Intervention in the renin-angiotensin-aldosterone-system (RAAS) is associated with slowing the progressive loss of renal function. During initiation of therapy, however, there may be an acute fall in ...glomerular filtration rate (GFR). We tested whether this initial fall in GFR reflects a renal hemodynamic effect and whether this might result in a slower decline in long-term renal function. We performed a post hoc analysis of the Reduction of Endpoints in Non-Insulin-Dependent Diabetes Mellitus with the Angiotensin II Antagonist Losartan (RENAAL) trial. Patients assigned to losartan had a significantly greater acute fall in estimated (eGFR) during the first 3 months compared to patients assigned to placebo, but a significantly slower long-term mean decline of eGFR thereafter. A large interindividual difference, however, was noticed in the acute eGFR change. When patients were divided into tertiles of initial fall in eGFR, the long-term eGFR slope calculated from baseline was significantly higher in patients with an initial fall compared to those with an initial rise. When eGFR decline was calculated from 3 months to the final visit, excluding the initial effect, patients with a large initial fall in eGFR had a significant lower long-term eGFR slope compared to those with a moderate fall or rise. This relationship was independent of other risk markers or change in risk markers for progression of renal disease such as blood pressure and albuminuria. Thus, the greater the acute fall in eGFR, during losartan treatment, the slower the rate of long-term eGFR decline. Hence, interpretation of trial results relying on slope-based GFR outcomes should separate the initial drug-induced GFR change from the subsequent long-term effect on GFR.
Chronic kidney disease (CKD) and worsening renal function (WRF) have been associated with poor outcome in heart failure (HF).
Articles were identified by literature search of MEDLINE (from inception ...to 1 July 2012) and Cochrane. We included studies on HF patients and mortality risk with CKD and/or WRF. In a secondary analysis, we selected studies investigating predictors of WRF. We retrieved 57 studies (1,076,104 patients) that investigated CKD and 28 studies (49,890 patients) that investigated WRF. The prevalence of CKD was 32% and associated with all-cause mortality: odds ratio (OR) 2.34, 95% confidence interval (CI) 2.20-2.50, P < 0.001). Worsening renal function was present in 23% and associated with unfavourable outcome (OR 1.81, 95% CI 1.55-2.12, P < 0.001). In multivariate analysis, moderate renal impairment: hazard ratio (HR) 1.59, 95% CI 1.49-1.69, P < 0.001, severe renal impairment, HR 2.17, 95% CI 1.95-2.40, P < 0.001, and WRF, HR 1.95, 95% CI 1.45-2.62, P < 0.001 were all independent predictors of mortality. Across studies, baseline CKD, history of hypertension and diabetes, age, and diuretic use were significant predictors for the occurrence of WRF.
Across all subgroups of patients with HF, CKD, and WRF are prevalent and associated with a strongly increased mortality risk, especially CKD. Specific conditions may predict the occurrence of WRF and thereby poor prognosis.
Abstract Background Randomized controlled trials provide robust data on the efficacy of interventions rather than on effectiveness. Health technology assessment (HTA) agencies worldwide are thus ...exploring whether real-world data (RWD) may provide alternative sources of data on effectiveness of interventions. Presently, an overview of HTA agencies’ policies for RWD use in relative effectiveness assessments (REA) is lacking. Objectives To review policies of six European HTA agencies on RWD use in REA of drugs. A literature review and stakeholder interviews were conducted to collect information on RWD policies for six agencies: the Dental and Pharmaceutical Benefits Agency (Sweden), the National Institute for Health and Care Excellence (United Kingdom), the Institute for Quality and Efficiency in Healthcare (Germany), the High Authority for Health (France), the Italian Medicines Agency (Italy), and the National Healthcare Institute (The Netherlands). The following contexts for RWD use in REA of drugs were reviewed: initial reimbursement discussions, pharmacoeconomic analyses, and conditional reimbursement schemes. We identified 13 policy documents and 9 academic publications, and conducted 6 interviews. Results Policies for RWD use in REA of drugs notably differed across contexts. Moreover, policies differed between HTA agencies. Such variations might discourage the use of RWD for HTA. Conclusions To facilitate the use of RWD for HTA across Europe, more alignment of policies seems necessary. Recent articles and project proposals of the European network of HTA may provide a starting point to achieve this.
