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Anaplastic lymphoma kinase; First line; Tyrosine kinase inhibitor Cinasa del linfoma anaplásico; Primera línea; Inhibidor de la tirosina quinasa Quinasa del limfoma anaplàsic; Primera línia; Inhibidor de la tirosina quinasa Background Brigatinib is a next-generation anaplastic lymphoma kinase (ALK) inhibitor with demonstrated efficacy in locally advanced and metastatic non–small cell lung cancer (NSCLC) in crizotinib-refractory and ALK inhibitor-naive settings. This analysis assessed brigatinib in Asian vs. non-Asian patients from the first-line ALTA-1L trial. Patients and Methods This was a subgroup analysis from the phase III ALTA-1L trial of brigatinib vs. crizotinib in ALK inhibitor–naive ALK+ NSCLC. The primary endpoint was progression-free survival (PFS) as assessed by blinded independent review committee (BIRC). Secondary endpoints included confirmed objective response rate (ORR) and overall survival (OS) in the overall population and BIRC-assessed intracranial ORR and PFS in patients with brain metastases. Results Of the 275 randomized patients, 108 were Asian. Brigatinib showed consistent superiority in BIRC-assessed PFS vs. crizotinib in Asian (hazard ratio [HR]: 0.35 [95% CI: 0.20-0.59]; log-rank P = .0001; median 24.0 vs. 11.1 months) and non-Asian (HR: 0.56 [95% CI: 0.38-0.84]; log-rank P = .0041; median 24.7 vs. 9.4 months) patients. Results were consistent with investigator-assessed PFS and BIRC-assessed intracranial PFS. Brigatinib was well tolerated. Toxicity profiles and dose modification rates were similar between Asian and non-Asian patients. Conclusion Efficacy with brigatinib was consistently better than with crizotinib in Asian and non-Asian patients with locally advanced or metastatic ALK inhibitor-naive ALK-+ NSCLC. There were no clinically notable differences in overall safety in Asian vs. non-Asian patients. This study was supported by ARIAD Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. The sponsor designed and conducted the study and collected the data together with the authors. The sponsor managed and analyzed the data. Data were interpreted by the authors and the sponsor. The sponsor together with the authors prepared, reviewed, and approved the manuscript and made the decision to submit the manuscript for publication.

The coronavirus disease 2019 (COVID-19) pandemic is a global public health event. Wuhan used to be the epicenter of China and finally controlled the outbreak through city lockdown and many other policies. However, the pandemic and the prevention strategies had a huge impact on the medical care procedures for breast cancer patients, leading to the delay or interruption of anticancer therapies. To better serve breast cancer patients under the premise of epidemic control, many strategies have been proposed and optimized in our center. One of the most important parts of these strategies is the promotion of telemedicine, including online consultation, online prescription, and drug mailing services. In keeping with the city and hospital policies, we have also introduced stricter ward management policies and more precise care. Here, we collected the diagnosis and treatment process of breast cancer patients in our center during the COVID-19 pandemic, which was found to be correlated to a reduction in chemotherapy-related myelosuppression and hepatic dysfunction, hoping to provide a reference for other cancer centers that may suffer from the similar situation. MicroAbstract The COVID-19 pandemic has a huge impact on the medical care procedures for breast cancer patients. Here we share our experience in the management of breast cancer patients during the pandemic in Wuhan, and it is found to be correlated to a reduction in chemotherapy-related myelosuppression and hepatic dysfunction, which may provide a reference for other centers.

ALK tyrosine kinase inhibitor; Brigatinib; Non–small cell lung cancer Inhibidor de la tirosina quinasa ALK; Brigatinib; Cáncer de pulmón de células no pequeñas Inhibidor de la tirosina cinasa ALK; Brigatinib; Càncer de pulmó de cèl·lules no petites Introduction In the phase 3 study entitled ALK in Lung cancer Trial of brigAtinib in 1st Line (ALTA-1L), which is a study of brigatinib in ALK inhibitor–naive advanced ALK-positive NSCLC, brigatinib exhibited superior progression-free survival (PFS) versus crizotinib in the two planned interim analyses. Here, we report the final efficacy, safety, and exploratory results. Methods Patients were randomized to brigatinib 180 mg once daily (7-d lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. The primary end point was a blinded independent review committee–assessed PFS. Genetic alterations in plasma cell-free DNA were assessed in relation to clinical efficacy. Results A total of 275 patients were enrolled (brigatinib, n = 137; crizotinib, n = 138). At study end, (brigatinib median follow-up = 40.4 mo), the 3-year PFS by blinded independent review committee was 43% (brigatinib) versus 19% (crizotinib; median = 24.0 versus 11.1 mo, hazard ratio [HR] = 0.48, 95% confidence interval [CI]: 0.35–0.66). The median overall survival was not reached in either group (HR = 0.81, 95% CI: 0.53–1.22). Posthoc analyses suggested an overall survival benefit for brigatinib in patients with baseline brain metastases (HR = 0.43, 95% CI: 0.21–0.89). Detectable baseline EML4-ALK fusion variant 3 and TP53 mutation in plasma were associated with poor PFS. Brigatinib exhibited superior efficacy compared with crizotinib regardless of EML4-ALK variant and TP53 mutation. Emerging secondary ALK mutations were rare in patients progressing on brigatinib. No new safety signals were observed. Conclusions In the ALTA-1L final analysis, with longer follow-up, brigatinib continued to exhibit superior efficacy and tolerability versus crizotinib in patients with or without poor prognostic biomarkers. The suggested survival benefit with brigatinib in patients with brain metastases warrants future study.

Background Previous studies examining the use of direct oral anticoagulants (DOACs) in atrial fibrillation (AF) have largely focused on patients newly initiating therapy. Little is known about the prevalence/patterns of switching to DOACs among AF patients initially treated with warfarin. Hypothesis To examine patterns of anticoagulation among patients chronically managed with warfarin upon the availability of DOACs and identify patient/practice‐level factors associated with switching from chronic warfarin therapy to a DOAC. Methods Prospective cohort study of AF patients in the NCDR PINNACLE registry prescribed warfarin between May 1, 2008 and May 1, 2015. Patients were followed at least 1 year (median length of follow‐up 375 days, IQR 154‐375) through May 1, 2016 and stratified as follows: continued warfarin, switched to DOAC, or discontinued anticoagulation. To identify significant predictors of switching, a three‐level multivariable hierarchical regression was developed. Results Among 383 008 AF patients initially prescribed warfarin, 16.3% (n = 62 620) switched to DOACs, 68.8% (n = 263 609) continued warfarin, and 14.8% (n = 56 779) discontinued anticoagulation. Among those switched, 37.6% received dabigatran, 37.0% rivaroxaban, 24.4% apixaban, and 1.0% edoxaban. Switched patients were more likely to be younger, women, white, and have private insurance (all P

Neurokinin-B (NKB)-Neurokinin-3-receptor (NK3R) pathway is remarkably sensitive to energy equilibrium; however, its role in metabolic regulation remains unexplored in polycystic ovary syndrome (PCOS). Therefore, this work aimed to investigate the role of NK3R antagonists (NK3Ra) on metabolic dysfunction and obesity in in vitro and in vivo PCOS models.First, an observational study using serum samples collected from 19 PCOS patients was performed. Second, prospective case-control experimental studies where NK3Ra (SB222200) was used to treat PCOS-like mice (BALB/c mice), ovariectomized+estrogen implanted obese mice (C57BL/6J mice) and 3T3-L1 murine preadipocytes were carried out to investigate its effect on metabolism in vivo and in vitro. The fat volumes, serum biochemical indexes, adipokines and inflammatory cytokines, metabolism-related gene expression and the concentrations of ATP, NAD+, NADPH…etc. were studied.We found a positive correlation between serum NKB and lipid metabolism indicators in PCOS women. Using the mouse models, we demonstrated that administration of NK3Ra regulates serum adipokines, inhibits weight gain with a marked decrease in fat volume, adipocyte size, and inflammatory cytokines, and promotes oxidative metabolism and energy consumption. NK3Ra reduces lipid accumulation in mature murine adipocytes by inhibiting the expression of peroxisome proliferator- activated receptor gamma (PPAR-γ) and fatty acid binding protein 4 (FABP4) genes. NK3Ras also enhances oxidative metabolism and energy consumption by maintaining intracellular redox homeostasis.This study backs the use of NK3Ras as a potential therapeutic for PCOS since it ameliorates both reproductive and metabolic aberrations.

