Abstract Background To investigate the outcomes of hospitalized patients with both de-novo and worsening heart failure (HF) with preserved left ventricular ejection fraction (LVEF) (HFpEF) (LVEF ≥ ...50%), compared to those with reduced LVEF (HFrEF). Methods and results We studied 1669 patients (22.6% HFpEF) hospitalized for acute HF in the prospective multi-center nationwide Italian Network on Heart Failure (IN-HF) Outcome Registry. In all patients LVEF was assessed during hospitalization. De-novo HF presentations constituted 49.6% of HFpEF and 43.1% of HFrEF hospitalizations. All-cause mortality during hospitalization was lower in HFpEF than HFrEF (2.9% vs 6.5%, p = 0.01), but this mortality difference was not significant at 1 year (19.6% vs 24.4%, p = 0.06), even after adjusting for clinical covariates. Similarly, there were no differences in 1-year mortality between HFpEF and HFrEF when compared by cause of death (cardiovascular vs non-cardiovascular) or mode of presentation (worsening HF vs de novo). Rehospitalization rates (all-cause, non-cardiovascular, cardiovascular, HF-related) at 90 days and 1 year were also similar. Mode of presentation influenced rehospitalizations in HFpEF, where those presenting with worsening HFpEF had higher all-cause (36.8% vs 21.6%, p = 0.001), cardiovascular (28.1% vs 14.9%, p = 0.002), and HF-related (21.1% vs 7.7%, p = 0.0003) rehospitalization rates at 1 year compared to those with de novo presentations. Conclusions Outcomes at 1 year following hospitalization for HFpEF are as poor as that of HFrEF. A prior history of HF decompensation or hospitalization identifies patients with HFpEF at particularly high risk of recurrent events. These findings may have implications for clinical practice, quality and process improvements and trial design.
Highlights • The mean deterioration in estimated GFR in patients with chronic heart failure was 1.5 mL • min−1 • 1.73 m−2 in the first year, which can be considered to be moderate. • A minority of ...patients (one sixth) experienced a strong decrease in renal function in the 1st year (15 mL • min−1 • 1.73 m−2 ). • Factors associated with progressive decline were baseline renal dysfunction, COPD, and loop diuretic use. • Lower renal function at baseline and any decrease over time was strongly associated with worse clinical outcomes, including cardiovascular death and heart failure hospitalization.
Abstract Objective This observational study aimed to identify clinical variables and health system characteristics associated with incomplete guideline application in drug treatment of patients with ...chronic heart failure (HF) across 15 countries. Methods Three data sets were used: European Society of Cardiology Heart Failure Registry, Organisation for Economic Co-operation and Development’s Health System Characteristics Survey, and Organisation for Economic Co-operation and Development Health Statistics 2013. Patient and country variables were examined by multilevel, multiple logistic regression. The study population consisted of ambulatory patients with chronic HF and reduced ejection fraction. Inappropriateness of prescription of pharmacological treatments was defined as patients not prescribed at least one of the two recommended treatments (angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers and beta-blockers) or treated with both medications but at suboptimal dosage and in absence of documented contraindication/intolerance. Results Of 4605 patients, 1097 (23.8%) received inappropriate drug prescriptions with a large variation within and across countries, with 18.5% of the total variability accounted for by between-country health structure characteristics. Patient-level characteristics such as having mitral regurgitation (odds ratio 1.4; 95% confidence interval 1.1–1.7) was significantly associated with inappropriate prescription of recommended drugs, whereas chronic obstructive pulmonary disease (odds ratio 0.7; 95% confidence interval 0.5–0.9) was associated with more appropriate prescriptions. Among the country-level variables, incentives or obligation to comply with guidelines increased the probability of prescription appropriateness. Conclusions Combining clinical variables with health system characteristics is a promising exercise to explain the appropriateness of recommended drug prescriptions. Such an understanding can help decision makers to design more effective policies to improve adherence to guidelines, improve health care outcomes, and potentially reduce costs.
In the recent Italian Network on Heart Failure (IN-HF) Outcome registry, including 1,855 patients with acute heart failure (AHF), we reviewed the use of inotropes and their prognostic implication on ...in-hospital and 12-month mortality.
