Carmelina Ariano

B-type natriuretic peptide-guided versus symptom-guided therapy in outpatients with chronic heart failure: a systematic review with meta-analysis.

Purpose It has been asserted that serial measurements of natriuretic peptides, specifically B-type natriuretic peptide (BNP) or the amino-terminal fragment of pro-B-type natriuretic peptide (NT-proBNP), may serve as an objective practical guide to better tailor the drug treatment for patients with chronic heart failure (CHF), and especially to detect the cases of subclinical congestion that would require an increase in drug dosing. However, considerable uncertainty remains about the alleged useful role of natriuretic peptide-guided therapy in this context. Therefore, we decided to execute a meta-analysis of published randomized controlled trials (RCTs) to test the hypothesis that an improvement of clinical outcomes in outpatients with CHF may be achieved by adjustment of pharmacologic dosing performed according to natriuretic peptide determinations. Methods The relevant studies were collected through a search across the PubMed database (January 1996 to September 2012). For our meta-analysis, parallel-group RCTs were eligible for inclusion if they met the following criteria: they enrolled patients with CHF, they randomized patients to a strategy of titrating drug therapy based on the level of a circulating natriuretic peptide (BNP or NT-proBNP) compared to a parallel control group treated according to the clinical conventional criteria, and they reported all-cause mortality. In addition, it was established that each RCT to be incorporated in the evaluation should have included more than 60 participants and its follow-up should have been longer than 90 days. The primary endpoint of the meta-analysis was all-cause mortality and hospitalization related to heart failure (combined endpoint). Results In the six pooled RCTs subjected to final meta-analysis (total of included patients = 1775), natriuretic peptide-guided therapy for outpatients with CHF was shown to be associated with a decreased risk of death and heart failure hospitalizations during follow-up (odds ratio – random effect model: 0.64; 95% confidence interval: 0.43–0.95; P = 0.026). Conclusion This meta-analysis supports the hypothesis that natriuretic peptide-guided therapy is superior to symptom-guided therapy for improving clinical outcomes in CHF outpatients. However, some large RCTs failed to document significant clinical improvement in terms of mortality and morbidity using a natriuretic peptide-guided strategy; thus, any attempt to clarify this still unresolved issue by means of further basic and clinical research is recommended in the future.

Hypertonic saline plus i.v. furosemide improve renal safety profile and clinical outcomes in acute decompensated heart failure

BackgroundIn advanced congestive heart failure (CHF), intravenous (i.v.) inotropic agents, i.v. diuretics, ultrafiltration, and hemodialysis have been shown to not yield better clinical outcomes. In this scenario, the simultaneous administration of hypertonic saline solution (HSS) and furosemide may offer a more effective therapeutic option with a good safety profile.MethodsTherefore, a meta-analysis was performed to compare combined therapy, consisting of i.v. furosemide plus concomitant administration of HSS, with i.v. furosemide alone for acute decompensated heart failure (ADHF). The outcomes we chose were all-cause mortality, risk of re-hospitalization for ADHF, length of hospital stay, weight loss, and variation of serum creatinine.ResultsBased on five randomized controlled trials (RCTs) involving 1,032 patients treated with i.v. HSS plus furosemide vs. 1,032 patients treated with i.v. furosemide alone, a decrease in all-cause mortality in patients treated with HSS plus furosemide was proven [RR = 0.57; 95 % confidence interval (CI) = 0.44–0.74, p = 0.0003]. Likewise, combined therapy with HSS plus furosemide was shown to be associated with a reduced risk of ADHF-related re-hospitalization (RR = 0.51; 95 % CI = 0.35–0.75, p = 0.001). Besides, combined therapy with HSS plus furosemide was found to be associated with a reduced length of hospital stay (p = 0.0002), greater weight loss (p < 0.00001), and better preservation of renal function (p < 0.00001).ConclusionHSS as an adjunct to i.v. furosemide for diuretic-resistant CHF patients led to a better renal safety profile and improved clinical endpoints such as mortality and heart failure-related hospitalizations.ZusammenfassungHintergrundBei fortgeschrittener kongestiver Herzinsuffizienz (CHF) haben intravenös (i.v.) applizierte inotrope Substanzen, i.v.-Diuretika, Ultrafiltration und Hämodialyse nachgewiesenermaßen nicht zu besseren klinischen Ergebnissen geführt. Im vorliegenden Szenario stellen die gleichzeitige Gabe von hypertoner Kochsalzlösung (HSS) und Furosemid möglicherweise eine wirksamere therapeutische Option mit gutem Sicherheitsprofil dar.MethodenDaher wurde eine Metaanalyse durchgeführt mit dem Ziel, die kombinierte Therapie aus Furosemid i.v. plus begleitender Gabe von HSS mit der Gabe von Furosemid i.v. allein bei akut dekompensierter Herzinsuffizienz (ADHF) zu vergleichen. Die gewählten Endpunkte waren Mortalität aus sämtlichen Ursachen, Risiko der Wiederaufnahme ins Krankenhaus wegen ADHF, Krankenhausverweildauer, Gewichtsabnahme und Veränderung des Serumkreatinins.ErgebnisseAuf der Grundlage von 5 randomisierten kontrollierten Studien mit 1032 Patienten, die mit HSS plus Furosemid i.v. behandelt wurden, versus 1032 Patienten, die mit Furosemid i.v. allein behandelt wurden, wurde eine Abnahme der Mortalität aus sämtlichen Ursachen bei Patienten mit der Gabe von HSS plus Furosemid nachgewiesen (RR = 0,57; 95%-Konfidenzintervall, 95%-KI: 0,44–0,74; p = 0,0003). Gleichermaßen wurde gezeigt, dass die kombinierte Therapie aus HSS plus Furosemid mit einem verminderten Risiko einer stationären Wiederaufnahme wegen ADHF einherging (RR = 0,51; 95%-KI: 0,35–0,75; p = 0,001). Außerdem stellte sich heraus, dass die kombinierte Therapie aus HSS plus Furosemid mit einer geringeren Krankenhausverweildauer (p = 0,0002), größerer Gewichtsabnahme (p < 0,00001) und besserer Aufrechterhaltung der Nierenfunktion (p < 0,00001) assoziiert war.SchlussfolgerungMit HSS zusätzlich zu Furosemid bei diuretikaresistenten CHF-Patienten wurde eine Verbesserung des renalen Sicherheitsprofils und klinischer Endpunkte wie Mortalität und herzinsuffizienzbedingte stationäre Aufnahme wahrscheinlich.