Guidelines for managing patients with atherosclerotic cardiovascular disease (ASCVD) recommend statin therapy initially. Target levels/goals for low-density lipoprotein-cholesterol (LDL-C) were initially included, subsequently de-emphasized in 2013, and then re-introduced as thresholds, leading to confusion in clinical practice. We designed a multicenter, observational registry of patients with ASCVD, to describe and track LDL-C treatment patterns in the United States over time.Patients with ASCVD receiving any pharmacologic lipid-lowering therapy were eligible for enrollment in one of three cohorts: 1) currently receiving a proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i), or not receiving PCSK9i with 2) LDL-C 70-99 mg/dL, or 3) LDL-C ≥100 mg/dL. Patients undergo a 1-year retrospective chart review, followed by chart reviews and phone interviews every 6 months for 2 years.A total of 5006 patients were enrolled at 119 centers. Mean age was 68 years, 40% of patients were female, 86% were white, 80% had coronary artery disease, and 33% had type 2 diabetes mellitus. Among those not on a PCSK9i, high-intensity statins and ezetimibe were utilized in only 44% and 9%, respectively. Among women vs men, only 36.6% vs 48.2% received high-intensity statins (P .001). Among patients on a PCSK9i, only one-third were receiving a statin, suggesting statin intolerance is a driver of PCSK9i use at present.Our data on current practice in the US continue to illustrate that high-intensity statins and ezetimibe are underutilized in at-risk patients outside of clinical trials, particularly women. This study will track temporal changes in treatment patterns and identify opportunities for improvement in lipid management in patients with ASCVD.

Two-way enriched design (TED) is a novel approach addressing placebo response in clinical trials. It is a two-stage, randomized, placebo-controlled trial design with enrichment in placebo non-responders and treatment responders at the second stage. All data from the first stage and data from placebo non-responders and treatment responders in the second stage are used for the final analysis of the treatment effect. The existing methods for the analysis of TED data include score tests with one, two, and three degrees of freedom. All these methods are only applicable to binary outcomes. However, there is an interest in continuous outcomes in clinical trials in psychiatry. In this manuscript, we apply some novel methods, including a repeated measures model, a weighted repeated measures model with weights from propensity score, and weights from K-means clustering, to analyze TED data for both binary outcomes and continuous outcomes. The simulation study indicates that the repeated measures model performs consistently well in preserving the type I error and achieving the minimum mean standard error as well as a higher power. The performance of the weighted repeated measures model with weights from K-means clustering improves with increasing sample size. Investigators can choose from these analytic approaches under different scenarios.

Background Because of an increasing number and complexity of treatment options for lipid‐lowering therapy in patients with atherosclerotic cardiovascular disease, guidelines recommend greater active involvement of patients in shared decision‐making. However, patients' understanding and perceptions of the benefits, risks, and treatment objectives of lipid‐lowering therapy are unknown. Methods and Results Structured questionnaires were conducted in 5006 US outpatients with atherosclerotic cardiovascular disease and suboptimal low‐density lipoprotein cholesterol (LDL‐C) control (LDL‐C ≥70 mg/dL) or on a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor and in 113 physician providers as a part of the GOULD (Getting to an Improved Understanding of Low‐Density Lipoprotein Cholesterol and Dyslipidemia Management) Registry. Mean age of the patients was 68±10 years, 60% were men, and 86% were White race. Across all patients, 63% believed heart disease was the leading cause of death in men and 46% the leading cause of death in women. Only 28% of patients thought the primary reason they were taking lipid‐lowering medication was to lower the risk of heart attack or stroke, 68% did not know their approximate LDL‐C level, and 69% did not know their LDL‐C goal. Patients on PCSK9 inhibitors (versus LDL‐C cohort), younger patients (versus age ≥65 years), and men (versus women) were somewhat more knowledgeable about their disease and its management. Most physicians (66%) felt that a lack of understanding of the importance and efficacy of statins was the primary factor contributing to nonadherence, as opposed to costs (9%) or side effects (1%). More education was the most commonly used strategy to address patient‐reported side effects. Conclusions A large proportion of patients with atherosclerotic cardiovascular disease remain unaware of their underlying atherosclerotic cardiovascular disease risk, reasons for taking lipid‐lowering medications, current LDL‐C levels, or treatment goals. These data highlight a large education gap which, if addressed, may improve shared decision‐making and treatment adherence. Registration URL: https://www.clinicaltrials.org ; Unique identifier: NCT02993120.

International audience; BACKGROUND THEMIS (The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study) (n ¼ 19,220) and its pre-specified THEMIS-PCI (The Effect of Ticagrelor on Health Outcomes in Diabetes Mellitus Patients Intervention Study-Percutaneous Coronary Intervention) (n ¼ 11,154) subanalysis showed, in individuals with type 2 diabetes mellitus (median duration 10.0 years; HbA 1c 7.1%) and stable coronary artery disease without prior myocardial infarction (MI) or stroke, that ticagrelor plus aspirin (compared with placebo plus aspirin) produced a favorable net clinical benefit (composite of all-cause mortality, MI, stroke, fatal bleeding, and intracranial bleeding) if the patients had a previous percutaneous coronary intervention. OBJECTIVES In these post hoc analyses, the authors examined whether the primary efficacy outcome (cardiovascular death, MI, stroke: 3-point major adverse cardiovascular events [MACE]), primary safety outcome (Thrombolysis In Myocardial Infarction-defined major bleeding) and net clinical benefit varied with diabetes-related factors. METHODS Outcomes were analyzed across baseline diabetes duration, HbA 1c , and antihyperglycemic medications. RESULTS In THEMIS, the incidence of 3-point MACE increased with diabetes duration (6.7% for #5 years, 11.1% for >20 years) and HbA 1c (6.4% for #6.0%, 11.8% for >10.0%). The relative benefits of ticagrelor plus aspirin on 3-point MACE reduction (hazard ratio [HR]: 0.90; p ¼ 0.04) were generally consistent across subgroups. Major bleeding event rate (overall: 1.6%) did not vary by diabetes duration or HbA 1c and was increased similarly by ticagrelor across all subgroups (HR: 2.32; p < 0.001). These findings were mirrored in THEMIS-PCI. The efficacy and safety of ticagrelor plus aspirin did not differ by baseline antihyperglycemic therapy. In THEMIS-PCI, but not THEMIS, ticagrelor generally produced favorable net clinical benefit across diabetes duration, HbA 1c , and antihyperglycemic medications. CONCLUSION Ticagrelor plus aspirin yielded generally consistent and favorable net clinical benefit across the diabetesrelated factors in THEMIS-PCI but not in the overall THEMIS population.

