BackgroundEarly aspirin withdrawal, also known as P2Y12-inhibitor monotherapy, following percutaneous coronary intervention (PCI) for non-ST-segment elevation acute coronary syndrome (NSTE-ACS) can... Show moreBackgroundEarly aspirin withdrawal, also known as P2Y12-inhibitor monotherapy, following percutaneous coronary intervention (PCI) for non-ST-segment elevation acute coronary syndrome (NSTE-ACS) can reduce bleeding without a trade-off in efficacy. Still the average daily bleeding risk is highest during the first months and it remains unclear if aspirin can be omitted immediately following PCI.MethodsThe LEGACY study is an open-label, multicenter randomized controlled trial evaluating the safety and efficacy of immediate P2Y12-inhibitor monotherapy versus dual antiplatelettherapy (DAPT) for 12 months in 3,090 patients. Patients are randomized immediately following successful PCI for NSTE-ACS to 75-100 mg aspirin once daily versus no aspirin. The primary hypothesis is that immediately omitting aspirin is superior to DAPT with respect to major or minor bleeding defined as Bleeding Academic Research Consortium type 2, 3, or 5 bleeding, while maintaining noninferiority for the composite of all-cause mortality, myocardial infarction and stroke compared to DAPT.ConclusionsThe LEGACY study is the first randomized study that is specifically designed to evaluate the impact of immediately omitting aspirin, and thus treating patients with P2Y12-inhibitor monotherapy, as compared to DAPT for 12 months on bleeding and ischemic events within 12 months following PCI for NSTE-ACS. Show less
Rong, L.Q.; Franco, A. di; Rahouma, M.; Dimagli, A.; Chan, J.; Lopes, A.J.; ... ; Gaudino, M. 2023
BackgroundIn the Posterior left pericardiotomy for the prevention of atrial fibrillation after cardiac surgery (PALACS) trial, posterior pericardiotomy was associated with a significant reduction... Show moreBackgroundIn the Posterior left pericardiotomy for the prevention of atrial fibrillation after cardiac surgery (PALACS) trial, posterior pericardiotomy was associated with a significant reduction in postoperative atrial fibrillation (POAF) after cardiac surgery. We aimed to investigate the mechanisms underlying this effect.MethodsWe included PALACS patients with available echocardiographic data (n = 387/420, 92%). We tested the hypotheses that the reduction in POAF with the intervention was associated with 1) a reduction in postoperative pericardial effusion and/or 2) an effect on left atrial size and function. Spline and multivariable logistic regression analyses were used.ResultsMost patients (n = 307, 79%) had postoperative pericardial effusions (anterior 68%, postero-lateral 51.9%). The incidence of postero-lateral effusion was significantly lower in patients undergoing pericardiotomy (37% vs 67%; P < .001). The median size of anterior effusion was comparable between patients with and without POAF (5.0 [IQR 3.0–7.0] vs 5.0 [IQR 3.0–7.5] mm; P = .42), but there was a nonsignificant trend towards larger postero-lateral effusion in the POAF group (5.0 [IQR 3.0–9.0] vs 4.0 [IQR 3.0–6.4] mm; P = .06). There was a non-linear association between postero-lateral effusion and POAF at a cut-off at 10 mm (OR 2.70; 95% CI 1.13, 6.47; P = .03) that was confirmed in multivariable analysis (OR 3.5, 95% CI 1.17, 10.58; P = 0.02). Left atrial dimension and function did not change significantly after posterior pericardiotomy.ConclusionsReduction in postero-lateral pericardial effusion is a plausible mechanism for the effect of posterior pericardiotomy in reducing POAF. Measures to reduce postoperative pericardial effusion are a promising approach to prevent POAF.Graphical abstractPathophysiological mechanisms explaining the association between postoperative pericardial effusion and the occurrence of postoperative atrial fibrillation. Hb, hemoglobin; MetHb, methemoglobin; OxyHb, oxyhemoglobin; ROS, reactive oxygen species. Show less
