Integrating 3Rs approaches in WHO guidelines for the batch release testing of biologicals: Responses from a survey of National Control Laboratories and National Regulatory Authorities.

The UK National Centre for the Replacement, Refinement, and Reduction of Animals in Research (NC3Rs) is reviewing World Health Organization (WHO) manuals, guidelines and recommendations for vaccines and biotherapeutics to identify the extent to which animal-based testing methods are described. The aim is to recommend where updates to these documents can lead to an increased and more harmonised adoption of 3Rs principles (i.e. Replacement, Reduction and Refinement of animal tests) in the quality control and batch release testing requirements for vaccines and biotherapeutics. Improved adoption of 3Rs principles and non-animal testing strategies will help to reduce the delays and costs associated with product release testing. Developing recommendations that are widely applicable by both the manufacturers and national regulatory authorities for vaccines and biological therapeutics globally requires a detailed understanding of how different organisations view the opportunities and barriers to better integration of the 3Rs. To facilitate this, we developed and distributed a survey aimed at individuals who work for national regulatory authorities (NRAs) and/or national control laboratories (NCLs). In this paper, we present the key findings from this survey and how these will help inform the recommendations for wider integration of 3Rs approaches by WHO in their guidance documents applicable to the quality control and batch release testing of vaccines and biotherapeutics.

Associations of physical and social workplace characteristics with movement behaviors at work.

Introduction/Purpose: Sedentary behavior (SB) is common in desk-based work and prolonged periods of SB are associated with negative health outcomes. This study assessed associations between workplace characteristics and setting and movement patterns during working hours. Methods: This secondary analysis used baseline data from the Reducing Sedentary Behavior to Decrease Blood Pressure (RESET BP) clinical trial which enrolled inactive, desk-based workers with elevated blood pressure (n=271; mean age: 45.3±11.6 years; body mass index (BMI): 30.66±7.1 kg/m2; 59.4% women). Physical and social workplace characteristics were assessed by a study-developed questionnaire and the Office Environment and Sitting Scale (OFFESS). Participants also wore an activPAL activity monitor for 7 days and reported working hours in a diary to measure SB and physical activity (PA) specifically while working. Linear regression was used to analyze cross-sectional associations between workplace characteristics and SB and PA. A stratified analysis was also conducted to assess associations among home-based and in-office desk workers separately. Analyses were adjusted for age, gender, BMI, and work wear time. Results: Participants spent 77% of working hours in SB. Public vs. private offices, working in-office vs. at home, higher local connectivity, and greater overall connectedness were associated with lower SB and/or greater PA (all p<0.05). Higher frequency of face-to-face interactions, and greater visibility and proximity to co-workers was associated with less SB and more PA (all p<0.05). For example, home-based workers had more total SB (+17.2±8.4 mins/day), more SB bouts ≥30 mins (+39.1±12.8 mins/day), and less steps (695±201 steps/day) than in-office employees. Stratification by office setting revealed differences in associations between SB and PA and workplace characteristics. Conclusions: More public, open spaces with more social interactions and physical walkways could improve SB and PA patterns during work. Home-based workers had more SB, less PA, and unique associations of these activities with workplace characteristics, suggesting a need for tailored interventions.

Integrating 3Rs approaches in WHO guidelines for the batch release testing of biologicals: Responses from a survey of vaccines and biological therapeutics manufacturers.

The UK National Centre for the Replacement, Refinement, and Reduction of Animals in Research (NC3Rs) has been tasked by the World Health Organization (WHO) to review the extent to which animal-based testing methods are described in their manuals, guidelines and recommendations for vaccines and biotherapeutics. The aim is to identify and recommend where updates to these documents can lead to an increased and more harmonised adoption of 3Rs principles (i.e. Replacement, Reduction and Refinement of animal tests) in the quality control and batch release testing requirements for vaccines and biotherapeutics. Developing recommendations that are widely applicable by both the manufacturers and national regulatory authorities for vaccines and biologicals globally requires a detailed understanding of how different organisations view the opportunities and barriers to better integration of the 3Rs. To facilitate this, we developed and distributed a survey aimed at vaccine and biotherapeutics manufacturers in July 2021. In this paper, we present the key findings from this survey and how these will help inform the recommendations for wider integration of 3Rs approaches by WHO in their guidance documents applicable to the quality control and batch testing of vaccines and biotherapeutics.

