Cluster Analysis of Cardiovascular Phenotypes in Patients With Type 2 Diabetes and Established Atherosclerotic Cardiovascular Disease: A Potential Approach to Precision Medicine

OBJECTIVE Phenotypic heterogeneity among patients with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD) is ill defined. We used cluster analysis machine-learning algorithms to identify phenotypes among trial participants with T2DM and ASCVD. RESEARCH DESIGN AND METHODS We used data from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) study (n = 14,671), a cardiovascular outcome safety trial comparing sitagliptin with placebo in patients with T2DM and ASCVD (median follow-up 3.0 years). Cluster analysis using 40 baseline variables was conducted, with associations between clusters and the primary composite outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina) assessed by Cox proportional hazards models. We replicated the results using the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial. RESULTS Four distinct phenotypes were identified: Cluster I included Caucasian men with a high prevalence of coronary artery disease; cluster II included Asian patients with a low BMI; cluster III included women with noncoronary ASCVD disease; and cluster IV included patients with heart failure and kidney dysfunction. The primary outcome occurred, respectively, in 11.6%, 8.6%, 10.3%, and 16.8% of patients in clusters I to IV. The crude difference in cardiovascular risk for the highest versus lowest risk cluster (cluster IV vs. II) was statistically significant (hazard ratio 2.74 [95% CI 2.29–3.29]). Similar phenotypes and outcomes were identified in EXSCEL. CONCLUSIONS In patients with T2DM and ASCVD, cluster analysis identified four clinically distinct groups. Further cardiovascular phenotyping is warranted to inform patient care and optimize clinical trial designs

Practice-level variation in use of recommended medications among outpatients with heart failure insights from the NCDR PINNACLE Program

The objective of this study is to examine practice-level variation in rates of guideline-recommended treatment for outpatients with heart failure and reduced ejection fraction, and to examine the association between treatment variation and practice site, independent of patient factors.Cardiology practices participating in the National Cardiovascular Disease Registry Practice Innovation and Clinical Excellence registry from July 2008 to December 2010 were evaluated. Practice rates of treatment with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers and β-blockers and an optimal combined treatment measure were determined for patients with heart failure and reduced ejection fraction and no documented contraindications. Multivariable hierarchical regression models were adjusted for demographics, insurance status, and comorbidities. A median rate ratio was calculated for each therapy, which describes the likelihood that the treatment of a patient with given comorbidities would differ at 2 randomly selected practices. We identified 12 556 patients from 45 practices. The unadjusted practice-level prescription rates ranged from 44% to 100% for angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (median, 85%; interquartile range, 75%-89%), from 49% to 100% for β-blockers (median, 92%; interquartile range, 83%-95%), and from 37% to 100% for optimal combined treatment (median, 79%; interquartile range, 66%-85%). The adjusted median rate ratio was 1.11 (95% confidence interval, 1.08-1.18) for angiotensin-converting enzyme inhibitors/angiotensin receptor blockers therapy, 1.08 (95% confidence interval, 1.05-1.15) for β-blockers therapy, and 1.17 (1.13-1.26) for optimal combined treatment.Variation in the use of guideline-recommended medications for patients with heart failure and reduced ejection fraction exists in the outpatient setting. Addressing practice-level differences may be an important component of improving quality of care for patients with heart failure and reduced ejection fraction.Pamela N. Peterson, Paul S. Chan, John A. Spertus, Fengming Tang, Philip G. Jones, Justin A. Ezekowitz ... et al

Assessment of dyspnea in acute decompensated heart failure: insights from ASCEND-HF (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure) on the contributions of peak expiratory flow

Objectives: This study hypothesized that peak expiratory flow rate (PEFR) would increase with acute heart failure (AHF) treatment over the first 24 h, related to a Dyspnea Index (DI) change and treatment effect. <p/>Background: Dyspnea is a key symptom and clinical trial endpoint in AHF, yet objective assessment is lacking. <p/>Methods: In a clinical trial substudy, 421 patients (37 sites) underwent PEFR testing at baseline, 1, 6, and 24 h after randomization to nesiritide or placebo. DI (by Likert scale) was collected at hours 6 and 24. <p/>Results: Patients were median age 70 years, and 34% were female; no significant differences between nesiritide or placebo patients existed. Median baseline PEFR was 225 l/min (interquartile range [IQR]: 160 to 300 l/min) and increased to 230 l/min (2.2% increase; IQR: 170 to 315 l/min) by hour 1, 250 l/min (11.1% increase; IQR: 180 to 340 l/min) by hour 6, and 273 l/min (21.3% increase; IQR: 200 to 360 l/min) by 24 h (all p < 0.001). The 24-h PEFR change related to moderate or marked dyspnea improvement by DI (adjusted odds ratio: 1.04 for each 10 l/min improvement [95% confidence interval (CI): 1.07 to 1.10]; p < 0.01). A model incorporating time and treatment over 24 h showed greater PEFR improvement after nesiritide compared with placebo (p = 0.048). <p/>Conclusions: PEFR increases over the first 24 h in AHF and could serve as an AHF endpoint. Nesiritide had a greater effect than placebo on PEFR, and this predicted patients with moderate/marked improvement in dyspnea, thereby providing an objective metric for assessing AHF. (Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure [ASCEND-HF]; NCT00475852)

Nesiritide, renal function, and associated outcomes during hospitalization for acute decompensated heart failure: results from the acute study of clinical effectiveness of nesiritide and decompensated heart failure (ASCEND-HF)