Ultrasound evaluation of the inferior vena cava collapsibility index in congestive heart failure patients treated with intravenous diuretics: new insights about its relationship with renal function: An observational study

OBJECTIVE In chronic heart failure (CHF), collapsibility index of the inferior vena cava (IVCCI) is used for noninvasive ultrasonographic appraisal of central venous pressure, but it also may be related both to estimated glomerular filtration rate (eGFR) and renal outcome. METHODS On the basis of retrospective observational cohort study, we analyzed 49 patients with right or biventricular CHF in III NYHA class, who had undergone intravenous intensive treatment with furosemide. Aggravated renal dysfunction (ARD) was defined by serum creatinine (Cr) increase of ≥0.3 mg/dL from baseline. IVCCI was categorized in three layers (IVCCI ≤15%, IVCCI 16-40% and IVCCI >40%). The predictors of ARD were searched for as well as any relation between basal IVCCI and both eGFR at admission and occurrence of ARD. RESULTS Overall, 15 cases and 34 controls were compared. Multivariate predictors of ARD were a lower basal eGFR (HR: 0.82 CI: 0.72-0.94 p=0.0045) and intravenous furosemide daily mean dose >80 mg (HR: 48.62 CI: 1.62-3841.5 p=0.0430). A very significant positive correlation was found between IVCCI at admission ≤ 15% and basal eGFR (r=0.96 p<0.0001), while a negative correlation with eGFR was detected in the IVCCI highest (>40%) range (r=-0.696 p=0.0013). Furthermore, the category with basal IVCCI >40% showed a higher rate of ARD compared to that with basal IVCCI 16-40% (p<0.05). CONCLUSION On the basis of the demonstrated u-shaped relationship between IVCCI and eGFR both the stratum with the highest (>40%) and the one with the lowest (≤15%) basal IVCCI may be associated with increased risk of ARD.

Statin use for nonrheumatic calcific aortic valve stenosis: a review with meta-analysis.

