Impact of Finerenone-Induced Albuminuria Reduction on Chronic Kidney Disease Outcomes in Type 2 Diabetes : A Mediation Analysis.

BACKGROUND: In patients with chronic kidney disease (CKD) and type 2 diabetes (T2D), finerenone, a nonsteroidal mineralocorticoid receptor antagonist, reduces cardiovascular and kidney failure outcomes. Finerenone also lowers the urine albumin-to-creatinine ratio (UACR). Whether finerenone-induced change in UACR mediates cardiovascular and kidney failure outcomes is unknown. OBJECTIVE: To quantify the proportion of kidney and cardiovascular risk reductions seen over a 4-year period mediated by a change in kidney injury, as measured by the change in log UACR between baseline and month 4. DESIGN: Post hoc mediation analysis using pooled data from 2 phase 3, double-blind trials of finerenone. (ClinicalTrials.gov: NCT02540993 and NCT02545049). SETTING: Several clinical sites in 48 countries. PATIENTS: 12 512 patients with CKD and T2D. INTERVENTION: Finerenone and placebo (1:1). MEASUREMENTS: Separate mediation analyses were done for the composite kidney (kidney failure, sustained ≥57% decrease in estimated glomerular filtration rate from baseline [approximately a doubling of serum creatinine], or kidney disease death) and cardiovascular (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) outcomes. RESULTS: At baseline, median UACR was 514 mg/g. A 30% or greater reduction in UACR was seen in 3338 (53.2%) patients in the finerenone group and 1684 (27.0%) patients in the placebo group. Reduction in UACR (analyzed as a continuous variable) mediated 84% and 37% of the treatment effect on the kidney and cardiovascular outcomes, respectively. When change in UACR was analyzed as a binary variable (that is, whether the guideline-recommended 30% reduction threshold was met), the proportions mediated for each outcome were 64% and 26%, respectively. LIMITATION: The current findings are not readily extendable to other drugs. CONCLUSION: In patients with CKD and T2D, early albuminuria reduction accounted for a large proportion of the treatment effect against CKD progression and a modest proportion of the effect against cardiovascular outcomes. PRIMARY FUNDING SOURCE: Bayer AG.

The importance of the design of observational studies in comparative effectiveness research: Lessons from the GARFIELD-AF and ORBIT-AF registries.

Randomized controlled trials (RCTs) are considered the gold standard for estimating the effectiveness of a treatment. However, in many instances they are impractical to conduct because of time limitations, cost restrictions, or ethical reasons. As a consequence, non-randomized observational studies have an important role in comparative effectiveness and safety research since they can address issues that would not be possible using conventional RCT methodology. Observational studies can be strategically designed to reduce the risk of potential sources of bias by emulating the design principles of an equivalent but ideal randomized trial - the target trial - that would answer the research question of interest. In this article, we review some of the necessary components of observational studies required for valid causal inference within the framework of target trial emulation, so as to avoid common methodological pitfalls of study design. We discuss the assumptions of consistency, time-zero specification, exchangeability and positivity. To illustrate these concepts in a context where existing knowledge is well-established through clinical trials, we evaluate and compare the treatment effects of vitamin K antagonists (VKA) against no VKA (No VKA) on the treatment of atrial fibrillation from two real-world observational studies, namely the GARFIELD-AF and ORBIT-AF registries. Results are compared with those of published RCTs.

Evaluation of Intraindividual Contrast Enhancement Variability for Determining the Maximum Achievable Consistency in CT.

OBJECTIVE. The purpose of this study was to quantify temporal variability in vascular and parenchymal enhancement within the same patient and to determine technique-related factors contributing to this variability. MATERIALS AND METHODS. We identified 100 patients who underwent four CT scans within 12 months with identical acquisition and contrast injection parameters. Enhancement was recorded in the abdominal aorta, main portal vein, liver parenchyma, and subcutaneous fat. Patient demographic and body habitus data were recorded. Injection-related factors were recorded including delay time from contrast injection to image acquisition. All pairwise differences in enhancement within each patient were evaluated for absolute and percentage change. RESULTS. Based on predetermined thresholds, we observed clinically relevant variability in 34% of patients for the abdominal aorta, 38% for the portal vein, and 33% for the liver parenchyma. A highly significant association was observed between higher variability in delay time and variability in the abdominal aorta (p = 0.009) and between female sex and variability in liver parenchyma (p = 0.008). A marginally significant association was seen between increasing age (p = 0.025) and female sex (p = 0.039) with variability in the abdominal aorta. No statistically significant association was found between all recorded variables and variability in the portal vein. CONCLUSION. Approximately one-third of patients may show clinically relevant variability in enhancement of the abdominal aorta, portal vein, and liver parenchyma even when using identical scanning and injection parameters. Delay time was the only controllable factor associated with variability in enhancement of the abdominal aorta; no other controllable factor is associated with variability in the portal vein or liver parenchyma.

