Biological Heart Valve Prostheses Research Articles

The Outcomes for Different Biological Heart Valve Prostheses in Surgical Aortic Valve Replacement before and after the Introduction of Transcatheter Aortic Valve Implantation

The Outcomes for Different Biological Heart Valve Prostheses in Surgical Aortic Valve Replacement before and after the Introduction of Transcatheter Aortic Valve Implantation

Dementia Development during Long-Term Follow-Up after Surgical Aortic Valve Replacement with a Biological Prosthesis in a Geriatric Population.

Surgical aortic valve replacement (SAVR) with a biological heart valve prosthesis (BHV) is often used as a treatment in elderly patients with symptomatic aortic valve disease. This age group is also at risk for the development of dementia in the years following SAVR. The research question is "what are the predictors for the development of dementia?". In 1500 patients undergoing SAVR with or without an associated procedure, preoperative (demographic, cardiac and non-cardiac comorbid conditions), perioperative (associated procedures, cross-clamp and cardiopulmonary bypass time) and postoperative 30-day adverse events (bleeding, thromboembolism, heart failure, conduction defects, arrhythmias, delirium, renal and pulmonary complications) were investigated for their effect on the occurrence of dementia by univariate analyses. Significant factors were entered in a multivariate analysis. The sum of the individual follow-up of the patients was 10,182 patient-years, with a mean follow-up of 6.8 years. Data for the development of dementia could be obtained in 1233 of the 1406 patients who left the hospital alive. Dementia during long-term follow-up developed in 216/1233 (17.2%) of the patients at 70 ± 37 months. Development of dementia reduced the mean survival from 123 (119-128) to 109 (102-116) months (p < 0.001). Postoperative delirium was the dominant predictor (OR = 3.55 with a 95%CI of 2.41-4.93; p < 0.00), followed by age > 80 years (2.38; 1.78-3.18; p < 0.001); preoperative atrial fibrillation (1.47; 1.07-2.01; p = 0.018); cardiopulmonary bypass time > 120 min (1.34; 1.02-1.78; p = 0.039) and postoperative thromboembolism (1.94; 1.02-3.70; p = 0.044). Postoperative delirium, as a marker for poor condition, and an age of 80 or more were the dominant predictors.

Optimization of biological heart valve prosthesis "UniLine": new tools for improving function

According to various estimates, more than 9,000 artificial heart valve implants were performed in specialized medical centers in Russian Federation in 2020 19.1 % of these implants were based on animal tissues. Such devices have high biocompatibility, but after 10–15 years from one third to one half require reoperation due to the development of various dysfunctions. Despite the advantages of biological prosthetic heart valves and the prevalence of their use in the clinic, there is a need for their optimization and refinement to improve postoperative hemodynamics and increase life spin. In this work, we applied an improved method to create the geometry of a leaflets and its evaluation to the commercial prosthesis «UniLine» (Kemerovo, CJSC «NeoKor») 23 standard sizes. An approach is demonstrated that includes a screening study of a large number of geometries (N = 6766) and detailed modeling (N = 4) of selected designs as part of the final product, taking into account interaction with the composite frame. The results obtained demonstrate the ability of the proposed method to optimize existing commercial models of prosthetic heart valves. An expanded set of construction parameters allowed us to select a design with peak maximum principal stresses of 1.89 and 0.68 MPa, as well as providing an open area of 233.08 and 267.34 mm2 with a maximum possible 314 mm2 for detailed and screening studies, respectively. At the same time, the area of the lumen in the diastolic phase in the prosthesis does not exceed 0.4 mm2 for the models shown. The presented results show the possibility of the method to create and evaluate "optimal" designs of flap devices according to a number of critical metrics for ensuring better hemo- and biomechanics – stresses occurring during the cardiac cycle, the presence of a twisting effect in the diastolic phase, as well as the ability to ensure maximum orifice area and locking quality.

Comparative assessment of the effectiveness of mechanical and biological heart valve prostheses in reverse remodeling of the left ventricle after aortic valve surgery (propensity score matching analysis and clinical-experimental comparison)

Comparative assessment of the effectiveness of mechanical and biological heart valve prostheses in reverse remodeling of the left ventricle after aortic valve surgery (propensity score matching analysis and clinical-experimental comparison)

Preservation of Mechanical and Morphological Properties of Porcine Cardiac Outflow Vessels after Decellularization and Wet Storage.