Background—Contradictory results have been reported on the effects of nesiritide on renal function in patients with acute decompensated heart failure. We studied the effects of nesiritide on renal function during hospitalization for acute decompensated heart failure and associated outcomes. Methods and Results—A total of 7141 patients were randomized to receive either nesiritide or placebo and creatinine was recorded in 5702 patients at baseline, after infusion, discharge, peak/nadir levels until day 30. Worsening renal function was defined as an increase of serum creatinine &#62;0.3 mg/dL and a change of ≥25%. Median (25th–75th percentile) baseline creatinine was 1.2 (1.0–1.6) mg/dL and median baseline blood urea nitrogen was 25 (18–39) mmol/L. Changes in both serum creatinine and blood urea nitrogen were similar in nesiritide-treated and placebo-treated patients (P=0.20 and P=0.41) from baseline to discharge. In a multivariable model, independent predictors of change from randomization to hospital discharge in serum creatinine were a lower baseline blood urea nitrogen, higher systolic blood pressure, lower diastolic blood pressure, previous weight gain, and lower baseline potassium (all P&#60;0.0001). The frequency of worsening renal function during hospitalization was similar in the nesiritide and placebo group (14.1% and 12.8%, respectively; odds ratio with nesiritide 1.12; confidence interval, 0.95–1.32; P=0.19) and was not associated with death alone and death or rehospitalization at 30 days. However, baseline, discharge, and change in creatinine were associated with death alone and death or rehospitalization for heart failure (all tests, P&#60;0.0001). Conclusions—Nesiritide did not affect renal function in patients with acute decompensated heart failure. Baseline, discharge, and change in renal function were associated with 30-day mortality or rehospitalization for heart failure.</p

Criteria for the trivial solution of differential algebraic equations with small nonlinearities to be asymptotically stable

Differential algebraic equations consisting of a constant coefficient linear part and a small nonlinearity are considered. Conditions that enable linearizations to work well are discussed. In particular, for index-2 differential algebraic equations there results a kind of Perron-Theorem that sounds as clear as its classical model expect for the expensive proofs. (orig.)Available from TIB Hannover: RR 6329(97-13) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Relationship between baseline systolic blood pressure and long-term outcomes in acute heart failure patients treated with TRV027: an exploratory subgroup analysis of BLAST-AHF

Introduction: TRV027, a ‘biased’ ligand of the angiotensin II type 1 receptor (AT1R), did not affect a composite clinical outcome at 30 days in a phase 2b acute heart failure (AHF) trial (BLAST-AHF). Methods: Post-hoc analyses from BLAST-AHF (n = 618) examined the effects of TRV027 by baseline systolic blood pressure (SBP) on changes in renal function and 180-day outcomes. Interactions between baseline SBP and select endpoints were identified utilizing a subpopulation treatment effect pattern plots (STEPP) analysis, then grouping of patients by SBP tertile: &lt; 127, ≥ 127 to &lt; 140, and ≥ 140 mmHg. Results: A trend towards increased creatinine in the first 3 days was noted in the lower SBP tertile, while in those in the higher two tertiles, TRV027, especially the 1 mg/h dose, reduced creatinine at days 5 and 30. Beneficial effects on 180-day all-cause mortality and cardiovascular (CV) death or readmission were observed in the two higher SBP tertiles (SBP ≥ 127 mmHg) in the TRV027 1 mg/h dose group (all-cause mortality HR 0.39, 95% CI 0.14–1.06, p = 0.056; CV death or HF/RF rehospitalization HR 0.53, 95% CI 0.28–1.01, p = 0.049), while more adverse outcomes were observed in patients in the lower SBP tertile. Conclusions: This post-hoc analysis of the BLAST-AHF study suggests contrasting effects of TRV027 by baseline SBP, with trends towards lower 180-day event rates in patients enrolled with higher baseline SBP, especially when given lower doses of TRV027. © 2017, Springer-Verlag GmbH Germany

Do countries or hospitals with longer hospital stays for acute heart failure have lower readmission rates?: findings from ASCEND-HF

Background—Hospital readmission is an important clinical outcome of patients with heart failure. Its relation to length of stay for the initial hospitalization is not clear.&lt;p&gt;&lt;/p&gt; Methods and Results—We used hierarchical modeling of data from a clinical trial to examine variations in length of stay across countries and across hospitals in the United States and its association with readmission within 30 days of randomization. Main outcomes included associations between country-level length of stay and readmission rates, after adjustment for patient-level case mix; and associations between length of stay and readmission rates across sites in the United States. Across 27 countries with 389 sites and 6848 patients, mean length of stay ranged from 4.9 to 14.6 days (6.1 days in the United States). Rates of all-cause readmission ranged from 2.5% to 25.0% (17.8% in the United States). There was an inverse correlation between country-level mean length of stay and readmission (r=–0.52; P&#60;0.01). After multivariable adjustment, each additional inpatient day across countries was associated with significantly lower risk of all-cause readmission (odds ratio, 0.86; 95% confidence interval, 0.75–0.98; P=0.02) and heart failure readmission (odds ratio, 0.79; 95% confidence interval, 0.69–0.99; P=0.03). Similar trends were observed across US study sites concerning readmission for any cause (odds ratio, 0.92; 95% confidence interval, 0.85–1.00; P=0.06) and readmission for heart failure (odds ratio, 0.90; 95% confidence interval, 0.80–1.01; P=0.07). Across countries and across US sites, longer median length of stay was independently associated with lower risk of readmission.&lt;p&gt;&lt;/p&gt; Conclusions—Countries with longer length of stay for heart failure hospitalizations had significantly lower rates of readmission within 30 days of randomization. These findings may have implications for developing strategies to prevent readmission, defining quality measures, and designing clinical trials in acute heart failure.&lt;p&gt;&lt;/p&gt

Learning by heart The role of emotional education in raising school achievement

SIGLEAvailable from British Library Document Supply Centre-DSC:99/36056 / BLDSC - British Library Document Supply CentreGBUnited Kingdo