International Outcome Study Research Articles

Three-Year Outcomes of VEGF Inhibitors in Naive Branch Retinal Vein Occlusion: Fight Retinal Blindness!

To evaluate the 3-year outcomes of VEGF inhibitors in the treatment of cystoid macular edema due to branch retinal vein occlusion (BRVO) in an international multicenter cohort of eyes. Multicenter, international, BRVO database study. Seven hundred forty-seven patients (760 eyes) undergoing intravitreal therapy for BRVO for 3 years in a multicenter international setting. Demographics, visual acuity (VA) in logarithm of the minimum angle of resolution letters, central subfield thickness (CST), treatments, number of injections, and visits data was collected using a validated web-based tool. Visual acuity gain at 3 years in logarithm of the minimum angle of resolution letters. Secondary outcome measures included anatomical results, treatment pattern, and percentage of completers. A subgroup analysis by study drug was conducted for clinical outcomes. Mean adjusted VA change was+11 letters (95% confidence interval 9-13), mean adjusted change in CST was-176 μm (-193,-159). Median number of injections/visits was 16 of 24 at 3 years of follow-up. Most eyes received VEGF inhibitors exclusively (89%, n= 677) and as a monotherapy in 71% (n= 538). Few eyes were switched to steroids (11%, n= 83). Suspensions in treatment >180 days occurred in 26% of study eyes. Aflibercept showed greater CST reductions (-147 vs.-128 vs.-114 μm; P < 0.001) and significantly lower switching rates (14% vs. 38% vs. 33%; P < 0.001) compared with ranibizumab and bevacizumab, respectively. This international study of 3-year BRVO outcomes after starting treatment with VEGF inhibitors found adequate visual and anatomical results in routine clinical care. Visual outcomes were similar among the different initiating VEGF inhibitors, although eyes starting with aflibercept had better anatomical outcomes and a lower switching rate. Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

P281 Quality of life in adults with dysferlinopathy: international clinical outcome study of dysferlinopathy

P281 Quality of life in adults with dysferlinopathy: international clinical outcome study of dysferlinopathy

Long-term Effectiveness and Safety of GH Replacement Therapy in Adults ≥60 Years: Data From NordiNet® IOS and ANSWER.

Effectiveness and safety data on GH replacement therapy (GHRT) in older adults with adult GH deficiency (AGHD) are limited. To compare GHRT safety and clinical outcomes in older (≥60 years and, for some outcomes, ≥75 years) and middle-aged (35-<60 years) patients with AGHD. Ten-year follow-up, real-world data from 2 large noninterventional studies-NordiNet® International Outcome Study (IOS) and the American Norditropin® Studies: Web-Enabled Research (ANSWER) Program-were analyzed. GH-naïve and non-naïve patients with AGHD. Norditropin® (somatropin). Outcomes included GH exposure, IGF-I standard deviation scores (SDS), body mass index (BMI), glycated hemoglobin (HbA1c), serious and nonserious adverse reactions (SARs and NSARs, respectively), and serious adverse events (SAEs). Adverse reactions were events with possible/probable causal relationship to GHRT. The effectiveness analysis set comprised 545 middle-aged and 214 older patients (19 aged ≥75 years) from NordiNet® IOS. The full analysis set comprised 1696 middle-aged and 652 older patients (59 aged ≥75 years) from both studies. Mean GH doses were higher in middle-aged vs older patients. For both age groups and sexes, mean IGF-I SDS increased following GHRT, while BMI and HbA1c changes were similar and small.Incidence rate ratios (IRRs) did not differ statistically between older and middle-aged patients for NSARs [IRR (mean, 95% confidence interval) 1.05 (.60; 1.83)] or SARs [.40 (.12; 1.32)]. SAEs were more frequent in older than middle-aged patients [IRR 1.84 (1.29; 2.62)]. Clinical outcomes of GHRT in AGHD were similar in middle-aged and older patients, with no significantly increased risk of GHRT-related adverse reactions in older patients.

