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International differences in management/outcomes among patients with type 2 diabetes and heart failure (HF) are not well characterized. We sought to evaluate geographic variation in treatment and outcomes among these patients. METHODS AND RESULTS: Among 14,671 participants in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS), those with HF at baseline and a documented ejection fraction (EF) (N = 1591; 10.8%) were categorized by enrollment region (North America, Latin America, Western Europe, Eastern Europe, and Asia Pacific). Cox models were used to examine the association between geographic region and the primary outcome of all-cause mortality (ACM) or hospitalization for HF (hHF) in addition to ACM alone. Analyses were stratified by those with EF <40% or EF ≥40%. The majority of participants with HF were enrolled in Eastern Europe (53%). Overall, 1,267 (79.6%) had EF ≥40%. β-Blocker (83%) and angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (86%) use was high across all regions in patients with EF <40%. During a median follow-up of 2.9 years, Eastern European participants had lower rates of ACM/hHF compared with North Americans (adjusted hazard ratio: 0.45; 95% CI: 0.32-0.64). These differences were seen only in the EF ≥40% subgroup and not the EF <40% subgroup. ACM was similar among Eastern European and North American participants (adjusted hazard ratio: 0.79; 95% CI: 0.44-1.45). CONCLUSIONS: Significant variation exists in the clinical features and outcomes of HF patients across regions in TECOS. Patients from Eastern Europe had lower risk-adjusted ACM/hHF than those in North America, driven by those with EF ≥40%. These data may inform the design of future international trials., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Subclinical inflammation is associated with an increased risk of heart failure and with adverse prognosis in patients with established heart failure. Yet, treatments specifically directed at reducing inflammation in patients with heart failure have not yet shown improved clinical outcomes. We tested the hypothesis that the interleukin-1β inhibitor canakinumab would prevent hospitalization for heart failure (HHF) and the composite of HHF or heart failure-related mortality., Methods: We randomized 10 061 patients with prior myocardial infarction and high-sensitivity C-reactive protein ≥2 mg/L to canakinumab 50, 150, or 300 mg or placebo, given subcutaneously once every 3 months. In total, 2173 (22%) reported a history of heart failure at baseline. We tested the hypothesis that canakinumab prevents prospectively collected HHF events and the composite of HHF or heart failure-related mortality., Results: A total of 385 patients had an HHF event during a median follow-up of 3.7 years. Patients who had HHF were older, had higher body mass index, and were more likely to have diabetes mellitus, hypertension, and prior coronary bypass surgery. As anticipated, median (quartile 1, 3) baseline concentrations of high-sensitivity C-reactive protein were higher among those who had HHF during follow-up than those who did not (5.7 [3.5, 9.9] mg/L versus 4.2 [2.8, 6.9] mg/L, respectively; P<0.0001). The unadjusted hazard ratios for HHF with each dose of canakinumab compared with placebo were 1.04 (95% CI, 0.79-1.36) for 50 mg, 0.86 (95% CI, 0.65-1.13) for 150 mg, and 0.76 (95% CI, 0.57-1.01) for 300 mg ( P for trend=0.025). The composite of HHF or heart failure-related mortality was also reduced by canakinumab, with unadjusted hazard ratios of 1.00 (95% CI, 0.78-1.29) for 50 mg, 0.88 (95% CI, 0.68-1.13) for 150 mg, and 0.78 (95% CI, 0.60-1.02) for 300 mg ( P for trend=0.042)., Conclusions: These randomized double-blind placebo-controlled data suggest that therapy with canakinumab, an interleukin-1β inhibitor, is related to a dose-dependent reduction in HHF and the composite of HHF or heart failure-related mortality in a population of patients with prior myocardial infarction and elevations in high-sensitivity C-reactive protein., Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01327846.