Widely used storage methods, including freezing or chemical modification, preserve the sterility of biological tissues but degrade the mechanical properties of materials used to make heart valve prostheses. Therefore, wet storage remains the most optimal option for biomaterials. Three biocidal solutions (an antibiotic mixture, an octanediol-phenoxyethanol complex solution, and a glycerol-ethanol mixture) were studied for the storage of native and decellularized porcine aorta and pulmonary trunk. Subsequent mechanical testing and microstructural analysis showed a slight increase in the tensile strength of native and decellularized aorta in the longitudinal direction. Pulmonary trunk elongation increased 1.3-1.6 times in the longitudinal direction after decellularization only. The microstructures of the tested specimens showed no differences before and after wet storage. Thus, two months of wet storage of native and decellularized porcine aorta and pulmonary trunks does not significantly affect the strength and elastic properties of the material. The wet storage protocol using alcohol solutions of glycerol or octanediol-phenoxyethanol mixture may be intended for further fabrication of extracellular matrix for tissue-engineered biological heart valve prostheses.

Impact of PPAR-gamma activation on the durability of biological heart valve prostheses in hypercholesterolaemic rats.

Hypercholesterolaemia and obesity are risk factors for the development of calcified aortic valve disease and common comorbidities in respective patients. Peroxisome proliferator-activated receptor gamma activation has been shown to reduce the progression of native aortic valve sclerosis, while its effect on bioprosthetic valve degeneration is yet unknown. This project aims to analyse the impact of pioglitazone, a peroxisome proliferator-activated receptor gamma agonist, on the degeneration of biological aortic valve conduits in an implantation model in obese and hypercholesterolaemic rats. Cryopreserved allogenic rat aortic valve conduits (n = 40) were infrarenally implanted into Wistar rats on high-fat (34.6%) diet. One cohort was treated with pioglitazone (75 mg/kg chow; n = 20, group PIO) and compared to untreated rats (n = 20, group control). After 4 or 12 weeks, conduits were explanted and analysed by (immuno-)histology and real-time polymerase chain reaction. A significantly decreased intima hyperplasia occurred in group PIO compared to control after 4 (P = 0.014) and 12 weeks (P = 0.045). Calcification of the intima was significantly decreased in PIO versus control at 12 weeks (P = 0.0001). No significant inter-group differences were shown for media calcification after 4 and 12 weeks. Echocardiographically, significantly lower regurgitation through the implanted aortic valve conduit was observed in PIO compared to control after 4 (P = 0.018) and 12 weeks (P = 0.0004). Inflammatory activity was comparable between both groups. Systemic peroxisome proliferator-activated receptor gamma activation decreases intima hyperplasia and subsequent intima calcification of cryopreserved allografts in obese, hypercholesterolaemic recipients. Additionally, it seems to inhibit functional impairment of the implanted aortic valve. Further preclinical studies are required to determine the long-term impact of peroxisome proliferator-activated receptor gamma agonists on graft durability.

Two approaches-one phenomenon-thrombocytopenia after surgical and transcatheter aortic valve replacement.

Postoperative thrombocytopenia after surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR) and aggravating causes were the aim of this retrospective study. Data of all patients treated with SAVR (n = 1068) and TAVR (n = 816) due to severe aortic valve stenosis was collected at our center from 2010 to 2017. Preprocedural and postprocedural values were collected from electronic patient records. There was a significant drop in platelets in both groups, the TAVR group showed overall superior platelet preservation compared to the AVR group (P < .001). In the SAVR subgroup analysis, a significant difference in platelet preservation was observed between the valve types (P < .001), particularly with the Freedom SOLO valve. In the TAVR subgroup analysis, the valve type did not influence platelet count (PLT) reduction (P = .13). In the SAVR subgroup analyses, PLT was found to be worsened with cardiopulmonary bypass (CPB) duration. Thrombocytopenia frequently occurs after implantation of a biological heart valve prosthesis, with a higher frequency observed in patients after cardiac surgery rather than TAVR. Although some surgical bioprosthetic models are more susceptible to this phenomenon, CPB duration seems to be a major determinant for the development of postoperative thrombocytopenia.