Cancer associated thrombosis in everyday practice: perspectives from GARFIELD-VTE.

Venous thromboembolism (VTE) is common in cancer patients and is an important cause of morbidity and mortality. The Global Anticoagulant Registry in the FIELD (GARFIELD)-VTE (ClinicalTrials.gov: NCT02155491) is a prospective, observational study of 10,684 patients with objectively diagnosed VTE from 415 sites in 28 countries. We compared baseline characteristics, VTE treatment patterns, and 1-year outcomes (mortality, recurrent VTE and major bleeding) in 1075 patients with active cancer, 674 patients with a history of cancer, and 8935 patients without cancer. Patients with active cancer and history of cancer were older than cancer-free patients, with median ages of 64.8, 68.9, and 58.4 years, respectively. The most common sites of active cancer were lung (14.5%), colorectal (11.0%), breast (10.6%), and gynaecological (10.3%). Active cancer patients had a higher incidence of upper limb and vena cava thrombosis than cancer-free patients (9.0% vs 4.8% and 5.1% vs 1.4%, respectively), and were more likely to receive parenteral anticoagulation as monotherapy than cancer-free patients (57.8% vs 12.1%), and less likely to receive DOACs (14.2% vs 50.6%). Rates of death, recurrent VTE, and major bleeding were higher in active cancer patients than in cancer-free patients, with hazard ratios (95% confidence intervals) of 14.2 (12.1-16.6), 1.6 (1.2-2.0) and 3.8 (2.9-5.0), respectively. VTE was the second most common cause of death in patients with active cancer or history of cancer. In patients with VTE, those with active cancer are at higher risk of death, recurrence, and major bleeding than those without cancer.

Virtual Unenhanced Images at Dual-Energy CT: Influence on Renal Lesion Characterization.

Background Dual-energy (DE) CT allows reconstruction of virtual noncontrast (VNC) images from a single-phase contrast agent-enhanced examination, potentially reducing the need for multiphasic CT to characterize renal lesions. However, data regarding diagnostic performance of VNC images for the characterization of renal lesions are limited. Purpose To determine whether renal mass CT performed by using VNC images allows for reliable identification of renal lesions and differentiation of contrast-enhanced from unenhanced lesions, compared with unenhanced images. Materials and Methods This is a retrospective study of 293 patients (105 women [mean age, 65 years; age range, 18-91 years] and 188 men [mean age, 66 years; age range, 23-90 years] with 379 renal lesions [craniocaudal diameter, 1.0-4.0 cm]) who underwent a single-energy unenhanced CT examination followed by a nephrographic-phase DE CT between June 2013 and October 2017 by using one of four different DE CT platforms from two vendors. VNC images were calculated by using vendor-specific algorithms. Each lesion was classified in a blinded and independent fashion by using the VNC or unenhanced image in combination with the nephrographic images. Attenuation measurements were obtained on the VNC, unenhanced, and nephrographic images. Unenhanced images and pathologic or imaging follow-up for more than 24 months served as reference standard. Results There was strong overall agreement between VNC and unenhanced images for renal lesion characterization (Cramer V = 0.85). VNC images yielded a high diagnostic performance (area under the receiver operating characteristic curve, 0.91; 95% confidence interval: 0.86, 0.95) for facilitation of differentiation of contrast-enhanced from unenhanced renal lesions. However, there was a reduction in diagnostic performance for depicting contrast-enhanced renal lesions by using VNC compared with unenhanced images (area under the receiver operating characteristic curve, 0.91 [95% confidence interval: 0.86, 0.95] vs 0.96 [95% confidence interval: 0.93, 0.99]; P < .001). Mean absolute difference between the VNC and unenhanced attenuation was 9.2 HU ± 8.7. Conclusion Virtual noncontrast images enabled accurate renal lesion characterization, albeit with a reduction in diagnostic performance for contrast-enhanced lesion characterization. © RSNA, 2019 Online supplemental material is available for this article.

High-Pitch Wide-Coverage Fast-Kilovoltage-Switching Dual-Energy CT: Impact of Pitch on Noise, Spatial Resolution, and Iodine Quantification in a Phantom Study.

