was to investigate the safety and efficacy of dabigatran dual therapy (110 or 150 mg twice daily, plus clopidogrel or ticagrelor) versus warfarin triple therapy in patients with atrial fibrillation and STEMI. Methods: In the RE-DUAL PCI trial, 305 patients with STEMI were randomised to dabigatran 110 mg (n=113 versus 106 warfarin) or 150 mg (n=86 versus 84 warfarin). The primary endpoint was the time to first major/clinically relevant non-major bleeding event (MBE/CRNMBE). The thrombotic endpoint was a composite of death, thromboembolic events, or unplanned revascularisation. Results: In STEMI patients, dabigatran 110 mg (HR 0.39, 95% CI: 0.20-0.74) and 150 mg (0.43, 0.21-0.89) dual therapy reduced the risk of MBE/CRNMBE versus warfarin triple therapy (p for interaction vs all other patients=0.31 and 0.16). The risk of thrombotic events for dabigatran 110 mg (HR 1.61, 95% CI: 0.85-3.08) and 150 mg (0.56, 0.20-1.51) had p interactions of 0.20 and 0.33, respectively. For net clinical benefit, the HRs were 0.74 (95% CI: 0.46-1.17) and 0.49 (0.27-0.91) for dabigatran 110 and 150 mg (p for interaction=0.80 and 0.12), respectively. Conclusions: After PCI for STEMI, patients on dabigatran dual therapy had lower risks of bleeding events versus warfarin triple therapy with similar risks of thromboembolic events, supporting dabigatran dual therapy even in patients with high thrombotic risk.

Background Glycoprotein IIb/IIIa inhibitors (GPI) are still used in patients with ST-segment elevation myocardial infarction (STEMI) who undergo primary percutaneous coronary intervention (PCI), although discussion about its clinical benefit is ongoing. Methods GPI use was analyzed in this subanalysis of the POPular Genetics trial, which randomized STEMI patients to CYP2C19 genotype-guided treatment (clopidogrel or ticagrelor) or standard treatment with ticagrelor/prasugrel. The composite thrombotic endpoint consisted of cardiovascular death, myocardial infarction (MI), definite stent thrombosis, and stroke at 30 days. The combined bleeding endpoint consisted of Platelet Inhibition and Patient Outcomes (PLATO) major and minor bleeding at 30 days. Univariable and multivariable analyses in addition to a propensity score-matched (PSM) analysis were conducted. Results In total, 2378 patients, of whom 1033 received GPI and 1345 did not, were included. In multivariable analysis, GPI administration was associated with fewer thrombotic events (hazard ratio [HR] 0.22, 95% confidence interval [CI] 0.09-0.55) and MIs (HR 0.24, 95% CI 0.08-0.73). Furthermore, GPI administration was associated with an increase in bleedings (HR 2.02, 95% CI 1.27-3.19), driven by minor bleedings (HR 2.32, 95% CI 1.43-3.76), without a significant difference in major bleedings (HR 0.69, 95% CI 0.19-2.57). In the PSM analysis, no significant association was found. Conclusion In STEMI patients undergoing primary PCI, GPI administration was associated with a reduction in thrombotic events at a cost of an increase in (mostly minor) bleedings in multivariable analysis, while propensity score analysis did not show significant associations.