2503 Background: Modakafusp alfa (TAK-573) is a first-in-class immune-targeting attenuated cytokine designed to deliver attenuated interferon alpha-2b (IFNα2b) moieties to CD38-expressing cells. It consists of two attenuated IFNα2b molecules genetically fused to the Fc portion of a humanized, anti-CD38, IgG4 monoclonal antibody. Specificity for CD38 and reduced IFN receptor binding affinity of the attenuated IFNα2b molecules significantly reduces the potential for off-target binding and toxicity. Modakafusp alfa has demonstrated immune cell activation and antitumor activities in preclinical mouse models, including tumor models that do not express CD38, and has shown strong clinical responses and immune activation in pts with refractory/relapsed multiple myeloma. The dose-escalation phase of this phase 1b/2 study (NCT04157517) investigated safety, pharmacokinetics, immunogenicity, pharmacodynamics (PD), and preliminary efficacy of modakafusp alfa in metastatic solid tumors. Methods: Adult pts with advanced/metastatic solid tumors received modakafusp alfa IV on day 1 of a 21-day cycle (Q3W). Dose escalation started at 0.1 mg/kg and proceeded based on cycle 1 safety data via a Bayesian model with overdose control principles. Results: Twenty-one pts were dosed in the escalation phase at 0.1 (n = 3), 0.2 (n = 3), 0.4 (n = 3), 0.75 (n = 3), 1.0 (n = 3), and 1.5 mg/kg (n = 6) Q3W; median age 63 y (range 42–80); male 57.1%; GI malignancies 71.4%; median prior lines of therapy 3 (range 2–7). Two pts had dose-limiting toxicities in cycle 1 at 1.5 mg/kg; 1 pt with baseline bone infiltration had grade 4 thrombocytopenia and 1 pt had grade 3 confusion. As of Nov 2021, across all doses, pts received a median of 2 treatment cycles (range 1–11). Modakafusp alfa treatment-related adverse events (TRAEs) reported in 81% of pts included infusion-related reactions (52.4%), chills (47.6%), and nausea (33.3%). Grade ≥3 TRAEs reported in 42.9% of pts included neutropenia (14.3%) and hypertension (9.5%). There was a greater than dose proportional exposure increase in the dose range 0.1–1.5 mg/kg, with no exposure accumulation after Q3W dosing. Incidence rate of post-treatment anti-drug antibody (ADA) was 100%. PD data suggested saturation of peak IFN pathway modulation at ≥0.2 mg/kg in the peripheral blood with duration of modulation increasing with dose. Among the 14 response-evaluable pts, 7 had best response of stable disease, including 1 with cutaneous melanoma who had 21% target lesion reduction. Conclusions: Modakafusp alfa had a manageable safety profile in the dose range 0.1–1.5 mg/kg in pts with solid tumors. Proof of mechanism was validated. The recommended phase 2 dose was determined as 1.0 mg/kg Q3W based on assessment of holistic data and will be tested in combination with a checkpoint inhibitor in selected tumor types. Characterization of ADA and its impact is ongoing. Clinical trial information: NCT04157517.

9072 Background: In patients (pts) with crizotinib (CRZ)-refractory advanced ALK+ NSCLC in the phase 2 ALTA trial (NCT02094573), the depth of target lesion response to brigatinib (BRG) correlated with PFS and OS. Here, we examine the association of maximum decrease in target lesions with PFS and OS in ALTA-1L (NCT02737501), a randomized phase 3 trial of BRG vs CRZ in pts with ALK inhibitor-naive advanced ALK+ NSCLC. Methods: Pts were randomized 1:1 to receive BRG 180 mg qd (7-day lead-in at 90 mg; n=137) or CRZ 250 mg bid (n=138). Pts with target lesion assessment by blinded independent review committee (BIRC) were grouped based on greatest decrease from baseline per RECIST v1.1: none–50%, 51%–75%, and 76%–100% shrinkage. Outcomes in the ≤50% target lesion shrinkage group served as the comparator for outcomes in the 51%–75% and 76%–100% groups. Results: At study end (last pt contact: Jan 29, 2021), 124/137 pts in the BRG arm and 125/138 pts in the CRZ arm had ≥1 evaluable target lesion assessment; female (BRG/CRZ), 51%/59%; median age, 57.5/60.0 years. Median follow-up was 40.8/15.7 months. In BRG/CRZ arms, 76%-100% shrinkage was observed in 56%/34% of pts, 51%-75% shrinkage in 27%/30%, and ≤50% shrinkage in 16%/35%, respectively. BRG was associated with significantly more pts with target lesion shrinkage >75% vs CRZ ( P=0.0005), and a Cochran-Armitage trend analysis demonstrated significantly deeper response across all shrinkage groups for BRG compared with CRZ ( P50% had lower risk of a PFS event (BRG HR [95% CI]: 51%–75% shrinkage, 0.58 [0.29–1.18]; 76%–100%, 0.23 [0.12–0.46]; CRZ: 51%–75% shrinkage, 0.68 [0.41–1.12]; 76%–100%, 0.26 [0.15–0.45]) or an OS event (BRG: 51%–75% shrinkage, 0.39 [0.17–0.89]; 76%–100%, 0.15 [0.07–0.35]; CRZ: 51%–75% shrinkage, 0.43 [0.21–0.85]; 76%–100%, 0.23 [0.10–0.50]) than pts with ≤50% shrinkage. Longer median time to PFS and OS and higher 4-year estimated OS rates were associated with depth of response in both arms (Table). Conclusions: In this exploratory post hoc analysis, BRG demonstrated significantly deeper target lesion response vs CRZ. Pts with >75% shrinkage had significantly reduced risk of a PFS or OS event vs pts with ≤50% target lesion shrinkage. Clinical trial information: NCT02737501. [Table: see text]

Renal denervation (RDN) is effective in lowering blood pressure (BP) in patients with hypertension. The issue remains how to best identify potential responders. Ambulatory BP monitoring may be useful. Baseline nighttime systolic BP (SBP) ≥136 mm Hg and its variability (SD) ≥12 mm Hg in DENER-HTN trial or 24-hour heart rate ≥73.5 bpm in SPYRAL HTN-OFF MED Trial were shown to predict the BP response to RDN. We applied these criteria to the patients with hypertension in the sham-controlled RADIANCE-HTN SOLO trial to predict the BP response to ultrasound RDN at 2 months while patients were maintained off medications. BP responders were defined as: clinical with 24-hour SBP 90% irrespective of definition) but low sensitivity (from 9.1% to 30% depending on the definition) to predict responders; the heart rate criterion had insufficient predictive value. This analysis suggests the potential role of nighttime SBP and its variability to predict BP response to RDN in patients with hypertension. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02649426.

Objectives This study reports the 12-month results of the RADIANCE-HTN (A Study of the ReCor Medical Paradise System in Clinical Hypertension) SOLO trial following unblinding of patients at 6 months. Background The blood pressure (BP)–lowering efficacy and safety of endovascular ultrasound renal denervation (RDN) in the absence (2 months) and presence (6 months) of antihypertensive medications were previously reported. Methods Patients with daytime ambulatory BP ≥135/85 mm Hg after 4 weeks off medication were randomized to RDN (n = 74) or sham (n = 72) and maintained off medication for 2 months. A standardized medication escalation protocol was instituted between 2 and 5 months (blinded phase). Between 6 and 12 months (unblinded phase), patients received antihypertensive medications at physicians’ discretion. Outcomes at 12 months included medication burden, change in daytime ambulatory systolic BP (dASBP) and office or home systolic BP (SBP), visit-to-visit variability in SBP, and safety. Results Sixty-five of 74 RDN patients and 67 of 72 sham patients had 12-month dASBP measurements. The proportion of patients on ≥2 medications (27.7% vs. 44.8%; p = 0.041), the number of medications (1.0 vs. 1.4; p = 0.015), and defined daily dose (1.4 vs. 2.2; p = 0.007) were less with RDN versus sham. The decrease in dASBP from baseline in the RDN group (−16.5 ± 12.9 mm Hg) remained stable at 12 months. The RDN versus sham adjusted difference at 12 months was −2.3 mm Hg (95% confidence interval [CI]: −5.9 to 1.3 mm Hg; p = 0.201) for dASBP, −6.3 mm Hg (95% CI: −11.1 to −1.5 mm Hg; p = 0.010) for office SBP, and −3.4 mm Hg (95% CI: −6.9 to 0.1 mm Hg; p = 0.062) for home SBP. Visit-to-visit variability in SBP was smaller in the RDN group. No renal artery injury was detected on computed tomographic or magnetic resonance angiography. Conclusions Despite unblinding, the BP-lowering effect of RDN was maintained at 12 months with fewer prescribed medications compared with sham.