510 Prospective, Multicenter, International Outcomes Study of Deep Brain Stimulation for Essential Tremor

INTRODUCTION: Essential Tremor (ET) treatment is focused on medical management of motor symptoms and includes pharmacotherapy and ventral intermediate nucleus (VIM) thalamotomy, which is being largely replaced by thalamic Deep Brain Stimulation (DBS) as the surgical treatment of choice. DBS of the VIM thalamus is recommended as a therapeutic option for appropriate subjects with ET (Elble RJ., et al. Expert Rev Neurother. 2018). METHODS: This is a prospective, on-label, multi-center, international DBS outcomes study conducted at up to 50 implanting centers. All participants are implanted with a multiple-source, constant-current directional DBS system (Vercise, Boston Scientific). Subjects are followed for up to 3-years post implantation where their overall improvement in quality of life and ET symptoms are evaluated. Clinical endpoints evaluated at baseline and follow-up timepoints include: The Essential Tremor Rating Assessment Scale (TETRAS), Quality of Life in Essential Tremor Questionnaire (QUEST), Fahn-Tolosa-Marin Rating Scale (TRS), and Global Impression of Change. Adverse events also collected. RESULTS: To date, 18-implanted subjects with a mean disease duration of 15.1 ± 14.6-years and a baseline QUEST Summary Index score of 35.0 ± 12.4. At 6-months post-DBS, a clinically significant improvement in quality of life (∆ = 19.5-point change in QUEST SI score) was reported. In addition, a mean 9-hours of tremor reduction was noted (14-hours at Baseline, 6.9-hours at 6-months) in a typical day at 6-months. All subjects (100%) reported mild disability, and no subject reported moderate or marked disability (89% at baseline) as reported by TRS at 6 months. CONCLUSIONS: This work represents the first comprehensive, large scale collection of real-world outcomes and evaluation of safety and effectiveness of a multiple-source, constant-current DBS system capable of providing directionality for use in treatment of Essential Tremor.

Early Growth Hormone Initiation Leads to Favorable Long-Term Growth Outcomes in Children Born Small for Gestational Age.

Early initiation of growth hormone (GH) therapy is recommended for short children born small for gestational age (SGA); however, real-world data indicate that treatment is often delayed. We aimed to assess the impact of patient age at GH therapy initiation on long-term growth outcomes and safety in short children born SGA. Analysis of pooled data from NordiNet® International Outcome Study (NCT00960128; 469 European clinics) and the ANSWER Program (NCT01009905; 207 US clinics), two large, complementary observational studies. Patients received GH as prescribed by their treating physician. Enrolled patients born SGA were categorized into three groups based on their age at GH treatment initiation: 2 to <4 years, 4 to <6 years, and ≥6 years. Patient characteristics at birth and GH initiation, auxology, and safety data were evaluated. The effectiveness analysis (treatment-naïve and prepubertal patients at GH initiation) included 3318 patients: 10.7% aged 2 to <4 years at therapy initiation, 31.6% aged 4 to <6 years, and 57.7% aged ≥6 years. Following 8 years of therapy, the mean improvement in height standard deviation score from baseline was significantly greater in the 2 to <4 years group vs the 4 to <6 years (+2.5 vs +2.2; P = 0.0054) and ≥6 years groups (+2.5 vs +1.7; P < 0.0001). No unexpected safety events were reported. Early initiation of GH therapy in short children born SGA may be an important contributor to height optimization. The data are reassuring regarding the long-term safety of GH therapy in this population.

LBMON197 Predictors Of Response To Growth Hormone Treatment In Pediatric Growth Disorders: Analysis From The Answer Program And Nordinet® IOS

Abstract Background The American Norditropin® Studies: Web-Enabled Research (ANSWER) Program and the NordiNet® International Outcome Study (NordiNet® IOS) were large-scale, non-interventional studies intended to gather long-term data on the effectiveness and safety of Norditropin® (somatropin) treatment in the real-world setting. Data were collected in the US and Europe from 2006 to 2016. Objective To determine predictors of response to daily growth hormone (GH) for height outcomes using a longitudinal analysis across 5 years of real-world data from pediatric patients with growth hormone deficiency (GHD), Turner syndrome (TS), Noonan syndrome (NS), and Prader-Willi syndrome (PWS). Methods Data were combined for ANSWER and NordiNet® IOS studies for GH-treatment-naïve pediatric patients on daily somatropin. Descriptive statistics for baseline demographics, outcomes, and GH (mg/kg/d) data were analyzed for each indication; statistics for outcome and GH data were analyzed over time for absolute values and change from baseline values at year 1 through year 5. A longitudinal statistical approach was used to identify factors, including age at treatment start and HSDS at baseline, significantly associated with change in height SDS from baseline (ΔHSDS) in a regression model. Repeated-measures regression analyses were performed on ΔHSDS, adjusting for covariates. Longitudinal growth responses over the follow-up years were evaluated. Results Overall, 14,295 patients were included in the analyses: 3766 females and 8917 males with GHD, 1307 patients with TS, 55 females and 148 males with NS, and 52 females and 50 males with PWS. Mean (SD) GH dose for patients with GHD was 0. 037 (0. 012) mg/kg/d (females) and 0. 038 (0. 012) mg/kg/d (males), for those with TS was 0. 045 (0. 011) mg/kg/d, those with NS was 0. 042 (0. 012) mg/kg/d, and those with PWS was 0. 031 (0. 013) mg/kg/d. HSDS improved over time across all indications. Greater improvement in HSDS was observed for years 1 and 2 of follow-up, with a plateau in years 4 and 5; this plateau was most apparent in patients with TS. Age at start of GH therapy had a significant effect on ΔHSDS for all indications (P&amp;lt;0. 001 for all). Lower baseline HSDS on average resulted in lower HSDS improvement over time. In a regression model, the GH dose (mg/kg/d) from the previous year was positively associated with ΔHSDS, with a significant positive slope for GHD and TS (P&amp;lt;0. 0001 for both). A 0. 01 increase in GH mg/kg/d increased the average HSDS improvement by 0. 02 to 0. 03 units in GHD and 0. 03 units in TS. Slopes for NS (P=0.3534) and PWS (P=0.1485) were not significant. Conclusions On average, GH treatment resulted in HSDS improvements over baseline across all indications; patients with GHD had the highest improvement, while patients with TS had the lowest improvement. Earlier treatment with GH led to better outcomes in HSDS. Increasing the dose of GH also led to better outcomes in HSDS. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m.