P2YThis review critically appraises the evidence for P2YP2Y

Acute kidney injury (AKI) is not uncommon in patients undergoing transcatheter aortic valve replacement (TAVR). We examined the incidence, predictors, and outcomes of AKI from the BRAVO 3 randomized trial. The BRAVO-3 trial included 802 patients undergoing transfemoral TAVR randomized to bivalirudin vs. unfractionated heparin (UFH). The primary endpoint of the trial was Bleeding Academic Research Consortium (BARC) type ≥ 3b bleeding at 48 h. Total follow-up was to 30 days. AKI was adjudicated using the modified RIFLE (Valve Academic Research Consortium, VARC 1) criteria through 30-day follow-up, and in a sensitivity analysis AKI was assessed at 7 days (modified VARC-2 criteria). We examined the incidence, predictors, and 30-day outcomes associated with diagnosis of AKI. We also examined the effect of procedural anticoagulant (bivalirudin or unfractionated heparin, UFH) on AKI within 48 h after TAVR. The trial population had a mean age of 82.3 ± 6.5 years including 48.8% women with mean EuroScore I 17.05 ± 10.3%. AKI occurred in 17.0% during 30-day follow-up and was associated with greater adjusted risk of 30-day death (13.0% vs. 3.5%, OR 5.84, 95% CI 2.62–12.99) and a trend for more BARC ≥ 3b bleeding (15.1% vs. 8.6%, OR 1.80, 95% CI 0.99–3.25). Predictors of 30-day AKI were baseline hemoglobin, body weight, and pre-existing coronary disease. AKI occurred in 10.7% at 7 days and was associated with significantly greater risk of 30-day death (OR 6.99, 95% CI 2.85–17.15). Independent predictors of AKI within 7 days included pre-existing coronary or cerebrovascular disease, chronic kidney disease (CKD), and transfusion which increased risk, whereas post-dilation was protective. The incidence of 48-h AKI was higher with bivalirudin compared to UFH in the intention to treat cohort (10.9% vs. 6.5%, p = 0.03), but not in the per-protocol assessment (10.7% vs. 7.1%, p = 0.08). In the BRAVO 3 trial, AKI occurred in 17% at 30 days and in 10.7% at 7 days. AKI was associated with a significantly greater adjusted risk for 30-day death. Multivariate predictors of AKI at 30 days included baseline hemoglobin, body weight, and prior coronary artery disease, and predictors at 7 days included pre-existing vascular disease, CKD, transfusion, and valve post-dilation. Bivalirudin was associated with greater AKI within 48 h in the intention to treat but not in the per-protocol analysis.

Background N-terminal fragment of the brain natriuretic peptide prohormone (NT-proBNP), a marker for neurohumoral activation, has been associated with adverse outcome in patients with myocardial infarction. NT-proBNP levels may reflect extensive ischemia and microvascular damage, therefore we investigated the potential association between baseline NTproBNP level and ST-resolution (STR), a marker of myocardial reperfusion, after primary percutaneous coronary intervention (pPCI).Methods we performed a post-hoc analysis of the On-TIME II trial (which randomized ST-elevation myocardial infarction (STEMI) patients to pre-hospital tirofiban administration vs placebo). Patients with measured NT-proBNP before angiography were included. Multivariate logistic-regression analyses was performed to investigate the association between baseline NTproBNP level and STR one hour after pPCI.Results Out of 984 STEMI patients, 918 (93.3%) had NT-proBNP values at baseline. Patients with STR 70% had higher NT-proBNP values compared to patients with complete STR (70%) [Mean +/- SD 375.2 +/- 1021.7 vs 1007.4 +/- 2842.3, Median (IQR) 111.7 (58.4-280.0) vs 168.0 (62.3-601.3), P < .001]. At multivariate logistic regression analysis, independent predictors associated with higher risk of poor myocardial reperfusion (STR < 70%) were: NT-proBNP (OR 1.17, 95%CI 1.041.31, P = .009), diabetes mellitus (OR 1.87, 95%CI 1.14-3.07, P = .013), anterior infarct location (OR 2.74, 95% CI 2.00-3.77, P < .001), time to intervention (OR 1.06, 95%CI 1.01-1.11, P = .021), randomisation to placebo (OR 1.45, 95%CI 1.05-1.99, P = .022).Conclusions In STEMI patients, higher baseline NT-proBNP level was independently associate with higher risk of poor myocardial reper fusion, suppor ting the potential use of NT-proBNP as an early marker for risk stratification of myocardial reperfusion after pPCI in STEMI patients.

OBJECTIVES We aimed to evaluate the effect of transcatheter aortic valve implantation (TAVI) approaches on mortality and identify effect modifiers and predictors for mortality. BACKGROUND Alternative access routes to transfemoral (TF) TAVI include the surgical intra-thoracic direct-aortic (DA) and transapical (TA) approach. TA TAVI has been associated with a higher mortality rate. We hypothesized that this is related to effect modifiers, in particular the left ventricular ejection fraction (LVEF). METHODS This multicentre study derived its data from prospective registries. To adjust for confounders, we used propensity-score based, stabilized inverse probability weighted Cox regression models. RESULTS In total, 5,910 patients underwent TAVI via TF (N = 4,072), DA (N = 524), and TA (N = 1,314) access. Compared to TF, 30-day mortality was increased among DA (HR 1.87, 95%CI 1.26-2.78, p = .002) and TA (HR 3.34, 95%CI 2.28-4.89, p