In the THEMIS trial of 19,220 patients with stable CAD and T2DM without prior MI or stroke followed for a median of 39.9 months, ticagrelor plus aspirin (ASA) lowered ischemic CV events but increased major bleeding events compared with placebo plus ASA, with a more favorable net clinical benefit in those with prior PCI. We now report the efficacy and safety by diabetes-related factors and background antihyperglycemic therapy. While the incidence of the primary efficacy outcome (CV death, MI, stroke; MACE) event rates (overall 8.1%) was higher with increasing diabetes duration (11.1% >20 years vs. 6.7% ≤5 years) and A1c (11.8% >10% vs. 6.4% ≤6%), the relative benefits of ticagrelor on MACE reduction (overall HR 0.90; p=0.04) did not differ across these various subgroups (p-values for interaction=0.83 and 0.16, respectively). In contrast, the primary safety outcome (TIMI major bleeding) event rate (overall 1.6%) did not vary by diabetes duration or A1c and was similarly increased by ticagrelor in all of these subgroups (overall HR=2.32 [1.82,2.94]; p Disclosure L.A. Leiter: Advisory Panel; Self; Abbott, Amgen, AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Boehringer Ingelheim International GmbH, Eli Lilly and Company, HLS Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk Inc., Sanofi, Servier. Research Support; Self; Amgen, AstraZeneca, Kowa Pharmaceuticals America, Inc., Medicines Company. Speaker’s Bureau; Self; Amgen, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, HLS Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Medscape, Merck & Co., Inc., Novo Nordisk Inc., Sanofi, Servier. D.L. Bhatt: Research Support; Self; Abbott, Afimmune, Amarin Corporation, Amgen, AstraZeneca, Bayer Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Cardax, Chiesi USA, Inc., CSL Behring, Ferring Pharmaceuticals, Fractyl Laboratories, Inc., Idorsia, Ironwood Pharmaceuticals, Ischemix, Lexicon Pharmaceuticals, Inc., Lilly Diabetes, Medtronic, Pfizer Inc., PhaseBio Pharmaceuticals, Inc., PLx Pharma Inc., Regeneron Pharmaceuticals, Roche Pharma, Sanofi-Aventis, Synaptic. D.K. McGuire: Consultant; Self; Afimmune, Applied Therapeutics, Merck Sharp & Dohme Corp., Metavant. Other Relationship; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Co., Ltd., Eli Lilly and Company, Esperion Therapeutics, Inc., GlaxoSmithKline plc., Janssen Pharmaceuticals, Inc., Lexicon Pharmaceuticals, Inc., Merck & Co., Inc., Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis. K. Fox: Other Relationship; Self; AstraZeneca, Servier. T. Simon: Advisory Panel; Self; Novartis Pharmaceuticals Corporation, Servier. Board Member; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc. Consultant; Self; Air Liquide, Sanofi. S. Mehta: Research Support; Self; AstraZeneca. E. Lev: None. R.G. Kiss: Speaker’s Bureau; Self; AstraZeneca, Bayer Healthcare Pharmaceuticals Inc., Boehringer Ingelheim International GmbH, Merck Sharp & Dohme Corp., Pfizer Inc. A.J. Dalby: None. H. Bueno: Advisory Panel; Self; AstraZeneca, Bayer AG, Novartis AG. Consultant; Self; Amgen, Bristol-Myers Squibb, Pfizer Inc. Research Support; Self; AstraZeneca, Novartis AG. W. Ridderstråle: Employee; Self; AstraZeneca. A. Himmelmann: Employee; Self; AstraZeneca. J. Prats: Other Relationship; Self; AstraZeneca. Y. Liu: None. J.J. Lee: None. J. Amerena: None. M.N. Kosiborod: Consultant; Self; Amarin Corporation, Amgen, Applied Therapeutics, AstraZeneca, Bayer AG, Boehringer Ingelheim Pharmaceuticals, Inc., Eisai Inc., Eli Lilly and Company, GlaxoSmithKline plc., Glytec, Intarcia Therapeutics, Janssen Scientific Affairs, LLC., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sanofi US, Vifor Pharma Group. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. P.G. Steg: Consultant; Self; Amgen, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb, Idorsia, Mylan, Novartis AG, Pfizer Inc., Sanofi, Servier. Research Support; Self; Amarin Corporation. Speaker’s Bureau; Self; Novo Nordisk A/S.

Background: Among people with ASCVD, those with T2D have excess CVD risk and derive greater absolute benefit from CVD risk reduction therapies. We describe the use of evidence-based therapies for secondary prevention in participants (pts) with T2D. Methods: We report a registry to longitudinally describe LDL-C treatment patterns among U.S. pts with ASCVD and LDL-C ≥70mg/dL taking lipid-lowering therapy. Pts (n=5006) were enrolled in 1 of 3 cohorts: taking PCSK9i (11%); LDL-C 70-99mg/dL (53%); and LDL-C ≥100mg/dL (36%). Results: Overall, 1655 (33%) had diabetes (96% with T2D): 146 in the PCSK9i cohort, 874 in the LDL-C 70-99mg/dL cohort, and 635 in the LDL-C ≥100mg/dL cohort. Mean age among pts with diabetes was 68 y, 60% were male, 81% had CAD (including 33% with prior MI), 17% with PAD, and 17% had HF. Mean LDL-C was 100mg/dL. Although overall statin use was at 87%, high-intensity statins were used in only 45% and ezetimibe in only 9.5% of pts. Aspirin and ACE-I/ARB were each used in 72% and beta blockers in 71% of pts. The most commonly used glucose-lowering medications among patients with T2D were metformin (56%), insulin (34%), and sulfonylurea (22%). Only 10% and 8% of pts with T2D were treated with SGLT2i or GLP-1RA, respectively. The proportion of pts with T2D that were receiving all guideline-recommended therapies for optimal risk reduction (high-intensity statins, aspirin, ACE-I/ARB, and either SGLT2i or GLP-1RA) was just 3%. Conclusion: In GOULD, among pts with T2D, ASCVD, and LDL-C ≥70mg/dL, most are not receiving high intensity statin therapy at baseline and few receive ezetimibe. Furthermore, less than 20% are treated with glucose-lowering therapies that have a proven CVD benefit, and a strikingly low proportion receive all guideline-recommended risk reduction strategies. These results highlight an opportunity to improve care and outcomes. Disclosure M.N. Kosiborod: Consultant; Self; Amgen Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Eisai Co., Ltd., GlaxoSmithKline plc., Glytec, LLC, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novartis AG, Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. J. De Lemos: Other Relationship; Self; Amgen Inc., Novo Nordisk A/S, Regeneron Pharmaceuticals. R.S. Rosenson: Consultant; Self; CVS/Caremark, Regeneron Pharmaceuticals. Research Support; Self; Akcea Therapeutics, Amgen Inc., Medicines Company, Regeneron Pharmaceuticals. Other Relationship; Self; Amgen Inc., Kowa Pharmaceutical Europe Co. Ltd. C.M. Ballantyne: Consultant; Self; Abbott, Akcea Therapeutics, Amarin Corporation, Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Esperion, Gilead Sciences, Inc., Matinas BioPharma, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Regeneron Pharmaceuticals, Roche Diagnostic USA, Sanofi. Research Support; Self; Abbott, Akcea Therapeutics, Amarin Corporation, Amgen Inc., Esperion, Novartis Pharmaceuticals Corporation, Regeneron Pharmaceuticals, Roche Diagnostic USA, Sanofi. Other Relationship; Self; Roche Diagnostic USA. K. Philip: Employee; Self; Amgen Inc. Stock/Shareholder; Self; Amgen Inc. Y. Liu: None. K.E. Mues: Employee; Self; Amgen Inc. Stock/Shareholder; Self; Amgen Inc. S. Alam: Employee; Self; Amgen Inc. Stock/Shareholder; Self; Amgen Inc. M. Elliott: Employee; Self; Amgen Inc. Stock/Shareholder; Self; Amgen Inc. D.L. Bhatt: Research Support; Self; Abbott, Amarin Corporation, Amgen Inc., AstraZeneca, Bayer Vital GmbH, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Chiesi USA, Inc., Eisai Inc., Eli Lilly and Company, Ethicon, Inc., FlowCo, Forest Laboratories, Inc., Idorsia, Ironwood Pharmaceuticals, Inc., Ischemix, Medicines Company, Medtronic, Merck & Co., Inc., Novo Nordisk Inc., Pfizer Inc., PhaseBio Pharmaceuticals, Inc., PLx Pharma, Regeneron Pharmaceuticals, Roche Pharma, Sanofi, Synaptic, Takeda Pharmaceutical Company Limited. C.P. Cannon: Consultant; Self; Alnylam, Amarin Corporation, Amgen Inc., Corvia Medical, Inc., Eisai Inc., Kowa Pharmaceutical Europe Co. Ltd., Pfizer Inc., Regeneron Pharmaceuticals, Sanofi. Research Support; Self; Daiichi Sankyo Company, Limited. Other Relationship; Self; Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Funding Amgen Inc.

