Global disparities in prescription of guideline-recommended drugs for heart failure with reduced ejection fraction.

BACKGROUND: Heart failure (HF) is a global challenge, with lower- and middle-income countries (LMICs) carrying a large share of the burden. Treatment for HF with reduced ejection fraction (HFrEF) improves survival but is often underused. Economic factors might have an important effect on the use of medicines. METHODS AND RESULTS: This analysis assessed prescription rates and doses of renin-angiotensin system (RAS) inhibitors, ß-blockers, and mineralocorticoid receptor antagonists at discharge and 6-month follow-up in 8669 patients with HFrEF (1458 from low-, 3363 from middle-, and 3848 from high-income countries) hospitalized for acute HF in 44 countries in the prospective REPORT-HF study. We investigated determinants of guideline-recommended treatments and their association with 1-year mortality, correcting for treatment indication bias.Only 37% of patients at discharge and 34% of survivors at 6 months were on all three medication classes, with lower proportions in LMICs than high-income countries (19 vs. 41% at discharge and 15 vs. 37% at 6 months). Women and patients without health insurance, or from LMICs, or without a scheduled medical follow-up within 6 months of discharge were least likely to be on guideline-recommended medical therapy at target doses, independent of confounders. Being on ≥50% of guideline-recommended doses of RAS inhibitors, and ß-blockers were independently associated with better 1-year survival, regardless of country income level. CONCLUSION: Patients with HFrEF in LMICs are less likely to receive guideline-recommended drugs at target doses. Improved access to medications and medical care could reduce international disparities in outcome.

A global perspective of racial differences and outcomes in patients presenting with acute heart failure.

Important racial differences in characteristics, treatment, and outcomes of patients with acute heart failure (AHF) have been described. The objective of this analysis of the International Registry to assess medical Practice with longitudinal observation for Treatment of Heart Failure (REPORT-HF) registry was to investigate racial differences in patients with AHF according to country income level.

Comparison of vildagliptin and sitagliptin in patients with type 2 diabetes and severe renal impairment: a randomised clinical trial.

AIMS/HYPOTHESIS: There are limited data comparing dipeptidyl peptidase-4 (DPP-4) inhibitors directly. We compared the safety and efficacy of vildagliptin and sitagliptin in patients with type 2 diabetes and severe renal impairment (RI). METHODS: This study was a parallel-arm, randomised, multicentre, double-blind, 24 week study conducted in 87 centres across Brazil and the USA. Patients with type 2 diabetes, either drug naive or treated with any glucose-lowering agents, who had inadequate glycaemic control (HbA1c 6.5-10.0% [48-86 mmol/mol]) and an estimated GFR <30 ml min(-1) [1.73 m](-2) were randomised (via interactive voice response technology) to vildagliptin 50 mg once daily or sitagliptin 25 mg once daily. These doses are recommended in this patient population and considered maximally effective. Participants, investigators and the sponsor were blinded to group assignment. Efficacy endpoints included change in HbA1c and fasting plasma glucose (FPG) at all visits and the primary safety endpoint was assessment of treatment-emergent adverse events. RESULTS: In total, 148 patients were randomised, 83 to vildagliptin and 65 to sitagliptin. All patients were analysed. After 24 weeks, the adjusted mean change in HbA1c was -0.54% (5.9 mmol/mol) from a baseline of 7.52% (59 mmol/mol) with vildagliptin and -0.56% (6.1 mmol/mol) from a baseline of 7.80% (62 mmol/mol) with sitagliptin (p = 0.874). FPG decreased by 0.47 ± 0.37 mmol/l with vildagliptin and increased by 0.16 ± 0.43 mmol/l with sitagliptin (p = 0.185). Both treatments were well tolerated with overall similar safety profiles. CONCLUSIONS/INTERPRETATION: At their recommended doses for severe RI, vildagliptin (50 mg once daily) compared with sitagliptin (25 mg once daily) demonstrated similar efficacy and both drugs were well tolerated. This study provides further support for the use of DPP-4 inhibitors in patients with severe RI. TRIAL REGISTRATION: ClinicalTrials.gov NCT00616811 (completed) FUNDING: This study was planned and conducted by Novartis.

Efficacy of vildagliptin versus sulfonylureas as add-on therapy to metformin: comparison of results from randomised controlled and observational studies.