IN-HF Outcome is a prospective, multicenter, observational, study involving 61 Italian cardiology centers. AHF patients have been enrolled over a 2-year period and followed-up for 1 year. Inotropes were used in 360 patients (19.4%).
Patients who received inotropes had a more severe clinical and hemodynamic profile than those who did not and exhibited a significantly higher rate of in-hospital (21.4% vs 2.7%, p < 0.01) and 1-year (50.6% vs 17.7%, p < 0.01) mortality. At entry, systolic blood pressure (SBP) was ≤ 110 mm Hg in 58%, 111 to 130 mm Hg in 24.5%, and > 130 mm Hg in 17.5%. Multivariable analyses showed use of inotropes was the strongest predictor of all-cause death. These data were confirmed by propensity score analyses. According to SBP at entry, the 2 groups with SBP > 110 mm Hg who took inotropes, despite a more favorable clinical profile, exhibited a similar worse prognosis, particularly at 1 year: 56.3% (≤ 110 mm Hg), 43.7% (111-130 mm Hg), and 40.3% (>130 mm Hg) vs 17.7%.
Inotropes were used in nearly 20% of the patient admitted for AHF, and this treatment was associated with a short-term to medium-term poor prognosis. An inappropriate use of inotropes in patients with normal to high SBP, and presumably preserved cardiac output, may have significantly contributed to affect the all-group outcome.
Background: Thymidylate synthase (TS), a key enzyme in DNA synthesis, is often overexpressed in cancer cells. Some chemotherapeutic agents, such as 5-fluorouracil (5-FU), act by inhibiting TS ...expression. We evaluated whether a novel 28-amino acid multiepitope peptide, TS/PP, that contains the sequences of three TS-derived epitopes with binding motifs for HLA-A(*)02.01 could induce a TS-directed cytotoxic T-lymphocyte (CTL) response with antitumor activity. Methods: TS/PP peptide immunologic activity in CTL lines derived from human leukocyte antigen (HLA)-A(*)02.01+ peripheral blood mononuclear cells (PBMCs) was tested in the presence of interleukin-2 and autologous TS/PP peptide-loaded dendritic cells. Immunologic and antitumor activities of TS/PP and its toxicity were also evaluated in vivo in HLA-A(*)02.01 transgenic (HHD) mice that were vaccinated with TS/PP, control, or TS-peptide cocktail and treated with or without 5-FU chemotherapy. The mice were also inoculated subcutaneously with TS-expressing EL-4/HHD lymphoma cells to assess immune response against these tumor cells. Results: TS/PP-specific CTL lines showed a TS-multiepitopic specificity and were able to kill TS+/HLA-A(*)02.01+ breast and colon carcinoma cells. The killing ability against target cells previously exposed to sublethal doses of 5-FU was statistically significantly greater than against untreated target cells (43.5% versus 26.5% at 25/1 effector to target ratio Difference {diff} = 17.0; 95% confidence interval CI = 12.6 to 20.4) for MDA-MB-231 breast carcinoma cells and 73.5 versus 48.5 (diff = 25.0; 95% CI = 16.2 to 33.8) for the SW-1463 colon carcinoma cells. HHD mice vaccinated with TS/PP manifested a TS-peptide-specific CTL response with no sign of autoimmunity or toxicity. Furthermore, treatment of these mice with 5-FU delayed or prevented the occurrence of tumors formed by inoculation with autologous (TS+)EL-4/HHD lymphoma cells. Conclusions: The multiepitopic TS/PP vaccine induces a tumor-specific immune response in mice and is especially potent when used in combination with 5-FU-based chemotherapy.
Aims
Co‐morbidities frequently accompany heart failure (HF), contributing to increased morbidity and mortality, and an impairment of quality of life. We assessed the prevalence, determinants, ...regional variation, and prognostic implications of co‐morbidities in patients with chronic HF in Europe.
