One-year follow-up after active aortic aneurysm sac treatment with shape memory polymer devices during endovascular aneurysm repair.

OBJECTIVE: To determine the safety and efficacy of treating abdominal aortic aneurysm (AAA) sacs with polyurethane shape memory polymer (SMP) devices during endovascular aneurysm repair (EVAR), using a technique to fully treat the target lumen after endograft placement (aortic flow volume minus the endograft volume). SMP devices self-expand in the sac to form a porous scaffold that supports thrombosis throughout its structure. METHODS: Two identical prospective, multicenter, single-arm studies were conducted in New Zealand and the Netherlands. The study population was adult candidates for elective EVAR of an infrarenal AAA (diameter of ≥55 mm in men and ≥50 mm in women). Key exclusion criteria were an inability to adequately seal a common iliac artery aneurysm, patent sac feeding vessels of >4 mm, and a target lumen volume of <20 mL or >135 mL. Target lumen volumes were estimated by subtracting endograft volumes from preprocedural imaging-based flow lumen volumes. SMP devices were delivered immediately after endograft deployment via a 6F sheath jailed in a bowed position in the sac. The primary efficacy end point was technical success, defined as filling the actual target lumen volume with fully expanded SMP at the completion of the procedure. Secondary efficacy outcome measures during follow-up were the change in sac volume and diameter, rate of type II endoleak and type I or III endoleaks, and the rate of open repair and related reinterventions, with data collection at 30 days, 6 months, and 1 year (to date). Baseline sac volumes and diameters for change in sac size analyses were determined from 30-day imaging studies. Baseline and follow-up volumes were normalized by subtraction of the endograft volume. RESULTS: Of 34 patients treated with SMP devices and followed per protocol, 33 patients were evaluable at 1 year. Preprocedural aneurysm volume was 181.4 mL (95% confidence interval [CI], 150.7-212.1 mL) and preprocedural aneurysm diameter was 60.8 mm (95% CI, 57.8-63.9 mm). The target lumen volume was 56.3 mL (95% CI, 46.9-65.8 mL). Technical success was 100% and the ratio of SMP fully expanded volume to estimated target lumen volume was 1.4 ± 0.3. Baseline normalized sac volume and diameter were 140.7 mL (95% CI, 126.6-154.9 mL) and 61.0 mm (95% CI, 59.7-62.3 mm). The adjusted mean percentage change in normalized volume at 1 year was -28.8% (95% CI, -35.3 to -22.3%; P < .001). The adjusted mean change in sac diameter at 1 year was -5.9 mm (95% CI, -7.5 to -4.4 mm; P < .001). At 1 year, 81.8% of patients (95% CI, 64.5%-93.0%) achieved a ≥10% decrease in normalized volume and 57.6% of patients (95% CI, 39.2%-74.5%) achieved a ≥5 mm decrease in diameter. No device- or study procedure-related major adverse events occurred through 1 year after the procedure. CONCLUSIONS: Treatment of AAA sacs with SMP devices during EVAR resulted in significant sac volume and diameter regression at 1 year with an acceptable safety profile in this prospective study.

Hysterosalpingo-foam sonography versus hysterosalpingography during fertility work-up: an economic evaluation alongside a randomized controlled trial.

STUDY QUESTION: What are the costs and effects of tubal patency testing by hysterosalpingo-foam sonography (HyFoSy) compared to hysterosalpingography (HSG) in infertile women during the fertility work-up? SUMMARY ANSWER: During the fertility work-up, clinical management based on the test results of HyFoSy leads to slightly lower, though not statistically significant, live birth rates, at lower costs, compared to management based on HSG results. WHAT IS KNOWN ALREADY: Traditionally, tubal patency testing during the fertility work-up is performed by HSG. The FOAM trial, formally a non-inferiority study, showed that management decisions based on the results of HyFoSy resulted in a comparable live birth rate at 12 months compared to HSG (46% versus 47%; difference -1.2%, 95% CI: -3.4% to 1.5%; P = 0.27). Compared to HSG, HyFoSy is associated with significantly less pain, it lacks ionizing radiation and exposure to iodinated contrast medium. Moreover, HyFoSy can be performed by a gynaecologist during a one-stop fertility work-up. To our knowledge, the costs of both strategies have never been compared. STUDY DESIGN, SIZE, DURATION: We performed an economic evaluation alongside the FOAM trial, a randomized multicenter study conducted in the Netherlands. Participating infertile women underwent, both HyFoSy and HSG, in a randomized order. The results of both tests were compared and women with discordant test results were randomly allocated to management based on the results of one of the tests. The follow-up period was twelve months. PARTICIPANTS/MATERIALS, SETTING, METHODS: We studied 1160 infertile women (18-41 years) scheduled for tubal patency testing. The primary outcome was ongoing pregnancy leading to live birth. The economic evaluation compared costs and effects of management based on either test within 12 months. We calculated incremental cost-effectiveness ratios (ICERs): the difference in total costs and chance of live birth. Data were analyzed using the intention to treat principle. MAIN RESULTS AND THE ROLE OF CHANCE: Between May 2015 and January 2019, 1026 of the 1160 women underwent both tubal tests and had data available: 747 women with concordant results (48% live births), 136 with inconclusive results (40% live births), and 143 with discordant results (41% had a live birth after management based on HyFoSy results versus 49% with live birth after management based on HSG results). When comparing the two strategies-management based on HyfoSy results versus HSG results-the estimated chance of live birth was 46% after HyFoSy versus 47% after HSG (difference -1.2%; 95% CI: -3.4% to 1.5%). For the procedures itself, HyFoSy cost €136 and HSG €280. When costs of additional fertility treatments were incorporated, the mean total costs per couple were €3307 for the HyFoSy strategy and €3427 for the HSG strategy (mean difference €-119; 95% CI: €-125 to €-114). So, while HyFoSy led to lower costs per couple, live birth rates were also slightly lower. The ICER was €10 042, meaning that by using HyFoSy instead of HSG we would save €10 042 per each additional live birth lost. LIMITATIONS, REASONS FOR CAUTION: When interpreting the results of this study, it needs to be considered that there was a considerable uncertainty around the ICER, and that the direct fertility enhancing effect of both tubal patency tests was not incorporated as women underwent both tubal patency tests in this study. WIDER IMPLICATION OF THE FINDINGS: Compared to clinical management based on HSG results, management guided by HyFoSy leads to slightly lower live birth rates (though not statistically significant) at lower costs, less pain, without ionizing radiation and iodinated contrast exposure. Further research on the comparison of the direct fertility-enhancing effect of both tubal patency tests is needed. STUDY FUNDING/COMPETING INTEREST(S): FOAM trial was an investigator-initiated study, funded by ZonMw, a Dutch organization for Health Research and Development (project number 837001504). IQ Medical Ventures provided the ExEm®-FOAM kits free of charge. The funders had no role in study design, collection, analysis, and interpretation of the data. K.D. reports travel-and speakers fees from Guerbet and her department received research grants from Guerbet outside the submitted work. H.R.V. received consulting-and travel fee from Ferring. A.M.v.P. reports received consulting fee from DEKRA and fee for an expert meeting from Ferring, both outside the submitted work. C.H.d.K. received travel fee from Merck. F.J.M.B. received a grant from Merck and speakers fee from Besins Healthcare. F.J.M.B. is a member of the advisory board of Merck and Ferring. J.v.D. reported speakers fee from Ferring. J.S. reports a research agreement with Takeda and consultancy for Sanofi on MR of motility outside the submitted work. M.v.W. received a travel grant from Oxford Press in the role of deputy editor for Human Reproduction and participates in a DSMB as independent methodologist in obstetrics studies in which she has no other role. B.W.M. received an investigator grant from NHMRC GNT1176437. B.W.M. reports consultancy for ObsEva, Merck, Guerbet, iGenomix, and Merck KGaA and travel support from Merck KGaA. V.M. received research grants from Guerbet, Merck, and Ferring and travel and speakers fees from Guerbet. The other authors do not report conflicts of interest. TRIAL REGISTRATION NUMBER: International Clinical Trials Registry Platform No. NTR4746.

