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

The role of cardiovascular magnetic resonance imaging and computed tomography angiography in suspected non-ST-elevation myocardial infarction patients:Design and rationale of the CARdiovascular Magnetic rEsoNance imaging and computed Tomography Angiography (CARMENTA) trial

BackgroundAlthough high-sensitivity cardiac troponin (hs-cTn) substantially improves the early detection of myocardial injury, it lacks specificity for acute myocardial infarction (MI). In suspected non–ST-elevation MI, invasive coronary angiography (ICA) remains necessary to distinguish between acute MI and noncoronary myocardial disease (eg, myocarditis), unnecessarily subjecting the latter to ICA and associated complications. This trial investigates whether implementing cardiovascular magnetic resonance (CMR) or computed tomography angiography (CTA) early in the diagnostic process may help to differentiate between coronary and noncoronary myocardial disease, thereby preventing unnecessary ICA.Study DesignIn this prospective, single-center, randomized controlled clinical trial, 321 consecutive patients with acute chest pain, elevated hs-cTnT, and nondiagnostic electrocardiogram are randomized to 1 of 3 strategies: (1) CMR, or (2) CTA early in the diagnostic process, or (3) routine clinical management. In the 2 investigational arms of the study, results of CMR or CTA will guide further clinical management. It is expected that noncoronary myocardial disease is detected more frequently after early noninvasive imaging as compared with routine clinical management, and unnecessary ICA will be prevented. The primary end point is the total number of patients undergoing ICA during initial admission. Secondary end points are 30-day and 1-year clinical outcome (major adverse cardiac events and major procedure-related complications), time to final diagnosis, quality of life, and cost-effectiveness.ConclusionThe CARMENTA trial investigates whether implementing CTA or CMR early in the diagnostic process in suspected non–ST-elevation MI based on elevated hs-cTnT can prevent unnecessary ICA as compared with routine clinical management, with no detrimental effect on clinical outcome

Genetic Disruption of Both Tryptophan Hydroxylase Genes Dramatically Reduces Serotonin and Affects Behavior in Models Sensitive to Antidepressants

The neurotransmitter serotonin (5-HT) plays an important role in both the peripheral and central nervous systems. The biosynthesis of serotonin is regulated by two rate-limiting enzymes, tryptophan hydroxylase-1 and -2 (TPH1 and TPH2). We used a gene-targeting approach to generate mice with selective and complete elimination of the two known TPH isoforms. This resulted in dramatically reduced central 5-HT levels in Tph2 knockout (TPH2KO) and Tph1/Tph2 double knockout (DKO) mice; and substantially reduced peripheral 5-HT levels in DKO, but not TPH2KO mice. Therefore, differential expression of the two isoforms of TPH was reflected in corresponding depletion of 5-HT content in the brain and periphery. Surprisingly, despite the prominent and evolutionarily ancient role that 5-HT plays in both vertebrate and invertebrate physiology, none of these mutations resulted in an overt phenotype. TPH2KO and DKO mice were viable and normal in appearance. Behavioral alterations in assays with predictive validity for antidepressants were among the very few phenotypes uncovered. These behavioral changes were subtle in the TPH2KO mice; they were enhanced in the DKO mice. Herein, we confirm findings from prior descriptions of TPH1 knockout mice and present the first reported phenotypic evaluations of Tph2 and Tph1/Tph2 knockout mice. The behavioral effects observed in the TPH2 KO and DKO mice strongly confirm the role of 5-HT and its synthetic enzymes in the etiology and treatment of affective disorders

Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine

Despite rapid technical progress and demonstrable effectiveness for some types of diagnosis and therapy, much remains to be learned about clinical genome and exome sequencing (CGES) and its role within the practice of medicine. The Clinical Sequencing Exploratory Research (CSER) consortium includes 18 extramural research projects, one National Human Genome Research Institute (NHGRI) intramural project, and a coordinating center funded by the NHGRI and National Cancer Institute. The consortium is exploring analytic and clinical validity and utility, as well as the ethical, legal, and social implications of sequencing via multidisciplinary approaches; it has thus far recruited 5,577 participants across a spectrum of symptomatic and healthy children and adults by utilizing both germline and cancer sequencing. The CSER consortium is analyzing data and creating publically available procedures and tools related to participant preferences and consent, variant classification, disclosure and management of primary and secondary findings, health outcomes, and integration with electronic health records. Future research directions will refine measures of clinical utility of CGES in both germline and somatic testing, evaluate the use of CGES for screening in healthy individuals, explore the penetrance of pathogenic variants through extensive phenotyping, reduce discordances in public databases of genes and variants, examine social and ethnic disparities in the provision of genomics services, explore regulatory issues, and estimate the value and downstream costs of sequencing. The CSER consortium has established a shared community of research sites by using diverse approaches to pursue the evidence-based development of best practices in genomic medicine

Iliofemoral Tortuosity Increases the Risk of Access-Site-Related Complications After Aortic Valve Implantation and Plug-Based Access-Site Closure

BACKGROUND: Access-site-related complications are often related to high-risk anatomy and technical pitfalls and impair the outcomes of transfemoral aortic valve implantations (TAVIs). Calcification and tortuosity are widely recognized risk factors, and their impact on procedural planning is left to the implanting experts’ discretion. To facilitate decision-making, we introduced a quantitative measure for iliofemoral tortuosity and assessed its predictive value for access-site-related vascular and bleeding complications. METHODS: We performed a single-centre prospective cohort study of consecutive, percutaneous transfemoral TAVI performed between April 2019 and March 2020. Medical history and all-cause mortality were extracted from the electronic patient files. Arterial anatomy and calcifications were evaluated using 3mensio Structural Heart software. The primary outcome was access-site-related vascular or bleeding complications. RESULTS: In this elderly, intermediate-risk population, we registered the primary outcome in 43 patients (39%), and major access-site complications in 10 patients (9.2%). Complete hemostasis was achieved in 77 patients (70.6%), by the application of the MANTA plug alone. In the group with access-site-related adverse events, compared with the group without, the tortuosity index was higher median (26% interquartile range [IQR 18%-33%] vs median 19% [IQR 13%-29%], respectively; P = 0.012), as was maximal angulation median (50° [IQR 40°-59°] vs median 43° [IQR 36°-51°], respectively; P = 0.026) were higher. Both variables had a significant effect on our primary outcome, with odds ratios (OR) of 3.1 (tortuosity, P = 0.005) and 2.6 (angulation, P = 0.020). The degree of angulation was a predictor of major complications too (odds ratio 7 [1.4-34.8]; P = 0.017). CONCLUSIONS: Steeper angles and greater arterial elongation increase the risk of vascular and bleeding complications after femoral TAVI with the utilization of a plug-based closure device

Iliofemoral Tortuosity Increases the Risk of Access-Site-Related Complications After Aortic Valve Implantation and Plug-Based Access-Site Closure

Background: Access-site-related complications are often related to high-risk anatomy and technical pitfalls and impair the outcomes of transfemoral aortic valve implantations (TAVIs). Calcification and tortuosity are widely recognized risk factors, and their impact on procedural planning is left to the implanting experts' discretion. To facilitate decision-making, we introduced a quantitative measure for iliofemoral tortuosity and assessed its predictive value for access-site-related vascular and bleeding complications. Methods: We performed a single-centre prospective cohort study of consecutive, percutaneous transfemoral TAVI performed between April 2019 and March 2020. Medical history and all-cause mortality were extracted from the electronic patient files. Arterial anatomy and calcifications were evaluated using 3mensio Structural Heart software. The primary outcome was access-site-related vascular or bleeding complications. Results: In this elderly, intermediate-risk population, we registered the primary outcome in 43 patients (39%), and major access-site complications in 10 patients (9.2%). Complete hemostasis was achieved in 77 patients (70.6%), by the application of the MANTA plug alone. In the group with access-site-related adverse events, compared with the group without, the tortuosity index was higher median (26% interquartile range [IQR 18%-33%] vs median 19% [IQR 13%-29%], respectively; P = 0.012), as was maximal angulation median (50° [IQR 40°-59°] vs median 43° [IQR 36°-51°], respectively; P = 0.026) were higher. Both variables had a significant effect on our primary outcome, with odds ratios (OR) of 3.1 (tortuosity, P = 0.005) and 2.6 (angulation, P = 0.020). The degree of angulation was a predictor of major complications too (odds ratio 7 [1.4-34.8]; P = 0.017). Conclusions: Steeper angles and greater arterial elongation increase the risk of vascular and bleeding complications after femoral TAVI with the utilization of a plug-based closure device