Aims To synthesize by meta-analysis the findings of recent experimental studies focusing on possible therapeutic effectiveness of statins for nonrheumatic calcific aortic stenosis Methods Observational studies and randomized controlled trials (RCTs) were selected from the Pubmed database to evaluate the hemodynamic progression of aortic stenosis in statin-treated patients compared with controls (i.e. patients with aortic stenosis taking placebo or no treatment). The endpoints were the annualized changes in one or more of the following ultrasonographic measurements: peak aortic valve jet velocity, peak aortic valve pressure gradient, mean aortic valve pressure gradient aortic valve area (AVA). For estimating the overall effect of statin therapy on each of the above-mentioned continuous variables across the considered studies, we used the weighted mean difference (WMD) as effect size measure. In addition, we calculated the odds of aortic valve replacement surgery and cardiovascular death in both statin-treated patients and controls for subsequently estimating the appropriate odds ratios. Results Nine studies were selected. A lower annualized increase in peak aortic valve jet velocity was found in statin-treated patients compared with controls (overall WMD: −0.09 m/s per year, 95% CI −0.16, −0.01 P = 0.018). Similarly, a smaller annualized increase in peak aortic valve pressure gradient was found in the statin group (overall WMD: −2.04 mmHg/year 95% CI: −3.56, −0.52, P = 0.0085). However, the overall effects in statin-treated patients on both annualized increases in mean aortic valve pressure gradient and decreases in AVA were not significantly different from those found in controls. Moreover, there was no significant difference in cardiovascular outcomes in the statin groups compared with placebo groups in each of the three analyzed RCTs and overall. Conclusion Significant benefit of statin therapy in retarding hemodynamic deterioration was identified by favorable effects concerning annualized changes in peak aortic valve jet velocity and peak aortic valve pressure gradient; on the contrary, in statin-treated patients with aortic stenosis, no significant improvement was found for annualized changes in mean aortic valve pressure gradient and AVA and clinical outcomes.

Change of Serum BNP Between Admission and Discharge After Acute Decompensated Heart Failure Is a Better Predictor of 6-Month All-Cause Mortality Than the Single BNP Value Determined at Admission

Background B-type natriuretic peptide (BNP) is regarded as a reliable predictor of outcome in patients with acute decompensated heart failure (ADHF). However, according to some scholars, a single isolated measurement of serum BNP at the time of hospital admission would not be sufficient to provide reliable prognostic information. Methods A retrospective study was carried out on patients hospitalized for ADHF, who had then undergone follow-up of at least 6 months, in order to see if there was any difference in midterm mortality among patients with rising BNP at discharge as compared to those with decreasing BNP at discharge. Medical records had to be carefully examined to divide the case records into two groups, the former characterized by an increase in BNP during hospitalization, and the latter showing a decrease in BNP from the time of admission to the time of discharge. Results Ultimately, 177 patients were enrolled in a retrospective study. Among them, 53 patients (29.94%) had increased BNPs at the time of discharge relative to admission, whereas 124 (70.06%) exhibited decreases in serum BNP during their hospital stay. The group with patients who exhibited BNP increases at the time of discharge had higher degree of congestion evident in the higher frequency of persistent jugular venous distention (odds ratio: 3.72; P = 0.0001) and persistent orthopnea at discharge (odds ratio: 2.93; P = 0.0016). Moreover, patients with increased BNP at the time of discharge had a lower reduction in inferior vena cava maximum diameter (1.58 ± 2.2 mm vs. 6.32 ± 1.82 mm; P = 0.001 (one-way ANOVA)). In contrast, there was no significant difference in weight loss when patients with increased BNP at discharge were compared to those with no such increase. A total of 14 patients (7.9%) died during the 6-month follow-up period. Cox proportional hazard analysis revealed that BNP increase at the time of discharge was an independent predictor of 6-month all-cause mortality after adjustment for age, sodium at discharge, creatinine at discharge and New York Heart Association (NYHA) class at discharge (hazard ratio 34.49; 95% confidence intervals: 4.55 - 261.06; P = 0.001). Conclusions Among patients with recent ADHF, increased BNP at the time of discharge from the hospital entailed a higher grade of congestion and higher 6-month mortality.

Platypnea-Orthodeoxia Syndrome: Multiple Pathophysiological Interpretations of a Clinical Picture Primarily Consisting of Orthostatic Dyspnea.

Platypnea–orthodexia syndrome (POS) is often a challenging diagnostic problem. It is characterized by dyspnea that is accentuated by standing or sitting positions due to a marked fall in blood oxygen saturation, and instead is improved by assuming the lying position. In the present brief review, the authors address the pathophysiology of POS, and outline its clinical symptoms as well as the main modalities of diagnostic evaluation and possible therapeutic options. Moreover, some problems concerning much-debated issues and persistent uncertainties about the pathophysiology of POS are presented along with the description of the diagnostic and therapeutic resources currently available for this syndrome.