AIMS/HYPOTHESIS: Randomised control trials (RCTs) do not always reflect real-life outcomes for glucose-lowering drugs. In this work we compared RCT and real-life data on the efficacy of the dipeptidyl peptidase-IV (DPP-4) inhibitor vildagliptin or sulfonylureas when added to metformin. METHODS: Data were pooled from five RCTs examining vildagliptin (n = 2,788) and sulfonylureas (glimepiride [n = 1,259] or gliclazide [n = 433]), added to metformin. For real-life conditions, data were extracted from an observational study examining vildagliptin (n = 7,002) or sulfonylureas (n = 3,702), added to metformin monotherapy. Linear regression analyses were performed between the baseline HbA1c and the change in HbA1c (Δ HbA1c) after 24 weeks. RESULTS: Baseline HbA1c correlated to Δ HbA1c (r (2) = 0.36, slope = -0.54 [95% CI -0.55, -0.53; p < 0.0001]) for both treatments. With sulfonylureas, the slope of the correlation was steeper in the observational study than in RCTs (interaction coefficient = -0.327, p < 0.001), whereas for vildagliptin, the slope was virtually identical in the observational study and the RCTs (interaction coefficient = 0.024, p = 0.175). For any given baseline HbA1c, Δ HbA1c with sulfonylureas was smaller in real life than in RCTs, whereas Δ HbA1c with vildagliptin was the same. CONCLUSIONS/INTERPRETATIONS: When comparing RCT to real-life data, the decrease in HbA1c from baseline with sulfonylurea treatment is smaller in real life than in RCTs, whereas the reduction with vildagliptin is essentially the same, suggesting that the full power of treatment is retained in real life for vildagliptin but not for sulfonylureas, possibly due to fear of hypoglycaemia.

Association of time-to-intravenous furosemide with mortality in acute heart failure: data from REPORT-HF.

AIM: Acute heart failure can be a life-threatening medical condition. Delaying administration of intravenous furosemide (time-to-diuretics) has been postulated to increase mortality, but prior reports have been inconclusive. We aimed to evaluate the association between time-to-diuretics and mortality in the international REPORT-HF registry. METHODS AND RESULTS: We assessed the association of time-to-diuretics within the first 24 h with in-hospital and 30-day post-discharge mortality in 15 078 patients from seven world regions in the REPORT-HF registry. We further tested for effect modification by baseline mortality risk (ADHERE risk score), left ventricular ejection fraction (LVEF) and region. The median time-to-diuretics was 67 (25th-75th percentiles 17-190) min. Women, patients with more signs and symptoms of heart failure, and patients from Eastern Europe or Southeast Asia had shorter time-to-diuretics. There was no significant association between time-to-diuretics and in-hospital mortality (p > 0.1). The 30-day mortality risk increased linearly with longer time-to-diuretics (administered between hospital arrival and 8 h post-hospital arrival) (p = 0.016). This increase was more significant in patients with a higher ADHERE risk score (pinteraction  = 0.008), and not modified by LVEF or geographic region (pinteraction > 0.1 for both). CONCLUSION: In REPORT-HF, longer time-to-diuretics was not associated with higher in-hospital mortality. However, we did found an association with increased 30-day mortality, particularly in high-risk patients, and irrespective of LVEF or geographic region. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT02595814.

Global Variations According to Sex in Patients Hospitalized for Heart Failure in the REPORT-HF Registry.

BACKGROUND: Previous reports suggest that risk factors, management, and outcomes of acute heart failure (AHF) may differ by sex, but they rarely extended analysis to low- and middle-income countries. OBJECTIVES: In this study, the authors sought to analyze sex differences in treatment and outcomes in patients hospitalized for AHF in 44 countries. METHODS: The authors investigated differences between men and women in treatment and outcomes in 18,553 patients hospitalized for AHF in 44 countries in the REPORT-HF (Registry to Assess Medical Practice With Longitudinal Observation for the Treatment of Heart Failure) registry stratified by country income level, income disparity, and world region. The primary outcome was 1-year all-cause mortality. RESULTS: Women (n = 7,181) were older than men (n = 11,372), were more likely to have heart failure with preserved left ventricular ejection fraction, had more comorbid conditions except for coronary artery disease, and had more severe signs and symptoms at admission. Coronary angiography, cardiac stress tests, and coronary revascularization were less frequently performed in women than in men. Women with AHF and reduced left ventricular ejection fraction were less likely to receive an implanted device, regardless of region or country income level. Women were more likely to receive treatments that could worsen HF than men (18% vs 13%; P < 0.0001). In countries with low-income disparity, women had better 1-year survival than men. This advantage was lost in countries with greater income disparity (Pinteraction < 0.001). CONCLUSIONS: Women were less likely to have diagnostic testing or receive guideline-directed care than men. A survival advantage for women was observed only in countries with low income disparity, suggesting that equity of HF care between sexes remains an unmet goal worldwide.