Background Due to the bleeding risk of full-dose systemic thrombolysis and the lack of major trials focusing on the clinical benefits of catheter-directed treatment, heparin antiocoagulation... Show moreBackground Due to the bleeding risk of full-dose systemic thrombolysis and the lack of major trials focusing on the clinical benefits of catheter-directed treatment, heparin antiocoagulation remains the standard of care for patients with intermediate-high-risk pulmonary embolism (PE). Methods and results The Higher-Risk Pulmonary Embolism Thrombolysis (HI-PEITHO) study (ClinicalTrials.gov Identifier: NCT04790370) is a multinational multicenter randomized controlled parallel-group comparison trial. Patients with: (1) confirmed acute PE; (2) evidence of right ventricular (RV) dysfunction on imaging; (3) a positive cardiac troponin test; and (4) clinical criteria indicating an elevated risk of early death or imminent hemodynamic collapse, will be randomized 1:1 to treatment with a standardized protocol of ultrasound-facilitated catheter-directed thrombolysis plus anticoagulation, vs anticoagulation alone. The primary outcome is a composite of PE-related mortality, cardiorespiratory decompensation or collapse, or non-fatal symptomatic and objectively confirmed PE recurrence, within 7 days of randomization. Further assessments cover, apart from bleeding complications, a broad spectrum of functional and patient-reported outcomes including quality of life indicators, functional status and the utilization of health care resources over a 12-month follow-up period. The trial plans to include 406 patients, but the adaptive design permits a sample size increase depending on the results of the predefined interim analysis. As of May 11, 2022, 27 subjects have been enrolled. The trial is funded by Boston Scientific Corporation and through collaborative research agreements with University of Mainz and The PERT Consortium. Conclusions Regardless of the outcome, HI-PEITHO will establish the first-line treatment in intermediate-high risk PE patients with imminent hemodynamic collapse. The trial is expected to inform international guidelines and set the standard for evaluation of catheter-directed reperfusion options in the future. Show less
Huijboom, M.; Maarse, M.; Aarnink, E.; Dijk, V. van; Swaans, M.; Heijden, J. van der; ... ; Boersma, L. 2022
Background: Left atrial appendage occlusion (LAAO) provides an alternative to oral anticoagulation (OAC) for stroke prevention in patients with atrial fibrillation (AF). In patients with a long... Show moreBackground: Left atrial appendage occlusion (LAAO) provides an alternative to oral anticoagulation (OAC) for stroke prevention in patients with atrial fibrillation (AF). In patients with a long-term or permanent contraindication for OAC ran-domized controlled trial (RCT) data is lacking. Study objectives: To assess the efficacy and safety of LAAO in AF patients who are ineligible to use OAC. The co-primary efficacy endpoint is (1) time to first occurrence of stroke (ischemic, hemorrhagic, or undetermined) and (2) time to first occurrence of the composite of stroke, transient ischemic attack (TIA), and systemic embolism (SE). The primary safety endpoint is the 30-day rate of peri-procedural complications. Study design: This is a multicenter, investigator-initiated, open-label, blinded endpoint (PROBE), superiority-driven RCT. Patients with AF, a CHA 2DS 2 -VASc score >= 2 for men and >= 3 for women and a long-term or permanent contraindica-tion for OAC will be randomized in a 2:1 fashion to the device- or control arm. Patients in the device arm will undergo percutaneous LAAO and will receive post-procedural dual antiplatelet therapy (DAPT) per protocol, while those in the control arm will continue their current treatment consisting of no antithrombotic therapy or (D)APT as deemed appropriate by the primary responsible physician. In this endpoint-driven trial design, assuming a 50% lower stroke risk of LAAO compared to conservative treatment, 609 patients will be followed for a minimum of 1 and a maximum of 5 years. Cost-effectiveness and budget impact analyses will be performed to allow decision-making on reimbursement of LAAO for the target population in the Netherlands. Summary: The COMPARE LAAO trial will investigate the clinical superiority in preventing thromboembolic events and cost-effectiveness of LAAO in AF patients with a high thromboembolic risk and a contraindication for OAC use. Show less