Comparative effectiveness of biologics in clinical practice: week 12 primary outcomes from an international observational psoriasis study of health outcomes (PSoHO).

Clinical trials study treatment outcomes under stringent conditions, capturing incompletely the heterogeneity of patient populations and treatment complexities encountered in real-world practice. To compare the effectiveness of anti-interleukin (IL)-17A biologics relative to other approved biologics in patients with moderate-to-severe psoriasis. The Psoriasis Study of Health Outcomes (PSoHO) is an ongoing 3-year observational cohort study in adults with chronic moderate-to-severe plaque psoriasis initiating or switching to a new biologic. Primary study endpoint is the proportion of patients achieving 90% improvement in Psoriasis Area and Severity Index (PASI 90) and/or static Physician Global Assessment (sPGA) 0/1 at Week 12 (W12) in the anti-IL-17A cohort (ixekizumab [IXE], secukinumab) vs. all other approved biologics. Secondary outcomes include the proportion of patients who achieve PASI 75/90/100, absolute PASI scores ≤5, ≤2 and ≤1, Dermatology Life Quality Index (DLQI) score of 0/1 at W12 between the two cohorts and among the individual biologics. Comparative effectiveness analyses were conducted using Frequentist Model Averaging (FMA), a novel causal inference machine learning approach. Missing data for binary outcomes were imputed as non-response. Patient profiles in the anti-IL-17A cohort and other biologics cohort were similar, with more frequent comorbid psoriatic arthritis and less frequent exposure to conventional treatments in the patients receiving anti-IL-17A biologics. At W12, 71.4% of patients who received an anti-IL-17A biologic achieved PASI 90 and/or sPGA 0/1 compared to 58.6% of patients who received other biologics (odds ratios [OR], 1.9; 95% confidence intervals [CI], [1.6, 2.4]). Similar findings were observed for secondary outcomes. These results reflect the high efficacy and early onset of skin clearance of IL-17A inhibitors observed in randomized clinical trials and confirm the effectiveness of anti-IL-17A biologics in the real-world setting.

Abstract 2: Effectiveness and safety of early growth hormone treatment in children born small for gestational age: Long-term data from NordiNet® International Outcome Study (IOS) and ANSWER program