Impact of left ventricular ejection fraction phenotypes on healthcare resource utilization in hospitalized heart failure: a secondary analysis of REPORT-HF.

AIM: Evidence on healthcare resource utilization (HCRU) for hospitalized patients with heart failure (HF) and reduced (HFrEF), mildly reduced (HFmrEF) and preserved (HFpEF) ejection fraction is limited. METHODS AND RESULTS: We analysed HCRU in relation to left ventricular ejection fraction (LVEF) phenotypes, clinical features and in-hospital and 12-month outcomes in 16 943 patients hospitalized for HF in a worldwide registry. HFrEF was more prevalent (53%) than HFmrEF (17%) or HFpEF (30%). Patients with HFmrEF and HFpEF were older, more often women, with milder symptoms and more comorbidities, but differences were not pronounced. HCRU was high in all three groups; two or more in- and out-of-hospital services were required by 51%, 49% and 52% of patients with HFrEF, HFmrEF and HFpEF, respectively, and intensive care unit by 41%, 41% and 37%, respectively. Hospitalization length was similar (median, 8 days). Discharge prescription of neurohormonal inhibitors was <80% for each agent in HFrEF and only slightly lower in HFmrEF and HFpEF (74% and 67%, respectively, for beta-blockers). Compared to HFrEF, 12-month all-cause and cardiovascular mortality were lower for HFmrEF (adjusted hazard ratios 0.78 [95% confidence interval 0.59-0.71] and 0.80 [0.70-0.92]) and HFpEF (0.64 [0.59-0.87] and 0.63 [0.56-0.71]); 12-month HF hospitalization was also lower for HFpEF and HFmrEF (21% and 20% vs. 25% for HFrEF). In-hospital mortality, 12-month non-cardiovascular mortality and 12-month all-cause hospitalization were similar among groups. CONCLUSIONS: In patients hospitalized for HF, overall HCRU was similarly high across LVEF spectrum, reflecting the subtle clinical differences among LVEF phenotypes during hospitalization. Discharge prescription of neurohormonal inhibitors was suboptimal in HFrEF and lower but significant in patients with HFpEF and HFmrEF, who had better long-term cardiovascular outcomes than HFrEF, but similar risk for non-cardiovascular events.

Multimorbidity in patients with acute heart failure across world regions and country income levels (REPORT-HF): a prospective, multicentre, global cohort study.

BACKGROUND: Multimorbidity (two or more comorbidities) is common among patients with acute heart failure, but comprehensive global information on its prevalence and clinical consequences across different world regions and income levels is scarce. This study aimed to investigate the prevalence of multimorbidity and its effect on pharmacotherapy and prognosis in participants of the REPORT-HF study. METHODS: REPORT-HF was a prospective, multicentre, global cohort study that enrolled adults (aged ≥18 years) admitted to hospital with a primary diagnosis of acute heart failure from 358 hospitals in 44 countries on six continents. Patients who currently or recently participated in a clinical treatment trial were excluded. Follow-up data were collected at 1-year post-discharge. The primary outcome was 1-year post-discharge mortality. All patients in the REPORT-HF cohort with full data on comorbidities were eligible for the present study. We stratified patients according to the number of comorbidities, and countries by world region and country income level. We used one-way ANOVA, χ2 test, or Mann-Whitney U test for comparisons between groups, as applicable, and Cox regression to analyse the association between multimorbidity and 1-year mortality. FINDINGS: Between July 23, 2014, and March 24, 2017, 18 553 patients were included in the REPORT-HF study. Of these, 18 528 patients had full data on comorbidities, of whom 11 360 (61%) were men and 7168 (39%) were women. Prevalence rates of multimorbidity were lowest in southeast Asia (72%) and highest in North America (92%). Fewer patients from lower-middle-income countries had multimorbidity than patients from high-income countries (73% vs 85%, p<0·0001). With increasing comorbidity burden, patients received fewer guideline-directed heart failure medications, yet more drugs potentially causing or worsening heart failure. Having more comorbidities was associated with worse outcomes: 1-year mortality increased from 13% (no comorbidities) to 26% (five or more comorbidities). This finding was independent of common baseline risk factors, including age and sex. The population-attributable fraction of multimorbidity for mortality was higher in high-income countries than in upper-middle-income or lower-middle-income countries (for patients with five or more comorbidities: 61% vs 27% and 31%, respectively). INTERPRETATION: Multimorbidity is highly prevalent among patients with acute heart failure across world regions, especially in high-income countries, and is associated with higher mortality, less prescription of guideline-directed heart failure pharmacotherapy, and increased use of potentially harmful medications. FUNDING: Novartis Pharma. TRANSLATIONS: For the Arabic, French, German, Hindi, Mandarin, Russian and Spanish translations of the abstract see Supplementary Materials section.

