SUGAR-DIP trial: Oral medication strategy versus insulin for diabetes in pregnancy, study protocol for a multicentre, open-label, non-inferiority, randomised controlled trial

Introduction In women with gestational diabetes mellitus (GDM) requiring pharmacotherapy, insulin was the established first-line treatment. More recently, oral glucose lowering drugs (OGLDs) have gained popularity as a patient-friendly, less expensive and safe alternative. Monotherapy with metformin or glibenclamide (glyburide) is incorporated in several international guidelines. In women who do not reach sufficient glucose control with OGLD monotherapy, usually insulin is added, either with or without continuation of OGLDs. No reliable data from clinical trials, however, are available on the effectiveness of a treatment strategy using all three agents, metformin, glibenclamide and insulin, in a stepwise approach, compared with insulin-only therapy for improving pregnancy outcomes. In this trial, we aim to assess the clinical effectiveness, cost-effectiveness and patient experience of a stepwise combined OGLD treatment protocol, compared with conventional insulin-based therapy for GDM. Methods The SUGAR-DIP trial is an open-label, multicentre randomised controlled non-inferiority trial. Participants are women with GDM who do not reach target glycaemic control with modification of diet, between 16 and 34 weeks of gestation. Participants will be randomised to either treatment with OGLDs, starting with metformin and supplemented as needed with glibenclamide, or randomised to treatment with insulin. In women who do not reach target glycaemic control with combined metformin and glibenclamide, glibenclamide will be substituted with insulin, while continuing metformin. The primary outcome will be the incidence of large-for-gestational-age infants (birth weight >90th percentile). Secondary outcome measures are maternal diabetes-related endpoints, obstetric complications, neonatal complications and cost-effectiveness analysis. Outcomes will be analysed according to the intention-to-treat principle. Ethics and dissemination The study protocol was approved by the Ethics Committee of the Utrecht University Medical Centre. Approval by the boards of management for all participating hospitals will be obtained. Trial results will be submitted for publication in peer-reviewed journals

Does arterial shear explain the magnitude of flow-mediated dilation?: a comparison between young and older humans

Flow-mediated dilatation (FMD) has become a commonly applied approach for the assessment of vascular function and health in humans. Recent studies emphasize the importance of normalizing the magnitude of FMD to its apparent eliciting stimulus, the postdeflation arterial shear. However, the relationship between shear stress and the magnitude of FMD may differ between groups. The aim of this study was to examine the relationship between the brachial FMD and four different indexes of postdeflation shear rate (SR) in healthy children (n = 51, 10 ± 1 yr) and young (n = 57, 27 ± 6 yr) and older (n = 27, 58 ± 4 yr) adults. SR was calculated from deflation (time 0) until 9 s (peak), 30 s (0–30), 60 s (0–60), or until the time-to-peak diameter in each individual (0-ttp). Edge detection and wall tracking of high resolution B-mode arterial ultrasound images were used to calculate the conduit artery diameter. In young adults, the brachial artery FMD demonstrated a significant correlation with the area under the SR curve (SRAUC) 0–30 s (r2 = 0.12, P = 0.009), 0–60 s (r2 = 0.14, P = 0.005), and 0-ttp (r2 = 0.14, P = 0.005) but not for the peak SRAUC 0–9 s (r2 = 0.04, P = 0.12). In children and older adults, the magnitude of the brachial artery FMD did not correlate with any of the four SRAUC stimuli. These findings suggest that in young subjects, postdeflation SRAUC correlates moderately with the magnitude of the FMD response. However, the relationship between FMD and postdeflation shear appears to be age dependent, with less evidence for an association in younger and older subjects. Therefore, we support presenting SRAUC stimuli but not normalizing FMD responses for the SRAUC when using this technique

The impact of baseline diameter on flow-mediated dilation differs in young and older humans