Study objective: The added value of computed tomography (CT) follow-up after elective proximal aortic surgery is unclear. We evaluated the benefit of CT follow-up by assessing the incidence of... Show moreStudy objective: The added value of computed tomography (CT) follow-up after elective proximal aortic surgery is unclear. We evaluated the benefit of CT follow-up by assessing the incidence of aorta-related complications and reinterventions detected during routine CT follow-up. Methods: Data on 314 patients undergoing first time elective proximal aortic surgery between 2000 and 2015 were collected. The primary study end points were aorta-related complications and reinterventions, detected during routine CT follow-up. Secondary study endpoints included all aorta-related complications and reinterventions, irrespective of the mode of detection and survival. Results: Median CT follow-up time was 6.8 (IQR 4.1-9.8) years, during which a total of 1303 routine follow-up CT-scans (median 4, IQR 3-5) were performed. During CT follow-up, aorta-related complications were detected in 18 (5.7%) patients, of which 6 (1.6%) underwent reintervention. In total, 28 aorta-related complications were observed in 23 (7.3%) patients, of which 9 led to reintervention. In order to detect 1 aorta-related complication leading to reintervention, 218 routine followup CT-scans were required. The unadjusted and EuroSCORE II adjusted hazard ratios of not undergoing CT follow-up on mortality were 1.260 (95% CI 0.705-2.251) and 0.830 (95% CI 0.430-1.605), respectively. Conclusions: Following first time elective proximal aor tic surgery, aor ta-related complications are uncommon, are not always detected during CT follow-up and, if detected, often do not result in reintervention. Therefore, a more conservative CT follow-up protocol could be considered in selected patients to reduce lifetime radiation burden and health care costs. Show less
Aim: To examine whether maternal angiogenic factors in the first half of pregnancy are associated with offspring left and right cardiac development. Methods: In a population-based prospective... Show moreAim: To examine whether maternal angiogenic factors in the first half of pregnancy are associated with offspring left and right cardiac development. Methods: In a population-based prospective cohort among 2,415 women and their offspring, maternal first and second trimester plasma PlGF and sFlt-1 concentrations were measured. Cardiac MRI was performed in their offspring at 10 years. Results: Maternal angiogenic factors were not associated with childhood cardiac outcomes in the total population. In children born small-for-their-gestational-age, higher maternal first trimester PlGF concentrations were associated with a lower childhood left ventricular mass (-0.24 SDS [95a/aCI-0.42,-0.05 per SDS increase in maternal PlGF]), whereas higher sFlt-1 concentrations were associated with higher childhood left ventricular mass (0.22 SDS [95a/aCI 0.09, 0.34 per SDS increase in maternal sFlt-1]). Higher second trimester maternal sFlt-1 concentrations were also associated with higher childhood left ventricular mass (P-value > .05). In preterm born children, higher maternal first and second trimester sFlt-1/PlGF ratio were associated with higher childhood left ventricular mass (0.30 SDS [95a/aCI 0.01, 0.60], 0.22 SDS [95a/aCI-0.03, 0.40]) per SDS increase in maternal sFlt-1/PlGF ratio in first and second trimester respectively). No effects on other childhood cardiac outcomes were present within these higher-risk children. Conclusions: In a low-risk population, maternal angiogenic factors are not associated with childhood cardiac ventricular structure, and function within the normal range. In children born small for their gestational age or preterm, an imbalance in maternal angiogenic factors in the first half of pregnancy was associated with higher childhood left ventricular mass only. Show less
Eltchaninoff, H.; Bonaros, N.; Prendergast, B.; Nietlispach, F.; Vasa-Nicotera, M.; Chieffo, A.; ... ; Tchetche, D. 2020