A deeper understanding of the interplay between the renal axis and cardiovascular (CV) disease is needed in type 2 diabetes mellitus (T2DM). We aimed to explore the prognostic value of a comprehensive panel of renal biomarkers in patients with T2DM at high CV risk. We evaluated the prognostic performance of both serum (Cystatin C) and urine renal biomarkers (neutrophil gelatinase-associated lipocalin, kidney injury molecule-1 protein, and indices of urinary protein excretion) in 5,380 patients with T2DM and recent acute coronary syndromes in the EXAMINE trial. Patients requiring dialysis within 14 days were excluded. Single- and multimarker covariate-adjusted Cox proportional hazards models were developed to predict times to events. Primary endpoint was composite nonfatal myocardial infarction, nonfatal stroke, or CV death. Median age was 61 years, 68% were men, and mean baseline estimated glomerular filtration rate (eGFR) was 74 mL/min/1.73 m2. During median follow-up of 18 months, 621 (11.5%) experienced the primary endpoint and 326 (6.1%) patients had died. All renal biomarkers were robustly associated with adverse CV events in step-wise fashion, independent of baseline eGFR. However, in the multimarker prediction model, only Cystatin C (per 1 SD) was associated with the primary endpoint (hazard ratio [HR] 1.28 [1.14 to 1.45]; p ≤ 0.001), death (HR 1.51 [1.30 to 1.74]; p ≤ 0.001), and heart failure hospitalization (HR 1.20 [0.96 to 1.49]; p = 0.11). Association between Cystatin C and the primary endpoint was similar in baseline eGFR above and below 60 mL/min/1.73 m2 (Pinteraction > 0.05). In conclusion, serum and urine renal biomarkers, when tested alone, independently predict long-term adverse CV events in high-risk patients with T2DM. In an integrative panel of renal biomarkers, only serum Cystatin C remained independently associated with subsequent CV risk. Renal biomarkers informing various aspects of kidney function may further our understanding of the complex interplay between diabetic kidney disease and CV disease.

This cohort study describes the use of drug therapies to prevent the progression of atherosclerotic cardiovascular disease in US patients with prior myocardial infarction and elevated low-density lipoprotein cholesterol levels.

AIMS Methods to identify patients at risk for incident HF would be welcome as such patients might benefit from earlier interventions. METHODS AND RESULTS From a registry of 1251 patients referred for coronary and/or peripheral angiography, we sought to identify independent predictors of incident HF during follow-up and develop a clinical and biomarker strategy to predict this outcome. There were 991 patients free of prevalent HF at baseline. Cox proportional hazard models were developed to predict adjudicated diagnosis of incident HF. Model discrimination and reclassification were evaluated. At follow-up, 177 (18%) developed new-onset HF. Independent predictors of new-onset HF included five clinical variables (age, male sex, heart rate, history of atrial fibrillation/flutter, and history of hypertension) and two biomarkers (amino-terminal pro-B type natriuretic peptide and ST2). The c-statistic for the model without biomarkers was 0.69; including biomarkers increased the c-statistic to 0.76 (P

