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Aims Prevalent atrial fibrillation (AF) is associated with excess cardiovascular (CV) death (D) and hospitalizations (H) in heart failure (HF) with preserved ejection fraction (pEF). We evaluated if it had an independent role in excess CVD in HFpEF and studied its impact on cause-specific mortality and HF morbidity. Methods and results We used propensity score–matched (PSM) cohorts from the TOPCAT Americas trial to account for confounding by other co-morbidities. Two prevalent AF presentations at study entry were compared: (i) subjects with Any AF event by history or on electrocardiogram (ECG) with PSM subjects without an AF event and (ii) subjects in AF on ECG with PSM subjects in sinus rhythm. We analyzed cause-specific modes of death and HF morbidity during a mean follow-up period of 2.9 years. A total of 584 subjects with Any AF event and 418 subjects in AF on ECG were matched. Any AF was associated with increased CVH [hazard ratio (HR) 1.33, 95% confidence interval (CI) 1.11–1.61, P = 0.003], HFH (HR 1.44, 95% CI 1.12–1.86, P = 0.004), pump failure death (PFD) (HR 1.95, 95% CI 1.05–3.62, P = 0.035), and HF progression from New York Heart Association (NYHA) classes I/II to III/IV (HR 1.30, 95% CI 1.04–1.62, P = 0.02). Atrial fibrillation on ECG was associated with increased risk of CVD (HR 1.46, 95% CI 1.02–2.09, P = 0.039), PFD (HR 2.21, 95% CI 1.11–4.40, P = 0.024), and CVH and HFH (HR 1.37, 95% CI 1.09–1.72, P = 0.006 and HR 1.65, 95% CI 1.22–2.23, P = 0.001, respectively). Atrial fibrillation was not associated with risk of sudden death. Both Any AF and AF on ECG cohorts were associated with PFD in NYHA class III/IV HF. Conclusion Prevalent AF can be an independent risk factor for adverse CV outcomes by its selective association with worsening HF, HFH, and PFD in HFpEF. Prevalent AF was not associated with excess sudden death risk in HFpEF. Atrial fibrillation was also associated with HF progression in early symptomatic HFpEF and PFD in advanced HFpEF. Trial registration TOPCAT trial is registered at www.clinicaltrials.gov:identifier NCT00094302.

In T2D, treatment targets include maintaining HbA1c ≤7.0%, LDL-C 2 mg/mmol. CANA consistently reduced risk of MACE, HHF/CV death, and ESKD or doubling of serum creatinine vs. placebo, regardless of whether BL targets were met or if UACR was elevated (Figure) . The number of uncontrolled targets at BL did not impact the beneficial effect of CANA on CV and kidney outcomes (all P interaction >0.17) . In conclusion, CANA demonstrated consistent CV and renal benefits in patients with T2D, regardless of risk factor control. Disclosure V.C.Woo: Advisory Panel; AstraZeneca, Boehringer Ingelheim International GmbH, Lilly, Novo Nordisk, Speaker's Bureau; Janssen Pharmaceuticals, Inc. M.Tsoukas: Speaker's Bureau; AstraZeneca, Bausch Health, Canada, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Johnson & Johnson, Novo Nordisk Canada Inc. S.Tobe: Other Relationship; Bayer AG, Speaker's Bureau; AstraZeneca, Otsuka Pharmaceutical Co., Ltd. A.Slee: Consultant; Alydia Health, Elixir Medical , IHP Therapeutics , iLumen Scientific, Intuitive Surgical, Janssen Global Services, LLC, Laborie, Providence Medical, Pulse Biosciences, SonoMotion. W.Rapattoni: Employee; Janssen Pharmaceuticals, Inc. F.Ang: Employee; Bristol-Myers Squibb Company, Janssen Pharmaceuticals, Inc. J.Seufert: Advisory Panel; Abbott, Sanofi-Aventis Deutschland GmbH, Research Support; Boehringer Ingelheim International GmbH, Speaker's Bureau; Abbott Diabetes, AstraZeneca, Bayer AG, Boehringer Ingelheim International GmbH, Lilly, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. D.C.Wheeler: Advisory Panel; Bayer AG, Boehringer Ingelheim International GmbH, Gilead Sciences, Inc., GlaxoSmithKline plc., Janssen Global Services, LLC, Merck Sharp & Dohme Corp., Mundipharma, Tricida, Inc., Vifor Pharma Management Ltd., Consultant; AstraZeneca, Speaker's Bureau; Amgen Inc., Astellas Pharma Inc. Funding Janssen Inc., Toronto, ON, Canada

BACKGROUND AND AIMS Type 2 diabetes mellitus (T2DM) is associated with comorbidities, such as chronic kidney disease (CKD) and peripheral vascular disease (PVD), which may increase risk of cardiovascular (CV) and kidney events. Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, reduced the risk of CV and kidney events in patients with T2DM and high CV risk or nephropathy in the CANVAS Program and CREDENCE trial, respectively. The effects of canagliflozin on CV and kidney outcomes in patients with CKD with and without PVD remain unknown. METHOD This post hoc analysis included integrated, pooled data from the CANVAS Program and the CREDENCE trial. The effects of canagliflozin compared with placebo on CV and kidney outcomes were assessed in patients with CKD with and without PVD at baseline. CKD was defined as estimated glomerular filtration rate (eGFR) RESULTS A total of 14 543 participants from the CANVAS Program (N = 10 142) and CREDENCE (N = 4401) were included. Of these, 3514 had CKD alone (canagliflozin, n = 1792; placebo, n = 1722; mean eGFR, 46 mL/min/1.73 m2; symptomatic CV disease history, 49%; insulin use, 64%) and 1156 had CKD + PVD (canagliflozin, n = 626; placebo, n = 530; mean eGFR, 46 mL/min/1.73 m2; symptomatic CV disease history, 96%; insulin use, 74%) at baseline. Canagliflozin was associated with a reduced risk of major adverse cardiovascular events (MACE), the composite of hospitalization for heart failure (HHF) or CV death (HHF/CV death), doubling of serum creatinine (dSCr), end-stage kidney disease (ESKD) and the composite of ESKD or dSCr compared with placebo in patients with CKD with and without PVD (Figure 1A). After matching, 3210 patients had CKD alone (mean eGFR, 46 mL/min/1.73 m2; symptomatic CV disease history, 49%; insulin use, 64%) and 966 had CKD + PVD (mean eGFR, 46 mL/min/1.73 m2; symptomatic CV disease history, 98%; insulin use, 74%), with equal numbers in the canagliflozin and placebo groups. In the PS-matched groups, canagliflozin was associated with a reduced risk of MACE, HHF/CV death, dSCr, ESKD and the composite of ESKD or dSCr compared with placebo in patients with CKD with and without PVD (Figure 1B). CONCLUSION Canagliflozin significantly reduced the risk of MACE, HHF/CV death, dSCr, ESKD, and the composite of ESKD or dSCr in patients with CKD with and without PVD, suggesting that the beneficial effects of canagliflozin on CV and kidney outcomes are consistent and can be seen in patients regardless of these comorbidities.

Introduction The Canagliflozin and Renal Endpoints in Diabetes with Established Nephropathy Clinical Evaluation (CREDENCE) study showed that compared with placebo, canagliflozin 100 mg significantly reduced the risk of major cardiovascular events and adverse renal outcomes in patients with diabetic kidney disease (DKD). We developed a simulation model that can be used to estimate the long-term health and economic consequences of DKD treatment interventions for patients matching the CREDENCE study population. Methods The CREDENCE Economic Model of DKD (CREDEM-DKD) was developed using patient-level data from CREDENCE (which recruited patients with estimated glomerular filtration rate 30 to 300–5000 mg/g, and taking the maximum tolerated dose of a renin–angiotensin–aldosterone system inhibitor). Risk prediction equations were fit for start of maintenance dialysis, doubling of serum creatinine, hospitalization for heart failure, nonfatal myocardial infarction, nonfatal stroke, and all-cause mortality. A micro-simulation model was constructed using these risk equations combined with user-definable kidney transplant event risks. Internal validation was performed by loading the model to replicate the CREDENCE study and comparing predictions with trial Kaplan–Meier estimate curves. External validation was performed by loading the model to replicate a subgroup of the CANagliflozin cardioVascular Assessment Study (CANVAS) Program with patient characteristics that would have qualified for inclusion in CREDENCE. Results Risk prediction equations generally fit well and exhibited good concordance, especially for the placebo arm. In the canagliflozin arm, modest underprediction was observed for myocardial infarction, along with overprediction of dialysis, doubling of serum creatinine, and all-cause mortality. Discrimination was strong (0.85) for the renal outcomes, but weaker for the macrovascular outcomes and all-cause mortality (0.60–0.68). The model performed well in internal and external validation exercises. Conclusion CREDEM-DKD is an important new tool in the evaluation of treatment interventions in the DKD population. Trial Registration ClinicalTrials.gov identifier, NCT02065791. Electronic Supplementary Material The online version of this article (10.1007/s13300-020-00923-w) contains supplementary material, which is available to authorized users.