Frequency, Penetrance, and Variable Expressivity of Dilated Cardiomyopathy-Associated Putative Pathogenic Gene Variants in UK Biobank Participants.

BACKGROUND: There is a paucity of data regarding the phenotype of dilated cardiomyopathy (DCM) gene variants in the general population. We aimed to determine the frequency and penetrance of DCM-associated putative pathogenic gene variants in a general adult population, with a focus on the expression of clinical and subclinical phenotype, including structural, functional, and arrhythmic disease features. METHODS: UK Biobank participants who had undergone whole exome sequencing, ECG, and cardiovascular magnetic resonance imaging were selected for study. Three variant-calling strategies (1 primary and 2 secondary) were used to identify participants with putative pathogenic variants in 44 DCM genes. The observed phenotype was graded DCM (clinical or cardiovascular magnetic resonance diagnosis); early DCM features, including arrhythmia or conduction disease, isolated ventricular dilation, and hypokinetic nondilated cardiomyopathy; or phenotype-negative. RESULTS: Among 18 665 individuals included in the study, 1463 (7.8%) possessed ≥1 putative pathogenic variant in 44 DCM genes by the main variant calling strategy. A clinical diagnosis of DCM was present in 0.34% and early DCM features in 5.7% of individuals with putative pathogenic variants. ECG and cardiovascular magnetic resonance analysis revealed evidence of subclinical DCM in an additional 1.6% and early DCM features in an additional 15.9% of individuals with putative pathogenic variants. Arrhythmias or conduction disease (15.2%) were the most common early DCM features, followed by hypokinetic nondilated cardiomyopathy (4%). The combined clinical/subclinical penetrance was ≤30% with all 3 variant filtering strategies. Clinical DCM was slightly more prevalent among participants with putative pathogenic variants in definitive/strong evidence genes as compared with those with variants in moderate/limited evidence genes. CONCLUSIONS: In the UK Biobank, ≈1 of 6 of adults with putative pathogenic variants in DCM genes exhibited early DCM features potentially associated with DCM genotype, most commonly manifesting with arrhythmias in the absence of substantial ventricular dilation or dysfunction.

Integrating 3Rs approaches in WHO guidelines for the batch release testing of biologicals.

Animal testing has long been integral to the development of biologicals, including vaccines. The use of animals can provide important information on potential toxicity, insights into their mechanism of action, pharmacokinetics and dynamics, physiologic distribution, and potency. However, the use of these same methods is often adopted into the post-licensure phase of the product life cycle for the monitoring of product qualities, such as potency or safety, as part of their routine batch release. The UK National Centre for the Replacement, Refinement, and Reduction of Animals in Research (NC3Rs) and the World Health Organization (WHO) are collaborating on a project to review animal-based testing methods described in WHO manuals, guidelines and recommendations for biologicals to identify where updates can lead to a more harmonised adoption of 3Rs principles (i.e. Replacement, Reduction, and Refinement of animal tests) in batch release testing requirements. An international working group consisting of more than 30 representatives from pharmaceutical and biotechnology companies, national control laboratories and regulatory bodies is performing this review. This project aims to address concerns about inconsistencies in the guidance for the scientifically justified use of animal methods required for the post-licensure quality control and batch release testing of biologicals, and the near absence of recommendations for the application of 3Rs principles within the relevant guidelines. Improved adoption of 3Rs principles and non-animal testing strategies will help to reduce the delays and costs associated with product release testing and help support faster access to products by the global communities who need them most urgently.

Harnessing the power of microphysiological systems for COVID-19 research.

