Cardiac troponin release following coronary artery bypass grafting: mechanisms and clinical implications.

The use of biomarkers is undisputed in the diagnosis of primary myocardial infarction (MI), but their value for identifying MI is less well studied in the postoperative phase following coronary artery bypass grafting (CABG). To identify patients with periprocedural MI (PMI), several conflicting definitions of PMI have been proposed, relying either on cardiac troponin (cTn) or the MB isoenzyme of creatine kinase, with or without supporting evidence of ischaemia. However, CABG inherently induces the release of cardiac biomarkers, as reflected by significant cTn concentrations in patients with uncomplicated postoperative courses. Still, the underlying (patho)physiological release mechanisms of cTn are incompletely understood, complicating adequate interpretation of postoperative increases in cTn concentrations. Therefore, the aim of the current review is to present these potential underlying mechanisms of cTn release in general, and following CABG in particular (Graphical Abstract). Based on these mechanisms, dissimilarities in the release of cTnI and cTnT are discussed, with potentially important implications for clinical practice. Consequently, currently proposed cTn biomarker cut-offs by the prevailing definitions of PMI might warrant re-assessment, with differentiation in cut-offs for the separate available assays and surgical strategies. To resolve these issues, future prospective studies are warranted to determine the prognostic influence of biomarker release in general and PMI in particular.

Aspirin with or without Clopidogrel after Transcatheter Aortic-Valve Implantation.

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<0.001; risk ratio, 0.74; 95% CI for superiority, 0.57 to 0.95; P = 0.04). A secondary composite 2 event occurred in 32 patients (9.7%) and 33 patients (9.9%), respectively (difference, -0.2 percentage points; 95% CI for noninferiority, -4.7 to 4.3; P = 0.004; risk ratio, 0.98; 95% CI for superiority, 0.62 to 1.55; P = 0.93). A total of 44 patients (13.3%) and 32 (9.6%), respectively, received oral anticoagulation during the trial. CONCLUSIONS: Among patients undergoing TAVI who did not have an indication for oral anticoagulation, the incidence of bleeding and the composite of bleeding or thromboembolic events at 1 year were significantly less frequent with aspirin than with aspirin plus clopidogrel administered for 3 months. (Funded by the Netherlands Organization for Health Research and Development; POPular TAVI EU Clinical Trials Register number, 2013-003125-28; ClinicalTrials.gov number, NCT02247128.).

Anticoagulation with or without Clopidogrel after Transcatheter Aortic-Valve Implantation.

BACKGROUND: The roles of anticoagulation alone or with an antiplatelet agent after transcatheter aortic-valve implantation (TAVI) have not been well studied. METHODS: We performed a randomized trial of clopidogrel in patients undergoing TAVI who were receiving oral anticoagulation for appropriate indications. Patients were assigned before TAVI in a 1:1 ratio not to receive clopidogrel or to receive clopidogrel for 3 months. The two primary outcomes were all bleeding and non-procedure-related bleeding over a period of 12 months. Procedure-related bleeding was defined as Bleeding Academic Research Consortium type 4 severe bleeding, and therefore most bleeding at the 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 at 12 months (secondary composite 1) and a composite of death from cardiovascular causes, ischemic stroke, or myocardial infarction (secondary composite 2), both tested for noninferiority (noninferiority margin, 7.5 percentage points) and superiority. RESULTS: Bleeding occurred in 34 of the 157 patients (21.7%) receiving oral anticoagulation alone and in 54 of the 156 (34.6%) receiving oral anticoagulation plus clopidogrel (risk ratio, 0.63; 95% confidence interval [CI], 0.43 to 0.90; P = 0.01); most bleeding events were at the TAVI access site. Non-procedure-related bleeding occurred in 34 patients (21.7%) and in 53 (34.0%), respectively (risk ratio, 0.64; 95% CI, 0.44 to 0.92; P = 0.02). Most bleeding occurred in the first month and was minor. A secondary composite 1 event occurred in 49 patients (31.2%) receiving oral anticoagulation alone and in 71 (45.5%) receiving oral anticoagulation plus clopidogrel (difference, -14.3 percentage points; 95% CI for noninferiority, -25.0 to -3.6; risk ratio, 0.69; 95% CI for superiority, 0.51 to 0.92). A secondary composite 2 event occurred in 21 patients (13.4%) and in 27 (17.3%), respectively (difference, -3.9 percentage points; 95% CI for noninferiority, -11.9 to 4.0; risk ratio, 0.77; 95% CI for superiority, 0.46 to 1.31). CONCLUSIONS: In patients undergoing TAVI who were receiving oral anticoagulation, the incidence of serious bleeding over a period of 1 month or 1 year was lower with oral anticoagulation alone than with oral anticoagulation plus clopidogrel. (Funded by the Netherlands Organization for Health Research and Development; POPular TAVI EU Clinical Trials Register number, 2013-003125-28; ClinicalTrials.gov number, NCT02247128.).