This study compared initiation of insulin and other AHAs with canagliflozin versus placebo for participants with type 2 diabetes and a history/high risk of cardiovascular disease in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. After 1 year fewer participants treated with canagliflozin versus placebo initiated any AHA (7% vs 16%), insulin (3% vs 9%;) or any non-insulin AHA (5% vs 12%; p

Background Behavioral mitigation strategies to slow the spread of COVID-19 have resulted in sweeping lifestyle changes, with short- and long-term psychological, well-being, and quality of life implications. The Attitudes About COVID-19 and Health (ATTACH) study focuses on understanding attitudes and beliefs while considering the impact on mental and physical health and the influence of broader demographic and geographic factors on attitudes, beliefs, and mental health burden. Objective In this assessment of our first wave of data collection, we provide baseline cohort description of the ATTACH study participants in the United Kingdom, the United States, and Mexico. Additionally, we assess responses to daily poll questions related to COVID-19 and conduct a cross-sectional analysis of baseline assessments collected in the UK between June 26 and October 31, 2020. Methods The ATTACH study uses smartphone app technology and online survey data collection. Participants completed poll questions related to COVID-19 2 times daily and a monthly survey assessing mental health, social isolation, physical health, and quality of life. Poll question responses were graphed using 95% Clopper–Pearson (exact) tests with 95% CIs. Pearson correlations, hierarchical linear regression analyses, and generalized linear models assessed relationships, predictors of self-reported outcomes, and group differences, respectively. Results By October 31, 2020, 1405, 80, and 90 participants had consented to participate in the UK, United States, and Mexico, respectively. Descriptive data for the UK daily poll questions indicated that participants generally followed social distancing measures, but worry and negative impacts on families increased as the pandemic progressed. Although participants generally reported feeling that the reasons for current measures had been made clear, there was low trust that the government was doing everything in its power to meet public needs. In the UK, 1282 participants also completed a monthly survey (94.99% [1326/1396] White, 72.22% [1014/1404] female, and 20.12% [277/1377] key or essential workers); 18.88% (242/1282) of UK participants reported a preexisting mental health disorder, 31.36% (402/1282) reported a preexisting chronic medical illness, and 35.11% (493/1404) were aged over 65; 57.72% (740/1282) of participants reported being more sedentary since the pandemic began, and 41.89% (537/1282) reported reduced access to medical care. Those with poorer mental health outcomes lived in more deprived neighborhoods, in larger households (Ps Conclusions Communities who have been exposed to additional harm during the COVID-19 pandemic were experiencing worse mental outcomes. Factors including having a medical condition, or living in a deprived neighborhood or larger household were associated with heightened risk. Future longitudinal studies should investigate the link between COVID-19 exposure, mental health, and sociodemographic and residential characteristics.

Background The sodium-glucose cotransporter 2 inhibitor canagliflozin has been shown to reduce the risk of cardiovascular and renal events in patients with Type 2 diabetes mellitus and high risk. Pooled analyses of data from early studies and interim data from the CANagliflozin cardioVascular Assessment Study (CANVAS) suggested that canagliflozin might lead to increases in serum potassium, particularly the 300 mg dose in patients with renal impairment, which is important because high serum potassium is associated with increased cardiovascular and renal risk. We examined the effect of canagliflozin on serum potassium levels and hyperkalemia rates in the completed CANVAS Program. Methods The CANVAS Program (n = 10,142) was comprised of two comparable double-blind, randomized, placebo-controlled trials (CANVAS and CANVAS-Renal). Participants received canagliflozin 100 or 300 mg or placebo. Serum potassium measurements were performed in a central laboratory0 and assessed at ∼6-month intervals. Results In the CANVAS Program, mean potassium levels were generally consistent with canagliflozin and placebo, overall and by baseline estimated glomerular filtration rate (eGFR; ≥60, 45 to Conclusions In the CANVAS Program, there were no meaningful effects of canagliflozin on serum potassium in the overall population or key subgroups. Hyperkalemia adverse events were uncommon and occurred at comparable rates with canagliflozin and placebo.

Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Electrophysiology Research Foundation Introduction Atrial fibrillation (AF) is known to impact cardiovascular(CV) mortality in heart failure (HF) patients (pts) with preserved ejection fraction (pEF) but its exact causes are unknown. Methods We analyzed demographic, clinical, ECG and AF presentation as predictors of CV mortality, sudden death( SCD) and pump failure death(PFD) in HFpEF pts in the TOPCAT AMERICAS trial. We analyzed two AF presentations 1. Pts in sinus rhythm (SR, n = 1319) compared to AF on ECG (n = 446) at entry or 2. Pts with no AF event by history or ECG ( n = 1007 ) to those with any AF event (n = 760 ). Results (Table): 5 year (yr) CV mortality was higher in pts with AF on ECG (30%) than SR (18%, p = 0.014) but 5 yr SCD was (10% in AF on ECG & 7% in any AF) & comparable to SR (7% & 9% respectively, p = ns). 5 yr PFD was higher in AF on ECG (13%) than SR (5%, p = 0.007) Conclusions : 1. CV death risk in HFpEF pts increased with AF on ECG.. 2. SCD was not more frequent with both AF presentations 3. PFD in HFpEF increased with age, ECG recorded AF & elevated heart rate. 4. The recording of AF on ECG was more strongly associated with CV death & PFD, possibly due to greater AF burden . Predictors of adverse outcomes in HFpEF AF on ECG* Any AF* Endpoint Covariate HR (95% CI) p-value HR (95% CI) p-value Time to cardiovascular death Atrial Fibrillation* 1.44 (1.08, 1.92) 0.014 1.15 (0.87, 1.51) 0.338 Age (years) 1.03 (1.02, 1.05)

BACKGROUND Behavioral mitigation strategies to slow the spread of COVID-19 have resulted in sweeping lifestyle changes, with short- and long-term psychological, well-being, and quality of life implications. The Attitudes About COVID-19 and Health (ATTACH) study focuses on understanding attitudes and beliefs while considering the impact on mental and physical health and the influence of broader demographic and geographic factors on attitudes, beliefs, and mental health burden. OBJECTIVE In this assessment of our first wave of data collection, we provide baseline cohort description of the ATTACH study participants in the United Kingdom, the United States, and Mexico. Additionally, we assess responses to daily poll questions related to COVID-19 and conduct a cross-sectional analysis of baseline assessments collected in the UK between June 26 and October 31, 2020. METHODS The ATTACH study uses smartphone app technology and online survey data collection. Participants completed poll questions related to COVID-19 2 times daily and a monthly survey assessing mental health, social isolation, physical health, and quality of life. Poll question responses were graphed using 95% Clopper–Pearson (exact) tests with 95% CIs. Pearson correlations, hierarchical linear regression analyses, and generalized linear models assessed relationships, predictors of self-reported outcomes, and group differences, respectively. RESULTS By October 31, 2020, 1405, 80, and 90 participants had consented to participate in the UK, United States, and Mexico, respectively. Descriptive data for the UK daily poll questions indicated that participants generally followed social distancing measures, but worry and negative impacts on families increased as the pandemic progressed. Although participants generally reported feeling that the reasons for current measures had been made clear, there was low trust that the government was doing everything in its power to meet public needs. In the UK, 1282 participants also completed a monthly survey (94.99% [1326/1396] White, 72.22% [1014/1404] female, and 20.12% [277/1377] key or essential workers); 18.88% (242/1282) of UK participants reported a preexisting mental health disorder, 31.36% (402/1282) reported a preexisting chronic medical illness, and 35.11% (493/1404) were aged over 65; 57.72% (740/1282) of participants reported being more sedentary since the pandemic began, and 41.89% (537/1282) reported reduced access to medical care. Those with poorer mental health outcomes lived in more deprived neighborhoods, in larger households (PsPs CONCLUSIONS Communities who have been exposed to additional harm during the COVID-19 pandemic were experiencing worse mental outcomes. Factors including having a medical condition, or living in a deprived neighborhood or larger household were associated with heightened risk. Future longitudinal studies should investigate the link between COVID-19 exposure, mental health, and sociodemographic and residential characteristics.

Background COVID-19 causes acute respiratory distress syndrome (ARDS) and depletes the lungs of surfactant, leading to prolonged mechanical ventilation and death. The feasibility and safety of surfactant delivery in COVID-19 ARDS patients have not been established. Methods We performed retrospective analyses of data from patients receiving off-label use of exogenous natural surfactant during the COVID-19 pandemic. Seven COVID-19 PCR positive ARDS patients received liquid Curosurf (720 mg) in 150 ml normal saline, divided into five 30 ml aliquots) and delivered via a bronchoscope into second-generation bronchi. Patients were matched with 14 comparable subjects receiving supportive care for ARDS during the same time period. Feasibility and safety were examined as well as the duration of mechanical ventilation and mortality. Results Patients showed no evidence of acute decompensation following surfactant installation into minor bronchi. Cox regression showed a reduction of 28-days mortality within the surfactant group, though not significant. The surfactant did not increase the duration of ventilation, and health care providers did not convert to COVID-19 positive. Conclusions Surfactant delivery through bronchoscopy at a dose of 720 mg in 150 ml normal saline is feasible and safe for COVID-19 ARDS patients and health care providers during the pandemic. Surfactant administration did not cause acute decompensation, may reduce mortality and mechanical ventilation duration in COVID-19 ARDS patients. This study supports the future performance of randomized clinical trials evaluating the efficacy of meticulous sub-bronchial lavage with surfactant as treatment for patients with COVID-19 ARDS.