The pharmaceutical industry is constantly striving for innovative ways to bridge the translational gap between preclinical and clinical drug development to reduce attrition. Substantial effort has focused on the preclinical application of human-based microphysiological systems (MPS) to better identify compounds not likely to be safe or efficacious in the clinic. The Coronavirus 2019 (COVID-19) pandemic provides a clear opportunity for assessing the utility of MPS models of the lungs and other organ systems affected by the disease in understanding the pathophysiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and in the development of effective therapeutics. Here, we review progress and describe the establishment of a global working group to coordinate activities around MPS and COVID-19 and to maximize their scientific, human health, and animal welfare impacts.

Risk of Intracranial Extension of Craniofacial Dermoid Cysts.

BACKGROUND: Dermoid cysts are benign lesions lined by keratinizing squamous epithelium that also contain epidermal adnexa (hair follicles, hair shafts, sebaceous glands, and both apocrine and eccrine sweat glands) and mesodermal derivatives (smooth muscle fibers, vascular stroma, nerves, and collagen fibers). Craniofacial dermoid cysts represent approximately 7 percent of all dermoids and have an incidence ranging between 0.03 and 0.14 percent. METHODS: The authors conducted a single-center, consecutive, nonrandomized comparative case series over a 20-year period of all patients treated surgically for craniofacial dermoid at the Royal Children's Hospital in Melbourne, Australia. Six hundred forty-seven patients had craniofacial dermoids and adequate information to be included in the study. The authors also conducted a thorough review of the literature using the MEDLINE and Embase databases. RESULTS: Six hundred forty-seven patients amounted to 655 lesions in our case series. The age at surgery ranged from 2 months to 18 years, with an average age of 25.65 months. The depth of the lesions was stratified using a classification system, and the risk of intracranial extension was assessed using these data. Midline nasal lesions are established as high risk by other studies, but frontal, temporal, and occipital lesions were found to be as risky if not more risky for intracranial extension. CONCLUSIONS: Several classification systems for craniofacial dermoid cysts have used both broader anatomical locations and physical characteristics to group these lesions and identify those warranting preoperative imaging. The authors propose a system using more specific classification of anatomical location to assist in the prompt identification of high-risk lesions and facilitate sound preoperative planning. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

Clinical End Points of Transcatheter Aortic Valve Implantation Compared With Surgical Aortic Valve Replacement in Patients <65 Years of Age (From the National Inpatient Sample Database).

It is unknown if transcatheter aortic valve implantation (TAVI) is a safe alternative to surgical aortic valve replacement (SAVR) in patients <65 years old. Data from the National Inpatient Sample database were utilized. Patients from 2011 to 2015, ages 18 to 64 years old (inclusive) who underwent TAVI and SAVR were included. Patients who underwent SAVR and who also received a concomitant nonaortic valve surgery were excluded. A propensity score analysis was used. A total of 18,970 (528 TAVI and 18,442 SAVR) patients were identified. Patients who underwent TAVI were older (57 ± 7 vs 54 ± 10 years old, p <0.001) with more frequent co-morbidities. Overall in-hospital mortality was similar between TAVI and SAVR (odds ratio [OR] = 0.52, p = 0.12). Postprocedure stroke (OR = 0.50, p = 0.24), acute kidney injury (OR = 0.98, p = 0.89), acute myocardial infarction (OR = 0.48, p = 0.08), and vascular complication requiring surgery (OR = 0.20, p = 0.11) were similar between patients who underwent TAVI and SAVR. Bleeding requiring transfusion (OR = 0.32, p <0.01) was less frequent in patients who underwent TAVI, but new pacemakers (OR = 1.7, p = 0.02) were more frequent in these patients. Patients who underwent TAVI had shorter hospital stays (7.9 vs 10.0 days, p <0.001) and were more likely to be discharged to home. Cost between TAVI and SAVR was similar ($49,014 vs $42,907, respectively, p = 0.82). In the <65 years old patient population, TAVI also conferred similar overall in-hospital mortality compared with patients who underwent SAVR. TAVI resulted in fewer major complications, shorter hospital stay, and more frequent discharge to home, but higher rates of pacemaker implantation compared with SAVR. Therefore, TAVI appears to be a safe alternative to SAVR in patients <65 years old.