Rationale and design of two trials assessing the efficacy, safety, and tolerability of inclisiran in adolescents with homozygous and heterozygous familial hypercholesterolaemia.

BACKGROUND: Inclisiran is a small interfering RNA molecule that reduces low-density lipoprotein cholesterol (LDL-C) by inhibition of proprotein convertase subtilisin/kexin type 9. This subcutaneous, twice-yearly administered agent has been shown to effectively and safely lower LDL-C in adult patients with established atherosclerotic cardiovascular disease, adults at high risk for atherosclerotic cardiovascular disease, as well as in adults with heterozygous familial hypercholesterolaemia. With the current, limited treatment options available to reach treatment goals in children with severe heterozygous familial hypercholesterolaemia, homozygous familial hypercholesterolaemia, or statin intolerance, inclisiran could be a valuable new therapeutic option. OBJECTIVES: The objective of these ongoing studies is to investigate the efficacy, safety, and tolerability of inclisiran in adolescents diagnosed with homozygous familial hypercholesterolaemia (ORION-13) or heterozygous familial hypercholesterolaemia (ORION-16). STUDY DESIGN: ORION-13 and ORION-16 are both two-part (1-year double-blind inclisiran vs. placebo/1 year open-label inclisiran) multicentre trials including adolescents aged 12 to <18 years diagnosed with familial hypercholesterolaemia. ORION-13 will include ∼12 participants diagnosed with homozygous familial hypercholesterolaemia and ORION-16 will include ∼150 participants diagnosed with heterozygous familial hypercholesteroleamia. The primary endpoint is the percentage change in LDL-C from baseline to Day 330. Secondary efficacy and safety endpoints include changes in other lipid parameters and treatment-emergent adverse events as well as laboratory parameters and vital signs. Exploratory endpoints include individual responsiveness of the participants and change in LDL-C according to the type of underlying causal mutation. CLINICAL TRIAL REGISTRATION: https://www.clinicaltrials.gov/. Unique identifier: NCT04659863 (ORION-13) and NCT04652726 (ORION-16).

Regional differences in precipitating factors of hospitalization for acute heart failure: insights from the REPORT-HF registry.

AIMS: Few prior studies have investigated differences in precipitants leading to hospitalizations for acute heart failure (AHF) in a cohort with global representation. METHODS AND RESULTS: We analysed the prevalence of precipitants and their association with outcomes in 18 553 patients hospitalized for AHF in REPORT-HF (prospective international REgistry to assess medical Practice with lOngitudinal obseRvation for Treatment of Heart Failure) according to left ventricular ejection fraction subtype (reduced [HFrEF] and preserved ejection fraction [HFpEF]) and presentation (new-onset vs. decompensated chronic heart failure [DCHF]). Patients were enrolled from 358 centres in 44 countries stratified according to Latin America, North America, Western Europe, Eastern Europe, Eastern Mediterranean and Africa, Southeast Asia, and Western Pacific. Precipitants were pre-with mutually exclusive categories and selected according to the local investigator's discretion. Outcomes included in-hospital and 1-year mortality. The median age was 67 (interquartile range 57-77) years, and 39% were women. Acute coronary syndrome (ACS) was the most common precipitant in patients with new-onset heart failure in all regions except for North America and Western Europe, where uncontrolled hypertension and arrhythmia, respectively, were the most common precipitants, independent of confounders. In patients with DCHF, non-adherence to diet/medication was the most common precipitant regardless of region. Uncontrolled hypertension was a more likely precipitant in HFpEF, non-adherence to diet/medication, and ACS were more likely precipitants in HFrEF. Patients admitted due to worsening renal function had the worst in-hospital (5%) and 1-year post-discharge (30%) mortality rates, regardless of region, heart failure subtype and admission type (pinteraction >0.05 for all). CONCLUSION: Data on global differences in precipitants for AHF highlight potential regional differences in targets for preventing hospitalization for AHF and identifying those at highest risk for early mortality.

Quality of life assessed 6 months after hospitalisation for acute heart failure: an analysis from REPORT-HF (international REgistry to assess medical Practice with lOngitudinal obseRvation for Treatment of Heart Failure).