The relation of structural valve deterioration to adverse remodelling and outcome in patients with biological heart valve prostheses.

Native valve aortic stenosis is associated with adverse remodelling of the left ventricle and remodelling is stopped or even reversed with aortic valve replacement (AVR). However, the degeneration of bioprostheses and development of structural valve deterioration (SVD) may affect this. To assess the association with SVD, remodelling and outcome 451 patients from a single surgical centre who had undergone AVR with a Mitroflow pericardial bioprosthesis were studied. All patients were assessed in 2014 and a subgroup of patients (N = 327) were re-exanimated again after at least 18 months [median time of 27 (interquartile range, IQR 26-33) months] including echocardiography, measurements of N-terminal pro-brain natriuretic peptide, and assessment of functional status. SVD was based on echocardiography. Moderate SVD was present in 63 patients (14%) and severe SVD in 19 (4%), in the subgroup with follow-up echocardiography 48 patients (15%) patients had moderate to severe SVD at first examination. Patients with SVD had significantly greater increase in left ventricular (LV) mass index [21.6 g/m2 (IQR 5.7-48.3 g/m2) vs. 9.1 g/m2 (-8.6 to 27.3 g/m2), P = 0.01]. Further, patients with SVD had lower LV ejection fraction [55% (IQR 51-62%) vs. 60% (IQR 54-63%), P = 0.01] at follow-up. During follow-up, 94 patients (21%) met the composite endpoint of death or reoperation due to SVD and 41 patient readmitted for heart failure. In multivariable Cox regression analysis, severe SVD [hazard ratio (HR) 2.64 (1.37-5.07), P = 0.004] was associated with composite endpoint, and readmission for heart failure [HR 3.82 (1.53-9.51), P = 0.004]. SVD in aortic bioprostheses is associated with adverse LV remodelling and adverse outcome.

Calcification Assessment of Bioprosthetic Heart Valve Tissues Using an Improved In Vitro Model.

Calcification is a recurrent problem in patients suffering from heart valve disease and it is the main cause of failure in biological heart valve prostheses. The development of reliable calcification tests that consider both the material properties of the prostheses and the fluid composition is of paramount importance for the effective testing and subsequent selection of new cardiovascular implants. In this article, a fast, reliable, and highly reproducible method for the assessment of the calcification potential of biomaterials was developed. The developed method simulated closely the chemical environment invivo, where the supersaturation levels of calcium and phosphate remain constant. Seeded hydroxyapatite (HAP) crystal growth experiments were used as the reference system and compared to the mineralization kinetics and extent of frozen untreated bovine and porcine pericardium, and glutaraldehyde-fixed bovine pericardium. Untreated pericardial patches did not calcify in the supersaturated calcium phosphate solutions whereas glutaraldehyde-fixed bovine pericardial patches mineralized at the same conditions. The present work suggested that the loose collagenous serosa side of the pericardium mineralized at lower rates compared to its dense collagenous fibrous side. Concordant with these findings, the mineralization of bioprostheses may also be attributed, to the structural deterioration of collagen-rich tissues, induced by chemical treatment used to control in vivo structural stability and immunomodulation of the implants.

The Use of Biological Heart Valves.

Biological heart-valve prostheses have undergone continuous devel- opment up to the present, and technological advances have been made in catheter- assisted valve systems (transcatheter aortic valve implantation, TAVI) and minimally invasive routes of application. These parallel trends have led to major changes in therapeutic strategies, widening the spectrum of patients who are candidates for biological aortic valve implantation. This review is based on pertinent publications retrieved by a systematic search in PubMed employing the search terms "conventional biological aortic pros- thesis," "rapid deployment prosthesis," and "transcatheter aortic valve implantation/ replacement." Among biological heart-valve prostheses, a distinction is drawn between stented (conventional, rapid-deployment, and catheter-assisted) and non-stented types. The long-term durability of conventional, surgically implantable biological valve protheses is by far the best documented: the reported 5-year reoperation rates range from 13.4% to 36.6%, and the pacemaker implantation rate is ca. 4%. Rapid-deployment prostheses combine the advantages of conventional and ca- theter-assisted techniques and facilitate minimally invasive approaches. The TAVI method is currently recommended for high- and intermediate-risk patients, while conventional valve replacement remains the method of choice for those at low risk. Rapid-deployment and TAVI prostheses is associated with a higher pacemaker im- plantation rate than conventional prostheses: these rates are 8.5-15.3% for TAVI and 6.0-8.8% for rapid-deployment valves. The intermediate-term durability of catheter-assisted and rapid-deployment prostheses appears promising, but their long-term durability is still unclear. The further development of biological heart-valve prostheses in the form of improved conventional, transcatheter, and rapid-deployment prostheses now enables individualized treatment. Before any such procedure is performed, the car- diac team must assess the patient's risk profile and the advantages and disadvan- tages of each type of prosthesis to determine which is best.