OBJECTIVE: The purpose of this study was to assess the impact of high pitch values on image noise, spatial resolution, and iodine quantification in single-source wide-coverage fast-kilovoltage-switching dual-energy CT (DECT). MATERIALS AND METHODS: Two phantom experiments were conducted. First, image noise and spatial resolution in the x-, y-, and z-directions were assessed. Second, the accuracy of iodine quantification was investigated with multiple-size phantoms with pure iodine and blood-iodine inserts. Both phantoms were scanned repeatedly with a third-generation fast-kilovoltage-switching DECT scanner with a collimation width of 80 mm at four different pitch values (0.5, 0.99, 1.375, 1.53) and three different gantry rotation times (0.6, 0.8, 1.0 second). Image noise, spatial resolution, and absolute error of iodine concentration (E) were measured. A linear mixed effects model was used to determine the effect of pitch, rotation time, and size on the error of iodine concentration. RESULTS: Image noise and xy spatial resolution were comparable among the four pitch values. Spatial resolution in the z-direction was inferior and had higher variance at a low pitch of 0.5 compared with pitches of 0.99, 1.375, and 1.53. Error of iodine concentration was significantly affected by pitch and rotation time (p < 0.001). E decreased with increasing pitch and decreasing rotation time. In detail, mean E was 0.91 ± 0.47 mg I/mL for a pitch of 0.5, 0.52 ± 0.29 mg I/mL for 0.99, 0.44 ± 0.25 mg I/mL for 1.375, and 0.40 ± 0.25 mg I/mL for 1.53. CONCLUSION: High-pitch wide-coverage fast-kilovoltage-switching DECT can be performed without impairing image quality or iodine quantification, and the results are superior to those of imaging at a low pitch of 0.5.

National estimations of airway foreign bodies in children in the United States, 2000 to 2009.

OBJECTIVE: Identify risk factors associated with airway foreign bodies in children in the United States and report observed trends over time. DATA SOURCE: KID database (2000-2009). METHODS: ICD-9-CM codes for airway foreign bodies were used to identify patients. Risk factors were used for univariate analysis and a multivariate model to identify any increased risk of mortality. These factors were then also trended over time. RESULTS: Children with airway foreign bodies demonstrate similar risk factors as previously reported, such as male gender, age less than five years and lack of private insurance. The weighted mortality rate for paediatric inpatients with airway foreign bodies was about 2.75%. Fortunately, the rate remained relatively unchanged from 2000 to 2009. Geographically, urban hospital settings appeared to be more affected. Increased risks of mortality were noted for older age, urban hospital setting and teaching hospital status. CONCLUSIONS: Our findings confirm previous findings and identified that the diagnosis of airway foreign bodies in children were associated with male gender, age <5 years, lack of private insurance and geographic location in an urban setting. Further investigation may be warranted to provide clarity on other factors found to have increased association with mortality for quality improvement.

Renal Lesion Characterization with Spectral CT: Determining the Optimal Energy for Virtual Monoenergetic Reconstruction.

Purpose To investigate the relationship between energy level of virtual monoenergetic (VM) imaging and sensitivity in the detection of minimally enhancing renal lesions. Materials and Methods Phantoms simulating unenhanced and contrast material-enhanced renal parenchyma were equipped with inserts containing different concentrations of iodine (range, 0-1.15 mg iodine per milliliter). A total of 180 patients (117 men; mean age, 65.2 years ± 13.0 [standard deviation]) with 194 (62 solid, 132 cystic) renal lesions larger than 10 mm in diameter underwent unenhanced single-energy CT and contrast-enhanced dual-energy CT. VM imaging data sets were created for 70, 80, 90, and 100 keV. Renal lesions were measured, and enhancement was calculated. Area under the receiver operating characteristic curve (AUC) for renal lesion characterization was determined by using the DeLong method. Results The AUC was highest at 70 keV and decreased as energy increased toward 100 keV. AUC in the phantom decreased from 98% (95% confidence interval [CI]: 95, 100) at 70 keV to 88% (95% CI: 79, 96) at 100 keV (P = .004). AUC in patients decreased from 96% (95% CI: 94, 98) at 70 keV to 79% (95% CI: 71, 86) at 100 keV (P = .001). In patients with an enhancement threshold of 15 HU, sensitivity in the detection of solid renal lesions decreased between from 91% (49 of 62 [95% CI: 78, 97]) at 70 keV to 48% (33 of 62 [95% CI: 25, 71]) at 100 keV (P < .05), with no change in specificity (93% [120 of 132 {95% CI: 87, 97}] at 70 keV, 97% [125 of 132 {95% CI: 92, 99}] at 100 keV). Conclusion There is a reduction in diagnostic accuracy for renal lesion characterization with increasing VM imaging energy. The 70-keV setting may provide an optimal trade-off between sensitivity and specificity. © RSNA, 2018 Online supplemental material is available for this article.

Reduction in Thyroid Nodule Biopsies and Improved Accuracy with American College of Radiology Thyroid Imaging Reporting and Data System.