AIMS: Recovery of well-being after hospitalisation for acute heart failure (AHF) is a measure of the success of interventions and the quality of care but has rarely been quantified. Accordingly, we measured health status after discharge in an international registry (REPORT-HF) of AHF. METHODS AND RESULTS: The analysis included 4606 patients with AHF who survived to hospital discharge, had known vital status at 6 months, and were enrolled in the United States of America, Russian Federation, or Western Europe, where the Kansas City Cardiomyopathy Questionnaire (KCCQ) was administered. Median age was 69 years (quartiles 59-78), 40% were women, and 34% had a left ventricular ejection fraction (LVEF) <40%, and 12% patients died by 6 months. Of 2475 patients with a follow-up KCCQ, 28% were 'alive and well' (KCCQ >75), while 43% had poor health status (KCCQ ≤50). Being 'alive and well' was associated with new-onset AHF, LVEF <40%, younger age, higher baseline KCCQ, country, and race. Associations were similar for increasing health status, with the exception of country and addition of comorbidities. CONCLUSION: In this international global registry, health status recovery after AHF hospitalisation was highly variable. Those with the best health status at 6 months were younger, had new-onset heart failure, and higher baseline KCCQ; nearly one-third of survivors were 'alive and well'. Investigating reasons for changes in KCCQ after hospitalisation might identify new therapeutic targets to improve patient-centred outcomes.

Global Differences in Burden and Treatment of Ischemic Heart Disease in Acute Heart Failure: REPORT-HF.

OBJECTIVES: The primary aim of the current study was to investigate global differences in prevalence, association with outcome, and treatment of ischemic heart disease (IHD) in patients with acute heart failure (AHF) in the REPORT-HF (International Registry to Assess Medical Practice With Longitudinal Observation for Treatment of Heart Failure) registry. BACKGROUND: Data on IHD in patients with AHF are primarily from Western Europe and North America. Little is known about global differences in treatment and prognosis of patients with IHD and AHF. METHODS: A total of 18,539 patients with AHF were prospectively enrolled from 44 countries and 365 centers in the REPORT-HF registry. Patients with a history of coronary artery disease, an ischemic event causing admission for AHF, or coronary revascularization were classified as IHD. Clinical characteristics, treatment, and outcomes of patients with and without IHD were explored. RESULTS: Compared with 8,766 (47%) patients without IHD, 9,773 (53%) patients with IHD were older, more likely to have a left ventricular ejection fraction <40% (heart failure with reduced ejection fraction [HFrEF]), and reported more comorbidities. IHD was more common in lower income compared with high-income countries (61% vs. 48%). Patients with IHD from countries with low health care expenditure per capita or without health insurance less likely underwent coronary revascularization or used anticoagulants at discharge. IHD was independently associated with worse cardiovascular death (hazard ratio: 1.21; 95% confidence interval: 1.09 to 1.35). The association between IHD and cardiovascular death was stronger in HFrEF compared with heart failure with preserved ejection fraction (pinteraction <0.001). CONCLUSIONS: In this large global contemporary cohort of patients with AHF, IHD was more common in low-income countries and conveyed worse 1-year mortality, especially in HFrEF. Patients in regions with the greatest burden of IHD were less likely to receive coronary revascularization and treatment for IHD.

Post-discharge prognosis of patients admitted to hospital for heart failure by world region, and national level of income and income disparity (REPORT-HF): a cohort study.

BACKGROUND: Heart failure is a global public health problem, affecting a large number of individuals from low-income and middle-income countries. REPORT-HF is, to our knowledge, the first prospective global registry collecting information on patient characteristics, management, and prognosis of acute heart failure using a single protocol. The aim of this study was to investigate differences in 1-year post-discharge mortality according to region, country income, and income inequality. METHODS: Patients were enrolled during hospitalisation for acute heart failure from 358 centres in 44 countries on six continents. We stratified countries according to a modified WHO regional classification (Latin America, North America, western Europe, eastern Europe, eastern Mediterranean and Africa, southeast Asia, and western Pacific), country income (low, middle, high) and income inequality (according to tertiles of Gini index). Risk factors were identified on the basis of expert opinion and knowledge of the literature. FINDINGS: Of 18 102 patients discharged, 3461 (20%) died within 1 year. Important predictors of 1-year mortality were old age, anaemia, chronic kidney disease, presence of valvular heart disease, left ventricular ejection fraction phenotype (heart failure with reduced ejection fraction [HFrEF] vs preserved ejection fraction [HFpEF]), and being on guideline-directed medical treatment (GDMT) at discharge (p<0·0001 for all). Patients from eastern Europe had the lowest 1-year mortality (16%) and patients from eastern Mediterranean and Africa (22%) and Latin America (22%) the highest. Patients from lower-income countries (ie, ≤US$3955 per capita; hazard ratio 1·58, 95% CI 1·41-1·78), or with greater income inequality (ie, from the highest Gini tertile; 1·25, 1·13-1·38) had a higher 1-year mortality compared with patients from regions with higher income (ie, >$12 235 per capita) or lower income inequality (ie, from the lowest Gini tertile). Compared with patients with HFrEF, patients with HFpEF had a lower 1-year mortality with little variation by income level (pinteraction for HFrEF vs HFpEF <0·0001). INTERPRETATION: Acute heart failure is associated with a high post-discharge mortality, particularly in patients with HFrEF from low-income regions with high income inequality. Regional differences exist in the proportion of eligible patients discharged on GDMT, which was strongly associated with mortality and might reflect lack of access to post-discharge care and prescribing of GDMT. FUNDING: Novartis Pharma.