Introduction: Presence of atrial fibrillation (AF) is known to increase mortality and impact cardiovascular(CV) outcomes in heart failure (HF) patients (pts) with preserved systolic function (pEF) but its causes are unknown Hypothesis: We hypothesized that AF presentation & clinical factors impact mode of death & CV outcomes of HFpEF pts in the TOPCAT AMERICAS trial. Methods: We analyzed demographic, clinical, ECG and AF presentation as predictors of CV mortality, sudden death( SCD) and pump failure death(PFD). We examined two AF presentations 1. Pts in sinus rhythm (SR, n=1319) compared to pts in AF (n=446) on ECG at study entry or 2. Pts with no AF event by history or ECG ( n=1007 ) compared to those with any AF event (n=760 ) during a mean follow up period of 2.9 years(yrs). Results: AF pts when compared to the rest of the study population were more likely to be older, male, Caucasian origin, have more alcohol use, diabetes, percutaneous coronary interventions. 5 yr CV mortality was higher in pts with AF on ECG (30%) than those in sinus rhythm (18%, p=0.014) but 5 yr SCD was lower (10% in AF on ECG & 7% in any AF) & comparable to SR (7% & 9% respectively, p=ns). 5 yr PFD was higher (13%) than SR (5%, p=0.007. )Table shows Cox proportional hazards analysis of covariates associated with time to CV death, time to SCD & time to PFD adjusted for baseline imbalances. Conclusions:: 1. CV death risk in HFpEF pts increased with age, in minorities, smokers, diabetics, with lower systolic bp, elevated heart rate & AF on ECG.. 2. SCD was more frequent in males, African Americans & diabetics but was low in both AF & SR, perhaps due to a dominant atrial & limited ventricular arrhythmogenic substrate in HFpEF. 3. PFD in HFpEF increased with age, ECG recorded AF & elevated heart rate.This may reflect importance of atrioventricular synchrony in HFpEF. 4. The recording of AF on ECG at study entry was more strongly associated with CV death & PFD, possibly due to greater AF burden in this group compared to those with any AF even..

BackgroundGeneralised anxiety disorder and symptoms are associated with poor physical, emotional and social functioning and frequent primary and acute care visits. We investigated recent temporal trends in anxiety and related mental illness in UK general practice.AimsThe aims of this analysis are to examine temporal changes in recording of generalised anxiety in primary care and initial pharmacologic treatments.MethodAnnual incidence rates of generalised anxiety diagnoses and symptoms were calculated from 795 UK general practices contributing to The Health Improvement Network (THIN) database between 1998 and 2018. Poisson mixed regression was used to account for age, gender and general practitioner practice. Subsequent pharmacologic treatment was examined.ResultsGeneralised anxiety recording rates increased in both genders aged 18–24 between 2014 and 2018. For women, the increase was from 17.06 to 23.33/1000 person years at risk (PYAR); for men, 8.59 to 11.65/1000 PYAR. Increases persisted for a composite of anxiety and depression (49.74 to 57.81/1000 PYAR for women; 25.41 to 31.45/1000 PYAR for men). Smaller increases in anxiety were seen in both genders age 25–34 and 35–44. Anxiety rates among older patients remained stable, although a composite of anxiety and depression decreased for older women. About half of drug-naïve patients were prescribed anxiety drugs within 1 year following diagnosis. The most common choice was a selective serotonin reuptake inhibitor. Benzodiazepine prescription rate has fallen steadily.ConclusionsWe observed a substantial increase in general practitioner consulting for generalised anxiety and depression recently, concentrated within younger people and in particular women.

Background The interscalene nerve block provides analgesia for shoulder surgery, but is associated with diaphragm paralysis. One solution may be performing brachial plexus blocks more distally. This noninferiority study evaluated analgesia for blocks at the supraclavicular and anterior suprascapular levels, comparing them individually to the interscalene approach. Methods One hundred-eighty-nine subjects undergoing arthroscopic shoulder surgery were recruited to this double-blind trial and randomized to interscalene, supraclavicular, or anterior suprascapular block using 15 ml, 0.5% ropivacaine. The primary outcome was numeric rating scale pain scores analyzed using noninferiority testing. The predefined noninferiority margin was one point on the 11-point pain scale. Secondary outcomes included opioid consumption and pulmonary assessments. Results All subjects completed the study through the primary outcome analysis. Mean pain after surgery was: interscalene = 1.9 (95% CI, 1.3 to 2.5), supraclavicular = 2.3 (1.7 to 2.9), suprascapular = 2.0 (1.4 to 2.6). The primary outcome, mean pain score difference of supraclavicular–interscalene was 0.4 (–0.4 to 1.2; P = 0.088 for noninferiority) and of suprascapular–interscalene was 0.1 (–0.7 to 0.9; P = 0.012 for noninferiority). Secondary outcomes showed similar opioid consumption with better preservation of vital capacity in the anterior suprascapular group (90% baseline [P < 0.001]) and the supraclavicular group (76% [P = 0.002]) when compared to the interscalene group (67%). Conclusions The anterior suprascapular block, but not the supraclavicular, provides noninferior analgesia compared to the interscalene approach for major arthroscopic shoulder surgery. Pulmonary function is best preserved with the anterior suprascapular nerve block.

Background Evidence from patient-reported outcomes in clinical trials may explain health-related behaviors observed in the real world. Objective The purpose of this analysis was to evaluate the effect of treatment with canagliflozin, a sodium glucose co-transporter 2 inhibitor, compared with placebo or sitagliptin on health-related quality-of-life outcomes in participants with type 2 diabetes mellitus from the clinical development program. Methods Patient-reported outcomes data from four randomized controlled trials of canagliflozin (n = 2536) were pooled and analyzed to evaluate participants’ interest in continuing study medication; satisfaction with weight; and physical, mental, and emotional health after 26–52 weeks of treatment with canagliflozin vs. placebo or sitagliptin. Results Upon trial completion, participants treated with canagliflozin were more likely to express interest in continuing study medication than participants treated with placebo or sitagliptin [odds ratio (95% confidence interval) of 1.54 (1.19–1.99); p = 0.001]. Those treated with canagliflozin were also more likely to be satisfied with their weight and report favorable outcomes (score improvement or maintenance of good scores) related to physical and emotional health. Conclusions The results of this pooled analysis suggest that people with type 2 diabetes mellitus treated with canagliflozin generally had positive experiences with treatment and improvements in health-related quality of life. Future research is needed to determine if these improvements result in improved type 2 diabetes mellitus management and treatment adherence. ClinicalTrials.gov identifiers NCT01106625, NCT01106677, NCT01137812, NCT02025907. Electronic supplementary material The online version of this article (10.1007/s40271-017-0290-4) contains supplementary material, which is available to authorized users.

Introduction It is important to capture the patient experience with a diabetes treatment in clinical trials; however, use of instruments to assess patient-reported outcomes (PROs) in diabetes trials is inconsistent and results may not be reported alongside primary efficacy data. In lieu of head-to-head data, indirect comparisons can be used to compare competing interventions. In this study, we used indirect comparison methods to assess differences in PRO score changes between canagliflozin and other antihyperglycemic agents as add-on to metformin. Methods Literature searches were performed to identify studies that reported the same PRO instruments that were collected across four trials of canagliflozin in dual or triple therapy. Extensive searches identified only one study that was sufficiently similar in design and reported common PRO results using the Impact of Weight on Quality of Life-Lite (IWQoL-Lite): the DURATION-2 study of exenatide once-weekly (QW) versus sitagliptin and pioglitazone. This study was compared with the CANTATA-D study of canagliflozin versus sitagliptin. Bayesian indirect comparisons were performed to assess mean change in IWQoL-Lite total score. A fixed-effects model with noninformative priors was used to estimate between-treatment differences. Sensitivity analyses examined differences in trial populations. Results In the primary analysis, the probability that canagliflozin treatment results in greater improvement in IWQoL-Lite total score versus exenatide, sitagliptin, and pioglitazone was 60.0%, 89.9%, and 99.5%, respectively. When the CANTATA-D population was restricted using DURATION-2 inclusion/exclusion criteria, canagliflozin was also associated with a higher probability of having greater improvement in IWQoL-Lite than exenatide, sitagliptin, and pioglitazone. Conclusions These findings suggest that improvements in the impact of weight on health-related quality of life may be greater with canagliflozin than exenatide, sitagliptin, and pioglitazone. This analysis also demonstrates the application of indirect comparison methodology to PRO data and provides examples of advantages and challenges associated with performing indirect comparisons of PRO data. Electronic supplementary material The online version of this article (10.1007/s13300-017-0343-7) contains supplementary material, which is available to authorized users.