Prehospital treatment with zalunfiban (RUC-4) in patients with ST- elevation myocardial infarction undergoing primary percutaneous coronary intervention: Rationale and design of the CELEBRATE trial.

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 prehospital setting. Thus, there is a need for antiplatelet agents that achieve prompt and potent platelet inhibition, and that restore patency in the prehospital setting. Zalunfiban, a novel subcutaneously administered glycoprotein IIb/IIIa inhibitor designed for prehospital administration, has shown to achieve rapid, high-grade platelet inhibition that exceeds that of P2Y12 inhibitors. Whether prehospital administration of zalunfiban can improve clinical outcome is unknown. HYPOTHESIS: The present study is designed to assess the hypothesis that a single, prehospital 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 3, 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, ie, 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 prehospital 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.

Prepercutaneous coronary intervention Zalunfiban dose-response relationship to target vessel blood flow at initial angiogram in st-elevation myocardial infarction - A post hoc analysis of the cel-02 phase IIa study.

BACKGROUND: Zalunfiban (RUC-4) is a novel, subcutaneously administered glycoprotein IIb/IIIa inhibitor (GPI) designed for prehospital treatment to initiate reperfusion in the infarct-related artery (IRA) before primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction (STEMI). Since GPIs have been reported to rapidly reperfuse IRAs, we assessed whether there was a dose-dependent relationship between zalunfiban treatment and angiographic reperfusion indices and thrombus grade of the IRA at initial angiogram in patients with STEMI. METHODS: This was a post hoc analysis from the open-label Phase IIa study that investigated the pharmacodynamics, pharmacokinetics, and tolerability of three doses of zalunfiban - 0.075, 0.090 and 0.110 mg/kg - in STEMI patients. This analysis explored dose-dependent associations between zalunfiban and three angiographic indices of the IRA, namely coronary and myocardial blood flow and thrombus burden. Zalunfiban was administered in the cardiac catheterization laboratory prior to vascular access, ∼10 to 15 minutes before the initial angiogram. All angiographic data were analyzed by a blinded, independent, core laboratory. RESULTS: Twentyfour out of 27 STEMI patients were evaluable for angiographic analysis (0.075 mg/kg [n=7], 0.090 mg/kg [n=9], and 0.110 mg/kg [n=8]). TIMI flow grade 2 or 3 was seen in 1/7 patients receiving zalunfiban at 0.075 mg/kg, in 6/9 patients receiving 0.090 mg/kg, and in 7/8 patients receiving 0.110 mg/kg (ptrend = 0.004). A similar trend was observed based on TIMI flow grade 3. Myocardial perfusion was also related to zalunfiban dose (ptrend = 0.005) as reflected by more frequent TIMI myocardial perfusion grade 3. Consistent with the dose-dependent trends in greater coronary and myocardial perfusion, TIMI thrombus ≥4 grade was inversely related to zalunfiban dose (ptrend = 0.02). CONCLUSION: This post hoc analysis found that higher doses of zalunfiban administered in the cardiac catheterization lab prior to vascular access were associated with greater coronary and myocardial perfusion, and lower thrombus burden at initial angiogram in patients with STEMI undergoing primary percutaneous coronary intervention.