Aims Patients with atrial fibrillation undergoing coronary intervention are at higher bleeding risk due to the concomitant need for oral anticoagulation and antiplatelet therapy. The RE-DUAL PCI trial demonstrated better safety with dual antithrombotic therapy (DAT: dabigatran 110 or 150 mg b.i.d., clopidogrel or ticagrelor) compared to triple antithrombotic therapy (TAT: warfarin, clopidogrel or ticagrelor, and aspirin). We explored the impact of baseline bleeding risk based on the PRECISE-DAPT score for decision-making regarding DAT vs. TAT. Methods and results A score ≥25 points qualified high bleeding risk (HBR). Comparisons were made for the primary safety endpoint International Society of Thrombosis and Haemostasis major or clinically relevant non-major bleeding, and the composite efficacy endpoint of death, thrombo-embolic events, or unplanned revascularization, analysed by time-to-event analysis. PRECISE-DAPT was available in 2336/2725 patients, and 37.9% were HBR. Compared to TAT, DAT with dabigatran 110 mg reduced bleeding risk both in non-HBR [hazard ratio (HR) 0.42, 95% confidence interval (CI) 0.31–0.57] and HBR (HR 0.70, 95% CI 0.52–0.94), with a greater magnitude of benefit among non-HBR (Pint = 0.02). Dual antithrombotic therapy with dabigatran 150 mg vs. TAT reduced bleeding in non-HBR (HR 0.60, 95% CI 0.45–0.80), with a trend toward less benefit in HBR patients (HR 0.92, 95% CI 0.63–1.34; Pint = 0.08). The risk of ischaemic events was similar on DAT with dabigatran (both 110 and 150 mg) vs. TAT in non-HBR and HBR patients (Pint = 0.45 and Pint = 0.56, respectively). Conclusions PRECISE-DAPT score appeared useful to identify AF patients undergoing PCI at further increased risk of bleeding complications and may help clinicians identifying the antithrombotic regimen intensity with the best benefit–risk ratio in an individual patient.

Atrial septal defect, persistent foramen ovale and the left atrial appendage are nowadays often percutaneously closed with implantable devices. These interventions may be complicated by thromboembolic events and the perfect post-procedural antithrombotic management is still under investigation. The mechanisms leading to left atrial device-related thrombus and thromboembolic complications are not fully understood. Biomarkers of coagulation activation are elevated following percutaneous device placement, peaking within one month and returning to baseline values after three months. By contrast, platelet reactivity shows no post-procedural increase. This suggests that an optimal antithrombotic regimen should perhaps include (oral) anticoagulation therapy rather than the currently more frequently prescribed antiplatelet-based regimen. Furthermore, biomarkers of endothelial activation, fibrinolysis, and on-treatment platelet reactivity may be of value in predicting device-related thrombus and bleeding and guide future medical strategy, facilitating personalized medicine.

ObjectivesTo validate the Global Registry of Acute Coronary Events (GRACE) risk score and examine the extent and impact of the risk–treatment paradox in contemporary patients with acute coronary syndrome (ACS).MethodsData from 5015 patients with ACS enrolled in the FORCE-ACS registry between January 2015 and December 2019 were used for model validation. The performance of the GRACE risk score for predicting in-hospital and 1-year mortality was evaluated based on indices of model discrimination and calibration. Differences in the delivery of guideline-recommended care among patients who survived hospitalisation (n=4911) per GRACE risk stratum were assessed and the association with postdischarge mortality was examined.ResultsDiscriminative power of the GRACE risk score was good for predicting in-hospital (c-statistic: 0.86; 95% CI: 0.83 to 0.90) and 1-year mortality (c-statistic: 0.82; 95% CI: 0.79 to 0.84). However, the GRACE risk score overestimated the absolute in-hospital and 1-year mortality risk (Hosmer-Lemeshow goodness-of-fit test pConclusionsThe GRACE risk score identified patients at higher risk for in-hospital and 1-year mortality, but overestimated absolute risk levels in contemporary patients. Optimal guideline-recommended care was associated with lower mortality in intermediate-risk and high-risk patients, but was less likely to be delivered with increasing mortality risk.