Flow-mediated dilation (FMD) has become a commonly applied approach for the assessment of vascular function and health, but methods used to calculate FMD differ between studies. For example, the baseline diameter used as a benchmark is sometimes assessed before cuff inflation, whereas others use the diameter during cuff inflation. Therefore, we compared the brachial artery diameter before and during cuff inflation and calculated the resulting FMD in healthy children (n = 45; 10 ± 1 yr), adults (n = 31; 28 ± 6 yr), and older subjects (n = 22; 58 ± 5 yr). Brachial artery FMD was examined after 5 min of distal ischemia. Diameter was determined from either 30 s before cuff inflation or from the last 30 s during cuff inflation. Edge detection and wall tracking of high resolution B-mode arterial ultrasound images was used to calculate conduit artery diameter. Brachial artery diameter during cuff inflation was significantly larger than before inflation in children (P = 0.02) and adults (P < 0.001) but not in older subjects (P = 0.59). Accordingly, FMD values significantly differed in children (11.2 ± 5.1% vs. 9.4 ± 5.2%; P = 0.02) and adults (7.3 ± 3.2% vs. 4.6 ± 3.3%; P < 0.001) but not in older subjects (6.3 ± 3.4% vs. 6.0 ± 4.2%; P = 0.77). When the diameter before cuff inflation was used, an age-dependent decline was evident in FMD, whereas FMD calculated using the diameter during inflation was associated with higher FMD values in older than younger adults. In summary, the inflation of the cuff significantly increases brachial artery diameter, which results in a lower FMD response. This effect was found to be age dependent, which emphasizes the importance of using appropriate methodology to calculate the FMD

Home Treatment Compared to Initial Hospitalization in Normotensive Patients with Acute Pulmonary Embolism in the Netherlands: A Cost Analysis

Background Venous thromboembolism constitutes substantial health care costs amounting to approximately 60 million euros per year in the Netherlands. Compared with initial hospitalization, home treatment of pulmonary embolism (PE) is associated with a cost reduction. An accurate estimation of cost savings per patient treated at home is currently lacking. Aim The aim of this study was to compare health care utilization and costs during the first 3 months after a PE diagnosis in patients who are treated at home versus those who are initially hospitalized. Methods Patient-level data of the YEARS cohort study, including 383 normotensive patients diagnosed with PE, were used to estimate the proportion of patients treated at home, mean hospitalization duration in those who were hospitalized, and rates of PE-related readmissions and complications. To correct for baseline differences within the two groups, regression analyses was performed. The primary outcome was the average total health care costs during a 3-month follow-up period for patients initially treated at home or in hospital. Results Mean hospitalization duration for the initial treatment was 0.69 days for those treated initially at home (n = 181) and 4.3 days for those initially treated in hospital (n = 202). Total average costs per hospitalized patient were €3,209 and €1,512 per patient treated at home. The adjusted mean difference was €1,483 (95% confidence interval: €1,181-1,784). Conclusion Home treatment of hemodynamically stable patients with acute PE was associated with an estimated net cost reduction of €1,483 per patient. This difference underlines the advantage of triage-based home treatment of these patients