Purpose To compare the biopsy rate and diagnostic accuracy before and after applying the American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS) criteria for thyroid nodule evaluation. Materials and Methods In this retrospective study, eight radiologists with 3-32 years experience in thyroid ultrasonography (US) reviewed US features of 100 thyroid nodules that were cytologically proven, pathologically proven, or both in December 2016. The radiologists evaluated nodule features in five US categories and provided biopsy recommendations based on their own practice patterns without knowledge of ACR TI-RADS criteria. Another three expert radiologists served as the reference standard readers for the imaging findings. ACR TI-RADS criteria were retrospectively applied to the features assigned by the eight radiologists to produce biopsy recommendations. Comparison was made for biopsy rate, sensitivity, specificity, and accuracy. Results Fifteen of the 100 nodules (15%) were malignant. The mean number of nodules recommended for biopsy by the eight radiologists was 80 ± 16 (standard deviation) (range, 38-95 nodules) based on their own practice patterns and 57 ± 11 (range, 37-73 nodules) with retrospective application of ACR TI-RADS criteria. Without ACR TI-RADS criteria, readers had an overall sensitivity, specificity, and accuracy of 95% (95% confidence interval [CI]: 83%, 99%), 20% (95% CI: 16%, 25%), and 28% (95% CI: 21%, 37%), respectively. After applying ACR TI-RADS criteria, overall sensitivity, specificity, and accuracy were 92% (95% CI: 68%, 98%), 44% (95% CI: 33%, 56%), and 52% (95% CI: 40%, 63%), respectively. Although fewer malignancies were recommended for biopsy with ACR TI-RADS criteria, the majority met the criteria for follow-up US, with only three of 120 (2.5%) malignancy encounters requiring no follow-up or biopsy. Expert consensus recommended biopsy in 55 of 100 nodules with ACR TI-RADS criteria. Their sensitivity, specificity, and accuracy were 87% (95% CI: 48%, 98%), 51% (95% CI: 40%, 62%), and 56% (95% CI: 46%, 66%), respectively. Conclusion ACR TI-RADS criteria offer a meaningful reduction in the number of thyroid nodules recommended for biopsy and significantly improve the accuracy of recommendations for nodule management. © RSNA, 2018 Online supplemental material is available for this article.

Tin-filtered low-dose chest CT to quantify macroscopic calcification burden of the thoracic aorta.

OBJECTIVES: To compare a low-dose, tin-filtered, nonenhanced, high-pitch Sn100 kVp CT protocol (Sn100) with a standard protocol (STP) for the detection of calcifications in the ascending aorta in patients scheduled for cardiac surgery. METHODS: Institutional Review Board approval for this retrospective study was waived and the study was HIPAA-compliant. The study included 192 patients (128 men; age 68.8 ± 9.9 years), of whom 87 received the STP and 105 the Sn100 protocol. Size-specific dose estimates (SSDE) and radiation doses were obtained using dose monitoring software. Two blinded readers evaluated image quality on a scale from 1 (low) to 5 (high) and the extent of calcifications of the ascending aorta on a scale from 0 (none) to 10 (high), subdivided into 12 anatomic segments. RESULTS: The Sn100 protocol achieved a mean SSDE of only 0.5 ± 0.1 mGy and 0.20 ± 0.04 mSv compared with the mean SSDE of 5.4 ± 2.2 mGy achieved with the STP protocol (p < 0.0001). Calcification burden was associated with age (p < 0.0001), but was independent of protocol with mean calcification scores of 0.48 ± 1.23 (STP) and 0.55 ± 1.25 (Sn100, p = 0.18). Reader agreement was very good (STP κ = 0.87 ± 0.02, Sn100 κ = 0.88 ± 0.01). The STP protocol provided a higher subjective image quality than the Sn100 protocol: STP median 4, interquartile range 4-5, vs. SN100 3, 3-4; p < 0.0001) and a slightly better depiction of calcification (STP 5, 4-5, vs. Sn100 4, 4-5; p < 0.0001). CONCLUSIONS: The optimized Sn100 protocol achieved a mean SSDE of only 0.5 ± 0.1 mGy while the depiction of calcifications remained good, and there was no systematic difference in calcification burden between the two protocols. KEY POINTS: • Tin-filtered, low-dose CT can be used to assess aortic calcifications before cardiac surgery • An optimized Sn100 protocol achieved a mean SSDE of only 0.5 ± 0.1 mGy • The depiction of atherosclerosis of the thoracic aorta was similar with both protocols • The depiction of relevant thoracic pathologies before cardiac surgery was similar with both protocols.

Interobserver Variability of Sonographic Features Used in the American College of Radiology Thyroid Imaging Reporting and Data System.