OBJECTIVES Longer aortic cross-clamp (ACC) time is associated with decreased early survival after cardiac surgery. Because maximum follow-up in previous studies on this subject is confined to 28 months, it is unknown whether this adverse effect is sustained far beyond this term. We aimed to determine whether longer ACC time was independently associated with decreased late survival after isolated aortic valve replacement in patients with severe aortic stenosis during 25 years of follow-up. METHODS In this retrospective cohort study, multivariable analysis was performed to identify possible independent predictors of decreased late survival, including ACC and cardiopulmonary bypass (CPB) time, in a cohort of 456 consecutive patients with severe aortic stenosis, who had undergone isolated aortic valve replacement between 1990 and 1993. RESULTS Mean follow-up was 25.3 ± 2.7 years. Median (interquartile range) and mean ACC times were normal: 63.0 (20.0) and 64.2 ± 16.1 min, respectively. Age, operative risk scores and New York Heart Association class were similar in patients with ACC time above, versus those with ACC time below the median. Longer ACC time was independently associated with decreased late survival: hazards ratio (HR) 1.01 per minute increase of ACC time (95% confidence interval [CI] 1.00–1.02; P = 0.012). Longer CPB time was not associated with decreased late survival (HR 1.00 per minute increase of CPB time [95% CI 1.00–1.00; P = 0.30]). CONCLUSIONS Longer ACC time, although still within normal limits, was independently associated with decreased late survival after isolated aortic valve replacement in patients with severe aortic stenosis.

BACKGROUND: Approximately 15% of saphenous vein grafts (SVGs) occlude during the first year after coronary artery bypass graft surgery (CABG) despite aspirin use. The POPular CABG trial (The Effect of Ticagrelor on Saphenous Vein Graft Patency in Patients Undergoing Coronary Artery Bypass Grafting Surgery) investigated whether ticagrelor added to standard aspirin improves SVG patency at 1 year after CABG. METHODS: In this investigator-initiated, randomized, double-blind, placebo-controlled, multicenter trial, patients with ≥1 SVGs were randomly assigned (1:1) after CABG to ticagrelor or placebo added to standard aspirin (80 or 100 mg). The primary outcome was SVG occlusion at 1 year, assessed with coronary computed tomography angiography, in all patients who had primary outcome imaging available. A generalized estimating equation model was used to perform the primary analysis per SVG. The secondary outcome was 1-year SVG failure, which was a composite of SVG occlusion, SVG revascularization, myocardial infarction in myocardial territory supplied by a SVG, or sudden death. RESULTS: Among 499 randomized patients, the mean age was 67.9±8.3 years, 87.1% were male, the indication for CABG was acute coronary syndrome in 31.3%, and 95.2% of procedures used cardiopulmonary bypass. Primary outcome imaging was available in 219 patients in the ticagrelor group and 224 patients in the placebo group. The SVG occlusion rate in the ticagrelor group was 9.6% (44 of 457 SVGs) versus 10.1% in the placebo group (50 of 497 SVGs; odds ratio, 0.87 [95% CI, 0.49–1.55]; P =0.64). SVG failure occurred in 32 patients (12.9%) in the ticagrelor group versus 32 patients (13.0%) in the placebo group (hazard ratio, 1.04 [95% CI, 0.63–1.69]). CONCLUSIONS: In this randomized, placebo-controlled trial, the addition of ticagrelor to standard aspirin did not reduce SVG occlusion at 1 year after CABG. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02352402. URL: https://eudract.ema.europa.eu/ ; Unique identifier: 2014-002142-50.

Background The fear of contagion during the coronavirus disease-2019 (COVID-19) pandemic may have potentially refrained patients with ST-segment elevation myocardial infarction (STEMI) from accessing the emergency system, with subsequent impact on mortality. Objectives The ISACS-STEMI COVID-19 registry aims to estimate the true impact of the COVID-19 pandemic on the treatment and outcome of patients with STEMI treated by primary percutaneous coronary intervention (PPCI), with identification of “at-risk” patient cohorts for failure to present or delays to treatment. Methods This retrospective registry was performed in European high-volume PPCI centers and assessed patients with STEMI treated with PPPCI in March/April 2019 and 2020. Main outcomes are the incidences of PPCI, delayed treatment, and in-hospital mortality. Results A total of 6,609 patients underwent PPCI in 77 centers, located in 18 countries. In 2020, during the pandemic, there was a significant reduction in PPCI as compared with 2019 (incidence rate ratio: 0.811; 95% confidence interval: 0.78 to 0.84; p, Central Illustration