Effects of Hyponatremia Normalization on the Short-Term Mortality and Rehospitalizations in Patients with Recent Acute Decompensated Heart Failure: A Retrospective Study

Background: Several studies have shown that hyponatremia is associated with increased risk of rehospitalization and death in patients with heart failure. In these studies, chronic heart failure (CHF) patients with persistent hyponatremia were compared only with CHF patients with a normal sodium level at hospital admission. Aims: In the present retrospective study, conducted in a cohort of patients with recent acute decompensated heart failure (ADHF), all with hyponatremia ascertained at the time of hospital admission, we aimed to evaluate the effect of the normalization of serum sodium on the composite endpoint of short-term rehospitalization and mortality. Methods: A retrospective study centered on medical records of patients hospitalized for ADHF in the period April 2013 to April 2016 was performed. Data regarding serum sodium measurements had to be collected from medical records of cardiology wards of two hospitals, and were then processed for statistical analysis. As an inclusion criterion for enrollment, patients had to be suffering from heart failure that had required at least one hospitalization. Moreover, they had to be suffering from a state of hyponatremia (serum sodium < 135 mEq/L) at admission on the occasion of the index hospitalization. Patients with hyponatremia at admission were divided into two groups, one comprising patients with hyponatremia that persisted at the time of discharge (persistent hyponatremia) and a second including patients who had achieved normalization of their serum sodium levels (serum Na+ ≥ 135 mEq/L) during hospitalization until discharge. For both groups, the risk of mortality and rehospitalization during a 30-day follow-up was assessed. Results: One hundred and sixty CHF patients with various degrees of functional impairment were enrolled in the study. Among them, 56 (35%) had persistent hyponatremia over the course of hospitalization. At multivariable Cox proportional-hazards regression analysis, the risk of having a 30-day unplanned readmission or death was significantly higher in patients with persistent hyponatremia compared to those who exhibited a sodium level normalized at discharge (adjusted hazard ratio = 3.0743; 95% CI: 1.3981–6.7601; p = 0.0054). Among the other variables included in the Cox regression model, the number of admissions in the last 12 months (p < 0.0001), the length of stay of the index admission (p = 0.0015) and the New York Heart Association (NYHA) class III at discharge (p = 0.0022) were also identified as risk factors associated with the composite endpoint of 30-day unplanned readmission or death. Conclusions: In the present retrospective study, the risk of 30-day rehospitalization or death was significantly higher in patients with recent ADHF and persistent hyponatremia in comparison with ADHF patients who had had their serum sodium normalized during the hospital stay. This association seemed to be independent of the heart failure severity.

Colapsibilidade da Veia Cava Inferior e sinais e sintomas de insuficiência cardíaca: novos insights e possíveis associações

BACKGROUND In chronic heart failure patients (CHF), ultrasound measurement of inferior vena cava collapsibility index (IVCCI) has been proposed to yield careful assessment and grading of the hemodynamic congestion. OBJECTIVE The purpose of this study was to correlate the findings of physical examination with IVCCI in CHF patients. METHODS According to a retrospective cohort design, we analyzed 54 CHF patients with right or biventricular CHF, belonging to III NYHA class. We planned to determine whether any basal IVCCI range would be able to predict persistent or worsening clinical congestion found at the end of subsequent follow up (i.e. after 1-2 months of oral optimized therapy). For this purpose, the patients were subdivided by three groups according to the basal IVCCI value: ≤ 15% (13 pts), 16 - 40% (21 pts) and > 40% (20 pts).Several clinical criteria of congestion were compared across the three groups and subsequently entered in the Cox multivariate model. RESULTS Multivariate predictors of high congestion score were jugular venous distension (HR: 13,38 95% C.I.: 2,13 - 84 p = 0,0059) and rales (HR: 11 95% C.I : 1,45 - 83,8 p = 0,0213). IVCCI ≤ 15% was always associated with high congestion score at the second visit; but IVCCI ≤ 15% failed to predict high congestion score at the second visit. CONCLUSION In CHF setting, low IVCCI did not reliably predict high congestion score. Nevertheless, the cluster with IVCCI ≤ 15% was always found associated with signs and symptoms from both right and left-sided decompensated CHF.

An Admission-to-Discharge BNP Increase Is a Predictor of Six-Month All-Cause Death in ADHF Patients: Inferences from Multivariate Analysis Including Admission BNP and Various Clinical Measures of Congestion

