Background-Quantification of the mitral valve area (MVA) is important to guide percutaneous mitral valve repair using the MitraClip system. However, little is known about how to best assess MVA in this specific situation. Methods and Results-Immediately before and after MitraClip implantation, transesophageal echocardiography data were acquired for MVA assessment by the pressure half-time method and by two 3D quantification methods (mitral valve quantification software and 3D quantification software). In addition, transmitral gradients by continuous-wave Doppler (dPmean CW ) were measured to indirectly assess MVA. Data are given as median (interquartile range). Thirty-three patients (39% women) with a median age of 77.1 years (12.4 years) were studied. Before intervention, the median MVAs by the pressure half-time method, mitral valve quantification software, and 3D quantification software were 4.4 cm 2 (2.0 cm 2 ), 4.7 cm 2 (2.4 cm 2 ), and 6.2 cm 2 (2.4 cm 2 ), respectively (P<0.001). After intervention, MVA was reduced to 1.9 cm 2 (0.7 cm 2 ), 2.1 cm 2 (1.1 cm 2 ), and 2.8 cm 2 (1.1 cm 2 ), respectively (P=0.001). The median values for dPmean CW before and after intervention were 1.0 mm Hg (1.0 mm Hg) and 3.0 mm Hg (3.0 mm Hg; P<0.001), respectively. At discharge, the median dPmean CW was 4.0 mm Hg (3.0 mm Hg). In multivariate regression analyses including body surface area, the 3 different MVA methods, and dPmean CW , a post-dPmean CW ≥5 mm Hg was the best independent predictor of an elevated transmitral gradient at discharge. Methods Patient PopulationWe included consecutive patients undergoing percutaneous MVR using the MitraClip system at the University Hospital Zurich, Zurich, Switzerland. Patients were selected for the procedure according to both the current guidelines on valvular heart disease and the previously published guidelines. 1,10,11 The clinical patient data were obtained by chart review. All patients gave written informed consent for inclusion in a prospective MitraClip registry (MitraSwiss registry). The protocol of the MitraSwiss registry was approved by the local institutional review board. EchocardiographyTEE was performed using a Philips iE33 platform and an X7-2t real-time 3D TEE probe (Philips Medical Systems, Andover, MA). A 2D TTE was performed in all patients at the time of discharge. All measurements were performed according to the guidelines.12 MR was graded mild (1+), moderate (2+), moderate to severe (3+), and severe (4+).11 Mitral stenosis was defined by an MVA <2 cm 2 : mild, by 1.5 to 1.99 cm 2 ; moderate, by 1.0 to 1.49 cm 2 ; and severe, by <1 cm 2 . In addition, a mean transvalvular gradient ≥5 mm Hg was considered stenosed mitral valve. 4,13 Immediately before the start of the procedure and after the last clip was placed, continuous-wave (CW) Doppler of mitral valve inflow was used for the assessment of the mean gradient across the mitral valve (dPmean CW ) and of MVA by PHT (MVA PHT ). 9 The beam of the CW Doppler was located in the center of the largest orifice after ...
Purpose Pasireotide is an effective treatment for acromegaly and Cushing’s disease, although treatment-emergent hyperglycemia can occur. The objective of this study was to assess incretin-based therapy versus insulin for managing pasireotide-associated hyperglycemia uncontrolled by metformin/other permitted oral antidiabetic drugs. Methods Multicenter, randomized, open-label, Phase IV study comprising a core phase (≤ 16-week pre-randomization period followed by 16-week randomized treatment period) and optional extension (ClinicalTrials.gov ID: NCT02060383). Adults with acromegaly (n = 190) or Cushing’s disease (n = 59) received long-acting (starting 40 mg IM/28 days) or subcutaneous pasireotide (starting 600 µg bid), respectively. Patients with increased fasting plasma glucose (≥ 126 mg/dL on three consecutive days) during the 16-week pre-randomization period despite metformin/other oral antidiabetic drugs were randomized 1:1 to open-label incretin-based therapy (sitagliptin followed by liraglutide) or insulin for another 16 weeks. The primary objective was to evaluate the difference in mean change in HbA1c from randomization to end of core phase between incretin-based therapy and insulin treatment arms. Results Eighty-one (32.5%) patients were randomized to incretin-based therapy (n = 38 received sitagliptin, n = 28 subsequently switched to liraglutide; n = 12 received insulin as rescue therapy) or insulin (n = 43). Adjusted mean change in HbA1c between treatment arms was – 0.28% (95% CI – 0.63, 0.08) in favor of incretin-based therapy. The most common AE other than hyperglycemia was diarrhea (incretin-based therapy, 28.9%; insulin, 30.2%). Forty-six (18.5%) patients were managed on metformin (n = 43)/other OAD (n = 3), 103 (41.4%) patients did not require any oral antidiabetic drugs and 19 patients (7.6%) were receiving insulin at baseline and were not randomized. Conclusion Many patients receiving pasireotide do not develop hyperglycemia requiring oral antidiabetic drugs. Metformin is an effective initial treatment, followed by incretin-based therapy if needed. ClinicalTrials.gov ID: NCT02060383.