Background According to European guidelines, alcohol septal ablation (ASA) for hypertrophic obstructive cardiomyopathy (HOCM) may be less effective in patients with extensive septal scarring on cardiac magnetic resonance (CMR). This study aimed to analyze the impact of late gadolinium enhancement (LGE) on CMR on the effectiveness of ASA. Method We conducted an observational retrospective study involving adult patients with symptomatic drug-refractory HOCM who underwent CMR before ASA at two European centres from May 2010 through June 2019. Patients were compared in binary format based on LGE presence. Moreover, a subanalysis focused on patients with septal fibrosis was performed. The effectiveness of ASA was evaluated by echocardiographic, ECG and clinical findings. Results Of the 113 study patients, 54 (48%) had LGE on CMR. The LGE quantification performed in 29 patients revealed septal fibrosis in 17. The mean follow-up was 4.4 ± 2.6 years. Baseline parameters were similar between groups except for basal septal thickness that was greater in LGE+ group (21.1 ± 3.9 mm for LGE+ vs. 19.2 ± 3.2 mm for LGE-: p = .005). ASA improved symptoms in all groups and reduced left ventricular outflow tract obstruction (LVOTO) (delta gradient reduction: LGE+: 62 ± 37.3%; septal LGE+: 75.6 ± 20.8%; LGE-: 72.5 ± 21.0%). However, 13% of the LGE+ and 2% of the LGE- group had residual LVOTO above 30 mmHg (p = .027). Conclusion ASA was effective in all patients with HOCM, whether they had LGE on CMR or not and whether they had septal fibrosis or not.

BACKGROUND: The effect of single as compared with dual antiplatelet treatment on bleeding and thromboembolic events after transcatheter aortic-valve implantation (TAVI) in patients who do not have an indication for long-term anticoagulation has not been well studied. METHODS: In a randomized, controlled trial, we assigned a subgroup of patients who were undergoing TAVI and did not have an indication for long-term anticoagulation, in a 1:1 ratio, to receive aspirin alone or aspirin plus clopidogrel for 3 months. The two primary outcomes were all bleeding (including minor, major, and life-threatening or disabling bleeding) and non-procedure-related bleeding over a period of 12 months. Most bleeding at the TAVI puncture site was counted as non-procedure-related. The two secondary outcomes were a composite of death from cardiovascular causes, non-procedure-related bleeding, stroke, or myocardial infarction (secondary composite 1) and a composite of death from cardiovascular causes, ischemic stroke, or myocardial infarction (secondary composite 2) at 1 year, with both outcomes tested sequentially for noninferiority (noninferiority margin, 7.5 percentage points) and superiority. RESULTS: A total of 331 patients were assigned to receive aspirin alone and 334 were assigned to receive aspirin plus clopidogrel. A bleeding event occurred in 50 patients (15.1%) receiving aspirin alone and in 89 (26.6%) receiving aspirin plus clopidogrel (risk ratio, 0.57; 95% confidence interval [CI], 0.42 to 0.77; P = 0.001). Non-procedure-related bleeding occurred in 50 patients (15.1%) and 83 patients (24.9%), respectively (risk ratio, 0.61; 95% CI, 0.44 to 0.83; P = 0.005). A secondary composite 1 event occurred in 76 patients (23.0%) receiving aspirin alone and in 104 (31.1%) receiving aspirin plus clopidogrel (difference, -8.2 percentage points; 95% CI for noninferiority, -14.9 to -1.5; P