Background: Growth hormone (GH) is indicated for the treatment of short stature in children born small for gestational age (SGA) who fail to show catch-up growth. In pilot studies, early initiation of GH has been associated with favorable growth responses in short SGA children. However, few studies have examined the short- and long-term effects of initiating GH in children born SGA who are <4 years (yr) of age, compared with those starting later. This analysis therefore investigated the effect of age at GH initiation on long-term effectiveness and safety in children born SGA.Methods: The NordiNet IOS (NCT00960128) and ANSWER (NCT01009905) programs are complementary, noninterventional, multicenter studies that evaluated the long-term effectiveness and safety of Norditropin (somatropin; Novo Nordisk A/S, Denmark) as prescribed in real-life clinical practice. In this analysis, children born SGA who were prepubertal at GH initiation were grouped according to age at GH start: <4 yr, 4-6 yr, and ≥6 yr. Patient characteristics at birth and at GH start, auxological measurements, and adverse events were evaluated in each group.Results: Overall, 3351 SGA patients were included in the effectiveness set (age at GH start: <4 yr [n=389, 54.8% male]; 4-6 yr [n=1048, 57.6% male]; and ≥6 yr [n=1914, 56.6% male]). The proportion of patients born pre-term (<37-week gestation) was 38.6% in the <4 yr group, 36.1% in the 4-6 yr group, and 28.2% in the ≥6 yr group. Mean (SD) birth length standard deviation score (SDS) and birth weight SDS were: −2.9 (1.6) and −2.3 (1.2) in the <4 yr group, −2.8 (1.3) and −2.2 (1.1) in the 4-6 yr group, and −2.5 (1.4) and −2.0 (1.2) in the ≥6 yr group. Mean (SD) age at GH start was 3.1 (0.7), 4.9 (0.6), and 9.3 (2.2) years in the <4 yr, 4-6 yr, and ≥6 yr groups, respectively. Mean (SD) GH duration and daily GH dose in the study were: 3.5 (3.1) yr and 0.044 (0.016) mg/kg in the <4 yr group, 4.1 (3.1) yr and0.039 (0.012) mg/kg in the 4-6 yr group, and 3.5 (2.5) yr and 0.042 (0.012) mg/kg in the ≥6 yr group. Mean (SD) height SDS (HSDS) at GH start was −3.3 (1.2) in the <4 yr group, −3.1 (0.9) in the 4-6 yr group, and −2.8 (0.8) in the ≥6 yr group. After 4 and 8 yr of GH, mean (SD) ÄHSDS from baseline was 1.7 (0.7) and 2.5 (0.6) in the <4 yr group, 1.6 (0.7) and 2.2 (0.8) in the 4-6 yr group and 1.3 (0.7), and 1.7 (0.6) in the ≥6 yr group. Among patients who reached near-adult height in the study, mean (SD) HSDS was −1.9 (0.6) in the <4 yr group (n=3), −1.9 (0.8) in the 4-6 yr group (n=10), and −1.8 (1.0) in the ≥6 yr group (n=220). In the safety set (n=5643), the most commonly reported non-serious adverse reactions (AR) were headache (n=20) and arthralgia (n=5). The most common serious ARs were headache (n=3) and epiphysiolysis (n=4). ARs and serious ARs were distributed equally among groups.Conclusions: This analysis of real-world data confirms the effectiveness and safety of GH in children born SGA, irrespective of patient age at treatment initiation.

COVID-19 in Lymphangioleiomyomatosis: An International Study of Outcomes and Impact of Mechanistic Target of Rapamycin Inhibition

Lymphangioleiomyomatosis is a rare low-grade neoplastic lung disease that occurs sporadically in women or in people with tuberous sclerosis complex. Mechanistic target of rapamycin (mTOR) inhibitors are used for patients with progressive or severe pulmonary impairment or extrapulmonary manifestations.1

Case-Fatality and Functional Outcome after Subarachnoid Hemorrhage (SAH) in INternational STRoke oUtComes sTudy (INSTRUCT)

BackgroundThere are few large population-based studies of outcomes after subarachnoid hemorrhage (SAH) than other stroke types. MethodsWe pooled data from 13 population-based stroke incidence studies (10 studies from the INternational STRroke oUtComes sTudy (INSTRUCT) and 3 new studies; N=657). Primary outcomes were case-fatality and functional outcome (modified Rankin scale score 3-5 [poor] vs. 0-2 [good]). Harmonized patient-level factors included age, sex, health behaviours (e.g. current smoking at baseline), comorbidities (e.g.history of hypertension), baseline stroke severity (e.g. NIHSS >7) and year of stroke. We estimated predictors of case-fatality and functional outcome using Poisson regression and generalized estimating equations using log-binomial models respectively at multiple timepoints. ResultsCase-fatality rate was 33% at 1 month, 43% at 1 year, and 47% at 5 years. Poor functional outcome was present in 27% of survivors at 1 month and 15% at 1 year. In multivariable analysis, predictors of death at 1-month were age (per decade increase MRR 1.14 [1.07-1.22]) and SAH severity (MRR 1.87 [1.50-2.33]); at 1 year were age (MRR 1.53 [1.34-1.56]), current smoking (MRR 1.82 [1.20-2.72]) and SAH severity (MRR 3.00 [2.06-4.33]) and; at 5 years were age (MRR 1.63 [1.45-1.84]), current smoking (MRR 2.29 [1.54-3.46]) and severity of SAH (MRR 2.10 [1.44-3.05]). Predictors of poor functional outcome at 1 month were age (per decade increase RR 1.32 [1.11-1.56]) and SAH severity (RR 1.85 [1.06-3.23]), and SAH severity (RR 7.09 [3.17-15.85]) at 1 year. ConclusionAlthough age is a non-modifiable risk factor for poor outcomes after SAH, however, severity of SAH and smoking are potential targets to improve the outcomes.