OBJECTIVE: The purpose of this study was to assess interobserver variability in assigning features in the American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) lexicon and in making recommendations for thyroid nodule biopsy. MATERIALS AND METHODS: The study cohort comprised 100 nodules in 92 patients who underwent fine-needle aspiration with definitive cytologic results (Bethesda category II or VI) or diagnostic lobectomy between April 2009 and May 2010. Eight board-certified radiologists evaluated the nodules according to the five feature categories that constitute ACR TI-RADS and gave a biopsy recommendation based on their own practice. Variability in feature assignment and biopsy recommendation was assessed with the Fleiss kappa statistic. RESULTS: Agreement in interpretation was fair to moderate for all features except shape (κ = 0.61) and macrocalcifications (κ = 0.73), which had substantial agreement. The features with the poorest agreement were margin and other types of echogenic foci, which had kappa values ranging from 0.25 to 0.39, indicating fair agreement. Interobserver agreement regarding biopsy recommendation was fair (κ = 0.22) based on radiologists' current practice. Applying ACR TI-RADS resulted in moderate agreement (κ = 0.51). CONCLUSION: Variability in interpreting thyroid nodule sonographic features was highest for margin and all types of echogenic foci, except for macrocalcifications. Because radiologists' interpretations of these features change the level of suspicion of thyroid malignancy, the results of this study suggest a need for further education. Despite the variability in assigning features, adoption of ACR TI-RADS improves agreement for recommending biopsy.

National Characteristics of Lymphatic Malformations in Children: Inpatient Estimates and Trends in the United States, 2000 to 2009.

With ever increasing demands to manage finite resources for health care utilization, we performed an investigation to identify inpatient clinical characteristics and trends in children with lymphatic malformations using the Kids' Inpatient Database, years 2000 to 2009, to help identify populations best suited for resource deployment. Subjects included children 18 years and below with International Classification of Diseases (ICD), ninth revision code: 228.1-lymphangioma, any site. In the United States, between 2000 and 2009, inpatient pediatric patients with lymphatic malformations most commonly affected children aged 3 years and younger, urban hospital locations, and the South and West regions. There was no significant change in age of children with lymphatic malformations or the distribution of their age from year to year, P=0.948 and 0.4223, respectively. No significant evidence for seasonal variation or effect on inpatient admission was identified, P=0.7071. A great majority of admissions (>96%) were in urban locations across each year. There was also no significant change in breakdown of admissions by geographic location, P=0.7133. Further investigation may help to elucidate how to improve access to multidisciplinary vascular anomalies teams to optimize care for these children with unique and complex lymphatic malformations.

Risk Factors for Delayed Referral to a Craniofacial Specialist for Treatment of Craniosynostosis.

OBJECTIVE: To assess the impact of age at referral on treatment options in craniosynostosis and to identify risk factors for referral delays in this population. STUDY DESIGN: A retrospective cohort study was performed on patients with an abnormal head shape diagnosis treated at a single academic medical center between January 1, 2004 and January 1, 2014. Newly diagnosed patients with craniosynostosis were identified and referral patterns were examined. A multivariate logistic regression model was used to identify risk factors associated with the range of ages at initial referral. RESULTS: A total of 477 patients were evaluated at our institution, 197 of whom were subsequently diagnosed with craniosynostosis. The median age at initial appointment was 5.6 months (mean 8.2 months). Only 28% of children were referred within 3 months of birth. Patients referred within 3 months of birth were less likely to have had preappointment imaging than those patients referred slightly later (OR 2.53, CI 1.07-5.98, P = .035). Several variables were associated with referral after 12 months of age including multiple suture involvement (OR 4.21, CI 1.06-16.68, P = .041), minority race (OR 4.96, CI 1.91-12.9, P ≤ .0001), and referral by a nonpediatrician (OR 6.9, CI 1.73-27.49, P = .006). CONCLUSIONS: Obtaining imaging before referral to a specialist for abnormal head shape was associated with a delay in evaluation and potentially increases radiation exposure and limits treatment options in patients with craniosynostosis. In addition, children from minority groups, children referred from someone other than a pediatrician's office, and those with multiple suture craniosynostosis are at increased risk of delayed referral. Further studies into the cause of these delays are warranted.

Characterization of Incidental Renal Mass With Dual-Energy CT: Diagnostic Accuracy of Effective Atomic Number Maps for Discriminating Nonenhancing Cysts From Enhancing Masses.

OBJECTIVE: The purpose of this study was to assess the diagnostic accuracy of effective atomic number maps reconstructed from dual-energy contrast-enhanced data for discriminating between nonenhancing renal cysts and enhancing masses. MATERIALS AND METHODS: Two hundred six patients (128 men, 78 women; mean age, 64 years) underwent a CT renal mass protocol (single-energy unenhanced and dual-energy contrast-enhanced nephrographic imaging) at two different hospitals. For each set of patients, two blinded, independent observers performed measurements on effective atomic number maps from contrast-enhanced dual-energy data. Renal mass assessment on unenhanced and nephrographic images, corroborated by imaging and medical records, was the reference standard. The diagnostic accuracy of effective atomic number maps was assessed with ROC analysis. RESULTS: Significant differences in mean effective atomic numbers (Zeff) were observed between nonenhancing and enhancing masses (set A, 8.19 vs 9.59 Zeff; set B, 8.05 vs 9.19 Zeff; sets combined, 8.13 vs 9.37 Zeff) (p < 0.0001). An effective atomic number value of 8.36 Zeff was the optimal threshold, rendering an AUC of 0.92 (95% CI, 0.89-0.94), sensitivity of 90.8% (158/174 [95% CI, 85.5-94.7%]), specificity of 85.2% (445/522 [95% CI, 81.9-88.2%]), and overall diagnostic accuracy of 86.6% (603/696 [95% CI, 83.9-89.1%]). CONCLUSION: Nonenhancing renal cysts, including hyperattenuating cysts, can be discriminated from enhancing masses on effective atomic number maps generated from dual-energy contrast-enhanced CT data. This technique may be of clinical usefulness when a CT protocol for comprehensive assessment of renal masses is not available.