Objective Patients undergoing open inguinal hernia repair may experience moderate to severe postoperative pain. We assessed opioid consumption in subjects who received a continuous transversus abdominis plane block in addition to standard multimodal analgesia. Design Randomized, double-blind, placebo-controlled. Setting Tertiary academic medical center. Subjects Adult patients undergoing open inguinal hernia repair at Virginia Mason Medical Center. A total of 90 patients were enrolled. Methods Subjects presenting for surgery were randomized to receive either a continuous transversus abdominis plane block or a subcutaneous sham block. The primary outcome was opioid consumption within the first 48 hours after surgery. Secondary outcomes included pain scores, activities assessment scores, and opioid-related adverse events. Multimodal analgesia utilized in both groups included acetaminophen, nonsteroidal anti-inflammatory drugs, and surgical local anesthetic infiltration. Results Eighty-two subjects, 42 from the block group and 40 from the sham group, completed the study, per protocol. The intention-to-treat analysis demonstrated no difference in 48-hour postoperative oxycodone equivalent consumption between the block and sham groups (27.8 mg ± 26.8 vs 32 mg ± 39.2, difference –4.4 mg, P = 0.55). There was a statistically significant reduction in pain scores at 24 hours in the block group. There were no other differences in secondary outcomes. Conclusions Continuous transversus abdominis plane blocks provide modest improvements in pain after open inguinal hernia repair but fail to significantly reduce opioid consumption or improve functional activity levels in the setting of multimodal analgesia use.

The impact of CANA treatment on the initiation of insulin and other antihyperglycemic agents (AHAs) was analyzed in the CANVAS Program, which randomly assigned 10,142 participants with type 2 diabetes and established cardiovascular (CV) disease or ≥2 CV risk factors to treatment with CANA or placebo (PBO). Fewer participants initiated new AHAs with CANA versus PBO (17.8% vs. 27.0%; P Disclosure D.R. Matthews: Advisory Panel; Self; Janssen Research & Development, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sanofi, Servier. Consultant; Self; Janssen Research & Development, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Servier. Research Support; Self; Janssen Research & Development. Speaker's Bureau; Self; Aché Laboratories, Janssen Research & Development, Mitsubishi Tanabe Pharma Corporation, Novartis Pharmaceuticals Corporation, Novo Nordisk Inc., Sanofi, Servier. C.H. Wysham: Advisory Panel; Self; Abbott Laboratories. Board Member; Self; Endocrine Society. Consultant; Self; Lexicon Pharmaceuticals, Inc. Research Support; Self; Mylan. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Dexcom, Inc. Other Relationship; Self; Janssen Pharmaceuticals, Inc., Novo Nordisk A/S, Sanofi. M.J. Davies: Advisory Panel; Self; Eli Lilly and Company, Janssen Global Services, LLC., Novo Nordisk A/S, Sanofi-Aventis, Servier. Research Support; Self; Boehringer Ingelheim International GmbH, Novo Nordisk Foundation. Speaker's Bureau; Self; Boehringer Ingelheim International GmbH, Eli Lilly and Company, Novo Nordisk A/S, Sanofi-Aventis, Takeda Pharmaceutical Company Limited. A. Slee: None. M. Alba: Employee; Self; Janssen Research & Development. M. Lee: Employee; Self; Janssen Research & Development. G. Capuano: Employee; Self; Janssen Research & Development. V. Perkovic: Advisory Panel; Self; AbbVie Inc., Astellas Pharma Inc., AstraZeneca, Baxter, Bayer US, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Durect Corporation, Eli Lilly and Company, Gilead Sciences, Inc., GlaxoSmithKline plc., Janssen Research & Development, Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Pfizer Inc., Pharmalink, Relypsa, Inc., Roche Pharma, Sanofi, Servier, Vitae. Research Support; Self; Australian National Health and Medical Research Council. Other Relationship; Self; AbbVie Inc., Boehringer Ingelheim Pharmaceuticals, Inc., GlaxoSmithKline plc., Janssen Research & Development, Pfizer Inc. K.W. Mahaffey: Consultant; Self; Abbott, Ablynx, Baim Institute, Boehringer Ingelheim Pharmaceuticals, Inc., Bristol-Myers Squibb Company, Cardiometabolic Health Congress, Elsevier, GlaxoSmithKline plc., Medergy, Medscape, Mitsubishi Tanabe Pharma Corporation, MyoKardia, Inc., Novo Nordisk Inc., Ocleuve, Portola Pharmaceuticals, Inc., Radiometer America, Springer Publishing, Theravance, UCSF. Research Support; Self; Afferent, Amgen Inc., Apple, Cardiva Medical, Inc, Daiichi, Ferring Pharmaceuticals, Google, Luitpold Pharmaceuticals, Inc., Medtronic, Sanofi, St.Jude, Tenax. Stock/Shareholder; Self; BioPrint Fitness. Other Relationship; Self; AstraZeneca, Johnson & Johnson, Merck & Co., Inc., National Institutes of Health, Novartis Pharmaceuticals Corporation. B. Neal: Advisory Panel; Self; Janssen Research & Development, Novartis Pharmaceuticals Corporation, Pfizer Inc., Roche Pharma, Servier. Research Support; Self; Abbott, Australian National Health and Medical Research Council, Janssen Research & Development, Merck & Co., Inc., Roche Pharma, Servier. Funding Janssen Research & Development, LLC

OBJECTIVES: Patients with Kawasaki disease can develop life-altering coronary arterial abnormalities, particularly in those resistant to intravenous immunoglobulin (IVIg) therapy. We tested the tumor necrosis factor α receptor antagonist etanercept for reducing both IVIg resistance and coronary artery (CA) disease progression. METHODS: In a double-blind multicenter trial, patients with Kawasaki disease received either etanercept (0.8 mg/kg; n = 100) or placebo (n = 101) subcutaneously starting immediately after IVIg infusion. IVIg resistance was the primary outcome with prespecified subgroup analyses according to age, sex, and race. Secondary outcomes included echocardiographic CA measures within subgroups defined by coronary dilation (z score >2.5) at baseline. We used generalized estimating equations to analyze z score change and a prespecified algorithm for change in absolute diameters. RESULTS: IVIg resistance occurred in 22% (placebo) and 13% (etanercept) of patients (P = .10). Etanercept reduced IVIg resistance in patients >1 year of age (P = .03). In the entire population, 46 (23%) had a coronary z score >2.5 at baseline. Etanercept reduced coronary z score change in those with and without baseline dilation (P = .04 and P = .001); no improvement occurred in the analogous placebo groups. Etanercept (n = 22) reduced dilation progression compared with placebo (n = 24) by algorithm in those with baseline dilation (P = .03). No difference in the safety profile occurred between etanercept and placebo. CONCLUSIONS: Etanercept showed no significant benefit in IVIg resistance in the entire population. However, preplanned analyses showed benefit in patients >1 year. Importantly, etanercept appeared to ameliorate CA dilation, particularly in patients with baseline abnormalities.

OBJECTIVE To assess the effects of canagliflozin, a sodium glucose cotransporter 2 inhibitor, on glycemic parameters and measures of glucose variability assessed by a 9-point self-monitoring blood glucose (SMBG) and continuous glucose monitoring (CGM) profiles, and patient-reported outcomes as an add-on to insulin among participants with type 1 diabetes. RESEARCH DESIGN AND METHODS In this randomized, double-blind study, 351 participants received canagliflozin 100 or 300 mg or placebo for 18 weeks. Change from baseline in daily mean glucose and SD was measured using a 9-point SMBG profile. In a subset of 89 participants who underwent CGM, the change from baseline in mean glucose, measures of glycemic variability (SD, coefficient of variation, and mean amplitude of glycemic excursions), and time spent in glycemic ranges were assessed. Change in treatment satisfaction was evaluated using the Diabetes Treatment Satisfaction Questionnaire (n = 328). RESULTS At week 18, reductions in daily mean glucose and SD measured using the 9-point SMBG profile were seen with canagliflozin 100 and 300 mg versus placebo. Reductions in mean glucose (−1.2, −0.7, and 0.6 mmol/L) and measures of glycemic variability assessed by CGM, such as changes in glucose SD (−0.3, −0.7, and 0.1 mmol/L), were also seen with canagliflozin 100 and 300 mg versus placebo, respectively. Canagliflozin 100 and 300 mg were associated with increases in time spent within target (glucose >3.9 to ≤10.0 mmol/L) compared with placebo (11.6%, 10.1%, and −3.5%, respectively) and commensurate reductions in time spent above the target level (glucose >10.0 mmol/L; −12.7%,−7.6%, and 5.7%, respectively). Participants showed greater improvement in treatment satisfaction with canagliflozin versus placebo; reductions in insulin dose, SD of glucose, and body weight contributed to the relationship between canagliflozin and satisfaction change. CONCLUSIONS Canagliflozin improved indices of glycemic variability and was associated with improvement in treatment satisfaction versus placebo over 18 weeks among participants with type 1 diabetes. Although these data from this study demonstrate the potential benefits of canagliflozin in people with type 1 diabetes, canagliflozin is not approved for the treatment of type 1 diabetes and should not currently be used in people with type 1 diabetes.