Long-term safety of growth hormone treatment in childhood: two Large observational studies: nordiNet IOS and ANSWER

Context: Growth hormone (GH) treatment has a generally good safety profile; however, concerns about increased mortality risk in adulthood have been raised. Objective: This work aims to assess the long-term safety of GH treatment in clinical practice. Methods: Data were collected from 676 clinics participating in 2 multicenter longitudinal observational studies: the NordiNet International Outcome Study (2006-2016, Europe) and ANSWER Program (2002-2016, USA). Pediatric patients treated with GH were classified into 3 risk groups based on diagnosis. Intervention consisted of daily GH treatment, and main outcome measures included incidence rates (events/1000 patient-years) of adverse drug reactions (ADRs), serious adverse events (SAEs), and serious ADRs, and their relationship to GH dose. Results: The combined studies comprised 37702 patients (68.4% in low-risk, 27.5% in intermediate-risk, and 4.1% in high-risk groups) and 130476 patient-years of exposure. The low-risk group included children born small for gestational age (SGA; 20.7%) and non-SGA children (eg, with GH deficiency; 79.3%). Average GH dose up to the first adverse event (AE) decreased with increasing risk category. Patients without AEs received higher average GH doses than patients with more than one AE across all groups. A significant inverse relationship with GH dose was shown for ADR and SAE incidence rates in the low-risk group (P=.003 and P=.001, respectively) and the non-SGA subgroup (both P=.002), and for SAEs in the intermediate-and high-risk groups (P=.002 and P=.05, respectively). Conclusions: We observed no indication of increased mortality risk nor AE incidence related to GH dose in any risk group. A short visual summary of our work is available (1).

Effectiveness and Safety of Early Growth Hormone Treatment in Children Born Small for Gestational Age: Long-Term Data From NordiNet® International Outcome Study (IOS) and ANSWER Program

Background: Growth hormone (GH) is indicated for the treatment of short stature in children born small for gestational age (SGA) who fail to show catch-up growth. In pilot studies, early initiation of GH has been associated with favorable growth responses in short SGA children. However, few studies have examined the short- and long-term effects of initiating GH in children born SGA who are <4 years (yr) of age, compared with those starting later. This analysis therefore investigated the effect of age at GH initiation on long-term effectiveness and safety in children born SGA. Methods: The NordiNet IOS (NCT00960128) and ANSWER (NCT01009905) programs are complementary, non-interventional, multicenter studies that evaluated the long-term effectiveness and safety of Norditropin (somatropin; Novo Nordisk A/S, Denmark) as prescribed in real-life clinical practice. In this analysis, children born SGA who were prepubertal at GH initiation were grouped according to age at GH start: <4 yr, 4-6 yr, and ≥6 yr. Patient characteristics at birth and at GH start, auxological measurements, and adverse events were evaluated in each group. Results: Overall, 3351 SGA patients were included in the effectiveness set (age at GH start: <4 yr [n=389, 54.8% male]; 4-6 yr [n=1048, 57.6% male]; and ≥6 yr [n=1914, 56.6% male]). The proportion of patients born pre-term (<37-week gestation) was 38.6% in the <4 yr group, 36.1% in the 4-6 yr group, and 28.2% in the ≥6 yr group. Mean (SD) birth length standard deviation score (SDS) and birth weight SDS were: −2.9 (1.6) and −2.3 (1.2) in the <4 yr group, −2.8 (1.3) and −2.2 (1.1) in the 4-6 yr group, and −2.5 (1.4) and −2.0 (1.2) in the ≥6 yr group. Mean (SD) age at GH start was 3.1 (0.7), 4.9 (0.6), and 9.3 (2.2) years in the <4 yr, 4-6 yr, and ≥6 yr groups, respectively. Mean (SD) GH duration and daily GH dose in the study were: 3.5 (3.1) yr and 0.044 (0.016) mg/kg in the <4 yr group, 4.1 (3.1) yr and 0.039 (0.012) mg/kg in the 4-6 yr group, and 3.5 (2.5) yr and 0.042 (0.012) mg/kg in the ≥6 yr group. Mean (SD) height SDS (HSDS) at GH start was −3.3 (1.2) in the <4 yr group, −3.1 (0.9) in the 4-6 yr group, and −2.8 (0.8) in the ≥6 yr group. After 4 and 8 yr of GH, mean (SD) ΔHSDS from baseline was 1.7 (0.7) and 2.5 (0.6) in the <4 yr group, 1.6 (0.7) and 2.2 (0.8) in the 4-6 yr group and 1.3 (0.7), and 1.7 (0.6) in the ≥6 yr group. Among patients who reached near-adult height in the study, mean (SD) HSDS was −1.9 (0.6) in the <4 yr group (n=3), −1.9 (0.8) in the 4-6 yr group (n=10), and −1.8 (1.0) in the ≥6 yr group (n=220). In the safety set (n=5643), the most commonly reported non-serious adverse reactions (AR) were headache (n=20) and arthralgia (n=5). The most common serious ARs were headache (n=3) and epiphysiolysis (n=4). ARs and serious ARs were distributed equally among groups. Conclusions: This analysis of real-world data confirms the effectiveness and safety of GH in children born SGA, irrespective of patient age at treatment initiation.