The use of human tissue in safety assessment.

INTRODUCTION: The safety-related failure of drugs during clinical phases of development is a significant contributor to drug attrition, wasting resources and preventing treatments from reaching patients. A lack of concordance between results from animal models and adverse events in the clinic has been identified as one potential cause of attrition. In vitro models using human tissue or cells have the potential to replace some animal models and improve predictivity to humans. METHODS: To gauge the current use of human tissue models in safety pharmacology and the barriers to greater uptake, an electronic survey of the international safety assessment community was carried out and a Safety Pharmacology Society European Regional Meeting was organised entitled 'The Use of Human Tissue in Safety Assessment'. RESULTS: A greater range of human tissue models is in use in safety assessment now than four years ago, although data is still not routinely included in regulatory submissions. The barriers to increased uptake of the models have not changed over that time, with inadequate supply and characterisation of tissue being the most cited blocks. DISCUSSION: Supporting biobanking, the development of new human tissue modelling technology, and raising awareness in the scientific and regulatory communities are key ways in which the barriers to greater uptake of human tissue models can be overcome. The development of infrastructure and legislation in the UK to support the use of post-mortem or surgical discard tissue will allow scientists to locally source tissue for research.

Meta-Analysis Comparing Patent Foramen Ovale Closure Versus Medical Therapy to Prevent Recurrent Cryptogenic Stroke.

New evidence suggests that closure of a patent foramen ovale (PFO) plus medical therapy (MT; antiplatelet or anticoagulation) is superior to MT alone to prevent recurrent cryptogenic stroke. We performed a meta-analysis of randomized controlled trials that compared PFO closure plus MT with MT alone in patients with cryptogenic stroke. The efficacy end points were recurrent stroke, transient ischemia attack, and death. The safety end points were major bleeding and newly detected atrial fibrillation. Trials were pooled using random effects and fixed effects models. A trial sequential analysis was performed to assess if the current evidence is sufficient. Risk ratios (RR) were calculated for pooled estimates of risk. Five randomized controlled trials (3,440 patients) were included. Mean follow-up was 4.1 years. PFO closure reduced the risk of recurrent stroke by 58% (RR 0.42, 95% CI 0.20 to 0.91, p = 0.03). The number needed to treat was 38. The cumulative Z-line crossed the trial sequential boundary, suggesting there is adequate evidence to conclude that PFO closure reduces the risk of recurrent stroke by 60%. PFO closure did not reduce the risk of transient ischemia attack (RR 0.78, 95% CI 0.53 to 1.15, p = 0.21), mortality (RR 0.74, 95% CI 0.35 to 1.60, p = 0.45), or major bleeding (RR 0.96, 95% CI 0.42 to 2.20, p = 0.93); it did increase the risk of atrial fibrillation (RR 4.69, 95% CI 2.17 to 10.12, p <0.0001).

Is myocardial repolarization duration associated with repolarization heterogeneity?

BACKGROUND: Dispersion of repolarization is theorized as one mechanism by which myocardial repolarization prolongation causes lethal torsades de pointes, (TdP). Our primary purpose was to determine whether prolongation of myocardial repolarization as measured by the heart rate-corrected J-to-T peak interval (JTpkc), is associated with repolarization heterogeneity as measured by transmural dispersion, defined as the median duration from the peak to the end of the T wave (TpTe). METHODS: A retrospective cohort study was performed at a single urban tertiary ED from July 2011-September 2012. Inclusion criteria included all consecutive ED patients with ECG based on QTc and QRS intervals. Automated measurements of all intervals were performed. The association of JTpkc with the dependent variable TpTe was assessed after adjustment for QRS and RR interval durations with a multiple linear regression model. A secondary analysis included a similar adjusted assessment of the association of JTpkc with QT dispersion, QTd. Finally, we constructed two multiple regression models to assess the association of clinical causative factors of TdP with TpTe and JTpkc. RESULTS: Eight hundred seventy-four cases were included: 186 with QTc <500 ms, 118 with QTc ≥500 and QRS ≥120 ms, and 570 with QTc ≥500 and QRS <120 ms. The coefficient for association of JTpkc with TpTe was -0.10 (95%CI -0.15 to -0.05), and for JTpkc with QTd was 0.03 (95% CI -0.01 to 0.06). Clinical causative TdP factors were associated more with JTpkc than TpTe. CONCLUSION: Repolarization duration as measured by JTpkc is not positively associated with dispersion of repolarization as measured by TpTe or QTd. Dispersion of repolarization may not be a critical mechanistic link between QTc prolongation and TdP.