Pregnancy-adapted YEARS algorithm for diagnosis of suspected pulmonary embolism

Acute pulmonary embolism is one of the leading causes of maternal death, with the overall incidence reported to be 1.72 cases per 1000 deliveries, accounting for approximately 1 death in every 100,000 deliveries. Since the D-dimer test has low specificity and sensitivity, it is common for pregnant women with suspected pulmonary embolism to undergo computed tomography (CT) pulmonary angiography or ventilation-perfusion (V/Q) scanning, both of which involve radiation exposure to the mother and fetus. It is unknown whether a pregnancy-adapted clinical screening algorithm could be used to safely avoid diagnostic imaging in a subset of pregnant women with suspected pulmonary embolism. The researchers performed a multicenter, international, prospective study of pregnant women with suspected pulmonary embolism. They assessed 3 criteria from the YEARS algorithm (clinical signs of deep vein thrombosis, hemoptysis, and pulmonary embolism as the most likely diagnosis) and measured the D-dimer level as components of the screening algorithm. Pulmonary embolism was ruled out if none of the 3 criteria were met and the D-dimer level was less than 1000 ng/mL, or if 1 or more of the 3 criteria were met and the D-dimer level was less than 500 ng/mL. Adaptation of the YEARS algorithm for pregnant women involved compression ultrasonography for women with symptoms of deep vein thrombosis; if the results were positive (ie, a clot was present), CT pulmonary angiography was not performed. All patients in whom pulmonary embolism had not been ruled out by screening criteria underwent CT pulmonary angiography. The primary outcome was the incidence of venous thromboembolism (VTE) at 3 months. The secondary outcome was the proportion of patients in whom CT pulmonary angiography was not indicated to safely rule out pulmonary embolism. A total of 510 women were screened, of whom 12 (2.4%) were excluded. Pulmonary embolism was diagnosed in 20 patients (4.0%) at baseline. During follow-up, popliteal deep vein thrombosis was diagnosed in 1 patient (0.21%; 95% confidence interval, 0.0%–1.2%); no patient had pulmonary embolism. CT pulmonary angiography was not indicated, and thus was avoided, in 195 patients (39%; 95% confidence interval, 35%–44%). The efficiency of the algorithm was highest during the first trimester of pregnancy and lowest during the third trimester; CT pulmonary angiography was avoided in 65% of patients who began the study in the first trimester and in 32% who began the study in the third trimester. The researchers concluded that the pregnancy-adapted YEARS diagnostic algorithm safely ruled out acute pulmonary embolism in pregnant patients who were referred for suspected pulmonary embolism. Using this approach, they found that the main advantage was that CT pulmonary angiography was averted in 32% to 65% of the patients, depending on the trimester of presentation, without compromising safety

Simplified diagnostic management of suspected pulmonary embolism (the YEARS study): a prospective, multicentre, cohort study

Validated diagnostic algorithms in patients with suspected pulmonary embolism are often not used correctly or only benefit subgroups of patients, leading to overuse of computed tomography pulmonary angiography (CTPA). The YEARS clinical decision rule that incorporates differential D-dimer cutoff values at presentation, has been developed to be fast, to be compatible with clinical practice, and to reduce the number of CTPA investigations in all age groups. We aimed to prospectively evaluate this novel and simplified diagnostic algorithm for suspected acute pulmonary embolism. We did a prospective, multicentre, cohort study in 12 hospitals in the Netherlands, including consecutive patients with suspected pulmonary embolism between Oct 5, 2013, to July 9, 2015. Patients were managed by simultaneous assessment of the YEARS clinical decision rule, consisting of three items (clinical signs of deep vein thrombosis, haemoptysis, and whether pulmonary embolism is the most likely diagnosis), and D-dimer concentrations. In patients without YEARS items and D-dimer less than 1000 ng/mL, or in patients with one or more YEARS items and D-dimer less than 500 ng/mL, pulmonary embolism was considered excluded. All other patients had CTPA. The primary outcome was the number of independently adjudicated events of venous thromboembolism during 3 months of follow-up after pulmonary embolism was excluded, and the secondary outcome was the number of required CTPA compared with the Wells' diagnostic algorithm. For the primary outcome regarding the safety of the diagnostic strategy, we used a per-protocol approach. For the secondary outcome regarding the efficiency of the diagnostic strategy, we used an intention-to-diagnose approach. This trial is registered with the Netherlands Trial Registry, number NTR4193. 3616 consecutive patients with clinically suspected pulmonary embolism were screened, of whom 151 (4%) were excluded. The remaining 3465 patients were assessed of whom 456 (13%) were diagnosed with pulmonary embolism at baseline. Of the 2946 patients (85%) in whom pulmonary embolism was ruled out at baseline and remained untreated, 18 patients were diagnosed with symptomatic venous thromboembolism during 3-month follow-up (0·61%, 95% CI 0·36-0·96) of whom six had fatal pulmonary embolism (0·20%, 0·07-0·44). CTPA was not indicated in 1651 (48%) patients with the YEARS algorithm compared with 1174 (34%) patients, if Wells' rule and fixed D-dimer threshold of less than 500 ng/mL would have been applied, a difference of 14% (95% CI 12-16). In our study pulmonary embolism was safely excluded by the YEARS diagnostic algorithm in patients with suspected pulmonary embolism. The main advantage of the YEARS algorithm in our patients is the absolute 14% decrease of CTPA examinations in all ages and across several relevant subgroups. This study was supported by unrestricted grants from the participating hospital