Comparison of the effects of the GPIIb-IIIa antagonist Zalunfiban and the P2Y12 antagonist Selatogrel on Platelet Aggregation.

Understanding the pharmacodynamic effects of platelet inhibitors is standard for developing more effective antithrombotic therapies. An example is the antithrombotic treatment of acute coronary syndrome (ACS), in particular ST-elevated myocardial infarction (STEMI) patients who are in need for rapid acting strong antithrombotic therapy despite the use of aspirin and oral P2Y12-inhibitors. In this study, we evaluated two injectable platelet inhibitors under clinical development (the P2Y12 antagonist selatogrel and the GPIIb-IIIa antagonist zalunfiban) that may be amenable to pre-hospital treatment of STEMI patients. Platelet reactivity was assessed at inhibitor concentrations that represent clinically relevant levels of platelet inhibition (IC20-50%, 1/2Cmax, and Cmax). Light transmission aggregometry (LTA), was used to evaluate the initial rate of aggregation (primary slope, PS) and maximal aggregation (MA). Both adenosine diphosphate (ADP) and thrombin receptor agonist peptide (TRAP) were used as agonists. Zalunfiban demonstrated similar inhibition of platelet aggregation when blood was collected in PPACK or TSC, whereas selatogrel demonstrated greater inhibition in PPACK. In this study, using PPACK anticoagulant, selatogrel and zalunfiban affected PS in response to ADP equivalently at all drug concentrations tested. In contrast, zalunfiban had significantly greater potency at its Cmax concentration compared to selatogrel using TRAP as agonist. Upon evaluation of MA responses at lower doses, selatogrel had greater inhibition of MA in response to ADP than zalunfiban; however, at concentrations that represent Cmax, the drugs were equivalent. Zalunfiban also had greater inhibition of MA in response to TRAP at the Cmax dose. These data suggest that zalunfiban may provide greater protection in reducing thrombus formation than selatogrel, especially since thrombin is an early, key primary agonist in the pathophysiology of thrombotic events.

Platelet glycoprotein IIb/IIIa inhibitor tirofiban in clopidogrel-naïve patients undergoing elective percutaneous coronary intervention.

BACKGROUND: The safety of administration of tirofiban, a platelet glycoprotein IIb/IIIa inhibitor, followed by a clopidogrel loading dose in clopidogrel-naïve patients undergoing ad-hoc percutaneous coronary intervention (PCI) is not yet clear. METHODS: In a retrospective observational cohort analysis, clopidogrel-naïve patients undergoing ad-hoc PCI who received a high-dose bolus of tirofiban (25 µg/kg) followed by a 600-mg clopidogrel loading dose (group 1) were compared with patients undergoing elective PCI who were pretreated with clopidogrel (group 2), between September 2014 and October 2021. The primary outcome was major adverse cardiovascular events (MACE) defined as the composite of death, myocardial infarction, stroke, target-lesion revascularisation and bleeding at 30 days. Secondary outcomes were MACE at 7 days and individual components of the primary outcome at 7 and 30 days. RESULTS: A total of 1404 patients were included: 432 (31%) in group 1 and 972 (69%) in group 2. Median age was 69 years, and 28% were female. At 7­day follow-up, MACE occurred in 1.4% in group 1 versus 3.0% in group 2 (p = 0.08). 30-day MACE were observed in 1.9% in group 1 and 4.2% in group 2 (p = 0.03). Secondary outcomes were comparable between the groups. Cox regression analysis, corrected for baseline differences, revealed no significant difference in the primary outcome (hazard ratio: 1.8; 95% confidence interval: 0.8-3.9). CONCLUSION: Ad-hoc PCI in clopidogrel-naïve patients who were treated with high-dose bolus of tirofiban followed by a clopidogrel loading dose immediately after the procedure appeared to be safe.