TPS3160 Background: Somatic gain-of-function mutations in the PIK3CA gene, encoding the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) catalytic α subunit (p110α), can result in PI3K pathway hyperactivation. PROS is an umbrella term for rare, phenotypically varied, but overlapping features driven by PIK3CA mutations. Disease onset is often congenital or in early childhood; presentation ranges widely from localized overgrowth to pleiotropic, severe overgrowth. Complications depend on anatomical site and extent of overgrowth. Management of PROS currently involves symptomatic treatment of its manifestations; an unmet need exists for targeted, systemic therapies. Alpelisib, a PI3Kα inhibitor, has demonstrated encouraging clinical observations and a promising safety profile; after 6 mo of treatment, pediatric and adult pts with PROS experienced improvements in symptoms without requiring surgery. A low rate of side effects was observed (Venot Q, et al. Nature. 2018;558:540-6). Methods: EPIK-P2 is a prospective, phase 2, multicenter study with an upfront 16-week, randomized, double-blind, placebo-controlled period. Key eligibility criteria include male or female ≥6 yr of age with PROS and symptomatic and/or progressive overgrowth; ≥1 PROS-related measurable lesion confirmed by a Blinded Independent Review Committee (BIRC) and documented somatic PIK3CA mutation. Pts with isolated cases of macrodactyly, epidermal nevus/nevi, or macrocephaly in absence of other PROS-related lesions; previous treatment with PI3K inhibitor(s); or debulking surgery within 3 mo are not eligible. Approximately 138 pts will be enrolled into 2 groups comprising adult (age ≥18 yr) and pediatric (ages 6-17 yr) pts. Pts will be randomized 2:1 to daily oral alpelisib or matching placebo; adults will receive 125 mg and pediatric pts 50 mg. After 16 weeks, pts randomized to placebo will switch to alpelisib in a blinded fashion; pts receiving alpelisib will continue alpelisib. Treatment will continue for up to 5 yr. The primary objective is to demonstrate the efficacy of alpelisib by the proportion of pts randomized to alpelisib with a response at Week 24 in each group. Response is defined as ≥20% volume reduction in the symptomatic target lesion(s) per BIRC. The key secondary objective is to demonstrate efficacy of alpelisib vs placebo based on the proportion of pts in each group with response at Week 16. Other secondary outcomes include safety and tolerability, duration of response, overall clinical response rates, changes in symptoms and comorbidities, patient-reported outcomes, pharmacokinetics, and healthcare utilization. An exploratory group of pts (n = 12) ages 2-5 yr will be later enrolled once a starting dose of alpelisib is confirmed in these pts. Enrollment of 150 pts is anticipated. Clinical trial information: NCT04589650.