Clinical Outcomes of 5000 IU Heparin Versus Activated Clotting Time-Guided Heparinization During Noncardiac Arterial Procedures: A Propensity Score Matched Analysis.

PURPOSE: Previous studies have shown that activated clotting time (ACT)-guided heparinization leads to better anticoagulation levels during noncardiac arterial procedures (NCAP) than a standardized bolus of 5000 IU. Better anticoagulation should potentially result in lower incidence of thrombo-embolic complications (TEC). Comparative investigations on clinical outcomes of these heparinization strategies are scarce. This study investigated clinical outcomes of ACT-guided heparinization with a starting dose of 100 IU/kg in comparison with a single standardized bolus of 5000 IU heparin during NCAP. MATERIALS AND METHODS: Analysis from a prospectively collected database of patients undergoing NCAP in 2 vascular centers was performed. Patients receiving ACT-guided heparinization were matched 1:1 with patients receiving 5000 IU heparin using propensity score matching (PSM). Primary outcomes were TEC, bleeding complications, and mortality within 30 days of procedure or during the same admission. RESULTS: A total of 759 patients (5000 IU heparin: 213 patients, ACT-guided heparinization: 546 patients) were included. Propensity score matching resulted in 209 patients in each treatment group. After PSM, the groups were comparable, with the exception of a higher prevalence of peripheral arterial disease in the ACT-guided heparinization group (103 patients, 49% vs 82 patients, 39%, p=0.039). The target ACT (>200 seconds) was reached in 198 patients (95%) of the ACT-guided group versus 71 patients (34%) of the 5000 IU group (p<0.001), indicating successful execution of the ACT-guided protocol. Incidence of TEC (13 patients, 6.2% vs 10 patients, 4.8%, p=0.52), mortality (3 patients, 1.4% vs 0 patients, p=0.25), and bleeding complications (32 patients, 15% vs 25 patients, 12%, p=0.32) did not differ between patients receiving ACT-guided heparinization and 5000 IU heparin. Protamine was administered in 118 patients (57%) in the ACT group versus 11 patients (5.3%) in the 5000 IU group (p<0.001), but did not influence incidence of TEC (17 patients, 5.9% vs 6 patients, 4.7%, p=0.61) or bleeding complications (34 patients, 12% vs 22 patients, 17%, p=0.14). CONCLUSION: No difference in TEC, bleeding complications, or mortality was found between ACT-guided heparinization and a single bolus of 5000 IU heparin during NCAP. CLINICAL IMPACT: Previous studies have shown that activated clotting time (ACT)-guided heparinization leads to better anticoagulation levels during non-cardiac arterial procedures (NCAP) then a standardized bolus of 5000 IU. Comparative investigations on clinical outcomes are scarce. This study focussed on clinical outcomes of both protocols in NCAP in a propensity score matched cohort. Thrombo-embolic complications (TEC), bleeding complications and mortality within 30 days after NCAP or during the same admission were comparable between groups. Future studies should focus on optimizing ACT-guided protocols, specifically in patients with a high risk of TEC and bleeding complications.

Systematic review of clinical guidelines and consensus statements concerning heparin and protamine dosing and monitoring of anticoagulation levels for non-cardiac arterial procedures.