Structural and mechanical characteristics of collagen tissue coated with chitosan in a liquid CO2/water system at different pressures

Chitosan coatings of biological heart-valve prostheses enhance their biocompatibility, resistance to pathogenic microflora and lifetime. Collagen tissues can be coated with chitosan in aqueous solution acidified, to make chitosan soluble, with H2CO3 formed from a coexisting liquid CO2 phase under pressure. The advantage of H2CO3 is that it can be easily removed after the coating procedure. This study assessed the effects of 6–50 MPa CO2 pressure during the coating procedure on the structure and mechanical properties of the resulting biocomposite matrices. The dependence of chitosan adsorption on CO2 pressure was bell-shaped, reaching a maximum adsorption of 0.8 mass % at 40 MPa. Tissue surface became highly porous upon pressure treatment. At 50 MPa, the pores merged to form furrows with lengths of several hundred micrometers, accompanied by collagen fibril reorganisation. Chitosan coating did not affect tissue tensile strength in the axial direction, but increased it by 75% in the radial direction in the tissue coated at 50 MPa pressure. Strain at break, a measure of elasticity, increased in both directions by up to 100% upon coating with chitosan. CO2 pressure of 30–50 MPa seems thus optimal in terms of chitosan incorporation and tissue mechanical properties.

A novel trileaflet mechanical heart valve: first in vitro results.

Heart valve prostheses are the therapy of choice for patients with severe heart valve diseases. Two types of prostheses that can be implanted in patients are available: biological and mechanical. Though mechanical heart valves have some disadvantages like necessity of life-long anticoagulation, biological heart valve prostheses often necessitate reinterventions due to limited durability. Therefore, a new trileaflet mechanical heart valve was developed, featuring hinges in the systolic flow with the aim of function and thrombogenicity. We first compared the new trileaflet mechanical heart valve to conventional bileaflet heart valves (St. Jude Medical and On-X valves) in vitro. Haemodynamic measurements were performed in a pulse duplicator system, and clot formation was examined with an implemented method using enzyme-activated milk as the test medium. Haemodynamic measurements showed the largest effective orifice areas and smallest pressure gradients for the trileaflet prosthesis compared to the bileaflet valve. Opening and closing characteristics of the trileaflet valve and of the St. Jude Medical valve were comparable. Clotting tests depicted only minor isolated deposits for the new trileaflet valve whereas the bileaflet valves showed distinct clots in the area of the hinge in all experiments. Haemodynamic and clotting tests showed improvements for the new trileaflet valve compared to common bileaflet valves. The off-wall systolic position of the hinges, which eluded adverse flow areas, was a major advantage of the new valve.

Cell typing of biological heart valves prosthesis explanated due to the development of calcium-associated dysfunctions

Purpose. To perform immunohistochemical typing of cells obtained from calcinated biological heart valve prosthesis removed during reoperations. Materials and methods. We investigated 19 models (“KemCor” and “PeriCor”) of biological heart valve prosthesis produced by NeoCor Company (Kemerovo, Russia) and removed from the mitral position due to the development of primary tissue inconsistency with calcification. The following markers were used for immunohistochemical cells typing in the analyzed samples: CD3 (T-lymphocytes), CD20 (B-lymphocytes), CD34 and VEGFR2 (endotheliocytes), CD68 (monocytes/macrophages), vimentin (fibroblasts), and α-smooth muscle actin (smooth myocytes). Results. Uneven distribution and wide variety of intercellular interactions, as well as contacts with matrix components and mineral deposits, were observed. In case of endotheliocytes (CD34 and VEGFR2 positive cells) two types of localization were described. In the first variant, they formed a monolayer on the surface of biological prosthesis flaps; in the second variant, they were a part of capillary-like structures in the surface of the xenomaterial. CD68 positive cells were found both in a surface and in deep layers of the samples. Near such cells fragmentation and stratification of collagen fibers with the formation of fine-fibrous cellular networks were detected. Vimentin-positive cells (fibroblasts) were located in groups or singly in the sites of destruction of the connective tissue and took part in the formation of a new matrix. The density of α-smooth muscle actin-positive cells, morphologically identical to myocytes, was high in the surface of biological prosthesis flaps and low in the deeper layers. CD3 and CD20 positive cells related to T- and B-lymphocytes, respectively, were represented by the single cells in most of analyzed samples. Conclusions. Maintaining of the structural and functional integrity of biological heart valve prosthesis, in addition to the characteristics of the implantable devices, defines a complex of recipient factors, including not only mechanical damage during operation, but also various immune and cellular mechanisms.