Importance: Previous trial results have suggested that dipeptidyl peptidase 4 inhibitor (DPP4i) use might increase heart failure (HF) risk in type 2 diabetes mellitus (T2DM). The DPP4i sitagliptin has been shown to be noninferior to placebo with regard to primary and secondary composite atherosclerotic cardiovascular (CV) outcomes in the Trial Evaluating Cardiovascular Outcomes With Sitagliptin (TECOS)., Objective: To assess the association of sitagliptin use with hospitalization for HF (hHF) and related outcomes., Design, Setting, and Participants: TECOS was a randomized, double-blind, placebo-controlled study evaluating the CV safety of sitagliptin vs placebo, each added to usual antihyperglycemic therapy and CV care among patients with T2DM and prevalent atherosclerotic vascular disease. The median follow-up was 2.9 years. The setting was 673 sites in 38 countries. Participants included 14 671 patients with T2DM and atherosclerotic vascular disease. The study dates were December 2008 through March 2015., Interventions: Patients were randomized to sitagliptin vs placebo added to standard care., Main Outcomes and Measures: Prespecified secondary analyses compared the effect on hHF, hHF or CV death, and hHF or all-cause death composite outcomes overall and in prespecified subgroups. Supportive analyses included total hHF events (first plus recurrent) and post-hHF death. Meta-analyses evaluated DPP4i effects on hHF and on hHF or CV death., Results: Of 14 671 patients, 7332 were randomized to sitagliptin and 7339 to placebo. Hospitalization for HF occurred in 3.1% (n = 228) and 3.1% (n = 229) of the sitagliptin and placebo groups, respectively (unadjusted hazard ratio, 1.00; 95% CI, 0.83-1.19). There was also no difference in total hHF events between the sitagliptin (n = 345) and placebo (n = 347) groups (unadjusted hazard ratio, 1.00; 95% CI, 0.80-1.25). Post-hHF all-cause death was similar in the sitagliptin and placebo groups (29.8% vs 28.8%, respectively), as was CV death (22.4% vs 23.1%, respectively). No heterogeneity for the effect of sitagliptin on hHF was observed in subgroup analyses across 21 factors (P > .10 for all interactions). Meta-analysis of the hHF results from the 3 reported DPP4i CV outcomes trials revealed moderate heterogeneity (I2 = 44.9, P = .16)., Conclusions and Relevance: Sitagliptin use does not affect the risk for hHF in T2DM, both overall and among high-risk patient subgroups., Trial Registration: clinicaltrials.gov Identifier: NCT00790205.

Background: Clinical outcomes and the effects of oral anticoagulants among patients with acute coronary syndrome (ACS) and either a history of or acute heart failure (HF) are largely unknown. We aimed to assess the relationship between prior HF or acute HF complicating an index ACS event and subsequent clinical outcomes and the efficacy and safety of apixaban compared with placebo in these populations., Methods: High-risk patients were randomly assigned post-ACS to apixaban 5.0 mg or placebo twice daily. Median follow-up was 8 (4-12) months. The primary outcome was cardiovascular death, myocardial infarction, or stroke. The main safety outcome was thrombolysis in myocardial infarction major bleeding., Results: Heart failure was reported in 2,995 patients (41%), either as prior HF (2,076 [28%]) or acute HF (2,028 [27%]). Patients with HF had a very high baseline risk and were more often managed medically. Heart failure was associated with a higher rate of the primary outcome (prior HF: adjusted hazard ratio [HR] 1.73, 95% CI 1.42-2.10, P < .0001, acute HF: adjusted HR 1.65, 95% CI 1.35-2.01, P < .0001) and cardiovascular death (prior HF: HR 2.54, 95% CI 1.82-3.54, acute HF: adjusted HR 2.52, 95% CI 1.82-3.50). Patients with acute HF also had significantly higher rates of thrombolysis in myocardial infarction major bleeding (prior HF: adjusted HR 1.22, 95% CI 0.65-2.27, P = .54, acute HF: adjusted HR 1.78, 95% CI 1.03-3.08, P = .04). There was no statistical evidence of a differential effect of apixaban on clinical events or bleeding in patients with or without prior HF; however, among patients with acute HF, there were numerically fewer events with apixaban than placebo (14.8 vs 19.3, HR 0.76, 95% CI 