O5 Outcomes of vascular and endovascular interventions performed during the COVID-19 pandemic: The Vascular and Endovascular Research Network (VERN) COvid-19 Vascular sERvice (COVER) Tier 2 study

IntroductionThe COVID-19 pandemic forced rapid adaptations to healthcare provision. The COvid-19 Vascular sERvice (COVER) Study aimed to contemporaneously report outcomes for patients undergoing vascular interventions worldwide during the pandemic.MethodsCOVER is an international multi-centre observational cohort study of outcomes following vascular interventions during the pandemic. The primary outcome was to capture procedural information on all open and endovascular interventions undertaken. Secondary outcomes included in-hospital mortality and changes in management resulting from the pandemic.Results1103 patients from 57 institutions in 19 countries were enrolled. Mean age was 66.9±13.9 (75·6% male). The rate of suspected/confirmed COVID-19 infection was 4·0%. Overall, in-hospital mortality was 11.0%. Aortic interventions had a mortality of 15·2% (23/151), amputations 12·1% (28/232), carotid interventions 10·7% (11/103) and lower limb revascularisation 9·8% (51/521). Increased risk of in-hospital mortality was noted for patients with chronic obstructive pulmonary disease, lower respiratory tract infection, Caucasian ethnicity and those undergoing urgent/immediate surgery. Choice of procedure deviated from standard management in 7·1% cases. Adjusting for confounders, antiplatelet (OR 0·503 (0·273-0·928) and oral anticoagulant (OR 0·411 (0·205-0·824) reduced risk of in-hospital mortality.ConclusionsPatients undergoing vascular intervention during the pandemic had substantially higher overall and condition-specific mortality compared to pre-pandemic cohort reports, despite low COVID-19 infection rates.

Pregnancy outcomes in women receiving growth hormone replacement therapy enrolled in the NordiNet\xae International Outcome Study (IOS) and the American Norditropin\xae Studies: Web-Enabled Research (ANSWER) Program

PurposeData on the safety of growth hormone (GH) replacement therapy during pregnancy are limited. We report a combined analysis of data from pregnant women treated with GH while enrolled in two non-interventional, multicenter studies: NordiNet® International Outcome Study (IOS) and the American Norditropin® Studies: Web-Enabled Research (ANSWER) Program.MethodsPregnancy data were pooled from NordiNet® IOS and the ANSWER Program. Data were collected during routine clinic visits by participating physicians using a web-based system. Patients exposed to GH replacement therapy during pregnancy were included in the analysis.ResultsThe study population included 40 female patients with typical causes of adult GH deficiency (GHD). Overall, there were 54 pregnancies. Of these, 47 were exposed to GH between conception and delivery. In 48.9% of pregnancies exposed to GH, the dose was > 0.6 mg/day. GH was continued past conception and then stopped during the first, second, and third trimester, in 27.7%, 17.0%, and 2.1% of pregnancies, respectively. In 29.8%, GH was continued throughout pregnancy, with an unchanged dose in most cases. Of the 47 GH-exposed pregnancies, 37 (78.7%) progressed to normal delivery. There were three adverse events reported in two pregnancies.ConclusionThese real-world data suggest that there were no new safety signals related to GH exposure in women with GHD during pregnancy. These results are consistent with findings from previous studies reporting data in pregnancies exposed to GH at conception or throughout pregnancy. This observational study in additional pregnancies provides further evidence that GH exposure does not adversely affect pregnancy outcome.Clinical trial registration: ClinicalTrials.gov NCT00960128 (date of registration: August 13, 2009) and NCT01009905 (date of registration: November 5, 2009).

Long-Term Safety of Growth Hormone Treatment in Childhood: Two Large Observational Studies: NordiNet IOS and ANSWER.