Modification of the Collagen Tissue of the Bioprothesis of Heart Valves in a Solution of Carbonic Acid: Effect of Pressure on Adsorption of Chitosan and the Structure of the Tissue

For the first time the influence of pressure of chitosan solutions in carbonic acid on the adsorption of chitosan onto a collagen tissue of biological heart-valve prostheses and on the structure of the resulting biocomposite was studied. It turned out that the dependence of an amount of the chitosan adsorbed onto the collagen tissue has bell-shaped form reaching a maximum adsorption of about 0.8 weight. % at 30-40 MPa and then falling to 0.3 wt. % with further pressure increase up to 50 MPa. It was found that this treatment leads to a significant change of the morphology of the tissue surface which depends on the pressure in the system. It was also revealed that under pressure growth collagen fibrils are compacted in the tissue bulk which leads to the extrusion of the polymer embedded in the collagen matrix.

LONG-TERM RESULTS OF MITRAL AND AORTIC VALVE REPLACEMENT WITH XENOPERICARDIAL PROSTHESIS «BIOLAB»

Background Heart valve replacement with mechanical prostheses in elderly patients is associated with increased risk of bleeding due to the need of lifelong indirect anticoagulant therapy. Therefore, biological heart valve prosthesis is an option of choice. Aim To estimate long-term results of aortic and mitral valve replacement with xenopericardial prosthesis «BioLAB». Methods 150 stented biological prostheses «BioLAB» were implanted into the aortic and mitral position in the Department of Emergency Surgery for Acquired Heart Disease in the period from January 1993 to December 2008. 50 stentless biological prostheses «BioLAB» were implanted in the aortic position in the period from January 2008 to December 2012. Results 1-, 5- and 10-years survival in the recipients of stented xenopericardial prostheses «BioLAB» implanted in aortic position was 91.1±2.9%, 85.3±6.1% and 85.3±6.1%, respectively. 5-, 10- and 15-years survival among those who received mitral valve replacement was 72.31%±5.56%, 55.18%±6.61%, and 22.77%±12.13%, respectively. There were no cases of redo surgeries for valve tissue degeneration among the recipients of stented and stentless aortic valve prostheses within the follow-up. 10-, 12- and 15-years freedom from mitral valve degeneration was 61.08±7.32%, 50.21±9.56%, and 43.6±10.65%. Conclusion Stented xenopericardial bioprostheses «BioLAB» implanted in the aortic position provide good and encouraging hemodynamic results in the long-term period time. There were no signs of tissue degeneration of the stented heart valves within the 10-years follow-up. Similar results were obtained for the stentless bioprosthesis within the 7-years follow-up. The period of 8.5 years after mitral valve replacement with «BioLAB» is critical for tissue degeneration of bioprosthesis.