A Genotype-Guided Strategy for Oral P2Y12 Inhibitors in Primary PCI.

BACKGROUND: It is unknown whether patients undergoing primary percutaneous coronary intervention (PCI) benefit from genotype-guided selection of oral P2Y12 inhibitors. METHODS: We conducted a randomized, open-label, assessor-blinded trial in which patients undergoing primary PCI with stent implantation were assigned in a 1:1 ratio to receive either a P2Y12 inhibitor on the basis of early CYP2C19 genetic testing (genotype-guided group) or standard treatment with either ticagrelor or prasugrel (standard-treatment group) for 12 months. In the genotype-guided group, carriers of CYP2C19*2 or CYP2C19*3 loss-of-function alleles received ticagrelor or prasugrel, and noncarriers received clopidogrel. The two primary outcomes were net adverse clinical events - defined as death from any cause, myocardial infarction, definite stent thrombosis, stroke, or major bleeding defined according to Platelet Inhibition and Patient Outcomes (PLATO) criteria - at 12 months (primary combined outcome; tested for noninferiority, with a noninferiority margin of 2 percentage points for the absolute difference) and PLATO major or minor bleeding at 12 months (primary bleeding outcome). RESULTS: For the primary analysis, 2488 patients were included: 1242 in the genotype-guided group and 1246 in the standard-treatment group. The primary combined outcome occurred in 63 patients (5.1%) in the genotype-guided group and in 73 patients (5.9%) in the standard-treatment group (absolute difference, -0.7 percentage points; 95% confidence interval [CI], -2.0 to 0.7; P<0.001 for noninferiority). The primary bleeding outcome occurred in 122 patients (9.8%) in the genotype-guided group and in 156 patients (12.5%) in the standard-treatment group (hazard ratio, 0.78; 95% CI, 0.61 to 0.98; P = 0.04). CONCLUSIONS: In patients undergoing primary PCI, a CYP2C19 genotype-guided strategy for selection of oral P2Y12 inhibitor therapy was noninferior to standard treatment with ticagrelor or prasugrel at 12 months with respect to thrombotic events and resulted in a lower incidence of bleeding. (Funded by the Netherlands Organization for Health Research and Development; POPular Genetics ClinicalTrials.gov number, NCT01761786; Netherlands Trial Register number, NL2872.).

Impact of vomiting on P2Y12 platelet inhibition in patients with ST-elevation myocardial infarction: A prespecified subanalysis of the ON-TIME 3 trial.

Vomiting is associated with lower levels of ticagrelor concentration and higher platelet reactivity in the early hours of ST-elevation myocardial infarction. These results support reloading with a ticagrelor loading dose and/or treatment with intravenous platelet inhibitors when patients vomit.

Efficacy and safety of glycoprotein IIb/IIIa inhibitors in addition to P2Y12 inhibitors in ST-segment elevation myocardial infarction: A subanalysis of the POPular Genetics trial.

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.

Point-of-care high-sensitivity troponin-I analysis in capillary blood for acute coronary syndrome diagnostics.