OBJECTIVES: This systematic review was performed to examine all published practice Guidelines and Consensus Statements (together: GCS) on heparin dosing and monitoring during non-cardiac arterial procedures (NCAP). The objective was to scrutinize the recommendations and advice outlined within these GCS documents and to evaluate the supporting evidence for these recommendations. Additionally, the use of the activated clotting time (ACT) and target ACT values were explored. METHODS: This systematic review was performed in accordance with the PRISMA Guidelines. Medline and Embase databases were searched to identify all GCSs in the English language on NCAP. The final literature search was performed in January 2023. This search was supplemented by searching websites of relevant professional vascular surgical organizations for GCSs. Titles and abstracts were assessed by two independent reviewers. RESULTS: Of 9716 titles identified, 27 GCSs met the predefined inclusion criteria: six GCSs regarding carotid intervention, seven regarding procedures for aneurysmal disease of the abdominal aorta and iliac arteries, 12 regarding interventions for acute and chronic peripheral arterial occlusive disease and two regarding open and endovascular interventions of thoraco-abdominal aortic aneurysms. Administration of heparin is advised for al NCAP. There was high variability concerning heparin dose: both standard dose as weight based dosing (30-150 IU/kg) was advised. Recommendations on repeated doses, ACT monitoring and heparin reversal using protamine also varied widely. In none of the GCSs, the type of the ACT measuring device or used cartridges were specified. CONCLUSIONS: Large variability was found between the included GCSs with regard to the recommendations on heparin dose and target ACT values during NCAP. Advice and recommendations in GCSs were based on low-quality studies or without providing any reference at all. The described variability in recommendations emphasizes the need for large prospective (randomized) studies or the incorporation of data on heparin and the use of ACT monitoring into verified vascular surgery registries, to develop evidence-based, practical and uniform applicable recommendations.

Post-implantation clinical cost analysis between transcutaneous and percutaneous bone conduction devices.

INTRODUCTION: Bone conduction devices (BCD) are effective for hearing rehabilitation in patients with conductive and mixed hearing loss or single-sided deafness. Transcutaneous bone conduction devices (tBCD) seem to lead to fewer soft tissue complications than percutaneous BCDs (pBCD) but have other drawbacks such as MRI incompatibility and higher costs. Previous cost analyses have shown a cost advantage of tBCDs. The purpose of this study is to compare long-term post-implantations costs between percutaneous and transcutaneous BCDs. MATERIALS AND METHODS: Retrospective data from 77 patients implanted in a tertiary referral centre with a pBCD (n = 34), tBCD (n = 43; passive (tpasBCD; n = 34) and active (tactBCD; n = 9) and a reference group who underwent cochlear implantation (CI; n = 34), were included in a clinical cost analysis. Post-implantation costs were determined as the sum of consultation (medical and audiological) and additional (all post-operative care) costs. Median (cumulative) costs per device incurred for the different cohorts were compared at 1, 3 and 5 years after implantation. RESULTS: After 5 years, the total post-implantation costs of the pBCD vs tpasBCD were not significantly different (€1550.7 [IQR 1174.6-2797.4] vs €2266.9 [IQR 1314.1-3535.3], p = 0.185), nor was there a significant difference between pBCD vs tactBCD (€1550.7 [1174.6-2797.4] vs €1428.8 [1277.3-1760.4], p = 0.550). Additional post-implantation costs were significantly highest in the tpasBCD cohort at all moments of follow-up. CONCLUSION: Total costs related to post-operative rehabilitation and treatments are comparable between percutaneous and transcutaneous BCDs up to 5 years after implantation. Complications related to passive transcutaneous bone conduction devices appeared significantly more expensive after implantation due to more frequent explantations.

Evaluation of a super powerful bone-anchored hearing system and its users: A retrospective study.

INTRODUCTION: Although the Baha 5SP has been commercially available for six years, very few studies have been performed on the device's efficacy. The current study aims to evaluate the characteristics and audiological results in patients with severe-to-profound mixed hearing loss fitted with this superpower sound processor. METHODS: This retrospective evaluation was conducted at a tertiary referral centre where a series of 82 adult patients with severe-to-profound mixed hearing loss were implanted with a percutaneous bone-anchored hearing system and fitted with a superpower sound processor between 2016 and 2019. Patients with incomplete or unreliable audiological data (n = 24) were excluded, resulting in 58 data sets for analysis. The main outcome measures were unaided and aided pure-tone thresholds and aided free-field speech perception in quiet. RESULTS: The median unaided air conduction (AC) threshold averaged across 0.5, 1 and 2 kHz (PTA0.5-2kHz) of all patients was 75 dB hearing loss (HL); the median unaided AC averaged across 1, 2 and 4 kHz (PTA1-4kHz) was 84 dB HL. For bone conduction and direct bone conduction, the median PTA0.5-2kHz was 52 and 47 dB HL, respectively. With the superpower device, the median free-field speech reception threshold was 54 dB sound pressure level (SPL), and the median speech perception score at 65 dB SPL was 80%. CONCLUSIONS: At least 75% of the patients reached a maximum phoneme score of 70%. For patients with lower scores, the superpower device still provides a substantial hearing benefit. This makes the superpower device particularly suitable for patients with severe-to-profound mixed hearing loss with a contraindication for conventional hearing aids and/or cochlear implants.

Mycobacterium avium Complex Infections: Detailed Phenotypic and Functional Immunological Work-Up Is Required despite Genetic Analyses.

INTRODUCTION: Cervical scrofulous lymphadenitis due to Mycobacterium avium complex (MAC) in immunocompetent adults is a rare disease. The presence of MAC infections demands meticulous clinical evaluation of patients along with detailed phenotypic and functional evaluation of their immune system including next-generation sequencing (NGS) analyses of target genes. METHODS: Exact clinical histories of the index patients both suffering from retromandibular/cervical scrofulous lymphadenitis were obtained along with phenotypic and functional immunological evaluations of leukocyte populations followed by targeted NGS-based sequencing of candidate genes. RESULTS: Immunological investigations showed normal serum immunoglobulin and complement levels, but lymphopenia, which was caused by significantly reduced CD3+CD4+CD45RO+ memory T-cell and CD19+ B-cell numbers. Despite normal T-cell proliferation to a number of accessory cell-dependent and -independent stimuli, the PBMC of both patients elaborated clearly reduced levels of a number of cytokines, including IFN-γ, IL-10, IL-12p70, IL-1α, IL-1ß, and TNF-α upon TCR-dependent T-cell stimulation with CD3-coated beads but also superantigens. The IFN-γ production deficiency was confirmed for CD3+CD4+ helper and CD4+CD8+ cytotoxic T cells on the single-cell level by multiparametric flow cytometry irrespective of whether PMA/ionomycin-stimulated whole blood cells or gradient-purified PBMC was analyzed. In the female patient L1, targeted NGS-based sequencing revealed a homozygous c.110T>C mutation in the interferon-γ receptor type 1 (IFNGR1) leading to significantly reduced receptor expression on both CD14+ monocytes and CD3+ T cells. Patient S2 presented with normal IFNGR1 expression on CD14+ monocytes but significantly reduced IFNGR1 expression on CD3+ T cells, despite the absence of detectable homozygous mutations in the IFNGR1 itself or disease-related target genes. Exogenous addition of increasing doses of IFN-γ resulted in proper upregulation of high-affinity FcγRI (CD64) on monocytes from patient S2, whereas monocytes from patient L1 showed only partial induction of CD64 expression after incubation with high doses of IFN-γ. CONCLUSION: A detailed phenotypic and functional immunological examination is urgently required to determine the cause of a clinically relevant immunodeficiency, despite detailed genetic analyses.