SummaryAims Patients with type 2 diabetes mellitus (T2DM) have increased risk of adverse events (AEs; e.g. dehydration, hypoglycaemia) in hot weather. This analysis assessed the efficacy and safety of canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor, in patients with T2DM who live in hot climates. Methods This post hoc analysis evaluated patients with T2DM using pooled data from four 26-week, placebo-controlled studies (N=2,313) and data from a 104-week, active-controlled study (add-on to metformin vs glimepiride; N=1,450). Changes in HbA1c, fasting plasma glucose (FPG), body weight and blood pressure (BP) were assessed in subsets of patients living in hot climates (pooled, placebo-controlled studies, n=611; active-controlled study, n=307) and those living in other climates (i.e. other climate subset; pooled, placebo-controlled studies, n=1,702; active-controlled study, n=1,143). Safety was assessed based on AE reports. Results Canagliflozin 100 and 300 mg lowered HbA1c, FPG, body weight and BP vs placebo over 26 weeks and glimepiride over 104 weeks in the hot climate subsets. Canagliflozin was generally well tolerated in the hot climate subsets, with a higher incidence of AEs related to the mechanism of SGLT2 inhibition (i.e. genital mycotic infections). Volume depletion–related AEs were low across groups. Conclusion Canagliflozin improved glycaemic control, lowered body weight and BP, and was generally well tolerated in patients with T2DM living in hot climates compared with placebo over 26 weeks or glimepiride over 104 weeks. Clinical Trials registration: ClinicalTrials.gov NCT01081834, NCT01106677, NCT01106625, NCT01106690, NCT00968812.

Background and aims Previous results of the AIM-HIGH trial showed that baseline levels of the conventional lipid parameters were not predictive of future cardiovascular (CV) outcomes. The aims of this secondary analysis were to examine the levels of cholesterol in high density lipoprotein (HDL) subclasses (HDL2-C and HDL3-C), small dense low density lipoprotein (sdLDL-C), and LDL triglyceride (LDL-TG) at baseline, as well as the relationship between these levels and CV outcomes. Methods Individuals with CV disease and low baseline HDL-C levels were randomized to simvastatin plus placebo or simvastatin plus extended release niacin (ERN), 1500 to 2000 mg/day, with ezetimibe added as needed in both groups to maintain an on-treatment LDL-C in the range of 40–80 mg/dL. The primary composite endpoint was death from coronary disease, nonfatal myocardial infarction, ischemic stroke, hospitalization for acute coronary syndrome, or symptom-driven coronary or cerebrovascular revascularization. HDL-C, HDL3-C, sdLDL-C and LDL-TG were measured at baseline by detergent-based homogeneous assays. HDL2-C was computed by the difference between HDL-C and HDL3-C. Analyses were performed on 3094 study participants who were already on statin therapy prior to enrollment in the trial. Independent contributions of lipoprotein fractions to CV events were determined by Cox proportional hazards modeling. Results Baseline HDL3-C was protective against CV events (HR: 0.84, p = 0.043) while HDL-C, HDL2-C, sdLDL-C and LDL-TG were not event-related (HR: 0.96, p = 0.369; HR: 1.07, p = 0.373; HR: 1.05, p = 0.492; HR: 1.03, p = 0.554, respectively). Conclusions The results of this secondary analysis of the AIM-HIGH Study indicate that levels of HDL3-C, but not other lipoprotein fractions, are predictive of CV events, suggesting that the HDL3 subclass may be primarily responsible for the inverse association of HDL-C and CV disease.

Background. SLCO-encoded transporters have been associated with progression to castration resistant prostate cancer (CRPC) after initiation of androgen deprivation therapy (ADT). Although expressed at lower levels than in CRPC tissues, SLCO-encoded transporters may also play a role in response of primary prostate cancer (PCa) to ADT and biochemical recurrence. Methods. We systematically explored expression of the 11 human SLCO genes in a large sample of untreated and ADT-treated normal prostate (NP) and primary PCa tissues, including tumors treated with neoadjuvant abiraterone. Results. Transporters with the most recognized role in steroid uptake in PCa, including SLCO2B1 (DHEAS) and 1B3 (testosterone), were consistently detected in primary PCa. SLCO1B3 was nearly 5-fold higher in PCa vs NP with no difference in Gleason 3 vs 4 and no change with ADT. SLCO2B1 was detected at 3-fold lower levels in PCa than NP but was nearly 7-fold higher in Gleason 4 vs Gleason 3 and increased 3-fold following ADT (p

Overweight and obesity increases the risk of heart and kidney disease. The effects of canagliflozin (CANA) in patients with BL BMI Disclosure H. Bays: Research Support; Self; Amgen Inc. L. Van Gaal: Advisory Panel; Self; Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen J & J, Merck MSD, Novo Nordisk, Sanofi and Servier/Intarcia. Speaker's Bureau; Self; Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Janssen J & J, Merck MSD, Novo Nordisk, Sanofi and Servier/Intarcia. Research Support; Self; EU (Hepadip & Resolve consortium) and National Research Funds. S. Aravind: None. N. Aggarwal: None. R. Violante: Advisory Panel; Self; Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Merck Sharp & Dohme Corp., Novo Nordisk A/S, AstraZeneca, Sanofi-Aventis. Research Support; Self; Novo Nordisk Inc., Merck Sharp & Dohme Corp., Eli Lilly and Company, Janssen Pharmaceuticals, Inc. A. Slee: Other Relationship; Self; Janssen Scientific Affairs, LLC. W. Shaw: Employee; Self; Janssen Research & Development. K.W. Mahaffey: Research Support; Self; Afferent, Amgen, AstraZeneca, Daiichi, Ferring, Google (Verily), Janssen, Medtronic, Merck, Novartis, Sanofi, and St. Jude. Consultant; Self; Ablynx, AstraZeneca, BAROnova, Bio2 Medical, Boehringer Ingelheim, Bristol-Myers Squibb, Cardiometabolic Health Congress, Cubist, Eli Lilly, Elsevier, Epson, GlaxoSmithKline, Janssen, Merck, Mt. Sinai, Radiometer, Springer Publishing, The Medicines Company, Theravance, Vindico, and WebMD. Stock/Shareholder; Self; BioPrint Fitness. D. de Zeeuw: Other Relationship; Self; AbbVie Inc., Astellas Pharma US, Inc., Eli Lilly and Company, Fresenius SE & Co. KGaA, Janssen Scientific Affairs, LLC., Boehringer Ingelheim GmbH, Bayer AG, Mitsubishi Tanabe Pharma Corporation. D.R. Matthews: Other Relationship; Self; Janssen Scientific Affairs, LLC., Novo Nordisk Inc., GlaxoSmithKline plc., Novartis Pharmaceuticals Corporation, Eli Lilly and Company, Sanofi-Aventis, Servier, Aché Laboratories.

A prespecified analysis of the CANVAS Program assessed the effects of CANA, an SGLT2 inhibitor, on the risk of cardiovascular (CV), mortality, and renal outcomes in participants with type 2 diabetes mellitus (T2DM) and established CV disease (CVD) or with ≥2 CV risk factors by baseline HbA1c. The primary composite outcome of CV death, nonfatal myocardial infarction, or nonfatal stroke was significantly reduced with CANA vs. placebo (PBO) in the total cohort by 14% (HR 0.86; 95% CI, 0.75, 0.97; P = 0.02). Among CANVAS Program participants, 4,411 (43%) had baseline HbA1c In summary, CV and renal outcomes appeared better in CANA-treated participants regardless of HbA1c in this hypothesis-generating subanalysis with a suggestion of greater effects on lowering mortality risk in those with higher HbA1c levels at baseline. Disclosure J. Rosenstock: Advisory Panel; Self; Eli Lilly and Company. Consultant; Self; Eli Lilly and Company. Research Support; Self; Novo Nordisk Inc.. Consultant; Self; Novo Nordisk Inc.. Advisory Panel; Self; Sanofi. Consultant; Self; Sanofi. Advisory Panel; Self; Janssen Pharmaceuticals, Inc.. Consultant; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Consultant; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Advisory Panel; Self; Intarcia Therapeutics, Inc.. Consultant; Self; Intarcia Therapeutics, Inc.. Research Support; Self; Merck & Co., Inc., Pfizer Inc., Sanofi, Novo Nordisk Inc., Bristol-Myers Squibb Company, Eli Lilly and Company, Intarcia Therapeutics, Inc., Genentech, Inc. G. Bantwal: Speaker's Bureau; Self; Abbott. Advisory Panel; Self; AstraZeneca. Speaker's Bureau; Self; Biocon, Boehringer Ingelheim Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi-Aventis. J.P. Wilding: Other Relationship; Self; Astellas, AstraZeneca, Boehringer Ingelheim GmbH, Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi, Eli Lilly and Company, Orexigen Therapeutics, Inc., Merck & Co., Inc. R. Dumas: Speaker's Bureau; Self; Janssen Ortho, Merck, Novo Nordisk, Lilly, Aventis, Boehringer Ingelheim Astra Zeneca, BMS. Consultant; Self; Janssen Ortho, Merck, Novo Nordisk, Lilly, Aventis, Boehringer Ingelheim Astra Zeneca, BMS. Research Support; Self; Janssen Ortho, Merck, Novo Nordisk, Lilly, Aventis, Boehringer Ingelheim Astra Zeneca, BMS. G. Gonzalez-Galvez: None. A. Slee: Other Relationship; Self; Janssen Scientific Affairs, LLC. F. Vercruysse: Employee; Self; Janssen Research & Development. K.W. Mahaffey: Research Support; Self; Afferent, Amgen, AstraZeneca, Daiichi, Ferring, Google (Verily), Janssen, Medtronic, Merck, Novartis, Sanofi, and St. Jude. Consultant; Self; Ablynx, AstraZeneca, BAROnova, Bio2 Medical, Boehringer Ingelheim, Bristol-Myers Squibb, Cardiometabolic Health Congress, Cubist, Eli Lilly, Elsevier, Epson, GlaxoSmithKline, Janssen, Merck, Mt. Sinai, Radiometer, Springer Publishing, The Medicines Company, Theravance, Vindico, and WebMD. Stock/Shareholder; Self; BioPrint Fitness. D. de Zeeuw: Other Relationship; Self; AbbVie Inc., Astellas Pharma US, Inc., Eli Lilly and Company, Fresenius SE & Co. KGaA, Janssen Scientific Affairs, LLC., Boehringer Ingelheim GmbH, Bayer AG, Mitsubishi Tanabe Pharma Corporation. G. Fulcher: Other Relationship; Self; Novo Nordisk Inc., Janssen Scientific Affairs, LLC., Boehringer Ingelheim GmbH, Merck Sharp & Dohme Corp. D.R. Matthews: Other Relationship; Self; Janssen Scientific Affairs, LLC., Novo Nordisk Inc., GlaxoSmithKline plc., Novartis Pharmaceuticals Corporation, Eli Lilly and Company, Sanofi-Aventis, Servier, Aché Laboratories.