Global Differences in Characteristics, Precipitants, and Initial Management of Patients Presenting With Acute Heart Failure.

Importance: Acute heart failure (AHF) precipitates millions of hospital admissions worldwide, but previous registries have been country or region specific. Objective: To conduct a prospective contemporaneous comparison of AHF presentations, etiologic factors and precipitants, treatments, and in-hospital outcomes among global regions through the International Registry to Assess Medical Practice with Longitudinal Observation for Treatment of Heart Failure (REPORT-HF). Design, Setting, and Participants: A total of 18 553 adults were enrolled during a hospitalization for AHF. Patients were recruited from the acute setting in Western Europe (WE), Eastern Europe (EE), Eastern Mediterranean and Africa (EMA), Southeast Asia (SEA), Western Pacific (WP), North America (NA), and Central and South America (CSA). Patients with AHF were approached for consent and excluded only if there was recent participation in a clinical trial. Patients were enrolled from July 23, 2014, to March 24, 2017. Statistical analysis was conducted from April 18 to June 29, 2018; revised analyses occurred between August 6 and 29, 2019. Main Outcomes and Measures: Heart failure etiologic factors and precipitants, treatments, and in-hospital outcomes among global regions. Results: A total of 18 553 patients were enrolled at 358 sites in 44 countries. The median age was 67.0 years (interquartile range [IQR], 57-77), 11 372 were men (61.3%), 9656 were white (52.0%), 5738 were Asian (30.9%), and 867 were black (4.7%). A history of HF was present in more than 50% of the patients and 40% were known to have a prior left-ventricular ejection fraction lower than 40%. Ischemia was a common AHF precipitant in SEA (596 of 2329 [25.6%]), WP (572 of 3354 [17.1%]), and EMA (364 of 2241 [16.2%]), whereas nonadherence to diet and medications was most common in NA (306 of 1592 [19.2%]). Median time to the first intravenous therapy was 3.0 (IQR, 1.4-5.6) hours in NA; no other region had a median time above 1.2 hours (P < .001). This treatment delay remained after adjusting for severity of illness (P < .001). Intravenous loop diuretics were the most common medication administered in the first 6 hours of AHF management across all regions (65.4%-89.9%). Despite similar initial blood pressure across all regions, inotropic agents were used approximately 3 times more often in SEA, WP, and EE (11.3%-13.5%) compared with NA and WE (3.1%-4.3%) (P < .001). Older age (odds ratio [OR], 1.0; 95% CI, 1.00-1.02), HF etiology (ischemia: OR, 1.65; 95% CI, 1.11-2.44; valvular: OR, 2.10; 95% CI, 1.36-3.25), creatinine level greater than 2.75 mg/dL (OR, 1.85; 95% CI, 0.71-2.40), and chest radiograph signs of congestion (OR, 2.03; 95% CI, 1.39-2.97) were all associated with increased in-hospital mortality. Similarly, younger age (OR, -0.04; 95% CI, -0.05 to -0.02), HF etiology (ischemia: OR, 0.77; 95% CI, 0.26-1.29; valvular: OR, 2.01; 95% CI, 1.38-2.65), creatinine level greater than 2.75 mg/dL (OR, 1.16; 95% CI, 0.31-2.00), and chest radiograph signs of congestion (OR, 1.02; 95% CI, 0.57-1.47) were all associated with increased in-hospital LOS. Conclusions and Relevance: Data from REPORT-HF suggest that patients are similar across regions in many respects, but important differences in timing and type of treatment exist, identifying region-specific gaps in medical management that may be associated with patient outcomes.