OBJECTIVES: Patients with acute coronary syndrome (ACS) should be referred promptly to the hospital to reduce mortality and morbidity. Differentiating between low-risk and high-risk patients remains a diagnostic challenge. Point-of-care testing can contribute to earlier disposition decisions for patients excluded from ACS. This study describes the validation of the Atellica® VTLi. Patient-side Immunoassay Analyzer for high-sensitivity troponin point-of-care (POC) analysis. (The Atellica VTLi is not available for sale in the USA. The products/features (mentioned herein) are not commercially available in all countries. Their future availability cannot be guaranteed). METHODS: A total of 152 patients with acute chest pain admitted at the cardiac emergency department (ED) were included in the study. Capillary blood was compared with a whole blood and plasma sample obtained by venipuncture. All samples were analyzed using the Atellica VTLi Patient-side Immunoassay Analyzer; in addition, plasma was analyzed by a central lab immunoassay analyzer. RESULTS: No significant difference was observed between venous whole blood vs. plasma analyzed by the Atellica VTLi Patient-side Immunoassay Analyzer. The difference between capillary blood and venous blood showed a constant bias of 7.1%, for which a correction factor has been implemented. No clinically relevant differences were observed for the capillary POC results compared to plasma analyzed with a standard immunoassay analyzer. CONCLUSIONS: The Atellica VTLi Patient-side Immunoassay Analyzer for high-sensitivity troponin analysis shows equivalent results for all sample types, including capillary blood. No clinically relevant discordances were observed between capillary POC and central laboratory results. With additional studies, this could pave the way towards rapid testing of high-sensitivity troponin in the ambulance or the general practitioner's office without the need for hospitalization of patients with acute chest pain.

NT-proBNP level before primary PCI and risk of poor myocardial reperfusion: Insight from the On-TIME II trial.

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 NT-proBNP 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 1.04-1.31, 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 reperfusion, supporting the potential use of NT-proBNP as an early marker for risk stratification of myocardial reperfusion after pPCI in STEMI patients.

Long-term outcome after deferred revascularization due to negative fractional flow reserve in intermediate coronary lesions.

OBJECTIVES: The aim was to assess long-term outcome after deferring intervention of coronary lesions with a fractional flow reserve (FFR) value of >0.80 in a real-world patient population and then to identify factors associated with deferred target lesion failure (DTLF). BACKGROUND: Deferring coronary interventions of intermediate lesions based on FFR measurement is safe, irrespective of the extent of coronary artery disease. However, FFR values near the cut-off of >0.80 may have less favorable outcome. METHODS: A retrospective analysis was performed in patients with deferred coronary intervention based on FFR value >0.80. The primary endpoint was DTLF, a composite of acute coronary syndrome (ACS) and any coronary revascularization, related to the initially deferred stenosis. RESULTS: A total of 600 patients, mean age of 66 ± 10 years, and 751 coronary lesions with negative FFR values (mean 0.88 ± 0.04) were included. The mean follow-up was 27 ± 15 months. DTLF occurred in 44 patients (7.3%), revascularization in 42 (7%), and ACS without revascularization in 2 patients (0.3%). Patients with DTLF more often had diabetes mellitus, previous coronary artery bypass grafting, multivessel disease (MVD), and lower FFR at inclusion. Multivariable regression analysis showed that lower deferred FFR values [FFR 0.81-0.85: hazard ratio (HR) 2.79 (95% CI [confidence interval]; 1.46-5.32), p .002], MVD [HR 1.98 (95% CI; 1.05-3.75), p .036], distal lesions [HR 2.43 (95% CI; 1.29-4.57), p .006], and lesions located in a saphenous vein graft (SVG) [HR 6.35 (95% CI; 1.81-22.28), p .004] were independent predictors for DTLF. CONCLUSIONS: The long-term rate of DTLF of initially deferred coronary lesions was 7.3%. Independent predictors for DTLF are lower deferred FFR value, the presence of MVD, distal lesions, and lesions in SVG.

Final five-year results of the REMEDEE Registry: Real-world experience with the dual-therapy COMBO stent.