Background Limited data suggest that transcatheter (TAVR) as compared with surgical aortic valve replacement (SAVR) may be more effective in female than male patients. To date, most evidence is... Show moreBackground Limited data suggest that transcatheter (TAVR) as compared with surgical aortic valve replacement (SAVR) may be more effective in female than male patients. To date, most evidence is derived from subgroup analyses of large trials, and a dedicated randomized trial evaluating whether there is a difference in outcomes between these interventions in women is warranted. The RHEIA trial will compare the safety and efficacy of TAVR with SAVR in women with severe symptomatic aortic stenosis requiring aortic valve intervention, irrespective of surgical risk.Methods/Design The RHEIA trial is a prospective, randomized, controlled study that will enroll up to 440 patients across 35 sites in Europe. Women with severe symptomatic aortic stenosis, with any but prohibitive surgical risk status, will be randomized 1:1 to undergo aortic valve intervention with either transfemoral TAVR with the SAPIEN 3 or SAPIEN 3 Ultra device or SAVR and followed up for 1 year. The objective is to determine whether TAVR is non-inferior to SAVR in this patient population and, if this is fulfilled whether TAVR is actually superior to SAVR. The primary safety/efficacy endpoint is a composite of all-cause mortality, all stroke, and re-hospitalization (for valve or procedure-related symptoms or worsening congestive heart failure) at 1 year post-procedure. Other outcomes (assessed at 30 days and/or 1 year) include all-cause mortality; bleeding, vascular, cardiac, cerebrovascular and renal complications; aortic valve prosthesis and left ventricular function; cognitive function, health status, and quality of life.Discussion The RHEIA study has been designed to evaluate the safety and efficacy of TAVR compared with SAVR specifically in women with severe symptomatic aortic stenosis, irrespective of the level of surgical risk. The results will be the first to provide specific randomized evidence to guide treatment selection in female patients with severe symptomatic aortic stenosis. Show less
Herkert, J.C.; Verhagen, J.M.A.; Yotti, R.; Haghighi, A.; Phelan, D.G.; James, P.A.; ... ; Laar, I.M.B.H. van de 2020
Introduction Biallelic damaging variants in ALPK3, encoding alpha-protein kinase 3, cause pediatric-onset cardiomyopathy with manifestations that are incompletely defined.Methods and Results We... Show moreIntroduction Biallelic damaging variants in ALPK3, encoding alpha-protein kinase 3, cause pediatric-onset cardiomyopathy with manifestations that are incompletely defined.Methods and Results We analyzed clinical manifestations of damaging biallelic ALPK3 variants in 19 pediatric patients, including nine previously published cases. Among these, 11 loss-of-function (LoF) variants, seven compound LoF and deleterious missense variants, and one homozygous deleterious missense variant were identified. Among 18 live-born patients, 8 exhibited neonatal dilated cardiomyopathy (44.4%; 95% CI: 21.5%-69.2%) that subsequently transitioned into ventricular hypertrophy. The majority of patients had extracardiac phenotypes, including contractures, scoliosis, cleft palate, and facial dysmorphisms. We observed no association between variant type or location, disease severity, and/or extracardiac manifestations. Myocardial histopathology showed focal cardiomyocyte hypertrophy, subendocardial fibroelastosis in patients under 4 years of age, and myofibrillar disarray in adults.Rare heterozygous ALPK3 variants were also assessed in adult-onset cardiomyopathy patients. Among 1548 Dutch patients referred for initial genetic analyses, we identified 39 individuals with rare heterozygous ALPK3 variants (2.5%; 95% CI: 1.8%3.4%), including 26 missense and 10 LoF variants. Among 149 U.S. patients without pathogenic variants in 83 cardiomyopathy-related genes, we identified six missense and nine LoF ALPK3 variants (10.1%; 95% CI: 5.7%-1 6.1%). LoF ALPK3 variants were increased in comparison to matched controls (Dutch cohort, P = 1.6x10(-5); U.S. cohort, P = 2.2x10(-13)).Conclusion Biallelic damaging ALPK3 variants cause pediatric cardiomyopathy manifested by DCM transitioning to hypertrophy, often with poor contractile function. Additional extracardiac features occur in most patients, including musculoskeletal abnormalities and cleft palate. Heterozygous LoF ALPK3 variants are enriched in adults with cardiomyopathy and may contribute to their cardiomyopathy. Adults with ALPK3 LoF variants therefore warrant evaluations for cardiomyopathy. Show less