Background: Modakafusp alfa (previously known as TAK-573) is a first-in-class immunocytokine designed to deliver interferon alpha-2b (IFNα2b) to CD38+ cells. It consists of two attenuated IFNα2b molecules genetically fused to the Fc portion of a humanized, anti-CD38, IgG4 monoclonal antibody (mAb). The specificity for CD38 and reduced IFN receptor binding affinity of the attenuated IFNα2b molecules significantly reduces the potential for off-target binding and toxicity. Furthermore, modakafusp alfa binds to a different epitope on CD38 than the currently approved anti-CD38 therapeutic mAbs, daratumumab and isatuximab. Preclinical evaluation of modakafusp alfa supports activation of type I IFN signaling in CD38+ cells, inducing direct anti-proliferative effects on myeloma cells, as well as direct and indirect immune cell activation. We have previously reported preliminary results from the first 59 patients (pts) in our first-in-human phase 1 trial of modakafusp alfa in pts with relapsed/refractory multiple myeloma (RRMM; NCT03215030), showing responses to single-agent therapy with doses starting at 0.1 mg/kg weekly; thrombocytopenia and neutropenia were dose-limiting toxicities when modakafusp alfa was administered weekly (QW), every 2 weeks (Q2W), and every 3 weeks (Q3W) (Vogl, Blood 2020). Here we report updated results from this trial, focusing on results from an expansion cohort with dosing every 4 weeks (Q4W). Methods: Eligible pts with RRMM who had received at least three previous lines of treatment received modakafusp alfa as a 1- to 4-hour intravenous infusion at 11 dose levels from 0.001 to 6 mg/kg following a 3+3 dose-escalation design. The initial dosing schedule was QW for 8 doses, then Q2W for 8 doses, and then monthly; subsequent cohorts evaluated dosing Q2W, Q3W or Q4W. Expansion cohorts were planned using modakafusp alfa at protocol-defined, biologically active doses that did not exceed the maximum tolerated dose (MTD). Results: As of May 2021, 83 pts had been treated across all planned dosing schedules. With Q4W dosing, the MTD was exceeded at the 6 mg/kg dose due to DLTs: a grade 3 infusion reaction and prolonged thrombocytopenia and neutropenia, which delayed the start of cycle 2 by >14 days. In total, 24 pts were treated with 1.5 mg/kg modakafusp alfa Q4W (5 pts during dose escalation and 19 pts in an expansion cohort). Analyses include data from all 24 pts. The median number of prior lines of therapy received was 6 (range 4-16); 21 pts (88%) were refractory to an anti-CD38 mAb, and 20 (83%) were triple class-refractory (to a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 mAb). Grade 3 or higher treatment-emergent adverse events (TEAEs) were reported in 18 pts (75%). The most frequent grade 3-4 TEAEs were neutropenia in 12 pts (50%; grade 4 in 6 [25%]), leukopenia in 9 (38%), decreased lymphocyte count in 9 (38%), anemia in 8 (33%), and thrombocytopenia in 8 (33%; grade 4 in 3 [13%]). One pt (4%) had a grade 3 bleeding event and continues on study treatment; 3 pts (13%) had infections (grade 3 in 2 [8%]); and 8 (33%) had infusion reactions (grade 3 in 1 [4%]). The overall response rate (ORR, ≥partial response [PR]) was 42% (complete response [CR], n=2; very good partial response [VGPR], n=5; PR, n=3), and the clinical benefit rate (ORR + minimal response [MR]) was 54% (MR, n=3). Median progression-free survival was 5.7 months (95% confidence interval [CI], 1.9-not reached [NR]), median time to response was 1.9 months (95% CI, 0.95-NR), and median duration of response was 7.4 months (95% CI, 2.3-NR). Among the 21 anti-CD38 mAb-refractory pts, the ORR was 43%, while among the 4 pts who received an anti-CD38 mAb in their most recent line of therapy prior to enrollment, the ORR was 75% (CR, n=1; VGPR, n=2). Correlative studies show evidence of T-cell and natural killer-cell activation, as well as activation of IFN signaling in CD38+ cells, including upregulation of CD38 expression. Conclusion: Modakafusp alfa (TAK-573) is a novel candidate for the treatment of RRMM, which has shown promising anti-myeloma activity in heavily pretreated pts, including anti-CD38 mAb-refractory pts and those who have received an anti-CD38 mAb in their most recent line of treatment. A Q4W dosing schedule of modakafusp alfa is feasible and the optimal dose and potential combinations are being explored. Disclosures Vogl: Takeda: Consultancy, Research Funding; Karyopharm: Consultancy; GSK: Consultancy; Oncopeptides: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; CSL Behring: Consultancy; Active Biotech: Research Funding. Kaufman: Genentech, AbbVie, Janssen: Consultancy, Research Funding; Amgen: Research Funding; Janssen: Honoraria; Roche/Genetech, Tecnopharma: Consultancy, Honoraria; Fortis Therapeutics: Research Funding; Novartis: Research Funding; Incyte, celgene: Consultancy; Sutro, Takeda: Research Funding; Tecnofarma SAS, AbbVie: Honoraria; BMS: Consultancy, Research Funding; Incyte, TG Therapeutics: Membership on an entity's Board of Directors or advisory committees; Heidelberg Pharma: Research Funding. Holstein: Oncopeptides: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, GSK, Janssen, Secura Bio, Sorrento: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Atrash: AMGEN: Research Funding; Jansen: Research Funding, Speakers Bureau; GSK: Research Funding. Nadeem: Takeda: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Janakiram: Kyowa Kirin Therapeutics: Honoraria; Takeda Pharmaceuticals: Research Funding; FATE Therapeutics: Research Funding; ADC Therapeutics: Research Funding. Suryanarayan: Takeda: Current Employment. Liu: Takeda: Current Employment. Parot: Takeda Pharmaceuticals: Current Employment. OffLabel Disclosure: Modakafusp alfa (TAK-573) is a first-in-class immunocytokine consisting of 2 attenuated interferon alpha-2b molecules genetically fused to an anti-CD38, IgG4 monoclonal antibody. This abstract contains information about investigational use of modakafusp alfa in patients with relapsed/refractory multiple myeloma. Safety and efficacy have not been determined.

IMPORTANCE: Guidelines for patients with atherosclerotic cardiovascular disease (ASCVD) recommend intensive statin therapy and adding nonstatin therapy if low-density lipoprotein cholesterol (LDL-C) levels are 70 mg/dL or more. Compliance with guidelines is often low. OBJECTIVE: To track LDL-C treatment patterns in the US over 2 years. DESIGN, SETTING, AND PARTICIPANTS: GOULD is a prospective observational registry study involving multiple centers. Patients with ASCVD receiving any lipid-lowering therapy (LLT) were eligible. Between December 2016 and July 2018, patients were enrolled in 1 of 3 cohorts: (1) those currently receiving proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) and 2 groups not receiving PCSK9i drugs, with (2) LDL-C levels of 100 mg/dL or more or (3) LDL-C levels of 70 to 99 mg/dL. Patients had medical record reviews and telephone interviews every 6 months. Analysis was done on data collected as of October 5, 2020. MAIN OUTCOMES AND MEASURES: The primary outcome was the change in LLT use in 2 years. Secondary outcomes included the number of LDL-C measurements, LDL-C levels, and responses to structured physician and patient questionnaires over 2 years. RESULTS: A total of 5006 patients were enrolled (mean [SD] age, 67.8 [9.9] years; 1985 women [39.7%]; 4312 White individuals [86.1%]). At 2 years, 885 (17.1%) had LLT intensification. In the cohorts with LDL-C levels of 100 mg/dL or more and 70 to 99 mg/dL, LLT intensification occurred in 403 (22.4%) and 383 (14.4%), respectively; statins were intensified in 115 (6.4%) and 168 (6.3%), ezetimibe added in 123 (6.8%) and 118 (4.5%), and PCSK9i added in 114 (6.3%) and 58 (2.2%), respectively. In the PCSK9i cohort, 508 of 554 (91.7%) were still taking PCSK9i at 2 years. Lipid panels were measured at least once over 2 years in 3768 patients (88.5%; PCSK9i cohort, 492 [96.1%]; LDL-C levels ≥100 mg/dL or more, 1294 [85.9%]; 70-99 mg/dL, 1982 [88.6%]). Levels of LDL-C fell from medians (interquartile ranges) of 120 (108-141) mg/dL to 95 (73-118) mg/dL in the cohort with LDL-C levels of 100 mg/dL or more, 82 (75-89) to 77 (65-90) mg/dL in the cohort with LDL-C levels of 70 to 99 mg/dL, and 67 (42-104) mg/dL to 67 (42-96) mg/dL in the PCSK9i cohort. Levels of LDL-C less than 70 mg/dL at 2 years were achieved by 308 patients (21.0%) and 758 patients (33.9%) in the cohorts with LDL-C levels of 100 mg/dL or more and 70 to 99 mg/dL, respectively, and 272 patients (52.4%) in the PCSK9i cohort. At 2 years, practice characteristics were associated with more LLT intensification (teaching vs nonteaching hospitals, 148 of 589 [25.1%] vs 600 of 3607 [16.6%]; lipid protocols or none, 359 of 1612 [22.3%] vs 389 of 2584 [15.1%]; cardiology, 452 of 2087 [21.7%] vs internal or family medicine, 204 of 1745 [11.7%] and other, 92 of 364 [25.3%]; all P

Aims We sought to assess the risk of major adverse cardiovascular events (MACE) by utilizing high‐sensitivity C‐reactive protein (hsCRP) level and low‐density lipoprotein cholesterol (LDL‐C) in patients with type 2 diabetes and recent acute coronary syndrome. Materials and methods Study participants enrolled in the EXAMINE trial (Clinical trials registration number: NCT00968708) and were stratified by baseline hsCRP levels (3 mg/L). They were also sub‐divided into 4 groups according to baseline hsCRP (≤3 or >3 mg/L) and achieved LDL‐C (3 mg/L, respectively (P 3 mg/L, the adjusted hazard ratio (95% confidence interval) was 1.42 (1.13, 1.78; P = .002) for MACE compared with patients with hsCRP