Post-Surgical Relapse in Metopic Synostosis and Limitations of the Interfrontal Angle as an Outcome Measure.

BACKGROUND: The interfrontal angle (IFA) has been utilized as a surrogate for morphologic assessment of the anterior cranial region in metopic synostosis with success in characterizing presenting severity. Its utility as an outcome measure has not been assessed similarly. In this study, we aimed to determine whether meaningful information relative to shape, and relapse in particular, could be assessed using the IFA. METHODS: Patients with operatively treated isolated metopic synostosis were identified and included based on the availability of "previously obtained" low-dose computerized tomography (CT) scans at (1) preoperative and 2 postoperative (2) postoperative day-3 and (3) 1 year time points. Relapse was calculated as the percentage of the operatively induced change in IFA that was retained after the first postoperative year. RESULTS: After exclusionary criteria, 19 patients were identified. The mean IFA values at the 3 time points were 119.3° (±9.8), 139.6° (±6.3), and 135.3° (±7.1), chronologically. Of the 19 patients, 14 (73.7%) experienced relapse, with this subgroup averaging 62.4% retention of their surgical change after 1 year. Increased preoperative severity and delayed age at surgical intervention were concurrently associated with an increased occurrence of relapse (P = 0.011). Another model utilizes preoperative IFA to predict the change in IFA that would accompany surgery on a case-by-case basis (P < 0.0001). CONCLUSIONS: (1) Fronto-orbital advancement offers immediate correction in the frontal bandeau. (2) Surgical impact, using fronto-orbital advancement, can be predicted using preoperative severity. (3) A component of postoperative relapse occurs within the frontal bandeau and is detectable at 1 year via the IFA. Exclusively, the IFA cannot characterize holistic postoperative relapse due to its inherent anatomical constraints; this supports the cessation of routine postoperative computerized tomography scans for determining outcomes.

Finerenone and left ventricular hypertrophy in chronic kidney disease and type 2 diabetes.

AIMS: Left ventricular hypertrophy (LVH) has been associated with an increased risk of cardiovascular (CV) disease and linked to increased morbidity and mortality. In patients with chronic kidney disease (CKD) and type 2 diabetes (T2D), hypertension is common, and patients with these co-morbidities additionally have a high prevalence of LVH. This analysis of the prespecified pooled FIDELITY analysis comprising the randomized, double-blind, placebo-controlled, multicentre FIDELIO-DKD and FIGARO-DKD phase III studies aimed to explore the CV and kidney effects of finerenone, a nonsteroidal mineralocorticoid receptor antagonist, in patients with CKD and T2D stratified by a diagnosis of LVH at baseline. METHODS AND RESULTS: A diagnosis of LVH in the FIDELITY patient population was determined at baseline using investigator-reported electrocardiogram (ECG) findings. The two efficacy outcomes, assessed by baseline LVH, were the composite CV outcome of time to CV death, non-fatal myocardial infarction, non-fatal stroke, or hospitalization for heart failure (HHF), and a composite kidney outcome of time to onset of kidney failure, a sustained decrease in estimated glomerular filtration rate (eGFR) ≥57% from baseline over ≥4 weeks, or kidney-related death. Safety outcomes by baseline LVH were reported as treatment-emergent adverse events. At baseline out of 13 026 patients in FIDELITY, 96.5% had hypertension and 9.6% had investigator-reported LVH. The relative risk reduction for the composite CV and kidney outcomes with finerenone versus placebo was lower in the LVH subgroup; however, the treatment effect of finerenone was not modified by baseline LVH for either outcome (Pinteraction = 0.1075 for composite CV outcome and Pinteraction = 0.1782 for composite kidney outcome). Analysis of the composite CV outcome components showed a greater reduction in the risk of HHF versus placebo for patients with baseline LVH compared with those without (Pinteraction = 0.0024). Overall safety events were comparable between the LVH subgroups and treatment arms. Treatment-emergent hyperkalaemia was observed more frequently with finerenone versus placebo, but discontinuation rates were low in both treatment arms and between LVH subgroups. CONCLUSIONS: In conclusion, the overall CV and kidney benefits of finerenone versus placebo were not modified by the presence of LVH at baseline, with overall safety findings being similar between LVH subgroups. A greater benefit was observed for HHF in patients with versus without LVH, suggesting that LVH may be a predictor of the treatment effect of finerenone on HHF.