Circumferential strain acquired by CMR early after acute myocardial infarction adds incremental predictive value to late gadolinium enhancement imaging to predict late myocardial remodeling and subsequent risk of sudden cardiac death.

PURPOSE: Late adverse myocardial remodeling after acute myocardial infarction (AMI) is strongly associated with sudden cardiac death (SCD). Cardiac magnetic resonance (CMR) performed early after AMI can predict late remodeling and SCD risk with moderate accuracy. This study assessed the ability of CMR-measured circumferential strain (CS) to add incremental predictive information to late gadolinium enhancement (LGE). METHODS: Patients with an AMI and LVEF < 50% were screened for inclusion. A total of 27 patients, totaling 432 myocardial segments, prospectively underwent CMR 7 ± 5 days after percutaneous coronary intervention (PCI). LGE, microvascular obstruction (MVO), and myocardial CS were measured for each segment. The primary endpoint was late segmental adverse remodeling defined as segmental wall motion score (WMS) > 1 measured by echocardiography 3 months after PCI. RESULTS: A total of 141 segments experienced the primary endpoint at 3 months. The mean LGE volume was higher in these segments, but LGE was also present in many segments with normal WMS (40 ± 28 versus 20 ± 26%, p < 0.01). Segments that met the primary endpoint also showed greater impairment of CS. Segments with both LGE > 17% and impaired CS >- 7.2% on CMR were more likely to experience late adverse remodeling (73%) as compared to segments with neither (9%, p < 0.001) or one abnormal parameter (36%, p < 0.001). CS >- 7.2% also added incremental accuracy to LGE > 17% for predicting late adverse remodeling (AUC 0.81 from 0.70, p < 0.001). CONCLUSIONS: When performed early after AMI, LGE is a moderate predictor of late remodeling and CS is a powerful predictor of late myocardial remodeling. When combined, they can predict late remodeling, a surrogate of SCD, with high accuracy.

Rising to the challenge: applying biofabrication approaches for better drug and chemical product development.

Many industrial sectors, from pharmaceuticals to consumer products, are required to provide data on their products to demonstrate their efficacy and that they are safe for patients, consumers and the environment. This period of testing typically requires the use of animal models, the validity of which has been called into question due to the high rates of attrition across many industries. There is increasing recognition of the limitations of animal models and demands for safety and efficacy testing paradigms which embrace the latest technological advances and knowledge of human biology. This perspective article highlights the potential for biofabrication approaches (encompassing bioprinting and bioassembly strategies) to meet these needs and provides case studies from three different industry sectors to demonstrate the potential for new markets in the bioprinting community. We also present a series of recommendations to create a thriving bioprinting environment. One that operates at the forefront of science, technology and innovation to deliver improved decision-making tools for the more rapid development of medicines, agrichemicals, chemicals and consumer products, and which may reduce our reliance on animals.