Aim To investigate adiponectin levels and cardiovascular (CV) outcomes in patients with diabetes and recent acute coronary syndrome (ACS). Materials and methods We analysed baseline adiponectin concentration and CV outcomes in 5213 patients with type 2 diabetes enrolled in the EXAMINE trial of alogliptin vs placebo 15 to 90 days (median 45 days) after ACS. Event rates at 18 months are reported. Results The median (interquartile range) baseline adiponectin concentration was 5.2 (3.5-7.9) μg/mL. Patients with the highest baseline adiponectin concentration (quartile [Q]4) were at significantly higher risk of death from a CV event (8.4% vs 1.7%; P

Background The optimal treatment approach for spontaneous coronary artery dissection (SCAD) remains unclear. Objectives The study aims to compare in-hospital and long-term clinical outcomes of SCAD patients initially managed with medical therapy (conservative approach) versus percutaneous coronary intervention or coronary artery bypass grafting (revascularization approach) based on published data. Methods We identified relevant studies by performing a systematic search in the Ovid MEDLINE and Embase databases. Studies with N at least 10 that report in-hospital outcomes [death, myocardial infarction (MI) and revascularization] or long-term outcomes (death, MI, revascularization, SCAD recurrence, and heart failure) were included. Risk difference between conservative and revascularization approach was estimated with the inverse variance-weighted method in a fixed-effect or random-effect model. Results A total of 22 nonrandomized, observational studies were analyzed (N = 1435). Compared with the initial revascularization approach, the conservative approach was associated with a comparable risk of in-hospital outcomes [risk difference: death, -0.61% (95% confidence interval, -2.13-0.91%), P = 0.43; MI, -0.99% (-4.65-2.67%), P = 0.60; revascularization, -3.02% (-8.79-2.75%), P = 0.31] and long-term outcomes [death, -0.06% (-2.33-2.20%), P = 0.96; MI, 0.96% (-2.35-4.27%), P = 0.57; revascularization, -3.31% (-7.63-1.02%), P = 0.13; SCAD recurrence, 3.75% (-2.05-9.55%), P = 0.21; heart failure, -0.01% (-3.13-3.11%), P = 0.99]. There was no significant heterogeneity across these studies. Conclusion Pooled results suggest that SCAD patients initially managed with a conservative strategy may have similar in-hospital and long-term outcomes compared with those who received revascularization in the absence of ongoing ischemia or left main artery involvement. More data from prospective studies are warranted to validate these findings.

Background: Among people with ASCVD, those with T2D have excess CVD risk and derive greater absolute benefit from CVD risk reduction therapies. We describe the use of evidence-based therapies for secondary prevention in participants (pts) with T2D. Methods: We report a registry to longitudinally describe LDL-C treatment patterns among U.S. pts with ASCVD and LDL-C ≥70mg/dL taking lipid-lowering therapy. Pts (n=5006) were enrolled in 1 of 3 cohorts: taking PCSK9i (11%); LDL-C 70-99mg/dL (53%); and LDL-C ≥100mg/dL (36%). Results: Overall, 1655 (33%) had diabetes (96% with T2D): 146 in the PCSK9i cohort, 874 in the LDL-C 70-99mg/dL cohort, and 635 in the LDL-C ≥100mg/dL cohort. Mean age among pts with diabetes was 68 y, 60% were male, 81% had CAD (including 33% with prior MI), 17% with PAD, and 17% had HF. Mean LDL-C was 100mg/dL. Although overall statin use was at 87%, high-intensity statins were used in only 45% and ezetimibe in only 9.5% of pts. Aspirin and ACE-I/ARB were each used in 72% and beta blockers in 71% of pts. The most commonly used glucose-lowering medications among patients with T2D were metformin (56%), insulin (34%), and sulfonylurea (22%). Only 10% and 8% of pts with T2D were treated with SGLT2i or GLP-1RA, respectively. The proportion of pts with T2D that were receiving all guideline-recommended therapies for optimal risk reduction (high-intensity statins, aspirin, ACE-I/ARB, and either SGLT2i or GLP-1RA) was just 3%. Conclusion: In GOULD, among pts with T2D, ASCVD, and LDL-C ≥70mg/dL, most are not receiving high intensity statin therapy at baseline and few receive ezetimibe. Furthermore, less than 20% are treated with glucose-lowering therapies that have a proven CVD benefit, and a strikingly low proportion receive all guideline-recommended risk reduction strategies. These results highlight an opportunity to improve care and outcomes. Disclosure M.N. Kosiborod: Consultant; Self; Amgen Inc., AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Eisai Co., Ltd., GlaxoSmithKline plc., Glytec, LLC, Intarcia Therapeutics, Inc., Janssen Pharmaceuticals, Inc., Merck & Co., Inc., Novartis AG, Novo Nordisk A/S, Sanofi. Research Support; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc. J. De Lemos: Other Relationship; Self; Amgen Inc., Novo Nordisk A/S, Regeneron Pharmaceuticals. R.S. Rosenson: Consultant; Self; CVS/Caremark, Regeneron Pharmaceuticals. Research Support; Self; Akcea Therapeutics, Amgen Inc., Medicines Company, Regeneron Pharmaceuticals. Other Relationship; Self; Amgen Inc., Kowa Pharmaceutical Europe Co. Ltd. C.M. Ballantyne: Consultant; Self; Abbott, Akcea Therapeutics, Amarin Corporation, Amgen Inc., AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Esperion, Gilead Sciences, Inc., Matinas BioPharma, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Regeneron Pharmaceuticals, Roche Diagnostic USA, Sanofi. Research Support; Self; Abbott, Akcea Therapeutics, Amarin Corporation, Amgen Inc., Esperion, Novartis Pharmaceuticals Corporation, Regeneron Pharmaceuticals, Roche Diagnostic USA, Sanofi. Other Relationship; Self; Roche Diagnostic USA. K. Philip: Employee; Self; Amgen Inc. Stock/Shareholder; Self; Amgen Inc. Y. Liu: None. K.E. Mues: Employee; Self; Amgen Inc. Stock/Shareholder; Self; Amgen Inc. S. Alam: Employee; Self; Amgen Inc. Stock/Shareholder; Self; Amgen Inc. M. Elliott: Employee; Self; Amgen Inc. Stock/Shareholder; Self; Amgen Inc. D.L. Bhatt: Research Support; Self; Abbott, Amarin Corporation, Amgen Inc., AstraZeneca, Bayer Vital GmbH, Boehringer Ingelheim International GmbH, Bristol-Myers Squibb Company, Chiesi USA, Inc., Eisai Inc., Eli Lilly and Company, Ethicon, Inc., FlowCo, Forest Laboratories, Inc., Idorsia, Ironwood Pharmaceuticals, Inc., Ischemix, Medicines Company, Medtronic, Merck & Co., Inc., Novo Nordisk Inc., Pfizer Inc., PhaseBio Pharmaceuticals, Inc., PLx Pharma, Regeneron Pharmaceuticals, Roche Pharma, Sanofi, Synaptic, Takeda Pharmaceutical Company Limited. C.P. Cannon: Consultant; Self; Alnylam, Amarin Corporation, Amgen Inc., Corvia Medical, Inc., Eisai Inc., Kowa Pharmaceutical Europe Co. Ltd., Pfizer Inc., Regeneron Pharmaceuticals, Sanofi. Research Support; Self; Daiichi Sankyo Company, Limited. Other Relationship; Self; Amgen Inc., Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Janssen Pharmaceuticals, Inc., Merck & Co., Inc. Funding Amgen Inc.

The enantioselective synthesis of a desulfur-scabrosin skeleton was reported. The synthesis began from 3-(hydroxymethyl)phenol, and key steps include asymmetric nucleophilic epoxidation, a Mitsunobu reaction using a sulfonamide as the nucleophile, the construction of a pyrrolidine ring by intramolecular nucleophilic substitution, and inversion of configuration through base-induced keto–enol isomerization. Additionally, two isomers of the carbon skeleton were also obtained via an alternative ring-closing strategy.