Experimental infection of rodent mammals for fungal virulence testing.

Invasive fungal infections comprise a group of serious and life-threatening diseases affecting immunocompromised patients. Molecular analysis of fungal virulence involves the deletion of genes that are suspected for contributing to fungal pathogenesis. Phenotypic analysis of the generated mutants includes in vivo infection experiments in order to assign a function during fungal disease to a gene of interest.

Characterization of the influence of vildagliptin on model-assessed -cell function in patients with type 2 diabetes and mild hyperglycemia.

OBJECTIVE: This study was conducted to characterize the effects of vildagliptin on beta-cell function in patients with type 2 diabetes and mild hyperglycemia. DESIGN: A 52-wk double-blind, randomized, parallel-group study comparing vildagliptin (50 mg every day) and placebo was conducted in 306 patients with mild hyperglycemia (glycosylated hemoglobin of 6.2-7.5%). Plasma glucose and C-peptide levels were measured during standard meal tests performed at baseline, wk 24 and 52, and after 4-wk washout. Insulin secretory rate (ISR) was calculated by C-peptide deconvolution, and beta-cell function was quantified with a mathematical model that describes ISR as a function of absolute glucose levels (insulin secretory tone and glucose sensitivity), the glucose rate of change (rate sensitivity), and a potentiation factor. RESULTS: Vildagliptin significantly increased fasting insulin secretory tone [between-group difference in adjusted mean change from baseline to wk 52 (AM Delta) = +34.1 +/- 9.5 pmol.min(-1).m(-2), P < 0.001] glucose sensitivity (AM Delta = +20.7 +/- 5.2 pmol.min(-1).m(-2).mm(-1), P < 0.001), and rate sensitivity (AM Delta = +163.6 +/- 67.0 pmol.m(-2).mm(-1), P = 0.015), but total insulin secretion (ISR area under the curve at 0-2 h) and the potentiation factor excursion during meals were unchanged. These improvements in beta-cell function were accompanied by a decrease in the glucose area under the curve at 0-2 h (AM Delta = -1.7 +/- 0.5 mm/h, P = 0.002) and in glycosylated hemoglobin (AM Delta = -0.3 +/- 0.1%, P < 0.001). None of the effects of vildagliptin remained after 4-wk washout from study medication. CONCLUSIONS: Consistent with previous findings from shorter-term studies in patients with more severe hyperglycemia, in patients with mild hyperglycemia, improved beta-cell function is maintained throughout 52-wk treatment with vildagliptin and underlies a sustained improvement in glycemic control. However, no effects remain after washout.

Comparison of vildagliptin and rosiglitazone monotherapy in patients with type 2 diabetes: a 24-week, double-blind, randomized trial.

OBJECTIVE: To compare the efficacy and tolerability of vildagliptin and rosiglitazone during a 24-week treatment in drug-naïve patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This was a double-blind, randomized, active-controlled, parallel-group, multicenter study of 24-week treatment with vildagliptin (100 mg daily, given as equally divided doses; n = 519) or rosiglitazone (8 mg daily, given as a once-daily dose; n = 267). RESULTS: Monotherapy with vildagliptin and rosiglitazone decreased A1C (baseline = 8.7%) to a similar extent during the 24-week treatment, with most of the A1C reduction achieved by weeks 12 and 16, respectively. At end point, vildagliptin was as effective as rosiglitazone, improving A1C by -1.1 +/- 0.1% (P < 0.001) and -1.3 +/- 0.1% (P < 0.001), respectively, meeting the statistical criterion for noninferiority (upper-limit 95% CI for between-treatment difference < or =0.4%). Fasting plasma glucose decreased more with rosiglitazone (-2.3 mmol/l) than with vildagliptin (-1.3 mmol/l). Body weight did not change in vildagliptin-treated patients (-0.3 +/- 0.2 kg) but increased in rosiglitazone-treated patients (+1.6 +/- 0.3 kg, P < 0.001 vs. vildagliptin). Relative to rosiglitazone, vildagliptin significantly decreased triglycerides, total cholesterol, and LDL, non-HDL, and total-to-HDL cholesterol (-9 to -16%, all P < or = 0.01) but produced a smaller increase in HDL cholesterol (+4 vs. +9%, P = 0.003). The proportion of patients experiencing an adverse event was 61.4 vs. 64.0% in patients receiving vildagliptin and rosiglitazone, respectively. Only one mild hypoglycemic episode was experienced by one patient in each treatment group, while the incidence of edema was greater with rosiglitazone (4.1%) than vildagliptin (2.1%). CONCLUSIONS: Vildagliptin is an effective and well-tolerated treatment option in patients with type 2 diabetes, demonstrating similar glycemic reductions as rosiglitazone but without weight gain.