OBJECTIVES: This final report from the REMEDEE Registry assessed the long-term safety and efficacy of the dual-therapy COMBO stent in a large unselected patient population. BACKGROUND: The bio-engineered COMBO stent (OrbusNeich Medical BV, The Netherlands) is a dual-therapy pro-healing stent. Data of long-term safety and efficacy of the this stent is lacking. METHODS: The prospective, multicenter, investigator-initiated REMEDEE Registry evaluated clinical outcomes after COMBO stent implantation in daily clinical practice. One thousand patients were enrolled between June 2013 and March 2014. RESULTS: Five-year follow-up data were obtained in 97.2% of patients. At 5-years, target lesion failure (TLF) (composite of cardiac death, target-vessel myocardial infarction, or target lesion revascularization) was present in 145 patients (14.8%). Definite or probable stent thrombosis (ST) occurred in 0.9%, with no additional case beyond 3-years of follow-up. In males, 5-year TLF-rate was 15.6 versus 12.6% in females (p = .22). Patients without diabetes mellitus (DM) had TLF-rate of 11.4%, noninsulin-treated DM 22.7% (p = .001) and insulin-treated DM 41.2% (p < .001). Patients presenting with non-ST segment elevation acute coronary syndrome (NSTE-ACS) had higher incidence of TLF compared to non-ACS (20.4 vs. 13.3%; p = .008), while incidence with STE-ACS was comparable to non-ACS (10.7 vs. 13.3%; p = .43). CONCLUSION: Percutaneous coronary intervention with the dual-therapy COMBO stent in unselected patient population shows low rates of TLF and ST to 5 years. Remarkably, no case of ST was noted beyond 3 years.

Urgent transcatheter aortic valve implantation in an all-comer population: a single-centre experience.

BACKGROUND: When compared with older reports of untreated symptomatic aortic valve stenosis (AoS), urgent transcatheter aortic valve implantation (u-TAVI) seems to improve mortality rates. We performed a single centre, retrospective cohort analysis to characterize our u-TAVI population and to identify potential predictors of worse outcomes. METHODS: We performed a retrospective analysis of 631 consecutive TAVI patients between 2013 and 2018. Of these patients, 53 were categorized as u-TAVI. Data was collected from the local electronic database. RESULTS: Urgent patients had more often a severely decreased left ventricular ejection fraction (LVEF < 30%) and increased creatinine levels (115.5 [88-147] vs 94.5 [78-116] mmol/l; p = 0.001). Urgent patients were hospitalised for 18 [10-28] days before and discharged 6 [4-9] days after the implantation. The incidence of peri-procedural complications and apical implantations was comparable among the study groups. Urgent patients had higher in-hospital (11.3% vs 3.1%; p = 0.011) and 1-year mortality rates (28.2% vs 8.5%, p < 0.001). An increased risk of one-year mortality was associated with urgency (HR 3.5; p < 0.001), apical access (HR 1.9; p = 0.016) and cerebrovascular complications (HR 4.3; p = 0.002). Within the urgent group, the length of pre-hospital admission was the only significant predictor of 1-year mortality (HR 1.037/day; p = 0.003). CONCLUSIONS: Compared to elective procedures, u-TAVI led to increased mortality and comparable complication rates. This detrimental effect is most likely related to the length of pre-procedural hospitalisation of urgent patients.

Barriers and potential solutions in the recruitment and retention of older patients in clinical trials-lessons learned from six large multicentre randomized controlled trials.

BACKGROUND: older people remain underrepresented in clinical trials, and evidence generated in younger populations cannot always be generalized to older patients. OBJECTIVE: to identify key barriers and to discuss solutions to specific issues affecting recruitment and retention of older participants in clinical trials based on experience gained from six current European randomised controlled trials (RCTs) focusing on older people. METHODS: a multidisciplinary group of experts including representatives of the six RCTs held two networking conferences and compiled lists of potential barriers and solutions. Every item was subsequently allocated points by each study team according to how important it was perceived to be for their RCTs. RESULTS: the six RCTs enrolled 7,612 older patients. Key barriers to recruitment were impaired health status, comorbidities and diverse health beliefs including priorities within different cultural systems. All trials had to increase the number of recruitment sites. Other measures felt to be effective included the provision of extra time, communication training for the study staff and a re-design of patient information. Key barriers for retention included the presence of severe comorbidities and the occurrence of adverse events. Long study duration, frequent study visits and difficulties accessing the study site were also mentioned. Solutions felt to be effective included spending more time maintaining close contact with the participants, appropriate measures to show appreciation and reimbursement of travel arrangements. CONCLUSION: recruitment and retention of older patients in trials requires special recognition and a targeted approach. Our results provide scientifically-based practical recommendations for optimizing future studies in this population.