The CANVAS Program demonstrated a reduced risk of cardiovascular (CV) and renal outcomes with the SGLT2 inhibitor CANA vs. placebo (PBO) in adults with T2DM and established CV disease or ≥2 CV risk factors (N = 10,142; mean age, 63.3 y; systolic BP [SBP], 136.6 mmHg; diastolic BP [DBP], 77.7 mmHg). This analysis assessed the effects of CANA on BP, pulse, and markers of arterial stiffness including pulse pressure (PP = SBP-DBP) and double product (DP = pulse × SBP). CANA lowered SBP and DBP compared with PBO over the CANVAS Program (mean differences of -3.93 mmHg [95% CI: -4.30, -3.56]) and -1.39 mmHg [95% CI: -1.61, -1.17]; both P Disclosure R. Townsend: None. M. Dharmalingam: None. S. Genovese: Speaker's Bureau; Self; Abbott Diabetes Care, AstraZeneca, Boehringer Ingelheim, Bruno Farmaceutici, Bristol-Myers Squibb, Eli Lilly, Janssen, Lifescan, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi, Takeda. Consultant; Self; Abbott Diabetes Care, AstraZeneca, Boehringer Ingelheim, Bruno Farmaceutici, Bristol-Myers Squibb, Eli Lilly, Janssen, Lifescan, Merck Sharp & Dohme, Novartis, Novo Nordisk, Sanofi, Takeda. Research Support; Self; Novartis AG. A. Steele: Speaker's Bureau; Self; Amgen, AZ, Bayer, BI, Lilly, Jansen, Merck, Pfizer, Otsuka, Valeant. Advisory Panel; Self; Amgen, BI/Lilly, Jansen, Otsuka, Shire. J.L. Arenas: None. A. Slee: Other Relationship; Self; Janssen Scientific Affairs, LLC. E. Fabbrini: Employee; Self; Janssen Research & Development. K.W. Mahaffey: Research Support; Self; Afferent, Amgen, AstraZeneca, Daiichi, Ferring, Google (Verily), Janssen, Medtronic, Merck, Novartis, Sanofi, and St. Jude. Consultant; Self; Ablynx, AstraZeneca, BAROnova, Bio2 Medical, Boehringer Ingelheim, Bristol-Myers Squibb, Cardiometabolic Health Congress, Cubist, Eli Lilly, Elsevier, Epson, GlaxoSmithKline, Janssen, Merck, Mt. Sinai, Radiometer, Springer Publishing, The Medicines Company, Theravance, Vindico, and WebMD. Stock/Shareholder; Self; BioPrint Fitness.

In the global CANVAS Program (n = 10,142), CANA, an SGLT2 inhibitor, demonstrated risk reductions in cardiovascular (CV) and renal outcomes in patients with type 2 diabetes and established CV disease or ≥2 CV risk factors. A pre-specified analysis evaluated outcomes in patients from different geographic regions. Overall, 2,430 (24.0%) were from North America, 1,021 (10.1%) were from Central/South America, 3,609 (35.6%) were from Europe, and 3,082 (30.4%) were from the rest of the world. The primary outcome was comprised of CV death, nonfatal myocardial infarction, or nonfatal stroke; other CV and renal outcomes were also analyzed. The primary outcome occurred in 2.80, 2.99, 3.07, and 2.69 patients per 100 patient-years (unadjusted) in North America, Central/South America, Europe, and the rest of the world, respectively. The effects of CANA on the primary outcome were consistent between patients from different geographic regions (interaction P = 0.89) and with the total population (HR [95% CI]: 0.86 [0.75, 0.97]; Figure). Similar effects between subgroups were observed in the individual components of the primary outcome, all-cause mortality, hospitalization for heart failure, and progression of albuminuria. The risk reduction observed with CANA on CV and renal outcomes was consistent across geographic regions. Disclosure C.H. Wysham: Advisory Panel; Self; Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Sanofi. Consultant; Self; AstraZeneca, Janssen Pharmaceuticals, Inc., Novo Nordisk Inc., Sanofi. Speaker's Bureau; Self; AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Janssen Pharmaceuticals, Inc., Insulet Corporation, Novo Nordisk Inc., Sanofi. A. Bhattacharyya: None. M. Tsoukas: Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc., Novo Nordisk Inc.. Advisory Panel; Self; Sanofi. Speaker's Bureau; Self; Eli Lilly and Company. E. Martinez-Abundis: Advisory Panel; Self; AstraZeneca. Speaker's Bureau; Spouse/Partner; AstraZeneca. Advisory Panel; Spouse/Partner; AstraZeneca. Speaker's Bureau; Spouse/Partner; AstraZeneca. Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company. Advisory Panel; Spouse/Partner; Eli Lilly and Company. Speaker's Bureau; Spouse/Partner; Eli Lilly and Company. Advisory Panel; Self; Janssen Pharmaceuticals, Inc.. Research Support; Self; Janssen Pharmaceuticals, Inc.. Speaker's Bureau; Self; Janssen Pharmaceuticals, Inc.. Advisory Panel; Spouse/Partner; Janssen Pharmaceuticals, Inc.. Research Support; Spouse/Partner; Janssen Pharmaceuticals, Inc.. Speaker's Bureau; Spouse/Partner; Janssen Pharmaceuticals, Inc.. Speaker's Bureau; Self; Novartis Pharmaceuticals Corporation, Sanofi. Speaker's Bureau; Spouse/Partner; Sanofi. Advisory Panel; Self; Takeda Development Center Americas, Inc.. Speaker's Bureau; Self; Takeda Development Center Americas, Inc.. Advisory Panel; Spouse/Partner; Takeda Development Center Americas, Inc.. Speaker's Bureau; Spouse/Partner; Takeda Development Center Americas, Inc.. Research Support; Self; Merck Sharp & Dohme Corp.. Research Support; Spouse/Partner; Merck Sharp & Dohme Corp., Pfizer Inc.. Advisory Panel; Self; Laboratorios Silanes. Speaker's Bureau; Self; Laboratorios Silanes. Advisory Panel; Spouse/Partner; Laboratorios Silanes. Research Support; Spouse/Partner; Laboratorios Silanes. Speaker's Bureau; Spouse/Partner; Laboratorios Silanes. A. Slee: Other Relationship; Self; Janssen Scientific Affairs, LLC. W. Shaw: Employee; Self; Janssen Research & Development. K.W. Mahaffey: Research Support; Self; Afferent, Amgen, AstraZeneca, Daiichi, Ferring, Google (Verily), Janssen, Medtronic, Merck, Novartis, Sanofi, and St. Jude. Consultant; Self; Ablynx, AstraZeneca, BAROnova, Bio2 Medical, Boehringer Ingelheim, Bristol-Myers Squibb, Cardiometabolic Health Congress, Cubist, Eli Lilly, Elsevier, Epson, GlaxoSmithKline, Janssen, Merck, Mt. Sinai, Radiometer, Springer Publishing, The Medicines Company, Theravance, Vindico, and WebMD. Stock/Shareholder; Self; BioPrint Fitness. D. de Zeeuw: Other Relationship; Self; AbbVie Inc., Astellas Pharma US, Inc., Eli Lilly and Company, Fresenius SE & Co. KGaA, Janssen Scientific Affairs, LLC., Boehringer Ingelheim GmbH, Bayer AG, Mitsubishi Tanabe Pharma Corporation.