Combination treatment in the management of type 2 diabetes: focus on vildagliptin and metformin as a single tablet.

Vildagliptin is a potent and selective inhibitor of dipeptidyl peptidase-IV (DPP-4), orally active, that improves glycemic control in patients with type 2 diabetes (T2DM) primarily by enhancing pancreatic (alpha and beta) islet function. Thus vildagliptin has been shown both to improve insulin secretion and to suppress the inappropriate glucagon secretion seen in patients with T2DM. Vildagliptin reduces HbA(1c) when given as monotherapy, without weight gain and with minimal hypoglycemia, or in combination with the most commonly prescribed classes of oral hypoglycemic drugs: metformin, a sulfonylurea, a thiazolidinedione, or insulin. Metformin, with a different mode of action not addressing beta-cell dysfunction, has been used for about 50 years and still represents the universal first line therapy of all guidelines. However, given the multiple pathophysiological abnormalities in T2DM and the progressive nature of the disease, intensification of therapy with combinations is typically required over time. Recent guidelines imply that patients will require pharmacologic combinations much earlier to attain and sustain the increasingly stringent glycemic targets, with careful drug selection to avoid unwanted adverse events, especially hypoglycemia. The combination of metformin and vildagliptin offers advantages when compared to currently used combinations with additive efficacy and complimentary mechanisms of action, since it does not increase the risk of hypoglycemia and does not promote weight gain. Therefore, by specifically combining these agents in a single tablet, there is considerable potential to achieve better blood glucose control and to improve compliance to therapy.

The dipeptidyl peptidase 4 inhibitor vildagliptin does not accentuate glibenclamide-induced hypoglycemia but reduces glucose-induced glucagon-like peptide 1 and gastric inhibitory polypeptide secretion.

BACKGROUND/AIMS: Inhibition of dipeptidyl peptidase 4 by vildagliptin enhances the concentrations of the active form of the incretin hormones glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP). The present study asked whether vildagliptin accentuates glibenclamide-induced hypoglycemia or affects endogenous secretion of GLP-1 and GIP after an oral glucose tolerance test. METHODS: There were 16 healthy male subjects studied on four occasions after an overnight fast in a double-blind, four-way crossover study. In random order, vildagliptin (100 mg) or placebo, with and without glibenclamide (5 mg), was administered 30 min before 75 g oral glucose. Blood was sampled to measure glucose, and total (sum of active and inactive) GLP-1 and GIP. Statistical evaluation was done using repeated-measures ANOVA. RESULTS: Glibenclamide provoked hypoglycemia (

Efficacy and tolerability of vildagliptin monotherapy in drug-naïve patients with type 2 diabetes.

UNLABELLED: This 24-week, double-blind, randomized, multicenter, placebo-controlled, parallel-group study performed in 354 drug-naïve patients with type 2 diabetes (T2DM) assessed efficacy and tolerability of vildagliptin (50mg qd, 50mg bid, or 100mg qd). The primary assessment was change from baseline to endpoint in hemoglobin A1c (A1C), comparing vildagliptin to placebo by ANCOVA. Baseline A1C averaged 8.4% and the between-treatment difference (vildagliptin-placebo) in adjusted mean change (AMDelta) in A1C was -0.5+/-0.2% (P=0.011), -0.7+/-0.2% (P<0.001), and -0.9+/-0.2% (P<0.001) in patients receiving vildagliptin 50 mg qd, 50 mg bid, or 100 mg qd, respectively. Baseline FPG averaged 10.5 mmol/L; the between-treatment difference in AMDelta FPG was -0.6+/-0.4 mmol/L in patients receiving vildagliptin 50mg qd and -1.3+/-0.4 mmol/L (P=0.001) in both groups receiving 100mg daily. Relative to baseline, body weight did not change significantly in any of the three vildagliptin groups and decreased by 1.4+/-0.4 kg in the placebo group. Adverse events (AEs) occurred with similar frequency in each group: 55.8%, 59.3%, 59.3%, and 57.6% of patients receiving vildagliptin 50 mg qd, 50 mg bid, 100 mg qd, or placebo, respectively, experienced an AE. No confirmed hypoglycemia was reported. CONCLUSION: Vildagliptin is effective and well-tolerated in drug-naïve patients with T2DM and 100 mg vildagliptin provides similar clinical benefit whether given as single or in divided doses.