Atrial fibrillation inducibility during cavo-tricuspid isthmus dependent atrial flutter ablation for the prediction of clinical atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) and cavo-tricuspid isthmus (CTI) dependent atrial flutter (AFL) are two separate entities that coexist in a significant percentage of patients. METHODS: We sought to investigate whether AF inducibility during CTI AFL ablation predicted the occurrence of AF at follow up after AFL ablation. Univariate and multivariate analyses were performed. RESULTS: A total of 154 patients (male: 72%, age: 61±13) with AFL and without history of AF were included. All patients underwent successful CTI dependent AFL ablation demonstrated by bidirectional block. During ablation, AF was seen or induced in 28 (18%) patients. After a mean follow up of 34±24months a total of 50 patients (32%) were noted with clinically manifest AF. From the patients who had inducible AF during AFL ablation, 50% developed post-procedural AF. From those in whom AF could not be induced, only 29% were documented with AF after ablation. Univariate and multivariate analyses revealed that only age and AF inducibility during AFL ablation were predictors of AF. Univariate analysis (age p=0.038 and inducible AF p=0.032 with odds ratio of 1.030 [95% CI (1.002-1.059)] and 2.500 [95% CI (1.084-5.765)], respectively) and multivariate analyses (age p=0.011 and inducible AF p=0.016 with adjusted odds ratio of 1.043 [95% CI (1.010-1.077)] and 3.293 [95% CI (1.250-8.676)], respectively). CONCLUSION: AF inducibility in patients undergoing CTI AFL without history of AF is a strong predictor of AF occurrence in the future. Appropriate cardiology follow-up must be encouraged in this high-risk population as stroke prevention strategies can be appropriately introduced in a timely matter especially in patients with elevated CHA2DS2-VASc scores (≥2).

Paradoxical low-flow aortic stenosis is defined by increased ventricular hydraulic load and reduced longitudinal strain.

AIMS: Patients with paradoxical low-flow severe aortic stenosis (PLF-AS) reportedly have higher left ventricular hydraulic load and more systolic strain dysfunction than patients with normal-flow aortic stenosis. This study investigates the relationship of systolic loading and strain to PLF-AS to further define its pathophysiology. METHODS: One hundred and twenty patients (age 79 ±â€Š12 years, 37% men) with an indexed aortic valve area (AVAi) of 0.6 cm/m or less and an ejection fraction of 50% or higher were divided into two groups based on indexed stroke volume (SVi): PLF-AS, SVi ≤ 35 ml/m, N = 46; normal-flow aortic stenosis, SVi > 35 ml/m, N = 74). Valvular and arterial load were assessed using multiple measurements, and strain was assessed using speckle-tracking echocardiography. RESULTS: Patients with PLF-AS were found to have more valvular load (lower AVAi, P = 0.028; lower energy loss coefficient, P = 0.001), more arterial load [decreased arterial compliance and increased systemic vascular resistance (SVR), both P < 0.001] and more total hydraulic load [increased valvuloarterial impedance (Zva), P < 0.001]. Transvalvular gradients and arterial pressures were similar. Longitudinal strain was lower in PLF-AS (P < 0.001), but circumferential and rotation strains were similar. On adjusted regression, AVAi, SVR and longitudinal strain were associated with PLF-AS [odds ratio (OR) = 1.34, P = 0.043; OR = 1.31, P = 0.004; OR = 1.34, P = 0.011, respectively]. When SVR and AVAi were replaced with Zva, longitudinal strain and Zva (OR = 1.38, P = 0.015; OR = 1.33, P < 0.001 for both, respectively) were associated with PLF-AS. CONCLUSION: Increased hydraulic load, from more severe valvular stenosis and increased vascular resistance, and longitudinal strain impairment are associated with PLF-AS and their interplay is likely fundamental to its pathophysiology.

Percutaneous versus surgical cut-down access in transfemoral transcatheter aortic valve replacement: A meta-analysis.