Biological versus mechanical heart valve prosthesis during pregnancy in women with congenital heart disease

BackgroundWe evaluate pregnancy outcome and anticoagulation regimes in women with mechanical and biological prosthetic heart valves (PHV) for congenital heart disease. MethodsRetrospective multicenter cohort studying pregnancy outcomes in an existing cohort of patients with PHV. Results52 women had 102 pregnancies of which 78 pregnancies (46 women) ≥20 weeks duration (59 biological, 19 mechanical PHV). Miscarriages (n = 19, ≤20 weeks) occurred more frequently in women using anticoagulation (P < .05). During 42% of pregnancies of women with mechanical PHV a combined low molecular weight heparin (LMWH) vitamin-K-antagonist anticoagulation regime was used (n = 8). Overall, cardiovascular, obstetric and fetal/neonatal complications occurred in 17% (n = 13), 68% (n = 42) and 42% (n = 27) of the pregnancies. Women with mechanical PHV had significantly higher cardiovascular (12% vs 32%, P < .05), obstetric (59% vs 85%, P = .02) and fetal/neonatal (34% vs 61%, P < .05) complication rates than women with biological PHV. This was related to PHV thrombosis (n = 3, P < .02), post-partum hemorrhage (P < .02), cesarean section (P < .02), low birth weight and small for gestational age (both P < .05). PHV thrombosis occurred in 3 pregnancies, including 2/5 pregnancies with pulmonary mechanical PHV. PHV thrombosis was related to necessary cessation of anticoagulation therapy or insufficient monitoring of LMWH. Other cardiovascular complications occurred equally frequent in both groups. ConclusionComplications occur more often in pregnancies of women with a mechanical PHV than in women with a biological PHV, mainly caused by PHV thrombosis and bleeding complications. Meticulous monitoring of anticoagulation in pregnant women is necessary. Women with a pulmonary mechanical PHV are at high risk of complications.

PROGNOSTIC VALUE OF DIMENSIONLESS INDEX IN PATIENTS WITH BIOLOGICAL HEART VALVE PROSTHESES

Echocardiographic assessment of structural and functional integrity of valve prostheses is essential in follow-up of patients after aortic valve surgery in order to detect indicators of adverse outcomes. A 2-year prospective follow-up study was performed on a cohort of patients with a Mitroflow (n=

Structural valve deterioration in the Mitroflow biological heart valve prosthesis.

Concern has been raised regarding the long-term durability of the Mitroflow biological heart valve prosthesis. Our aim was to assess the incidence of structural valve degeneration (SVD) for the Mitroflow bioprosthesis in a nationwide study in Denmark including all patients alive in Denmark who had received a Mitroflow aortic bioprosthesis since 2000. Patients alive in Denmark with a Mitroflow bioprosthesis implanted since January 2000 were invited to participate in a nationwide cross-sectional study with a predefined definition of SVD. Of 1552 patients, 861 patients had died and 47 patients had been reoperated with 40 reoperations due to SVD. The remaining 644 patients were invited for evaluation; 574 patients accepted and were evaluated for SVD. The incidence of SVD was calculated using competing risk regression analysis with death as the competing event. A total of 173 patients were diagnosed with SVD by echocardiography. Of these, 64 (11%) patients had severe SVD and 109 (19%) patients moderate SVD. Severe SVD was associated with the age of the prosthesis and small prosthesis size [Size 21: hazard ratio (95% confidence interval, CI) 2.72 (0.97-8.56), P = 0.06; Size 19: 6.26 (1.63-24.06), P = 0.008]. The cumulative incidences of reoperation or severe SVD at Year 9 were 12.5% for Size 19, 7.6% for Size 21 and 3.1 (1.2-6.4)% for Size 23. Median survival in patients with prosthesis Sizes 23-29 was 6.4 (95% CI 5.7-7.0) years, with Size 21 it was 6.5 (95% CI 5.9-7.1) years and with Size 19 it was 6.9 (95% CI 5.7-8.2) years (P = 0.78). The incidence of undetected severe SVD was as high as the incidence of operated SVD. The overall risk for SVD is high for the Mitroflow bioprosthesis, especially if the prosthesis is small and older than 5 years.

Effects of Nanosize Coatings Consisting of Two-Dimensionally Ordered Linear Chain Carbon on the Microbial Colonization of Bioprostheses

Creation of nanosize coatings from two-dimensionally ordered linear chain carbon (TDOLCC) on the surfaces of biological heart valve prostheses had no significant influence on the adhesion of clinical strains of microorganisms. However, studies of the viability of test cultures on modified biotissue surfaces showed that adherent staphylococcal cultures did not retain viability, with the exception of Staphylococcus saprophyticus. Viability results for Gram-negative cultures varied: from the absence of growth in the case of Klebsiella pneumoniae on biotissues with TDOLCC to continuous growth of strains of Pseudomonas aeruginosa and Acetinobacter baumannii on the same surfaces. Doping of TDOLCC coatings with nitrogen prevented test culture adhesion and colonization (except for Candida albicans) after artificial inoculation of modified bioprostheses with clinical strains of microorganism