ContextGrowth hormone (GH) treatment has a generally good safety profile; however, concerns about increased mortality risk in adulthood have been raised.ObjectiveThis work aims to assess the long-term safety of GH treatment in clinical practice.MethodsData were collected from 676 clinics participating in 2 multicenter longitudinal observational studies: the NordiNet International Outcome Study (2006-2016, Europe) and ANSWER Program (2002-2016, USA). Pediatric patients treated with GH were classified into 3 risk groups based on diagnosis. Intervention consisted of daily GH treatment, and main outcome measures included incidence rates (events/1000 patient-years) of adverse drug reactions (ADRs), serious adverse events (SAEs), and serious ADRs, and their relationship to GH dose.ResultsThe combined studies comprised 37 702 patients (68.4% in low-risk, 27.5% in intermediate-risk, and 4.1% in high-risk groups) and 130 476 patient-years of exposure. The low-risk group included children born small for gestational age (SGA; 20.7%) and non-SGA children (eg, with GH deficiency; 79.3%). Average GH dose up to the first adverse event (AE) decreased with increasing risk category. Patients without AEs received higher average GH doses than patients with more than one AE across all groups. A significant inverse relationship with GH dose was shown for ADR and SAE incidence rates in the low-risk group (P = .003 and P = .001, respectively) and the non-SGA subgroup (both P = .002), and for SAEs in the intermediate- and high-risk groups (P = .002 and P = .05, respectively).ConclusionsWe observed no indication of increased mortality risk nor AE incidence related to GH dose in any risk group. A short visual summary of our work is available (1).

Miyoshi myopathy and limb girdle muscular dystrophy R2 are the same disease

This study aims to determine clinically relevant phenotypic differences between the two most common phenotypic classifications in dysferlinopathy, limb girdle muscular dystrophy R2 (LGMDR2) and Miyoshi myopathy (MMD1). LGMDR2 and MMD1 are reported to involve different muscles, with LGMDR2 showing predominant limb girdle weakness and MMD1 showing predominant distal lower limb weakness. We used heatmaps, regression analysis and principle component analysis of functional and Magnetic Resonance Imaging data to perform a cross-sectional review of the pattern of muscle involvement in 168 patients from the Jain Foundation's international Clinical Outcomes Study for Dysferlinopathy. We demonstrated that there is no clinically relevant difference in proximal vs distal involvement between diagnosis. There is a continuum of distal involvement at any given degree of proximal involvement and patients do not fall into discrete distally or proximally affected groups. There appeared to be geographical preference for a particular diagnosis, with MMD1 being more common in Japan and LGMDR2 in Europe and the USA. We conclude that the dysferlinopathies do not form two distinct phenotypic groups and therefore should not be split into separate cohorts of LGMDR2 and MM for the purposes of clinical management, enrolment in clinical trials or access to subsequent treatments.

Outcomes of Vascular and Endovascular Interventions Performed During the Coronavirus Disease 2019 (COVID-19) Pandemic.

Objective:The aim of the COVER Study is to identify global outcomes and decision making for vascular procedures during the pandemic.Background Data:During its initial peak, there were many reports of delays to vital surgery and the release of several guidelines advising later thresholds for vascular surgical intervention for key conditions.Methods:An international multi-center observational study of outcomes after open and endovascular interventions.Results:In an analysis of 1103 vascular intervention (57 centers in 19 countries), 71.6% were elective or scheduled procedures. Mean age was 67 ± 14 years (75.6% male). Suspected or confirmed COVID-19 infection was documented in 4.0%. Overall, in-hospital mortality was 11.0% [aortic interventions mortality 15.2% (23/151), amputations 12.1% (28/232), carotid interventions 10.7% (11/103), lower limb revascularisations 9.8% (51/521)]. Chronic obstructive pulmonary disease [odds ratio (OR) 2.02, 95% confidence interval (CI) 1.30–3.15] and active lower respiratory tract infection due to any cause (OR 24.94, 95% CI 12.57–241.70) ware associated with mortality, whereas elective or scheduled cases were lower risk (OR 0.4, 95% CI 0.22–0.73 and 0.60, 95% CI 0.45–0.98, respectively. After adjustment, antiplatelet (OR 0.503, 95% CI: 0.273–0.928) and oral anticoagulation (OR 0.411, 95% CI: 0.205–0.824) were linked to reduced risk of in-hospital mortality.Conclusions:Mortality after vascular interventions during this period was unexpectedly high. Suspected or confirmed COVID-19 cases were uncommon. Therefore an alternative cause, for example, recommendations for delayed surgery, should be considered. The vascular community must anticipate longer term implications for survival.