PurposeOctreotide (OCT) has been successfully used for treatment of acromegaly and neuroendocrine tumors for more than 30 years. However, long-term safety of OCT has not been documented in placebo-controlled setting. This present analysis pooled safety data from two similarly-designed, randomized, and placebo-controlled studies to evaluate long-term safety of long-acting OCT (20, 30 mg); targeted post-hoc analyzes focused on cardiac, hepatic, and renal safety.MethodsTwo studies (NCT00131144, NCT001308450) were conducted in patients with diabetic retinopathy (OCT20 = 191, OCT30 = 348, placebo = 347). In this analysis, patients were stratified based on baseline glomerular filtration rate. Hepatic, cardiac, and renal adverse events (AEs) were identified by standardized MedDRA queries.ResultsMedian duration of exposure was >3.5 years. Most common AEs reported with OCT were diarrhea, cholelithiasis, hypoglycemia, nasopharyngitis, and hypertension. Incidence of cardiac events (QT prolongation and arrhythmia) with OCT20 and OCT30 were comparable to placebo (OCT20, RR = 1.11 [95% CI, 0.61–2.03]; OCT30, RR = 1.09 [95% CI, 0.70–1.68]). For ECG findings, changes in QTcF were similar in treatment groups, and outliers did not exceed 480 ms. Incidence of cardiac ischemia was lower with OCT than placebo (OCT20 = 12.6%, OCT30 = 10.6%, placebo = 15.3%). Incidence of liver-related AEs was higher with OCT30 than placebo (RR = 2.04 [95% CI, 1.28–3.26]); incidences were comparable with OCT20 and placebo (RR = 1.50 [95% CI, 0.69–3.25]). Overall incidences of renal AEs were comparable between treatment groups (OCT20 = 5.8%; OCT30 = 6.3%; placebo = 7.2%). Drug-related SAEs were reported more frequently with OCT (OCT20 = 7.9%; OCT30 = 10.1%; placebo = 3.5%); predominantly gallbladder-related, GI-related, and hypoglycemia.ConclusionsThe results from these long-term placebo-controlled studies confirm the established safety profile of long-acting OCT, in particular low risk of cardiac, hepatic and renal toxicity in a high-risk population.
Background: Pasireotide has proven efficacy in acromegaly and CD, although pasireotide-associated hyperglycemia occurs in some patients (pts). We present results from a Phase IV, randomized, open-label study investigating optimal management of pasireotide-associated hyperglycemia uncontrolled by metformin/other oral antidiabetic therapy (OAD) in acromegaly or CD pts (NCT02060383). Methods: Adults with acromegaly or CD were enrolled and treated with long-acting pasireotide 40 mg/28 days or subcutaneous pasireotide 600 µg bid, respectively. Pts with an increase in fasting plasma glucose (≥126 mg/dL on three consecutive days) in the first 16 weeks that continued despite metformin/other OAD were randomized 1:1 to incretin-based therapy (sitagliptin followed by liraglutide; rescue therapy: insulin) or insulin for a further 16 weeks. Primary objective: assess incretin-based therapy versus insulin for HbA 1c control at end of randomized period. Secondary objectives: assess sustainability of glycemic control and safety in the incretin and insulin arms. Results: A total of 249 pts (acromegaly, n=190; CD, n=59) were enrolled, 103 (41%) did not require OAD, 46 (19%) were managed on OAD, 19 (8%) had prior insulin; 81 (33%) were randomized to incretin-based therapy (n=38) or insulin (n=43). In the incretin and insulin arms, respectively, 24 (63%) and 29 (67%) pts had diabetes at baseline (not receiving insulin). Median months (range) of exposure to pasireotide: acromegaly, 5.5 (3.7-8.0); CD, 4.1 (1.9-6.8); duration of exposure was similar between treatment arms. In the incretin arm, rescue therapy (addition of insulin to existing treatment) was given in 12/38 (32%) patients for a median (range) duration of 1.8 (0.5-3.7) months. Estimated difference in adjusted mean change in HbA 1c between treatment arms at end of core study was -0.28% (95% CI -0.63, 0.08) in favor of incretin-based therapy: -0.36% (95% CI -0.74, 0.02) for acromegaly, -0.01% (95% CI -0.96, 0.95) for CD. Mean change in HbA 1c from baseline to end of core study was -0.12% (95% CI -0.36, 0.13) with incretin-based therapy and 0.26% (95% CI -0.01, 0.53) with insulin. Adverse events (AEs) were reported in 36 (95%) pts on incretin-based therapy and 35 (81%) on insulin, most commonly hyperglycemia (incretin-based therapy, n=11 [29%]; insulin, n=8 [19%]); grade 3/4 AEs were recorded in 14 (37%) and six (14%) pts, and serious AEs occurred in four (11%) and one (2%) pt. Three (8%) pts receiving incretin-based therapy discontinued treatment because of AEs, compared with none on insulin. Conclusion: Many patients (41%) did not require antidiabetic medication while on pasireotide. For pts in whom hyperglycemia occurred, metformin/other OAD was an effective initial treatment choice. For hyperglycemia uncontrolled by metformin/other OAD, incretin-based therapy was an effective treatment option. Unless...
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