BACKGROUND: The transfemoral (TF) approach has become the preferred approach for transcatheter aortic valve replacement (TAVR) because of its low risk profile. However, the relative safety of the percutaneous approach (PC) compared to surgical cut-down (SC) remains unclear. Our aim was to compare the outcomes between PC versus SC access in patients undergoing TF-TAVR using a meta-analysis. METHODS: We conducted a systematic electronic database search for studies reporting major and minor vascular complications (VC), major and minor bleeding, and perioperative all-cause mortality, in PC versus SC TF-TAVR cases. Complications were reported based on the Valve Academic Research Consortium criteria. A random-effects model was used to calculate odds ratios and 95% confidence intervals. RESULTS: Eight observational cohort studies and one randomized control trial (2513 patients in PC and 1767 patients in SC) were included in the analysis. Major and minor VC, as well as bleeding complications, were comparable between the two approaches. The need for surgical intervention for VC was comparable between PC and SC. There was no difference in perioperative all-cause mortality. CONCLUSIONS: PC and SC have similar safety profiles and outcomes when used appropriately in selected patients.

Sapien 3 versus Sapien XT prosthetic valves in transcatheter aortic valve implantation: A meta-analysis.

OBJECTIVES: The S3 prosthetic valve was introduced to overcome several issues with its predecessor, the SXT, in transcatheter aortic valve implantation (TAVI), however, the clinical outcomes of this new model are not clearly defined. We performed a meta-analysis to compare the outcomes in Sapien 3 (S3) and Sapien XT (SXT) recipients. METHODS: A literature search through PUBMED and EMBASE was conducted. Articles that included at least one of the clinical outcomes of interest were included in the meta-analysis: moderate to severe paravalvular regurgitation (PVR), permanent pacemaker implantation (PPI), major vascular complications (MVC), cerebrovascular events (stroke and transient ischemic attack) (CVE), failure rate of device implantation, life-threatening, disabling or major bleeding, need for post-dilation and early all-cause-mortality. RESULTS: A total of 9 observational cohort studies were included. S3 was implanted in 945 and SXT in 1553 patients. S3 was associated with a lower incidence of moderate to severe PVR (1.6% vs 6.9%, p<0.0001), lower MVC (5.1% vs 8.9%, p=0.01) and less serious bleeding (8.1% vs 15.2%, p=0.003) compared to the SXT. Device deployment failure rate was lower in the S3 (1.2% vs 5.9%, p=0.004) and the S3 required less post-dilation (16.9% vs 26.9%, p=0.05). Rates of CVE, perioperative mortality and PPI were similar between the two valves. CONCLUSIONS: Implantation of the S3 prosthetic valve results in lower rates of moderate to severe PVR, MVC, post-dilation and serious bleeding however it does not improve on the SXT in terms of CVE, PPI and early mortality.

Iatrogenic Ventricular Septal Defect Following Transcatheter Aortic Valve Replacement: A Systematic Review.

BACKGROUND: Ventricular septal defects (VSD) are rarely reported as a complication following transcatheter aortic valve replacement (TAVR). We sought to characterise the patients, clinical management, and outcomes regarding this rare phenomenon. METHODS: Relevant articles were identified by a systematic search of MEDLINE and EMBASE databases from January, 2002 to September, 2015. RESULTS: A total of 18 case reports, including 20 patients, were identified. The median age was 83 years and six were male. Twelve were performed by trans-femoral approach. Pre-dilation was performed in 12 patients and post-dilation in four. Balloon expandable valves were used in the majority (85%) of cases. The clinical presentation varied from asymptomatic to progressive heart failure. The timing of the diagnosis also varied significantly from immediately post valve implantation to one year afterwards. There were two cases of Gerbode-type defect while the rest were inter-ventricular defects. The location was mostly membranous or perimembranous (79%) and adjacent to the valve landing zone. A total of seven interventions (one open surgery and six percutaneous closure) were performed. Four patients died during the same hospital admission. Sixteen survived past discharge (range 12 days to two years). CONCLUSIONS: Ventricular septal defects post-TAVR were seen more with balloon expandable valves and with pre-dilation or post-dilation. Percutaneous treatment of the VSD was preferred over open cardiac surgery given the high surgical risk in this patient population. Some, but not all, patients survived TAVR and VSD and had a good prognosis for both patient groups with or without VSD closure.