The impact of coronary stenting on long-term quality of life in patients with stable coronary heart disease

The purpose of the work is to assess the impact of percutaneous coronary intervention (PCI) on quality of life (QOL) parameters in patients with stable coronary heart disease (CHD).Material and methods. 175 people with stable CHD were examined, group I consisted of 77 people who underwent PCI for 1 year, group II - 98 patients who did not undergo myocardial revascularization. During the study, all patients underwent general clinical examination, ECG recording in standard 12 leads, echocardiography (ECHOCG), daily ECG monitoring to determine heart rate variability, determination of QOL parameters according to the Ukrainian version of the international questionnaire Medical Outcomes Study Short Form (MOS SF-36).Results. It was established that for patients with stable CHD is characterized by a decrease in all indicators of QOL. No significant difference was found in the parameters of QOL of persons who underwent PCI and patients who were not revascularized. There was a tendency to greater limitation of vital activity due to physical problems in the group of persons without revascularization - (13.9 ± 3.6) points against (22.3 ± 4.9) points in group I, (p = 0.16). The physical status of patients of group I was (44.8 ± 2.8) points, persons of group II - (41.7 ± 2.6) points, p = 0.42. Mental status was in group I (36.8 ± 1.8) points, in group II - (35.1 ± 2.0) points (p = 0.54). The general status of persons who underwent revascularization was (61.6 ± 3.1) points, persons without revascularization - (62.7 ± 3.2) points (p = 0.8). The negative correlation of physical status with the age of patients (r = -0.36), the presence of chronic respiratory diseases (r = -0.41), the presence of ventricular extrasystoles (VE) when recording the ECG (r = -0.25) , as well as the number of VE during the day according to daily monitoring (r = -0.29), the number of paired VE (r = -0.27), the number of episodes of ventricular bigeminy (r = -0.23) and trigeminy (r = -0.26).Conclusions. In persons with stable CHD there is a decrease in physical, mental and general status of QOL according to the questionnaire MOS SF36. The QOL values of patients with stable CHD who underwent PCI during the year do not differ significantly from the parameters of persons who did not undergo revascularization. The physical and mental status of patients with stable CHD is most associated with age, the presence of concomitant chronic pathology, ventricular arrhythmias.

Author response: Sex differences in treatment and outcome after stroke: Pooled analysis including 19,000 participants.

The authors thank Drs. Ganesh and Varma for their interest in our article.1 We agree with Drs. Ganesh and Varma's comments on premorbid disability potentially influencing the sex differences in 90-day mRS. Indeed, the findings from the INternational STRoke oUtComes sTudy (INSTRUCT),2 which was individual participant data (IPD) for incident strokes obtained from 13 population-based incidence studies, showed that prestroke functional limitation was one of the confounding factors—along with age, stroke severity, and history of atrial fibrillation—that reversed the greater mortality in women compared with men after adjustments.

Hyperglycemia and Adverse Pregnancy Outcome Follow-Up Study: newborn anthropometrics and childhood glucose metabolism.

We aimed to examine associations of newborn anthropometric measures with childhood glucose metabolism with the hypothesis that greater newborn birthweight, adiposity and cord C-peptide are associated with higher childhood glucose levels and lower insulin sensitivity. Data from the international, multi-ethnic, population-based Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study and the HAPO Follow-Up Study were used. The analytic cohort included 4155 children (mean age [SD], 11.4 [1.2] years; 51.0% male). Multiple linear regression was used to examine associations of primary predictors, birthweight, newborn sum of skinfolds (SSF) and cord C-peptide, from HAPO with continuous child glucose outcomes from the HAPO Follow-Up Study. In an initial model that included family history of diabetes and maternal BMI during pregnancy, birthweight and SSF demonstrated a significant, inverse association with 30min and 1h plasma glucose levels. In the primary model, which included further adjustment for maternal sum of glucose z scores from an oral glucose tolerance test during pregnancy, the associations were strengthened, and birthweight and SSF were inversely associated with fasting, 30min, 1h and 2h plasma glucose levels. Birthweight and SSF were also associated with higher insulin sensitivity (Matsuda index) (β = 1.388; 95% CI 0.870, 1.906; p < 0.001; β = 0.792; 95% CI 0.340, 1.244; p < 0.001, for birthweight and SSF higher by 1 SD, respectively) in the primary model, while SSF, but not birthweight, was positively associated with the disposition index, a measure of beta cell compensation for insulin resistance (β = 0.034; 95% CI 0.012, 0.056; p = 0.002). Cord C-peptide levels were inversely associated with Matsuda index (β = -0.746; 95% CI -1.188, -0.304; p < 0.001 for cord C-peptide higher by 1 SD) in the primary model. This study demonstrates that higher birthweight and SSF are associated with greater childhood insulin sensitivity and lower glucose levels following a glucose load, associations that were further strengthened after adjustment for maternal glucose levels during pregnancy. Graphical abstract.