Objectives The aim of this study is to evaluate the impact of percutaneous transluminal septal myocardial ablation (PTSMA) on remodeling in asymptomatic patients with hypertrophic obstructive cardiomyopathy (HOCM) and severe left ventricular outflow tract (LVOT) obstruction. Background Symptoms justify invasive treatment in HOCM patients with LVOT obstruction. Adverse structural and functional changes (remodeling) in the heart occur preceding heart failure and sudden cardiac death. Early invasive treatment in asymptomatic patients may reverse adverse remodeling to the same extent as in symptomatic patients. Methods Reverse remodeling after PTSMA in severe but asymptomatic LVOT obstruction (RASTA) study is a prospective single-blind randomized trial (ClinicalTrials.gov number: NCT04230551). Ten asymptomatic HOCM patients with an exertional LVOT gradient ≥50 mmHg (or >30 mmHg in rest) are randomized 1:1 to PTSMA versus conservative therapy, in the absence of mitral valve disease or other indications for cardiac surgery. Five symptomatic (reference group) will undergo PTSMA according to the current guidelines. Results Remodeling is assessed using extensive cardiac imaging with transthoracic echocardiography and late gadolinium enhancement cardiac magnetic resonance at baseline and during follow-up at 1, 12, and 24 months. Extracellular volume fraction, global, and regional strain analysis, geometry, pressure gradients and changes in four-dimensional velocity mapping are primary parameters to study (reversal of) adverse remodeling. Conclusions The RASTA study gives insight in cardiac remodeling that may occur in asymptomatic patients after PTSMA. It will provide arguments whether to pursue (or not) a larger trial with clinical endpoints in asymptomatic HOCM patients with severe LVOT obstruction.

Transcatheter aortic valve replacement (TAVR) is an accepted treatment in patients with severe aortic stenosis. Dedicated and validated computer simulation modeling offers additional information, a...

Although current literature indicates both a clinical and a cost-effective benefit of routine genotype-guided treatment of patients treated with clopidogrel, this strategy is not recommended in guidelines. In cardiology, but also in neurology and vascular surgery, the current scientific evidence for this is still insufficient. Nevertheless, the role of pharmacogenetics will gain importance in today's medical world, where the demand for personalised medicine is on the rise. The implementation of genotyping in the clinic will nonetheless be a practical challenge due to a lack of clarity about who will bear the associated costs. In patients with coronary artery disease and a higher bleeding risk, it is valuable to determine the CYP2C19 genotype prior to treatment with clopidogrel. Pending further studies, we recommend that specialists prescribing clopidogrel should determine the CYP2C19 genotype in patients at high risk of recurrent ischemic events.

BaCKgrouNd: The effect of prosthesis-patient mismatch (PPM) on late survival after aortic valve replacement (aVr) in patient with symptomatic severe aortic stenosis (AS) remains unclear. Also, late follow-up in previous studies is confined to only one decade. We aimed to determine the effect of PPM on late survival after isolated aVr for symptomatic severe as during 25 years of follow-up. MeThods: in this retrospective cohort study, Kaplan-Meier survival analysis was performed to determine late survival in 404 consecutive patients with moderate PPM (N.=86), severe (N.=11), or no/mild PPM (N.=307) after isolated aVr for symptomatic severe as during a mean follow-up of 25.0±2.9 years. Moderate, severe, and no/mild PPM were defined as indexed effective orifice area of >0.65≤0.85, ≤0.65, and >0.85 cm 2/m 2, respectively. Multivariable analysis was performed to identify possible independent predictors of decreased late survival, including moderate or severe PPM. RESULTS: Late survival of patients with severe PPM was worse in comparison with those with no/mild PPM: 7.4±2.6 (95% confidence interval 2.2-12.5) vs. 13.6±0.5 (95% confidence interval 12.6-14.6) years, respectively; P=0.020. Late survival of patients with moderate PPM was similar to those with no/mild PPM. Severe PPM was an independent predictor of decreased late survival: hazards ratio 4.002 (95% confidence interval 1.869-8.569); P