Finerenone cardiovascular and kidney outcomes by age and sex: FIDELITY post hoc analysis of two phase 3, multicentre, double-blind trials.

OBJECTIVES: This study aimed to evaluate the efficacy and safety of finerenone, a selective, non-steroidal mineralocorticoid receptor antagonist, on cardiovascular and kidney outcomes by age and/or sex. DESIGN: FIDELITY post hoc analysis; median follow-up of 3 years. SETTING: FIDELITY: a prespecified analysis of the FIDELIO-DKD and FIGARO-DKD trials. PARTICIPANTS: Adults with type 2 diabetes and chronic kidney disease receiving optimised renin-angiotensin system inhibitors (N=13 026). INTERVENTIONS: Randomised 1:1; finerenone or placebo. PRIMARY AND SECONDARY OUTCOME MEASURES: Cardiovascular (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or hospitalisation for heart failure (HHF)) and kidney (kidney failure, sustained ≥57% estimated glomerular filtration rate (eGFR) decline or renal death) composite outcomes. RESULTS: Mean age was 64.8 years; 45.2%, 40.1% and 14.7% were aged <65, 65-74 and ≥75 years, respectively; 69.8% were male. Cardiovascular benefits of finerenone versus placebo were consistent across age (HR 0.94 (95% CI 0.81 to 1.10) (<65 years), HR 0.84 (95% CI 0.73 to 0.98) (65-74 years), HR 0.80 (95% CI 0.65 to 0.99) (≥75 years); Pinteraction=0.42) and sex categories (HR 0.86 (95% CI 0.77 to 0.96) (male), HR 0.89 (95% CI 0.35 to 2.27) (premenopausal female), HR 0.87 (95% CI 0.73 to 1.05) (postmenopausal female); Pinteraction=0.99). Effects on HHF reduction were not modified by age (Pinteraction=0.70) but appeared more pronounced in males (Pinteraction=0.02). Kidney events were reduced with finerenone versus placebo in age groups <65 and 65-74 but not ≥75; no heterogeneity in treatment effect was observed (Pinteraction=0.51). In sex subgroups, finerenone consistently reduced kidney events (Pinteraction=0.85). Finerenone reduced albuminuria and eGFR decline regardless of age and sex. Hyperkalaemia increased with finerenone, but discontinuation rates were <3% across subgroups. Gynaecomastia in males was uncommon across age subgroups and identical between treatment groups. CONCLUSIONS: Finerenone improved cardiovascular and kidney composite outcomes with no significant heterogeneity between age and sex subgroups; however, the effect on HHF appeared more pronounced in males. Finerenone demonstrated a similar safety profile across age and sex subgroups. TRIAL REGISTRATION NUMBERS: NCT02540993, NCT02545049.

Validation of the Klinrisk chronic kidney disease progression model in the FIDELITY population.

Background: Chronic kidney disease (CKD) affects >800 million individuals worldwide and is often underrecognized. Early detection, identification and treatment can delay disease progression. Klinrisk is a proprietary CKD progression risk prediction model based on common laboratory data to predict CKD progression. We aimed to externally validate the Klinrisk model for prediction of CKD progression in FIDELITY (a prespecified pooled analysis of two finerenone phase III trials in patients with CKD and type 2 diabetes). In addition, we sought to identify evidence of an interaction between treatment and risk. Methods: The validation cohort included all participants in FIDELITY up to 4 years. The primary and secondary composite outcomes included a ≥40% decrease in estimated glomerular filtration rate (eGFR) or kidney failure, and a ≥57% decrease in eGFR or kidney failure. Prediction discrimination was calculated using area under the receiver operating characteristic curve (AUC). Calibration plots were calculated by decile comparing observed with predicted risk. Results: At time horizons of 2 and 4 years, 993 and 1795 patients experienced a primary outcome event, respectively. The model predicted the primary outcome accurately with an AUC of 0.81 for 2 years and 0.86 for 4 years. Calibration was appropriate at both 2 and 4 years, with Brier scores of 0.067 and 0.115, respectively. No evidence of interaction between treatment and risk was identified for the primary composite outcome (P = .31). Conclusions: Our findings demonstrate the accuracy and utility of a laboratory-based prediction model for early identification of patients at the highest risk of CKD progression.

Finerenone in Black Patients With Type 2 Diabetes and CKD: A Post hoc Analysis of the Pooled FIDELIO-DKD and FIGARO-DKD Trials.