0.57-1.01, interaction P = .13), a trend that was not seen in patients with prior HF or no HF., Conclusions: In high-risk patients post-ACS, both prior and acute HFs are associated with an increased risk of subsequent clinical events. Apixaban did not significantly reduce clinical events and increased bleeding in patients with and without HF; however, there was a tendency toward fewer clinical events with apixaban in patients with acute HF., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: We investigated whether plasma amino-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of cardiac dysfunction and prognosis measured in CORONA (Controlled Rosuvastatin Multinational Trial in Heart Failure), could be used to identify the severity of heart failure at which statins become ineffective., Background: Statins reduce cardiovascular morbidity and mortality in many patients with ischemic heart disease but not, overall, those with heart failure. There must be a transition point at which treatment with a statin becomes futile., Methods: In CORONA, patients with heart failure, reduced left ventricular ejection fraction, and ischemic heart disease were randomly assigned to 10 mg/day rosuvastatin or placebo. The primary composite outcome was cardiovascular death, nonfatal myocardial infarction, or stroke., Results: Of 5,011 patients enrolled, NT-proBNP was measured in 3,664 (73%). The midtertile included values between 103 pmol/l (868 pg/ml) and 277 pmol/l (2,348 pg/ml). Log NT-proBNP was the strongest predictor (per log unit) of every outcome assessed but was strongest for death from worsening heart failure (hazard ratio [HR]: 1.99; 95% confidence interval [CI]: 1.71 to 2.30), was weaker for sudden death (HR: 1.69; 95% CI: 1.52 to 1.88), and was weakest for atherothrombotic events (HR: 1.24; 95% CI: 1.10 to 1.40). Patients in the lowest tertile of NT-proBNP had the best prognosis and, if assigned to rosuvastatin rather than placebo, had a greater reduction in the primary end point (HR: 0.65; 95% CI: 0.47 to 0.88) than patients in the other tertiles (heterogeneity test, p = 0.0192). This reflected fewer atherothrombotic events and sudden deaths with rosuvastatin., Conclusions: Patients with heart failure due to ischemic heart disease who have NT-proBNP values <103 pmol/l (868 pg/ml) may benefit from rosuvastatin., (2009 by the American College of Cardiology Foundation)

Aims: Few prognostic models in heart failure have been developed in typically elderly patients treated with modern pharmacological therapy and even fewer included simple biochemical tests (such as creatinine), new biomarkers (such as natriuretic peptides), or, especially, both. In addition, most models have been developed for the single outcome of all-cause mortality., Methods and Results: We built a series of models for nine different fatal and non-fatal outcomes. For each outcome, a model was first built using demographic and clinical variables (Step 1), then with the addition of biochemical measures (serum creatinine, alanine aminotransferase, creatine kinase, thyrotrophin, apolipoproteins A-1 and B, and triglycerides) (Step 2) and finally with the incorporation of high-sensitivity C-reactive protein (hsCRP) and N-terminal pro B-type natriuretic peptide (NT-proBNP). Ranked according to the Wald chi(2) value, age (56), ejection fraction (44), and body mass index (42) were most predictive of all-cause mortality in Step 1 (total model chi(2) 343). Creatinine was the most powerful predictor at Step 2 (48) and ApoA-1 ranked fifth (25), with the overall chi(2) increasing to 440. Log NT-proBNP (167) was the most powerful of the 14 independently predictive variables identified at Step 3 and the overall chi(2) increased to 600. NT-proBNP was the most powerful predictor of each other outcome. hsCRP was not a predictor of all-cause mortality but did predict the composite atherothrombotic outcome., Conclusion: Of the two new biomarkers studied in prognostic models in heart failure, NT-proBNP, but not hsCRP, added substantial and independent predictive information, for a range of clinical outcomes, to that provided by simple demographic, clinical, and biochemical measures. ApoA-1 was more predictive than LDL or HDL.