Leerink, J.M.; Feijen, E.L.A.M.; Pal, H.J.H. van der; Kok, W.E.M.; Mavinkurve-Groothuis, A.M.C.; Kapusta, L.; ... ; LATER Study Grp 2020
Background Cancer therapy-related cardiac dysfunction and heart failure are major problems in long-term childhood cancer survivors (CCS). We hypothesize that assessment of more sensitive echo- and... Show moreBackground Cancer therapy-related cardiac dysfunction and heart failure are major problems in long-term childhood cancer survivors (CCS). We hypothesize that assessment of more sensitive echo- and electrocardiographic measurements, and/or biomarkers will allow for improved recognition of patients with cardiac dysfunction before heart failure develops, and may also identify patients at lower risk for heart failure.Objective To describe the methodology of the Dutch LATER cardiology study (LATER CARD).Methods The LATER CARD study is a cross-sectional study in long-term CCS treated with (potentially) cardiotoxic cancer therapies and sibling controls. We will evaluate 1) the prevalence and associated (treatment related) risk factors of subclinical cardiac dysfunction in CCS compared to sibling controls and 2) the diagnostic value of echocardiography including myocardial strain and diastolic function parameters, blood biomarkers for cardiomyocyte apoptosis, oxidative stress, cardiac remodeling and inflammation and ECG or combinations of them in the surveillance for cancer therapy-related cardiac dysfunction. From 2017 to 2020 we expect to include 1900 CCS and 500 siblings.Conclusions The LATER CARD study will provide knowledge on different surveillance modalities for detection of cardiac dysfunction in long-term CCS at risk for heart failure. The results of the study will enable us to improve long-term follow-up surveillance guidelines for CCS at risk for heart failure. Show less
GLORIA-AF is a large, ongoing, prospective, global registry program run in 3 phases, assessing long-term safety and effectiveness of dabigatran etexilate (dabigatran) in patients with newly... Show moreGLORIA-AF is a large, ongoing, prospective, global registry program run in 3 phases, assessing long-term safety and effectiveness of dabigatran etexilate (dabigatran) in patients with newly diagnosed atrial fibrillation (AF) in clinical practice. This report provides the final analysis of 2-year clinical outcomes of the full cohort of 4873 patients prescribed dabigatran and followed for a mean of 18.0 +/- 9.4 months out of the 15,308 eligible patients enrolled in Phase II (2011-2014). The overall incidence rates per 100 person-years were: stroke 0.65 (95% CI 0.48-0.87), major bleeding 0.97 (0.76-1.23) and myocardial infarction (MI) 0.50 (0.35.0.69), with observed event rates broadly consistent in all study regions, which confirms the sustained safety and effectiveness of dabigatran over 2 years of observation in clinical practice. Show less
Background Persistent, low-grade inflammation likely participates in the pathophysiology of both atherosclerosis and kidney disease. Although high-sensitivity C-reactive protein (hsCRP) predicts... Show moreBackground Persistent, low-grade inflammation likely participates in the pathophysiology of both atherosclerosis and kidney disease. Although high-sensitivity C-reactive protein (hsCRP) predicts future cardiovascular risk in patients with chronic kidney disease (CKD), it is unknown whether hsCRP levels predict adverse renal outcomes in patients with cardiovascular disease.Methods We studied all myocardial infarction (MI) survivors undergoing hsCRP testing >30 days after their MI during routine health care in Stockholm, Sweden (2006-2011), with available information on estimated glomerular filtration rate (eGFR). HsCRP tests measured during hospitalization/emergency room visits, followed by antibiotics or indicative of acute illness, were excluded, together with patients with ongoing/recent cancer, chronic infections, or immunosuppression. Inflammation was defined over a 3-month baseline window. Study outcomes were CKD progression (composite of doubling plasma creatinine, renal replacement therapy, or renal death) and acute kidney injury (AKI, acute creatinine peaks according to Kidney Disease: Improving