Perprocedural Heparinization in Non-cardiac Arterial Procedures: The Current Practice in the Netherlands.

PURPOSE: Heparin is the most widely-used anticoagulant to prevent thrombo-embolic complications during non-cardiac arterial procedures (NCAP). Unfortunately, there is a lack of evidence and consequently non-uniformity in guidelines on perprocedural heparin management. Detailed insight into the current practice of antithrombotic strategies during NCAP in the Netherlands is important, aiming to identify potential optimal protocols and local differences concerning perprocedural heparinization. MATERIALS AND METHODS: A comprehensive online survey was distributed electronically to vascular surgeons of every hospital in the Netherlands in which NCAP were performed. Data were collected from September 2020 to October 2021. RESULTS: The response rate was 90% (53/59 hospitals). During NCAP, all surgeons generally administered heparin before arterial clamping. In 74% (39/54) of hospitals, a single heparin dosing protocol was used for all types of patients and vascular procedures. In 40%, there was no uniformity in heparin dosing between vascular surgeons. Depending on the procedure, a fixed bolus heparin, predominantly 5000 IU, was administered in 73% to 93%. In the remaining hospitals (7%-27%), a bodyweight-based heparin protocol was used, with an initial dose of 70 or 100 IU/kg. A minority (28%) monitored the effect of heparin in patients using the activated clotting time add (ACT) after activated clotting time. Target values varied between 180 and 250 seconds or 2 times the baseline ACT. CONCLUSION: This survey demonstrates considerable variability in perprocedural heparinization during NCAP in the Netherlands. Future research on heparin dosing is needed to harmonize and optimize heparin dosage protocols and contemporary guidelines during NCAP, and thereby improve vascular surgical care and patient safety. CLINICAL IMPACT: This survey demonstrated persisting intra- and inter-hospital variability in perprocedural heparinization during non-cardiac arterial procedures (NCAP) in the Netherlands. The observed variability in heparinization strategies highlights the need for high quality evidence on perprocedural anticoagulation strategies. This is needed in order to harmonize and optimize heparin dosage protocols and contemporary guidelines and thereby improve vascular surgical patient care. Based on the current results, an international survey will be conducted by the authors to gain additional insight into the antithrombotic strategies used during NCAP, aiming to harmonize anticoagulation protocols worldwide.

The Additional Value of Activated Clotting Time-Guided Heparinization During Interventions for Peripheral Arterial Disease.

PURPOSE: Unfractionated heparin is widely used to lower the risk of arterial thromboembolic complications (ATECs) during interventions for peripheral arterial disease (PAD), but it is still unknown which heparin dose is the safest in terms of preventing ATECs and bleeding complications. This study aims to evaluate the incidence of complications during interventions for PAD and the relation between this incidence and different heparinization protocols. MATERIALS AND METHODS: A retrospective analysis of a prospective multicenter cohort study was performed. Between June 2015 and September 2022, 355 patients who underwent peripheral interventions for PAD were included. All patients who were included before July 2018 received 5000 international units (IU) of heparin (group 1). Starting from July 2018, all included patients received an initial dose of 100 IU/kg, with potential additional heparin doses based on activated clotting time (ACT) values (group 2). Data on ACT values and complications within 30 days post-procedurally were collected. RESULTS: In total, 24 ATECs and 48 bleeding complications occurred. In group 1, 8.7% (n=11) of patients suffered from ATEC, compared with 5.7% (n=13) in group 2. Thirteen percent of patients (n=17) in group 1 had a bleeding complication, compared with 14% (n=31) in group 2. Arterial thromboembolic complications were more often found in patients with peak ACT values of <200 seconds, compared with ACT values between 200 and 250 seconds, 15% (n=6) versus 5.9% (n=9), respectively, p=0.048. Patients with peak ACT values >250 seconds had a higher incidence of bleeding complications compared with an ACT between 200 and 250 seconds, 24% (n=21) versus 9.8% (n=15), respectively, p=0.003. Forty-four percent of patients (n=23) in group 1 reached a peak ACT of >200 seconds, compared with 95% (n=218) of patients in group 2 (p=0.001). CONCLUSION: ATEC was found in 6.8% (n=24) and bleeding complications in 14% (n=48) of patients who underwent a procedure for PAD. There was a significantly higher incidence of ATECs in patients with a peak ACT value <200 seconds, and a higher incidence of bleeding complications in patients with a peak ACT value >250 seconds. The findings obtained from this study may serve as a basis for conducting future research on heparinization during procedures for PAD, with a larger sample size. CLINICAL IMPACT: Heparin is administered during arterial interventions for peripheral arterial disease (PAD) to decrease the risk of arterial (thrombo)embolic complications (ATEC) during or shortly following surgery. The effect of heparin is unpredictable in the individual patient, and the optimal dosage of this anticoagulant has not yet been established. Using the activated clotting time (ACT), the anticoagulatory effect of heparin can be monitored periprocedurally. Previous research on the incidence of both ATEC and bleeding complications, or on the optimal dosage of heparin administration, is scarce. This study aims to investigate the incidence of ATEC and bleeding complications between 2 different dosage protocols of heparin-a standard bolus of 5000 IU or ACT-guided heparinization-and thereby provide clarity on the optimal dose of heparin during peripheral arterial interventions for PAD.

The Effect of Smoking on the Activated Clotting Time and the Incidence of Complications in Noncardiac Arterial Procedures.