Summary Background Generalised anxiety disorder is a disease that can be associated with substantial dysfunction. Pharmacological treatment is often the first choice for clinicians because of the cost and resource constraints of psychological alternatives, but there is a paucity of comparative information for the multiple available drug choices. Methods A systematic review and network meta-analysis was performed on randomised trials in adult outpatients with generalised anxiety disorder identified from MEDLINE, Web of Science, Cochrane Library, ClinicalTrials.gov, Chinese National Knowledge Infrastructure (CNKI), Wanfang data, Drugs@FDA and commercial pharmaceutical registries. Placebo and active control trials were included. Data were extracted from all manuscripts and reports. Primary outcomes were efficacy (mean difference [MD] in change in Hamilton Anxiety Scale Score) and acceptability (study discontinuations for any cause). We estimated summary mean treatment differences and odds ratios using network meta-analyses with random effects. This study is registered with PROSPERO, number CRD42018087106. Findings Studies were published between Jan 1, 1994 and Aug 1, 2017, in which 1992 potential studies were screened for inclusion. This analysis is based on 89 trials, which included 25 441 patients randomly assigned to 22 different active drugs or placebo. Duloxetine (MD −3·13, 95% credible interval [CrI] −4·13 to −2·13), pregabalin (MD −2·79, 95% CrI −3·69 to −1·91), venlafaxine (MD −2·69, 95% CrI −3·50 to −1·89), and escitalopram (MD −2·45, 95% CrI −3·27 to −1·63) were more efficacious than placebo with relatively good acceptability. Mirtazapine, sertraline, fluoxetine, buspirone, and agomelatine were also found to be efficacious and well tolerated but these findings were limited by small sample sizes. Quetiapine (MD −3·60 95% CrI −4·83 to −2·39) had the largest effect on HAM-A but it was poorly tolerated (odds ratio 1·44, 95% CrI 1·16–1·80) when compared with placebo. Likewise, paroxetine and benzodiazepines were effective but also poorly tolerated when compared with placebo. Risk of reporting bias was considered low, and when possible all completed studies were included to avoid publication bias. Interpretation To our knowledge, this is the largest contemporary review of pharmacological agents for the treatment of generalised anxiety disorder by use of network analysis. There are several effective treatment choices for generalised anxiety disorder across classes of medication. The failure of initial pharmacological therapy might not be a reason to abandon a pharmacological treatment strategy. Funding No funding was received for this research.

Questionnaires are noninvasive, inexpensive measures that can identify key elements of the patient perspective that are important for the achievement of better outcomes in diabetes care.

Introduction The aim of this study was to examine the influence of weight change experiences over time on motivation to perform diabetes self-care behaviors using data from a study of canagliflozin (an agent that inhibits sodium glucose co-transporter 2) versus glimepiride in dual therapy with metformin and background diet/exercise. Methods Weight and motivation for performing healthy behaviors were collected at baseline and over time. The motivation questionnaire enabled categorization into two groups: those performing or not performing health behaviors. Four distinct patterns of weight change were determined: losing weight, gaining weight, and two patterns for fluctuating weight. The relationships between these patterns and motivation for weight loss, following a diet, and exercise were examined using logistic regression models. Results Of 1182 subjects, more than half were already performing behaviors to lose weight, diet, and exercise at baseline. Among those who were not, 52% (246/474) started taking action to lose weight after baseline, 54% (241/448) started following a diet, and 42% (232/556) started exercising. Weight change patterns were significantly related to performance of healthy behaviors at follow-up (week 36). Compared to the weight gain pattern, those who experienced a continuous weight loss pattern from baseline to week 36 were 2.2 (95% confidence interval 1.49, 3.37) times more likely to perform the healthy behaviors. Baseline behavior and confidence were also predictive of performing healthy behaviors. Conclusion The current work highlights the importance of weight change patterns for performance of diabetes self-care. Tracking weight patterns over time, assessing confidence for performance of healthy behaviors, and being aware of the relationship between weight changes and diabetes self-care behaviors are viable, concrete ways to practice patient-centered care. Funding Janssen Global Services, LLC. Electronic supplementary material The online version of this article (doi:10.1007/s13300-015-0145-8) contains supplementary material, which is available to authorized users.

Background: Pain is common in multiple sclerosis (MS). Duloxetine has a potential therapeutic role in treating MS-related pain. Methods: Thirty-eight MS patients were randomized 1:1 to receive duloxetine (n = 18) or matched placebo (n = 20). The dosing regimen was 30 mg daily for 1 week, then 60 mg daily for 5 weeks. The primary outcome measure was change in worst pain for week 6 relative to baseline recorded on a daily pain diary. Results: Of 38 randomized patients, 14 (78%) patients randomized to duloxetine and 18 (90%) randomized to placebo completed treatment per protocol. These participants had an average age of 55.5 years, 25% were male, and 66% had relapsing-remitting MS (RRMS). Baseline characteristics were similar. Discontinuations were due primarily to drug intolerance. Among those who completed treatment, worst pain at 6 weeks was reduced by 29% (±20%) for duloxetine versus 12% (±18%) for placebo (P = .016). Average daily pain at 6 weeks was reduced by 39% (±29%) in the duloxetine group compared to 10% (±18.8%) in the placebo group (P = .002). There were no significant changes (week 6 vs. baseline) or between-group differences for subject global impression, Beck Depression Inventory, 36-item Short Form Health Status Survey (SF-36), or sleep quality score. Conclusions: Fewer patients could tolerate duloxetine compared to placebo. Among patients who completed 6 weeks of treatment, there were significant reductions in average and worst daily pain scores with duloxetine compared to placebo. This study suggests that duloxetine has a direct pain-relieving effect in MS.

BACKGROUND Within the new digital health landscape, the rise of health apps creates novel prospects for health promotion. The market is saturated with apps that aim to increase physical activity (PA). Despite the wide distribution and popularity of PA apps, there are limited data on their effectiveness, user experience, and safety of personal data. OBJECTIVE The purpose of this review and content analysis was to evaluate the quality of the most popular PA apps on the market using health care quality indicators. METHODS The top-ranked 400 free and paid apps from iTunes and Google Play stores were screened. Apps were included if the primary behavior targeted was PA, targeted users were adults, and the apps had stand-alone functionality. The apps were downloaded on mobile phones and assessed by 2 reviewers against the following quality assessment criteria: (1) users’ data privacy and security, (2) presence of behavior change techniques (BCTs) and quality of the development and evaluation processes, and (3) user ratings and usability. RESULTS Out of 400 apps, 156 met the inclusion criteria, of which 65 apps were randomly selected to be downloaded and assessed. Almost 30% apps (19/65) did not have privacy policy. Every app contained at least one BCT, with an average number of 7 and a maximum of 13 BCTs. All but one app had commercial affiliation, 12 consulted an expert, and none reported involving users in the app development. Only 12 of 65 apps had a peer-reviewed study connected to the app. User ratings were high, with only a quarter of the ratings falling below 4 stars. The median usability score was excellent—86.3 out of 100. CONCLUSIONS Despite the popularity of PA apps available on the commercial market, there were substantial shortcomings in the areas of data safety and likelihood of effectiveness of the apps assessed. The limited quality of the apps may represent a missed opportunity for PA promotion.

Adductor canal blocks have shown promise in reducing postoperative pain in total knee arthroplasty patients. No randomized, controlled studies, however, evaluate the opioid-sparing benefits of a continuous 0.2% ropivacaine infusion at the adductor canal. We hypothesized that a continuous adductor canal block would decrease postoperative opioid consumption.Eighty subjects presenting for primary unilateral total knee arthroplasty were randomized to receive either a continuous ultrasound-guided adductor canal block with 0.2% ropivacaine or a sham catheter. All subjects received a preoperative single-injection femoral nerve block with spinal anesthesia as is standard of care at our institution. Cumulative IV morphine consumption 48 hours after surgery was evaluated with analysis of covariance, adjusted for baseline characteristics. Secondary outcomes included resting pain scores (numeric rating scale), peak pain scores during physical therapy on postoperative days 1 and 2, quadriceps maximum voluntary isometric contraction, distance ambulated during physical therapy, postoperative nausea and vomiting, and satisfaction with analgesia.Eighty subjects were randomized, and 76 completed the study per-protocol. The least-square mean difference in cumulative morphine consumption over 48 hours (block-sham) was--16.68 mg (95% confidence interval, -29.78 to -3.59, P = 0.013). Total morphine use between 24 and 48 hours (after predicted femoral nerve block resolution) also differed by least-square mean -11.17 mg (95% confidence interval,: -19.93 to -2.42, P = 0.013). Intention-to-treat analysis was similar to the per-protocol results. Functional outcomes revealed subjects in the adductor canal catheter group had better quadriceps strength (P = 0.010) and further distance ambulated (P = 0.034) on postoperative day 2.A continuous adductor canal block for total knee arthroplasty reduces opioid consumption compared with that of placebo in the first 48 hours after surgery. Other outcomes including quadriceps strength, distance ambulated, and pain scores all show benefit from an adductor canal catheter after total knee arthroplasty but require further study before being interpreted as conclusive.