Aims To investigate relationships between glycated haemoglobin (HbA1c) and reported hypoglycaemia and risk of major adverse cardiovascular events (MACE). Methods The EXAMINE trial randomized 5380 patients with type 2 diabetes (T2DM) and a recent acute coronary syndrome (ACS) event, in 49 countries, to double-blind treatment with alogliptin or placebo in addition to standard of care. We used Cox proportional hazards models to analyse relationships among MACE, HbA1c levels and hypoglycaemic events. Results Patients randomized to alogliptin achieved lower HbA1c levels than the placebo group in all baseline HbA1c categories without differences in hypoglycaemia rates. No systematic change was found in MACE rates according to baseline HbA1c (Pinteraction = 0.971) or HbA1c category at 1 month. Patients in the combined treatment groups (n = 5380) who experienced serious hypoglycaemia (n = 34) had higher MACE rates than those who did not (35.3% vs 11.4%, adjusted hazard ratio [HR] 2.42, 95% confidence interval [CI] 1.27–4.60; P = .007), although the association was less strong when analysing only events after the hypoglycaemic event (adjusted HR 1.60, 95% CI 0.80, 3.20). Conclusions There were no relationships between baseline HbA1c levels or HbA1c levels after 1 month of treatment and the risk of MACE. Alogliptin improved glycaemic control without increasing hypoglycaemia. Reported events of hypoglycaemia and serious hypoglycaemia were associated with MACE. These data underscore the safety of alogliptin in improving glycaemic control in T2DM post-ACS. Further study of hypoglycaemia as an independent risk factor for MACE in patients with T2DM and coronary disease is needed.

An effective method for the synthesis of multi-substituted β-keto thioethers via Stevens rearrangement of simple β-keto thioethers with arynes has been developed. In these reactions, successive C-S/C-H/C-C bonds were formed in one pot under mild and transition-metal free conditions to afford multi-substituted β-keto thioethers in moderate to good yields.

Background Concerns raised regarding adverse cardiovascular (CV) outcomes with new therapies for type 2 diabetes mellitus (T2DM) have led to several large-scale CV outcome trials. The EXAMINE trial confirmed noninferiority of the dipeptidyl dipeptidase 4 inhibitor alogliptin to placebo on major adverse cardiac event rates in a post–acute coronary syndrome (ACS) T2DM population. We present data on additional ischemic cardiac events and CV hospitalizations in EXAMINE. Methods Patients with T2DM and an ACS event in the previous 15 to 90 days were randomly assigned to alogliptin or placebo on a background of standard treatment for diabetes. The incident rates of a 5-component composite end point of CV death, stroke, myocardial infarction, unstable angina, and coronary revascularization as well as CV hospitalization were calculated in all participants and according to macrovascular disease at baseline. Results There were no significant differences between alogliptin (n = 2,701) and placebo (n = 2,679) in the event rate of the 5-component composite endpoint with median follow-up 533 days (21.0% vs 21.5%, hazard ratio [HR] 0.98 [0.87-1.10], P = .72). No differences were observed in terms of CV hospitalization (25.0% vs 25.4%, HR 0.98 [0.88-1.09], P = .70) or coronary revascularization (10.6% vs 10.2%, HR 1.05 [0.88-1.09], P = .60). No interactions were observed for treatment and prior macrovascular disease. Conclusions EXAMINE demonstrates that there was no increase in the risk of cardiac ischemic events and CV hospitalizations with alogliptin in a high-risk post-ACS patient population. Because these are major driver of overall health care costs, these data suggest that there would be no adverse impact on health care resource utilization.

Background The COGENT (Clopidogrel and the Optimization of Gastrointestinal Events Trial) showed that proton-pump inhibitors (PPIs) safely reduced rates of gastrointestinal (GI) events in patients requiring dual antiplatelet therapy (DAPT). However, utilization of appropriate prophylactic PPI therapy remains suboptimal, especially with low-dose aspirin. Objectives The authors investigated the safety and efficacy of PPI therapy in patients receiving DAPT in low- and high-dose aspirin subsets. Methods Randomized patients with available aspirin dosing information in COGENT (N = 3,752) were divided into “low-dose” (≤100 mg) and “high-dose” (>100 mg) aspirin groups. The primary GI and cardiovascular endpoints were composite upper GI events and major adverse cardiac events, respectively. All events were adjudicated by independent, blinded gastroenterologists and cardiologists. Results Median duration of follow-up was 110 days. Low-dose aspirin users (n = 2,480; 66.1%) were more likely to be older, female, and have higher rates of peripheral artery disease, prior stroke, and hypertension, whereas high-dose aspirin users (n = 1,272; 33.9%) had higher rates of hyperlipidemia, smoking, a history of percutaneous coronary intervention, and were more than twice as likely to be enrolled from sites within the United States (80.4% vs. 39.8%). High-dose aspirin was associated with similar 180-day Kaplan-Meier estimates of adjudicated composite GI events (1.7% vs. 2.1%; adjusted hazard ratio: 0.88; 95% confidence interval: 0.46 to 1.66) and major adverse cardiac events (4.8% vs. 5.5%; adjusted hazard ratio: 0.73; 95% confidence interval: 0.48 to 1.11) compared with low-dose aspirin. Randomization to PPI therapy reduced 180-day Kaplan-Meier estimates of the primary GI endpoint in low-dose (1.2% vs. 3.1%) and high-dose aspirin subsets (0.9% vs. 2.6%; p for interaction = 0.80), and did not adversely affect the primary cardiovascular endpoint in either group. Conclusions Gastroprotection with PPI therapy should be utilized in appropriately selected patients with coronary artery disease requiring DAPT, even if the patients are on low-dose aspirin. (Clopidogrel and the Optimization of Gastrointestinal Events Trial [COGENT]; NCT00557921 )

With the pervasive use of information technologies, the increasing availability of data provides new opportunities for understanding user behaviors. Unearthing anomalies in user behavior is of particular importance as it helps signal harmful incidents such as network intrusions, terrorist activities, and financial frauds. In this work, we survey state-of-the-art research work in visual analytics of anomalous user behaviors and classify them into four application domains, which are social interaction, travel, network communication, and financial transaction. We further examine the research work in each category in terms of data types, visualization techniques, and interactive analysis methods. We hope that our survey can provide systematic guidelines for researchers and practitioners to find effective solutions to their research problems in specific application domains. Finally, we discuss trends of academic interest over the past decades and suggest potential directions across visual analytics of these user behaviors for future research.

Item does not contain fulltext BACKGROUND: Patients with stable coronary artery disease and diabetes mellitus who have not had a myocardial infarction or stroke are at high risk for cardiovascular events. Whether adding ticagrelor to aspirin improves outcomes in this population is unclear. METHODS: In this randomized, double-blind trial, we assigned patients who were 50 years of age or older and who had stable coronary artery disease and type 2 diabetes mellitus to receive either ticagrelor plus aspirin or placebo plus aspirin. Patients with previous myocardial infarction or stroke were excluded. The primary efficacy outcome was a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety outcome was major bleeding as defined by the Thrombolysis in Myocardial Infarction (TIMI) criteria. RESULTS: A total of 19,220 patients underwent randomization. The median follow-up was 39.9 months. Permanent treatment discontinuation was more frequent with ticagrelor than placebo (34.5% vs. 25.4%). The incidence of ischemic cardiovascular events (the primary efficacy outcome) was lower in the ticagrelor group than in the placebo group (7.7% vs. 8.5%; hazard ratio, 0.90; 95% confidence interval [CI], 0.81 to 0.99; P = 0.04), whereas the incidence of TIMI major bleeding was higher (2.2% vs. 1.0%; hazard ratio, 2.32; 95% CI, 1.82 to 2.94; P