Retrospectively ECG-gated helical vs. non-ECG-synchronized high-pitch CTA of the aortic root for TAVI planning

BACKGROUND:Multidetector computed tomography (MDCT) plays a key role in patient assessment prior to transcatheter aortic valve implantation (TAVI). However, to date no consensus has been established on what is the optimal pre-procedural imaging protocol. Variability in pre-TAVI acquisition protocols may lead to discrepancies in aortic annulus measurements and may potentially influence prosthesis size selection. PURPOSE:The current study evaluates the magnitude of differences in aortic annulus measurements using max-systolic, end-diastolic, and non-ECG-synchronized imaging, as well as the impact of method on prosthesis size selection. MATERIAL AND METHODS:Fifty consecutive TAVI-candidates, who underwent retrospectively-ECG-gated CT angiography (CTA) of the aortic root, directly followed by non-ECG-synchronized high-pitch CT of the entire aorta, were retrospectively included. Aortic root dimensions were assessed at each 10% increment of the R-R interval (0-100%) and on the non-ECG-synchronized scan. Dimensional changes within the cardiac cycle were evaluated using a 1-way repeated ANOVA. Agreement in measurements between max-systole, end-diastole and non-ECG-synchronized scans was assessed with Bland-Altman analysis. RESULTS:Maximal dimensions of the aortic root structures and minimum annulus-coronary ostia distances were measured during systole. Max-systolic measurements were significantly and substantially larger than end-diastolic (p<0.001) and non-ECG-synchronized measurements (p<0.001). Due to these discrepancies, the three methods resulted in the same prosthesis size selection in only 48-62% of patients. CONCLUSIONS:The systematic differences between max-systolic, end-diastolic and non-ECG-synchronized measurements for relevant aortic annular dimensions are both statistically significant and clinically relevant. Imaging strategy impacts prosthesis size selection in nearly half the TAVI-candidates. End-diastolic and non-ECG-synchronized imaging does not provide optimal information for prosthesis size selection. Systolic image acquisition is necessary for assessment of maximal annular dimensions and minimum annulus-coronary ostia distances

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 7-day 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

High genetic diversity of Staphylococcus aureus strains colonizing patients with epidermolysis bullosa

Patients with the blistering disease, epidermolysis bullosa (EB), frequently suffer from chronic wounds that become colonized by pathogenic bacteria, such as Staphylococcus aureus. To determine S.similar to aureus colonization rates in patients with EB, swabs were collected from the anterior nares, throats and wounds of 52 Dutch patients with EB. Swabs were also collected from nares and throats of 13 healthcare workers who occasionally meet the sampled patients with EB. All EB patients with chronic wounds and 75% of the patients without chronic wounds were colonized with S.similar to aureus. In contrast, 39% of the sampled healthcare workers were colonized with S.similar to aureus. Typing revealed a high degree of genetic diversity of 184 collected S.similar to aureus isolates. Autoinoculation of S.similar to aureus in individual patients with EB was shown to occur frequently, whereas transmission of S.similar to aureus between patients with EB is apparently rare. There was no evidence for S.similar to aureus transmission between patients with EB and healthcare workers