Rationale & Objective: In FIDELITY, finerenone improved cardiorenal outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes (T2D). This analysis explored the efficacy and safety of finerenone in Black patients. Study Design: Subanalysis of randomized controlled trials. Setting & Participants: Patients with T2D and CKD. Intervention: Finerenone or placebo. Outcomes: Composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure; composite of kidney failure, sustained ≥57% estimated glomerular filtration rate (eGFR) decline from baseline maintained for ≥4 weeks, or renal death. Results: Of the 13,026 patients, 522 (4.0%) self-identified as Black. Finerenone demonstrated similar effects on the cardiovascular composite outcome in Black (HR, 0.79 [95% CI, 0.51-1.24]) and non-Black patients (HR, 0.87 [95% CI, 0.79-0.96; P = 0.5 for interaction]). Kidney composite outcomes were consistent in Black (HR, 0.71 [95% CI, 0.43-1.16]) and non-Black patients (HR, 0.76 [95% CI, 0.66-0.88; P = 0.9 for interaction]). Finerenone reduced urine albumin-to-creatinine ratio by 40% at month 4 (least-squares mean treatment ratio, 0.60 [95% CI, 0.52-0.69; P < 0.001]) in Black patients and 32% at month 4 (least-squares mean treatment ratio, 0.68 [95% CI, 0.66-0.70; P < 0.001]) in non-Black patients, versus placebo. Chronic eGFR decline (month 4 to end-of-study) was slowed in Black and non-Black patients treated with finerenone versus placebo (between-group difference, 1.4 mL/min/1.73 m2 per year [95% CI, 0.33-2.44; P = 0.01] and 1.1 mL/min/1.73 m2 per year [95% CI, 0.89-1.28; P < 0.001], respectively). Safety outcomes were similar between subgroups. Limitations: Small number of Black patients; analysis was not originally powered to determine an interaction effect based on Black race. Conclusions: The efficacy and safety of finerenone appears consistent in Black and non-Black patients with CKD and T2D. Funding: Bayer AG. Trial Registration: ClinicalTrials.gov NCT02540993, NCT02545049. Plain-Language Summary: Diabetes is a major cause of chronic kidney disease (CKD), affecting more Black adults than White adults. Most adults with CKD ultimately die from heart and vascular complications (eg, heart attack and stroke) rather than kidney failure. This analysis of 2 recent trials shows that the drug finerenone was beneficial for patients with diabetes and CKD. Along with reducing kidney function decline and protein in the urine, it also decreased heart and vascular issues and lowered blood pressure in both Black and non-Black adults with diabetes and CKD. These findings have promising implications for slowing the progression of CKD and protecting against cardiovascular problems in diverse populations.

36-month clinical outcomes of patients with venous thromboembolism: GARFIELD-VTE.

BACKGROUND: Venous thromboembolism (VTE), encompassing both deep vein thrombosis (DVT) and pulmonary embolism (PE), is a leading cause of morbidity and mortality worldwide. METHODS: GARFIELD-VTE is a prospective, non-interventional observational study of real-world treatment practices. We aimed to capture the 36-month clinical outcomes of 10,679 patients with objectively confirmed VTE enrolled between May 2014 and January 2017 from 415 sites in 28 countries. FINDINGS: A total of 6582 (61.6 %) patients had DVT alone, 4097 (38.4 %) had PE ± DVT. At baseline, 98.1 % of patients received anticoagulation (AC) with or without other modalities of therapy. The proportion of patients on AC therapy decreased over time: 87.6 % at 3 months, 73.0 % at 6 months, 54.2 % at 12 months and 42.0 % at 36 months. At 12-months follow-up, the incidences (95 % confidence interval [CI]) of all-cause mortality, recurrent VTE and major bleeding were 6.5 (7.0-8.1), 5.4 (4.9-5.9) and 2.7 (2.4-3.0) per 100 person-years, respectively. At 36-months, these decreased to 4.4 (4.2-4.7), 3.5 (3.2-2.7) and 1.4 (1.3-1.6) per 100 person-years, respectively. Over 36-months, the rate of all-cause mortality and major bleeds were highest in patients treated with parenteral therapy (PAR) versus oral anti-coagulants (OAC) and no OAC, and the rate of recurrent VTE was highest in patients on no OAC versus those on PAR and OAC. The most frequent cause of death after 36-month follow-up was cancer (n = 565, 48.6 %), followed by cardiac (n = 94, 8.1 %), and VTE (n = 38, 3.2 %). Most recurrent VTE events were DVT alone (n = 564, 63.3 %), with the remainder PE, (n = 236, 27.3 %), or PE in combination with DVT (n = 63, 7.3 %). INTERPRETATION: GARFIELD-VTE provides a global perspective of anticoagulation patterns and highlights the accumulation of events within the first 12 months after diagnosis. These findings may help identify treatment gaps for subsequent interventions to improve patient outcomes in this patient population.