Global Outcomes criteria). Multivariable Cox regression was used to adjust for age, sex, eGFR, hemoglobin, time since MI, comorbidities, undertaken procedures, and medications.Results A total of 12,905 patients (62% men, mean age 73 years and 3 years since MI) were included, of whom 35% had an eGFR<60 mL/min/1.73 m(2). The mean (SD) hsCRP was 3.0 (4.4) mg/L. Baseline hsCRP levels were increasingly higher across lower eGFR categories. During a median follow-up of 3.2 years, 1,019 CKD progressions and 1,481 AKI events were recorded. Patients with hsCRP >= 2 mg/L were at higher risk of both CKD progression (adjusted hazard ratio 1.42; 95% CI 1.21-1.66) and AKI (1.29; 1.13-1.47) compared to those with hsCRP <2 mg/L. This association persisted across single CKD severity stages and after further hsCRP categorization into 4 groups (<= 1, 1-3, 3-10, >10 mg/L). Results were robust across subgroups of patients and after exclusion of events occurring during the first 6-12 months.Conclusions In post-MI patients undergoing routine health care, elevated hsCRP was associated with subsequent risk of AKI and progression of CKD, irrespective of baseline kidney function. Show less
Warfarin has been showed to increase vascular calcification. Apixaban, a direct factor Xa inhibitor, has no interaction with vitamin K and its effect on coronary plaques is unknown. We randomized... Show moreWarfarin has been showed to increase vascular calcification. Apixaban, a direct factor Xa inhibitor, has no interaction with vitamin K and its effect on coronary plaques is unknown. We randomized and compared warfarin and apixaban on progression of coronary atherosclerotic plaques measured by coronary computed tomographic angiography in 66 subjects with non-valvular atrial fibrillation over the period of one-year follow up. There was significant higher total, calcified and low attenuation plaque volume in the group randomized to warfarin as compared to apixaban (all P < .05). Greater volume of total (beta(2) = 28.54; P = .03), low attenuation plaque (beta(2) = 3.58; P = .02) and calcified (beta(2) = 14.10; P = .005) plaque progression was observed in the VKA_group. Show less
Bol, M.E.; Suverein, M.M.; Lorusso, R.; Delnoij, T.S.R.; Bruinsma, G.J.B.B.; Otterspoor, L.; ... ; Poll, M.C.G. van de 2019
Background Return of spontaneous circulation occurs in less than 10% of patients with cardiac arrest undergoing cardiopulmonary resuscitation (CPR) for more than 15 minutes. Studies suggest that... Show moreBackground Return of spontaneous circulation occurs in less than 10% of patients with cardiac arrest undergoing cardiopulmonary resuscitation (CPR) for more than 15 minutes. Studies suggest that extracorporeal life support during cardiopulmonary resuscitation (ECPR) improves survival rate in these patients. These studies, however, are hampered by their non-randomized, observational design and are mostly single-center. A multicenter, randomized controlled trial is urgently warranted to evaluate the effectiveness of ECPR.Hypothesis We hypothesize that early initiation of ECPR in refractory out-of-hospital cardiac arrest (OHCA) improves the survival rate with favorable neurological status.Study design The INCEPTION trial is an investigator-initiated, prospective, multicenter trial that will randomly allocate 110 patients to either continued CPR or ECPR in a 1: 1 ratio. Patients eligible for inclusion are adults (<= 70 years) with witnessed OHCA presenting with an initial rhythm of ventricular fibrillation (VF) or ventricular tachycardia (VT), who received bystander basic life support and who fail to achieve sustained return of spontaneous circulation within 15 minutes of cardiopulmonary resuscitation by emergency medical services. The primary endpoint of the study is 30-day survival rate with favorable neurological status, defined as 1 or 2 on the Cerebral Performance Category score. The secondary endpoints include 3, 6 and 12-month survival rate with favorable neurological status and the cost-effectiveness of ECPR compared to CCPR.Summary The INCEPTION trial aims to determine the clinical benefit for the use of ECPR in patients with refractory OHCA presenting with VF/VT. Additionally, the feasibility and cost-effectiveness of ECPR will be evaluated. Show less