Rationale and Design of a Phase IIb/III Open-Label, Multicenter Study of Dabigatran Etexilate for Venous Thromboembolism in Children: The Diversity Study

BackgroundVenous thromboembolism (VTE) is increasing in children. The current standard of care comprises unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) for at least 5 days followed by UFH, LMWH or Vitamin K antagonists (VKA) for approximately 3 months in general. All of the current options have limitations: UFH and LMWH require parenteral administration; VKA requires frequent international normalized ratio (INR) monitoring and is associated with multiple food and drug interactions. The direct thrombin inhibitor, dabigatran, which is orally administered as the prodrug, dabigatran etexilate (DE) is effective for the treatment of VTE in adults and may overcome some of the limitations associated with standard of care.ObjectiveTo describe the design of a study evaluating the appropriateness of a proposed DE dosing algorithm and assessing the safety and efficacy of DE versus standard of care in pediatric patients with VTE.MethodsThis open-label, randomized, parallel-group, active-controlled, multi-center, non-inferiority study (NCT01895777) will be conducted in approximately 100 sites in approximately 30 countries. Patients aged 0 to < 18 years with an imaging-confirmed diagnosis of VTE initially receiving parenteral treatment with UFH or LMWH for 5-7 days (but no more than 21 days) who are expected to require anticoagulation therapy for at least 3 months will be eligible for inclusion. Main exclusion criteria include conditions associated with an increased risk of bleeding, renal dysfunction, active infective endocarditis, mechanical or biological heart valve prosthesis, hepatic disease and anemia or thrombocytopenia.Patients will be stratified into three age groups: stratum 1 (12 to < 18 years), stratum 2 (2 to < 12 years) and stratum 3 (birth to < 2 years). Recruitment will begin in stratum 1, being subsequently escalated to strata 2 and 3, respectively based on recommendations from the Data Monitoring Committee.Patients will be randomized (2:1) to receive DE versus standard of care (LMWH or VKA). DE will be administered twice daily as capsules, pellets or an oral liquid formulation depending on patient age and the patient's ability to swallow pellets or capsules. Upon completion of a 3-month treatment period (including the initial parenteral treatment phase) patients will be followed off-study drug for any adverse events.DE will be dosed to achieve steady-state measured trough circulating plasma concentrations (≥50 and < 250 ng/mL); the initial dose required will be calculated using a nomogram, which adjusts dosing according to the age and weight of the child. Dabigatran plasma concentrations will be evaluated at all study visits (7 scheduled during treatment period); DE will be up- or down-titrated as required.ResultsIn terms of efficacy, the study will evaluate the proportion of patients with complete thrombus resolution, freedom from recurrent VTE (including symptomatic and asymptomatic, contiguous progression or non-contiguous new thrombus, deep vein thrombosis, pulmonary and paradoxical embolism, and thrombus progression) and freedom from VTE-related mortality. With regards to safety, the key endpoint will be freedom from major bleeding events, as per International Society on thrombosis and Haemostasis (ISTH) pediatric-specific criteria. All components of the primary efficacy and key safety endpoints will be adjudicated by an independent blinded committee.ConclusionThis study, one of the largest controlled pediatric studies for VTE, will provide data on the safety and efficacy of DE compared with standard of care for the treatment of VTE in children aged 0 to < 18 years. DisclosuresAlbisetti:Boehringer Ingelheim: Other: Pediatric Expert Working Group. Manastirski:Boehringer Ingelheim: Employment. Brueckmann:Boehringer Ingelheim: Employment. Gropper:Boehringer Ingelheim: Employment. Wang:Boehringer Ingelheim: Employment. Tartakovsky:Boehringer Ingelheim: Employment. Biss:Boehringer Ingelheim: Employment. Huang:Boehringer Ingelheim: Employment. Mitchell:Boehringer Ingelheim: Consultancy; Pfizer: Consultancy; Bristol Myers Squibb: Consultancy. Halton:Boehringer Ingelheim: Other: Pediatric Expert Working Group for Boehringer Ingelheim.