PURPOSE: Smoking is a well-known risk factor for developing arterial diseases and for an increase of complications during and after vascular procedures. Although smoking has a proven effect on hemostasis, no literature is available on the effect of smoking on the activated clotting time (ACT), which is used to monitor the effect of heparin during noncardiac arterial procedures (NCAP). The aim of this study was to examine the effect of smoking on ACT values and the incidence of complications during the same admission or 30 day follow-up of NCAP. MATERIALS AND METHODS: A post hoc analysis of a prospective multicenter cohort study was performed. Patients older than 18 years, who underwent NCAP between December 2016 and April 2021, were enrolled. Patients were divided into 2 groups based on smoking status: never/former smokers and current smokers. Two heparin dosing protocols were used: an initial bolus of 5000 IU or 100 IU/kg bodyweight. RESULTS: In total, 773 patients met the inclusion criteria. Five minutes after administration of 5000 IU of heparin, mean ACT values were 190 and 196 seconds for nonsmokers and smokers, respectively (p=0.078). After 100 IU/kg of heparin, mean ACT values were 229 and 226 seconds for nonsmokers and smokers, respectively (p=0.37). Incidence of complications in the whole study cohort was not significantly different for nonsmokers compared with smokers (arterial thrombo-embolic complication [ATEC] 4.7% vs 5.7% p=0.55; hemorrhagic complications 15% vs 18% p=0.29). In subgroup-analysis, a significant difference between smoking groups was found for hemorrhagic complications after open aneurysm repair (p=0.024). However, after adjusting for confounders, the difference between the smoking groups annulled. CONCLUSION: The results of this study suggest that smoking does not have a significant effect on ACT values or on the incidence of complications in NCAP. Large-scale studies are required to further analyze potential factors having an effect on the ACT and perioperative and postoperative complications, which could help individualize heparinization strategy. CLINICAL IMPACT: There is high variance between patients in their response on administration of heparin, this is not yet fully understood. This study investigated the effect of smoking in a large prospective multicentre cohort. The results suggests that active smoking does not have an effect on the activated clotting time after administration of heparin. Also no significant effect of smoking could be found on the incidence of all registered complications. Monitoring of the effect of heparin remains important to provide patients with safe anticoagulation during vascular procedures.

Major Bleeding During Thrombolytic Therapy for Acute Lower Limb Ischaemia: Value of Laboratory Tests for Clinical Decision Making, 17 Years of Experience.

OBJECTIVE: Regular measurement of fibrinogen as dose guidance in catheter directed thrombolysis (CDT) for acute limb ischaemia (ALI) has recently been dropped from European guidelines based on inconsistent literature. This study aimed to determine whether low fibrinogen levels and high activated partial thromboplastin time (APTT) are associated with an increased major bleeding risk during CDT. METHODS: All consecutive patients treated with CDT for ALI in two Dutch hospitals between January 2004 and April 2021 were analysed retrospectively. Patients were treated with two dosing regimens (low dose: 50 000 IU/hour; high dose: 100 000 IU/hour) of urokinase and, after 2018, with a single low dose regimen of alteplase (rtPA) due to urokinase manufacturing problems. The incidence of major bleeding and associated APTT and fibrinogen levels were reviewed from patient charts. RESULTS: Of the 443 included cases, 277 underwent CDT with urokinase and 166 with rtPA. The incidence of major bleeding in the whole cohort was 7%. Patients with a fibrinogen levels < 1.0 g/L developed more major bleeding than those in whom the fibrinogen level did not drop below 1.0 g/L (15% vs. 6%; p = .041). Systemic heparinisation during CDT or high (> 80 seconds) APTT were not significantly associated with major bleeding. Angiographic success (47% vs. 72%; p = .003) and 30 day amputation free survival (53% vs. 82%; p < .001) were lower for cases with major bleeding. Older age (odds ratio [OR] 1.06, 95% confidence interval [CI] 1.02 - 1.11), cardiac history (OR 3.35, 95% CI 1.39 - 8.06), high dose regimens (≥ 75 000 IU/hour urokinase; OR 2.67, 95% CI 1.18 - 6.04), and fibrinogen values < 1.0 g/L (OR 5.59, 95% CI 1.98 - 15.77) were independent predictors for major bleeding during CDT. CONCLUSION: High dose thrombolytic regimens and fibrinogen levels of ≤ 1.0 g/L are associated with more major bleeding during thrombolytic therapy. Major bleeding significantly worsened the clinical outcome. A prospective comparative study is needed to assess the benefit of monitoring fibrinogen levels.

Active monitoring versus an abduction device for treatment of infants with centered dysplastic hips: study protocol for a randomized controlled trial (TReatment with Active Monitoring (TRAM)-Trial).

BACKGROUND: Developmental Dysplasia of the Hip (DDH) is one of the most common pediatric orthopedic disorders, affecting 1-3% of all newborns. The optimal treatment of centered DDH is currently under debate. This randomized controlled trial aims to study the (cost-)effectiveness of active monitoring versus abduction treatment for infants with centered DDH. METHODS: This is a multicenter, parallel-group, open-label, non-inferiority randomized controlled trial studying the (cost-)effectiveness of active monitoring versus abduction treatment for infants with centered DDH in fourteen hospitals in the Netherlands. In total, 800 infants with centered DDH (Graf IIa-/IIb/IIc), aged 10-16 weeks, will be randomly allocated to the active monitoring or abduction treatment group. Infants will be followed up until the age of 24 months. The primary outcome is the rate of normal hips, defined as an acetabular index lower than 25 degrees on an antero-posterior radiograph, at the age of 12 months. Secondary outcomes are the rate of normal hips at the age of 24 months, complications, time to hip normalization, the relation between baseline patient characteristics and the rate of normal hips, compliance, costs, cost-effectiveness, budget impact, health-related quality of life (HRQoL) of the infant, HRQoL of the parents/caregivers, and parent/caregiver satisfaction with the treatment protocol. DISCUSSION: The outcomes of this randomized controlled trial will contribute to improving current care-as-usual for infants with centered DDH. TRIAL REGISTRATION: Dutch Trial Register, NL9714, registered September 6, 2021. https://clinicaltrialregister.nl/en/trial/29596.