Background: Patients with systolic heart failure have generally been excluded from statin trials. Acute coronary events are uncommon in this population, and statins have theoretical risks in these patients., Methods: A total of 5011 patients at least 60 years of age with New York Heart Association class II, III, or IV ischemic, systolic heart failure were randomly assigned to receive 10 mg of rosuvastatin or placebo per day. The primary composite outcome was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. Secondary outcomes included death from any cause, any coronary event, death from cardiovascular causes, and the number of hospitalizations., Results: As compared with the placebo group, patients in the rosuvastatin group had decreased levels of low-density lipoprotein cholesterol (difference between groups, 45.0%; P<0.001) and of high-sensitivity C-reactive protein (difference between groups, 37.1%; P<0.001). During a median follow-up of 32.8 months, the primary outcome occurred in 692 patients in the rosuvastatin group and 732 in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.83 to 1.02; P=0.12), and 728 patients and 759 patients, respectively, died (hazard ratio, 0.95; 95% CI, 0.86 to 1.05; P=0.31). There were no significant differences between the two groups in the coronary outcome or death from cardiovascular causes. In a prespecified secondary analysis, there were fewer hospitalizations for cardiovascular causes in the rosuvastatin group (2193) than in the placebo group (2564) (P<0.001). No excessive episodes of muscle-related or other adverse events occurred in the rosuvastatin group., Conclusions: Rosuvastatin did not reduce the primary outcome or the number of deaths from any cause in older patients with systolic heart failure, although the drug did reduce the number of cardiovascular hospitalizations. The drug did not cause safety problems. (ClinicalTrials.gov number, NCT00206310.), (2007 Massachusetts Medical Society)

Aim: To determine whether an intensive intervention at a heart failure (HF) clinic by a combination of a clinician and a cardiovascular nurse, both trained in HF, reduces the incidence of hospitalisation for worsening HF and/or all-cause mortality (primary end point) and improves functional status (including left ventricular ejection fraction, New York Heart Association (NYHA) class and quality of life) in patients with NYHA class III or IV., Setting: Two regional teaching hospitals in The Netherlands., Methods: 240 patients were randomly allocated to the 1-year intervention (n = 118) or usual care (n = 122). The intervention consisted of 9 scheduled patient contacts-at day 3 by telephone, and at weeks 1, 3, 5, 7 and at months 3, 6, 9 and 12 by a visit-to a combined, intensive physician-and-nurse-directed HF outpatient clinic, starting within a week after hospital discharge from the hospital or referral from the outpatient clinic. Verbal and written comprehensive education, optimisation of treatment, easy access to the clinic, recommendations for exercise and rest, and advice for symptom monitoring and self-care were provided. Usual care included outpatient visits initialized by individual cardiologists in the cardiology departments involved and applying the guidelines of the European Society of Cardiology., Results: During the 12-month study period, the number of admissions for worsening HF and/or all-cause deaths in the intervention group was lower than in the control group (23 vs 47; relative risk (RR) 0.49; 95% confidence interval (CI) 0.30 to 0.81; p = 0.001). There was an improvement in left ventricular ejection fraction (LVEF) in the intervention group (plus 2.6%) compared with the usual care group (minus 3.1%; p = 0.004). Patients in the intervention group were hospitalised for a total of 359 days compared with 644 days for those in the usual care group. Beneficial effects were also observed on NYHA classification, prescription of spironolactone, maximally reached dose of beta-blockers, quality of life, self-care behaviour and healthcare costs., Conclusion: A heart failure clinic involving an intensive intervention by both a clinician and a cardiovascular nurse substantially reduces hospitalisations for worsening HF and/or all-cause mortality and improves functional status, while decreasing healthcare costs, even in a country with a primary-care-based healthcare system.