Methods and results
A total of 3226 European outpatients with chronic HF were included in this analysis of the European Society of Cardiology (ESC) Heart Failure Pilot Survey. The following co‐morbidities were considered: diabetes, hyper‐ and hypothyroidism, stroke, COPD, sleep apnoea, chronic kidney disease (CKD), and anaemia. Prognostic implications of co‐morbidities were evaluated using population attributable risks (PARs), and patients were divided into geographic regions. Clinical endpoints were all‐cause mortality and HF hospitalization. The majority of patients (74%) had a least one co‐morbidity, the most prevalent being CKD (41%), anaemia (29%), and diabetes (29%). Co‐morbidities were independently associated with higher age (P < 0.001), higher NYHA functional class (P < 0.001), ischaemic aetiology of HF (P < 0.001), higher heart rate (P = 0.011), history of hypertension (P < 0.001), and AF (P < 0.001). Only diabetes, CKD, and anaemia were independently associated with a higher risk of mortality and/or HF hospitalization. There were marked regional differences in prevalence and prognostic implications of co‐morbidities. Prognostic implications of co‐morbidities (PARs) were: CKD = 41%, anaemia = 37%, diabetes = 14%, COPD = 10%, and <10% for all other co‐morbidities.
Conclusion
In this pilot survey, co‐morbidities are prevalent in patients with chronic HF and are related to the severity of the disease. The presence of diabetes, CKD, and anaemia was independently related to increased mortality and HF hospitalization, with the highest PAR for CKD and anaemia.
Background and Objective
Nimodipine is a dihydropyridine calcium channel blocker used in the treatment of ischemic damage in subarachnoid hemorrhage. Recent investigations have shown that it is able ...to inhibit adenosine transport in human red blood cells and parietal cortex neurons. In this study we investigated the pharmacokinetics of nimodipine and the effect on plasma adenosine levels in patients affected by cerebral ischemia.
Methods
Twelve patients with cerebral ischemia (9 men and 3 women; mean age, 68.8 ± 11.2 years; mean weight, 67.9 ± 9.3 kg) were admitted to the study. They received nimodipine intravenously (a bolus of 0.03 mg/kg) and orally (single doses of 30, 60, and 90 mg) during different sessions. Blood samples for adenosine and nimodipine were collected at fixed intervals up to 480 minutes. Adenosine and nimodipine plasma levels were detected by HPLC methods.
Results
Both the intravenous and oral administrations induced a statistically significant increase in plasma adenosine levels (P < .001), which appeared to be related to the dose and route of drug administration. In particular, a 67.8% increase was observed after intravenous administration, and increases of 28.9%, 43.6%, and 60.2% were observed after 30 mg, 60 mg, and 90 mg of nimodipine, respectively. The pharmacokinetic parameters of nimodipine after intravenous administration were as follows: peak concentration (Cmax), 319.6 ± 38.9 ng/mL at the first sampling time; area under the curve (AUC), 239 ± 25 ng · h/mL; and terminal half‐life, 3.12 ± 0.97 hours. After oral administration, the drug kinetics was linear in the administered dose range and the pharmacokinetic parameters were as follows: Cmax(30 mg), 46.1 ± 5.8 ng/mL; Cmax(60 mg), 81.7 ± 14.6 ng/mL; Cmax(90 mg), 131.6 ± 16.3 ng/mL; AUC(30 mg), 119 ± 25 ng · h/mL; AUC(60 mg), 256 ± 48 ng · h/mL; and AUC(90 mg), 389 ± 54 ng · h/mL. The half‐life was similar to the values observed after intravenous administration, whereas the bioavailability ranged between 2% and 5.9%.
Conclusions
Our data indicate that the administration of nimodipine induces an increase in plasma adenosine levels, and we hypothesize that the drug activity could be associated, at least partially, with adenosine mediation.
Clinical Pharmacology & Therapeutics (2002) 72, 556–561; doi: 10.1067/mcp.2002.128127
Aims
The ESC‐HF Pilot survey was aimed to describe clinical epidemiology and 1‐year outcomes of outpatients and inpatients with heart failure (HF). The pilot phase was also specifically aimed at ...validating structure, performance, and quality of the data set for continuing the survey into a permanent Registry.