Can hysterosalpingo-foam sonography replace hysterosalpingography as first-choice tubal patency test? A randomized non-inferiority trial.

STUDY QUESTION: Does hysterosalpingo-foam sonography (HyFoSy) lead to similar pregnancy outcomes, compared with hysterosalpingography (HSG), as first-choice tubal patency test in infertile couples? SUMMARY ANSWER: HyFoSy and HSG produce similar findings in a majority of patients and clinical management based on the results of either HyFoSy or HSG, leads to comparable pregnancy outcomes. HyFoSy is experienced as significantly less painful. WHAT IS KNOWN ALREADY: Traditionally, tubal patency testing during fertility work-up is performed by HSG. HyFoSy is an alternative imaging technique lacking ionizing radiation and iodinated contrast medium exposure which is less expensive than HSG. Globally, there is a shift towards the use of office-based diagnostic methods, such as HyFoSy. STUDY DESIGN, SIZE, DURATION: This multicentre, prospective, comparative study with a randomized design was conducted in 26 hospitals in The Netherlands. Participating women underwent both HyFoSy and HSG in randomized order. In case of discordant results, women were randomly allocated to either a management strategy based on HyFoSy or one based on HSG. PARTICIPANTS/MATERIALS, SETTING, METHODS: We included infertile women between 18 and 41 years old who were scheduled for tubal patency testing during their fertility work-up. Women with anovulatory cycles not responding to ovulation induction, endometriosis, severe male infertility or a known iodine contrast allergy were excluded. The primary outcome for the comparison of the HyFoSy- and HSG-based strategies was ongoing pregnancy leading to live birth within 12 months after inclusion in an intention-to-treat analysis. MAIN RESULTS AND THE ROLE OF CHANCE: Between May 2015 and January 2019, 1026 women underwent HyFoSy and HSG. HyFoSy was inconclusive in 97 of them (9.5%), HSG was inconclusive in 30 (2.9%) and both were inconclusive in 9 (0.9%). In 747 women (73%) conclusive tests results were concordant. Of the 143/1026 (14%) with discordant results, 105 were randomized to clinical management based on the results of either HyFoSy or HSG. In this group, 22 of the 54 women (41%) allocated to management based on HyFoSy and 25 of 51 women (49%) allocated to management based on HSG had an ongoing pregnancy leading to live birth (Difference -8%; 95% CI: -27% to 10%). In total, clinical management based on the results of HyFoSy was estimated to lead to a live birth in 474 of 1026 women (46%) versus 486 of 1026 (47%) for management based on HSG (Difference -1.2%; 95% CI: -3.4% to 1.5%). Given the pre-defined margin of -2%, statistically significant non-inferiority of HyFoSy relative to HSG could not be demonstrated (P = 0.27). The mean pain score for HyFoSy on the 1-10 Visual Analogue Scale (VAS) was 3.1 (SD 2.2) and the mean VAS pain score for HSG was 5.4 (SD 2.5; P for difference < 0.001). LIMITATIONS, REASONS FOR CAUTION: Since all women underwent both tubal patency tests, no conclusions on a direct therapeutic effect of tubal flushing could be drawn. WIDER IMPLICATIONS OF THE FINDINGS: HyFoSy or HSG produce similar tubal pathology findings in a majority of infertile couples and, where they differ, a difference in findings does not lead to substantial difference in pregnancy outcome, while HyFoSy is associated with significantly less pain. STUDY FUNDING/COMPETING INTEREST(S): The FOAM study was an investigator-initiated study funded by ZonMw, The Netherlands organization for Health Research and Development (project number 837001504). ZonMw funded the whole project. IQ Medical Ventures provided the ExEm-foam® kits free of charge. The funders had no role in study design, collection, analysis and interpretation of the data. K.D. reports travel and speaker fees from Guerbet. F.J.M.B. reports personal fees as a member of the external advisory board for Merck Serono, The Netherlands, and a research support grant from Merck Serono, outside the submitted work. C.B.L. reports speakers' fee from Ferring in the past, and his department receives research grants from Ferring, Merck and Guerbet. J.S. reports a research agreement with Takeda on MR of motility outside the submitted work. M.V.W. reports leading The Netherlands Satellite of the Cochrane Gynaecology and Fertility Group. B.W.J.M. is supported by an NHMRC Investigator grant (GNT1176437). B.W.J.M. reports consultancy for Guerbet and research funding from Merck and Guerbet. V.M. reports non-financial support from IQ medicals ventures, during the conduct of the study; grants and personal fees from Guerbet, outside the submitted work. The other authors do not report conflicts of interest. TRIAL REGISTRATION NUMBER: NTR4746/NL4587 (https://www.trialregister.nl). TRIAL REGISTRATION DATE: 19 August 2014. DATE OF FIRST PATIENT'S ENROLMENT: 7 May 2015.

Editor's Choice - Sex Differences in Response to Administration of Heparin During Non-Cardiac Arterial Procedures.

OBJECTIVE: Females are more prone to complications during non-cardiac arterial procedures (NCAPs) than males. The current study investigated the difference in the effect of peri-procedural prophylactic heparin in males and females, using the activated clotting time (ACT). This was a retrospective analysis of a prospective multicentre cohort study. METHODS: All patients undergoing elective NCAP using heparin and ACT measurements between January 2016 and March 2020 were included. Two heparin dosage protocols were used: weight based dosing of 100 IU/kg (international units per kilogram) or a bolus of 5 000 IU. The primary outcome was the anticoagulatory effect of heparin after five minutes, measured by ACT. Secondary outcomes were the effect of heparin after 30 minutes, bleeding complications, and arterial thromboembolic complications (ATECs). RESULTS: A total of 778 patients were included; 26% were female. After 100 IU/kg (n = 300), females more often reached longer ACT (< 200 seconds: 22% vs. 25%, p = .62; 200 - 250 seconds: 41% vs. 53%, p = .058; 251 - 280 seconds, 26% vs. 15%, p = .030). The mean ACT after 100 IU/kg heparin was 233 seconds (95% confidence interval [CI] 224 - 243) for females and 226 seconds (95% CI 221 - 231) for males (p = .057). After a bolus of 5 000 IU of heparin (n = 411), females reached significantly higher levels of anticoagulation than males (mean ACT 204 seconds vs. 190 seconds: p ≤ .001; ACT < 200 seconds: 44% vs. 66%; p < .001; ACT 200 - 250 seconds: 47% vs. 30%, p = .001; ACT 251 - 280 seconds: 7.8% vs. 2.3%, p = .009). Thirty minutes after heparin administration, 58% of all patients had an ACT < 200 seconds. ATECs did not differ between females and males (6.9% vs. 5.1%, p = .33) but bleeding complications were higher in females (27% vs. 16%, p = .001). CONCLUSION: Heparin leads to significantly longer ACT in females during NCAP. Further research is needed to investigate whether individually based heparin protocols lead to fewer bleeding complications and lower incidence of ATECs.