ObjectivesTo explore the relationship between popularity of mobile application (apps) for physical activity (PA) and their likely efficacy. The primary objective was to assess the association between app popularity (indicated by user ratings) and likely efficacy (indicated by the number of Behaviour Change Techniques (BCT) present). The secondary objective was to assess the relationship between user ratings and those BCTs that have been shown to be effective in increasing PA.DesignObservational study.Methods400 top-ranked free and paid apps from iTunes and Google Play stores were screened, and were included if the primary behaviour targeted was PA and they had stand-alone functionality. The outcome variable of user rating was dichotomised into high (4, 5 stars) or low (1, 2, 3 stars) rating.SettingiTunes and Google Play app stores.ParticipantsNo individual participants but the study used user-led rating system in the app store.Primary and secondary outcome measuresBCTs and user rating.ResultsOf 400 apps, 156 were eligible and 65 were randomly selected, downloaded and assessed by two reviewers. There was no relationship overall between star ratings and the number of BCTs present, nor between star ratings and the presence of BCTs known to be effective in increasing PA. App store was strongly associated with star ratings, with lower likelihood of finding 4 or 5 stars in iTunes compared with Google Play (OR 0.74, 95% CI 0.73 to 0.76, pConclusionsThe findings of this study suggest that popularity does not necessarily imply the likelihood of effectiveness. Hence, public health impact is unlikely to be achieved by allowing market forces to ‘prescribe’ what is used by the public.

Objectives This study sought to examine the relationship between niacin treatment, lipoproteins, and cardiovascular (CV) outcomes in this secondary analysis of the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes) trial. Background During a 3-year follow-up in 3,414 patients with established CV disease and low high-density lipoprotein cholesterol (HDL-C) levels, combined niacin + low-density lipoprotein cholesterol (LDL-C)–lowering therapy did not reduce CV events compared with LDL-C–lowering therapy alone. Methods Subjects taking simvastatin and/or ezetimibe were randomized to receive extended-release (ER) niacin 1,500 to 2,000 mg or minimal immediate-release niacin (≤150 mg) as placebo at bedtime. LDL-C levels in both groups were maintained from 40 to 80 mg/dl. Hazard ratios were estimated by using Cox proportional hazards models for relationships between lipoproteins and the composite endpoint of CV death, myocardial infarction, acute coronary syndrome, ischemic stroke, or symptom-driven revascularization. Results CV outcomes were not associated with ER niacin in any baseline lipoprotein tertile. In a subset of patients in both the highest triglyceride (≥198 mg/dl) and lowest HDL-C ( Conclusions Baseline lipoprotein tertiles did not predict differential benefit or harm with ER niacin added to LDL-C–lowering therapy, but a small dyslipidemic subgroup may benefit. ER niacin attenuated expected relationships of lipoprotein risk factors with CV events, raising the possibility that nonlipoprotein actions of niacin could affect risk. (Niacin Plus Statin to Prevent Vascular Events [AIM-HIGH]; NCT00120289 )

Objectives This study sought to examine the relationship between baseline and on-study apolipoproteins (apo) A-1 and B and lipoprotein(a) [Lp(a)] levels and the development of subsequent cardiovascular (CV) events in the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes) trial. Background Niacin has been reported to lower apoB and Lp(a) and to raise apoA-1. Methods Individuals with CV disease and low baseline levels of high-density lipoprotein cholesterol were randomized to simvastatin plus placebo or simvastatin, plus extended-release niacin ([ERN], 1,500 to 2,000 mg/day), with ezetimibe added as needed, in both groups, to maintain an on-treatment low-density lipoprotein cholesterol in the range of 40 to 80 mg/dl. Hazard ratios (HRs) were used to evaluate the relationship between levels of apoA-1, apoB, and Lp(a), and CV events in each treatment group. Results Baseline apoB and the apoB/apoA-I ratio were significantly predictive of CV events only for the placebo group (HR: 1.17 [p = 0.018] and HR: 1.19 [p = 0.016]). Baseline and on-study Lp(a) were predictive of CV events in both simvastatin plus placebo (baseline HR: 1.24 [p = 0.002] and on-study HR: 1.21 [p = 0.017]) and the simvastatin plus ERN group (baseline HR: 1.25 [p = 0.001] and on-study HR: 1.18 [p = 0.028]). The ERN modestly increased 1-year apoA-1 (7%), decreased apoB (13%), decreased the ApoB/ApoA-1 ratio (19%), and decreased Lp(a) 21%, but did not reduce CV events. Conclusions Lp(a) was associated with increased CV risk in both treatment groups indicating that it contributes to residual CV risk. However, there was no evidence that ERN reduced CV risk, despite favorable lipoprotein changes.

The saphenous nerve block using a landmark-based approach has shown promise in reducing postoperative pain in patients undergoing arthroscopic medial meniscectomy. We hypothesized that performing an ultrasound-guided adductor canal saphenous block as part of a multimodal analgesic regimen would result in improved analgesia after arthroscopic medial meniscectomy.Fifty patients presenting for ambulatory arthroscopic medial meniscectomy under general anesthesia were prospectively randomized to receive an ultrasound-guided adductor canal block with 0.5% ropivacaine or a sham subcutaneous injection of sterile saline. Our primary outcome was resting pain scores (numerical rating scale; NRS) upon arrival to the postanesthesia care unit (PACU). Secondary outcomes included NRS at six hours, 12 hr, 18 hr, and 24 hr; postoperative nausea; and postoperative opioid consumption.There was a statistically significant difference in mean NRS pain scores upon arrival to the PACU (P = 0.03): block group NRS = 1.71 (95% confidence interval [CI] 0.73 to 2.68) vs sham group NRS = 3.25 (95% CI 2.27 to 4.23). Cumulative opioid consumption (represented in oral morphine equivalents) over 24 hr was 71.8 mg (95% CI 56.5 to 87.2) in the sham group vs 44.9 mg (95% CI 29.5 to 60.2) in the block group (P = 0.016).An ultrasound-guided block at the adductor canal as part of a combined multimodal analgesic regimen significantly reduces resting pain scores in the PACU following arthroscopic medial meniscectomy. Furthermore, 24-hr postoperative opioid consumption and pain scores were also reduced.

Background This study evaluated the efficacy and safety of oral triiodothyronine (T3; Tetronine, Dalim BioTech, Korea) for infants and children undergoing cardiopulmonary bypass in an Indonesian population. Methods We performed a single-center, randomized, double-blind, and placebo-controlled trial in children aged 3 years and younger undergoing congenital heart disease operations with cardiopulmonary bypass. We administered oral T3 (1 μg/kg per body weight/dose) or placebo (saccharum lactis) by nasogastric tube every 6 hours for 60 hours after induction of anesthesia. The primary end point, time to extubation, was compared with Cox regression. Results The modified intention-to-treat group included 101 placebo and 104 treated patients. The stratified log-rank test did not show a significant treatment difference ( p = 0.061) for time to extubation, but after adjustment for age, the nutritional Z score, and Aristotle surgical complexity, the hazard ratio was 1.33 (95% confidence interval, 1.00 to 1.76; p = 0.049). The effect of T3 was stronger in the strata aged 5 months and younger (hazard ratio, 1.86; 95% confidence interval 1.02 to 3.39; p = 0.043). Median intubation time was 47.3 hours for the placebo and 32.1 hours for the T3 group in aged 5 months and younger. Adverse events rates, including arrhythmia, were similar between groups, although sepsis was more frequent with placebo. Conclusions Oral T3 supplementation may shorten time to extubation in children undergoing congenital heart disease operations, particularly infants aged 5 months or younger. Administration is relatively safe, simple and inexpensive.

Background Metabolic syndrome increases risk for atherosclerotic coronary artery disease, and its prevalence increases with increasing age and body mass index. Adults with congenital heart disease ( ACHD ) are now living longer and accruing coronary artery disease risk factors. However, the prevalence of metabolic syndrome in ACHD patients is unknown. Methods and Results We conducted a retrospective cohort study of ACHD patients at our center to quantify the prevalence of metabolic syndrome in an ACHD population. Using case‐control matching, we constructed a comparable control group from a population‐based sample of 150 104 adults. International Diabetes Federation criteria were used to define metabolic syndrome. We used logistic regression to compare the risk of metabolic syndrome across the resulting cohorts, which were composed of 448 ACHD patients and 448 controls matched by age and sex. Mean age of both groups was 32.4±11.3 years, and 51.3% were female. Obesity was present in 16.1% of the ACHD patients and 16.7% of the controls. Metabolic syndrome was more common in ACHD patients than in controls (15.0% versus 7.4%; odds ratio 1.82, 95% CI 1.25–2.65). Conclusions Our data suggest that metabolic syndrome is more common among adults with congenital heart disease than in the general population. Thus, patients with congenital heart disease should be screened for metabolic syndrome and risk factors mitigated where possible to prevent atherosclerotic coronary artery disease. Preventive cardiology should be included during routine ACHD care.