Objectives We sought to investigate the relationship between increased central venous pressure (CVP), renal function, and mortality in a broad spectrum of cardiovascular patients. Background The ...pathophysiology of impaired renal function in cardiovascular disease is multifactorial. The relative importance of increased CVP has not been addressed previously. Methods A total of 2,557 patients who underwent right heart catheterization in the University Medical Center Groningen, the Netherlands, between January 1, 1989, and December 31, 2006, were identified, and their data were extracted from electronic databases. Estimated glomerular filtration rate (eGFR) was assessed with the simplified modification of diet in renal disease formula. Results Mean age was 59 ± 15 years, and 57% were men. Mean eGFR was 65 ± 24 ml/min/1.73 m2 , with a cardiac index of 2.9 ± 0.8 l/min/m2 and CVP of 5.9 ± 4.3 mm Hg. We found that CVP was associated with cardiac index ( r = −0.259, p < 0.0001) and eGFR ( r = −0.147, p < 0.0001). Also, cardiac index was associated with eGFR ( r = 0.123, p < 0.0001). In multivariate analysis CVP remained associated with eGFR ( r = −0.108, p < 0.0001). In a median follow-up time of 10.7 years, 741 (29%) patients died. We found that CVP was an independent predictor of reduced survival (hazard ratio: 1.03 per mm Hg increase, 95% confidence interval: 1.01 to 1.05, p = 0.0032). Conclusions Increased CVP is associated with impaired renal function and independently related to all-cause mortality in a broad spectrum of patients with cardiovascular disease.
Aims
Inflammation is a central process in the pathophysiology of heart failure (HF), but trials targeting tumour necrosis factor (TNF)‐α were largely unsuccessful. Interleukin (IL)‐6 is an important ...inflammatory mediator and might constitute a potential pharmacologic target in HF. However, little is known regarding the association between IL‐6 and clinical characteristics, outcomes and other inflammatory biomarkers in HF. We thus aimed to identify and characterize these associations.
Methods and results
Interleukin‐6 was measured in 2329 patients 89.4% with a left ventricular ejection fraction (LVEF) ≤ 40% of the BIOSTAT‐CHF cohort. The primary outcome was all‐cause mortality and HF hospitalization during 2 years, with all‐cause, cardiovascular (CV), and non‐CV death as secondary outcomes. Approximately half (56%) of all included patients had plasma IL‐6 values greater than the previously determined 95th percentile of normal values at baseline. Elevated N‐terminal pro‐brain natriuretic peptide, procalcitonin and hepcidin, younger age, TNF‐α/IL‐1‐related biomarkers, or having iron deficiency, atrial fibrillation and LVEF > 40% independently predicted elevated IL‐6 levels. IL‐6 independently predicted the primary outcome HR (95% confidence interval) per doubling: 1.16 (1.11–1.21), P < 0.001, all‐cause mortality 1.22 (1.16–1.29), P < 0.001 and CV as well as non‐CV mortality 1.16 (1.09–1.24), P < 0.001; 1.31 (1.18–1.45), P < 0.001, but did not improve discrimination in previously published risk models.
Conclusions
In a large, heterogeneous cohort of HF patients, elevated IL‐6 levels were found in more than 50% of patients and were associated with iron deficiency, reduced LVEF, atrial fibrillation and poorer clinical outcomes. These findings warrant further investigation of IL‐6 as a potential therapeutic target in specific HF subpopulations.
Abstract Background Despite increasing recognition of the value of real-world data (RWD), consensus on the definition of RWD is lacking. Objectives To review definitions publicly available for RWD to ...shed light on similarities and differences between them. Methods A literature review and stakeholder interviews were used to compile data from eight groups of stakeholders. Data from documents and interviews were subjected to coding analysis. Definitions identified were classified into four categories: 1) data collected in a non-randomized controlled trial setting, 2) data collected in a non-interventional/non-controlled setting, 3) data collected in a non-experimental setting, and 4) others (i.e., data that do not fit into the other three categories). The frequency of definitions identified per category was recorded. Results Fifty-three documents and 20 interviews were assessed. Thirty-eight definitions were identified: 20 out of 38 definitions (53%) were category 1 definitions, 9 (24%) were category 2 definitions, 5 (13%) were category 3 definitions, and 4 (11%) were category 4 definitions. Differences were identified between, and within, definition categories. For example, opinions differed on the aspects of intervention with which non-interventional/non-controlled settings should abide. No definitions were provided in two interviews or identified in 33 documents. Conclusions Most of the definitions defined RWD as data collected in a non-randomized controlled trial setting. A considerable number of definitions, however, diverged from this concept. Moreover, a significant number of authors and stakeholders did not have an official, institutional definition for RWD. Persisting variability in stakeholder definitions of RWD may lead to disparities among different stakeholders when discussing RWD use in decision making.