Weight Based Heparin Dosage with Activated Clotting Time Monitoring Leads to Adequate and Safe Anticoagulation in Non-Cardiac Arterial Procedures.

BACKGROUND: Unfractionated heparin has an unpredictable effect in an individual patient. The activated clotting time (ACT) can be used to measure the effect of heparin in the individual patient and guide additional heparin dosages. Previous cohort studies showed that a standardized bolus of 5,000 IU during noncardiac arterial procedures (NCAP) does not lead to an adequate ACT in the vast majority of patients. The aim of this study was to investigate whether an initial heparin dose of 100 IU/kg leads to an adequate but safe ACT, from 200 to 300 s. METHODS: In this multicenter prospective study, 186 patients undergoing NCAP were enrolled and received an initial heparin dose of 100 IU/kg. Target ACT was set at ≥250 s initially; during the course of the study the target ACT was lowered to ≥200 s. After the initial heparin dose, additional heparin dosages were administered depending on the ACT values following a heparin dose protocol. ACT measurements and complications were monitored. RESULTS: The mean baseline ACT was 134 ± 17 s. The mean ACT 5 minutes after the initial heparin dose was 227 ± 37 s. After the initial dose of heparin, 78 and 46% of patients reached an ACT of 200 and 250 s, respectively. Seven patients (4%) reached an ACT of 300 s or more. Ninety-four patients (51%) received at least one additional dose of heparin. After one additional dose of heparin, 91% of patients reached an ACT of 200 s and 13 patients (7%) reached an ACT of 300 s or more. Arterial thromboembolic complications occurred in 4.3% and bleeding complications occurred in 9.7%. CONCLUSIONS: A bolus of 100 IU/kg of heparin during NCAP results in adequate coagulation in most patients. ACT measurements enable accurate additional dosing, ensuring the individual patient tailored and safe coagulation. KEY WORDS: anticoagulants; heparin; blood coagulation tests; vascular surgical procedures; peripheral vascular disease.

Nationwide Experience with EVAS Relining of Previous Open or Endovascular AAA Treatment in The Netherlands.

OBJECTIVE: Relining of a previously placed surgical graft or endograft for an abdominal aortic aneurysm (AAA) is a reintervention to treat progression of disease or failure of the primary (endo)graft. Endovascular Aneurysm Sealing (EVAS) relining is a technique with potential advantages due to the absence of a bifurcation, the possibility for a unilateral approach, and sealing concept of the endobags. The purpose of this study was to describe the nationwide experience with EVAS relining of previous AAA repair in the Netherlands. METHODS: A retrospective analysis of all patients who underwent EVAS relining in 7 high volume vascular centres in the Netherlands between 2014 and 2019 was performed. Primary outcomes were technical and clinical success. Secondary outcomes were perioperative outcomes, complications and survival. RESULTS: Thirty-three patients underwent EVAS relining of open (n = 10) or endovascular (n = 23) repair. 26 were elective cases, 5 were urgent and 2 were acute (ruptured). Mean time between primary treatment and EVAS relining was 99 ± 74 months. Indications after open repair were proximal progression of disease (n = 7) and graft defect (n = 3). Indications after EVAR were type IA (n = 10), type IB (n = 3), type IIIA (n = 4), type IIIB (n = 3) endoleak, and endotension (n = 3). 18 patients underwent regular EVAS, 4 unilateral EVAS and 11 chimney-EVAS. In-hospital mortality was 6% (both patients with rAAA). Technical success was achieved in 97%. Median follow-up after EVAS relining was 20 months (range 0-43). Freedom from reintervention at 1-year and 2-year were 83% and 61% and the estimated survival 79% and 71%, respectively. EVAS relining after open repair had a clinical success of 90% at 1-year and of 70% at latest follow-up, while after EVAR clinical success rates were 70% and 52%, respectively. CONCLUSION: EVAS relining of previous AAA repair is associated with high technical success, however with limited clinical success at median follow-up of 20 months. Clinical success was higher in patients with EVAS relining after open repair than after EVAR. In patients with failed AAA repair, EVAS relining should only be considered, when established techniques such as fenestrated repair or open conversion are not available or indicated.

Survival and Living Situation After Ruptured Abdominal Aneurysm Repair in Octogenarians.

OBJECTIVE: To determine the 30 day and one year mortality and post-operative living situation in octogenarians treated for ruptured abdominal aortic aneurysm (rAAA). METHODS: A retrospective study was performed at four centres in the Netherlands. All consecutive patients aged ≥80 years, presenting with a rAAA between January 2013 and October 2018, were included. The primary outcomes were post-operative living situation and one year mortality. RESULTS: In total, 157 patients were included. Forty-seven received palliative care and 110 patients had surgery. After endovascular or open repair, the one year mortality rate was 50.0%. The 30 day mortality rate was 40.8% (95% confidence interval [CI] 27-55) and 31.7% (95% CI 20-44), for endovascular and open repair, respectively (p = .32). Sixty-five per cent of survivors were discharged home, while 34.8% went to a nursing home for rehabilitation. Of the surviving patients, 82.6% went back to living in their pre-rupture home situation. Of the investigated variables, only a high body mass index proved a significant predictor of death at 30 days and one year. Compared with operated patients, patients turned down for surgery were older (mean age 87.5 ± 3.8 vs. 84.0 ± 3.5; p < .001), lived significantly more often in a nursing home (odds ratio 1.02, 95% CI 1.00-1.03; p < .001), were more often dependent (odds ratio 3.69, 95% CI 2.31-5.88; p < .001) and had a lower Glasgow Coma Scale score on arrival (odds ratio 0.42, 95% CI 0.25-0.69; p = .002). All palliative patients died within three days. CONCLUSION: Overall treatment outcomes showed that octogenarians should not be denied surgery based on age alone, as half of the octogenarians that undergo surgical treatment are still alive one year after rAAA repair. In addition, > 80% returned to their own home after rehabilitation.