Noninvasive diagnostic work-up for suspected acute pulmonary embolism during pregnancy: a systematic review and meta-analysis of individual patient data

BACKGROUND: Few studies evaluated the performance of noninvasive diagnostic strategies for suspected acute pulmonary embolism (PE) in pregnant women. OBJECTIVES: The aim of this study was to establish the safety and efficiency of the Wells rule with fixed and adapted D-dimer threshold, and the YEARS algorithm, combined with compression ultrasonography (CUS), in pregnant women with suspected PE in an individual patient data meta-analysis. METHODS: We performed a systematic review to identify prospective diagnostic management studies in pregnant women with suspected PE. Primary outcomes were safety, defined as the failure rate, ie, the 3-month venous thromboembolism (VTE) incidence after excluding PE without chest imaging, and efficiency, defined as the proportion of patients in whom chest imaging could be avoided. RESULTS: We identified 2 relevant studies, of which individual patient-level data were analyzed in a fixed-effect meta-analysis, totaling 893 pregnant women. The Wells rule with fixed and adapted D-dimer threshold as well as the YEARS algorithm could safely rule out acute PE (failure rate, 0·37%-1·4%), but efficiency improved considerably when applying pretest probability-adapted D-dimer thresholds. The efficiency of bilateral CUS was limited (2·3% overall; number needed to test 43), especially in patients without symptoms of deep-vein thrombosis (efficiency 0·79%; number needed to test 127). CONCLUSION: This study supports the latest guideline recommendations (European Society of Cardiology 2019) to apply pretest probability assessment and D-dimer tests to rule out PE in pregnant women. From an efficiency perspective, the use of a strategy with pretest probability-adapted D-dimer threshold is preferred. The yield of CUS was very limited in patients without concomitant symptoms of deep-vein thrombosis

Noninvasive diagnostic work-up for suspected acute pulmonary embolism during pregnancy: a systematic review and meta-analysis of individual patient data.

BACKGROUND Few studies evaluated the performance of noninvasive diagnostic strategies for suspected acute pulmonary embolism (PE) in pregnant women. OBJECTIVES The aim of this study was to establish the safety and efficiency of the Wells rule with fixed and adapted D-dimer threshold, and the YEARS algorithm, combined with compression ultrasonography (CUS), in pregnant women with suspected PE in an individual patient data meta-analysis. METHODS We performed a systematic review to identify prospective diagnostic management studies in pregnant women with suspected PE. Primary outcomes were safety, defined as the failure rate, ie, the 3-month venous thromboembolism (VTE) incidence after excluding PE without chest imaging, and efficiency, defined as the proportion of patients in whom chest imaging could be avoided. RESULTS We identified 2 relevant studies, of which individual patient-level data were analyzed in a fixed-effect meta-analysis, totaling 893 pregnant women. The Wells rule with fixed and adapted D-dimer threshold as well as the YEARS algorithm could safely rule out acute PE (failure rate, 0·37%-1·4%), but efficiency improved considerably when applying pretest probability-adapted D-dimer thresholds. The efficiency of bilateral CUS was limited (2·3% overall; number needed to test 43), especially in patients without symptoms of deep-vein thrombosis (efficiency 0·79%; number needed to test 127). CONCLUSION This study supports the latest guideline recommendations (European Society of Cardiology 2019) to apply pretest probability assessment and D-dimer tests to rule out PE in pregnant women. From an efficiency perspective, the use of a strategy with pretest probability-adapted D-dimer threshold is preferred. The yield of CUS was very limited in patients without concomitant symptoms of deep-vein thrombosis