INTRODUCTION: The POPular Genetics trial demonstrated that a CYP2C19 genotype-guided P2Y12 inhibitor strategy reduced bleeding rates compared with standard treatment with ticagrelor or prasugrel without increasing thrombotic event rates after primary percutaneous coronary intervention (PCI).OBJECTIVE: In this analysis, we aimed to evaluate the cost effectiveness of a genotype-guided strategy compared with standard treatment with ticagrelor or prasugrel.METHODS: A 1-year decision tree based on the POPular Genetics trial in combination with a lifelong Markov model was developed to compare costs and quality-adjusted life-years (QALYs) between a genotype-guided and a standard P2Y12 inhibitor strategy in patients with myocardial infarction undergoing primary PCI. The cost-effectiveness analysis was conducted from a Dutch healthcare system perspective. Within-trial survival and utility data were combined with lifetime projections to evaluate lifetime cost effectiveness for a cohort of 1000 patients. Costs and utilities were discounted at 4 and 1.5%, respectively, according to Dutch guidelines for health economic studies. Besides deterministic and probabilistic sensitivity analyses, several scenario analyses were also conducted (different time horizons, different discount rates, equal prices for P2Y12 inhibitors, and equal distribution of thrombotic events between the two strategies).RESULTS: Base-case analysis with a hypothetical cohort of 1000 subjects demonstrated 8.98 QALYs gained and €725,550.69 in cost savings for the genotype-guided strategy (dominant). The deterministic and probabilistic sensitivity analysis confirmed the robustness of the model and the cost-effectiveness results. In scenario analyses, the genotype-guided strategy remained dominant.CONCLUSION: In patients undergoing primary PCI, a CYP2C19 genotype-guided strategy compared with standard treatment with ticagrelor or prasugrel resulted in QALYs gained and cost savings.TRIAL REGISTRATION: Clinicaltrials.gov number: NCT01761786, Netherlands trial register number: NL2872.

Objectives The aim of this study was to assess if prior oral anticoagulant agent (OAC) use modifies the lower bleeding risk observed with dabigatran dual therapy (dabigatran twice daily plus a P2Y12 inhibitor) versus warfarin triple therapy (warfarin plus a P2Y12 inhibitor plus aspirin) in patients with atrial fibrillation who underwent percutaneous coronary intervention (PCI). Background In the RE-DUAL PCI (Randomized Evaluation of Dual Antithrombotic Therapy With Dabigatran Versus Triple Therapy With Warfarin in Patients With Nonvalvular Atrial Fibrillation Undergoing Percutaneous Coronary Intervention) trial, the primary outcome of major bleeding or clinically relevant nonmajor bleeding was lower with dabigatran dual therapy versus warfarin triple therapy in patients with atrial fibrillation who underwent PCI. Methods A total of 2,725 patients were randomized to dual therapy with dabigatran (110 or 150 mg twice daily) plus clopidogrel or ticagrelor or triple therapy with warfarin plus aspirin and clopidogrel or ticagrelor. Subgroup analysis compared risk for major bleeding or clinically relevant nonmajor bleeding and a composite thromboembolic endpoint in patients with prior OAC use and in those who were OAC treatment naive. Results Risk for major bleeding or clinically relevant nonmajor bleeding was reduced with both dabigatran dual therapies compared with warfarin triple therapy in both the prior OAC use group (hazard ratios: 0.58 [95% confidence interval (CI): 0.42 to 0.81] and 0.61 [95% CI: 0.41 to 0.92] with 110 and 150 mg dabigatran, respectively) and the OAC-naive group (hazard ratios: 0.49 [95% CI: 0.38 to 0.63] and 0.76 [95% CI: 0.59 to 0.97] with 110 and 150 mg dabigatran) (p for interaction = 0.42 and 0.37, 110 and 150 mg dabigatran, respectively). The risk for thromboembolic events seemed similar with dabigatran dual therapy (both doses) and warfarin triple therapy across subgroups. Conclusions Bleeding risk was reduced with dabigatran dual therapy versus warfarin triple therapy in patients with atrial fibrillation after PCI, regardless of whether they were prior OAC users or OAC treatment naive. These results suggest that it is also safe to switch patients on OAC pre-PCI to dabigatran dual therapy post-PCI.