Unexplained Variation in Benefit of Treatment of Congenital Unilateral Aural Atresia: A Review of the Literature.

OBJECTIVE: A review of published data regarding binaural hearing after treatment of congenital unilateral conductive hearing loss (UCHL) due to aural atresia. Treatment options concern atresia surgery (reconstructive surgery), application of a bone conduction device (BCD), or application of a middle ear implant (MEI). DATA SOURCES: Database PubMed was searched for articles published in English and German between January 1, 1994, and January 1, 2019. STUDY SELECTION: The initial search identified 52 studies, of which 9 met the inclusion criteria. DATA SYNTHESIS: Comparison of studies was based on a structured review. Meta-analysis was not feasible because of the heterogeneity of outcome measures, the limited number of relevant papers (9), and diverse types of treatment (5). CONCLUSIONS: Treatment of UCHL results in bilateral hearing instead of binaural hearing. The large intersubject variability in benefit of treatment is unexplained with a clear improvement in the minority of listeners and a limited improvement or binaural interference in most listeners after atresia repair or amplification with a BCD or MEI.

A Standardized Bolus of 5 000 IU of Heparin Does not Lead to Adequate Heparinization during Non-cardiac Arterial Procedures.

BACKGROUND: In non-cardiac arterial procedures (NCAP), heparin is administered to prevent arterial thromboembolic complications (ATEC). Heparin has a nonpredictable effect in the individual patient, also known as variation in heparin sensitivity. Various dosing protocols are in use, but the optimal dose is currently still unknown. A standardized bolus of 5 000 IU heparin is most frequently used by vascular surgeons and interventional radiologists. The activated clotting time (ACT) is an established method to measure the level of anticoagulation, but has, until now, not gained widespread use in NCAP. The purpose of this study was to evaluate the anticoagulant effect during NCAP of a standardized bolus of 5 000 IU heparin by measuring the ACT. METHODS: In this prospective study, 190 patients undergoing NCAP were enrolled between December 2016 and September 2018. The ACT was measured during open and endovascular/hybrid procedures. All patients received a standardized bolus of 5 000 IU heparin. The ACT was measured by the Hemostasis Management System Plus (HMS Plus, Medtronic®), before, 5 minutes after administration of heparin, and every 30 minutes thereafter. The primary outcome was periprocedural ACT values measured. Secondary outcomes were ATEC and hemorrhagic complications. RESULTS: A large individual patient variability in the response to heparin was found. The mean baseline ACT in all patients was 129 ± 18 s., and the mean ACT 5 minutes after the initial bolus of heparin was 191 ± 36 s. After the initial dose of 5 000 IU heparin 60 (33%) and 10 (6%) patients reached an ACT of 200 and 250 s., respectively. Despite the use of heparin, ATEC occurred in 17 patients (9%). The lowest number of ATEC occurred in the group of patients with an ACT between 200 and 250 s. CONCLUSIONS: A standardized bolus of 5 000 IU heparin does not lead to adequate and safe heparinization in non-cardiac arterial procedures. Patient response to heparin shows a large individual variability. Therefore, routine ACT measurements are necessary to ascertain adequate anticoagulation. Further research is needed to investigate if heparin dosing based on the ACT could result in less arterial thromboembolic complications, without increasing hemorrhagic complications.

More Effective Anticoagulation During Non-Cardiac Arterial Procedures Using Activated Clotting Time Guided Heparin Administration.

OBJECTIVES: Arterial thrombo-embolic complications (ATEC) are still common during and after non-cardiac arterial procedures (NCAP) despite the administration of (a fixed bolus of) heparin. These ATEC could be due to existing individual differences in heparin sensitivity. The purpose of this study was to evaluate the feasibility and safety of an ACT guided heparin dose protocol and to evaluate if a more effective target ACT can be achieved during NCAP. METHODS: In this multi-center prospective study, 194 patients undergoing elective and non-elective NCAP were enrolled and received heparin according to a heparin dose protocol which aimed to obtain a target ACT of 250 seconds (s.), measured by the Medtronic HMS Plus. Patients received a standardized bolus of 5 000 IU followed by additional boluses depending on the actual ACT. Primary outcome was the ACT value reached. Secondary outcomes were incidence of all ATEC and haemorrhagic complications. RESULTS: The mean baseline ACT was 138 ± 17 s. The mean ACT five minutes after the initial heparin bolus of 5 000 IU was 197 ± 31 s. 48% of patients reached an ACT of 200 s. and six per cent of patients reached an ACT of 250 s. Additional dosages of heparin were administered in 72% of patients. With this ACT guided heparin protocol 86% of patients reached an ACT of 200 s. and 26% of patients reached an ACT of 250 s. A negative correlation was found between body weight and the ACT at T1 (P ˂ 0.001). ATEC and haemorrhagic complications occurred in 11.3% and 16.5% of patients. The lowest incidence of ATEC was found in patients with peak ACT between 200 and 250 s, namely 6.3%. CONCLUSION: This ACT guided heparin protocol proved to be feasible, safe and more patients reached an ACT > of 200 s. compared to a standardized heparin bolus of 5 000 IU. Further research is needed to investigate if ACT guided heparin administration could be preferable over not monitoring the anticoagulant effect of peri-procedural heparin and results in a lower incidence of ATEC, without an increase in haemorrhagic complications.