Background: According to some authors, a single isolated measurement of serum B-type natriuretic peptide (BNP) executed on hospital admission would not be a sufficiently accurate method to predict the outcome of patients with acute decompensated heart failure (ADHF). Aims: To verify this assumption, a retrospective study was conducted on patients hospitalized for ADHF. Our main objective was to ascertain whether there was any difference in midterm mortality among patients with increasing BNP at discharge as compared with those with decreasing BNP at discharge. Methods: Medical records were examined so as to make a partition of the ADHF patient population into two groups, the former characterized by a rise in BNP during hospitalization, and the latter exhibiting a decrease in BNP in the measurement taken at hospital discharge. Results: 177 patients were enrolled in a retrospective study. Among them, 53 patients (30%) had increased BNP at the time of discharge, whereas 124 (70%) showed decreases in serum BNP during their hospital stay. The group with patients who exhibited BNP increases at the time of discharge had a higher degree of congestion evident in the higher frequency of persistent jugular venous distention and persistent orthopnea at discharge. Moreover, patients with increased BNP at the time of discharge had a lower reduction in inferior vena cava maximum diameter (1.58 ± 2.2 mm vs. 6.32 ± 1.82 mm; p (one-way ANOVA) = 0.001). In contrast, there was no significant difference in weight loss when patients with increased BNP at discharge were compared with those with no such increase. A total of 14 patients (7.9%) died during the six-month follow-up period. Multivariable Cox proportional-hazards regression analysis revealed that a BNP increase at the time of discharge was an independent predictor of six-month all-cause mortality after adjustment for persistent jugular venous distention, persistent orthopnea, reduction in inferior vena cava maximum diameter at discharge, weight loss, serum urea, systolic blood pressure at admission, and BNP at admission (hazard ratio = 30.5424; 95% CI: 1.7409–535.8294, p = 0.0199). Conclusions: Among patients with a history of ADHF, more elevated BNP levels at the time of discharge from the hospital compared with those detected at admission identify a patient subset with a higher grade of congestion and higher six-month mortality.

Graphical representation of network meta-analysis: an iconographic support to the complexity of multiple data comparisons

Traditional meta-analysis is able to compare two treatments against each other, but is not able to analyze the cases in which the treatment regimens to be compared are ≥ 3. For example, considering two innovative treatments T1 and T2 and the corresponding standard treatment S, it is frequent the case in which there are randomized controlled trials (RCTs) comparing T1 vs. S and also T2 vs. S, but there is a lack of controlled head-to-head comparison studies between T1 and T2. The network metaanalysis (NeMa) [1–3] overcomes this major limit by making both direct and indirect comparisons. Within a NeMa, the comparison between two treatments involved in an RTC is defined Bdirect^ (e.g., the comparisons T1 vs S and T2 vs S), while instead, we usually term Bindirect^ the comparison between two treatments for which a specific comparative assessment (RCT) does not exist yet (e.g., T1 vs T2). Several NEMa graphic representations have already been used by other authors, e.g., with the use of intertwining lines connecting circles that however do not report within the plot the values of relative risk (RR) derived from the indirect comparisons. According to our personalized way of representing the NeMa graphs, the direct comparisons are depicted by means of continuous arrows, while the indirect ones are represented by dashed arrows (Fig. 1). Interestingly, our new graphical approach is aimed at visually synthesizing the experimental evidence by presenting the RR values of direct and indirect comparisons, whereas the previous NeMa graphs were conceived only for showing the network of studies and/or treatments. Additionally, the distinction between continuous arrows and dashed arrows seems to be very functional to us in order to identify direct and indirect comparisons. Moreover, in our opinion, the symbols +, −, and =, adopted to indicate the data with statistical significance of each comparison, represent a useful notation. To illustrate the practical application of NeMa, an example is given below, centered about two widely known anticoagulants, i.e., dabigatran and rivaroxaban. No RCT has been reported to directly compare dabigatran with rivaroxaban in the clinical setting of non-valvular atrial fibrillation (NVAF). In truth, the three currently available studies of direct comparison of dabigatran with rivaroxaban [7–9] are observational studies and therefore, as such, burdened by the threat of possible biases. Instead, as regards prevention of cardioembolic stroke in NVAF, there are two large RCTs, the former of which includes dabigatran [4] whereas the latter is centered around rivaroxaban [5, 6], both having the warfarin administered according to International Normalized Ratio (INR) as the comparator drug. Notably, in the RE-LY trial [4], dabigatran was administered at a dose of 110 or 150 mg twice daily to two distinct groups of patients, whereas a third group of patients received warfarin according to their INR. Conversely, in the ROCKET-AF trial [5, 6], rivaroxaban was given at a dose of 20 mg per day. In the RE-LY trial, dabigatran at a dose of 150 mg twice daily showed greater efficacy and substantial overlapping of the risk of major bleeding compared to warfarin, while at a dose of 110 mg twice daily, it was equally effective and exhibited less cases of major bleeding. On the other hand, the rivaroxaban trial shows that this anticoagulant has an overlapping efficacy compared to warfarin. * Renato De Vecchis devecchis.erre@virgilio.it