The administration of loop diuretics to achieve decongestion is the cornerstone of therapy for acute heart failure. Unfortunately, impaired response to diuretics is common in these patients and ...associated with adverse outcomes. Diuretic resistance is thought to result from a complex interplay between cardiac and renal dysfunction, and specific renal adaptation and escape mechanisms, such as neurohormonal activation and the braking phenomenon. However, our understanding of diuretic response in patients with acute heart failure is still limited and a uniform definition is lacking. Three objective methods to evaluate diuretic response have been introduced, which all suggest that diuretic response should be determined based on the effect of diuretic dose administered. Several strategies have been proposed to overcome diuretic resistance, including combination therapy and ultrafiltration, but prospective studies in patients who are truly unresponsive to diuretics are lacking. An enhanced understanding of diuretic response should ultimately lead to an improved, individualized approach to treating patients with acute heart failure.
Objectives This study sought to determine the prognostic value of B-type natriuretic peptide (BNP) in patients with heart failure with preserved ejection fraction (HFPEF), in comparison to data in HF ...patients with reduced left ventricular (LV) EF (≤40%). Background Management of patients with HFPEF is difficult. BNP is a useful biomarker in patients with reduced LVEF, but data in HFPEF are scarce. Methods In this study, 615 patients with mild to moderate HF (mean age 70 years, LVEF 33%) were followed for 18 months. BNP concentrations were measured at baseline and were related to the primary outcome, that is, a composite of all-cause mortality and HF hospitalization, and to mortality alone. The population was divided in quintiles, according to LVEF, and patients with reduced LVEF were compared with those with HFPEF. Results There were 257 patients (42%) who had a primary endpoint and 171 (28%) who died. BNP levels were significantly higher in patients with reduced LVEF than in those with HFPEF (p < 0.001). BNP was a strong predictor of outcome, but LVEF was not. Importantly, if similar levels of BNP were compared across the whole spectrum of LVEF, and for different cutoff levels of LVEF, the associated risk of adverse outcome was similar in HFPEF patients as in those with reduced LVEF. Conclusions BNP levels are lower in patients with HFPEF than in patients with HF with reduced LVEF, but for a given BNP level, the prognosis in patients with HFPEF is as poor as in those with reduced LVEF.
Stated preference studies in which information on the willingness to trade‐off between the benefits and harms of medicines is elicited from patients or other stakeholders are becoming increasingly ...mainstream. Such trade‐offs can mathematically be represented by a weighted additive function, with the weights, whose ratios determine how much an individual is willing to trade‐off between the treatment attributes, being the response vector for the statistical analysis. One way of eliciting trade‐off information is through multi‐dimensional thresholding (MDT), which is a bisection‐based approach that results in increasingly tight bounds on the values of the weights ratios. While MDT is cognitively less demanding than other, more direct elicitation methods, its use complicates the statistical analysis as it results in weights data that are region censored. In this article, we present a simulated maximum likelihood (SML) procedure for fitting a Dirichlet population model directly to the region‐censored weights data and perform a series of computational experiments to compare the proposed SML procedure to a naive approach in which a Dirichlet distribution is fitted to the centroids of the weights boundaries obtained with MDT. The results indicate that the SML procedure consistently outperformed the centroid‐based approach, with the centroid‐based approach requiring three bisection steps per trade‐off to achieve a similar precision as the SML procedure with one bisection step per trade‐off. Using the newly proposed SML procedure, MDT can be applied with smaller sample sizes or with fewer questions compared to the more naïve centroid‐based approach that was applied in previous applications of MDT.
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