Methods
The ESC‐HF Pilot study is a prospective, multicentre, observational survey conducted in 136 Cardiology Centres in 12 European countries selected to represent the different health systems across Europe. All outpatients with HF and patients admitted for acute HF on 1 day per week for eight consecutive months were included. From October 2009 to May 2010, 5118 patients were included: 1892 (37%) admitted for acute HF and 3226 (63%) patients with chronic HF. The all‐cause mortality rate at 1 year was 17.4% in acute HF and 7.2% in chronic stable HF. One‐year hospitalization rates were 43.9% and 31.9%, respectively, in hospitalized acute and chronic HF patients. Major regional differences in 1‐year mortality were observed that could be explained by differences in characteristics and treatment of the patients.
Conclusion
The ESC‐HF Pilot survey confirmed that acute HF is still associated with a very poor medium‐term prognosis, while the widespread adoption of evidence‐based treatments in patients with chronic HF seems to have improved their outcome profile. Differences across countries may be due to different local medical practice as well to differences in healthcare systems. This pilot study also offered the opportunity to refine the organizational structure for a long‐term extended European network.
Obesity is a major risk factor for arterial hypertension, coronary artery disease, dyslipidemias, and type 2 diabetes. Spa therapy has long been used for treating obesity and its comorbidities. ...Enlargement of adipose tissue has been linked to a dysregulation of adipokine secretion and adipose tissue inflammation. Adipokines are currently investigated as potential drug targets in these conditions. Our primary aim was to assess the clinical efficacy of a 3-week program of diet combined with spa therapy in obese patients with and without type 2 diabetes. The secondary aim was to examine whether this combined program influences the response of serum levels of leptin, adiponectin, visfatin, and high-sensitivity C-reactive protein. Fifty obese males were enrolled and 21 of these featured a type 2 diabetes. During the 3-week period of the study, the patients were on a 1,000-kcal diet and were involved in mineral bath and total body’s mud-pack applications (15 procedures). Patients were assessed at baseline and at the end of the therapy for clinical and biochemical parameters (total cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, glycemia, and adipokines). We showed that a 3-week program of spa therapy in obese patients induced significant decrease of body weight, body mass index, triglycerides, total cholesterol, low-density lipoprotein (LDL) cholesterol, glycemia, and serum levels of leptin and high-sensitivity C-reactive protein. So, a cycle of mud-bath therapy associated with a controlled diet may be a promising treatment for obesity and type 2 diabetes decreasing body weight and many risk factors for atherosclerosis and metabolic syndrome.
We developed a prognostic model to assess the risk of all-cause mortality in patients with chronic heart failure.
We examined 6975 patients with chronic heart failure enrolled in the Gruppo Italiano ...per lo Studio della Streptochinasi nell'Infarto Miocardico-Heart Failure (GISSI-HF) trial (3.9 years follow-up). Multivariable Cox regression models were developed to predict mortality (1969 deaths). By stepwise selection, the full final model included 25 predictors. A reduced model, considering the most significant variables ranked according to the Wald χ(2) (P<0.0001) accounted for most of the prognostic information. Internal validation of the model was performed with bootstrap techniques. The discrimination ability of the reduced model constituted by 12 factors (concordance probability estimate, 0.693) was as good as the full final model (concordance probability estimate, 0.70). Among the first 12 independent risk factors emerging in the reduced model, the 3 most powerful predictors were older age, higher New York Heart Association class, and lower estimated glomerular filtration rate. Other independent predictors that increased risk included lower left ventricular ejection fraction, chronic obstructive pulmonary disease, lower systolic blood pressure, diabetes mellitus, male sex, higher uricemia, lower body mass index, lower hemoglobin, and aortic stenosis. The reduced model was used to build a nomogram to estimate the risk of death in individual patients. In a subgroup of patients, the 2 well-known biomarkers (high-sensitivity cardiac troponin T and N-terminal pro-brain natriuretic peptide) emerged as the most powerful predictors of outcome.
In a large contemporary population with chronic heart failure, this model offers good ability to assess the risk of death, confirming most of the risk factors that have emerged in recent trials.
URL: http://www.clinicaltrials.gov. Unique identifier: NCT00336336.
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