Background: Recent studies demonstrated that rate control is an acceptable alternative for rhythm control in patients with persistent atrial fibrillation (AF). However, optimal heart rate during AF is still unknown., Objective: To show that in patients with permanent AF, lenient rate control is not inferior to strict rate control in terms of cardiovascular mortality, morbidity, neurohormonal activation, New York Heart Association class for heart failure, left ventricular function, left atrial size, quality of life, and costs., Methods: The RACE II study is a prospective multicenter trial in The Netherlands that will randomize 500 patients with permanent AF (< or = 12 months) to strict or lenient rate control. Strict rate control is defined as a mean resting heart rate < 80 beats per minute (bpm) and heart rate during minor exercise < 110 bpm. After reaching the target, a 24-hour Holter monitoring will be performed. If necessary, drug dose reduction and/or pacemaker implantation will be performed. Lenient rate control is defined as a resting heart rate < 110 bpm. Patients will be seen after 1, 2, and 3 months (for titration of rate control drugs) and yearly thereafter. We anticipate a 25% 2.5-year cardiovascular morbidity and mortality in both groups., Results: Enrollment started in January 2005 in 29 centers in The Netherlands and is expected to be concluded in June 2006. Follow-up will be at least 2 years with a maximum of 3 years., Conclusion: This study should provide data how to treat patients with permanent AF.

Background: Several randomised studies of heart failure (HF) management programmes in the United States, Australia and Europe have shown a considerable reduction in hospitalisation rates for HF. In this article, a comprehensive review of these studies will be provided and their applicability to countries, with a primary care-based healthcare system, will be discussed. In addition, the design of the Deventer-Alkmaar HF Project (DEAL-HF), a randomised study of the effect of a nurse and physician-directed intervention over 1 year in The Netherlands, will also be presented., Aim: To discuss the applicability of the results of available studies on heart failure management programmes to countries with well-structured primary care facilities and to determine whether additional trials should be conducted in these countries., Methods: We performed a literature search in PubMed. In a review of the available studies, essential methodological aspects, in particular, the population involved, the sample size, follow-up period, setting, type of intervention, and the outcome parameters, are discussed critically. Also, the applicability of these studies to countries with a primary care-based healthcare system and easy access to medical care is evaluated., Conclusion: Applicability of the results of the available studies on the efficacy of heart failure management programmes to countries with a primary care-based health care system is doubtful. An efficacy trial in a country with a well-established primary care-based healthcare system, such as The Netherlands, is due to report soon (DEAL-HF).

Aim: To determine whether an intensive intervention at a heart failure (HF) clinic by a combination of a clinician and a cardiovascular nurse, both trained in HF, reduces the incidence of hospitalisation for worsening HF and/or all-cause mortality (primary end point) and improves functional status (including left ventricular ejection fraction, New York Heart Association (NYHA) class and quality of life) in patients with NYHA class III or IV. Setting: Two regional teaching hospitals in The Netherlands. Methods: 240 patients were randomly allocated to the 1-year intervention (n = 118) or usual care (n = 122). The intervention consisted of 9 scheduled patient contacts-at day 3 by telephone, and at weeks 1, 3, 5, 7 and at months 3, 6, 9 and 12 by a visit-to a combined, intensive physician-and-nurse-directed HF outpatient clinic, starting within a week after hospital discharge from the hospital or referral from the outpatient clinic. Verbal and written comprehensive education, optimisation of treatment, easy access to the clinic, recommendations for exercise and rest, and advice for symptom monitoring and self-care were provided. Usual care included outpatient visits initialised by individual cardiologists in the cardiology departments involved and applying the guidelines of the European Society of Cardiology. Results: During the 12-month study period, the number of admissions for worsening HF and/or all-cause deaths in the intervention group was lower than in the control group (23 vs 47; relative risk (RR) 