Background Whether factor V Leiden is associated with lower bleeding risk in patients with acute coronary syndromes using (dual) antiplatelet therapy has yet to be investigated. Methods and Results We pooled data from 3 randomized clinical trials, conducted in patients with acute coronary syndromes, with adjudicated bleeding outcomes. Cox regression models were used to obtain overall and cause‐specific hazard ratios (HRs) to account for competing risk of atherothrombotic outcomes (ie, composite of ischemic stroke, myocardial infarction, and cardiovascular death) in each study. Estimates from the individual studies were pooled using fixed effect meta‐analysis. The 3 studies combined included 17 623 patients of whom 969 (5.5%) were either heterozygous or homozygous (n=23) carriers of factor V Leiden. During 1 year of follow‐up, a total of 1289 (7.3%) patients developed major (n=559) or minor bleeding. Factor V Leiden was associated with a lower risk of combined major and minor bleeding (adjusted cause‐specific HR, 0.75; 95% CI, 0.56–1.00; P =0.046; I 2 =0%) but a comparable risk of major bleeding (adjusted cause‐specific HR, 0.93; 95% CI, 0.62–1.39; P =0.73; I 2 =0%). Adjusted pooled cause‐specific HRs for the association of factor V Leiden with atherothrombotic events alone and in combination with bleeding events were 0.75 (95% CI, 0.55–1.02; P =0.06; I 2 =0%) and 0.75 (95% CI, 0.61–0.92; P =0.007; I 2 =0%), respectively. Conclusions Given that the lower risk of bleeding conferred by factor V Leiden was not counterbalanced by a higher risk of atherothrombotic events, these findings warrant future assessment for personalized medicine such as selecting patients for extended or intensive antiplatelet therapy.

Background and aims SARS-Cov-2 predisposes patients to thrombotic complications, due to excessive inflammation, endothelial dysfunction, platelet activation, and coagulation/fibrinolysis disturbances. The aim of the present study was to evaluate clinical characteristics and prognostic impact of SARS-CoV-2 positivity among STEMI patients undergoing primary percutaneous coronary intervention (PPCI). Methods We selected SARS-CoV-2 positive patients included in the ISACS-STEMI COVID-19, a retrospective multicenter European registry including 6609 STEMI patients treated with PPCI from March 1st until April 30th, in 2019 and 2020. As a reference group, we randomly sampled 5 SARS-Cov-2 negative patients per each SARS-CoV-2 positive patient, individually matched for age, sex, and hospital/geographic area. Study endpoints were in-hospital mortality, definite stent thrombosis, heart failure. Results Our population is represented by 62 positive SARS-CoV-2 positive patients who were compared with a matched population of 310 STEMI patients. No significant difference was observed in baseline characteristics or the modality of access to the PCI center. In the SARS-CoV-2 positive patients, the culprit lesion was more often located in the RCA (p, Graphical abstract Image 1

Background: Studies on very long-term outcomes after aortic valve replacement are sparse. Methods: In this retrospective cohort study, long-term outcomes during 25.1 ± 2.8 years of follow-up were determined in 673 patients who underwent aortic valve replacement with or without concomitant coronary artery bypass surgery for severe aortic stenosis and/or regurgitation. Independent predictors of decreased long-term survival were determined. Cumulative incidence rates of major adverse events in patients with a mechanical versus those with a biologic prosthesis were assessed, as well as of major bleeding events in patients with a mechanical prosthesis under the age of 60 versus those above the age of 60. Results: Impaired left ventricular function, severe prosthesis–patient mismatch, and increased aortic cross-clamp time were independent predictors of decreased long-term survival. Left ventricular hypertrophy, a mechanical or biologic prosthesis, increased cardiopulmonary bypass time, new-onset postoperative atrial fibrillation, and the presence of symptoms did not independently predict decreased long-term survival. The risk of major bleeding events was higher in patients with a mechanical in comparison with those with a biologic prosthesis. Younger age (under 60 years) did not protect patients with a mechanical prosthesis against major bleeding events. Conclusions: Very long-term outcome data are invaluable for careful decision-making on aortic valve replacement.

The POPular Genetics trial demonstrated that a CYP2C19 genotype-guided P2YIn this analysis, we aimed to evaluate the cost effectiveness of a genotype-guided strategy compared with standard treatment with ticagrelor or prasugrel.A 1-year decision tree based on the POPular Genetics trial in combination with a lifelong Markov model was developed to compare costs and quality-adjusted life-years (QALYs) between a genotype-guided and a standard P2YBase-case analysis with a hypothetical cohort of 1000 subjects demonstrated 8.98 QALYs gained and €725,550.69 in cost savings for the genotype-guided strategy (dominant). The deterministic and probabilistic sensitivity analysis confirmed the robustness of the model and the cost-effectiveness results. In scenario analyses, the genotype-guided strategy remained dominant.In patients undergoing primary PCI, a CYP2C19 genotype-guided strategy compared with standard treatment with ticagrelor or prasugrel resulted in QALYs gained and cost savings.Clinicaltrials.gov number: NCT01761786, Netherlands trial register number: NL2872.