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

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

Drug-eluting or bare-metal stents for percutaneous coronary intervention: a systematic review and individual patient data meta-analysis of randomised clinical trials.

BACKGROUND: New-generation drug-eluting stents (DES) have mostly been investigated in head-to-head non-inferiority trials against early-generation DES and have typically shown similar efficacy and superior safety. How the safety profile of new-generation DES compares with that of bare-metal stents (BMS) is less clear. METHODS: We did an individual patient data meta-analysis of randomised clinical trials to compare outcomes after implantation of new-generation DES or BMS among patients undergoing percutaneous coronary intervention. The primary outcome was the composite of cardiac death or myocardial infarction. Data were pooled in a one-stage random-effects meta-analysis and examined at maximum follow-up and a 1-year landmark. Risk estimates are reported as hazard ratios (HRs) with 95% CIs. This study is registered in PROSPERO, number CRD42017060520. FINDINGS: We obtained individual data for 26 616 patients in 20 randomised trials. Mean follow-up was 3·2 (SD 1·8) years. The risk of the primary outcome was reduced in DES recipients compared with BMS recipients (HR 0·84, 95% CI 0·78-0·90, p<0·001) owing to a reduced risk of myocardial infarction (0·79, 0·71-0·88, p<0·001) and a possible slight but non-significant cardiac mortality benefit (0·89, 0·78-1·01, p=0·075). All-cause death was unaffected (HR with DES 0·96, 95% CI 0·88-1·05, p=0·358), but risk was lowered for definite stent thrombosis (0·63, 0·50-0·80, p<0·001) and target-vessel revascularisation (0·55, 0·50-0·60, p<0·001). We saw a time-dependent treatment effect, with DES being associated with lower risk of the primary outcome than BMS up to 1 year after placement. While the effect was maintained in the longer term, there was no further divergence from BMS after 1 year. INTERPRETATION: The performance of new-generation DES in the first year after implantation means that BMS should no longer be considered the gold standard for safety. Further development of DES technology should target improvements in clinical outcomes beyond 1 year. FUNDING: Bern University Hospital.

Accuracy of pre-hospital HEART score risk classification using point of care versus high sensitive troponin in suspected NSTE-ACS.

INTRODUCTION: Pre-hospital risk classification by the HEART score is performed with point of care troponin assessment. However, point of care troponin is less sensitive than high sensitive troponin measurement which is used in the hospital setting. In this study we compared pre-hospital HEART-score risk classification using point of care troponin versus high sensitive troponin. METHODS: In 689 consecutive patients with suspected NSTE-ACS, point of care troponin and laboratory high-sensitive troponin were measured in pre-hospital derived blood. For every patient the HEART score with both point of care troponin (HEART-POC) and high sensitive troponin (HEART-hsTnT) was determined. Endpoint was MACE within 45 days. RESULTS: Mean age was 64 (SD ±â€¯14), 163 (24%) patients were considered low-risk by HEART-hsTnT and 170 (25%) by HEART-POC. MACE was observed in 17%. Although high sensitive versus POC troponin scoring was different in 130 (19%) of patients, in 678 (98%) patients risk classification in low versus intermediate-high risk was similar. The predictive values of HEART-POC versus HEART-HsTnT was similar (AUC 0.75 versus 0.76, p = 0.241). CONCLUSION: Although high sensitive versus POC troponin scoring was dissimilar in one fifth of patients, this resulted in different patient risk classification in only 2 percent of patients. Therefore POC troponin measurement suffices for pre-hospital risk stratification of suspected NSTE-ACS.