0.49; 95% confidence interval (CI) 0.30 to 0.81; p=0.001). There was an improvement in left ventricular ejection fraction (LVEF) in the intervention group (plus 2.6%) compared with the usual care group (minus 3.1%; p=0.004). Patients in the intervention group were hospitalised for a total of 359 days compared with 644 days for those in the usual care group. Beneficial effects were also observed on NYHA classification, prescription of spironolactone, maximally reached dose of β-blockers, quality of life, self-care behaviour and healthcare costs. Conclusion: A heart failure clinic involving an intensive intervention by both a clinician and a cardiovascular nurse substantially reduces hospitalisations far worsening HF and/or all-cause mortality and improves functional status, while decreasing healthcare costs, even in a country with a primary-care-based healthcare system. [ABSTRACT FROM AUTHOR]

Background: In chronic heart failure augmented wall stress leads to increased energy demand. Supply, however, may be reduced due to coronary vasoconstriction and endothelial dysfunction. This might lead to a mismatch between demand and supply. In the present study we further explored the effect of increased demand during dobutamine stress echocardiography.Methods and Results: Sixteen patients with idiopathic dilated cardiomyopathy (mean age 44+/-13 years, New York Heart Association class II-III, mean left ventricular ejection fraction 0.27+/-0.10) underwent dobutamine stress echocardiography (5-40 microg/min per kg bodyweight+atropine if required). Wall motion and thickening was assessed in 16 segments using a four-point scale. Eleven patients (69%) showed regions with worsening of wall motion or a biphasic response during dobutamine infusion. Of the remaining five patients one patient did not show any wall motion changes and one patient showed a partial improvement while only in three patients wall motion improvement in the whole heart was found.Conclusion: A majority of patients with idiopathic dilated cardiomyopathy showed decreased wall motion during increased demand, i.e. ischemia-like myocardial contractile responses during dobutamine stress echocardiography. These findings further support the concept that an energy mismatch between demand and supply might play a pathophysiological role in idiopathic dilated cardiomyopathy. [ABSTRACT FROM AUTHOR]

Introduction: Subclinical inflammation associates with an increased risk of heart failure, and with adverse prognosis in patients with established heart failure. Yet, treatments specifically directed at reducing inflammation in patients with heart failure have not succeeded in improving clinical outcomes. Hypothesis: We tested the pre-specified exploratory hypothesis that the IL-1β inhibitor canakinumab would prevent hospitalization for heart failure (HHF). Methods: We randomized 10,061 patients with prior myocardial infarction and high-sensitivity C-reactive protein (hsCRP) ≥ 2 mg/L to canakinumab 50 mg, 150 mg, 300 mg, or placebo, given subcutaneously once every three months. HHF events were reported by local physicians, and required a combination of symptoms, physical exam findings, laboratory and/or radiographic abnormalities, and alterations in therapy to meet the definition of HHF. Results: A total of 390 patients had a HHF event during a median follow up of 3.7 years. Patients who had HHF were older, had higher BMI, and were more likely to have diabetes, hypertension, and prior coronary bypass surgery. As anticipated, median (Q1, Q3) baseline concentrations of hsCRP were higher among those who had HHF during follow up than those who did not [5.6 mg/L (3.5, 9.9) vs. 4.2 mg/L (2.8, 6.9), respectively, P<0.0001] The unadjusted hazard ratios (95% CI) for HHF with each dose of canakinumab compared to placebo were 1.02 (0.78-1.33) for 50 mg, 0.87 (0.66-1.14) for 150 mg, and 0.76 (0.57-1.01) for 300 mg (P-trend = 0.028). After adjustment for a wide array of potential confounders, patients who achieved on-treatment hsCRP concentrations < 2 mg/L regardless of canakinumab dose had significant reductions in HHF rates compared to placebo (HR 0.80, 95% CI 0.70-0.91), while those with on-treatment hsCRP concentrations ≥ 2 mg/L did not (HR 0.98, 95% CI 0.79-1.23) (Table). These effects persisted when analyzed by alternative on-treatment hsCRP thresholds (Table). Conclusions: IL-1β inhibition with canakinumab led to statistically significant reductions in hospitalization for heart failure. Those reductions were particularly apparent amongst those who achieved low hsCRP on-treatment hsCRP concentrations, regardless of canakinumab dose. [ABSTRACT FROM AUTHOR]